Thiadiazine derivatives

Pyrido[2,l-4][l,3,5]thiadiazine derivatives 175 were prepared from pyridine precursor treatment of iV-iucthylruor-pholinium salt of pyridine thiolates 174 with primary amines and formaldehyde afforded compounds 175 (Equation 27) <2003DOC92>. 

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. 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

The thiohydrazonate ester 321 obtained from reaction of bromide 28c and sodium p-nitrothiophenolate was converted to thiadiazine derivative 322 when it was refluxed with triethylamine in ethanol (75CJC1484). 

The treatment of the derivatives (517) with potassium thioacetate affords the 1,3,4-thiadiazine derivatives (518) which when heated in alkali loses sulfur to give compounds (519) which are formed most likely via the intermediates (520) (Scheme 52) <84CPB4437, 84H(22)479>. Compounds (519) are also formed by irradiation of the hydrazones (521) <84JHC1249,85CPB982,90AHC(48)223>. 

The thiadiazine derivative (165) decomposed thermally to afford the 2//-compound (166)... 

Reaction of the aminoimidazolylpyridine (278) with SOCl2 gave the imidazo[l, 2-6]pyrido[3,2-J]-1,2,6-thiadiazine derivative (279) (43%) <85SC1013>. 

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 electrochemical oxidation of catechols in the presence of 6-methyl-l,2,4-triazin-3-thion-5-one and 4-amino-6-methyl-l,2,4-triazin-3-thion-5-one as nucleophiles in aqueous solutions provided an efficient electrosynthesis of thiazolo[3,2-fi][l,2,4]triazin-7-one and l,2,4-triazino[3,4- ]l,3,4-thiadiazine derivatives respectively <06TL1713> <06TL8553>. 

Sulfamoyl chloride (125) can also be used in cyclisation reactions for example, the imidazole (134) may be converted to the thiadiazine derivative (135) (Scheme 54). 

Except for compound 4a, all thiadiazine derivatives and fused systems with one or two double bonds in the ring show the same molecular conformation more or less distorted. This is an envelope conformation, with the S atom at the flap. Thus, the six-membered ring, excluding the S atom, is almost planar, the S atom being from [0.171 to 0.753 A out of plane. 

Some of the compounds studied contain two types of nitrogens in the ring. The pyridine-type nitrogen chemical shifts in mononuclear thiadiazine rings studied are between 70 and 181 ppm and those corresponding to pyrrole-type shifts are between 210 and 276 ppm. In 1,2,6-thiadiazine derivatives, replacement of an NH by an N-methyl group results in an upheld shift (14— 16 ppm) (86MRC444). 

In the solid state, compounds (R = phenyl) are in their NH form (88JCR(S)94), which is the tautomer preferred in polar aprotic solvents (DMSO), except for compounds in which R = NHj, which always exist as the CH (B) tautomer (Section II,A,3,b). In nonpolar solvents (CDClj), mixtures of NH (A) and CH (B) tautomers are present. The value of depends on the nature of R. In basic solvents (pyridine), the common anionic form exists (Section II,B,l,a). The OH (C) tautomer, which exists in related pyrazoles in a high percentage (76AHC(Suppl)316), is not present in these thiadiazine derivatives. On the other hand, 6-substituted derivatives, which... 

The pKa values in water of some 1,2,6-thiadiazine derivatives and of quite a large number of fused systems have been determined by UV spectrophotometry. In general, all of the compounds have acidic properties as a result of the presence of the SO2 group. 

Corresponding to their acidic character, metallic salts of several 1,2,6-thiadiazine dioxides have been prepared. The 4-nitro- (7b) and 4-cyano-thiadiazine derivatives form with sodium metal stable compounds from which they cannot easily be recovered, whereas acid treatment of the potassium salts readily yields the free thiadiazines (81JHC459). The X-ray analyses of these compounds show significant changes in the electronic distribution of the free derivatives and their salts (Section II,A,2). 

This fragmentation is apparently thermodynamically controlled, with the equilibrium favoring the cyclized compound 65 (80JOC72I). Reaction of 65 and ynamines afford thiadiazine derivatives 68 and 69 (Section II,C,l,d). 2,6-Dichloro-l,4,3,5-oxathiadiazine 4,4-dioxide (202) decomposes above 100°C (Section IV,C,2) to give CSI and cyanogen chloride. 

The cross-conjugated thione (20 X = S), prepared from the corresponding ketone (20 X = O) with phosphorus pentasulfide, participates in a diene-transmissive Diels-Alder reaction with diethyl azodicarboxylate <90BCJ284>. The 3,4-dihydro-2//-l,2,3-thiadiazine (21) so formed is isolable (see Section 6.13.7.2.2) and on prolonged heating with diethyl azodicarboxylate undergoes further cycloaddition to yield the pyridazino[3,4-e]-l,2,3-thiadiazine derivative (23) in 74% yield (Scheme... 

Sulphamoyl chloride has been used in the cyclization of 5-amino-4-ethoxy carbonyl imidazoles (289) to give the corresponding imidazo[4,5-C]-l,2,6-thiadiazine derivatives 290 (equation 91)298. The attempted cyclization of 289 where R = l-(tetra-0-acetyl-/ -D-glucopyranose) using sulphamoyl chloride failed. 

Some H and C NMR data for selected 1 -oxa-2,5-diazine systems are shown in Table 2. Additional examples may be found in the indicated references. No recent nuclear magnetic resonance (NMR) data are available for the corresponding thiadiazine derivatives. The reader is referred to Section 6.15.2.1.2 in CHEC-II(1996) for some earlier data. 

A CoMFA study was conducted on a series of fused thiadiazine derivatives (86 and 87) with PDF 7 inhibitory activity in order to determine alternative molecular regions that could be modified to improve both activity on PDE 7 and selectivity versus PDE 4 and PDE 3. The main conclusion of this three-dimensional quantitative structure-activity relationship (3-D QSAR) study revealed the importance of hydrogen bond interactions for phosphodiesterase activity <2001EJM333, 2000JMC3218>. This is consistent with the lack of activity shown by disubstituted compounds 88 <2000JMC683>. 

An interesting synthetic method is the one-pot reaction of arylketones 259 with iodine and thiosemicarbazides under microwave irradiation. Initially, the a-halo ketones are formed by this reaction, followed by cyclization with the thiosemicarbazide to afford the 1,3,4-thiadiazine derivatives 260 (Equation 41) <2004IJH283, 2005IJB2158>. 

The cyclization of ethenetetracarbonitrile with diarylidenethiocarbohydrazides affords 1,3,4-thiadiazine derivatives 289. 1,3,4-Thiadiazoles 290 are obtained as by-products through oxidative cyclization of the diarylidenethiocarbohydrazides (Equation 48) <1997M61>. 

Similar chemistry has been utilized to further elicit new derivatives as medicinal chemistry targets. Thus, preparation of new thiadiazine derivatives 253 and 254 has been accomplished via the incorporation of glycine and glycinamide at the N, N, or at both positions of the thiadiazine ring stmcture (Schemes 51 and 52) <2002MI438>. 

Regioselective [4-F2] cycloadditon of a-thioxothioamides 334 to the C=N bond of heterocumulenes, followed by S extrusion, typically affords 2-thioxothiazoles. However, attempts at using the phenylene-l,2-diisothiocyanate 335 as the heterocumulene did not give the expected mono- or bis-thioxothiazoles 338. Instead, the reaction afforded primarily the pentacyclic thiadiazine derivative 337, which is formed by the rapid cyclization/dimerization of the diisothiocyanate, and precipitates out of the reaction mixture (Scheme 69) <2001HAC617>. 

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