Triazolo thiadiazines

An attempt to prepare triazolotliiadiazepines 31 by reacting bromoalkenecarbonyl substituted thiophenes withiV-aminotriazole thiols failed and triazolo[3,4-h]-l, 3,4-thiadiazines 32 were produced <951JCB939>. 

Bakulev et al. reported the synthesis of 5//-[l,2,3]triazolo[5,l-i>] [l,3,4]thiadiazines starting from 5-N-nitrosylamino-l,2,3-thiadiazole 68. Reduction of 68 with SnCh and 1A/HC1 and then subsequent reaction with a ketone gave the imine 69. Treatment of 69 with thionyl chloride at -80 °C led to the formation of the isolable triazolothiazine 70 which on further reaction with thionyl chloride at room temperature gave the corresponding chloro derivative 71 <00MC19>. 

In a study on [l,2,4]triazolo[3,4-3][l,3,5]thiadiazines, mass spectral fragmentation of the 3-aryl-6-methyl derivative 33 (see Scheme 2) has been determined by Wang et al. <2001SC2841>. These authors found that elimination of the methylimine formaldehyde takes place first to form a thiazetidine ring 34 and, finally, removal of a CH2 group the 2-mercapto-5-aryl[l,2,4]triazole 35 can be observed. 

Syntheses of four different triazolo[l,3,5]thiadiazine ring systems are discussed in this section. The chemical transformations are shown in Schemes 21-25. 

Reiter and co-workers found in the course of their extended research on fused [l,2,4]triazines <1994JHC997> that the N-protected methylthiotriazine derivative 110 when reacted with carbon disulfide under strongly basic conditions yields a mixture of two products 111 and 112. When this mixture was treated with dibromomethane, product 113 was easily removed from the reaction mixture, and workup of the mother liquor allowed the isolation of the [l,2,4]triazolo[l,5-c][l,3,5]thiadiazine derivative 114 in 49% yield (Scheme 21). The same authors carried out ring closure of the ring-closed semithiocarbazide 115 to the triazolothiadiazine derivative 118 as shown in Scheme 21 <1997JHC1575>. The starting compound was treated with triethyl orthoformiate. The authors assume that first intermediate 116 is formed which cyclizes to a second intermediate 117 and, finally, ethanol elimination yields the isolated product 118. 

Ring closure to [l,2,4]triazolo[3,4- ][l,3,5]thiadiazines by utilizing the Mannich reaction has been published by a Chinese team <1999SC2027, 2001SC2841, 2001JF1C929> (Scheme 23). 5-Aryl-substituted 3-mercapto[l,2,4]tri-azoles 123 were treated with formaldehyde and primary amines under acidic conditions to yield the fused thiadiazines 124. The reaction was interpreted to proceed via formation of intermediate 125 upon the reaction of 123 with a... 

Table 4 Synthesis of [1,2,4]triazolo[3,4-b]thiadiazines by reaction of 3-mercapto-4-amino[1,2,4]triazoles with a-halo-oxo reagent...

Some rearrangements in the 1,3,4-oxadiazole series are explained by an /pso-nucleophilic attack by the side-chain (Scheme 72). Thus, under amination conditions, oxadiazolyl ketones 458 give the rearranged thia-zoles 460 via the enamino compounds 459 as intermediates. Sometimes, performing the reaction in refluxing acetic acid causes direct cyclodehydration into thiazolo[2,3-c]-s-triazoles. In a similar way, hydrazine in refluxing acetic acid converts compounds 458 into triazolo(3,4-b)thiadiazines 463... 

Several papers have dealt with 1,2,4-triazolo[3,4-fc][ 1,3,4]thiadiazines including synthesis of new derivatives and tautomeric studies <02SC3455 02ZN(B)552 02PS487> and a one-pot synthesis starting from 4-amino-5-substituted-l,2,4-triazole-3-thiones involving a solid acid-induced cyclocondensation <02PS2403>. 

Hydrazido derivatives of l,2,3-triazolo[4,5-d]pyrimidines when heated in Dowtherm underwent intramolecular cyclization to give tricyclic l,2,3-triazolo[4,5-e]l,2,4]triazolo[4,3-c]pyrimidine derivatives <02JHC885>. A highly resigoselective anodic mono- and difluorination of l,2,4-triazolo[3,4-6][l,3,4]thiadiazine derivatives 61 to give 62 and 63 has been described <02TL273>. 

The practical utility of the facile addition of mercaptoacetic acid across the double bond of an azomethine has been used in the synthesis of thiazolo-triazolothiadiazin-6(7//)-one (328). Thus, 7//-3-methyl-5-triazolo[3,4-f>]thiadiazine hydrochloride (327), obtained by reacting l-amino-2-methyl-j-triazolyl-2-thione (326) with chloroacetaldehyde di-ethylacetal, reacts with mercaptoacetic acid in the presence of p-toluenesulfonic acid in boiling anhydrous benzene for 40 hr using a Dean-Stark water separator followed by basification with sodium bicarbonate to furnish 8a//,9//-3-methylthiazolo[3,2-u]-[l,3,4]triazolo(3,4-f>](1,3,4]-thiadiazin-6(7//)-one (328) (74IJC287) (Scheme 77). The absorption at 1725 cm (lactam carbonyl) in product 328 supports the cyclic structure in preference to the open-chain acid structure. 

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