Crown Darzens condensation

Interestingly, phase-transfer catalysts including crown ethers have been used to promote enantioselective variations of Darzens condensation. Toke and coworkers showed that the novel 15-crown-5 catalyst derived from d-glucose 33 could promote the condensation between acetyl chloride 31 and benzaldehyde to give the epoxide in 49% yield and 71% A modified cinchoninium bromide was shown to act as an effective phase transfer catalyst for the transformation as well. ... 

P. Bako, A. Szolloy, P. Bombicz, L. Toke, Asymmetric C-C Bond Forming Reactions by Chiral Crown Catalysts Darzens Condensation and Nitroalkane Addition to the Double Bond , Synlett 1997, 291-292. 

Darzens condensation using crown ethers and cinchona alkaloids-derived catalysts, respectively, obtaining epoxides with moderate enantioselectivity. 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Scheme 8.5 Crown ether-catalyzed Darzens condensation.

All catalytic enantioselective versions of the Darzens condensation are based on the use of chiral phase-transfer agents, e.g. the cations 184a,b derived from ephed-rine, quinine/quinidine-based ammonium ions such as 185a,b, or the crown ether 186. 

DARZENS CONDENSATION Chloroacetonitrile. Dibenzo-18-crowns-6. Sodium hydride-Dimethylformamide. 

Akabari, S., Ohtomi, N., and Yatabe, S., Two-phase Darzene condensation reaction with octopus compounds as catalysts. Bull. Soc. Chem. Japan, 53, 1463, 1980. Dehmlow, E. W, and Lissel, H., Alkyne synthesis using tert-BuOH-18C6 crown ether-petroleum ether as catalytic system, Liebigs Ann., 1980, 1. 

Carbon acids such as chloroacetonitrile and chloromethyl p-tolyl sulfone are readily deprotonated by concentrated aqueous sodium hydroxide under phase transfer conditions. In the presence of aldehydes or ketones, the carbanion undergoes condensation to yield an intermediate a-alkoxy chloride. Intramolecular nucleophilic displacement of halide yields either a glycidic nitrile or a, j3-epoxysulfone. The overall process is, in fact, a phase transfer variant of the Darzens condensation [13] (see Eq. 5.9). Either benzyltriethylammonium chloride (BTEAC) or dibenzo-18-crown-6 (DB-18-C-6) catalyzes the phase transfer Darzens condensation of chloroacetonitrile [14, 15]. The results are presented in Table 5.8. 

The structural motifs of some excellent chiral crown ethers have been derived from easily accessible natural products. For example, a (+)-camphor-based chiral aza-crown ether 7 was developed and successfully apphed in asymmetric conjugate addition by Brunet [11]. The use of D-glucose-based crown ethers 8 and 9 as chiral phase-transfer catalysts has been intensively studied by Bako and colleagues in the asymmetric Michael addition [12], Darzens condensation [13], and epoxidation [14]. Another carbohydrate-derived chiral crown ether 10 was prepared from chiro-inositol by Aldyama and coworkers, which successfully enabled the enantioselective conjugate addition of N-(diphenylmethylene) glycine tert-butyl ester to several electrophiles [15]. 

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