2-Arylamino-l,3,4-thiadiazoles

Fig.32 General structure of 5-[l-aryl-l,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-arylamino-l,3,4-thiadiazoles and oxadiazoles associated with antifungal activity...

J. Indian Chem. Soc., 1973,50,742 [5 -(2-arylamino-l,3,4-thiadiazol-5-yl) mercaptoaoetic acids] ... 

When solutions of iminophosphorane 366 in anhydrous DMF are treated with an aromatic isocyanate at room temperature, 2-arylamino-imidazo[2,TA][l,3,4]thiadiazol-5(67/)-ones 135 are isolated (Equation 70) <2004S1067>. 

Zou et al. [193] have explored the QSAR of the antifimgal profile of 5- [ l-aryl- l,4-dihydro-6-methylpyridazin-4-one-3-yl] -2-arylamino-1,3,4-thiadiazoles (Fig. 32, Table 22) in terms of the sum of the physicochemical properties of all the substituent groups namely, hydrophobic effects ( n), meta- and para- Hammett s sigma constants steric effects ( Es), and the inductive effects (J]F)-... 

The reaction of iminophosphorane (264) with aromatic iso(thio)cyanates leads to anhydro 2-arylamino-5-phenyl-thiazolo[2,3-h][l,3,4]thiadiazol-4-ium hydroxides (54) which upon treatment with tetrafluoroboric acid give the corresponding 2-arylamino-5-phenylthiazolo[2,3-h][l,3,4]-thiadiazolium tetrafluoroborates (53) (Scheme 25) <92T1282>. 

The reaction of 2-arylamino-5-hydrazino[l,2,4]thiadiazoles (115) with methyl chloroformate gives 6-arylamino-3-hydroxy[l,2,4]triazolo[3,4- >][l,3,4]thiadiazoles (116) with carbon disulfide the corresponding 3-sulfonyl derivatives (117) are formed (Scheme 10) <92IJC(B)467>. 

When the reaction of (118) with arylisothiocyanates is carried out in the presence of dicyclo-carbodiimide 3-arylamino-6-phenyl[l,2,4]triazolo[3,4-i][l,3,4]thiadiazoles (120) are formed instead (Scheme 11) <86JHC1339>. 

Adducts of thiocarbonohydrazides and carbodi-imides are also suitable precursors of 1,3,4-thiadiazoles. l-AW -Diarylamidino-S-phenylthiocar-bonohydrazides (86), arising from 1-phenylthiocarbonohydrazide (85) and diarylcarbodi-imides, are cyclized to the expected substituted 1,2,4-triazoles (87) by aqueous alkali, but yield 2-arylamino-5-phenylazo-l,3,4-thiadiazoles (89) on treatment with ethanolic potassium hydroxide. The observed formation of a 1,3,4-thiadiazole (89) in an alkaline medium conflicts with the general experience that linear compounds of general type (86) are cyclized to 1,2,4-triazoles in alkaline, and to 1,3,4-thiadiazoles in acidic media accordingly, the production of (91) could reasonably have been expected. 

The majority of chemical reactions of 1,3,4-thiadiazoIes that have recently been studied concern interactions with nucleophiles. Halogenation and nitration of 2-arylamino-5-methyl-l,3,4-thiadiazoles significantly occurs in the aryl nucleus, in accordance with the electron-attracting character of the 1,3,4-thiadiazole nucleus. 

The Delepine reaction appears to be the most favourable procedure for converting 2-arylamino-5-chloromethyl-l,3,4-thiadiazoles into the corresponding 5-aminomethyl compounds. Thus, treatment of (164) with urotropine produces the hexamethylenetetramino-salts (165) which afford (166) under the influence of ethanolic hydrochloric acid at room tanperature. ... 

Cyclization of aminothiones 198 with carbon disulfide, bromocyanogen, aryl isothiocyanates, and l-bromo-2-acetylacetylene leads to mercapto, amino, arylamino, and acetylmethyl derivatives of triazolo[3,4-/>]-1,3,4-thiadiazole (446, R = SH, NH2, NHAr, CHjCOMe), respectively [64CI(L)1919 66JOC3528 81JHC1353 86JHC1439 87JHC1173,... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

Arylamino-3-nitroamino-l,2,4-thiadiazoles are crystalline solids which explode at their melting points. They are monobasic acids, remarkably stable to alkalis and to the action of boiling sodium plumbite. Mild reduction by sulfur dioxide reconverts 5-anilino-3-nitroamino-l,2,4-thiadiazole into its parent amidinothiourea from which it arises by oxidation. Attempts to reduce 3-nitroamino compounds to the corresponding 3-hydrazines were not successful.141... 

Arylamino-3-nitroamino-l,2,4-thiadiazoles l,3-Bis[3-alkyl(or aryl)-l,2,4-thiadiazol-5-yl]triazens... 

Mass spectra of 5-amino-3-arylamino-l,2,4-thiadiazoles exhibit a new fragmentation process involving two consecutive hydrogen shifts and ring cleavage leading to the elimination of the NHSH radical (Scheme 8) (77AJC563). 

Reactions of 1,2,4-thiadiazoles with radicals and electron deficient species are virtually unknown. Catalytic and dissolving metal reductions usually result in S—N bond cleavage. For example, the 5-anilino-3-hydroxy derivative (51) gives a good yield of l-phenyl-2-thiobiuret (52) on Zn-HCl reduction (Scheme 27). Reduction of the diamino derivative (53) gives amidinothiourea (54) from which it may be prepared by oxidation (Scheme 28). Under similar conditions, cleavage of the 3,5-diphenyl derivative (55) results in loss of sulfur and formation of benzylbenzamidine (56 Scheme 29). Reduction of 5-alkylamino-or 5-arylamino-3-alkylthio derivatives (57) with H2S in pyridine-triethylamine or sodium in liquid ammonia yields 1-substituted dithiobiurets (58 Scheme 30). 

Under mild conditions, amino-l,2,4-thiadiazoles are resistant to the action of acids but prolonged treatment with hot mineral acid can lead to decomposition with liberation of sulfur (65AHC(5)ll9). 5-Amino-l,2,4-thiadiazoles generally decompose in hot alkali but the rate of degradation is dependent on the nature of the 3-substituent. Under similar conditions, 3-amino-1,2,4-thiadiazoles are much more stable. Thus, 3-amino-5-arylamino-l,2,4-thiadiazoles are unaffected after being refluxed in 3N sodium hydroxide (65AHC(5)119). 

By contrast, 3-hydrazino-l,2,4-thiadiazoles (163), which are prepared by ring closure methods, are very sensitive to acids and undergo elimination of sulfur with formation of 5-arylamino-l,2,4-triazoles (164) as indicated in Scheme 61 (63JCS4566). The mechanism of this conversion is not known but presumably involves the attack of a hard nucleophile at the 5-position followed by ring opening, loss of sulfur and recyclization as has been observed with the quaternary salts (77JCS(P1)1791) (see Schemes 22, 23, and 24). Hydrazine (163) reacts with aldehydes to produce hydrazones (165) and with dimethyl malonate to yield pyrazoles (166). Diazonium salts of type (153) have been prepared by the methods... 

Structure (74), with strong S—N interaction, is not entirely ruled out. On treatment with sodium ethoxide, (70) forms l,3-bis(arylamino)-l,2,4-thiadiazoles (71). The thermal decomposition of (69 Ar = Ar = Ph or p-MeCjHJ likewise produces (70) (ca. 50%), together with (71), as a by-product. Similarly, the 1,3-dipolar cycloaddition of acetylenes to Hector s bases (69) gives 2-aryl-amino-thiazoles (73), probably by way of the intermediate 1,2,4-thiadiazolo-[5,l-fl][l,3]thiazoles (72). ... 

---