Methyl oxalic ester synthesis with

Oxalic ester synthesis—Enolesters from ketones. 6 g. dl-zl5,14-3.Ethylenedioxy-lly ,18-oxido-16-oxo-18-tetrahydropyranyloxyandrostadiene and dimethyl oxalate in benzene added dropwise to NaH in oil (Metal Hydrides, Inc., Beverly, Mass., USA) and benzene, stirred 48 hrs. at 30° in a slow Ng-stream, the crude product dissolved in benzene, and allowed to stand at room temp, overnight with acetic anhydride and pyridine 6.61 g. methyl dl-J5,14,17(20)-3-ethylene-dioxy-1 ly, 18- oxid o-16- oxo-18- tetrahydropyranyloxy - 20 - acetoxypregnatrien-21-ate, 6 g. suspended in an ice-cold 10 1 mixture of morpholine and water, stirred 3-4 hrs. until a clear soln. results, allowed to stand 24 hrs. at ca. 10°, evaporated almost to dryness at 35-40°/0.05 mm., a mixture of benzene and ether then pyridine added, ice-cooled, acetic anhydride added, and allowed to stand 24 hrs. at room temp. 5.55 g. dl-j5,14,17(20)-3-ethylenedioxy-ll, 18-oxido-16-oxo-18-tetrahydropyranyloxy-20-acetoxypregnatrien-21-ic acid morpholide.—Morpholine is preferred to other sec. amines because of its good solvent properties (cf. Synth. Meth. lA, 87). Use of anhydrous amines caused decomposition. K. Heus-ler, P. Wieland, and A. Wettstein, Helv. A2, 1586 (1959). 

In a development, the nitrogen is already at the oxidation level of amine, but carries a t-butoxycarbonyl group to assist the methyl (alkyl) lithiation, reaction with oxalate as in the classical sequence and removal of the iV-substituent with acid at the end, again leads to an indole-2-ester. " The synthesis of 2-unsubstituted indoles is achieved by reaction of the iV,C-dilithiated species with dimethylformamide. ... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Kompa s Synthesis of Camphoric Acid.— The synthesis of camphoric acid is accomplished by starting with di-ethyl oxalate and condensing it with the di-ethyl ester of di-methyl glutaric acid. 

The reaction of diethyl oxalate with ketones in the presence of sodium ethoxide, or other bases, has been used extensively examples are given in Scheme 66. Reaction may occur with esterketone ratios of 1 1, 2 1, or 1 2, but only the 1 1 case finds substantial use in modem synthetic practice. Frequently the a-oxalyl ketone is thermally decarbonylated to give the 3-heto ester.An early example of this was provided by Bachmann s synthesis of equilenin. The mechanism of this reaction has teen examined labeling studies showed that it was the ester carbonyl that was eliminated. The intact oxalyl group has teen used as a directing group in steroid methylation while, more recently, 2-oxalylcyclohexanone has provided a route to (R)-(-)-hexahydromandelic acid (Scheme 67). The products of acylation of suitable acyclic ketones can cyclize to form (enolic) cyclopentane-1,2,4-triones (equation 39). ... 

Workers at the India Orchid company have shown that the condensation of 2-pentanone with diethyl oxalate may be catalyzed by sodium methoxide which is cheaper than sodium ethoxide. After further condensation with hydrazine hydrate, the pyrazole 18 was obtained as a mixture of methyl and ethyl esters. Methylation with dimethyl sulfate was performed neat, as in the Pfizer medicinal chemistry synthesis. The mixture of the methylated pyrazoles 19 was then nitrated and subjected to ammonolysis to give the desired pyrazole intermediate 5 (Scheme 16.8). 

Japanese workers76 claim the superiority of a phosgene-triethylamine mixture (ratio 1 2) over other conventional dehydrating agents. Thus, they devised a novel synthesis of 4-methyl-5-alkoxyoxazole-2-carboxylic acid esters (17) by condensation of alkyl alaninate hydrochloride with diethyl or dimethyl oxalate followed by cyclization of the product (16). 

---