Thiadiazoline, derivs

Table 7 13C and H NMR Chemical Shifts for 2,5-Disubstituted-A2-l,3,4-thiadiazoline Derivatives... 

A number of other nitrogenous and sulfur-containing sugar derivatives can be prepared by a reaction that Wuyts and Lacourt recommended in the early thirties for the identification of aldehydes and ketones. The principle underlying this reaction is that, with aldehydes and ketones, the thionic phenylhydrazides give thiadiazoline derivatives with extraordinary ease. The reaction proceeds as follows. 

On the evidence of analysis and of the color reaction, the produet obtained is a thiadiazoline derivative. 

Acetamido-5-mercapto-l, 3,4-thiadiazole is prepared as described under acetazolamide. This on treatment with/>-chlorobenzyl ehloride forms the corresponding />-chloro benzyl mercapto derivative, which when reacted with methyl bromide in the presenee of sodium methoxide yields the acetylamino thiadiazoline derivative. On oxidation with aqueous ehlorine it gives rise to the 2-sulphonyl chloride derivative which finally yields methazolamide on amidation with ammonia. 

In a series of papers. Moss and Taylor have described the synthesis and reactions of a number of A -l,3,4-thiadiazoline derivatives, i.e. (322), from acyclic thioureas. The reactions proceed in high yield and appear to be general, apart from some steric limitations, which are apparent when t-butyl groups are... 

The action of iron pentacarbonyl on the meso-ionic dehydrodithizone (136), expected to yield (137) by carbonyl-insertion, produces the 1,3,4-thiadiazoline derivative (138) (54%), the structure of which has been established by JT-ray analysis. The mechanism of its formation is not yet clear. ... 

A -l,3,4-Thiadiazolines.—The cycloaddition of aromatic sulphines to nitril imines is a regiospecific non-stereospecific reaction resulting in the formation of A -l,3,4-thiadiazoline derivatives. Interaction of the sulphines (137) and diphenylnitrilimine [generated in situ by the action of triethylamine on N-a-chlorobenzylidene-N -phenylhydrazine (138) in boiling benzene] gave uniform 1 1 adducts that were identified as the A -l,3,4-thiadiazoline S-oxides (139), the alternative 1,2,3-thiadiazoline structure (141) being conclusively eliminated on the basis of chemical and spectroscopic evidence. The non-stereo specific nature of the reaction was demonstrated and its significance discussed. ... 

Several related derivatives have also been utilized in this type of synthesis. Imino-chloromethanesulfenyl chlorides (184), prepared by the controlled addition of chlorine to isothiocyanates, react with amidines (161) to give 1,2,4-thiadiazolines (185) (71T4117). Chlorocarbonylsulfenyl chloride (186), prepared by the hydrolysis of trichloromethanesulfenyl chloride with sulfuric acid, reacted with ureas, thioureas and guanidines to give 1,2,4-thiadiazolidine derivatives (187) <70AG(E)54, 73CB3391). 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

A new method for the synthesis of 1,2,5-thiadiazoline 5,5-dioxides 231 was achieved by reacting activated aryl nucleophiles to the C=N double bond of the corresponding thiadiazoles 230 in the presence of AlClj as a catalyst at room temperature (00MI4). The yields of 4-aryl-derivatives ranged from 38 to 92%. 

A new method for the synthesis of 1,2,3-thiadiazoles has been reported. The method starts with the thioanilide derivative 72, which is converted into the hydrazone 73. Oxidative heterocyclization by treatment with hydrogen peroxide gave exclusively the 1,2,3-thiadiazoline 74 (Scheme 8) <2003S2559>. 

Thiadiazolines are less stable compared to 1,2,4-thiadiazoles and this can be attributed to the loss of aromatic character. They are readily cleaved at the N-S bond under fairly mild conditions (H2S in pyridine) in some cases, the product from ring cleavage can recyclize to give new heterocyclic ring systems. The 3-imino-l,2,3-thiadiazoline 24 when reduced with H2S affords the two J-triazine derivatives 25 and 26 (Scheme 3) <1996CHEC-II(4)307>. 

A difference in reactivity was observed between the phenanthro[9,10-r]- and acenaphtho[l,2-c]-l,2,5-thiadiazole 1,1-dioxides 51 and 53 when treated with thiourea. The acenaphtho derivative 53 gave the expected addition product however, the phenanthro thiadiazole 51 was reduced to the thiadiazoline 1,1-dioxide 52 (Equation 2) <2004JP01091>. The difference in reactivity was attributed to the enhanced resonance stability offered by the phenanthrene group. 

The thiadiazole thione 112 was treated with an alkyl halide in sodium hydroxide to afford the thiadiazole derivatives 113 in 35-92% yields (Equation 35, Table 3) < 1999JME1161 >. This reaction results in the aromatization of the reduced thiadiazoline ring (see Section 5.10.9.5.1). The 2-(methylsulfanyl)-l,3,4-thiadiazoles can be S-demeth-ylated to afford 1,3,4-thiadiazole-2-thiones <1994JHC1439>. 

Thiadiazolines are readily cleaved at the N—S bond by reducing agents under very mild conditions. Thus the diethylamino derivative (41) is reduced with HjS in pyridine/triethylamine to... 

The final step in the synthesis of the thiadiazole nucleoside (178) is achieved by prolonged treatment of (179) with methanolic sodium methoxide (Equation (25)) <82AHC(32)285). Reaction of the A"-1,2,4-thiadiazoline (180) with dry HCl in methanol leads to the 2-carbamoyl compound (181). When (180) is treated with a mixture of free amines and amine hydrochlorides in the ratio of 2 1 in refluxing ethanol, 2-amidino-3-imino-5-methylthio derivatives (182) are formed in good yield (Scheme 42) <84CHEC-i(6)463>. 

The reaction of arylisothiocyanates with guanidines (233) affords amidinothioureas (234), which can be converted into 3,5-diarylimino-l,2,4-thiadiazolines (235) directly on treatment with bromine in ethanol. Alternatively, (234) can be alkylated with benzyl chloride to give the S-benzyl derivative (236) which on treatment with bromine in chloroform gives (235) (Scheme 51) <87JIC675>. 

Reaction of alkyl or aryl isocyanates with benzimidazolinethione (254) affords the iV-carbamyl derivative (255). Treatment of (255) with bromine in triethylamine gives the benzimidazolo[l,2-r/]-1,2,4-thiadiazoline (256) (Scheme 58). A related thioanalogue (258) was obtained by a similar process from the A-thiocarbomyl derivative (257) (Equation (35)) <83X2311). 

A useful method for the synthesis of 5-chloro-l,2,4-thiadiazoles (206) is the reaction of amidines with trichloromethylsulfenyl chloride (see Equation (30)). 3-Halo derivatives (349) (X = Cl, Br, I) (Equation (57)) have been obtained in moderate yields from the corresponding amines (348) via the Sandmeyer-Gatterman reaction <84CHEC-I(6)463>. 3-Chloro-l,2,4-thiadiazolin-5-ones (350) and (351) can be prepared by reacting chlorocarbonylsulfenyl chloride with carbodiimides or cyanamides respectively (Scheme 79) <84CHEC-I(6)463>. 

Ando and co-workers have carried out photolysis and thermolysis on 2-alkylidene-l,3,4-thia-diazolines (34) synthesized from the thioketene (35) and diazo compounds (36). Irradiation of a benzene solution of (34) (R,R = —Me2C(CH2)2CMe2—) with a medium pressure mercury lamp produced (37) in a 51% yield, the bicyclo derivative (38) in a 15% yield, and a smaller amount of (35). In contrast, thermolysis of (34) at 130°C gave the thioketone (39) and the ethyne (40) in a quantitative yield. The episulfide (37) was isomerized quantitatively into the thiadiazoline (34) when treated with a trace of acid. A number of mechanisms were suggested for these transformations <90TL3571>. 

This method was extensively reviewed in <84CHEC-I(4)545> and a brief summary is presented here interestingly, since the mid-1980s, this reaction has become less popular. A(-Aryl benzhydrazonyl chlorides react with thiobenzamides to form trisubstituted thiadiazolines which on treatment with alcohols furnish the 2-alkoxy derivative (Scheme 25). A-Arylbenzhydrazonyl chlorides also react with thioketenes to yield 5-methylene thiadiazolines (Equation (16)). Other examples involve the addition of the nitrileimine generated from A-trifluoroacetobenzhydrazonyl bromide to the 0=S of potassium isothiocyanate and methyl isocyanate <87JHC1391>. 

When thiocarbonyl and ot-diazocarbonyl compounds are combined, acyl-substituted thiocarbonyl ylides 158 are generated from a nonisolable 3-acyl-1,2,4-thiadiazoline 157 (Scheme 8.36). In addition to giving acylthiiranes 159 and 1,3-dithiolanes 160, dipoles 158 can also 1,5-cyclize to produce 1,3-oxathioles 161. Acyl-thiocarbonyl ylides derived from diazoketones [e.g., HC(0)C(N2)R, R = Ph, f-Bu (219,220) 2-diazocyclohexanone (221)] produce 1,3-oxathioles [e.g., 162 (220), Scheme 8.36], while those derived from diazoesters (218,222,223) lead to thiiranes by 1,3-cyclization. Ylides derived from a-diazocarboxamides form 1,3-oxathioles (e.g., 163) and thiiranes (e.g., 159, R = f-Bu, R = NMePh, R = R" = Ph), depending on the nature of the substituents (220). A related 1,5-cyclization of an aminomethyl-thiocarbonyl ylide formed from dimethyl 3-anilino-2-diazobutanedioate was also reported (224). 

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