Nucleophilic Addition-Cyclization

Trimethylsilylepoxides can be prepared by an addition-cyclization process. Reaction of chloromethyltrimethylsilane with vec-butyllithium at very low temperature gives an a-chloro lithium reagent which gives an epoxide on reaction with an aldehyde or ketone. 175 176 

Braun in Advances in Carbanion Chemistry, Vol. 1. V Snieckus, ed., JAI Press, Greenwich, Connecticut, 1992. 

Heathcock, in Comprehensive Carbanion Chemistry, E. Buncel and T. Durst, eds., Elsevier, Amsterdam, 

Heathcock, in Asymmetric Synthesis, Vol 3, J. D. Morrison, ed., Academic Press, New York, 1984. 

Bohme and M. Heake, in Iminium Salts in Organic Chemistry, H. Bohrnne and H. G. Viehe, eds., Wiley-Interscience, New York, 1976, pp. 107—223. 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

A similar pattern of reactivity was demonstrated for carbanions formed by deproton- 

The pattern of nucleophilic addition at a carbonyl group followed by intramolecular nucleophilic displacement of a leaving group present in the nucleophile can also be recognized in a much older synthetic technique, the Darzens reaction (glycidic ester synthesis). 

The first step is an addition of the enolate derived from an a-halo ester to the carbonyl compound. The alkoxide oxygen then effects nucleophilic attack on the 

The epoxy esters formed in the Darzens condensation have been used in the synthesis of ketones and aldehydes. The acids formed by saponification of the esters 

---

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

Each of the approaches reported thus far to these rare ring systems appears rather promising. The nucleophilic addition/cyclization and [3,3]-rearrangement routes appear potentially well-suited for the rather general preparation of substituted analogues. The azomethine ylide route will presumably be somewhat limited in scope, given the basic reaction motif and its structural requirements, while the bicyclic thione rearrangement route will perhaps be of some use for the preparation of specialty compounds related to (54). 

Representative procedure for the gold-catalyzed nucleophilic addition/cyclization of 2-alkynylbenzaldehydes. 3-Phenyl-l-(phenylethynyl)-lH-isochromen ... 

Heterocyclization Reactions. AgOTf and AgSbFe efficiently catalyzed the cascade nucleophilic addition-cyclization of alkynyl >rffe>-(phenylethynyl)phenyl ketones. Allenyl isochromenes were thus obtained in good yields (eq 48). ... 

In a closely related reaction, silver salts, and especially AgOTf, catalyzed a nucleophilic addition-cyclization cascade toward 2-alkynyl enones. In the presence of methanol as nucleophile, this reaction led to the formation of substituted furans (eq 49). ... 

---