Thiadiazolines synthesis

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

A/-Chloroamidines are usehil for preparation of biocidal imidazoles (106) and thiadiazolines (107). Ai-Chloroguanidines, RNHC(=NC1)NHR, serve as starting materials for synthesis of imidazoles, oxadiazoles, and thiadiazoles (108,109). 

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%. 

Thiadiazoline S-oxides, synthesis of 275 Thiane dioxides formula of 382 synthesis of 468 Thiane oxides 750-752 conformational analysis of 465-467 formula of 382... 

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>. 

In another variation on a type C synthesis which yields 5-substituted-3-oxo-l,2,4-thiadiazolines, the reaction of arylthioamides with phenylisocyanate affords the arenethiocarboxamide 89, which can then be transformed into product 90 by direct oxidation with bromine (Equation 26) <1996CHEC-II(4)307>. 

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>. 

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>. 

The synthesis of 2-alkylidene-l,3,4-thiadiazolines from thioketene and diazo compounds was discussed in the photochemical Section 4.10.6.1 <90TL357i>. 

The scope of the synthesis is greatly widened by the preliminary preparation of the N-halogenoamidines (56), preferably in situ subsequent displacement of halogen by thiocyanate results in the formation of the desired 5-amino-1,2,4-thiadiazoles (58) in good yields (50-80%).6,79, 80 The use of formamidine affords the parent, 5-amino-1,2,4-thiadiazole (58 R = H) while use of AT-methylformamidine (59) leads to 5-imino-4-methyl-Zl4-1,2,4-thiadiazolines (60).81... 

The trisubstituted amidinothioureas (98) required as precursors of the thiadiazolines are obtained by the interaction of isothiocyanate esters and s-diarylguanidines,115 or by the action of aromatic amines on dithiazolidines (102).117 The former reaction might conceivably yield the isomeric amidinothioureas (98a) instead if so, however, oxidation and isomerization would give rise to a 2-(diphenylguanidino)benz-thiazole (100a) isomeric with, but different from, the product (100) actually obtained. The structure of this product is confirmed by synthesis from 2-aminobenzthiazole (101) and carbodiimides.115... 

Methylamino-l,2,4-thiadiazole (195) (but not its 3-phenyl homolog) arises irreversibly171 by isomerization of 5-imino-4-methyl-1,2,4-thiadiazoline (193) in ethanol on prolonged storage or brief heating.81, 171 The structure is confirmed by its alternative synthesis from 201.6 Further methylation (of 195) (to 194, and 194 + 196 when R = Ph) follows the general scheme.81... 

Freund and Wolf10 reported that 2,4-diphenyl-l,2,4-thiadiazolidine-3,5-dithione was formed by heating l,3-diphenyl-2-thiourea with thiophosgene in benzene whereas, a 1,3-thiazetidine was produced at lower temperatures in ether (see Section II). Ohande181 has reported that 3,5-diamino-l,2,4-thiadiazoles are formed by the reaction of thiopseudoureas with carbon disulfide in the presence of bromine. Use has also been made of thioureas in the synthesis of 1,3,4-thiadiazolines (79) via reaction with the halohydrazones 78.185,186 The analogous reaction with solenoureas was recently reported by Bulka and Ehlers187 to yield 1,3,4-selenadiazolines. 

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