1.2.4- Thiadiazine 1,1-dioxide

The cycloaddition reaction of compound 6 with N-aryl- and N-aralkylazides 23 was also investigated (967(52)7183). Thiadiazabicyclo[3.1.0]hexene derivatives 25 were obtained from the labile triazoline intermediate 24 through nitrogen elimination. This bicyclic system underwent thermal transformation, producing thiadiazine dioxides 26 as the main product together with thiazete dioxides 27 and pyrazoles 28. 

Thieno[3,4-( ]-l,2,4-thiadiazine dioxide 33 and thieno[2,3-i ]-l,2,4-thiadiazine dioxide 34 (prepared as shown in Scheme 8 and Equation (10), Section 10.09.9.1.1) undergo electrophilic substitution on the thiophene ring regio-selectively as shown in Scheme 6 <1997H(45)1767>. 

The parent thieno[3,4- ]-l,2,4-thiadiazine dioxide 35 undergoes regioselective alkylation at N-2 to give, for example, compound 36. This can then be followed by alkylation at N-4 (Scheme 7) <1999BMC2811, 2000EJM751>. 

The single crystal X-ray structure of 3-methyl-4//-pyrido[2,3- ] l>2,4-thiadiazine 1,1,-dioxide 13 was compared to that of diazoxide 14 in order to determine the predominant tautomeric form and it was found that both these thiadiazine-dioxides exist in the AH tautomeric form in the solid state <1995AXG2064>. 

Other thiadiazine dioxides have been investigated (70CRV593). The 2//-tautomer (48) is favoured over the 4JT-tautomer (49) and structure (50) in which the tautomeric proton is on oxygen. The dihydro-1,2,6-thiadiazine dioxides are also thought to exist in the tautomeric equilibrium (51) i(52). 

The NH groups of sulfonamide functions are also readily alkylated. The 1,2,6-thiadiazine dioxide (74) gives the 2-methyl derivative on treatment with iodomethane in acetone in the presence of potassium carbonate <65CI(L)182). The 1,3,2,4,6-dithiatriazine (75) forms a silver salt (64MI22800), and reaction of the salt with iodomethane gives the expected TV-methyl compound. 

In the latter example, cyclization occurs exclusively to the carbonyl carbon rather than with nucleophilic displacement of chloride at the a-carbon. Intramolecular alkylation of nitrogen does occur in other systems the 3-chloropropylsulfonylhydrazide (194), for example, ring closes to give the 1,2,3-thiadiazine dioxide (195) on treatment with base (62JPR(19)56). 

Pyrido[2,3-c]-1,2,6-thiadiazine 2,2-dioxides may be glycosylated under standard conditions to yield glycosides of potential biological interest. Thus, the pyrido-l,2,6-thiadiazine dioxide (51a) yielded nucleosides (170) and (171) <90MI 717-01). 

The imidazo[4,5-c][l,2,6]thiadiazine system has been synthesized from both imidazole and thiadiazine precursors. Treatment of the thiadiazine dioxide (713) with potassium dithioformate under mild conditions allowed the isolation of (714), which was readily cyclized to (715a) upon heating. Direct conversion of (713) to (7l5a) also occurs, with an improvement in yield over the two separate steps (76JHC793). This type of ring closure has... 

The pKg values of 1,2,6-thiadiazine dioxides fused to heterocyclic fivemembered rings have also been determined (76JHC793 77JHC427 79JMC944). An example is the ionization sequence of furazano[3,4-c]-1,2,6-thiadiazine 24a. 

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). 

Fused systems are preferentially glycosylated at the thiadiazine moiety and in the case of triazolo[4,5-c]- and imidazo[4,5-c]-1,2,6-thiadiazine dioxides 16a and 29, diribosides were also obtained (82JHC3O5 84MI1). Selective... 

Condensation of triamine (171) with arylaldehydes in dimethylformamide at room temperature affords 4-amino-6-aryl-l,5-dihydroimidazo[4,5-c][l,2,6]thiadiazine 2,2-dioxides (177) in 63-95% yield. The reaction is also successful with ethanal, but proceeds in lower yield (45%) <87H(26)3123). Studies in the late 1980s, revealed that under anhydrous conditions and with electron rich aldehydes, mixtures of the imidazo[4,5-c]-thiadiazine dioxides (177) and pyrazino[2,3-c]thiadiazine dioxides (180) are produced <88JHC89i, 89MI616-01). The latter products arise by electrocyclization of the bis-anils (178), formed by condensation of the triamine with two equivalents of aldehyde, followed by... 

Decarboxylation of P-keto-esters is facile in aqueous DMSO, but in less reactive cases decarboxylation is accelerated by sodium chloride. Condensation reactions of dibenzocycloheptadienone (334) with aromatic aldehydes have been reported. Syntheses of the heterocyclic carboxylic acids (335) have been described. No effect of the heterocycle s ring current on the chemical shifts of the methylene protons could be detected in the n.m.r. spectrum of the nonamethylene-thiadiazine dioxide (336), which was prepared from cyclododecane-l,3-dione. ... 

Stamford AW, Gilbert EJ, Gumming JN (2012) Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use. WO2012138590... 

In the oxathiolane area, a paper from Wellcome Laboratories describes work done there on the preparation of 3-thiacytosine and related compounds, whilst a synthesis of 3TC involving an enantioselective enzymic hydrolysis has been reported. The difluorophosphonate analogue 200 of FTC has been made as a racemate with other diastereomers, and 1,2,6-thiadiazine dioxide analogues of 3TC have been reported. A full account has appeared concerning the synthesis of regioisomeric systems such as 201 (see Vol.28, p.297). ... 

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