1,2,4,6-Thiatriazine 1,1 -dioxides

The 1,2,4,6-thiatriazine system is the most common in all the oxa- and thi-atriazine series, and some investigations of the tautomeric behavior of 1,2,4,6-thiatriazine 1,1-dioxides 135, which can exist as N[2(6)]H 135a and N(4)H 135b tautomers (Scheme 39), have been performed. 

Of the thiatriazines, the 1,2,4,6-system has been the most studied. There has been particular interest in TV-alkyl-1,2,4,6-thiatriazine 1,1-dioxides because of their herbicidal, fungicidal, and histamine H2-antagonist activity (86TL123,87S170). The preparation of l-chloro-l,2,4,6-thiatriazines (576) by reaction of imidoylamidines (575) with an excess of sulfur dichloride was reported (80JOU1303). 

These heterocycles include thiatriazine 1,1-dioxides, which have been the most studied six-membered heterocycles containing other heteroatoms besides the sulfamide moiety. The herbicidal activity claimed in a number of patents for 1,2,4,6-thiatriazine 1,1-dioxides has prompted the preparation and study of several of its derivatives. The less reported oxathiadiazine 4,4-dioxides and dithiadiazine 1,1-dioxides are also included in this section. 

N-NMR spectra of 4//-1,2,4,6-thiatriazine 1,1-dioxide (64a) and its 4-methyl derivative (64b) have been recorded in DMSO usingNOjMe reference (86MRC444). The spectra show two signals in both cases, one of them corresponding to a pyrrole-type nitrogen and the other one to a pyridine-type nitrogen (the equivalent N-2 and N-6). 

In 1,2,4,6-thiatriazine derivatives, alkylation occurs preferentially at N-4, as demonstrated by C-NMR in 133b and 134b (85TL1105) (Section IV,A,2,a) and by C- and N-NMR in 4-methyl-1,2,4,6-thiatriazine 1,1-dioxide 64b (86MRC444) (Section IV,A,2,a). In several other papers, alkylation at position 4 in 1,2,4,6-thiatriazine 1,1-dioxides has also been reported (60JOC970 61JOC43I5 75GEP2508832). 

Several 1,2,4,6-thiatriazine 1,1-dioxides have been synthesized from other thiatriazine derivatives by nucleophilic substitution of 3- and/or 5-oxo, -thio, -chloro, -methoxy, -aryloxy, and -thiomethyl by ammonia or amines (84JHC1553 85TL11O1, 85TL1105). Other nucleophilic substitutions have been claimed to give derivatives such as 153 (83GEP3134145), 154 (76CB2107), and 155 (83GEP134141). 

A wide variety of 1,2,4,6-thiatriazine 1,1-dioxide derivatives have been claimed as herbicidal in numerous patents (75GEP2508832 81GEP3013268 83GEP3134141, 83GEP3134145). In other reports, fungicidal and bactericidal activities have been claimed for these heterocycles (52GEP831248 75GEP2508832). 

Condensation of ethoxymethylenemalononitrile [EtOCH=C(CN)2] with sulfamide furnishes 5-amino-4-cyano-27/-l,2,6-thiadiazine 1,1-dioxide which is identical to the product formed by ring-transformation of 1,2,4,6-thiatriazine 1,1-dioxide with malononitrile anion (Section 6.16.10) <84H(22)471>. 

The interest in the biological activity of certain 1,2,4,6-thiatriazine 1,1-dioxides has led to the development of synthetic routes to a variety of 2-alkyl-, 2,4-dialkyl- and 4//-derivatives (Scheme 8) <85TL1101, 85TL1105, 85TL4149, 86TL123, 87S170>. 

A simple, efficient synthesis of 4-substituted 1,2,4,6-thiatriazine 1,1-dioxides involves reacting 0,0 -diaryl carbonimidates with thionyl chloride and triethylamine to give sulfoxides which are oxidized with MCPBA. The resulting sulfamides are then reacted with primary amines to give the required products (Scheme 9) <87S170>. 

Diphenyl A-sulfamoylcarbonimidate (54) is a useful reagent for the synthesis of heterocyclic S-oxides, including 1,2,4,6-thiatriazine 1,1-dioxides (Scheme 10) <91S753>. 

At room temperature and below, hydrolysis of oxathiadiazines 111 with water bound to 7-alumina affords 1,2,3,5-oxathiadiazine 2,2-dioxides 24, CX3CO2H, and ammonia (path 1), while at 30-50 °C, elimination of the CX3CO group is accompanied by a rearrangement (path 2) to furnish the 1,2,4,6-thiatriazine 1,1-dioxides 72 (Scheme 9) <2000RJ01229>. 

Heating the 2,4,6-trisubstituted-l,2,3,5-oxathiadiazine 2-oxide 111 (X = Cl, NR2 = piperidino or pyrrolidine) at 60 °C in benzene, toluene, or chloroform with an equimolar amount of water resulted in conversion to the salts 26 (Scheme 10). This process apparently involves initial hydrolysis of the trichloroacetamide fragment followed by an unusual substitution of the piperidino or pyrrolidino moiety by the CCI3 group with concomitant loss of CO2. Treatment of salts 26 with sulfuric acid affords the 1,2,4,6-thiatriazine 1,1-dioxide 112 which revert to salts 26 with piperidine or pyrrolidine <2002RJ01702>. 

The 3,5-diaryl-l,2,4,6-thiatriazine 1-oxides 47 were converted to the 1-chloro derivatives 140 with sulfuryl chloride (Scheme 18). Treatment of 47 with MCPBA gave the unexpected 1,3,5-triazine product 141 and an unknown byproduct (m.p. >300°C) (Scheme 18). No 1,2,4,6-thiatriazine 1,1-dioxides were isolated. A mechanism for formation of 141 was proposed <2000T7153>. 

The 1,2,4,6-thiatriazine 1,1-dioxides 39 and 40 were obtained from a novel base-promoted ring expansion reaction of the 1,2,3,5-thiatriazole 1,1-dioxides 250 (Scheme 49). Treatment of 250 with methyl 2-bromopropanoate and... 

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