Selective reactions methylation with diazomethane

CHEC-II(1996) <1996CHEC-II(8)345> covered a range of reactions of substituents, including hydrolyses of esters to carboxylic acids and geminal dihalides to aldehydes, reduction of aldehydes and halogens directly attached to the ring, O-methylation with diazomethane, and reduction of nitroso compounds. A selection of reactions which have... 

Selective monomethylation of dicarboxylic acids has been reported using A/ /wi a as an additive (eq 9) " It is thought that one of the two carboxylic acid groups is bound to the surface of the alumina and is therefore not available for reaction. Carboxylic acids that are engaged as lactols will also undergo methylation with diazomethane to provide the methyl ester and aldehyde (eq 10). ... 

Thus, the acidity oi a lactam is evidently not a reliable quantity for predicting the course of the methylation. The acidity gives information only as to the reaction velocity. In this connection the reaction course of isomethylreductone (6) is illuminating, " With diazomethane in ether containing 1 mole of water, the enolraethyl ether (7) is formed. However, if water is present only in traces, then the alcoholic hydroxyl group is selectively attacked to give 8. 

Reaction of 1,4-diazocinediones with methylating agents leads to different products depending on the conditions. With dimethyl sulfate, the annulated derivative 6 gives JV-methylation selectively 7 however, on reaction with diazomethane, a mixture of the O- and iV-methylated products is obtained.9... 

Methylation of Heteroatoms. The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likely an Sn2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carhoxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester. 

Other acidic functional groups will also undergo reaction with diazomethane. Thus phosphonic acids (eq 5) and phenols (eq 6) are methylated in high yields, as are hydroxytropolones (eq 7) and vinylogous carboxylic acids (eq 8). The origin of the selectivity in eq 6 is due to the greater acidity of the A-ring phenol. 

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