2- Amino-1.3.4-thiadiazoles, acylation

A somewhat different scheme is used to gain entry to the alternate symmetrical 1,3,4-thiadiazole ring system. Reaction of thiosemicarbazide with isovaleric acid affords the ring system (217) in one step. The reaction may be rationalized by positing acylation to intermediate 216 as the first step. Sulfonylation of the amino group of 217 with p-methoxybenzenesulfonyl chloride affords the oral... 

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 >. 

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>. 

Amino-l,2,5-thiadiazole is a weak base but is sufficiently nucleophilic to readily form acyl, aroyl, sulfanilyl, and sulfinyl derivatives on the exocyclic nitrogen atom. Similarly, all the observed reactions of diaminothiadiazole <76JHC13> involve the exocyclic nitrogen atoms. IR, UV, and NMR spectroscopic evidence clearly indicate, however, that aminothiadiazole protonates on the ring nitrogen atom <68AHC(9)107>. 

The synthesis of numerous thiadiazoles substituted in the 5-position with carbamoyl or heteroaryl moieties and hydroxyl or amino groups in the 2-position (Scheme 20), was achieved by reacting dithioesters with semicarbazide or thiosemicarbazide and cyclizing the resulting acylated sem-... 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

In general, acylation of the amino group increases the stability of the resulting 1,2,4-thiadiazole towards acid and alkaline hydrolysis6,86... 

Amino-5-methylamino-l,2,4-thiadiazole similarly gives a 3-toluene-p-sulfonamido111,122 (237) and a monobenzamido derivative (for structure, see ref. 122) an excess of the appropriate reagent yields non-acidic di- and tri-substitution products, the latter probably of structure 239. With acetic anhydride, however, acylation terminates with the formation of the 3-monoacyl derivative.111,122 Similar observations areon record concerning 3-amino-5-anilino-1,2,4-thiadiazole86 the only anomalous observation is the ability of this compound to form di- and tri-acetyl derivatives.58... 

Alkylthio-5-amino-l,2,4-thiadiazoles are generally insoluble in acids and alkalis, and resist desulfurization by alkaline sodium plum-bite.132 The higher members are Bomewhat sensitive to hydrolysis85,90 the 3-phenylthio homolog is slowly destroyed by concentrated alkali, but its stability is much increased by acylation.85... 

Alkylthio- 5-amino-l,2,4-thiadiazoles and homologs Acyl derivatives thereof... 

Reaction of an amino-substituted heterocyclic thiol such as (81) with acylating agents gives compounds (82), which are cyclized by POCl3 to form, for example, imidazo[2, l -b [l,3,4]thiadiazoles... 

Acylation of 3-amino-5-methylamino-l,2,4-thiadiazole (28) with benzoyl chloride (or arenesulfonyl chlorides) introduces one acyl group when one equivalent is employed, and three when a large excess is used to produce (29) and (30), respectively (Scheme 16). With acetic anhydride, however, acylation terminates with the formation of the 3-monoacyl derivative (65AHC(5)ll9). For the mechanism of acylation, see Scheme 3. In the case of 3,5-diarylamino-l,2,4-thiadiazoles, no triacyl derivative is obtained even when excess of acylating agent is employed. Acetyl and benzoyl chlorides give monoacyl derivatives and p-toluenesulfonyl chloride forms 3,5-di(p-toIuenesulfonyl) derivatives (65AHC(5)119). 

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