A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

An Efficient and Convenient Synthesis of Ethyl 1‐(4‐Methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate

The “click chemistry” of using organic azides and terminal alkynes is arguably the most efficient and straightforward route to the synthesis of 1,2,3‐triazoles. In this paper, an alternative and direct access to ethyl 1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate is described. Treatment of ethyl diazoacetate with 4‐methoxyaniline derived aryl imines in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene provided fully substituted 1,2,3‐triazoles in good to high chemical yields. The base‐mediated reaction tolerates various substituted phenyl imines as well as ethyl diazoacetate or the more bulky diazoacetamide. A reasonable mechanism is proposed that involves the addition of an imine nitrogen atom to the terminal nitrogen atom of the diazo compound, followed by aromatization to give the 1,2,3‐triazole. The presence of the 4‐carboxy group is advantageous as it can be easily transformed into other functional groups.     

Syntheses of 1‐(4‐methylsulfonylphenyl)‐5‐aryl‐1,2,3‐triazoles and ‐(4‐aminosulfonylphenyl)‐5‐aryl‐1,2,3‐triazoles

Condensation of 4‐methylsulfonylaniline with aryl aldehyde in ethanol‐tetrahydrofuran afforded the imino compound 3 . 1,3‐Cycloaddtion of diazomethane with compound 3 followed by oxidazation of the triazoline 4 with potassium permanganate gave 1‐(4‐methylsulfonylphenyl)‐5‐aryl‐1,2,3‐triazoles 5 . Similarly, condensation of 4‐(N,N‐dibenzylaminosulfonyl)aniline with aryl aldehyde followed by 1,3‐cycloaddition of diazomethane with the imino compound 11 and the subsequent oxidation of triazoline 12 with potassium permanganate yielded the triazole 13 . Debenzylation of compound 13 with sulfuric acid gave the desired compound 1‐(4‐aminosulfonylphenyl)5‐aryl‐1,2,3‐triazoles 14 .     

2‐Triazolylpyrimido[1,2,3‐cd]purine‐8,10‐diones via 1,3‐dipolar cycloadditions to 2‐ethynylpyrimido[1,2,3‐cd]purine‐8,10‐dione

This paper presents the synthesis of a series of 5,6‐dihydro‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ring system derivatives with a [1,2,3]triazole ring bonded in position 2. The procedure is based on cycloaddition of substituted alkyl azides to the terminal triple bond of 5,6‐dihydro‐2‐ethynyl‐9‐methyl‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 4 ). This cycloaddition produced two regioisomers ?5,6‐dihydro‐9‐methyl‐2‐(1‐substituted‐1H‐[1,2,3]triazol‐5‐yl)‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 7 ) and 2‐(1‐substituted‐1H‐[1,2,3]triazol‐4‐yl) derivative 8 . The required 2‐ethynyl deriva tive 4 was obtained from the starting 2‐unsubstituted compound 1 by bromination to yield the 2‐bromo derivative 2 , which was converted by Sonogashira reaction to trimethylsilylethyne 3 and finally, the protective trimethylsilyl group was removed by hydrolysis.     

Efficient Atropodiastereoselective Access to 5,5′‐Bis‐1,2,3‐triazoles: Studies on 1‐Glucosylated 5‐Halogeno 1,2,3‐Triazoles and Their 5‐Substituted Derivatives as Glycogen Phosphorylase Inhibitors

Whereas copper‐catalyzed azide–alkyne cycloaddition (CuAAC) between acetylated β‐D ‐glucosyl azide and alkyl or phenyl acetylenes led to the corresponding 4‐substituted 1‐glucosyl‐1,2,3‐triazoles in good yields, use of similar conditions but with 2 equiv CuI or CuBr led to the 5‐halogeno analogues (>71 %). In contrast, with 2 equiv CuCl and either propargyl acetate or phenyl acetylene, the major products (>56 %) displayed two 5,5′‐linked triazole rings resulting from homocoupling of the 1‐glucosyl‐4‐substituted 1,2,3‐triazoles. The 4‐phenyl substituted compounds (acetylated, O‐unprotected) and the acetylated 4‐acetoxymethyl derivative existed in solution as a single form (d.r.>95:5), as shown by NMR spectroscopic analysis. The two 4‐phenyl substituted structures were unambiguously identified for the first time by X‐ray diffraction analysis, as atropisomers with aR stereochemistry. This represents one of the first efficient and highly atropodiastereoselective approaches to glucose‐based bis‐triazoles as single atropisomers. The products were purified by standard silica gel chromatography. Through Sonogashira or Suzuki cross‐couplings, the 1‐glucosyl‐5‐halogeno‐1,2,3‐triazoles were efficiently converted into a library of 1,2,3‐triazoles of the 1‐glucosyl‐5‐substituted (alkynyl, aryl) type. Attempts to achieve Heck coupling to methyl acrylate failed, but a stable palladium‐associated triazole was isolated and analyzed by ¹H NMR and MS. O‐Unprotected derivatives were tested as inhibitors of glycogen phosphorylase. The modest inhibition activities measured showed that 4,5‐disubstituted 1‐glucosyl‐1,2,3‐triazoles bind weakly to the enzyme. This suggests that such ligands do not fit the catalytic site or any other binding site of the enzyme.     

Synthesis of New 1,2,3‐Triazole Derivatives Possessing 4H‐Pyran‐4‐one Moiety by 1,3‐Dipolar Cycloaddition Reaction of Azidomethyl Phenylpyrone with Various Alkynes

A series of new 1,2,3‐triazole derivatives were synthesized by 1,3‐dipolar cycloaddition reaction of 2‐(4‐azidomethylphenyl)‐6‐phenyl‐4H‐pyran‐4‐one with different alkynes in 40–71% yields. In the case of terminal alkynes, the reaction was proceeded in the presence of Cu(I) catalyst. The structure of the synthesized compounds were confirmed by FTIR, ¹H‐NMR, and ¹³C‐NMR spectroscopy and elemental analysis.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

An Efficient Synthesis of Mono and Bis‐1,2,3‐triazole AZT Derivatives via Copper(I)‐catalyzed Cycloaddition

An efficient synthesis of novel mono and bis‐1,2,3‐triazoles 3′‐azido‐2′‐deoxythymidine (AZT) derivatives via copper(I)‐catalyzed 1,3‐dipolar cycloaddition reaction is described. Starting from AZT and terminal alkyne derivatives, mono and bis‐1,2,3‐triazole AZT derivatives are regioselectively obtained in good yields under mild conditions using CuSO4·5H2O and sodium ascorbate as a catalyst system, and t‐BuOH/H₂O (1:1, v/v) as a co‐solvent. The structures of these compounds were elucidated by IR, HR MS and NMR.     

Highly Efficient Cycloaddition Reaction of 1,3‐Diynes with Sodium Azide: A New Way to 5‐Substituted‐4‐acetylene‐1H‐1,2,3‐triazoles

A cycloaddition reaction of a range of 1,3‐diynes with sodium azide has been realized, which provided 5‐substituted‐4‐acetylene‐1H‐1,2,3‐triazoles in 75–99% yields. The chemical structures of the new compounds 3 are established by IR, NMR, Mass, and HRMS.     

Synthesis of 5H‐1,2,3‐triazolo[4,3‐a][2]benzazepines from the baylis‐hillman adducts of 2‐alkynylbenzaldehydes

The facile synthesis of 5H‐1,2,3‐triazolo[4,3‐a][2]benzazepines 5a‐d by the intramolecular 1,3‐dipolar cycloaddition reaction of 2‐alkynylphenylallyl azides 4a‐d is described. The latter were readily obtained from 2‐alkynylbenzaldehydes 1a‐d through the Baylis‐Hillman adducts 2a‐d followed by acetylation to compounds 3a‐d and nucleophilic substitution by azide to compounds 4a‐d.     

Synthesis of 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines as precursors for novel tetraazapentalene derivatives

A series of 1‐substituted 4,5‐diformyl‐[1,2,3]triazole derivatives were prepared by 1,3‐dipolar cyclo‐addition of aryl azides with acetylene dicarboxaldehyde mono‐diethylacetal. The triazoles were readily converted into 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines in good yields. The 1‐(2‐nitrophenyl)‐[1,2,3]triazolo[4,5‐d]pyridazine was found to be a useful intermediate for the generation of the novel 5H‐benzo[1,2,3]triazolo[1′,2′:1,2]triazolo[4,5‐d]pyridazin‐6‐ium inner salt ring system.     

The structures of 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles related to J147, a drug for treating Alzheimer's disease

J147 [N‐(2,4‐dimethylphenyl)‐2,2,2‐trifluoro‐N′‐(3‐methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X‐ray structures of seven new 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles, namely 1‐(3,4‐dimethylphenyl)‐4‐phenyl‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₇H₁₄F₃N₃, 1 ), 1‐(3,4‐dimethylphenyl)‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 2 ), 1‐(3,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 3 ), 1‐(2,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 4 ), 1‐[2,4‐bis(trifluoromethyl)phenyl]‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₀F₉N₃O, 5 ), 1‐(3,4‐dimethoxyphenyl)‐4‐(3,4‐dimethoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₉H₁₈F₃N₃O₄, 6 ) and 3‐[4‐(3,4‐dimethoxyphenyl)‐5‐(trifluoromethyl)‐1H‐1,2,3‐triazol‐1‐yl]phenol (C₁₇H₁₄F₃N₃O₃, 7 ), have been determined and compared to that of J147 . B3LYP/6‐311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147 , and to examine the correlation between hydrazone J147 and the 1,2,3‐triazoles, both bearing a CF₃ substituent. Using MEPs, it was found that the minimum‐energy conformation of 4 , which is nearly identical to its X‐ray structure, is closely related to one of the J147 seven minima.     

2‐Azido‐2‐deoxycellulose: Synthesis and 1,3‐Dipolar Cycloaddition

Chitosan ( 1 ) was prepared by basic hydrolysis of chitin of an average molecular weight of 70000 Da, ¹H‐NMR spectra indicating almost complete deacetylation. N‐Phthaloylation of 1 yielded the known N‐phthaloylchitosan ( 2 ), which was tritylated to provide 3a and methoxytritylated to 3b . Dephthaloylation of 3a with NH₂NH₂?H₂O gave the 6‐O‐tritylated chitosan 4a . Similarly, 3b gave the 6‐O‐methoxytritylated 4b . CuSO₄‐Catalyzed diazo transfer to 4a yielded 95% of the azide 5a , and uncatalyzed diazo transfer to 4b gave 82% of azide 5b . Further treatment of 5a with CuSO₄ produced 2‐azido‐2‐deoxycellulose ( 7 ). Demethoxytritylation of 5b in HCOOH gave 2‐azido‐2‐deoxy‐3,6‐di‐O‐formylcellulose ( 6 ), which was deformylated to 7 . The 1,3‐dipolar cycloaddition of 7 to a range of phenyl‐, (phenyl)alkyl‐, and alkyl‐monosubstituted alkynes in DMSO in the presence of CuI gave the 1,2,3‐triazoles 8 – 15 in high yields.     

A simple and efficient synthesis of novel N,N′‐bis (1H‐pyrrol‐1‐yl)‐1‐[2‐(2‐aryl‐5‐methyl‐3‐oxo‐2,4‐dihydro‐3H‐1,2,4‐triazol‐4‐yl)ethyl]‐1H‐1,2,3‐triazole‐4,5‐dicarboxamides

One‐pot reaction of 3‐aryl‐5‐methyl‐1,3,4‐oxadiazolin‐2‐ones 1a‐g with ethanolamine yielded the 4‐(2‐hydroxyethyl)‐2‐aryl‐5‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazolin‐3‐ones 2a‐g which were converted to the azido compounds 6a‐g . These azides on 1,3‐dipolar cycloaddition with DMAD afforded the dimethyl‐1‐[2‐(2‐aryl‐5‐methyl‐3‐oxo‐1,2,4‐triazol‐4‐yl)ethyl]‐1H‐1,2,3‐triazol‐4,5‐dicarboxylates 7a‐g which on conversion to bishydrazides 8a‐g and further cyclisation with 2,5‐hexanedione afforded the title compounds 9a‐g . This new short route for the so far unkown bis‐(triazolinone‐triazole)ethanes involves mild and convergent 1,3‐dipolar cycloaddition reaction yielding overall good yields of the products.     

Metal‐Free Route for the Synthesis of 4‐Acyl‐1,2,3‐Triazoles from Readily Available Building Blocks

Functionalized 1,2,3‐triazole heterocycles have been known for a long time and hold an extraordinary potential in diverse research areas ranging from medicinal chemistry to material science. However, the scope of therapeutically important 1‐substituted 4‐acyl‐1H‐1,2,3‐triazoles is much less explored, probably due to the lack of synthetic methodologies of good scope and practicality. Here, we describe a practical and efficient one‐pot multicomponent reaction for the synthesis of α‐ketotriazoles from readily available building blocks such as methyl ketones, N,N‐dimethylformamide dimethyl acetal, and organic azides with 100 % regioselectivity. This reaction is enabled by the in situ formation of an enaminone intermediate followed by its 1,3‐dipolar cycloaddition reaction with an organic azide. We effectively utilized the developed strategy for the derivatization of various heterocycles and natural products, a protocol which is difficult or impossible to realize by other means.     

A General Proline‐Catalyzed Synthesis of 4,5‐Disubstituted N‐Sulfonyl‐1,2,3‐Triazoles from 1,3‐Dicarbonyl Compounds and Sulfonyl Azide

An efficient proline‐catalyzed synthesis of 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles has been accomplished from 1,3‐dicarbonyl compounds and sulfonyl azides. The developed reaction is suitable for various symmetrical and unsymmetrical 1,3‐dicarbonyl compounds, tolerates various functional groups and affords 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles in good yield with excellent regioselectivity. Rhodium‐catalyzed denitrogenative functionalization of 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles further demonstrates their utility in organic synthesis.     

Nitropyridyl isocyanates in 1,3‐dipolar cycloaddition reactions

The reactivity of 3‐nitro‐4‐pyridyl isocyanate ( 7 ) and 5‐nitropyridin‐2‐yl isocyanate ( 9 ) in 1,3‐dipolar cycloaddition reactions with azides and pyridine N‐oxides has been investigated. 1,3‐Dipolar cycloaddition to trimethylsilylazide (TMSA) afforded the respective tetrazolinones, 1‐(3‐nitropyridin‐4‐yl)‐1H‐tetrazol‐5(4H)one ( 8 , 50 %) and 1‐(5‐nitropyridin‐2‐yl)‐1H‐tetrazol‐5(4H)one ( 11 , 64 %). Respectively, 1,3‐dipolar cycloaddition of nitropyridyl isocyanates 7 and 9 to 3,5‐dimethylpyridine N‐oxide ( 14 ), 3‐methylpyridine N‐oxide ( 21 ) and pyridine N‐oxide ( 22 ) gave the substituted amines, 3,5‐dimethyl‐N‐(3‐nitropyridin‐4‐yl)pyridin‐2‐amine ( 17 ), 3,5‐dimethyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 20 ), N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 24 ), 5‐methyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 23 ) and 3‐methyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 25 ) in 65 ‐ 80 % yield, obtained by cycloaddition, rearrangement and decarboxylation. The results demonstrate that the nitropyridyl isocyanates ( 7,9 ) readily undergo 1,3‐dipolar cyloaddition reactions similar to phenyl isocyanates.     

One‐Pot,Three‐Component Synthesis of 1‐(2‐Hydroxyethyl)‐1H‐1,2,3‐triazole Derivatives by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of 2‐Azido Alcohols and Terminal Alkynes under Mild Conditions in Water

A safe, efficient, and improved procedure for the regioselective synthesis of 1‐(2‐hydroxyethyl)‐1H‐1,2,3‐triazole derivatives under ambient conditions is described. Terminal alkynes reacted with oxiranes and NaN₃ in the presence of a copper(I) catalyst, which is prepared by in situ reduction of the copper(II) complex 4 with ascorbic acid, in H₂O. The regioselective reactions exclusively gave the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazoles in good to excellent yields. This procedure avoids the handling of organic azides as they are generated in situ, making this already powerful click process even more user‐friendly and safe. The remarkable features of this protocol are high yields, very short reaction times, a cleaner reaction profile in an environmentally benign solvent (H₂O), its straightforwardness, and the use of nontoxic catalysts. Furthermore, the catalyst could be recovered and recycled by simple filtration of the reaction mixture and reused for ten consecutive trials without significant loss of catalytic activity. No metal‐complex leaching was observed after the consecutive catalytic reactions.     

Acid Catalyzed tert‐Butylation and Tritylation of 4‐Nitro‐1,2,3‐triazole: Selective Synthesis of 1‐Methyl‐5‐nitro‐1,2,3‐triazole via 1‐tert‐Butyl‐4‐nitro‐1,2,3‐triazole

4‐Nitro‐1,2,3‐triazole was found to react with tert‐butanol in concentrated sulfuric acid to yield 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole as the only reaction product, whereas tert‐butylation and tritylation of 4‐nitro‐1,2,3‐triazole in presence of catalytic amount of sulfuric acid in benzene was found to provide mixtures of isomeric 1‐ and 2‐alkyl‐4‐nitro‐1,2,3‐triazoles with predominance of N2‐alkylated products. A new methodology for preparation of 1‐alkyl‐5‐nitro‐1,2,3‐triazoles from 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole via exhaustive alkylation followed by removal of tert‐butyl group from intermediate triazolium salts was demonstrated by the example of preparation of 1‐methyl‐5‐nitro‐1,2,3‐triazole.     

‘Click Synthesis’ of 1H‐1,2,3‐Triazolyl‐Based Oxiconazole (=(1Z)‐1‐(2,4‐Dichlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone O‐[(2,4‐Dichlorophenyl)methyl]oxime) Analogs

The ‘click synthesis’ of some oxiconazole analogs 5a – 5v having 1H‐1,2,3‐triazolyl residues by Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride ( 1 ) followed by azidation of 2‐chloro‐1‐phenylethanone oxime ( 2 ) provided azido ketoxime 3 . The CuI‐catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4‐substituted (at the triazole) 2‐(1H‐1,2,3‐triazol‐1‐yl)‐1‐phenylethanone oximes 4a – 4i . The O‐alkylation of 4a – 4i with various alkyl halides resulted in the formation of the target molecules 5a – 5v in good yields.