Aldehydes, reaction with imine carbanions

This chapter focuses the attention on the reactions of nonstabilized carbanionic compounds such as alkyl, vinyl, aryl, alkynyl metals, etc., and the chemistry of the stabilized system, i.e. allylic, propargylic or oxaallylic carbanions is presented in Volume 2 of this series. Electrophiles with C=X bonite which are discussed include aldehydes, ketones, epoxides, aziridines, acetals, orthoesters and imines, all of which turn into highly reactive electrophiles in the presence of Lewis acids. 

A new stereocenter is formed when a synthon 143 with umpoled carbonyl reactivity (d reactivity) is introduced into aldehydes or imines. The enantioselective variant of this type of reaction was a longstanding problem in asymmetric synthesis. The very large majority of a-hetero-snbstitnted carbanions which serve as eqnivalents for synthons like 142 and 143 lead to racemic products with aldehydes or imines. However, enantiomerically pnre acylions and a-hydroxy carboxylic acids or aldehydes (144 and ent-144, respectively) as well as a-amino acids and aldehydes (145 and ent-145) are accessible either by nsing chiral d reagents or by reacting the components in the presence of chiral additives (Scheme 18). 

Groups other than a carbonyl can stabilize a carbanion. Meyers described the preparation of a-lithio derivatives of dihydro-1,3-oxazines (282) and 2-oxazolines (284) and their use in alkylation and condensation reactions via a-lithio derivatives such as (283). Meyers treated the commercially available 285 with n-butyl-lithium to form the a-lithio derivative (286), stabilized by chelation with the nitrogen. When iodomethane was added, a carbanion displacement reaction occurred to give 287.The imine unit in 287 was reduced with borohydride (sec. 4.4.A) to give amine 288, and hydrolysis produced the aldehyde (in this case propanal). 

In Section 9.4.A, it was noted that there were problems with aldol-type reactions, especially with the directed aldol condensation. In particular, aldehydes with an a-hydrogen have great difficulty adding to ketones due to their propensity for self-condensation. The ability to use kinetic control conditions in enolate reactions of ketones and aldehydes often solves this problem. There are also several alternative approaches that involve the use of carbanions derived from imines and hydrazones and these can be very useful. l... 

Coupling reactions have also been carried out in a reversal of the imine strategy, by adding a carbanion to an appropriate aldehyde. Thus addition of anion 7.4.21 to acrolein gave racemic adduct 7.4.22 which could be protected, oxidized, and resolved with (+)-ephedrine to give the protected acids 7.4.23 and 7.4.24 (275). 

The modification of the Peterson reaction using an N-trimethylsilylamide anion instead of an a-silyl carbanion offers a promising route to the corresponding imines. Treatment of N-(p-tolyl)-N-trimethylsilylamide anion with carbonyl compounds yields the corresponding ketimines [400]. In particular, LiHMDS has been utilized for the preparation of N-trimethylsilylimines, which are useful as masked imine derivatives in the synthesis of yS-lactam antibiotics [401-407]. Reactions of LiHMDS with non-enolizable aldehydes, enolizable aldehydes, ketones, a diketone, and a-keto esters give the respective imines (Scheme 2.153) [408-413]. Chloro-trimethylsilane is added to convert the generated lithium trimethylsilanolate into hexamethyldisiloxane. 

---