Chloro keto esters

TL 29 1555, 6327 (1988) (both /J-keto esters) 31 5509 (1990) (y-keto esters) 35 3325, 4559 (1994) (both /J-keto esters) 36 2063 (a-chloro-/ -keto ester), 5769 (a-acetamido-/J-keto phosphonate)... 

The success of the last reaction depends upon the inertness of the ester carbonyl groups towards the organocadmium compound with its aid and the use of various ester acid chlorides, a carbon chain can be built up to any reasonable length whilst retaining a reactive functional group (the ester group) at one end of the chain. Experimental details are given for l-chloro-2-hexanone and propiophenone. The complete reaction (formation of ketones or keto-esters) can be carried out in one flask without isolation of intermediates, so that the preparation is really equivalent to one step. 

This procedure illustrates a new method for the preparation of 6-alkyl-a,g-unsaturated esters by coupling lithium dialkylcuprates with enol phosphates of g-keto esters. The procedure for the preparation of methyl 2-oxocyclohexanecarboxylate described in Part A Is based on one reported by Ruest, Blouin, and Deslongcharaps. Methyl 2-methyl-l-cyc1ohexene-l-carboxylate has been prepared by esterification of the corresponding acid with dlazomethane - and by reaction of methyl 2-chloro-l-cyclohexene-l-carboxyl ate with lithium dimethylcuprate. -... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Baker s yeast has been widely used for the reduction of ketones. The substrate specificity and enantioselectivity of the carbonyl reductase from baker s yeast, which is known to catalyze the reduction of P-keto ester to L-hydroxyester (L2-enzyme) [15], was investigated, and the enzyme was found to reduce chloro-, acetoxy ketones with high enantioselectivity (Figure 8.32) [24aj. 

Kaluzna, I.A., Feske, B.D., Wittayanan, W. et al. (2005) Stereoselective, biocatalytic reductions of alpha-chloro-beta-keto esters. The Journal of Organic Chemistry, 70 (1), 342-345. 

This chemistry is applicable to the hydrogenation of acyclic compounds such as a-acylamino-, a-ammonio-, a-amidomethyl-, and a-chloro-substituted / -keto esters (Fig. 32.26) [14n, 74a, 77-79]. The (R)-BINAP-Ru-catalyzed hydrogenation of the a-acylamino and a-amidomethyl ketones in CH2C12 leads to the 2S,3R (syn) alcohols in up to 98% ee [14n, 74a]. The use of sterically hindered... 

Many synthetic routes have been developed to access the saturated oxazolo[3,2- ]pyridine ring system. Among those, the most efficient ones rely on a similar strategy starting from an amino alcohol 360 and a bis-electrophile 361, the latter being either a bis-aldehyde, a keto-ester, a chloro-ketone, or a chloroalkyne (Scheme 96). Among these electrophiles, the first two have demonstrated their utility and generality over the years and have been used for the preparation of many saturated oxazolo[3,2- ]pyridines 362. 

Another approach to the syntheses of quinazolines involves 3-(o-azido-phenyl)isoxazoles (210) which are accessible from a-chloro-Z-azido benzal-doximes (209) and /3-keto esters (R = Ph, = OEt). As shown in Scheme 78, the iminophosphorane resulting from the Staudinger reaction is transformed without isolation by an aza-Wittig reaction into 3,4-disubstituted isoxazolo[4,3-c]quinolines (211) (92MI1). 

Reaction of the chloro ester 1-Me with the enol silyl ether 23 a in the presence of dimethylaluminum chloride afforded the [2-1-2] cycloadduct 20 (67% yield) (Scheme 6). Deprotection of the alcohol moiety with uBu4NF in THF gave an 83% yield of a mixture of the 5-keto ester 21a and the spiropentane derivative 22 (ratio 1 90). Upon running the reaction in a mixture of THF/water (ratio 1 1) instead of anhydrous THF, the 5-keto ester 21a was isolated exclusively [331. 

But the trimethylsilyloxycyclohexadienes (51 a,b) reacted with the chloro ester 1-Me only under more drastic conditions to give in moderate yield about equal amounts of the regioisomeric cycloadducts 52 and 53, each as a mixture of endo-and exo-isomers (Scheme 13) [281. Upon treatment with acid or acidic work-up of the reaction mixture, compounds 52 and 53 were converted to the tricyclic keto esters 54a and 54b in 25 and 28% yield, respectively (cf. Sect. 4.4). 

Pyrazolinones and isoxazolinones are prepared from (3-keto esters and hydrazine or hydroxylamine by reactions such as (34 — 35) similar to those in (i) above. Diketene behaves as a masked (3-keto ester. Acetylenecarboxylic esters can be used in place of (3-keto esters to give pyrazolinones such as (36) and (37) and the corresponding isoxazolinones. (3-Chloro-a,(3-unsaturated acid chlorides react similarly (cf. 38 — 39). 

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