3- Methyl-7- triazolo

HOAt, 7-aza-l-hydroxybenzotriazole HATU (CAS Registry No. 148893-10-1), A-[(dimethylamino) (3//-1,2,3-triazolo(4,5- )pyridin-3-yloxy)methylene]-A-methyl-methanaminium hexafluorophosphate, previously known as G-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. [Note Assignment of structure to HATU as a guanidinium species rather than as a uronium species, i.e., attachment of the (Mc2NC=NMe2) unit to N3 of 7-azabenzotriazole 1-A-oxide instead of to the O, is based on X-ray analysis (ref. 33b)]. 

Tliis conclusion is supported by the data on the azide-tetrazole equilibrium for s-triazolo[2,3-d]tetrazoles (128) [79JCS(P1)2886]. Methylation of neutral azide resulted in the 1-methyl derivatives of 3-azidotriazole 128A only, whereas on methylation of the anion 128A, the tetrazoles 129 and 130 were also trapped in 25 and 10% yields, respeetively. Tire predominanee of 128T over 128T" was attributed to these two bieyelie anions but no ealeu-lations on relative energies have been performed. Tire azide-tetrazole equilibrium eonstants were measured for 128A7T in DMSO-dg 0.45 at 27°C (R = H), and 0.78 at 23°C and 1.80 at 80°C (R = Ph). 

Hydrolytic fragmentation of the C5-N6 part took place upon heating 7-methyl-5-propyl-2-thioxo-l,2,4-triazolo[l,5-c]pyrimidine (129) with hydrochloric acid. 3-Acetonyl-5-mercapto-l,2,4-triazole (130) and butanoic acid were obtained as a result of N4-C5, C5-N6, and N6-C7 bond cleavages (65JCS3369) (Scheme 50). 

Triazole ring cleavage of the 7-amino-5-benzyl-5-mercapto-l,2,4-triazolo-[l,5-c]pyrimidinium iodide 135 at the N3-N4 bond occurred upon treatment with potassium carbonate to give the 4-amino-2-benzylmercapto-l-methyl-... 

Aliphatic and aromatic aldehydes condensed with 2-amino-(62BRP898414), 5-amino- (80AJC1147), or 8-amino-l,2,4-triazolo[l,5-cjpyrimidines (68JOC530) to give the related Schiff bases. Treatment of the 2-amino-5-methyl-l,2,4-triazolo[l,5-c]quinazoline 11 with formaldehyde and piperidine in the presence of acetic acid gave the 2-hydroxymethyl-amino-5-(2-piperidinoethyl) derivative 172. Utilization of aromatic aldehydes and piperidine in this reaction gave the 2-arylideneamino-5-styryl derivatives 173 (68CB2106) (Scheme 67). 

Comparison of the UV speetra of 5-amino-2-(2-furyl)-l,2,4-triazolo[l,5-cjquinazolines (196) and its 5-methylamino derivative (197) in neutral, aeidie, and basie media with the speetra of the two tautomerieally looked derivatives—2-(2-furyl)-5-dimethylamino-l,2,4-triazolo[l,5-c]quinazolines (198) (amino-loeked tautomers) and the imino-loeked tautomers 2-(2-furyl)-5-imino-6-methyl-l,2,4-triazolo[l,5-c]quinazolines (199)—indieated that eompounds 196 and 197 are best represented as a mixture of their amino and imino tautomers (88JMC1014) (Seheme 75). 

Methylbenzotriazole derivatives with an aminoethylene substituent in position 4 also regioselectively produce only the angularly annelated 7-ethoxycarbonyl-6-0X0-6,9-dihydro-2-methyl-2//-triazolo[4,5-/i]quinoline 158. Under alkaline hydrolysis the ester 158 yielded the corresponding acid 159 (90CCC1038, 92FA1001). 

Angularly annelated H- -methy 1-8-ethoxy carbonyl-9-oxo-6,9-dihydrotriazolo [5,4-/]quinolone is formed preferably 164 over the sterically less hindered (9-0X0 group vs 1-methyl group) linearly annelated triazolo[4,5-g]quinoline 165 in a reaction starting from 6-aminoethylene substituted 1-methyIbenzotriazole. Hydrolysis of the cyclization product produced the corresponding acid 166 (Scheme 52) (94CCC1145). 

These amines gave, with methyl propiolate, products of Michael mono- and bis-addition. Adducts underwent further reaction leading to triazolo[4,5-/]quinolones 181, after retro Diels-Alder reaction and acetylene elimination to its methoxycar-... 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

Methyl-A -(3-methoxyphenyl)-l//-l,2,3-triazolo[5,4-/]quinoline-9-amine was prepared and tested as an immunostimulant (93MI2). 

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