AMIDES AS NUCLEOPHILES - REACTION OF ALKYL-HALIDES WITH AMIDES OR WITH AMIDES AND WATER - A NEW LOOK AT AN OLD REACTION

Heating of formamide with an alkyl halide (with or without water) affords a mild, nonhydrolytic, high-yield synthesis of alcohols and formate esters. Yet the way in which substitution on the alkyl halide actually occurs remains obscure. To explore this question, thermal reaction of 1-bromooctane (1a) with formamides (HC(O)NHR, R = H, Me; 2a, 2b) was studied quantitatively. Major products are 1-octanol (3) and n-octyl formate (5); minor products are 1-octene (4), di-n-octyl ether (6), and N-octylformamide (7, from 2a, only). Solid coproduct is HC(=NR)NHR+ Br- (e.g., ga, R = H, methanimidamide hydrobromide). Analogously, la and N-methylformamide (2b) give alkylated products 3,5, and 6 along with 8b (R = Me). 1-Iodooctane (1b) reacts similarly. Probe samples show that 1-octanol (3) is first formed, followed by 5 and 6. Occurrence of 8a-c is key to a mechanistic interpretation of the reaction. An imidate (''salt I''), e.g., [HC(=NHMe)O(CH2)7CH3.HBr] from 1a and 2b, is first formed and reacts with amide 2b to give [HC(=NMe)N(Me)CHO.HBr] and 3. Now alcohol 3 is converted to ester 5 and 8b by reaction with this same formylamidine. Water, if present, adds to the imidate and gives a new tetrahedral intermediate that cleaves to ester 5 and amide salt, RNH3X. Analogous reaction steps are proposed to generate side products 4, 6, and 7. Alkylation of formamide by C6F13CH2CH2I (1C) is considerably slower and less efficient than alkylation by 1-bromooctane. This result stands in sharp contrast to fast, efficient reaction of 1c with N-methylformamide or with DMF and water.