Synthesis and Utility of α Silylamines: A Brief Overview. Literature Presentation 4/6/2K4 Dave Ballweg

Transcription

1 Synthesis and Utility of α Silylamines: A Brief verview Literature Presentation 4/6/2K4 Dave Ballweg

2 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. itrogen containing ligands in organometallic chemistry 6. itrogen bases provide important pka range (32-37) 7. Additive for breaking lithium aggregates (TMEDA)

3 verview 1) General synthesis 2) adical pathways 3) Amide precursors A) Brook rearrangement B) Peterson olefination 4) Iminium precursors 5) eterocycle synthesis 6) Carbocycle synthesis A) Sommelet auser rearrangement B) Stevens rearrangement 7) Disilylation 8) Biological use MA inhibitor 9) Useful deprotonations

4 General Synthesis First synthesis of an α silylamine Cl Si 3 Li 1 3 (l) 3 C Si 3 can be alkyl, alkoxyl, oxy, and/or aryl 1 can be, or alkyl Later expanded to include disubstituted amine igh heat can become nessecary for addition oll, J. E.; Speier, J. L.; Daubert, B. F. J. Am. Chem. Soc. 1951, C MgBr Cl 3 C C Cl Cl 3 C C 3 C 80 o 2 C C C Si 2 C 3 3 C 3 C 3 C Chan, T..; orvath,. F. J. rg. Chem. 1989, 54, S

5 adical Pathways 3 C a, TMSCl Toluene 3 C SiMe 3 69% a eaction mechanism not clearly understood, but first step is presumed to be a radical anion +e (3 F/mol), TMSCl LiCl 4 / TF Mg electrode SiMe 3 64% aving alkyl substituents instead of aryl groups yields a different product n -C 3 7 +e (3 F/mol), TMSCl LiCl 4 / TF Mg electrode 3 C n -C 3 7 n -C 3 7 TMS 70% Kashimura, S.; Ishifune, M.; Murai, Y.; Murase,.; Shimomura, M.; Shono, T. Tetrahedron Lett. 1998, 39,

6 adical Pathways Electrophile + e TMSCl (3 eq.) E Electrophiles: aliphatic aldehydes, aryl aldehydes, anhydrides, amides, esters If reaction done without electrophiles, then the below mixture of products are obtained: TMS 30% 21% 31% Shono, T.; Kise,.; Kunimi,.; omura,. Chem. Lett. 1991,

7 Amide Precurser 3 C Me 2 Me 2 SiLi (1.2 equiv.) TF, 78 o C 3 C Me 2 SiMe2 1) Me 2 SiLi (1.2 eqiuv.) TF, 20 o C 2) ac 3 / 2 3 C Me 2 SiMe 2 96% Brook 2 Me 2 SiMe 2 SiMe 2 3 C 3 C SiMe 2 Me 2 3 C Me 2 igh yielding eeds phenyl groups either on amide, or on silyl anion to promote Brook rearrangement Product is dialkyl amine, limits further functionalization on nitrogen Fleming, I.; Mack, S..; Clark, B.P. Chem. Commun. 1998, 713.

8 Amide Precurser Me 2 SiMe2 Me 2 SiMe2 E D D 2 MeI or AllylBr E = Me (54%) E = Allyl (63%) Me 2 Me 2 SiLi (2.4 eq.) TF, 78 o C Me 2 SiMe 2 Li 3 C Me 2 SiMe 2 3 C Peterson Me 2 Cl, 2 3 C 3 C 73% Fleming, I.; Mack, S..; Clark, B.P. Chem. Commun. 1998, 713.

9 Amide eduction Me 2 SiCl 3 (2.4 eq.) n Pr 3 (1.2 eq.) 64% Me 2 SiCl3 K Et eat 90% Me 2 SiCl 3 MgI Et 2 SiCl 3 Me 2 SiCl 3 Cl Cl Si SiCl 3 Me 2 2 Me 2 SiMe3 Mozdzen, E. C.; Li, G. S.; Benkeser,. A. J. rganomet. Chem. 1979, 178, 21-28

10 Iminium Precursors Me 3 Si' 2 LiCl 4 /ether rt ' ' 1) Me 2 SiLi 2) Me 2 SiLi 3) 3 SiLi rt ' 2 Si" 3 Dialkyl substituted amine severly hinders further functionalization eaction 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 aimi-jamal, M..; Mojtahedi, M. M.; Ipaktschi, J.; Saidi, M.. J. Chem. Soc., Perkin Trans. 1, 1999,

11 Iminium Precursors ' Cl ' 1 2 MeSiLi 2 1 Si Me 2 1 Si Me n-buli 2 1 Si Li SS 2 1 Si S 2 1 Si S n-buli 2 1 Si Li S Strohmann, C.; Abele, B. C. in rganosilicon Chemistry III, Eds.. Auner and J. Weis, VC, Weinheim, 1997,

12 Pyrrole/Aziridine Synthesis TMS eat TMS 1) DEAD 2) 2 Et 2 C C 2 Et TMS Et 2 C C 2 Et hshiro, Y.; Tsuno, S.; hno, M.; Komatsu, M. Chem. Lett. 1990,

13 Pyrrole Synthesis TMS eat " TMS " ' ' ovel generation of azomethine ylide TMS ' " Me 2 C C 2 Me Toluene eflux, 5h ' " Me 2 C C 2 Me Proposed intermediate ' " TMS Me 2 C C 2 Me eactions also run with dimethyl maleate (84% of one isomer-trans) and dimethyl fumarate (47% trans, 46% cis) hshiro, Y.; Miyata,.; Komatsu, M.; hno, M. Tetrahedron Lett. 1991, 32,

14 ucleophilic Attack by itrogen 1) ClC 2 Et, K 2 C 3, TF, 99% IC 2 TMS, MeC 2 2) LiAl 4, TF, reflux, 99% C3 reflux, 88% SiMe3 Cl 4, Me 2 a/ 3, Et TF, 78 o C 94% SiMe3 SiMe3 reflux, 95% SiMe3 Mariano, P. S.; Zhang, x.; Xu, W. J. Am. Chem. Soc. 1991, 113,

15 Carbocycle Formation hν, Me A C2 SiMe 3 37h 91% of a 40:51 Η A = α : β 1% C2 SiMe 3 air-purged Me 14.5h 9,10-dicyanoanthracene in C 2 Cl 2 15% A = α 31% A = β 34% exclusively Solvent C2 SiMe 3 hν, MeC 25h SiMe3 C2 50%, 3:3:2 isomers minor Mariano, P. S.; Zhang, x.; Xu, W. J. Am. Chem. Soc. 1991, 113,

16 earrangements Me 2 CsF Me 2 C 2 SiMe 3 Me 2 DBU hν Me Me 2 Me 2 Sommelet auser rearrangement product Stevens rearrangement products = = Alkyl [2,3] sigmatropic rearrangement [1,2] shift of ylide through radical intermediate Sato, Y.; Maeda, Y. J. Chem. Soc., Perkin Trans. 1, 1997, Sato, Y.; Shirai,.; Sugimori, J. Tanaka, T. J. rg. Chem. 1992, 57,

17 ing Enlargement eactions SiMe 3 Ar Li SiMe 3 LiAl 4 SiMe 3 MeI Me 1) Me 3 SiC 2 Tf Me SiMe 3 2) KI Me Me Me MPA CeF Different ratios of cis-trans were studied, and yielded different product ratios Sato, Y.; Kurono, Y.; atano, K.; Shirai,.; Sakuragi, A. J. rg. Chem. 1994, 59,

18 Disilylation Alkyl FMe 2Si Alkyl FSiMe 2 SiMe 2 F Pd(P 3 ) 4 (2%) 60 or 120 o C SiMe 2 F igh temperatures in sealed tubes Substituents on nitrogen affect product, Me and n-bu yield disilylation while benzyl yields unidentified products The 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,. A. J. Chem. Soc., Dalton Trans., 2003,

19 Monoamine xidase Inactivation 3 C 3 C Cl 4 Et SiMe 3 2 MeC 3 C 3 C Et SiMe 3 3-methyl-5-ethyllumiflavinium perchlorate MA Flavin u 3 SiC C MA u 3 Si C 2 -Acid MA Flavin 2 u Si 3 Mariano, P. S.; oegy, S. E.; Kim, J. J. Am. Chem. Soc. 1995, 117,

20 Deprotonation Between Silicon and itrogen 'Li Li SiMe 3 X Boc 1 SiMe 3 Boc SiMe 3 SiMe 3 Li Boc SiMe 3 X isolated yield 1 : 2 D 97% 0.9 : 1 2 Br 59% 0.7 : 1 Et Cl 76% 1 : 1 Me 3 Si Cl 50% 1 : 0 'are,. K.; Somers, J. J.; Sieburth, S. M. Tetrahedron, 1996, 52,

21 Enantioenriched α Silylamines Li Si 3 Si 3 s BuLi sparteine Si 3 Si 3 = TMS, TIPS Yields ranging from 51% to 67% and ee's from 35% to 70% Voyer,.; Barberis, C. Tetrahedron Lett. 1998, 39, Me s BuLi sparteine Li Me TMSCl ( ) 3 Si Me 48% yield and 68% ee Voyer,.; oby, J. Tetrahedron Lett. 1995, 37,

22 Enantioenriched α Silylamines Si 2 1) Boc 2 (100%) 3 2) 3 SiTf (80%) Boc s BuLi sparteine 82% Boc Si 3 >90% ee Boc Si 3 s BuLi sparteine Boc Si 3 88%, 90-95% ee Boc Si 3 Boc Si 3 s BuLi sparteine 38%, 98% ee Boc SiMe 2 p-clc Boc SiMe 2 2:1 mix of diastereomers C 6 4 Cl Boc Si Grubbs Boc 82% Si Sieburth, S. M.; 'are,. K.; Xu, J.; Chen, Y.; Liu, G. rg. Lett. 2003, 5,

23 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