Halogen-containing heteroaromatic carbenes of the 1,2,4-triazole series and their transformations

A series of new stable halogenated carbenes, 1-tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidenes, has been synthesized. According to quantum chemical calculations, 4-(2,3,4-trifluorophenyl)-substituted 1-tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidene is the least basic in comparison with the known sterically open stable heteroaromatic carbenes. Upon heating in organic solvents these carbenes undergo a tandem induced reaction thereby forming 5-amidino-1,2,4-triazoles. The interaction of carbenes with benzylidenemalononitrile, propanesultone and phenyl isothiocyanate results in zwitterionic compounds of the 1,2,4-triazole series. The data for X-ray diffraction study of 1-tert-butyl-3-phenyl-4-(2,4-difluorophenyl)-1,2,4-triazol-5-ylidene, its protonated salt, complex with copper(i) iodide, related complex of 1-tert-butyl-3-phenyl-4-(2-trifluoromethylphenyl)-1,2,4-triazol-5-ylidene, and adduct of 1-tert-butyl-3-phenyl-4-(4-bromophenyl)-1,2,4-triazol-5-ylidene and propansultone are given.

A series of new stable halogenated carbenes, 1-tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidenes, has been synthesized.     

Regioselective microwave synthesis and derivatization of 1,5-diaryl-3-amino-1,2,4-triazoles and a study of their cholinesterase inhibition properties

Herein we describe the development of an efficient one-pot regioselective synthesis protocol to obtain N-protected or N-deprotected 1,5-diaryl-3-amino-1,2,4-triazoles from N-acyl-N-Boc-carbamidothioates. This improved protocol using microwave irradiation and low reaction times (up to 1 h) furnished desired compounds in yields ranging from 50 to 84%. This chemistry is useful for a variety of aromatic groups with electronically diverse substituents. The design and correct derivation of the amino group led to compounds able to inhibit cholinesterases with good IC₅₀ of up to 1 μM. Also, the mode of action (mixed-type) and SAR analysis for this series of compounds was described by means of kinetic and molecular modelling evaluations, showing potential for this class of compounds as new scaffolds for this biological activity.

Regioselective microwave synthesis of N-protected and N-deprotected 1,5-diaryl-3-amino-1,2,4-triazoles in up to 1 h. Derivatizations furnish new scaffolds for cholinesterase mixed-type inhibition.     

A practically simple,catalyst free and scalable synthesis of N-substituted ureas in water

A practically simple, mild and efficient method is developed for the synthesis of N-substituted ureas by nucleophilic addition of amines to potassium isocyanate in water without organic co-solvent. Using this methodology, a variety of N-substituted ureas (mono-, di- and cyclic-) were synthesized in good to excellent yields with high chemical purity by applying simple filtration or routine extraction procedures avoiding silica gel purification. The developed methodology was also found to be suitable for gram scale synthesis of molecules having commercial application in large volumes. The identified reaction conditions were found to promote a unique substrate selectivity from a mixture of two amines.

A wide range of amines can be converted to N-substituted ureas using KOCN and aq. HCl without heating, organic solvent or catalyst.     

Two decades of the synthesis of mono- and bis-aminomercapto[1,2,4]triazoles

4-Amino-5-mercapto[1,2,4]triazole and its 3-substituted derivatives have proven to be of biological interest and provide access to a new class of biologically active heterocyclic compounds for biomedical applications. This study will be helpful for scientific researchers interested in the chemistry of bifunctional versatile compounds as it provides a collection of all the methods for the preparation of 3-substituted-4-amino-5-mercapto[1,2,4]triazoles with aliphatic, aromatic, and heterocyclic moieties during the period from 2000 to mid-2020.

4-Amino-5-mercapto[1,2,4]triazole and its 3-substituted derivatives have proven to be of biological interest and provide access to a new class of biologically active heterocyclic compounds for biomedical applications.     

An efficient and atom-economical route to N-aryl amino alcohols from primary amines

In this paper we reported a novel method for generation of N-aryl amino alcohols from N,N-disubstituted picolinamides through reduction/ring-opening reaction with NaBH₄. The N,N-disubstituted picolinamides can be easily obtained from primary amines after convenient condensation with picolinic acid and coupling with cyclic ethers. The whole route proceeded under simple and mild conditions with high efficiency. Picolinic acid can be recovered in the form of piconol after reaction. It indicated an efficient and atom-economical route for the preparation of N-aryl amino alcohols from primary amines.

A novel method for generation of N-aryl amino alcohols from N,N-disubstituted picolinamides through reduction/ring-opening reaction with NaBH₄ was developed.     

A facile,practical and metal-free microwave-assisted protocol for mono- and bis-[1,2,4]triazolo[1,5-a]pyridines synthesis utilizing 1-amino-2-imino-pyridine derivatives as versatile precursors

A facile and effective assembly of several substituted functionalized mono- and bis-[1,2,4]triazolo[1,5-a]pyridines from conveniently attainable 1-amino-2-imino-pyridines has been established. Using microwave irradiation speeds up the reaction efficiently, proceeding with a higher rate and yields than with conventional heating. In the presented protocol, a broad variety of carboxylic acids could be employed effectively to synthesize the respective derivatives via direct metal-free C–N bond construction. Interestingly, other substrates such as aldehydes (or their arylidene malononitriles), phenyl isothiocyanate, glyoxalic acid, and acrylonitriles could also provide the corresponding 1,2,4-triazolo[1,5-a]pyridines successfully. This versatile and convergent approach performs well with both deactivating and activating substrates in an environmentally benign manner compared with other already reported protocols. Other notable merits of the current strategy involve no need for column chromatography, no tedious work-up, and a direct pathway for the fast design of triazolopyridine frameworks. The identity of the newly synthesized compounds was established using several spectroscopic techniques, and X-ray single-crystal tools were employed to authenticate the suggested structures of some representative samples.

A novel and highly efficient, protocol for synthesizing mono- and bis-[1,2,4]triazolo[1,5-a]pyridines has been established utilizing the readily attainable 1-amino-2-imino-pyridines and microwave irradiation as green energy source.     

Catalyst free N-formylation of aromatic and aliphatic amines exploiting reductive formylation of CO2 using NaBH4

Herein, we report a sustainable approach for N-formylation of aromatic as well as aliphatic amines using sodium borohydride and carbon dioxide gas. The developed approach is catalyst free, and does not need pressure or a specialized reaction assembly. The reductive formylation of CO₂ with sodium borohydride generates formoxy borohydride species in situ, as confirmed by ¹H and ¹¹B NMR spectroscopy. The in situ formation of formoxy borohydride species is prominent in formamide based solvents and is critical for the success of the N-formylation reactions. The formoxy borohydride is also found to promote transamidation reactions as a competitive pathway along with reductive functionalization of CO₂ with amine leading to N-formylation of amines.

Herein, we report a sustainable approach for N-formylation of aromatic as well as aliphatic amines using sodium borohydride and carbon dioxide gas.     

Transition metal- and catalyst-free one-pot green method for the synthesis of N-sulfonyl amidines via direct reaction of sulfonyl azides with amines

In this report, a green synthesis of N-sulfonyl amidines via the direct reaction of tertiary or secondary amines with sulfonyl azides is described. Transition metal- and catalyst-free conditions were used for the synthesis of biologically important N-sulfonyl amidines. Further studies showed that the reaction proceeded via in situ aerobic oxidation of amines under reflux conditions.

A green synthesis of N-sulfonyl amidines via the direct reaction of tertiary or secondary amines with sulfonyl azides.     

A facile approach to 2-alkoxyindolin-3-one and its application to the synthesis of N-benzyl matemone

2-Alkoxycarbonylindolin-3-one is synthesized from a methoxyglycine derivative via a 1,2-aza-Brook rearrangement followed by cyclization with bis(trimethylsilyl)aluminum chloride. A short-step synthesis of N-benzyl matemone is successfully carried out using the present indolin-3-one synthesis.

A short-step synthesis of N-benzyl matemone has been successfully carried out using a newly discovered 2-ethoxycarbonylindolin-3-one synthesis.     

Electrophilic activation of nitroalkanes in efficient synthesis of 1,3,4-oxadiazoles

A novel methodology for general and chemoselective preparation of non-symmetric 1,3,4-oxadiazoles is developed. This unusual reaction proceeds via polyphosphoric acid-assisted activation of nitroalkanes towards nucleophilic attack with acylhydrazides.

A novel methodology for chemoselective preparation of non-symmetric 1,3,4-oxadiazoles via PPA-assisted activation of nitroalkanes towards nucleophilic attack with acylhydrazides is developed.     

Practical one-pot amidation of N-Alloc-, N-Boc-, and N-Cbz protected amines under mild conditions

A facile one-pot synthesis of amides from N-Alloc-, N-Boc-, and N-Cbz-protected amines has been described. The reactions involve the use of isocyanate intermediates, which are generated in situ in the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, to react with Grignard reagents to produce the corresponding amides. Using this reaction protocol, a variety of N-Alloc-, N-Boc-, and N-Cbz-protected aliphatic amines and aryl amines were efficiently converted to amides with high yields. This method is highly effective for the synthesis of amides and offers a promising approach for facile amidation.

One-pot efficient transformation of N-Alloc-, N-Boc-, and N-Cbz protected amines to amides was achieved by using 2-chloropyridine and trifluoromethanesulfonyl anhydride as well as Grignard reagent and MgCl₂.     

Rapid synthesis of 3-amino-1H-isochromene from ortho-ynamidyl het(aryl) aldehyde derivatives

A simple and original efficient synthesis of 3-amino-1H-isochromene bearing a bromine atom at the C-1 position via a 6-endo-cyclization approach from in situ generated ortho-ynamidyl het(aryl) aldehyde derivatives is achieved under mild reaction conditions and with good yields. Original ortho-ynamidyl benzaldehyde compounds were also successfully obtained.

Fast synthesis of 3-amino-1H-isochromene from in situ generated ortho-ynamidyl het(aryl) aldehyde derivatives.     

Preparation of 1,2-substituted benzimidazoles via a copper-catalyzed three component coupling reaction

1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts, N-substituted o-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediate N-sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminated via cyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize benzimidazoles.

The intermediate N-sulfonylketenimine occurred with two nucleophilic addition, and the sulfonyl group was easily eliminated through cyclization.     

Synthesis of some new acylhydrazone compounds containing the 1,2,4-triazole structure and their neuritogenic activities in Neuro-2a cells

In the present study, a novel series of acylhydrazone compounds (A0–A10) with the structure of 1,2,4-triazole have been designed and synthesized. In addition, all the synthesized compounds have been evaluated for neuritogenic activity in mouse neuroblastoma (Neuro-2a) cells. Notably, we found that one of these 11 acylhydrazone compounds, compound A5 (2-(4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N′-(2-hydroxybenzylidene)-acetohydrazide) displays excellent neuritogenic activity. Moreover, our present study revealed that compound A5 had the ability to induce neurite outgrowth through the PI3K/Akt and MEK-ERK signaling pathway in Neuro-2a cells. These findings suggest that compound A5 might exert neuritogenic effects and thus may be useful for the treatment of neural repair and regeneration.

In the present study, a novel series of acylhydrazone compounds (A0–A10) with the structure of 1,2,4-triazole have been designed and synthesized.     

Recyclable Cu/C3N4 composite catalyzed AHA/A3 coupling reactions for the synthesis of propargylamines

The heterogeneous Cu/C₃N₄ catalyst was found to be efficient for the synthesis of propargylamines using a three-component coupling reaction of alkynes, CH₂Cl₂ and amines (AHA) without additional base. Moreover, the catalyst also showed highly catalytic activity in the synthesis of C1-alkynylated tetrahydroisoquinolines (THIQs) via an A³ reaction of alkynes, aldehydes and THIQ. The Cu/C₃N₄-catalyzed multicomponent reactions exhibited good functional group tolerance in most examples. Furthermore, the easily prepared Cu/C₃N₄ catalyst could be recovered and reused conveniently over 5 times without losing catalytic activities.

Recyclable Cu/C₃N₄ composite, a highly efficient catalyst for the synthesis of propargylamines via an AHA/A³ reaction.     

Nitrileimines as an alternative to azides in base-mediated click [3 + 2] cycloaddition with methylene active nitriles

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition. The reaction proceeds at room temperature in a short time with base catalysis and no chromatographic purification. High purity products were isolated by simple filtration. The selectivity of the reaction was observed.

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition.     

Facile assembly of 1,5-diazocan-2-ones via cyclization of tethered sulfonamides to cyclopropenes

The sulfonamide moiety was evaluated as an activating and stabilizing functional group in the metal-templated strain release-driven intramolecular nucleophilic addition of amines to cyclopropenes to generate 1,5-diazocan-2-ones.

The sulfonamide moiety was evaluated as an activating and stabilizing functional group in the metal templated strain release-driven intramolecular nucleophilic addition of amines to cyclopropenes to generate 1,5-diazocan-2-ones.     

Impact of an aryl bulky group on a one-pot reaction of aldehyde with malononitrile and N-substituted 2-cyanoacetamide

In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and N-substituted 2-cyanoacetamide in the presence of piperidinium acetate as the catalyst. It involved the Knoevenagel condensation of the aldehyde and malononitrile to produce arylidene malononitrile as an intermediate, which was further treated with N-substituted 2-cyanoacetamide to give 6-amino-2-pyridone-3,5-dicarbonitrile derivatives when the less steric bulky group was involved. High steric hindrance changed the earlier reaction route and gave N-substituted 2-cyanoacrylamides via a slower route.

Impact of aryl bulky group on the one-pot reaction of aldehyde with malononitrile and N-substituted 2-cyanoacetamide is examined in the presence of piperidinium acetate as reusable catalyst.     

Fullerene C60 promoted photochemical hydroamination reactions of an electron deficient alkyne with trimethylsilyl group containing tertiary N-alkylbenzylamines

C₆₀-promoted photoaddition reactions of both trimethylsilyl- and a variety of alkyl group containing tertiary benzylamines (i.e., N-α-trimethylsilyl-N-alkylbenzylamines) with dimethyl acetylenedicarboxylate (DMAD) were carried out to explore the synthetic utility of trimethylsilyl group containing tertiary amines as a substrate in the photochemical hydroamination reactions with dimethyl acetylenedicarboxylate (DMAD). The results showed that photoreactions of all the trimethylsilyl containing N-alkylbenzylamines with DMAD, under an O₂-purged environment, produced non-silyl containing enamines efficiently through a pathway involving addition of secondary amines to DMAD, the former of which are produced by hydrolytic cleavage of in situ formed iminium ions. Exceptionally, five-membered N-heterocyclic rings, pyrroles, could be produced competitively in photoreaction of bulky alkyl (i.e., tert-butyl) group substituted benzylamines through a pathway involving 1,3-dipolar cycloaddition of azomethine ylides to DMAD. Furthermore, C₆₀-sensitized photochemical reactions of non-silyl containing benzylamines with DMAD under oxygenated conditions took place in a less efficient and non-regioselective manner to produce enamine photoadducts. The observations made in this study show that regioselectivity of C₆₀-promoted photochemical reactions of N-α-trimethylsilyl-N-alkylbenzylamines, leading to formation of secondary amines, can be controlled by the presence of the trimethylsilyl group, and that these trimethylsilyl containing tertiary amines can serve as a precursor of secondary amines for hydroamination reactions with a variety of electron deficient acetylenes.

C₆₀-promoted photoaddition reactions of N-α-trimethylsilyl-N-alkylbenzylamines with dimethyl acetylenedicarboxylate (DMAD) were carried out.     

Meso-functionalization of calix[4]arene with 1,3,7-triazapyrene in the design of novel fluorophores with the dual target detection of Al3+ and Fe3+ cations

A meso-functionalization strategy has successfully been applied to the synthesis of novel 1,3,7-triazapyrene derivatives of calixarenes. The key synthetic step in these transformations providing the direct C–C bond formation is nucleophilic substitution of hydrogen (S_N^H) in 1,3,7-triazapyrene. General photophysical characteristics for these macrocyclic compounds, as well as features in emission properties upon addition of various metal cations have been elaborated. Studies using NMR spectroscopy have also shown a mutual effect of both calix[4]arene and 1,3,7-triazapyrene moieties on the coordination process. The complex stoichiometry and binding constants for Al³⁺ and Fe³⁺ guests have been explored with titration experiments.

Novel bifunctional fluorophores with the dual target detection of Al³⁺ and Fe³⁺ cations were synthesized in yields up to 70% via bridge-functionalization of calix[4]arenes with the 1,3,7-triazapyrene scaffold.