1.2.4- Thiadiazoles nitriles

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

The oxidation of thioamides 63 with a wide variety of oxidizing agents is a well-employed method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 64 <1982AHC285>. However, this method is limited mainly to arylthioamides. The most common oxidizing agents tend to be halogens, hydrogen peroxide, dimethyl sulfoxide (DMSO), and nitrous acid. Yields from these reactions are variable and depend on the thioamide, oxidant, and conditions used (Equation 19). By-products such as nitriles and isothiocyanates are usually formed. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

A novel high-yielding synthetic route to 3,5-disubstituted-l,2,4-thiadiazoles 104 has been reported which involves the reaction of nitriles with the arsenic complex S AsFg in liquid SO2 (Equation 29) <1999CC1801>. 

An alternative route to C-linked derivatives involves the 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles which yields 3,5-disubstituted-l,2,4-thiadiazoles of unequivocal structure (see Section 5.08.9.8). 

Alkyl and aryl nitriles 151 react with thiosemicarbazide 138 under acidic conditions to give 1,3,4-thiadiazoles (Scheme 14 and Table 8) <1995BML1995, 1996IJB273, 1997IJB394>. The acidic conditions promote the elimination of ammonia from the intermediate iminothioacylhydrazine 152. 

Table 8 Preparation of 1,3,4-thiadiazoles from thiohydrazide and nitrile derivatives...

A new, simple, high yielding synthetic route to 3,5-disubstituted 1,2,4-thiadiazoles 75 was described by Passmore and co-workers which involved the reaction of nitriles with S (AsF6)2 in liquid S02 <99CC1801>. 

Betaine 81 or its neutral mesomeric form (Scheme 23) reacted with nitriles affording the thiadiazole 82, and a dipolar addition was suggested <1996H2657>. In a similar reaction, isocyanates and isothiocyanates gave oxo and thiono thiadiazoles 83 (X = 0, S) <1997BMC1275>. 

Thioamides 176 react photochemically with 2,3-dimethyl-2-butene in the absence of oxygen to give ketones (equation 116)172. In the absence of oxygen, the photoproducts of 176 include nitriles, 1,2,4-thiadiazole and isothiazoline (equation 117). 

Thioamides are dehydrosulphurated to nitriles, or converted into 1,2,4-thiadiazoles, depending on whether the reactions are performed in non-acidic solvents such as dichloromethane, chloroform and methanol or in acetic acid. 

Bis(p-methoxyphenyl) tellurium diacetate or ditosylate is generated by the electrolysis of the parent telluride in the presence of BU4N+ acetate or tosylate. Like the telluroxide, they accomplish the conversion of thioamides into nitriles and 1,2,4-thiadiazoles. Taking into consideration of these facts, the above conversion can be performed in an electrochemical... 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

The reactivity of 5-amidinoisothiazoles (221) was explored to demonstrate the equilibrium 221 222 (Scheme 37). However, on reacting with nitriles or imidates, 5-amino compounds 220 (R = Me, Ph) give directly the rearranged thiadiazoles 222. The equilibrium between the two heterocycles (in different solvents at room temperature) is not observed, and this result is attributed to the greater stability of the 1,2,4-thiadiazole... 

The condensation of 5-amino-3-methyl-l,2,4-thiadiazole (118) with aliphatic or aromatic nitriles yields 1 1 adducts, which are, according to their H NMR spectra, equilibrium mixtures of (119) and (120) (Scheme 28) <82AHC(32)285>. These adducts are produced by a bond switch at the n-hypervalent sulfur in (121). X-ray analysis of the adduct formed from the reaction of (118) with chloroacetonitrile showed the adduct to exist as (122) in the crystals <81AX(B)185>. Further examples of this type of bond switch at rc-hypervalent sulfur are observed in the reaction of 5-imino-1,2,4-thiadiazolines with various electrophilic reagents (Section 4.08.6.1). 

The thermolysis of thioamides (183) with 7V-sulfinylsulfonamides (190) gives moderate yields of 1,2,4-thiadiazoles (Equation (27)), a competing and sometimes dominant side reaction is the formation of nitriles <84CHEC-I(6)463>. No new examples of this type of reaction have been found in the 12 years since 1984. 

The reaction of sulfur dichloride with benzonitrile in the presence of a Lewis acid catalyst yields 3,5-diphenyl-l,2,4-thiadiazole (39), along with the 3-o-chlorophenyl (278) and 3-p-chlorophenyl (279) analogues in a total yield of 80%. The proposed mechanism proceeds via a complex between benzonitrile, Lewis acid for example, aluminum trichloride, and sulfur dichloride to give an intermediate (280) which then adds a second molecule of nitrile (Scheme 62) <83BCJ180>. 

The thermolysis of 4-benzyl-5-sulfonyliminothiatriazolines (318) in the presence of a variety of nitriles yields 5-imino-l,2,4-thiadiazolines (320). These reactions have been interpreted as proceeding via a thiaziridinimine intermediate (319) (Scheme 70) <76JOC3403>. 1,2,4-Thiadiazoles are also obtained when the thermolysis is carried out in the presence of isocyanates to give (321) and carbodiimides to give (322) <84CHEC-I(6)463>. 

Although 1,2,5-thiadiazoles have been shown to undergo cycloaddition with benzyne <82CC299>, the predominant mode of attack is at sulfur. The result is extrusion of a nitrile and formation of a 1,2-benzisothiazole (22) (Scheme 4) <88JCS(Pl)2l4l>. 

The thermal stability of 1,2,5-thiadiazole is remarkable. The parent ring and its alkyl derivatives can withstand heating to at least 250-300 °C. Under UV photolytic conditions, the aromatic thia-diazoles slowly fragment to nitriles and sulfur. 

The principal fragmentation of 1,3,4-thiadiazoles in the mass spectrometer is loss of a nitrile group as shown in Scheme 1. In the presence of a methylthio substituent, the major process is loss of SH and fragmentation at the heterocyclic sulfur atom (Scheme 2). In 1,3,4-thiadiazolines the major pathway is loss of PhS (Scheme 3) while 1,3,4-thiadiazolidinediones decompose by fragmentation of the ring . 

Reaction of the 5-substituted aminothiadiazole (88 R = Bu ) with aryl nitriles produced amidines (89) in yields dependent on the reactivity of the nitriles (Scheme 14). Decreasing the electron density of the cyano group by such electron-withdrawing groups as p-nitrophenyl-, and 2- and 4-cyanopyridyl, led to higher yields as compared to unsubstituted benzonitrile. A bis thiadiazole (92 R = Bu ) was prepared by reacting the sodium salt of (88) with 2-methanesulfonyl-5-(-butyl-1,3,4-thiadiazole (91) <84JHC1377>. 

Reaction of 2-amino-5-aryl-thiadiazole (88 R = Ar) with aryl nitriles in the presence of aluminum chloride produced the aryl amidine (89) which was oxidized with lead tetraacetate to yield the 2,6-diaryl-[ 1,2,4]-triazolo[5,1 -( ]-1,3,4-thiadiazoles (90) <91 UC(B)435>. 

Nitriles undergo 1,3-cycloaddition to 5-amino-l,2,4-dithiazoline-5-imines (79) across N=C—S grouping with rupture of the SS bond to give 1,2,4-thiadiazoles (80) regiospecifically. Electron-accepting substituents in (79) decrease the reactivity (Equation (4)) <85CB324i>. 

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