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

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

References

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7

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.

8

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

9

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.