Methyl formate, reaction with hydroxide

Isotope labeling by derivative formation with deuterated reagents is useful for the preparation of analogs such as dg-acetonides, da-acetates, da-methyl ethers, dg-methyl esters, etc. The required reagents are either commercially available or can be easily prepared. (The preparation of da-methyl iodide is described in section IX-F. Various procedures are reported in the literature for the preparation of dg-acetone, da-diazometh-ane57.i63.i73 and da-acetyl chloride. ) These reactions can be carried out under the usual conditions and they need no further discussion. A convenient procedure has been reported for the da-methylation of sterically hindered or hydrogen bonded phenolic hydroxyl functions by using da-methyl iodide and sodium hydroxide in dimethyl sulfoxide solution. This procedure should be equally applicable to the preparation of estradiol da-methyl ether derivatives. 

Ethynylation of 3j -hydroxy-16a-methyl-5a-androstan-17-one in a mixture of diethylene glycol dimethyl ether and diethylene glycol monoethyl ether in the presence of potassium hydroxide produces two isomeric 17-ethynyl derivatives. This result is not unexpected since molecular models suggest that the steric influence of the 13/ -methyl group is nearly offset by the 16a-methyl group. The presence of a 16a-acetoxy group in the estrone series also leads to the formation of epimeric 17-ethynyl compounds (61) and (62) on reaction with acetylenedimagnesium bromide. 

The three-necked flask is charged with 750 ml. of formamide, 25 ml. of water, and 50 g. of ammonium chloride (Note 2). The mixture is heated to 180-190° in an oil bath, and 400 g. (3.02 moles) of 4,4-dimethoxy-2-butanone (Note 3) is added dropwise with stirring over the course of 6 hours (Note 4). The flow of cooling water in the reflux condenser should be adjusted to a rate such that the methanol and methyl formate formed during the reaction distil out (Note 5). After all the acetal has been added, heating is continued for 1 hour (Note 6). The mixture is allowed to cool and is poured into 1 1. of IN sodium hydroxide. The resultant solution is extracted with chloroform in a liquid-liquid extractor for 24 hours. The chloroform is separated, dried over sodium sulfate, and removed by distillation through a short column on a steam bath. 

Ab initio molecular orbital calculations are being used to study the reactions of anionic nucleophiles with carbonyl compounds in the gas phase. A rich variety of energy surfaces is found as shown here for reactions of hydroxide ion with methyl formate and formaldehyde, chloride ion with formyl and acetyl chloride, and fluoride ion with formyl fluoride. Extension of these investigations to determine the influence of solvation on the energy profiles is also underway the statistical mechanics approach is outlined and illustrated by results from Monte Carlo simulations for the addition of hydroxide ion to formaldehyde in water. 

When sodium ethoxide is used in place of sodium hydroxide in the carbonylation reaction of benzyl halides with dicobalt octacarbonyl, ethyl esters are produced instead of the acids [15], Esters are also produced directly from iodoalkanes through their reaction with molybdenum hexacarbonyl in the presence of tetra-/i-butylammo-nium fluoride [16]. Di-iodoalkanes produce lactones [16]. The reaction can be made catalytic in the hexacarbonyl by the addition of methyl formate [16]. t-Butyl arylacetic esters are produced in moderate yield (40-60%) under phase-transfer catalytic conditions in the palladium promoted carbonylation reaction with benzyl chlorides [17]. 

Methylal and sodium formate may be obtained from the first distillate of the main reaction mixture. The crude distillate is placed in a flask fitted with a reflux condenser and to it is added a solution of 200 g. of sodium hydroxide in 300 cc. of water. The methyl formate is hydrolyzed to sodium formate. The methylal layer is separated, dried over calcium chloride and distilled. In this way 240-260 g. of methylal, boiling at 37-420, is obtained. By evaporating the watery portion to dryness there is obtained a residue of about 280 g. of crude sodium formate. 

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