Grignard reaction with ethyl orthoformate

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. 

Grignard reaction, (Continual) with ethyl formate, 16, I r with ethyl orthoformate, 16, 41 with water, 11, 84... 

Apart from the technical route described to p-apo-8 -carotenal, readily available vitamin A alcohol (Cjo) has served as an intermediate in the form of the phosphonium salt by reaction with the monodiethyl acetal of a Cio dial (ref. 54). The required Cjo monodiethylacetal was obtained (ref.5, p409) by the reaction of the mono aldehyde-protected derivative, the enol ether of methylmalonaldehyde, (C4) with the acetylenic Grignard reagent from trans 3-methyl-2-penten-4-yn-l-ol (C ) followed by acidic dehydration and partial reduction with Lindlar catalyst to give firstly 8-hydroxy-2,6-dimethylocta-2, 4,6-triene-l-al (Cio). Protection of the hydroxyl group by acetylation in pyridine solution with acetyl chloride and formation of the diethyl acetal with ethyl orthoformate followed by hydrolysis of the acetyl group and oxidation afforded the final CIO aldehyde component (D)shown in Scheme 15a. 

Grignard reaction in -butyl ether, 11, 84 with acetaldehyde, 12, 48 with butyl / -toluenesullonate, 10, 4 with carbon dioxide, 11, 80 with dimethyl sulfate, 11, 66 with ethyl carbonate, 11, 98 with ethyl formate, 15, n with ethyl orthoformate, 16, 41 with water, 11, 84... 

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 preparation of acetals is effected by refluxing an ethereal solution of ethyl orthoformate and a Grignard reagent. Prolonged heating is necessary for maximum yields. The reaction mixtures are then carefully processed by the addition of ice and dilute acetic acid followed by extraction with ether and distillation to give the acetal (80-90%). Further studies have been made in conjunction with the preparation of aldehydes (method 165). ... 

Condensation of the Grignard complex of 58 with triethyl orthoformate (59) gave a 75% yield of distilled hydroxyacetal 60. Partial hydrogenation of 60 to 61, followed by acidic hydrolysis, provided hydroxyaldehyde 62, which was isolated in the (all- -configuration. A Wittig reaction of 62 with the ylide of (a-ethoxycarbonylethyl)-tris(dimethylamino)-phosphonium bromide (63) furnished the hydroxyester 64. Treatment of 64 with ca. 0.5 mol equivalents of PBr3 in ether/hexane at -5°C in the presence of a small amount of pyridine gave an 84% yield of crystalline ester bromide 65, which could be transformed to the phosphonium bromide 55 (yield 93%) by reaction with triphenylphosphine in ethyl acetate. 

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