Grignard reaction with ethyl carbonate

The two racemic tetroses have been prepared from 43 by a sequence of reactions involving the extension of the carbon atom chain by a Grignard reaction with ethyl orthoformate to four atoms, acetylation, and half-reduction of the triple bond to a cis olefin (48). cw-Hyroxylation of 48 with potassium permanganate, peracetylation (for the purpose of isolation), and final hydrolytic deprotection gave DL-erythrose. franj-Hydroxylation of 48 with peroxyacids failed. Therefore acetal 48 was hydrolyzed with 70% aq. formic acid to 4-acetoxycro-tonaldehyde (49). Reacetalization of 49 followed by cii-hydroxylation led to dl-threose in about 14% yield. 

Glycine ethyl ester hydrochloride, 14, 46 16, 86 17, 92 Grignard reaction in -butyl ether, 11, 84 with acetaldehyde, 12, 48 with butyl p-toluenesulfonate, 10, 4 with carbon dioxide, 11, 80 with dimethyl sulfate, 11, 66 with ethyl carbonate, 11, 98... 

Cyclopropyl thien-2-yl ketone (34), available commercially, was subjected to a Grignard reaction with 21 to yield a carbinol (31) in excellent yield. Bromotrimeth-ylsilane-mediated opening of the cyclopropyl ring led to the 4-bromo derivative 32. Condensation with ethyl i -(-)-pipeildme-3-carboxylate (16) was conducted in isopropyl acetate as a solvent with anhydrous lithium carbonate as the base. The transformation was cleaner and did not provide any of the diene (26) arising from elimination of hydrogen bromide. The alkylation of the nipecotate residue could also be directly effected with a mixture of the tartrate salt of 16, lithium carbonate, and isopropyl acetate. Compound 33 was readily isolated as the hydrochloride isopropyl acetate was superior to all other solvents used in this reaction. Since it is not itself prone to hydrolysis, it is preferable to ethyl acetate. Moreover, it appears to crystallize hydrochlorides much better. 

The Grignard reagent from 2-thenyl chloride can be obtained by the use of the "cyclic reactor.However, rearrangement occurs in its reaction with carbon dioxide, ethyl chlorocarbonate, acetyl chloride, formaldehyde, and ethylene oxide to 3-substituted 2-methylthio-phenes, Only in the case of carbon dioxide has the normal product also been isolated. 

Grignard reagents can also act as sources of negative carbon in displacement reactions, e.g. in the synthetically useful reaction with triethoxymethane (ethyl orthoformate, 58) to yield acetals (59) and, subsequently, their parent aldehydes (60) ... 

The methyl ester has also been obtained by esterification of cyclopentanecarboxylic acid.8 The acid, in turn, has been prepared by the Favorskii rearrangement,6 7 9-11 by the reaction of cyclopentyl Grignard reagent with carbon dioxide,12 by the carbonylation of cyclopentyl alcohol with nickel carbonyl13 or with formic acid in the presence of sulfuric acid,14 and by the hydrogenation of cyclopentene-1-carboxylic acid prepared from ethyl cyclopentanone-2-carboxylate 15 or from cyclopentanone cyanohydrin.16... 

The target molecule has four carbon atoms, suggesting a route involving reaction of an ethyl Grignard reagent with ethylene oxide. 

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