A cu[I] catalyzed mild and general synthesis of 1,4-disubstituted-1,2,3- triazoles from terminal acetylenes and in situ generated Alkyl azides

Article abstract of DOI:10.3987/COM-13-12764

Cuprous cyanide, generated in situ from cupric sulfate and sodium cyanide, catalyzes the synthesis of 1,4-disubstituted-1,2,3-triazoles from in situ generated alkyl azides and mono-substituted alkynes in a one pot room temperature process.

Full text of DOI:10.3987/COM-13-12764

HETEROCYCLES, Vol. 89, No. 1, 2014
27
HETEROCYCLES, Vol. 89, No. 1, 2014, pp. 27 - 41. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2013, Accepted, 31st October, 2013, Published online, 22nd November, 2013
DOI: 10.3987/COM-13-12764
A CU[I] CATALYZED MILD AND GENERAL SYNTHESIS OF
1,4-DISUBSTITUTED-1,2,3-TRIAZOLES
FROM
TERMINAL
ACETYLENES AND IN SITU GENERATED ALKYL AZIDES
José Emilio de la Cerda-Pedro, Yoarhy Alejandro Amador-Sánchez, Mayra
Cortés-Hernández, Jovana Pérez-Pérez, Susana Rojas-Lima,*and Heraclio
López-Ruiz*
Chemistry Academic Area (AAQ), Autonomous University of Hidalgo (UAEH)
University City, Pachuca-Tulancingo road Km 4.5, Mineral de la Reforma, Hidalgo,
México, CP 42184. address: *corresponding author: heraclio@uaeh.edu.mx
Abstract –Cuprous cyanide, generated in situ from cupric sulfate and sodium
cyanide, catalyzes the synthesis of 1,4-disubstituted-1,2,3-triazoles from in situ
generated alkyl azides and mono-substituted alkynes in a one pot room temperature
process.
INTRODUCTION
The Cu(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) has become the preferred synthetic
route to 1,4-disubstituted 1,2,3-triazoles, some of which have interesting biological properties and/or
applications in drug design.1-3 Because of the thermodynamic instability of Cu(I), Cu(II) is usually reduced
in situ to Cu(I), by the addition of reducing agents, such as sodium ascorbate,4 glucose in the presence of
Fehling’s reagent,5 or NaN3.6 Indeed, although longer reaction times are required when the Cu(II)/ascorbate
process is used, we felt these finding had substantial implications and the potential for further development.
In this article, we describe an efficient, room temperature synthesis of 1,4-disubstituted-1,2,3-triazoles
from alkyl acetylenes and in situ generated alkyl azides, catalyzed by Cu(I)CN generated via the sodium
cyanide reduction7 of CuSO4 (Scheme 1).
R X
+
NaN3
NaCN
N
R
CuSO4
CuCN
N
N
H2O:iPrOH:DMF (1:1:1.5)
rt
+
R'
R'
Scheme 1

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HETEROCYCLES, Vol. 89, No. 1, 2014
Although the generation of CuCN by means of the NaCN reduction of CuSO4 has been known for some
time,7 as far as we are aware, Cu(I) generated in this manner has not been used to catalyze the formation of
1,4-disubstituted-1,2,3-triazoles from alkyl azides and mono-substituted acetylenes. We chose to
investigate this very reasonable possibility.
RESULTS AND DISCUSSION
Optimization studies were carried out using phenylacetylene and benzyl azide (generated in situ from
benzyl bromide and sodium azide) in the presence of varying amounts of CuSO4 and NaCN, at room
temperature, in a 1:1:1.5 water:iPrOH:DMF solvent mixture (Table 1). The data clearly show that the best
conditions for the formation of 3a involved the use of 36 mol% CuSO4 and 69 mol% NaCN (entry 9).
Table 1. Optimization experiments for the one-pot generation of triazole 3a from benzyl halide and
phenylacetylenea
H
N
N
N
1. NaN3
Br
+
H2O:iPrOH:DMF (1:1:1.5)
2. Conditions
3a
1a
2a
Entry
Conditions
Time (h.)
Yield (%)b
CuSO4
(%mol)
---
NaCN
(%mol)
20
1
2
2
nr
nr
12
5
---
10
20
30
40
30
60
69
80
2
3
24
24
24
24
24
24
0.5
0.5
trace
45
4
10
20
20
30
30
36
40
5
52
6
63
7
72
8
94
9
98
10
94
aAll reactions were performed with 2 eq. of NaN3 at rt. bProducts
purified by crystallization
With the optimized conditions in hand, the scope of the reaction was explored by reacting various benzyl
bromides (1a-c), alkyl bromides (1d and 1f) and allyl bromide (1e) with terminal alkynes (2a-j) in presence
of NaN3. The results are summarized in Table 2. It is obvious that a wide variety of benzyl, and alkyl

HETEROCYCLES, Vol. 89, No. 1, 2014
29
bromide possessing different functional groups reacted successfully. The reaction showed considerable
tolerance for substituents in the phenylalkynes with both benzyl bromide (1a) and allyl bromide (1e) (Table
2). Both electron donating and attracting substituents in the phenylalkynes led to the desired products in
high yields with little obvious differences in reaction times. In contrast, both the reaction of benzyl
bromide with propargyl alcohol and ethyl bromoacetate with phenylacetylene gave rise to more modest
yields of the expected products 3f and 3n, respectively.
Table 2. One-Pot synthesis of 1,4-disubstituted-1,2,3-triazoles from alkyl bromide and monoalkyl
acetylenes
N
CuSO4(0.36), NaCN (0.69)
R
N
N
NaN +
+
Br
R'
H
R
3
H2O:iPrOH:DMF (1:1:1.5), rt
1
R'
2
3
Entry
Halide
Alkyne
Product
Time
(min.)
Yield (%)
[Ref.]
N
N
Br
Br
N
1
30
98[5, 9, 11, 12,
16, 20, 22, 23,]
1a
2a
3a
N
N
N
2
3
35
50
91[15]
F
1a
1a
3b
2b
F
N
N
Br
N
94
NC
3c
2c
CN
N
N
Br
N
4
50
99[9g, 12, 13,
14, 15, 16, 20]
MeO
1a
3d
2d
OMe

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HETEROCYCLES, Vol. 89, No. 1, 2014
N
N
Br
Br
Br
N
5
6
7
50
70
50
88[9i, 15]
Cl
1a
1a
1a
3e
2e
Cl
N
N
N
60[5, 9a, 9c,
9i, 9m, 10,
14,15,16]
OH
2f
OH
3f
N
N
N
N
79[9j, 20]
N
2g
3g
N
N
N
N
N
8
50
92[9a, 9d, 9f,
9h, 17, 20]
O
Br
O
3h
2h
1a
N
N
Br
9
97
60
3i
H2N
1a
2i
NH2
N
N
O
N
O
Br
O
10
92[9a]
O
50
60
3j
1a
2j
N
MeO
Br
N
Br
N
11a
80
N
N
N
N
MeO
1b
3k
2d
OMe

HETEROCYCLES, Vol. 89, No. 1, 2014
31
Br
N
N
12a
N
2a
Br
60
N
N
80[9a]
N
1b
3l
N
N
N
Br
N
N
N
13b
60
60
75[ 9a, 9k, 9l]
N
2a
3m
Br
Br
N
N
1c
N
O
N
N
O
72 [9a, 9d, 9g,
9h, 9k, 12, 14,
19,20,23]
EtO
14
15
Br
2a
3n
EtO
1d
N
N
N
60
3o
Br
85
NC
H2N
Cl
1e
2c
CN
N
N
N
70
80
16
Br
73
3p
1e
2i
NH2
N
N
N
17
Br
76
3q
1f
2e
Cl

32
HETEROCYCLES, Vol. 89, No. 1, 2014
N
N
N
60
Br
Br
18
19
89
3r
1e
1e
MeO
2d
OMe
N
N
N
70
70
70[10]
3s
2a
N
N
N
Br
20
85
O
3t
O
1e
2h
a 4 eq of NaN3 and 2 eq of arylacetylene were used. b 6 eq of NaN3 and 3 eq of arylacetylene were used.
The cuprous cyanide catalyzed cycloaddition process was also successfully applied to the azido compound
4 with phenylacetylene and three para substituted derivatives thereof (see Scheme 2). Compound 4 was
prepared as described in the Experimental Section.
NaCN
O
N
O
N
CuSO4
CuCN
+
R
R
N3
H2O:iPrOH:DMF (1:1:1.5)
rt
N
N
OMe
OMe
4
2
N
5
O
O
N
OMe
Cl
N
N
N
N
N
OMe
N
N
5a 67%
5b
53%
O
N
O
OMe
N
N
N
OMe
F
N
OMe
N
N
N
5c 85%
5d 67%
Scheme 2

HETEROCYCLES, Vol. 89, No. 1, 2014
33
The structure of most of the 1,2,3-triazoles was supported by the usual spectroscopic data, and that of
triazoles 3d, 3e, 3i, 3o and 5c was established unequivocally by X-ray crystallography (Figure 1).8
Figure 1. X-Ray structures of compounds 3d, 3e, 3i, 3o and 5c
Experiments were conducted to show that cuprous cyanide generated in situ by the reduction of Cu(II)
sulfate with NaCN both catalyzes the cycloaddition of azides with acetylenes, and is superior in this regard
to commercial CuCN.25 Firstly, as expected, commercial CuCN catalyzes the cycloaddion of benzyl azide
(6), both generated in situ (experiment a, Scheme 3) or ex situ (experiment c), to phenylacetylene in yields
of 84 % and 73 %, respectively, after 12 h at room temperature. Secondly, CuSO4 fails to effect this
cycloaddition with in situ generated benzyl azide under the same conditions (experiment b). Thirdly, in situ
generation of CuCN from copper (II) sulfate and sodium cyanide in the presence of benzyl azide and
phenylacetylene resulted in the formation of 3a in 95% yield in 30 min (experiment d).
A possible mechanism for the catalytic CuSO4/CuCN reaction is delineated in Figure 2.6,26
CONCLUSIONS
We describe in this letter a facile, room temperature, high yield, one pot preparation of 1,4-disubstituted
1,2,3-triazoles from organic azides, generated in situ, and various monosubstituted alkynes. The cuprous
cyanide was generated in situ from copper(II) sulfate and sodium cyanide, the reactions time was reduced
from 12h to 30 min giving the triazole in 95% yield. Considering the operational ease with which these
reactions can be carried out, and the inexpensive chemicals involved, we believe this protocol will be of
great benefit to medicinal and synthetic organic chemistry.

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HETEROCYCLES, Vol. 89, No. 1, 2014
H
N
N
N
Br
Br
N3
N3
1. NaN3 2. CuCN(0.36)
(a)
(b)
+
+
H2O:iPrOH:DMF (1:1:1.5)
rt, 84%
3a
2a
2a
1a
1a
H
N
N
N
N
N
2. CuSO4(0.36)
1. NaN3
H2O:iPrOH:DMF (1:1:1.5)
rt,
3a
3a
H
N
CuCN(0.36)
(c)
(d)
+
H2O:iPrOH:DMF (1:1:1.5)
rt, 73%
6
6
2a
2a
H
N
N
N
CuSO4(0.36), NaCN (0.69)
+
H2O:iPrOH:DMF (1:1:1.5)
rt, 95%
3a
Scheme 3
CuSO4
NaCN ref. 7
Ar
H
N
N
[Cu(CN)2]
CuCN
N
N
R
Ar
Ar
H
H+
[Cu]
Ar
[Cu]
H
N
N
[Cu]
R
[Cu]
H+
R
N N
[Cu]
N
[Cu]
[Cu]
Ar
[Cu]
R N3
R
N
Ar
NaN3
N
N
R X
[Cu]
[Cu]
Ar
Figure 2. Postulated Mechanism

HETEROCYCLES, Vol. 89, No. 1, 2014
35
EXPERIMENTAL
TLC was performed on Merck-DC-F254 plates, detection was made by shining UV light. Flash column
chromatography was performed using Merck silica gel (230-240 mesh). Melting points were measured in
1
13
open capillary tubes on a Büchi Melting Point B-540 apparatus and have not been corrected. H and C
NMR spectra were recorded on a Varian VNMRS 400 (400 and 100 MHz) spectrometers. Chemical shifts
(δ) are indicated in ppm downfield from internal TMS used as reference; the coupling constants (J) are
given in Hz. IR spectra were measured on a Perkin Elmer GX FT-IR. Elemental analyses were performed
on a Perkin-Elmer Series II CHNS/O Analyzer 2400. High resolution mass spectra were obtained with an
agilent G1969A spectrometer.
General procedure for the preparation of 1,2,3-triazoles (3).
In a 25 mL round-bottomed flask containing a magnetic stirring bar was placed 100 mg of (1a-f) in 3.5 mL
of mixture of 1 mL of H2O, 1 mL of isopropanol and 1.5 mL of DMF as solvent, followed by the addition of
2 eq of NaN3, 0.36 eq of CuSO4, 0.69 eq of NaCN, 1.0 equiv. of alkyne (2a-h), and 1 mL of Et3N. The
resulting solution was stirred at room temperature for the time show in the Table 2. Followed by extraction
with EtOAc (3 x 20 mL). The collected organic layers were dried with MgSO4 and the solvent was removed
under vacuum to give the corresponding triazole. In all cases the crude product was purified by
recrystallization General procedure for the preparation of 1,2,3-triazoles.
Compound 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3l, 3m, 3n and 3s are known, and their spectra are consistent
with literatures show in the Table 2.
1,4-Bis((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)benzene (3k): The general procedure was
followed using 0.50 mL (0.38 mmol) of α,α’-dibromo-p-xylene (1b), 0.155 g (1.51 mmol) of
4-ethynylanisol (2d) and 0.099 g (1.52 mmol) of NaN3 to give 0.143 g (83% yield) of 3k as white solid; mp
1
239-241 °C; IR (film) νmax/cm-1: 3121, 2101, 1614, 1499, 1251, 819; H NMR (DMSO-d6, 400 MHz)
δ/ppm: 8.61(s, 2H), 7.79 (d, J = 8.8 Hz, 4H), 7.41 (s, 4H), 7.03(d, J = 8.8 Hz, 4H), 5.68 (s, 4H), 4.47 (s, 6H).
13C NMR (DMSO-d6, 100 MHz) δ/ppm: 159.3, 146.9, 136.4, 129.3, 128.6, 126.9, 123.6, 114.7, 55.6, 53.6.
Anal. Calcd for C26H24N6O2: C, 69.01; H, 5.35; N, 18.57. Found C, 69.35; H, 5.14; N, 18.65.
1-Allyl-4-(4-cyanophenyl)-1H-1,2,3-triazole (3o): The general procedure was followed using 0.071 mL
(0.83 mmol) of allyl bromide (1e), 0.105 g (1.51 mmol) of 4-ethynylbenzonitrile (2c) and 0.106 g (1.62
mmol) of NaN3 to give 0.147 g (85% yield) of 3o as yellow solid; mp 103-105 °C; IR (film) νmax/cm-1: 3132,
2221, 1612, 1233, 726, 553; 1H NMR (CDCl3, 400 MHz) δ/ppm: 7.92 (d, J = 8.8 Hz, 2H) 7.85 (s, 1H), 7.68

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HETEROCYCLES, Vol. 89, No. 1, 2014
(d, J = 8.4 Hz, 2H), 6.04 (ddt, J = 6.4 Hz, J = 10.0 Hz, J = 17.2 Hz, 1H), 5.38 (m, 2H), 5.03 (d, J = 6.4 Hz,
13
2H). C NMR (CDCl3, 100 MHz) δ/ppm: 146.2, 134.9, 132.7, 130.9, 126.0, 120.7, 120.5, 118.8, 111.5,
52.9. Anal. Calcd for C12H10N4: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.48; H, 4.84; N, 26.67%.
1-Allyl-4-(4-aminophenyl)-1H-1,2,3-triazole (3p): The general procedure was followed using 0.071 mL
(0.83 mmol) of allyl bromide (1e), 0.097 mL (0.83 mmol) of 4-ethynylaniline (2i) and 0.108 g (1.66 mmol)
of NaN3 to give 0.121 g (73% yield) of 3p as brown solid mp 110-112 °C; IR (film) νmax/cm-1: 3442, 3313,
2232, 1617, 1503, 801; 1H NMR (CDCl3, 400 MHz) δ/ppm: 7.53 (s, 1H) 7.50 (d, J = 8.4 Hz, 2H), 6.61 (d, J
= 8.4 Hz, 2H), 5.92 (ddt, J = 6.4 Hz, J = 10.0 Hz, J = 19.2 Hz, 1H), 5.25-5.17 (m, 2H), 4.86 (dt, J = 1.6 Hz,
J = 6.4 Hz, 2H), 3.78 (a, 2H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 148.3, 146.6, 131.4, 126.8, 120.8, 119.9,
118.3, 115.2, 52.6. Anal. Calcd for C11H12N4: C, 65.98; H, 6.04; N, 27.98. Found: C, 66.00; H, 6.13; N,
27.72%.
4-(4-Chlorophenyl)-1-ethyl-1H-1,2,3-triazole (3q): The general procedure was followed using 0.068 mL
(0.92 mmol) of bromoethane (1f), 0.125 g (0.92 mmol) of 1-chloro-4-ethynylbenzene (2e) and 0.120 g
(1.85 mmol) of NaN3 to give 0.145 g (76% yield) of 3q as yellow solid; mp 101-103 °C; IR (film) νmax/cm-1:
3116, 1637, 1459, 1094, 929, 525, 506; 1H NMR (CDCl3, 400 MHz) δ/ppm: 7.68 (m, 3H) 7.31 (d, J = 9.2
Hz, 2H), 4.38 (q, J = 7.6 Hz, 2H) 1.52 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 146.7, 133.7,
129.1, 128.9, 126.8, 119.0, 45.4, 15.5. Anal. Calcd for C10H10ClN3: C, 57.84; H, 4.85; N, 20.24. Found: C,
58.16; H, 4.88; N, 20.38%.
1-Allyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (3r): The general procedure was followed using 0.071
mL (0.83 mmol) of allyl bromide (1e), 0.108 mL (0.83 mmol) of 4-ethynylanisole (2d) and 0.108 g (1.62
mmol) of NaN3 to give 0.159 g (89% yield) of 3r as white solid; mp 89-91 °C; IR (film) νmax/cm-1: 3099,
2934, 1618, 1502, 1249, 1031, 821, 528; 1H NMR (CDCl3, 400 MHz) δ/ppm: 7.64 (d, J = 9.2 Hz, 2H), 7.57
(s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 5.95 (ddt, J = 6.4 Hz, J = 10.0 Hz, J = 17.2 Hz, 1H), 5.25-5.19 (m, 2H),
4.89 (dt, J = 1.2 Hz, J = 6.4 Hz, 2H), 3.73 (s, 3H,). 13C NMR (CDCl3, 100 MHz) δ/ppm: 159.5, 147.8, 131.4,
129.6, 123.3, 120.1, 118.7, 114.1, 55.3, 52.7. Anal. Calcd for C12H13N3O C, 66.96; H, 6.09; N, 19.52.
Found: C, 67.31; H, 6.06; N, 19.14%.
1-Allyl-4-(phenoxymethyl)-1H-1,2,3-triazole (3t): The general procedure was followed using 0.143 mL
(1.65 mmol) of allyl bromide (1e), 0.168 g (1.27 mmol) of (prop-2-yn-yloxy)benzene (2h) and 0.214 g
(3.28 mmol) of NaN3 to give 0.28 g (87% yield) of 3t as brown oil; (3t) IR (film) νmax/cm-1: 2924, 1738,
1
1600, 1491, 1226, 1010, 757; H NMR (CDCl3, 400 MHz) δ/ppm: 7.49 (s, 1H), 7.13-7.09 (m, 2H),

HETEROCYCLES, Vol. 89, No. 1, 2014
37
6.84-6.80 (m, 3H), 5.81 (ddt, J = 6.4 Hz, J = 10.4 Hz, J = 19.2 Hz, 1H), 5.16-5.06 (m, 2H), 5.00 (s, 2H),
4.75 (dt, J = 1.6 Hz, J = 6.4 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 153.1, 144.7, 131.2, 129.5, 122.9,
121.1, 120.0, 114.7, 61.7, 52.6. Anal. Calcd for C12H13N3O: C, 66.96; H, 6.09. Found: C, 67.01; H, 6.31%.
5-Azido-2-(2-methoxyphenyl)benzoxazole (4)
In a 250 mL hydrogenation flask was placed 300 mg of 5-nitro-2-(2-methoxyphenyl)benzoxazole,24 60 mg
of Pd/C and 25 mL of CH2Cl2. The flask was pressurized to 60 psi of H2 for 5 h. The reaction mixture was
filtered over Celite and concentrated in a rotary evaporator to afford the corresponding amine in 85% yield
(227 mg). This product was transfer to a 100 mL of round bottom flask with a magnetic bar and 10 mL of
HCl (10%). The resulting solution was allowed to react for 45 min before the addition of 0.11 g (1.5 equiv)
of NaN3 and the reaction mixture was stired at room temperature fo 2 h. The reaction was quenched with
brine and the product was extracted with EtOAc (3 x 25 mL). The collected organic layers were dried with
Na2SO4 and the solvent was removed under vacuum to give 0.27
g
(92%) of
5-azido-2-(2-methoxyphenyl)benzoxazole (4) as yellow solid; mp 98-99 °C; IR (CH2Cl2) νmax/cm-1: 2118,
3082, 1631, 1265; 1H NMR(CDCl3, 400 MHz) δ/ppm: 8.13 (ddd, J = 7.5 Hz, J = 2.3 Hz, J = 0.5 Hz, 1H),
7.55 (dd, J = 8.6 Hz, J = 0.6 Hz, 1H), 7.53 (m, 1H), 7.53 (dd, J = 2.3 Hz, J = 0.5 Hz, 1H), 7.11 (m, 1H), 7.17
(d, J = 7.5 Hz, 1H), 7.01 (dd, J = 8.6 Hz, J = 2.3 Hz, 1H), 4.01 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ/ppm:
163.3, 158.5, 148.0, 143.4, 136.9, 133.3, 131.5, 120.9, 116.6, 115.9, 112.3, 111.4, 110.3, 56.4. Anal. Calcd
for C14H10N4O2: C, 63.15; H, 3.79. Found: C, 63.38; H, 4.06%.
General procedure for the preparation of 1,2,3-triazoles (5a-d).
In a 50 mL round-bottomed flask containing a magnetic stirring bar was placed 133 mg (1 eq.) of
5-azido-2-(2-methoxyphenyl)benzoxazole (4) in 3.5 mL of mixture of 1 mL of H2O, 1 mL of isopropanol
and 1.5 mL of DMF as solvent, followed by the addition of 1 eq of alkyne (2a,b,d,e), 0.36 eq of CuSO4,
0.69 eq of NaCN, and 1.5 mL of Et3N. The resulting solution was stirred at room temperature for 24 h.
Followed by extraction with EtOAc (3 x 25 mL). The collected organic layers were dried with MgSO4 and
the solvent was removed under vacuum to give the corresponding triazole. After removal of the solvent, the
crude residue was purified by column chromatography (EtOAc/hexane) to afford 1,2,3-triazoles 5a-d.
2-(2-Methoxyphenyl)-5-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoxazole (5a): The general procedure was
followed using 0.333 g (0.5 mmol) of 5-azido-2-(2-methoxyphenyl)benzoxazole (4) and 0.055 mL (0.5
mmol) of phenylacetylene (2a) to give 0.123 g (67% yield) of 5a as orange solid; mp 132-133 C; IR
followed using 0.333 g (0.5 mmol) of 5-azido-2-(2-methoxyphenyl)benzoxazole (4) and 0.055 mL (0.5
mmol) of phenylacetylene (2a) to give 0.123 g (67% yield) of 5a as orange solid; mp 132-133 C; IR

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HETEROCYCLES, Vol. 89, No. 1, 2014
(CH2Cl2) νmax/cm-1: 2938, 2838, 1656, 1607, 1498, 1478, 1263, 1026, 766, 756, 964; 1H NMR(CDCl3, 400
MHz) δ/ppm: 8.15 (s, 1H), 8.09 (m, 2H), 7.86 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6),
7.48 ( t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 8.7 Hz, 2H), 3.97 (s,
13
3H). C NMR (CDCl3, 100 MHz) δ/ppm: 163.6, 158.6, 150.1, 148.4, 143.0, 134.0, 133.5, 131.4, 130.1,
128.9, 128.4, 125.8, 120.8, 118.3, 118.2, 115.3, 112.4, 112.1, 111.4, 56.2. HRMS (ESI-TOF) m/z calcd for
C22H16N4O2 [M+H]+: 369.1307, found m/z 369.1348.
5-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-2-(2-methoxyphenyl)benzoxazole (5b): The general
procedure was followed using 0.333 g (0.5 mmol) of 5-azido-2-(2-methoxyphenyl)benzoxazole (4) and
0.068 g (0.5 mmol) of 1-cloro-4-etynylbenzene (2e) to give 0.170 g (85% yield) of 5b as white solid; mp
213-214 C; IR (CH2Cl2) νmax/cm-1: 2926, 2842, 1621, 1604, 1588, 1551, 1483, 1311, 1271, 1040, 795, 753;
1H NMR (DMSO-d6, 400 MHz) δ/ppm: 9.35 (s, 1H), 8.32 (dd, J = 2.0 Hz, J = 0.7 Hz, 1H), 8.05 (d, J = 1.8
Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.99 (d, J = 0.7 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H),
7.95 (d, J = 2.1 Hz, 1H), 7.94 (t, J = 2.1 Hz, 1H), 7.93 – 7.91 (m, 1H), 7.61 (ddd, J = 8.5 Hz, J = 7.3 Hz, 1.8
Hz, 1H), 7.57–7.55 (m, 1H), 7.55–7.53 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.14 (td, J = 7.6 Hz, 1.0 Hz, 1H),
3.92 (s, 2H). 13C NMR (DMSO-d6, 400 MHz) δ/ppm: 163.8, 158.6, 150.2, 146.7, 142.5, 134.3, 134.1, 133.1,
131.6, 129.5, 127.4, 121.2, 121.0, 118.4, 115.2, 113.3, 112.4, 112.0, 56.5. HRMS (ESI-TOF) m/z calcd for
C22H15ClN4O2 [M+H]+: 403.0962, found m/z 403.0958.
2-(2-Methoxyphenyl)-5-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)benzoxazole (5c): The general
procedure was followed using 0.333 g (0.5 mmol) of 5-azido-2-(2-methoxyphenyl)benzoxazole (4) and
0.065 mL (0.5 mmol) of 4-ethynylanisol (2d) to give 0.169 g (85% yield) of 5c as red solid; mp 172-173 C;
IR (CH2Cl2) νmax/cm-1: 2938, 2842, 1617, 1601, 1548, 1495, 1484, 1251, 1178, 1028, 834, 792, 750, 702; 1H
NMR (CDCl3, 400 MHz) δ/ppm: 8.07 (dd, J = 7.9 Hz, J = 1.7 Hz, 1H), 8.12 (m, 1H), 8.11 (s, 1H), 7.84 (m,
1H), 7.82 (m, 1H), 7.79 (dd, J = 8.0 Hz, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.52 (ddd, J = 8.3 Hz, J =
7.4 Hz, J = 1.8 Hz, 1H), 7.12-7.07 (m, 2H), 6.98 (m, 1H), 6.96 (m, 1H), 4.02 (s, 3H), 3.83 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ/ppm: 163.9, 160.0, 158.9, 150.3, 148.6, 143.2, 134.3, 133.7, 131.7, 127.4, 123.1,
121.1, 118.4, 117.6, 115.6, 114.6, 112.6, 112.4, 111.6, 56.5, 55.6. HRMS (ESI-TOF) m/z calcd for
C23H18N4O3 [M+H]+: 399.1457, found m/z 399.1452.
5-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(2-Methoxyphenyl)benzoxazole (5d): The general
procedure was followed using 0.333 g (0.5 mmol) of 5-azido-2-(2-methoxyphenyl)benzoxazole (4) and
0.057 mL (0.5 mmol) of 1-ethynyl-4-fluorobenzene (2d) to give 0.133 g (67% yield) of 5d as white solid;
mp 223-225 C; IR (CH2Cl2) νmax/cm-1: 2929, 2847, 1654, 1601, 1495, 1483, 1265, 1036, 1024, 789, 750,

HETEROCYCLES, Vol. 89, No. 1, 2014
39
711; 1H NMR (CDCl3, 400 MHz) δ/ppm: 8.18 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H), 8.18, (s, 1H), 8.14 (d, J = 2.1
Hz, 1H), 7.94-7.88 (m, 2H), 7.84 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.56 (ddd, J =
8.3 Hz, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.20 (m, 4H), 4.06 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 164.4,
164.1, 162.0, 159.0, 150.5, 148.0, 143.4, 134.3, 133.9, 131.8, 128.0, 127.9, 126.7, 121.2, 118.7, 118.3,
116.4, 116.2, 115.7, 112.9, 112.5, 111.8. 56.6. HRMS (ESI-TOF) m/z calcd for C22H15FN4O2 [M+H]+:
187.1257, found m/z 387.1253.
ACKNOWLEDGEMENTS
We are indebted to Dr. Joseph M. Muchowski for friendly, helpful discussions and to CONACyT for
financial support (grant CB-2009-01-135172).
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