Synthesis and Utility of α–Silylamines:A Brief Overview

Literature Presentation 4/6/2K4Dave Ballweg

Utility of Amines

1. Amines are ubiquitous in organic/medicinal chemistry

2. Important precursers to imines, amides, sulfonamides

3. Main component in amino acid synthesis

4. Useful in library construction

5. Nitrogen containing ligands in organometallic chemistry

6. Nitrogen bases provide important pKa range (32-37)

7. Additive for breaking lithium aggregates (TMEDA)

Overview1) General synthesis

2) Radical pathways

3) Amide precursors

A) Brook rearrangement B) Peterson olefination 4) Iminium precursors

5) Heterocycle synthesis

6) Carbocycle synthesis

A) Sommelet–Hauser rearrangement B) Stevens rearrangement

7) Disilylation

8) Biological use – MAO inhibitor

9) Useful deprotonations

General Synthesis

ClSiR3

R can be alkyl, alkoxyl, oxy, and/or aryl

LiNHR1 H3CSiR3NH3(l)

R1 can be H, or alkyl

Noll, J. E.; Speier, J. L.; Daubert, B. F. J. Am. Chem. Soc. 1951, 3867-3871

First synthesis of an α–silylamine

Later expanded to include disubstituted amine

High heat can become nessecary for addition

H3C

MgBr H3CC

Cl

CH3Cl

H3CC

CH3

ClCH2

80 oCNH3CO

HN

H3C

SiH2C

CH3CH3

Chan, T. H.; Horvath, R. F. J. Org. Chem. 1989, 54, 317-327 S

H3C CH3

Radical Pathways

O

NNa, TMSCl

TolueneCH3

CH3H3C

SiMe3

NCH3

CH3H3C 69%

Reaction mechanism not clearly understood, but first step is presumed to be a radical anion R

O

NCH3

CH3

Na

O

NCH3

CH3

+e (3 F/mol), TMSClLiClO4 / THFMg electrode

SiMe3

NCH3

CH3

64%

Having alkyl substituents instead of aryl groups yields a different product

n -C3H7

O

NCH3

CH3

+e (3 F/mol), TMSClLiClO4 / THFMg electrode

n -C3H7

OTMS

N

n -C3H7

CH3H3C

70%

Kashimura, S.; Ishifune, M.; Murai, Y.; Murase, H.; Shimomura, M.; Shono, T. Tetrahedron Lett. 1998, 39, 6199-6202

Radical Pathways

NR

Electrophile+ e

TMSCl (3 eq.)

HNR

E

Electrophiles: aliphatic aldehydes, aryl aldehydes, anhydrides, amides, esters

If reaction done without electrophiles, then the below mixture of products are obtained:

HNR

TMS

HNR

NH NH

30% 21% 31%

Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett. 1991, 2191-2194

H

H

Amide Precurser

O

NMe2H3C

CH3

PhMe2SiLi (1.2 equiv.)

THF, –78 oCH3C

CH3

NMe2

SiMe2PhO

1) PhMe2SiLi (1.2 eqiuv.)THF, –20 oC

2) NaHCO3/H2OSiMe2Ph

H3C

CH3

NMe2

96%Brook

H3C

CH3

NMe2

OSiMe2Ph NMe2H3C

CH3

–SiMe2Ph

NMe2H3C

CH3

SiMe2Ph

H2O

Fleming, I.; Mack, S. R.; Clark, B.P. Chem. Commun. 1998, 713.

High yielding

Needs phenyl groups either on amide, or on silyl anion to promote Brook rearrangement

Product is dialkyl amine, limits further functionalization on nitrogen

Amide Precurser

SiMe2PhNMe2

Fleming, I.; Mack, S. R.; Clark, B.P. Chem. Commun. 1998, 713.

Li

NMe2

OPhMe2SiLi (2.4 eq.)

THF, –78 oC

NMe2

SiMe2PhD

NMe2

SiMe2PhE

E = Me (54%)E = Allyl (63%)

Me2N SiMe2Ph

O

CH3H3C

CH3

H3CO

H

D2O

MeI orAllylBr

NMe2

H3C CH3

Peterson

HCl, H2O

O

H3C CH3

73%

Amide Reduction

O

NMe2SiHCl3 (2.4 eq.)

n–Pr3N (1.2 eq.)H

NMe2

SiCl3

64%

KOHEtOHHeat

NMe2

90%

CH3MgIEt2O

H2O

H

NMe2

SiMe3

–SiCl3

OSiCl3

NMe2

HSiCl3O

SiCl3NMe2

Mozdzen, E. C.; Li, G. S.; Benkeser, R. A. J. Organomet. Chem. 1979, 178, 21-28

SiH

ClCl

Iminium Precursors

R

O

HMe3SiNR'2

LiClO4/etherrt

R

NR'R'

H

1) MePh2SiLi2) Me2PhSiLi3) Ph3SiLi

rtR

NR'2

SiR"3

Naimi-Jamal, M. R.; Mojtahedi, M. M.; Ipaktschi, J.; Saidi, M. R. J. Chem. Soc., Perkin Trans. 1, 1999, 3709-3711.

Dialkyl substituted amine severly hinders further functionalization

Reaction doesn't proceed with trimethylsilyl lithium species

Yields vary from 70-95% with aromatic aldehydes, 50% with isobutyraldehyde

Convenent one pot synthesis

Dangers involved with using lithium perchlorate

Iminium Precursors

H

NR'R'

H

Cl

R1R2MeSiLi SiMe

R2

R1

NR

R

Strohmann, C.; Abele, B. C. in Organosilicon Chemistry III, Eds. N. Auner and J. Weis, VCH, Weinheim, 1997, 206-210

SiMe

R2

R1

NR

R

SiR2

R1

NR

R

Li

PhSSPh SiR2

R1

NR

R

SPh

SiR2

R1

NR

R

SPhSi

R2

R1

NR

R

SPhLi

n-BuLi

n-BuLi

Pyrrole/Aziridine Synthesis

PhN

TMS Ph

Heat

PhN

Ph

TMS

N

Ph Ph

TMS

N

CO2EtEtO2C

Ph Ph

EtO2CCO2Et

1) DEAD2) H2O

Ohshiro, Y.; Tsuno, S.; Ohno, M.; Komatsu, M. Chem. Lett. 1990, 575-576

Pyrrole Synthesis

R N

TMS

R'

O

R" R NR'

OTMS

R"

Novel generation of azomethine ylide

Ph N

TMS

R'

O

R" MeO2C CO2Me TolueneReflux, 5h

N

MeO2C CO2Me

Ph R"

R'

N

MeO2C CO2Me

Ph

HR"

OTMS

R'

Proposed intermediate

Reactions also run with dimethyl maleate (84% of one isomer-trans) and dimethyl fumarate (47% trans, 46% cis)

Ohshiro, Y.; Miyata, H.; Komatsu, M.; Ohno, M. Tetrahedron Lett. 1991, 32, 5813-5816

Heat

Nucleophilic Attack by Nitrogen

OCH3

NH2

1) ClCO2Et, K2CO3, THF, 99%

2) LiAlH4, THF, reflux, 99%

OCH3

HN

CH3

ICH2TMS, MeCN

reflux, 88%

OCH3

NCH3

SiMe3

Na/NH3, EtOHTHF, –78

oCO

CH3

NCH3

SiMe3

HClO4, MeOH–H2O

reflux, 95%

94%O

NCH3

SiMe3

O

NCH3

SiMe3

Mariano, P. S.; Zhang, x.; Xu, W. J. Am. Chem. Soc. 1991, 113, 8863-8878

Carbocycle Formation

O

NCH2SiMe3

CH3

Mariano, P. S.; Zhang, x.; Xu, W. J. Am. Chem. Soc. 1991, 113, 8863-8878

O

NCH2SiMe3

CH3

hν, MeOH

hν, MeCN

N

O

CH3

H

HA

N

O

H

HCH3

37h 91% of a 40:51 ΗA = α : β

1%

14.5hair-purged MeOH 15% HA = α31% HA = β

34%

25hN

O

CH3

H

HSiMe3

50%, 3:3:2isomers

N

O

H

HCH3

minor

9,10-dicyanoanthracenein CH2Cl2

exclusively

O

NCH2SiMe3

CH3

Solvent–H

O

NCH2

CH3

Rearrangements

NMe2

SiMe3

CsF

R

NMe2

R

CH2

NMe2

R

Me

NMe2

RR

NMe2

hνDBU

Sommelet–Hauser rearrangement product Stevens rearrangement productsR = H R = Alkyl

[2,3] sigmatropic rearrangement [1,2] shift of ylide through radical intermediate

Sato, Y.; Shirai, N.; Sugimori, J. Tanaka, T. J. Org. Chem. 1992, 57, 5034-5036Sato, Y.; Maeda, Y. J. Chem. Soc., Perkin Trans. 1, 1997, 1491-1493

Ring Enlargement Reactions

N

O

O

SiMe3 Ar–Li N

O

SiMe3

OH

LiAlH4 NSiMe3

MeI

NMe

SiMe3N Me

1) Me3SiCH2OTf

2) KI

Sato, Y.; Kurono, Y.; Hatano, K.; Shirai, N.; Sakuragi, A. J. Org. Chem. 1994, 59, 148-153

HMPACeFN

Me NMe

N Me

Different ratios of cis-trans were studied, and yielded different product ratios

Disilylation

NAlkyl

FSiMe2SiMe2FPd(PPh3)4 (2%)

60 or 120 oC

NAlkylFMe2Si

SiMe2F

High temperatures in sealed tubes

Substituents on nitrogen affect product, Me and n-Bu yield disilylationwhile benzyl yields unidentified productsThe palladium catalyst choosen affects disilylation vs. ortho-disilylation

The combination f disilane and catalyst is important for yields

Quantitative yields

Tanaka, M.; Uchimaru, Y.; Williams, N. A. J. Chem. Soc., Dalton Trans., 2003, 236-243

H

Monoamine Oxidase Inactivation

N

N

N

NH3C

H3C

CH3

EtClO4

–

O

OCH3

3-methyl-5-ethyllumiflavinium perchlorate

NH2

SiMe3

N

N

N

NH3C

H3C

CH3

Et

O

OCH3NH

Ph SiMe3

MeCN

Mariano, P. S.; Hoegy, S. E.; Kim, J. J. Am. Chem. Soc. 1995, 117, 100-105

MAO–Flavin

Nu

R3SiCH2NH2N

N

N

N

H3CH

O

OCH3NH

CH2R3Si

H-AcidMAO

Nu

MAO–Flavin–H2

Nu–SiR3

Deprotonation Between Silicon and Nitrogen

N SiMe3

Ph

Boc

R'Li

NSiMe3

Ph

O

O

Ph

N SiMe3

O

O

Li

Li

RX

N

PhR

SiMe3Boc

N

Ph

SiMe3BocPh

D–OCH3 97% 0.9 : 1

1

2

R–X isolated yield 1 : 2

Br 59% 0.7 : 1

EtO

O

Cl76% 1 : 1

Me3Si–Cl 50% 1 : 0

O'Hare, H. K.; Somers, J. J.; Sieburth, S. M. Tetrahedron, 1996, 52, 5669-5682

Enantioenriched α–Silylamines

NSiR3

O

O s–BuLisparteine

NSiR3

O

O

Li

NH

O

O

SiR3

SiR3 = TMS, TIPS

Yields ranging from 51% to 67% and ee's from 35% to 70%

Voyer, N.; Barberis, C. Tetrahedron Lett. 1998, 39, 6807-6810

NMe

O

O

HH

s–BuLisparteine

NMe

O

O

LiH

TMSCl N

O

O

(CH3)3Si

Me

48% yield and 68% ee

Voyer, N.; Roby, J. Tetrahedron Lett. 1995, 37, 6627-6630

Enantioenriched α–Silylamines

H2N Ph 1) Boc2O (100%)2) Ph3SiOTf (80%) BocN Ph

SiPh3 s–BuLisparteine

BocHN Ph

SiPh3

H82%

>90% ee

BocNSiPh3 s–BuLi

sparteine

BocHN SiPh3

H 88%, 90-95% ee

BocNPhSiPh3 s–BuLi

sparteine

BocHN SiPh3

H

Ph

38%, 98% ee

BocHN SiMePh2

Hp-ClPhCNO

ON

C6H4Cl

SiMePh2

HBocHN

2:1 mix of diastereomers

BocN Si Grubbs 82%N

SiBoc

Sieburth, S. M.; O'Hare, H. K.; Xu, J.; Chen, Y.; Liu, G. Org. Lett. 2003, 5, 1859-1861

Conclusions

α–Silylamines are easily synthesized from commercailly available starting materials

Wide variety of silicon substituents

Synthesis of many different amines, with and without protecting groups

Methods availibe for synthesizing heterocycles and carbocycle

Potential biological applications

Use of sparteine to obtain chiral molecules

Coming soon, Addition of Silyl anions to imines