Mannich reaction in the synthesis of N,S-containing heterocycles. 1. Synthesis of novel derivatives of imidazo[2,1-b][1,3,5]thiadiazine

Abstract

Reactions of (Z ) 5 benzylidene 2 thiohydantoin with formaldehyde and primary aro matic amines afforded novel derivatives of imidazo[2,1 b] [1,3,5]thiadiazine in 50-69% yields.The Mannich reaction is known to be one of the most important synthetic methods in organic chemistry. 1 At present, the great potentialities of this reaction are far from being exhausted and are still of interest for chemists. For instance, a number of recent studies are devoted to the "nonclassical" Mannich synthesis using new substrates under modified aminomethylation conditions. 2 The in tramolecular Mannich reactions 3 are of particular atten tion since they are very promising for design of novel carbo and heterocyclic systems. With the present work, we open up a series of publications concerned with the study of the structures, methods for the synthesis, and chemical transformations of nitrogen and sulfur con taining heterocyclic compounds obtained by the Mannich reaction.1,3,5 Thiadiazine derivatives belong to a promising class of heterocyclic compounds 4 with a broad spectrum of biological activities. In particular, some functionalized thiadiazines have been found to exhibit fungicidal, herbi cidal, 5,6 acaricidal, insecticidal, 7 and antibacterial prop erties. 8,9 Fused derivatives of 1,3,5 thiadiazine are most suitably synthesized by the "double" Mannich condensa tion of mercaptoazoles and mercaptoazines with forma lin and primary amines. 9-14 Earlier, we have demon strated that pyrido[2,1 b][1,3,5]thiadiazine derivatives can be obtained under the conditions of this reaction. 15 Proceeding further in those investigations, we studied condensation of easily accessible (Z ) 5 benzylidene 2 thiohydantoin (1) with formaldehyde and primary amines and found that this reaction readily occurs in boiling DMF without any catalyst to give novel imid azo[2,1 b] [1,3,5]thiadiazine derivatives (2) (Scheme 1). Scheme 1Ar = Ph (a); 4 FC 6 H 4 (b); 2 MeC 6 H 4 (c)It should be noted that the aminomethylation of thiohydantoin 1 and some of its structural analogs has been repeatedly studied earlier; 1b,16 however, we were the first to obtain imidazothiadiazine derivatives in such a way. It has been shown with a number of examples that the aminomethylation of 5,5 disubstituted 2 thiohydantoins exclusively involves the N(3) atom. 1b,16 Based on this, we assumed that the reaction intermediate is aminomethyl thiohydantoin 3, whose structure permits subsequent cyclocondensation with formaldehyde along the only possible pathway leading to imidazo[2,1 b][1,3,5]thia diazines 2. It is worth noting that documented examples * Dedicated to Academician N. S. Zefirov on the occasion of his 70th birthday.

Synthesis of partially hydrogenated 1,3,5-thiadiazines by Mannich reaction

“…Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] were observed, and the major products were dithiazines 20. Aniline and meta-substituted anilines under these conditions tended to form mixtures of compounds 13, 20, and 22 in various ratios (Scheme 5), with the fraction of dithiazines 20 increasing after longer reaction time; complete conversion of amine was achieved after 10 h. In general, it was noted 37а that 3,5-diaryl-substituted perhydro-1,3,5-thiadiazines were more stable than 3,5-dialkyl analogs, which readily disproportionated with the formation of dithiazines.…”

“…The reaction was sensitive both to the reactant ratio and reaction temperature, as well as the amount of catalyst used. Derivatives of perhydro-1,3,5-thiadiazine 38 could be Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] obtained in up to 66% yield by heating (thio)urea with a mixture of CH 2 O and H 2 S (1 : 2 : 1 ratio) in the presence of n-BuONa (4 equiv) (Scheme 12). 43,84 It has been noted 43 that mostly macrocyclic condensation products were obtained under different conditions.…”

“…146,147 An unusual method for the construction of imidazo[1,5-c]-[1,3,5]thiadiazine system has been described. 148 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] Various S,N-binucleophilic compounds reacted with perfluoromethyleneimine 123; 151 the reaction can be considered as a special case of aminoalkylation. The reaction mechanism includes an attack by thiolate ion at the C=N bond of methyleneimine 123, elimination of F -ion with regenerating the С=N bond and subsequent N-aminoalkylation with cyclization.…”

“…Thus, tetrahydropyridine-2-thiolates 95 and 96 participated in Mannich reaction, forming the respective bispidines 97 and 98 (Scheme 38). [135][136][137] Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] The Mannich reaction with thiolates 91 was studied in detail. The yields of products 19 were found to vary widely and substantially depended on the nature of primary amine and the structure of substituent at position 4 of the thiolate 91.…”

“…15 The most widely used compound of THTT series is 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (5), known by the trade names Dazomet, Tiazone (in USSR), Basamid, Mylone, DMTT, and applied as highly potent soil fumigant, fungicide, herbicide, and powerful insecticide, as well as for the prevention of biofilm accumulation in paper industry. 16 Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] rapidly decomposes by forming MeNCS, MeNH 2 , СН 2 О, and Н 2 S, which provide for its fumigant activity. 18, 19 It has also been reported that thiazone 5 has ovicidal activity against...…”