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[reaction: see text] An efficient and practical N-methylation of amino acid derivatives with dimethyl sulfate in the presence of sodium hydride and a catalytic amount of water is described. Reaction of water with sodium hydride generated highly reactive dry sodium hydroxide, which led to much faster reaction rates than powdered sodium hydroxide itself.

The synthesis of N-unsubstituted anilines generally requires nitration of an aromatic compound followed by reduction of the nitro group. This route is not desirable on a large scale because of the unsafe nature of the nitration reaction. Palladium-and nickel-catalyzed aminations of aromatic halides and triflates, pioneered by Buchwald 2,3 and Hartwig, 4,5 provide not only an efficient route to substituted anilines but also a safer route to N-unsubstituted anilines when using benzophenone imine as an ammonia equivalent. 6 Commonly used bases in palladium-catalyzed aminations are sodium tert-butoxide, cesium carbonate, and tripotassium phosphate. The use of -hydrogen-containing sodium alkoxide bases, e.g., sodium methoxide or sodium isopropoxide, has not been reported in these amination reactions because of their known ability 6 to reduce palladium-aryl-alkoxide complexes to palladium-aryl-hydride complexes, which results in the reduction of aryl halide to arene, as was observed during palladium-catalyzed etherification of aromatic halides with sodium methoxide. 7,8 A method for the palladium-catalyzed reduction of aromatic halides by sodium methoxide has also been reported. 9 In this paper, we report that sodium methoxide and sodium isopropoxide, both of which contain a -hydrogen, are suitable bases for palladium-catalyzed aminations of aromatic halides.Nitrations have been successfully eliminated in a number of projects in our laboratories using palladiumcatalyzed aminations of aryl halides with benzophenone imine as an ammonia equivalent. In one of our projects, amination of a highly substituted aromatic halide (I, Scheme 1), which also contained a methylcarbamate moiety, with benzophenone imine (1.2 equiv) using sodium tert-butoxide (1.4 equiv) as a base in the presence of Pd 2 (dba) 3 (0.5 mol %) and (()-BINAP (1.5 mol %) at 105 or 80°C yielded a complicated mixture. In addition to the desired product (II, 55%), substantial amounts of the corresponding tert-butylcarbamate (III, 9%) and dimeric urea (IV, 11%) byproducts were also isolated. Thus, sodium tert-butoxide was not compatible with the methylcarbamate functionality. Reactions were also not clean or were incomplete with other bases, e.g., cesium carbonate and tripotassium phosphate. This prompted us to investigate this reaction with sodium methoxide, even though palladium-catalyzed reduction of aromatic halides with sodium methoxide had been identified. 7-9 Sodium methoxide not only would eliminate the tertbutylcarbamate byproduct (III) but also would minimize the urea dimer (IV), as it is less basic than sodium tertbutoxide. We rationalized that sodium methoxide could be a suitable base, because these amination reactions do not necessarily require a palladium-aryl-alkoxide complex as an intermediate, which might undergo reduction in the case of sodium methoxide. This supposition was based on the fact that cesium carbonate and tripotassium phosphate are also suitable bases, and amination reaction using these bases may involve a pentacoordinated intermedi...