Lithium N-Benzyltrimethylsilylamide

LiN(SiMe3)CH2Ph

[113709-50-5]  · C10H16LiNSi  · Lithium N-Benzyltrimethylsilylamide  · (MW 185.31)

(less-basic lithium amide capable of regioselective conjugate addition to a,b-unsaturated esters;1 amide cuprates have increased selectivity and reactivity toward enoates2)

Alternate Name: LSA.

Solubility: sol THF.

Preparative Method: to a solution of freshly distilled N-benzyltrimethylsilylamine (0.2 mL, 1.0 mmol)3 in THF at -78 °C is slowly added a solution of n-Butyllithium (0.61 mL, 1.64 M in hexane, 1.0 mmol) under Ar; a pale yellow solution of lithium N-benzyltrimethylsilylamide in THF is obtained after stirring for several min at -78 °C.1

Handling, Storage, and Precautions: is moisture- and air-sensitive, and should thus be handled under inert atmosphere; prepare just prior to use; use in a fume hood.

Conjugate Additions.

Lithium dialkylamides (e.g. Lithium Diisopropylamide, LDA) with weak nucleophilicity are commonly used as strong bases for deprotonation. However, lithium N-benzyltrimethylsilylamide acts as a nucleophile with a basicity weaker than LDA. For example, the reaction of LSA with (E)-crotonates affords the conjugate adducts, b-amino esters, in high yields without formation of 1,2-adducts (amides) or products arising from deprotonation at the g-position of the enoates (eq 1).1 On the other hand, the reaction of LDA with (E)-methyl crotonate gives a mixture of the conjugate adduct and deprotonation product (eq 2).1,4 The reaction of lithium benzylamide gives the 1,2-adduct as a major product. The (E) geometry of a,b-unsaturated esters is essential for conjugate addition, since the treatment of (Z)-methyl 2-decenoate with LSA gives the deconjugated ester, methyl 3-decenoate, in high yield.5 Since the N-Si bond is cleaved easily under weak acidic conditions, purification of the conjugate adduct (see eq 1) by silica gel column chromatography provides desilylated benzylamino esters.

The conjugate addition of LSA to methyl crotonate followed by trapping of the resulting enolate with Chlorotrimethylsilane affords the (Z)-ketene silyl acetal nearly exclusively (Z:E = 99:1) (eq 3). On the other hand, if the conjugate addition reaction is quenched with methanol, deprotonation of the resulting b-amino ester with LDA followed by treatment with Me3SiCl gives the (E)-ketene silyl acetal with very high stereoselectivity (Z:E = 2:98) (eq 4). Accordingly, the stereodivergent synthesis of (Z)- or (E)-enolates of b-amino esters is achieved via the direct conjugate addition of LSA or the two-step procedure, respectively.6

The conjugate addition of LSA to enoates followed by trapping with alkyl halides gives a-alkyl-b-amino esters, which are converted to a-alkylated a,b-unsaturated esters upon deamination with silica gel.1 The reaction of the enolates with aldehydes produces b-amino-b-hydroxy esters, which are converted to b-lactams having a 1-hydroxyalkyl group at the C-3 position (eq 5). Thus the b-lactam skeleton is prepared stereoselectively and expeditiously via a three-component coupling reaction.6 The amide cuprate reagents, prepared from 2 equiv LSA and Copper(I) Cyanide, react effectively with a,b,g,d-unsaturated esters to give the corresponding b-amino esters. Based upon this procedure, asymmetric syntheses of b-lactams have been accomplished (eq 6).2

The reaction of LSA with o-halo-a,b-unsaturated esters produces cyclization products.5 In the case of a,b,χ,y-unsaturated dioic acid esters, tandem conjugate additions occur stereoselectively; this cyclization strategy has been applied to the synthesis of racemic cyclopentane monoterpenes.5


1. (a) Uyehara, T.; Asao, N.; Yamamoto, Y. CC 1987, 1410. (b) Asao, N.; Uyehara, T.; Yamamoto, Y. T 1988, 44, 4173.
2. Yamamoto, Y.; Asao, N.; Uyehara, T. JACS 1992, 114, 5427.
3. Diekman, J.; Thomson, J. B.; Djerassi, C. JOC 1967, 32, 3904.
4. (a) Rathke, M. W.; Sullivan, D. TL 1972, 4249. (b) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. TL 1973, 2433.
5. (a) Uyehara, T.; Shida, N.; Yamamoto, Y. CC 1989, 113. (b) Uyehara, T.; Shida, N.; Yamamoto, Y. JOC 1992, 57, 3139.
6. (a) Uyehara, T.; Asao, N.; Yamamoto, Y. CC 1989, 753. (b) Asao, N.; Uyehara, T.; Yamamoto, Y. T 1990, 46, 4563.

Naoki Asao & Yoshinori Yamamoto

Tohoku University, Sendai, Japan



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