Facile synthesis of 1,2,4-triazolines via PPh3-triggered reaction of azodicarboxylate with 2-azidoacrylates

Article abstract of DOI:10.1016/j.tet.2010.11.043

A convenient method for the synthesis of 1,2,4-triazolines by triphenylphosphine-triggered reaction of dialkyl azodicarboxylate with 2-azidoacrylates is described. The cascade reaction procedure is general and efficient.

Full text of DOI:10.1016/j.tet.2010.11.043

Tetrahedron 67 (2011) 650e654
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of 1,2,4-triazolines via PPh3-triggered reaction
of azodicarboxylate with 2-azidoacrylates
*
*
Deng Hong, Yuanxun Zhu, Xufeng Lin , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the synthesis of 1,2,4-triazolines by triphenylphosphine-triggered reaction of
dialkyl azodicarboxylate with 2-azidoacrylates is described. The cascade reaction procedure is general
and efficient.
Received 8 September 2010
Received in revised form 1 November 2010
Accepted 9 November 2010
Available online 13 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Huisgen zwitterion
Triazoline
Azidoacrylates
Cascade reaction
Heterocycle
N
RO2C
1. Introduction
Ar
CO2Et
CO2R
Cat. PPh3
N
N
CO2Et
N3
+
N
N
PhMe/MeCN
80 oC, 10 h, N2
CO2R
1,2,4-Triazolines are an underutilized class of heterocyclic small
molecules whose bioactivity remains unexplored. Some work has
been devoted to the development of synthetic methods for con-
struction of the 1,2,4-triazoline core, the majority of which involve
Ar
RO2C
Scheme 1. Synthesis 1,2,4-triazolines.
Mitsunobu reaction of
a
-amino acids,1 cycloaddition of oxazoles,2
2. Results and discussion
addition of imidazopyridine with azodicarboxylates,3 and reaction of
azodicarboxylates with N-[(trimethylsilyl) methyl] iminium triflates.4
Recently, Tepe and Saleem have reported the efficient synthesis of
1,2,4-triazolines utilizing oxazolones.5 Still, the development of more
efficient route to substituted 1,2,4-triazolines is of great interest.
Triphenylphosphine and dialkyl azodicarboxylates were utilized
for the formation of Huisgen zwitterion,6 which plays an important
role in Mitsunobu reaction.7 Nair and co-workers used this zwit-
terion to synthesize a variety of important compounds.8 Recently,
we have utilized the Huisgen zwitterions to synthesize pyrazolines
and triazolinones.9 Inspired by these works and our recent findings
around the reactions of azidoacrylates,10 we are interested in the
cascade reaction of the Huisgen zwitterion with 2-azidoacrylates.
Herein, we report the triphenylphosphine-triggered reaction of
dialkyl azodicarboxylate with azidoacrylates leading to the for-
mation of 1,2,4-triazolines in good yields under mild conditions
(Scheme 1).
We initially examined the reaction of ethyl 2-azido-3-PMP-ac-
rylate 1a (1.0 equiv PMP¼p-methoxyphenyl) with diethyl azodi-
carboxylate (DEAD) 2a (2.5 equiv) in the presence of PPh3 (1.0 equiv)
using THF as a solvent under reflux (Table 1, entry 1). The reaction
was completed in 24 h to give 3a in 30% yield. It is noteworthy that
solvent system is crucial to the success of this annulation chemistry
(Table 1, entries 1e6). By using MeCN/PhMe as the co-solvent, we
could improve the yield of product 3a to 71%. The effect of amount of
PPh3 on this reactionwas also evaluated. We found that reducing the
amount of PPh3 from 100 mol % to 20 mol % gave almost the same
yield (Table 1, entry 7). When the reaction was catalyzed by 10 mol %
PPh3, the yield was obviously decreased (Table 1, entry 8). Further-
more, we found that using 2.5 equiv DEAD in this reaction gave the
best yield (Table 1, entries 7, 9e10). The yield was highly dependent
upon the reaction temperature and the time (Table 1, entries 11e13).
Thus, the most suitable reaction conditions for the formation of 3a
were established (Table 1, entry 11).
Since ethyl 2-azidoacrylates are readily available from the con-
* Corresponding authors. Fax: þ86 571 87951512; e-mail addresses:
lxfok@zju.edu.cn (X. Lin), orgwyg@zju.edu.cn (Y. Wang).
densation of aromatic aldehyde and ethyl azidoacetate,11 we
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.043

D. Hong et al. / Tetrahedron 67 (2011) 650e654
651
compound 3j (Table 2, entry 10) was unambiguously confirmed by
single-crystal X-ray analysis (Fig. 1).12
Table 1
Screening for the reaction conditionsa
N
PMP
CO2Et
CO2Et
EtO2C
CO2Et
N3
PPh3
N
N
N
N
+
sovlent
PMP
EtO2C
CO2Et
1a
2a
3a
Entry Solvent
PPh3 (equiv) Temp (ꢀC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
THF
PhMe
CH3CN
DCE
2,6-dioxane
1
1
1
1
1
1
Reflux
80
Reflux
Reflux
Reflux
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
10
5
30
0
0
0
0
71
69
58
60c
65d
68
38
Trace
PhMe/CH3CN¼1:1
PhMe/CH3CN¼1:1 0.2
PhMe/CH3CN¼1:1 0.1
PhMe/CH3CN¼1:1 0.2
PhMe/CH3CN¼1:1 0.2
PhMe/CH3CN¼1:1 0.2
PhMe/CH3CN¼1:1 0.2
PhMe/CH3CN¼1:1 0.2
9
10
11
12
13
80
80
50
24
a
Conditions: 1a (1 mmol), 2a (2.5 mmol), solvent (10 mL).
b
c
Isolated yield.
2.0 mmol of 2a.
3.0 mmol of 2a.
d
therefore extended the substrate scope to a variety of reactants under
the optimized reaction conditions, and the results are presented in
Table 2. From the results of Table 2, the protocol has proven to be
useful cascade reaction of 2-azidoacrylates 1aeh with variety of
dialkyl azodicarboxylate 2aed. The reaction could give higher yields
when 2-azidoacrylates were bearing electron-deficient groups, such
as NO2 (Table 2, entries 5, 14, and 17). Furthermore, when naphthyl
2-azidoacrylate 1g was subjected to the cascade reactions, 1,2,4-tri-
azolines (3g, 3l, and 3r) were obtained in 75e78% yields (Table 2,
entries 7, 12, and 18). It should be noted that the reaction with the
bulky di-tert-butyl azodicarboxylate proceeded smoothly, leading to
good yields of triazoline product 3 (Table 2, entries 16e18).
Fig. 1. X-ray crystal structure of 3j.
To understand the mechanism of the cascade sequence, vinyl
iminophosphorane 10 prepared from 2-azidoacrylate 1a and PPh3
via the StaudingereMeyer reaction was used instead of 1a to per-
form the reaction (Scheme 2). We found that it did not follow the
same reaction as 1a and we did not obtain the desired 1,2,4-tri-
azoline product 3a. These results suggest that the present reaction
does not undergo the iminophosphorane intermediate.
CO2Et
N
PMP
CO2Et
CO2Et
PMP
EtO2C
(20 mol%)
PPh3
N
N
+
N
N
N
The structures of products 3 (3aer) were characterized by 1H
NMR, 13C NMR, IR, MS, and HRMS spectra. The structure of
PhMe/MeCN
80 oC, 10 h, N2
EtO2C
PPh3
CO2Et
3b (Yield: 0)
1' (1.0 eq)
2a (2.5 eq)
Table 2
Scope of the reactiona
Scheme 2. Reaction of iminophosphorane 10 with DEAD.
N
RO2C
Ar
CO2Et
CO2R
(20 mol%)
PPh3
CO2Et
N3
On the basis of these results, a tentative mechanism for the
cascade reaction is proposed in Scheme 3. The Huisgen zwitterion A
formed from triphenylphosphine and dialkyl azodicarboxylate 2
adds to 2-azidoacrylate 1 via a Michael-type reaction to give an
intermediate B, which gives the 1,2-diazetidine C and releases PPh3
via a cyclization reaction. C subsequently releases N2, followed by
a Curtius-type rearrangement, to form 1,2,4-triazoline 3.
N
N
N
N
+
PhMe/MeCN
80 oC, 10 h, N2
CO2R
Ar
RO2C
1
3
2
Entry
Ar
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 (1a)
Ph (1b)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
PhCH2 (2b)
PhCH2 (2b)
PhCH2 (2b)
PhCH2 (2b)
(CH3)2CH (2c)
(CH3)2CH (2c)
(CH3)2CH (2c)
t-Bu (2d)
t-Bu (2d)
t-Bu (2d)
3a
3b
3c
3d
3e
3f
3g
3h
3i
68
70
71
74
83
77
78
73
73
76
79
75
75
85
77
72
82
76
RO2C
PPh3
4-MeC6H4 (1c)
4-BrC6H4 (1d)
3-NO2C6H4 (1e)
4-PhC6H4 (1f)
2-naphthyl (1g)
4-PhCH2OC6H4 (1h)
4-MeOC6H4 (1a)
4-BrC6H4 (1d)
4-PhC6H4 (1f)
2-naphthyl (1g)
4-BrC6H4 (1d)
3-NO2C6H4 (1e)
4-PhC6H4 (1f)
4-MeOC6H4 (1a)
3-NO2C6H4 (1e)
2-naphthyl (1g)
RO2C
RO2C
PPh3
PPh3
CO2R
RO2C
N
N
N
N
O
N
N
CO2R
O
A
Ar
OEt
2
N3
B
9
OEt
10
11
12
13
14
15
16
17
18
3j
3k
3l
Ar
Ar
N3
−PPh3
N
N
1
3m
3n
3o
3p
3q
3r
N
Ar
N
N
−N2
CO2Et
CO2Et
CO2R
N
N
N
RO2C
RO2C
CO2R
a
Reaction conditions: 1 (1 mmol), 2 (2.5 mmol), PPh3 (0.2 mmol), Toluene/
CH3CN¼1:1 (10 mL), 80 ꢀC, 10 h.
C
3
b
Scheme 3. Tentative mechanism for the cascade reaction.
Isolated yield.

652
D. Hong et al. / Tetrahedron 67 (2011) 650e654
3. Conclusion
([MþNa]þ); HRMS (ESI): m/z calcd for (C18H23N3O6þNa): 400.1479;
found: 400.1479.
In conclusion, we have demonstrated a triphenylphosphine-
triggered cascade reaction between dialkyl azodicarboxylate and 2-
azidoacrylates, which furnished functionalized 1,2,4-triazolines.
The major features of this procedure include: (1) mild conditions,
(2) high yields (68e85%), (3) N2 as the only by-product, (4) the use
of catalytic amount of PPh3, and (5) metal-free.
4.2.4. Triethyl 5-(4-bromophenyl)-5H-1,2,4-triazole-1,2,3-tricarbox-
ylate (Table 2, entry 4). Light yellow liquid; IR 1755, 1732, 1645,
1488, 1467, 1373, 1246, 1201, 1104, 1057, 1011, 858 cmꢁ1 1H NMR
;
(500 MHz, CDCl3):
d
7.51 (d, J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H),
6.82 (s, 1H), 4.45e4.37 (m, 3H), 4.31e4.26 (m, 3H), 1.40 (t, J¼7.1 Hz,
3H), 1.35 (t, J¼7.1 Hz, 3H), 1.28 (t, J¼7.1 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3):
d 158.53, 157.76, 151.82, 149.49, 135.77, 132.22,
4. Experimental
127.97, 123.33, 86.72, 64.55, 64.08, 63.59, 14.60, 14.31, 14.15 ppm;
MS (ESI) m/z 464 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C17H20BrN3O6þNa): 464.0428; found: 464.0432.
4.1. General experimental
NMR spectra were recorded for 1H NMR at 500 MHz and for 13
NMR at 125 MHz. For 1H NMR, tetramethylsilane (TMS) served as
internal standard (
C
4.2.5. Triethyl 5-(3-nitrophenyl)-5H-1,2,4-triazole-1,2,3-tricarbox-
ylate (Table 2, entry 5). Light yellow liquid; IR 1755, 1643, 1535,
d
¼0) and data are reported as follows: chemical
1468, 1374, 1322, 1203, 1095, 1059, 702 cmꢁ1 1H NMR (500 MHz,
;
shift, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
CDCl3):
d
8.32(s, 1H), 8.22(q, J¼9.5 Hz, 1H), 7.81 (d, J¼7.8 Hz, 1H),
q¼quartet, m¼multiplet, br¼broad), and coupling constant in
7.59 (t, J¼8.0 Hz, 1H), 6.95 (s, 1H), 4.46e4.41 (m, 3H), 4.35e4.30
(m, 3H), 1.40 (t, J¼7.1 Hz, 3H), 1.37 (t, J¼7.1 Hz, 3H), 1.32 (t,
hertz. For 13C NMR, TMS (
d
¼0) or CDCl3
(d
¼77.25) was used as in-
ternal standard and spectra were obtained with complete proton
decoupling. Low-resolution MS and HRMS data were obtained us-
ing ESI ionization. Mp data were measured with micro melting
point apparatus. IR spectra were recorded on an FTIR spectrometer
(KBr).
J¼7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d 158.31, 157.64,
151.67, 149.95, 148.80, 138.94, 132.48, 130.20, 124.09, 121.36, 86.29,
64.81, 64.33, 63.73, 14.56, 14.27, 14.10 ppm; MS (ESI) m/z 431
([MþNa]þ); HRMS (ESI): m/z calcd for (C17H20N4O8þNa): 431.1173;
found: 431.1181.
4.2.6. Triethyl
ylate (Table 2, entry 6). Light yellow liquid; IR 1755, 1638, 1489,
1396, 1373, 1322, 1200, 1103, 1057, 1008, 857, 759 cmꢁ1 1H NMR
(500 MHz, CDCl3): 7.61e7.56 (m, 4H), 7.49e7.42 (m, 4H), 7.36 (d,
5-(biphenyl-4-yl)-5H-1,2,4-triazole-1,2,3-tricarbox-
4.2. General procedure for the synthesis of 1,2,4-triazolines 3
;
To a solution of PPh3 (0.2 mmol) in the mixture solvent of an-
hydrous toluene/acetonitrile¼1:1 (5 mL) was added dropwise
a solution of 1 (1 mmol), and 2 (2.5 mmol) in the mixture solvent
(5 mL) at 80 ꢀC over 30 min. After the mixture was stirred for 10 h,
the solvent was evaporated in vacuum and residual oil was purified
by column chromatography on silica gel using hexane/EtOAc (4:1)
as the eluent to give pure product 3.
d
J¼7.3 Hz, H), 6.92 (s, 1H), 4.46e4.38 (m, 3H), 4.33e4.27 (m, 3H),1.41
(t, J¼7.1 Hz, 3H), 1.36 (t, J¼7.1 Hz, 3H), 1.29 (t, J¼7.1 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3):
d 158.68, 157.88, 152.05, 149.34, 142.18,
140.79, 135.59, 129.07, 127.85, 127.80, 127.40, 126.67, 87.28, 64.46,
63.97, 63.51, 14.63, 14.34, 14.16 ppm; MS (ESI) m/z 462 ([MþNa]þ);
HRMS (ESI): m/z calcd for (C23H25N3O6þNa): 462.1636; found:
462.1645.
4.2.1. Triethyl 5-(4-methoxyphenyl)-5H-1,2,4-triazole-1,2,3-tricarbox-
ylate (Table 2, entry 1). Light yellow liquid; IR 1755, 1728, 1612, 1513,
4.2.7. Triethyl 5-(naphthalen-2-yl)-5H-1,2,4-triazole-1,2,3-tricarbox-
1466, 1397, 1305, 1247, 1176, 1031, 831 cmꢁ1
;
1H NMR (500 MHz,
ylate (Table 2, entry 7). Light yellow liquid; IR 1755, 1643, 1466, 1373,
CDCl3):
d
7.31 (d, J¼8.7 Hz, 2H), 6.89 (d, J¼8.7 Hz, 2H), 6.82 (s, 1H),
1319, 1198, 1097, 1057, 858, 756 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
4.45e4.36 (m, 3H), 4.30e4.25 (m, 3H), 3.79 (s, 3H), 1.39 (t, J¼7.1 Hz,
d 7.88e7.82 (m, 4H), 7.54e7.48 (m, 4H), 7.05 (s, 1H), 4.46e4.40 (m,
3H), 1.34 (t, J¼7.1 Hz, 3H), 1.27 (t, J¼7.1 Hz, 3H) ppm; 13C NMR
3H), 4.34e4.27 (m, 3H), 1.40 (t, J¼7.1 Hz, 3H), 1.36 (t, J¼7.2 Hz, 3H),
(125 MHz, CDCl3):
d
160.22, 158.63, 157.75, 152.05, 149.04, 128.71,
1.28 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d 158.66,
127.46, 114.34, 87.05, 64.31, 63.77, 63.40, 55.48, 14.54, 14.25,
14.08 ppm; MS (ESI) m/z 416 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C18H23N3O7þNa): 416.1428; found: 416.1423.
157.93, 152.03, 149.43, 133.93, 133.67, 133.33, 129.05, 128.55, 127.94,
126.83, 126.66, 125.25, 123.89, 87.49, 64.43, 63.99, 63.52, 14.62,
14.33, 14.14 ppm; MS (ESI) m/z 436 ([MþNa]þ); HRMS (ESI): m/z
calcd for (C21H23N3O6þNa): 436.1479; found: 436.1483.
4.2.2. Triethyl 5-phenyl-5H-1,2,4-triazole-1,2,3-tricarboxylate (Table
2, entry 2). Light yellow liquid; IR 1755, 1732, 1645, 1467, 1374,
1321, 1199, 1097, 1056, 1011, 852 cmꢁ1; 1H NMR (500 MHz, CDCl3):
4.2.8. Triethyl 5-(4-(benzyloxy)phenyl)-5H-1,2,4-triazole-1,2,3-tri-
carboxylate (Table 2, entry 8). Light yellow liquid; IR 1755, 1643,
1611,1511,1466,1373,1321,1242,1106,1012, 858, 753 cmꢁ1; 1H NMR
d
7.42e7.34 (m, 5H), 6.78 (s, 1H), 4.45e4.37 (m, 3H), 4.31e4.26 (m,
3H), 1.40 (t, J¼7.2 Hz, 3H), 1.34 (t, J¼7.1 Hz, 3H), 1.27 (t, J¼7.2 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3):
158.65, 157.84, 152.01, 149.24,
(500 MHz, CDCl3):
d
7.42e7.36 (m, 4H), 7.32 (t, J¼8.4 Hz, 3H), 6.97 (d,
d
J¼7.3 Hz, 2H), 6.82 (s,1H), 5.06 (s, 2H), 4.45e4.35 (m, 3H), 4.30e4.26
(m, 3H), 1.40 (t, J¼7.1 Hz, 3H), 1.34 (t, J¼7.1 Hz, 3H), 1.27 (t, J¼7.1 Hz,
136.59, 129.13, 129.05, 126.19, 87.37, 64.39, 63.90, 63.48, 14.60,
14.30, 14.13 ppm; MS (ESI) m/z 386 ([MþNa]þ); HRMS (ESI): m/z
calcd for (C17H21N3O6þNa): 386.1323; found: 386.1318.
3H) ppm; 13C NMR (125 MHz, CDCl3):
d 159.49,158.69,157.82,152.10,
149.12, 136.99, 129.07, 128.84, 128.25, 127.64, 127.57, 115.35, 87.11,
70.27, 64.36, 63.83, 63.45, 14.60, 14.33, 14.14 ppm; MS (ESI) m/z 492
([MþNa]þ); HRMS (ESI): m/z calcd for (C24H27N3O7þNa): 492.1741;
found: 492.1766.
4.2.3. Triethyl 5-p-tolyl-5H-1,2,4-triazole-1,2,3-tricarboxylate (Table
2, entry 3). Yellow liquid; IR 1755, 1732, 1645, 1514, 1467, 1397,
1373, 1323, 1200, 1105, 1058, 858 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
7.51 (t, J¼7.4 Hz, 2H), 7.18 (d, J¼8.0 Hz, 2H), 6.84(s, 1H), 4.45e4.36
4.2.9. 1,2-Dibenzyl 3-ethyl 5-(4-methoxyphenyl)-5H-1,2,4-triazole-
(m, 3H), 4.30e4.25 (m, 3H), 2.34 (s, 3H),1.39 (t, J¼7.1 Hz, 3H),1.34 (t,
1,2,3-tricarboxylate (Table 2, entry 9). Light yellow liquid; IR 1754,
J¼7.1 Hz, 3H),1.28 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
1644, 1611, 1513, 1456, 1386, 1305, 1248, 1176, 1029, 829 cmꢁ1 1H
;
d
158.68, 157.83, 152.07, 149.13, 139.01, 133.68, 129.70, 126.09, 87.32,
NMR (500 MHz, CDCl3):
6.83 (t, J¼8.4 Hz, 3H), 5.34 (d, J¼12.3 Hz, 1H), 5.25 (q, J¼7.7 Hz, 2H),
d
7.32 (t, J¼7.8 Hz, 8H), 7.25e7.23 (m, 4H),
64.35, 63.83, 63.43, 21.40, 14.59, 14.30, 14.12 ppm; MS (ESI) m/z 400

D. Hong et al. / Tetrahedron 67 (2011) 650e654
653
5.12(d, J¼12.1 Hz, 1H), 4.22 (q, J¼6.2 Hz, 2H), 3.78 (s, 3H), 1.27 (t,
([MþNa]þ); HRMS (ESI): m/z calcd for (C19H24N4O8þNa): 459.1486;
J¼7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d
160.29, 158.43,
found: 459.1482.
157.69, 152.09, 149.04, 135.39, 134.48, 128.95, 128.85, 128.65, 128.51,
128.42, 128.12, 127.52, 114.42, 87.16, 69.80, 69.13, 63.45, 55.52,
13.96 ppm; MS (ESI) m/z 540 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C28H27N3O7þNa): 540.1741; found: 540.1755.
4.2.15. 3-Ethyl 1,2-diisopropyl 5-(biphenyl-4-yl)-5H-1,2,4-triazole-
1,2,3-tricarboxylate (Table 2, entry 15). Yellow liquid; IR 1755, 1642,
1488, 1467, 1374, 1313, 1183, 1102, 1052, 1008, 760 cmꢁ1 1H NMR
;
(500 MHz, CDCl3):
d
7.60e7.56 (m, 4H), 7.48 (d, J¼8.2 Hz, 2H), 7.43
4.2.10. 1,2-Dibenzyl 3-ethyl 5-(4-bromophenyl)-5H-1,2,4-triazole-
(t, J¼7.6 Hz, 2H), 7.35 (d, J¼7.4 Hz, 1H), 6.90 (s, 1H), 5.12e5.03 (m,
2H), 4.43 (q, J¼6.4 Hz, 2H), 1.41 (t, J¼7.1 Hz, 3H), 1.35 (t, J¼6.8 Hz,
6H), 1.27 (q, J¼6.0 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3):
1,2,3-tricarboxylate (Table 2, entry 10). White solid, mp 96e97 ꢀC;
IR 1759, 1635, 1455, 1396, 1336, 1242, 1155, 983, 871 cmꢁ1 1H
;
NMR (500 MHz, CDCl3):
d
7.45 (q, J¼8.4 Hz, 2H), 7.35 (q, J¼6.7 Hz,
d 158.74, 157.37, 151.64, 149.49, 142.04, 140.74, 135.70, 129.01,
8H), 7.25(t, J¼10.9 Hz, 4H), 6.86 (s, 1H), 5.36 (d, J¼12.3 Hz, 1H),
5.27 (t, J¼12.5 Hz, 2H), 5.13(d, J¼12.0 Hz, 1H), 4.24 (q, J¼6.4 Hz,
2H), 1.26 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
127.75, 127.35, 126.59, 87.04, 72.87, 72.07, 63.42, 22.13, 21.86,
14.12 ppm; MS (ESI) m/z 490 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C25H29N3O6þNa): 490.1949; found: 490.1949.
d
158.25, 157.62, 151.84, 149.49, 135.39, 134.39, 135.23, 134.32,
132.22, 129.11, 128.91, 128.89, 128.77, 128.60, 128.18, 127.93,
123.37, 86.74, 69.99, 69.35, 63.58, 13.96 ppm; MS (ESI) m/z 588
([MþNa]þ); HRMS (ESI): m/z calcd for (C27H24BrN3O6þNa):
588.0741; found: 588.0738.
4.2.16. 1,2-Di-tert-butyl 3-ethyl 5-(4-methoxyphenyl)-5H-1,2,4-tri-
azole-1,2,3-tricarboxylate (Table 2, entry 16). Colorless liquid; IR
1755, 1639, 1612, 1514, 1459, 1395, 1332, 1250, 1153, 1032, 962,
832 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
7.28 (t, J¼7.0 Hz, 2H), 6.89
(d, J¼8.7 Hz, 2H), 6.71 (s,1H), 4.40 (q, J¼3.8 Hz, 2H),1.53 (s, 9H),1.47
4.2.11. 1,2-Dibenzyl 3-ethyl 5-(biphenyl-4-yl)-5H-1,2,4-triazole-
(s, 9H), 1.40 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
1,2,3-tricarboxylate (Table 2, entry 11). Colorless liquid; IR 1754,
d 158.97, 157.45, 150.42, 149.75, 134.47, 133.65, 133.41, 128.96,
1643, 1489, 1456, 1386, 1323, 1195, 1054, 756, 697 cmꢁ1
;
1H NMR
128.50, 127.94, 126.69, 126.57, 125.21, 123.98, 87.03, 85.12, 83.72,
63.28, 28.34, 28.10, 14.15 ppm; MS (ESI) m/z 472 ([MþNa]þ); HRMS
(ESI): m/z calcd for (C22H31N3O7þNa): 472.2054; found: 472.2040.
(500 MHz, CDCl3):
d
54 (t, J¼8.8 Hz, 4H), 7.46e7.40 (m, 4H),
7.37e7.24 (m, 11H), 6.94 (s, 1H), 5.36 (d, J¼12.4 Hz, 1H), 5.27 (t,
J¼13.1 Hz, 2H), 5.13(d, J¼12.1 Hz, 1H), 4.23 (q, J¼6.8 Hz, 2H), 1.25 (t,
J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d
158.41, 157.73,
4.2.17. 1,2-Di-tert-butyl 3-ethyl 5-(3-nitrophenyl)-5H-1,2,4-triazole-
1,2,3-tricarboxylate (Table 2, entry 17). White solid, mp 104e105 ꢀC;
IR 1756, 1631, 1536, 1369, 1351, 1311, 1247, 1153, 843, 700 cmꢁ1; 1H
152.01, 149.23, 142.15, 140.73, 135.35, 135.19, 134.43, 129.06, 129.01,
128.88, 128.79, 128.71, 128.58, 128.18, 127.84, 127.81, 127.37, 126.64,
87.30, 69.92, 69.26, 63.52, 13.97 ppm; MS (ESI) m/z 586 ([MþNa]þ);
HRMS (ESI): m/z calcd for (C33H29N3O6þNa): 586.1949; found:
586.1936.
NMR (500 MHz, CDCl3):
d
8.30 (s, 1H), 8.21(d, J¼7.1 Hz, 1H), 7.80 (d,
J¼7.7 Hz, 1H), 7.58 (t, J¼7.9 Hz, 1H), 6.84 (s, 1H), 4.42 (q, J¼3.8 Hz,
2H), 1.56 (s, 9H), 1.52 (s, 9H), 1.40 (t, J¼7.6 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3):
d 158.67, 156.18, 150.30, 150.02, 148.86, 139.51,
4.2.12. 1,2-Dibenzyl 3-ethyl 5-(naphthalen-2-yl)-5H-1,2,4-triazole-
132.61,130.16,123.99,121.30, 85.86, 85.81, 84.37, 63.51, 28.31, 28.05,
14.13 ppm; MS (ESI) m/z 487 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C21H28N4O8þNa): 487.1800; found: 487.1799.
1,2,3-tricarboxylate (Table 2, entry 12). Colorless liquid; IR 1755,
1645, 1498, 1456, 1385, 1318, 1195, 1055, 974, 860, 754 cmꢁ1 1H
;
NMR (500 MHz, CDCl3):
d
7.81 (q, J¼5.2 Hz, 4H), 7.49e7.46 (m, 3H),
7.37e7.33 (m, 5H), 7.25e7.19 (m, 5H), 7.09 (s,1H), 5.37 (d, J¼12.4 Hz,
1H), 5.27 (q, J¼5.7 Hz, 2H), 5.11(d, J¼12.0 Hz, 1H), 4.23 (q, J¼6.8 Hz,
2H), 1.25 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
4.2.18. 1,2-Di-tert-butyl 3-ethyl 5-(naphthalen-2-yl)-5H-1,2,4-tri-
azole-1,2,3-tricarboxylate (Table 2, entry 18). Colorless liquid; IR
1755, 1639, 1477, 1371, 1334, 1256, 1152, 1059, 849, 754 cmꢁ1 1H
;
d
158.40, 157.73, 151.97, 149.35, 135.32, 134.39, 133.65, 133.58,
NMR (500 MHz, CDCl3):
(s,1H), 4.17 (q, J¼8.0 Hz, 2H),1.56 (s, 9H),1.49 (s, 9H),1.40 (t, J¼7.1 Hz,
3H) ppm; 13C NMR (125 MHz, CDCl3):
160.18,159.02,156.37,150.44,
d 7.88e7.84 (m, 4H), 7.53e7.49 (m, 3H), 6.95
133.26, 129.06, 128.84, 128.76, 128.70, 128.62, 128.43, 128.17, 127.89,
126.85, 126.61, 125.29, 123.81, 87.51, 69.87, 69.27, 63.51, 13.95 ppm;
MS (ESI) m/z 560 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C31H27N3O6þNa): 560.1792; found: 560.1766.
d
149.47,129.40,127.52,114.35, 86.61, 85.02, 83.52, 63.21, 55.53, 28.31,
28.07, 14.15 ppm; MS (ESI) m/z 492 ([MþNa]þ); HRMS (ESI): m/z
calcd for (C25H31N3O6þNa): 492.2105; found: 492.2101.
4.2.13. 3-Ethyl 1,2-diisopropyl 5-(4-bromophenyl)-5H-1,2,4-triazole-
1,2,3-tricarboxylate (Table 2, entry 13). Yellow liquid; IR 1756, 1642,
Acknowledgements
1488, 1467, 1375, 1314, 1182, 1102, 1011, 912, 810 cmꢁ1 1H NMR
;
(500 MHz, CDCl3):
d
7.50 (d, J¼8.4 Hz, 2H), 7.29 (d, J¼8.4 Hz, 2H),
This work was supported by the National Natural Science
Foundation of China (No. 20872128 and J0830413) as well as the
Fundamental Research Funds for the Central Universities
(2009QNA3011) for financial support.
6.79 (s, 1H), 5.10e5.01 (m, 2H), 4.42 (q, J¼8.5 Hz, 2H), 1.40 (t,
J¼7.1 Hz, 3H), 1.33 (t, J¼7.1 Hz, 6H), 1.27 (q, J¼5.8 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3):
d 158.63, 157.30, 151.45, 149.68, 135.92,
132.16, 127.93, 123.24, 86.54, 73.03, 72.27, 63.51, 22.13, 21.87,
14.13 ppm; MS (ESI) m/z 492 ([MþNa]þ); HRMS (ESI): m/z calcd for
(C19H24N3O6þNa): 492.0741; found: 492.0762.
Supplementary data
Supplementary data related to this article can be found online
version, at doi:10.1016/j.tet.2010.11.043.
4.2.14. 3-Ethyl 1,2-diisopropyl 5-(3-nitrophenyl)-5H-1,2,4-triazole-
1,2,3-tricarboxylate (Table 2, entry 14). Colorless liquid; IR 1755,
1642, 1536, 1468, 1352, 1312, 1184, 1102, 1056, 736 cmꢁ1 1H NMR
;
References and notes
(500 MHz, CDCl3):
d
8.30 (s, 1H), 8.21(d, J¼9.6 Hz, 1H), 7.80 (d,
J¼7.8 Hz, 1H),7.58 (t, J¼8.0 Hz, 1H), 6.91 (s, 1H), 5.14e5.04 (m, 2H),
1. Kolasa, T.; Miller, M. Tetrahedron Lett. 1988, 29, 4661.
2. (a) Ibata, T.; Isogami, Y.; Tamura, H. Chem. Lett. 1988, 1551; (b) Hassner, A.;
Fischer, B. Tetrahedron 1989, 45, 3535; (c) Shi, X.; Ibata, T.; Suga, H.; Matsumoto,
K. Bull. Chem. Soc. Jpn. 1992, 65, 3315; (d) Ibata, T.; Suga, H.; Isogami, Y.; Tamura,
H.; Shi, X. Bull. Chem. Soc. Jpn. 1992, 65, 2998.
4.40 (q, J¼8.5 Hz, 2H), 1.41 (t, J¼7.2 Hz, 3H), 1.36 (q, J¼5.5 Hz, 6H),
1.32 (t, J¼6.8 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3):
d 158.45,
157.25, 151.28, 150.11, 148.83, 139.15, 132.53, 130.17, 124.07, 121.30,
86.20, 73.43, 72.66, 63.67, 22.13, 21.87, 14.12 ppm; MS (ESI) m/z 459
3. Anderson, D. J.; Watt, W. J. Heterocycl. Chem. 1995, 32, 1525.

654
D. Hong et al. / Tetrahedron 67 (2011) 650e654
4. Tsuge, O.; Hatta, T.; Tashiro, H.; Maeda, H. Heterocycles 2001, 55, 243.
5. Saleem, R.; Tepe, J. J. J. Org. Chem. 2010, 75, 4330.
6. (a) Huisgen, R.; Blaschke, H.; Brunn, E. Tetrahedron Lett. 1966, 7, 405; (b) Brunn,
E.; Huisgen, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 513.
10. (a) Chen, Z. B.; Hong, D.; Wang, Y. G. J. Org. Chem. 2009, 74, 903; (b) Yang, Y. Y.;
Shou, W. G.; Chen, Z. B.; Wang, Y. G. J. Org. Chem. 2008, 73, 3928; (c) Yang, Y. Y.;
Shou, W. G.; Hong, D.; Wang, Y. G. J. Org. Chem. 2008, 73, 3574; (d) Hong, D.;
Chen, Z. B.; Lin, X. F.; Wang, Y. G. Org. Lett. 2010, 12, 4608.
7. (a) Hughs, D. L. Org. Prep. Proced. Int. 1996, 28, 127; (b) Prakash, G. K. S.; Chacko, S.;
Alconcel, S.;Stewart, T.;Mathew, T.;Olah, G. A. Angew. Chem.,Int. Ed.2007, 46, 4933.
8. (a) Nair, V.; Biju, A. T.; Abhilash, K. G.; Menon, R. S.; Suresh, E. Org. Lett. 2005, 7,
2121; (b) Nair, V.; Biju, A. T.; Vinod, A. U.; Suresh, E. Org. Lett. 2005, 7, 5139; (c)
Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E. Org. Lett. 2006, 8, 2213; (d) Nair, V.;
Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem., Int. Ed. 2007, 46, 2070.
9. (a) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2008, 10, 13; (b) Su, Y.; Jiang, Z.;
Hong, D.; Lu, P.; Wang, Y. G.; Lin, X. F. Tetrahedron 2010, 66, 2427.
11. The 2-azidoacrylates employed herein were synthesized by the condensation of
an aromatic or cinnamic aldehyde with ethyl azidoacetate. see: (a) Stokes, B. J.;
Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129,
7500; (b) Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1970, 101,
161.
12. CCDC 784753 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.