5- Amino-2- -benzotriazol

Strelevitz TJ, Foti RS, Fisher MB. In vivo use of the P450 inactivator 1-amino-benzotriazole in the rat varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance. J Pharm Sci 2006 95 1334-1341. 

The direct amination of benzotriazole by the use of HOSA was first reported in a patent (65USP3184471). The total yield of 1- and 2-amino-benzotriazoles, separated by crystallization, was not high (20%). Later, Rees and co-workers changes the conditions of amination and achieved yields of 38% and 11% for 1- and 2-amino derivatives, respectively [69JCS(C)742], Amination of the sodium salt of benzotriazole with chloroamine failed. An attempt to exchange the chlorine atom for the amino group in 1-chlorobenzotriazole under the action of sodium amide was also unsuccessful [69JCS(C)1474]. 

Only a single patent reports arylation of A-aminoazoles. 2-(t>-Nitrophe-nyUaminobenzotriazole was obtained on heating 2-aminobenzotriazole with o-nitrofluorobenzene in DMF in the presence of anhydrous soda (65USP3184471). An attempt to carry out such a reaction for I-amino-benzotriazole failed, probably because of the poor NH-acidity of this compound. 

This positive halogen compound oxidizes alcohols to aldehydes or ketones and hydrazo compounds to azo compounds under mild conditions and in high yields. The oxidant is converted into bcnzo-triazole hydrochloride. It also oxidizes 1-amino-benzotriazole to benzyne (80% yield, 2 moles of oxidant required) and 2-amino-benzotriazole to cis.cis-1,4-dicyanobutadienc-1,3. ... 

When 4-amino-5-methyl-l-(p-toluenesulfonyl)benzotriazole (283) was boiled in toluene for 3 h, rearrangement into 7-methyl-4-[(p-toluenesul-fonyl)amino]benzotriazole (284) was complete. However, the same compound was boiled in benzene for 1.5 h and produced a trace of 284. The bis-tosylate 285 was stable in nonpolar solvents and its rearrangement to 286 was accelerated on raising the temperature. No rearrangement of 285 to 286 was observed in chloroform and it was slow in toluene. No rearrangement from 286 to 285 was observed in DMSO-d6 at room temperature (92JOC190). Furthermore, when 4-aminobenzotriazole 287 was treated with one equivalent of p-toluenesulfonyl chloride in pyridine, 4-[(p-tolu-enesulfonyl)amino]benzotriazole (288) was obtained either by the rearrangement of the 1-sulfonyl-substituted compound or by its direct formation. Compound 288 was stable when heated in toluene for 5 h (Scheme 92). 

When ambrox (391) was biotransformed by A. niger for 9 days in the presence of 1-amino-benzotriazole, an inhibitor of CYP450, compounds 396 and 397 were obtained instead of the... 

Fig. 2. Differential effect of amino-benzotriazole on chlorotoluron degradation in wheat and Veronica persica. Modified and redrawn from Gonneau et al. [13]...

It should be emphasized that the correct description of the peculiar effect brought about by the presence of two or more sp -nitrogen centers within a molecule can be reproduced reliably only by high level ah initio calculations accounting for electron correlation. This conclusion is well justified by the examples of benzotriazole, 3-amino-l,2,4-triazole, and tetrazole, as described in Sections II,B,3 II,B,4 and II,B,5, respectively. 

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). 

Amino-2-phenyl-2//-benzotriazole reacted with epichlorhydrin in chlorobenzene at 140-145°C to give the A-benzyl-7-hydroxy-6,7,8,9-tetrahydrotriazolo-quinoline derivative 194. This was benzylated and rearranged by heating in DMSO to give the isomeric 7-benzyloxy derivative 195 (Scheme 59) (77MI2). 

R=H) where the 2-aminobenzenediazonium ion first produced reacts rapidly with the amino group to yield benzotriazole, which can be regarded as an intramolecular triazene (Scheme 6-32). However, in contrast to open-chain triazenes this compound contains the triazeno group in the (Z)-configuration, and here the heterocycle cannot be opened by the action of an acid. 

Amino acids activated at the amino group by a benzotriazolide moiety react with amino acids under elimination of benzotriazole and C02 to give peptides. Reaction is achieved by warming up equimolar amounts of the components in anhydrous acetonitrile or aqueous acetone.[45] The benzotriazolylcarbonylamino acids are prepared from benzo-triazolyl-1-carboxylic acid chloride and amino acids.[46]... 

Benzotriazole-Mediated Amino-, Amido-, and Alkylthio-Alkylation <2005T2555> and... 

Compound 642, obtained by condensation of glyoxal with benzotriazole and morpholine undergoes interesting [2+3] cyclocondensation with 2-aminopyridine to give imidazo[l,2- ]pyridine 643 (Equation 15) <2003JOC4935>. Similar derivatives of piperidine and pyrrolidine are also described. 2-Amino- and 6-aminopyrimidines react similarly to give imidazo[l,2- ]- and imidazoll - pyrimidines, respectively. 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

---