Phosphine-mediated annulation of N-protected imines with DEAD

Article abstract of DOI:10.1016/j.tet.2011.01.072

In the presence of triphenylphosphine, the reactions of N-protected imines or their precursors with DEAD proceeded smoothly to give the corresponding functionalized 1H-1,2,4-triazole-1,4(5H)-dicarboxylate derivatives in good to high yields under mild cond

Full text of DOI:10.1016/j.tet.2011.01.072

Tetrahedron 67 (2011) 2018e2024
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Phosphine-mediated annulation of N-protected imines with DEAD
*
Zhong Lian, Xiao-Yang Guan, Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of triphenylphosphine, the reactions of N-protected imines or their precursors with
DEAD proceeded smoothly to give the corresponding functionalized 1H-1,2,4-triazole-1,4(5H)-di-
carboxylate derivatives in good to high yields under mild conditions. A plausible mechanism has been
proposed on the basis of the control experiments.
Received 22 November 2010
Received in revised form 21 January 2011
Accepted 24 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Triphenylphosphine
N-Protected imine
DEAD
Annulations
1. Introduction
2. Results and discussion
The discovery of novel synthetic methodologies to facilitate the
construction of heteroatom-containing ring systems in an efficient
way from readily available starting materials remains a challenging
goal in organic synthesis because these heterocyclic compounds
may exhibit antitumor or antibiotic activity or other biological
properties, which make them to be attractive synthetic targets in
their own right.1 Recently, the nucleophilic phosphine-catalyzed/
mediated reactions for the synthesis of carbo- and heterocycles
have attracted much attention.2 The most interesting examples are
the Lu’s [3þ2] cycloaddition to form cyclopentene and pyrrolidine
derivatives3 and [4þ2] process to construct six-membered het-
erocyclic rings by Kwon4 and Fu.5 These phosphine-catalyzed [3þ2]
or [4þ2] cyclization reactions of allenoates have been proven to be
powerful synthetic tools in the rapid formation of cyclic molecular
complexity. In this paper, we wish to report a novel phosphine-
mediated annulation of N-protected imines with diethyl azo
dicarboxylate (DEAD) to form functionalized 1H-1,2,4-triazole-1,4
(5H)-dicarboxylate derivatives in good yields under mild condi-
tions. To our delight, we found that these nitrogen-containing
heterocyclic compounds could be formed in good to excellent
yields from the easily available precursors of these N-protected
imines under mild conditions. In this paper, we wish to report this
finding.
The investigation aroused from the reaction of N-Boc-protected
imine 1 (1.0 equiv) and DEAD in the presence of a stoichiometric
amount of triphenylphosphine (1.0 equiv) in tetrahydrofuran
(THF) at room temperature (20 ꢀC) (Table 1, entry 1). Two nitro-
gen-containing five-membered cyclic products 4-tert-butyl 1-ethyl
3-ethoxy-5-phenyl-1H-1,2,4-triazole-1,4(5H)-dicarboxylate 2 and
diethyl 3-ethoxy-5-phenyl-1H-1,2,4-triazole-1,4(5H)-dicarboxylate
3a were obtained in 49% yield and 18% yield, respectively. The
structure of products 2 and 3a were assigned on the basis of
spectroscopic analyses. Their structures were further un-
ambiguously obtained from single-crystal X-ray analysis (Figs. 1
and 2).6,7 Raising the reaction temperature to 60 ꢀC or increasing
the employed amounts of DEAD and triphenylphosphine to
2.0 equiv did not significantly improve the yields of 2 and 3a (Table
1, entries 2 and 3). When the reaction was carried out using
1:DEAD:PPh3¼1:1.5:1.5 in THF at room temperature, it was found
that the corresponding annulation products 2 and 3a were obtained
in 58% yield and 23% yield, respectively (Table 1, entry 4). Changing
the concentration of the reaction system revealed that products 2
and 3a could be formed in quantitative yields under high concen-
tration (Table 1, entry 7). The examination of solvent effects in-
dicated that THF is the solvent of choice for this reaction and when
the reaction was carried out in protic solvent, such as tert-amyl-OH,
no reaction occurred (Table 1, entries 8e15).
Having identified optimal reaction conditions, we attempted to
obtain a single product using NeCO2Et-protected imine 4 to replace
N-Boc-protected imine 1 in this interesting annulation reaction
under the standard conditions (Scheme 1). As shown in Scheme 1,
* Corresponding author. Fax: þ86 21 64166128; e-mail addresses: weiyin@
mail.sioc.ac.cn, mshi@mail.sioc.ac.cn (M. Shi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.072

Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
2019
Table 1
Optimization of the reaction conditionsa
EtO2C
EtO2C
N N
Boc
N N
N
DEAD, PPh3
Solvent, rt, 12 h
N
+
Ph
OEt
Ph
OEt
N
Ph
Boc
2
CO2Et
3a
1
Entry
1:DEAD:PPh3
Solvent
mol/L
Yield (%)b
2
3a
1
1:1:1
1:1:1
1:2:2
THF
THF
THF
THF
THF
THF
THF
DCM
0.1
0.1
0.1
0.1
0.2
0.04
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
49
47
44
58
72
60
75
58
69
64
40
NR
35
62
65
18
15
22
23
25
25
25
30
28
22
28
NR
27
23
22
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
Toluene
Acetonitrile
DMF
t-Amyl-OH/THF (1:1)
DMSO
Ether
Dioxane
Fig. 2. Single-crystal X-ray structure of 3a.
a
Compound 1 (0.2 mmol) was dissolved in THF, then PPh3 (0.2 mmol), and DEAD
(0.2 mmol) were added and the reaction mixture was stirred for 12 h.
b
Isolated yields.
The reaction was carried out at 60 ꢀC.
dimethylpyridine
(DMAP)
or
1,4-diazabicyclo[2,2,2]octane
c
(DABCO) did not promote the reaction (Table 2, entries 4e6), in-
dicating that PPh3 is the best promoter for this reaction.
Next, we turned our attention to substrate scope with respect to
a variety of precursors 5 (Table 3, entries 1e9). We were pleased to
isolate the nitrogen-containing heterocyclic compounds 3 in good
to excellent yields. The yields of the corresponding five-membered
heterocyclic product 3 were not influenced significantly by the
electronic nature of 5. Interestingly, the aliphatic substrate 5i with
DEAD also proceeded smoothly, furnishing the product 3i in 76%
yield (Table 3, entry 8). Their structures were determined by
spectroscopic data, Mass and HRMS.
Using N-Boc-protected imine 1’s precursor 6 as the substrate to
react with di-tert-butyl azo dicarboxylate (DTAD) produced the
corresponding heterocyclic product 7 in 37% yield under the stan-
dard conditions (Table 4, entry 1). Using other phosphines, such as
PPh2Me, PPhMe2 or PBu3 did not improve the yield of 7, presumably
due to the steric hindrance of DTAD (Table 4, entries 2e4). In the
presence of other nitrogen-containing Lewis bases, such as DMAP
or DABCO, no reaction occurred either (Table 4, entries 5 and 6).
The mechanism suggested in Scheme 2 may be invoked to ra-
tionalize the reaction. Initially, the reaction of triphenylphosphine
with DEAD A generates the zwitterionic intermediate B, which
undergoes nucleophilic addition to imino group of N-Boc-protected
imine to form intermediate C. The intramolecular addition of Boc-
Nꢁ anion to the carbonyl group in intermediate C gives in-
termediate D, which subsequently undergoes elimination of tri-
phenylphosphine oxide to generate the product 2 via intermediate
E. The mechanism for the formation of 3a is also proposed in
Scheme 2. The elimination of BocOꢁ from intermediate C gives
intermediate F and the released BocOꢁ anion can attack DEAD to
give intermediate G, which undergoes the elimination of EtOꢁ an-
ion to give product H. The released EtOꢁ anion attacks the N]C]O
group in intermediate F generates intermediate I, which can un-
dergo the similar intramolecular nucleophilic attack to produce
intermediate J. The elimination of triphenylphosphine oxide gives
product 3a via intermediate K (Scheme 2).
Fig. 1. Single-crystal X-ray structure of 2.
we found that the corresponding annulation product 3a was
obtained as a sole product in >99% yield under the optimal con-
ditions. Further examination revealed that using its precursor 5a as
the substrate also afforded the corresponding product 3a in >99%
yield in the presence of DEAD (3.0 equiv) and PPh3 (3.0 equiv)
under otherwise identical conditions (Scheme 1) in which the extra
amounts of DEAD and PPh3 were used to generate the corre-
sponding N-protected imine from its precursor. This finding pro-
vided a more convenient access to this type of heterocyclic
compounds under mild conditions.
As shown in Scheme 3, the extra amounts of DEAD and PPh3 are
required to generate the zwitterionic intermediate B, which
deprotonates N-Boc-protected imine’s precursor to form the cor-
responding N-Boc-protected imine (Scheme 3).
Using other phosphines, such as PPh2Me, PPhMe2, and PBu3 did
not further improve the yield of 3a (Table 2, entries 1e3) and ni-
trogen-containing Lewis bases, such as triethylamine (TEA), 4-N,N-

2020
Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
EtO2C
Ph
N
N
DEAD (1.5 equiv), PPh3 (1.5 equiv)
THF, rt, 12 h
CO2Et
SO2Ph
OEt
CO2Et
3a
N
Ph
N
4
, > 99% yield
EtO2C
Ph
Ph
N N
DEAD (3.0 equiv), PPh3 (3.0 equiv)
THF, rt, 12 h
EtO2C
OEt
CO2Et
3a
N
H
N
5a
, > 99% yield
Scheme 1. Annulation of N-protected imine 4 or its precursor 5a and DEAD in the presence of triphenylphosphine.
Table 2
Table 4
Annunation of precursor 5a with DEAD in the presence of different Lewis basesa
Annunation of precursor 6 with DTAD in the presence of Lewis basesa
EtO2C
Boc
Ph
DEAD (3.0 equiv),
Ph
DTAD (3.0 equiv),
N N
N
CO2Et
3a
N N
Lewis base (3.0 equiv)
Lewis base (3.0 equiv)
EtO2C
Boc
Ph
OEt
N
H
SO2Ph
Ph
Ot-Bu
N
H
SO2Ph
N
Boc
7
THF, rt, 12 h
THF, rt, 12 h
6
5a
Entry
Lewis base
Yield (%)b
Entry
Lewis base
Yield (%)b
3a
7
1
2
3
4
5
6
PPh2Me
PPhMe2
PBu3
TEA
DMAP
DABCO
90
81
1
2
3
4
5
6
PPh3
37
33
30
Complex
NRc
NRc
PPh2Me
PPhMe2
PBu3
DMAP
DABCO
80
NRc
NRc
NRc
a
Compound 5a (0.2 mmol) was dissolved in THF, then Lewis base (0.6 mmol) and
DEAD (0.6 mmol) were added and the reaction mixture was stirred at room tem-
perature for 12 h.
a
Compound 6 (0.3 mmol) was dissolved in THF, then Lewis base (0.9 mmol) and
DTAD (0.9 mmol) were added and the reaction mixture was stirred for 12 h.
b
Isolated yields.
No reaction.
b
Isolated yields.
No reaction.
c
c
Table 3
In general, products 2 and 8 are quite stable and they are difficult to
be used for the Heck or Suzuki coupling reactions.
Scope of the annulation in the presence of triphenylphosphinea
EtO2C
R1
N
N
DEAD (3.0 equiv), PPh3 (3.0 equiv)
SO2Ph
THF, rt, 12 h
3. Conclusion
R1
OEt
EtO2C
N
CO2Et
3
N
H
In summary, we have disclosed a facile synthesis of function-
alized 1H-1,2,4-triazole-1,4(5H)-dicarboxylate derivatives in good
yields by phosphine-mediated annulation reactions of N-protected
imines or their precursors with DEAD under mild conditions. The
electron-withdrawing imino-group is believed to play an important
role in these transformations,2d,8 and a plausible mechanism is
proposed. Efforts are underway to elucidate the mechanistic details
of this annulation and to extend the scope of substrates in this
interesting annulation reaction.
5
Entry
R1
Yield (%)b
3
1
2
3
4
5
6
7
8
p-CF3C6H4, 5b
3b, 94
3c, 97
3d, 95
3e, 94
3f, 88
3g, 93
3h, 95
3i, 76
p-NO2C6H4, 5c
o-NO2C6H4, 5d
m-NO2C6H4, 5e
3,5-(CF3)2C6H3, 5f
3,4-Cl2C6H3, 5g
2-Cl-4-NO2C6H3, 5h
4. Experimental section
4.1. General remarks
, 5i
9
p-ClC6H4, 5j
3j, 91
a
Compound 5 (0.3 mmol) was dissolved in THF, then PPh3 (0.9 mmol) and DEAD
(0.9 mmol) were added and the reaction mixture was stirred for 12 h.
Mps were obtained with a Yanagimoto micro melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded for a solution in CDCl3 with tetramethylsilane (TMS) as
internal standard. J-values are in 300 M or 400 MHz. Mass spectra
were recorded with an HP-5989 instrument and HRMS was mea-
sured by a Finnigan MAþ mass spectrometer. The solid compounds
reported in this paper gave satisfactory CHN microanalyses with
a Carlo-Erba 1106 analyzer. Commercially obtained reagents were
b
Isolated yields.
The further transformation of compound 2 has been shown in
Scheme 4. Upon treatment of heterocyclic product 2 with tri-
fluoroacetic acid (TFA) in dichloromethane (DCM) at room tem-
perature produced the corresponding cyclic product 8 in 95% yield.

Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
2021
Ph3
P
O
C
EtO2C
Ph
PPh3
O
EtO2C
Ph
O
C
Ot-Bu
N N
N
N
N
O
Ot-Bu
N
N
OEt
N
N
N
OEt
CO2Et
K
EtO
OEt
CO2Et
J
EtO
O
EtO
N
H
O
G
O
CO2Et
EtO2C
Ph
Ph
Ph
N
N N
N
CO2Et
3a
OEt
O
OEt
N
OEt
N
EtO2C
N
EtO2C
N
O
O
C
PPh3
PPh3
I
OEt
t-BuO
N
F
N
EtO
O
A
O
N
Ot-Bu
Boc
N
EtO2C
PPh3
O
N N
Ph
N
N
Ph
OEt
OEt
Ph
N
Boc
D
N
OEt
EtO2C
EtO2C
a
N
PPh3
C
O
O
PPh3
C
h
t
a
p
Ph3
P
Boc
EtO2C
Ph
N
N
N
O
Ph
N
OEt
Boc
E
N
CO2Et
N
CO2Et
EtO2C
N
EtO2C
N
PPh3
A
PPh3
B
EtO2C
Ph
N N
OEt
N
Boc
2
Scheme 2. A plausible mechanism for the formation of 2 and 3.
used without further purification. All reactions were monitored by
TLC with Huanghai GF254 silica gel coated plates. Flash column
chromatography was carried out using 300e400 mesh silica gel at
increased pressure. Reaction experiments were performed under
argon condition.
4.2. Typical reaction procedure for the preparation of diethyl
3-ethoxy-5-phenyl-5H-1,2,4-triazole-1,4-dicarboxylate 3a
To
a
mixture of ethyl phenyl(phenylsulfonyl)methyl-
carbamate 5a (0.2 mmol) and DEAD (0.6 mmol) in THF (0.6 mL)
SO2Ph
Ph
Boc
N
PhSO2
Boc
+
N
H
Ph
N
CO2Et
N
CO2Et
EtO2C
N
EtO2C
N
PPh3
A
PPh3
B
Scheme 3. A plausible mechanism for the formation of N-Boc-protected imine.

2022
Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
(%): 381.4 [MþH]þ (100); MS (ESI) calcd for C16H21N4O7 [MþH]þ
EtO2C
EtO2C
Ph
requires 381.1411, found: 381.1405.
N N
TFA/CH2Cl2
rt, 2h
N N
N
Ph
OEt
N
Boc
2
4.2.5. Diethyl 3-ethoxy-5-(2-nitrophenyl)-5H-1,2,4-triazole-1,4-di-
OEt
carboxylate (3d). Mp 143e145 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
1.13 (t, 3H, J¼7.2 Hz, CH3), 1.25e1.30 (m, 3H, CH3), 1.48 (t, 3H,
8, 95% yield
J¼7.2 Hz, CH3), 4.10 (q, 2H, J¼7.2 Hz, CH2), 4.10e4.24 (m, 2H, CH2),
4.52 (q, 2H, J¼7.2 Hz, CH2), 6.64 (s, 1H, CH), 7.49e7.55 (m, 1H, ArH),
7.64e7.68 (m, 2H, ArH), 7.90e7.93 (m, 1H, ArH); 13C NMR (CDCl3,
Scheme 4. Transformation of compound 2.
75 MHz, TMS)
130.0, 132.9, 133.5, 148.1, 148.5, 152.3; IR (CH2Cl2):
d
13.9, 14.2, 14.3, 62.1, 63.3, 68.3, 71.2, 124.3, 128.0,
2982, 2930,
was added triphenylphosphine (0.6 mmol) under argon atmo-
sphere and the reaction mixture was stirred for 12 h at room
temperature. After the reaction solution was concentrated under
reduced pressure, the residue was purified by flash chromatog-
raphy on silica gel (Eluent: EtOAc/petroleum¼1/4) to afford pure
product 3a.
n
1761, 1730, 1648, 1609, 1534, 1449, 1375, 1344, 1270, 1123, 1016, 916,
853, 819, 788, 753, 711 cmꢁ1; MS (ESI) m/z (%): 403.3 [MþH]þ
(100); MS (ESI) calcd for C18H19N4O7 [MþH]þ requires 403.1248,
found: 403.1228.
4.2.6. Diethyl 3-ethoxy-5-(3-nitrophenyl)-5H-1,2,4-triazole-1,4-di-
4.2.1. 4-tert-Butyl 1-ethyl 3-ethoxy-5-phenyl-5H-1,2,4-triazole-
carboxylate (3e). Mp 141e143 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
1,4-dicarboxylate (2). Mp 135e138 ꢀC; 1H NMR (CDCl3, 400 MHz,
d
1.22 (t, 3H, J¼7.2 Hz, CH3), 1.31e1.36 (m, 3H, CH3), 1.48 (t, 3H,
TMS)
d
1.19e1.21 (m, 3H, CH3), 1.31 (s, 9H, CH3), 1.47 (t, 3H,
J¼7.2 Hz, CH3), 4.17 (q, 2H, J¼7.2 Hz, CH2), 4.28e4.36 (m, 2H, CH2),
4.50 (q, 2H, J¼7.2 Hz, CH2), 6.80 (s, 1H, CH), 7.58 (t, 1H, J¼7.8 Hz,
ArH), 7.83 (d, 1H, J¼7.8 Hz, ArH), 8.22e8.26 (m, 1H, ArH), 8.32e8.34
J¼7.2 Hz, CH3), 4.15e4.20 (m, 2H, CH2), 4.49 (q, 2H, J¼7.2 Hz, CH2),
6.62 (s, 1H, CH), 7.34e7.37 (m, 3H, ArH), 7.43e7.45 (m, 2H, ArH);
13C NMR (CDCl3, 100 MHz, TMS)
d
14.3, 14.5, 27.8, 62.0, 67.7, 76.7,
(m, 1H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.9, 14.2, 14.4, 62.5,
83.5, 126.8, 128.3, 129.1, 138.3, 147.2, 153.0; IR (CH2Cl2): 2981,
n
63.3, 68.2, 76.2, 122.3, 124.2, 129.6, 133.0, 139.9, 148.2, 148.5, 152.2;
2933, 1751, 1722, 1700, 1643, 1459, 1408, 1369, 1266, 1218, 1140,
1019, 906, 853, 743, 699 cmꢁ1; MS (ESI) m/z (%): 364.4 [MþH]þ
(100); MS (ESI) calcd for C18H25N3NaO5 [MþNa]þ requires
386.1684, found: 386.1686; Anal. Calcd for C18H25N3O5 (%)
(363.4): C, 59.49; H, 6.93; N, 11.56%. Found: C, 59.55; H, 6.73; N,
11.43%.
IR (CH2Cl2): n 2961, 1731, 1648, 1536, 1457, 1376, 1351, 1262, 1098,
1022, 805, 732, 706 cmꢁ1; MS (ESI) m/z (%): 381.4 [MþH]þ (100);
MS (ESI) calcd for C16H21N4O7 [MþH]þ requires 381.1405, found:
381.1416.
4.2.7. Diethyl 5-(3,5-bis(trifluoromethyl)phenyl)-3-ethoxy-5H-1,2,4-
triazole-1,4-dicarboxylate (3f). Mp 152e155 ꢀC; 1H NMR (CDCl3,
4.2.2. Diethyl 3-ethoxy-5-phenyl-5H-1,2,4-triazole-1,4-dicarboxy-
300 MHz, TMS)
d
1.22 (t, 3H, J¼7.2 Hz, CH3), 1.27e1.31 (m, 3H, CH3),
late (3a). Mp 137e138 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
1.16
1.48 (t, 3H, J¼7.2 Hz, CH3), 4.18 (q, 2H, J¼7.2 Hz, CH2), 4.16e4.23 (m,
(t, 3H, J¼7.2 Hz, CH3), 1.19e1.28 (m, 3H, CH3), 1.47 (t, 3H, J¼7.2 Hz,
CH3), 4.12 (q, 2H, J¼7.2 Hz, CH2), 4.13e4.21 (m, 2H, CH2), 4.49 (q,
2H, J¼7.2 Hz, CH2), 6.70 (s, 1H, CH), 7.34e7.37 (m, 3H, ArH),
2H, CH2), 4.52 (q, 2H, J¼7.2 Hz, CH2), 6.80 (s, 1H, CH), 7.89 (s, 1H,
ArH), 7.91 (s, 2H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.8, 14.2,
14.4, 62.7, 63.5, 68.4, 76.2, 117.6, 121.2, 123.2, 123.29, 123.34, 124.8,
127.1,127.5,128.4,131.3,131.8,132.2,132.7,140.0,140.6,148.4,152.3;
7.44e7.46 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.8,
14.2, 14.4, 62.0, 62.7, 67.8, 76.5, 126.7, 128.3, 129.2, 137.9, 148.5,
19F NMR (CDCl3, 376 MHz, CFCl3)
d
ꢁ62.9; IR (CH2Cl2):
n 2927, 2855,
152.5; IR (CH2Cl2):
n
2958, 2928, 2855, 1746, 1646, 1458, 1376, 1261,
1750, 1725, 1642, 1510, 1460, 1407, 1370,1348, 1267, 1171, 1140, 1023,
929, 905, 834, 781, 737, 701 cmꢁ1; MS (ESI) m/z (%): 472.5 [MþH]þ
(100); MS (ESI) calcd for C18H19F6N3NaO5 [MþNa]þ requires
494.1121, found: 494.1136.
1094, 1023, 803, 740, 701 cmꢁ1; MS (ESI) m/z (%): 336.3 [MþH]þ
(100); MS (ESI) calcd for C16H21N3NaO5 [MþNa]þ requires
358.1385, found: 358.1373.
4.2.3. Diethyl 3-ethoxy-5-(4-(trifluoromethyl)phenyl)-5H-1,2,4-tri-
azole-1,4-dicarboxylate (3b). Mp 145e147 ꢀC; 1H NMR (CDCl3,
4.2.8. Diethyl 5-(3,4-dichlorophenyl)-3-ethoxy-5H-1,2,4-triazole-1,4-
dicarboxylate (3g). Mp 149e151 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
300 MHz, TMS)
d
1.19 (t, 3H, J¼7.2 Hz, CH3), 1.20e1.32 (m, 3H, CH3),
d
1.22 (t, 3H, J¼7.2 Hz, CH3), 1.24e1.28 (m, 3H, CH3), 1.47 (t, 3H,
1.47 (t, 3H, J¼7.2 Hz, CH3), 4.15 (q, 2H, J¼7.2 Hz, CH2), 4.17e4.23 (m,
J¼7.2 Hz, CH3), 4.17 (q, 2H, J¼7.2 Hz, CH2), 4.18e4.20 (m, 2H, CH2),
4.48 (q, 2H, J¼7.2 Hz, CH2), 6.65 (s, 1H, CH), 7.31 (dd, 1H, J1¼2.0 Hz,
J2¼8.0 Hz ArH), 7.44 (d, 1H, J¼8.0 Hz, ArH), 7.55 (d, 1H, J¼2.0 Hz,
2H, CH2), 4.50 (q, 2H, J¼7.2 Hz, CH2), 6.76 (s, 1H, CH), 7.55e7.66 (m,
4H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.8, 14.1, 14.4, 62.3, 63.1,
68.0, 76.4, 121.9, 125.4, 125.5, 127.2, 128.5, 129.1, 129.4, 131.0, 131.5,
ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 13.9, 14.2, 14.5, 62.5, 63.3,
134.1, 137.8, 141.5, 148.5, 151.2, 152.3; 19F NMR (CDCl3, 282 MHz,
68.1, 76.1, 126.3, 129.0, 130.6, 132.7, 133.5, 138.1, 148.5, 152.3; IR
CFCl3)
d
ꢁ63.1; IR (CH2Cl2):
n
2929, 2856, 1752, 1725, 1703, 1643,
(CH2Cl2): n 2956, 2926, 2855, 1731, 1648, 1536, 1459, 1375, 1350,
1457, 1407, 1370, 1348, 1303, 1269, 1166, 1141, 1021, 927, 905, 847,
779, 738, 700 cmꢁ1; MS (ESI) m/z (%): 404.3 [MþH]þ (100); MS (ESI)
calcd for C17H20F3N3NaO5 [MþH]þ requires 426.1256, found:
426.1247.
1266, 1170, 1018, 742 cmꢁ1; MS (ESI) m/z (%): 404.2 [MþH]þ (100);
MS (ESI) calcd for C16H19Cl2N3NaO5 [MþNa]þ requires 426.0594,
found: 426.0600.
4.2.9. Diethyl
azole-1,4-dicarboxylate (3h). Mp 145e146 ꢀC; 1H NMR (CDCl3,
400 MHz, TMS)
5-(2-chloro-4-nitrophenyl)-3-ethoxy-5H-1,2,4-tri-
4.2.4. Diethyl 3-ethoxy-5-(4-nitrophenyl)-5H-1,2,4-triazole-1,4-di-
carboxylate (3c). Mp 142e144 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
1.18 (t, 3H, J¼6.8 Hz, CH3), 1.24e1.28 (m, 3H, CH3),
d
1.20 (t, 3H, J¼7.2 Hz, CH3), 1.25e1.34 (m, 3H, CH3), 1.49 (t, 3H,
1.50 (t, 3H, J¼6.8 Hz, CH3), 4.14 (q, 2H, J¼6.8 Hz, CH2), 4.13e4.19 (m,
2H, CH2), 4.53 (q, 2H, J¼6.8 Hz, CH2), 7.12 (s, 1H, CH), 7.57 (d, 1H,
J¼8.8 Hz, ArH), 8.15 (dd, 2H, J1¼2.8 Hz, J2¼8.8 Hz ArH), 8.34 (d, 1H,
J¼7.2 Hz, CH3), 4.16 (q, 2H, J¼7.2 Hz, CH2), 4.18e4.27 (m, 2H, CH2),
4.50 (q, 2H, J¼7.2 Hz, CH2), 6.79 (s, 1H, CH), 7.64e7.68 (m, 2H, ArH),
8.22e8.27 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d
14.1, 14.3,
J¼2.8 Hz, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 13.9, 14.2, 14.4,
62.6, 63.3, 68.3, 74.2, 124.3, 124.9, 130.8, 137.5, 140.2, 146.9, 148.2,
14.6, 62.7, 63.4, 68.4, 76.2, 123.9, 128.1, 144.5, 148.5, 148.6, 152.4; IR
(CH2Cl2): 2931, 2856, 1750, 1733, 1700, 1684, 1558, 1533, 1464,
1373, 1269, 1140, 1019, 909, 852, 784, 739, 700 cmꢁ1; MS (ESI) m/z
n
152.1; IR (CH2Cl2):
n 2982, 2957, 2928, 2856, 1730, 1650, 1530, 1449,
1376, 1271, 1147, 1055, 901, 858, 741 cmꢁ1; MS (ESI) m/z (%): 415.3

Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
2023
[MþH]þ (100); MS (ESI) calcd for C16H19ClN4NaO7 [MþNa]þ
(CH2Cl2):
n 3321, 3097, 3062, 2975, 2931, 1697, 1532, 1448, 1350,
requires 437.0835, found: 437.0841.
1309, 1282, 1253, 1175, 1082, 1047, 819, 736, 724 cmꢁ1
.
4.2.10. Diethyl
5-cyclohexyl-3-ethoxy-5H-1,2,4-triazole-1,4-di-
4.3.3. Ethyl
(3,4-dichlorophenyl)(phenylsulfonyl)methylcarbamate
1.12 (t, 3H,
carboxylate (3i). Mp 132e135 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
(5g). Mp 133e135 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
d
1.09e1.15 (m, 5H, CH2), 1.31 (t, 3H, J¼7.2 Hz, CH3), 1.30e1.35 (m,
J¼6.9 Hz, CH3), 3.95 (q, 2H, J¼6.9 Hz, CH2), 5.91 (d, 1H, J¼9.6 Hz,
CH), 6.04 (d, 1H, J¼9.6 Hz, NH), 7.29e7.32 (m, 1H, ArH), 7.47e7.59
(m, 4H, ArH), 7.70 (t, 1H, J¼7.5 Hz, ArH), 7.89 (d, 2H, J¼7.5 Hz, ArH);
3H, CH3), 1.42 (t, 3H, J¼7.2 Hz, CH3), 1.67e1.78 (m, 5H, CH2), 4.24 (q,
2H, J¼7.2 Hz, CH2), 4.22e4.29 (m, 2H, CH2), 4.40 (q, 2H, J¼7.2 Hz,
CH2), 5.90 (d, 1H, J¼3.3 Hz, CH); 13C NMR (CDCl3, 75 MHz, TMS)
13C NMR (CDCl3,100 MHz, TMS)
d 14.3, 62.2, 73.2,128.1,129.2,129.4,
d
14.1, 14.6, 25.8, 26.0, 26.2, 26.9, 43.0, 62.2, 62.8, 67.6, 76.6, 149.8,
130.0, 130.6, 130.7, 133.0, 134.3, 134.4, 136.0, 154.8; IR (CH2Cl2):
3317, 3066, 2981, 2960, 2932, 1710, 1563, 1528, 1471, 1447, 1375,
1320, 1241, 1146, 1083, 1047, 772, 742, 720 cmꢁ1
n
154.0; IR (CH2Cl2): n 2982, 2931, 2855, 1753, 1728, 1642, 1449, 1399,
1375,1302,1231, 1134,1062, 1019, 964, 912, 890, 760 cmꢁ1; MS (ESI)
m/z (%): 342.3 [MþH]þ (100); MS (ESI) calcd for C16H28N3O5
[MþH]þ requires 342.2024, found: 342.2031.
.
4.3.4. Ethyl (2-chloro-4-nitrophenyl)(phenylsulfonyl)methylcarbamate
(5h). Mp 132e134 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
1.15 (t, 3H,
d
4.2.11. Diethyl
5-(4-chlorophenyl)-3-ethoxy-5H-1,2,4-triazole-1,4-
J¼6.9 Hz, CH3), 3.99 (q, 2H, J¼6.9 Hz, CH2), 6.49 (d, 1H, J¼10.5 Hz,
CH), 6.65 (d, 1H, J¼10.5 Hz, NH), 7.57e7.64 (m, 3H, ArH), 7.70e7.75
(m, 1H, ArH), 7.96 (d, 2H, J¼7.5 Hz, ArH), 8.21e8.25 (m, 1H, ArH),
dicarboxylate (3j). Mp 147e148 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
1.19 (t, 3H, J¼7.2 Hz, CH3), 1.17e1.22 (m, 3H, CH3), 1.46 (t, 3H,
J¼7.2 Hz, CH3), 4.14 (q, 2H, J¼7.2 Hz, CH2), 4.13e4.19 (m, 2H, CH2),
4.48 (q, 2H, J¼7.2 Hz, CH2), 6.68 (s, 1H, CH), 7.32e7.41 (m, 3H, ArH);
8.51 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.3, 62.3, 70.2,
124.7, 125.4, 129.4, 130.7, 130.8, 131.1, 134.7, 136.2, 142.1, 146.8,
154.8; IR (CH2Cl2): 3327, 3254, 3102, 2982, 2931, 1714, 1525,
1469, 1447, 1345, 1323, 1277, 1241, 1082, 1055, 828, 773, 741,
687 cmꢁ1
13C NMR (CDCl3, 100 MHz, TMS)
d
13.9, 14.3, 14.5, 62.3, 63.0, 68.0,
n
76.6, 128.3, 128.7, 135.2, 136.5, 148.6, 152.4; IR (CH2Cl2):
n 2984,
2935, 1756, 1726, 1645, 1448, 1400, 1341, 1263, 1127, 1014, 914, 832,
751 cmꢁ1; MS (ESI) m/z (%): 370.3 [MþH]þ (100); MS (ESI) calcd for
C16H20ClN3NaO5 [MþNa]þ requires 392.0984, found: 392.0993.
.
4.3.5. Ethyl 3-ethoxy-5-phenyl-1H-1,2,4-triazole-1-carboxylate (8). Mp
120e122 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
1.32 (t, 3H,
d
4.2.12. Di-tert-butyl 3-tert-butoxy-5-phenyl-5H-1,2,4-triazole-1,4-
J¼6.8 Hz, CH3), 1.46 (t, 3H, J¼6.8 Hz, CH3), 4.40 (q, 2H, J¼6.8 Hz,
dicarboxylate (7). Mp 140e142 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
CH2), 4.45 (q, 2H, J¼6.8 Hz, CH2), 7.43e7.53 (m, 3H, ArH),
d
1.32 (s, 9H, tert-(CH3)3), 1.36 (s, 9H, tert-(CH3)3), 1.64 (s, 9H, tert-
(CH3)3), 6.47 (s, 1H, CH), 7.32e7.34 (m, 3H, ArH), 7.40e7.42 (m, 2H,
ArH); 13C NMR (CDCl3, 100 MHz, TMS)
27.8, 28.0, 28.2, 75.8, 81.0,
82.8, 85.9, 126.9, 128.2, 128.8, 139.2,147.7,150.0; IR (CH2Cl2): 2979,
7.63e7.66 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 13.9,
14.6, 64.9, 66.1, 127.9, 128.4, 129.5, 130.7, 148.4, 159.2, 167.2; IR
d
(CH2Cl2): n 2957, 2927, 2855, 1767, 1730, 1555, 1530, 1448, 1379,
n
1351, 1323, 1268, 1083, 829, 742, 701 cmꢁ1; MS (ESI) m/z (%): 262.1
[MþH]þ (100); MS (ESI) calcd for C13H15N3NaO3 [MþNa]þ requires
284.1006, found: 284.1012.
2932, 1715, 1636, 1478, 1427, 1367, 1342, 1254, 1134, 929, 907, 850,
791, 750, 698 cmꢁ1; MS (ESI) m/z (%): 418.3 [MþH]þ (100); MS (ESI)
calcd for C22H33N3NaO5 [MþNa]þ requires 442.2312, found:
442.2317.
Acknowledgements
We thank theShanghai Municipal Committee of Science and
Technology (08dj1400100-2), National Basic Research Program of
China (973)-2009CB825300, and theNational Natural Science
Foundation of China for financial support (21072206, 20872162,
20672127, 20732008, 20821002 and 20702013) and Mr. Jie Sun for
performing X-ray diffraction.
4.3. Typical reaction procedure for the preparation of ethyl
phenyl(phenylsulfonyl)methylcarbamate 5a
To a mixture of benzaldehyde (10.8 mmol) and ethyl carba-
mate (10.0 mmol) in THF (4.0 mL) was added water (10 mL), so-
dium benzenesulfinate dihydrate (10.0 mmol) and formic acid
(2.4 mL). After the reaction mixture was stirred for 12e24 h, the
reaction solution was treated with water (20 mL), and filtrated.
The solid product was washed with ether (10 mLꢂ3) to afford
pure product 5a.
Supplementary data
The spectroscopic charts (1H, 13C NMR spectra data) of the
compounds shown in Tables 1e3 and X-ray of 2 and 3a are included
in the Supplementary data. Supplementary data related to this
article can be found online at doi:10.1016/j.tet.2011.01.072.
4.3.1. Ethyl (2-nitrophenyl)(phenylsulfonyl)methylcarbamate (5d). Mp
130e132 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
1.14 (t, 3H, J¼7.2 Hz,
CH3), 3.99 (q, 2H, J¼7.2 Hz, CH2), 6.30 (d, 1H, J¼6.8 Hz, CH), 7.45 (d,
1H, J¼6.8 Hz, NH), 7.57e7.66 (m, 3H, ArH), 7.69e7.75 (m, 3H, ArH),
7.97 (d, 2H, J¼7.6 Hz, ArH), 8.15 (d, 1H, J¼7.6 Hz, ArH); 13C NMR
References and notes
1. (a) Kasai, M.; Kono, M. Synlett 1992, 778e790; (b) Regueiro-Ren, A.; Borzilleri, R.
M.; Zheng, X.; Kim, S.; Johnson, J. A.; Fairchild, C. R.; Lee, F. Y. F.; Long, B. H.; Vite,
G. D. Org. Lett. 2001, 3, 2693e2696; (c) Louw, A.; Swart, P.; Allie, F. Biochem.
Pharmacol. 2000, 59, 167e175; (d) Dvorakova, K.; Payne, C. M.; Tome, M. E.;
Briehl, M. M.; McClure, T.; Dorr, R. T. Biochem. Pharmacol. 2000, 60, 749e758;
(e) Furmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649e659.
(CDCl3, 100 MHz, TMS)
d 14.3, 62.2, 69.0, 125.3, 125.8, 129.1, 129.3,
129.4, 130.6, 133.6, 134.6, 136.6, 149.1, 154.6; IR (CH2Cl2):
3003, 1735, 1582, 1534, 1480, 1351, 1309, 1279, 1149, 1083, 859, 788,
757, 707 cmꢁ1
n 3349,
.
2. (a) Ye, L.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140e1152; (b) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035e1050; (c) Lu, X.; Zhang, C.; Xu, Z.
Acc. Chem. Res. 2001, 7, 535e544; (d) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 8, 520e530; (e) Lu, X.; Du, Y.; Lu, C.
Pure Appl. Chem. 2005, 77, 1985e1990; (f) Kwong, C. K.; Fu, M. Y.; Lam, C. S.; Toy,
4.3.2. Ethyl (3-nitrophenyl)(phenylsulfonyl)methylcarbamate (5e). Mp
129e131 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
1.13 (t, 3H, J¼6.9 Hz,
CH3), 3.96 (q, 2H, J¼6.9 Hz, CH2), 6.09 (d, 1H, J¼10.8 Hz, CH), 6.24
(br s, 1H, NH), 7.56e7.62 (m, 3H, ArH), 7.65e7.74 (m, 1H, ArH), 7.85
(d, 1H, J¼7.8 Hz, ArH), 7.91e7.94 (m, 2H, ArH), 8.30 (d, 2H, J¼7.8 Hz,
€
P. H. Synthesis 2008, 15, 2307e2317; (g) Lesch, B.; Torang, J.; Vanderheiden, S.;
€
Brase, S. Adv. Synth. Catal. 2005, 347, 555e562; (h) Shi, Y.-L.; Shi, M. Org. Biomol.
Chem. 2005, 3, 1620e1621; (i) Qi, M.-J.; Shi, M. Tetrahedron 2007, 63,
€
10415e10424; (j) Nising, C.; Brase, S. Chem. Soc. Rev. 2008, 37, 1218e1228;
ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.3, 62.3, 73.4, 76.7, 123.7,
(k) Cowen, B. J.; Miller, J. S. Chem. Soc. Rev. 2009, 38, 3102e3113; (l) Wei, Y.; Shi,
M. Acc. Chem. Res. 2010, 43, 1005e1018.
124.6, 129.3, 129.5, 129.7, 132.1, 134.6, 135.1, 135.9, 148.2, 154.8; IR

2024
Z. Lian et al. / Tetrahedron 67 (2011) 2018e2024
3. For reviews, see Ref. 2c, for some examples see: (a) Zhang, C.; Lu, X. J. Org. Chem.
1995, 60, 2906e2908; (b) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461e3464; (c)
Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481e4484; (d) Lu, Z.; Zheng, S.; Zhang, X.;
Lu, X. Org. Lett. 2008, 10, 3267e3270; (e) Du, Y.; Lu, X.; Zhang, C. Angew. Chem.,
Int. Ed. 2003, 42, 1035e1037.
4. (a) Zhu, X.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716e4717; (b) Tran, Y. S.;
Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632e12633; (c) Zhao, G.-L.; Huang, J.-W.;
Shi, M. Org. Lett. 2003, 5, 4737e4739; (d) Zhu, X.-F.; Henry, C. E.; Kwon, O. J. Am.
Chem. Soc. 2007, 129, 6722e6723; (e) Moreno-Clavijo, E.; Carmona, A. T.; Reissig,
H.-U.; Moreno-Vargas, A. J.; Alvarez, E.; Robina, I. Org. Lett. 2009, 11, 4778e4781;
(f) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276e6282; (g) Zhao,
G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975e9984; (h) Song, M.; Montgomery, J.
Tetrahedron 2005, 62, 457e460; (i) Creech, G. S.; Kwon, O. Org. Lett. 2008, 10,
429e432; (j) Yu, X.; Lu, X. Org. Lett. 2009, 11, 4366e4369.
6. The crystal data of 2 have been deposited in CCDC with number 798642. Em-
pirical Formula: C16H20N4O7; Formula Weight: 380.36; Crystal size: 0.269ꢂ0.
225ꢂ0.137; Crystal Color, Habit: colorless; Crystal System: Orthorhombic; Lat-
ꢀ
ꢀ
tice Type: Primitive; Lattice Parameters: a¼26.476(4) A, b¼8.5138(12) A, c¼16.
3
ꢀ
ꢀ
ꢀ
707(2) A,
a
¼90ꢀ,
b
¼90ꢀ,
g
¼90 , V¼3766.0(9) A ; Space group: Pca2(1); Z¼8;
Dcalcd¼1.342 g/cm3; F000¼1600; R1¼0.0667, wR2¼0.1760. Diffractometer: Rigaku
AFC7R
7. The crystal data of 3a havebeen deposited in CCDC with number 798091. Empirical
Formula: C18H25N3O5; Formula Weight: 363.41; Crystal size: 0.369ꢂ0.303ꢂ0.217;
Crystal Color, Habit: colorless; Crystal System: Orthorhombic; Lattice Type:
ꢀ
ꢀ
ꢀ
Primitive; Lattice Parameters: a¼7.1904(5) A, b¼11.3451(8) A, c¼24.3590(17) A,
3
ꢀ
ꢀ
a
¼90ꢀ,
b
¼90ꢀ,
¼90 , V¼1987.1(2) A ; Space group: P2(1)2(1)2(1); Z¼4; Dcalcd¼1.
g
215 g/cm3; F000¼776; R1¼0.0693, wR2¼0.2227. Diffractometer: Rigaku AFC7R
8. (a) Brunn, E.; Huisgen, R. Angew. Chem., Int. Ed. Engl. 1969, 513e515; (b) Cookson,
R. C.; Locke, J. M. J. Chem. Soc. 1963, 6062e6064.
5. (a) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234e12235.