A Novel Synthesis of N-Methoxy-N-methylamides from 4,6-Pyrimidyl Urethane and Grignard Reagents

Abstract

The N-methoxy-N-methylamides (Weinreb amides) have enjoyed tremendous popularity because they react with organometallics (RM, M=Li, MgX) to provide various ketones through stable metal-chelated intermediates without side products. Among the various methods for the preparation of N-methoxy-N-methylamides, the condensation of carboxylic acids and N,O-dimethylhydroxylamine hydrochloride (MeONH2MeCl) using peptide coupling reagents has been frequently employed. The treatment of carboxylic acids with Ph3P/CBr4, Bu3P/(2-pyridine-N-oxide)disulfide, 1,1'-carbonyldiimidazole (CDI), S,S-di(2-pyridyl)dithiocarbonate, DCC/HOBT, 2-halo-1-methylpyridinium iodide, BOP, HBTU, and 2-chloro-4,6-dimethoxy[1.3.5]triazine (CDMT) in the presence of base gives the activated ester intermediates, which are converted to the corresponding Nmethoxy-N-methylamides by nucleophilic acyl substitution with MeONHMe. Although most of these methods are especially useful for the preparation of N-methoxy-Nmethylamides of N-protected α-amino acids without any racemization, some of them require the use of an excess of base and coupling reagents such as BOP and HBTU are expensive. The conversion of carboxylic acids to the corresponding N-methoxy-N-methylamides can also be carried out via anhydride intermediates. The treatment of carboxylic acids with trimethylacetyl chloride, alkyl chloroformates, and phosphonate reagents (DEPC and PPA) affords in situ anhydrides, mixed anhydrides, and phosphonic anhydrides, respectively, in the presence of base, which are converted to the corresponding N-methoxy-N-methylamides by nucleophilic displacement with MeONHMe. However, the removal of isobutyl alcohol is often tedious in case of using isobutyl chloroformate and phosphonate reagents are expensive. The recent method via acyl mesylates, generated from carboxylic acids and methanesulfonyl chloride, is especially useful for the preparation of sterically hindered N-methoxy-N-methylamides, but it can be complicated by the formation of Nmethoxy-N-methylmethanesulfonamides as by-products. Alternatively the preparation of N-methoxy-N-methylamides has been accomplished by the reaction of carboxylic acid derivatives and MeONH2MeCl. The treatment of acid chlorides, carboxylic esters, and oxazolidinones/thiazolidinones with MeONH2MeCl/pyridine, MeONMeM (M = Li, MgCl), AlMe3/MeONH2MeCl, respectively, affords the corresponding N-methoxy-N-methylamides, but these methods proceed in two steps from carboxylic acids. Although various methods for the preparation of N-methoxy-N-methylamides have been reported, they only afford 1 equiv of N-methoxyN-methylamides from carboxylic acids or their derivatives. As part of our continuing study on the preparation of Nmethoxy-N-methylamides we report that N-methoxy-Nmethylamides can be novely prepared from 4,6-pyrimidyl urethane and Grignard reagents in high yields. 4,6-Pyrimidyl urethane 1 was prepared by the addition of 2 equiv of N-methoxy-N-methylcarbamoyl chloride 3, prepared from one third equiv of bis(trichloromethyl)carbonate and MeONH2MeCl, to a mixture solution of 1 equiv of 4,6-dihydroxypyrimidine 2 and 2 equiv of triethyl-