Methyl Orthocarboxylates as Methylating Agents of Heterocycles

Abstract

Methylation reactions occurring between trimethyl orthocarboxylates or N,N‐dimethylcarboxamide dimethyl acetals and various hydroxylated heterocycles, involving a lactam‐lactim tautomeric equilibrium, were investigated as an alternative to classic methylation methods. The corresponding O‐methylated or N‐methylated compounds were isolated in a number of instances and the reaction’s regioselectivity was shown to sometimes follow and sometimes differ from the corresponding outcome using standard methylation methods. In the course of this work, previously unreported effects were noticed. In one case the use of toluene as a reaction solvent led to much more N‐methylated material. In other instances, the influence of the reagent’s steric bulk and/or stability (orthoformate vs. orthoacetate or N,N‐dimethylformamide dimethyl acetal vs. its acetamide homologue) was also noticed. An unwanted formylation reaction could sometimes be avoided and, less often, an increase of O‐methylated material was observed. The previously unreported 1‐dimethoxymethylpyridin‐2(1H)‐one was characterized and its acid‐catalyzed rearrangement into, mostly, 1‐methylpyridin‐2(1H)‐one was studied. The new techniques described here (methanol trapping with 4 Å molecular sieves and Lewis acid‐catalyzed reaction) greatly increase the potential of trimethyl orthocarboxylates. These reagents can be considered as possible alternatives to the dimethyl formamide‐producing N,N‐dimethylformamide dimethyl acetal and may sometimes be attractive options compared to the usual carcinogenic and salt‐producing methylating agents. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

“…4). Actually, HC(OCH 3 ) 3 as an efficient reagent for C -, N -, and O -methylation has been reported [21–24], but the mechanism of these methylations is elusive. The other chiral ammonium salt 7a was obtained under the same conditions as those for the preparation of 7b .…”

Synthesis and reactions of 3‐cyano‐4,6‐dimethyl‐2‐pyridone

“…In contrast to the known behavior of alkylheteroaromatic carbonitriles condensing 3 with DMFDMA afforded 3‐cyano‐4‐(2‐(dimethylamino)vinyl)‐6‐methyl‐2‐pyridone 21 in low yield (Scheme ), identified from gas chromatography‐mass spectrometry (GC/MS), which showed m/z 203; rather methylation of 3 took place in good yield. Alkylation of pyridones with N,N‐dimethylformamide dimethylacetal (DMFDMA), has been reported recently [22]. The alkylation product can, thus, be assigned as structures 3‐cyano‐1,4,6‐trimethyl‐2‐pyridone 20 , or its isomeric form 2‐methoxy‐4,6‐dimethylnicotinonitrile 22 (Scheme ).…”

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…When DMF‐DMA or TMOA was used, the methylated product 2 was the major product. The reaction of DMA‐DMA with hydantoin selectively afforded the methylated product 3 …”