1.2.6- Thiadiazines, 1-oxides, 1,1-dioxides

Although 2H- and 4//-thiadiazines with divalent sulfur are virtually unknown, both isomers have been prepared as the 1-oxides and, more commonly, as the 1,1-dioxides 109 (X = SO2) and 110 (X = SO2). 

Oxidation of pyrido[23-c][l,2,4]thiadiazines 94 with sodium hypochlorite and, separately, iR-chloroperbenzoic add affords the 1,1-dioxide derivatives 95 and the 5-oxide derivatives 97, respectively. Oxidation of 1,1-dioxide derivatives yields the novel 1,13-trioxides 96 <98T13645>. 

An equimolar ratio of a substrate and oxidizing agent gives oxides 23 and 24 in yields of 71% and 4%, respectively, whereas triple the amount of oxidizing agent leads only to dioxide 24 in 93% yield. The intermediate naphtho[nitrogen elimination even at room temperature. Dioxide 24 may be obtained only on oxidation of monoxide 23, and not via the formation of... 

Established methods for making 1,2,6-thiadiazines that have no 1,1-dioxide group include reactions of (i) sulfur diimides with malonyl chlorides and 1,3-diaminopropanes, (ii) sulfur dichloride with 1,3-diaminopropanes, and (iii) thionyl chloride with N.N-l,5-dinucleophiles such as 1,3-diaminopropanes or /3-amino a,/3-unsaturated aldimines and ketimines to give 5-oxides (79MI1 84MI1). 

The derivative (22) has been prepared in two ways (Scheme 4). The diazo compound (59), made by diazotization of the 3,4,5-triamino-l,2,6-thiadiazine 1,1-dioxide (61), cyclizes upon heating in water to give the bicyclic heterocycle (22) in 80% yield. Alternatively, the same product (22) has been obtained by treatment of the 3,5-diamino derivative (60) with tosylazide. With phenyl-diazonium chloride, the diamine (60) gives the diazo compound (63) which, upon oxidation with lead tetraacetate, gives the 2-phenyl derivative (62). Attempts to oxidize the corresponding m-Cl and p-N02 phenyl compounds failed <77JHC427,77MI714-01). 

Oxidation of the pyrido[2,3-e]-l,3,4-thiadiazine (52) to the corresponding dioxide (53) was achieved using H202 in AcOH in 61% yield <80JOC3677>. 

The nucleophilic substitution, amination, aldol-type condensation, oxidation, and hydrolysis of the l//-pyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxide system, structurally related to pteridine, were studied in detail <03HCA139>. Chlorinated pyrazines were directly oxidized to their corresponding iV-oxides using dimethyldioxirane in a completely regioselective fashion <03HEC221 >. 1,6-Dibenzoyl-5//, 10//-diimidazo[ 1,5-a 1, 5 -[Pg.374]

Concerning reactions of 1,2,6-thiadiazines with oxidants, reaction of 3,5-diaminothiadiazine Ila with chromium trioxide in acetic acid resulted in smooth conversion to ketone 44 in high yield. Compound Ila with selenium dioxide afforded 4,4 -bisthiadiazine 45, which by oxidation with chromium trioxide yielded ketone 44 (77JHC431) (Scheme 5). 

In some instances, the dioxides can be obtained from the corresponding sulfur compounds by oxidation with hydrogen peroxide (71 LAI71 81AP168), as in the case of pyrrolo[2,3-c]-1,2,6-thiadiazine 85 (Scheme 34). 

The oxidation of 2-benzenesulfonylisothiazol-2-imines 7T, 130 and their perchlorates 73,132 with hydrogen peroxide gave 1,2,3-thiadiazine 1-oxides 402 and 403 in 26-52% yield they were then converted into the corresponding 1,2,3-thiadiazine 1,1-dioxides 406 and 407 in 24-90% yield using m-chloroperoxybenzoic acid. 

The oxidation of isothiazolium chlorides 135 with hydrogen peroxide in acetic acid at room temperature gave the 1,2,3-thiadiazine 1-oxides 408a,b in 15-51% yield. They were also converted into 1,2,3-thiadiazine 1,1-dioxides 409a-c in 16-43% yield. The structure 408b was confirmed by X-ray diffraction (00SUL109, Scheme 137). 

A superior synthesis of 3-amino-4-alkyl- and 3-amino-4-aryl-4//-l,2,4-benzothiadiazine 1,1-dioxides (135), involving the amino-dechlorination of chloro compounds (130 R = alkyl or aryl) with aqueous ammonia in chloroform has been reported <86S864> yields are excellent (86-94%). It has been shown that l,5-diphenyl-6-bromo-lA 2,4-thiadiazine 1-oxide (136) (see Section 6.14.6.3.3) undergoes metal exchange with butyllithium and, on quenching the mixture with ethyl chloro-formate, the 6-ethoxycarbonyl derivative (137) is obtained in moderate yield (31%). Displacement... 

Antihistamine and anxiolytic properties are claimed for 3-alkylamino-5,6-dihydro-4/7-l,2,4-thi-adiazine 1,1-dioxides (280) <85JAP(K)601 12781), and for 1-phenyl-lA , 2,4-thiadiazine 1-oxides (281) <85EUP161143). 

There are only a few examples of the oxidation of the divalent ring sulfur atom in 1,2,6-thiadiazines to the S-mono- and 5,5-dioxides. Oxidation of 1,2,6-thiadiazines and their 1-oxides to the 1,1-dioxides can be effected in high yields (71-75%) with w-chloroperbenzoic acid in chloroform solution at room temperature <8iJCS(Pi)l89i, 93JOC700). In contrast, similar oxidations of 3-aryl-4,5-dihydro-l//-2,l,3-benzothiadiazine 1-oxides (Section 6.16.9.2.2.2) yield only uncharacterized oily products <85TL2813>. 

Ring-closure of the 3-allyl-4-arylamino-l-aza-l,3-butadiene (283 Ar = 4-MeQH4) with thionyl chloride produces the fully substituted 1,2,6-thiadiazine 1-oxide (284), which is not isolated but is oxidised in situ with w-chloroperbenzoic acid (Section 6.16.6.4) to furnish the 1,1-dioxide (285) in 91% yield overall (Equation (40)) <93JOC700>. 

The A-oxides of 1,2,6-thiadiazine 1,1-dioxides are obtainable by cyclization of anti- -benzylamino-oximes with sulfuryl chloride (Section 6.16.9.2.3.1). 

Oxidation of 3,5-dialkyl tetrahydro-4//-l,3,5-thiadiazin-4-ones with one equivalent of MCPBA in chloroform at room temperature yields the 1-oxides (91) in 31-60% yield. With an excess of oxidant, the 1,1-dioxides (92) are produced <72JHC23l>. 

---