1.2.4- Thiadiazole, 5-amino-3-phenyl

The interaction of l,2-dihydro-4//-benzo[with acid hydrazides provides very satisfactory yields of 5-substituted 3-(o-amino-phenyl)-l,3,4-thiadiazoles (94), undoubtedly by way of the intermediate iV-(2-aminothiobenzoyl)-N -acyl-hydrazines (93). ... 

Pyrazblin-5-one, 3-alkyl-(l,2,4-thiadiazol-5-yl)-reactions, 6, 483 2-Pyrazolin-5-one, 3-amino-tautomerism, 5, 215 2-Pyrazolin-5-one, 4,4-diazido-rearrangement, 5, 720 2-Pyrazolin-5-one, 3-hydroxy-tautomerism, 5, 215 2-Pyrazolin-5-one, 3-methyl-1 -phenyl-reactions, 5, 252... 

Thiadiazole, 2-amino-5-phenyl-copper sulfate complex... 

In Section 3.4 we discussed the problem of reversibility of diazotization of aromatic and heteroaromatic amines. Simple stoichiometric considerations indicate that the reverse reaction (ArNJ -> ArNH2) may take place under strongly acidic conditions. Experimentally the reverse reaction was found only with heteroaromatic diazonium salts (Kavalek et al., 1989). Reaction conditions of hydroxy-de-diazonia-tion are comparable to those used for the reverse reactions of diazotization (e.g., 10 m H2S04, but at 0°C for the formation of 2-amino-5-phenyl-l,3,4-thiadiazol from the corresponding diazonium salt, Kavalek et al., 1979). So far as we know, however, amines have never been detected in aromatic hydroxy-de-diazoniations, not even in small amounts. 

Mg (3-methacryloxy)propyl, methyl, phenyl, 3-aminopropyl, 3-mercaptopropyl, [n-(2-aminoethyl)-3-aminopropyl], [(10-amino)-4,7-diazanonyl], hexadecyl, n-propyl-ethylenediamine, n-propyltriethylenediamine, 3-chloropropyl, 5 -amino-1,3,4-thiadiazol-2-thiol, (CH3CH20)Si(CH2)3NHC(0)NH-R (R = 3-propyl, 3-pentyl, 3-heptyl) [11-13,15,16,18,19,21-23,26,33]... 

Perhaps the earliest reported method for the synthesis of the 1,2,3-thiadiazole ring system was the one described by Pechmann and Nold in which diazomethane was reacted with phenyl isothiocyanate. Of the four possible isomers that could be obtained from the reaction, 5-anilino-l,2,3-thiadiazole 62 (R1 Ph, R2 = H) was the only product formed (Equation 16) <1896CB2588>. This method continues to be used as a route to 5-amino substituted 1,2,3-thiadiazoles. 4,5-Disubstituted 1,2,3-thiadiazoles have been produced in excellent yield by reaction of l,l -thiocar-bonyl diimidazole with ethyl diazoacetate <1988SUL155>. 

Azido-5-phenyl-l,2,4-thiadiazole 3-Amino-5-phenyl-1,2,4-thiadiazole 5-Cyano-3-phenyl-l,2,4-thiadiazole-4-oxide... 

Amino derivatives of 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles interact with phenyl isocyanate to produce various 3-substituted 5-amino-l,2,4-thiadiazoles, via intermediate thioureides which can be isolated. The tendency to rearrange follows the order 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles <1996CHEC-II(4)307>. 

More recently, some AMPA agonists showing unusual stereostructure-activity have been compared using the commercial docking package Glide (21). These include the enantiomers of 2-amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid (TDPA) and 2-amino-3-hydroxy-5-phenyl-4-isoxazolyl propionic acid (APPA) (28), as well as 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA). 

The Schiff base derivatives 73 of the 3-hetaryl-substituted 4-amino-3-thiol-l,2,4-triazoles, on treatment with acetic anhydride, undergo cyclization to give the corresponding 3-substituted-5-acetyl-5,6-dihydro-6-phenyl[l,2,4]triazolo[3,4-7][l,3,4]thiadiazoles 76 (Equation 16) <1990IJB135>. Similar treatment of 4-(A-bcnzoylamino)-4,5-dihydro-l-methyl-3-mcthylthio-1 //-[ 1,2,4 triazolc-5-thione 77 leads to the [l,2,4]triazolo[3,4-4][l,3,4]thiadiazolium trifluoromethanesulfonate 78 (Equation 17) <1986LA1540>. 

Refluxing the 4-amino-3-ethoxycarbonylthio-5-phenyM//-[l,2,4]triazole 79 in pyridine induces cyclization to 3-phenyl[l,2,4]triazolo[3,4- ][l,3,4]thiadiazol-6(5//)-one 80 (Equation 18) <1991RRC619>. 

The last example for the synthesis of this ring system discussed in this section is somewhat different from the previous ones as it presents formation of a positively charged thiadiazolo[3,2-tf][l,3,5]triazinium salt as published by Okide 1994JHC535 the 2 amino 5 alkyl[l,3,4]thiadiazole 167 was reacted with l chloro l,3 bis(dimethylamino) 3-phenyl-2-azaprop-2-enylium perchlorate (a reagent which was synthesized by the same author earlier <1992JHC1551>) to give the quaternary salt 168 in moderate yield (45%) (Scheme 32). 

The amino group of 3-amino-1,2,4-oxadiazoles shows little nucleophilic character. For example, addition to phenyl isothiocyanate to give 3-(phenylthioureido) compounds requires heating of the components without solvent at 120-130 °C or the use of polar aprotic solvents (DMSO, DMF) and long reaction times (30 days at 23°C) <77JCS(P1)1616>. 3-(Thioureido)-1,2,4-oxadiazoles undergo fast ring transformations to thiadiazoles (see Section 4.04.5.1.1). 

The triacyl compound (30) is obtained when an excess of benzoyl chloride is used in the acylation of 3-amino-5-methylamino-l,2,4-thiadiazole (29). However, when acetic anhydride is used no ring nitrogen acylated product is obtained <84CHEC-i(6)463>. Acetylation of 3-hydroxy-5-phenyl-1,2,4-thiadiazole (23) with acetic anhydride and dbu at room temperature gives a small amount of the N-2 compound (28) (Equation (6)) <85JHC1497>. 

Alkylation of 5-amino-1,2,4-thiadiazoles (17) with methyl iodide leads to N-4 derivatives of type (18) which undergo a Dimroth rearrangement to (110) on warming in ethanol when R = H (Scheme 26). When R = methyl, phenyl, or benzyl the reaction is severly hindered <84CHEC-I(6)463>. In contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (17) at the 5-amino function to give compounds of type (109) (Scheme 26). 

Methylation of 3-amino-5-phenyl-l,2,4-thiadiazole (111) with trimethyloxonium tetrafluoro-borate produces the N-2 quaternary salt (112) which on basification undergoes a Dimroth rearrangement to give the 3-methylamino derivative (113) (Scheme 27) <82AHC(32)285>. By analogy with 5-amino-l,2,4-thiadiazole (17) (R = H), the 3-amino-1,2,4-thiadiazole (111) is alkylated by benzhydryl and trityl chlorides to give (114) (Scheme 27). 

A similar transformation occurs during the thermolysis of l-thiacarbamyl-5-phenyl tetrazole (286) to give 5-amino-3-phenyl-1,2,4-thiadiazole (287) (Equation (43)) <92JPR283>. 

Alkyl-3-aminoisoxazoles, 5-alkyl-3-amino-l,2,4-oxadiazoles, and 5-alky 1-3-amino-1,2,5-oxa-diazoles, when heated with phenyl isothiocyanate produce the corresponding thioureas (308) (Equation (46)), (310) (Equation (47)) and (312) (Equation (48)) which subsequently rearrange by a common mechanism to yield 1,2,4-thiadiazoles (309), (311), and (313), respectively <84CHEC-I(6)463>. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

The A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

Only one representative of this class has been described. 3-Amino-5-phenyl-l,2,4-thiadiazole (269) and methyl iodide gave the iodide (270) which with silver oxide gave the meso-ionic l,2,4-thiadiazol-3-imine (268, R = Ph, R2 = Me, R = H). ... 

Similarly, 4-(furan-2-ylmethylene)-2-phenyl-1 -substituted-5(477)-imidazolones 820, evaluated as antibacterial and antifungal agents, have been synthesized from the 4-(furan-2-yhnethylene)-2-phenyl-5(4//)-oxazolone 819 (Scheme 7.253). ° Using 4-arylmethylene-2-phenyl-5(4//)-oxazolones as substrates and 2-amino-5-methyl-l,3,4-thiadiazoles as nucleophiles the synthesis of the corresponding... 

Stellt man 5-Phenyl-2-phenylazo-l, 3,4-tkiadiazol durch Kondensation von 2-Amino-5-phe-nyl-l,3,4-thiadiazol mit Nitrosobenzol her, vgl. S. 56, erzielt man 88% Ausbeute. 

Amidoximes (46) were first used as a source of 1,2,4-thiadiazoles in 1889 their condensation with carbon disulfide or with an excess of aryl isothiocyanate yields 3-aryl-5-mercapto- (47)6 -73 or 3-aryl-5-aryl-amino- 1,2,4-thiadiazoles (50),71,74,75 respectively. The latter reaction has been reexamined and discussed by Gheorgiu and Barbos76 who suggest that an initial addition of two moles of phenyl isothiocyanate to one of benzamidoxime is followed by cyclization of the intermediate (49), with elimination of phenylthiocarbamic acid (51). Decomposition of the latter gives rise to the by-products observed (cf. following scheme). 

The conversion of 5-amino-3,5-diphenyl-1,2,4-oxadiazoline (48) into 5-mercapto-3-phenyl-l,2,4-thiadiazole (47)78 under the influence... 

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