The Mannich reaction of the S,N-binucleophilic species derived from Meldrum's acid with HCHO and primary amines

1,3,5-Thiadiazines are an important class of heterocyclic compounds with a wide range of practical uses. Among all possible strategies for constructing a 1,3,5-thiadiazine scaffold, one should especially highlight the direction based on various variants of the Mannich reaction – double aminomethylation of various S,N-binucleophilic substrates (thioamides, dithiocarbamates, 2-mercaptoazoles and –azines, thiolactams, etc.), thiomethylation of amines and other N-nucleophiles, etc. Due to its efficiency, ease of implementation, and availability of initial reagents, this approach is now perhaps the most popular method among heterocyclist chemists that allows for the production of partially hydrogenated 1,3,5-thiadiazines (or perhydro-1,3,5-thiadiazines) in a single synthetic operation.

It is known from the literature that active methylene compounds, and in particular Meldrum's acid, readily react with heterocumulenes such as isothiocyanates, carbon disulfide etc. to form 1,3-dinucleophilic reagents. We decided to study the behavior of the reaction product of Meldrum's acid with phenyl isothiocyanate – triethylammonium 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(phenylamino)methanethiolate – under the conditions of the aminomethylation reaction. It has been established that the mentioned thiolate reacts by double aminomethylation with aqueous HCHO and primary aliphatic and aromatic amines to form 1,3,5-thiadiazine derivatives - 2,2-dimethyl-5-(3-phenyl-1,3,5-thiadiazinan-2-ylidene)-1,3-dioxane-4,6-diones that were not previously described in the literature. The sope and limitations of the reaction as well as the properties of the obtained 1,3,5-thiadiazine derivatives are discussed.