Synthesis and Transformations of 2-Hydroxy-2-(benzotriazol-1-yl)-1,4-naphthoquinone

2-Hydroxy-3-(benzotriazol-1-yl)-1,4-naphthoquinone reacts with o-phenylenediamine and 4-chloro-2-aminophenol to give cyclization products: 5-oxo-6-(benzotriazol-1-yl)-5,6H-benzo[a]phenazine and 5-oxo-6-(benzotriazol-1-yl)-10-chlorobenzo[a]phenoxazine; the reaction with aniline yields the quaternary anilinium salt, and benzoyl chloride and benzenesulfonyl chloride acylate the nitrogen atom of the benzotriazolyl moiety.     

Syntheses and transformations of substituted benzazolyl- and tetrazolyl(benzotriazol-1-yl)methanes

Condensation reactions of o-hydroxy- and o-mercaptoanilines, and o-phenylenediamine with (benzotriazol-1-yl)acetic acid result in (1,3-benzazol-2-yl)(benzotriazol-1-yl)methanes. Cycloaddition of sodium azide to (benzotriazol-1-yl)acetonitrile leads to (1,2,3,4-tetrazol-5-yl)(benzotriazol-1-yl)methane. The diazolo-substituted benzotriazolylmethanes thus obtained were mono- and di-alkylated at the methylene group and the displacement of the benzotriazole group by nucleophiles was investigated.     

Novel routes to 1-aryl-1,4-dihydro-3(2H)-isoquinolinones and 2-substituted or 2,3-disubstituted benzofurans by intramolecular cyclizations

N-(α-Benzotriazolylalkyl)arylacetamides, readily available from an arylacetamide, an aldehyde and benzotriazole, undergo intramolecular cyclization under acidic conditions to give 1-aryl-1,4-dihydro-3(2H)-isoquinolinones in good to excellent yields. Similarly, 2-(benzotriazol-1-yl)-2-(o-hydroxyphenyl)ethanols, obtained by lithiation of 2-(benzotriazol-1-ylmethyl)phenols followed by quenching with aldehydes or ketones, eliminate a molecule of water and a molecule of benzotriazole yielding 2-substituted and 2,3-disubstituted benzofurans.     

Kinetics,catalysis, and mechanism of isomerization of N-[(benzotriazol-1-yl)methyl]anilines into the benzotriazol-2-yl derivatives

The ¹H NMR technique was applied for the measurement of the isomerization rates of N-ethyl-N-[(benzotriazol-1-yl)methyl]aniline ( 4 ) and 4-butyl-N-[(benzotriazol-1-yl)methyl]aniline ( 7 ) to the corresponding benzotriazol-2-yl isomers in dioxane-d₈ at 35°C. The rate constants obtained for pure dioxane-d₈ were 1.62 and 0.28 h^?1 for 4 and 7 , respectively. For both compounds, addition to acetic acid to the dioxane solutions accelerated the isomerizations whereas addition of triethylamine retarded it strongly. Addition of water slowed the isomerization of 4 but accelerated that of 7 : the different effects operating in the two cases are discussed and rationalized. © 1995 John Wiley & Sons, Inc.     

1,3-Dipolar cycloadditions of electron-rich benzotriazol-1-ylpropenes

The preparation of trans-3-benzotriazol-1-yl-1-(N-rnorpholino)prop-1-ene ( 1 ), trans-3-benzotriazol-1-yl-1-ethoxyprop-1-ene ( 2 ) and trans-1,3-bis-(benzotriazol-1-yl)propene ( 3 ) and their reactions with a benzonitrile oxide ( 4 ), N-(2,4-dibromophenyl)-1-phenylnitrilimine ( 5 ), and p-nitrophenyl azide ( 6 ) are described.     

Preparation,lithiation and transformation of N-(benzotriazol-1-ylmethyl) heterocycles

Indole, carbazole, pyrrole, imidazole, benzimidazole, 2-methyl- and 2-phenylbenzimidazole, and 1, 2, 4-triazole have each been converted into their N-(benzotriazol-1-ylmethyl) derivatives. The pyrrole, indole, and carbazole adducts undergo smooth lithiation at the inter-ring methylene group and subsequent reaction there with electrophiles. For the imidazole, benzimidazole, and triazole systems, lithiations at other molecular positions competed.     

Unusual deoxygenation and reactivity studies related to O6-(benzotriazol-1-yl)inosine derivatives

New and unusual developments related to the chemistry of O6-(benzotriazol-1-yl)inosine derivatives are reported. First, a simple, scalable method for their syntheses via the use of PPh3/I2/HOBt has been developed and has been mechanistically investigated by 31P(1H) NMR. Studies were then conducted into a unique oxygen transfer reaction between O6-(benzotriazol-1-yl)inosine nucleosides and bis(pinacolato)diboron (pinB-Bpin) leading to the formation of C-6 (benzotriazol-1-yl)purine nucleoside derivatives and pinB-O-Bpin. This reaction has been investigated by 11B(1H) NMR and compared to pinB-O-Bpin obtained by oxidation of pinB-Bpin. The structures of the C-6 (benzotriazol-1-yl)purine nucleosides have been unequivocally established via Pd-mediated C-N bond formation between bromo purine nucleosides and 1H-benzotriazole. Finally, short and extremely simple synthesis of 1,N6-ethano- and 1,N6-propano-2'-deoxyadenosine are reported in order to demonstrate the synthetic versatility of the O6-(benzotriazol-1-yl)inosine nucleoside derivatives for the assembly of relatively complex compounds.     

O6-(benzotriazol-1-yl)inosine derivatives: easily synthesized, reactive nucleosides

A novel class of O6-(benzotriazol-1-yl)inosine as well as the corresponding 2'-deoxy derivatives can be conveniently prepared by a reaction between sugar-protected or -unprotected inosine or 2'-deoxyinosine nucleosides and 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The reaction appears to proceed via a nucleoside phosphonium salt, and in the absence of any additional nucleophile, the released 1-hydroxybenzotriazole undergoes reaction with the formed phosphonium salt leading to the requisite O6-(benzotriazol-1-yl)inosine or 2'-deoxyinosine derivatives. Isolation and characterization of the phosphonium salt as well as analysis by 31P{1H} NMR appear to be consistent with this reaction pathway. The resulting O6-(benzotriazol-1-yl)inosine derivatives are effective as electrophilic nucleosides, undergoing facile reactions with a variety of nucleophiles such as alcohols, phenols, amines, and a thiol. Unusual and challenging nucleoside derivatives such as an aryl-bridged dimer, a nucleoside-amino acid conjugate, and a nucleoside-nucleoside dimer have also been synthesized from the O6-(benzotriazol-1-yl)-2'-deoxyinosine derivative. Finally, a fully protected DNA building block, the O6-(benzotriazol-1-yl)-2'-deoxyinosine 5'-O-DMT 3'-O-phosphoramidite, has been prepared and a preliminary evaluation of its use for DNA modification has been performed. Results from these studies indicate several important facts: A single, simple methodological approach provides a class of stable, isolable ribo and 2'-deoxyribonucleoside derivatives that possess excellent reactivity for SNAr chemistry with a wide range of nucleophiles. Also, a benzotriazolyl nucleoside phosphoramidite appears to be a suitable reagent for incorporation into DNA for purposes of site-specific DNA modification.     

New 4-(benzotriazol-1-yl)-1,2,3-triazole derivatives

A new 4-(benzotriazol-1-yl)-1,2,3-triazole structure was obtained by the diazotization reaction of either of 1-(2-aminophenyl)-4-carboxamido-5-amino-1H-1,2,3-triazole ( 1c ) or of the corresponding Dimroth isomer 1d . It underwent some common reactions to evaluate its chemical behaviour and structure. An analogous reaction sequence was carried out from the 2-nitro-4-methylphenyl azide, to assign the structure to the nitro derivatives prepared. The structure of the new compounds prepared was confirmed by chemical and spectroscopic methods.     

Synthesis of new amides of the <Emphasis Type="Italic">N</Emphasis>-methylpiperazine series

New carboxylic acid amides containing an N-methylpiperazine fragment were synthesized by reactions of 1-methylpiperazine or 3- and 4-(4-methylpiperazin-1-ylmethyl)aniline with 4-chlorobenzoyl chloride and of 4-methyl-3-nitroaniline with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride or benzotriazol-1-yl 4-(4-methylpiperazin-1-ylmethyl)benzoate. 4-Chloro-N-[4-(4-methylpiperazin-1-ylmethyl)phenyl]benzamide reacted with imidazole, quinolin-5-amine, and 2-methylquinolin-5-amine to give substituted 4-amino-N-[4-(4-methylpiperazin-1-ylmethyl)phenyl]benzamides. 4-Methyl-3-nitrophenyl-4-methylpiperazin-1-yl-substituted benzamides were reduced with hydrazine hydrate over Raney nickel to obtain N-(3-amino-4-methylphenyl)-4-(4-methylpiperazin-1-ylmethyl)benzamide as key intermediate in the synthesis of antileukemic agent imatinib and its isomer with alternative position of the amide group, 4-[(3-amino-4-methylphenylamino)methyl]phenyl-(4-methylpiperazin-1-yl)methanone.     

Facile Synthesis of Benzotriazines and Indoles by Ring-Scissions of α-Benzotriazol-1-yl Hydrazones

Abstract: α-(Benzotriazol-1-yl)hydrazones 2a-d and 13a-c were prepared by refluxing the corresponding α-(benzotriazol-1-yl)ketones with p-tosyl hydrazide or benzenesulfonyl hydrazide. Treatment of 2a-b with n-butyllithium in the presence of TMEDA gave benzotriazines 6a-b, while lithiation of 13a-c resulted in indole derivatives 16a-c, depending on the structure of the hydrazones.     

Synthesis of 3-(Benzotriazol-1-yl)naphthoquinone Derivatives

2,3-Bis(benzotriazol-1-yl)-1,4-naphthoquinone reacts with aliphatic and aromatic amines to give the corresponding 2-amino-3-(benzotriazol-1yl)-1,4-naphthoquinones, and its reaction with alkali gives 2-hydroxy-3-(benzotriazol-1-yl)-1,4-naphthoquinone.     

Synthetic transformations of 1-cyanomethylbenzotriazole

Lithiation of 1-cyanomethylbenzotriazole ( 4 ) with LDA and subsequent reactions with alkyl halides or carbonyl compounds afforded the corresponding 1-(α-cyanoalkyl)- and 1-(α-cyanoalkenyl)-benzotriazoles. Bromination of 4 with NBS formed 1-(bromocyanomethyl)benzotriazole. 1-Cyanoalkylbenzotriazoles condensed with hydrazine hydrate to give 4-amino-3,5-bis(benzotriazol-1-yl)triazoles which underwent deamination with sodium nitrite to yield 3,5-bis(benzotriazol-1-yl)triazoles.     

Efficient Syntheses of Substituted Carbazoles and Cyclopent[b]indoles from 1-Methyl-3-(benzotriazol-1-ylmethyl)indole

1-Methyl-3-(benzotriazol-1-ylmethyl)indole (1) undergoes lithiation and 1,4-addition with a variety of alpha,beta-unsaturated ketones and aldehydes. Subsequent treatment with an acidic resin in refluxing 1,4-dioxane causes intramolecular cyclization followed by aromatization to furnish a wide range of 1,3-di-, 2,3-di-, and 1,2,3-trisubstituted carbazoles 6a-j and 8 in moderate to excellent yields. NMR study is described to discriminate between structures of types 6 and 8 on the basis of (1)H-(13)C long-range correlation. Treatment of 1 with styrenes in the presence of zinc bromide results in formal [3 + 2] cycloaddition to give cyclopent[b]indoles 14a-c in good yields. When 1 is first lithiated and reacts with electrophiles, the resulting alkylation products undergo similar [3 + 2] additions with styrenes to give 1-functionalized cyclopent[b]indoles 15 and 16with a high degree of stereoselectivity.     

1,4-Disubstituted and 1,4,5-Trisubstituted 2-[(Benzotriazol-1-yl)methyl]pyrroles as Versatile Synthetic Intermediates

The CH(2)Bt substituent, unlike previously used CH(2)X substituents, enables (i) the synthetic elaboration of pyrroles with unsubstituted ring positions and (ii) electrophilic as well as nucleophilic substitutions to give pyrroles of type pyrrolyl-2-CHENu. Thus, 1,4-disubstituted (7) and 1,4,5-trisubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles (15) were easily prepared from the reaction of 5-(benzotriazol-1-yl)-1,2-epoxy-3-pentynes 4 or 14 with primary amines in i-PrOH. The 2-(benzotriazol-1-yl)methyl side chains of compounds 7 and 15 were elaborated by nucleophilic substitution and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety to afford a variety of 1,2,4-trisubstituted (6, 8-9, 11-13) and 1,2,4,5-tetrasubstituted pyrroles (18, 20-22).     

Construction of 3-aryl-1,2,4-benzotriazines via unprecedented rearrangement of bis(benzotriazol-1-yl)methylarenes

3-Aryl-1,2,4-benzotriazines were formed unexpectedly by the treatment of 1,l-bis(benzotriazol-1-yl)methylarenes with allylsamarium bromide. A radical pathway was proposed involving steps, such as fragmentation, ring-opening, and cyclization.     

Nucleophilic substitution in 4-bromo-5-nitrophthalodinitrile: VIII. Synthesis of 4-(benzotriazol-1-yl)-5-[4-(1-methyl-1-phenylethyl)phenoxy]phthalodinitrile and phthalocyanines on its basis

Nucleophilic aromatic substitution of the bromine atom in 4-bromo-5-nitrophthalodinitrile by a 2-aminophenylamine residue followed by conversion of the resulting compound to 4-(1-benzothiazol-1-yl)-5-nitrophthalodinitrile and nucleophilic substitution of the nitro group by a 4-(1-methyl-1-phenylethyl)-phenoxy group gave 4-(benzotriazol-1-yl)-5-[4-(1-methyl-1-phenylethyl)phenoxy]phthalodinitrile. The latter product was reacted with certain metal acetates and chlorides to obtain the corresponding metal complexes of octasubstituted phthalocyanines. Spectral properties of the complexes were studied.     

Synthesis of benzotriazolylsuccinimides in melt

N-Phenyl-3-(benzotriazol-1-yl)pyrrolidine-2,5-dione was synthesized by condensation of N-phenylmaleimide with benzotriazole in melt. The adducts of 2 moles of benzotriazole to different bismaleimides, namely, bis[3-(benzotriazol-1-yl)pyrrolidine-2,5-diones] were obtained under analogous conditions. These adducts, according to the data from ¹H and ¹³C NMR spectroscopy, contain also (benzotriazol-2-yl)succinimide and residual maleimide fragments.     

Lithiation of 1-alkyl-1H-1,2,4-triazol-5-yl phosphonic acid esters: Novel anion-mediated carbon-to-carbon phosphonate migrations

The lithiation chemistry of 1-alkyl-1H-1,2,4-triazol-5-yl phosphonic acid esters 3 has been investigated. Lithiation occurs exclusively on the 1-alkyl group, α to nitrogen, to give carbanionic intermediates 10 . No evidence was found for any lithiation at the 3-position of the triazole ring. On warming, intermediates 10 undergo an unusual anion-mediated phosphonate migration, giving rise to 1H-1,2,4-triazol-1-yl-methylphos-phonates 14 .     

Preparation of various enantiomerically pure (benzotriazol-1-yl)- and (benzotriazol-2-yl)-alkan-2-ols

(S)-(−)-(Benzotriazol-1-yl)- and (S)-(−)-(benzotriazol-2-yl)-alkan-2-ols 7a–9a, 7b–9b and their (R)-(+)-acetates 10a–12a and 10b–12b were prepared in high enantiomeric excess via lipase from Pseudomonas fluorescens (Amano AK) catalyzed enantioselective acetylation of racemic alcohols 4a–6a and 4b–6b with vinyl acetate in tert-butyl methyl ether or toluene at 23 °C. The enantioselectivity of this transformation was dependent on the length of the alkyl chain with E-values ranging from 30 to 57. Several benzotriazole substituted ketones 1a–3a and 1b–3b were synthesized from 1H-benzotriazole and corresponding haloketones. These compounds were stereoselectively reduced with Baker’s yeast in water or in organic solvent containing 5% v/v of water at 30 °C to give the (S)-(−)-alcohol. Better stereoselectivity was observed in the kinetic resolution of racemic alcohols 4a–6a and 4b–6b (ee = 69–92% at 44–52% conversion) compared to reduction of corresponding prochiral ketones 1a–3a and 1b–3b with Baker’s yeast (ee = 40–67% at 39–89% conversion). Enhanced enantioselectivities were observed at lower temperatures.