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CuLn-1
O
R1
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O
R1
N
N
R2
CuLn-2
N
N
N
N
O
N
C
R2
N
N
R2
B
R1
CuLn-2
O
[LnCu]+
N+ N-
R2
N
A
R1
CuLn-1
TsO
H
R1
N
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O
O
N+ N-
NaN3
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R2
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Figure 1. Mechanistic pathway for the formation of 1,2,3-triazoles.
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them safely. Initial formation of the
was unambiguously confirmed by reacting equimolar quantities
of -tosyloxy ketone and sodium azide in aqueous PEG 400. After
the formation of
a-azido ketone intermediate
a
21. General procedure for the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles (2a–p):
To a stirred solution of
a-tosyloxy ketone (1 mmol), sodium azide (1 mmol) in
a
-azido ketone, as indicated by TLC and IR
aqueous PEG 400 (2 ml, 1:1, v/v), phenyl acetylene (1 mmol), 10 mol % of
copper iodide were added and allowed to stir at room temperature for 30 min.
The reaction mixture appeared turbid. On completion of the reaction as was
indicated by the TLC, the reaction mixture was diluted with water and filtered
at the pump to collect the product or extracted with ethyl acetate (3 Â 2 ml).
The organic layer was dried over anhydrous sodium sulfate and distilled using
rotary vacuum evaporator to afford pure 1,4-disubstituted-1H-1,2,3-triazoles
(Table 1, entries 1–16). 4-Phenyl-1-(2-phenylethan-2-on-1-yl)-1H-1,2,3-triazole
(2a): 1H NMR (400 MHz, DMSO-d6): d 8.19 (s, 1H), 8.08–8.06 (m, 2H), 7.88–
7.86 (m, 2H), 7.71–7.68 (m, 1H), 7.61–7.57 (m, 2H), 7.46–7.42 (m, 2H), 7.31–
7.38 (m, 1H), 6.08 (s, 2H). HRMS: calcd for C16H13N3O 263.2939, found
263.2415. IR (cmÀ1): 1695.
(2100 cmÀ1), phenylacetylene was added to the reaction mixture.
The products of this reaction and the one-pot condensation reac-
tion (Table 1, entry 1) were found to be identical.
The step-wise mechanism22 involves the initial formation of the
a
-azido ketone from the reaction of
dium azide. The copper(I) quickly forms an acetylide with the ter-
minal alkyne, which in turn forms adduct A with -azido ketone.
a-tosyloxy ketone with so-
a
Subsequent intramolecular cyclization of A produces another
cyclic adduct B which rearranges to copper-containing 1,2,3-tria-
zole C. Finally, the protonation of C leads to 1,2,3-triazole 2 and
catalyst regeneration (Fig. 1).
In conclusion, we have developed a simple, benign, and one-pot
regioselective synthesis of biologically significant 1,4-disubsti-
tuted-1H-1,2,3-triazoles in good yields under catalytic conditions.
1-(2-(4-Chlorophenyl)-ethan-2-on-1-yl)-4-phenyl-1H-1,2,3-triazole (2b): 1H
NMR (400 MHz, CDCl3): d 7.97–7.93 (m, 3H), 7.85 (d, J = 8.48 Hz, 2H), 7.51
(d, J = 8.60 Hz, 2H), 7.45–7.41 (m, 2H), 7.37–7.33 (m, 1H), 5.85 (s, 2H). HRMS:
calcd for C16H12ClN3O 297.7389, found 297.2148. IR (cmÀ1): 1685.
1-(2-(4-Methylphenyl)-ethan-2-on-1-yl)-4-phenyl-1H-1,2,3-triazole (2c): 1H
NMR (400 MHz, CDCl3): d 7.88–7.85 (m, 3H), 7.79 (d, J = 7.32 Hz, 2H), 7.39–
7.35 (m, 2H), 7.29–7.27 (m, 3H), 5.81 (s, 2H), 2.38 (s, 3H). HRMS: calcd for
C17H15N3O 277.3205, found 277.3172. IR (cmÀ1): 1690.
The protocol is applicable to a wide range of
a-tosyloxy ketones
4-Phenyl-1-(2-(thiophen-2-yl)-ethan-2-on-1-yl)-1H-1,2,3-triazole (2d): 1H NMR
(400 MHz, CDCl3): d 7.91 (s, 1H), 7.82–7.79 (m, 3H), 7.74–7.73 (m, 1H), 7.39–
7.35 (m, 2H), 7.30–7.26 (m, 1H), 7.17–7.15 (m, 1H), 5.73 (s, 2H). HRMS: calcd
for C14H11N3OS 269.3216, found 269.1185. IR (cmÀ1): 1665.
and acetylenic compounds, and allows the assembly of a diverse
set of 1,4-disubstituted-1H-1,2,3-triazoles. The use of copper(I) as
a reusable catalyst in aqueous PEG makes this method facile, cost
effective, and eco-friendly.
4-Phenyl-1-(2-[1-(phenylsulfonyl)-1H-indol-3-yl]-ethan-2-on-1-yl)-1H-1,2,3-
triazole (2e): 1H NMR (400 MHz, CDCl3): d 8.34 (s, 1H), 8.18 (d, J = 7.48 Hz, 1H),
7.89–7.87 (m, 4H), 7.77 (d, J = 7.28 Hz, 2H), 7.52–7.48 (m, 1H), 7.40–7.24 (m,
7H), 5.70 (s, 2H). HRMS: calcd for C24H18N4O3S 442.4897, found 442.3253. IR
(cmÀ1): 1680.
Acknowledgments
1-(Cyclopentan-1-on-2-yl)-4-phenyl-1H-1,2,3-triazole (2f): 1H NMR (400 MHz,
CDCl3): d 7.89 (s, 1H), 7.84 (d, J = 7.48 Hz, 2H), 7.40–7.44 (m, 2H), 7.35–7.31 (m,
1H), 4.96 (dd, J = 11.46 Hz and J = 8.44 Hz, 1H), 2.86–2.79 (m, 1H), 2.65–2.42
(m, 3H), 2.36–2.29 (m, 1H), 2.12–2.01 (m, 1H). HRMS: calcd for C13H13N3O
227.2618, found 227.1572. IR (cmÀ1): 1720.
Authors are grateful for the financial support received from
DRDO, New Delhi (Project No. ERIP/ER/ 0505034/M/01/902) and
Birla Institute of Technology and Science, Pilani.
1-(Cyclohexan-1-on-2-yl))-4-phenyl-1H-1,2,3-triazole (2g): 1H NMR (400 MHz,
CDCl3): d 7.86–7.84 (m, 3H), 7.44–7.41 (m, 2H), 7.35–7.31 (m, 1H), 5.47 (dd,
J = 13.14 Hz and 5.68 Hz, 1H), 2.72–2.52 (m, 3H), 2.29–2.20 (m, 2H), 2.14–2.12
(m, 1H), 2.01–1.81 (m, 2H). HRMS: calcd for C14H15N3O 241.2884, found
241.1719. IR (cmÀ1): 1715.
References and notes
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Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris,
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D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
1-(Cycloheptan-1-on-2-yl)-4-phenyl-1H-1,2,3-triazole (2 h): 1H NMR (400 MHz,
CDCl3): d 7.94 (s, 1H), 7.84–7.90 (m, 2H), 7.49–7.32 (m, 3H), 5.77–5.69 (m, 1H),
2.88–2.55 (m, 2H), 2.40–1.70 (m, 8H). HRMS: calcd for C15H17N3O 255.3149,
found 255.1032. IR (cmÀ1): 1710.
4-(2-Pyridyl)-1-(2-phenyl ethan-2-on-1-yl)-1H-1,2,3-triazole (2i): 1H NMR
(400 MHz, CDCl3): d 8.64–8.59 (m, 1H), 8.30 (s, 1H), 8.25–8.19 (m, 1H), 8.01–
8.10 (m, 2H), 7.87–7.52 (m, 4H), 7.30–7.22 (m, 1H), 5.94 (s, 2H). +EMS (turbo
spray): calcd for C15H12N4O 264.2819, found: 265.2. IR (cmÀ1): 1690.
4-(2-Pyridyl)-1-(2-[1-(phenylsulfonyl)-1H-indol-3-yl]-ethan-2-on-1-yl)-1H-
1,2,3-triazole (2j): 1H NMR (400 MHz, CDCl3): d 8.60 (d, J = 4.28 Hz, 1H), 8.40–
8.36 (m, 2H), 8.27 (d, J = 7.44 Hz, 1H), 8.21 (d, J = 7.96 Hz, 1H), 7.99–7.97 (m,
3H), 7.83–7.79 (m, 1H), 7.63–7.59 (m, 1H), 7.52–7.48 (m, 2H), 7.45–7.35 (m,
2H), 7.27–7.24 (m, 1H), 5.79 (s, 2H). +EMS (turbo spray): calcd for C23H17N5O3S
443.4778, found 443.9. IR (cmÀ1): 1680.
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4-Phenyl-1-(propan-2-on-1-yl)-1H-1,2,3-triazole (2k): 1H NMR (400 MHz,
CDCl3): d 7.84–7.83 (m, 3H), 7.46–7.42 (m, 2H), 7.37–7.33 (m, 1H), 5.26 (s,