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Synlett 2010(11): 1617-1622  
DOI: 10.1055/s-0030-1258086
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Metal- and Base-Free Three-Component Reaction of Ynones, Sodium Azide, and Alkyl Halides: Highly Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-NH-Triazoles

Jihui Lia,b, Yuanqing Zhanga,b, Dong Wanga,b, Wen Wanga,b, Tingting Gaoa,b, Lu Wanga,b, Jiting Lic, Guosheng Huanga,b, Baohua Chen*a,b
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou 730000, P. R. of China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University, Gansu Lanzhou 730000, P. R. of China
Fax: +86(9319)8912582; e-Mail: chbh@lzu.edu.cn;
c College of Chemical Engineering, Northwest Minoritise University, Gansu Lanzhou 730030, P. R. of China
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Publication History

Received 7 April 2010
Publication Date:
11 June 2010 (online)

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Abstract

A base- and metal-free three-component reaction of ynones, sodium azide, and alkyl halides is developed for the ­regioselective synthesis of 2,4,5-trisubstituted-1,2,3-triazoles. The method is general, convenient, environmentally benign, atom-­economical, and high-yielding.

Key words

2,4,5-trisubstituted 1,2,3-NH-triazole - three-component reaction - green chemistry - click chemistry

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Three isomers can be readily isolated by column chroma-tography. According to the ref. 5b, N2-alkylation of 4,5-disubstituted 1,2,3-triazoles is the most favorable and the polarity of N2 product is the lowest. Additionally, N1-alkylation was the least favored in almost all cases due to the conformation of 1,4,5-trisubstituted 1,2,3-triazoles. Therefore, we can distinguish the N-1, N-2, and N-3 products easily.

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The CCDC number of 4f (C21H13FN4O3): 752728, the CCDC number of 9e (C21H13ClN4O3): 752729.

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Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-Triazoles - General Procedure for the Reaction between Ynones, Sodium Azide, and Aliphatic Alkyl Halides, Regioselective Sythesis of (2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)methanone (1a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.275 mmol) and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) reacted at r.t. until ynones disappeared by TLC test (about 20 min), then benzyl bromide (0.375 mmol) was added to the mixture and the reaction continued at r.t. for 160 min. Following, to the reaction mixture was added H2O (2 mL), 20% HCl solution (1 mL), and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (40:1, 20:1, 5:1) as eluent to obtain the desired isomers 1a (1a: 63mg), 2a (6 mg), 3a (12 mg), 98% yield.
(2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)-methanone (1a)
Mp 93-95 ˚C. IR: 3063.48, 1661.58, 1597.39 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.03-8.06 (m, 2 H), 7.79-7.82 (m, 2 H), 7.56-7.61 (m, 1 H), 7.35-7.48 (m, 10 H), 5.68 (s, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 187.84, 150.01, 142.24, 137.25, 134.47, 133.30, 130.44, 129.61, 129.07, 128.86, 128.71, 128.60, 128.32, 128.27, 128.17, 59.24. HRMS: m/z calcd for C22H18N3O [M + H]+: 340.14444; found: 340.14426.5b
General Procedure of the Reaction between Ynones, Sodium Azide, and Aryl Halides: Regioselective Synthesis of [2-(4-Nitrophenyl)-5-phenyl-2 H -1,2,3-triazol-4-yl](phenyl) Methanone (2a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.25 mmol), 4-O2NC6H4Cl (0.375 mmol), and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) and reacted at 120 ˚C for 48 h, then H2O (2 mL), 20% HCl solution (1 mL) were added to the reaction mixture after cooled and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (20:1) as eluent to obtain the desired 4a (79 mg, yield 85%); mp 145-147 ˚C. IR: 3074.59, 2918.34, 1652.74, 1593.64 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.33-8.35 (m, 4 H), 8.11-8.13 (m, 2 H), 7.87-7.90 (m, 2 H), 7.64-7.67 (m, 1 H), 7.44-7.54 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 187.45, 151.34, 146.89, 144.36, 143.09, 136.65, 133.90, 130.44, 129.82, 128.69, 128.58, 128.56, 128.52, 125.20, 119.50. MS (EI): m/z = 370 [M]+. Anal. Calcd for C21H14N4O3: C, 68.10; H, 3.81; N, 15.13. Found: C, 68.14; H, 3.79; N, 15.15.6 Copies of NMR spectroscopic, ESI-HRMS analysis, MS (EI) element analysis, and X-ray crystallography are found in the Supporting Information.