Thiazolo 3,2-b l,2,4-triazoles

Ring closure of 167 to thiazolo[3,2-b][l,2,4]triazoles can also be effected by acid anhydride, but the course of the reaction depends on the starting materials. Refluxing 167 with acetic or propionic anhydride (3-4 h) leads directly to 176. With pentafluoropropionic, heptafluorobutanic, and benzoic anhydride only diacetylated products 177 were produced (further details [76JHC(13)1225]). 

Arylthiazole-5-carboxylic acids on treatment with base and bromine yield the corresponding 5-bromothiazole (76AP128). The same behavior is observed for thiazolo[3,2-b][l,2,4]triazoles (91AP49 94MI2). 

Aminothiazole[3,2-fe][l,2,4]triazoles are readily bis-N-acylated (Ae20, reflux). The 5-alkylation of thiazolo[3,2-b][l,2,4]triazoles with chloro- and aeetoxymethylcephem was also reported (91MI2). An 5-alkylated thia-zolo[3,2-fe][l,2,4]triazole was converted to a sulfonyl ehloride and aminated (88EUP244098). 

Dimethoxy-3-methyl-l-(4-nitrophenyl)-iV-(5, 6 -dihydrothiazolo[3,2-b][l,2,4]triazol-2 -yl)isoquinolinmm bromide 45 is also prepared by reacting 4,5-dimethoxy-2-(4-nitrobenzoyl)phenylacetone 219 with 2-amino-5,6-dihydro-thiazolo[3,2- ][ 1,2,4]triazole 42 <2003JHC821, 2003JHC1041> (Equation 23). 

Thiazolo[3,2-h][l,2,4]triazoles have been prepared either from suitably substituted 1,2,4-triazoles [route (a)] or from 1,3-thiazoles [route (b)j. 

For further examples of thiazolo[3,2-ft][l,2,4]triazoles, see several references [72JMC332 85IJC(B)1221 86JHC1439 88CAT91]. 

Coumarinyl-substituted thiazolo[3,2-h][l,2,4]triazoles have also been reported. They are available in one step by reaction of 5-aryl-3-mercapto[l,2, 4]triazoles with 3-bromoacetylcoumarin (ethanol, reflux, 8 h yield 44-65%) (81AP435) or in a two-step reaction from the corresponding S-alkylated intermediates with PPA [93MI2 94IJC(B)579]. 2-Aminothiazolo[3,2-h][l,2,4]triazoles are also available from 3-mercaptotriazoles. Treatment of 5-amino-3-mercaptotriazole with chloroacetone (DMF, K2CO3) and subsequent acid-catalyzed cyclization yields 146 [90JAP(K)02/142797]. 

Compound 185 can also be obtained by direct bromination of the corresponding thiazolo[3,2-ft][l,2,4]triazole (Bt2, acetie acid) (91AP49). Bromination at C-5 can also be affected by bromine/NBS in chloroform (72YZ935). Thiocyanation, which was possible in the imidazo[2,l-b]thia-zole and -[l,3,4]thiadiazole series (see Sections VI,B,l,a and VII,B,l) failed (72YZ935). 

The tetrazole procedure that has been proved to be of value in the thiazolo[3,2-6][l,2,4]triazole series (see Section VIII) has also been applied in this field. V-Acylated 2-aminothiadiazoles 193 on treatment with phosphorus pentachloride (120°C) and subsequently with sodium azide (aqueous acetone) yield tetrazoles 194. Thermolysis in tetraline (160-180°C) gives the heterocycles 195 in moderate yields [85IJC(B)908 WFA953]. 

Bicyclic 5-5 Systems, One Ring Junction N Atom Three Extra Heteroatoms 2 1 Table 22 Thiazolo[2,3-b][l,2,4]triazoles (58). 

Treatment of aroylthiosemicarbazides with a-haloketones provide thiazole derivatives 283, which after POCI3-promoted cyclization give thiazolo[2,3-c][l,2,4]triazoles 93 (Scheme 28) < 1996IJH21, 2002IJC(B)403,... 

The reaction of thiocarboxamidocinnamonitrile derivative 389 with 2-hydrazinothiazoM(5//)-one in absolute ethanol containing a catalytic amount of triethylamine affords 5-oxopyrano[2,3-z/]thiazolc 390. It has been found that the reaction of compound 390 with chloroacetic acid gives the 5-oxopyrano[ 2,3-z/]thiazole 391. The structure of this compound has been confirmed by its reaction with 4-methoxybenzaldehyde in acetic acid to give the 6-oxopyr-ano[2, 3 4,5]thiazolo[2,3-c][l,2,4]triazole derivative 84 (Scheme 44) <1999ZN(B)1589>. 

The reaction of compound 390 with ethyl chloroformate has also been investigated and gives 8-(4-nitrophenyl)-3,6-dioxo-7-thiocarboxamidopyrano[2, 3 4,5]thiazolo[2,3-c][l,2,4]triazole 392 (Equation 74) <1999ZN(B)1589>. 

Jain and Handa reported [82IJC(B)732] that the mode of ring closure may depend critically on the 5-substituent of the triazole. 3-Mercapto-5-(4 -pyridyl)[l,2,4]triazole 143 was reacted with phenacyl bromides to give 144, which on treatment with PPA resulted in the formation of thiazolo[2,3-c][l,3,4]triazoles 145. The structure of 145 [R = (4-Cl)C6H4] was proved by an independent synthesis starting with isonicotinyl thiosemicarbazide. 

Phenylhydrazono-2-thiazolidinones are cyclized upon treatment with aliphatic and aromatic aldehydes to give thiazolo[4,3-c][l,2,4]triazol-5-ones (equation 22) (76ZN(B)380, 76ZN(B)853). Similar reactions of 2-(and 4-)phenylhydrazono-l-phenylhydantoins with aliphatic aqd aromatic aldehydes gave imidazo[2,3-c][l,2,4]triazoles and imidazo[4,3-c]-[l,2,4]triazoles (82H(19)1375>. 

The last step in a stereospecific total synthesis of ( )-biotin consists of the facile reaction of the precursor diamine with phosgene (equation 5) (77JA6754). The reaction of a cyclic amidrazone precursor with phosgeniminium chloride gives thiazolo[3,2- b] -s-triazoles (equation 6) (73AG(E)405). Treatment of 4,5-diaminopyrazoles with thionyl chloride forms pyrazolo[3,4-c][l,2,5]thiadiazoles (equation 7) (68JMC1164). 

Another pathway occurs in the reaction of chloroacetylenephospho-nates 4.981 with 5-substituted 4-amino-3-thiolo-l,2,4-triazoles. The reaction leads to the formation of condensed bicyclic heterocycles, that is, 3-amino(or 3-methyl)-2-alkyl(aryl)-3H-thiazolo[3,2-b][1,2,4]-triazolo-7-ylium chlorides 4.992 (Scheme 4.16) [451]. Note that in this case, both acetylenic carbon atoms are involved in the formation of the heterocycle. 

Thiazolo[3,2-/>][l,2,4]triazoles are often sufficiently reactive to be brominated in the thiazole nucleus (see also B,5). Thus, although the unsubstituted substrate and the 2-phenyl and 2-methyl derivatives would not react with NBS in refluxing chloroform, the 5-methyl, 2,5-dimethyl, and 5-methyl-2-phenyl compounds gave 6-bromo products (71JAP71/26498 74JHC459). 

Triazoles 431 react with chloroacetic acid to furnish 3-heteroaryl-thiazolo[2,3-c][l,2,4]triazole-5-(6//)-ones 185 (R = Het) (Equation 98) <2001IJC(B)636>. 

Ghloro-l, 2,4-triazino[3,4-Z ]benzothiazoM//-onc 481 gives the rearranged compound 91, with a thiazolo[2,3-c][l,2,4]triazole nucleus, after refluxing with a 10% aqueous solution of NaOH (Equation 111) <1996IJC(B)842>. 

Thiazolo[4,3-/)][l,2,4]oxadiazoles 110 react with hydrazine hydrate to give thiazolo[3,4-/)][l,2,4]triazoles 114 (Equation 113) <2001IJC(B)440>. 

Substituted 1,2,3-triazolium-l-aminide 1,3-dipoles (382) react with aryl isothiocyanates at both the N=C (path a) and C=S (path b) sites to give mixtures of substituted imidazolo[4,5-fi(][l,2,3]triazoles (383) and new thiazolo[4,5-fi(][l,2,3]-triazoles (384) including tricyclic derivatives with the C(3a) and C(6a) bridgeheads linked via (CH2)4 and phenanthro groups (Scheme 50). The product distribution is controlled by the para-substituent of the aryl isothiocyanate. Theoretical calculations at the 3-210 and 6-3IG levels suggest that linear triple-bonded canonical forms of the aryl isothiocyanate system play a key role in the ambident reactivity of these systems. 

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