2- Amino- thiadiazoles, reaction with

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

The most widely used method for the preparation of [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 85 employs 4-amino-5-thio-4/7-[l,2,4]triazoles 83 or 4-amino[l,2,4]-triazole-5(47T)-thiones 84 as starting materials. The reaction of the triazoles 83 or 84 with carbonic acid derivatives furnishes [l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles with a heteroatom substituent (N, O, S) at position 6 the O- and S-functions are formulated as 6-hydroxy and 6-thio derivatives 85a or as thiadiazol-(5/7)6-ones and -thiadiazole-(577)6-thiones 85b, respectively reaction with carboxylic acid derivatives provides the 6-substituted-[l,2,4]triazolo[3,4-4][l,3,4]-thiadiazoles 85c (Equation 20 Table 3). 

Amino-5-ethyl[l,3,4]thiadiazole 105 upon reaction with 1-chloro-l-phenyliminomethanesulfenyl chloride yields 6-ethyl-3-phenylimino-37/-[l,3,4]thiadiazolo[2,3-7][l,2,4]thiadiazole 106 (Equation 27) <1986S1027>. For another synthesis of a compound related to compound 106, see Section 11.07.9.2 <1994T7019>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

In the presence of triethylamine, the reaction of 2-amino-5-methyl[l,3,4]thiadiazole 134 with 2-benzyl-5-chloro-[l,2,4]thiadiazol-2-one 135 gives 3-(benzylcarbamoylimino)-6-methyl-3//-[l,3,4]thiadiazolo[2,3-c][l,2,4]thiadiazole 138. Presumably, the first-formed intermediate 136 rearranges through the thiapentalene intermediate 137 to the fused thiadiazole product 138 (Scheme 10) <1994T7019>. 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Nitrogen-15 NMR has been used to study the course of acylation and carbamidization reactions of 3-amino-5-methylthio-1,2,4-thiadiazole (3). Using a N label in the 2-position of (3), its reaction with hard nucleophiles was found to proceed via initial reactioa on the 2-position followed by a Dimroth rearrangement to give the acylated product (4) with the N label in the exocyclic position. The reaction of (3) with soft nucleophiles, such as methyl isocyanate occurs directly on the exocyclic nitrogen to give the urea (5) (Scheme 1) <84CHEC-l(6)463 >. 

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). 

Both 3-amino and 5-amino-1,2,4-thiadiazoles form the expected derivatives with isocyanates, carbamates, and chloroformates the products from the reaction with the 5-amino isomer have been claimed as herbicides and bactericides <84CHEC-I(6)463>. 

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). 

In a variation of this approach the reaction of amidrazone ylides (230) with both alkyl and aryl isothiocyanates yields thiocarbonyl substituted amidrazone ylides (231) which can be thermally cyclized to 5-amino-1,2,4-thiadiazoles (232) with the elimination of trimethylamine (Scheme 50) <81JHC201>. 

Tsuji obtained two isomeric l,3,4-thiadiazolo[3,2-a]pyrimidino compounds by changing the pH (Scheme 13) <91JHC489>. Thus treatment of 2-amino-5-substituted-thiadiazoles (82) with ethyl cyanoacetate (83) in the presence of sodium methoxide gave the 2-substituted 5-imino-6//-[ 1,3,4]-thiadiazolo[3,2-a]pyrimidine-7-one (84). When the same reaction was carried out in the presence of P2O5 and CH3SO3H instead of sodium methoxide, 7-amino[l,3,4]thiadiazolo[3,2-a]pyrimidine-5-one... 

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. ... 

Reaction of the amino-1,3.4-thiadiazole 86 with a series of benzaldehydes gave the arylidene amines 87 which when treated with arylacetyl chlorides and triethylamine gave 5-substituted l,3,4-thiadiazolo[3,2-fc]pyrimidin-6-ones 88 in good yields (75-95%). The reaction was thought to proceed by a (4+2) cycloaddition reaction between 87 and the ketene which was produced in situ by the interaction of arylacetyl chlorides and triethylamine <99JCR(S)36>. 

The novel heterocyclic system 92 has been prepared by reaction of 2-amino-1,3,4-thiadiazoles 91 with either l-(haloalkyl)pyridinium halides 89 or N,N -methylenebis(pyridinium) dihalides 90. A mechanism for the formation of 92 was proposed and involved a series of specific proton migrations, bond-breaking and bond-forming processes <98EJOC2923>. 

Amino-5-alkyl- or 5-phenyI-l,3,4-thiadiazoles are prepared most conveniently from thiosemicarbazide. For example, benzalthiosemicarbazone by oxidation with iron(III) chloride gives the 5-phenyl derivative. Thiosemicarbazide is also used in the synthesis of 2-amino-5-mercapto-l,3,4-thiadiazole by reaction with carbon disulfide. The product may be alkylated to yield the 5-alkylthio derivatives using a variety of alkylating agents (58MI11201). 

The reaction of Tentagel-bound carboxylic esters with amidooximes has been used to prepare oxadiazoles (Entry 11, Table 15.20). Thiadiazoles have been prepared from support-bound iV-sulfonylhydrazones by treatment with thionyl chloride. Thiadiazole formation and cleavage from the support occurred simultaneously (Entry 12, Table 15.20). Perhydro-l-thia-2,5-diazole-2,2-dioxides (sulfahydantoins) have been prepared by aminosulfonylation of amino acids esterified with Wang resin, followed by ring-closure with simultaneous cleavage from the support [257]. 

By contrast, however, 3,5-diamino-l,2,4-thiadiazoles are selectively converted into amides and sulfonamides in good yields. Thus, acetylation of 3,5-diamino-l,2,4-thiadiazole (53) with excess acetic anhydride yields the symmetrical derivative (133) whereas under similar conditions 3-amino-5-methylamino-l,2,4-thiadiazole and 3,5-diarylamino-l,2,4-thiadiazoles (65AHC(5)119) produce the monoacylated derivatives (134) and (135), respectively. Sulfonylation also results in the preferential formation of the 3-sulfonamides but reaction with excess reagent eventually produces the 3,5-disubstituted derivatives (136) and (137) in good yields (65AHC(5)119). 

The reaction of 5-amino-l,2,4-thiadiazoles (16) with aldehydes produces a-amino alcohols (145), azomethines (146) or bis-amines (147) depending on the reactants and reaction conditions, as illustrated in Scheme 58. The nitration of 5-amino-3-methyl-l,2,4-thiadiazole (25) in a mixture of 98% sulfuric acid and 95% nitric acid at 0°C is reported to produce (148) in good yield (65AHC(5)119), but a similar reaction with 3-amino-l,2,4-thiadiazoles has not been described. Products of type (149) can be obtained, however, by the ring closure of Af-nitro-AT-thiocarbamylguanidines with alkaline hydrogen peroxide. 

The reaction of unsubstituted 2-amino-1,3,4-thiadiazole (131) with 1,3-dicarbonyl compounds is dependent on the nature of the dicarbonyl compound (Scheme 13). Thus, reaction of (131) with pentane-2,4-dione gives the 4,6-dimethyl-2-thiocyanatopyrimidine (132). The formation of (132) may proceed via the cation (132a). With ethyl acetoacetate, however, a mixture of (133) and (134) is formed, (133) also being converted into (134) on heating. 

Azole approach. 2-Amino-l,3,4-thiadiazoles react with appropriately substituted a,/3-unsaturated carbonyl compounds to form fused pyrimidines (729). The orientation of the substituents in the fusion products suggests that the reaction is initiated by Michael addition of the amino group. 1,3-Dicarbonyl compounds will condense in the same manner to yield the salt (729) from a /3-keto ester the 5-oxo derivative (730) is formed (73ABC1197). 

From a.-Amino Acid Amides and Amidines a-Amino acid amides, which fall into the amine-imine class according to the general model (beginning of Section II,B), are converted to 3-alkyl-4-hydroxy-l,2,5-thiadiazoles by reaction with sulfur mono-chloride, thionyl chloride, or thionyl aniline. A large number of -amino acid amides were employed in the synthesis (see Table I)... 

---