A Versatile Pinner Preparation of Orthoesters. The model Case of Trimethylorthobenzoate

A novel procedure was designed and implemented for the synthesis of trimethylorthoesters through the Pinner reaction, in the absence of added solvents. At 5 °C, the reaction of both aliphatic and aromatic nitriles (RCN; R = Et, Bu, Ph) with a moderate excess of MeOH and gaseous HCl, gave the corresponding imidate hydrochlorides [RC(=NH)OMe•HCl] in excellent yields (>90%). The methanolysis of alkyl imidate salts provided trimethylortho- propionate and valerate, along with negligible amounts of the corresponding methylesters and amides as side-products . Trimethylorthobenzoate (TMOB) cannot be prepared from benzonitrile using this procedure due to the very low selectivity towards the desired compound caused by competing reactions. However, the aromatic hydrochloride could be readily converted into the hydrogenphosphate salt [PhC(=NH)OMe•H3PO4] which in turn, underwent a selective (>80%) reaction with MeOH to produce TMOB in a 62% isolated yield. This allowed an unprecedented Pinner-type synthesis of TMOB starting from benzonitrile, rather than from the highly toxic trichloromethylbenzene. Overall, remarkable improvements in safety and process intensification were achieved.