万伯顺 [email protected]

Catalytic Heterocycle Synthesis Group http://www.chs.dicp.ac.cn/

万伯顺[email protected]

杂环合成中的环加成与环化反应

N[2 + 2 + 2]

R2

R1

R4

R3

NR5

Why Cycloadditon?

Advantages: Two C-C bonds & One C-N bond simultaneously High atom efficiency

Problems: Regioselectivity Chemoselectivity

D. Siegel et al, J. Am. Chem. Soc. 2010, 132, 5924.

N

N

NR'

NR'

H

Me

MeH

Complanadine A

NNR'

H

Me

SiR3

Desilylation

[2 + 2 + 2] cycloaddition

+

NR'

H

Me

CNNR'

H

Me

CN+

SiR3

SiR3

[2 + 2 + 2] cycloaddition

2

Why Iron?

Iron (0.02 US$/mol)

Oct/92

Oct/93

Oct/94

Oct/95

Oct/96

Oct/97

Oct/98

Oct/99

Oct/00

Oct/01

Oct/02

Oct/03

Oct/04

Oct/05

Oct/06

Oct/07

Oct/08

Oct/09

Oct/10

Oct/11

0

5000

10000

15000

20000

25000

30000

35000Pt (9357 US$/mol)Pd (2011 US$/mol)Rh (5468 US$/mol)Ir (6705 US$/mol)Ru (513 US$/mol)

US

$ pe

r mol

2011

1876Ramsay

HCN (g)

C2H2 (g) hot iron N

HH

HH

H 1996Zenneck

Iron(0) complexOrganometallics, 1996, 15, 2713

2002Guerchais

Organometallics, 2002, 21, 2578Iron(I) complex

Co, Ru, Rh, Ni, Ti, etc....

Wan

Cheap Nontoxic

Benign Abundant

Iron Catalytic System

C N

+

Fe

20 oC, 48~96 h NR1 R2

R1

+

TON(pyridine): TON(benzene) = 0.24~0.69

R2

CHC

R1

HCC

R1

Two regioisomers

R1

R1

R1

Two regioisomers

PSiMe3

FeNCCH3

NCCH3CH3CN

HC C

N

EtOOC

H3C COOEt

73% yield

2

SolventFe

NH3C

R

RR

Zenneck's Work: Organometallics 1996, 15, 2713

Guerchais's Work:

Organometallics 2002, 21, 2578.

Harsh reaction condition for the formation of iron complexLow chemoselectivity

R = COOEtSolvent = CH3CN

or

R = COOEt, CH2NMe2Solvent = CH2Cl2

R

L1 (5 mol%)Zn (10 mol%)

ZnI2 (10 mol%)

CH3CN, 50 C

RR

R

+

R

R R

11~94% yieldRatio of I:II : 58:42~>99:1

NN

Me

N

NMe

Me

Me

FeCl Cl

L1

Catal. Commun. 2011, 12, 489.Yang's Work:

I II

Holland’s investigation:

The binding affinity toward the low-valent iron:

Holland, P. L. et al. Inorg. Chem. 2006, 45, 5742.

Problems and Solutions

Ph > Et Et > Ph >Et

Et~ PPh3 > benzene

Low-valent Iron "P"R R

Low-valent Iron

R

R"P"

??

Simple iron salt

Phosphine ligands

Reductant

Low-valentiron species

[2 + 2 + 2] N

R2R1

R1

R1

R1

R1 R1

NR2

in situ

Step 1

Fe(L)nNR2

orOxidative Cyclization

Fe(L)nR1

R1

R1 R1 NR2

R1R1

R1R1

R1 R1

NR2

azaferracyclopentadiene ferracyclopentadiene

benzenes(byproduct)

chemoselectivity

Step 2

Step 3

Fe(0)/P

Problems and Solutions

Entry Iron salt Ligand Fe% Conv.(%) 3a%

1 FeCl3 - 20% 0 02 FeCl3 dppe 20% 99 973 FeCl3 dppp 20% 100 974 FeBr3 dppp 20% 99 895 FeBr2 dppp 20% 100 996 FeI2 dppp 20% 100 >997 FeCl3 dppp 10% 16 98 FeBr2 dppp 10% 75 689 FeI2 dppp 10% 100 >99

10 FeI2 dppp 5% 100 9911 FeI2 dppp 2.5% 13 6

MeO2C

MeO2C+ PhCN

x% Iron salt/L (1:2)N

PhMeO2C

MeO2C2x% Zn, THFRT, 24 h

1a 2a 3an = 2, dppen = 3, dpppPh2P PPh2n

NMeO2C

MeO2C

Ph

3a, 98% (94%)a

NMeO2C

MeO2C

3b, 96%

NMeO2C

MeO2C

3c, 62%

NMeO2C

MeO2C

CH3

3d, 91% (93%)b

NMeO2C

MeO2C

3e, 48%

NMeO2C

MeO2C

3f, 96%

NMeO2C

MeO2C

3g, 96%

PhN

MeO2C

MeO2C

3h, 66%

NMeO2C

MeO2C

3i, 49%

NMeO2C

MeO2C

3j, 43%

NN

R3

Ts

3k, R3 = Ph, 98%3l, R3 = Me, 93%

NO

Ph

3m, 98%

N

Et

Et

R3

3n, R3 = Ph, 95%3o, R3 = Me, 85%

ZR1

R2+

10 mol% FeI2/dppp (1:2)

N

R2

R1

ZR3

20 mol% Zn, THF, RT

1 3

R3 CN

2

a 5% catalyst b 5% catalyst, 20 equiv nitrile

10 equiv(unactivated)

Cycloaddition of Diynes and Unactivated Nitriles

Cycloaddition of Diynes and Unactivated Nitriles(Continued)

Cycloaddition of Tetrayne

NN

R3

Ts

3q, R3 = Ph, 69%3r, R3 = Me, 64%

NO

PhR3

3t, R3 = Ph, 65%3u, R3 = Me, 56%

NMeO2C

MeO2C

3p, 83%

NMeO2C

MeO2C

3s, 79%

NMeO2C

MeO2C

TMSR3

3v, R3 = Ph, 91%3w, R3 = Me, 83%

E

E E

E

10 mol%FeI2/2dppp/Zn

THF, rt+ PhCN

N

N

Ph

Ph

E

E

E

E

+N

PhE

E

E

E

(E = CO2Me)4 (85%)

10 equiv

5 (<5%)

All-intramolecular Cycloaddition

Cycloaddition of Alkynenitrile and Alkyne

E

E

N

E

E


THF, rtN

E

E

EE

(E = CO2Me) 6 (72%)

N

Ph

PhN

+ PhTHF, 48 h N

Ph20 mol%

FeI2/2 dppp/Zn

(3 equiv)

+

7 (39%) 8 (trace)nPr TMSFor , no reaction.or

Control Experiments

Ph


THF, rt, 48 h

Ph

Ph

Ph+

Ph

Ph

5 (55%) 6 (trace)

Ph(1)

Ph + CH3CN


THF, rt

Ph

Ph

Ph Ph

Ph PhN

Ph

Ph

CH3

N

PhCH3

Ph

6 8

+ + +

5 748 hours: ND ND ND

96 hours:

8%

ND ND47%7%

(1/3 equiv)(2)

Ph + CH3CN(5 equiv)

N

Ph

Ph

CH3+

N

PhCH3

Ph

7 (60%) 8 (6%)


THF, rt, 48 h

(3)

Fe(L)n

R'

R

ferracyclopentadieneintermediate

Fe(L)nNR'

R

azaferracyclopentadieneintermediate

TMSMeO2C

MeO2C


rt, 24 h+ PhCN

N

MeO2C

MeO2C

TMS

NMeO2C

MeO2C

TMS

Ph

Ph

3v (58%)

(1 equiv)

8 (ND)

1b

More bulky

Less bulky

RL

RS

R CN[FeLn],

FeN

RL R

RS

Ln

Less bulkyFavorable

N

RL

RS

R

Observed56~91% yield

regioselectivity: >99:1

Zn

19

Pathway B

17

Z

Z

Z

or

FeN

RS R

RL

Ln

18

Z

N

RL

RS

R

Not Observed

Fe

RL

RS

Ln

[FeLn]

N

R

Zn

Fe

RL

RSLn

Fe

RL

RS

Ln

N

R

More bulkyLess favorable

Less favorableintermediate

R CN

R CN

13

14

15

16

Z

Z

Z

Pathway A

Z

Supposed to be favoredbut not observed

More bulkyLess favorable

Possible Pathways to Form Pyridines

With Wang, C. X. Angew. Chem. Int. Ed. 2011, 50, 7162

a 5 mol% catalyst, 5 equiv nitrileb 10 mol% catalyst, 2 equiv nitrile

XR1

R2+

x mol% FeI22x mol% dppp2x mol% Zn

THF, rt NX

R1

R2

NR3

R4N

NR4R3

N

NE

E

92%a (88%)b

N

NE

EE = CO2Me

82% (85%)

N

E

E

N

N

E

E

N

N

E

E

NPh

N

E

E

NO

N

E

E

N

NN

NBn

Bn

Ts

NN

N

86% (96%) 78% (95%)

76% (83%)

Ts

83% (91%) 40% (75%) 91% (99%)

98% (90%)

N

E

E

N

NN

NTs N

ON

N

NE

E

48% (67%)

N

PhNE

E

94%selectivity: 74/26

96% (95%) 81% (78%) 70% (73%)

N

N

(75%)

With Wang, C. X. J. Org. Chem. 2013, 78, 3065

[2+2+2] Cycloaddition in Pure Water

+N

R1

R1

R2

[2 + 2 + 2]cycloaddition

H2O

R2

R1 R1

R1

R1

N

Problems:

[M], Substrates

H2O

poor solubility

R2 N

R2 NH2

O

H2O hydrolysis

1) 2)

H2O/Organic Solventh or

water-soluble catalyst

water-soluble substrates

Previous Work: Our Work:

in situgenerated catalyst

pure water(no organic solvent)

+Solutions:

With Xu, F. ChemSusChem. 2012, 5, 854

[2+2+2] Cycloaddition in Pure Water

P

SO3Na

SO3Na

NaO3S

Up to 87%

XR1

R2+

N

R2

R1

XR

R CNCp*Ru(COD)Cl, tppts

H2O, 50 oC

X = C(CO2Me)2, NTs, O, CH2R1, R2 = H, MeR = CH2Cl, CH2Br, CHCl2

[2+2+2] Cycloaddition

H

NOH

RX

N

R

NX

R

NX

R

New Cycloaddition of Oximes and Diynes

Aldehyde

[Ru]

H

O

R

NH2OH

+Oxime

Catalyst

H2O

Reactivity of the C=N double bond Water generated from cycloadducts

Rearrangement of oximes into amides


NR3

N R3N R3

OH

sp bondaddition

sp2 bondaddition - H2O

2)

higher energy

R3 H

NOH

XR1

R2+

R3 H

NOH

NX

R1

R2

R3

Challenges:R3 H

NOH

R3

HN H

O

1) [M]

+TsNN

TsNCO2Et

[Rh(NBD)2BF4]/L

80 C, 48 hN

EtO2C

OH

entry Rh (mol%) ligand yield (%)

1 5 BINAP 382 5 Segphos 543 5 MeO-Biphep 754 5 dppf trace5 10 dppe trace6 10 MeO-Biphep 96

PPh2

PPh2

BINAP

O

O

O

O

PPh2

PPh2

Segphos

PPh2

PPh2

MeOMeO

MeO-Biphep

Fe

PPh2

PPh2

PPh2

PPh2

dppe

dppf


NR

R'

RhI

N

R'

R

R

HO

H

- H2OR

RhIII

R R

NRhIII

R' R

RHOHorN

RhIII

R'R

R

HOH

R

RhIN

OH

R'

R

R

R

R'

NOH

RhI

NHO

R'

R

R

R R

R

RR

R

R

R

R

R

RhIIINHO

R' R

RRhIIINHO

R' R

R


XR1

R2+

R3 H

N OH

NX

R1

R2

R310 mol% Rh(NBD)2BF4/L

EtOHMeOMeO PPh2

PPh2

Up to 96% yieldKey Point

With Xu, F. Chem Eur J 2013, 19, 2252.

TsN +N

TsNPh

(4 equiv) 19% yield

PhCN

N

Ph

OH

PhCN<5% yield

+ dimer

N

R

OH - H2ONR

[2 + 2 + 2]N

R

Pathway A: Dehydration/Cycloaddition NO

Pathway B: Cycloaddition/Dehydration Yes

N

R

OH

[2 + 2 + 2]N

R

OH - H2O N

R

Nickel-catalyzed [3 + 2] cycloaddition of diynes with MAs

Chem. Commun. 2013, ASAP C3CC41061G

C-C bond cleavage

XRL

RS

NR N

R

RL X RS1,4-dioxane

rt

Ni(cod)2+

1

NR

2 3

CO

R'

O

NR

O

NR'

R

Alper's work

Yamamoto's workO

R'

R'O

N

O

NRN

Methyleneaziridine(MAs)

a

b

c

N-C bond cleavage

NR XRS

RL

NR

Me

XRS

RL

3

NR

XRS

RL

NR

XRS

RL

Ni

C

Ni (0)1+ 2

4

H

oxidative addition

reductive elimination

-carbon elimination

N

XRS

RL

Ni

B

N

XRL

RS

Ni

A orfavoredless favored

N

XRS

RL

Ni

D

RN

Me

X

RSRL

R

H

5 (not observed)

possible C-N cleavage process

RR

Proposed mechanism

CO2Me

CO2Me

R2N

R1

SO2R3

Building blocks

What ?

Synthesis of Pyrroles via Cyclization

R5XR3

R2

R1

R4

杂原子

叁键双键

电子 /空间调控基团

×Ph

Ph N CO2Me

CO2Me

Ts

×

N

CO2Me

CO2Me

Ph

Ph

O TsN CO2Me

CO2MePh

Ts

Ph

HDMF, Ar140 oC


Ts = p-CH3PhSO2-


With Xin, X. Y. Angew. Chem. Int. Ed. 2012, 51, 1693.

R2

R1 NSO2R3

CO2Me

CO2MeNH

CO2Me

CO2Me

R1

DMF

140 °C, 6 h

R3O2S

R2

"" Migration

up to 98%

"" MigrationN

CO2Me

CO2MeR1

H

R2

R3O2S

DMF, 80 C, 4 h

Cs2CO3 (10 mol%)

up to 97%

"α" Migration

R2

R1

CO2Me

CO2MeNSO OR3

N

CO2Me

CO2Me

R2

R1

SOR3

ON

CO2Me

CO2Me

R2

R1

S OOR3

N

CO2Me

CO2Me

S

R2

R1

OOR3

R2

R1 NSO2R3

CO2Me

CO2Me Aza-Claisen Rearrangement

NH

CO2Me

CO2Me

R2

R1

S OOR3Ion-Pair

Mechanism Study

"β" MigrationMechanism Study

R1 N CO2Me

CO2Me

S OOR3

HR2

SO

O

R3

N

CO2Me

CO2MeR1

R2

N CO2Me

CO2Me

R1

R2

SO

OR3

N

CO2Me

CO2MeR1

R2

S OOR3

R2

R1 NSO2R3

CO2Me

CO2Me

NH

CO2Me

CO2Me

R1

R2

SO

OR3

Ion-Pair

Base

H

R1 N CO2Me

CO2Me

S OOR3

R2 H Base

CO2MeN

TsPh

CO2MeH

F

N

CO2Me

CO2MePh

H

TsCs2CO3

DMF, 80 oC, 4 h

F

CO2MeNTs

Ph

CO2Me

F

Cs2CO3

94%DMF, 80 oC, 4 h

94%

Mechanism Study

Crossover Experiment

CO2MeNSO2Ph

Ph

CO2Me

F

CO2MeNSO2Tol

Ph

CO2Me

Br

DMF140 oC

N

CO2Me

CO2Me

Ph

PhO2S H

F

N

CO2Me

CO2Me

Ph

TolO2S HBr

41%

47%

N

CO2Me

CO2Me

Ph

PhO2S HBr

N

CO2Me

CO2Me

Ph

TolO2S H

F

46%

52%

Crossover Experiment

Competition Experiment

DMF, 80 oC

Cs2CO3 (10 mol%)

CO2MeNSO2Ph

Ph

CO2Me

Br

TolSO2Na+(1 equiv.) N

CO2Me

CO2Me

H

PhPhO2S

Br

N

CO2Me

CO2Me

H

Ph

Br

TolO2S

+

36% 59%

CO2MeNSO2Tol

Ph

CO2Me

Br

PhSO2Na+(1 equiv.) N

CO2Me

CO2Me

H

PhPhO2S

Br

N

CO2Me

CO2Me

H

Ph

Br

TolO2S+

36%60%

DMF, 80 oC

Cs2CO3 (10 mol%)

DMF, 80 oC

Cs2CO3 (10 mol%)CO2MeN

SO2Ph

Ph

CO2Me

F

CO2MeNSO2Tol

Ph

CO2Me

Br

N

CO2Me

CO2Me

H

Ph

F

N

CO2Me

CO2Me

H

Ph

Br

PhO2S

TolO2S

40%

47%

N

CO2Me

CO2Me

H

Ph

F

N

CO2Me

CO2Me

H

PhO2S

TolO2S

Br

Ph

43%

38%

Cyclization of Aza-enynes

Entry Catalyst Solvent 3a(%) 1 - DMF - 85

2 BPO (20) DMF 15 263 AIBN (20) DMF 29 434 NHPI (20) DMF 42 315 TEMPO (20) DMF - 666 Anthraquinone (20) DMF - 93

7 DDQ (20) DMF 84 - 8 DDQ (20) CCl4 80 -

9 DDQ (20) Benzene 85 -11 DDQ (10) THF 89 -12 DDQ (10) THF 92 -

N

CO2Me

CO2Me

Ph

Ph

Ts H

3a

O

OO

O

AIBN

NNH3C

NCH3C

CN

CH3CH3

NHPI

N

O

O

OH

TEMPO

NO

H3CH3C

CH3

CH3

Anthraquinone

O

O

BPO

ClCl

NC CN

OO

DDQ

CO2MeNTs

Ph

Ph

CO2Me

1a 2a

N

PhCO2Me

CO2MePhTs

Catalyst +

2a(%)

J. Org. Chem. 2013 ASAP jo400387b

Entry Catalyst Solvent Time(h)

2a%

1 DDQ-H2 THF 48 972 Hydroquinone THF 48 953 Phenol THF 48 744 H2O THF 48 875 MeOH (50) THF 48 936 MeOH

(solvent)MeOH 48 97

OHHO

Hydroquinone

ClCl

NC CN

OHHO

DDQ-H2

OH

Phenol

ClCl

NC CN

OO

DDQ

Cyclization of Aza-enynes

CO2MeNTs

Ph

Ph

CO2Me

1a 2a

N

PhCO2Me

CO2MePhTs

Catalyst


N

CO2Me

CO2Me

Ph

Ts

R

EWG2NSO2R3

R2

R1

EWG1

N

R2

R1

SO2R3

EWG1

EWG2

1 2

MeOH 60 oC 48-120 h

(1) R = H, 2a (95%, 65%[c])(2) R = 2-Me, 2b (91%)(3) R = 3-Me, 2c (95%)(4) R = 4-Me, 2d (78%)(5) R = 2-CF3, 2e (81%)(6) R = 4-F, 2f (88%)(7) R = 2-Cl, 2g (87%)(8) R = 2-Br, 2h (86%)

N

CO2Me

CO2Me

Ph

Ts

(9) 2i, (72%)

N

CO2Me

CO2Me

Ph

Ts N

CO2Me

CO2Me

Ph

Ts(10) 2j[d], (97%)(11) 2k[e], (69%)

N

CO2Me

CO2MePhTs

R'(12) R' = 2-Me, 2l (94%)(13) R' = 3-Me, 2m (95%)(14) R' = 4-Me, 2n (93%)(15) R' = 4-MeO, 2o (73%)(16) R' = 4-F, 2p (88%)(17) R' = 4-Cl, 2q (87%)

N

CO2Me

CO2Me

nPr

PhTs

N

CO2Me

CO2Me

nBu

PhTs

N

CO2Me

CO2Me

Cy

PhTs

(18) 2r, (96%)

(19) 2s, (97%)

(20) 2t, (93%)

N

CO2Me

CO2Me

Ph

PhSO2Ph

N

CO2Me

CO2Me

Ph

PhO2S

Cl

N

CO2Et

CO2Et

Ph

PhTs

(21) 2u, (92%)

(22) 2v, (95%)(23) 2w, (94%)

2a-D

N

PhCO2Me

CO2MeTs

(a) 60 oC, 48h

DC6D5

(100 % D) (100 % D)CO2MeN

Ts

Ph

CO2Me

1a-D

DC6D5

H H12

345

6

123

45

6

60 oC, 48hMeOD

CO2MeNTs

Ph

Ph

CO2Me

1a 2a-D'

N

PhCO2Me

CO2MePhTs

D(96% D)

MeOH

(b)

2a

N

PhCO2Me

CO2MePhTs

H(c)

60 oC, 48h

MeOD

2a-D'

N

PhCO2Me

CO2MePhTs

D

Mechanism Study

R2

R1 NSO2R3

CO2Me

CO2Me

1

2

O HMe

N

R2

R1

SO2R3

CO2Me

CO2Me

H

A

B

R2

R1 NSO2R3

CO2Me

CO2MeO HMe

R1 NSO2R3

CO2Me

CO2Me

N

R2

R1

SO2R3

CO2Me

CO2Me

HH

O Me

C

HOMe

R2

Proposed Mechanism


With Yu, X. Z. J. Org. Chem. 2013, jo4004635

Another example of cyclization with Ts migrationR1

R2 NTs

R3

O DBU

N

OR3

R2

R1

Ts

CH3CN, rt.

DABCO

R2 N

TsR3

O

R1

DCM, rt.

HDG

R

N

Ar

SO2R+

[Cp*RhCl2]2 (5 mol%)AgSbF6 (30 mol%)

PhCl, 100 oC

DG

R

NHSO2RAr

RhNN

O

Ph

SO

R

+

Via

25 examples

SbF6-

Xingwei Li,* Boshun Wan*, Angew. Chem. Int. Ed. 2013, 52, 2577

Other important finding

环加成与环化反应小结

六元环 : (1) JOC jo400387b (2) Unpublished results五元环 : ACIE, 2012, 51, 1693四元环 : Unpublished results三元环 : Unpublished results

R2

R1 NS

CO2R4

CO2R4

OOR3

R1 R1

NR2

N

R3

OH

N

R1

R1

R2R1

R1

[Ru][2]

in water

[Fe][1]

r.t.

[2+2+2]

[Rh][3]

[1] ACIE, 2011, 50, 7162.[2] CSC, 2012, 5, 854.

[3] CEJ, 2013,19, 2252

Documents

万伯 顺 [email protected]

万伯顺 [email protected]