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DOI: 10.1055/s-0030-1258086
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
Publication History
Publication Date:
11 June 2010 (online)

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
- Supporting Information for this article is available online:
- Supporting Information (PDF)
- 1a
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References
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.
8The 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.