Development of New Synthetic Methods for Introducing Alkyl ... · human nutrition2 and the discovery of indole-3-acetic acid as a plant hormone3 served to bring about a renaissance

明治大学大学院理工学研究科

２０１７年度

博士学位請求論文

Development of New Synthetic Methods for Introducing Alkyl Groups

onto Indoles and Pyrroles

（インドール類およびピロール類へのアルキル

基導入を目的とする新規合成法の開発）

学位請求者応用化学専攻

野見山翔太

Development of New Synthetic Methods

for Introducing Alkyl Groups

onto Indoles and Pyrroles

Organic Reaction Control Laboratory Shota Nomiyama

School of Science and Technology Meiji University

2017

1

Table of Contents 1

Chapter I. General Introduction 4

I-1. Historical Background of Indole 5

I-2. Chemical Properties of Indole 6

I-2-1 Characteristic and Construction of Indoles 6

I-2-2 Reactivity of Indoles 7

I-3. Synthesis of Alkylindoles 9

I-3-1 Alkylation of Indoles by Electrophilic Aromatic Substitution 9

I-3-2 Annulation Reactions 10

I-4. Historical Background of Pyrrole 11

I-5. Chemical Properties of Pyrrole 12

I-5-1 Characteristics and Construction of Pyrroles 12

I-5-2 Reactivity of Pyrroles 13

I-6. Synthesis of b-Alkylpyrroles 15

I-6-1 Direct Introduction of an Alkyl Group onto a b-Position 15

I-6-1-1 Via Electrophilic Aromatic Substitution 15

I-6-1-2 Not via Electrophilic Aromatic Substitution 17

I-6-2 Annulation Reactions 18

I-7. Purpose and Scope of this Thesis 19

I-8. References and Notes 22

26

II-1. Introduction 27

II-2. Results & Discussion 29

29

35

II-2-3. Reaction Mechanism 36

II-3. Experimental 39

Chapter II. Easy Access to a Library of Alkylindoles: Reductive Alkylation

of Indoles with Carbonyl Compounds and Hydrosilanes under Indium

Catalysis

II-2-1. Indium-Catalyzed Reductive Alkylation of Indoles with Carbonyl

Compounds and HSiMePh2

II-2-2. Indium-Catalyzed Alkylation of Indoles with Carbonyl

Compounds and Carbon Nucleophiles

2

II-4. References and Notes 55

60 III-1. Introduction 61

III-2. Results & Discussion 64 64

70

III-2-3. N-Deprotection: Synthesis of N-Unsubstituted !-Alkylpyrroles 72 73 III-2-5. Reaction Mechanism 77

III-3. Experimental 81 III-4. References and Notes 113

119

IV-1. Introduction 120 IV-2. Results & Discussion 121

121 126

IV-2-3. Reaction Mechanism 127 IV-3. Experimental 129 IV-4. References and Notes 143

Chapter V. Conclusions and Prospects 146

Chapter III. Indium-Catalyzed Regioselective !-Alkylation of Pyrroles with Carbonyl Compounds and Hydrosilanes, and Its Application to Constructing

a Quaternary Carbon Center with a !-Pyrrolyl Group

Chapter IV. Metal-Free Regioselective !-Alkylation of Pyrroles with Carbonyl Compounds and Hydrosilanes: Use of a Brønsted Acid as a Catalyst

III-2-1. Indium-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH

III-2-2. Indium-Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles

III-2-4. Synthesis of Methanes with Four Different Aryl Groups

Including a !-Pyrrolyl Group

IV-2-1. HNTf2 Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH

IV-2-2. HNTf2 Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles

3

List of Publications 149 Acknowledgment 150

Chapter I. General Introduction

5

I-1. Historical Background

Indole is a heterocyclic aromatic organic compound that is composed of a

benzene ring fused to a pyrrole ring (Figure 1). Indole chemistry began with the intensive

study of indigo; the drama of which antedates the birth of organic chemistry as a science.

The discovery of indole and its structure elucidation date from 1866 when A. Baeyer first

synthesized indole by zinc-dust pyrolysis of oxyindole.1

Figure 1

In the 1930’s, large number of alkaloids contain the indole nucleus were

discovered. Additionally, the recognition of the importance of tryptophan in animal and

human nutrition2 and the discovery of indole-3-acetic acid as a plant hormone3 served

to bring about a renaissance in indole chemistry (Figure 2).

Figure 2

Nowadays, indole derivatives are found in not only natural products and

biologically active compounds but also functional organic materials. Therefore, indole

chemistry is essential for many scientific fields.

N H

indole

N Hindigo

NO

O

H

N H

O

oxyindole

N H

tryptophan

NH2

OOH

N H

indole-3-acetic acid

OH

O

ロいロ

口／

6

I-2. Chemical Properties of Indole

I-2-1. Characteristics and Construction of Indoles

Indole is an aromatic heterocycle with 10 "-electrons. The lone pair of the

nitrogen atom, which features sp2 hybridization, participates the 10 "-electrons

conjugation. The structure of indole has been investigated by X-ray diffraction and the

bond lengths and angles are in accord with other aromatic structures (Figure 3).4

Figure 3

C C

C

NH

C

1.406 �

108.0º

CC

C

C

1.407 �

1.401 �

1.388 �1.390 �

1.399 �

1.382 �1.407 �

1.402 �

1.404 �108.4º108.4º

107.9º

108.1º

119.7º

120.6º119.8º

120.5º

119.8º119.8º

~

□ ¥ ＼／

7

I-2-2. Reactivity of Indoles

In an unsubstituted indole, electrophilic aromatic substitution is preferred with

almost all reagents at the 3-position because the reaction at this position simply involves

the isolated enamine system in the five-membered ring and does not disturb the

aromaticity of the benzene ring (Scheme 1).5

Scheme 1

Several studies on the nucleophilicity parameters (N) have been carried out

using reactions of nucleophiles with benzhydryl cations or 4,6-dinitrobenzofruoxan.6,7 N

for indole is 5.55. The reaction rate of indole with an electrophile is approximately 15

times faster than that of pyrrole (N = 4.63). 1-Methylindole (N = 5.75) and 2-methylindole

(N = 6.91) are more reactive than indole because the methyl group acts as an electron-

donating group. These results suggest a general reactivity order of 2-methylindole > 1-

methylindole > indole. C2-substituted and unsubstituted indoles (in the case of C5-

substituted indoles) behave differently. Thus, it appears that the substituent at the C5-

position exerts a similar electronic effect in both compounds, but that the presence of the

methyl group at the C2-position reduces the rate of electrophile addition. For example,

the N of 5-methoxyindole (6.22) is increased 0.67 times compared with indole, but the N

of 5-methoxy-2-methylindole (7.26) is increased 0.35 times compared with 2-

methylindole. The steric hindrance of the C3-position would be affected by the size of

the electrophiles. In fact, acid-catalyzed exchange at the C3-position is approximately 80

times faster for 2-methylindole than for indole, whereas the reaction of 2-methylindole

with 4,6-dinitrobenzofruoxan is 20 times faster than that of indole.8

N H

N H

N H

N H

N H

N H

El

El

El = electrophile El

El

N H

El'H

HEl'

+

+

El'

El'

benzene ring intact

benzene ring disrupted

C3

C2

ー`ごミーロ(0

/

亥亨—ごーロ〗

8

Electrophilic substitution at C2-position can be achieved in indoles with a

substituent at the C3-position. The reaction usually starts with electrophilic attack at C3

followed by a rearrangement to produce the C2-substituted indole (Scheme 2).9

Scheme 2

Nitrogen substitution of indole can be achieved through base-promoted

processes, such as alkylations and acylations (Scheme 3). Because the indole N–H (pKa

value 16.7 in water) is weakly acidic, it can be deprotonated by strong bases to provide

the indolyl anion.9

Scheme 3

N H

N H

El = electrophile

El'R

+

R

N H

ElR

N H

R+

El'H

El'

NN H

Base

– [H–Base]+

N

N

alkyl–X

R X

Oalkyl

RO

~ ーローロ交— (0-

~()) ()) --------())

0~()) }-

9

I-3. Synthesis of Alkylindoles

Alkylindoles are widely recognized as structural motifs, especially in natural

products and pharmaceuticals. Therefore, a large number of synthetic approaches for

alkylindoles have been reported.10,11 The synthetic strategy toward alkylindoles can be

broadly classified into two categories, i.e., direct introduction of an alkyl group onto the

aromatic ring and annulation reactions for alkylindoles. In this section, the author

discusses some representative reported examples of alkylindole synthesis.

I-3-1. Alkylation of Indoles by Electrophilic Aromatic Substitution

Due to the sufficient aromaticity and "-excessive nature of indoles, direct

introduction of alkyl groups onto indoles by electrophilic aromatic substitution (SEAr)

appears to be a straightforward route to access alkylindoles. Therefore, various indole

alkylation reactions with electrophiles have been reported. However, only the use of

highly reactive alkylating agents, including alkenes, 12 alcohols, 13 alkyl halides, 14

aziridines,15 allenes,16 and #-halo ketone17 achieve the reaction that can introduce for primary, secondary, and tertiary alkyl groups (Scheme 4).

Scheme 4

N R1

+ El

El:

N R1

El'

R3

R2

R4

EWG

El' = YR3

R2

R2,3 = H, alkyl, aryl,...; R4 = H, EWG; EWG = COR, CO2R, NO2, SO2R; X = OH, Br

X

R3

R2OH

COR

Br

R3

R2

R3

R2 R

R'NEWG

R3

R2

El = electrophile

(0 ~co 士’

日

(,-,::-、)r、りオャI

p >=-==<

10

I-3-2. Annulation Reactions

The synthesis of alkylindoles can be also achieved by numerous ring closure

reactions. One of the most widely used reactions is the Fischer indole synthesis, which

was first discovered in 1883. 18 , 19 The treatment of aryl hydrazones, coupled from

aromatic hydrazines and ketones or aldehydes, with acids leads to supply many kinds of

C3-alkylated indoles (Scheme 5). Numerous reports also exist for transition metal-

catalyzed annulation reactions. 20 One example involves the synthesis of an ortho-

alkynylaniline followed by intramolecular cyclization, and it is an excellent synthetic

method for C2 alkylindole because various types of alkyl groups can be introduced at the

C2-position (Scheme 5). In general, as shown in Scheme 5, the synthesis of alkylindoles

though annulation reactions requires multistep reactions from the original starting

materials to obtain indoles with various alkyl groups.

Scheme 5

Fischer indole synthesis

the annulation of ortho-alkynylaniline

NH

NH2

O

R1

+NH

N

R

NH

R

NH2

X+

R

ENH2

R

NH

R

X = Br, I,... E = H, Sn,...

u_~~u~~co

er ,ff 一a:'=co-

11

I-4. Historical Background of Pyrrole

Pyrrole is a heterocyclic aromatic five-membered ring organic compound

containing a nitrogen atom (Figure 4). The first discovery of a pyrrole was made by Runge

in 1834 as a constituent of coal tar.21 Anderson characterized this compound in 1858,22

and Bayer determined its constitution in 1870.23 Pyrrole and several pyrrole derivatives, especially the methyl homologs are

found in coal tar and bone oil. Interest in the chemistry of pyrrole derivatives was

originally stimulated by the discovery of indigo which was one of most important indole

derivatives and an important commodity. However, pyrrole itself is the fundamental

building block of hemin and chlorophyll, which are the impetus for the study of pyrroles.

In 1868, Hoppe–Seyler undertook the preparation of crystalline hemin on a large scale

for chemical studies.24 In 1879, the relationship between hemin and chlorophyll was also

obtained by Hoppe–Seyler (Figure 4).25

Figure 4

Nowadays, pyrrole derivatives are found not only in natural products and

biologically active compounds but also in functional organic materials. Pyrrole chemistry

is essential for many scientific fields.

N

N

N

N

HO O OHO

ClFe

hemin

N

N

N

N

R

R'

R''

MgMeO2C

O

Chlorophyll

R'''NH

pyrrole

0

12

I-5. Chemical Properties of Pyrrole

I-5-1. Characteristics and Construction of Pyrroles

Pyrrole is a five-membered aromatic heterocycle with six "-electrons. The presence of nitrogen in the ring results in loss of radial symmetry, so that pyrrole does not

have five equivalent mesomeric forms (i.e., the five forms contribute unequally). The

order of stability is A > C > B (Scheme 6).26 The length of the bonds in pyrrole are in

accord with this exposition; thus, the 3,4 bond is longer than the 2,3 and 4,5 bonds but is

appreciably shorter than a normal single sp2 C–C bond (Figure 5).27 The most important

thing is that the nitrogen lone pair electrons are part of the aromatic sextet.

Scheme 6

Figure 5

NR

NR+–

NR+ –

NR+

–

NR+

–

ABC B C

C2C5

C3C4

C C

C

N

C

H

H

H

H

H

1.431 �

1.361 �

1.362 �109.8º

125.1º

107.7º

121.5º

130.8º

106.0º126.1º

127.9º

ご←口← 口←口←ご

¥ I # ¥

-----~/---------------

13

I-5-2. Reactivity of Pyrroles

Generally, pyrrole undergoes electrophilic substitution predominantly at C2 (#-

position). An inspection of the Wheland intermediates resulting from attack on an

electrophile (El) at C2 or C3 gives an answer to the preferred C2 substitution pathway

observed for simple pyrroles because the intermediate resulting from the attack of El at

the #-position is stabilized to a higher degree by more extensive delocalization of the positive charge (Scheme 7).9

Scheme 7

Several studies have been carried out on the relative nucleophilicity (N) of

pyrrole by examining the reactivity toward a series of benzhydrylium ions. It has been

found that the relative nucleophilicity of pyrrole is 4.63, which is lower than that of indole

(N = 5.55). Alkyl groups were found to show an enormous activating effect on the

nucleophilicities of pyrrole. The more alkyl substituted the pyrrole rings are, the more

nucleophilic the pyrroles become. The general order of nucleophilicity (as suggested in

the literature) is as follows: 1,2,5-trimethylpyrrole (8.69) > 2,5-dimethylpyrrole (8.01) >

1-methylpyrrole (5.85) > pyrrole.28

NR

α

β

NR

El' NR

El' NR

El'

+

+ +NR

El'

+ NR+

El'

El+

more stable intermediate less stable intermediate

口

lf>__ -~-~J l図-Oj

14

Substitution at the nitrogen of pyrrole can be achieved through metalation on

the nitrogen atom. This is because the pyrrole N–H (pKa value 17.5) is weakly acidic and

can be deprotonated by strong bases to generate the pyrrolyl anion, which is able to react

with several electrophiles (Scheme 8).26

Scheme 8

NH

N NR

R–X

R = alkyl, acyl, iPr3Si,...

Base– [H–Base]+□ -ローロ

゜

15

I-6. Synthesis of !-Alkylpyrroles

Pyrroles having alkyl chains at the !-positions are key structural units found in

many natural products and functional organic materials. In this context, a large number

of synthetic approaches for !-alkylpyrroles have been reported.10b,11,29 Synthesis of !-alkylpyrroles can be broadly classified into two categories, i.e., direct introduction of an

alkyl group onto the ring and annulation reactions. In this section, the author discusses

some representative examples for !-alkylpyrrole synthesis.

I-6-1. Direct Introduction of an Alkyl Group onto a !-Position

I-6-1-1. Via Electrophilic Aromatic Substitution

Due to the sufficient aromaticity and "-excessive nature of pyrroles, the direct

introduction of alkyl groups onto pyrroles by SEAr appears to be a straightforward route

to access !-alkylpyrroles. However, as was mentioned in Chapter I-5-2, the preferential

#-nucleophilicity of pyrroles actually makes the !-alkylation considerably difficult.

Despite such characteristics of pyrrole, three major strategies through the SEAr

mechanism have been utilized to change the #-orientation to !-orientation: (i) use of pyrroles with an electron-withdrawing group at N1 or C2 position (Scheme 9),30 (ii) use

of pyrroles with a bulky substituent (RL) at the N1 position (Scheme 10),31,32 and (iii) use

of pyrrolyl–metal complexes (Scheme 11).33

Scheme 9

NH

NH

+removal of EWG

NH

ClN

+

SO2PhNSO2Ph

KOHNH

aq. MeOH

El'

EWG EWG

El'

El

EWG = COR, CO2R, CHCNMe2•Cl, CN El = iPrCl, tert-BuCl, CH2=CHCOR, HCOR,...

El = electrophile

口 -f=⇒ I

?~r?-.Jo ~Jj 0

16

Scheme 10

Scheme 11

NRL

NRL

El'removal of R

RL = Si(iPr)3

+ El

RL = tert-Bu, Si(iPr)3

NH

El'

El:

El = electrophile

OR'O

R

CCl3

NH

O

R R'

N OR'

R

–+

R2N EWGEWG

, , , ,...CO2Et

N2

,

NH

El

NH

El'

El = electrophileN

[M]

[M]

[M] = Mg, Zn, Ga, Cd, Re

El: OMe–OTf,Br R'

RBr ,,

口一⇒ 0~ ~0

‘‘’

丈 yy~ ハ八

ロー [O] = 0

へへー

17

I-6-1-2. Not via Electrophilic Aromatic Substitution

Other strategies for !-alkylation that do not rely on the natural aromaticity of

pyrroles have also been reported. One method is the alkylation of the $-pyrrole–osmium(II) complex. The pyrrole ring is changed such that it is no longer an enamine by

coordinating one of the C=C double bonds to osmium (Scheme 12).34 Another method

is the activation of transition metal-catalyzed selective C–H bond by directing groups

(DG) (Scheme 13).35 However, the DGs for guiding transition metals toward the !-C–H

bond of pyrroles must be preliminarily introduced onto the pyrrole rings at the #-position.

Scheme 12

Scheme 13

1.2. MeCN, heat NN

Os(NH3)5(OTf)3/Mg

N

[Os(NH3)5]2+O

O

NR

NR

alkyl

NR

DGDG' alkyl reagents removal of DG

NR

alkyl

DG

R = Me, Bn

alkyl reagents

Bu–Br, Bu–B(OH)2CO2Me,ClCl

O , ,

DG:

,

NO

NH

R

□

|

ジロ／

ロー 0-- = 0-- (~0)

I~-~• こ-~- I

18

I-6-2. Annulation Reactions

Numerous studies on annulation reactions for pyrrole ring construction have

been reported. The synthesis for C mono-substituted !-alkylpyrroles is still a challenging issue and has only been reported through multistep reactions. For example, the ring

closure reaction for C mono-substituted !-alkylpyrroles was recently achieved by olefin

cross-metathesis reactions36 and hetero-Diels–Alder reactions (Scheme 14).37 However,

synthetic versatility on the installed alkyl group through ring closure reactions was

limited due to the need for unique starting material syntheses.

Scheme 14

NR1

R2

NR1

R2

NR1

R2

R2

E

E = H, boryl

R2

O NR1

NR1

R2

olefin cross metathesis reaction

hetero-Diels–Alder reaction

l) =[M]=o

~= [~l = o

19

I-7. Purpose and Scope of this Thesis

The purpose of this thesis is the development of novel alkylations for

alkylindoles and !-alkylpyrroles through electrophilic aromatic substitution. As discussed above, few reports exist on general alkylation strategies for the introduction of

all types of alkyl groups onto the rings, and variation of installable alkyl chains has been

limited. This has prompted the author to develop a more convenient method for the

alkylation of indoles and pyrroles.

The research group to which the author belongs has already reported on the

reductive alkylation of indoles and pyrroles by simply mixing indoles and pyrroles with

alkynes and hydrosilanes under indium Lewis acid catalysis (Scheme 15).38,39 However,

cyclic and primary alkyl units, as well as diarylmethyl groups (CHAr2), are unable to be

introduced in this manner inevitably due to the use of alkynes as alkyl sources.

Regioselective introduction of an unsymmetrical dialkylmethyl group is also difficult to

control. The author anticipated that, instead of alkynes, the use of carbonyl compounds

as sources of the alkyl group would drastically extend the diversity of installable alkyl

groups onto the rings.

Scheme 15

NR1

+ + Si–H

O R3

R2' HR3

NR1

R2'

R3

+ +

HR3

NR1

previous work

cat. InR2

R2

cat. InSi–H

newly accessible alkyl groups

R3

R2'=

alkyl

H

, aryl

H

, alkyl

alkyl

, aryl

aryl

,

this work

NR1

r----ヘ、くり；{、;,~-D ’'-’ `

11 11 rー：：ーヘヽ , ,.. ... ―-... , (、ク:,、~-ロネ、 ’'-’ ヽ

Iふ .. ¥0どえ、え、ふ I

20

To further enhance the practicality and utility of the present strategy, the author also

exploited a more reasonable catalyst instead of the previously used indium salt (a

comparatively expensive chemical). Eventually, it was revealed that an inexpensive and

easily accessible Brønsted acid could effectively activate the !-alkylation of pyrroles with carbonyl compounds (Scheme 16).

Scheme 16

Chapter II discusses indium-catalyzed alkylation of indoles using carbonyl

compounds instead of alkynes. This is a reliable and practical method capable of offering

a wide range of alkylindoles. An important feature of this method is that the loading of

the indium catalyst can be reduced compared with the original alkyne-based system. Due

to the abundance of alkylindoles, not only in numerous natural products and

pharmaceuticals but also in functional organic materials, this study would have a spillover

effect on a variety of scientific fields.

Chapter III discusses the synthesis of !-alkylpyrroles under indium catalysis

using carbonyl compounds as alkyl sources without contamination with #-alkylpyrroles.

This is the first example that can afford all types of alkyl groups (primary, secondary, and

tertiary alkyl groups) on the !-position of pyrrole rings in one step and catalytically.

Additionally, applying this pyrrole !-alkylation enabled the synthesis of !-pyrrolyl-

group-connected unsymmetrical tetraarylmethanes that had been previously inaccessible,

albeit in two steps.

NR1

O R3

R2' HR3

NR1

R2'

+ + cat. InSi–H

cat. Brønsted acidNR1

O R3

R2' HR3

NR1

R2'

+ + Si–H

□ 人

□ 人

-

＞

if

if

21

Chapter IV discusses how a Brønsted acid was found to catalyze the !-alkylation of pyrroles with a carbonyl compound. This metal-free process features lower

catalyst loadings compared with the original indium variant (Chapter III) while

maintaining exclusive !-selectivity for pyrroles. Due to the significance of !-alkylpyrroles in a number of valuable compounds, the studies in Chapters III and IV

would be very usefull scientific fields.

22

I-8. References and Notes

1 a) A. Baeyer A. Ann. 1866, 140, 295; b) A. Baeyer, A. Emmerling, Ber. Dtsch. Chem.

Ges. 1869, 2, 679. 2 W. C. Rose, Physiol. Revs. 1938, 18, 108. 3 F. Kögl, A. J. Haagen-Smit, Z. Physiol. Chem. 1936, 243, 209. 4 A. R. Katritzky, C. A. Ramsden, J. A. Joule, V. V. Zhdankin, In Handbook of Heterocyclic Chemistry, 3rd ed. Elsevier, Oxford, 2010, p 100. 5 J. Clayden, N. Greeves, S. Warren, In Organic Chemistry, 2nd ed. Oxford University

Press, New York, 2012, pp. 745–746. 6 H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66. 7 S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont, T. Boubaker, A. R. Ofial, H. Mayr,

J. Org. Chem. 2006, 71, 9088. 8 a) F. Terrier, E. Kizilian, J.-C. Hallé, E. Buncel, J. Am. Chem. Soc. 1992, 114, 1740; b)

F. Terrier, M.-J. Pouet, J.-C. Hallé, S. Hunt, J. R. Jones, E. Buncel, J. Chem. Soc. Perkin

Trans. 2 1993, 1665. 9 J. Bergman, T. Janosik, In Modern Heterocyclic Chemistry, Vol. 1 (Eds: J. Alvare-Builla,

J. J. Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011, pp 269–375. 10 For general reviews, see: J. A. Joule, In Science of Synthesis, Vol. 10 (Ed:

E. J. Thomas), Thieme, Stuttgrat, 2000. b) B. A. Trofimov, N. A. Nedolya in

Comprehensive Heterocyclic Chemistry III, Vol. 3 (Eds.: A. R. Katritzky, C. A. Ramsden,

E. F. V. Scriven, R. J. K. Taylor, G. Jones), Elsevier, Oxford, 2008. 11 For selected recent reviews, see: a) J. S. Russel, E. T. Pelkey, S. J. P. Yoon-Miller, Prog. Heterocycl. Chem. 2009, 21, 145. b) J. S. Russel, E. T. Pelkey, S. J. P. Yoon-Miller, Prog.

Heterocycl. Chem. 2011, 22, 143. c) J. S. Russel, E. T. Pelkey, J. G. Greger, Prog. Heterocycl. Chem. 2011, 23, 155. d) J. M. Lopchuk, Prog. Heterocycl. Chem. 2012, 24,

169. e) J. M. Lopchuk, Prog. Heterocycl. Chem. 2013, 25, 137. 12 Electrophilic alkenes with electron-withdrawing groups have been used, see: a) P. E.

Harrington, M. A. Kerr, Synlett 1996, 1047; b) P. Harrington, M. A. Kerr, Can. J. Chem. 1998, 76, 1256; c) N. Srivastava, B. K. Banik, J. Org. Chem. 2003, 68, 2109; d) A. V.

Reddy, K. Ravinder, T. V. Goud, P. Krishnaiah, T. V. Raju, Y. Venkateswarlu, Tetrahedron Lett. 2003, 44, 6257; e) B. K. Banik, M. Fernandez, C. Alvarez, Tetrahedron Lett. 2005,

46, 2479; f) V. Kumar, S. Kaur, S. Kumar, Tetrahedron Lett. 2006, 47, 7001; g) Z.-H.

23

Huang, J.-P. Zou, W.-Q. Jiang, Tetrahedron Lett. 2006, 47, 7965. 13 Allyl and benzyl type alcohols have been used, see: a) M. Kimura, M. Futamata, R.

Mukai, Y. Tamaru, J. Am. Chem. Soc. 2005, 127, 4592; b) S. Shirakawa, S. Kobayashi,

Org. Lett. 2007, 9, 311; c) I. Usui, S. Schmidt, M. Keller, B. Breit, Org. Lett. 2008, 10,

1207; d) S. Gruber, A. B. Zaitsev, M. Wörle, P. S. Pregosin, Organometallics 2008, 27,

3796; e) T. Hirashita, S. Kuwahara, S. Okochi, M. Tsuji, S. Araki, Tetrahedron Lett. 2010,

51, 1847; f) D. Das, S. Roy, Adv. Synth. Catal. 2013, 355, 1308. 14 Allyl, benzyl and tertiary alkyl bromides have been used, see: X. Zhu, A. Ganesan, J.

Org. Chem. 2002, 67, 2705. 15 A. Onistschenko, H. Stamm, Chem. Ber. 1989, 122, 2397. 16 K. L. Toups, G. T. Liu, R. A. Widenhoefer, J. Organomet. Chem. 2009, 694, 571. 17 a) P. E. Reyes-Gutiérrez, R. O. Torres-Ochoa, R. Martínez, L. D. Miranda, Org. Biomol. Chem. 2009, 7, 1388; b) Q. Tang, X. Chen, B. Tiwari, Y. R. Chi, Org. Lett. 2012, 14, 1922. 18 E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241. 19 Comprehensive Organic Name Reactions and Reagents, Vol. 1, (Ed.: Z. Wang), Wiley,

Hoboken, 2009, pp 1069–1075. 20 For selected reviews, see: a) S. Cacchi, G. Fabrizi, Chem. Rev. 2011, 11, PR215; b) M.

Platon, R. Amardeil, L. Djakovitch, J.-C. Hierso, Chem. Soc. Rev. 2012, 41, 3929. 21 F. F. Runge, Ann. Physik. 1834, 107, 65. 22 T. Anderson, Ann. 1858, 105, 335. 23 A. Bayer, H. Emmerling, Ber. Dtsch. Chem. Ges. 1870, 3, 514. 24 F. A. Hoppe-Seyler, Med. Chem. Untersuchungen 1868, 3, 379. 25 F. A. Hoppe-Seyler, Z. Physiol. Chem. 1879, 3, 339. 26 Heterocyclic Chemistry, 5th ed. (Eds.: J. A. Joule, K. Mills) Wiley, New York, 2010. 27 L. Nygaard, J. T. Niselsen, J. Kirchheiner, G. Maltesen, J. Rastrup-Andersen, G. O.

Sørensen, J. Mol. Structure 1969, 3, 491. 28 T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr, Eur. J. Org. Chem. 2008, 2369. 29 For a general review, see: D. S. C. Black, In Science of Synthesis, Vol. 9 (Ed: G. Maas),

Thieme, Stuttgrat, 2001, pp. 441–552. 30 a) H. J. Anderson, L. C. Hopkins, Can. J. Chem. 1964, 42, 1279; b) H. J. Anderson, L.

C. Hopkins, Can. J. Chem. 1966, 44, 1831; c) H. J. Anderson, C. W. Huang, Can. J. Chem. 1970, 48, 1550; d) J. K. Groves, H. J. Anderson, H. Nagy, Can. J. Chem. 1971, 49, 2427;

24

e) H. J. Anderson, C. E. Loader, R. X. Xu, N. Lê, N. J. Gogan, R. McDonald, L. G.

Edwards, Can. J. Chem. 1985, 63, 896; f) P. L. Barker, C. Bahia, Tetrahedron 1990, 46,

2691; g) U. T. Mueller-Westerhoff, G. F. Swiegers, Synth. Commun. 1994, 24, 1389; h)

M. Kawatsura, M. Fujiwara, H. Uehara, S. Nomura, S. Hayase, T. Itoh, Chem. Lett. 2008,

37, 794; i) L. M. Broomfield, J. A. Wright, M. Bochmann, Dalton Trans. 2009, 8269; j)

J. Majer, P. Kwiatkowski, J. Jurczak, Org. Lett. 2011, 13, 5944; k) T.-W. Chung, Y.-T.

Hung, T. Thikekar, V. V. Paike, F. Y. Lo, P.-H. Tsai, M.-C. Liang, C.-M. Sun, ACS Comb. Sci. 2015, 17, 442. 31 a) B. E. Maryanoff, J. Org. Chem. 1979, 44, 4410; b) D. J. Armitt, M. G. Banwell, C.

Freeman, C. R. Parish, J. Chem. Soc. Perkin Trans. 1 2002, 1743; c) B. Kempf, N. Hampel,

A. R. Ofial, H. Mayr, Chem. Eur. J. 2003, 9, 2209; d) N. L. Hungerford, D. J. Armitt, M.

G. Banwell, Synthesis 2003, 1837; e) J. Renner, I. Kruszelnicki, B. Adamiak, A. C. Willis,

E. Hammond, S. Su, C. Burns, E. Trybala, V. Ferro, M. G. Banwell, Aust. J. Chem. 2005,

58, 86; f) E. J. Corey, Y. Tian, Org. Lett. 2005, 7, 5535; g) C. Berini, F. Minassian, N.

Pelloux-Léon, J.-N. Denis, Y. Vallée, C. Philouze, Org. Biomol. Chem. 2008, 6, 2574; h)

C. Berini, N. Pelloux-Léon, F. Minassian, J.-N. Denis, Org. Biomol. Chem. 2009, 7, 4512;

i) J. Barluenga, A. Fernández, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2009, 15, 8121;

j) L. Boiaryna, M. K. E. Mkaddem, C. Taillier, V. Dalla, M. Othman, Chem. Eur. J. 2012,

18, 14192; k) F. de Nanteuil, J. Loup, J. Waser, Org. Lett. 2013, 15, 3738; l) M. L. Murat-

Onana, C. Berini, J.-N. Denis, J.-F. Poisson, F. Minassian, N. Pelloux-Léon, Eur. J. Org.

Chem. 2014, 3773; m) S. C. Gadekar, B. K. Reddy, S. P. Panchal, V. G. Anand, Chem. Commun. 2016, 52, 4565. 32 Petrini, Palmieri and co-workers have reported on synthesis of functionalized !-

alkylpyrroles by the two-step approach, which is !-sulfonylmethylation of 1-

triisopropylpyrrole followed by replacing the sulfonyl group with various nucleophiles:

a) F. Martinelli, A. Palmieri, M. Petrini, Chem. Eur. J. 2011, 17, 7183; b) S. Lancianesi,

A. Palmieri, M. Petrini, Adv. Synth. Catal. 2013, 355, 3285; c) A. Palmieri, M. Petrini,

Chem. Rec. 2016, 16, 1353. 33 a) A. J. Castro, W. G. Duncan, A. K. Leong, J. Am. Chem. Soc. 1969, 91, 4304; b) M.

R. DuBois, L. D. Vasquez, L. Peslherbe, B. C. Noll, Organometallics 1999, 18, 2230; c)

J. S. Yadav, B. V. S. Reddy, P. M. Reddy, C. Srinivas, Tetrahedron Lett. 2002, 43, 5185;

d) D. Prajapati, M. Gohain, B. J. Gogoi, Tetrahedron Lett. 2006, 47, 3535.

25

34 a) L. M. Hodges, J. Gonzalez, J. I. Koontz, W. H. Myers, W. D. Harman, J. Org. Chem. 1995, 60, 2125; b) W. D. Harman, Chem. Rev. 1997, 97, 1953. 35 a) B. M. Monks, E. R. Fruchey, S. P. Cook, Angew. Chem. Int. Ed. 2014, 53, 11065; b)

E. R. Fruchey, B. M. Monks, S. P. Cook, J. Am. Chem. Soc. 2014, 136, 13130; c) K.

Shibata, N. Chatani, Org. Lett. 2014, 16, 5148; d) J. Wippich, I. Schnapperelle, T. Bach,

Chem. Commun. 2015, 51, 3166; e) G. Cera, T. Haven, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55, 1484. 36 For selected recent examples, see: a) B. Schmidt, S. Krehl, E. Jablowski, Org. Biomol.

Chem. 2012, 10, 5119; b) W. Chen, J. Wang, Organometallics 2013, 32, 1958; c) A. Bunrit,

S. Sawadjoon, S. Tšupova, P. J. R. Sjöberg, J. S. M. Samec, J. Org. Chem. 2016, 81, 1450. 37 For selected recent examples, see: a) S. Zhu, X. Liu, S. Wang, Tetrahedron 2003, 59,

9669; b) F. Tripoteu, L. Eberlin, M. A. Fox, B. Carboni, A. Whiting, Chem. Commun. 2013, 49, 5414. 38 T. Tsuchimoto, T. Wagatsuma, K. Aoki, J. Shimotori, Org. Lett. 2009, 11, 2129. 39 T. Tsuchimoto, M. Kanbara, Org. Lett. 2011, 13, 912.

Charter II. Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles with Carbonyl Compounds and

Hydrosilanes under Indium Catalysis

27

II-1. Introduction

Organic molecules containing an indole skeleton are prominent structural

motifs, due to their significance not only as natural products and pharmaceuticals but also

as functional materials.1 In this context, a large number of synthetic transformations of

indoles have been reported,2 and the author has also been engaging in exploring new

catalytic reactions of indoles under Lewis acid catalysis.3 One of these is the reductive

alkylation of indoles performed by simply mixing indoles 1, alkynes 2 and hydrosilanes

3 under indium Lewis acid catalysis (Scheme 1).3d The features are (1) high to excellent

levels of reaction efficiency capable of providing alkylindoles in 70–99% isolated yields,

(2) perfect regioselection on both indoles and alkynes, and (3) a remarkable degree of

functional group compatibility. These are significant aspects that reliable and practical

organic transformation should fulfill. However, cyclic and primary alkyl groups as well

as a diarylmethyl unit (CHAr2) are unable to be installed intrinsically onto 1 when using

alkynes 2 as sources of alkyl groups. Regioselective introduction of a dialkylmethyl group

with two same alkyl groups, CH(alkyl)2, is also a difficult task. The author therefore

envisaged that development of an indium-catalyzed variant using carbonyl compounds 5

instead of 2 would lead to removing all of the above limitation while keeping the

advantage of the original indium reaction. That is because carbonyl compounds have

much higher skeletal and substitutional diversities than alkynes as commercial sources.4

There are some precedents for the reductive alkylation of indoles with carbonyl

compounds,[5] and the redox system through in situ oxidation of alcohols to carbonyl

compounds then reacting with indoles has also emerged in the literature.6,7 Among these,

however, there has been no method that can offer alkylindoles with primary, secondary

and tertiary alkyl groups. These three types are able to be prepared by utilizing simple

non-reductive processes, in which, however, highly reactive alkylating agents including

alkenes,8 alcohols,9 alkyl halides,10 and others11 as well as intramolecularly reacting

substrates 12 have only been the starting substrate of choice, to the best of my

knowledge.13 In contrast to the studies reported thus far, the author discloses a reliable

system capable of providing a variety of alkylindoles with structural diversity, based on

the reductive approach with carbonyl compounds and hydrosilanes.14

28

Scheme 1. Indium-catalyzed reductive alkylation of indoles: alkynes versus carbonyl compounds as sources of alkyl groups (In = an indium salt).

R5+ H–Si+

cat.In

2 3

R6

previous work

this work

N R1

R2R4

4: 70–99% yield

R6R3

N R1

R2R4

R3

1

R5

cat.In

N R1

R2R4

4

R6

RR3 5'

5

O R6

R5'

+ H–Si+

3N R1

R2R4

R3

1

FG = H, Ph, OH, OMe, CN, NO2, Cl, Br, I, boryl, phthalimidoyl

R1–3 = H, Me, Ph; R4 = FG; R5 = H, Me, Bu; R6 = (CH2)nFG, tBu, (C6H4)FG, thienyl

• high yield of products• non-formation of regioisomers• high functional group tolerance


R6

R5'=

alkyl

alkyl

,, alkyl

H

,aryl

aryl

,aryl

H

~=• -o:f

0- J-_ →'():?

I.\~ 、＼〇兄兄芯応 I

29

II-2. Results & Discussion

II-2-1. Indium-Catalyzed Reductive Alkylation of Indoles with Carbonyl Compounds and HSiMePh2

Due to the potent activity of In(NTf2)3 (Tf = SO2CF3) found in a preceding

research of the research group to which the author belongs,3d this study began with its

testing in the reductive alkylation of indole (1a) with 2-octanone (5a) (Table 1). Thus,

treating 1a, 5a and HSiMePh2 (3a) with 30 mol% of In(NTf2)3 in PhCl (dried) at 45 ºC

for 24 h gave 3-(1-methylheptyl)-1H-indole (4a) in 17% yield (entry 1). Reducing the

catalyst loading to 10 mol% resulted in the much lower reaction rate but, in contrast, in

the improvement of the reaction efficiency (entry 2). The use of PhMe (dried) as a solvent

gave no enhancement of the yield (entry 3). However, the reactions carried out in other

solvents (dried) including DCE, EtCN, MeNO2, THF, EtOAc, DME and 1,4-dioxane

provided 4a in higher yields (entries 4–10). Among the solvents tested, 1,4-dioxane was

found to be the most effective medium to afford 4a in 94% GC yield and in 86% isolated

yield (entry 10). The author subsequently tested non-dried 1,4-dioxane as a solvent, and

found that pre-drying of 1,4-dioxane is unnecessary (entries 10 vs. 11). Accordingly, non-

dried 1,4-dioxane was used as a solvent hereafter. The use of such a non-dried solvent

should thus be a technical advantage of this reaction. Screening of other hydrosilanes 3b–

3e showed that 3a is the most promising (entries 12–15). Under the conditions with 3a in

1,4-dioxane, the fine-tuning by changing the reaction temperature from 45 to 50 °C raised

the isolated yield to 88% (entry 16).15

30

Table 1. Indium-catalyzed reductive alkylation of indole with 2-octanone and hydrosilanes.a

Entry

Solventb

HnSiR4–n

Conv. (%)c of 5a

Yield (%)c,d

of 4a

1 PhCl HSiMePh2 3a 68 17

2 PhCl 3a 37 22

3 PhMe 3a 47 2

4 DCE[e] 3a 45 31

5 EtCN 3a 62 27

6 MeNO2 3a 45 44

7 THF 3a 94 48

8 EtOAc 3a 91 70

9 DMEf 3a 97 93

10 1,4-dioxane 3a 97 94 (86)

11 1,4-dioxane 3a 97 95 (86)

12 1,4-dioxane HSiPh3 3b 97 48

13 1,4-dioxane HSiMe2Ph 3c 60 49

14 1,4-dioxane HSiEt3 3d 74 42

15 1,4-dioxane H3SiPh 3e 59 18

16g 1,4-dioxane 3a 99 95 (88) aReagents: 1a (0.60 mmol), 5a (0.40 mmol), 3 (0.60 mmol), In(NTf2)3 (0.12 mmol for entry 1, 0.040 mmol for other entries), solvent (0.40 mL). bDried solvents were used for entries 1–10. Non-dried 1,4-dioxane was used for entries 11–16. See the experimental section for further details. cDetermined by GC. dIsolated yields are shown in parentheses. eDCE = 1,2-dichloroethane. fDME = 1,2-dimethoxyethane. gThe reaction was performed at 50 ºC.

N H

+O C6H13

HnSiR4–n+

In(NTf2)3(30 or 10 mol%)solvent45 ºC, 24 h

N H

C6H13

4a1a 5a 3

1.5:1:1.5□ よ ~er{

31

As shown in Scheme 2, the introduction of 2-octyl group can be also achieved

by 1-octyne (2a) instead of 2-octanone (5a), as previously demonstrated.[3d] While the

most favorable conditions for 5a are slightly different from those for 2a, the same high

performance was also observed here, and, preferably, using carbonyl compound 5a has

the following two advantages over alkyne 2a: 1) the reaction of 5a can be carried out with

a more reduced amount of In(NTf2)3 (10 mol%) than that (30 mol%) of the reaction of

2a, and 2) 5a is much more reasonable in price than 2a.

Scheme 2. Reductive 2-octylation of indole: 2-octanone versus 1-octyne as sources of

alkyl groups. Isolated yields of 4a are shown here. With the suitable reaction conditions in hand, the author next explored the scope

of this reaction (Table 2). Besides simple indole (1a) appeared in Table 1, N-, C2- and/or

C5-substituted indoles with Me, Ph, OMe, Br, CN, and B(pin) (pin = pinacolate) groups

participated well in this reaction, giving the corresponding 2-octylated and 2-propylated

indoles in good to excellent yields (4a and 4b–4j). The C(sp3)–Cl part with the good

leaving Cl group, which is possible to undergo a nucleophilic attack by the indole, was

retained here (4k). The 5-nonyl group, which is difficult to install regioselectively when

using 4-nonyne as an unsymmetrical alkyne, is readily available from 5-nonanone (5b)

(4l).16 However, in order to obtain 4l in a high yield, method A in which all of the starting

substrates are mixed concurrently with the indium catalyst is ineffective, thus resulting in

a lower conversion of 5b (53%) and yield of 4l (53%), as separately indicated in Scheme

3. After checking the reaction mixture, the reaction was found to have co-produced a

significant amount of N-methylindoline (6) that is likely to have been formed via

1.5:1:1.5

N H

1a

In(NTf2)3(10 mol%)1,4-dioxane50 ºC, 24 h

N H

C6H13

4a; 88% yieldcf. 4a; 86% yield at 45 ºC

In(NTf2)3(30 mol%)PhCl45 ºC, 24 h

US$ 27.70/100 mLfrom Merck

US$ 68.90/25 mLfrom Merck

+ +O C6H13

5a 3a

HSiMePh2

+ +

2a

HSiMePh2N H

C6H13

4a; 84% yield

C6H13N H

1a

1.5:1:1.5

3a

□ よ—/

():)=―/

32

reduction of N-methylindole (1b) by 3a. It was then assumed that the slow reaction would

be ascribed to a lowering of the catalytic activity of In(NTf2)3 by coordinating the nitrogen

atom of 6 to the indium center. In fact, as a control experiment, adding 20 mol% of 6 to

the reaction of 1a with 5a proved to inhibit completely the progress of the reaction

(Scheme 4), in sharp contrast to the reaction without 6 (see entry 16 of Table 1). With the

intention of suppressing the undesired reduction of N-methylindole (1b), the synthesis of

4l was performed by modifying the procedure to method B where 3a is added after

promoting the consumption of 1 and 5. As expected, method B is effective for this case,

and the yield of 4l was improved to 76%. Accordingly, method B was adopted hereafter

when a non-negligible reduction of not only indoles but also carbonyl compounds was

observed with method A (4m–p, 4u and 4ad). The ester group was tolerated without acid

hydrolysis under the reaction conditions including the indium Lewis acid catalyst and in

situ generated H2O (4n).17 The cyclic alkyl groups that are also inaccessible from alkynes

can be easily connected with the indole rings (4o–q and 4v). The scope of the reaction

can be extended to aryl ketones (4q–4v). Importantly, the diarylmethyl unit (CHAr2)

including the fluorenyl group is a framework installable only by this carbonyl-based

reaction (4u and 4v). One of the major highlights is to ensure installation of primary alkyl

groups that are impossible to handle in the previous system,3d because terminal alkynes

accept indoles exclusively at the internal carbon atom of the C≡C bond. Linear and #-branched aliphatic aldehydes as well as aromatic ones and ferrocenecarboxaldehyde thus

reacted with indoles 1 and 3a under indium catalysis to afford good to high yields of the

corresponding alkylindoles (4w–4ac). The C=C bond in the cyclohexene ring remained

intact without isomerization 18 and hydrosilylation19 (4y). The less nucleophilic C-2

compared to C-3 is also available as a reaction site (4ad).

With this system, alkylindoles are readily prepared on gram-scale. For example,

the synthesis of 4x was performed on a 5.0-mmol scale to provide 1.0 g of the target in

88% yield (4x in Table 2).

33

Table 2. Indium-catalyzed reductive alkylation of indoles with carbonyl compounds and HSiMePh2.a

aReagents: 1 (0.60 or 1.2 mmol), 5 (0.40 mmol), 3a (0.60 mmol), In(NTf2)3 (4.0–40 µmol), 1,4-dioxane (0.40 mL). Yields of isolated 4 based on 5 are shown here. The method (A or B) used, and the yield of 4x when performed on a 5.0 mmol scale are shown in parentheses. See experimental section for further details. bIn(NTf2)3 (20 mol%) was used.

O R6

R5

N R1

R2R4

3a

T3 ºCt3 h

In(NTf2)3(1–10 mol%)1,4-dioxaneT1 ºC, t1 h

+ +

In(NTf2)3(10 mol%)1,4-dioxaneT2 ºC, t2 h

O R6

R5

+N R1

R4R3

1 5 5 1

mehotd A mehotd B

N R1

R2R4

4

R6

R5R3

3a

N R1

4b (R1 = Me, R2 = H);97% yield (A), T1 = 50, t1 = 244c (R1 = H, R2 = Me);94% yield (A), T1 = 50, t1 = 244d (R1 = Me, R2 = Me); 94% yield (A), T1 = 50, t1 = 244e (R1 = Ph, R2 = H);87% yield (A), T1 = 85, t1 = 24

C6H13

N

4f; 84% yield (A)T1 = 50, t1 = 24

PhN H

4g (R2 = Me, R4 = OMe);99% yield (A), T1 = 50, t1 = 244h (R2 = H, R4 = Br);92% yield (A), T1 = 60, t1 = 244i (R2 = H, R4 = CN);65% yield (A), T1 = 85, t1 = 244j [R2 = H, R4 = B(pin)];93% yield (A), T1 = rt, t1 = 9

C6H13

R2R4

N H

4k; 87% yield (A)T1 = 50, t1 = 24

Cl

N

4o; 76% yield (B)T2 = 85, t2 = 48T3 = 50, t3 = 24

N

4p; 74% yield (B)T2 = 100, t2 = 48T3 = 100, t3 = 30

N

4r; 96% yield (A)T1 = 85, t1 = 50

N

4s; 89% yield (A)T1 = 85, t1 = 40

N

4t; 60% yield (A)T1 = 100, t1 = 24

OH

N H

4v; 72% yield (A)T1 = 85, t1 = 48

N

4w; 80% yield (A)T1 = 70, t1 = 24

C9H19

N H

4x; 90% (88%) yield (A)T1 = 50, t1 = 24

N H

4z; 86% yield (A)T1 = 50, t1 = 24

N

4aa; 61% yield (A)T1 = 100, t1 = 24

CF3

N

4ab; 83% yield (A)T1 = 50, t1 = 24

S

N H

4ac; 83% yield (A)T1 = 50, t1 = 48

Fe

N

4ad; 43% yield (B)T2 = 50, t2 = 24T3 = 100, t3 = 48

C3H7

N

4l; 53% yield (A)T1 = 85, t1 = 204l; 76% yield (B)T2 = 85, t2 = 20, T3 = 50, t3 = 15

BuBu

C9H19

N

4m; 84% yield (B)T2 = 85, t2 = 20T3 = 50, t3 = 15

C3H7 C5H11

N

4n; 93% yield (B)T2 = 60, t2 = 18T3 = 70, t3 = 48

OO

N

4u; 87% yieldb (B)T2 = 100, t2 = 48T3 = 100, t3 = 36

N

4q; 99% yield (A)T1 = 85, t1 = 18

N

4y; 96% yield (A)T1 = 50, t1 = 24

R2

;__ v) 人

―

e/‘

34

Scheme 3. 5-Nonylation of N-methylindole by method A.

Scheme 4. A control experiment: effect of N-methylindoline in the reaction of 1a with

5a.

N+ O

Bu

Bu +


N

BuBu

4l; 53% yield1b 5b; 53% conv.

3aN

6; 14% yield

+

1.5:1:1.5

N H

+ O C6H13+

In(NTf2)3 (10 mol%)6 (20 mol%)1,4-dioxane50 ºC, 24 h

N H

C6H13

4a; <1% yield1a 5a

3a

1.5:1:1.5

N6

Ct; A~~OC:

oo ょ ~oS(ex:)

35

II-2-2. Indium-Catalyzed Alkylation of Indoles with Carbonyl Compounds and Carbon Nucleophiles

This approach can be applied to the use of carbon nucleophiles such as

Me3SiCN (3f) and 2-methoxythiophene (3g) instead of HSiMePh2 to introduce tertiary

alkyl groups onto indoles (Scheme 5). Worthy of note is that when using 3g as a

nucleophile, two different heteroaryl units can be introduced onto the carbonyl carbon in

one shot. The results discussed so far show that choosing a proper combination of

carbonyl compounds and nucleophiles enables preparing all of the three types of

alkylindoles with primary, secondary and tertiary alkyl groups. This is the first

demonstration in the reductive alkylation of indoles.

Scheme 5. Indium-catalyzed alkylation of indoles with carbonyl compounds and

carbon nucleophiles.

N O C6H13+

In(NTf2)3(10 mol%)1,4-dioxane70 ºC, 30 min

Me3SiCN 3f(2 equiv.)50 ºC, 8 h N

CN3:1

N H

O Ar+


3g(3 equiv.)50 ºC, 30 h N

H

3:1S

O

S

C6H13

Ar

7a; 87% yield

7b; 50% yield(Ar = C6H4–p-CF3)

1b 5a

1a

O

method B

method B

〇よ＼ ~

〇よ0-¥ ~\

36

II-2-3. Reaction Mechanism

The author next performed some reactions to get insight into the reaction

mechanism (Scheme 6). To begin with, the indium-catalyzed reaction of N-methylindole

(1b) with acetophenone (5c) was conducted in the absence of 3a, and thereby provided

di(indolyl)alkane 8a quantitatively, while no 8a was formed in the absence of In(NTf2)3.

In the presence of H2O formed along with 8a in the above reaction, the treatment of 8a

and 3a with In(NTf2)3 (10 mol%) for 30 min provided 4r in 98% yield, whereas the

absence of H2O resulted in the much slower reaction (120 h). Moreover, no 4r was

produced in the presence of H2O but without In(NTf2)3. Interestingly, the use of C2-

substituted indole 1c instead of 1b gave not the corresponding di(indolyl)alkane, but

alkenylindole 9a as a sole product, which was then readily converted to alkylindole 4s by

treated with 3a under indium catalysis. Here again, H2O greatly accelerated the hydride

reduction of 9a. These results suggest that the di(indolyl)alkane and alkenylindole are

likely to be intermediates, and that the structure of the intermediate should depend on

whether the indole substrate has a substituent at the C2 position, and, in addition, that

H2O possibly works as an activator for enhancing nucleophilicity of 3a by its

coordination.20,21 The exclusive generation of 8a from 1b should be due mainly to little

or no steric congestion in the structure of 8a, in contrast to steric stress that would arise

between the two methyl groups at the C2, in the case that 9a would further react with 1c to give the corresponding di(indolyl)alkane.

37

Scheme 6. Indium-catalyzed reactions for mechanistic studies.

On the basis of the above results and the previous discussion,3d path A and B

for C2-unsubstituted and C2-substituted indoles, respectively, are proposed as plausible

reaction routes in Scheme 7. In path A where C2-unsubstituted indole 1 (R2 = H)

participates, the indium salt (In) first catalyzes the formation of di(indolyl)alkane 8 and

H2O from 1 and 5.22 One indolyl ring of 8 then coordinates to the In and eliminates to

give cationic species 10 by way of the C(sp3)–C(indolyl) bond cleavage.23 The hydride

transfer to 10 from H–SiR3•H2O complex 11, which would possess higher nucleophilicity

than the free HSiR3, gives alkylindole 4. On the other hand, path B starts with providing

alkenylindole 9 via nucleophilic attack of C2-substituted indole 1 (R2 ≠ H) to 5 followed

by dehydration. The activation of the C=C bond of 9 by the In24 induces the hydride

reduction from 11. Finally, the protonation of the C–In bond of 12 affords alkylindole 4.

N

Ph

N+


3:1

N N

Ph

8a; 99% yieldwithout In(NTf2)3; 8a; <1% yield

1b

In(NTf2)3 (10 mol%)H2O (1 equiv.)1,4-dioxane, 85 ºCN N

Ph

8a

3aN

Ph

30 min; 4r; 98% yieldwithout H2O, 120 h; 4r; 88% yield

without In(NTf2)3 10 h; 4r; <1% yield

+

In(NTf2)3 (10 mol%)H2O (1 equiv.)1,4-dioxane, 85 ºC

3aN

Ph

15 min; 4s; 89% yieldwithout H2O, 24 h; 4s; 90% yield

9a; 81% yield

N

Ph

9a

1:1.5

+1:1.5

In(NTf2)3 (10 mol%)1,4-dioxane50 ºC, 40 h

O Ph

N+

3:1

1c

O Ph

5c

5c

□ よ--------~¥ I ¥

QyY9 ／＼

〇よ＼

~ ~

三三

38

Scheme 7. Proposed reaction mechanisms.

H2O is co-produced in the early stage of the present reaction, as discussed thus

far. This is clearly different from the corresponding alkyne-based reaction without

producing H2O.3d However, H2O is not just a by-product here but it effectively affects the

progress of the reaction by accelerating the process of the hydride reduction. It can thus

be assumed that the formation of H2O positively contributes to reducing the amount of

In(NTf2)3 used, compared to that of the alkyne-based reaction.

O R3

R4

N NR1 R1

R3

N NR1 R1

R3

N R1

R2

R3

R4

N R1

R2

R3

R4

N R1

R2

R3

R4

In

R4 R4

N R1

R3

R4

+

N R1

R3

R4

N R1

O H

SiR3

H +

–

–

In

R2

O H

SiR3

H

H

O H

SiR3

H +

In + HOSiR3

In

In

8

In

In

4

5

9

path A: route through the di(indolyl)alkane intermediate

path B: route through the alkenylindole intermediate

10

In

HOSiR3 ++1

+

+

In

In

2

N R11

N R11

R2 = H

R2

R2

R2 ≠ H

H2O

H2O

δ+

δ–

11

12

O H

SiR3

H

H

δ+

δ–

11

→`叫/) ← -~',

三三/

39

II-3. Experimental

General Remarks

All manipulations were conducted with a standard Schlenk technique under an

argon atmosphere. Nuclear magnetic resonance (NMR) spectra were taken on a JEOL

JMN-ECA 400 (1H, 400 MHz; 13C, 100 MHz) or JEOL JMN-ECA 500 (1H, 500 MHz; 13C, 125 MHz) spectrometer using tetramethylsilane (1H and 13C) as an internal standard.

Analytical gas chromatography (GC) was performed on a Shimadzu model GC-2014

instrument equipped with a capillary column of InertCap 5 (5% diphenyl- and 95%

dimethylpolysiloxane, 30 m x 0.25 mm x 0.25 µm) using nitrogen as carrier gas. Gas chromatography–mass spectrometry (GC–MS) analyses were performed with a

Shimadzu model GCMS-QP2010 instrument equipped with a capillary column of ID-

BPX5 (5% phenyl polysilphenylene-siloxane, 30 m x 0.25 mm x 0.25 µm) or InertCap 5

(5% diphenyl- and 95% dimethylpolysiloxane, 30 m x 0.25 mm x 0.25 µm) by electron

ionization at 70 eV using helium as carrier gas. Preparative recycling gel permeation

chromatography (GPC) was performed with JAI LC-9105 equipped with JAIGEL-1H

and JAIGEL-2H columns using chloroform as eluent. High-resolution mass spectra

(HRMS) were obtained with a JEOL JMS-T100GCV spectrometer. All melting points

were measured with a Yanaco Micro Melting Point apparatus and uncorrected. Kugelrohr

bulb-to-bulb distillation was carried out with a Sibata glass tube oven GTO-250RS

apparatus. 1,4-Dioxane was purchased from Kanto Chemical Co. and used as received

without pre-drying. For the reaction of entry 10 in Table 1, 1,4-dioxane distilled under

argon from sodium was used. Other solvents used in this research were pre-dried as

follows. Toluene (PhMe) and chlorobenzene (PhCl) were distilled under argon from

calcium chloride just prior to use. 1,2-Dichloroethane (DCE), nitromethane (MeNO2),

ethylacetate (EtOAc) and 1,2-dimethoxyethane (DME) were stored over molecular sieves

4A (MS 4A) under argon. Propionitrile (EtCN) was distilled under argon from P2O5 just

prior to use. Tetrahydrofuran (THF) was distilled under argon from sodium benzophenone

ketyl just before use. In(NTf2)3 was prepared by the reported method.25 Unless otherwise

noted, other substrates and reagents were commercially available and used as received.

40

Synthesis of 1,5-Dimethyl-3-propyl-1H-indole as a Substrate. Under an argon atmosphere, potassium hydroxide (449 mg, 8.00 mmol) and

dimethyl sulfoxide (5.0 mL) were placed in a flame-dried 20 mL Schlenk tube, which

was stirred at room temperature for 10 min. To the tube was added 5-methyl-3-propyl-

1H-indole[26] (347 mg, 2.00 mmol), and then iodomethane (284 mg, 2.00 mmol) was

slowly added dropwise with stirring. After stirring at room temperature for 45 min, the

reaction mixture was filtered to remove an excess amount of potassium hydroxide, and

the filtrate was diluted with Et2O (100 mL). The organic layer was washed with water (10

mL x 4) and brine (10 mL), and then dried over anhydrous sodium sulfate. Filtration and

evaporation of the solvent followed by column chromatography on silica gel

(hexane/EtOAc = 30/1) gave 1,5-dimethyl-3-propyl-1H-indole (342 mg, 91% yield) as a

pale yellow oil. 1H NMR (500 MHz, CDCl3) % 0.99 (t, J = 7.4 Hz, 3 H), 1.71 (sext, J = 7.5 Hz, 2 H), 2.46 (s, 3 H), 2.68 (t, J = 7.5 Hz, 2 H), 3.71 (s, 3 H), 6.77 (s, 1 H), 7.03 (d,

J = 8.0 Hz, 1 H), 7.16 (d, J = 8.1 Hz, 1 H), 7.36 (s, 1 H); 13C NMR (CDCl3, 125 MHz) �

14.2, 21.5, 23.6, 27.2, 32.5, 108.8, 114.8, 118.8, 122.9, 126.2, 127.6, 128.2, 135.5. HRMS

(FI) Calcd for C13H17N: M, 187.1361. Found: m/z 187.1382.

Indium-Catalyzed Reductive Alkylation of Indoles with Carbonyl Compounds and HSiMePh2. A General Procedure of Method A for Scheme 2 and Table 2.

In(NTf2)3 [(3.82 mg, 4.00 µmol), (11.5 mg, 12.0 µmol), (19.1 mg, 20.0 µmol),

(38.2 mg, 40.0 µmol) or (76.4 mg, 80.0 µmol)] was placed in a 20 mL Schlenk tube,

which was heated at 150 ºC in vacuo for 2 h. The tube was cooled down to room

temperature and filled with argon. 1,4-Dioxane (0.40 mL) was added to the tube, and then

the mixture was stirred at room temperature for 5 min. To this were added carbonyl

compound 5 (0.400 mmol), indole derivative 1 (0.600 mmol) and HSiMePh2 (3a) (119

mg, 0.600 mmol) successively, and the resulting solution was then stirred at the

temperature shown in Scheme 2 and Table 2 (see T1). After the time specified in Scheme

2 and Table 2 (see t1), a saturated NaHCO3 aqueous solution (0.5 mL) was added, and the

aqueous phase was extracted with EtOAc (5 mL x 3). The combined organic layer was

washed with brine (1 mL) and then dried over anhydrous sodium sulfate. Filtration and

evaporation of the solvent followed by purification gave the corresponding product (4).

41

The results are summarized in Scheme 2 and Table 2. Unless otherwise noted, products 4

synthesized here were fully characterized by 1H and 13C NMR spectroscopy, and HRMS.

Indium-Catalyzed Reductive Alkylation of Indoles with Carbonyl Compounds and HSiMePh2. A General Procedure of Method B for Table 2.

In(NTf2)3 (38.2 mg, 40.0 µmol) was placed in a 20 mL Schlenk tube, which

was heated at 150 ºC in vacuo for 2 h. The tube was cooled down to room temperature

and filled with argon. 1,4-Dioxane (0.40 mL) was added to the tube and then the mixture

was stirred at room temperature for 5 min. To this were added carbonyl compound 5

(0.400 mmol) and indole derivative 1 (1.20 mmol), and the resulting solution was then

stirred at 50, 60, 85 or 100 ºC (see T2) for 18, 20, 24 or 48 h (see t2). HSiMePh2 (3a) (119

mg, 0.600 mmol) was then added, and the resulting solution was stirred further at 50, 70,

85 or 100 ºC (see T3). After the time specified in Table 2 (see t3), the work-up process was

carried out similarly as above. The results are summarized in Table 2. Unless otherwise

noted, products 4 prepared here were fully characterized by 1H and 13C NMR

spectroscopy, and HRMS.

3-(1-Methylheptyl)-1H-indole (4a). The title compound was synthesized with

the following reagents based on method A: 1a (0.600 mmol), 5a (0.400 mmol), 3a (0.600

mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane (0.40 mL), and isolated by column

chromatography on silica gel (hexane/EtOAc = 40/1). Compound 4a has already

appeared in the literature, and its spectral and analytical data are in good agreement with

those reported in reference 3d. Therefore, only 1H NMR data are provided here. 1H NMR

(500 MHz, CDCl3) % 0.86 (t, J = 7.2 Hz, 3 H), 1.16–1.41 (m, 8 H), 1.34 (d, J = 6.9 Hz, 3

H), 1.56–1.67 (m, 1 H), 1.71–1.85 (m, 1 H), 3.02 (sext, J = 7.1 Hz, 1 H), 6.95 (d, J = 2.3

Hz, 1 H), 7.09 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.17 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H), 7.35

(dd, J = 7.4, 1.1 Hz, 1 H), 7.65 (dd, J = 8.0, 1.2 Hz, 1 H), 7.87 (bs, 1 H).

1-Methyl-3-(1-methylheptyl)-1H-indole (4b). The title compound was

synthesized with the following reagents based on method A: 1b (0.600 mmol), 5a (0.400

mmol), 3a (0.600 mmol), In(NTf2)3 (12.0 µmol) and 1,4-dioxane (0.40 mL), and isolated

by column chromatography on silica gel (hexane/EtOAc = 60/1). Compound 4b has

already appeared in the literature, and its spectral and analytical data are in good

agreement with those reported in reference 3d. Therefore, only 1H NMR data are provided

42

here. 1H NMR (500 MHz, CDCl3) % 0.86 (t, J = 6.9 Hz, 3 H), 1.19–1.39 (m, 8 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.55–1.64 (m, 1 H), 1.71–1.82 (m, 1 H), 3.00 (sext, J = 7.0 Hz, 1 H),

3.74 (s, 3 H), 6.79 (s, 1 H), 7.08 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.20 (ddd, J = 8.4, 7.0,

1.3 Hz, 1 H), 7.28 (d, J = 7.4 Hz, 1 H), 7.63 (dt, J = 6.9, 1.2 Hz, 1 H).

2-Methyl-3-(1-methylheptyl)-1H-indole (4c). The title compound was

synthesized with the following reagents based on method A: 2-methyl-1H-indole (0.600

mmol), 5a (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (12.0 µmol) and 1,4-dioxane (0.40

mL), and isolated by column chromatography on silica gel (hexane/EtOAc = 40/1).

Compound 4c has already appeared in the literature, and its spectral and analytical data

are in good agreement with those reported in reference 3d. Therefore, only 1H NMR data

are provided here. 1H NMR (500 MHz, CDCl3) % 0.83 (t, J = 7.2 Hz, 3 H), 1.10–1.33 (m, 8 H), 1.38 (d, J = 7.2 Hz, 3 H), 1.65–1.74 (m, 1 H), 1.79–1.88 (m, 1 H), 2.36 (s, 3 H),

2.87–2.97 (m, 1 H), 7.02 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 7.07 (ddd, J = 8.1, 7.1, 1.1 Hz,

1 H), 7.26 (dt, J = 8.1, 0.9 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.63 (bs, 1 H).

1,2-Dimethyl-3-(1-methylheptyl)-1H-indole (4d). The title compound was

synthesized with the following reagents based on method A: 1c (0.600 mmol), 5a (0.400


by column chromatography on silica gel (hexane/EtOAc = 40/1). A viscous yellow oil. 1H NMR (500 MHz, CDCl3) % 0.83 (t, J = 6.9 Hz, 3 H), 1.05–1.30 (m, 8 H), 1.38 (d, J = 7.5 Hz, 3 H), 1.65–1.75 (m, 1 H), 1.77–1.88 (m, 1 H), 2.34 (s, 3 H), 2.89–2.99 (m, 1 H),

3.63 (s, 3 H), 7.01 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.12 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H),

7.23 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 10.5, 14.1, 21.6, 22.7, 28.4, 29.42, 29.44, 31.7, 31.9, 37.2, 108.6, 115.9, 118.1, 119.5, 120.0,

126.4, 131.8, 136.8. HRMS (FI) Calcd for C18H27N: M, 257.2144. Found: m/z 257.2173.

3-(1-Methylheptyl)-1-phenyl-1H-indole (4e). The title compound was

synthesized with the following reagents based on method A: 1-phenyl-1H-indole (0.600


mL), and isolated by recycling GPC after column chromatography on silica gel

(hexane/CHCl3 = 20/1). A light green oil. 1H NMR (500 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.21–1.43 (m, 8 H), 1.38 (d, J = 6.9 Hz, 3 H), 1.59–1.69 (m, 1 H), 1.79–1.87

(m, 1 H), 3.07 (sext, J = 6.9 Hz, 1 H), 7.11 (s, 1 H), 7.15 (ddd, J = 7.9, 7.0, 1.0 Hz, 1 H),

7.20 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 H), 7.28–7.34 (m, 1 H), 7.47–7.52 (m, 4 H), 7.56 (dd, J

= 7.5, 1.2 Hz, 1 H), 7.69 (dd, J =7.5, 1.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 14.1,

43

21.4, 22.7, 27.7, 29.5, 30.8, 31.9, 37.6, 110.5, 119.6, 119.7, 122.2, 123.8, 124.0, 124.1,

125.9, 128.5, 129.5, 136.2, 140.1. HRMS (FI) Calcd for C22H27N: M, 305.2144. Found:

m/z 305.2157.

1-Methyl-3-(1-methylethyl)-2-phenyl-1H-indole (4f). The title compound

was synthesized with the following reagents based on method A: 1-methyl-2-phenyl-1H-

indole (0.600 mmol), acetone (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and

1,4-dioxane (0.40 mL), and isolated by recycling GPC after column chromatography on

silica gel (hexane/CHCl3 = 5/1). A pale yellow oil. 1H NMR (500 MHz, CDCl3) % 1.38 (d, J = 6.9 Hz, 6 H), 3.07 (sept, J = 7.1 Hz, 1 H), 3.51 (s, 3 H), 7.12 (ddd, J = 8.0, 6.9, 1.1

Hz, 1 H), 7.23 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.31–7.38 (m, 3 H), 7.40–7.50 (m, 3 H),

7.81 (d, J = 8.1 Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 23.4, 26.3, 30.6, 109.5, 118.7, 119.3, 120.5, 121.3, 126.0, 128.0, 128.2, 130.9, 132.6, 136.5, 137.4. HRMS (FI) Calcd

for C18H19N: M, 249.1518. Found: m/z 249.1533.

5-Methoxy-2-methyl-3-(1-methylheptyl)-1H-indole (4g). The title

compound was synthesized with the following reagents based on method A: 5-methoxy-

2-methyl-1H-indole (0.600 mmol), 5a (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (20.0

µmol) and 1,4-dioxane (0.40 mL), and isolated by column chromatography on silica gel

(hexane/EtOAc = 15/1). A colorless oil. 1H NMR (500 MHz, acetone-d6) % 0.83 (t, J =

6.9 Hz, 3 H), 1.12–1.34 (m, 8 H), 1.36 (d, J = 7.2 Hz, 3 H), 1.65–1.74 (m, 1 H), 1.82–

1.93 (m, 1 H), 2.35 (s, 3 H), 2.90–3.00 (m, 1 H), 3.78 (s, 3 H), 6.64 (dd, J = 8.6, 2.4 Hz,

1 H), 7.05 (d, J = 2.4 Hz, 1 H), 7.14 (dd, J = 8.7, 0.5 Hz, 1 H), 9.54 (bs, 1 H); 13C NMR

(125 MHz, acetone-d6) % 12.2, 14.3, 21.7, 23.3, 29.0, 30.6, 31.9, 32.7, 37.7, 55.9, 102.6, 110.1, 111.7, 116.0, 128.8, 132.12, 132.14, 154.1. HRMS (FI) Calcd for C18H27NO: M,

273.2093. Found: m/z 273.2092. 5-Bromo-3-(1-methylheptyl)-1H-indole (4h). The title compound was

synthesized with the following reagents based on method A: 5-bromo-1H-indole (0.600



Compound 4h has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) % 0.86 (t, J = 6.9 Hz, 3 H), 1.17–1.36 (m, 8 H), 1.31 (d, J = 7.1 Hz, 3 H), 1.51–1.65 (m, 1 H), 1.68–1.80 (m, 1 H), 2.96 (sext, J =

44

7.0 Hz, 1 H), 6.95 (d, J = 2.5 Hz, 1 H), 7.22 (dd, J = 8.6, 0.6 Hz, 1 H), 7.23–7.26 (m, 1

H), 7.72–7.77 (m, 1 H), 7.92 (bs, 1 H).

5-Cyano-3-(1-methylheptyl)-1H-indole (4i). The title compound was

synthesized with the following reagents based on method A: 5-cyano-1H-indole (0.600


mL), and isolated by column chromatography on silica gel (hexane/EtOAc = 5/1). A

colorless oil. 1H NMR (500 MHz, CDCl3) % 0.86 (t, J = 6.9 Hz, 3 H), 1.17–1.37 (m, 8 H), 1.34 (d, J = 6.9 Hz, 3 H), 1.54–1.67 (m, 1 H), 1.68–1.80 (m, 1 H), 3.01 (sext, J = 7.0 Hz,

1 H), 7.07 (d, J = 2.3 Hz, 1 H), 7.36–7.43 (m, 2 H), 7.99 (s, 1 H), 8.26 (bs, 1 H); 13C NMR

(125 MHz, CDCl3) % 14.1, 21.4, 22.7, 27.6, 29.4, 30.7, 31.8, 37.7, 101.7, 112.1, 121.2, 122.2, 123.7, 124.5, 125.1, 126.8, 138.2. HRMS (FI) Calcd for C17H22N2: M, 254.1783.

Found: m/z 254.1779.

1-Methyl-3-(1-methylheptyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (4j). The title compound was synthesized with the following reagents

based on method A: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

(0.600 mmol), 5a (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane

(0.40 mL), and isolated by column chromatography on silica gel (hexane/EtOAc/Et3N =

88/9/3). A viscous yellow oil. 1H NMR (500 MHz, CDCl3) % 0.86 (t, J = 6.9 Hz, 3 H),

1.19–1.37 (m, 8 H), 1.31 (d, J = 6.9 Hz, 3 H), 1.37 (s, 12 H), 1.54–1.64 (m, 1 H), 1.71–

1.80 (m, 1 H), 3.08 (sext, J = 6.9 Hz, 1 H), 3.74 (s, 3 H), 6.78 (s, 1 H), 7.26 (dd, J = 8.0,

0.6 Hz, 1 H), 7.65 (dd, J = 8.0, 1.2 Hz, 1 H), 8.13 (t, J = 1.1 Hz, 1 H); 13C NMR (125

MHz, CDCl3) % 14.1, 22.0, 22.7, 24.88, 24.90, 27.6, 29.5, 30.4, 31.9, 32.6, 37.8, 83.3, 108.5, 122.5, 124.7, 127.07, 127.12, 127.6, 139.0 (A signal of the boron-bound carbon

atom was not detected due to quadrupolar relaxation of boron). HRMS (FI) Calcd for

C23H36BNO2: M, 369.2839. Found: m/z 369.2859.

3-(5-Chloro-1-methylpentyl)-2-methyl-1H-indole (4k). The title compound

was synthesized with the following reagents based on method A: 2-methyl-1H-indole

(0.600 mmol), 6-chlorohexan-2-one (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0


(hexane/EtOAc =10/1). A pale yellow oil. 1H NMR (400 MHz, CDCl3) % 1.21–1.46 (m,

2 H), 1.40 (d, J = 6.9 Hz, 3 H), 1.65–1.79 (m, 3 H), 1.81–1.94 (m, 1 H), 2.36 (s, 3 H),

2.88–3.00 (m, 1 H), 3.37–3.51 (m, 2 H), 7.02 (td, J = 7.4, 1.1 Hz, 1 H), 7.08 (td, J = 7.6,

1.2 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.66 (ds, 1 H); 13C NMR

45

(100 MHz, CDCl3) % 12.1, 21.3, 25.7, 31.3, 32.8, 36.2, 45.1, 110.3, 116.1, 118.7, 119.3, 120.6, 127.4, 130.1, 135.5. HRMS (FI) Calcd for C15H20ClN: M, 249.1284. Found: m/z 249.1310.

3-(1-Butylpentyl)-1-methyl-1H-indole (4l). The title compound was

synthesized with the following reagents based on method A: 1b (0.600 mmol), 5b (0.400


by column chromatography on silica gel twice (first: hexane/EtOAc/Et3N = 90/5/5;

second: hexane/EtOAc = 20/1), or with the following reagents based on method B: 1b

(1.20 mmol), 5b (0.400 mmol) 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane

(0.40 mL), and isolated by recycling GPC after column chromatography on silica gel

(hexane/EtOAc = 10:1). A colorless oil. 1H NMR (400 MHz, CDCl3) % 0.82 (t, J = 6.9 Hz, 6 H), 1.15–1.33 (m, 8 H), 1.69 (q, J = 7.3 Hz, 4 H), 2.80 (quint, J = 7.1 Hz, 1 H), 3.74

(s, 3 H), 6.77 (s, 1 H), 7.06 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.19 (ddd, J = 8.1, 7.0, 1.0

Hz, 1 H), 7.28 (dt, J = 7.8, 1.1 Hz, 1 H), 7.63 (dt, J = 7.8, 0.9 Hz, 1 H); 13C NMR (125

MHz, CDCl3) % 14.1, 22.9, 30.0, 32.6, 36.0, 36.8, 109.1, 118.2, 119.4, 119.7, 121.1, 125.6,

127.7, 137.1. HRMS (FI) Calcd for C18H27N: M, 257.2144. Found: m/z 257.2131.

N-Methylindoline (6). The title compound was formed as a by-product in the

reaction of 5b with 1b by method A (Scheme 3). A colorless oil. 1H NMR (500 MHz,

CDCl3), % 2.76 (s, 3 H), 2.94 (t, J = 8.0 Hz, 2 H), 3.29 (t, J = 8.2 Hz, 2 H), 6.47–6.51 (m,

1 H), 6.67 (td, J = 7.3, 0.9 Hz, 1 H), 7.05–7.11 (m, 2 H); 13C NMR (125 MHz, CDCl3) % 28.7, 36.3, 56.1, 107.2, 117.7, 124.2, 127.3, 130.3, 153.4. HRMS (FI) Calcd for C9H11N:

M, 133.0892. Found: m/z 133.0918.

1-Methyl-3-(1-propylhexyl)-1H-indole (4m). The title compound was

synthesized with the following reagents based on method B: 1b (1.20 mmol), 4-nonanone

(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane (0.40 mL), and

isolated by column chromatography on silica gel (hexane/EtOAc = 100/1). A colorless

oil. 1H NMR (500 MHz, CDCl3) % 0.83 (t, J = 6.6 Hz, 3 H), 0.85 (t, J = 7.5 Hz, 3 H),

1.18–1.30 (m, 8 H), 1.62–1.72 (m, 4 H), 2.83 (quint, J = 7.1 Hz, 1 H), 3.74 (s, 3 H), 6.77

(s, 1 H), 7.06 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 7.19 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.27

(dt, J = 8.3, 0.9 Hz, 1 H), 7.62 (dt, J = 8.0, 0.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) %

14.1, 14.3, 20.9, 22.7, 27.5, 32.1, 32.6, 36.2, 36.6, 38.6, 109.1, 118.2, 119.5, 119.7, 121.1,

125.6, 127.8, 137.2. HRMS (FD) Calcd for C18H27N: M, 257.2144. Found: m/z 257.2138.

46

!-Ethyl-1-methyl-1H-indole-3-propanoic acid methyl ester (4n). The title compound was synthesized with the following reagents based on method B: 1b (1.20

mmol), methyl 3-oxovalerate (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and

1,4-dioxane (0.40 mL), and isolated by column chromatography on silica gel

(hexane/EtOAc = 8/1). A colorless oil. 1H NMR (400 MHz, CDCl3) % 0.86 (t, J = 7.3 Hz, 3 H), 1.78 (quint, J = 7.3 Hz, 2 H), 2.71 (d, J = 7.4 Hz, 2 H), 3.37 (quint, J = 7.2 Hz, 1

H), 3.59 (s, 3 H), 3.74 (s, 3 H), 6.84 (s, 1 H), 7.08 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.20

(ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.28 (dt, J = 8.2, 0.9 Hz, 1 H), 7.63 (dt, J = 8.0, 0.9 Hz,

1 H); 13C NMR (125 MHz, CDCl3) % 12.0, 28.4, 32.6, 35.1, 40.8, 51.4, 109.2, 117.1,

118.6, 119.4, 121.4, 125.8, 127.2, 137.1, 173.4. HRMS (FD) Calcd for C15H19NO2: M,

245.1416. Found: m/z 245.1407. 3-Cyclooctyl-1-methyl-1H-indole (4o). The title compound was synthesized

with the following reagents based on method B: 1b (1.20 mmol), cyclooctanone (0.400


by column chromatography on silica gel (hexane/EtOAc = 5/1). A viscous yellow oil. 1H

NMR (500 MHz, CDCl3) % 1.56–1.89 (m, 12 H), 1.96–2.05 (m, 2 H), 3.13 (tt, J = 9.5, 3.6 Hz, 1 H), 3.73 (s, 3 H), 6.81 (s, 1 H), 7.08 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.20 (ddd, J =

8.0, 6.9, 1.2 Hz, 1 H), 7.27 (dd, J = 7.8, 0.9 Hz, 1 H), 7.61 (dd, J = 8.0, 1.1 Hz, 1 H); 13C

NMR (100 MHz, CDCl3) % 25.8, 26.3, 27.4, 32.6, 33.0, 35.0, 109.1, 118.3, 119.4, 121.3, 122.9, 124.6, 127.0, 137.0. HRMS (FI) Calcd for C17H23N: M, 241.1831. Found: m/z 241.1826.

3-(Adamantan-2-yl)-1-methyl-1H-indole (4p). The title compound was

synthesized with the following reagents based on method B: 1b (1.20 mmol), 2-

adamantanone (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane


(hexane/CHCl3 = 4/1). A white solid, mp 138–139 ºC. 1H NMR (500 MHz, CDCl3) % 1.61 (d, J = 12.6 Hz, 2 H), 1.80 (s, 2 H), 1.86 (quint, J = 3.0 Hz, 1 H), 1.93–2.15 (m, 7

H), 2.33 (s, 2 H), 3.37 (s, 1 H), 3.76 (s, 3 H), 6.98 (s, 1 H), 7.06 (ddd, J = 8.0, 6.9, 1.2 Hz,

1 H), 7.20 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.28 (dd, J = 7.5, 1.2 Hz, 1 H), 7.60 (d, J = 8.0

Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 28.1, 28.3, 32.4, 32.6, 32.7, 38.2, 39.5, 42.5,

109.0, 118.3, 118.9, 119.7, 121.3, 126.1, 127.9, 136.8. HRMS (FI) Calcd for C19H23N:

M, 265.1831. Found: m/z 265.1823.

47

3-(2,3-Dihydro-1H-inden-1-yl)-1-methyl-1H-indole (4q). The title

compound was synthesized with the following reagents based on method A: 1b (0.600

mmol), 1-indanone (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-

dioxane (0.40 mL), and isolated by column chromatography on silica gel (hexane/CHCl3

= 4/1). Compound 4q has already appeared in the literature, and its spectral and analytical

data are in good agreement with those reported in reference.27 Therefore, only 1H NMR

data are provided here. 1H NMR (400 MHz, CDCl3) % 2.21 (dq, J = 12.4, 8.4 Hz, 1 H), 2.58 (ddt, J = 12.3, 7.8, 4.4 Hz, 1 H), 2.91–3.11 (m, 2 H), 3.73 (s, 3 H), 4.65 (t, J = 8.0

Hz, 1 H), 6.74 (s, 1 H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.09–7.15 (m, 2 H), 7.15–

7.24 (m, 2 H), 7.28–7.33 (m, 2 H), 7.46 (dt, J = 8.0, 0.9 Hz, 1 H).

1-Methyl-3-(1-phenylethyl)-1H-indole (4r). The title compound was

synthesized with the following reagents based on method A: 1b (0.600 mmol), 5c (0.400


by recycling GPC after column chromatography on silica gel (hexane/EtOAc = 30/1).

Compound 4r has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) % 1.69 (d, J = 7.5 Hz, 3 H), 3.75 (s, 3 H), 4.36 (q, J = 7.1 Hz, 1 H), 6.83 (s, 1 H), 6.99 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.14–7.21

(m, 2 H), 7.24–7.31 (m, 5 H), 7.36 (dd, J = 8.1, 1.2 Hz, 1 H).

1,2-Dimethyl-3-(1-phenylethyl)-1H-indole (4s). The title compound was

synthesized with the following reagents based on method A: 1c (0.600 mmol), 5c (0.400


by recycling GPC after column chromatography on silica gel (hexane/EtOAc = 30/1).

Compound 4s has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) % 1.78 (d, J = 7.3 Hz, 3 H), 2.33 (s, 3 H), 3.65 (s, 3 H), 4.44 (q, J = 7.4 Hz, 1 H), 6.96 (t, J = 7.5 Hz, 1 H), 7.07–7.17 (m, 2 H),

7.22–7.25 (m, 3 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 1 H).

3-[1-(4-Hydroxyphenyl)ethyl]-1-methyl-1H-indole (4t). The title compound

was synthesized with the following reagents based on method A: 1b (0.600 mmol), p-

acetylphenol (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane


(hexane/EtOAc = 4/1). A white solid, mp 101–102 ºC. 1H NMR (500 MHz, CDCl3) %

48

1.65 (d, J = 7.2 Hz, 3 H), 3.75 (s, 3 H), 4.31 (q, J = 7.2 Hz, 1 H), 4.50 (s, 1 H), 6.72 (dt,

J = 8.6, 2.5 Hz, 2 H), 6.81 (s, 1 H), 6.99 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.12–7.22 (m, 3

H), 7.26–7.29 (m, 1 H), 7.36 (dt, J = 7.8, 0.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) %

22.6, 32.6, 36.0, 109.1, 115.1, 118.6, 119.8, 120.2, 121.5, 125.9, 127.2, 128.5, 137.3,

139.3, 153.5. HRMS (FI) Calcd for C17H17NO: M, 251.1310. Found: m/z 251.1308.

3-(Diphenylmethyl)-1-methyl-1H-indole (4u). The title compound was

synthesized with the following reagents based on method B: 1b (1.20 mmol),

benzophenone (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (80.0 µmol) and 1,4-dioxane

(0.40 mL), and isolated by column chromatography on silica gel (hexane/CHCl3 = 4/1).

Compound 4u has already appeared in the literature, and its spectral and analytical data

are in good agreement with those reported in reference.28 Therefore, only 1H NMR data

are provided here. 1H NMR (400 MHz, CDCl3) % 3.70 (s, 3 H), 5.66 (s, 1 H), 6.41 (d, J =

0.9 Hz, 1 H), 6.97 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.16–7.25 (m, 8 H), 7.26–7.30 (m, 5

H).

3-(Fluoren-9-yl)-1H-indole (4v). The title compound was synthesized with the

following reagents based on method A: 1a (0.600 mmol), 9-fluorenone (0.400 mmol), 3a

(0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane (0.40 mL), and isolated by column

chromatography on silica gel (hexane/EtOAc = 5/1). A pale purple solid, mp 121–122 ºC. 1H NMR (500 MHz, CDCl3) % 5.38 (s, 1 H), 6.94 (t, J = 8.0 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 1 H), 7.13 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.22 (td, J = 7.5, 1.2

Hz, 2 H), 7.33 (dt, J = 8.0, 0.9 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.42 (dd, J = 7.6, 0.7

Hz, 2 H), 7.84 (d, J = 7.7 Hz, 2 H), 7.96 (bs, 1 H); 13C NMR (125 MHz, CDCl3) % 45.9, 111.2, 115.5, 119.41, 119.44, 119.8, 122.1, 122.2, 125.2, 126.7, 127.1, 136.6, 140.7,

147.7 (one carbon signal is missing due to overlapping). HRMS (FD) Calcd for C21H15N:

M, 281.1205. Found: m/z 281.1214.

3-Decyl-1-methyl-1H-indole (4w). The title compound was synthesized with

the following reagents based on method A: 1b (0.600 mmol), 1-decanal (0.400 mmol),

3a (0.600 mmol), In(NTf2)3 (20.0 µmol) and 1,4-dioxane (0.40 mL), and isolated by

column chromatography on silica gel (hexane/CHCl3 = 4/1). A colorless oil. 1H NMR

(500 MHz, CDCl3) % 0.88 (t, J = 6.9 Hz, 3 H), 1.20–1.43 (m, 14 H), 1.69 (quint, J = 7.5

Hz, 2 H), 2.73 (t, J = 7.5 Hz, 2 H), 3.74 (s, 3 H), 6.82 (s, 1 H), 7.09 (ddd, J = 8.0, 6.9, 1.2

Hz, 1 H), 7.20 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 H), 7.27 (dd, J = 7.5, 1.2 Hz, 1 H), 7.59 (dd, J

= 6.9, 1.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 14.1, 22.7, 25.1, 29.4, 29.6, 29.7,

49

30.5, 31.9, 32.5, 109.0, 115.7, 118.4, 119.1, 121.3, 125.9, 128.0, 137.0 (two carbon

signals are missing due to overlapping). HRMS (FI) Calcd for C19H29N: M, 271.2300.

Found: m/z 271.2303.

3-(Cyclohexylmethyl)-2-methyl-1H-indole (4x). The title compound was

synthesized with the following reagents based on method A: 2-methylindole (0.600

mmol), cyclohexanecarboxaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (4.00


(hexane/EtOAc = 10/1). A white solid, mp 102–103 ºC. 1H NMR (500 MHz, CDCl3) % 0.93–1.04 (m, 2 H), 1.09–1.21 (m, 3 H), 1.53–1.77 (m, 6 H), 2.34 (s, 3 H), 2.55 (d, J =

6.9 Hz, 2 H), 7.01–7.12 (m, 2 H), 7.24 (dt, J = 8.0, 1.0 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1

H), 7.65 (bs, 1 H); 13C NMR (125 MHz, CDCl3) % 11.8, 26.4, 26.6, 32.1, 33.6, 39.4, 110.0, 111.1, 118.4, 118.8, 120.6, 129.3, 131.2, 135.1. HRMS (FI) Calcd for C16H21N: M,

227.1674. Found: m/z 227.1700.

3-(3-Cyclohexen-1-ylmethyl)-1-methyl-1H-indole (4y). The title compound

was synthesized with the following reagents based on method A: 1b (0.600 mmol), 3-

cyclohexene-1-carboxaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol)

and 1,4-dioxane (0.40 mL), and isolated by bulb-to-bulb distillation (100 ºC/100 Pa) after

column chromatography on silica gel (hexane/CHCl3 = 6/1). A colorless oil. 1H NMR

(500 MHz, CDCl3) % 1.24–1.35 (m, 1 H), 1.72–1.86 (m, 2 H), 1.89–2.15 (m, 4 H), 2.64–2.76 (m, 2 H), 3.74 (s, 3 H), 5.61–5.69 (m, 2 H), 6.82 (s, 1 H), 7.08 (ddd, J = 7.9, 7.0, 1.0

Hz, 1 H), 7.20 (ddd, J = 8.2, 7.0, 1.1 Hz, 1 H), 7.28 (dt, J = 8.3, 0.9 Hz, 1 H), 7.59 (dt, J

= 7.8, 0.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) % 25.3, 28.8, 32.02, 32.04, 32.6, 34.7, 109.0, 113.6, 118.5, 119.2, 121.3, 126.6, 126.8, 127.0, 128.4, 137.0. HRMS (FD) Calcd

for C16H19N: M, 225.1518. Found: m/z 225.1501.

3-(2,2-Dimethylpropyl)-2-methyl-1H-indole (4z). The title compound was

synthesized with the following reagents based on method A: 2-methylindole (0.600

mmol), trimethylacetaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (4.00 µmol)

and 1,4-dioxane (0.40 mL), and isolated by column chromatography on silica gel

(hexane/EtOAc = 10/1). A white solid, mp 71–72 ºC. 1H NMR (500 MHz, CDCl3) % 0.96 (s, 9 H), 2.35 (s, 3 H), 2.57 (s, 2 H), 7.02–7.12 (m, 2 H), 7.25 (dd, J = 6.6, 0.9 Hz, 1 H),

7.50 (d, J = 8.0 Hz, 1 H), 7.74 (bs, 1 H); 13C NMR (125 MHz, CDCl3) % 12.6, 30.0, 34.1, 38.0, 109.9, 110.3, 118.9, 119.3, 120.6, 130.1, 132.2, 135.1. HRMS (FI) Calcd for

C14H19N: M, 201.1518. Found: m/z 201.1489.

50

1-Methyl-3-{[4-(trifluorometyl)phenyl]methyl}-1H-indole (4aa). The title

compound was synthesized with the following reagents based on method A: 1b (0.600

mmol), 4-(trifluoromethyl)benzaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3

(40.0 µmol) and 1,4-dioxane (0.40 mL), and isolated by column chromatography on silica

gel (hexane/EtOAc = 4/1). A colorless oil. 1H NMR (500 MHz, CDCl3) % 3.75 (s, 3 H), 4.15 (s, 2 H), 6.78 (s, 1 H), 7.08 (ddd, J = 7.9, 7.0, 1.0 Hz, 1 H), 7.22 (ddd, J = 8.5, 7.0,

1.3 Hz, 1 H), 7.31 (dd, J = 8.0, 1.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.46 (dd, J = 8.3,

0.9 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) % 31.4, 32.6, 109.3, 113.1, 119.0, 121.8, 124.4 (q, J = 270.4 Hz), 125.2 (q, J = 3.7 Hz), 127.2, 127.6, 128.2

(q, J = 32.1 Hz), 128.89, 128.91 137.2, 145.6. HRMS (FI) Calcd for C17H14F3N: M,

289.1078. Found: m/z 289.1056. 1,2-Dimethyl-3-(3-thienylmethyl)-1H-indole (4ab). The title compound was

synthesized with the following reagents based on method A: 1c (0.600 mmol), 3-

thienylaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane


(hexane/EtOAc = 10/1). A white solid, mp 84–85 ºC. 1H NMR (500 MHz, CDCl3) % 2.36 (s, 3 H), 3.66 (s, 3 H), 4.06 (s, 2 H), 6.85 (dd, J = 3.2, 1.5 Hz, 1 H), 6.93 (dd, J = 4.6, 1.1

Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 7.14 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.18 (dd, J = 5.2,

2.9 Hz, 1 H), 7.24 (s, 1 H), 7.43 (d, J = 8.1 Hz, 1 H); 13C NMR (125 MHz, CDCl3) % 10.3, 25.3, 29.5, 108.5, 109.5, 118.2, 118.8, 120.2, 120.5, 125.2, 127.7, 128.2, 133.2, 136.5,

142.5. HRMS (FI) Calcd for C15H15NS: M, 241.0925. Found: m/z 241.0947.

(1H-Indol-3-ylmethyl)ferrocene (4ac). The title compound was synthesized

with the following reagents based on method A: 1a (0.600 mmol),

ferrocenecarboxaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (4.00 µmol) and 1,4-

dioxane (0.40 mL), and isolated by column chromatography on silica gel (hexane/EtOAc

= 5/1). A orange solid, mp 159–160 ºC. 1H NMR (500 MHz, CDCl3) % 3.83 (s, 2 H), 4.06 (t, J = 1.8 Hz, 2 H), 4.14 (s, 5 H), 4.18 (t, J = 1.7 Hz, 2 H), 6.87–6.91 (m, 1 H), 7.11 (ddd,

J = 8.0, 6.9, 1.2 Hz, 1 H), 7.18 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.33 (dd, J = 7.7, 0.9 Hz,

1 H), 7.62 (dd, J = 8.0, 1.2 Hz, 1 H), 7.89 (bs, 1 H); 13C NMR (100 MHz, CDCl3) % 25.6, 67.2, 68.6, 68.7, 88.2, 111.0, 116.9, 119.0, 119.2, 121.6, 121.9, 127.3, 136.2. HRMS (FI)

Calcd for C19H17FeN: M, 315.0710. Found: m/z 315.0726.

1,5-Dimethyl-2-decyl-3-propyl-1H-indole (4ad). The title compound was

synthesized with the following reagents based on method B: 1,5-dimethyl-3-propyl-1H-

51

indole (1.20 mmol), 1-decanal (0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 µmol)

and 1,4-dioxane (0.40 mL), and isolated by recycling GPC after column chromatography

on silica gel (hexane/EtOAc = 10/1). A pale yellow oil. 1H NMR (500 MHz, CDCl3) %

0.88 (t, J = 7.0 Hz, 3 H), 0.97 (t, J = 7.3 Hz, 3 H), 1.21–1.42 (m, 14 H), 1.54 (quint, J =

7.6 Hz, 2 H), 1.64 (sext, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.64 (t, J = 7.6 Hz, 2 H), 2.70 (t,

J = 7.7 Hz, 2 H), 3.62 (s, 3 H), 6.96 (dd, J = 8.2, 1.3 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H),

7.28–7.31 (m, 1 H); 13C NMR (125 MHz, CDCl3) % 14.1, 14.4, 21.5, 22.7, 24.5, 24.6, 26.8, 29.3, 29.5, 29.60, 29.61, 30.3, 31.9, 108.2, 110.9, 118.1, 121.8, 127.6, 128.1, 135.1,

137.3 (two carbon signals are missing due to overlapping). HRMS (FD) Calcd for

C23H37N: M, 327.2926. Found: m/z 327.2942.

Indium-Catalyzed Alkylation of Indoles with Carbonyl Compounds and Carbon

Nucleophiles. A General Procedure for Scheme 5. In(NTf2)3 (38.2 mg, 40.0 µmol) was placed in a 20 mL Schlenk tube, which

was heated at 150 °C in vacuo for 2 h. The tube was cooled down to room temperature

and filled with argon. 1,4-Dioxane (0.40 mL) was added to the tube and then the mixture

was stirred at room temperature for 5 min. To this were added indole 1 (1.20 mmol) and

carbonyl compound 5 (0.400 mmol), and the resulting mixture was stirred at 70 ºC for

0.5 or 3 h. Carbon nucleophile 3 (0.800 or 1.20 mmol) was then added, and the resulting

solution was stirred further at 50 ºC for 8 or 30 h. A saturated NaHCO3 aqueous solution

(0.5 mL) was added to the mixture, and the aqueous phase was extracted with EtOAc (5

mL x 3). The combined organic layer was washed with brine (1 mL) and then dried over

anhydrous sodium sulfate. Filtration and evaporation of the solvent followed by column

chromatography on silica gel using hexane–EtOAc as eluent gave the corresponding

product (7a or 7b).

2-Methyl-2-(1-methyl-1H-indol-3-yl)octanenitrile (7a). The title compound

was synthesized with the following reagents: 1b (1.20 mmol), 5a (0.400 mmol),

Me3SiCN (3f) (0.800 mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane (0.40 mL), and

isolated by column chromatography on silica gel (hexane/EtOAc = 20/1). Compound 7a

has already appeared in the literature, and its spectral and analytical data are in good


here. 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 6.9 Hz, 3 H), 1.16–1.41 (m, 7 H), 1.42–

52

1.53 (m, 1 H), 1.82 (s, 3 H), 1.92–2.02 (m, 1 H), 2.10–2.21 (m, 1 H), 3.77 (s, 3 H), 7.06

(s, 1 H), 7.14 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 7.23–7.28 (m, 1 H), 7.33 (dt, J = 8.2, 0.9

Hz, 1 H), 7.74 (dt, J = 8.0, 0.9 Hz, 1 H).

3-{1-(5-Methoxythiophen-2-yl)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-indole (7b). The title compound was synthesized with the following reagents: 1a (1.20

mmol), 4’-(trifluoromethyl)acetophenone (0.400 mmol), 2-methoxythiophene (3g) (1.20

mmol), In(NTf2)3 (40.0 µmol) and 1,4-dioxane (0.40 mL), and isolated by recycling GPC

after column chromatography on silica gel (hexane/EtOAc = 5/1). Compound 7b has

already appeared in the literature, and its spectral and analytical data are in good


here. 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 3 H), 3.83 (s, 3 H), 5.99 (d, J = 3.9 Hz, 1 H),

6.33 (d, J = 3.9 Hz 1 H), 6.73 (d, J = 2.5 Hz, 1 H), 6.96 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H),

7.12 (dd, J = 8.1, 0.9 Hz, 1 H), 7.16 (ddd, J = 8.2, 7.1, 1.1 Hz, 1 H), 7.36 (dt, J = 8.1, 0.8

Hz, 1 H), 7.45 (dt, J = 8.2, 0.7 Hz, 2 H), 7.52 (dt, J = 8.2, 0.7 Hz, 2 H), 7.98 (bs, 1 H).

Indium-Catalyzed Reaction of Acetophenone (5c) with N-Methylindole (1b). A Procedure for Synthesis of 3,3’-(1-Phenylethylidene)bis[1-methyl-1H-indole] (8a) (Scheme 6).



and filled with argon. 1,4-Dioxane (0.40 mL) was added to the tube, and the resulting

mixture was stirred at room temperature for 5 min. To this were added 5c (48.1 mg, 0.400

mmol) and 1b (157 mg, 1.20 mmol), and the resulting mixture was stirred at 50 °C for 12

h. A saturated NaHCO3 aqueous solution (0.5 mL) was added to the mixture, and the




(hexane/EtOAc = 10/1) gave 3,3’-(1-phenylethylidene)bis[1-methyl-1H-indole] (8a)

(145 mg, 99% yield). Compound 8a has already appeared in the literature, and its spectral

and analytical data are in good agreement with those reported in reference 3d. Therefore,

only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) % 2.35 (s, 3 H), 3.66

53

(s, 6 H), 6.48 (s, 2 H), 6.92 (ddd, J = 8.1, 7.0, 1.0 Hz, 2 H), 7.13–7.36 (m, 9 H), 7.37–

7.47 (m, 2 H).

Indium-Catalyzed Reduction of 3,3’-(1-Phenylethylidene)bis[1-methyl-1H-indole] (8a) with HSiMePh2 (3a) in the Presence or Absence of H2O. A Procedure for Synthesis of 1-Methyl-3-(1-phenylethyl)-1H-indole (4r) (Scheme 6).




mixture was stirred at room temperature for 5 min. To this were added 8a (72.9 mg, 0.200

mmol) and 3a (59.5 mg, 0.300 mmol). In the case of the reaction with H2O, to the tube

was further added H2O (3.60 mg, 0.200 mmol). The resulting mixture was stirred at 85 °C

for 30 min for the reaction with H2O, or 120 h for the reaction without H2O. A saturated

NaHCO3 aqueous solution (0.5 mL) was added to the mixture, and the aqueous phase was

extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (1

mL) and then dried over anhydrous sodium sulfate. Filtration and evaporation of the

solvent followed by column chromatography on silica gel (hexane/EtOAc = 30/1) gave

4r (46.3 mg, 98% yield for the reaction with H2O; 41.7 mg, 88% yield for the reaction

without H2O). Compound 4r has already appeared in this experimental section, and its

full data on 1H NMR, 13C NMR spectroscopy and HRMS analysis have also been

collected in reference 3d.

Indium-Catalyzed Reaction of Acetophenone (5c) with 1,2-Dimethylindole (1c). A

Procedure for Synthesis of 1,2-Dimethyl-3-(1-phenylethenyl)-1H-indole (9a) (Scheme 6).




mixture was stirred at room temperature for 5 min. To this were added 5c (48.1 mg, 0.400

mmol) and 1c (174 mg, 1.20 mmol), and the resulting mixture was stirred at 50 °C for 40

h. A saturated NaHCO3 aqueous solution (0.5 mL) was added to the mixture, and the

54




(hexane/EtOAc/Et3N = 92/5/3) gave 1,2-dimethyl-3-(1-phenylethenyl)-1H-indole (9a)

(80.7 mg, 81% yield). Compound 9a has already appeared in the literature, and its spectral

and analytical data are in good agreement with those reported in reference 3d. Therefore,

only 1H NMR data are provided here. 1H NMR (500 MHz, CDCl3) % 2.28 (s, 3 H), 3.72 (s, 3 H), 5.30 (d, J = 1.2 Hz, 1 H), 5.75 (d, J = 1.1 Hz, 1 H), 6.99 (ddd, J = 7.7, 6.9, 0.9

Hz, 1 H), 7.14 (ddd, J = 7.6, 7.0, 0.7 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 7.26–7.34 (m, 4

H), 7.36–7.45 (m, 2 H).

Indium-Catalyzed Reduction of 1,2-Dimethyl-3-(1-phenylethenyl)-1H-indole (9a)

with HSiMePh2 (3a) in the Presence or Absence of H2O. A Procedure for Synthesis of 1,2-Dimethyl-3-(1-phenylethyl)-1H-indole (4s) (Scheme 6).




mixture was stirred at room temperature for 5 min. To this were added 9a (49.5 mg, 0.200

mmol) and 3a (59.5 mg, 0.300 mmol). In the case of the reaction with H2O, to the tube

was further added H2O (3.60 mg, 0.200 mmol). The resulting mixture was stirred at 85 °C

for 15 min for the reaction with H2O, or 24 h for the reaction without H2O. A saturated

NaHCO3 aqueous solution (0.5 mL) was added to the mixture, and the aqueous phase was



solvent followed by column chromatography on silica gel (hexane/EtOAc = 30/1) gave

4s; yield: 44.7 mg (89% yield for the reaction with H2O) or 45.2 mg (90% yield for the

reaction without H2O). Compound 4s has already appeared in this experimental section,

and its full data on 1H NMR, 13C NMR spectroscopy and HRMS analysis have also been

collected in reference 3d.

55

II-4. References and Notes

1 For selected recent reviews, see: a) A. J. Kochanowska-Karamyan, M. T. Hamann,

Chem. Rev. 2010, 110, 4489; b) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29; c) M.

Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod. Rep. 2013, 30, 694; d) M.-Z. Zhang, Q.

Chen, G.-F. Yang, Eur. J. Med. Chem. 2015, 89, 421. For selected recent reports, see: e)

N. Kaila, A. Huang, A. Moretto, B. Follows, K. Janz, M. Lowe, J. Thomason, T. S.

Mansour, C. Hubeau, K. Page, P. Morgan, S. Fish, X. Xu, C. Williams, E. Saiah, J. Med. Chem. 2012, 55, 5088; f) A. K. Deka, R. J. Sarma, J. Lumin. 2014, 147, 216; g) T. Tomoo,

T. Nakatsuka, T. Katayama, Y. Hayashi, Y. Fujieda, M. Terakawa, K. Nagahira, J. Med. Chem. 2014, 57, 7244; h) M. Quernheim, H. Liang, Q. Su, M. Baumgarten, N. Koshino,

H. Higashimura, K. Müllen, Chem. Eur. J. 2014, 20, 14178; i) R. Sydam, A. Ghosh, M.

Deepa, Org. Electron. 2015, 17, 33. 2 For selected reviews, see: a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873; b) T.

Janosik, N. Wahlström, J. Bergman, Tetrahedron 2008, 64, 9159; c) L. Joucla, L.

Djakovitch, Adv. Synth. Catal. 2009, 351, 673; d) B. M. Trost, M. K. Brennan, Synthesis

2009, 3003; e) M. Bandini, A. Eichholzer, Angew. Chem. 2009, 121, 9786; Angew. Chem. Int. Ed. 2009, 48, 9608; f) A. Palmieri, M. Petrini, R. R. Shaikh, Org. Biomol. Chem.

2010, 8, 1259; g) G. Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010, 39,

4449; h) S. M. Bronner, A. E. Goetz, N. K. Garg, Synlett 2011, 2599; i) C.-X. Zhuo, C.

Zheng, S.-L. You, Acc. Chem. Res. 2014, 47, 2558. 3 a) T. Tsuchimoto, Y. Ozawa, R. Negoro, E. Shirakawa, Y. Kawakami, Angew. Chem. 2004, 116, 4327; Angew. Chem. Int. Ed. 2004, 43, 4231; b) T. Tsuchimoto, H.

Matsubayashi, M. Kaneko, Y. Nagase, T. Miyamura, E. Shirakawa, J. Am. Chem. Soc.

2008, 130, 15823; c) T. Tsuchimoto, M. Iwabuchi, Y. Nagase, K. Oki, H. Takahashi,

Angew. Chem. 2011, 123, 1411; Angew. Chem. Int. Ed. 2011, 50, 1375; d) T. Tsuchimoto,

M. Kanbara, Org. Lett. 2011, 13, 912; e) Y. Nagase, T. Miyamura, K. Inoue, T.

Tsuchimoto, Chem. Lett. 2013, 42, 1170. 4 For example, see: SIGMA–ALDRICH Product Catalog at

http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=16273490. 5 a) J. E. Appleton, K. N. Dack, A. D. Green, J. Steele, Tetrahedron Lett. 1993, 34, 1529;

b) A. Mahadevan, H. Sard, M. Gonzalez, J. C. McKew, Tetrahedron Lett. 2003, 44, 4589;

c) J. A. Campbell, V. Bordunov, C. A. Broka, J. Dankwardt, R. T. Hendricks, J. M. Kress,

56

K. A. M. Walker, J.-H. Wang, Tetrahedron Lett. 2004, 45, 3793; d) J. R. Rizzo, C. A. Alt,

T. Y. Zhang, Tetrahedron Lett. 2008, 49, 6749; e) L.-L. Cao, D.-S. Wang, G.-F. Jiang, Y.-

G. Zhou, Tetrahedron Lett. 2011, 52, 2837; f) A. Taheri, B. Lai, C. Cheng, Y. Gu, Green Chem. 2015, 17, 812. 6 a) E. F. Pratt, L. W. Botimer, J. Am. Chem. Soc. 1957, 79, 5248; b) S. Whitney, R. Grigg,

A. Derrick, A. Keep, Org. Lett. 2007, 9, 3299; c) X. Han, J. Wu, Angew. Chem. 2013, 125,

4735; Angew. Chem. Int. Ed. 2013, 52, 4637; d) R. Cano, M. Yus, D. J. Ramón,

Tetrahedron Lett. 2013, 54, 3394; e) S. M. A. H. Siddiki, K. Kon, K. Shimizu, Chem. Eur.

J. 2013, 19, 14416; f) A. E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe, T. Ohta, Eur. J. Org. Chem. 2013, 6344; g) S. Bartolucci, M. Mari, A. Bedini, G. Piersanti, G. Spadoni,

J. Org. Chem. 2015, 80, 3217. 7 N-Alkylation of indoles based on the redox system has been also reported, see: a) S.

Bähn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. J. Williams, M. Beller, Chem. Eur. J. 2010, 16, 3590; b) Y. Zhang, X. Qi, X. Cui, F. Shi, Y. Deng, Tetrahedron Lett. 2011, 52,

1334; c) S. M. A. H. Siddiki, K. Kon, K. Shimizu, Green Chem. 2015, 17, 173. 8 Electrophilic alkenes with electron-withdrawing groups have been used, see: a) P. E.

Harrington, M. A. Kerr, Synlett 1996, 1047; b) P. Harrington, M. A. Kerr, Can. J. Chem.

1998, 76, 1256; c) N. Srivastava, B. K. Banik, J. Org. Chem. 2003, 68, 2109; d) A. V.

Reddy, K. Ravinder, T. V. Goud, P. Krishnaiah, T. V. Raju, Y. Venkateswarlu, Tetrahedron Lett. 2003, 44, 6257; e) B. K. Banik, M. Fernandez, C. Alvarez, Tetrahedron Lett. 2005,

46, 2479; f) V. Kumar, S. Kaur, S. Kumar, Tetrahedron Lett. 2006, 47, 7001; g) Z.-H.

Huang, J.-P. Zou, W.-Q. Jiang, Tetrahedron Lett. 2006, 47, 7965. 9 Allyl and benzyl type alcohols have been used, see: a) M. Kimura, M. Futamata, R.

Mukai, Y. Tamaru, J. Am. Chem. Soc. 2005, 127, 4592; b) S. Shirakawa, S. Kobayashi,

Org. Lett. 2007, 9, 311; c) I. Usui, S. Schmidt, M. Keller, B. Breit, Org. Lett. 2008, 10,

1207; d) S. Gruber, A. B. Zaitsev, M. Wörle, P. S. Pregosin, Organometallics 2008, 27,

3796; e) T. Hirashita, S. Kuwahara, S. Okochi, M. Tsuji, S. Araki, Tetrahedron Lett. 2010,

51, 1847; f) D. Das, S. Roy, Adv. Synth. Catal. 2013, 355, 1308. 10 Allyl, benzyl and tertiary alkyl bromides have been used, see: X. Zhu, A. Ganesan, J.

Org. Chem. 2002, 67, 2705. 11 For aziridines, see: a) A. Onistschenko, H. Stamm, Chem. Ber. 1989, 122, 2397. For

allenes, see: b) K. L. Toups, G. T. Liu, R. A. Widenhoefer, J. Organomet. Chem. 2009,

57

694, 571. For #-halo ketones and their derivatives, see: c) P. E. Reyes-Gutiérrez, R. O.

Torres-Ochoa, R. Martínez, L. D. Miranda, Org. Biomol. Chem. 2009, 7, 1388; d) Q. Tang,

X. Chen, B. Tiwari, Y. R. Chi, Org. Lett. 2012, 14, 1922. 12 a) C. Liu, X. Han, X. Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 3700;

b) C. Liu, R. A. Widenhoefer, Chem. Eur. J. 2006, 12, 2371; c) Z. Ding, N. Yoshikai,

Angew. Chem. 2013, 125, 8736; Angew. Chem. Int. Ed. 2013, 52, 8574; d) E. Álvarez, P.

García-García, M. A. Fernández-Rodríguez, R. Sanz, J. Org. Chem. 2013, 78, 9758; e) P.

J. Gritsch, E. Stempel, T. Gaich, Org. Lett. 2013, 15, 5472. 13 Oxidative coupling of N-lithioindoles with lithium enolates promoted by a copper salt

has been also reported, see: J. M. Richter, B. W. Whitefield, T. J. Maimone, D. W. Lin,

M. P. Castroviejo, P. S. Baran, J. Am. Chem. Soc. 2007, 129, 12857. 14 a) T. Tsuchimoto, M. Igarashi, K. Aoki, Chem. Eur. J. 2010, 16, 8975; b) T. Tsuchimoto,

Chem. Eur. J. 2011, 17, 4064. 15 The author tested the effect of 10 mol% of CF3CO2H instead of In(NTf2)3, but no 4a

was formed under the same reaction conditions as those used for entry 16 of Table 1. 16 As expected, the use of 4-nonyne instead of 5-nonanone as an alkyl group source

provided a 1:1 regioisomeric mixture of products 4l and 4m, with respect to the C&C

bond.

17 For hydrolysis of an ester group under aqueous Lewis acidic conditions, see: a) R. N.

Ram, L. Singh, Tetrahedron Lett. 1995, 36, 5401; b) S. V. Reddy, R. J. Rao, U. S. Kumar,

J. M. Rao, Chem. Lett. 2003, 32, 1038. 18 For isomerization of a C=C bond under Lewis acidic conditions, see: a) G. S. Cameron,

V. R. Stimson, Aust. J. Chem. 1977, 30, 923; b) M. Pérez, L. J. Hounjet, C. B. Caputo, R.

Dobrovetsky, D. W. Stephan, J. Am. Chem. Soc. 2013, 135, 18308. 19 For hydrosilylation of a C=C bond under Lewis acid catalysis, see: Y. Nakajima, S.

Shimada, RSC Adv. 2015, 5, 20603 (review). 20 For coordination of H2O to a silicon center, see: J. Kobayashi, K. Kawaguchi, T.

Kawashima, J. Am. Chem. Soc. 2004, 126, 16318.

N

5:1

1b

C4H9 C3H7

+

In(NTf2)3(30 mol%)

o-Cl2C6H4135 ºC24 h

N4m

C3H7

N4l

C4H9

+

36% yield4l:4m = 1:1

HSiMePh2(1.5 equiv.)H2O(0.5 equiv.)

70 ºC, 12 h

C3H7

C4H9er: ocf~

58

21 In order to obtain additional experimental results supporting the role of H2O as a Lewis

base activator, the effect of other Lewis bases than H2O was examined in the reductive

carbon–carbon bond cleavage of 8a with 3a. In contrast to the extremely slow reaction

requiring 120 h in the absence of an additive (Scheme 6), adding MeOH (1 equiv.) or P(2-

furyl)3 (2 equiv.) resulted in a much faster reaction that was completed in just 1 h or 7 h,

respectively (vide infra). These results are considered to be due to the enhancement of the

nucleophilicity of the H–Si bond, possibly resulting from the coordination of MeOH and

P(2-furyl)3 to the silicon center, as previously reported. Accordingly, H2O should be

reasonably considered to have behaved as a Lewis base activator in the same way. For

coordination of an alcohol to a silicon center, see: reference 20. For activation of a silicon

nucleophile by a phosphine, see: S. Matsukawa, N. Okano, T. Imamoto, Tetrahedron Lett.

2000, 41, 103.

22 For a review of acid-catalyzed formation of di(indolyl)alkanes from carbonyl

compounds and indoles, see: M. Shiri, M. A. Zolfigol, H. G. Kruger, Z. Tanbakouchian,

Chem. Rev. 2010, 110, 2250. 23 For a report of C(sp3)–C(indolyl) bond cleavage, see: M. L. Deb, P. J. Bhuyan, Synlett 2008, 325. 24 For selected studies including the activation of unsaturated carbon–carbon multiple

bonds by an indium(III) salt as a crucial step, see: a) T. Tsuchimoto, T. Maeda, E.

Shirakawa, Y. Kawakami, Chem. Commun. 2000, 1573; b) T. Tsuchimoto, S. Kamiyama,

R. Negoro, E. Shirakawa, Y. Kawakami, Chem. Commun. 2003, 852; c) T. Tsuchimoto,

K. Hatanaka, E. Shirakawa, Y. Kawakami, Chem. Commun. 2003, 2454; d) R. Takita, Y.

Fukuta, R. Tsuji, T. Ohshima, M. Shibasaki, Org. Lett. 2005, 7, 1363; e) M. Nakamura,

Pure Appl. Chem. 2006, 78, 425; f) N. Sakai, K. Annaka, T. Konakahara, J. Org. Chem. 2006, 71, 3653; g) M. Y. Yoon, J. H. Kim, D. S. Choi, U. S. Shin, J. Y. Lee, C. E. Song,

Adv. Synth. Catal. 2007, 349, 1725; h) Y. Nishimoto, R. Moritoh, M. Yasuda, A. Baba,

Angew. Chem. 2009, 121, 4647; Angew. Chem. Int. Ed. 2009, 48, 4577; i) G. Bhaskar, C.

Saikumar, P. T. Perumal, Tetrahedron Lett. 2010, 51, 3141; see also a review: j) Z.-L.

Shen, S.-Y. Wang, Y.-K. Chok, Y.-H. Xu, T.-P. Loh, Chem. Rev. 2013, 113, 271.

In(NTf2)3 (10 mol%)additive1,4-dioxane, 85 ºCN N

Ph

8a

3aN

Ph

additive: MeOH (1 equiv.), 1 h; 4r; 98% yieldadditive: P(2-furyl)3 (2 equiv.), 7 h; 4r; 87% yield

+1:1.5~

／＼ ~

59

25 a) C. G. Frost, J. P. Hartley, D. Griffin, Tetrahedron Lett. 2002, 43, 4789; b) M.

Nakamura, K. Endo, E. Nakamura, Adv. Synth. Catal. 2005, 347, 1681. 26 Y. Nagase, T. Sugiyama, S. Nomiyama, K. Yonekura, T. Tsuchimoto, Adv. Synth. Catal. 2014, 356, 347. 27 M.-Z. Wang, M.-K. Wong, C.-M. Che, Chem. Eur. J. 2008, 14, 8353. 28 M. Yasuda, T. Somyo, A. Baba, Angew. Chem. 2006, 118, 807; Angew. Chem. Int. Ed. 2006, 45, 793.

Chapter III. Indium-Catalyzed Regioselective !-Alkylation of Pyrroles with Carbonyl Compounds and Hydrosilanes, and Its

Application to Constructing a Quaternary Carbon Center with a !-Pyrrolyl Group

61

III-1. Introduction

A pyrrole ring is an important five-membered heteroaromatic motif containing

one nitrogen atom. Alkyl-substituted pyrroles are of particular concern because the

structure is found in not only many natural products and biologically active compounds1

but also functional organic materials.2 Because of sufficient aromaticity and "-excessive

nature of the pyrrole ring, a straightforward approach to the alkyl-substituted pyrrole is

likely to be direct installation of an alkyl unit onto the pyrrole ring by electrophilic

aromatic substitution (SEAr), and a large number of relevant studies have actually been

reported.3 The pyrrole ring has two electrically different carbon reaction sites, which are

thus #-position of the C2 (C5) and !-position of the C3 (C4), and the SEAr reaction on

the pyrrole ring has been known to occur most predominantly at the #-position. 4

Accordingly, SEAr-based regioselective !-alkylation of pyrroles is still a challenging research topic in the field of synthetic organic chemistry. In spite of such characteristics

of pyrroles, three major strategies through the SEAr mechanism have been utilized to

change the #-orientation to !-orientation, albeit sometimes incompletely:5 (i) use of pyrroles with an electron-withdrawing group (EWG) at the N1 or at the C2,6,7 (ii) use of

pyrroles with a bulky substituent (RL) at the N1,8 ,9 and (iii) use of pyrrolyl–metal

complexes (Scheme 1).10

62

Scheme 1. Representative strategies for !-alkylation of pyrroles.

Other strategies not through the SEAr route but including direct alkylation of

the pyrrole ring have also emerged in the literature. For example, the $2-pyrrole–osmium(II) complex, the pyrrole ring of which behaves as no longer an aromatic

compound but as an enamine, has reportedly reacted with electrophiles at the !-position.11

Moreover, the strategy of chelation-assisted C–H bond activation by transition metals

such as Fe, Rh, and Pd has recently attracted attention (since 2014).12 Although chemists

have relied mainly on these SEAr- and non-SEAr-based strategies to obtain !-

alkylpyrroles,13 there has been no method capable of offering a series of !-alkylpyrroles with primary, secondary and tertiary as well as cyclic and functionalized alkyl groups, to

the best of my knowledge.

Different from these precedents,6–12 in 2009, the research group to which the

author belongs has developed a conceptually new strategy to synthesize !-alkylpyrroles, by simply mixing pyrroles 1, alkynes 2 and Et3SiH (3a) in the presence of an indium

catalyst (Scheme 2).14 This is the first case of the SEAr-based pyrrole !-alkylation, performed in a catalytic single-step. As key intermediates, dipyrrolylalkanes 5 are found

to be formed as a mixture of regioisomers concerning the pyrrole ring but lead to the

single isomer of !-alkylpyrroles after reductive C–C(pyrrolyl) bond cleavage. The originality of the process will be attributed to such unique reaction profile, and the feature

of the process will be the exclusive formation of !-alkylpyrroles. However, when using

α

β

NEWG

(i)

NH

El'

EWG = sulfonyl, COR, CO2R, CHNMe2•Cl, CN

NH

EWG

or

NEWG

NH

EWG

or

El'

El' – EWG

α

β

NRL

NRL

El'(ii)

RL = t-Bu, Si(iPr)3

– RL[= Si(iPr)3]

NH

El'

NH

α

β

N

(iii)

NH

El'

[M] = Mg, Zn, Ga, Cd, Re

– [M][M]

α

βEl

El

El[M]

口

~

:,, ｀ Jo

一→ n

ローロ— n

ロー［ローロ

63

alkynes 2, cyclic and primary alkyl groups as w

ell as a diarylmethyl unit (C

HA

r2 ) are

unable to

be introduced

intrinsically onto

1. R

egioselective introduction

of a

dialkylmethyl group w

ith two identical alkyl m

oieties [CH

(alkyl)2 ] is also not an easy

task. The author therefore envisaged that, instead of alkynes 2, the use of carbonyl com

pounds 6 having much higher skeletal and substitutional diversities w

ould lead to

overcoming the lim

itations of the alkyl groups. The author discloses herein the details of

the indium-catalyzed !-alkylation of pyrroles w

ith carbonyl compounds and 3a. 15,16,17

Carbon nucleophiles other than 3a as a hydride nucleophile are available as w

ell, and thus

The author also demonstrates here that the indium

method is highly effective for creating

a quaternary carbon center with a !-pyrrolyl group. 18

Scheme 2. Indium

-catalyzed reductive !-alkylation of pyrroles: previous work w

ith alkynes versus this w

ork with carbonyl com

pounds (In = an indium salt).

+NR

1

+Et3 SiH

12

OR

3

R2'

6

HR3

NR1

R2'

β-4

R3

3a

++

HR3

NR1

β-4

previous work

cat. In

NN

R1

R1 R35

R2

R2

R2

NR11

cat. In

NN

R1

R1 R3

R2'

5

Et3 SiH

3a


R3

R2'

=alkyl

H

,aryl

H

,alkyl

alkyl

,aryl

aryl

,

this work

ぶ I □ 口

y じ》仁コ 11

y )-

j

¥

』

□

||↓＼

□

]

]

忙ゲぶャ／

64

III-2. Results & Discussion

III-2-1. Indium-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH

Because of the high reliability of In(NTf2)3 (Tf = SO2CF3) as a catalyst for the

alkyne-based reaction,14 the author first examined its catalytic performance in the reaction

of 1-methylpyrrole (1a, 0.90 mmol) with 2-decanone (6a, 0.30 mmol) and Et3SiH (3a,

0.45 mmol) (eq. 1, 1a:6a:3a = 3:1:1.5). The reaction in 1,4-dioxane with 10 mol% of

In(NTf2)3 at 85 °C for 3 h provided 3-(decan-2-yl)-1-methylpyrrole (!-4a) as a single

regioisomer in 92% yield. The exclusive formation of !-4a without contamination by its

#-isomer is remarkable. Reducing the quantity of 1a to 0.60 mmol and then 0.30 mmol

lowered the yield of !-4a gradually, indicating that 3 molar equivalents of 1a is a favorable amount used to 6a. However, the good yield can be maintained safely even with

the reduced amount of 1a. Considering these results, in the case that a pyrrole substrate

is expensive and/or elaborate, its use less than 3 molar equivalents should be a possible

and smart choice.

As already demonstrated, the same product (!-4a) can be prepared with 1-decyne instead of 6a.14 However, the use of carbonyl compound 6a as the alkyl group

source has the following advantages over using 1-decyne: (1) the reaction of 6a is able to

be performed with a smaller amount of In(NTf2)3 (10 mol%), compared to that (25 mol%)

used for the reaction of 1-decyne, and (2) 6a (e.g., 6,600 Japanese yen/25 g) is much

cheaper than 1-decyne (e.g., 14,200 Japanese yen/25 g). Inspired by the above result, the

author next examined the substrate scope of this reaction, where methods A and B were

adopted as experimental procedures. Method A is simply a simultaneous treatment of 1,

6 and 3a in the presence of an indium catalyst. Regarding method B, 3a is added into a

reaction vessel after consumption of 6, which means that dipyrrolylalkanes 5 are formed

in situ as crucial intermediates.19 Method B is particularly useful when 3a-induced

reduction of 6 and slight co-formation of an #-alkylpyrrole are observed in the use of

O C8H17NIn(NTf2)3 (10 mol%)1,4-dioxane85 °C, 3 h

6a(0.30 mmol)

1a

X:1:1.5

C8H17

N

3a

Et3SiH+ +

β-4a; 92% yield (1a: 0.90 mmol, X = 3)β-4a; 81% yield (1a: 0.60 mmol, X = 2)β-4a; 71% yield (1a: 0.30 mmol, X = 1)

(1)ー□

|

1/'

65

method A. In order to avoid overlapping, new experimental results that have not appeared

in the preceding communication15 are collected in Table 1, and achievements that should

be noted in Table 1 are as follows. To begin with, the benzyl group on the nitrogen atom

of !-4d–!-4f underwent no N-debenzylation even under the heating Lewis acidic conditions. 20 The diphenylmethyl group, which is unavailable in the alkyne-based

reaction, is derived from diphenylketone (!-4f). As pieces of pyrrole substrates, N-

substituted pyrroles with sulfonylethyl (RSO2CH2CH2; R = Me, Ph) and a series of

ethoxycarbonylethyl (EtO2CCH2CY2; Y = H, Me) units participated well in this protocol

(!-4h–!-4l). These substituents are useful because they are removable from the nitrogen

atom, when required, with easily available bases such as NaH and t-BuOK (see Scheme

4). While 1,2-dimethylpyrrole has the two unsymmetrical !-sites, the reductive alkylation

with tetrahydro-4H-thiopyran-4-one proceeded regioselectively at the less hindered !-site

of the C4 (!-4n). A particularly interesting observation is that even 1,3-dimethylpyrrole

was alkylated selectively at the sterically congested !-site, despite that 1,3-

dimethylpyrrole has the two more intrinsically nucleophilic #-sites (!-4o). This result

triggered us to successively investigate whether the trend is compatible with !-alkylpyrroles synthesized by the present method. Thus, the 3-decylpyrrole, which has

been prepared from decanal and 1-tert-butylpyrrole and 3a, was again alkylated at the !-

site in a regioselective manner (!-4p). Importantly, through column chromatography on silica gel, the starting 3-decylpyrrole remained unreacted was recovered with efficiency

of 98% (see Table 1), which was calculated on the basis of the excess amount of the 3-

decylpyrrole used to acetone, thus indicating that the starting !-alkylpyrrole of one’s own making are recoverable and will be reusable. Not only the secondary alkyl group, but

linear and branched primary alkyl groups are also installable to the unoccupied !-position

of the 3-decylpyrrole (!-4q and !-4r). The iterative !-alkylation also proceeded regioselectively when the 3-(2-propyl)pyrrole with the bulkier pre-alkyl group was used

(!-4s and !-4t). The !-alkylpyrrole substrates of other entries were always recovered with

high efficiency over 90%.

66

Tabl

e 1.

Indi

um-c

atal

yzed

red

uctiv

e ! -

alky

latio

n of

pyr

role

s

a Y

ield

s of !

-4 b

ased

on

6 ar

e sh

own

here

. In(

NTf

2)3 w

as u

sed

as a

cat

alys

t for

synt

hesi

zing

!-4

b–! -

4l a

nd

! -4n

–!-4

p, a

nd In

(ON

f)3 (

Nf =

SO

2C4F

9) w

as u

sed

a ca

taly

st fo

r the

reac

tion

to in

trodu

ce a

prim

ary

alky

l gr

oup

(!-4

m a

nd !

-4q–! -

4t).

See

the

Expe

rimen

tal S

ectio

n fo

r the

det

ails

incl

udin

g th

e am

ount

of 1

(0.1

–0.

3 m

mol

), 6,

3a

and

an i

ndiu

m c

atal

yst

used

. b The

met

hod

A o

r B

use

d is

sho

wn

in t

he p

aren

thes

es.

c Rec

over

y ef

ficie

ncy

of th

e py

rrol

e su

bstra

te (1

) is s

how

n in

the

pare

nthe

ses.

++

+N R1

cat.

In(N

Tf2)

31,

4-di

oxan

eT2

ºC, t2 h

T3 ºC

t3 h

61

61

met

hod

Am

etho

d B

3a

OR5

R43a

OR5

R4ca

t.In

(NTf

2)3

1,4-

diox

ane

T1 °C

, t1 h

R5N R1

R4 β-4

N R1R3

R2R2

R3

NC 8

H 17

β-4e

; 76%

yie

ld (A

)bT1

= 1

00, t1 =

3

NC 8

H 17

β-4h

; 86%

yie

ld (A

)bT1

= 8

5, t1

= 3

MeO

2SN

C 8H 1

7

β-4i

; 90%

yie

ld (A

)bT1

= 8

5, t1

= 3

PhO

2S

NC 8

H 17

β-4k

; 93%

yie

ld (A

)bT1

= 8

5, t1

= 2

EtO

2C

N

β-4b

; 90%

yie

ld (A

)bT1

= 8

5, t1

= 4

NC 8

H 17

β-4j

; 97%

yie

ld (A

)bT1

= 8

5, t1

= 2

EtO

2CN

β-4g

; 84%

yie

ld (A

)bT1

= 5

0, t1

= 1

8

N

β-4d

; 89%

yie

ld (A

)bT1

= 5

0, t1

= 3

0

NPr

β-4m

; 54%

yie

ld (A

)bT1

= 8

5, t1

= 7

N

β-4l

; 80%

yie

ld (A

)bT1

= 8

5, t1

= 3

EtO

2C

N

β-4n

; 60%

yie

ld (B

)bT2

= 8

5 ºC

, t2 =

3T3

= 8

5 ºC

, t3 =

48

N

β-4f

; 93%

yie

ld (B

)bT2

= 1

20, t2 =

48

T3 =

100

, t3 =

24

PhPh

N β-4c

; 97%

yie

ld (A

)bT1

= 8

5, t1

= 5

Cl

S

N

β-4o

; 80%

yie

ld (A

)bT1

= 8

5, t1

= 5

Ph

N

β-4p

; 93%

yie

ld (A

)bT1

= 5

0, t1

= 2

4 (9

8%)c

H 19C

9

N

β-4t

; 73%

yie

ld (A

)bT1

= 8

5, t1

= 2

0 (9

2%)c

SN

β-4s

; 84%

yie

ld (A

)bT1

= 8

5, t1

= 5

(96%

)c

N

β-4q

; 91%

yie

ld (A

)bT1

= 8

5, t1

= 3

(100

%)c

C 9H 1

9

H 19C

9

N

β-4r

; 93%

yie

ld (A

)bT1

= 8

5, t1

= 3

(90%

)c

H 19C

9

ロ` ＼---{ I )

）

＼

¥

＼

＼

＼

＼

予＼

[

＼

ペロ

＼予＼予 : 予

~>

/

i

＼

[

[

＼

＼

予

67

In order to understand the whole aspect, in particular, the scope of carbonyl

compounds 6 with respect to the indium-catalyzed reductive !-alkylation of pyrroles, the results that have been disclosed in the preceding communication are summarized in

Scheme 3.15 Including the results of Table 1 for which no particular explanation was

provided, important features of this method are described as follows. (1) Regioselective

introduction of a dialkylmethyl group with two identical alkyl moieties, e.g., the 5-nonyl

group (CHBu2) is possible. (2) The cyclic frameworks can be handled with ease. (3)

Primary alkyl groups can be installed through the treatment of aldehydes. (4) A variety of

functional groups, which are chloro, sulfonyl, ester, sulfide, alkenyl, boryl, cyano, and

alkoxy functionalities, are well-tolerated under the reaction conditions. (5) In all cases,

the !-regioselectivity is controlled perfectly. In particular, (1), (2) and (3) cannot be achieved through the alkyne-based reaction.14

Scheme 3. Summary of the other substrate scope on indium-catalyzed reductive !-alkylation of pyrroles with carbonyl compounds and Et3SiH.

Bu

Bu S

OAc

CO2Et

S

C9H19

NC

Et EtO

C8H17

BO

O

B O

O

+ +

6(0.30 mmol)

1

method A

Et3SiHO R3

R2

3a

cat. In(NTf2)3or In(ONf)31,4-dioxane60 or 85 °C3–24 h R3

NR1

R2

β-4; 51–94% yield

NR1

cat. In(NTf2)31,4-dioxane85 °C, 1–20 h

85 or 100 °C1–20 h

method BEt3SiH 3a+

1NR1

R3

R2

:

R1 = Me, CH2Ph, t-Bu, Ph

R1 = t-Bu, CMe2Ph

R3

R2

:

6(0.30 mmol)

O R3

R2

□ 人

ぐ□ 人

諮入人 ),,_人入。ここ／

;,,,_U ;,,,_,l,, ;,,,_J ~

;,,,_\>入□'、;,,,_¥}_ ;,,,_~

'-{ --- -- --- ---- -- --- ---- -- --- ---- -- --- ---- -- ---

諮予い。;,,,_r<入＼〕／い。

68

As shown in Table 1 and Scheme 3, the bulkiness such as the tert-butyl and 2-

phenyl-2-propyl (cumyl) groups is required on the nitrogen atom of 1 to attain complete

!-selectivity and also high conversion of 5 in the reaction of an aldehyde for introducing

a primary alkyl group. In fact, when the pyrrole substrate has the sterically less hindered

N-methyl group, the #-alkylpyrrole was formed predominately in a low yield (eq. 2). Different from the series of electron-rich pyrroles that successfully participated in this

reaction, no desired !-alkylation occurred in the use of an electron-deficient pyrrole such as 1-Ts–pyrrole (1b; Ts = p-toluenesulfonyl), thus being recovered quantitatively (eq. 3).

Simple pyrrole 1c without a substituent on the nitrogen atom was also subjected to the

standard reaction conditions, but was found not to show good performance in view of

both of the !-selectivity and the yield (eq. 4).

In order to evaluate the practical utility of this system, the author attempted the

preparation of the !-alkylpyrrole in a larger scale than the 0.1–0.3-mmol scale reactions shown in Table 1 and Scheme 3. The results are collected in Table 2. For example, the

reductive !-alkylation of 1-tert-butylpyrrole with decanal (6b) and 3a was performed on

a 25-mmol scale, thereby giving 3.96 g of !-4x in 60% yield, which is comparable to the yield of 64% when performed on the 0.3-mmol small scale. The other cases of different

scales also proceeded comparably to each of the corresponding small scale reactions, thus

indicating that the present method can respond to a range of scalability as a synthetic

organic reaction.

O C9H19NIn(ONf)3 (10 mol%)1,4-dioxane85 °C, 24 h N

Et3SiH+ + (2)C9H19

4u; 36% yieldα:β = 82:18

4:1:1.5

6b 3a1a

O C8H17NTs

In(NTf2)3 (10 mol%)1,4-dioxane85 °C, 20 h3:1:1.5

C8H17

NTs

Et3SiH+ + (3)

6aconv. of 1b: <1%

3a β-4v; <1% yield1b

O C8H17NH

In(NTf2)3 (10 mol%)1,4-dioxane85 °C, 20 h N

H

Et3SiH+ + (4)C8H17

7a; 28% yieldα:β = 46:54

3:1:1.5

6a 3a1c

《口—

('?i 3¥ ／

口よ if

ロよ ~--{

69

Table 2. Preparative scale synthesis of !-alkylpyrrolesa

aYields of !-4 based on 6 are shown here. Further details on the reaction conditions for each reaction are given in the Experimental Section. bThe yield of the 0.1- or 0.3-mmol scale reaction is shown in the parentheses. cRecovery efficiency of the pyrrole substrate (1) is shown in the parentheses.

+ +

61

method A

Et3SiHO R4

R3

3a

cat. In(NTf2)3or In(ONf)31,4-dioxaneT °C, t h

R4

NR1

R3

β-4NR1

R2 R2

N

β-4g; 85% yield1.41 g (84%)bT = 50, t = 18

N

β-4d; 84% yield840 mg (89%)bT = 50, t = 30

NPr

β-4m; 49% yield445 mg (54%)bT = 85, t = 7

NC9H19

β-4x; 60% yield3.96 g (64%)bT = 85, t = 7

NC9H19

Phβ-4w; 53% yield1.75 g (54%)bT = 85, t = 10

Ph

5-mmol scale

10-mmol scale 25-mmol scale

N

β-4r; 90% yield 1.51 g (93%)bT = 85, t = 3 (99%)c

H19C9

h A --------if

_jr1' 7'if r

~if i if メ、 7'i--f、

70

III-2-2. Indium-Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles

As shown in the preceding section, the combination of ketones 6 as

electrophiles and Et3SiH (3a) as a hydride nucleophile is incorporated as a secondary

alkyl group onto the pyrrole ring. The author therefore considered that the combination

of ketones and carbon nucleophiles [Nu(C)] would be available for the introduction of a

tertiary alkyl group. 21 The results of the reactions performed on the basis of this

consideration are shown in Table 3, which includes only the experimental results that

have not been disclosed previously.15 With method B at 85 °C in the presence of a

catalytic amount of In(OTf)3, the reaction of 1-methylpyrrole (1a) and 5-acetyloxy-2-

pentanone with Me3SiCN (3b) as a cyanide carbon nucleophile proceeded as expected,

thus providing !-8a with the 5-acetyloxy-2-cyano-2-pentyl framework on the !-carbon

in 71% yield. Here again, the corresponding #-isomer was not formed at all. The 5-acetyloxy-2-pentyl moiety can be easily replaced with other alkyl chains by the choice of

carbonyl compounds 6 (!-8b–!-8k and !-8m), and other pyrroles also serve as one piece

for the alteration of the target structure (!-8e–!-8i). Importantly, carbon nucleophiles can be extended to not only heteroarenes such as 2-methylfuran (3c) and 1-methylindole (3d),

but also 2-(trimethylsilyloxy)furan (3e) and tetraallyltin (3g), whereas some of the

reactions resulted in low yields. It should be noted that, by the use of 3c and 3d, two

different heteroaryl rings can be introduced onto the carbonyl carbon by the single-step

method without complicated operation (!-8h–!-8j). Besides the carbon nucleophiles shown here, 2,3-dimethylthiophene and 4-vinylanisole have been found to be available,

as previously demonstrated.15 Contrary to the successful entries, silyl enolate 3f did not

work as a carbon nucleophile (!-8l).

71

Table 3. Indium-catalyzed !-alkylation of pyrroles with carbonyl compounds and carbon nucleophilesa

aYields of isolated !-8 based on 6 are shown here. Further details on the reaction conditions for each reaction are given in the Experimental Section. bIn(OTf)3 instead of In(NTf2)3 was used. cIn(ONf)3 instead of In(NTf2)3 was used, and the process before adding 3d was performed for 1 h.

Nu(C)'

R2

NR1

1,4-dioxane85 ºC, 3 h

Nu(C) 3T ºC, t h

β-8

method B

+NR11

O R3

R2

6

R3

carbon nucleophiles [Nu(C)]

Me3SiCN

3b 3c

3g

3d

cat. InX3

OSiMe3O

3f

4Sn

O N

3eO OSiMe3

N OO

CNNN

CN

β-8b; 65% yieldwith 3bT = 110, t = 5

S

NCN

β-8a; 71% yieldwith 3bT = 85, t = 1

OAc

NCN

β-8d; 71% yieldwith 3bT = 85, t = 12

Ph

β-8c; 84% yieldwith 3bT = 85, t = 1

NCN

NCN

β-8f; 87% yieldwith 3bT = 85, t = 1

β-8g; 75% yieldwith 3bT = 85, t = 3

NCN

β-8e; 73% yieldwith 3bT = 85, t = 1

C6H13 C6H13

N

β-8h; 72% yieldwith 3cT = 70, t = 1

C6H13

O

N

β-8m; 21% yieldwith 3gT = 85, t = 3

C6H13

Ph Ph

N

β-8ib; 75% yieldwith 3cT = 85, t = 24

O

β-8j; 30% yieldwith 3dT = 50, t = 15

N N

β-8k; 45% yieldwith 3eT = 50, t = 3

N O O

C8H17

β-8l; <1% yieldwith 3fT = rt, t = 16

口人ぐ

('>--- (1) ／

>ごー口

~;F ? ;Jr 三-J if if _j~

+ 0

~~~~~ +

72

III-2-3. N-Deprotection: Synthesis of N-Unsubstituted !-Alkylpyrroles

Removal of the functional group on the nitrogen atom of !-alkylpyrroles

prepared by this approach enables the access to N-unsubstituted !-alkylpyrroles (Scheme

4). For instance, the sulfonylethyl groups (RSO2CH2CH2) of !-4h and !-4i are able to be

removed with NaH in DMF at room temperature, thereby giving N-deprotected !-7a in good to high yields (Scheme 4, (i)).22 Similarly, the deprotection reaction of a series of

ethoxycarbonylethyl groups (EtO2CCH2CY2) proceeded smoothly with t-BuOK in THF

to afford !-7a and !-7b in good yields (Scheme 4, (ii)).23 In addition to these substituents, The research group to which the author belongs has previously demonstrated that the

benzyl and cumyl groups of, for instance, !-4e and !-4w can be also deprotected by

treating with the system consisting of TiCl3/Li/I2 in THF.14,15,24 At present, the direct

synthesis of the N-unsubstituted !-alkylpyrrole with a high yield and a high !-selectivity seems to be difficult for this strategy. However, utilizing the sequence of the indium-

catalyzed !-alkylation of N-substituted pyrroles followed by the deprotection reactions

enables preparation of all six types including N-substituted and N-unsubstituted !-alkylpyrroles having primary, secondary and tertiary alkyl units.

Scheme 4. N-Deprotection of N-substituted !-alkylpyrroles

NR2

R1

NH

R2

R1

t-BuOK (5 equiv.)THF, rt, 30 min

NC8H17

NH

C8H17NaH (3 equiv.)DMF, rt

β-7a; 65% yield (6 h) from β-4hβ-7a; 87% yield (4 h) from β-4i

EtO2C

RO2S

(ii) deprotection of ethoxycarbonylethyl groups

(i) deprotection of sulfonylethyl groups

β-4h (R = Me)β-4i (R = Ph)

Y2Y1

NH

C8H17

β-7a; 54% yieldfrom β-4j (Y1 = Y2 = H)β-7a; 82% yieldfrom β-4k (Y1 = Me, Y2 = H)

NH

β-7b; 66% yieldfrom β-4l (Y1 = Y2 = Me)

~if

,_fl' if

if

ぐ

<Jf>

73

III-2-4. Synthesis of Methanes with Four Different Aryl Groups Including a !-Pyrrolyl Group

A tetraarylmethane structure has played a significant role for the development

of molecular chemistry, and is thus widely found in functional organic molecules

associated with not only material chemistry25 but also medical chemistry.26 But in this

context, there are only a handful of reports for the synthesis of methanes having four

different aryl groups,27 which itself have formative beauty genuinely and, in addition,

would be expected to impart unique properties that are not observed in simple

tetraarylmethanes. At present, a synthetic strategy of methanes with four different aryl

groups, one of which is a !-pyrrolyl group, has no precedent, to the best of my knowledge.28 The author expected that the utilization of the strategy by mixing the N-

substituted pyrrole, an unsymmetrical diaryl ketone and a heteroarene would be just

suited for the synthesis of such unique molecules like no others. With such a prospect, a

mixture of 1-methylpyrrole (1a) and 4-methylbenzophenone (6c) was treated with a

catalytic amount of In(NTf2)3, followed by the addition of 2-methylfuran (3c) as a carbon

nucleophile (eq. 5). As a result, desired tetraarylmethane !-9a consisting of all different (hetero)aryl parts was obtained as a single isomer, albeit disappointingly in a low NMR

yield, and phenyl(p-tolyl)dipyrrolylmethane 5a, which is an intermediate for !-9a, was also produced in 25% NMR yield as a regioisomeric mixture. The low yield may be

attributed in part to oligomerization of !-9a and/or 5a, based on analysis of 1H NMR

spectra.

O

N


O3d

(4 equiv.)85 ºC, 24 h

N O

+ 1:5

β-9a; 5% NMR yield1a(6)

6cconv. of 6c: 63%

NN

+

5a; 25% NMR yieldα,α':α,β':β,β' = 1:16:83

口 ~

vyO op 『、〉 ~1

¥ I

74

On the basis of this result, the author successively investigated the potentiality

of the two-step approach: the first stage is the synthesis of intermediary

diaryldipyrrolylmethane 5, and replacing the one pyrrolyl group of 5 with the other

heteroaryl ring is the next step to yield !-9.18 In order to realize the two-step approach, the catalytic activity of some indium salts by the reaction of 1a with 6c was first tested in

case to confirm the generation efficiency of 5a, and In(NTf2)3 was found to exhibit the

better performance, thus giving 5a as a mixture of #,!’- and !,!’-isomers (13:87) in 53% yield (Table 4). With the aid of catalyst In(NTf2)3, the author successively explored the

scope of the diaryldipyrrolylmethane synthesis. In addition to the phenyl and p-tolyl

groups, a diaryl ketone with a m-tolyl, naphthyl or 3-thienyl group reacted with 1-

methylpyrrole (1a) to give the corresponding product in a moderate yield, respectively

(5b–5d). In the use of the pyrrole substrate bearing the benzyl group on the nitrogen atom,

only !,!’-5e was obtained without producing other regioisomers, the reason of which will

be due mainly to steric constraints in the #,#’- and #,!’-isomers based on the larger benzyl group, as previously demonstrated. 29 Fluorenone derivatives including the

symmetrical simple type were found to be quite promising, thereby giving 5f–5h in high

yields.

Table 4. Indium-catalyzed synthesis of diaryldipyrrolylmethanesa

aYields of 5 based on 6 are shown here. Further details on the reaction conditions for each reaction are given in the Experimental Section.

NR1

4–5:16

X = CH=CH, SO

R2X

+R4

1

cat. In(NTf2)31,4-dioxane 85–100 ºC 3–40 h

R3

NR1N

R1

R3

X R4R2

5

N N

Br

N

OH

5f; 99% yieldα,β':β,β' = 9:9185 ºC, 4 h

5g; 82% yieldα,β':β,β' = 3:9785 ºC, 24 h

5h; 84% yieldα,β':β,β' = 14:86100 ºC, 10 h

Nβ,β'-5e; 70% yield100 ºC, 24 h

5c; 48% yieldα,β':β,β' = 8:92100 ºC, 24 h

N5b; 50% yieldα,β':β,β' = 15:85100 ºC, 40 h

N5d; 41% yieldα,β':β,β' = 14:86100 ºC, 24 h

N

N

NN N

N NNPhPh

S

5a; 53% yieldα,β':β,β' = 13:87T = 100, t = 24

N N

ロ VF~

＼ー

／

／

／

／

―J ¥__ I ／

／

75

With some diaryldipyrrolylmethanes 5 in hand, the author moved to the next

stage, and again first examined the effect of indium catalysts in the reaction of 5a with 2-

methylfuran (3c), where 5a was used as a mixture of the #,!’- and !,!’-isomers (13:87)

without separation (Table 5). Even though the starting substrate includes the #,!’-isomer,

desired !-9a with the p-tolyl, phenyl, 1-methyl-3-pyrrolyl and 5-methyl-2-furanyl groups

at the same carbon atom was produced in a yield of 69% without contamination by its #-

isomer, by using catalyst In(OTf)3. Table 5 shows the scope of the tetraarylmethane

synthesis. A series of diaryldipyrrolylmethanes 5b–5h, which were used as a mixture of

the #,!’- and !,!’-isomers as in the case of 5a, also reacted with 3c to produce the

corresponding tetraarylmethanes in moderate to good yields (!-9b–!-9h). Among them,

!-9d seems to have the most unique structure consisting of essentially four different rings, which are the phenyl, thienyl, pyrrolyl and furanyl groups. Besides 2-methylfuran (3c),

2-methoxythiophene (3h) is available, where In(NTf2)3 showed a better catalytic

performance (!-9i–!-9k). Different from the successful heteroaryl nucleophiles, aromatic ones such as 1,2-dimethoxybenzene (3i) and N,N-dimethylaniline (3j) unfortunately did

not participate in this reaction.30 As eq. 6 shows, the benzyl group on the nitrogen atom

of !-9e can be also removed by the TiCl3/Li/I2 reagent system.

76

Table 5. Indium-catalyzed synthesis of methanes with four different aryl groups

including a !-pyrrolyl groupa

aYields of isolated !-8 based on 6 are shown here. Further details on the reaction conditions for each reaction are given in the Experimental Section. bIn(OTf)3 instead of In(NTf2)3 was used. cIn(ONf)3 instead of In(NTf2)3 was used, and the process before adding 3d was performed for 1 h.

NR1

+Z R5

N ZR1 R5

R3

X R4R2

β-9

cat. In(OTf)3or In(NTf2)31,4-dioxaneT °C, t h

3Z = O, S, CH=CH

NR1

R3

X R4R2

5X = CH=CH, S

1:2.5–4

R6

R6

3c

Z R5

R6

:

3

O3h

S ONO

O3i 3j

O

β-9f; 55% yieldwith 3d, 70 C, 48 h

O

Br

N

β-9g; 53% yieldwith 3d, 70 ºC, 15 h

N O

OH

β-9h; 55% yieldwith 3d, 50 ºC, 18 h

N

β-9i; 47% yieldwith 3g, 70 ºC, 5 h

N SOMe

β-9j; 44% yieldwith 3g, 70 ºC, 3 h

N SOMe

N SOMe

Br

β-9k; 52% yieldwith 3g, 70 ºC, 5 h

N O

β-9e; 72% yieldwith 3d, 70 ºC, 15 h

N O

β-9d; 71% yieldwith 3d, 70 ºC, 15 h

S

β-9c; 72% yieldwith 3d, 70 ºC, 15 h

β-9b; 67% yieldwith 3d, 70 ºC, 15 h

N ON O

Ph

β-9a; 69% yieldwith 3c, T = 70, t = 15

N O

N

β-9l; <1% yieldwith 3i, T = 100, t = 48

O

ON

N

β-9m; tracewith 3j, T = 100, t = 48

β-7c; 63% yield

TiCl3 (2 equiv.)Li (13 equiv.)I2 (1 equiv.)THF, rt, 16 h

(6)

β-9e

N OPh

N OH

0-- :,,

口□、 V>--Q-, 0-~

／

／

／

／

77

III-2-5. Reaction Mechanism

Some experimental observations are available for the mechanistic study of this

transformation (Scheme 5). At first, the indium-catalyzed reaction of 1-methylpyrrole

(1a) with 2-decanone (6a) was conducted but in the absence of Et3SiH (3a), and was

confirmed to indeed give an isomeric mixture of dipyrrolyldecanes 5i in 92% yield

(Scheme 5, (i)). Subsequently, in the presence of H2O as the by-product in the preceding

reaction (Scheme 5, (i)), the treatment of the isomeric mixture of 5i with 3a and In(NTf2)3

(10 mol%) resulted in the exclusive of and in the high-yield formation of !-4a (Scheme

5, (iii)). Neither of the reactions proceeded at all without the indium catalyst (Scheme 5,

(ii) and (iv)). These results indicate that dipyrrolylalkanes 5 are intermediates for the

reductive !-alkylation, and the indium catalyst is essential for both the stages. Importantly,

using single isomer #,!’-5i, which has the possibility to lead to another isomer #-4a when

the !-pyrrolyl group is eliminated, again provided !-4a exclusively, thus suggesting that

the #-pyrrolyl group compared to the !-pyrrolyl group has a superior leaving ability

(Scheme 5, (v)). With 3a-d instead of 3a in the three-component reaction, the deuterium

atom of 3a-d was incorporated regioselectively at the carbon atom within the alkyl chain

(Scheme 5, (vi)).

78

Scheme 5. Mechanistic studies

+ C8H17

N

In(NTf2)3(10 mol%)H2O (1 equiv.)1,4-dioxane85 °C, 40 min

C8H17

1:1.5

3a β-4a; 93% yield

Et3SiHN N

α,β'-5i

(v)

+N

α-4a; not formed

C8H17

NNO C8H17N

C8H17

+ C8H17

N

+In(NTf2)3(10 mol%)1,4-dioxane85 °C, 1 h

In(NTf2)3(10 mol%)H2O (1 equiv.)1,4-dioxane85 °C, 1 h

NN

C8H17

5i; 92% yieldα,α':α,β':β,β' = 1:12:87

6a1a

4:1

1:1.5

5i; α,α':α,β':β,β'= 1:12:87

3a β-4a; 94% yield

Et3SiH

+ H2O

O C8H17N

6a1a

3:1:1.5

3a-d

Et3SiD+ + C8H17

N

β-4a-d; 92% yield, >99%-d

DIn(NTf2)3(10 mol%)1,4-dioxane85 °C, 3 h

(i)

(iii)

(vi)

NNO C8H17N

C8H17

+1,4-dioxane85 °C, 10 h

5i; <1% yield6a1a

4:1

+ C8H17

NH2O (1 equiv.)1,4-dioxane85 °C, 10 h

NN

C8H17

1:1.5

5i; α,α':α,β':β,β'= 1:12:87

3a β-4a; <1% yield

Et3SiH

(ii)

(iv)

withoutIn(NTf2)3

withoutIn(NTf2)3

口よ一『~")I ¥ /

ロょ---------➔ C~1 I ¥ /

r~1 ----------if ¥ I I

r~1 --------if ＼／／

~ -if ／ (>;))

ー□

|

----------if ／

79

On the basis of these experimental results shown in Scheme 5, and, in addition,

of the previous ones reported by us and others, plausible reaction mechanisms are

depicted in Scheme 6, where #,#’-5 is omitted, due actually to the non-formation of #-4

derived inevitably from #,#’-5. At first, the indium(III) Lewis acid (In), which will work as an activator of the C=O bond of 6, assembles 1 and 6 into dipyrrolylalkanes 5, the

formation of which is the well-known process most frequently promoted by a (Lewis)

acid.31 The predominant generation of !,!’-5 over the other two isomers results from the highest thermodynamic stability, probably because of the least steric repulsion between

the two R1 groups (Scheme 7, (i)), as previously observed.29 Next, the #-pyrrolyl group

of #,!’-5 would coordinate to In,32 and then eliminate as anionic #-pyrrolylindium #-10

to give cationic species !-11 through the C–C(#-pyrrolyl) bond cleavage. Although there

may be a possibility to afford another cationic species #-11 from same intermediate #,!’-

5, the selective formation of !-11 thus leading to !-4 is likely to be due, at least in part,

to two synergistic effects. One is the higher stability of !-11 itself compared to the

corresponding #-11 that has the higher 1,3-allylic-type strain between R1 (≠ H) and R2

(Scheme 7, (ii)).33 The other is the higher leaving group character of the #-pyrrolyl group

than the !-pyrrolyl group (see Scheme 5, (v)), and this experimental fact should thus be

attributed to the higher stability of #-pyrrolylindium #-10 than !-pyrrolylindium !-10

(Scheme 7, (iii)) because, in general, an #-pyrrolylmetal, which means an #-pyrrolyl

anion, is relatively more stable.34 Finally, !-11 reacts with hydride or carbon nucleophile 3 at the carbon atom sandwiched between R2 and R3, not at the iminium-like carbon,

thereby arriving at the exclusive formation of !-4. The process from !,!’-5 to !-4 is also considered to proceed in a similar way.

80

Scheme 6. Plausible reaction mechanisms

Scheme 7. Stability profiles of key intermediates

R3

NR1

R2Nu'

N NR1 R1

R3R2

Nu 3

N NR1 R1

R3R2

β-4 (β-8, β-9)

N

In–

R1

In

NR1

–α-4 (α-8, α-9)

NR1

R2

R3Nu'

α-11

β-11

R2

R3

N

R3

R2

N

N

In–

R1

R1+

R1

+

α,β'-5

β,β'-5N N

N N

R1

R1 R1

R1

R3R2

R3R2

N NR1 R1

R3R2

In

In

In

β-10

α-10

β-10

Nu 3In

In

In

+

N

6

1

O R3

R2

R1

In– H2O

O R3

R2In

C=O bondactivation

C–C bondactivation

N

In–

R1

β-10

In

NR1

–

α-10

<α-11 (R1 ≠ H)

R3

R2

NR1

+

β-11

R2

R3

NR1

+<(iii)(ii)

R3R2

α,α'-5

N NR1R1

R3R2

α,β'-5

NR1N

R1

R3R2

NNR1 R1

β,β'-5

< <(i)

H

• >

I A I↓ ~- rifニ/ifD ーr~)、 1 -X

'O

ぐ~

り口 lf'0 ぃごゞ/

:》¢、)(J'r)

81

III-3. Experimental

General Remarks. All manipulations were conducted with a standard Schlenk

technique under an argon atmosphere. Nuclear magnetic resonance (NMR) spectra (1H,

400 and 500 MHz; 13C{1H}, 100 and 125 MHz) were taken using tetramethylsilane as an

internal standard. 2H NMR spectral data were recorded at 61 MHz and chemical shifts

are reported relative to CDCl3 (7.26 ppm) as an internal standard. Analytical gas

chromatography (GC) was performed with a capillary column coated with 5% phenyl

polysilphenylene-siloxane (30 m x 0.25 mm x 0.25 µm) or with 5% diphenyl- and 95%

dimethylpolysiloxane (30 m x 0.25 mm x 0.25 µm) using nitrogen as carrier gas. Gas chromatography-mass spectrometry (GC-MS) analyses were performed with a capillary

column coated with 5% phenyl polysilphenylene-siloxane (30 m x 0.25 mm x 0.25 µm)

or with 5% diphenyl- and 95% dimethylpolysiloxane (30 m x 0.25 mm x 0.25 µm) by electron ionization at 70 eV using helium as carrier gas. High resolution mass spectra

(HRMS) were obtained by GC-FI-TOF or FD-TOF. Preparative recycling high-

performance liquid chromatography (HPLC) was performed with a standard normal

phase column packed with pore size 120 Å silica gel using a mixture of hexane–ethyl

acetate (EtOAc) as eluent. Preparative recycling gel permeation chromatography (GPC)

was performed with a highly cross-linked polystyrene/divinylbenzene packed column

using chloroform as eluent. Melting points were determined on a micro hot stage

apparatus and are uncorrected. 1,4-Dioxane was distilled under argon from sodium just

prior to use. Tetrahydrofuran (THF) was distilled under argon from sodium benzophenone

ketyl just prior to use. The following compounds, 5-acetyloxy-2-pentanone,35 1-[2-

(phenylsulfonyl)ethyl]-1H-pyrrole, 36 1-tert-butyl-1H-pyrrole,15 3-benzoylthiophene, 37

2-(1-methylpyrrol-2-yl)-2-(1-methylpyrrol-3-yl)decane (#,!’-5i)14 were prepared according to the respective literature methods. In(ONf)3

38 and In(NTf2)339 were prepared

by the respective literature procedures. Unless otherwise noted, other substrates and

reagents were commercially available and used as received without further purification.

Synthesis of 1-[2-(Methylsulfonyl)ethyl]-1H-pyrrole. Based on the literature

procedure,36 1-[2-(methylsulfonyl)ethyl]-1H-pyrrole was synthesized with the following

reagents and conditions: 1H-pyrrole (1c) (67.1 mg, 1.00 mmol), methyl vinyl sulfone

(106 mg, 1.00 mmol), KOH (56.1 mg, 1.00 mmol), MeCN (5.0 mL), room temperature,

6 h, and was isolated by column chromatography on silica gel (hexane/EtOAc = 3/1) in

82

87% yield (151 mg) as a white solid; mp 88–89 ºC. 1H NMR (400 MHz, CDCl3) % 2.41 (t, J = 0.7 Hz, 3 H), 3.40 (tq, J = 6.2, 0.8 Hz, 2 H), 4.38–4.47 (m, 2 H), 6.19 (t, J = 2.2

Hz, 2 H), 6.74 (t, J = 2.1 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) % 41.1, 43.6, 55.9,

109.7, 120.6. HRMS (FI) Calcd for C7H11NO2S: M, 173.0510. Found: m/z 173.0491.

Synthesis of Ethyl 1H-pyrrole-1-propionate. Based on the literature

procedure,40 ethyl 1H-pyrrole-1-propionate was synthesized with the following reagents

and conditions: ethyl 3-aminopropanoate hydrochloride (5.04 g, 32.8 mmol), 2,5-

dimethoxytetrahydrofuran (4.33 g, 32.8 mmol), NaOAc (2.96 g, 36.1 mmol), acetic acid

(13.7 mL), 80 ºC, 3 h, and was isolated by short-path distillation under reduced pressure

(81 ºC/3.0 hPa) in 27% yield (1.51 g) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 1.24 (t, J = 7.1 Hz, 3 H), 2.76 (t, J = 7.0 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.21 (t, J =

7.0 Hz, 2 H), 6.13 (t, J = 2.2 Hz, 2 H), 6.66 (t, J = 2.2 Hz, 2 H); 13C{1H} NMR (100 MHz,

CDCl3) % 14.1, 36.6, 44.9, 60.9, 108.4, 120.5, 171.1. HRMS (FI) Calcd for C9H13NO2: M, 167.0946. Found: m/z 167.0926.

Synthesis of Ethyl !-methyl-1H-pyrrole-1-propionate. Based on the

literature procedure,41 ethyl !-methyl-1H-pyrrole-1-propionate was synthesized with the following reagents and conditions: ethyl 3-aminobutyrate (5.25 g, 40.0 mmol), 2,5-

dimethoxytetrahydrofuran (5.29 g, 40.0 mmol), acetic acid (10.0 mL), 80 ºC, 8 h, and was

isolated by short-path distillation under reduced pressure (78 ºC/2.5 hPa) in 69% yield

(5.03 g) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 1.21 (t, J = 7.1 Hz, 3 H), 1.52 (d, J = 6.9 Hz, 3 H), 2.62–2.83 (m, 2 H), 4.05–4.15 (m, 2 H), 4.59 (sext, J = 7.0 Hz, 1 H),

6.13 (t, J = 2.2 Hz, 2 H), 6.71 (t, J = 2.2 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) % 14.1, 21.7, 43.3, 51.9, 60.7, 108.0, 118.5, 170.7. HRMS (FD) Calcd for C10H15NO2: M,

181.1103. Found: m/z 181.1111.

Synthesis of Ethyl !,!-dimethyl-1H-pyrrole-1-propionate. Based on the

literature procedure,40 ethyl !,!-dimethyl-1H-pyrrole-1-propionate was synthesized with the following reagents and conditions: ethyl 3-amino-3-methylbutyrate hydrochloride

(1.21 g, 6.64 mmol), 2,5-dimethoxytetrahydrofuran (878 mg, 6.64 mmol), NaOAc (599

mg, 7.30 mmol), acetic acid (5.3 mL), 80 ºC, 2 h, and was isolated by Kugelrohr bulb-to-

bulb distillation under reduced pressure (80 ºC/90 Pa) in 71% yield (923 mg) as a

colorless oil. 1H NMR (500 MHz, CDCl3) % 1.17 (t, J = 7.2 Hz, 3 H), 1.69 (s, 6 H), 2.72 (s, 2 H), 4.04 (q, J = 7.2 Hz, 2 H), 6.15 (t, J = 2.2 Hz, 2 H), 6.83 (t, J = 2.2 Hz, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.0, 28.4, 48.4, 55.8, 60.5, 107.9, 117.7, 170.1.

83

HRMS (FI) Calcd for C11H17NO2: M, 195.1259. Found: m/z 195.1245.

Synthesis of 1,2-Dimethyl-1H-pyrrole. Based on the literature procedure,42

1,2-dimethyl-1H-pyrrole was synthesized with the following reagents and conditions: 2-

formyl-1-methyl-1H-pyrrole (3.44 g, 31.5 mmol), hydrazine monohydrate (6.47 g, 129

mmol), KOH (6.01 g, 107 mmol), ethylene glycol (45.0 ml), 180 ºC, 1.5 h, and was

isolated by Kugelrohr bulb-to-bulb distillation under reduced pressure (90 ºC/11 kPa) in

57% yield (1.73 g) as a colorless oil. 1H NMR (500 MHz, CDCl3) % 2.21 (d, J = 0.6 Hz, 3 H), 3.52 (s, 3 H), 5.85–5.89 (m, 1 H), 6.03 (t, J = 3.2 Hz, 1 H), 6.54 (dd, J = 2.1, 1.6

Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 11.9, 33.5, 106.35, 106.45, 120.9, 128.8.

HRMS (FI) Calcd for C6H9N: M, 95.0735. Found: m/z 95.0748.

Synthesis of 1,3-Dimethyl-1H-pyrrole. Based on the literature procedure,43

1,3-dimethyl-1H-pyrrole was synthesized with the following reagents and conditions: 3-

methyl-1H-pyrrole (852 mg, 10.5 mmol), iodomethane (1.79 g, 12.6 mmol), KOH (2.36

g, 42.0 mmol), dimethyl sulfoxide (DMSO) (26.0 mL), room temperature, 30 min, and

was isolated by short-path distillation under reduced pressure (75 ºC/23 kPa) in 30% yield

(302 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 2.09 (s, 3 H), 3.59 (s, 3 H), 5.95 (t, J = 2.1 Hz, 1 H), 6.36–6.40 (m, 1 H), 6.49 (t, J = 2.4 Hz, 1 H); 13C{1H} NMR

(100 MHz, CDCl3) % 11.8, 35.9, 109.2, 118.9, 119.7, 121.4. HRMS (FI) Calcd for C6H9N:

M, 95.0735. Found: m/z 95.0715.

Synthesis of 1-(2-Phenylpropan-2-yl)-1H-pyrrole. Based on the literature

procedure,41 1-(2-phenylpropan-2-yl)-1H-pyrrole was synthesized with the following

reagents and conditions: cumylamine (4.06 g, 30.0 mmol), 2,5-dimethoxyhydrofuran

(3.96 g, 30.0 mmol), acetic acid (13.5 mL), 80 ºC, 7 h, and was isolated by short-path

distillation under reduced pressure (80 ºC/1.3 hPa) in 80% yield (4.45 g). This compound


agreement with those reported in reference 15. Therefore, only 1H NMR data are provided

here. 1H NMR (500 MHz, CDCl3) % 1.89 (s, 6 H), 6.20 (t, J = 2.0 Hz, 2 H), 6.79 (t, J =

2.3 Hz, 2 H), 6.98 (dt, J = 7.5, 2.3 Hz, 2 H), 7.22 (tt, J = 7.2, 1.6 Hz, 1 H), 7.28 (td, J =

6.6, 1.7 Hz, 2 H).

Indium-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH; A General Procedure of Method A for eq. 1–4, and Table 1, 2. The experimental procedure performed on a 0.3-mmol scale based on carbonyl

compound 6 is shown here as a representative. In(NTf2)3 (28.7 mg, 30.0 µmol) or

84

In(ONf)3 [(15.2 mg, 15.0 µmol) or (30.4 mg, 30.0 µmol)] was placed in a 20 mL Schlenk

tube, which was heated at 150 ºC in vacuo for 2 h. The tube was cooled down to room

temperature and filled with argon. 1,4-Dioxane (0.50 mL) was added to the tube, and the

mixture was then stirred at room temperature for 10 min. To this were added carbonyl

compound 6 (0.300 mmol), pyrrole derivative 1 (0.300, 0.600, 0.840, 0.900 or 1.20 mmol)

and Et3SiH (3a) (52.3 mg, 0.450 mmol), and the resulting mixture was stirred at T1 °C.

After stirring for t1 h, a saturated NaHCO3 aqueous solution (0.3 mL) was added, and the



evaporation of the solvent followed by purification gave the corresponding product (4 or

7a). In the preceding communication, the synthesis of !-4a, !-4w and !-4x has been already achieved, and their spectral and analytical data are thus provided in reference 15.

Unless otherwise noted, new products 4 synthesized here were fully characterized by 1H

and 13C{1H} NMR spectroscopy, and HRMS.

Indium-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH; A General Procedure of Method B for Table 1. In(NTf2)3

[(57.3 mg, 60.0 µmol) or (86.0 mg, 90.0 µmol)] was placed in a 20 mL Schlenk tube,

which was heated at 150 ºC in vacuo for 2 h. The tube was cooled down to room


mixture was then stirred at room temperature for 10 min. To this were added carbonyl

compound 6 (0.300 mmol), pyrrole derivative 1 (0.900 or 1.50 mmol), and the resulting

mixture was stirred at T2 °C for t2 h. Et3SiH (3a) [(52.3 mg, 0.450 mmol) or (105 mg,

0.900 mmol)] was then added to this solution, and the resulting mixture was stirred further

at T3 ºC. After stirring for t3 h, the work-up process was carried out similarly as above.

Unless otherwise noted, new products !-4 synthesized here were fully characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS.

3-Cyclohexyl-1-methyl-1H-pyrrole (!-4b). The title compound was

synthesized with the following reagents based on method A: 1-methylpyrrole (1a) (73.0

mg, 0.900 mmol), cyclohexanone (29.4 mg, 0.300 mmol), Et3SiH (3a) (52.3 mg, 0.450

mmol), In(NTf2)3 (28.7 mg, 30.0 µmol) and 1,4-dioxane (0.50 mL), and was isolated by

column chromatography on silica gel (hexane/EtOAc = 40/1) in 90% yield (44.1 mg) as

a colorless oil. 1H NMR (500 MHz, CDCl3) % 1.16–1.41 (m, 5 H), 1.69 (dtt, J = 14.0, 4.7, 3.2 Hz, 1 H), 1.74–1.81 (m, 2 H), 1.90–1.98 (m, 2 H), 2.42 (tt, J = 11.2, 3.6 Hz, 1 H),

85

3.60 (s, 3 H), 6.01 (t, J = 2.3 Hz, 1 H), 6.38 (t, J = 1.9 Hz, 1 H), 6.50 (t, J = 2.3 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 26.4, 26.7, 34.8, 36.0, 36.3, 106.5, 117.6, 121.2, 131.3. HRMS (FI) Calcd for C11H17N: M, 163.1361. Found: m/z 163.1359.

3-(6-Chlorohexan-2-yl)-1-methyl-1H-pyrrole (!-4c). The title compound was synthesized with the following reagents based on method A: 1a (73.0 mg, 0.900

mmol), 6-chlorohexan-2-one (40.4 mg, 0.300 mmol), 3a (52.3 mg, 0.450 mmol),

In(NTf2)3 (28.7 mg, 30.0 µmol) and 1,4-dioxane (0.50 mL), and was isolated by column

chromatography on silica gel (hexane/EtOAc = 20/1) in 97% yield (58.6 mg). Compound

!-4c has already appeared in reference 14, and its spectral and analytical data are in good

agreement with those reported in the literature. Therefore, only 1H NMR data are

provided here. 1H NMR (500 MHz, CDCl3) % 1.19 (d, J = 6.9 Hz, 3 H), 1.37–1.59 (m, 4 H), 1.76 (quint, J = 7.1 Hz, 2 H), 2.62 (sext, J = 6.8 Hz, 1 H), 3.52 (t, J = 6.9 Hz, 2 H),

3.60 (s, 3 H), 5.98 (t, J = 2.2 Hz, 1 H), 6.37 (t, J = 1.9 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H).

1-Benzyl-3-isopropyl-1H-pyrrole (!-4d). The title compound was synthesized with the following reagents based on method A: for the 0.3-mmol scale

reaction: 1-benzylpyrrole (141 mg, 0.900 mmol), acetone (17.4 mg, 0.300 mmol), 3a

(52.3 mg, 0.450 mmol), In(NTf2)3 (28.7 mg, 30.0 µmol) and 1,4-dioxane (0.50 mL), and

was isolated by column chromatography on silica gel twice (first: hexane/EtOAc = 40/1;

second: hexane/CHCl3 = 5/1) in 89% yield (53.3 mg) as a colorless oil; for the 5-mmol

scale reaction: 1-benzylpyrrole (2.36 g, 15.0 mmol), acetone (290 mg, 5.00 mmol), 3a

(872 mg, 7.50 mmol), In(NTf2)3 (478 mg, 0.500 mmol) and 1,4-dioxane (8.3 mL), and

was isolated by column chromatography on silica gel (hexane/CHCl3 = 5/1) in 84% yield

(840 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 1.20 (d, J = 6.9 Hz, 6 H), 2.81 (sept, J = 6.9 Hz, 1 H), 5.00 (s, 2 H), 6.07 (t, J = 2.3 Hz, 1 H), 6.46 (t, J = 1.8 Hz, 1 H),

6.59 (t, J = 2.3 Hz, 1 H), 7.12 (d, J = 7.4 Hz, 2 H), 7.23–7.29 (m, 1 H), 7.29–7.35 (m, 2

H); 13C{1H} NMR (100 MHz, CDCl3) % 24.1, 26.5, 53.3, 106.9, 117.0, 120.8, 127.1, 127.5, 128.7, 132.3, 138.4. HRMS (FD) Calcd for C14H17N: M, 199.1361. Found: m/z

199.1360.

1-Benzyl-3-(decan-2-yl)-1H-pyrrrole (!-4e). The title compound was synthesized with the following reagents based on method A: 1-benzylpyrrole (141 mg,

0.900 mmol), 2-decanone (6a) (46.9 mg, 0.300 mmol), 3a (52.3 mg, 0.450 mmol),


chromatography on silica gel (hexane/CHCl3 = 5/1) in 76% yield (68.0 mg). Compound

86

!-4e has already appeared in reference 14, and its spectral and analytical data are in good agreement with those reported in the literature. Therefore, only 1H NMR data are

provided here. 1H NMR (500 MHz, CDCl3) % 0.87 (t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.9

Hz, 3 H), 1.20–1.34 (m, 12 H), 1.38–1.47 (m, 1 H), 1.48–1.58 (m, 1 H), 2.61 (sext, J =

6.9 Hz, 1 H), 5.00 (s, 2 H), 6.03 (dd, J = 2.5, 2.0 Hz, 1 H), 6.44 (t, J = 1.8 Hz, 1 H), 6.59

(t, J = 2.5 Hz, 1 H), 7.07–7.11 (m, 2 H), 7.24–7.28 (m, 1 H), 7.31 (tt, J = 7.2, 1.6 Hz, 2

H).

1-Benzyl-3-(diphenylmethyl)-1H-pyrrole (!-4f). The title compound was synthesized with the following reagents based on method B: 1-benzylpyrrole (236 mg,

1.50 mmol), benzophenone (54.7 mg, 0.300 mmol), 3a (52.3 mg, 0.450 mmol), In(NTf2)3

(86.0 mg, 90.0 µmol) and 1,4-dioxane (0.50 mL), and was isolated by column

chromatography on silica gel (hexane/CHCl3 = 3/1) in 93% yield (91.1 mg) as a white

solid; mp 96–97 ºC. 1H NMR (500 MHz, CDCl3) % 4.97 (s, 2 H), 5.35 (s, 1 H), 5.95 (dd, J = 2.4, 1.9 Hz, 1 H), 6.22–6.27 (m, 1 H), 6.61 (t, J = 2.6 Hz, 1 H), 7.06–7.12 (m, 2 H),

7.17 (tt, J = 7.0, 1.8 Hz, 2 H), 7.13–7.20 (m, 9 H), 7.31 (tt, J = 7.3, 1.7 Hz, 2 H); 13C{1H}

NMR (125 MHz, CDCl3) % 50.1, 53.3, 109.4, 120.6, 121.3, 125.9, 126.9, 127.2, 127.5, 128.1, 128.7, 128.9, 138.3, 145.3. HRMS (FI) Calcd for C24H21N: M, 323.1674. Found:

m/z 323.1666.

1-tert-Butyl-3-isopropyl-1H-pyrrole (!-4g). The title compound was synthesized with the following reagents based on method A: for the 0.3-mmol scale

reaction: 1-tert-butylpyrrole (111 mg, 0.900 mmol), acetone (17.4 mg, 0.300 mmol), 3a


was isolated by column chromatography on silica gel (hexane/EtOAc = 50/1) in 84%

yield (41.9 mg) as a colorless oil; for the 10-mmol scale reaction: 1-tert-butylpyrrole

(3.70 g, 30.0 mmol), acetone (581 mg, 10.0 mmol), 3a (1.74 g, 15.0 mmol), In(NTf2)3

(955 mg, 1.00 mmol) and 1,4-dioxane (16.7 mL), and was isolated by column

chromatography on silica gel (hexane/CHCl3 = 10:1) in 85% yield (1.41 g) as a colorless

oil. 1H NMR (400 MHz, CDCl3) % 1.21 (d, J = 6.9 Hz, 6 H), 1.51 (s, 9 H), 2.82 (sept, J = 6.8 Hz, 1 H), 6.03 (t, J = 2.3 Hz, 1 H), 6.57–6.62 (m, 1 H), 6.74 (t, J = 2.5 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 24.0, 26.5, 30.7, 54.4, 105.7, 113.5, 117.0, 131.0.


3-(Decan-2-yl)-1-[2-(methylsulfonyl)ethyl]-1H-pyrrole (!-4h). The title compound was synthesized with the following reagents based on method A: 1-[2-

87

(methylsulfonyl)ethyl]-1H-pyrrole (156 mg, 0.900 mmol), 6a (46.9 mg, 0.300 mmol), 3a


was isolated by column chromatography on silica gel (hexane/EtOAc = 2/1) in 86% yield

(81.3 mg) as a white solid; mp 78–79 ºC. 1H NMR (400 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.14 (d, J = 6.9 Hz, 3 H), 1.17–1.35 (m, 12 H), 1.36–1.54 (m, 2 H), 2.38 (t, J =

0.7, 3 H), 2.58 (sext, J = 6.9 Hz, 1 H), 3.37 (tq, J = 6.1, 0.8 Hz, 2 H), 4.32–4.39 (m, 2 H),

6.03 (dd, J = 2.5, 1.8 Hz, 1 H), 6.49 (t, J = 1.9 Hz, 1 H), 6.64 (t, J = 2.5 Hz, 1 H); 13C{1H}

NMR (100 MHz, CDCl3) % 14.1, 22.3, 22.7, 27.6, 29.4, 29.7, 29.8, 31.8, 31.9, 38.5, 40.9, 43.7, 55.9, 108.3, 116.7, 120.4, 132.5. HRMS (FD) Calcd for C17H31NO2S: M, 313.2075.

Found: m/z 313.2064.

3-(Decan-2-yl)-1-[2-(phenylsulfonyl)ethyl]-1H-pyrrole (!-4i). The title compound was synthesized with the following reagents based on method A: 1-[2-

(phenylsulfonyl)ethyl]-1H-pyrrole (212 mg, 0.900 mmol), 6a (46.9 mg, 0.300 mmol), 3a



(102 mg) as a white solid; mp 33–34 ºC. 1H NMR (400 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 1.15–1.52 (m, 14 H), 2.52 (sext, J = 6.9 Hz, 1 H),

3.47–3.55 (m, 2 H), 4.21–4.29 (m, 2 H), 5.93 (dd, J = 2.8, 1.8 Hz, 1 H), 6.28 (t, J = 1.9

Hz, 1 H), 6.44 (t, J = 2.5 Hz, 1 H), 7.46–7.60 (tt, J = 7.8, 1.6 Hz, 2 H), 7.66 (tt, J = 7.4,

1.5 Hz, 1 H), 7.84–7.90 (m, 2 H); 13C{1H} NMR (100 MHz, CDCl3) % 14.1, 21.9, 22.7, 27.6, 29.4, 29.6, 29.8, 31.8, 31.9, 38.5, 42.8, 57.2, 107.9, 116.5, 120.1, 127.8, 129.4, 132.0,

134.0, 139.0. HRMS (FD) Calcd for C22H33NO2S: M, 375.2232. Found: m/z 375.2228.

Ethyl 3-(decan-2-yl)-1H-pyrrole-1-propionate (!-4j). The title compound was synthesized with the following reagents based on method A: ethyl 1H-pyrrole-1-

propionate (150 mg, 0.900 mmol), 6a (46.9 mg, 0.300 mmol), 3a (52.3 mg, 0.450 mmol),

In(NTf2)3 (28.7 mg, 30.0 µmol) 1,4-dioxane (0.50 mL), and was isolated by column

chromatography on silica gel (hexane/EtOAc = 8/1) in 97% yield (89.7 mg) as a colorless

oil. 1H NMR (400 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.18–1.33 (m, 15 H), 1.35–1.45 (m, 1 H), 1.46–1.53 (m, 1 H), 2.58 (sext, J = 6.8 Hz, 1

H), 2.74 (t, J = 7.1 Hz, 2 H), 4.13 (t, J = 7.6 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.97 (dd,

J = 2.5, 1.8 Hz, 1 H), 6.40 (t, J = 1.8 Hz, 1 H), 6.55 (t, J = 2.4 Hz, 1 H); 13C{1H} NMR

(125 MHz, CDCl3) % 14.13, 14.15, 22.0, 22.7, 27.6, 29.4, 29.7, 29.9, 31.8, 31.9, 36.7, 38.7, 44.9, 60.8, 107.0, 116.8, 120.1, 131.1, 171.2. HRMS (FD) Calcd for C19H33NO2: M,

88

307.2511. Found: m/z 307.2509.

Ethyl 3-(decan-2-yl)-!-methyl-1H-pyrrole-1-propionate (!-4k). The title

compound was synthesized with the following reagents based on method A: ethyl !-

methyl-1H-pyrrole-1-propionate (163 mg, 0.900 mmol), 6a (46.9 mg, 0.300 mmol), 3a



(90.2 mg) as a colorless oil. This compound has two chiral centers, and thus was produced

as a mixture of diastereomers in an approximately 1:1 ratio. 1H NMR as a mixture of

diastereomers (500 MHz, CDCl3) % 0.87 (t, J = 7.0 Hz, 3 H), 1.16 (d, J = 6.9 Hz, 3 H),

1.19–1.33 (m, 15 H), 1.36–1.44 (m, 1 H), 1.46–1.53 (m, 1 H), 1.49 (d, J = 6.9 Hz, 3 H),

2.58 (sext, J = 7.0 Hz, 1 H), 2.61–2.80 (m, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.50 (sext, J =

7.0 Hz, 1 H), 5.97 (t, J = 2.2 Hz, 1 H), 6.45 (t, J = 1.9 Hz, 1 H), 6.60 (t, J = 2.6 Hz, 1 H); 13C{1H} NMR as a mixture of diastereomers (125 MHz, CDCl3) % 14.1, 21.6, 21.91, 21.93, 22.7, 27.6, 29.4, 29.7, 29.9, 31.90, 31.94, 38.7, 43.4, 51.8, 60.7, 106.52, 106.55,

114.75, 114.80, 117.88, 117.94, 130.65, 130.66, 170.9. HRMS (FD) Calcd for

C20H35NO2: M, 321.2668. Found: m/z 321.2662.

Ethyl 3-cyclopentyl-!,!-dimethyl-1H-pyrrole-1-propionate (!-4l). The title

compound was synthesized with the following reagents based on method A: ethyl !,!-

dimethyl-1H-pyrrole-1-propionate (176 mg, 0.900 mmol), cyclopentanone (25.2 mg,

0.300 mmol), 3a (52.3 mg, 0.450 mmol), In(NTf2)3 (28.7 mg, 30.0 µmol) and 1,4-dioxane

(0.50 mL), and was isolated by column chromatography on silica gel (hexane/EtOAc =

30/1) in 80% yield (63.2 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 1.16 (t, J = 7.1 Hz, 3 H), 1.42–1.53 (m, 2 H), 1.55–1.64 (m, 2 H), 1.66 (s, 6 H), 1.68–1.79 (m, 2

H), 1.91–2.03 (m, 2 H), 2.68 (s, 2 H), 2.87 (tt, J = 9.5, 7.4 Hz, 1 H), 4.03 (q, J = 7.1 Hz,

2 H), 6.01 (dd, J = 2.7, 1.9 Hz, 1 H), 6.56–6.61 (m, 1 H), 6.72 (t, J = 2.6 Hz, 1 H); 13C{1H}

NMR (100 MHz, CDCl3) % 14.0, 25.1, 28.2, 34.5, 38.4, 48.6, 55.6, 60.4, 106.7, 114.1, 117.3, 128.7, 170.3. HRMS (FD) Calcd for C16H25NO2: M, 263.1885. Found: m/z

263.1906.

1-tert-Butyl-3-butyl-1H-pyrrole (!-4m). The title compound was synthesized with the following reagents based on method A: for the 0.3-mmol scale reaction: 1-tert-

butylpyrrole (148 mg, 1.20 mmol), butanal (21.6 mg, 0.300 mmol), 3a (52.3 mg, 0.450

mmol), In(ONf)3 (30.4 mg, 30.0 µmol) and 1,4-dioxane (0.50 mL), and was isolated by


89

a colorless oil; for the 5-mmol scale reaction: 1-tert-butylpyrrole (2.66 g, 20.0 mmol),

butanal (361 mg, 5.00 mmol), 3a (872 mg, 7.50 mmol), In(ONf)3 (506 mg, 0.500 mmol)

and 1,4-dioxane (8.3 mL), and was isolated by column chromatography on silica gel

(hexane/EtOAc = 50:1) in 49% yield (445 mg) as a colorless oil. 1H NMR (400 MHz,

CDCl3) % 0.92 (t, J = 7.3 Hz, 3 H), 1.37 (sext, J = 7.4 Hz, 2 H), 1.50 (s, 9 H), 1.51–1.60 (m, 2 H), 2.46 (t, J = 7.8 Hz, 2 H), 5.99 (t, J = 2.3 Hz, 1 H), 6.57–6.62 (m, 1 H), 6.73 (t,

J = 2.5 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 14.0, 22.7, 27.0, 30.7, 33.4, 54.3, 107.3, 114.9, 117.1, 124.0. HRMS (FI) Calcd for C12H21N: M, 179.1674. Found: m/z

179.1666.

1,2-Dimethyl-4-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrole (!-4n). The title compound was synthesized with the following reagents based on method B: 1,2-

dimethylpyrrole (85.6 mg, 0.900 mmol), tetrahydro-4H-thiopyran-4-one (34.9 mg, 0.300

mmol), 3a (105 mg, 0.900 mmol), In(NTf2)3 (57.3 mg, 60.0 µmol) and 1,4-dioxane (0.50

mL), and was isolated by column chromatography on silica gel (hexane/EtOAc = 20/1)

in 60% yield (35.6 mg). Compound !-4n has already appeared in reference 44, and its

spectral and analytical data are in good agreement with those reported in the literature.

Therefore, only 1H NMR data are provided here. 1H NMR (500 MHz, CDCl3) % 1.71 (dtd, J = 13.2, 12.2, 3.4 Hz, 2 H), 2.16–2.22 (m, 2 H), 2.18 (d, J = 0.9 Hz, 3 H), 2.42 (tt, J =

11.7, 3.2 Hz, 1 H), 2.62–2.69 (m, 2 H), 2.78 (ddd, J = 12.0, 7.3, 5.9 Hz, 2 H), 3.46 (s, 3

H), 5.72–5.78 (m, 1 H), 6.31 (d, J = 2.1 Hz, 1 H).

3-Cyclohexyl-1,4-dimethyl-1H-pyrrole (!-4o). The title compound was

synthesized with the following reagents based on method A: 1,3-dimethylpyrrole (85.6

mg, 0.900 mmol), cyclohexanone (29.4 mg, 0.300 mmol), 3a (52.3 mg, 0.450 mmol),


chromatography on silica gel (hexane/EtOAc/Et3N = 100/1/3) in 80% yield (42.6 mg) as

a colorless oil. 1H NMR (400 MHz, acetone-d6) % 1.15–1.30 (m, 3 H), 1.36 (qt, J = 12.7, 3.1 Hz, 2 H), 1.65–1.80 (m, 3 H), 1.81–1.89 (m, 2 H), 1.95 (s, 3 H), 2.34 (tt, J = 11.7, 3.4

Hz, 1 H), 3.50 (s, 3 H), 6.27 (s, 2 H); 13C{1H} NMR (100 MHz, acetone-d6) % 10.5, 27.2, 27.7, 35.3, 35.7, 36.3, 116.6, 118.0, 120.4, 129.7. HRMS (FI) Calcd for C12H19N: M,

177.1517. Found: m/z 177.1542.

1-tert-Butyl-3-(decan-1-yl)-4-(propan-2-yl)-1H-pyrrole (!-4p). The title compound was synthesized with the following reagents based on method A (0.1-mmol

scale reaction): 1-tert-butyl-3-(decan-1-yl)-1H-pyrrole (!-4x) (79.0 mg, 0.300 mmol),

90

acetone (5.81 mg, 0.100 mmol), 3a (17.4 mg, 0.150 mmol), In(NTf2)3 (9.55 mg, 10.0

µmol) and 1,4-dioxane (0.17 mL), and was isolated by column chromatography on silica

gel (hexane) in 93% yield (28.6 mg) as a colorless oil. Through the purification process,

51.9 mg of pyrrole substrate !-4x was recovered at an efficiency of 98% [= 51.9 mg/52.7

mg (0.200 mmol)]. 1H NMR (400 MHz, CDCl3) % 0.88 (t, J = 6.7 Hz, 3 H), 1.19 (d, J = 6.9 Hz, 6 H), 1.22–1.42 (m, 14 H), 1.48 (s, 9 H), 1.53–1.64 (m, 2 H), 2.42 (t, J = 8.0 Hz,

2 H), 2.82 (sept, J = 6.9 Hz, 1 H), 6.51 (d, J = 2.9 Hz, 1 H), 6.52 (d, J = 3.0 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 14.1, 22.7, 24.1, 25.3, 25.7, 29.4, 29.62, 29.67, 29.69, 30.0, 30.4, 30.7, 31.9, 54.2, 112.8, 114.6, 121.5, 128.9. HRMS (FD) Calcd for C21H39N:

M, 305.3083. Found: m/z 305.3089.

1-tert-Butyl-3,4-di(decan-1-yl)-1H-pyrrole (!-4q). The title compound was

synthesized with the following reagents based on method A (0.1-mmol scale reaction): !-4x (79.0 mg, 0.300 mmol), decanal (6b) (15.6 mg, 0.100 mmol), 3a (17.4 mg, 0.150

mmol), In(ONf)3 (5.06 mg, 5.00 µmol) and 1,4-dioxane (0.17 mL), and was isolated by

column chromatography on silica gel (hexane) in 91% yield (36.9 mg) as a colorless oil.

Through the purification process, 53.1 mg of pyrrole substrate !-4x was recovered at an

efficiency of 100% [= 53.1 mg/52.7 mg (0.200 mmol)] 1H NMR (500 MHz, CDCl3) % 0.88 (t, J = 7.2 Hz, 6 H), 1.20–1.40 (m, 28 H), 1.48 (s, 9 H), 1.54 (quint, J = 7.6 Hz, 4 H),

2.37 (t, J = 8.0 Hz, 4 H), 6.52 (s, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.1, 22.7, 25.6, 29.4, 29.6, 29.7, 29.9, 30.5, 30.8, 32.0, 54.1, 114.6, 122.2 (One carbon signal is

missing due to overlapping). HRMS (FD) Calcd for C28H53N: M, 403.4178. Found: m/z

403.4204.

1-tert-Butyl-3-(decane-1-yl)-4-(2,2-dimethylpropan-1-yl)-1H-pyrrole (!-4r). The title compound was synthesized with the following reagents based on method A:

for the 0.1-mmol scale reaction: !-4x (73.7 mg, 0.280 mmol), trimethylacetaldehyde (8.61 mg, 0.100 mmol), 3a (17.4 mg, 0.150 mmol), In(ONf)3 (10.1 mg, 10.0 µmol) and

1,4-dioxane (0.17 mL), and was isolated by column chromatography on silica gel

(hexane/EtOAc = 30/1) in 93% yield (31.2 mg) as a colorless oil. Through the purification

process, 42.9 mg of pyrrole substrate !-4x was recovered at an efficiency of 90% [= 42.9

mg/47.4 mg (0.180 mmol)]; for the 5-mmol scale reaction: !-4x (3.69 g, 14.0 mmol),

trimethylacetaldehyde (431 mg, 5.00 mmol), 3a (872 mg, 7.50 mmol), In(ONf)3 (506 mg,

0.500 mmol) and 1,4-dioxane (10.0 mL), and was isolated by column chromatography on

silica gel twice (first: hexane/EtOAc = 30/1; second: hexane/CHCl3 = 10/1) in 90% yield

91

(1.51 g) as a colorless oil. Through the purification process, 2.36 g of pyrrole substrate !-4x was recovered at an efficiency of 99% [= 2.36 g/2.37 g (9.00 mmol)]. 1H NMR (500

MHz, CDCl3) % 0.88 (t, J = 7.2 Hz, 3 H), 0.89 (s, 9 H), 1.21–1.40 (m, 14 H), 1.48 (s, 9

H), 1.51–1.59 (m, 2 H), 2.27 (s, 2 H), 2.36 (t, J = 8.0 Hz, 2 H), 6.49 (d, J = 2.3 Hz, 1 H),

6.51 (d, J = 2.3 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.1, 22.7, 25.8, 29.4, 29.5, 29.64, 29.67, 29.69, 30.0, 30.4, 30.7, 31.89, 31.94, 39.1, 54.0, 113.7, 116.6, 118.8, 123.3.

HRMS (FD) Calcd for C23H43N: M, 333.3396. Found: m/z 333.3412.

1-tert-Butyl-3-cyclohexylmethyl-4-(propan-2-yl)-1H-pyrrole (!-4s). The title compound was synthesized with the following reagents based on method A (0.2-

mmol scale reaction): 1-tert-butyl-3-(propan-2-yl)-1H-pyrrole (!-4g) (132 mg, 0.800 mmol), cyclohexanecarboxaldehyde (22.4 mg, 0.200 mmol), 3a (34.9 mg, 0.300 mmol),

In(ONf)3 (20.2 mg, 20.0 µmol) and 1,4-dioxane (0.35 mL), and was isolated by column

chromatography on silica gel (hexane/CHCl3 = 20/1) in 84% yield (44.1 mg) as a

colorless oil. Through the purification process, 95.3 mg of pyrrole substrate !-4g was recovered at an efficiency of 96% [= 95.3 mg/99.2 mg (0.600 mmol)]. 1H NMR (400

MHz, CDCl3) % 0.90 (qd, J = 11.9, 3.0 Hz, 2 H), 1.12–1.27 (m, 3 H), 1.18 (d, J = 6.9 Hz, 6 H), 1.36–1.45 (m, 1 H), 1.48 (s, 9 H), 1.60–1.73 (m, 3 H), 1.75–1.82 (m, 2 H), 2.29 (d,

J = 6.9 Hz, 2 H), 2.80 (sept, J = 6.8 Hz, 1 H), 6.47 (d, J = 2.8 Hz, 1 H), 6.50 (d, J = 2.8

Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 24.4, 25.2, 26.5, 26.8, 30.7, 33.6, 33.7, 38.9, 54.1, 112.6, 115.5, 119.5, 129.3. HRMS (FI) Calcd for C18H31N: M, 261.2457.

Found: m/z 261.2460.

1-tert-Butyl-3-(propan-2-yl)-4-(3-thienylmethyl)-1H-pyrrole (!-4t). The title compound was synthesized with the following reagents based on method A (0.2-

mmol scale reaction): !-4g (132 mg, 0.800 mmol), 3-thiophenecarboxaldehyde (22.4 mg,

0.200 mmol), 3a (34.9 mg, 0.300 mmol), In(ONf)3 (20.2 mg, 20.0 µmol) and 1,4-dioxane

(0.35 mL), and was isolated by column chromatography on silica gel (hexane/CHCl3 =

20/1) in 73% yield (38.3 mg) as a white solid; mp 78–79 ºC. Through the purification

process, 91.6 mg of pyrrole substrate !-4g was recovered at an efficiency of 92% [= 91.6

mg/99.2 mg (0.600 mmol)]. 1H NMR (400 MHz, CDCl3) % 1.15 (d, J = 6.9 Hz, 6 H), 1.46 (s, 9 H), 2.78 (septd, J = 6.8, 0.6 Hz, 1 H), 3.80 (t, J = 1.0 Hz, 2 H), 6.42 (dt, J = 2.6, 0.7

Hz, 1 H), 6.54 (dd, J = 2.6, 0.7 Hz, 1 H), 6.90–6.94 (m, 1 H), 6.97 (dd, J = 4.9, 1.3 Hz, 1

H), 7.22 (dd, J = 4.9, 3.0 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 24.0, 25.3, 26.7, 30.7, 54.3, 113.1, 115.9, 119.5, 120.6, 124.8, 128.8, 129.0, 142.9. HRMS (FI) Calcd for

92

C16H23NS: M, 261.1551. Found: m/z 261.1557.

2-Decyl-1-methyl-1H-pyrrole (#-4u). The title compound was synthesized with the following reagents based on method A (1.2-mmol scale reaction): 1a (389 mg,

4.80 mmol), 6b (188 mg, 1.20 mmol), 3a (209 mg, 1.80 mmol), In(ONf)3 (121 mg, 0.121

mmol) and 1,4-dioxane (2.0 mL). Column chromatography on silica gel (hexane/EtOAc

= 50/1) of the resulting crude reaction mixture provided a mixture of #-4u and !-4u

(82:18) in 36% yield (97.4 mg), which was then separated by recycling GPC to give pure

#-4u as a colorless oil. 1H NMR (500 MHz, CDCl3) % 0.88 (t, J = 7.0 Hz, 3 H), 1.19–1.44 (m, 14 H), 1.62 (quint, J = 7.6 Hz, 2 H), 2.51 (t, J = 7.6 Hz, 2 H), 3.52 (s, 3 H), 5.84–5.90

(m, 1 H), 6.04 (t, J = 3.0 Hz, 1 H), 6.53 (t, J = 2.3 Hz, 1 H); 13C{1H} NMR (125 MHz,

CDCl3) % 14.1, 22.7, 26.3, 28.9, 29.3, 29.50, 29.55, 29.62, 29.63, 31.9, 33.5, 105.3, 106.4, 120.9, 133.8. HRMS (FI) Calcd for C15H27N: M, 221.2143. Found: m/z 221.2143.

3-Decyl-1-methyl-1H-pyrrole (!-4u). The title compound was synthesized and purified in the same way as the above, and was obtained as a colorless oil. 1H NMR

(500 MHz, CDCl3) % 0.88 (t, J = 7.0 Hz, 3 H), 1.22–1.36 (m, 14 H), 1.49–1.55 (m, 2 H),

2.43 (t, J = 7.7 Hz, 2 H), 3.59 (s, 3 H), 5.97 (t, J = 2.2 Hz, 1 H), 6.37 (t, J = 2.0 Hz, 1 H),

6.50 (t, J = 2.3 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.1, 22.7, 27.1, 29.4, 29.6, 29.67, 29.72, 31.4, 31.9, 36.0, 108.2, 119.0, 121.3, 125.0 (One carbon signal is missing

due to overlapping). HRMS (FI) Calcd for C15H27N: M, 221.2143. Found: m/z 221.2136.

A Mixture of 2-(Decan-2-yl)-1H-pyrrole (#-7a) and 3-(Decan-2-yl)-1H-pyrrole (!-7a). The mixture was synthesized with the following reagents based on

method A: pyrrole (1c) (60.4 mg, 0.900 mmol), 6a (46.9 mg, 0.300 mmol), 3a (52.3 mg,

0.450 mmol), In(NTf2)3 (28.7 mg, 30.0 µmol) and 1,4-dioxane (0.50 mL), and was

isolated by column chromatography on silica gel (hexane/EtOAc = 30/1) in 28% yield

(17.9 mg, #-7a:!-7a = 46:54). The two isomers, #-7a and !-7a, have already appeared in reference 14, and their spectral and analytical data are in good agreement with those

reported in the literature.

3-(Decan-1-yl)-1-(2-phenylpropan-2-yl)-1H-pyrrole (!-4w). The title compound was synthesized with the following reagents based on method A (10-mmol

scale reaction): 1-(2-phenylpropan-2-yl)-1H-pyrrole (7.41 g, 40.0 mmol), 6b (1.56 g, 10.0

mmol), 3a (1.74 g, 15.0 mmol), In(ONf)3 (1.01 g, 1.00 mmol) and 1,4-dioxane (16.7 mL),

and was isolated by column chromatography on silica gel (hexane/EtOAc = 70/1) in 53%

yield (1.75 g). The corresponding 0.3-mmol scale reaction has been already reported in

93

the previous communication, and its spectral and analytical data are collected in reference

15. Therefore, only 1H NMR data are provided here. 1H NMR (500 MHz, CDCl3) % 0.88 (t, J = 7.2 Hz, 3 H), 1.21–1.37 (m, 14 H), 1.56 (quint, J = 7.3 Hz, 2 H), 1.86 (s, 6 H), 2.45

(t, J = 7.7 Hz, 2 H), 6.03 (t, J = 2.3 Hz, 1 H), 6.53 (t, J = 2.0 Hz, 1 H), 6.70 (t, J = 2.6 Hz,

1 H), 6.95–6.99 (m, 2 H), 7.21 (tt, J = 7.5, 1.6 Hz, 1 H), 7.24–7.29 (m, 2 H).

1-tert-Butyl-3-decyl-1H-pyrrole (!-4x). The title compound was synthesized

with the following reagents based on method A (25-mmol scale reaction): 1-tert-butylpyrrole (12.3 g, 100 mmol), 6b (3.91 g, 25.0 mmol), 3a (4.36 g, 37.5 mmol),

In(ONf)3 (2.53 g, 2.50 mmol) and 1,4-dioxane (42.0 mL), and was isolated by column

chromatography on silica gel (hexane/EtOAc = 30/1) in 60% yield (3.96 g). The

corresponding 0.3-mmol scale reaction has been already reported in the previous

communication, and its spectral and analytical data are collected in reference 15.

Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) % 0.88 (t, J = 6.9 Hz, 3 H), 1.20–1.39 (m, 14 H), 1.44–1.61 (m, 2 H), 1.50 (s, 9 H), 2.44 (t, J = 7.8

Hz, 2 H), 5.99 (t, J = 2.3 Hz, 1 H), 6.59 (t, J = 2.1 Hz, 1 H), 6.73 (t, J = 2.5 Hz, 1 H).

Indium-Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles; A General Procedure for Table 3. The experimental

procedure performed on a 0.3-mmol scale based on carbonyl compound 6 is shown here

as a representative. In(NTf2)3 [(43.0 mg, 45.0 µmol) or (57.3 mg, 60.0 µmol)], In(OTf)3

[(25.3 mg, 45.0 µmol), (33.7 mg, 60.0 µmol) or (42.2 mg, 90.0 µmol)] or In(ONf)3 (60.7

mg, 60.0 µmol) was placed in a 20 mL Schlenk tube, which was heated at 150 ºC in vacuo

for 2 h. The tube was cooled down to room temperature and filled with argon. 1,4-

Dioxane (0.30, 0.84 or 2.4 mL) was added to the tube, and the mixture was then stirred

at room temperature for 10 min. To this were added carbonyl compound 6 (0.300 mmol),

pyrrole derivative 1 (1.20 mmol), and the resulting mixture was stirred at 85 °C for 1 or

3 h. Carbon nucleophile 3 (0.0900, 0.450, 0.750, 0.900 or 1.50 mmol) was then added to

this solution, and the resulting mixture was stirred further at T ºC. After stirring for t h,

the work-up process was carried out in the same way as in the reaction with 3a as a

nucleophile. Unless otherwise noted, new products !-8 synthesized here were fully characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS.

5-Acetyloxy-2-methyl-2-(1-methyl-1H-pyrrol-3-yl)pentanenitrile (!-8a). The title compound was synthesized with the following reagents (0.25-mmol scale

reaction): 1-methylpyrrole (1a) (81.1 mg, 1.00 mmol), 5-acetyloxy-2-pentanone (36.0 mg,

94

0.250 mmol), Me3SiCN (3b) (37.2 mg, 0.375 mmol), In(OTf)3 (21.1 mg, 37.5 µmol) and

1,4-dioxane (0.25 mL), and was isolated by column chromatography on silica gel

(hexane/EtOAc = 3/1) in 71% yield (42.0 mg) as a colorless oil. 1H NMR (500 MHz,

CDCl3) % 1.64 (s, 3 H), 1.65–1.94 (m, 4 H), 2.04 (s, 3 H), 3.63 (s, 3 H), 4.05 (t, J = 6.3 Hz, 2 H), 6.02 (dd, J = 2.9, 1.7 Hz, 1 H), 6.56 (t, J = 2.9 Hz, 1 H), 6.62 (t, J = 1.8 Hz, 1

H); 13C{1H} NMR (125 MHz, CDCl3) % 20.9, 25.0, 27.8, 36.1, 36.3, 38.6, 63.9, 105.3,

118.9, 122.6, 124.08, 124.12, 171.1. HRMS (FI) Calcd for C13H18N2O2: M, 234.1368.

Found: m/z 234.1369.

Tetrahydro-4-(1-methyl-1H-pyrrol-3-yl)-2H-thiopyran-4-carbonitrile (!-8b). The title compound was synthesized with the following reagents (0.25-mmol scale

reaction): 1a (81.1 mg, 1.00 mmol), tetrahydro-4H-thiopyran-4-one (29.0 mg, 0.250

mmol), 3b (37.2 mg, 0.375 mmol), In(OTf)3 (28.1 mg, 50.0 µmol) and 1,4-dioxane (0.25

mL), and was isolated by column chromatography on silica gel (hexane/EtOAc = 5/1) in

65% yield (33.5 mg) as a white solid; mp 73–74 ºC. 1H NMR (500 MHz, CDCl3) % 2.04 (ddd, J = 13.9, 12.7, 3.3 Hz, 2 H), 2.38–2.44 (m, 2 H), 2.59–2.70 (m, 2 H), 3.13 (ddd, J

= 14.6, 12.3, 2.3 Hz, 2 H), 3.64 (s, 3 H), 6.10 (t, J = 2.6 Hz, 1 H), 6.57 (t, J = 2.6 Hz, 1

H), 6.63 (t, J = 2.0 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 25.7, 36.3, 38.0, 38.6, 105.5, 118.2, 122.3, 122.5, 125.3. HRMS (FI) Calcd for C11H14N2S: M, 206.0878. Found:

m/z 206.0873.

2-(1-Methyl-1H-pyrrol-3-yl)adamantane-2-carbonitrile (!-8c). The title compound was synthesized with the following reagents (0.25-mmol scale reaction): 1a

(81.1 mg, 1.00 mmol), 2-adamantanone (37.6 mg, 0.250 mmol), 3b (37.2 mg, 0.375

mmol), In(OTf)3 (21.1 mg, 37.5 µmol) and 1,4-dioxane (0.25 mL), and was isolated by

column chromatography on silica gel (hexane/EtOAc = 7/1) in 84% yield (50.6 mg).

Compound !-8c has already appeared in reference 44, and its spectral and analytical data are in good agreement with those reported in the literature. Therefore, only 1H NMR data

are provided here. 1H NMR (500 MHz, CDCl3) % 1.61 (ddd, J = 13.0, 3.8, 2.6 Hz, 2 H),

1.69–1.79 (m, 3 H), 1.92 (ddd, J = 13.4, 3.6, 2.7 Hz, 2 H), 1.97–2.06 (m, 3 H), 2.41 (dd,

J = 13.1, 2.1 Hz, 2 H), 2.46 (t, J = 2.7 Hz, 2 H), 3.64 (s, 3 H), 6.10 (dd, J = 2.8, 2.0 Hz, 1

H), 6.55 (t, J = 2.0 Hz, 1 H), 6.57 (t, J = 2.5 Hz, 1 H).

2-(1-Methyl-1H-pyrrol-3-yl)-2-phenylpropanenitrile (!-8d). The title compound was synthesized with the following reagents: 1a (97.3 mg, 1.20 mmol),

acetophenone (36.0 mg, 0.300 mmol), 3b (44.6 mg, 0.450 mmol), In(NTf2)3 (57.3 mg,

95

60.0 µmol) and 1,4-dioxane (0.30 mL), and was isolated by column chromatography on

silica gel (hexane/EtOAc = 10/1) in 71% yield (44.8 mg) as a colorless oil. 1H NMR (500

MHz, CDCl3) % 2.00 (s, 3 H), 3.62 (s, 3 H), 6.04 (dd, J = 2.9, 1.7 Hz, 1 H), 6.52 (t, J =

2.0 Hz, 1 H), 6.56 (t, J = 2.6 Hz, 1 H), 7.28 (tt, J = 7.5, 1.5 Hz, 1 H), 7.35 (tt, J = 7.5, 1.8

Hz, 2 H), 7.44–7.49 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 29.0, 36.3, 40.9, 107.1, 119.7, 122.6, 124.0, 125.1, 126.1, 127.5, 128.6, 142.3. HRMS (FI) Calcd for C14H14N2:

M, 210.1157. Found: m/z 210.1153.

2-(1-Benzyl-1H-pyrrol-3-yl)-2-propylpentanenitrile (!-8e). The title compound was synthesized with the following reagents (3-mmol scale reaction): 1-

benzylpyrrole (1.89 g, 12.0 mmol), 4-heptanone (343 mg, 3.00 mmol), 3b (446 mg, 4.50

mmol), In(NTf2)3 (573 mg, 0.600 mmol) and 1,4-dioxane (3.0 mL), and was isolated by

column chromatography on silica gel (hexane/EtOAc = 20/1) in 73% yield (618 mg) as a

reddish oil. 1H NMR (500 MHz, CDCl3) % 0.90 (t, J = 7.4 Hz, 6 H), 1.23–1.39 (m, 2 H), 1.41–1.54 (m, 2 H), 1.65–1.74 (m, 2 H), 1.79–1.88 (m, 2 H), 5.02 (s, 2 H), 6.00 (t, J = 2.3

Hz, 1 H), 6.63 (t, J = 2.6 Hz, 1 H), 6.69 (t, J = 1.7 Hz, 1 H), 7.08 (d, J = 6.9 Hz, 2 H),

7.27–7.38 (m, 3 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.0, 18.6, 42.0, 43.0, 53.4, 105.6, 119.2, 122.0, 123.4, 123.7, 126.8, 127.7, 128.7, 137.9. HRMS (FI) Calcd for

C19H24N2: M, 280.1939. Found: m/z 280.1937.

2-(1-tert-Butyl-1H-pyrrol-3-yl)-2-methyloctanenitrile (!-8f). The title compound was synthesized with the following reagents: 1-tert-butylpyrrole (148 mg,

1.20 mmol), 2-octanone (38.5 mg, 0.300 mmol), 3b (44.6 mg, 0.450 mmol), In(NTf2)3


chromatography on silica gel (hexane/EtOAc = 10/1) in 87% yield (68.7 mg) as a

colorless oil. 1H NMR (500 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.21–1.50 (m, 8 H),

1.51 (s, 9 H), 1.62 (s, 3 H), 1.73–1.82 (m, 2 H), 6.02 (dd, J = 2.9, 1.7 Hz, 1 H), 6.77 (t, J

= 2.6 Hz, 1 H), 6.80 (t, J = 2.3 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 14.1, 22.6, 25.4, 27.6, 29.1, 30.7, 31.6, 36.5, 42.2, 54.9, 104.5, 114.7, 118.2, 124.1, 124.8. HRMS

(FI) Calcd for C17H28N2: M, 260.2252. Found: m/z 260.2252.

2-Methyl-2-(1-phenyl-1H-pyrrol-3-yl)octanenitrile (!-8g). The title compound was synthesized with the following reagents: 1-phenylpyrrole (172 mg, 1.20

mmol), 2-octanone (38.5 mg, 0.300 mmol), 3b (44.6 mg, 0.450 mmol), In(NTf2)3 (57.3

mg, 60.0 µmol) and 1,4-dioxane (0.30 mL), and was isolated by column chromatography

on silica gel (hexane/EtOAc = 10/1) in 75% yield (63.3 mg) as a colorless oil. 1H NMR

96

(500 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.23–1.57 (m, 8 H), 1.68 (s, 3 H), 1.79–1.89 (m, 2 H), 6.25 (dd, J = 2.9, 1.7 Hz, 1 H), 7.05 (t, J = 2.9 Hz, 1 H), 7.09 (t, J = 2.0

Hz, 1 H), 7.24–7.29 (m, 1 H), 7.38 (dt, J = 7.5, 1.4 Hz, 2 H), 7.43 (tt, J = 8.0, 1.8 Hz, 2

H); 13C{1H} NMR (125 MHz, CDCl3) % 14.1, 22.6, 25.5, 27.5, 29.1, 31.6, 36.5, 41.9, 107.7, 116.3, 120.0, 120.3, 124.3, 125.9, 127.0, 129.6, 140.3. HRMS (FI) Calcd for

C19H24N2: M, 280.1939. Found: m/z 280.1940.

2-(1-Benzyl-1H-pyrrol-3-yl)-2-(5-methylfuran-2-yl)octane (!-8h). The title compound was synthesized with the following reagents: 1-benzylpyrrole (189 mg, 1.20

mmol), 2-octanone (38.5 mg, 0.300 mmol), 2-methylfuran (3c) (61.6 mg, 0.750 mmol),

In(NTf2)3 (43.0 mg, 45.0 µmol) and 1,4-dioxane (2.4 mL), and was isolated by recycling

GPC after column chromatography on silica gel (hexane/EtOAc = 10/1) in 72% yield

(76.0 mg). Compound !-8h has already appeared in reference 18, and its spectral and

analytical data are in good agreement with those reported in the literature. Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) % 0.85 (t, J = 6.8 Hz, 3 H), 1.07–1.35 (m, 8 H), 1.51 (s, 3 H), 1.76–1.87 (m, 1 H), 1.89–2.01 (m, 1 H), 2.24 (d, J =

0.9 Hz, 3 H), 5.00 (s, 2 H), 5.81 (dq, J = 3.0, 1.0 Hz, 1 H), 5.85 (d, J = 3.0 Hz, 1 H), 6.06

(dd, J = 2.7, 1.8 Hz, 1 H), 6.45 (t, J = 2.0 Hz, 1 H), 6.56 (t, J = 2.5 Hz, 1 H), 7.04–7.10

(m, 2 H), 7.22–7.34 (m, 3 H).

1-(1-tert-Butyl-1H-pyrrol-3-yl)-2,2-dimethyl-1-(5-methylfuran-2-

yl)propane (!-8i). The title compound was synthesized with the following reagents: 1-tert-butylpyrrole (148 mg, 1.20 mmol), pivalaldehyde (25.8 mg, 0.300 mmol), 3c (61.6

mg, 0.750 mmol), In(ONf)3 (60.7 mg, 60.0 µmol) and 1,4-dioxane (2.4 mL), and was

isolated by column chromatography on silica gel (hexane/CHCl3 = 6/1) in 75% yield

(62.1 mg) as a white solid; mp 46–47 ºC. 1H NMR (400 MHz, CDCl3) % 0.91 (s, 9 H),

1.49 (s, 9 H), 2.26 (d, J = 1.2 Hz, 3 H), 3.58 (s, 1 H), 5.82 (dq, J = 3.0, 1.0 Hz, 1 H), 5.94

(d, J = 3.0 Hz, 1 H), 6.13 (t, J = 2.4 Hz, 1 H), 6.66–6.70 (m, 2 H); 13C{1H} NMR (125

MHz, CDCl3) % 13.7, 28.4, 30.7, 34.7, 49.6, 54.2, 105.5, 106.7, 109.0, 116.1, 116.9, 121.7,

149.4, 156.3. HRMS (FI) Calcd for C18H27NO: M, 273.2093. Found: m/z 273.2119.

2-(1-Methyl-1H-indol-3-yl)-2-(1-methyl-1H-pyrrol-3-yl)adamantane (!-8j). The title compound was synthesized with the following reagents: 1a (97.3 mg, 1.20

mmol), 2-adamantanone (45.1 mg, 0.300 mmol), 1-methylindole (3d) (197 mg, 1.50



97

a viscous colorless oil. 1H NMR (500 MHz, CDCl3) % 1.64–1.84 (m, 8 H), 2.25 (d, J = 11.7 Hz, 2 H), 2.35 (ddd, J = 12.8, 4.9, 3.2 Hz, 2 H), 3.04 (s, 2 H), 3.48 (s, 3 H), 3.67 (s,

3 H), 6.05 (dd, J = 2.7, 1.9 Hz, 1 H), 6.34 (t, J = 2.5 Hz, 1 H), 6.47 (t, J = 2.0 Hz, 1 H),

6.87 (s, 1 H), 7.00 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.10 (ddd, J = 8.8, 6.5, 1.0 Hz, 1 H),

7.17 (dt, J = 8.1, 0.9 Hz, 1 H), 7.86 (dt, J = 8.0, 0.9 Hz, 1 H); 13C{1H} NMR (125 MHz,

CDCl3) % 14.2, 27.8, 27.9, 32.7, 33.8, 33.9, 34.2, 36.1, 38.7, 45.1, 106.0, 109.1, 117.9,

118.1, 120.36, 120.38, 121.4, 124.2, 126.0, 126.1, 133.4, 137.1. HRMS (FD) Calcd for

C24H28N2: M, 344.2252. Found: m/z 344.2245.

5-[1-Methyl-1-(1-methyl-1H-pyrrol-3-yl)ethyl]-2(5H)-furanone (!-8k). The title compound was synthesized with the following reagents: 1a (97.3 mg, 1.20

mmol), acetone (17.4 mg, 0.300 mmol), 2-(trimethylsilyloxy)furan (3e) (117 mg, 0.750


column chromatography on silica gel (hexane/EtOAc = 3/1) in 45% yield (28.0 mg) as a

white solid; mp 73–74 ºC. 1H NMR (500 MHz, CDCl3) % 1.18 (s, 3 H), 1.41 (s, 3 H), 3.62 (s, 3 H), 4.94 (dd, J = 2.0, 1.4 Hz, 1 H), 6.02 (dd, J = 2.7, 1.9 Hz, 1 H), 6.05 (dd, J = 5.7,

2.0 Hz, 1 H), 6.44 (t, J = 2.2 Hz, 1 H), 6.54 (t, J = 2.4 Hz, 1 H), 7.28 (dd, J = 5.9, 1.6 Hz,

1 H); 13C{1H} NMR (125 MHz, CDCl3) % 22.4, 26.8, 36.2, 37.7, 91.0, 106.5, 118.7, 121.8, 122.2, 128.2, 155.4, 173.7. HRMS (FD) Calcd for C12H15NO2: M, 205.1103. Found: m/z

205.1099.

4-Methyl-4-(1-methyl-1H-pyrrol-3-yl)dec-1-ene (!-8m). The title compound was synthesized with the following reagents (0.25 mmol-scale reaction): 1a (81.1 mg,

1.00 mmol), 2-octanone (32.1 mg, 0.250 mmol), tetraallyltin (3g) (21.2 mg, 75.0 µmol),

In(OTf)3 (35.1 mg, 62.5 µmol) and 1,4-dioxane (0.70 mL), and was isolated by column

chromatography on silica gel (hexane/EtOAc = 20/1) in 21% yield (12.7 mg). Compound

!-8m has already appeared in reference 18, and its spectral and analytical data are in good agreement with those reported in the literature. Therefore, only 1H NMR data are

provided here. 1H NMR (500 MHz, CDCl3) % 0.86 (t, J = 7.2 Hz, 3 H), 1.14 (s, 3 H),

1.15–1.30 (m, 8 H), 1.39–1.53 (m, 2 H), 2.19–2.33 (m, 2 H), 3.60 (s, 3 H), 4.93–5.02 (m,

2 H), 5.72 (ddt, J = 17.2, 9.8, 7.9 Hz, 1 H), 5.97 (t, J = 2.3 Hz, 1 H), 6.32 (t, J = 2.0 Hz,

1 H), 6.51 (t, J = 2.6 Hz, 1 H).

N-Deprotection of N-Substituted !-Alkylpyrroles; A Procedure for Scheme 4, (i).22 A flame-dried 20 mL Schlenk tube was filled with argon, and then charged with

anhydrous N,N-dimethylformamide (DMF) (0.70 mL), !-4h (31.3 mg, 0.100 mmol) or

98

!-4i (37.6 mg, 0.100 mmol), and a 55% dispersion of sodium hydride (13.1 mg, 0.300 mmol) in paraffin oil. The resulting mixture was stirred at room temperature for 6 h (for

the case of !-4h) or 4 h (for the case of !-4i) followed by dilution with Et2O (5 mL). The

organic phase was washed with water (5 mL x 4) and brine (5 mL), and then dried over


chromatography on silica gel (hexane/EtOAc = 15/1 for the case of !-4h or

hexane/EtOAc/Et3N = 100/6/1 for the case of !-4i) gave 3-(decan-2-yl)-1H-pyrrole (!-7a) in 65% yield (13.6 mg) for the case of !-4h or in 87% yield (18.1 mg) for the case of

!-4i. Compound !-7a has already appeared in reference 14, and its spectral and analytical

data are in good agreement with those reported in the literature. Therefore, only 1H NMR

data are provided here. 1H NMR (400 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.20 (d, J = 6.9 Hz, 3 H), 1.21–1.34 (m, 12 H), 1.39–1.61 (m, 2 H), 2.65 (sext, J = 6.9 Hz, 1 H),

6.11 (dt, J = 2.7, 1.5 Hz, 1 H), 6.56 (q, J = 1.7 Hz, 1 H), 6.73 (q, J = 2.4 Hz, 1 H), 7.97

(bs, 1 H).

N-Deprotection of N-Substituted !-Alkylpyrroles; A Procedure for Scheme

4, (ii).23b The experimental procedure for the synthesis of !-7a is shown here as a representative. tert-BuOK (29.2 mg, 0.260 mmol) was placed in a 20 mL Schlenk tube,

which was heated at 80 ºC in vacuo for 30 min. The tube was cooled down to room

temperature and filled with argon. To this were added THF (1.00 mL), and !-4j (16.0 mg,

0.0520 mmol) or !-4k (16.7 mg, 0.0520 mmol), and the resulting mixture was stirred at room temperature for 30 min. A saturated NH4Cl aqueous solution (1 mL) was added to

the mixture, and the aqueous phase was extracted with EtOAc (5 mL x 3). The combined

organic layer was washed with brine (1 mL) and then dried over anhydrous sodium sulfate.

Filtration and evaporation of the solvent followed by column chromatography on silica

gel (hexane/EtOAc/Et3N = 100:6:3) gave 3-(decan-2-yl)-1H-pyrrole (!-7a) in 54% yield

(5.90 mg) for the case of !-4j or in 82% yield (8.90 mg) for the case of !-4k. As described

in the above section, the spectral and analytical data of !-7a are shown in reference 14.

3-Cyclopentyl-1H-pyrrole (!-7b). The title compound was synthesized with

the following reagents (0.1-mmol scale reaction): !-4l (26.3 mg, 0.100 mmol), tert-BuOK (56.1 mg, 0.500 mmol) and THF (1.9 mL), and was isolated by column chromatography

on silica gel (hexane/EtOAc/Et3N = 100/6/3) in 66% yield (9.00 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) % 1.46–1.55 (m, 2 H), 1.58–1.80 (m, 4 H), 1.94–2.07 (m, 2 H), 2.93 (tt, J = 9.2, 7.4 Hz, 1 H), 6.13 (td, J = 2.7, 1.6 Hz, 1 H) 6.57–6.62 (m, 1 H), 6.73

99

(td, J = 2.6, 2.1 Hz, 1 H), 7.98 (bs, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 25.1, 34.5, 38.2, 107.5, 113.9, 117.7, 129.0. HRMS (FI) Calcd for C9H13N: M, 135.1048. Found: m/z

135.1024.

Indium-Catalyzed Synthesis of Diaryldipyrrolylmethanes; A General Procedure for Table 4. The experimental procedure performed on a 0.4-mmol scale

based on diaryl ketone 6 is shown here as a representative. In(NTf2)3 [(38.2 mg, 40.0

µmol) or (76.4 mg, 80.0 µmol)] was placed in a 20 mL Schlenk tube, which was heated

at 150 ºC in vacuo for 2 h. The tube was cooled down to room temperature and filled with

argon. 1,4-Dioxane (0.40 mL) was added to the tube, and the mixture was then stirred at

room temperature for 10 min. To this were added diaryl ketone 6 (0.400 mmol), pyrrole

derivative 1 (1.60 or 2.00 mmol), and the resulting mixture was stirred at T °C. After

stirring for t h, a saturated NaHCO3 aqueous solution (0.3 mL) was added, and the



evaporation of the solvent followed by purification gave the corresponding products (5).

Unless otherwise noted, products 5 synthesized here were fully characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS.

(4-Methylphenyl)(1-methyl-1H-pyrrol-2-yl)(1-methyl-1H-pyrrol-3-

yl)phenylmethane (#,!’-5a). The title compound was synthesized with the following reagents: 1-methylpyrrole (1a) (162 mg, 2.00 mmol), 4-methylbenzophenone (6c) (78.5

mg, 0.400 mmol), In(NTf2)3 (76.4 mg, 80.0 µmol) and 1,4-dioxane (0.40 mL). Column

chromatography on silica gel (hexane/CHCl3 = 3/1) of the resulting crude reaction

mixture provided a mixture of #,!’-5a and !,!’-5a (13:87) in 53% yield (72.7 mg). In the

course of the purification, some fractions including pure #,!’-5a were collected.

Accordingly, #,!’-5a as a viscous colorless oil could be characterized by 1H and 13C{1H}

NMR spectroscopy, and HRMS. 1H NMR (400 MHz, CDCl3) % 2.32 (s, 3 H), 2.95 (s, 3 H), 3.58 (s, 3 H), 5.59 (dd, J = 3.7, 2.3 Hz, 1 H), 5.80 (t, J = 2.3 Hz, 1 H), 6.01 (dd, J =

3.7, 2.7 Hz, 1 H), 6.22 (t, J = 2.1 Hz, 1 H), 6.54 (t, J = 2.5 Hz, 1 H), 6.59 (t, J = 2.3 Hz,

1 H), 7.02–7.10 (m, 4 H), 7.15–7.25 (m, 5 H); 13C{1H} NMR (125 MHz, CDCl3) % 20.9, 36.2, 36.4, 54.3, 105.4, 111.0, 111.1, 121.3, 121.8, 123.2, 125.8, 127.3, 128.1, 129.7,

129.8, 135.3, 139.2, 144.1, 147.3 (one carbon signal is missing due to overlapping).

HRMS (FD) Calcd for C24H24N2: M, 340.1939. Found: m/z 340.1929.

(4-Methylphenyl)bis(1-methyl-1H-pyrrol-3-yl)phenylmethane (!,!’-5a).

100

The title compound was synthesized and purified in the same way as the above, and was

obtained as a white solid; mp 108–109 ºC. 1H NMR (400 MHz, CDCl3) % 2.32 (s, 3 H), 3.55 (s, 6 H), 5.96 (dd, J = 2.8, 1.8 Hz, 2 H), 6.16 (t, J = 2.1 Hz, 2 H), 6.53 (t, J = 2.5 Hz,

2 H), 7.02 (d, J = 8.0 Hz, 2 H), 7.13 (dt, J = 8.2, 1.8 Hz, 2 H), 7.15–7.27 (m, 5 H); 13C{1H}

NMR (100 MHz, CDCl3) % 20.9, 36.1, 53.7, 111.0, 120.9, 122.1, 125.4, 127.0, 127.7, 129.7, 129.8, 132.2, 134.8, 146.4, 149.5. HRMS (FD) Calcd for C24H24N2: M, 340.1939.

Found: m/z 340.1969.

(4-Methylphenyl)bis(1-methyl-1H-pyrrol-2-yl)phenylmethane (#,#’-5a). The title compound was formed as a minor isomer in the reaction performed with the

intention of synthesizing 5a (#,#’-5a:#,!’-5a:!,!’-5a = 1:15:84). However, in the case

of 0.4-mmol scale reaction of 6c, pure #,#’-5a could not be obtained in an amount that is required for measuring NMR spectra. Accordingly, a larger-scale reaction using In(OTf)3

instead of In(NTf2)3 was carried out with the following reagents and conditions: 1a (487

mg, 6.00 mmol), 6c (235 mg, 1.20 mmol), In(OTf)3 (135 mg, 0.240 mmol), 1,4-dioxane

(1.20 mL), 100 ºC, 2.5 h, and was isolated by recycling GPC after column

chromatography on silica gel (hexane/CHCl3 = 3/1) in 2% yield (11.9 mg) as a viscous

colorless oil. 1H NMR (400 MHz, CDCl3) % 2.32 (s, 3 H), 2.88 (s, 6 H), 5.84 (s, 2 H), 6.03 (dd, J = 3.6, 2.8 Hz, 2 H), 6.61 (t, J = 2.3 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 2 H), 7.06

(d, J = 8.2 Hz, 2 H), 7.09 (d, J = 7.1 Hz, 2 H), 7.19 (tt, J = 6.9, 2.0 Hz, 1 H), 7.22–7.28

(m, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 21.0, 35.7, 55.2, 105.8, 111.8, 123.9, 126.3, 127.6, 128.3, 129.7, 129.8, 135.9 (three carbon signals are missing due to overlapping).

HRMS (FD) Calcd for C24H24N2: M, 340.1939. Found: m/z 340.1947.

(3-Methylphenyl)(4-methylphenyl)(1-methyl-1H-pyrrol-2-yl)(1-methyl-

1H-pyrrol-3-yl)methane (#,!’-5b). The title compound was synthesized with the

following reagents (10-mmol scale reaction): 1a (4.06 g, 50.0 mmol), 3,4’-

dimethylbenzophenone (2.10 g, 10.0 mmol), In(NTf2)3 (1.91 g, 2.00 mmol) and 1,4-

dioxane (10.0 mL). Column chromatography on silica gel (hexane/CHCl3 = 3/2) of the

resulting crude reaction mixture provided a mixture of #,!’-5b and !,!’-5b (15:85) in

50% yield (1.78 g). In the course of the purification, some fractions including pure #,!’-5b were collected. Accordingly, #,!’-5b as a viscous colorless oil could be characterized

by 1H and 13C{1H} NMR spectroscopy, and HRMS. 1H NMR (500 MHz, CDCl3) % 2.27 (s, 3 H), 2.32 (s, 3 H), 2.95 (s, 3 H), 3.58 (s, 3 H), 5.58 (dd, J = 3.5, 1.7 Hz, 1 H), 5.79 (t,

J = 2.3 Hz, 1 H), 6.01 (t, J = 3.2 Hz, 1 H), 6.21 (t, J = 2.0 Hz, 1 H), 6.53 (t, J = 2.6 Hz, 1

101

H), 6.58 (t, J = 2.3 Hz, 1 H), 6.96–7.01 (m, 2 H), 7.02–7.09 (m, 5 H), 7.12 (t, J = 7.7 Hz,

1 H); 13C{1H} NMR (125 MHz, CDCl3) % 21.0, 21.7, 36.2, 36.4, 54.3, 105.4, 110.9, 111.2, 121.2, 121.8, 123.2, 126.6, 127.0, 127.2, 128.0, 129.66, 129.69, 130.3, 135.2, 136.7,

139.3, 144.3, 147.1. HRMS (FD) Calcd for C25H26N2: M, 354.2096. Found: m/z 354.2118.

(3-Methylphenyl)(4-methylphenyl)bis(1-methyl-1H-pyrrol-3-yl)methane

(!,!’-5b). The title compound was synthesized and purified in the same way as the above,

and was obtained as a white solid; mp 122–123 ºC. 1H NMR (500 MHz, CDCl3) % 2.26 (s, 3 H), 2.31 (s, 3 H), 3.54 (s, 6 H), 5.96 (t, J = 2.3 Hz, 2 H), 6.15 (t, J = 2.3 Hz, 2 H),

6.53 (t, J = 2.6 Hz, 2 H), 6.98 (d, J = 6.9 Hz, 1 H), 7.00–7.05 (m, 3 H), 7.08–7.14 (m, 4

H); 13C{1H} NMR (125 MHz, CDCl3) % 20.9, 21.7, 36.1, 53.7, 111.0, 120.9, 122.1, 126.2, 126.8, 127.1, 127.7, 129.7, 130.4, 132.2, 134.7, 136.3, 146.5, 149.4. HRMS (FD) Calcd

for C25H26N2: M, 354.2096. Found: m/z 354.2125.

(1-Methyl-1H-pyrrol-2-yl)(1-methyl-1H-pyrrol-3-yl)(2-

naphthyl)phenylmethane (#,!’-5c). The title compound was synthesized with the following reagents: 1a (162 mg, 2.00 mmol), 2-benzoylnaphthalene (92.9 mg, 0.400

mmol), In(NTf2)3 (76.4 mg, 80.0 µmol) and 1,4-dioxane (0.40 mL). Column


mixture provided a mixture of #,!’-5c and !,!’-5c (8:92) in 48% yield (73.4 mg). In the

course of the purification, some fractions including pure #,!’-5c were collected.

Accordingly, #,!’-5c as a viscous colorless oil could be characterized by 1H and 13C{1H}

NMR spectroscopy, and HRMS. 1H NMR (500 MHz, CDCl3) % 2.98 (s, 3 H), 3.59 (s, 3

H), 5.66 (dd, J = 3.5, 2.3 Hz, 1 H), 5.83 (dd, J = 2.9, 1.7 Hz, 1 H), 6.05 (t, J = 3.2 Hz, 1

H), 6.26 (t, J = 2.3 Hz, 1 H), 6.56 (t, J = 2.6 Hz, 1 H), 6.62 (t, J = 2.6 Hz, 1 H), 7.17–7.31

(m, 5 H), 7.33 (dd, J = 8.6, 1.8 Hz, 1 H), 7.40–7.46 (m, 2 H), 7.64 (d, J = 1.8 Hz, 1 H),

7.69 (d, J = 8.6 Hz, 1 H), 7.72 (dd, J = 6.9, 2.3 Hz, 1 H), 7.79 (dd, J = 6.6, 2.6 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 36.2, 36.5, 54.8, 105.6, 111.18, 111.22, 121.4, 121.9, 123.5, 125.62, 125.65, 126.0, 126.5, 127.0, 127.3, 127.5, 128.4, 129.2, 129.6, 129.9,

131.9, 133.0, 138.7, 144.7, 146.7. HRMS (FD) Calcd for C27H24N2: M, 376.1939. Found:

m/z 376.1961.

Bis(1-methyl-1H-pyrrol-3-yl)(2-naphthyl)phenylmethane (!,!’-5c). The

title compound was synthesized and purified in the same way as the above, and was

obtained as a white solid; mp 183–184 ºC. 1H NMR (400 MHz, CDCl3) % 3.56 (s, 6 H), 6.00 (dd, J = 2.7, 1.8 Hz, 2 H), 6.20 (t, J = 2.1 Hz, 2 H), 6.56 (t, J = 2.5 Hz, 2 H), 7.12–

102

7.23 (m, 3 H), 7.27–7.33 (m, 2 H), 7.37–7.44 (m, 3 H), 7.63–7.72 (m, 3 H), 7.78 (dd, J =

6.2, 2.5 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 36.1, 54.2, 111.0, 121.1, 122.2, 125.3, 125.4, 125.6, 126.0, 127.1, 127.2, 127.3, 128.4, 129.7, 129.9, 131.8, 132.9, 147.0,

149.1 (One carbon signal is missing due to overlapping). HRMS (FD) Calcd for

C27H24N2: M, 376.1939. Found: m/z 376.1963.

(1-Methyl-1H-pyrrol-2-yl)(1-methyl-1H-pyrrol-3-yl)phenyl(thien-3-

yl)methane (#,!’-5d). The title compound was synthesized with the following reagents (4-mmol scale reaction): 1a (1.62 g, 20.0 mmol), 3-benzoylthiophene (753 mg, 4.00

mmol), In(NTf2)3 (764 mg, 0.800 mmol) and 1,4-dioxane (4.0 mL). Column


mixture provided a mixture of #,!’-5d and !,!’-5d (14:86) in 41% yield (547 mg). In the

course of the purification, some fractions including pure #,!’-5d were collected.

Accordingly, #,!’-5d as a white solid; mp 136–137 ºC could be characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS. 1H NMR (500 MHz, CDCl3) % 2.99 (s, 3 H), 3.58 (s, 3 H), 5.61 (dd, J = 3.7, 2.0 Hz, 1 H), 5.85 (dd, J = 2.9, 1.7 Hz, 1 H), 6.02 (dd, J

= 3.7, 2.6 Hz, 1 H), 6.21 (t, J = 2.0 Hz, 1 H), 6.54 (t, J = 2.6 Hz, 1 H), 6.58 (t, J = 2.3 Hz,

1 H), 6.84 (dd, J = 4.9, 1.4 Hz, 1 H), 6.88 (dd, J = 2.9, 1.2 Hz, 1 H), 7.17–7.29 (m, 6 H); 13C{1H} NMR (125 MHz, CDCl3) % 36.20, 36.21, 51.7, 105.5, 110.2, 110.4, 121.25,

121.33, 122.5, 123.3, 124.0, 126.1, 127.5, 129.1, 129.6, 130.4, 138.8, 146.7, 148.7.

HRMS (FD) Calcd for C21H20N2S: M, 332.1347. Found: m/z 332.1370.

Bis(1-methyl-1H-pyrrol-3-yl)phenyl(thien-3-yl)methane (!,!’-5d). The title

compound was synthesized and purified in the same way as the above, and was obtained

as a white solid; mp 145–146 ºC. 1H NMR (400 MHz, CDCl3) % 3.55 (s, 6 H), 5.99 (dd, J = 2.8, 1.8 Hz, 2 H), 6.17 (t, J = 2.1 Hz, 2 H), 6.54 (t, J = 2.5 Hz, 2 H), 6.87 (dd, J = 3.0,

1.1 Hz, 1 H), 6.98 (dd, J = 5.0, 1.4 Hz, 1 H), 7.13–7.24 (m, 6 H); 13C{1H} NMR (125

MHz, CDCl3) % 36.1, 51.1, 110.2, 121.1, 121.5, 122.5, 123.6, 125.6, 127.1, 129.2, 130.3, 131.9, 149.2, 150.8. HRMS (FD) Calcd for C21H20N2S: M, 332.1347. Found: m/z

332.1371.

Bis(1-benzyl-1H-pyrrol-3-yl)(4-methylphenyl)phenylmethane (!,!’-5e). The title compound was synthesized with the following reagents: 1-benzylpyrrole (314

mg, 2.00 mmol), 6c (78.5 mg 0.400 mmol), In(NTf2)3 (76.4 mg, 80.0 µmol) and 1,4-

dioxane (0.40 mL), and was isolated by column chromatography on silica gel

(hexane/EtOAc = 10/1) in 70% yield (139 mg) as a white solid; mp 121–122 ºC. 1H NMR

103

(500 MHz, CDCl3) % 2.31 (s, 3 H), 4.95 (s, 4 H), 6.02 (dd, J = 2.6, 2.0 Hz, 2 H), 6.31 (t, J = 2.3 Hz, 2 H), 6.58 (t, J = 2.3 Hz, 2 H), 6.97–7.09 (m, 6 H), 7.11–7.39 (m, 13 H); 13C{1H} NMR (125 MHz, CDCl3) % 20.9, 53.2, 53.8, 111.5, 120.4, 121.9, 125.4, 126.6,

127.0, 127.4, 127.8, 128.6, 129.7, 129.9, 132.3, 134.9, 138.7, 146.3, 149.4. HRMS (FD)

Calcd for C36H32N2: M, 492.2565. Found: m/z 492.2590.

9-(1-Methyl-1H-pyrrol-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-fluorene

(#,!’-5f). The title compound was synthesized with the following reagents: 1a (130 mg, 1.60 mmol), 9-fluorenone (72.1 mg, 0.400 mmol), In(NTf2)3 (38.2 mg, 40.0 µmol) and

1,4-dioxane (0.40 mL). Column chromatography on silica gel (hexane/CHCl3 = 1/1) of

the resulting crude reaction mixture provided a mixture of #,!’-5f and !,!’-5f (9:91) in

99% yield (129 mg). In the course of the purification, some fractions including pure #,!’-5f were collected. Accordingly, #,!’-5f as a viscous colorless oil could be characterized

by 1H and 13C{1H} NMR spectroscopy, and HRMS. 1H NMR (400 MHz, CDCl3) % 2.46 (s, 3 H), 3.46 (s, 3 H), 6.02 (dd, J = 3.6, 2.8 Hz, 1 H), 6.07 (t, J = 2.1 Hz, 1 H), 6.25 (dd,

J = 3.7, 1.8 Hz, 1 H), 6.37 (dd, J = 2.8, 1.8 Hz, 1 H), 6.39 (t, J = 2.3 Hz, 1 H), 6.50 (t, J

= 2.5 Hz, 1 H), 7.24–7.30 (m, 2 H), 7.35 (td, J = 7.3, 1.4 Hz, 2 H), 7.44 (dd, J = 7.3, 1.4

Hz, 2 H), 7.74 (dd, J = 7.3, 1.4 Hz, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 34.0, 36.1, 55.5, 105.4, 109.6, 111.5, 120.1, 120.2, 121.6, 123.6, 125.4, 126.4, 127.3, 127.5, 134.8,

139.6, 150.9. HRMS (FD) Calcd for C23H20N2: M, 324.1626. Found: m/z 324.1645.

9,9-Bis(1-methyl-1H-pyrrol-3-yl)-9H-fluorene (!,!’-5f). The title compound was synthesized and purified in the same way as the above, and was obtained as a white

solid; mp 220–221 ºC. 1H NMR (400 MHz, CDCl3) % 3.49 (s, 6 H), 6.04 (dd, J = 2.7, 1.8 Hz, 2 H), 6.26 (t, J = 2.1 Hz, 2 H), 6.46 (t, J = 2.5 Hz, 2 H), 7.22–7.27 (m, 2 H), 7.30 (dt,

J = 7.3, 1.4 Hz, 2 H), 7.52 (dd, J = 6.6, 1.1 Hz, 2 H), 7.71 (dd, J = 6.9, 1.4 Hz, 2 H); 13C{1H} NMR (100 MHz, CDCl3) % 36.1, 54.7, 108.5, 119.7, 119.9, 121.5, 125.4, 126.7, 127.2, 128.8, 139.3, 153.5. HRMS (FD) Calcd for C23H20N2: M, 324.1626. Found: m/z

324.1653.

2-Bromo-9-(1-methyl-1H-pyrrol-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-

fluorene (#,!’-5g). The title compound was synthesized with the following reagents: 1a (130 mg, 1.60 mmol), 2-bromo-9-fluorenone (104 mg, 0.400 mmol), In(NTf2)3 (38.2 mg,

40.0 µmol) and 1,4-dioxane (0.40 mL). Column chromatography on silica gel

(hexane/CHCl3 = 1/1) of the resulting crude reaction mixture provided a mixture of #,!’-5g and !,!’-5g (3:97) in 82% yield (134 mg). In the course of the purification, some

104

fractions including pure #,!’-5g were collected. Accordingly, #,!’-5g as a viscous colorless oil could be characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS. 1H NMR (400 MHz, CDCl3) % 2.50 (s, 3 H), 3.48 (s, 3 H), 6.02 (dd, J = 3.7, 2.8 Hz, 1 H),

6.06 (t, J = 2.1 Hz, 1 H), 6.23 (dd, J = 3.6, 1.8 Hz, 1 H), 6.33 (dd, J = 2.7, 1.8 Hz, 1 H),

6.42 (t, J = 2.5 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H), 7.30 (td, J = 7.3, 1.4 Hz, 1 H), 7.35 (td,

J = 7.3, 1.4 Hz, 1 H), 7.41 (dd, J = 7.1, 1.1 Hz, 1 H), 7.47 (dd, J = 8.0, 2.1 Hz, 1 H), 7.57

(d, J = 1.8 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.71 (dd, J = 7.8, 0.9 Hz, 1 H); 13C{1H}

NMR (125 MHz, CDCl3) δ 34.1, 36.1, 55.5, 105.5, 109.5, 111.8, 120.1, 120.3, 121.3,

121.6, 121.9, 124.0, 125.4, 125.8, 127.5, 127.9, 128.5, 130.5, 133.8, 138.5, 138.6, 150.7,

153.0. HRMS (FD) Calcd for C23H19BrN2: M, 402.0732. Found: m/z 402.0752.

2-Bromo-9,9-bis(1-methyl-1H-pyrrol-3-yl)-9H-fluorene (!,!’-5g). The title compound was synthesized and purified in the same way as the above, and was obtained

as a yellow solid; mp 174–175 ºC. 1H NMR (500 MHz, CDCl3) % 3.51 (s, 6 H), 6.00 (t, J = 2.0 Hz, 2 H), 6.25 (t, J = 2.0 Hz, 2 H), 6.47 (t, J = 2.6 Hz, 2 H), 7.25–7.33 (m, 2 H),

7.41 (dd, J = 8.0, 1.7 Hz, 1 H), 7.49 (dd, J = 6.6, 1.4 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H),

7.63 (d, J = 1.7 Hz, 1 H), 7.67 (d, J = 6.9 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 36.1, 54.8, 108.4, 119.8, 119.9, 120.9, 121.1, 121.7, 125.5, 126.9, 127.7, 128.0, 128.7,

129.9, 138.2, 138.3, 153.3, 155.6. HRMS (FD) Calcd for C23H19BrN2: M, 402.0732.

Found: m/z 402.0749.

2-Hydroxy-9-(1-methyl-1H-pyrrol-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-

fluorene (#,!’-5h). The title compound was synthesized with the following reagents

(0.25-mmol scale reaction): 1a (81.1 mg, 1.00 mmol), 2-hydroxy-9-fluorenone (49.1 mg,

0.250 mmol), In(NTf2)3 (23.9 mg, 25.0 µmol) and 1,4-dioxane (0.25 mL). Column

chromatography on silica gel (hexane/EtOAc = 2/1) of the resulting crude reaction

mixture provided a mixture of #,!’-5h and !,!’-5h (14:86) in 84% yield (72.1 mg). In

the course of the purification, some fractions including pure #,!’-5h were collected.

Accordingly, #,!’-5h as a viscous colorless oil could be characterized by 1H and 13C{1H}

NMR spectroscopy, and HRMS. 1H NMR (400 MHz, CDCl3) % 2.50 (s, 3 H), 3.47 (s, 3 H), 4.77 (bs, 1 H), 6.02 (t, J = 3.2 Hz, 1 H), 6.09 (t, J = 1.9 Hz, 1 H), 6.24 (dd, J = 3.6,

1.8 Hz, 1 H), 6.35 (t, J = 2.1 Hz, 1 H), 6.40 (t, J = 2.3 Hz, 1 H), 6.50 (t, J = 2.5 Hz, 1 H),

6.83 (dd, J = 8.1, 2.2 Hz, 1 H), 6.88 (d, J = 2.3 Hz, 1 H), 7.20 (t, J = 7.3 Hz, 1 H), 7.31 (t,

J = 7.3 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 7.63 (d, J = 7.6 Hz,

1 H); 13C{1H} NMR (100 MHz, CDCl3) % 34.0, 36.1, 55.3, 105.4, 109.5, 111.5, 112.5,

105

114.6, 119.4, 120.1, 121.3, 121.7, 123.7, 125.2, 126.35, 126.40, 127.3, 132.7, 134.7,

139.4, 150.4, 153.0, 155.5. HRMS (FD) Calcd for C23H20N2O: M, 340.1576. Found: m/z

340.1558.

2-Hydroxy-9,9-bis(1-methyl-1H-pyrrol-3-yl)-9H-fluorene (!,!’-5h). The title compound was synthesized and purified in the same way as the above, and was

obtained as a yellow solid; mp 230–231 ºC. 1H NMR (400 MHz, CDCl3) % 3.50 (s, 6 H),

4.67 (bs, 1 H), 6.03 (dd, J = 2.5, 1.8 Hz, 2 H), 6.27 (t, J = 1.9 Hz, 2 H), 6.47 (t, J = 2.4

Hz, 2 H), 6.77 (dd, J = 8.1, 2.4 Hz, 1 H), 6.96 (d, J = 2.5 Hz, 1 H), 7.18 (td, J = 7.3, 1.1

Hz, 1 H), 7.26 (td, J = 7.4, 1.1 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1

H), 7.60 (d, J = 7.6 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 36.1, 54.6, 108.4, 112.6, 114.1, 118.9, 120.0, 120.7, 121.5, 125.3, 126.2, 126.7, 128.7, 132.4, 139.1, 153.1, 155.1,

155.6. HRMS (FD) Calcd for C23H20N2O: M, 340.1576. Found: m/z 340.1601.

Indium-Catalyzed Synthesis of Tetraarylmethanes; A General Procedure for Table 5. In(OTf)3 [(11.2 mg, 20.0 µmol) or (22.5 mg, 40.0 µmol)] or In(NTf2)3 (38.2

mg, 40.0 µmol) was placed in a 20 mL Schlenk tube, which was heated at 150 ºC in vacuo

for 2 h. The tube was cooled down to room temperature and filled with argon. 1,4-

Dioxane (1.00 mL) was added to the tube, and the mixture was then stirred at room

temperature for 10 min. To this were added diaryldipyrrolylmethane 5 (0.200 mmol), 2-

methylfuran (3c) [(41.1 mg, 0.500 mmol) or (65.7 mg, 0.800 mmol)] or 2-

methoxythiophene (3h) (91.3 mg, 0.800 mmol), and the resulting mixture was stirred at

T °C. After stirring for t h, a saturated NaHCO3 aqueous solution (0.3 mL) was added,

and the aqueous phase was extracted with EtOAc (5 mL x 3). The combined organic layer

was washed with brine (1 mL) and then dried over anhydrous sodium sulfate. Filtration

and evaporation of the solvent followed by purification gave the corresponding product

(!-9). Unless otherwise noted, products !-9 synthesized here were fully characterized by 1H and 13C{1H} NMR spectroscopy, and HRMS.

(5-Methylfuran-2-yl)(4-methylphenyl)(1-methyl-1H-pyrrol-3-

yl)phenylmethane (!-9a). The title compound was synthesized with the following

reagents: a 13:87 mixture of #,!’-5a and !,!’-5a (68.1 mg, 0.200 mmol), 2-methylfuran (3c) (41.1 mg, 0.500 mmol), In(OTf)3 (22.5 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL),

and was isolated by column chromatography on silica gel (hexane/CHCl3 = 2/1) in 69%

yield (47.2 mg) as a white solid; mp 148–149 ºC. 1H NMR (400 MHz, CDCl3) % 2.28 (d, J = 0.4 Hz, 3 H), 2.33 (s, 3 H), 3.56 (s, 3 H), 5.80 (d, J = 3.2 Hz, 1 H), 5.84–5.88 (m, 1

106

H), 6.01 (dd, J = 2.8, 1.8 Hz, 1 H), 6.17 (t, J = 2.1 Hz, 1 H), 6.55 (t, J = 2.5 Hz, 1 H), 7.00

(dt, J = 8.2, 2.1 Hz, 2 H), 7.05 (d, J = 8.2 Hz, 2 H), 7.13 (dt, J = 6.4, 1.8 Hz, 2 H), 7.18–

7.25 (m, 3 H); 13C{1H} NMR (100 MHz, CDCl3) % 13.9, 21.0, 36.2, 55.1, 105.5, 110.4,

110.8, 121.0, 122.2, 126.1, 127.3, 128.1, 129.1, 129.5, 129.6, 135.6, 143.8, 146.9, 151.3,

158.3. HRMS (FD) Calcd for C24H23NO: M, 341.1780. Found: m/z 341.1770.

(5-Methylfuran-2-yl)(3-methylphenyl)(4-methylphenyl)(1-methyl-1H-

pyrrol-3-yl)methane (!-9b). The title compound was synthesized with the following

reagents: a 15:85 mixture of #,!’-5b and !,!’-5b (70.9 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3 (22.5 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL), and was isolated

by column chromatography on silica gel (hexane/CHCl3 = 2/1) in 67% yield (47.9 mg)

as a white solid; mp 133–134 ºC. 1H NMR (500 MHz, CDCl3) % 2.27 (s, 3 H), 2.28 (s, 3 H), 2.33 (s, 3 H), 3.56 (s, 3 H), 5.80 (d, J = 3.5 Hz, 1 H), 5.84–5.87 (m, 1 H), 6.01 (dd, J

= 2.9, 1.7 Hz, 1 H), 6.16 (t, J = 2.0 Hz, 1 H), 6.55 (t, J = 2.6 Hz, 1 H), 6.90 (d, J = 8.0 Hz,

1 H), 6.96 (dd, J = 2.3, 1.7 Hz, 1 H), 6.98–7.07 (m, 5 H), 7.13 (t, J = 7.7 Hz, 1 H); 13C{1H}

NMR (125 MHz, CDCl3) % 13.9, 21.0, 21.7, 36.2, 55.1, 105.5, 110.4, 110.8, 121.0, 122.2,

126.8, 126.9, 127.1, 128.0, 129.2, 129.5, 130.2, 135.6, 136.7, 143.9, 146.7, 151.2, 158.4.

HRMS (FD) Calcd for C25H25NO: M, 355.1936. Found: m/z 355.1959.

(5-Methylfuran-2-yl)(1-methyl-1H-pyrrol-3-yl)(2-

naphthyl)phenylmethane (!-9c). The title compound was synthesized with the

following reagents: a 8:92 mixture of #,!’-5c and !,!’-5c (75.3 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3 (22.5 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL), and

was isolated by column chromatography on silica gel (hexane/CHCl3 = 2/1) in 72% yield

(54.9 mg) as a white solid, mp 120–121 ºC. 1H NMR (400 MHz, CDCl3) % 2.29 (d, J = 0.9 Hz, 3 H), 3.57 (s, 3 H), 5.85 (d, J = 3.2 Hz, 1 H), 5.87–5.90 (m, 1 H), 6.04 (dd, J =

2.8, 1.8 Hz, 1 H), 6.20 (t, J = 1.8 Hz, 1 H), 6.58 (t, J = 2.5 Hz, 1 H), 7.15–7.20 (m, 2 H),

7.21–7.30 (m, 3 H), 7.36–7.48 (m, 4 H), 7.65–7.73 (m, 2 H), 7.80 (dd, J = 7.3, 1.4 Hz, 1

H); 13C{1H} NMR (100 MHz, CDCl3) % 13.9, 36.2, 55.6, 105.6, 110.6, 110.9, 121.2, 122.3,

125.5, 125.6, 126.3, 126.5, 127.3, 127.4, 127.7, 128.4, 128.8, 128.9, 129.7, 132.1, 132.9,

144.3, 146.5, 151.4, 158.0. HRMS (FD) Calcd for C27H23NO: M, 377.1780. Found: m/z

377.1802.

(5-Methylfuran-2-yl)(1-methyl-1H-pyrrol-3-yl)phenyl(thien-3-yl)methane

(!-9d). The title compound was synthesized with the following reagents: a 14:86 mixture

of #,!’-5d and !,!’-5d (66.5 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3 (22.5

107


on silica gel (hexane/CHCl3 = 3/1) in 71% yield (47.5 mg) as a white solid; mp 139–140

ºC. 1H NMR (400 MHz, CDCl3) % 2.28 (d, J = 0.9 Hz, 3 H), 3.56 (s, 3 H), 5.83 (d, J = 3.2

Hz, 1 H), 5.85–5.89 (m, 1 H), 6.02 (dd, J = 2.8, 1.8 Hz, 1 H), 6.11 (t, J = 2.1 Hz, 1 H),

6.55 (t, J = 2.3 Hz, 1 H), 6.81 (dd, J = 3.2, 1.4 Hz, 1 H), 7.04 (dd, J = 5.0, 0.9 Hz, 1 H),

7.07 (dt, J = 6.4, 1.8 Hz, 2 H), 7.18–7.28 (m, 4 H); 13C{1H} NMR (100 MHz, CDCl3) %

13.9, 36.2, 52.5, 105.5, 109.8, 110.2, 121.2, 121.7, 123.3, 123.9, 126.3, 127.5, 128.8,

128.9, 130.0, 146.8, 147.7, 151.3, 157.7. HRMS (FD) Calcd for C21H19NOS: M, 333.1187.

Found: m/z 333.1212.

(1-Benzyl-1H-pyrrol-3-yl)(5-methylfuran-2-yl)(4-

methylphenyl)phenylmethane (!-9e). The title compound was synthesized with the

following reagents: !,!’-5e (98.5 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3


chromatography on silica gel (hexane/CHCl3 = 3/1) in 72% yield (60.6 mg) as a white

solid; mp 136–137 ºC. 1H NMR (500 MHz, CDCl3) % 2.27 (d, J = 0.6 Hz, 3 H), 2.32 (s,

3 H), 4.98 (s, 2 H), 5.80 (d, J = 2.9 Hz, 1 H), 5.85–5.88 (m, 1 H), 6.08 (dd, J = 2.9, 1.7

Hz, 1 H), 6.31 (t, J = 2.0 Hz, 1 H), 6.60 (t, J = 2.6 Hz, 1 H), 7.01 (dt, J = 8.6, 2.1 Hz, 2

H), 7.03–7.09 (m, 4 H), 7.13 (dt, J = 6.9, 1.7 Hz, 2 H), 7.18–7.28 (m, 4 H), 7.29–7.33 (m,

2 H); 13C{1H} NMR (125 MHz, CDCl3) % 13.9, 21.0, 53.2, 55.2, 105.5, 110.4, 111.3, 120.5, 122.0, 126.1, 126.7, 127.3, 127.4, 128.1, 128.6, 129.2, 129.4, 129.6, 135.7, 138.4,

143.7, 146.7, 151.3, 158.3. HRMS (FD) Calcd for C30H27NO: M, 417.2093. Found: m/z

417.2117.

9-(5-Methylfuran-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-fluorene (!-9f). The title compound was synthesized with the following reagents: a 9:91 mixture of #,!’-

5f and !,!’-5f (64.8 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3 (11.2 mg, 20.0 µmol) and 1,4-dioxane (1.00 mL), and was isolated by column chromatography on

silica gel (hexane/CHCl3 = 2/1) in 55% yield (36.0 mg) as a white solid; mp 118–119 ºC. 1H NMR (500 MHz, CDCl3) % 2.24 (s, 3 H), 3.50 (s, 3 H), 5.75–5.79 (m, 1 H), 5.83 (d, J = 3.5 Hz, 1 H), 6.01 (dd, J = 2.6, 2.0 Hz, 1 H), 6.23 (t, J = 2.0 Hz, 1 H), 6.47 (t, J = 2.3

Hz, 1 H), 7.29 (td, J = 7.5, 1.2 Hz, 2 H), 7.35 (td, J = 7.5, 1.2 Hz, 2 H), 7.66 (d, J = 7.5

Hz, 2 H), 7.73 (d, J = 7.5 Hz, 2 H); 13C{1H} NMR (125 MHz, CDCl3) % 13.9, 36.1, 55.4, 105.5, 106.9, 107.9, 119.6, 119.9, 121.7, 125.8, 126.3, 127.3, 127.4, 139.6, 149.8, 151.8,


108

2-Bromo-9-(5-methylfuran-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-fluorene

(!-9g). The title compound was synthesized with the following reagents: a 3:97 mixture

of #,!’-5g and !,!’-5g (80.7 mg, 0.200 mmol), 3c (65.7 mg, 0.800 mmol), In(OTf)3 (22.5


on silica gel (hexane/CHCl3 = 2/1) in 53% yield (43.1 mg) as a yellow solid; mp 124–

125 ºC. 1H NMR (500 MHz, CDCl3) % 2.25 (d, J = 0.6 Hz, 3 H), 3.52 (s, 3 H), 5.77–5.80

(m, 1 H), 5.85 (d, J = 3.4 Hz, 1 H), 5.97 (t, J = 2.0 Hz, 1 H), 6.23 (t, J = 2.0 Hz, 1 H),

6.48 (t, J = 2.6 Hz, 1 H), 7.32 (td, J = 7.3, 1.3 Hz, 1 H), 7.36 (td, J = 7.5, 1.2 Hz, 1 H),

7.46 (dd, J = 8.0, 1.7 Hz, 1 H), 7.58 (d, J = 8.6 Hz, 1 H), 7.62 (dd, J = 6.9, 1.2 Hz, 1 H),

7.69 (dd, J = 6.9, 1.1 Hz, 1 H), 7.77 (d, J = 1.7 Hz, 1 H); 13C{1H} NMR (125 MHz,

CDCl3) % 13.9, 36.2, 55.5, 105.6, 107.3, 107.9, 119.6, 120.0, 121.0, 121.3, 121.9, 125.5, 125.9, 127.6, 127.7, 129.0, 130.6, 138.6, 149.5, 151.8, 152.1, 154.3. (One carbon signal

is missing due to overlapping). HRMS (FD) Calcd for C23H18BrNO: M, 403.0572. Found:

m/z 403.0586.

2-Hydroxy-9-(5-methylfuran-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-

fluorene (!-9h). The title compound was synthesized with the following reagents: a

14:86 mixture of #,!’-5h and !,!’-5h (68.1 mg, 0.200 mmol), 3c (41.1 mg, 0.500 mmol), In(OTf)3 (22.5 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL), and was isolated by column

chromatography on silica gel (hexane/EtOAc = 3/1) in 55% yield (37.7 mg) as a yellow

solid; mp 148–149 ºC. 1H NMR (500 MHz, CDCl3) % 2.25 (d, J = 0.6 Hz, 3 H), 3.51 (s, 3 H), 4.72 (bs, 1 H), 5.76–5.79 (m, 1 H), 5.85 (d, J = 3.4 Hz, 1 H), 6.00 (dd, J = 2.9, 1.8

Hz, 1 H), 6.24 (t, J = 2.0 Hz, 1 H), 6.48 (t, J = 2.6 Hz, 1 H), 6.83 (dd, J = 8.0, 2.3 Hz, 1

H), 7.12 (d, J = 2.3 Hz, 1 H), 7.23 (td, J = 7.5, 1.2 Hz, 1 H), 7.32 (td, J = 7.4, 1.1 Hz, 1

H), 7.57–7.61 (m, 2 H), 7.63 (d, J = 7.5 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) %

13.9, 36.1, 55.4, 105.6, 107.1, 108.0, 113.1, 114.8, 119.1, 119.6, 120.9, 121.8, 125.7,

126.3, 126.4, 127.4, 132.7, 139.5, 149.4, 151.89, 151.92, 155.0, 155.2. HRMS (FD) Calcd

for C23H19NO2: M, 341.1416. Found: m/z 341.1423.

(5-Methoxythien-2-yl)(4-methylphenyl)(1-methyl-1H-pyrrol-3-

yl)phenylmethane (!-9i). The title compound was synthesized with the following

reagents: a 13:87 mixture of #,!’-5a and !,!’-5a (68.1 mg, 0.200 mmol), 2-

methoxythiophene (3h) (91.3 mg, 0.800 mmol), In(NTf2)3 (38.2 mg, 40.0 µmol) and 1,4-

dioxane (1.00 mL), and was isolated by recycling HPLC (hexane/EtOAc = 10:1) after

column chromatography on silica gel (hexane/toluene = 1/1) in 47% yield (35.2 mg) as a

109

viscous colorless oil. 1H NMR (400 MHz, CDCl3) % 2.33 (s, 3 H), 3.56 (s, 3 H), 3.82 (s, 3 H), 5.99 (d, J = 3.7 Hz, 1 H), 6.02 (dd, J = 2.8, 1.8 Hz, 1 H), 6.16 (t, J = 2.3 Hz, 1 H),

6.33 (d, J = 4.1 Hz, 1 H), 6.57 (t, J = 2.5 Hz, 1 H), 7.05 (dt, J = 8.2, 2.3 Hz, 2 H), 7.11

(dt, J = 8.3, 1.9 Hz, 2 H), 7.18–7.25 (m, 5 H); 13C{1H} NMR (125 MHz, CDCl3) % 21.0, 36.2, 56.5, 60.0, 102.3, 111.2, 121.3, 122.6, 124.9, 126.2, 127.2, 128.0, 129.7, 129.8,

130.8, 135.7, 139.7, 144.9, 148.0, 165.3. HRMS (FD) Calcd for C24H23NOS: M,

373.1500. Found: m/z 373.1502.

(5-Methoxythien-2-yl)(1-methyl-1H-pyrrol-3-yl)(2-

naphthyl)phenylmethane (!-9j). The title compound was synthesized with the

following reagents: a 8:92 mixture of #,!’-5c and !,!’-5c (75.3 mg, 0.200 mmol), 3h (91.3 mg, 0.800 mmol), In(NTf2)3 (38.2 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL), and

was isolated by column chromatography on silica gel (hexane/benzene = 1/1) in 44%

yield (36.5 mg) as a white solid; mp 155–156 ºC. 1H NMR (400 MHz, CDCl3) δ 3.56 (s,

3 H), 3.82 (s, 3 H), 6.01 (d, J = 3.6 Hz, 1 H), 6.06 (dd, J = 2.5, 2.1 Hz, 1 H), 6.20 (t, J =

2.1 Hz, 1 H), 6.37 (d, J = 4.1 Hz, 1 H), 6.59 (t, J = 2.5 Hz, 1 H), 7.20–7.32 (m, 5 H),

7.38–7.47 (m, 3 H), 7.62 (d, J = 1.4 Hz, 1 H), 7.71 (dd, J = 7.8, 2.8 Hz, 2 H), 7.80 (dd, J

= 7.1, 2.1 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) % 36.2, 56.9, 60.0, 102.3, 111.2, 121.4, 122.6, 125.2, 125.6, 125.7, 126.29, 126.31, 127.26, 127.34, 127.6, 128.5, 129.3,

129.9, 130.6, 132.1, 132.9, 139.2, 145.5, 147.6, 165.5. HRMS (FD) Calcd for

C27H23NOS: M, 409.1500. Found: m/z 409.1524.

2-Bromo-9-(5-methoxythien-2-yl)-9-(1-methyl-1H-pyrrol-3-yl)-9H-

fluorene (!-9k). The title compound was synthesized with the following reagents: a 3:97

mixture of #,!’-5g and !,!’-5g (80.7 mg, 0.200 mmol), 3h (91.3 mg, 0.800 mmol), In(NTf2)3 (38.2 mg, 40.0 µmol) and 1,4-dioxane (1.00 mL), and was isolated by column

chromatography on silica gel (hexane/benzene = 1/1) in 52% yield (46.0 mg) as a white

solid; mp 132–133 ºC. 1H NMR (400 MHz, CDCl3) % 3.52 (s, 3 H), 3.78 (s, 3 H), 5.91 (d, J = 4.1 Hz, 1 H), 6.13 (dd, J = 2.8, 1.8 Hz, 1 H), 6.26 (dd, J = 2.3, 1.8 Hz, 1 H), 6.36 (d,

J = 4.1 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H), 7.27–7.37 (m, 2 H), 7.46 (dd, J = 8.2, 1.8 Hz,

1 H), 7.54 (dt, J = 7.8, 1.2 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.66–7.70 (m, 2 H); 13C{1H}

NMR (100 MHz, CDCl3) % 36.2, 57.1, 60.0, 102.6, 108.7, 120.0, 120.3, 121.1, 121.4,

122.1, 122.5, 125.6, 126.4, 127.6, 127.8, 128.9, 130.6, 135.5, 138.1, 138.3, 151.6, 153.8,

165.1. HRMS (FD) Calcd for C23H18BrNOS: M, 435.0292. Found: m/z 435.0288.

N-Deprotection of !-9e; A Procedure for eq. 6.14,15,24 Under an argon

110

atmosphere, a mixture of TiCl3 (92.5 mg, 0.600 mmol) and Li (27.1 mg, 3.90 mmol) in

THF (6.0 mL) was placed in a 20 mL Schlenk tube, which was stirred at 65 ºC for 3 h.

Iodine (76.1 mg, 0.300 mmol) was then added in one portion at room temperature and the

mixture was stirred for 5 min. To this was added a THF (0.30 mL) solution of !-9e (125 mg, 0.300 mmol), and the mixture was stirred at room temperature for 16 h. The resulting

mixture was diluted with hexane (10 mL) and filtered through a pad of Celite, which was

then rinsed out with a mixture of hexane–EtOAc (4:1, 20 mL). The filtrate was washed

with brine (2 mL) and then dried over anhydrous sodium sulfate. Filtration and


(hexane/EtOAc = 5/1) gave (5-methylfuran-2-yl)(4-methylphenyl)phenyl(1H-pyrrol-3-

yl)methane (!-7c) in 63% yield (62.2 mg) as a viscous colorless oil. 1H NMR (500 MHz,

CDCl3) % 2.27 (d, J = 0.6 Hz, 3 H), 2.32 (s, 3 H), 5.81 (d, J = 2.9 Hz, 1 H), 5.84–5.88 (m,

1 H), 6.15 (td, J = 2.7, 1.4 Hz, 1 H), 6.36 (td, J = 2.3, 1.7 Hz, 1 H), 6.76 (td, J = 2.3, 1.7

Hz, 1 H), 7.00 (dt, J = 8.6, 2.0 Hz, 2 H), 7.05 (d, J = 8.6 Hz, 2 H), 7.13 (dt, J = 6.9, 1.7

Hz, 2 H), 7.18–7.25 (m, 3 H), 8.01 (bs, 1 H); 13C{1H} NMR (125 MHz, CDCl3) % 13.9,

21.0, 55.1, 105.5, 110.5, 111.0, 117.2, 118.3, 126.2, 127.3, 128.1, 129.2, 129.5, 129.6,

135.7, 143.7, 146.8, 151.3, 158.2. HRMS (FD) Calcd for C23H21NO: M, 327.1623.

Found: m/z 327.1643.

Indium-Catalyzed Synthesis of Dipyrrolyldecanes 5i; A Procedure for Scheme 5, (i). In(NTf2)3 (287 mg, 0.300 mmol) was placed in a 200 mL Schlenk tube,

which was heated at 150 °C in vacuo for 2 h. The tube was cooled down to room


mixture was then stirred at room temperature for 10 min. To this were added 2-decanone

(6a) (469 mg, 3.00 mmol) and 1-methylpyrrole (1a) (973 mg, 12.0 mmol), and the

resulting mixture was stirred at 85 °C for 1 h. A saturated NaHCO3 aqueous solution (3

mL) was added, and the aqueous phase was extracted with EtOAc (50 mL x 3). The

combined organic phase was washed with brine (10 mL) and then dried over anhydrous

sodium sulfate. Filtration and evaporation of the solvent followed by column

chromatography on silica gel (hexane/EtOAc = 30:1) gave dipyrrolyldecanes 5i (833 mg,

92% yield) as a mixture of three isomers that are #,#’-5i, #,!’-5i and !,!’-5i. The ratio

of #,#’-5i:#,!’-5i:!,!’-5i was determined to be 1:12:87 by GC analysis. The three

isomers, #,#’-5i, #,!’-5i and !,!’-5i have already appeared in references 14 and 44, and their spectral and analytical data are in good agreement with those reported in the

111

literatures. The reaction of (ii) in Scheme 5 was performed in a similar way, but without

catalyst In(NTf2)3.

Indium-Catalyzed Synthesis of 3-(Decan-2-yl)-1-methyl-1H-pyrrole (!-4a) from Dipyrrolyldecanes 5i; A Procedure for Scheme 5, (iii). In(NTf2)3 (28.7 mg, 30.0

µmol) was placed in a 20 mL Schlenk tube, which was heated at 150 °C in vacuo for 2 h.

The tube was cooled down to room temperature and filled with argon. 1,4-Dioxane (0.50

mL) was added to the tube, and the mixture was then stirred at room temperature for 10

min. To this were added a 1:12:87 mixture of dipyrrolyldecanes 5i (90.1 mg, 0.300 mmol),

Et3SiH (3a) (52.3 mg, 0.450 mmol) and H2O (5.40 mg, 0.300 mmol), and the resulting

mixture was stirred at 85 °C for 1 h. A saturated NaHCO3 aqueous solution (0.3 mL) was

added and the aqueous phase was extracted with EtOAc (5 mL x 3). The combined

organic layer was washed with brine (1 mL) and then dried over anhydrous sodium sulfate.

Filtration and evaporation of the solvent followed by column chromatography on silica

gel (hexane/EtOAc = 60/1) gave !-4a in 94% yield (62.9 mg). The full data on 1H and 13C{1H} NMR spectroscopy and HRMS analysis of !-4a have been already collected in

the preceding communication.15 The reaction of (iv) in Scheme 5 was performed in a

similar way, but without catalyst In(NTf2)3. The reaction of (v) in Scheme 5 was also

carried out in a similar way, but with #,!’-5i instead of the isomeric mixture of 5i.

Indium-Catalyzed Reductive !-Alkylation of 1-Methylpyrrole with 2-Decanone and Et3SiD; A Procedure for Scheme 5, (vi). In(NTf2)3 (14.3 mg, 15.0 µmol)

was placed in a 20 mL Schlenk tube, which was heated at 150 ºC in vacuo for 2 h. The

tube was cooled down to room temperature and filled with argon. 1,4-Dioxane (0.25 mL)

was added to the tube, and the mixture was then stirred at room temperature for 10 min.

To this were added 2-decanone (6a) (23.4 mg, 0.150 mmol), 1-methylpyrrole (1a) (36.5

mg, 0.450 mmol) and Et3SiD (3a-d) (26.4 mg, 0.225 mmol), and the resulting mixture

was stirred at 85 ºC for 3 h. A saturated NaHCO3 aqueous solution (0.3 mL) was added,

and the aqueous phase was extracted with EtOAc (5 mL x 3). The combined organic layer


and evaporation of the solvent followed by column chromatography on silica gel

(hexane/EtOAc = 60/1) gave 3-(decan-2-yl-2-d)-1-methyl-1H-pyrrole (!-4a-d) in 92%

yield (30.7 mg) with a deuterium content of >99% determined by 1H NMR, as a colorless

oil. 1H NMR (500 MHz, CDCl3) % 0.87 (t, J = 6.9 Hz, 3 H), 1.16 (s, 3 H), 1.20–1.34 (m, 12 H), 1.38–1.46 (m, 1 H), 1.47–1.58 (m, 1 H), 3.60 (s, 3 H), 5.98 (dd, J = 2.4, 1.9 Hz, 1

112

H), 6.37 (t, J = 2.0 Hz, 1 H), 6.50 (t, J = 2.5 Hz, 1 H); 13C{1H} NMR (125 MHz, CDCl3)

% 14.1, 22.1, 22.7, 27.6, 29.4, 29.7, 29.9, 31.4 (t, J = 19.1 Hz), 31.9, 36.0, 38.7, 106.7,

118.0, 121.2, 131.0; 2H NMR (61 MHz, CHCl3) % 2.61 (bs). HRMS (FI) Calcd for

C15H26DN: M, 222.2206. Found: m/z 222.2209.

113

III-4. References and Notes

1 For selected recent reviews, see: a) N. K. Garg, B. M. Stoltz, Chem. Commun. 2006,

3769; b) N. R. Williamson, P. C. Fineran, F. J. Leeper, G. P. C. Salmond, Nat. Rev. Microbiol. 2006, 4, 887; c) C.-C. Chang, W.-C. Chen, T.-F. Ho, H.-S. Wu, Y.-H. Wei, J. Biosci. Bioeng. 2011, 111, 501. For selected recent reports, see: d) U. Robben, I. Lindner,

W. Gärtner, J. Am. Chem. Soc. 2008, 130, 11303; e) C. P. Soldermann, R. Vallinayagam,

M. Tzouros, R. Neier, J. Org. Chem. 2008, 73, 764; f) J. H. Frederich, P. G. Harran, J. Am. Chem. Soc. 2013, 135, 3788; g) C. Vergeiner, S. Banala, B. Kräutler, Chem. Eur. J.

2013, 19, 12294. 2 For selected recent examples, see: a) L. Jiao, E. Hao, M. G. H. Vicente, K. M. Smith,

J. Org. Chem. 2007, 72, 8119; b) G. Zotti, B. Vercelli, A. Berlin, Chem. Mater. 2008, 20,

397; c) X. Lv, L.-J. Hong, Y. Li, M.-J. Yang, J. Appl. Polym. Sci. 2009, 112, 1287; d) M.

Krayer, M. Ptaszek, H.-J. Kim, K. R. Meneely, D. Fan, K. Secor, J. S. Lindsey, J. Org. Chem. 2010, 75, 1016; e) J. T. Lee, D.-H. Chae, Z. Ou, K. M. Kadish, Z. Yao, J. L. Sessler,

J. Am. Chem. Soc. 2011, 133, 19547; f) T.-T. Bui, A. Iordache, Z. Chen, V. V.

Roznyatovskiy, E. Saint-Aman, J. M. Lim, B. S. Lee, S. Ghosh, J.-C. Moutet, J. L. Sessler,

D. Kim, C. Bucher, Chem. Eur. J. 2012, 18, 5853. 3 For selected reviews on the SEAr-based C-alkylation of pyrroles, see: a) B. A. Trofimov,

N. A. Nedolya, In Comprehensive Heterocyclic Chemistry III, Vol. 3 (Eds: A. R. Katritzky,

C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor, G. Jones), Elsevier, Oxford, 2008, pp

110–134; b) J. S. Russel, E. T. Pelkey, S. J. P. Yoon-Miller, Prog. Heterocycl. Chem. 2009,

21, 145; c) J. S. Russel, E. T. Pelkey, S. J. P. Yoon-Miller, Prog. Heterocycl. Chem. 2011,

22, 143; d) J. S. Russel, E. T. Pelkey, J. G. Greger, Prog. Heterocycl. Chem. 2011, 23,

155; e) J. M. Lopchuk, Prog. Heterocycl. Chem. 2012, 24, 169; f) J. M. Lopchuk, Prog. Heterocycl. Chem. 2013, 25, 137. 4 J. Bergman, T. Janosik, In Modern Heterocyclic Chemistry, Vol. 1 (Eds: J. Alvare-Builla,

J. J. Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011, pp 269–375 5 For some reactions that do not belong to the three categories, see: a) H. Takaya, S.

Makino, Y. Hayakawa, R. Noyori, J. Am. Chem. Soc. 1978, 100, 1765; b) L. Liguori, H.-

R. Bjørsvik, F. Fontana, D. Bosco, L. Galimberti, F. Minisci, J. Org. Chem. 1999, 64,

8812; c) O. I. Shmatova, N. E. Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G.

Nenajdenko, Eur. J. Org. Chem. 2013, 3049.

114

6 a) H. J. Anderson, L. C. Hopkins, Can. J. Chem. 1966, 44, 1831; b) H. J. Anderson, C.

E. Loader, R. X. Xu, N. Lê, N. J. Gogan, R. McDonald, L. G. Edwards, Can. J. Chem.

1985, 63, 896; c) P. L. Barker, C. Bahia, Tetrahedron 1990, 46, 2691; d) M. Kawatsura,

M. Fujiwara, H. Uehara, S. Nomura, S. Hayase, T. Itoh, Chem. Lett. 2008, 37, 794; e) L.

M. Broomfield, J. A. Wright, M. Bochmann, Dalton Trans. 2009, 8269; f) J. Majer, P.

Kwiatkowski, J. Jurczak, Org. Lett. 2011, 13, 5944; g) T.-W. Chung, Y.-T. Hung, T.

Thikekar, V. V. Paike, F. Y. Lo, P.-H. Tsai, M.-C. Liang, C.-M. Sun, ACS Comb. Sci. 2015,

17, 442. See also references cited in references 6b, 6c and 6e. 7 The three-step strategy that consists of !-acylation of 1-(arylsulfonyl)pyrroles followed

by de-arylsulfonylation and reduction of the carbonyl group introduced at the first stage

has been also reported: a) J. Rühe, T. Ezquerra, G. Wegner, Makromol. Chem., Rapid

Commun. 1989, 10, 103; b) J. Rühe, T. A. Ezquerra, G. Wegner, Synth. Met. 1989, 28,

C177. 8 a) B. E. Maryanoff, J. Org. Chem. 1979, 44, 4410; b) B. Kempf, N. Hampel, A. R. Ofial,

H. Mayr, Chem. Eur. J. 2003, 9, 2209; c) J. Renner, I. Kruszelnicki, B. Adamiak, A. C.

Willis, E. Hammond, S. Su, C. Burns, E. Trybala, V. Ferro, M. G. Banwell, Aust. J. Chem. 2005, 58, 86; d) E. J. Corey, Y. Tian, Org. Lett. 2005, 7, 5535; e) J. Barluenga, A.

Fernández, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2009, 15, 8121; f) F. de Nanteuil,

J. Loup, J. Waser, Org. Lett. 2013, 15, 3738; g) M. L. Murat-Onana, C. Berini, J.-N. Denis,

J.-F. Poisson, F. Minassian, N. Pelloux-Léon, Eur. J. Org. Chem. 2014, 3773. See also

references cited in references 8b and 8g. 9 Petrini, Palmieri and co-workers have reported on synthesis of functionalized !-

alkylpyrroles by the two-step approach, which is !-sulfonylmethylation of 1-

triisopropylpyrrole followed by replacing the sulfonyl group with various nucleophiles:

a) F. Martinelli, A. Palmieri, M. Petrini, Chem. Eur. J. 2011, 17, 7183; b) S. Lancianesi,

A. Palmieri, M. Petrini, Adv. Synth. Catal. 2013, 355, 3285; c) A. Palmieri, M. Petrini,

Chem. Rec. 2016, 16, 1353. 10 a) A. J. Castro, W. G. Duncan, A. K. Leong, J. Am. Chem. Soc. 1969, 91, 4304; b) M.

R. DuBois, L. D. Vasquez, L. Peslherbe, B. C. Noll, Organometallics 1999, 18, 2230; c)

J. S. Yadav, B. V. S. Reddy, P. M. Reddy, C. Srinivas, Tetrahedron Lett. 2002, 43, 5185;

d) D. Prajapati, M. Gohain, B. J. Gogoi, Tetrahedron Lett. 2006, 47, 3535. 11 a) L. M. Hodges, J. Gonzalez, J. I. Koontz, W. H. Myers, W. D. Harman, J. Org. Chem.

115

1995, 60, 2125; b) W. D. Harman, Chem. Rev. 1997, 97, 1953. 12 a) B. M. Monks, E. R. Fruchey, S. P. Cook, Angew. Chem. Int. Ed. 2014, 53, 11065; b)

E. R. Fruchey, B. M. Monks, S. P. Cook, J. Am. Chem. Soc. 2014, 136, 13130; c) K.

Shibata, N. Chatani, Org. Lett. 2014, 16, 5148; d) J. Wippich, I. Schnapperelle, T. Bach,

Chem. Commun. 2015, 51, 3166; e) G. Cera, T. Haven, L. Ackermann, Angew. Chem. Int.

Ed. 2016, 55, 1484. 13 Intra- and intermolecular ring closing reactions are possible ways to access !-mono-

alkylpyrroles. For selected recent examples, see: a) Y.-W. Sun, X.-Y. Tang, M. Shi, Chem.

Commun. 2015, 51, 13937; b) M. N. Kneeteman, A. F. L. Baena, C. D. Rosa, P. M. E.

Mancini, Int. Res. J. Pure Appl. Chem. 2015, 8, 229; c) H. Chachignon, N. Scalacci, E.

Petricci, D. Castagnolo, J. Org. Chem. 2015, 80, 5287; d) L. Eberlin, B. Carboni, A.

Whiting, J. Org. Chem. 2015, 80, 6574; e) A. Bunrit, S. Sawadjoon, S. Tšupova, P. J. R.

Sjöberg, J. S. M. Samec, J. Org. Chem. 2016, 81, 1450; f) A. Keeley, S. McCauley, P.

Evans, Tetrahedron 2016, 72, 2552. 14 T. Tsuchimoto, T. Wagatsuma, K. Aoki, J. Shimotori, Org. Lett. 2009, 11, 2129. 15 Preliminary communication: T. Tsuchimoto, M. Igarashi, K. Aoki, Chem. Eur. J. 2010,

16, 8975. 16 For selected examples on indium-catalyzed transformations based on the activation of

a carbon–heteroatom bond, see: a) H.-B. Zhang, L. Liu, Y.-J. Chen, D. Wang, C.-J. Li,

Adv. Synth. Catal. 2006, 348, 229; b) J.-F. Zhao, B.-H. Tan, T.-P. Loh, Chem. Sci. 2011,

2, 349; c) Y. Nishimoto, A. Okita, M. Yasuda, A. Baba, Angew. Chem. Int. Ed. 2011, 50,

8623; d) B. V. S. Reddy, A. Venkateswarlu, P. Borkar, J. S. Yadav, M. Kanakaraju, A. C.

Kunwar, B. Sridhar, J. Org. Chem. 2013, 78, 6303; e) Y. Yamashita, Y. Saito, T. Imaizumi,

S. Kobayashi, Chem. Sci. 2014, 5, 3958; f) Y. Ogiwara, K. Takahashi, T. Kitazawa, N. Sakai, J. Org. Chem. 2015, 80, 3101; g) Y. Tian, L. Tian, X. He, C. Li, X. Jia, J. Li, Org. Lett. 2015, 17, 4874. 17 For selected reports on indium-catalyzed transformations based on the activation of a

carbon–carbon unsaturated bond, see: a) T. Tsuchimoto, T. Maeda, E. Shirakawa, Y.

Kawakami, Chem. Commun. 2000, 1573; b) T. Fujimoto, K. Endo, H. Tsuji, M. Nakamura,

E. Nakamura, J. Am. Chem. Soc. 2008, 130, 4492; c) K. Takahashi, M. Midori, K.

Kawano, J. Ishihara, S. Hatakeyama, Angew. Chem. Int. Ed. 2008, 47, 6244; d) G. Bhaskar,

C. Saikumar, P. T. Perumal, Tetrahedron Lett. 2010, 51, 3141; e) Y. Nishimoto, T.

116

Nishimura, M. Yasuda, Chem. Eur. J. 2015, 21, 18301; f) Y. Hamachi, M. Katano, Y.

Ogiwara, N. Sakai, Org. Lett. 2016, 18, 1634. See also a representative review: g) Z.-L.

Shen, S.-Y. Wang, Y.-K. Chok, Y.-H. Xu, T.-P. Loh, Chem. Rev. 2013, 113, 271. 18 For the corresponding alkyne variant, see: T. Tsuchimoto, T. Ainoya, K. Aoki, T.

Wagatsuma, E. Shirakawa, Eur. J. Org. Chem. 2009, 2437. 19 Disappearance of 6 leading to the formation of 5 is able to be confirmed by GC analysis. 20 A benzyl-type group on the nitrogen atom of pyrroles has been reported to undergo N-

debenzylation under acidic conditions, for instance, at a range of rt–90 °C. For a review,

see: B. Jolicoeur, E. E. Chapman, A. Thompson, W. D. Lubell, Tetrahedron 2006, 62,

11531. 21 For enantioselective !-tertiary alkylation of 2,5-disubstituted pyrroles, see: Q. Ma, L.

Gong, E. Meggers, Org. Chem. Front. 2016, 3, 1319. 22 For N-deprotection of the PhSO2CH2CH2 group, see: C. Gonzalez, R. Greenhouse, R.

Tallabs, Can. J. Chem. 1983, 61, 1697. In pyrrole chemistry, there is no precedent for

using the MeSO2CH2CH2 group as a protective group, to the best of my knowledge. 23 For N-deprotection of the EtO2CCH2CHMe group, see: a) A. V. Kel’in, A. W. Sromek,

V. Gevorgyan, J. Am. Chem. Soc. 2001, 123, 2074; b) A. S. Dudnik, A. W. Sromek, M.

Rubina, J. T. Kim, A. V. Kel’in, V. Gevorgyan, J. Am. Chem. Soc. 2008, 130, 1440. In

pyrrole chemistry, there is no precedent for using the EtO2CCH2CH2 and EtO2CCH2CMe2

groups as protective groups, to the best of my knowledge. 24 S. Talukdar, S. K. Nayak, A. Banerji, J. Org. Chem. 1998, 63, 4925. 25 For selected recent reports, see: a) W.-K. An, M.-Y. Han, C.-A. Wang, S.-M. Yu, Y.

Zhang, S. Bai, W. Wang, Chem. Eur. J. 2014, 20, 11019; b) M. Xue, Y. Yang, X. Chi, X.

Yan, F. Huang, Chem. Rev. 2015, 115, 7398; c) Z. Yang, H. Zhang, B. Yu, Y. Zhao, Z. Ma,

G. Ji, B. Han, Z. Liu, Chem. Commun. 2015, 51, 11576; d) Y. Ye, L. Zhang, Q. Peng, G.-

E. Wang, Y. Shen, Z. Li, L. Wang, X. Ma, Q.-H. Chen, Z. Zhang, S. Xiang, J. Am. Chem.

Soc. 2015, 137, 913; e) S. Bibi, J. Zhang, New J. Chem. 2016, 40, 3693. 26 For selected recent examples, see: a) X. Huang, Y.-I. Jeong, B. K. Moon, L. Zhang, D.

H. Kang, I. Kim, Langmuir 2013, 29, 3223; b) B. J. Hong, I. Eryazici, R. Bleher, R. V.

Thaner, C. A. Mirkin, S. T. Nguyen, J. Am. Chem. Soc. 2015, 137, 8184; c) R. S.

Kalhapure, S. J. Sonawane, D. R. Sikwal, M. Jadhav, S. Rambharose, C. Mocktar, T.

Govender, Colloids Surf. B 2015, 136, 651; d) S. Lee, G. Barin, C. M. Ackerman, A.

117

Muchenditsi, J. Xu, J. A. Reimer, S. Lutsenko, J. R. Long, C. J. Chang, J. Am. Chem. Soc. 2016, 138, 7603. 27 a) H.-D. Becker, J. Org. Chem. 1967, 32, 2131; b) W. P. Neumann, A. Penenory, U.

Stewen, M. Lehnig, J. Am. Chem. Soc. 1989, 111, 5845; c) K. Matsumoto, T. Inagaki, T.

Nehira, M. Kannami, D. Inokuchi, H. Kurata, T. Kawase, G. Pescitelli, M. Oda, Chem.

Asian J. 2007, 2, 1031; d) K. Matsumoto, K. Miki, H. Kurata, N. Rikitake, T. Nehira, T.

Inagaki, G. Pescitelli, Y. Hirao, T. Kawase, M. Oda, T. Kubo, Chem. Lett. 2008, 37, 1236;

e) K. Matsumoto, K. Miki, T. Inagaki, T. Nehira, G. Pescitelli, Y. Hirao, H. Kurata, T.

Kawase, T. Kubo, Chirality 2011, 23, 543; f) M. Nambo, M. Yar, J. D. Smith, C. M.

Crudden, Org. Lett. 2015, 17, 50; g) K. Tsuchida, Y. Senda, K. Nakajima, Y. Nishibayashi,

Angew. Chem. Int. Ed. 2016, 55, 9728. 28 a) T. Kowada, S. Yamaguchi, K. Ohe, Org. Lett. 2010, 12, 296; b) T. Kowada, T.

Kuwabara, K. Ohe, J. Org. Chem. 2010, 75, 906; c) T. Kowada, S. Yamaguchi, H.

Fujinaga, K. Ohe, Tetrahedron 2011, 67, 3105; d) J. D. Ng, S. P. Upadhyay, A. N.

Marquard, K. M. Lupo, D. A. Hinton, N. A. Padilla, D. M. Bates, R. H. Goldsmith, J. Am. Chem. Soc. 2016, 138, 3876. 29 T. Tsuchimoto, K. Hatanaka, E. Shirakawa, Y. Kawakami, Chem. Commun. 2003,

2454. 30 The possible formation of !-9m was detected only by GC-MS analysis. 31 Dipyrrolylmethane derivatives are important building blocks in porphyrin chemistry.

For selected reviews, see: a) J. S. Lindsey, Acc. Chem. Res. 2010, 43, 300; b) D. T. Gryko,

D. Gryko, C.-H. Lee, Chem. Soc. Rev. 2012, 41, 3780; c) K. Singh, S. Sharma, P. Kaur,

C.-H. Lee, Tetrahedron 2015, 71, 8373. 32 K. Yonekura, K. Oki, T. Tsuchimoto, Adv. Synth. Catal. 2016, 358, 2895. 33 For examples, see: a) W. Adam, J. Gläser, K. Peters, M. Prein, J. Am. Chem. Soc. 1995,

117, 9190; b) Y. Yokoyama, Chem. Eur. J. 2004, 10, 4388. 34 a) C. H. DePuy, S. R. Kass, G. P. Bean, J. Org. Chem. 1988, 53, 4427; b) K. Shen, Y.

Fu, J.-N. Li, L. Liu, Q.-X. Guo, Tetrahedron 2007, 63, 1568. 35 For synthesis of 5-acetyloxy-2-pentanone, see: a) D. Hawksley, D. A. Griffin, F. J.

Leeper, J. Chem. Soc., Perkin Trans. 1 2001, 144. For spectral and analytical data of 5-

acetyloxy-2-pentanone, see: b) J. Joseph, C. C.-Y. Shih, C.-S. Lai, Chem. Phys. Lipids

1991, 58, 19; c) T. Nishimura, T. Onoue, K. Ohe, S. Uemura, J. Org. Chem. 1999, 64,

118

6750. 36 L. N. Sobenina, L. A. Es’Kova, A. I. Mikhaleva, D-S. D. Toryashinova, A. I. Albanov,

B. A. Trofimov, N. S. Zefirov, Russ. J. Org. Chem. 1999, 35, 1199. 37 For synthesis of 3-benzoylthiophene, see: a) L. J. Gooßen, L. Winkel, A. Döhring, K.

Ghosh, J. Paetzold, Synlett 2002, 1237. For spectral and analytical data of 3-

benzoylthiophene, see: b) H. Neumann, A. Brennführer, M. Beller, Chem. Eur. J. 2008,

14, 3645; c) A. T. Biju, F. Glorius, Angew. Chem. Int. Ed. 2010, 49, 9761. 38 T. Tsuchimoto, H. Matsubayashi, M. Kaneko, E. Shirakawa, Y. Kawakami, Angew.

Chem. Int. Ed. 2005, 44, 1336. 39 a) C. G. Frost, J. P. Hartley, D. Griffin, Tetrahedron Lett. 2002, 43, 4789; b) M.

Nakamura, K. Endo, E. Nakamura, Adv. Synth. Catal. 2005, 347, 1681. 40 V. G. Nenajdenko, A. L. Reznichenko, E. S. Balenkova, Tetrahedron 2007, 63, 3031. 41 A. D. Josey, Org. Synth. 1967, 47, 81. 42 D. O. A. Garrido, G. Buldain, B. Frydman, J. Org. Chem. 1984, 49, 2619. 43 H. Heaney, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1973, 499. 44 S. Nomiyama, T. Tsuchimoto, Adv. Synth. Catal. 2014, 356, 3881.

Chapter IV. Metal-Free Regioselective !-Alkylation of Pyrroles with Carbonyl Compounds and Hydrosilanes: Use of a Brønsted

Acid as a Catalyst

120

IV-1. Introduction !-Alkylpyrroles are key structural motifs in natural products and biologically

active compounds1 as well as functional materials.2 Due to sufficient aromaticity and "-

excessive nature of pyrroles, a straightforward approach to !-alkylpyrroles seems to be SEAr-based direct introduction of an alkyl group onto the pyrrole ring. 3 However,

preferential #-nucleophilicity of pyrroles actually makes the !-alkylation considerably difficult.4,5,6 Despite such characteristics of pyrroles, The research group to which the

author belongs has recently achieved SEAr-based regioselective !-alkylation of pyrroles

by simply mixing pyrroles 1, alkynes 2, and Et3SiH (3a) under indium catalysis (Scheme

1).7 This was the first example of the SEAr-based !-alkylation of pyrroles performed in one-step and in catalytic. However, the alkyl unit installable onto 1 was restricted to the

secondary alkyl group with the methyl substituent since 2 has been limited mainly to

terminal alkynes. Therefore, the research group to which the author belongs improved the

issue by replacing 2 with carbonyl compounds 5, which serve as a source of a broad range

of alkyl groups including primary, secondary and tertiary as well as cyclic structures.8 In

addition to the improvement, the author envisaged that exploiting a new catalyst in lieu

of the indium salt, which includes a rather expensive indium metal9 and is required to be

pre-synthesized,10,11 would further enhance the practicality and utility of the strategy. In

terms of the social requirements of sustainable development, the author aimed at

achieving the !-alkylation as a metal-free process. The author now reports details of more

sophisticated !-alkylation of pyrroles, where a Brønsted acid as a commercial source shows outstanding catalytic performance.

Scheme 1. Catalytic reductive !-alkylation of pyrroles.

+N

+cat. In

Et3SiH1

O R2

R3

5

HR2

NR1

R3

4

3a

+ + 3a

HR2

NR1

Me

4α

β

cat. In

α

β

HR2

NR1

R3

4

cat. H+

α

β

previous work

this work

R1 2

R2

O R2

R3

5

+ + 3a

N1R2

N1R2

/

:

/

―

ニ

ニ

5

9《

ロ

ロ

ロ

121

IV-2. Results & Discussion

IV-2-1. HNTf2 Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH

The author first examined the effect of Brønsted acid catalysts in the reaction

of 1-methylpyrrole (1a) with 2-decanone (5a) and Et3SiH (3a) under the conditions in

1,4-dioxane at 85 ºC for 5 h (Table 1). Despite that HNTf2 (25 mol%, Tf = SO2CF3) was

totally inactive in the preceding study with the corresponding alkyne (1-decyne),7 3 mol%

of HNTf2 successfully catalyzed the reaction of 5a, giving 3-(decan-2-yl)-1-

methylpyrrole (4a) as a single isomer in 91% yield (entry 1). The non-formation of its #-isomer and complete consumption of dipyrrolylalkanes 6a as plausible intermediates are

noteworthy. Although using other sulfonimides as well as oxygen and carbon analogues

of HNTf2 resulted in a complete conversion of 5a, a significant amount of 6a remained

unconsumed (entries 2–6). In addition to HO(O)CCF3, inorganic Brønsted acids such as

HBF4, H2SO4 and HNO3 were much less effective (entries 7–10). With HNTf2 as a

promising catalyst, the continuous survey of the solvent effect showed that 1,4-dioxane

is the solvent of choice for the reaction (entries 1 and 11–16). The effect of the amounts

of 1a and 3a was also examined. Reducing the amount of 1a from 3 to 2 and 1 molar

equivalents to 5a lowered the yield of 4a but not significantly (entries 17 and 18).

Accordingly, in the case that pyrrole substrates are expensive and elaborate, the use of

less than 3 molar equivalents of the pyrrole should be a possible choice of the reaction

conditions. On the other hand, reducing the quantity of both 1a and 3a resulted in further

decrease of the yield (entry 19).

122

Table 1. Brønsted acid-catalyzed reductive !-2-decylation of 1a.a

Entry Catalyst Solvent Conv.b

(%) 5a Yield (%)c 4a 6a

1 HNTf2 1,4-dioxane >99 91 <1

2 HNNf2d 1,4-dioxane >99 79 8

3

1,4-dioxane >99 62 21

4 HOTf 1,4-dioxane >99 15 50

5 HONfd 1,4-dioxane >99 12 51

6 HCTf2(C6F5) 1,4-dioxane >99 66 25

7 HO(O)CCF3 1,4-dioxane <1 <1 <1

8 HBF4 aq. 1,4-dioxane 74 5 49

9 H2SO4 1,4-dioxane 21 <1 5

10 HNO3 1,4-dioxane <1 <1 <1

11 HNTf2 Bu2O 93 19 <1

12 HNTf2 PhMe 96 46 <1

13 HNTf2 PhCl >99 69 10

14 HNTf2 MeNO2 83 61 <1

15 HNTf2 EtCN >99 88 <1

16 HNTf2 DMFe <1 <1 <1

17f HNTf2 1,4-dioxane >99 87 <1

18g HNTf2 1,4-dioxane 98 84 <1

19h HNTf2 1,4-dioxane >99 76 <1 aReagents: 1a (1.8 mmol), 5a (0.60 mmol), 3a (0.90 mmol), catalyst (18 µmol), solvent (0.60 mL). bDetermined by GC. cDetermined by 1H NMR. dNf = SO2C4F9. eDMF = N,N-dimethylformamide. fPerformed with 1a (1.2 mmol). gPerformed with 1a (0.60 mmol). gPerformed with 1a (0.60 mmol) and 3a (0.60 mmol).

NC8H17

N+

catalyst(3 mol%)

solvent85 °C5 h1a 4a

NN

C8H17

6a

+ 3a +

3:1:1.5

O C8H17

5a

SHNS

OO F

F

OO F

FFF

口よ .if r~>I ¥ I

：

‘、I

、

/

/

123

As shown in Scheme 2, the performance of 3 mol% of HNTf2 is comparable

enough to that of 10 mol% of In(NTf2)3. HNTf2 as a catalyst has several advantages over

In(NTf2)3: 1) no indium as a rather rare metal is required, 2) no metallic waste remains

after the reaction, 3) pre-synthesis of In(NTf2)3 from In2O3 and HNTf2 is unnecessary, 4)

HNTf2 is commercially available and reasonable in price,12 5) the weight used of the

catalyst can be reduced to less than one-tenth, that is, from 57.3 mg of In(NTf2)3 to 5.1

mg of HNTf2 in the 0.6 mmol-scale reaction.

Scheme 2. Reductive !-2-decylation of 1a: HNTf2 versus In(NTf2)3. Yields of isolated 4a based on 5a are shown here. With the suitable reaction conditions in hand, the author next explored the scope

of the HNTf2-catalyzed reaction (Table 2). Besides the 2-decyl group, the different length

of the secondary alkyl chains and the cyclic structures were installed onto the !-position of 1a exclusively (4b–4f). In the use of 2-adamantanone, its direct reduction occurred,

giving 2-adamantanol (6% NMR yield). The undesired reduction was suppressed entirely

by switching the procedure (method A) to method B, where 3a is added after consumption

of carbonyl compounds 5 (4e).13 The compatibility of the functional groups, sulfide,

alkenyl, alkynyl, ester, chloro, and boryl [B(pin) = B(pinacolate)], is noteworthy (4f–4k,

4q and 4t). The tolerance of the alkynyl part is especially remarkable and is thus an

additional advantage of this method over the corresponding indium reaction because an

indium catalyst is capable of activating the C≡C bond (4h).14,15 In fact, use of In(NTf2)3

instead of HNTf2 as a catalyst provided no 4h due to the formation of a complex mixture

of products. Pyrroles with a benzyl (Bn), iPr, 1-phenylethyl, tBu, Ph, and cumyl group on

the nitrogen atom also participated in this protocol (4l–4p and 4s–4x). Of these, the

reactions of N-iPr– and N-tBu–pyrrole with 5a allowed us to further reduce the loading

of HNTf2 to 1 mol% (4m and 4o). Despite that 1,2-dimethylpyrrole has the two

O C8H17

N

+1a

3a

1.5:

1:3

5a (0.6 mmol)+

C8H17

N

4a; 90% yield

HNTf2 (3 mol%, 5.1 mg)

1,4-dioxane, 85 ºC, 5 h

In(NTf2)3 (10 mol%, 57.3 mg)

1,4-dioxane, 85 ºC, 3 h4a; 92% yield

□

|

よ1/'

124

unsymmetrical !-sites, only the C4-position was alkylated (4q). In contrast to the pyrroles

that have been used so far, no !-alkylation proceeded in the reaction using an electron-deficient pyrrole such as N-Boc–pyrrole (Boc = tert-butoxycarbonyl); reagents and

conditions used are given in the reference section.16 The reaction of pyrrole with no

substituent on the nitrogen atom also led to a poor result; a reaction scheme is provided

in the reference section.17 These results suggest that electron-rich pyrroles with alkyl and

aryl groups on the nitrogen atom should be essential for the progress of the reductive !-alkylation of pyrroles. When using aryl and heteroaryl ketones, method B is valid to

exclude a small extent of #-alkylation that was concurrent with the !-alkylation in the

use of method A (4r–4u). Upon introducing a primary alkyl group, the yield of the

product was found to tend to increase with increasing the size of the alkyl unit (4v–4x).

As Table 2 shows, 3–4 molar equivalents of 1 are used to 5, but the excess amount of 1

can be recovered if desired. For example, 3 molar equivalents of N-(1-

phenylethyl)pyrrole to acetone were used in the reaction giving 4n. The pyrrole remained

unreacted was thus recovered with efficiency of 95%, which was calculated based on the

excess amount of the pyrrole: 2 molar equivalents in this case (see the Experimental

Section for further details). This result indicates that pyrrole substrates used as an excess

amount are recoverable and reusable. As a practical application, gram-scale synthesis can

be performed. For example, 4b and 4n were prepared on 7.5 and 7.0 mmol scales,

respectively, to provide 1.15 g of 4b (92% yield) and 1.40 g of 4n (92% yield).

125

Table 2. HNTf2-catalyzed reductive !-alkylation of pyrroles.a

aReagents: 1 (1.8 or 2.4 mmol), 5 (0.60 mmol), 3a (0.90 or 1.8 mmol), HNTf2 (6.0–42 µmol), 1,4-dioxane (0.60 mL). Yields of isolated 4 based on 5 are shown here. The methods used are shown in parentheses. See experimental section for further details. bThe yield when performed on 7.5 mmol scale is shown in parentheses. cAc = acetyl. dThe product was obtained as a 78:22 mixture of diastereomers. ePerformed on 7.0 mmol scale. f 3a (4.2 mmol) was used.

+NR1

+ +NR1

cat. HNTf21,4-dioxane85 or 100 °Ct2 h

t3 h5 5

method A method B

Et3SiH

Et3SiH3a

O R3

R4

3aO R3

R4

R2cat. HNTf21,4-dioxane50–100 °Ct1 h

R3

NR1

R4

4

R2

1 1

4e; 85% yield (A), 85 ºC, t1 = 54e; 95% yield (B), 100 ºC, t2 = 24, t3 = 3

N

4j; 72% yield (A)100 ºC, t1 = 48d

N OO

Cl

4k; 86% yield (A)100 ºC, t1 = 10

N

4c; 72% yield (A)100 ºC, t1 = 5

4d; 76% yield (A)85 ºC, t1 = 5

N N

4h; 87% yield (A)100 ºC, t1 = 24

N

4g; 53% yield (A)85 ºC, t1 = 24

N

OAc

4i; 77% yield (A)85 ºC, t1 = 48c

N

4r; 60% yield (B)100 ºC, t2 = 3, t3 = 72

N

4l; 96% yield (A)85 ºC, t1 = 5

C8H17

4m; 98% yield (A)85 ºC, t1 = 5

N

4u; 77% yield (B)85 ºC, t2 = 3, t3 = 4

N S

C8H17

4o; 99% yield (A)85 ºC, t1 = 5

N

4p; 93% yield (B)85 ºC, t2 = 4, t3 = 24

NPh

C8H17

4q; 80% yield (A)100 ºC, t1 = 48

N

C9H19

4v; 32% yield (A)100 ºC, t1 = 15f

N

Ph4w; 54% yield (A)100 ºC, t1 = 15

N

Ph4x; 73% yield (A)100 ºC, t1 = 15

N

4b; 90% (92%)b yield (A)85 ºC, t1 = 9

N

4t; 87% yield (B)85 ºC, t2 = 3, t3 = 4

N

4s; 91% yield (B)85 ºC, t2 = 3, t3 = 30

N

4f; 85% yield (A)100 ºC, t1 = 9

N

S

S

C8H17

N

4n; 92% yield (A)50 ºC, t1 = 24e

NPh

B(pin)

Ph

ロ人ーロ人口

r r~ ~ ~~r• JJ 1/'P r if if≪" if

ノペ、ペメ

≪ ~ro~«u 口~if«u if'r< ペ -f -f 7¥

126

IV-2-2. HNTf2 Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles

Besides hydride nucleophile 3a, carbon nucleophiles [Nu(C)] 3 such as

Me3SiCN (3b), 2-methylfuran (3c) and 4-vinylanisole (3d) can be used for extending a

carbon–carbon bond (Scheme 3).8 The use of such nucleophiles enables us to create the

quaternary carbon center with the !-pyrrolyl group. Here again, the !-selectivities were perfectly controlled in all the cases. In the use of 3d, the bicyclic ring was formed at once

via a regioselective three carbon–carbon bond-forming cascade, where a benzylic cation

generated after nucleophilic attack of the C=C bond of 3d is likely to accept the #-carbon

of the pyrrolyl group. As thus far described, nitrogen-substituted !-alkylpyrroles with primary, secondary and tertiary alkyl groups can be prepared by utilizing the present

method. Importantly, the author has previously demonstrated that the benzyl and cumyl

groups on the nitrogen atom are easily removable.8 Therefore, combining this method and

the deprotection reaction enables preparation of all six types including nitrogen-

substituted and -unsubstituted !-alkylpyrroles with primary, secondary and tertiary alkyl groups.

Scheme 3. HNTf2-catalyzed !-alkylation of pyrroles with carbonyl compounds and carbon nucleophiles (3b: Me3SiCN, 3c: 2-methylfuran, 3d: 4-vinylanisole).

+

HNTf2(5–7 mol%)1,4-dioxaneT1 °C, t1 h5

O R1

R24:1

7a; 85% yieldwith 3b (1.5 equiv.)T1 = 100, t1 = 20T2 = 100, t2 = 24

7c; 75% yieldwith 3d (3 equiv.)(Ar = C6H4–p-OMe)T1 = 100, t1 = 20T2 = 85, t2 = 5

7b; 74% yieldwith 3c (2.5 equiv.)T1 = 85, t1 = 8T2 = 70, t2 = 15

NCN

N O

NR3

1

C6H13

N Ar

method B

T2 °Ct2 h

Nu(C) 3 Nu(C)'N

R3

R2

7

R1

Ph

ロ A C 二/

? J~$

127

IV-2-3. Reaction Mechanism Some pieces of experimental observations are available for the mechanistic

studies (Scheme 4). Thus, the reaction of 1a with 5a and HNTf2 (3 mol%), but without

Et3SiH (3a), gave an isomeric mixture of dipyrrolylalkanes 6a, as observed in the reaction

performed by method B. The isolated mixture (6a) then reacted with 3a in the presence

of HNTf2 (3 mol%) and H2O,18 giving 4a exclusively in 94% yield. These results indicate

that dipyrrolylalkanes 6 are intermediates in the three-component reaction. On the basis

of these results and the previous ones,7,8 a plausible mechanism is shown in Scheme 5, in

which one pyrrole ring of 6 is fixed as the !-pyrrolyl ring, due actually to the non-

formation of an #-alkylpyrrole derived inevitably from #,#’-6. The HNTf2 (H+) first assembles 1 and 5 into 6, one pyrrole ring of which undergoes protonation and then

eliminates to give cationic species !-8 via the C(sp3)–C(pyrrolyl) bond cleavage, as

previously reported.19 The trapping of !-8 by nucleophile (Nu) 3 leads to product 4 or 7.

As previously noted, the origin of the observed !-selectivity would be ascribed to the

dominant generation of !-8 being much more stable than possible alternative cationic

species #-8 that has 1,3-allylic-type strain between R1 and R3.20

Scheme 4. HNTf2-catalyzed reaction for mechanistic studies.

NNO C8H17N

C8H17

+ C8H17

N

+

HNTf2(3 mol%)1,4-dioxane85 °C, 5 h

HNTf2(3 mol%)H2O (1 equiv.)1,4-dioxane85 °C, 5 h

NN

C8H17

6a; 92% yieldα,α':α,β':β,β' = 2:13:85

5a1a

4:1

1:1.5

6a: α,α':α,β':β,β'= 2:13:85

3a 4a; 94% yield

Et3SiH

口よー：ご〗I ¥ /

f~"] --------≪ ¥ I I

128

Scheme 5. A plausible reaction mechanism.

+

N

5

1

O R1

R2

R1 H+

– H2O

R2

NR1

R3Nu'

4 or 7

R2

N

R3

+

α-8R1

H+

β-8

α,β'-6 β,β'-6N NN N

R1R1 R1 R1

R2R3R2R3

R2

NR1

R3

+N N

R1 R1

R2R3

H +

Nu 3

N NR1 R1

R2R3

H +

NR12

H+

NR12

口 ~[<TY)~~J A /4 □ ↓

：口／ょ：↓

[~] if

129

IV-3. Experimental

General Remarks

All manipulations were conducted with a standard Schlenk technique under an

argon atmosphere. Nuclear magnetic resonance (NMR) spectra were taken on a JEOL

JMN-ECA 400 (1H, 400 MHz; 13C, 100 MHz) or JEOL JMN-ECA 500 (1H, 500 MHz; 13C, 125 MHz) spectrometer using tetramethylsilane (1H and 13C) as an internal standard.

Analytical gas chromatography (GC) was performed on a Shimadzu model GC-2014

instrument equipped with a capillary column of InertCap 5 (5% phenyl polysilphenylene-

siloxane, 30 m x 0.25 mm x 0.25 µm) using nitrogen as carrier gas. Gas chromatography–mass spectrometry (GC–MS) analyses were performed with a Shimadzu model GCMS-

QP2010 instrument equipped with a capillary column of ID-BPX5 (5% phenyl

polysilphenylene-siloxane, 30 m x 0.25 mm x 0.25 µm) by electron ionization at 70 eV using helium as carrier gas. Preparative recycling high-performance liquid

chromatography (HPLC) was performed with JAI LC-9104 equipped with JAIGEL-SIL

SH-043-15 column using a mixture of hexane–ethyl acetate (EtOAc) as eluent.

Preparative recycling gel permeation chromatography (GPC) was performed with JAI

LC-9105 equipped with JAIGEL-1H and JAIGEL-2H columns using chloroform as

eluent. High-resolution mass spectra (HRMS) were obtained with a JEOL JMS-

T100GCV spectrometer. All melting points were measured with a Yanaco Micro Melting

Point apparatus and uncorrected. Kugelrohr bulb-to-bulb distillation was carried out with

a Sibata glass tube oven GTO-250RS apparatus. Dibutyl ether and 1,4-dioxane were

distilled under argon from sodium just prior to use. Toluene (PhMe) and chlorobenzene

(PhCl) were distilled under argon from calcium chloride just prior to use. Propionitrile

(EtCN) was distilled under argon from P2O5 just prior to use. Nitromethane was stored

over molecular sieves 4A (MS 4A) under argon. Anhydrous N,N-dimethylformamide

(DMF) was purchased from Wako pure chemical industries and used as received. N-(2-

Phenylpropan-2-yl)pyrrole,8 6-heptyn-2-one, 21 and 1-[3-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)phenyl]ethanone8 were prepared according to the respective literature

procedures. Unless otherwise noted, other substrates and reagents were commercially

available and used as received.

130

Synthesis of N-isopropylpyrrole.

Based on the literature procedure,22 N-isopropylpyrrole was synthesized with

the following reagents: isopropylamine (5.91 g, 100 mmol), 2,5-

dimethoxytetrahydrofuran (13.2 g, 100 mmol) and acetic acid (50.0 mL), and isolated in

29% yield (3.17 g) by vacuum distillation (85 ºC/160 hPa). A colorless oil. 1H NMR (400

MHz, CDCl3) δ 1.45 (d, J = 5.4 Hz, 6 H), 4.25 (sept, J = 5.4 Hz, 1 H), 6.15 (t, J = 1.7 Hz,

2 H), 6.73 (t, J = 1.7 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 24.0, 50.7, 107.7, 118.1.


Synthesis of N-(1-phenylethyl)pyrrole.

Based on the literature procedure,22 N-(1-phenylethyl)pyrrole was synthesized

with the following reagents: 1-phenylethylamine (6.06 g, 50.0 mmol), 2,5-

dimethoxytetrahydrofuran (6.61 g, 50.0 mmol) and acetic acid (22.5 mL), and isolated in

60% yield (5.15 g) by vacuum distillation (82 ºC/133 Pa). A colorless oil. 1H NMR (500

MHz, CDCl3) δ 1.83 (d, J = 6.9 Hz, 3 H), 5.28 (q, J = 7.1 Hz, 1 H), 6.19 (dd, J = 2.3, 1.7

Hz, 2 H), 6.76 (dd, J = 2.3, 1.7 Hz, 2 H), 7.09 (d, J = 7.5 Hz, 2 H), 7.22–7.27 (m, 1 H),

7.31 (t, J = 7.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3) δ 22.1, 58.1, 108.0, 119.5, 125.8,

127.4, 128.6, 143.5. HRMS (FI) Calcd for C12H13N: M, 171.1048. Found: m/z 171.1020.

Synthesis of N-tert-butylpyrrole. N-tert-Butylpyrrole was synthesized according to the following modified

literature procedure.22 Under an argon atmosphere, a 300 mL two-necked round-bottomed

flask was charged with tert-butylamine (29.3 g, 400 mmol), acetic acid (90.0 mL) and

2,5-dimethoxytetrahydrofurran (26.4 g, 200 mmol). After stirring at 80 ºC for 50 h, the

reaction mixture was diluted with Et2O (200 mL). The resulting solution was washed with

a 2 M NaOH aqueous solution (100 mL x 3), H2O (100 mL) and brine (100 mL), and then

dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent followed

by vacuum distillation (78 ºC/80 hPa) provided N-tert-butylpyrrole (16.6 g, 67% yield)

as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9 H), 6.16 (t, J = 2.2 Hz, 2 H),

6.84 (t, J = 2.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 30.8, 54.6, 107.4, 117.5. HRMS

131

(FI) Calcd for C8H13N: M, 123.1048. Found: m/z 123.1017.

HNTf2-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH. A General Procedure of Method A for Table 2. A flame-dried 20 mL Schlenk tube was filled with argon and then charged with

HNTf2 [(1.69 mg, 6.00 µmol), (5.06 mg, 18.0 µmol), (8.43 mg, 30.0 µmol) or (11.8 mg,

42.0 µmol)] and 1,4-dioxane (0.60 mL). The solution was stirred at room temperature for

3 min. To this were added carbonyl compound 5 (0.600 mmol), pyrrole derivative 1 (1.80

or 2.40 mmol) and Et3SiH (3a) (0.900, 1.80 or 4.20 mmol), and the resulting mixture was

stirred at 50, 85 or 100 °C. After the time specified in Table 2 (see t1), a saturated NaHCO3

aqueous solution (0.3 mL) was added, and the aqueous phase was extracted with EtOAc

(5 mL x 3). The combined organic layer was washed with brine (1 mL) and then dried

over anhydrous sodium sulfate. Filtration and evaporation of the solvent followed by

column chromatography on silica gel using hexane–EtOAc or hexane–CHCl3 as eluent

gave the corresponding product (4). The results are summarized in Table 2. Unless

otherwise noted, products 4 synthesized here were fully characterized by 1H and 13C NMR


HNTf2-Catalyzed Reductive !-Alkylation of Pyrroles with Carbonyl Compounds and Et3SiH. A General Procedure of Method B for Table 2.

A flame-dried 20 mL Schlenk tube was filled with argon and then charged with

HNTf2 [(5.06 mg, 18.0 µmol) or (11.8 mg, 42.0 µmol)] and 1,4-dioxane (0.60 mL). The

solution was stirred at room temperature for 3 min. To this were added carbonyl

compound 5 (0.600 mmol) and pyrrole derivative 1 (1.80 or 2.40 mmol), and the resulting

mixture was stirred at 85 or 100 °C for 3, 4 or 24 h. Et3SiH (3a) (0.900 or 1.80 mmol)

was then added, and the resulting solution was stirred further at 85 or 100 ºC. After the

time specified in Table 2 (see t3), the work-up process was carried out similarly as above.

The results are summarized in Table 2. Unless otherwise noted, products 4 prepared here

were fully characterized by 1H and 13C NMR spectroscopy, and HRMS.

3-(Decan-2-yl)-1-methyl-1H-pyrrole (4a). The title compound was

synthesized with the following reagents based on method A: 5a (0.600 mmol), 1a (1.80

132

mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60 mL), and isolated by

column chromatography on silica gel (hexane/EtOAc = 80/1). Compound 4a has already

appeared in the literature, and its spectral and analytical data are in good agreement with

those reported in reference 8. Therefore, only 1H NMR data are provided here. 1H NMR

(400 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.20–1.35 (m,

12 H), 1.36–1.47 (m, 1 H), 1.48–1.58 (m, 1 H), 2.60 (sext, J = 7.0 Hz, 1 H), 3.60 (s, 3 H),

5.98 (t, J = 2.1 Hz, 1 H), 6.37 (dd, J = 2.0, 1.8 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H).

3-(Hexan-2-yl)-1-methyl-1H-pyrrole (4b). The title compound was

synthesized with the following reagents based on method A: for the reaction performed

on 0.600 mmol scale: 2-hexanone (0.600 mmol), 1a (1.80 mmol), 3a (0.900 mmol),

HNTf2 (18.0 µmol) and 1,4-dioxane (0.60 mL), and isolated by column chromatography

on silica gel (hexane/EtOAc = 80:1); for the reaction performed on 7.50 mmol scale: 2-

hexanone (7.50 mmol), 1a (22.5 mmol), 3a (11.3 mmol), HNTf2 (225 µmol) and 1,4-


= 80/1). A colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3 H), 1.17 (d,

J = 6.9 Hz, 3 H), 1.22–1.34 (m, 4 H), 1.37–1.48 (m, 1 H), 1.49–1.59 (m, 1 H), 2.60 (sext,

J = 6.9 Hz, 1 H), 3.60 (s, 3 H), 5.99 (t, J = 2.2 Hz, 1 H), 6.37 (t, J = 2.0 Hz, 1 H), 6.50

(dd, J = 2.6, 2.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.2, 22.9, 29.9, 31.8,

36.0, 38.5, 106.7, 118.0, 121.2, 131.1. HRMS (FI) Calcd for C11H19N: M, 165.1518.

Found: m/z 165.1504.

1-Methyl-3-(pentan-3-yl)-1H-pyrrole (4c). The title compound was

synthesized with the following reagents based on method A: 3-pentanone (0.600 mmol),

1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (30.0 µmol) and 1,4-dioxane (0.60 mL), and

isolated by column chromatography on silica gel (hexane/EtOAc = 100/1). A colorless

oil. 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 7.5 Hz, 6 H), 1.40–1.51 (m, 2 H), 1.51–

1.65 (m, 2 H), 2.25 (tt, J = 8.1, 5.6 Hz, 1 H), 3.60 (s, 3 H), 5.93 (t, J = 2.2 Hz, 1 H), 6.35

(t, J = 1.9 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 12.1, 29.0,

36.0, 41.2, 106.9, 119.0, 121.1, 128.6. HRMS (FI) Calcd for C10H17N: M, 151.1361.

Found: m/z 151.1334.

3-Cycloheptyl-1-methyl-1H-pyrrole (4d). The title compound was

synthesized with the following reagents based on method A: cycloheptanone (0.600

mmol), 1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60 mL),

and isolated by column chromatography on silica gel (hexane/EtOAc = 40/1). Compound

133

4d has already appeared in the literature, and its spectral and analytical data are in good


here. 1H NMR (400 MHz, CDCl3) δ 1.45–1.78 (m, 10 H), 1.91–2.03 (m, 2 H), 2.57–2.71

(m, 1 H), 3.59 (s, 3 H), 5.99 (dd, J = 2.3, 2.1 Hz, 1 H), 6.37 (t, J = 1.9 Hz, 1 H), 6.49 (dd,

J = 2.5, 2.3 Hz, 1 H).

3-(Adamant-2-yl)-1-methyl-1H-pyrrole (4e). The title compound was

synthesized with the following reagents based on method A: 2-adamantanone (0.600

mmol), 1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60 mL)

or with the following reagents based on method B: 2-adamantanone (0.600 mmol), 1a

(2.40 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60 mL), and

isolated by column chromatography on silica gel (hexane/EtOAc = 30/1). Compound 4e



here. 1H NMR (500 MHz, CDCl3) δ 1.51 (d, J = 13.2 Hz, 2 H), 1.75 (s, 3 H), 1.84–1.96

(m, 5 H), 1.99 (d, J = 12.6 Hz, 2 H), 2.15 (dd, J = 4.9, 3.2 Hz, 2 H), 2.92 (s, 1 H), 3.63 (s,

3 H), 6.02 (t, J = 2.0 Hz, 1 H), 6.42 (dd, J = 3.2, 2.0 Hz, 1 H), 6.54 (t, J = 2.3 Hz, 1 H).

1-Methyl-3-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrole (4f). The title

compound was synthesized with the following reagents based on method A: tetrahydro-

2H-thiopyran-4-one (0.600 mmol), 1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (30.0 µmol)


(hexane/EtOAc = 20/1). Compound 4f has already appeared in the literature, and its

spectral and analytical data are in good agreement with those reported in reference 8.

Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) δ 1.73 (dtd,

J = 13.3, 12.0, 3.4 Hz, 2 H), 2.21 (dq, J = 13.8, 3.4 Hz, 2 H), 2.47 (tt, J = 11.8, 3.3 Hz, 1

H), 2.62–2.70 (m, 2 H), 2.79 (td, J = 12.9, 2.5 Hz, 2 H), 3.61 (s, 3 H), 5.99 (t, J = 2.2 Hz,

1 H), 6.38 (t, J = 1.8 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1 H).

1-Methyl-3-(6-methyl-5-hepten-2-yl)-1H-pyrrole (4g). The title compound

was synthesized with the following reagents based on method A: 6-methyl-5-hepten-2-

one (0.600 mmol), 1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (42.0 µmol) and 1,4-dioxane


(hexane/CHCl3 = 5/1). Compound 4g has already appeared in the literature, and its


Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) δ 1.19 (d,

134

J = 6.9 Hz, 3 H), 1.41–1.52 (m, 1 H), 1.55–1.63 (m, 1 H), 1.58 (s, 3 H), 1.68 (d, J = 0.9

Hz, 3 H), 1.97 (q, J = 7.6 Hz, 2 H), 2.62 (sext, J = 7.0 Hz, 1 H), 3.60 (s, 3 H), 5.08–5.16

(m, 1 H), 5.99 (t, J = 2.2 Hz, 1 H), 6.37 (dd, J = 2.1, 1.8 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1

H).

3-(6-Heptyn-2-yl)-1-methyl-1H-pyrrole (4h). The title compound was

synthesized with the following reagents based on method A: 6-heptyn-2-one (0.600


and isolated by column chromatography on silica gel (hexane/EtOAc = 20/1). A colorless

oil. 1H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.9 Hz, 3 H), 1.49–1.66 (m, 4 H), 1.93 (t,

J = 2.6 Hz, 1 H), 2.17 (td, J = 6.7, 2.8 Hz, 2 H), 2.63 (sext, J = 6.8 Hz, 1 H), 3.60 (s, 3

H), 5.98 (dd, J = 2.2, 1.9 Hz, 1 H), 6.38 (t, J = 1.9 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1 H); 13C

NMR (125 MHz, CDCl3) δ 18.6, 22.3, 26.6, 31.5, 36.0, 37.7, 68.0, 84.9, 106.6, 118.1,


4-(1-Methyl-1H-pyrrol-3-yl)pentyl acetate (4i). The title compound was

synthesized with the following reagents based on method A: 5-acetoxypentan-2-one

(0.600 mmol), 1a (1.80 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane

(0.60 mL), and isolated by column chromatography on silica gel (hexane/EtOAc = 8/1).

Compound 4i has already appeared in the literature, and its spectral and analytical data

are in good agreement with those reported in reference 8. Therefore, only 1H NMR data

are provided here. 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J = 7.1 Hz, 3 H), 1.46–1.68 (m,

4 H), 2.03 (s, 3 H), 2.64 (sext, J = 6.9 Hz, 1 H), 3.60 (s, 3 H), 4.04 (t, J = 6.6 Hz, 2 H),

5.98 (dd, J = 2.3, 2.1 Hz, 1 H), 6.38 (dd, J = 2.1, 1.8 Hz, 1 H), 6.51 (dd, J = 2.5, 2.3 Hz,

1 H).

Dihydro-3-[1-(1-methyl-1H-pyrrol-3-yl)ethyl]-2(3H)-furanone (4j). The

title compound was synthesized with the following reagents based on method A: 3-

acetyldihydro-2(3H)-furanone (0.600 mmol), 1a (1.80 mmol), 3a (1.80 mmol), HNTf2


gel (hexane/EtOAc = 3/1) as a 78/22 mixture of diastereomers. The mixture was then

separated by recycling HPLC (hexane/EtOAc = 3:1). For the major isomer: A colorless

oil. 1H NMR (500 MHz) δ 1.27 (d, J = 7.2 Hz, 3 H), 2.10–2.23 (m, 2 H), 2.88 (td, J = 9.5,

3.8 Hz, 1 H), 3.34 (qd, J = 7.1, 3.8 Hz, 1 H), 3.61 (s, 3 H), 4.10–4.20 (m, 2 H), 6.01 (t, J = 2.3 Hz, 1 H), 6.44 (t, J = 1.7 Hz, 1 H), 6.53 (t, J = 2.4 Hz, 1 H); 13C NMR (125 MHz,

CDCl3) δ 16.5, 24.3, 31.7, 36.1, 45.8, 66.7, 107.1, 118.8, 121.8, 126.5, 178.8. HRMS (FI)

135

Calcd for C11H15NO2: M, 193.1103. Found: m/z 193.1085. For the minor isomer: A

colorless oil. 1H MNR (500 MHz) δ 1.34 (d, J = 7.2 Hz, 3 H), 2.05 (dq, J = 12.7, 8.5 Hz,

1 H), 2.12–2.20 (m, 1 H), 2.68 (td, J = 9.0, 4.5 Hz, 1 H), 3.42 (qd, J = 7.2, 4.3 Hz, 1 H),

3.59 (s, 3 H), 3.93 (td, J = 8.7, 4.4 Hz, 1 H), 4.09 (dt, J = 8.6, 8.0 Hz, 1 H), 6.00 (t, J =

2.3 Hz, 1 H), 6.43 (dd, J = 2.0, 1.7 Hz, 1 H), 6.50 (t, J = 2.5 Hz, 1 H); 13C NMR (125

MHz, CDCl3) δ 19.7, 23.8, 31.7, 36.1, 46.5, 66.8, 107.5, 119.8, 121.5, 124.1, 179.4.

HRMS (FI) Calcd for C11H15NO2: M, 193.1103. Found: m/z 193.1097.

3-(6-Chlorohexan-2-yl)-1-methyl-1H-pyrrole (4k). The title compound was

synthesized with the following reagents based on method A: 6-chlorohexan-2-one (0.600


and isolated by column chromatography on silica gel (hexane/EtOAc = 20/1). Compound

4k has already appeared in the literature, and its spectral and analytical data are in good


here. 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J = 6.9 Hz, 3 H), 1.36–1.61 (m, 4 H), 1.76

(quint, J = 7.1 Hz, 2 H), 2.62 (sext, J = 6.8 Hz, 1 H), 3.51 (t, J = 6.9 Hz, 2 H), 3.60 (s, 3

H), 5.98 (dd, J = 2.3, 2.1 Hz, 1 H), 6.37 (dd, J = 2.1, 1.8 Hz, 1 H), 6.51 (dd, J = 2.5, 2.3

Hz, 1 H).

1-Benzyl-3-(decan-2-yl)-1H-pyrrole (4l). The title compound was

synthesized with the following reagents based on method A: 5a (0.600 mmol), 1-benzyl-

1H-pyrrole (1.80 mmol), 1a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60

mL), and isolated by column chromatography on silica gel (hexane/CHCl3 = 8/1).

Compound 4l has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3 H), 1.17 (d, J =

6.9 Hz, 3 H), 1.21–1.34 (m, 12 H), 1.37–1.48 (m, 1 H), 1.49–1.57 (m, 1 H), 2.61 (sext, J = 6.9 Hz, 1 H), 5.00 (s, 2 H), 6.03 (dd, J = 2.6, 1.7 Hz, 1 H), 6.44 (dd, J = 2.0, 1.7 Hz, 1

H), 6.59 (t, J = 2.5 Hz, 1 H), 7.07–7.12 (m, 2 H), 7.24–7.28 (m, 1 H), 7.31 (tt, J = 7.3, 1.6

Hz, 2 H).

3-(Decan-2-yl)-1-isopropyl-1H-pyrrole (4m). The title compound was

synthesized with the following reagents based on method A: 5a (0.600 mmol), N-

isopropylpyrrole (1.80 mmol), 3a (0.900 mmol), HNTf2 (6.00 µmol) and 1,4-dioxane

(0.60 mL), and isolated by column chromatography on silica gel (hexane/EtOAc = 50/1).

A colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 6.9 Hz, 3 H), 1.18 (d, J = 6.9

136

Hz, 3 H), 1.20–1.35 (m, 12 H), 1.37–1.47 (m, 1 H), 1.43 (d, J = 6.6 Hz, 6 H), 1.50–1.60

(m, 1 H), 2.60 (sext, J = 6.9 Hz, 1 H), 4.16 (sept, J = 6.7 Hz, 1 H), 5.99 (t, J = 2.3 Hz, 1

H), 6.48 (t, J = 2.0 Hz, 1 H), 6.63 (dd, J = 2.6, 2.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3)

δ 14.1, 21.9, 22.7, 23.9, 27.7, 29.4, 29.7, 29.9, 31.91, 31.94, 38.8, 50.4, 105.9, 114.5,


3-Isopropyl-1-(1-phenylethyl)-1H-pyrrole (4n). The title compound was

synthesized with the following reagents based on method A: acetone (7.00 mmol), N-(1-

phenylethyl)pyrrole (21.0 mmol), 3a (10.5 mmol), HNTf2 (0.350 mmol), and 1,4-dioxane

(7.0 mL), and isolated by column chromatography on silica gel (hexane/CHCl3 = 3/1). In

the process of purifying 4n, N-(1-phenylethyl)pyrrole was also collected with a recovery

efficiency of 95% (13.3 mmol), which was calculated based on 14.0 mmol of N-(1-

phenylethyl)pyrrole used as an excess amount. A colorless oil. 1H NMR (400 MHz,

CDCl3) δ 1.19 (d, J = 6.6 Hz, 3 H), 1.20 (d, J = 6.9 Hz, 3 H), 1.80 (d, J = 7.1 Hz, 3 H),

2.81 (sept, J = 6.9 Hz, 1 H), 5.20 (q, J = 7.1 Hz, 1 H), 6.07 (t, J = 2.2 Hz, 1 H), 6.49–6.54

(m, 1 H), 6.66 (t, J = 2.5 Hz, 1 H), 7.04–7.11 (m, 2 H), 7.21–7.25 (m, 1 H), 7.27–7.33 (m,

2 H); 13C NMR (100 MHz, CDCl3) δ 22.1, 24.05, 24.07, 26.5, 58.0, 106.5, 115.4, 119.0,

125.9, 127.3, 128.6, 131.7, 143.9. HRMS (FI) Calcd for C15H19N: M, 213.1518. Found:

m/z 213.1530.

1-tert-Butyl-3-(decan-2-yl)-1H-pyrrole (4o). The title compound was

synthesized with the following reagents based on method A: 5a (0.600 mmol), N-tert-butylpyrrole (1.80 mmol), 3a (0.900 mmol), HNTf2 (6.00 µmol) and 1,4-dioxane (0.60


Compound 4o has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 6.9 Hz, 3 H), 1.18 (d, J =

7.2 Hz, 3 H), 1.21–1.35 (m, 12 H), 1.36–1.61 (m, 2 H), 1.50 (s, 9 H), 2.61 (sext, J = 6.9

Hz, 1 H), 6.00 (dd, J = 2.6, 2.0 Hz, 1 H), 6.58 (dd, J = 2.3, 1.7 Hz, 1 H), 6.73 (t, J = 2.3

Hz, 1 H).

3-(Decan-2-yl)-1-phenyl-1H-pyrrole (4p). The title compound was

synthesized with the following reagents based on method B: 5a (0.600 mmol), N-

phenylpyrrole (2.40 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane (0.60

mL), and isolated by column chromatography on silica gel (hexane/CHCl3 = 5/1).

Compound 4p has already appeared in the literature, and its spectral and analytical data

137


are provided here. 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 6.9 Hz, 3 H), 1.19–1.39 (m,

12 H), 1.23 (d, J = 6.9 Hz, 3 H), 1.42–1.64 (m, 2 H), 2.68 (sext, J = 6.9 Hz, 1 H), 6.21

(dd, J = 2.9, 1.7 Hz, 1 H), 6.86–6.89 (m, 1 H), 7.02 (dd, J = 2.7, 2.4 Hz, 1 H), 7.19 (tt, J = 6.9, 1.7 Hz, 1 H), 7.35–7.42 (m, 4 H).

1,2-Dimethyl-4-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrole (4q). The title

compound was synthesized with the following reagents based on method A: tetrahydro-

2H-thiopyran-4-one (0.600 mmol), 1,2-dimethylpyrrole (1.80 mmol), 3a (1.80 mmol),


on silica gel (hexane/EtOAc = 20/1). A white solid, mp = 60–61 ºC. 1H NMR (500 MHz,

CDCl3) δ 1.71 (dtd, J = 13.2, 12.1, 3.4 Hz, 2 H), 2.16–2.22 (m, 2 H), 2.18 (d, J = 1.4 Hz,

3 H), 2.42 (tt, J = 11.6, 3.3 Hz, 1 H), 2.62–2.68 (m, 2 H), 2.78 (ddd, 13.7, 12.2, 2.4 Hz, 2

H), 3.46 (s, 3 H), 5.75 (d, J = 0.9 Hz, 1 H), 6.31 (d, J = 2.0 Hz, 1 H); 13C NMR (125 MHz,

CDCl3) δ 11.9, 29.1, 33.4, 35.6, 36.0, 105.0, 116.7, 128.5, 128.7. HRMS (FI) Calcd for

C11H17NS: M, 195.1082. Found: m/z 195.1082.

1-Methyl-3-(1-phenylethyl)-1H-pyrrole (4r). The title compound was

synthesized with the following reagents based on method B: acetophenone (0.600 mmol),

1a (1.80 mmol), 3a (1.80 mmol), HNTf2 (42.0 µmol) and 1,4-dioxane (0.60 mL), and

isolated by bulb-to-bulb distillation (100 ºC/100 Pa) after column chromatography on

silica gel (hexane/EtOAc = 20/1). Compound 4r has already appeared in the literature,

and its spectral and analytical data are in good agreement with those reported in reference

8. Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) δ 1.56

(d, J = 7.3 Hz, 3 H), 3.58 (s, 3 H), 4.00 (q, J = 7.2 Hz, 1 H), 5.96 (t, J = 2.1 Hz, 1 H),

6.29–6.33 (m, 1 H), 6.51 (dd, J = 2.5, 2.3 Hz, 1 H), 7.14–7.20 (m, 1 H), 7.24–7.31 (m, 4

H).

1-Isopropyl-3-(1-phenylethyl)-1H-pyrrole (4s). The title compound was

synthesized with the following reagents based on method B: acetophenone (0.600 mmol),

N-isopropylpyrrole (2.40 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane

(0.60 mL), and isolated by column chromatography on silica gel (hexane/CHCl3 = 10/3).

A colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J = 6.6 Hz, 3 H), 1.42 (d, J = 6.6

Hz, 3 H), 1.56 (d, J = 7.2 Hz, 3 H), 4.01 (q, J = 7.2 Hz, 1 H), 4.15 (sept, J = 6.7 Hz, 1 H),

5.95 (t, J = 2.3 Hz, 1 H), 6.41–6.45 (m, 1 H), 6.63 (t, J = 2.6 Hz, 1 H), 7.14–7.19 (m, 1

H), 7.24–7.30 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 22.8, 23.86, 23.91, 38.2, 50.5,

138

106.9, 115.5, 117.9, 125.6, 127.4, 128.1, 128.7, 148.1. HRMS (FI) Calcd for C15H19N: M,

213.1518. Found: m/z 213.1509.

1-Isopropyl-3-{1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)phenyl]ethyl}-1H-pyrrole (4t). The title compound was synthesized with the

following reagents based on method B: 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)phenyl]ethanone (0.600 mmol), N-isopropylpyrrole (2.40 mmol), 3a (0.900 mmol),


on silica gel (hexane/EtOAc/NEt3 = 92/5/3). A viscous colorless oil. 1H NMR (500 MHz,

CDCl3) δ 1.34 (s, 12 H), 1.40 (d, J = 6.6 Hz, 3 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.56 (d, J =

7.2 Hz, 3 H), 4.03 (q, J = 7.2 Hz, 1 H), 4.14 (sept, J = 6.7 Hz, 1 H), 5.95 (dd, J = 2.3, 2.0

Hz, 1 H), 6.39–6.46 (m, 1 H), 6.62 (t, J = 2.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.34

(ddd, J = 7.7, 1.8, 1.4, Hz, 1 H), 7.63 (ddd, J = 7.2, 1.5, 1.2 Hz, 1 H), 7.72–7.75 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 22.8, 23.86, 23.90, 24.9, 38.2, 50.5, 83.6, 107.0, 115.6,

117.8, 127.7, 128.8, 130.4, 132.3, 133.9, 147.3 (A signal of the boron-bound carbon atom

was not detected due to quadrupolar relaxation of boron). HRMS (FD) Calcd for

C21H30BNO2: M, 339.2370. Found: m/z 339.2396.

1-Isopropyl-3-[1-(3-thienyl)ethyl]-1H-pyrrole (4u). The title compound was

prepared with the following reagents based on method B: 3-acetylthiophene (0.600

mmol), N-isopropylpyrrole (2.40 mmol), 3a (0.900 mmol), HNTf2 (42.0 µmol) and 1,4-


= 20/1). A colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.411 (d, J = 6.6 Hz, 3 H), 1.413

(d, J = 6.6 Hz, 3 H), 1.56 (d, J = 7.0 Hz, 3 H), 4.09 (q, J = 7.1 Hz, 1 H), 4.15 (sept, J =

6.7 Hz, 1 H), 5.98 (t, J = 2.2 Hz, 1 H), 6.42–6.44 (m, 1 H), 6.63 (t, J = 2.5 Hz, 1 H), 6.94–

6.97 (m, 1 H), 7.00 (dd, J = 4.9, 1.3 Hz, 1 H), 7.21 (dd, J = 5.0, 3.0 Hz, 1 H); 13C NMR

(125 MHz, CDCl3) δ 22.8, 23.88, 23.90, 33.6, 50.5, 106.7, 115.3, 117.8, 119.3, 124.8,

127.8, 128.5, 148.9. HRMS (FI) Calcd for C13H17NS: M, 219.1082. Found: m/z 219.1088.

3-(Decan-1-yl)-1-(2-phenylpropan-2-yl)-1H-pyrrole (4v). The title

compound was synthesized with the following reagents based on method A: 1-decanal

(0.600 mmol), N-(2-phenylpropan-2-yl)pyrrole (2.40 mmol), 3a (4.20 mmol), HNTf2


gel (hexane/EtOAc = 5/1). Compound 4v has already appeared in the literature, and its


Therefore, only 1H NMR data are provided here. 1H NMR (500 MHz, CDCl3) δ 0.88 (t,

139

J = 7.0 Hz, 3 H), 1.21–1.38 (m, 14 H), 1.56 (quint, J = 7.5 Hz, 2 H), 1.86 (s, 6 H), 2.45

(t, J = 7.8 Hz, 2 H), 6.04 (dd, J = 2.0, 1.6 Hz, 1 H), 6.52–6.55 (m, 1 H), 6.70 (t, J = 2.6

Hz, 1 H), 6.95–6.99 (m, 2 H), 7.21 (tt, J = 7.3, 1.6 Hz, 1 H), 7.24–7.30 (m, 2 H).

3-(1-Cyclohexylmethyl)-1-(2-phenylpropan-2-yl)-1H-pyrrole (4w). The

title compound was synthesized with the following reagents based on method A:

cyclohexanecarboxaldehyde (0.600 mmol), N-(2-phenylpropan-2-yl)pyrrole (2.40 mmol),

3a (1.80 mmol), HNTf2 (42.0 µmol) and 1,4-dioxane (0.60 mL), and isolated by column

chromatography on silica gel (hexane/CHCl3 = 4/1). A colorless oil. 1H NMR (500 MHz,

CDCl3) δ 0.89 (qd, J = 12.0, 2.9 Hz, 2 H), 1.08–1.28 (m, 3 H), 1.41 (ttt, J = 11.2, 7.3, 3.7

Hz, 1 H), 1.59–1.78 (m, 5 H), 1.85 (s, 6 H), 2.32 (d, J = 7.2 Hz, 2 H), 6.00 (dd, J = 2.8,

1.9 Hz, 1 H), 6.50 (dd, J = 2.5, 1.9 Hz, 1 H), 6.70 (t, J = 2.6 Hz, 1 H), 6.93–6.97 (m, 2

H), 7.20 (tt, J = 7.3, 1.6 Hz, 1 H), 7.24–7.29 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ

26.5, 26.7, 30.5, 33.4, 35.3, 39.5, 59.9, 108.4, 117.5, 118.7, 122.6, 124.9, 126.8, 128.3,

148.6. HRMS (FI) Calcd for C20H27N: M, 281.2144. Found: m/z 281.2158.

1-tert-Butyl-3-neopentyl-1H-pyrrole (4x). The title compound was

synthesized with the following reagents based on method A: pivalaldehyde (0.600 mmol),

N-tert-butylpyrrole (2.40 mmol), 3a (0.900 mmol), HNTf2 (18.0 µmol) and 1,4-dioxane

(0.60 mL), and isolated by column chromatography on silica gel (hexane/EtOAc = 100:1).

Compound 4x has already appeared in the literature, and its spectral and analytical data


are provided here. 1H NMR (500 MHz, CDCl3) δ 0.88 (s, 9 H), 1.50 (s, 9 H), 2.31 (s, 2

H), 5.93 (dd, J = 2.6, 2.0 Hz, 1 H), 6.55 (dd, J = 2.3, 2.0 Hz, 1 H), 6.70 (t, J = 2.6 Hz, 1

H).

HNTf2-Catalyzed !-Alkylation of Pyrroles with Carbonyl Compounds and Carbon Nucleophiles. A General Procedure for Scheme 3.

A flame-dried 20 mL Schlenk tube was filled with argon and then charged with HNTf2

[(4.22 mg, 15.0 µmol) or (5.90 mg, 21.0 µmol)] and 1,4-dioxane (0.30 or 2.4 mL). The

solution was stirred at room temperature for 3 min. To this were added carbonyl

compound 5 (0.300 mmol) and pyrrole derivative 1 (1.20 mmol), and the resulting

mixture was stirred at 85 or 100 °C for 8 or 20 h. Carbon nucleophile 3 (0.450, 0.750 or

0.900 mmol) was then added, and the resulting solution was stirred further at 70, 85 or

140

100 ºC. After the time specified in Scheme 3 (see t2), a saturated NaHCO3 aqueous

solution (0.3 mL) was added, and the aqueous phase was extracted with EtOAc (5 mL x

3). The combined organic layer was washed with brine (1 mL) and then dried over


chromatography on silica gel using hexane–EtOAc or hexane–CHCl3 as eluent gave the

corresponding product (7). The results are summarized in Scheme 3. Unless otherwise

noted, products 7 synthesized here were fully characterized by 1H and 13C NMR


2-(1-Methyl-1H-pyrrol-3-yl)-2-adamantanecarbonitrile (7a). The title

compound was synthesized with the following reagents based on method B: 2-

adamantanone (0.300 mmol), 1a (1.20 mmol), 3b (0.450 mmol), HNTf2 (21.0 µmol) and

1,4-dioxane (0.30 mL), and isolated by column chromatography on silica gel

(hexane/EtOAc = 3/1). A white solid, mp = 106–107 ºC. 1H NMR (500 MHz, CDCl3) δ

1.61 (ddd, J = 13.1, 3.6, 2.7 Hz, 2 H), 1.70–1.77 (m, 3 H), 1.92 (ddd, J = 13.3, 3.6, 2.7

Hz, 2 H), 1.97–2.05 (m, 3 H), 2.41 (dd, J = 13.2, 2.3 Hz, 2 H), 2.46 (t, J = 2.9 Hz, 2 H),

3.64 (s, 3 H), 6.10 (dd, J = 2.9, 1.7 Hz, 1 H), 6.55 (dd, J = 2.3, 1.7 Hz, 1 H), 6.57 (dd, J = 2.9, 2.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 26.9, 31.5, 34.1, 34.9, 36.4, 37.63,

37.64, 42.9, 106.5, 119.6, 122.1, 123.0, 124.9. HRMS (FD) Calcd for C16H20N2: M,

240.1627. Found: m/z 240.1624.

2-(1-Benzyl-1H-pyrrol-3-yl)-2-(5-methylfuran-2-yl)octane (7b). The title

compound was synthesized with the following reagents based on method B: 2-octanone

(0.300 mmol), 1-benzyl-1H-pyrrole (1.20 mmol), 3c (0.750 mmol), HNTf2 (15.0 µmol)


(hexane/CHCl3 = 4/1). Compound 7b has already appeared in the literature, and its


Therefore, only 1H NMR data are provided here. 1H NMR (400 MHz, CDCl3) δ 0.85 (t,

J = 6.9 Hz, 3 H), 1.07–1.31 (m, 8 H), 1.51 (s, 3 H), 1.75–1.86 (m, 1 H), 1.88–2.00 (m, 1

H), 2.24 (d, J = 0.9 Hz, 3 H), 5.00 (s, 2 H), 5.80–5.83 (m, 1 H), 5.85 (d, J = 3.2 Hz, 1 H),

6.06 (dd, J = 2.7, 1.8 Hz, 1 H), 6.45 (dd, J = 2.3, 1.8 Hz, 1 H), 6.56 (dd, J = 2.7, 2.3 Hz,

1 H), 7.04–7.10 (m, 2 H), 7.22–7.34 (m, 3 H).

5’,6’-Dihydro-6’-(4-methoxyphenyl)-1’-methyl-spiro[adamantane-2,4’(1’H)-cyclopenta[b]pyrrole] (7c). The title compound was synthesized with the

following reagents based on method B: 2-adamantanone (0.300 mmol), 1a (1.20 mmol),

141

3d (0.900 mmol), HNTf2 (21.0 µmol) and 1,4-dioxane (0.30 mL), and isolated by column

chromatography on silica gel (hexane/CHCl3 = 2/1). A viscous colorless oil. 1H NMR

(500 MHz, CDCl3) δ 1.56–1.72 (m, 6 H), 1.76 (s, 2 H), 1.78–1.85 (m, 2 H), 1.95 (quint,

J = 2.9 Hz, 1 H), 2.02 (ddd, J = 12.7, 5.4, 3.3 Hz, 1 H), 2.11 (dd, J = 13.2, 6.6 Hz, 1 H),

2.33 (ddd, J = 12.6, 6.3, 3.5 Hz, 1 H), 2.46 (ddd, J = 13.3, 6.0, 3.5 Hz, 1 H), 3.03 (dd, J = 13.2, 8.3 Hz, 1 H), 3.16 (s, 3 H), 3.79 (s, 3 H), 4.17 (dd, J = 8.0, 6.9 Hz, 1 H), 6.21 (d,

J = 2.9 Hz, 1 H), 6.50 (d, J = 2.6 Hz, 1 H), 6.83 (dt, J = 8.9, 2.6 Hz, 2 H), 7.07 (dt, J =

8.6, 2.4 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 27.4, 27.6, 33.9, 34.3, 34.4, 34.8, 35.1,

37.4, 38.9, 39.8, 42.2, 49.8, 54.3, 55.2, 106.0, 113.9, 123.2, 128.4, 134.8, 137.7, 137.9,


HNTf2-Catalyzed Synthesis of Dipyrrolyldecanes 6a by Treatment of 2-Decanone

(5a) and 1-Methylpyrrole (1a) (Scheme 4).


HNTf2 (59.0 mg, 210 µmol) and 1,4-dioxane (7.0 mL). The solution was stirred at room temperature for 3 min. To this were added 5a (1.09 g, 7.00 mmol) and 1a (2.27 g, 28.0

mmol) successively, and the resulting mixture was stirred at 85 °C for 5 h. A saturated

NaHCO3 aqueous solution (2 mL) was added, and the aqueous phase was extracted with

EtOAc (50 mL x 3). The combined organic layer was washed with brine (20 mL) and

then dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent

followed by column chromatography on silica gel (hexane/EtOAc = 20:1) gave

dipyrrolyldecanes 6a (1.92 g, 92% yield) as a mixture of three isomers including #,#’-6a, #,!’-6a and !,!’-6a. The result is summarized in Scheme 4. 1H NMR spectra showed

that !,!’-6a is a major isomer, along with #,!’-6a and a small amount of #,#’-6a. The

ratio of #,#’-6a:#,!’-6a:!,!’-6a was determined to be 2:13:85 by GC analysis. The two

major isomers, #,!’-6a and !,!’-6a, have already appeared in the literature, and their

spectral and analytical data are in good agreement with those reported in reference 7. Due

to the small amount of #,#’-6a produced here, other reaction for synthesizing #,#’-6a

was carried out under the reaction conditions shown in the next section, and #,#’-6a was

obtained as a pure form.

142

HNTf2-Catalyzed Synthesis of 2,2-Bis(1-methyl-1H-pyrrol-2-yl)decane (#,#’-6a) by Treatment of 2-Decanone (5a) and 1-Methylpyrrole (1a).


HNTf2 (5.06 mg, 18.0 µmol) and 1,4-dioxane (0.60 mL). The solution was stirred at room

temperature for 3 min. To this were added 5a (93.8 mg, 0.600 mmol) and 1a (195 mg,

2.40 mmol) successively, and the resulting mixture was stirred at room temperature for 3

h. A saturated NaHCO3 aqueous solution (0.3 mL) was added, and the aqueous phase was



solvent followed by column chromatography on silica gel (hexane/CHCl3 = 6/1) gave

#,#’-6a (29.0 mg, 16% yield) as a viscous colorless oil. 1H NMR (500 MHz, CDCl3) δ

0.87 (t, J = 7.0 Hz, 3 H), 1.04–1.34 (m, 12 H), 1.59 (s, 3 H), 2.01–2.09 (m, 2 H), 3.02 (s,

6 H), 6.02 (dd, J = 3.6, 2.7 Hz, 2 H), 6.07 (dd, J = 3.8, 2.0 Hz, 2 H), 6.45 (t, J = 2.3 Hz,

2 H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 24.0, 26.7, 29.4, 29.6, 30.2, 31.9, 34.3,

38.7, 39.7, 105.8, 106.7, 122.8, 137.7. HRMS (FI) Calcd for C20H32N2: M, 300.2566.

Found: m/z 300.2568.

HNTf2-Catalyzed Synthesis of 3-(Decan-2-yl)-1-methyl-1H-pyrrole (4a) by Treatment of Dipyrrolyldecanes 6a, Et3SiH (3a) and H2O (Scheme 4).


HNTf2 (2.53 mg, 9.00 µmol) and 1,4-dioxane (0.30 mL). The solution was stirred at room

temperature for 3 min. To this were added 6a (90.1 mg, 0.300 mmol), 3a (52.3 mg, 0.450

mmol) and H2O (5.40 mg, 0.300 mmol) successively, and the resulting mixture was

stirred at 85 °C for 5 h. A saturated NaHCO3 aqueous solution (0.3 mL) was added, and

the aqueous phase was extracted with EtOAc (5 mL x 3). The combined organic layer


and evaporation of the solvent followed by column chromatography on silica gel

(hexane/EtOAc = 40/1) gave 4a (62.6 mg, 94% yield). The result is summarized in

Scheme 4. The full data on 1H NMR, 13C NMR spectroscopy and HRMS analysis of 4a

have been already collected in reference 8.

143

IV-4. References and Notes

1 For selected recent reviews, see: a) N. K. Garg, B. M. Stoltz, Chem. Commun. 2006,

3769; b) N. R. Williamson, P. C. Fineran, F. J. Leeper, G. P. C. Salmond, Nat. Rev. Microbiol. 2006, 4, 887; c) C.-C. Chang, W.-C. Chen, T.-F. Ho, H.-S. Wu, Y.-H. Wei, J. Biosci. Bioeng. 2011, 111, 501. For selected recent reports, see: d) U. Robben, I. Lindner,

W. Gärtner, J. Am. Chem. Soc. 2008, 130, 11303; e) C. P. Soldermann, R. Vallinayagam,

M. Tzouros, R. Neier, J. Org. Chem. 2008, 73, 764; f) J. H. Frederich, P. G. Harran, J. Am. Chem. Soc. 2013, 135, 3788; g) C. Vergeiner, S. Banala, B. Kräutler, Chem. Eur. J.

2013, 19, 12294. 2 For selected recent examples, see: a) L. Jiao, E. Hao, M. G. H. Vicente, K. M. Smith,

J. Org. Chem. 2007, 72, 8119; b) G. Zotti, B. Vercelli, A. Berlin, Chem. Mater. 2008, 20,

397; c) X. Lv, L.-J. Hong, Y. Li, M.-J. Yang, J. Appl. Polym. Sci. 2009, 112, 1287; d) M.

Krayer, M. Ptaszek, H.-J. Kim, K. R. Meneely, D. Fan, K. Secor, J. S. Lindsey, J. Org. Chem. 2010, 75, 1016; e) J. T. Lee, D.-H. Chae, Z. Ou, K. M. Kadish, Z. Yao, J. L. Sessler,

J. Am. Chem. Soc. 2011, 133, 19547; f) T.-T. Bui, A. Iordache, Z. Chen, V. V.

Roznyatovskiy, E. Saint-Aman, J. M. Lim, B. S. Lee, S. Ghosh, J.-C. Moutet, J. L. Sessler,

D. Kim, C. Bucher, Chem. Eur. J. 2012, 18, 5853. 3 Heterocyclic Chemistry, 5th ed. (Eds.: J. A. Joule, K. Mills) Wiley, New York, 2010, pp.9–10. 4 For a selected review on the Friedel–Crafts alkylation of pyrroles, see: B. A. Trofimov,

N. A. Nedolya in Comprehensive Heterocyclic Chemistry III, Vol. 3 (Eds.: A. R. Katritzky,

C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor, G. Jones), Elsevier, Oxford, 2008, pp.

110–134. 5 For reviews on !-alkylation of pyrroles, see: a) H. J. Anderson, C. E. Loader, Synthesis

1985, 353; b) W. D. Harman, Chem. Rev. 1997, 97, 1953; c) B. C. Brooks, T. B. Gunnoe,

W. D. Harman, Coord. Chem. Rev. 2000, 206–207, 3; d) T. Tsuchimoto, Chem. Eur. J.

2011, 17, 4064. For selected recent reports on !-alkylation of pyrroles, see: e) D. Prajapati,

M. Gohain, B. J. Gogoi, Tetrahedron Lett. 2006, 47, 3535; f) O. I. Shmatova, N. E.

Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G. Nenajdenko, Eur. J. Org. Chem.

2013, 3049; See also references 6–8. 6 Among the strategies for the SEAr-based !-alkylation of pyrroles, a bulky

triisopropylsilyl group on the nitrogen atom has been known to direct incoming

144

electrophiles to the !-position, due to its effective steric shielding of the #-position. For

selected recent reports on the !-alkylation of N-(iPr)3Si–pyrrole, see: a) C. Berini, F.

Minassian, N. Pelloux-Léon, J.-N. Denis, Y. Vallée, C. Philouze, Org. Biomol. Chem. 2008, 6, 2574; b) J. Barluenga, A. Fernández, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2009, 15, 8121; c) C. Berini, N. Pelloux-Léon, F. Minassian, J.-N. Denis, Org. Biomol.

Chem. 2009, 7, 4512; d) F. Martinelli, A. Palmieri, M. Petrini, Chem. Eur. J. 2011, 17,

7183; e) L. Boiaryna, M. K. El Mkaddem, C. Taillier, V. Dalla, M. Othman, Chem. Eur. J. 2012, 18, 14192; f) F. de Nanteuil, J. Loup, J. Waser, Org. Lett. 2013, 15, 3738; g) S.

Lancianesi, A. Palmieri, M. Petrini, Adv. Synth. Catal. 2013, 355, 3285. 7 T. Tsuchimoto, T. Wagatsuma, K. Aoki, J. Shimotori, Org. Lett. 2009, 11, 2129. 8 T. Tsuchimoto, M. Igarashi, K. Aoki, Chem. Eur. J. 2010, 16, 8975. 9 For a report on increases in consumption and price of indium during the last few

decades, see: T. G. Goonan, “Materials Flow of Indium in the United States in 2008 and

2009” that can be found at http://pubs.usgs.gov/circ/1377. 10 For synthesis of In(NTf2)3 (Tf = SO2CF3), see: a) C. G. Frost, J. P. Hartley, D. Griffin,

Tetrahedron Lett. 2002, 43, 4789; b) M. Nakamura, K. Endo, E. Nakamura, Adv. Synth.

Catal. 2005, 347, 1681. For synthesis of In(ONf)3 (Nf = SO2C4F9), see: c) T. Tsuchimoto,

H. Matsubayashi, M. Kaneko, E. Shirakawa, Y. Kawakami, Angew. Chem. Int. Ed. 2005,

44, 1336. 11 In(NTf2)3 is currently commercially available from Sigma-Aldrich, but is expensive;

20,700 yen/1 g. 12 HNTf2 is commercially available at 20,000 yen/250 g (= 80 yen/1 g) from Kanto

Chemical Co., Inc. 13 Disappearance of carbonyl compounds 5 followed by formation of dipyrrolylalkanes

6 can be confirmed by GC and GC–MS analysis. 14 For representative reports of the research group to which the author belongs on indium-

catalyzed transformation via activation of C≡C bonds, see: a) T. Tsuchimoto, T. Maeda,

E. Shirakawa, Y. Kawakami, Chem. Commun. 2000, 1573; b) T. Tsuchimoto, K. Hatanaka,

E. Shirakawa, Y. Kawakami, Chem. Commun. 2003, 2454; c) T. Tsuchimoto, H.

Matsubayashi, M. Kaneko, Y. Nagase, T. Miyamura, E. Shirakawa, J. Am. Chem. Soc. 2008, 130, 15823; d) T. Tsuchimoto, M. Kanbara, Org. Lett. 2011, 13, 912; e) Y. Nagase,

H. Shirai, M. Kaneko, E. Shirakawa, T. Tsuchimoto, Org. Biomol. Chem. 2013, 11, 1456.

145

See also references 7 and 10c. 15 Other research groups have also reported indium-catalyzed transformation by way of

activation of C≡C bonds. See an important review: Z.-L. Shen, S.-Y. Wang, Y.-K. Chok,

T.-P. Loh, Chem. Rev. 2013, 113, 271. 16 N-Boc–pyrrole (1.8 mmol), 5a (0.60 mmol), 3a (0.90 mmol), HNTf2 (18 µmol), 1,4-

dioxane (0.60 mL), 85 °C, 5 h. 17

18 The process of the HNTf2-catalyzed reaction of 5a with 1a produces one molar

equivalent of H2O along with the formation of 6a. Accordingly, the reaction was

performed in the presence of H2O (1 equiv.). 19 a) D. M. Wallace, S. H. Leung, M. O. Senge, K. M. Smith, J. Org. Chem. 1993, 58,

7245; b) G. R. Geier III, B. J. Littler, J. S. Lindsey, J. Chem. Soc. Perkin Trans. 2, 2001,

701; c) A. Auger, A. J. Muller, J. C. Swarts, Dalton Trans. 2007, 3623. 20 a) W. Adam, J. Gläser, K. Peters, M. Prein, J. Am. Chem. Soc. 1995, 117, 9190; b) Y.

Yokoyama, Chem. Eur. J. 2004, 10, 4388. 21 For synthesis of 6-heptyn-2-one, see: a) P. E. Peterson, R. J. Kamat, J. Am. Chem. Soc.

1969, 91, 4521; for spectral and analytical data of 6-heptyn-2-one, see: b) C. Le Drian, A.

E. Greene, J. Am. Chem. Soc. 1982, 104, 5473; c) B. M. Trost, M. J. Bartlett, Org. Lett. 2012, 14, 1322. 22 A. D. Josey, Org. Synth. 1967, 47, 81. 23 T. Tsuchimoto, T. Ainoya, K. Aoki, T. Wagatsuma, E. Shirakawa, Eur. J. Org. Chem. 2009, 2437.

NH

HNTf2(7 mol%)

1,4-dioxane85 °C, 24 h

+ 3aC8H17

5% NMR yieldα:β = 45:55

3:1:1.5

NH

NH

C8H17

+5a

26% NMR yieldα,α':α,β':β,β'= 73:26:1

NH+ロ--------<J-{ r*>

Chapter V. Conclusions and Prospects

147

This thesis discusses a novel alkylation reaction of indoles and pyrroles with

the carbonyl compound as the source of the alkyl group in the presence of a catalytic

amount of indium salt or Brønsted acid.

In Chapter II, the author describes a new approach for alkylating indoles by

using carbonyl compounds in a reductive process. This method features a wide range of

substrate coverage, and thus would be a useful and reliable tool to obtain alkylindoles

with structural diversity. In fact, this process makes it possible to provide indoles with

primary, secondary and tertiary alkyl groups including CHAr2, CH(alkyl)2 and cyclic

structures. The reaction mechanism in which two different routes depending on the

structure of the indole substrate operate is also unique.

In Chapter III, the author describes that a broad range of !-alkylpyrroles can be easily constructed by simply mixing N-substituted pyrroles, carbonyl compounds and

nucleophiles under indium catalysis. Using the carbonyl compound as the source of the

alkyl group has several distinct advantages over the corresponding alkyne-based variant:

(1) the reaction with the carbonyl compound can be performed with a more reduced

amount of an indium catalyst, (2) the carbonyl compound is more reasonable in price in

many cases, and (3) the most marked superiority is that alkyl groups with structural

diversity including primary, secondary and tertiary alkyl units as well as cyclic and

functionalized types can be introduced onto the pyrrole ring. The perfect regioselectivities

achieved in all the cases will enhance the reliability of this process. Since the N-

deprotection of the product is readily performable by utilizing the literature methods,

preparing a series of N-unsubstituted !-alkylpyrroles is also feasible. Importantly, this protocol is well applicable to the synthesis of unique tetraarylmethanes with four different

aryl moieties, one of which is a !-pyrrolyl group. Mechanistic investigations revealed

that the formation of the dipyrrolylalkane intermediate is the first stage, and the

elimination of the one pyrrolyl group from the dipyrrolylalkane is the second stage for

providing the !-alkylpyrrole. The indium catalyst is necessary for both the processes. The

selective generation of the !-alkylpyrrole was proved to be attributed to the selective

elimination of the #-pyrrolyl group from the intermediate dipyrrolylalkane. In Chapter IV, the author describes that HNTf2 works as a powerful catalyst for

the regioselective !-alkylation of pyrroles with carbonyl compounds and nucleophiles. The use of the Brønsted acid catalyst has several distinct advantages in comparison to the

corresponding indium-catalyzed reaction. This method also features a wide range of

148

substrate coverage with the high functional group tolerance, and thus would be useful and

reliable tool for the synthesis of !-alkylpyrroles. In summary, the author improved upon the alkylation of indoles and pyrroles

with alkynes as alkyl sources by replacing alkynes with carbonyl compounds. The

improvement enables access to all types of alkyl groups (i.e., the installation of primary,

secondary, and tertiary groups on both indoles and pyrroles). Additionally, in the case of

pyrroles, the use of HNTf2 instead of indium salts leads to a more practical and utilizable

strategy.

The studies discussed in this thesis have successfully demonstrated that the

alkylation reactions of indoles and pyrroles with carbonyl compounds and nucleophiles

(as an alkyl source) are attractive not only for synthetic organic synthesis but also for

potential applications in medicinal and material chemistry. Therefore, studies on the

alkylation reactions of indoles and pyrroles with carbonyl compounds and nucleophiles

(as an alkyl source) will continue to be significant and challenging, even in the future.

149

List of Publications

Chapter II

S. Nomiyama, T. Hondo, T. Tsuchimoto, Adv. Synth. Catal. 2016, 358, 1136. Chapter III

S. Nomiyama, T. Ogura, H. Ishida, K. Aoki, T. Tsuchimoto, J. Org. Chem. 2017, 82,

5178.

Chapter IV S. Nomiyama, T. Tsuchimoto, Adv. Synth. Catal. 2014, 356, 3881.

150

Acknowledgment

The research work described in this thesis was carried out under the supervision

of Professor Teruhisa Tsuchimoto of the Department of Applied Chemistry, School of

Science and Technology, Meiji University from 2004 until 2017. The author would like

to express his deepest gratitude to Professor Teruhisa Tsuchimoto for his instructive

directions, helpful suggestions, and continuous encouragement through the course of this

work.

Special thanks are due to Mr. Kazuki Aoki, Mr. Motohiro Igarashi, Mr.

Takahiro Ogura, Mr. Takehiro Hondo, Mr. Hiroaki Ishida, Mr. Mitsutaka Kanbara, Mr.

Tatsuya Wagatsuma, Mr. Taku Ainoya, and Mr. Jun Shimotori for their contribution to a

part of this thesis and/or preceding studies. The author wishes to thank Mr. Hiroyuki

Shirai, Mr. Kensuke Inoue, Mr. Kenji Oki, Mr. Motonari Sakai, Mr. Kazuhiro Sambai,

Mr. Takahiro Johshita, Mr. Tetsuya Sugiyama, Mr. Masaru Sekine, Mr. Kyohei Yonekura,

and Mr. Tomohiro Tani for their daily discussion and suggestion, hearty encouragement,

and much advice. The author thanks all members of the Tsuchimoto Groups for their

valuable discussion, kind help, and friendship.

Finally, the author would like to appreciate his parents, Akira Nomiyama and

Yumiko Nomiyama, for their constant support and endless encouragement.

June 2017

Shota Nomiyama

Documents

Development of New Synthetic Methods for Introducing Alkyl ... · human nutrition2 and the discovery of indole-3-acetic acid as a plant hormone3 served to bring about a renaissance