Synthesis of new 2,3-disubstituted pyridines containing a 1,2,3-triazole in the side-chain via one-pot copper-catalyzed azide-alkyne cycloaddition

A series of 1,2,3-triazole-containing pyridines has been synthesized using the Cu(II) catalyzed ‘click approach’ from sodium azide and corresponding halides. The synthesis involves the amidation of 2-amino-3-hydroxypyridine with benzoyl chloride or cinnamic acid followed by reaction with propargyl bromide to obtain N -(3-(prop-2-ynyloxy)pyridin-2-yl)benzamide 5 and 3-phenyl-N -(3-(prop-2-ynyloxy)-pyridin-2-yl)acrylamide 10 respectively. These compounds underwent one-pot tandem copper-catalyzed azidation and CuAAC reactions to provide compounds 6a-h and 11a-g in moderate to good yields.

0][11] The azidation reaction has been used as a facile method for the transformation of an aryl halide into an aryl azide.Synthetic applications of these ar-yl/alkyl azides have become highly attractive alternatives to establish nitrogen-linked aryl/alkyl scaffolds.This high yield and regioselective reaction has found numerous applications ranging from chemistry to biology.Copper-catalyzed azide-alkyne cycloaddition (Cu-AAC) reaction (click chemistry) has been widely utilized for the synthesis of biologically active 1,2,3-triazole compounds.][14][15][16] Moreover, Cu-promoted azidation and 1,3-dipolar [3 + 2] cycloaddition reactions between azides and terminal alkynes that can be carried out in one-pot synthesis are an attractive method.Herein, we demonstrate an efficient synthesis of novel 2,3-disubstituted pyridines by performing one-pot tandem copper-catalyzed azidation and CuAAC reaction.

Results and Discussion
In our present work, the precursor of N-(3-(prop-2-ynyloxy)-pyridin-2-yl)benzamide 5 was synthesized from an easily available starting material 2-amino-3-hydroxypyridine 1 (Scheme 1).Compound 1 was reacted with benzoyl chloride 2 in the presence of potassium carbonate and acetonitrile using tetrabutylammonium hydrogen sulfate (TBAHSO 4 ) as catalyst at reflux temperature for eight hours to give of N-(3-hydroxy-pyridin-2-yl)benzamide 3 and benzoic acid 2-amino-pyridin-3-yl ester 4 as white solids in 65% and 10% yields respectively.The crude 3 was > 95% pure according to 1 H NMR and was used in the next stage without further purification.The reaction of 3 with propargyl bromide and potassium carbonate in acetonitrile with TBAHSO 4 proceeded at reflux temperature for eight hours to give 5 as a brown coloured liquid in 70% yield.The final step was the synthesis of pyridine analogues containing a 1,2,3-triazole unit 6a-h from 5 and various benzyl halides.A Cu-catalyzed click reaction was performed with 5 and benzyl chloride using sodium azide, copper(II) acetate as catalyst, sodium ascorbate as reducing agent and 1,10-phenanthroline.H 2 O as ligand in EtOH:H 2 O (6:4) at room temperature for 24 h to afford the crude product.Addition of cold water to the reaction mixture resulted in formation of a white precipitate.The crude product was then subjected to column chromatography to afford N-(3-((1-benzyl-1H-1,2,3-triazol-4yl)methoxy)pyridin-2-yl)benzamide 6a in 55% yield (Table 1, entry 1).Similarly, other 1,2,3triazoles (6b-h, Table 1, entry 2-8) were synthesized by the reaction of compound 5 with other substituted benzyl halides and allyl bromide in moderate to good yields (55-82%).The structure of 6a was confirmed by 1 H and 13 C NMR analysis as well as mass spectrometry.In the 1 H NMR spectrum, the C5-proton of the triazole ring resonated at δ 7.57, the protons of the OCH 2 group appeared as a singlet at δ 5.50 and the protons of the NCH 2 group as a singlet at δ 5.29, along with aromatic proton signals.In the 13 C NMR spectra, the OCH 2 carbon appeared at δ 62.7, the NCH 2 carbon appeared at δ 54.2, thje C5-carbon of the triazole was at δ 123.1, and carbonyl group of the amide at δ 164.8, along with other carbons.In EI-MS, peak appeared at m/z = 386.3for (M + +1) ion of 6a.Higher yields of 1,2,3-triazoles were obtained when a fluorine atom was present in the benzyl moiety.Compound 10 underwent a copper-catalyzed click reaction with benzyl chloride using sodium azide in the presence of copper(II) acetate, sodium ascorbate and 1,10phenanthroline.H 2 O in EtOH:H 2 O at room temperature for 20 hours.Addition of cold water to the reaction mixture resulted in a white precipitatesof crude product which was then purified by column chromatography to give N- [3-(1-benzyl-1H-[1,2,3]triazol-4-ylmethoxy)pyridin-2-yl]-3-phenyl-acrylamide 11a in 50% yield (Table 1, entry 9).In the 1 H NMR spectrum of this compound there was a singlet at δ 7.59 for the C5-proton of the triazole ring, proton signals for the OCH 2 at δ 5.64, for the NCH 2 at δ 5.30 and signals for other protons.In the 13 C NMR of 11a, the C5 carbon of the triazole ring resonated at δ 123.2, the OCH 2 carbon resonated at δ 62.4, the NCH 2 carbon at δ 54.3 and amide carbonyl group carbon resonated at δ 164.8, along with signals for the other carbons.In EI-MS, a peak appeared at m/z = 412.2for (M + +1) ion of 11a.An array of novel triazole derivatives 11a-g was synthesized by varying the substitution on the benzyl grojup as well as allyl groups (Table 1, entry 9-15).The overall yields of compounds 6 and 11 were very good and the method is high yielding, simple, convenient and general.Structures of all newly synthesized compounds were characterized by 1 H and 13 C NMR as well as mass spectrometry (Supporting Information).

Conclusions
An efficient and straightforward one pot copper catalyzed azidation and CuAAC reaction for constructing novel 1,2,3-triazole-containing pyridines has been developed.Utilizing easily available reaction materials, a small library of pyridine derivatives carrying side-chain 1,2,3triazoles was rapidly and efficiently synthesized.Overall, we believe that the developed reaction method and novel series of pyridine substituted triazine should be considered as an important advance in medicinal and pharmaceutical chemistry.

Experimental Section
General.All chemicals and solvents were of commercial grade and used without further purification, supplied by spectrochemicals and Sigma-Aldrich.Melting points were determined in open capillaries and are uncorrected.

Table 1 .
Physical data of compounds 6a-h and 11a-g
(100 mg, 0.40 mmol), sodium azide (76 mg, 1.17 mmol) and the benzyl halide (0.40 mmol) were added to the reaction mixture with stirring at room temperature.Reaction time varied from 10 min to 24 h for various benzyl halides.After completion of the reaction (monitored by TLC), ice cold water was added to the reaction mixture till the product precipitated, it was filtered off and washed with cold water.The crude product was then dried under vacuum.