Preparation of Novel 1,2,3-Triazoles and a Comparative Study Involving Two Recent Methods for 1,2,3-Triazole Synthesis

Abstract

The syntheses of three novel 1,2,3-triazoles and a comparative study involving two recent methods of 1,2,3-triazole synthesis by diazo group transfers to enaminones, 5,7-dinitro-3-diazo-isatine and mesyl azide, are described. It was observed that the former is the more general and promising method for the synthesis of any 1,2,3-triazole but, when both methods work the mesyl azide one generally gives better yields.     

High-load, soluble oligomeric benzenesulfonyl azide: application to facile diazo-transfer reactions

The development of a high-load, soluble oligomeric sulfonyl azide using ROM polymerization is reported. The utility in diazo transfer reactions with active methylene compounds is demonstrated using an efficient protocol, with most reactions showing completion in 30 min. The sulfonamide byproduct, being insoluble in the reaction solvent, can be completely removed by simple filtration through a silica gel SPE cartridge.     

Synthesis and transformations of substituted 4,6-dimethylpyrazolo[3,4-b]pyridyl-3-azides and -sulfonyl chlorides

Diazotization of the amino group of 3-amino-4,6-dimethylpyrazolo[3,4-b]pyrimidines and subsequent replacement of the diazo group in the formed diazonium chlorides by an azide group gave the corresponding 3-azido derivatives. Their reactions with active methylene compounds have been studied. Substitution of the diazo group by a sulfo group gave the related 4,6-dimethylpyrazolo-[3,4-b]pyridyl-3-sulfonyl chlorides and sulfonylamides. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1556–1565, October, 2008.     

Azidoimidazolinium Salts: Safe and Efficient Diazo‐transfer Reagents and Unique Azido‐donors

2‐Azido‐1,3‐dimethylimidazolinium chloride (ADMC) and its corresponding hexafluorophosphate (ADMP) were found to be efficient diazo‐transfer reagents to various organic compounds. ADMC was prepared by the reaction of 2‐chloro‐1,3‐dimethylimidazolinium chloride (DMC) and sodium azide. ADMP was isolated as a crystal having good thermal stability and low explosibility. ADMC and ADMP reacted with 1,3‐dicarbonyl compounds under mild basic conditions to give 2‐diazo‐1,3‐dicarbonyl compounds in high yields, which were easily isolated in virtue of the high water solubility of the by‐products. ADMP showed high diazo‐transfer ability to primary amines even in the absence of metal salt such as Cu(II). Using this diazotization approach, various alkyl/aryl azides were directly obtained from their corresponding primary amines in high yields. Furthermore, naphthols reacted with ADMC to give the corresponding diazonaphthoquinones in good to high yields. In addition, 2‐azido‐1,3‐dimethylimidazolinium salts were employed as azide‐transfer and migratory amidation reagents.     

Reactions of Thioketones Possessing a Conjugated CC Bond with Diazo Compounds

The reactions of several thioketones containing a conjugated C?C bond with diazo compounds were investigated. All of the selected compounds reacted via a 1,3‐dipolar cycloaddition with the C?S group and subsequent N₂ elimination to yield thiocarbonyl ylides as intermediates, which underwent a 1,3‐dipolar electrocyclization to give the corresponding thiirane 25 , or, by a subsequent desulfurization, to give the olefins 33a and 33b . None of the intermediate thiocarbonyl ylides reacted via 1,5‐dipolar electrocyclization. If the α,β‐unsaturated thiocarbonyl compound bears an amino group in the β‐position, the reactions with diazo compounds led to the 2,5‐dihydrothiophenes 40a – 40d . In these cases, the proposed mechanism of the reactions led once more to the thiocarbonyl ylides 36 and thiiranes 38 , respectively. The thiiranes reacted via an S_Ni′‐like mechanism to give the corresponding thiolate/ammonium zwitterion 39 , which underwent a ring closure to yield the 2,5‐dihydrothiophenes 40 . Also in these cases, no 1,5‐dipolar electrocyclization could be observed. The structures of several key products were established by X‐ray crystallography.     

Synthesis and use of a cost-effective,aqueous soluble diazo transfer reagent – m-carboxybenzenesulfonyl azide

Herein, we report the preparation and use of m-carboxybenzenesulfonyl azide as a diazo transfer reagent. This compound is an inexpensive and potentially scalable alternative to many of the diazo transfer reagents currently available, most of which have hazards associated with their use. Its usefulness and suitability as a diazo transfer reagent was assessed on the basis of cost, safety and its effectiveness in diazo transfer to a variety of different substrates.     

Synthesis and thermal properties of novel calix[4]arene derivatives containing 1,2,3-triazole moiety via K2CO3-catalyzed 1,3-dipolar cycloaddition reaction

Two calix[4]arene derivatives containing 1,2,3-triazole moiety were synthesized via K2CO3-catalyzed1,3-dipolar cycloaddition reaction between calix[4]arene-based azide and active methylene compounds in good yields.The structures of the two compounds synthesized herein were fully confirmed by 1HNMR,,（13）C NMR,and MS（ESI）.The thermal analysis showed that the mass losses of the synthesized compounds 4 and 5 containing 1,2,3-triazole groups are similar to each other.     

An N-Trifluoromethylation/Cyclization Strategy for Accessing Diverse N-Trifluoromethyl Azoles from Nitriles and 1,3-Dipoles

N-Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N-CF₃ azoles relies on the functional group interconversions but suffers from tedious N-pre-functionalization and unfriendly agents. Introduction of the CF₃ onto the nitrogen of heterocycles provides a direct route to such motifs, but the N-trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF₃-containing synthons for constructing N-CF₃ azoles. The approach involves the N-trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N-CF₃ nitrilium derivatives and 1,3-dipoles. PhICF₃Cl was an effective CF₃ source for the transformation. As a result, a generic platform is established to divergently synthesize N-trifluoromethylated tetrazoles, imidazoles, and 1,2,3-triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.     

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.     

An improved procedure for the preparation of 1-benzyl-1H-1,2,3-triazoles from benzyl azides

A procedure for the preparation of substituted 1-benzyl-1H-1,2,3-triazoles from benzyl azides under very mild conditions is described. The method provides improved yields and extends the scope of the Dimroth Reaction to other types of active methylene compound to those previously used. Benzyl azides react with active methylene compounds in dimethyl sulphoxide catalysed by potassium carbonate at 35–40° to give 1H-1,2,3-triazoles usually in good yield. Acetonitrile derivatives gave 5-amino-1H-1,2,3-triazoles whereas diethyl malonate gave 5-hydroxy-1H-1,2,3-triazoles. 1H-1,2,3-Triazole-4-carboxylate esters and 1H-1,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and β-diketones respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-1H-1,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds which did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate and ethyl nitroacetate.     

Neue 1,5-benzodiazepinderivate

The 1,5-benzodiazepines 1,6 add benzoylphenylketene ( 3 ) across the azomethine bond to produce the 1,3-oxazino[3,2-a]-1,5-benzodiazepines 4,5,7. In 6a azo coupling occurs at the exocyclic methyl group leading to the formation of 10 , while diazo group transfer takes place at the cyclic methylene group to afford 11. The latter compounds react with 3 without loss of the diazo nitrogen, yielding the diazo-oxazinobenzodiazepine 12 ; whereas, by interaction with phenyl isocyanate, the pyrazolo[4,3-b]-1,5-benzodiazepine 14 is formed.     

One-pot procedure for diazo transfer and azide-alkyne cycloaddition: triazole linkages from amines

[reaction: see text] A one-pot reaction for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (sometimes called click reaction) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields from a variety of readily available amines without the need for isolation of the azide intermediates. The reaction has a broad scope and is especially practical for the synthesis of multivalent structures because compounds substituted with multiple azides are potentially unstable.     

Reactions of (1E)‐Buta‐1,3‐dien‐1‐yl Acetate with Diazocarbonyl Compounds

Carbene transfer to appropriate substrates is a highly versatile tool for the construction of carbon frameworks with increased functional and structural complexity. In this study, some novel cyclopropane derivatives were synthesized via carbenoid reactions and their further reactivities were investigated. (1E)‐Buta‐1,3‐dien‐1‐yl acetate was reacted with four different diazocarbonyl compounds, ethyl diazoacetate, dimethyl diazomalonate, 1‐diazo‐1‐phenylpropan‐2‐one, and methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate, in the presence of two catalysts. All synthesized substituted cyclopropanes were obtained chemoselectively with respect to less‐hindered C?C bonds. Under the applied conditions, while cyclopropanes 7a and 7d underwent further reactions, cyclopropanes 7b and 7c were stable enough. Cyclopropanes 7a and an additional equivalent of ethyl diazoacetate yielded polyfunctionalized cyclohexenes. Cyclopropanes from methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate yielded polyfunctionalyzed cycloheptadiene isomers by Cope rearrangement.     

Synthesis of chalcone precursor via Cu(I) catalyzed 1,3-dipolar reaction of functionalized acetylene and pyrazole embedded dipole

A new class of functionalized pyrazole bearing 1,2,3-triazole has been synthesized via Cu(I) mediated 1,3-dipolar cycloaddition of pyrazole bearing azide with various aromatic/heteroaromatic bearing terminal dipolarophile (acetylene). Structures of the newly synthesized compounds were explicated by analytical and spectral analysis. All the newly synthesized compounds were evaluated for their in-vitro antibacterial and antioxidant activity. Among the synthesized compound, triazole bearing 2,5-thiazolidinone 5b (20 ± 0.70) and triazole bearing thiocarboamide 5e (19 ± 0.70) showed good antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, respectively. The newly synthesized compounds further tested for their ability to bleach DPPH radical using DPPH scavenging assay. Among the synthesized compounds 1,2,3-triazole bearing 2,5-thiazolidinone 5b (58.81%) exhibited good DPPH scavenging activity compared to the rest of the compounds. From the X-ray and Hirshfield analysis, it was observed that compound 3 , crystallizes in a triclinic crystal system with a P-1 space group. The major intercontacts present in these molecules are H…H (39.7%), C…H (23.9%), N…H (20.3%).     

1,5‐Dipolar Electrocyclizations of Thiocarbonyl Ylides Bearing CN Groups: Reactions of N‐[(Dimethylamino)methylene]thiobenzamide and 2‐(Dimethylhydrazono)‐1‐phenylethane‐1‐thione with Diazo Compounds

The reactions of thiobenzamide 8 with diazo compounds proceeded via reactive thiocarbonyl ylides as intermediates, which underwent either a 1,5‐dipolar electrocyclization to give the corresponding five membered heterocycles, i.e., 4‐amino‐4,5‐dihydro‐1,3‐thiazole derivatives (i.e., 10a, 10b, 10c , cis‐ 10d , and trans‐ 10d ) or a 1,3‐dipolar electrocyclization to give the corresponding thiiranes as intermediates, which underwent a S_Ni′‐like ring opening and subsequent 5‐exo‐trig cyclization to yield the isomeric 2‐amino‐2,5‐dihydro‐1,3‐thiazole derivatives (i.e., 11a, 11b, 11c , cis‐ 11d , and trans‐ 11d ). In general, isomer 10 was formed in higher yield than isomer 11 . In the case of the reaction of 8 with diazo(phenyl)methane ( 3d ), a mixture of two pairs of diastereoisomers was formed, of which two, namely cis‐ 10d and trans‐ 10d , could be isolated as pure compounds. The isomers cis‐ 11d and trans‐ 11d remained as a mixture. In the reactions of the thioxohydrazone 9 with diazo compounds 3b and 3d , the main products were the alkenes 18 and 23 , respectively. Their formation was rationalized by a 1,3‐dipolar electrocyclization of the corresponding thiocarbonyl ylide and subsequent desulfurization of the intermediate thiiran. As minor products, 2,5‐dihydro‐1,3‐thiazol‐5‐amines 21 and 24 were obtained, which have been formed by 1,5‐dipolar electrocyclization of the thiocarbonyl ylide, followed by a 1,3‐shift of the dimethylamino group.     

Potential ambifunctionality of 2-azidopyrido[1,2-a] pyrimidin-4-one

2-Azidopyrido[1,2-a]pyrimidin-4-one can exit only in the azido form and undergoes cyclo-addition reaction with 1,3-dicarbonyl compounds to form 1,2,3-triazole derivatives. Under the influence of bases or hydrochloric acid the carbonyl group is attacked with subsequent opening of the pyrimidine ring. This causes an immediate cyclization of the azide group to give a tetrazolo derivative. In a similar way a triazole ring can be formed from the appropriate hydrazino derivatives of pyrido[1,2-a]pyrimidin-4-one.     

Efficient One-Pot,Four-Component Synthesis of 1,2,3-Triazole-Linked Tetrahydrobenzo[b]pyrans

A one-pot procedure has been developed for the synthesis of (1,2,3-triazolyl) methoxyphenyl tetrahydro-5-oxo-4H-chromene derivatives by concurrent reaction of aryloxy propargylated aldehydes, various azides, active methylene compounds, and 1,3-cyclohexanediones using catalytic amounts of Cu(OAc)₂ / sodium ascorbate and diammonium hydrogen phosphate in aqueous ethanol media. Excellent conversion of starting materials was achieved to the desired (1,2,3-triazolyl) methoxyphenyl tetrahydro-5-oxo-4H-chromene products.     

Tandem Knoevenagel-[3+2] cycloaddition-elimination reactions: one-pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles

Sodium azide has been found to catalyse Knoevenagel condensation between aromatic aldehyde and cyano compound with active methylene hydrogens and this has led to a successful route for the one pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles from aldehydes through Knoevenagel-[3+2]cycloaddition-elimination sequence. In the formation of 5-aryl-2H-1,2,3-triazole-4-carbonitrile derivatives, the reaction has been found to occur efficiently in water.     

1D Azido bridged Cu(II) coordination polymer with 1,3-oxazolidine ligand as an effective catalyst for green click synthesis of 1,2,3-triazoles

A new 1D azido bridged Cu(II) coordination polymer with 1,3-oxazolidine based ligand, [Cu(H₃L)(μ_1,3-N₃)(N₃)]_n ( 1 ), was synthesized and characterized by elemental analysis and spectroscopic methods. The structure of 1 was also determined by single crystal X-ray analysis which indicated the 1D polymeric chain is generated by end-to-end (EE) azide bridge. The obtained compound was employed as catalyst in green click synthesis of β-hydroxy-1,2,3-triazoles from one-pot three-component cycloaddition reaction of epoxide-azide-alkyne. The catalytic reactions were carried out in water as a safe, cheap and green solvent. The catalytic studies indicated that the obtained 1D azido bridged Cu(II) coordination polymer is an active catalyst for preparing β-hydroxy-1,2,3-triazoles. The effect of temperature on the selectivity of the catalytic system was studied and the results indicated this catalytic system has high selectivity at low temperatures. The structure the product obtained from the reaction of 2,3-epoxypropylphenylether, azide and 1-ethynyl-1-cyclohexanol ( T4 ) was determined by single crystal X-ray analysis. The results indicate Cu(II) coordination polymers can be a new class of catalytic systems for green click synthesis of 1,2,3-triazoles.     

An efficient, inexpensive, and shelf-stable diazotransfer reagent: imidazole-1-sulfonyl azide hydrochloride

The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compounds. Crucially, this reagent can be prepared in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently crystalline.