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.     

Synthesis of 1-(benzotriazol-1-yl)alkyldiphenylphosphine oxides and their transformations to novel benzotriazol-1-yl-substituted cyclopropanes

Diphenylphosphinous anion reacted with chloromethylbenzotriazole to give (benzotriazol-1-yl)methyldiphenylphosphine oxide, which, after lithiation, was alkylated to give 1-(benzotriazol-1-yl)alkyldiphenylphosphine oxides in good yield. Treatment of 1-(benzotriazol-1-yl)alkyldiphenylphosphine oxides with n-butyllithium followed by condensation with epoxides, afforded benzotriazol-1-yl-substituted cyclopropanes, which underwent further lithiation and subsequent reaction with numerous electrophiles to provide a variety of novel benzotriazol-1-yl-substituted cyclopropane derivatives.     

Preparation,characterization and reactions of novel vicinal dibenzotriazol-1-yl derivatives of benzotriazole and glyoxal

A variety of novel 1,2-disubstituted-1,2-di(benzotriazol-1-yl)ethane and 1,2-di(benzotriazol-1-yl)ethylene derivatives were prepared from the adduct of benzotriazole and glyoxal.     

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.     

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.     

A novel synthesis of 5-acylaminooxazoles

1,2-Diacylamino-1,2-di(benzotriazol-1-yl)ethanes 2 , easily prepared from the condensation of 1,2-di(benzotriazol-1-yl)ethane-1,2-diol (1) and primary amides, were converted to 5-acylaminooxazoles in good to moderate yields via intramolecular cyclization upon treatment with sodium hydride.     

Novel synthesis of bicycles with fused pyrrole, indole, oxazole, and imidazole rings

Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11 with diverse ketones, isocyanates, and isothiocyanates in the presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and imidazo[1,5-a]indoles 4 by a simple one-step procedure.     

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.     

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.     

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.     

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).     

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.     

Methyl β-(Benzotriazol-l-yl) vinyl Ketone: A New p-Acetylvinyl Cation Equivalent

A simple and efficient two-step approach to methyl β-(benzotriazol-1-yl)vinyl ketone 7 is described. The synthetic utility of compound 7 has been demonstrated by nucleophilic substitutions of the benzotriazolyl group with a range of nucleophiles. Thus, methyl β-(benzotriazol-1-yl)vinyl ketone provides a new β-acetylvinyl cation equivalent.     

Convenient Synthesis of Julolidines Using Benzotriazole Methodology

Reaction of N,N-bis[(benzotriazol-1-yl)methyl]aniline (2) with 1-vinylpyrrolidin-2-one gives a mixture of diastereomeric 1,7-bis(2-oxopyrrolidin-1-yl)julolidines 3. After reduction of 3 with LAH, the predominant trans diastereomer of 1,7-di(pyrrolidin-1-yl)julolidine (4) is separated. Reaction of 2 with ethyl vinyl ether yields predominantly trans-1,7-di(benzotriazol-1-yl)julolidine (11). Stepwise synthesis from tetrahydroquinoline 15 gives access to julolidines with two different substituents on C-1 and C-7. Reaction of 1-[(benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydroquinoline (25) with enolizable aldehydes gives a mixture of tetrahydroquinolines 26-29 which are converted into single julolidine products upon treatment with sodium hydride, LAH, or phenylmagnesium bromide. Reactions of 1,2,3,4-tetrahydroquinolines with benzotriazole and 2 molar equiv of enolizable aldehydes gives 1,2,3-trisubstituted julolidines 38-41, which with lithium aluminum hydride, sodium hydride, or a Grignard reagent produce single diastereomers of products 42, 43, and 45, respectively.     

Preparation of 1,5-disubstituted pyrrolidin-2-ones

1,5-Disubstituted pyrrolidin-2-ones 18a-g, 19a-h, and 20a-f were synthesized in good to excellent yields via the nucleophilic substitution of 5-(benzotriazol-1-yl)-1-substituted-pyrrolidin-2-ones 9 with allylsilanes, organozinc reagents, and phosphorus compounds. Compounds 9 and 5-(benzotriazol-2-yl)-1-substituted-pyrrolidin-2-one isomers 10 are readily prepared in total 70-84% yields from 2, 5-dimethoxy-2,5-dihydrofuran (7), primary amines 8, and benzotriazole; 9 and 10 react identically with nucleophiles.     

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.     

Synthesis of α-Benzotriazole Sulfides Promoted by Samarium Diiodide

1-(Benzotriazol-1-yl) unsymmetrical diorganyl sulfides were synthesized via replacement of chlorine atom in 1-(benzotriazol-1-yl)-1-chloromethane with thiolate anions promoted by SmI₂.     

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.     

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.