Regioselective Synthesis of New Triheterocyclic Compounds from 1,4-Benzodiazepine

As part of our program on the synthesis of new heterocyclic compounds, we report here a one-step synthesis of [1,2,4]triazolo[4,3-d][1,4]benzodiazepine 3 and [1,2,4]oxadiazolo[4,5-d][1,4]benzodiazepine 5 by 1,3-dipolar cycloaddition of nitrilimines and nitrile oxides with 1,4-benzodiazepines 1.     

MICROWAVE-INDUCED ONE-POT SYNTHESIS OF SOME NEW SPIRO[3H-INDOLE-3,5′(4′H)-[1,2,4]- TRIAZOLINE]-2-ONES

A rapid and efficient method for the synthesis of title compounds by 1,3-dipolar cycloaddition reaction or nitrilimines with isatin imines using microwave-induced and conventional methods is reported.     

Synthèses de 1,2,4-triazolo[4,3-d][1,4]diazépines et de 1,2,4-oxadiazolo[4,5-d][1,4]diazépines par cycloaddition dipolaire-1,3

We report here a one-step synthesis of the 4,5,6,7-tetrahydro-1H- 1,2,4,-triazolo[4,3-d][1,4]diazepine, 4-6, and 1,2,4-oxadiazolo[4,5-d][1,4]-diazepine, 7-10, by 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides with 2,3-dihydro-H-1,4-diazepine, 1. In all cases these cycloaddition are peri- and regioselectives (the C ? N bond is sole affected) and occures with high yields. Structure and conformations of cycloadducts have been assigned by means of nmr analysis     

Solid-phase synthesis of linked heterocycles from a selenopolystyrene resin

A linked heterocycle library of isoxazoles, 1,2,3-triazoles, bicyclo[2.2.1]hepta-2,5-diene or 4-methylcyclohexa-1,3-diene and 1,2,4-oxadiazoles was prepared by solid-phase organic synthesis. Key steps on resin-bound selenium were electrophilic additions; 1,3-dipolar cycloaddition; Porco's two-step, one-pot condensation of amidoxime and carboxylate; and Diels-Alder reaction.     

Polymer-supported 1,3-oxazolium-5-olates: synthesis of 1,2,4-triazoles

A traceless synthesis of 3,5-disubstituted 1,2,4-triazoles has been developed on polymeric supports. The synthetic process utilizes immobilized mesoionic 1,3-oxazolium-5-olates (munchnones) as key intermediates in the 1,3-dipolar cycloaddition reaction. The initial step in the synthesis involves reductive alkylation of phenylglycine methyl esters with Ameba resin. The resulting immobilized amino acid esters were subsequently acylated with a variety of carboxylic acid chlorides and subjected to hydrolysis with 15% KOH to yield the polymer-bound carboxylic acids. Finally, the cycloaddition between diethyl diazocarboxylate or 4-phenyl-4H-1,2,4-triazoline-3,5-dione and the polymer-bound munchnones generated from the corresponding carboxylic acids afforded the polymer-bound 3,5-disubstituted 1,2,4-triazoles. Cleavage from the polymeric support using trifluoroacetic acid gave the desired 3,5-disubstituted 1,2,4-triazoles with excellent yield and high purity.     

‘One-flask’ synthesis to 3,5-disubstituted 1,2,4-triazoles from aldehydes with hydrazonoyl hydrochlorides via 1,3-dipolar cycloaddition

A new ‘one-flask’ synthesis of 3,5-disubstituted 1,2,4-triazoles has successfully been developed to synthesize a series of 3,5-disubstituted 1,2,4-triazoles. The transformation involves the 1,3-dipolar cycloaddition reaction of hydrazonoyl hydrochlorides with oxime intermediates prepared from aldehydes with hydroxylamine hydrochloride in the presence of excess amount of triethylamine. In this ‘one-flask’ 1,3-dipolar reaction, hydrazonoyl hydrochlorides was concerned as the masked 1,3-dipole nitrilimine under basic condition. Furthermore, this newly developed methodology can be applied to various aldehyde substrates including aliphatic, cyclic aliphatic, aromatic, and heterocyclic aldehydes.     

Soluble Polymer-Supported Synthesis of Pyrazoles via 1,3-Dipolar Cycloaddition Strategy

Rapid parallel liquid-phase synthesis of pyrazoles has first been developed. The 1,3-dipolar cycloaddition between nitrilimines generated in situ and soluble polymer-supported alkynyl or alkenyl dipolarophiles in parallel one-pot fashion gave the corresponding PEG-supported regioisomeric pyrazoles or regiospecific pyrazolines. The latter was assuredly oxidated by DDQ to PEG-supported regiospecific pyrazoles. Cleavage from the support under mild conditions afforded pyrazoles in good yields and high ouritv.     

Peptide ligation through click chemistry for the generation of assembled and scaffolded peptides

The synthesis of [1,2,3]-triazoles through copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition was examined for its utility to generate assembled and scaffolded peptides from peptide and scaffold precursors, which were N-terminally modified with azido and alkyne moieties, respectively.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

Simple synthesis of 1-substituted-4-vinyl-1,2,3-triazoles based on polystyrene-supported sulfonyl chloride

Polystyrene-supported but-3-ynyl sulfonate reagent has been developed and applied to the traceless solid-phase organic synthesis of 1-substituted-4-vinyl-1,2,3-triazoles by CuI-promoted 1,3-dipolar cycloaddition reaction with various organic azides and subsequent cleavage from the polymer support through elimination reaction mediated by 1.8-diazabicyclo[5,4,0]undec-7-ene (DBU). The advantages of this new synthetic method include simple operation and moderate to good yields of the products, as well as good stability of the reagent.     

Synthesis of 1-(1,2,4-triazol-3-yl)-1,2,3-triazoles

1-(1,2,4-Triazol-3-yl)-1,2,3-triazoles were obtained by 1,3-dipolar cycloaddition of 3-azido-1,2,4-triazole to acetylene derivatives. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 262–264, February, 1980.     

Diastereoselective Synthesis of Pyrazolo[1,2-a][1,2,4]triazine Derivatives via Cross-1,3-dipolar Cyclizations of Azaoxyallyl Cations with N,N′-Cyclic Azomethine Imines

A cross-1,3-dipolar cycloaddition reaction of α-halohydroxamates (in situ generated azaoxyallyl cations) with N,N′-cyclic azomethine imines was developed. The synthetic protocol provided facile and rapid access to pyrazolo[1,2-a][1,2,4]triazine derivatives in good yields and excellent diastereoselectivities under mild metal-free conditions.     

Efficient catalytic effects of Lewis acids in the 1,3-dipolar cycloaddition reactions of carbonyl ylides with imines

[reactions: see text] 1,3-Dipolar cycloaddition reactions between imines and carbonyl ylides generated by tandem intramolecular carbenoid-carbonyl cyclizations were found to be effectively catalyzed by Lewis acids (10 mol %). The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)-alpha-diazoacetophenone with imines such as N-[2-(benzyloxy)benzylidene]aniline in the absence of Lewis acid gave no 1,3-dipolar cycloaddition products, but rather the dimeric product of the corresponding carbonyl ylide. In contrast, in the presence of Lewis acids such as Yb(OTf)3, the 1,3-dipolar cycloaddition reactions of the corresponding 1-methoxy-2-benzopyrylium-4-olate proceeded smoothly with several imines, giving in most cases exo-selectivity and no formation of the dimeric product. When Yb(OTf)3 was used as a Lewis acid catalyst, a fundamental catalytic effect was also observed in the cycloaddition reactions of imines with carbonyl ylides generated from 1-diazo-5-phenyl-2,5-pentanedione, 1-diazo-2,5-hexanedione and diazomethyl 2,3,4,5-tetrachloro-6-methoxycarbonylphenly ketone. This efficient catalytic effect can be satisfactorily explained in terms of energetics of the cycloaddition in the absence and the presence of Lewis acid by calculations using the ONIOM (B3LYP/6-31G(d):PM3) method.     

Ruthenium-catalyzed 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols with azides

The 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols 1 with azides in the presence of catalytic [Cp*RuCl₂]_n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles 2 in high yields.     

Cycloaddition of benzoheteroazepine II Reactions and conformations of cycloadducts on1,5-benzothiazepines and 1,5-benzodiazepines with nitrile imine and nitrile oxides

Benzodiazepine and benzothiazepine derivatives have been well known as therapeutically important compounds. Four new tricyclic heterocyclic compounds, 3a,4,5,11-tetrahydro-3H-1,2,4-triazolo[4,3-d] [1, 5]benzothiazepines (3), 3a,4,5,11-tetrahydro-3H,6H-1,2,4-triazolo[4,3-d][1,5]benzodiazepine (4), 3a, 4,5,11-tetrahydro-1,2,4-oxadiazolo[4,5-d] [1,5]benzothiazepines (5, 6) and 3a,4,5,11-tetrahydro-6H-1, 2,4-oxadiazolo[4, 5-d] [ 1, 5 ] benzodiazepines (7,8), have been synthesized by 1,3-dipolar cycloaddition reactions of 2, 3-dihydro-1, 5-benzothiazepines and 2, 3-dihydro-1H-1, 5-benzodiazepine with benzonitrile N-phenylimine and benzonitrile oxides, respectively. The conformations of some cycloadducts and cycloaddition mechanism are described.     

Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles

[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.     

Heterocyclic synthesis using nitrilimines: Part 19. Synthesis of novel 1,3,5-trisubstituted-1,2,4-triazoles

This paper describes the synthesis of a new series of 1,3,5-trisubstituted-1,2,4-triazoles by 1,3-dipolar cycloaddition reaction of C-phenyl-aminocarbonyl-N-arylnitrilimines with guanidine derivatives. The structures of the newly synthesized compounds were elucidated by spectral methods (IR, ¹H NMR, ¹³C NMR and MS spectroscopy) and elemental analysis. The microbial features of the synthesized compounds were studied using well-established methods from the literature.     

1,3-Dipolar cycloaddition of arynes with azomethine imines: synthesis of 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones

A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed. The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild reaction conditions.     

Regioselective synthesis of 1-(2,6-dichloro-4-trifluoromethylphenyl)- 4-alkyl-1H-[1,2,3]-triazoles

A new and efficient method for the synthesis of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkyl-1H-[1,2,3]-triazoles by the room temperature 1,3-dipolar cycloaddition of (2-azido-1,3-dichloro-5-trifluoromethyl)benzene with terminal alkynes in the presence of Cu (I) salt as catalyst is reported. All the reactions gave 1,4-disubstituted products with high regioselectivity, as no 1,5-disubstituted product was formed. The structures of all the title compounds have been confirmed by elemental analysis, 1H- and 13C-NMR and in addition, the structure of compound 5a was investigated by X-ray crystallography.     

Solid-phase synthesis of 1,2-diheterocyclic-substituted (E)-olefins from a supported selenium resin

A library of 1,2,3-triazoles, isoxazoles, 1,2,4-oxadiazoles, and isoxazoline-containing 1,2-di-heterocyclic-substituted compounds with three points of diversity linked by an E double bond were prepared. Key steps include a 1,3-dipolar cycloaddition and Porco's two-step, one-pot condensation and alpha-alkylation reaction of selenium resins.