Mannich reactions of heterocycles with dimethyl(methylene) ammonium chloride: A high yield,one-step conversion of estazolam to adinazolam

The readily prepared ammonium salt, (CH₃)₂N⁺ = CH₂Cl^?, 4 , functionalized heterocycles differently, but in a predictable fashion, under neutral, basic or acidic conditions. Triazolo- and imidazobenzophenones 1b ′ and 5 , which primarily underwent intramolecular isomerization to indolols 2a ′ and 6a rather than intermolecular electrophilic substitution under conditions of the normal aqueous Mannich reaction, were converted with 4 to the desired benzophenone derivatives, 1c ′ and 7 , respectively, in moderate yields. The 1-unsubstituted triazolo- or imidazobenzodiazepines, 10a (estazolam) and 10b , were transformed to the corresponding 1-(dimethylamino)methyl derivatives, 11a (adinazolam) and 11b , in good to moderate yields (61% and 32%, respectively.) Under acidic reaction conditions, 1-methyl triazolobenzodiazepine, 10d (alprazolam), afforded 12e , the product of attack at C-4 of the triazolo4,3-a]1,4]benzodiazepine ring system. Under strongly basic conditions in which the anion of 10d was generated prior to reaction with 4 , both 12e and its isomer, 15 , were formed. These results complement the report that 4 may be used to functionalize the 1-methyl position of triazolobenzodiazepines, and further demonstrate the versatility of reagent 4 in heterocyclic synthesis.