THE NITRO GROUP IN ORGANIC SYNTHESIS - … Nitro...THE NITRO GROUP IN ORGANIC SYNTHESIS Noboru Ono NewYork Chichester Weinheim Brisbane Singapore Toronto A JOHN WILEY & SONS, INC.,

THE NITRO GROUP IN ORGANIC SYNTHESIS

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ORGANIC NITRO CHEMISTRY SERIES

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THE NITRO GROUP IN ORGANIC SYNTHESIS

Noboru Ono

New York Chichester Weinheim Brisbane Singapore Toronto

A JOHN WILEY & SONS, INC., PUBLICATION

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2PREPARATION OF NITRO

COMPOUNDS

2.1 NITRATION OF HYDROCARBONS

2.1.1 Aromatic Compounds

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C6H13CHO CH3CN

OH

C6H13C6H13

NO2

OH

CF3CH3

NO2

RT, 24 h

DBU (0.1 equiv)

RT, 24 h

65%

DBU (1 equiv)CH3CH2NO2

95%

+ C6H13CH2NO2

OH

CF3 OH+

7''8

7',8

H

O

OH

NO2

OH

Et3N 0.5 h

4 h

95

90

2:1

Ph O

Catalyst

2:1cat.

N

Yield (%) syn:anti

3

Time+ O2NCH2CH2OH

7'8

CHOKF, i-PrOH OH

NO2

NO2

O

O O

O

OH

CH3CHO

RT, 6 h 90%

Bu4NF3H2O (0.48 equiv)

06 C, 23 h+

CH3NO2

O2N

52% (anti/syn = 62/38)

7'.8

7')8

H

OOH

NO2CH3NO2

94%

0 C, 30 min

TMG (0.1 equiv)+ 7'$8

32 THE NITRO-ALDOL (HENRY) REACTION

02 2 E

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01-1

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2'01$ 5C$,

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(#I$1'I$1'

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NMe3+OH-

OHNO2

R

OHNO2

R

OHNO2

R

OHNO2

R

OHNO2

RN

OHNO2

RMeO O2N F F

O O O

NMeO O2N F F

O O O

R-CH2NO2R: Me, Et

7'8

CHO

NaOH, CTACl

NO2

HO(CH2)6OHH2O, RT, 3 h

HO(CH2)6CH2NO2

75%

+ 7'.8

O NH

Me2N NMe2

HONO2

RT, 48 h

71%

CH3NO2+ 7')8

A-21

NO2

HO(CH2)6OH

20 h

70%

HO(CH2)6CH2NO2 + CH3NO2 7',8


I"#"

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7'$$8

ON

N

NPR R

NR

MgSO4, 7 h

HO

NO2cat.

CH3CH2NO2+

82%

7'$*8

O HO

NO2

2 BuLi, HMPA

65%

THF, 90 CNO2 7'8

OH2NCH2CH2NH2

NO2

MeO MeO

CH3NO2

70%

+

7'$8

O HO NO2Me

Me

9 kbar, 30 C

50%

Bu4NFCH3NO2+ 7'8

O

R NO2

H2NCH2CH2NMe2

R NO2

benzene, 80 C

6199%

+

3.1 PREPARATION OF -NITRO ALCOHOLS 37

2K#(

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5""$, (" (I

',2"

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758

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3.2 DERIVATIVES FROM -NITRO ALCOHOLS

3.2.1 Nitroalkenes

>"" " 5

$("

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#"+>I

NO2 Et3NOH

NO2HCHO

80%

+ 7'$,8

NO2CHO

NO2

OH

NHCHO

OTBSOHOH

N

O

OTBS

N

O

OTBS

I

N

O

OTBS

O

N

61% (ds = 5.5:1)

Dabco

2) H2 / Raney Ni

O 3) HCOCCH3

O

1) NaIO4

2) Ph3P, I2

BuLi

I2

N

O Ph

Me3Sn

Pd(PPh3)4

1) O5O4

Scheme 3.2. Model studies on the synthesis of hennoxazole A

O

RH2NCH2CH2NMe2

R NO2

benzene, 80 CCH3NO2

5580%

+ 7'$'8


2,"##

,$

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7)';8

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,.9.%)

H2G*#

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I10 7;8,. 7;8

,9 H2G'

#7-:'$8

>"#"##

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, I$1I10 E'E

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7EE8 7-: '$8/ 78

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E0G %)H2" $1$#

787-:'$8$

O2N R

HO

O

O

O O2N R

140180 C80 mmHg

R = H (80%)R = Me (73%)

7'$8

OH

n-C4H9 DCC, CuCl n-C4H9 NO2

NO

PhO CHO

An

NO

PhO

An

NO2

35 C, 10 h 90%

NO2

85%

2) MeSO2Cl, Et3N

1) CH3NO2, Et3N

7'$.8

7'$)8

n-C3H7 Me

NO2TPP

Me Me

NO2

PhSeNaAcOH

NO2

MeMe

SePh

Me

NO2

n-C3H7

H2O2

Me NO2

Me

70 % (anti/syn = 91/9)

20 h100% (E/Z = 100/0)E/Z = 55/45

78 C99% (Z/E = 90/10)

7'$8

7'$8

3.2 DERIVATIVES FROM -NITRO ALCOHOLS 39

I$1'"##

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95%

Envirocat EPZG

100 C, 20 min+ NO2

CHONO2

Me

7''.8

OMe

MeO CHO

OMe

MeO NO2

NH4OAc/ AcOH100 C, 3 h

Condition Yield (%)

35

CH3NO2

99NH4OAc/ AcOH22 C, 3 h, ))))

+

7'')8

CHO

Cl NH

Microwave400 W8 min 64%

+ CH3CH2NO2Me

NO2Cl

7''8

NMe

CHO

TiCl4

NO Me NMe

NO2

CO2Me

THF, 025 C

+

75%

O2N CO2Me

7''8


7-: ',*8. 0EE " ""

00

$-:',"#

0" 0EE " # "

#-:',$','

MeO

OMe

NO2

NO2

NMeO

OMe Me

NMeO

OMe Me

NO2

NMeO

OMe Me

NH2CHO

OHC

O

O

SiMe3

NMeO

OMe Me

N H

H NMeO

OMe Me

N

H

OO

Oi-PrO

aspidophytine

1) Fe, AcOH, silica gel, toluene, 2) MeI, KOH, Bu4NI, THF, 23 C

1) POCl3, DMF, 35 C, 1 h, then NaOH aq

2) MeNO2, NH4OAc, , 1 h

LiAlH4, THF, , 1 h

MeCN, 23 C, then TFA, 0 C, then NaBH3CN, 23 C

67%

91% 88%

66%

Scheme 3.4. Synthesis of aspidophytine

CH3NO2

HCHO

NO2OHHO

NO2O Ot-Bu t-Bu

OO

AcONa

NO2O t-Bu

ONPP

1) MeONa/MeOH

45%

75%2) Salicylic acid

+t-BuCOCl

7',*8

HO

HO

CHOCH3NO2

HO

HO

NO2

HO

HO NO2

NO2

NH

HO

HO

C(NO2)4, ZnSO4

95%

70%

Na2S2O4, ZnSO4

NH4OAc-AcOH EtOH

pH 4

52%

Scheme 3.3. Synthesis of 5,6-dihydroxyindole


2# # "

" " "$ '

7-: ',,8

#7E=-8.

"#$'

"

#"

7-:',8)*

7','8

NPPNO2

Nu1NO2

Nu1 Nu2

O

Nu1 Nu2

NH2Nu1 Nu2

Li

NPP

NO2OEt

OLi

NO2

O

OEt

NHH2/Ni

82%

88%

O

Nu1 Nu2Nef

Reduction

66%

THF, 70 C THF, 70 C

Et2O-EtOH

7',8

7',$8

n-C4H9LiNPP

NO2

OLi

O

O

78%

1) MeONa/ MeOH

2) H2SO4

O

NO277%

75%

THF, 70 CTHF, 70 C

AcO OAc

NO2HO OAc

NO2O

NO2

90% (95% ee)

1) Piv2O

2) MeOH/H+

3) DCC/CuCl

t-Bu

O

67%

PLE

7',,8

1) HCHO, MeONa

2) PhCOClheat

65% (overall)

CH3NO2

O

OHNO2

OTHPNO2

O

NO2

Ph

O

NO2

O

MeONa H+

7',8


""$$

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I

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2,8

3.2.2 Nitroalkanes

&"05,""

) ! " "

#"#)$#

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:05,)'

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",

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7-:',.8)#

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0205'"(M+7-:',8)

0"#"

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"+IE8

"#"

NO2NO21) NaBH4, dioxane-EtOH

30 C, 1.5 h

95%

2) AcOH7',.8

NO2MeO

MeO

ZnBH4

NO2MeO

MeODME

86%

7',)8

O

NO2

O

NO2

NaCNBH3Zeolite H-ZSM5

70%

7',8


".

&.

) :0"

7-:',8)

I

""-:

'*%'$* # "

"##

2.

1) CH3NO2, KF, i-PrOH

3) NaBH4 100%

Nef2) Ac2O, DMAPCO2Me

CHO

CO2Me CO2Me

CHONO2

7',8

O N

N

N

N

O O

NHBz

O

Ph2CHO

O

H

NHBoc

O N

N

N

N

O O

NHBz

NO2

Ph2CHO

O

NHBoc

O

OOO

OONO2OAc

AcOAcO

OAc OOO

OO

NO2O

2) Ac2O

70%

3) NaBH4, EtOH

1) n-Bu4NF, THF, 18 h

+

71%

1) KF

3) NaBH4

CHO

2) Ac2O, DMAP

+

OAc

AcOAcO OAc

OO2N N

N

N

N

O O

NHBz

O

BnO

O

H

NHCbz

O N

N

N

N

O O

NHBz

NO2

BnO

O

NHCbz

53%

1) KOt-Bu, t-BuOH, THF

3) NaBH4, EtOH, THF

+

2) Ac2O, DMAP, THF

O2N

7'*8

7'8

7'$8


&""#5N

#7-:''8

3.2.3 -Nitro Ketones

0"##"72$8 "I"(##"

"7287-:',8

! " "78"

# 21'0$2$1) #$

7E228'

)I#"#

" 51+1

#(#.*%*;7$I"0287-:')8

#"5'

=I,"#(7-:'8*>"

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2" "# #"

#""""

'%')D 78KK

""K"

''.')""

$'

NO2

OOOO NO2

n-C6H13

On-C6H13

O

NN

2)

1) t-BuOK/ DMSO

88%

7')8

OO NO2O

H R

OO NO2R

O

TsNHNH2

OO NO2R

NNHTs

LiAlH4 OOR

NNHTs

R

O

O

OHO

R CH2R =

R =

(CH2)4CH3

2) K2Cr2O7

1) Al2O3+

H+

acetone

Scheme 3.5.

R1

O

R2

NO2 Bu3SnH, AIBNR1

O

R2

R1

NNHTs

R2

NO2 LiAlH4

80 C

TsNHNH2 7'8


3.2.4 -Amino Alcohols

0 ""#"

#"&0-1EG2D+17

,$8'$''

3.2.5 Nitro Sugars and Amino Sugars

"##

" #

O

H3C H

NO2OCH3

O

NO2OCH3

OOH

PCC

NO2OCH3

OO

OCH3

OO

OCH3

OO

SCH3

OCH3

OO

OH

OO

71%

1) NaIO4

71%

1) (CH2OH)2, H+

2) LDA, 78 C

3) (CH3S)2, HMPA, 0 C4) (CO2H)2

+

80%

86%

amberlyst A-21

86%

2) 100 C

benzene

Bu3SnH, AIBN

CH2Cl2

Scheme 3.6.

C5H11NO2

O

H (CH2)9CH3

C5H11NO2

(CH2)9CH3

O

TsNHNH2MeOH

C5H11NO2

(CH2)9CH3

NNHTs

LiAlH4

C5H11 (CH2)9CH3

NNHTs

C5H11 (CH2)9CH3

Oamberlyst A-15

Me2CO/ H2O95%

+1) amberlyst A-21

2) K2Cr2O778%

90%

THF, 0 C

90%

Scheme 3.7.


,"#""

" # /

@

.1

"

5D""#

'

' ''

"

####"

#.

"#-:'

(=#768""#">#

"> =# 7-:

'.8

"

""#"

#" "**$I$

>#7>

#8"#"

#""#

"7-:'.$8*

XOHC

OHC

X

+

OH

NO2HO

MeNO2KF

i-PrOHX = O, S 7'8

HOOH

OH

OH

OO

OHC

OHC

OO

OH

OHO2N

OO

X

H2NOH

OHHO

Severalsteps

MeNO2NaOMeMeOH

NaIO4

X = SMe (mannostatin A)X = SOMe (mannostatin B) 7'.*8

OHO

OO

OMe

HO OMeMe

O2NHO

HO

OMe

HOHO

O2N

OMeOH

HO OMeMe

O2NHO

F

OMe

FHO

O2N

OMeOH

EtNO2+NaOMe

7'.8


!"##

"#"7'$$8

""##*$I

-:'.'*$

'0 ' # "

#'*'

'I$'. = 7I>'8"##

"*,

" "#

I("'(>

# >7 8.';

=

)*

7''8 ?#

" = "

$(= '

'**.

''

OHOHO

OH

NO2NHAc

OHOHO

OH

CHONHAc

OHOHO

OH

CO2HNHAc

OHOHO

OH

NHAcNO2

OHOHO

HO

OH

NHAcNO2

OHOHO

OH

NHAcNO2

NaOH

H2O, O3+

MeNO2NaOMeMeOH

Ac2O

H2SO4

1) H2, Pd/C AcOEt2) NaOMe MeOH 7'.$8

O

OO

MTMO CHO

OO

O

OO

MTMO

O2N NO2O

O

OH

+KF

i-PrOH

MTM = CH2SCH3

7'.'8

X

O

NH2 (NO2)

OH

OH

R

O

NO2R

O

X

OH

X = H, OHR = H, Me

+

Scheme 3.8.


3.3 STEREOSELECTIVE HENRY REACTIONS AND APPLICATIONS TOORGANIC SYNTHESIS

0##""#9""

##'*)

!## "

I##

"7"8

"

#K

7-:'.,8*

CH3

O

H2N

HO

HO

CH3

O

HO

HO

NH2

CH3

O

H2N

HO

OH

CH3

O

HO

OH

NH2

O OO

O

MeO OH

OH

R

O

OH

NH2

OH

L-ritosamine(L-ribo)

L-acosamine(L-arabino)

3-epi-L-daunosamine(L-xylo)

L-daunosamine(L-lyxo)

daunomycin (R = H, 4 -OH )adriamycin (R = OH, 4 -OH )epirubicin (R = H, 4 -OH )

4

A B C D

Scheme 3.9.

O

OR[Si]O2N OMe

OMe OMe

OH

NO2 OMe+

0.1 Bu4NF ("anhydrous")

ROTHF, 78 to 3 C, 14 hca. 60% (dr: 29:51:3:12)

1) separation

2) H2, Pd/CL-acosamine

82%

Scheme 3.10.

3.3 STEREOSELECTIVE HENRY REACTIONS AND APPLICATIONS TO ORGANIC SYNTHESIS 51

""

7'$8

+ I6 > # ""K

76)%,)6'8 %** H2 D+EI #

7+EI8

7>+EC8

+ 56 ! "

#7,6%68

+26#"("#

"

%)H2D

#""

" " 75ID8 # "#7;8(

'$#&0$""#"7'$8

7E8

#

O2N

OH

OH

NHCOCHCl2

OH

NHMe OHN N

SO2O

OH

NH2HO

NH2

OH

NH

OAcHO OMe

PhOH

NH2

OH

O

Anisomycin (Ref. 107d) Allophenylnorstatine (Ref. 107e)

Ephedrin (Ref. 107a)

Sphingosine (Ref. 107c)(Anti-HIV) (Ref. 107b)

Chloramphenicol (Ref. 107a)

Scheme 3.11 Biological active -amino alcohol derivatives

O

R1 H

R2 NO2

OH

R1R2

NO2

OH

R1R2

NO2

H

R2

NO2

R1H OH

H

R2

NO2

R1HO H+

+

synerythroanti threo

7'.,8


#""E

#"#

7)O;85("#

7-:'.'..8*

NO O

Li

Li

O

NO2

EHO R C+

OH

H

R C+

O

R+, ,E+ =

2) H+THP

1) E+

7'.8

RHO

NO2Li

Li RR

R

NO2Li

HXTHF-HMPA

AcOHOH

RR

NO2

OLi

O

RR

NO2

RR

NO2Li

AcOHOH

RR

NO2

Bu4NFO

RR

NO2

+

H

O

R

NO2

R

RCHO

Method A

RCHO

90 C

Method BSit-BuMe2 O

Sit-BuMe2

N

R

90 CMe2t-BuSi

OOLi

LDA

Method C

70 C

100 C

NR O

O

Sit-BuMe2Sit-BuMe2

DMPU = N N

OH3C CH3

Scheme 3.12.

C12H25 C C

p-MeOC6H4-

Ph-

68

79

93O NO2

74

THP

>95

80

91HO R

NO2

OH

1) n-BuLi, THF-HMPA R

Me2CH-

Overall yield (%) ds (%)

75

2) RCHO, H+

7'..8


$&0 "

"#7-:'.)8*

5 #(

" " # # #

7;87-:'.8*

OH

OH

NO2MeO

H2

OH

OH

NH2MeO

Raney Ni

98%

7'.)8

0 I 2 E G

8$5= D+EI G

$8I1%**H2 7+I8

8$5= D+EI

*G*

$8I1%**H2

8$5= D+EI

,G.

$8I1%**H2

5,0D7+28

G

5,0D $$G)

I17+58

*G*

I1 G

I1 G$

CH3CH2NO2 C5H11CHO

CH3CH2CH2NO2 PhCHO

CH3CH2CH2NO2 MeO CHO

NO

H CH2CH3C2H5CHO

NO O

H CH2CH3

C3H7

O

C2H5

NO2Li

C5H11

O

CH3

NO2Li

Ph

O

C2H5

NO2Li

CHO

OMe2t-BuSi

Me2t-BuSi

Sit-BuMe2

Sit-BuMe2

Sit-BuMe2

NO2

C5H11

OH

NO2

Ph

OH

NO2

OH

NO2

O

C3H7

OC2H5

NO2

C5H11

OC2H5

NO2

Ph

OC2H5

NO2

NO2

O

OMe

Sit-BuMe2

Sit-BuMe2

Sit-BuMe2

Sit-BuMe2

Sit-BuMe2


"$$$""5,0D

D#

"-:'."#""#

G : " 2D'

""#

7-:')*8

I " #""

D"

#

7-:')8$

""

"

"":"

I# +#I"

" # +#I ##"

5###>",

($(##

**; '

7-:')$8

NO

Me3SiO

HPh

O

Bu4NF

OMe3SiO

HPh

Ph

NO2

86% (95% ds)

PhCHO7'.8

Bu4NF

i-Pr-

Ph-

p-MeOC6H4-

F3C NO2

F3C H

NO O

Sit-BuMe2R Yield (%) syn/anti

R

O

CF3

NO2

Sit-BuMe2

52

72

72

76/24

75/ 25

O

C6H13CF3

NO2

O

C6H13CF3

NO2

73/ 27

RCHO

anti/syn = 93/7

2) AcOH, 95 C

Sit-BuMe2Sit-BuMe2

1) LDA

7'.8

7')*8

O2N CHO

THF, RT

OH

NO2O2N

1) n-BuLi

72% (anti/syn = 7/1)

+ NO22) TiCl3(Oi-Pr)

7')8


+

" $

":(

1#-:')',

"

$-:'),

! " "

."(

# "-:'), !

("-:'),(

''""

+

" ( # " ,

)

"7>!5I=8#

:"

.# ( #

K

"# "

#

1 " ""

".

&

',"

=75!01=8""#

'

+

+

$

"

'."7#

='PI

'P

'P@

'P87#=

P0

P&/5+MM+%%/0''.7'8

'$ &+>1*%,'.7.8

'' 10!I5#I25&I

' &@&5+1E 78

, +??/&/"+4!!@##)

).%))

(&4$)'7.'8

. I/5/>D?*8'*7)8

) >@-+&**7.*8

&(@+*,-A,B$)7..8

+>-&+(')7))8

10(>&&'7)8

. D&-1#?+#*"'$78

. &I>(+&-@ )%$'7.8

.. 0=+N!@E)'78

.) DF5?>I-?2*!.))78

. >E

10I*"%'.7)8

+&-?(>(1!

'78

$ 5I@+2&2>#*%$$''78

' 54?4>4I4

%%$78

, -#4>+!(.7)8

/>('7$8

. E@&@&E!!!&I5+&5I/+ *,%"

.$7'8

) ?2E

$$ II-

4MICHAEL ADDITION

!

"

#$%

4.1 ADDITION TO NITROALKENES

4.1.1 Conjugate Addition of Heteroatom-Centered Nucleophiles

&"

"

'

(

"

)"

'

%

%%

*+'$%,

70

NO2

NO2

XXH

syn / anti = 1/ 1

+

X = RS, RO, R2N, R2P

base*$%,

!"!#$%$&'() *#+&&(

-"

.

-

*+'$.,/

*+'$/,$

R1 R2

NO2 Nu

R1NO2

R2Nu

R1R2

O

Nu

R1NH2

R2

Nu

R1H

R2

Nu

R1 CNO

R1

X

R1

R2 NO2

X

R1

R2 O

X

R1

R2 NH2

X

R1

R2 H

XR1

CNO

X

X= COR, CO2R, CN, SO2R, etc.

+ R2CH2NO2

R2 = H

+ Nu H+

R2 = H

Nu = RO, RS, RNH, carbanions

Nef

(Chapter 6)

(Chapter 6)

(Chapter 6) (Chapter 7)

Scheme 4.1.

O

H CO2Me

S CO2Me

NO2HO O

S

NHHN

O

H H

CO2HH

+ CH3NO2 + HSCH2CO2H

d-biotin

*$.,

4.1 ADDITION TO NITROALKENES 71

-

##$.

0

$/

"*1,

#2/$3"4+'$$

'"4!

4

*+'$0,1*,*+'$ ,5- '

SH

O2N

(CH2)4CO2Me

O2N

S

O2N

(CH2)4CO2Me

O2N

POCl3

NO

N

S (CH2)4CO2Me

O

HN NH

S (CH2)4CO2Me

O

2) Pd/C, H23) COCl2

81%

1) Zn/Ag, (CF3CO)2O

+

80%

Scheme 4.2.

O2NOAc

O2NSPh+ PhSH

~100%

THF

Et3N*$/,

O

MeO2N

Me

HS

Et3N

O

MeMe

S NO2PhNCO

Et3NS O

NMe

OMe

H99%

+

82% (ds 71/29)

THF

*$$,

AcS

NO2

EtONa

O2N

S

Ph N C O

Et3NS

NO

LiAlH4

S

H2NHO

S

H2NCHN

O

2) COCl23) Beckmann rearrangement

1) OH1) DMSO, Ac2O2) NH2OH biotin

Scheme 4.3.

72 MICHAEL ADDITION

6%7

+' $! 8

!

9:

;!1

+ "*+'$%%,

*%.,

-&;!1,?

@

'-&/;!1

*+' $%. $%/,

%!

A "

.7;$7>

Me

NO2Me

AcOH Me Me

SePh

NO2

+ PhSeNa78 C

68% (syn/anti = 91/9)

*$5,

NO2

Ph

Me AcOH

MePh

OCH2Ph

NO2

EtOH, HCl

MePh

OH

NH2

PhCH2ONa

72% (syn/anti = 91/9)78 C 73% (syn/anti = 91/9)

Pd/C, H2

*$%7,

+

O

HHN

OH

Ph

Me

Me

NO2Me

O

PhNHCHO

NO2

Me

MeNHBoc

OH OR OH

1) NaH, 78 C

2) AcOH

66% (de 94%)

1) NaBH4, Pd/C Na/ NH3

78 C2) Boc2O80% (NO2 NHBoc) 75% (ee 96%)

*$%%,

OH KH, THFPh

NO2 O

PhNO2

2) 1 N-HCl

1)

RT

80%

*$%.,

OH NaH, THF NO2O

NO2

94%

RT

1)

2) 1 N-HCl *$%/,

74 MICHAEL ADDITION

" '4

"

)"/.

*+'$%$,%1

" . /. 07> %1

# /.

%5

*# 1., 4 *+'

$%0,.7

B*,"

423%

"$".49:7

*+' $% ,.%

# $.% *+' $%!,

..

.

*+'$%1,./ 9:

@"

%/..

+'$%1#(.

/ %."4*+'$%5,

-9%$.$

2./3

.$

#

.0

R1

R2

CHO

OH

Ar

NO2

R1

R2O

NO2

Ar+

7084%R1, R2 = H, Cl, OMe

1) Et3N, RT

2) Al2O3

Ar = Ph, p-MeOC6H4, 2-thienyl

*$%$,

Me

NO2HO

t-BuOKMe

O

NO2 Me3SiCl

Me

O

NOSiMe3

O O ON

Me OSiMe3Bu4NF O O

NMe

+98 C

74%(tandem reaction)

*$%0,

NO2

CO2MeHO t-BuOK

O

O2N

H

CO2Me

+

100%

0 C*$% ,


4.

-

*0,.

".%%

.!

.!

.!;

+'$.7

$.%

( %$%/

*+'$..,.1

@"*+'$./,

.5

NO2 HO t-BuOK

O

O2N

H

Cl

+0 C

7078%

*$%!,

NO2

HO

t-BuOKO

O2N

HO

O2N

H

+

78% (5-exo/6-endo = 1.7/1)

+

0 C

*$%1,

O

O2N

H

SmI2

OH

HNO

6090%

*$%5,

PhSNO2

MeONaH

MeONO2MeO

PhSNO2 N

H

NNO2

+RT, 2 h

78%RT, 24 h

85%

THF*$.7,

*$.%,

PhSNO2

NNO2N

H 80%

+CH2Cl2

RT *$..,

76 MICHAEL ADDITION

%.

"

&.CD*+'$.$,/7

?

,."*#C,*BC,

/7

) -

*,."%%1

#$.

*+'$.0,

@*,

/%

B

%.

#

.%.*+'$. ,/.

PhNO2

H2NOMe

t-BuOK

Ph

NO2H2N

H

94%

*$./,

R1NO2

R2

NH2

R1NH2

R2

1) EtONH2HCl, NaHCO3, THF

2) H2, Pd/C, EtOH

5490%

*$.$,

O NNO2

NH OMe N

OMe

NO2

+RT

THF*$.0,

30 min

NO2

NH

OH

NO2N

OH

SmI2MeOH-THF

NH2N

OH

facial selectivity = 97/3)

+

90%95% (trans/cis = 99/1

CH2Cl2, RT

*$. ,


%. *./$0,%/$"

.0*", " *5/;5 > ,

+'$.!//

,$."44

9: ;!1

@

+'$/%

..%/!

+'$/.

/1

E

C.C9&

0*,*+'$/.,*%%=%,

4

*+'$//,/5

+'$.$/

'

"

N

O

NO2

O PhNaNO2, AcOH

N

O

CO2H

O PhNH2

CO2H

DMSO, 40 C

62% (96% ee)

2) DOWEX 50W-X4-400

1) Li/NH3

51%

*$/7,

NSiMe3O NO2

KFN

O

H

NO278%

0 C*$/%,

O

MeO O

O

NO2

Ph2PHO

O

MeO O

O

H PPh2

O

NO2

H

(de = 11:1) *$/.,

H

Ph Me

NO2

Et3N

Ph

(MeO)2P Me

H

O

+ (MeO)2P(O)H

72% (E/Z = 3/1)

THF*$//,


" *+'$/$,$7

"* ,

%-..*,

%7

4.1.2 Conjugate Addition of Heteroatom Nucleophiles and Subsequent NefReaction

"

%"%

"-*# %,4

$%

@%*,F

"*#

$$,$.

'&*

/,

%*4",

"*+'$/0,$/

84

$-)

4 4 "A*,*4",

"*+'$/ ,$$

MeO

CHO

PhS

NO2

MeO

1) Zn/HCl

MeO

82%NHCHO

2) HOCOCOCF33) NaIO4

CH3NO2, PhSH

Et3N

53%

*$/$,

NO2

XR

NO2

XR

NuO3 O

XR

Nu

, CH(CO2Me)2N

O

O

NO2

XR

t-BuOOLi NO2

XR

OXR

O

Nu

Nu = OMe,

Nu

6080%

Nu

X = O, S

Scheme 4.4.

80 MICHAEL ADDITION

#

"

*,*,*+'$/!,$0

@"

%*,%'4

@%*,

8

4"

"*#$0,

$

' 0*,

$0

0*,

*+'$/1,$!

$1

NO

O

Si

NO2

OCH2Ph N

O

OCO2CH2Ph

NO

O

Si

NO2

SPh N

O

OCOSPh

Bu4NF, O3

64%

THF

52%

1) Bu4NF, THF, O32) DBU *$/0,

*$/ ,

O OMe

O2N SPh

H

O O

NK

O

O

O OMe

COSPh

H

O O

N

O

O

80% (ds 15:1)

2) O3

1)

*$/1,

NO

S

Si

NO2

OCH2PhN

S

OCO2CH2Ph

HO

HO

N

S

OCO2

HH3N

1) CF3SO2Cl

80%

2) LiN33) H2, Pd/C

THF

Si

Bu4NF, O3

*$/!,


8"

*G,4"*+'$/5,(*,

$5

%*C,"

)""

"%*,

*5%=%,*+'$$7,

'07

O

O O

OMeOH

O

O O

OMeH

O2N SPh

O

O O

OMeH

COSPh

HO

O

HO OH

NH

CO2

H3NNH

O

O

OH

1) PhSCH2NO2, t-BuOK

1) KOTMS, DMF, 0 C

94% (ds 50:1)

2) MsCl, i-Pr2NEt

O2N H

PhS

O

OMe

O

O2) O3, MeOH, 78 C

83%

OTMS

Scheme 4.5.

SO2NiPr2

S

NO2

NK

O

O

SO2NiPr2

S

O

N

O

O

(R)

1)

2) O3

, 40 C

61% (de 71%) *$/5,

SiO Ph

NO2

SPh

OPh COSPh

O NO2H

SPh

HH

Ph

HF, pyridine

t-BuOK, O3

*$$7,

82 MICHAEL ADDITION

F"*,"8(

%%

"*#$ ,"%%

"

"0%

4*%,%

%

4 %/ *., "

"*6,"

*:,H

"

*#$!,0.

+" 8 6

"

*#$1,0/

""%%*+'$$%,

0$

NO2

STolOO

t-BuOOLi

Ph3COOK

NO2

STolO

O

NO2

STolOO

O

O

NH3

NH3

STol

OOO

STol

OOO

NH2

NH2

78 C

anti 15:1

78C

syn 12:1

Scheme 4.6.

H

OOO2N

TolS

LiOt-BuO

H

OOO2N

TolS

syn anti

Ph3COO K

Scheme 4.7.

Ph NO2

STolNH

O

t-BuO

Ph NO2

STolNH

O

t-BuO OOHN

O

Ph COSTol

LiOOBut

78 C

43%

*$$%,


@*0 1, *",.*",/"-

*#$5,00

NO2

STolO NH3

BF3Et2O

NO2

STolOH

NO2

STolOHO

TBSOTf NH3

82% (ds 20:1)

THF, 78 C

Ph3CO2Li

Si

NO2

STolOSi

OSTol

OOSi

NH2

65% (ds 100%)

Ph3CO2K

NO2

STolOSi

O

THF, 78 C

STol

OOSi

NH282% (ds 20:1) 65%

86%

Scheme 4.8.

NH

OC(O)Ph

O

O

Me

SiNO2

KS

KS

NH

S

O

O

Me

Si

SMe

NO2

Cl CO2PNB

O

N

S

O

O

Me

Si

SMe

NO2

CO2PNB

N

S SMe

NO2

OSi

Me

O

1)

N

S OCONH2

CO2MeO

OH

Me

2) Me2SO4

76%

1)

2) P(OMe)3

1) 75%, 2) 90%

LiN(SiMe3)2

60%

Scheme 4.9.

84 MICHAEL ADDITION

4.1.3 Conjugate Addition of Carbon-Centered Nucleophiles

4.1.3a Active Methylene Compounds -

G-&.

G*I9,B

%/0

4B9*I, )

"

51>

!1>

0!

"-*,.

01

E

4%/

*+'$$.,-*+'$$/

$$$,05

4

%/*+'$$0, 7

(

*+'$$ , %

O

OMe

Me

Me

NO2 O

O

MeMe

O

Me

O

Me

NO2

O

O

MeMe

O

O

CO2Et

Me

NO2

OCO2Et

Me

O

OCO2Et

Me

NO2

+KF, xylene

reflux

KF, xylene+

52%

96%

reflux

+KF, xylene

reflux

+

20% 47%

*$$.,

*$$/,

*$$$,

NO2R1

R2

R3 NO2O2N NO2

R2

R1 R3+

Et3N or K2CO3

51-98%

*$$0,


%/

*+'$$!, .

B

%/

#$%7

0 > "

*"4,

*-,5%>

#$%7 /

4.1.3b Enolates Derived From Ketones and Esters and Carbanions Stabilizedby Sulfur ( #

Me NO2

Me HPh

NO2

CO2Et

ON

CO2Et

O

Ph

MeMe

+KF/Al2O3

MeCN

70%

*$$ ,

Me Me

O O PhNO2

ONO2

Me

MeO

Ph

()-quinine+

89% (16% ee)

*$$!,

Me OEt

O O

PhNO2

MeNO2

Ph

CO2Et

Oligand (5.5 mol%)Mg(OTf)2 (5 mol%)NMM (6 mol%)

CHCl3, sieves

RT, 3 h

Entry Ligand Selectivity (%) Conversion (%)

12

3

4

5

6

7

1a1b1c

2c3c

N

OO

N

RR

4c4a

95

65

77

58

0

N

OO

NR1

R2R2

R1

RR

33

76

82

96

9

44

15

99

1

2: R1 = Ph, R2 = H

3: R1 = CMe3, R2 = H

4: R1 = R2 = Ph

7

a: R = -CH2CH2-; b: R = H, c: R = Me

ligand:

Scheme 4.10.

86 MICHAEL ADDITION

#"+'$$1

$$5 $

8

%/

4*+'$07, $

- "

*+'$0% 0

$%,

-";%77

B& - C E*>, B

68@ 1% 0

68@ !. 0

68@ . !%

68@ 0! 0

68@ 5$ 0

68@ 57 !.

68@ 10 !/

68@ !$

Ph Me

O

O

NCH2Ph

O

BuO

O

Me

MeO

O

PhO2S

O

OEt

SPh

CO2Et

NPh

Ph

CO2Et

NO2

NO2

NO2

NO2

NO2

NO2

NO2

NO2

Me

Ph

Ph

O

ONO2

NO2

NCH2Ph

OO2N

BuONO2

O

Me

NO2MeO

O

MePhO2S

NO2

O

OEt

NO2

SPhCO2Et

Ph NO2

N CO2Et

Ph

Ph

PhS CO2H

NO2

CO2H

SPhO1) LDA, THF, 78 C

SO2Ph

2)

3) H+80%

Et

NO2

1) LDA2)

O3) H+

4) DBU82% (E/Z = 2/1)

*$0.,

*$0/,

88 MICHAEL ADDITION

@*

,#$%%/0

".%%

-

1

C

(

*+'

$0$$00, 5

@

NO

Ph

CO2MeNBoc

NO2

NO

Ph

NO2CO2Me

NBoc

LiHMDS

55%

*$0$,

PhS

O

MeNO2

Me

O

PhS

NO2

CHO

Me

O

PhS

HO Me

O

1) MeONa/MeOH

2) H+, H2O

1) NaH

2)

84%

81%

EtONaEtOH

67%

Scheme 4.11.

NBoc

O CO2Me

NBoc

NO2

NBoc

NO2

NBoc

O

CO2Me

59%

LiHMDS*$00,


*#!.,-

*# %,*+'$0 ,!7

@

H

$%

#

"+'$0!*#/.,!0

@

"""*+'$01,

!

%/"$%/"4$"%/

4$ *, *,

*,*#$%.,!!

+

"4

#$%/!1

#

"4

+'$05&

J

O

ButMe2SiO

Li

OSiMe2But

CO2Me

NO2

ButMe2SiO

OCO2Me

NO2

+

OSiMe2But

+

71%

CuI

THF*$0 ,

NO2

OCOBut

S

S

Li

Ph

OLi

OEt PhOEt

NO2

O

SS

1)

2)

66%

*$0!,

CO2Et

HH

HO

Me

H

NO2 OEt

OOH

NO2

LDA

78 C

56%

*$01,

90 MICHAEL ADDITION

*, "

D!5

*6?K,

*+' $ 7,17

*,.*%%

","

*L5 >L5 >,17

H

R

NO

O

PhPh

O

PhNO2

Base/additive Yield (%) ds

BuLi 58

NO

O

PhPh

O

60

THF 90:10

>99:1

Solvent

EtN(i-Pr)2/2TiCl4

NO2

Ph

CH2Cl2

2)

75 C

1) base

NOO

MXn

R

R

H

O

N O

O

PhPh

TiCl4

(S)

Si

Si

*$05,

NH

CO2H

H CO2H

HH2N

CH2OH

CO2H

H2N H

OHH

CH3

N

O O

NO2

OMe

OMe

N

O

HO

NO2

Me

CO2MeN

OPh

NO2

Me

CO2MeN

OPh

NO2

Me

CO2Me

NO

OLi

N

OOMe

OLiO

H N

OPh

Me

OLi

OMe N

OPh

Me

OLi

OMe

40% (85% ds) 27% (>90% ds) 75% (>95% ds) 78% (>95% ds)

NO2NO2NO2

Me

NO2

MeO OMe

Scheme 4.12.


-

'@GG

+'$ %1%

4

BC#

-.D-&$4*%7,

Base/additive Yield (%) ds

BuLi 81 50:42:5:3

BuLi/ClTi(NEt2)3 51

N

NMeO

OMe

MeNO2

99:1

N

NMeO

OMeHO2N

Me

2)

1) base*$ 7,

NO

O

Me

Ph

OBnO

MeO

NO2

NO

O

Ph

O

OBn

OMe

NO2

NH

HO

MeO OO

MO

N

O

Bn

Ar

H

HH

O2N

H

O

MO

N

O

Bn

HHAr

H

NO2

H

NaN(SiMe3)2

65% (ds 94:6)

H2, Raney Ni

Re: >94Si: < 6 72%

Scheme 4.13.

MeO

O

SPh

CO2MeMe

SPhNO2

MeOSPh

CO2Me

Me

NO2SPh

O

N

O O

1) LDA

2)

3)

NiCl2

78%

NaBH4

76%

*$ %,

92 MICHAEL ADDITION

4.1.3c Silyl Enolates and Enamines E6

@%$*+'$ .$ /,1.

@

6@8

6*+'$ $,1/

?"

%$-*+'$ 0,

1$

*+'$ ,10

6

2/G.3410

OSiMe3

NO2

Me Me

O

O

1) SnCl4+

2) H+, H2O

85%

*$ .,

MeOSiMe3

OMe

NO2

Me

Me CO2Me

MeO

+

58%

TiCl4

78 C*$ /,

78 C

MeOSiMe2Bu

t

OEtPh

NO2

O2N OEt

OPh O

But

But

Me AlMe

+

MAD

58% (ds 6.3/1)

(23) 2

MAD =

*$ $,

O

N MeNO2

O

N Me

NO2

Me

NO2

O

+0 C24 h

85% 80%

10% HCl *$ 0,


!"#$!%

&' ' ()*

!$

+()*$"

,'',''-' '

./0/12'

!)*+(3*# !($$4 !$

O

N

O

PhNO2

Me

N

O

O

Me

NO2

Ph

+MeCN

1. RT2.

~100%

!!#

O

NPh NO2

O

NNO2

HPh

O

N

NO2H

Ph+

O

NNO2

HPh

O

N PhNO2

O

N

NO2H

Ph

+

+

!"#

NOMe

PhNO2

NO2

OH

Ph

+Et2O, RT

70% (de > 90%)

!$#

O

N

Me

Me

NO2

Ph

O But

O

NO2Ph

Me Me

O

+1) CH2Cl2, 78 C

2) HCl

59% (de >95%)

!(#

94 MICHAEL ADDITION

2#'-'','#'

'2 ")#

$(

,','

#'-'

' "-#()

- '5

/#'3'''/''-'.-,'

126

4

7'8'

",#(-

4.1.3d Organometallic Reagents 9

:6:;:,'--' "/#(,8

:; " #

(/

NNMeO

H

HO2N

NNMeO

O2N

CH2Cl2

88% (80% de)

RT

")#

NH

Me Ph

Me Me

NO2

Me Me

NO2H

O

Me H

NO2Me

O

OMe

Me

O

+1) THF, 0 C

2) AcOH-H2O+

77% (1 : 8)

68% (95% ee)

1) NaOH

2) HCl "-#

N

Me

ButMe2SiO

OPh

NO2N

O

Me

O

Ph

NO2

+SnCl4

78 C

66% (90% de)

",#


- '

:;:6

#

? - #(

- '

'2-'

"3#(3

?

2

26&,4,(!@

6 ? -3#("

:

PhNO2 S MgBr

S NO2Ph H

NO2NO2

Me

89%

1) Et2O

2) H+

CeCl3THF

78%

+

MeMgBr+

"/#

" #

CONEt2 NO2

CONEt2

O2N

NH

O

H

H

2)

1) sec-BuLi TMEDA, 78 C

79% 63%

1) NaBH4, NiCl22) sec-BuLi

"3#

PhNO2

NPh

PhH2C

OMgClO

Ph

PhCH2 NO2

Ph

PhCH2 N

Cl

OH

Ph

PhCH2

CO2HH

+

PhCH2MgBr

85% H2SO4

concn HCl

dil. HCl95%

93%

53%

Scheme 4.14.

96 MICHAEL ADDITION

- '

5A,:

"!($ ""

(( "$

-))

"(#-)-

'527B

$)#

-),

6

$-#-)/

?

=

$,#-)

ArNO2

ArNO2

R

ArR

R2Zn, MgBr220 C

R2Zn20 C

up to 99% yield

up to 40% yield

Scheme 4.15.

+ THFreflux

80%

NO2

Cl

C5H11

Cl

PhNO2 Ph

Et

PhNO2

+Ni(acac)2, Et3N

THF

90%

PhEt

Et3GaHexane

Cl

N

Ph

Et OH

68%

+PhNO2 Ph

Et

+ Et3Alconcn HCl +

24% 49%

C5H11ZnI

Et3B

RT

"!#

"$#

"(#

""#

PhNO2

ZnBr PhNO2

PhNO2 SnBu3

NO2

Me

Ph

+ DMF

83%

+TiCl4

53% (anti/syn = 7/3)

RT

CH2Cl2

$)#

$-#


C

22'

:==5#6

!1($!4()! "

9

6! !

?3333 , 6> 6

!"+#! $

63 $#! 4)! 5

83

6

?29""$56#

.&.#

!"1#! %6

29 $#! (

Me H

Me NO2SOPh

O2N SOPh

Me Me

Me H

Me NO2CO2Me

Me

O2N CO2Me

Me Me

Me

+

RT, 24 hMeCN

base (1.0 equiv)(2)

Base

0

Yield (%)

TMG

Et3N

60

95DBU

MeCN

+

base (1.0 equiv)

RT, 24 h

0

(3)

Yield (%)

DBU

Et3N

TMG

Base

19

61

!"%#

!"(#

MeMe

NO2CN

CN

Me

NO2

+TMG (0.1 equiv)

MeCN

72%

!"+#

Me H

Me NO2 Me

O

O2N

Me MeMe

O

+NaOH (0.025 M)

CTACl, RT, 1 h

!"1#

O

NO2Me

O

O

Me

ONO2

+PPh3

THFRT, 24 h 94%

!"5#

104 MICHAEL ADDITION

& @-3$ +4# !4(

.94.9$# 2$ 6> % # !41

.942$ 6> ((# ! "

.94#$.92$

F6 !!"#

! 1

.3

3

!!5#!54.33

!!%#!5 ,

!!(G

E62 !55

63

?

* %!3 #

!3 !5%)

7!5(C

3

?3* !1!5%

OHC CO2HO2N H

Me Me O2N CO2-

NH3+

MeMe+ +NH3

50%

KOH-H2O !!%#

Ph NH

Ph

SO2PhO

Ph NH

Ph

ONO2

Ph NH

Ph

CO2HO

88%

NaH-CH3NO2THF, RT, 1 h

90%

KMnO4

!!(#

CHO

HO OH NO2

O

O

O

NO2

O

OO

O

O

OO

CHO

O

O

O

O

+

CH3NO2

O

1) Bu3P

2) H+,

62% 95%

85%

H2O2K2CO3

H+

Ph3P=CHCH2CH3

90%

60% 83%

TMG

OH

O

CO2Me

O

CO2Me

NO2

O

CO2Me

CHO

O

CO2MeWittig(Nef)

O

CH3NO2

CH2NO2 CHO

TMG

70%

1. NaOMe, MeOH2. H2SO4 71%

Scheme 4.20.

Scheme 4.19.

4.3 MICHAEL ADDITION OF NITROALKANES 107

6

* $"#!5+

93

OHO

OHO

OH

O

O2N

OO

OO

O

O

H2N

NHO

NHO

O

R

OOO

OO

OO

OO

O

HN

OO

O

O

OOO

O

OHO

OHO

OH

OO2N NH

O

NHO

O

OOO

OO

OO

OO

O

HN

OO

O

O

OOO

O

HNO

NH

O

O

O

OO

O

OOO

OO

ONH

O

O

O

O

O

OO

O

NH

O

HNOO

O

OO

O

O

OO O

H2, Raney NiR = NO2R = NH2

OO

+

HN

O O

DCC: dicyclohexylcarbodiimideHOBT: 1-hydroxybenzotriazole

DCC, HOBT

OO

DMF

3

O

O

R = NO2R = NH2

H2, Raney Ni

O

O

DMFDCC, HOBT

OHN

ONH

HN

O

R

Scheme 4.24.

NO2 PhEt

NO2

NHPhH2C

1) n-BuLi, THF, 78 C2) PhCH2N=CHPh

3) THF, AcOH, 78 to 0 C

95% (anti/syn = 10/1)

!$!#


6

?

!$$#!%+

O O2NMe

O

CO2Me Me

O

O2N

CO2Me

SO2PhMe

O

O2N

CO2MePhO2S

Me

O

H

CO2MePhO2S

80 C

Bu3SnH

DBU benzene

MeNO2

AIBN

!$$#

CHO

Me

TBDMSO

Me

Me

TBDMSO

Me

NO2

Me

RO

Me

NO2

O OTBDMS

Me

O

Me

NO2

O

OTBDMSO

Me

Me

O

Me

62%

O

OTBDMSO

1) MeONa, MeNO2, MeOH, RT, 2 h

Me

2) MsCl, Et3N, CH2Cl2 0 C, 1 h

Me

O

Me

2) CH3CN/H2O, HF, RT, 24 h

O

1) NaBH4, CHCl3/i-PrOH, RT, 40 min amberlyst A-21, Et2O,

RT, 2 h

Me

70%

O

O

3) (S)-2-methylbutyric anhydride, DMAP, 40 C, 20 min 59%

HO

55% (+)-dihydromevinolin

n-Bu3SnH, AIBN

toluenereflux, 30 min

Scheme 4.25.


9J#

* $5#!%1

6 3 !3

!4 !A

!3533

!$(#!(

63

.!"

#

4.3.2 Intramolecular Addition

86

6

! 62 629

4 !$+#!(5

O

PhNO2

O Ph

NO2

OH

HPh

NO2

OH

HPh

NO2

1) LDA

2)

75%

MeONa-MeOH +

45% (7:93)

RT !$+#

Ph

O

NO2 OPh

OO

NO2

Ph

OO

PPh3

71%

+

AIBN

Bu3SnH

70%

!$(#

O

NO2

O O

NO2

O

NO2

MeO MeO

PPh3

(S)-alpinehydride

72%

Bu3SnH

44%

AIBN

!$%#


;6

4

$9

;

!$1#!(%

6

* $%#!((3

3

,

63

!4!#!(1

4.4 ASYMMETRIC MICHAEL ADDITION

4.4.1 Chiral Alkenes and Chiral Nitro Compounds

;?33

!+5

?9

? 3!+% 3

!+(

!++9

!+16

(%)1"B# !4$#!1"A

E$$$$

3$$

#3

$$3#3

!4 #!1

6

!45#!15

'3 3 3

O

O

OS

N

O

O

OS

N

O2N

OO

OBn

O

N

S

OO

OBn

O

N

S

NO2

ButMe2SiO

OO O

O O N

SButMe2SiO

OO O

O O N

S

NO2

MeNO2DBU

92% (88% de)

MeNO2

94% (83% de)

MeNO2

DBU

DBU

92% (86% de)

Scheme 4.27.

O

O

CO2Me

CO2Me

O

O

CO2Me

CO2MeMe SO2Ph

Me

O

O

CO2Me

CO2MeMe NO2

Me

Me LiMe SO2Ph

Me Li

Me NO272% (92% de)

71% (100% de)

THF

THF

!4 #

EtO

O

Me

NHBoc EtO

O

Me

NHBoc

MeNO2

O2NDBU

95% (60% de)

!45#


!1%

6

6>,

3

$I!!I$15B#G

6

!3% !4%#!1( 8 3 $I!

&

$I!#.9$.$6>!I$

&>

4.4.2 Chiral Catalysts

.

&6

:

3

# $"B#!11

6

$,

%"B !4(#$""

6

6!"

5"B$"!

.,

6$

1"B !4+#$"$

F,

6:$#'3

##.## !41#$"4

-39'4K(B#$35,

?

$"

N

N

HHO

H

O

NO2O

O O

NO2+ CCl4, 20 C, 60 h

84% (54.6% ee)

!4(#

O

H NO2

MeMeO

O2NMe

MeO O

OO

O

N

H

HR1O

MeO

R1O

R

+ *

82% (90% ee)

NaOtBu, toluene

!4+#

O NO2NH

CO2Rb

O2N

O

+(510 mol%)

20 h

84% (84% ee)

!41#


9 &O8

3

7$!3.!5$ 3*3!1153$!"

! A3 A 8 ! "

3 2

.*3713AA323!11$

! 78#

" $%A!3*A3

O:3F3!11%3544)%$%

$ A3:3C''&'" ' '33!$14!15!#

$ 233930O3&E?#(33$$((!1+(#

4 73O3O&>3*;9

3-.:3O:*3;-A3CCC&'" ' '33( $4!1(+#

233&E3&E?&'' 33$!41!1(+#

5 6363C63O-3-*3*.&'" ' '33%(5 !1((#

% .3A3>A,,3;''.36-= &'" ' '3

3!15 !1+"#

( &363-*3A>3-3O-")' '*''33$4++!11%#

!% C39#

$%3$383F3!4!!1("#

!( ;3O'3O&E36OE#('33!$51!114#

!+ -?3*73E63:E>

3 +%!1+%#

Ph

O

Ph

OO2N

(R)-LPB, tBuOHCH3NO2 (1.2 equiv)

toluene20 C, 109 h

(S)

59% (97% ee)

! "#

Ph NPPh2

Ocatalyst (20 mol%)

(Yb/K/binaphthol = 1/1/3)Ph N

HPPh2

O

toluene/THF (7/1)40 C

+ CH3NO2

NO2

(5 equiv)

79% (91% ee)

! !#

REFERENCES 119

!+ ;,

3;3--

34 +!1+ #

!1 233E*323*&&' '' ' '3!(+!!114#

$" 93&32C3:; ("35+(!11(#

$" F3.F3.*F

39FC

#(33% !1!11(#

$! F333F63*F36831+5!11%#

$$ ;3OA3;, ' 31(!!11(#

$4 ;,33O-,3OA; ' 3!+4!!11(#

$ ;,33OA; ' 3 (1!11+#

$ ;,33O-,3OA; ' '3$""1!111#

$5 -,3O35"5!111#

$% A3773*'3763&A,,37

3$ $!11%#

+5 3*A37#33$ !!1+ #

+5 C3C3A3>A37&' '',+#-3!% 5!11!#

+% *3;3O>.' '"3! !4!1+!#

+% *3;3&E3O93'.' '"3!%$!1+5#

+( .3:'63&63'2

33!+4!1+5#

+1 C,3-3.>3O6'3O6'#(33 (!!11 #

1" 3.3*-3;;3OH&

3.-#" 33

$"!5!111#

1" H&

3O3..3;;3&>3.3.-33

($5!11+#

1! =393EE3233!"!!$"""#

1$ &36*3'&93*9.3AE &'' 335$"$

!1+1#

!"% *3'3F>3E7&3;::#('33$$5!115#

!"( 63O3-6 ' '3144!11+#

!"+ E39A36AC

36O-,3AE&'' 3351( !11!#

!"1 -3*&3*.3O*3AE#33$"$5!11$#

!!" -3.E3&;?3AE#(33 15!11%#

!!! A3&3-6&'' 33 5!1++#

!!! A3&3-6&'' 33$41!!1+1#

!!! 63-3.6

37>#(33$+%(!11$#

!!$ 7?3OA>3&6'3

!$" 363-E3E9383E323EC? #

(3311!115#

!$" 3E3-E3E9398,3836323EC?

#33!"+5(!115#

!$! 36393EC?&'" ' ''33(1"!!1+(#

!$! 36393EC?&'' 335!(!11"#

!$$ 36309393EC?#(33 ! !!1+1#

!$$ 363093EC? '(35(!11!#

!$4 C?3E3*/

36309 ', '/33$"$!11!#

!$4 930363EC?&' '',+#-3!5"5!11$#

!$ C?3E3E323634%(!115#

!$5 '3>3E36*

3EC?&'' 33!%11!111#

!$% 363&83E39&3E3F63EC?

3!!!1!11$#

!$( C?3E3639&3&83F636*#(33$ !1!11"#

!$+ 363&83F63EC?33!("5!11!#

!$1 -3.3AE#(33 !!11!#

!4" O3.3AE&'' 335 $5!11$#

!4! O3.3AE&'' 335 4!!11$#

!4$ E3A3*.3.O3;-?&'' 335++!114#

!44 .339:3

3 3

6370@A!3>73*3!1(!

!4 3369.' '"33+ 5!1+%#

!4 233963&E?&' '' ' 3+(5!1+5#

!4 233&E3963893&E?&'' 334%1$!1+5#

!45 233963&E33&E? #(33$15(!1+$#

!45 233963-3&E?&'' 335"!(!1+$#

!4% 233&E3&E?3$$%!1+ #

!4( A3>A3&;>

3 !1($#

!4+ 3O9.3;O6 3%$5!11+#

!5$ .36O3F6C

3OOA3&:*&' '',+#-3!!!4

!11+#

!54 .36O3F6C

3E3OOA&' '',+#-3!!$4

!11+#

!5 .3A&3.O&' '',+#-3$%51!111#

!55

!5% 633** 3345!1+$#

!5% 633** 33$4!!1+$#

!5% 3--3.63C707.93:3!11%

!%% 3>-3.6EO3&'' 33555$!1++#

!%% 3>-3->3.63C.3'3A.39

'

")' '*'''33$"$4!115#

!%% . &'' 3

35(%%!11"#

!("

!++ '3O3>-3A&*3%!4!11"#

!+1 -3:3-'3:.

3;9&'" ' ''33$1+ !1+1#

!1" A37'3A--.3.-;.

3 ( !11 #

!1! .3O*3&>;3&'&36;637'A3A--. &'

' '33 ""$!11(#

!1$ ;3&3&63&&O3C

5ALKYLATION, ACYLATION,AND HALOGENATION OF

NITRO COMPOUNDS

!"

5.1 ALKYLATION OF NITRO COMPOUNDS

#

$#

$

$

%

&'("()$

*$+

,(( &-.("/

126

Me

Me NO2N

O

O

Me

Me

Me Me

O2NR N

O

OCH2R

Me

Me

NO

OCH2R

Me

MeN

Me

Me OH

orRCH2Br

RCHO +

7080%

Scheme 5.1.

!"

+8779.:+%

;(-!$7.)

# %

9:'("*:

7

;

7B=#

$* 9:'8"9).*

=4C)> &,7

"

(*

=

&'*"

(7#

47&) &

,*"

&'6''

5.2 ACYLATION OF NITROALKANES

$

61A'!? (6

$(8

.

D* 9:'!"(,

E

(!;

,6&(@

.

9:'@"*1

. &*('

" $ & 7*7 ) "

>

$

9:'(1"

*()>

=

9:'(*"*6

9: '(7"*' G -H

: ")HIHA*'

.

'#B#"H

&'7"*8

&

'#B#)@6?

# ,!

9:'(6*,

CO2HMeO MeONO2

OCH3NO2 +

(EtO)2P(O)CN

Et3N, DMF

81%

'(*"

O

Me

O

NO2

O

O

Me

CH3NO2+DMSONaH

81%

'(7"

NN OEt

O OEtNO2, t-BuOK, DMSO OEt

O OMe

NO276%

OEt

O OMe

NH2HCl

H2/Raney Ni

AcOH/HCl '(6"

ClCl

O

O

N

NH

NOEt

O

ON

OEt

O

O

O2N OEt

O

O

HClH2N

2

100%

1) MeNO2, t-BuOK, DMSO

EtOH, THF

2) AcOH

60%

H2, 10% Pd/C, HCl

94%

Scheme 5.3. Synthesis of -aminolevulinic acid (5-ALA).

130 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

5.3 RING CLEAVAGE OF CYCLIC -NITRO KETONES (RETRO-ACYLATION)

4

*!.

*@:

4

$ #*(" 9:'('"71. ,(A@,?": 11'

$*$$9:'(!

77

9:'(@"

76)

9:'*1"7'

4

:

*(7 9:'*("78

O

NO2

RMeO

OMe

O

n

R

n = 07, 10R = Me, Ph, t-Bu

K2S2O8, H2SO4

MeOH, 80 CO

n

8092%

'(!"

RMgX

O

NO2 O

NO

OMg

XR

HO RNO2

PhC C,

CH2O

O

THF30 to 0 C

RMgX

6085%

R = Me, Et, n-Bu, CH2=CH,(CH3)2CHCH2, PhCH2,CH2=C=CH,

'(@"

O

NO2O

NO

OMg

Me3SiCH2

Me3Si

O

NO

ClMgO

Me3Si

O

O2N

n

2 Me3SiCH2MgCl

n

n

NH4Cl

n

Satd. soln

n = 0, 2

7585%

'*1"

O

NO2

R

HO

O

NO2

OHHO

R

n

30% CH2O aq

K2CO3, RTn

4875%n = 0, 1, 2, 7, 10R = Me, t-Bu

'*("


-$$9:'**

7,

)*9:'*7

7!

5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS

&-.("7@

&

F

-&-.(%

7@

%

9:'*6&

'6 &-.("61

O

NO2

OH O

NO2

ONaH (cat.) or NaOH

MeOH

85%

'**"

OHNO2 CuSO4SiO2 NO2

Obenzenereflux 73%

'*7"

CH2ClO2NMe

Me NO2CH2ClO2N

Me

Me NO2

CH2O2NCH2ClO2N

CH2O2NMe

Me NO2 O2NNO2

MeMe

O2NNO2

MeMe

CH2ClO2N

O2NNO2

MeMe

CH2ClO2N

+ +

+

+

+

+

Cl

Scheme 5.4. SRN1 reaction.

5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS 133

&-.(6(

F %

7@

#-&-.(

9:'*'"6*

&,7"

&-.(9:'*867

9:'*,66

J6'686,6!

&-.(9:'*!'*@

'71'7( &,("

Me

CN

NC

Me

NO2Me

CN

NC

SO2Ph

Me

MeO2N Me

MeMe

Me CN

Me Br Me

NO2Me

MeMe

NO2

MeMe

NC

+ HMPA

84%

+ DMSO

82%

Li+

Li+

'*8"

'*,"

NO2

NO2

Me

NO2Me

NO2

Me

NO2+

Me

91%

Li+ DMSO '*!"

NO2

SO2Ph

Me

NO2Me

NO2

Me

NO2Me

+

85%

DMSOLi+ '*@"

CH2ClO2NMe

Me NO2O2N

NO2Me

Me

+Li+ DMSO

92%

'*6"

Me NO2

Me Cl Et

CO2EtEtO2CMe

Me NO2CO2Et

Et CO2Et

+DMSO

68%

Li+ '*'"

MeMeO2N

CO2EtMe

NO2Me NO2EtO2CMeMe

MeMe

+ DMSO

70%

Li+ '71"


&-.(3

&,("6@

*

" 6112C3*

8!? 9:'7*"'1

(

'1

&-.(

$ & ,7

">$*'*

*'

).* 9:'77"'(

&-.('(

-9:'76

&-.('*

*

&-.(" 9:'7'"

'7

NO2

CN

Me

NO2MeMe

NO2

Me

CN

+DMSO

92%

Li+

I

H3C CH2

O

CH2NO2

+ CH2NO2h

68%

Na+

'7("

'7*"

N

N

Me

O2N CH2ClMe

NO2Me

N

N

Me

O2N

Me

NO2

Me

N

N

Me

O2N Me

Me

DMSO

88%

+

base

Li+

'77"

N

SO2NMe

Me NO2

Me

NO2Me

N

SO2N

Me

NO2

Me

Me Me

+ Li+ DMF

71%

'76"

N

N

Me

O2N CH2Cl

NO2

MeOEt

O

N

N

Me

O2NOEt

O

Me NO2

+NaH, DMSO

h

70%

'7'"

5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS 135

J&-.(

9:'78'6

!1A@1?

47&) ,"

&-.( *11A'112"

$

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5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METALCATALYSIS

-))J

,',7 (@@!"

7* 4-

'@ F#-

(11 >!!+!&*!*3).

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178 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS

3 4H*59('

+$-.-#@.-$

H(*9 $,*-!-.-6#@.-$

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; ?9 &:$-3#@.-$

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73 (,&>

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7@ ,H???!%66@#@@7$

63 I H,!,'M -0-;#@.@$

63 **H4?&&:

M

@0-;#@7.$

REFERENCES 179

63 ? >4H*!!!!

5(8E!.706@::

1

#@@$

63 ' (!%&,*4

),@@7

6 H : +! &:

M

#@6@$

6% 48-6#@-$

6 (8I;3#@-$

6- (*&:!I*73#@-$

6- E5&I-7#@6$

6; , '44'-;;#@-$

6; '44L5) L>*6;#@-$

67 )?&5':,H3#@6$

67 H,8H554>&&;@#@;;$

67 &>E'L!&7#@;;$

66 &HEI,%-3#@-$

6. (>):&**.%@#@6$

6@ 5:(>3#@6$

.3 5L'H*5 376#@6$

.3 '44'I*.%#@;;$

. ***9 M*9 M(9G!%-;;;#@7.$

. &?&.;@#@.$

. *?**9 &..6#@6$

. ('( M(*!%@#@.%$

.% ,&HE' #-@#@66$

.% (*:H,1*&73#@@.$

.% ' H E&! &:

I-.0-%

#@.;$

. H(,85 ;;%#@6$

.- M&&?* #%3#@@@$

.; ')>&>I!%7;#@..$

.7 (,L(H:3%.#@@.$

.6 &(L4%3;#@@7$

.. *LI)LI'5?#%%6#@.$

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@3 )'LL'LHH'4)I:&>&,

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%@#@.3$

@3 E),)>8(:).6@#@@.$

@ 5 &?)*.%.@6#@@$

@ (H8L'9)*%$

@#@@;$

@ :(&>E9*>I(#;7#@@@$

@% *)&?5 ( 8+$3#@.%$

@% *)&?5 EI48,$,*-!-@6

#@.$

@% 8()*#$73#@.;$

@ 4('*(!%7%7@#@.;$

@ E M'?'**.#

..3#@.%$

@ * 11*?9 *.#3;6#@.6$

@ ??*1*.#%36@#@.6$

@- (*?5+$%3-#@..$

@- &

9 9HH5*@;#@.@$

@; 4!!L$,*-!-7@#@@3$

180 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS

@; ?E(::*:

!L @#@@.$

@7 H*H88 !%-;#@.-$

@7 H*888 #@.7$

@7 ?>8) ?*!-%;#@@-$

@6 GH'KH%$

;;#@.@$

@. 5&>(,5*!%;6#@..$

@@ ,84&?5 )* +$%%7-#@.$

33 I)')8#-%@-#@.7$

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3 M(L,;#@@$

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3; 1L15>!%7-#@.;$

37 '9*45>#$7.3#@.%$

36 ,9L(5,(I8(,HLI

!-

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3. EH4E&I99!%73#@@-$

3@ ,>&E)8H:(4!%-67#@@;$

3 '*>!6-3#@@3$

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% )!LHL#$;%#@--$

% 5''4H #%@%#@6%$

4:&5*7-@#@66$

- ?(!%-;#@@7$

; ((::IE'H#

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; ML*5!*HH*H--6#%333$

7 *'''( '

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%% 5(:HEKL!!;.6#@@3$

% I(5N**GG!%73;#@@7$

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%- )&K$,*-!-7.#%333$

%; ,MI!!!!*

E*:%6L4M #@.%$

%7 '

):(:

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%7 '

):(:

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%. !L:>H&H

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3 L>,#@7@$

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REFERENCES 181

7SUBSTITUTION AND

ELIMINATION OF NO2 INRNO2

!" #

"$%&

#

# "

"

"

'##

()

"'#*#

7.1 RNu FROM RNO2

7.1.1 Radical Reactions (SRN1)

+,'- " )

) " #* ".(/#'# )

.#

"'#&

"#

0

"(/#'#1'#2#

3

182

NO2A NO2

O2N ANO2

A = CO2Et, COPh CN, NO 2

++DMSO

'#

!"

+8779.:+%

;(-!$7.)

6 (/# '#'& " ) . (/#'#,#'

""

/(/#'#-#;

84 4%7

477

"

$#-

=.

(/#

'##,

6 .

-

.

:

:4 :4.

'##

)'#$

#>.

""

/#

"

;

7.1.2 Ionic Process

)

#3

+

(/#'#*2

)(/#'#3#:

O

BnO

BnO

OBnNO2

OCH2OMe

O

BnO

BnO

OBn

NO2

OCH2OMe

O

BnO

BnO

OBn

O

BnO

BnO

OBn

OCH2OMe

NO2

OCH2OMe

NO2

O

BnO

BnO

OBn

O

BnO

BnO

OBn

OCH2OMe

CHO

OCH2OMe

CHO

OO OPh

NO2AcHNMOMO

OO

OMOMOO OPh

AcHNMOMO

OO

OMOM

NO2

OO OPh

RAcHNMOMO

OO

OMOM

OO OPh

AcHNMOMO

OO

OMOM

OH

OO OPh

AcHNMOMO

OO

OMOM

O

OO OPh

AcHNMOMO

OO

OMOM

OO OPh

MeAcHNMOMO

OO

OMOM

HOHO O

MeAcHNMOMO

OO

OMOM

OMOM

HOHO O

AcHNMOMO

OO

OMOM

OMOM

SMeS

+

NaCH2NO2

17%

NaCH2NO2

+49%

R = CHO, CO2Me94%

DMSO

1) MeONa

2) O3

1) MeONa

2) O3

DMSO

1) MeONa2) O3

NaBH488%

86%

89%

70%

+

+

Bu3SnH

AIBN

1) CS2, NaOH

2) Me2 SO4 DMSO

Na/NH3MeOCH2ClEt(i-Pr2)N

Na/NH3

88%

87%91%

Scheme 7.2.

NO2SPh

+ PhSNaHMPA

50 C62%

O2N CO2Me

Me n-C5H11Me

CO2Me

+ether

30 C70% (E/Z = 96/4)

(n-Bu)2CuLi

'#*

'#3

7.1 RNu FROM RNO2 185

+,; ""%&

-#'1 ;1

#&

.#4

#

"(/#

'#21'#;#,

>

)

#-

7"

"#>

)#

)(/#'#,#+

#

Pd(PPh3)4

Me

Me NO2

Me

Me CH(CO2Me)2Me

Me

H

CH(CO2Me)2

H

NO2SO2Ph

NO2

NH

N

NO2

+ NaCH(CO2Me)2Pd(PPh3)4

THF+

PPh3+ NO2

63% (7:3)

+ PhSO2NaPd(PPh3)4

DMF20 C, 10 h

70%

+DMF

80 C, 10 h

87%

+ PPh3MeOH-THF65 C, 24 h

Pd(PPh3)4

80%

'#2

'#:

'#'

'#;

NO2 NO2

NO2

EI Nu

EI

MeNO2

Me

O Me O

Me

NO2

NO2 +

mixture

EI Nu, Pd(0)

TMG

75%

El: electrophilesNu: nucleophiles

186 SUBSTITUTION AND ELIMINATION OF NO2 IN RNO2

"%#

/?)"@)

#

?#/

A " @

"

"(/#'#-#

>/#>

(/#'#

(/#'##

")&)

(/# '#*#3

"

MeO2C CO2Me

Me

O

Me

Pd(PPh3)4 (5 mol%)

NaCH(CO2Me)2

79% (E/Z = 89/11)

terpenoid

'#,

N

OSi

OCO2PNB

OTf

HN SO2

OH

N

OSi

OCO2PNB

NO2

N

OSi

OCO2PNB

N SO2

OH

Pd(OAc)4 (5%)(EtO)3P (15%)

CH3NO2

TMG

6070%

34%

PNB : p-nitrobenzyl

'#-

84%

NO2

Me

SO2Ph

Me

MeO OMe

NO2O O

O

MeO

OO

AcOH-H2O+ PhSO2Na

AcOH-H2O

reflux, 1 h

reflux, 1.25 h

75%

'#

'#


2

#3

4>:

"'#*#

):

*#'

!"

#

" ;

;

,

43

(/#'#31'#:#

O

NO2

R1

O

SO2Ph

R1

O

N

R1 R2

O R1

NO2

n

n

n

NH

PhSO2Na

R2

DMFRT, 0.5 h

MeCN

NO2

RT, 1 h

DMF

n = 1, 2, 3

7090%

7395%

60%

'#*

87% (96% ee)

O

NO2

SiMe3

NH

OMe O

N

OMe O

Me

O

Me

O

Me

Me

O97%

Me2CuLi

TiCl4

41% (cis/trans = 94/6)Clavularin A

Scheme 7.3.

C6H13

Me NO2Me3Si

C6H13

Me

Me

Me NO2OSiMe3

O

Me

Me

+SnCl4

10 C, 10 min

+SnCl4

10 C, 30 min

75%

65% '#3

'#2


"

"9 !" *

#B

") "

*)"'#3#*-

$:."

" ? /

#/" *

#8#=

'##

>#

". ."#+ !"

*#

*

(/#'#''#;4 @"?*C

CD4 43"@7>%7#

Me NO2Me CN

CO2MeCO2Me

CN

Me

CO2Me+Me3SiCN

SnCl4

RT, 30 min

75% (7:3)'#:

MeO

O

MeO

O2N

MeO

O2N OAc

O O

MeO

O2N

MeO

O2N

O

O

CH3NO2cat.(CH2NH2)2

MeO

reflux

O2N

1) CH2O aq, Et3N, THF-i PrOH

O

O

Et3N

2) Ac2O, DMAP, CH2Cl2

THF-i PrOH

73%

AcOH

OH

O

MeO

55 C

77%

DBU NO2MeOH

89%

Scheme 7.4.

SPh

C9H19 NO2

SiMe3SPh

C9H19 CN

SPh

C9H19

OAc

O

NO2

SPh

OAc

O

SPh

SPh

SnCl4

Me3SiCN

SnCl495% 84%

PhSHAcOH

70%

'#'

'#;


&

.

. (/#'#,#**

#

.) "">4*(/#'#*2#

*:

7.1.3 Intramolecular Nucleophilic Substitution Reaction

> )

.?43

.#+,'; "

"

(/#'#*:#*:

? .

" (/# '#*' '#*; "

)

C) *)"

) "? *)/

.)(/#

'#3-#3

+ )"

".#"

.

""(/#'#3#3

?")

) "(/#'#3#3*

7.1.4 Allylic Rearrangement

>

F#*G

"(/#'#3*3:

(/#'#33#3'

8

7?

#

O

O H

NO2

SPh

OSPh

O

O

O

+KF

xylenereflux

81% 91%

NaIO4, CCl4reflux

'#3-

H

Ph CN

CO2Me

NH

CO2MeNCNH2

CO2Me

Ph

O2N

Ph

+ MeNO2 microwaveirradiation

70%

'#3

OLi

NO2Me

OMe

Me Me

+THF/HMPA

78 C 65 C

63%

'#3

AcO

OAc

NO2

OAc

AcO

OAcOAc

OH

O

NO2Me

PhMe

Me OPh

Me

Me

Me OH

OPhMe

Me

85%

214 C

Me H

tetralin

O

190 C

+

15% 18%

'#3*

'#33


7.2 RH FROM RNO2

"

"

#H

"

#3;

")

#

) / ) # >)

D#2-7

)D#-47%

""#"

"

."#

7.2.1 Radical Denitration

% @ CE #

?

")

"?#2

#

#

'##% %

")

"

7 ?

"#

"8*7#" / 7 ?

#

.

(/#'#21'#2*#

"

4 %7 4?% 4 % %#/? ) "

A

)#2:

8*7

.#

") 8*79

2'

2;

" 2,

.#:-

4:724=*#

//..

474#"/

(/#'#23#

Ph C C

O

Me

NO2

H

HMPA-H2O

Ph C C

O

Me

H

H

Na2S2O4

70%

Et3SiH+

25 C

'#2-

Ph NO2

CO2Me

Ph

NO2

CO2Me

Bu3SnH, AIBNPh CO2Me

NO2

O O

NO2 DBU

SOPh

O

NO2

SOPh

Bu3SnHO

SOPh

CH3NO2

O

O

NO2

CO2Me

O

NO2

CO2Me

SO2Ph

O2N

O

SO2Ph

CO2MeBu3SnH

O

CO2Me

SO2Ph

48%

TMGTMG

73%

74%

85%

TMG

+ TMG

72% 72% 70%

+benzene, 80 C

AIBN

AIBN

'#2

'#2

'#2*

7.2 RH FROM RNO2 195

?**7 8*7

#:

7"

))#:

+,,; =8*7

)) -E8*7@7*

(/# '#22 '#2# " "

8*7'##:*!)

)

)

"

) #

))

" 8*7

8*7

#

O2N

OSO2Me

OSO2Me

OSO2Me

AIBN, C6H5CF3

H

OSO2Me

OSO2Me

OSO2Me

88%

(C6F13CH2CH2)3SnH

reflux, 24 h

'#23

!"##

CE

4

': ''

' '3

'2 ';

'- :'

: 2;

a-E837 @7

3-#2/ >47-#/ -I4 2#

b837#2/ >47-#/ -I4 2#

NO2

H

Bu3SnH

Bu3SnONO

PhSiONO

PhSiH3

Scheme 7.5. Bu3SnH-catalyzed reduction of nitroalkanes to alkanes


>

"

8*7

#

"8*7

:-1;-E#

)"8*7(/#'#2:#

2:

#

.8*7./

#:3

>3-1:-E

#.

(/#'#2' :3

(/#'#2; :2

(/#'#2,#::

(/#'#2,

.#>"8*7

#

@#+

/

#

/ . .

'##7" ,,2 0)!

" 8*7

.>84(/#'#:-#:'

R

R

NO2

R

R

R

H

R

10% Bu3SnH

0.5 equiv PhSiH3initiator, toluene,

'#22

O

SPh

NO2

Bu3SnH, AIBN O

SPh CO2Me

benzene

75%

CO2Me'#2:

O

O Me

NO2

Bu3SnH, AIBN O

O Me

O

O

CO2Me

O

NO2

Bu3SnH

OAc

NO2

CO2MeBu3SnH, AIBN

OAc

CO2Mebenzene

toluene

toluene

48%

Si

Si

30%

O

O

CO2Me

O

Si

Si

93%

AIBN

'#2'

'#2;

'#2,


#"'#:#

0

)#7" 1%

.

"#

""

.

"8*7(/#'#:#:;

+

.

(/#'#:#:,

(/#'#:-

.#

"8*7

"'#:#)8*1

/)#4

")

.#

""#'-

8 8*7

"

"#+"

"

4 4=* 47% @%#

7 ) "

# #=

O

O

O2NOH NO2

Bu3SnH, AIBN O

O

Me OHMe

70%

toluene '#:-

OAcO

AcO NO2

OAc

OAc

Bu3SnH, AIBN OAcO

AcOCH=NOH

OAc

OAc

O

O

OO

O

Me

Me

MeMe

OO

O

Me

Me

O

MeMe

NO2

NO2

Bu3SnH

ABCN

O

O

OO

O

Me

Me

MeMe

OO

O

Me

Me

O

MeMe

NO2

HCN

OH

70%

benzene

90%

'#:

'#:

O

NO RBu3Sn

R-NO + Bu 3SnOnitroxide

R-NO2 + B u3Sn

R + Bu3SnONO

Scheme 7.6.


. .""

""4

(/#'#:* '

(/#'#:3 '

(/#'#:2#'

? : )4

"'#'#

'*4

'#'#

OBnOBnO

BnO

BnO

NO2OAc

Bu3SnH, AIBNOBnO

BnOOBn

BnO

OAc

ONO2

OO

OAcH

O

O

O

OO

OO

Bu3SnH, AIBN

OH

OO

OOOPh

AcOAcHN

NO2Bu3SnH, AIBN

OH

OO

OOOPh

AcOAcHN

H

benzene

95%

89%

benzene

97%

O

OO

OAcH

O

O

O

OO

OO

benzene '#:*

'#:3

'#:2

O

AcO

OAc

OAc

CH2NO2O

O

OO

O OKF

O

AcO

OAc

OAc

NO2OH

O

OO

O O

Ac2O

O

AcO

OAc

OAc

NO2O

OO

OO

NaBH4

O

AcO

OAc

OAc

NO2

O

OO

O O

Bu3SnH

AIBN

O

AcO

OAc

OAc

O

OO

O O

OHOHO

CH2OH

OHO

OHOH

HO

OH

AcO

AcO

AcO

AcO

AcO1) MeO

pyridine

+

2) H3O+

57%

CH3CN

91%

52%

71%

89%

Scheme 7.7.


?)"

4

#?

/ 4

:;E'#;#'3

(?)"

J '#,#'2

OBnO

BnO BnOOH

OBnNO2

O

O

O

TMG

OBnO

BnO BnOOH

OBn

NO2

O

O

O

Bu3SnH, AIBN

OBnO

BnO BnOOH

OBnO

O

O

OO

OAc

AcOAcO

OAc

OAc

OAc

OAc

3) Pd(OH)2/C, H2 4) Ac2O

68%

toluene

1) BF3Et2O, Et3SiH 2) L-Selectride

+

Scheme 7.8.

O

Me

CHO

MeO

Me

Me

NO2

O

Me

Me

NO2O

O

O

Me

Me

O

NO2

O

O Bu3SnH, AIBN

2) (S)-2-methylbutyric anhydride, DMAP

amberlyst A-21

Si

2) CH3SO2Cl, Et3N

Me

Me

O

O

O Si

Si

Si Si1) MeNO2, MeONa

1) HF

3) NaBH4

70%

70%

toluene reflux

70% 55%

Scheme 7.9.


8))2# .

*##* ##2 ))'#-#>"(/#'#::#

':

?

")".

)'##''

)) 7 ?.

#

@*@ 414

# 2

';

', ) "(/#'#:''#:; #

8

") 2

?"(/#'#:,#;-

#

OMe

MeO NO2 t-BuOKDMSO

MeONaO

(CH2)6CO2Me

+

2) H+

73%

1) Bu3SnH, AIBN

O2N (CH2)7CO2Me

O

OMe

OMe80%

(CH2)7CO2Me

O

H

O

(CH2)7CO2MeNN

O

'#::

n-C7H15

O

Me

NO2

H

O

n-C7H15

O

NO2

H

MeO

Bu3SnH, AIBNn-C7H15

O

Me

H

O

O

Me C6H13NO2

OO

Me C6H13

O

70% (overall)

+

87%

1) HCHO, Ph3P2) Ac2O

3) Bu3SnH, AIBN4) DBU

Ph3P

87%

benzene'#:'

'#:;

O

PhNO2

O

O

Ph

O+

50% (overall)

1) Ph3P

2) Bu3SnH, AIBN'#:,


8/

#;

7

")

..)

#6

"2#*#;

)")..#

"8*7#=. 3

2#2"

. " '##;*

+ "

12.'#*;3

J*'#3 ;2

'#2;:

#

O

H

NC

OTBS

Me

O

O

NC

OTBS

Me

O

HO2N

O

OHC

OTBS

Me

O

HO2NO OTBS

Me

O

H

HO

O2N

O OTBS

Me

O

H

O

O2NO OTBS

Me

O

H

O

MeNO2, DBU

90%

79%

85% (: = 2:1)

90%

60%

CH2Cl2, 15 C

DIBAL

CH2Cl2, 78 C

TMG

benzene, reflux

Bu3SnH, AIBN

CH2Cl2, 25 C

Dess-Martin oxidation

CH2Cl2

Scheme 7.11.

R2 C

O

Im

R1R2

OAc

NO2+

NO2

R1R2

O

Bu3SnH

R1R2

O

NO2

R1R2

O

NO2

R1R2

OE

Bu3SnHE

R1R2

O

+ E

R1CH2NO2 +

+

Oxidation

R1CH2NO2

R2CHObase

AIBN

base

E = electrophiles

Scheme 7.10.


(*#*?

3#3"

3)(/#'#'-;'(/#'#';;#

O

NO2

O

NO2 O3,Zn

O

NO2

CHO

O

O

NO2

Bu3SnHO

O91%

28%

98%

85%

OCO2Et

Pd (0)

DIBAL

AIBN

Scheme 7.12.

O

NO2H

O OO Me

NO2

OO Me

O

O

Me

Me O

OTi

O

Me

Me

Me

63%

47%

Bu3SnH, AIBN

toluene, reflux

+Et2O, 30 C, 3 h

Scheme 7.13.

Me CHO

OCOPh

Me

NO2

H

Me

Me

OCOPh

OH

Me

MeNO2

Me

OCOPh

OH

Me

MeH

O NO2

NH

CO2Rb

O

O2N

O

(R)

cat.: La-K-(S)-6,6-bis(triethylsilyl)ethynyl BINOL (see Section 3.3)

Bu3SnH

(5 mol%)

(R)

cat.

65% (88% ee) 70%

+Bu3SnH

84% (84% ee)84% (84% ee)

AIBN

AIBN '#'-

'#'


)")K

#;,

2 " )K

")#6

# +'#:

"

"

)#;,

?)3##"

#

O

NO2 O

O

NO2Me

O

O

NO2

O Me

Bu3SnH

OO Me

44%72%

(S)-Alpine hydride

Base

AIBN

Scheme 7.14.

O

NO2

CHO

Bu3P

O

NO2

HO Me

MeONa

Me NO2

OH

MeO

O

CrO3Me NO2

O

MeO

O

Bu3SnHMe

O

MeO

O

KOH

Me

O47%

61%

57%

toluene

51%

AIBN

100%()-muscone

Scheme 7.15.


$"

")

.#1

?)# +)

")

FG / ?

."3.8%$

"(/#'#'3#,3

"

.

"

(/#'#'2#,2

!4%3#

"8*7(/#'#':#,:

#

"7"#

O

NO2

O

MeO2N

Bu3SnH

O

Me83%

AIBN+

86%

benzenereflux

'#'2

O

O

Ph

Cl

NO2 Bu3SnH, AIBN

O

O

Phbenzene

97%

'#'*

CO2Me

HO

NO2

O

CO2MeO2N

O

CO2Me

100%

+

86%

2) H+

1) Bu3SnH, AIBN, toluenet-BuOK

THF, 0 C '#'3

HO

HN

OTHPBn

NO2

N

O2N OH

Bn

OHBu3SnH, AIBN

N

OH

Bn

OH1)

2) Swern oxidation toluene

70%

'#'

'#':


?/"7

"(/#'#''#,'

$

%

CE7 # %

CE7 #

;' -- ,2

'; -3 '; -'

'; -* ;* -:

'2 -* :* -;

;- - 2; '

* - ;' :

;- -2 ;2 2

:3 -, :2 '

2, *- ; ;

;2 3 , -

: ,-

, * ;2

NO2

Cl

ClCl

O

OMeCl

ClNO2

H

NO2CO2Me

OO

Me

O

CO2Me

O2N CO2MeF

CH2Ph

NO2

F3CMe

O

NO

NO2

NO2OH

O

OH

NO2

MeO

OMeO

O

MeMe

NO2

(S)

NO2

NO2

NO2

O

O N

Ph

EtO2C

6

6

Me

MeNO2

SS

ONO2

P(OEt)2

O

O

O O

OAcOO2N

MeAcOH

OAc

OMe

O

O

O

O

OO2N

HPh

AcO

ONO2

CN

O

O

O O

O

O

O

O

O2N CO2Et O Si

C4H9 C CO

CH2NO2

EtCH CHPh

NHCbz

CO2Et

NO2

O

HOCH2

NO2

RO N

HN

O

OMe

ON

CO2Et

NO2

NO

Ph NO2

CPhO

CMe

MeN

MeNO2

Me

N


8

" 8*7

)

) #

#=. /?

.

/

(/#'#',#:

")

(/#'#;-#'

?

&)(/#'#;#;

H "(/#'#;#,

%

% CE7 # %

CE7 #

2; * ;* 3O

O2N

MeO

NO

Ph

Me

OMe

NO2

O2N

MeCN

O

OEt

CO2EtBu3SnH, AIBN

MeCN

O

OEtbenzene, 80 C+

41%

CO2Et

'#;

ORNO2

CN

O OCN

Bu3SnHOR

CN

O O CN+

55%

AIBN'#;

MeNO2

Me CO2EtCO2Me

Bu3SnH, AIBNMe

Me

CO2Et

CO2Me

O2N

OCH2Ph

OCH2Ph

OCH2Ph CN

Bu3SnH, AIBN

OCH2Ph

OCH2Ph

OCH2PhNC

HO

HO

OH

OH

HO

HO

OH

OH

HO OH

OH

61%

benzene, 80 C

+

+

60%

HO

'#',

'#;-


>

"

.

#?

)/"

(/#'#;*'#;3#:

"

>+

7.2.2 Ionic Denitration

73 " 3 7% )

(/#'#;'#*3

NO2

O

HNO2

HOBu3SnH, AIBN

HO

OH

HH

amberlyst A-21

62 %

Cedrene

benzene

80% (3 steps)

1) CrO3

2) MeLi3) SOCl2

52%

Scheme 7.19.

O

R1R2

NO2

TsNHNH2 N

R1R2

NO2

HN

LiAlH4

N

R1R2

H

HN

H3O+

O

R1R2

H

010 C

Ts

Ts

'#;'

O2NSPh

MeCHO

DBUSPhO2N

MgBr

SPhO2N

Bu3SnH, AIBN

HO

66%

55%

HO

HO

60%

Scheme 7.20.

7.2

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