With Ortho Esters Followed by Ammonia or an Amine

With Ortho Esters Followed by Ammonia or an Amine 

It was discovered in 1959 that o-aminonitriles could be condensed simultaneously136 or in turn131 137 with an ortho ester and ammonia (or a primary amine) to give a 4-amino (or 4-alkylamino) derivative of a fused pyrimidine. 

The best yields were obtained when the aminonitrile (such as 105) was refluxed with a mixture of triethyl orthoformate and acetic anhydride for 2-4 hr, followed by removal of the volatile portion, which left an imidate (such as 106, l-methyl-4-cyano-5-ethoxymethyleneaminopyrazole). These imidates are fairly stable solids which can be recrystallized from hydro- 

The further isomerization of the imine 108 to l-methyl-4-methylamino-pyrazolo[3,4-d]pyrimidine (109a) occurred slowly in the presence of methyl-amine. This change, at least in the 8-azapurine series,138 can be greatly accelerated by boiling in ethanolic methylamine acetate for 2 hr. When the reagent is not a primary amine but ammonia, no barrier exists to instant prototropy, which gives 109b. 

This Dimroth rearrangement apparently begins with nucleophilic addition of the amine (e.g., MeNH2) to the 1,2-C=N group to give 110, after which the 2,3-bond breaks to form 111. Rotation is followed by cyclization, in which one molecule of the primary amine is expelled.139 

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