1.2.4- Thiadiazine 5-imines

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>. 

Thiadiazines (535) are obtained by the cycloaddition of thioaryl isocyanates (R CSNCO) with imines R2R3C = NR4. 

A very useful preparation of 1,3,5-thiadiazine type rings involves the report of Goerdeler and Ludke167 that 154 undergoes reaction with phenyl isocyanate to give 162 (X = Ph, Y = 0) and with carbodi-imides to give 162 (X = R, Y = NR ). Other compounds 163 may be prepared by treatment of 154 with benzaldehyde imines,167 a process which was also recently utilized by Kristian et al.3oa... 

The IR spectrum of 8 has been reported (63FRP2166), and the UV spectra of some 1,2,3-benzothiadiazines have been reviewed (70CRV593). Mass spectrometry has been used to establish the structure of 1,2,3-thiadiazines 24, and the fragmentation pattern enabled the alternative isothiazol-N-imines to be ruled out (750MS579). 

If the reaction of thiosemicarbazide with chloroacetone is carried out in a warm dilute solution of hydrochloric acid, the thiosemicarbazone of chloroacetone (242) is formed in 85% yield. Heating 242 in ethanol cyclizes it to thiadiazine 243, whereas heating in anhydrous ethanolic benzaldehyde yields the benzylidene derivative of 4-methyl-2-hydrazinothiazole (244). At the same time, refluxing 242 in concentrated hydrochloric acid gives rise to 4-methyl-3-aminothiazoline-2-imine (245) in 95% yield. The latter compound can be also obtained by the action of concentrated HCl on thiadiazine 243. On using various a-halogenoketones and thiosemicarba-... 

S-T h i ocy a n a to v i n y 1 aide h y des 119 were also versatile C3S building blocks in the synthesis of acceptor substituted 2-amino-isothiazolium salts 131 and 132 by intramolecular cyclocondensation of thiocyanatovinylaldehyde hydrazones 129 (93TL1909). The alternative cyclization route to 1,2,3-thiadiazines was not observed. Alicyclic aldehydes 119 reacted with benzhydrazides (R = ArCO) to unstable benzhydrazones 129 (R = ArCO) that cyclized spontaneously to 130 (R = ArCO). The imines 130... 

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. 

When 2-methyl-4-alkyl(aryl)thiosemicarbazides are reacted with a-halo ketones in ethanol, /V-alkyl(aryl)-3-alkyl-6//-l,3,4-thiadiazin-2(3//)-imines 5 are formed exclusively.46-48 Open-chain intermediates or other isomers could not be isolated. 

The compounds with a 2-to7-butylimino or 2-(2,2,4-trimethylpent-4-yl)imino substituent undergo dealkylation to the 3-alkyl-6/M,3,4-thiadiazin-2(3//>imine 0n heating in hydrochloric or hydrobromic acid or simultaneous dealkylation and extrusion of sulfur with reduction of ring size to the l-alkylpyrazol-5-imines.10... 

Alkyl(aryl)-3-alkyl-5-aryl-6//-l,3,4-thiadiazin-2(3//)-imines 5 General Procedure 46-48... 

The synthesis of Ar-alkyl-5-aryl-3,4-dimethyl-4//-thiadiazin-2(3//)-imines 6 involves heating the 1,2,3-trimethyl- or 1,2-dimethyl-4-isopropylthiosemicarbazide with a phenacyl halide in ethanol for 1 hour.49... 

When 1,2,4-trimethylthiosemicarbazide is allowed to react with 2-bromo-l,2-diphenylethan-l-one under analogous conditions, a 4//-l,3,4-thiadiazine is not obtained.45 Microanalytical as well as mass and IR spectroscopic data indicate the existence of a product with structure A. 4-Isopropyl- and 4-terf-butyl-l, 2-dimethylthiosemicarbazides react analogously. Worthy of note is the fact that hydrolysis of the alkylimino group occurs readily under the condensation conditions, especially since reactions of this type are not observed for jV-alkyl-3-alkyl-67/-1,3,4-thiadiazin-2(3//)-imines. Even by varying the reaction conditions, an (V,3,4-trimethyl-5,6-diphenyl-6//-l,3,4-thiadiazin-2(3//)-imine could not be isolated. 

V-Alkyl-5-aryl-3,4-dmiethyl-4//-l,3,4-thiadiazin-2(3f/)-imine Hydrobromides 6 General Procedure 49... 

Catalytic reduction of imine (190) yields 3,5-diamino-4-p-toluidino-2//-l,2,6-thiadiazine 1,1-diox-ide (191 53% yield) (Equation (21)) <91AF264>. 

Treatment of 4//-l,2,4,6-thiatriazine 1,1-dioxide (295) with malononitrile anion leads to the formation of 5-amino-4-cyano-2/7-l,2,6-thiadiazine 1,1-dioxide (296 R = NH2) in 60% yield (see also Section 6.16.9.2.1.1) <84H(22)47i>. This ring transformation is proposed to go by a double carbanion addition at the 2,3- and 5,6- imine bonds followed by ring-opening and ring-closure, with... 

Methyl-5-phenyl-3,6-dihydro-27/-l,3,4-thiadiazin-2-imine (164) is available in excellent yield by de-r-butylation of the 2-(t-butylamino)-derivative (163) with 48% HBr <90EGP280760>. Deallyl-ation is achieved in a similar manner. Curiously, in both instances, ring contraction to a pyrazole (Section 6.17.5.2) does not appear to occur. 

I- 2] Cycloadditions of A-thioacylimines with carbonitriles and with imines constitute well-established and popular routes to the 1,3,5-thiadiazine system <70CB3393,72BCJ2877). 

Alkoxythiocarbonyl isothiocyanates (172 X = S) are also useful 47t components and with imines at room temperature furnish 6-alkoxy-2//-l,3,5-thiadiazine-4(3//)-thiones (173) albeit in variable yields <83CB2044>. In a similar manner ethoxythiocarbonyl isocyanate (172 R = Et, X = O) and benzylideneaniline produce 2,3-diphenyl-6-ethoxy-2/f-l,3,5-thiadiazin-4(3//)-one (174) <82CB1252>. In warm toluene the ethoxythiocarbonyl isocyanate dimerizes to give the 0-ethyl ester (175) of 6-ethoxy-3,4-dihydro-2,4-dioxo-2//-l,3,5-thiadiazine-3-thiocarboxylic acid (Scheme 24). 

A(-(Benzimidoyl)imines (191 R = 2,4,6-Me3QH2) undergo cycloaddition with CS2 to yield 3,6-dihydro-6,6-bis(trifluoromethyl)-2/f-l,3,5-thiadiazine-2-thiones (192). Addition to phenyl isothiocyanate, however, is nonregioselective and produces a mixture of the 6-phenylimino-2/f-1,3,5-thiadiazine (193 51%) and the isomeric 3,6-dihydro-2/f-l,3,5-triazine-2(l//)-thione (194 28%) (Scheme 29) <84ZN(B)1442>. 

Alkoxycarbonyl isocyanates and isothiocyanates (216 X = O or S) in the presence of an excess of a benzylideneamine yield 2-acyliminoperhydro-l,3,5-thiadiazines (218). A two-stage process involving addition of the imine to the initially formed 1,4-dipolar 1 1-adduct (217), which in some instances is isolated as the ring-closed 1,3-thiazetidine, is likely (Scheme 35) (83CB1297, 85CB4196). 

Treatment of dianion 38 derived from AT-monosubstituted alkanesulfonamides 37 with cyanides gives a new imine dianion which, upon treatment with phenyl chloroformate, affords the pharmacologically interesting 2H-l,2,4-thiadiazin-3(4H)-one 1,1-dioxide ring system (39) as shown in equation 2334. The reported method for these heterocycles required a multistep procedure and was restricted to compounds possessing a phenyl... 

Several 1,2,3-thiadiazine 1-oxides were prepared in moderate yields by oxidation of 2-benzenesulfonylaminothia-zolium salts and the corresponding imines with hydrogen peroxide at 0° C (Scheme 4) <1999JHC1081>. The X-ray crystal structure of the 1,2,3-thiadiazine 1-oxide 27e, where R = R = CH3 and R = 4-Br, has also been reported. The structures of the products were confirmed by IR and H and NMR spectroscopy. Conversion of the 1,2,3-thiadiazine 1-oxides to the more common 1,2,3-thiadiazine 1,1-dioxides was achieved by treatment with meta-chloroperbenzoic acid (Scheme 4). 

The tosyloxylation of suitable ketones followed by heterocyclization has been utilized in the syntheses of the following heterocyclic systems 2-aroylbenzo[fe]furans [194], 3-aryl-5,6-dihydroimidazo[2,l- ][l,3]-thiazoles [194], 6-arylimidazo[2,l- ]thiazoles [195], (15 ,2/ )-indene oxide [196], 2-mercaptothiazoles [197], triazolo-[3,4-fc]-l,3,4-thiadiazines [198], dihydroindeno[l,2-e][l,2,4]triazolo[3,4- ][l,3,4]thiadiazines [199], furo[3,2-c]coumarins [200], 4,5-diarylisoxazoles [201], 2-substituted 4,5-diphenyloxazoles [202], quinoxaline [203], 3-carbomethoxy-4-arylfuran-2-(5//)-ones [204], thiazol-2(3//)-imine-linked glycoconju-gates [205] and other important heterocycles. 

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