An efficient and convenient synthesis of ethyl 1-(4-Methoxyphenyl)-5- phenyl-1H-1,2,3-triazole-4-carboxylate

Article abstract of DOI:10.1002/asia.200900320

The "click chemistry" of using organic azides and terminal alkynes is arguably the most efficient and straightforward route to the synthesis of 1,2,3-triazoles. In this paper, an alternative and direct access to ethyl 1-(4-methoxyphenyl)-5-phenyl-1H-1,2,3

Full text of DOI:10.1002/asia.200900320

FULL PAPERS
DOI: 10.1002/asia.200900320
An Efficient and Convenient Synthesis of Ethyl 1-(4-Methoxyphenyl)-5-
phenyl-1H-1,2,3-triazole-4-carboxylate
Jung-Hsuan Chen, Shuan-Ru Liu, and Kwunmin Chen*[a]
Abstract: The “click chemistry” of
using organic azides and terminal al-
kynes is arguably the most efficient
and straightforward route to the syn-
thesis of 1,2,3-triazoles. In this paper,
an alternative and direct access to
diazabicyclo
[5.4.0]undec-7-ene provid-
diazoacetamide. A reasonable mecha-
nism is proposed that involves the ad-
dition of an imine nitrogen atom to the
terminal nitrogen atom of the diazo
compound, followed by aromatization
to give the 1,2,3-triazole. The presence
of the 4-carboxy group is advantageous
as it can be easily transformed into
other functional groups.
ed fully substituted 1,2,3-triazoles in
good to high chemical yields. The base-
mediated reaction tolerates various
substituted phenyl imines as well as
ethyl diazoacetate or the more bulky
ethyl
1-(4-methoxyphenyl)-5-phenyl-
1H-1,2,3-triazole-4-carboxylate is de-
scribed. Treatment of ethyl diazoace-
tate with 4-methoxyaniline derived aryl
imines in the presence of 1,8-
Keywords: aromaticity · cycloaddi-
tion · diazo compounds · heterocy-
cles · triazoles
Introduction
ods that involved the introduction of a functional group to
the existing 1,2,3-triazoles[5] or the use of activated acety-
lides or haloalkynes met with varying degrees of success.[6]
However, several problems are commonly associated with
these methods, such as slow reaction rates, high reaction
temperature, the formation of regioisomers, and sometimes
modest chemical yields. In addition, troublesome substrates,
such as aryl azides and 1-aryl 5-substituted 1,2,3-triazoles,
required the use of microwave irradiation at elevated tem-
peratures to give the corresponding triazoles.[7] By examin-
ing the fully substituted 1,2,3-triazole structures, one can
easily find that most of the substituents are either alkyl and
aryl groups. This highlights the need for the synthesis of
structurally diverse substituted 1,2,3-triazoles that can be
used for further chemical transformation (for example, a 4-
or 5-carbonyl group). A convenient direct synthesis of 1,4,5-
trisubstituted 1,2,3-triazoles is lacking and alternative routes
are yet to be developed.[8]
1,2,3-Triazoles are interesting nitrogenous heterocycles be-
cause of their unique structure and chemical characteristics.
These compounds have many applications in materials sci-
ence, medicinal chemistry, and pharmacology.[1] Among
methods for their synthesis, Hꢀisgenꢁs 1,3-dipolar [3+2] cy-
cloaddition of azides with alkynes is arguably the most pop-
ular and straightforward route to the five-membered hetero-
cycles.[2] However, this methodology often requires an ele-
vated temperature, and usually results in a mixture of 1,4-
and 1,5-regioisomers. Meldal and co-workers and the group
of Sharpless independently reported efficient routes to as-
semble the 1,4-disubstituted 1,2,3-triazoles by the cycloaddi-
tion of terminal alkynes to azides with CuI catalysis.[3] Selec-
tive access to the complementary 1,5-disubstituted triazoles
was realized by using pentamethyl cyclopentadienyl rutheni-
um chloride [Cp*RuCl] complexes.[4] A welcome feature of
the ruthenium-catalyzed cycloaddition reaction is its ability
to catalyze internal alkynes with organic azides for the gen-
eration of 1,4,5-trisubstituted 1,2,3-triazoles. Previous meth-
The organic diazo compound is a versatile reagent and
can participate in diverse chemical transformations under
various reaction conditions. These reactions involve aldol-
or Mannich-type reactions,[9] cyclopropane ring forma-
[11]
tions,[10] X H (X=O, N, C) bond insertion, and unusual
À
migration reactions.[12] The diazo compound could also react
as a good 1,3-dipolar molecule by [3+2] cycloaddition to
give heterocyclic compounds.[13] Herein, we report an alter-
native route for easy access to ethyl 1-(4-methoxyphenyl)-5-
phenyl-1H-1,2,3-triazole-4-carboxylate using ethyl diazoace-
[a] J.-H. Chen, S.-R. Liu, Prof. Dr. K. Chen
Department of Chemistry
National Taiwan Normal University
Taipei, Taiwan 116, (ROC)
Fax : (+886)2-29324249
E-mail: kchen@ntnu.edu.tw
328
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 328 – 333

tate with 4-methoxyaniline derived imines under mild reac-
tion conditions.
ical yields were obtained (Table 1, entries 2 and 3). Both the
reactivity and chemical yields decreased when oxygenated
solvents were used (Table 1, entries 7, 8, and 10). It was ob-
vious that CH3CN was the most suitable solvent for the re-
action. Interestingly, the chemical yields decreased when
(E)-N-(2-nitrobenzylidene)benzenamine and (E)-N-(2-nitro-
benzylidene)-4-nitrobenzenamine were used (Table 1, en-
tries 11 and 12).
Results and Discussion
We first examined the reaction between ethyl diazoacetate
(1a) and various imines in the presence of a base. An exten-
sive screen of amine bases (e.g., 1,5-diazabicyclo
5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), 1,4-
diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyri-
[4.3.0]non-
To optimize the reaction conditions further, the effect of
the substrate ratio was also examined (Table 2). The use of
stoichiometric amounts of 1a and 2a resulted in 45% chem-
ACHTUNGTRENNUNG
dine (DMAP)) and imines (BocNH2, OBnNH2 derived aryl
imines; Boc=tert-butyloxycarbonyl) failed to give the 1,2,3-
triazole nucleus. To our surprise, N-PMP (N-p-methoxyphe-
nyl)imine 2a and ethyl diazoacetate (1a) in CH3CN and in
the presence of 1,8-diazabicycloACTHUNTGRNEUNG[5.4.0]undec-7-ene (DBU)
provided an unexpected 1,4,5-trisubstituted 1,2,3-triazole
Table 2. Optimization of the [3+2] cycloaddition reaction.
Entry
1a [equiv]
2a [equiv]
t [h]
Yield (3aa) [%][a]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
2.0
4.0
6.0
8.0
10.0
1.0
1.2
4.0
1.0
1.0
1.0
1.0
1.0
24
1
2
24
24
24
24
24
45
76
90
62
53
47
36
26
3aa (Table 1). It was further observed that 3.0 equiv of
Table 1. Survey of N-substituents and solvents in DBU-promoted 1,2,3-
triazole synthesis.[a]
[a] Yield of isolated product.
ical yield (Table 2, entry 1). The chemical yield was signifi-
cantly improved when 4.0 equiv of the electrophile 2a was
used (Table 2, entry 3). In contrast, the reactivity dropped
and the chemical yields decreased when higher concentra-
tions of 1a were used (Table 2, entries 4–8). Decomposition
of ethyl diazoacetate was observed under these reaction
conditions. The optimum reaction conditions were realized
for the direct assembly of fully substituted 1,2,3-triazoles by
the reaction of 1a and N-PMP aryl imines.
The scope of the reaction with a variety of N-PMP aryl
imines was investigated (Table 3). Various substituted N-
PMP imines 2a–m reacted efficiently with 1a to produce
fully substituted 1,2,3-triazoles. The use of nonsubstituted
and electron-withdrawing substituted aryl imines yielded the
desired adduct in good to high chemical yields (Table 3, en-
tries 1–6). However, for some of the substrates (Table 3, en-
tries 2–4 and 6) the reaction proceeded with the isolation of
the oxidized amides 4 in yields of 15–25%. The structure of
the N-PMP derived amide compound 4 was confirmed by
1H and 13C NMR spectroscopy, mass spectrometry, and X-
ray analysis. The reactivity decreased when halogenated aryl
imines were used, and reasonable to good chemical yields
were obtained (Table 3, entries 7–9).
Entry
Ar
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
phenyl
4-nitrophenyl
CH3CN
none
MeOH
CH3CH2CN
DMF
CH2Cl2
1
4
24
4
1
4
24
24
24
48
2
76
34
35
60
47
55
30
20
25
26
64
54
THF
diethyl ether
toluene
1,4-dioxane
CH3CN
CH3CN
9
10
11
12
2
[a] Reaction conditions: aryl imine (2; 1.2 equiv) was dissolved in the sol-
vent indicated and ethyl diazoacetate (1a; 50 mL, 1.0 equiv) and base
(3.0 equiv) were subsequently introduced. [b] Yield of isolated product.
DBU was essential to give 1,2,3-triazoles with a good chemi-
cal yield (Table 1, entry 1). To further improve the chemical
yield, solvent effects were examined. When the reaction was
carried out under neat conditions or in methanol, low chem-
For electron-donating substituent aryl imines, the reaction
temperature was raised to 508C to give the triazoles in 67%
and 64% chemical yields (Table 3, entries 10 and 11). Heter-
ocyclic substituted N-PMP imines were also good substrates
for the 1,2,3-triazole synthesis at 508C, and high chemical
yields were obtained (Table 3, entries 12 and 13). The struc-
tures of compound 3aa, 3ab, and 3al were further con-
firmed by single-crystal X-ray analyses.[14] In addition to 1a,
camphor pyrazolidinone[15] derived a-acetamide 1b is also
effective in this reaction (Table 3, entries 14 and 15). This
Abstract in Chinese:
Chem. Asian J. 2010, 5, 328 – 333
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
329

K. Chen et al.
FULL PAPERS
Table 3. DBU-promoted [3+2] cycloaddition reaction.[a]
reaction then forms triazoline
heterocycle B. Subsequently,
base-mediated elimination/aro-
matization gives the desired
1,2,3-triazole.[16] For some poor-
electron-donating aryl imines,
elevated temperature is re-
quired to promote the process
(Table 3, entries 8–13). The gen-
eration of the known N-PMP
amide 4 may come from the hy-
drolysis of the heterocycle in-
termediates during the elimina-
tion/workup process.[17]
To demonstrate the utility of
this methodology, the newly
synthesized carboxylate group
containing 1,2,3-triazole 3ac
was transformed into its chlo-
ride 6. Treatment of 3ac with
Entry
1
R2
Product
T [8C]
t [h]
Yield (3:4) [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
o-NO2-Ph (2a)
m-NO2-Ph (2b)
p-NO2-Ph (2c)
p-CN-Ph (2d)
p-CF3-Ph (2e)
Ph (2 f)
p-F-Ph (2g)
p-Cl-Ph (2h)
p-Br-Ph (2i)
o-Me-Ph (2j)
p-Me-Ph (2k)
2-pyridinyl (2l)
3-pyridinyl (2m)
2c
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3bc
3bd
RT
RT
RT
RT
RT
RT
RT
50
50
50
50
50
2
2
2
90
90 (72:18)
95 (80:15)
86 (61:25)
81
4
21
24
21
24
24
24
24
4
87 (70:17)
77
60
64
67
64
83
75
75
75
9
10
11
12
13
14
15
lithium
aluminum
hydride
50
RT
RT
4
24
24
(LAH) in THF afforded the
corresponding primary alcohol,
which was treated with toluene-
p-sulfonyl chloride (TsCl) in
pyridine to give 6 in an overall
2d
[a] Reaction conditions: N-PMP aryl imine (1.92 mmol, 4.0 equiv) was dissolved in CH3CN (2.5 mL), and then
ethyl diazoacetate (0.48 mmol) and DBU (3.0 equiv) were added. [b] Yield of isolated product.
chemical
yield
of
80%
result demonstrated that the ester and amide linkage of
diazo compounds are effective for the cycloaddition reac-
tion.
(Scheme 2). The structure of compound 6 was confirmed by
X-ray analysis.[14]
The exact mechanism for this transformation is not cur-
rently clear, but
a proposed mechanism is given in
Scheme 1. It is believed that the addition of N-PMP aryli-
mine nitrogen atom in 2 to the terminal diazo nitrogen atom
to give a zwitterionic species (A). The zwitterionic species is
stabilized by the many possible resonance forms, as well as
the use of a polar aprotic solvent (CH3CN). A cyclization
Scheme 2. Synthetic application of ethyl 1-(4-methoxyphenyl)-5-phenyl-
1H-1,2,3-triazole-4-carboxylate (3ac).
Conclusions
In summary, a convenient and direct assembly of fully sub-
stituted 1,2,3-triazoles is presented for the first time. Ethyl
diazoacetate was treated with aryl imines in the presence of
DBU to provide ethyl 1-(4-methoxyphenyl)-5-phenyl-1H-
1,2,3-triazole-4-carboxylates in good to high chemical yields
under mild reaction conditions. The installation of the car-
bonyl functionality in the 1,2,3-triazole nucleus allows fur-
ther chemical transformation. The structures of the products
were well characterized and a reasonable mechanism was
proposed. Further development of triazoles synthesis is un-
derway.
Scheme 1. Proposed mechanism for the formation of the fully substituted
1,2,3-triazole.
330
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 328 – 333

An Efficient and Convenient Synthesis of a 1,2,3-triazole
3ab: Pale-yellowish crystal; Rf =0.21 (hexanes/EtOAc 2:1); m.p.: 163–
1658C; FTIR: n˜ =3081, 2983, 2934, 2840, 1725, 1668, 1608, 1530, 1515,
Experimental Section
1351, 1252, 1220 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.28 (dt, J=8.0,
;
Infrared spectra were obtained using a Perkin–Elmer Spectrum RX spec-
trometer using thin films of products coated on NaCl plates. Only absorp-
tion frequencies higher than 1200 cmÀ1 are reported. 1H and 13C NMR
spectra were measured on the Bruker Avance 400 MHz instruments, and
spectral data are reported in ppm relative to tetramethylsilane (TMS) as
internal standard using CDCl3 as solvent. High-resolution mass spectrom-
etry (HRMS; EI) analysis was performed at the Department of Chemis-
try, National Chung Hsing University. The X-ray crystal structures were
obtained at the National Taiwan Normal University for Crystallographic
Studies. Melting points were taken on Fargo MP-1D or EZ-Melt appara-
tus without correction. All reactions under standard conditions were
monitored by thin-layer chromatography (TLC) on Merck precoated
TLC plates (silica gel 60 F254). The products were purified by flash
column chromatography silica gel 60 (Merck, 230–400 mesh) using the in-
dicated eluent.
1.9 Hz, 1H), 8.23–8.22 (m, 1H), 7.63–7.55 (m, 2H), 7.19 (d, J=8.9 Hz,
2H), 6.90 (d, J=8.9 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.82 (s, 3H),
1.34 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=160.7,
160.7, 147.9, 138.5, 137.3, 136.2, 129.4, 127.9, 127.8, 126.8, 125.6, 124.6,
114.8, 61.5, 55.6, 14.1 ppm; HRMS (EI) m/z calcd. for C18H16N4O5:
368.1121, found: 368.1113; crystal data for 3ab at 296(2) K; C18H16N4O5,
Mr =368.35; monoclinic, P2/c; a=24.2894(18), b=6.6791(5), c=
25.8889(18) ꢄ; b=111.850(4)8; V=3898.3(5) ꢄ3,
F000 =1536; l=
0.71073 ꢄ, Z=8, D=1.255 MgmÀ3, m=0.094 mmÀ1, 25253 reflections, 0
restraints, 481 parameters, R=0.2936, Rw=0.3385 for all data.
3ac: Brownish crystal; Rf =0.26 (hexanes/EtOAc 2:1); m.p.: 133–1348C;
FTIR: n˜ =3110, 2984, 2938, 2843, 1732, 1606, 1591, 1520, 1348, 1254,
1218 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.23 (d, J=8.7 Hz, 2H), 7.54
;
(d, J=8.7 Hz, 2H), 7.19 (d, J=8.9 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 4.37
(q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.33 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=160.7, 160.6, 148.4, 138.6, 137.2, 132.5, 131.6,
127.9, 126.6, 123.4, 114.7, 61.5, 55.6, 14.1 ppm; HRMS (EI) m/z calcd. for
C18H16N4O5: 368.1121; found: 368.1127.
All p-methoxyphenyl (PMP) imines 2a–m were prepared from p-anisi-
dine and the corresponding aldehydes according to the literature
method.[18] Commercially obtained reagents were used as received.
Preparation of N-phenylcamphor pyrazolidinone derived a-acetamide
(1b):[19] Glyoxylic acid p-toluenesulfonyl hydrazone (2.84 g, 11.7 mmol)
was heated at reflux with thionyl chloride (12 mL) at 708C for 2 h under
a nitrogen atmosphere. Excess SOCl2 was removed by evaporation to
give the corresponding acid chloride as a yellowish solid. To a solution of
N-phenylcamphor pyrazolidinone (1.00 g, 3.9 mmol) in CH2Cl2 at 08C
was added a solution of the freshly prepared acid chloride in CH2Cl2
dropwise. The mixture was stirred for 10 min, and then triethylamine
(4.0 mL, 27.8 mmol) was added dropwise to the reaction solution. Stirring
was continued for 30 min at 08C and then for 30 min at room tempera-
ture. The reaction mixture was washed with saturated aqueous NaHCO3
and Na2CO3 and then extracted with CH2Cl2 (30 mLꢃ2). The combined
organic layers were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (eluting with hexanes/ethyl acetate=4:1) to give the
title compound as a yellowish solid (1.09 g, 86%). Rf =0.38 (hexanes/
EtOAc 3:1); m.p.: 120–1228C; FTIR: n˜ =3116, 2996, 2960, 2111, 1719,
3ad: Yellowish oil; Rf =0.21 (hexanes/EtOAc 2:1); FTIR: n˜ =3060, 2916,
2850, 2231, 1730, 1609, 1591, 1516, 1498, 1379, 1254, 1218 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.67 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H),
7.16 (d, J=8.9 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H),
3.83 (s, 3H), 1.35 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=160.7, 160.6, 138.9, 137.2, 132.0, 131.2, 130.7, 128.1, 126.6, 117.9, 114.7,
113.8, 61.5, 55.6, 14.1 ppm; HRMS (EI) m/z calcd. for C19H16N4O3:
348.1222; found: 348.1229.
3ae: Brownish crystal; Rf =0.33 (hexanes/EtOAc 3:1); m.p.: 127–1288C;
FTIR: n˜ =3066, 2988, 2930, 2843, 1732, 1610, 1592, 1517, 1327, 1255,
1218 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.64 (d, J=8.2 Hz, 2H), 7.44
;
(d, J=8.2 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.38
(q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.34 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=160.9, 160.5, 139.4, 137.1, 132.0, 131.6, 130.8,
129.7, 128.3, 126.6, 125.3 (q, J=4 Hz, C-CF3), 123.6 (q, J=271 Hz, CF3),
61.4, 55.6, 14.1 ppm; HRMS (EI) m/z calcd. for C19H16F3N3O3: 391.1144;
found: 391.1149.
1664, 1596, 1490, 1366 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.44–7.36
;
(m, 4H), 7.19 (t, J=7.1 Hz, 1H), 4.73 (s, 1H), 4.01 (dd, J=8.1, 4.8 Hz,
1H), 2.71 (ddd, J=13.5, 7.2, 3.5 Hz, 1H), 2.27 (td, J=11.6, 4.8 Hz, 1H),
2.11–1.96 (m, 3H), 1.51–1.45 (m, 1H), 1.42–1.36 (m, 1H), 1.10 (s, 3H),
1.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=171.9, 169.8, 139.1,
128.9, 125.6, 120.7, 67.7, 58.8, 54.1, 49.2, 46.3, 38.5, 28.3, 27.0, 20.5,
20.1 ppm; HRMS (EI) m/z calcd. for C18H20N4O2: 324.1586; found:
324.1582.
3af: Brownish crystal; Rf =0.28 (hexanes/EtOAc 3:1); m.p.: 108–1108C;
FTIR: n˜ =3056, 2923, 2857, 1729, 1610, 1591, 1516, 1378, 1253, 1215 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.42–7.35 (m, 3H), 7.30–7.27 (m, 2H),
7.18 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H),
3.81 (s, 3H), 1.32 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=161.0, 160.2, 140.8, 136.8, 130.3, 129.8, 128.8, 128.3, 126.6, 125.9, 114.4,
61.1, 55.5, 14.1 ppm; HRMS (EI) m/z calcd. for C18H17N3O3: 323.1270;
found: 323.1277.
General procedure for DBU-mediated cycloaddition: To a stirred solu-
tion of N-PMP aryl imine (1.92 mmol) in MeCN (2.5 mL) was added
ethyl diazoacetate (0.48 mmol) at the specified temperature. The mixture
was stirred for 2 min and then DBU (1.44 mmol) was added dropwise.
Stirring was continued until the starting material disappeared completely
upon inspection by TLC. The solvent was removed under reduced pres-
sure, and the product was purified by flash column chromatography on
silica gel (eluting with hexanes/ethyl acetate=4:1 to 2:1) to give the cor-
responding 1,2,3-triazoles as a yellowish solid. The solid was recrystal-
lized from hexanes/EtOAc.
3ag: Brownish oil; Rf =0.28 (hexanes/EtOAc 3:1); FTIR: n˜ =3072, 2926,
2842, 1732, 1610, 1593, 1516, 1504, 1379, 1254, 1218 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.31–7.27 (m, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.07
(t, J=8.6 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.82
(s, 3H), 1.35 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
163.4 (d, J=250 Hz), 161.0, 160.3, 139.9, 136.8, 132.4 (d, J=8 Hz), 128.6,
126.6, 121.8 (d, J=4 Hz), 115.7 (d, J=22 Hz), 114.5, 61.2, 55.5, 14.2 ppm;
HRMS (EI) m/z calcd. for C18H16FN3O3: 341.1176; found: 341.1184.
3ah: Brownish solid; Rf =0.33 (hexanes/EtOAc 3:1); m.p.: 126–1278C;
FTIR: n˜ =3062, 2982, 2936, 2841, 1732, 1608, 1590, 1516, 1488, 1378,
3aa: Pale-yellowish crystal; Rf =0.47 (hexanes/EtOAc 1:1); m.p.: 168–
1718C; FTIR: n˜ =3074, 2982, 2936, 2841, 1736, 1610, 1578, 1530, 1516,
1254, 1216 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.35 (d, J=8.5 Hz,
;
1351, 1255, 1225, 1208 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.21–8.17
;
2H), 7.24 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.9 Hz,
2H), 4.37 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.34 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=160.9, 160.3, 139.7, 136.8, 136.1, 131.6,
128.6, 128.4, 126.6, 124.2, 114.5, 61.2, 55.5, 14.1 ppm; HRMS (EI) m/z
calcd. for C18H16ClN3O3: 357.0880; found: 357.0883.
(m, 1H), 7.66–7.61 (m, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.24–7.22 (m, 1H),
6.86 (d, J=8.9 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 1.25 ppm
(t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=160.6, 160.5, 148.7,
137.9, 136.7, 133.3, 132.3, 131.1, 128.2, 126.4, 125.0, 122.6, 114.6, 61.4,
55.5, 14.0 ppm; HRMS (EI) m/z calcd. for C18H16N4O5: 368.1121, found:
368.1113; crystal data for 3aa at 200(2) K; C18H16N4O5, Mr =368.35; tri-
3ai: Brownish oil; Rf =0.32 (hexanes/EtOAc 3:1); FTIR: n˜ =2959, 2925,
2854, 1732, 1609, 1590, 1516, 1485, 1378, 1254, 1215 cmÀ1 1H NMR
;
ꢀ
clinic, P1; a=8.8287(2), b=10.0418(2), c=10.6487(2) ꢄ; a=
104.7160(10), b=103.3140(10), g=100.3250(10)8; V=859.75(3) ꢄ3, F000
=
(400 MHz, CDCl3): d=7.51 (d, J=8.4 Hz, 2H), 7.18–7.16 (m, 4H), 6.89
(d, J=9.0 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 1.35 ppm (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=161.0, 160.4, 139.8, 136.8,
384; l=0.71073 ꢄ, Z=2, D=1.423 MgmÀ3, m=0.107 mmÀ1, 9904 reflec-
tions, 0 restraints, 245 parameters, R=0.0539, Rw=0.1272 for all data.
Chem. Asian J. 2010, 5, 328 – 333
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
331

K. Chen et al.
FULL PAPERS
131.9, 131.7, 128.4, 126.6, 124.8, 124.5, 114.6, 61.3, 55.6, 14.2 ppm; HRMS
(EI) m/z calcd. for C18H16BrN3O3 401.0375; found 401.0366.
3.83 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=157.2, 148.3, 136.7,
133.3, 130.2, 130.1, 126.3, 122.4, 121.7, 114.4, 55.5 ppm; MS (EI) m/z (%):
272 (M+, 100), 150 (48), 124 (40).
4c:[21] Dark-yellowish solid; m.p.: 190–1928C; 1H NMR (400 MHz,
CDCl3): d=8.34 (d, J=8.6 Hz, 2H), 8.03 (d, J=8.6 Hz, 2H), 7.76 (brs,
NH), 7.54 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 3.83 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=157.2, 140.6, 130.3, 128.2, 124.0, 122.3,
116.4, 114.9, 114.4, 55.5 ppm; MS (EI) m/z (%): 272 (M+, 100), 150 (16),
122 (15).
4d: Brownish solid; 1H NMR (400 MHz, CDCl3): d=7.97 (d, J=8.0 Hz,
2H), 7.81 (brs, NH), 7.78 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H),
6.92 (d, J=8.7 Hz, 2H), 3.82 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=163.7, 157.1, 139.0, 132.6, 130.3, 127.7, 122.3, 117.9, 115.3, 114.4,
55.5 ppm; MS (EI) m/z (%): 252 (M+, 100), 130 (24), 122 (14).
4 f:[21] Brownish solid; 1H NMR (400 MHz, CDCl3): d=7.86 (d, J=
7.2 Hz, 2H), 7.74 (brs, NH), 7.55–7.46 (m, 5H), 6.91 (d, J=9.0 Hz, 2H),
3.82 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=156.7, 135.1, 131.7,
131.0, 128.8, 127.0, 122.1, 114.3, 55.5 ppm; MS (ESI), m/z: 477 [2M+
Na]+.
3aj: Brownish crystal; Rf =0.33 (hexanes/EtOAc 3:1); m.p.: 109–1108C;
FTIR: n˜ =2924, 2911, 2902, 2837, 1729, 1609, 1516, 1379, 1254, 1215 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.34 (td, J=7.5, 1.3 Hz, 1H), 7.24–7.14
(m, 5H), 6.83 (d, J=9.0 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 3.78 (s, 3H),
1.99 (s, 3H), 1.26 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=160.8, 160.1, 140.5, 137.6, 137.4, 130.3, 130.0, 128.9, 126.2, 125.8, 125.6,
114.4, 61.0, 55.5, 19.7, 14.0 ppm; HRMS (EI) m/z calcd. for C19H19N3O3:
337.1426; found: 337.1422.
3ak: Brownish oil; Rf =0.31 (hexanes/EtOAc 3:1); FTIR: n˜ =2985, 2903,
2841, 1727, 1610, 1516, 1378, 1253, 1214 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=7.20–7.17 (m, 6H), 6.87 (d, J=9.0 Hz, 2H), 4.37 (q, J=
7.1 Hz, 2H), 3.81 (s, 3H), 2.36 (s, 3H), 1.34 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=161.1, 160.1, 141.0, 140.0, 136.7, 130.1,
129.0, 128.9, 126.6, 122.7, 114.4, 61.1, 55.5, 21.4, 14.2 ppm; HRMS (EI)
m/z calcd. for C19H19N3O3: 337.1426; found: 337.1424.
3al: Colorless crystal; Rf =0.37 (hexanes/EtOAc 1:1); m.p.: 166–1688C;
FTIR: n˜ =2995, 2936, 2854, 1731, 1609, 1591, 1516, 1465, 1253, 1221 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.61 (d, J=4.4 Hz, 1H), 7.78 (td, J=7.8,
1.7 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.35–7.32 (m, 1H), 7.25 (d, J=
9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.80 (s,
3H), 1.31 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
160.8, 160.2, 149.7, 146.3, 139.7, 137.4, 136.3, 129.0, 126.5, 126.4, 124.1,
114.2, 61.2, 55.5, 14.1 ppm; HRMS (EI) m/z calcd. for C17H16N4O3:
324.1222, found: 324.1213; crystal data for 3al at 293(2) K; C17H16N4O3,
Mr =324.34; monoclinic, P21/n; a=8.1644(2), b=14.4846(5), c=
13.5393(4) ꢄ; b=93.844(2)8; V=1597.53(8) ꢄ3, F000 =680; l=0.71073 ꢄ,
Z=4, D=1.349 MgmÀ3, m=0.095 mmÀ1, 7594 reflections, 0 restraints, 217
parameters, R=0.0753, Rw=0.1505 for all data.
Preparation of {1-(4-methoxyphenyl)-5-(4-nitrophenyl)-1H-1,2,3-triazol-4-
yl}methanol (5): To a stirred suspension of LAH (20 mg, 0.50 mmol) in
dry THF (0.5 mL) at room temperature was added a solution of triazole
3ac (50 mg, 0.14 mmol) in dry THF (0.5 mL) dropwise under a nitrogen
atmosphere. The solution was stirred for 2 h and then 15% aqueous
NaOH (5 mL) and H2O (5 mL) were added. The reaction was further di-
luted with diethyl ether, filtered through a pad of Celite, and the filtered
bed was thoroughly washed with diethyl ether. The filtrate was washed
with brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
(eluting with hexanes/ethyl acetate=1:1) to give the title compound as a
colorless liquid (40 mg, 90%); Rf =0.24 (hexanes/EtOAc 1:1); FTIR: n˜ =
3am: Brownish solid; Rf =0.26 (hexanes/EtOAc 1:1); m.p.: 115–1178C;
FTIR: n˜ =2961, 2924, 2851, 1732, 1668, 1608, 1590, 1516, 1254, 1220 cmÀ1
;
3333, 2930, 2869, 2853, 1605, 1519, 1345, 1256 cmÀ1 1H NMR (400 MHz,
;
1H NMR (400 MHz, CDCl3): d=8.64 (d, J=4.1 Hz, 1H), 8.50 (s, 1H),
7.70 (d, J=7.9 Hz, 1H), 7.35 (dd, J=7.9, 4.1 Hz, 1H), 7.19 (d, J=9.0 Hz,
2H), 6.90 (d, J=9.0 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.82 (s, 3H),
1.34 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=160.8,
160.5, 150.6, 150.4, 137.8, 137.8, 137.4, 128.1, 126.8, 123.0, 122.5, 114.7,
61.4, 55.6, 14.1 ppm; HRMS (EI) m/z calcd. for C17H16N4O3: 324.1222;
found: 324.1228.
CDCl3): d=8.21 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 7.20 (d, J=
8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.81 (s, 2H), 4.29 (brs, OH),
3.84 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=160.4, 147.9, 145.7,
133.8, 133.0, 130.5, 128.8, 126.5, 123.9, 114.7, 55.5, 55.3 ppm; MS (EI) m/z
(%): 326 (M+, 29), 298 (94), 281 (100), 268 (27), 108 (19); HRMS (EI)
m/z calcd. for C16H14N4O4: 326.1015, found: 326.1008.
Preparation of 4-(chloromethyl)-1-(4-methoxyphenyl)-5-(4-nitrophenyl)-
3bc: Yellowish solid; Rf =0.20 (hexanes/EtOAc 2:1); m.p.: 168–1708C;
FTIR: n˜ =3058, 2963, 2939, 2842, 1720, 1655, 1604, 1517, 1492, 1458,
1H-1,2,3-triazole (6): A solution of the primary alcohol 5 (60 mg,
0.18 mmol) and TsCl (0.17 g, 0.89 mmol) in pyridine (1.2 mL) was stirred
at 08C for 2 h and then at room temperature for 24 h. The reaction mix-
ture was extracted with CH2Cl2 (2ꢃ10 mL). The combined organic layers
were then washed with 2.4m aqueous HCl and brine. The organic layer
was dried over MgSO4 and concentrated in vacuo. The residue was puri-
fied by flash column chromatography on silica gel (eluting with hexanes/
ethyl acetate=3:1) and then recrystallized from hexanes/EtOAc to give 6
(56.34 mg, 89%) as a colorless crystal; Rf =0.33 (hexanes/EtOAc 3:1);
m.p.: 160–1628C; 1H NMR (400 MHz, CDCl3): d=8.28 (d, J=8.8 Hz,
2H), 7.51 (d, J=8.8 Hz, 2H), 7.21 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz,
2H), 4.74 (s, 2H), 3.84 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
160.5, 148.3, 142.6, 133.8, 132.7, 130.4, 128.7, 126.5, 124.2, 114.8, 55.6,
35.9 ppm; MS (EI) m/z (%): 344 (M+, 7), 281 (100), 134 (7); HRMS (EI)
m/z calcd. for C16H13ClN4O3: 344.0676, found: 344.0670; crystal data for 6
at 200(2) K; C16H13ClN4O3, Mr =344.75; monoclinic, C2/c; a=14.3184(4),
b=10.6488(3), c=20.4476(6) ꢄ; b=91.0100(10)8; V=3117.24(15) ꢄ3,
1347, 1303, 1255 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.13 (d, J=
;
8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 7.33 (t, J=
7.8 Hz, 2H), 7.18–7.16 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 4.81 (dd, J=7.2,
4.9 Hz, 1H), 3.84 (s, 3H), 2.31 (td, J=11.9, 5.0 Hz, 1H), 2.22–2.17 (m,
1H), 2.03–1.99 (m, 1H), 1.93–1.88 (m, 2H), 1.58–1.52 (m, 1H), 1.43–1.37
(m, 1H), 1.19 (s, 3H), 1.16 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=170.3, 160.8, 156.0, 148.3, 139.7, 137.6, 137.5, 131.9, 131.4, 128.6, 128.1,
126.6, 126.1, 123.6, 121.7, 114.9, 70.4, 59.6, 55.7, 51.9, 47.1, 39.1, 28.6, 26.6,
20.6, 20.1 ppm; MS (EI) m/z (%): 578 (M+, 25), 323 (16), 295 (33), 255
(100), 249 (23); HRMS (EI) m/z calcd. for C32H30N6O5: 578.2278; found:
578.2280.
3bd: Yellowish solid; Rf =0.16 (hexanes/EtOAc 2:1); m.p.: 167–1698C;
FTIR: n˜ =3058, 2961, 2938, 2842, 2231, 1722, 1658, 1609, 1593, 1515,
1
1496, 1360, 1303, 1255 cmÀ1; H NMR (500 MHz, CDCl3): d=7.55 (d, J=
6.6 Hz, 2H), 7.41–7.38 (m, 4H), 7.32 (t, J=6.6 Hz, 2H), 7.16–7.13 (m,
3H), 6.92 (d, J=7.1 Hz, 2H), 4.80 (m, 1H), 3.83 (s, 3H), 2.29 (td, J=9.6,
4.1 Hz, 1H), 2.21–2.18 (m, 1H), 2.03–1.98 (m, 1H), 1.92 (t, J=3.0 Hz,
1H), 1.88 (dd, J=11.0, 6.4 Hz, 1H), 1.56–1.51 (m, 1H), 1.41–1.36 (m,
1H), 1.19 (s, 3H), 1.15 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
170.1, 160.5, 156.0, 139.3, 137.6, 137.5, 132.0, 130.8, 129.9, 128.4, 128.0,
126.4, 125.8, 121.5, 117.7, 114.7, 113.4, 70.2, 59.5, 55.5, 51.8, 46.9, 38.9,
28.4, 26.5, 20.4, 19.9 ppm; MS (EI) m/z (%): 558 (M+, 22), 303 (23), 276
(71), 255 (100), 235 (22), 205 (10); HRMS (EI) m/z calcd. for
C33H30N6O3: 558.2379; found: 558.2377.
F
000 =1424; l=0.71073 ꢄ, Z=8, D=1.469 MgmÀ3, m=0.268 mmÀ1, 8322
reflections, 0 restraints, 217 parameters, R=0.0618, Rw=0.1336 for all
data.
Acknowledgements
4b:[20] Colorless crystal; 1H NMR (400 MHz, CDCl3): d=8.69 (s, 1H),
8.41 (d, J=7.6 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.85 (brs, NH), 7.71 (t,
J=7.6 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H),
We thank the National Science Council of the Republic of China (NSC
96-2113-M-003-005-MY3) for its financial support of this work. Our grati-
tude extends to the Academic Paper Editing Clinic at NTNU, and to the
332
www.chemasianj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 328 – 333

An Efficient and Convenient Synthesis of a 1,2,3-triazole
National Center for High-Performance Computing for providing us with
computer time and facilities.
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Received: July 28, 2009
Published online: December 22, 2009
Chem. Asian J. 2010, 5, 328 – 333
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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