Lithium alkyls, conjugate addition

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

Preparation of the quaternary anticholinergic agent benzilonium bromide (47) is begun by conjugate addition of ethylamine to methylacrylate, giving aminoester 42. Alkylation of 42 with methyl bromo-acetate leads to diester 43, which is transformed into pyrrolidone 44 by Dieckmann cyclization, followed by decarboxylation. Reduction of 44 by lithium aluminum hydride leads to the corresponding amino-alcohol (45). Transesterification of alcohol 45 with methyl benzilate leads to 46. Benzilonium bromide (47) is obtained by alkylation of ester 46 with ethyl bromide. 2... 

Preparation from activated Cb(O).1 An activated Cu, prepared by lithium naphthalenide reduction of CuIPBu3 (12,140), reacts with primary alkyl bromides at -50 to -78° to form alkylcopper reagents that undergo 1,4-addition to cyclo-hexenone in moderate to high yield. This conjugate addition is facilitated by ClSi(CH3)3 and a phosphine. 

In spite of the apparent difference between conjugate addition and carbocupra-tion reactions (Sect. 10.3.2), the similarities between the key organometallic features of the two reactions are now evident. In both reactions, inner sphere electron-transfer converts the stable C-Cu bond into an unstable C-Cu bond, and the cluster-opening generates a nucleophilic, tetracoordinated alkyl group. The difference is that the product of conjugate addition (PD) remains as a lithium enolate complexed with RCu (Scheme 10.5), while the initial product of carbocupration... 

Conjugate addition to (35 ,7a/ )-3,7a-dihydro-3-phenyl-l//,5f/-pyrrolof1,2-r ]oxazol-5-onc (8) yields the saturated -substituted bicyclic lactams 9 with complete diastereoselectivity13. Treatment of the latter with 2.2 equivalents of lithium diisopropylamide in tetrahydrofuran at — 78 °C, followed by alkylation with a haloalkane, furnishes the a,/i-dialkylatcd products 10 with excellent selectivity (d.r. >98.5 1.5, determined by H and 13CNMR)13. In this case the major diastereomer has the cw-relationship between the newly introduced substituent (R2) in the pyrrolidine ring and the fused oxazolidinc ring rcsiduc13. 

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