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