Highly controlling selectivity of copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC) between sulfonyl azids and normal alkynes or propynoates

Article abstract of DOI:10.1016/j.tet.2011.06.017

In this article, a combination of Cu(OAc)₂·H ₂O/2-aminophenol was developed as a highly efficient and controlling catalytic system for sulfonyl azids involved CuAAC. By using this catalytic system, sulfonyl azids reacted with normal

Full text of DOI:10.1016/j.tet.2011.06.017

Tetrahedron 67 (2011) 6294e6299
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly controlling selectivity of copper(I)-catalyzed azide/alkyne cycloaddition
(CuAAC) between sulfonyl azids and normal alkynes or propynoates
*
*
Yantao Liu, Xinyan Wang , Jimin Xu, Qun Zhang, Yi Zhao, Yuefei Hu
Department of Chemistry, Tsinghua University, Beijing 100084, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2011
Received in revised form 27 May 2011
Accepted 7 June 2011
Available online 14 June 2011
In this article, a combination of Cu(OAc)2$H2O/2-aminophenol was developed as a highly efficient and
controlling catalytic system for sulfonyl azids involved CuAAC. By using this catalytic system, sulfonyl
azids reacted with normal alkynes or propynoates to selectively give the ring products or the chain
products, respectively, in excellent yields within minutes. HOAc in situ produced in the reaction has been
proved to be a super protonation reagent, by which the unstable intermediate 5-cuprated 1,2,3-triazole
was protonated efficiently to yield ring-product 1-sulfonyl 1,2,3-trizoles. The control experiments also
proved that 2-aminophenol played dual roles as both ligand and reductant, which led to the cheap and
chemically stable Cu(OAc)2$H2O being an efficient copper source for our purpose.
Keywords:
Copper(I) catalyst
Azide/alkyne cycloaddition
Sulfonyl azids
Ó 2011 Elsevier Ltd. All rights reserved.
Copper(II) acetate
2-Aminophenol
1. Introduction
ring-product
R
R
SO2R1
SO2R1
R
N
N N
3
X
1
In 2002, the first copper(I)-catalyzed azide/alkyne cycloaddition
(CuAAC) was discovered independently by the groups of Sharpless1
and Meldal,2 by which 1,4-disubstituted 1,2,3-triazoles were pre-
pared regioselectively under mild conditions.3 3 years later, Chang4
discovered that when an electron-deficient sulfonyl azide (2) was
used as a substrate, instead of the ring-product 1-sulfonyl-1,2,3-
triazole (3), a chain-product N-sulfonylamidine (4) was obtained
in the presence of a primary or secondary amine (Scheme 1). His
further works proved that the chain-product N-sulfonylimidate
(5)5a or N-sulfonyl amide (6)5b could also be synthesized by the
similar procedures when alcohol or H2O was used as a nucleophile,
respectively. To date, Chang’s reaction and products have widely
used in organic synthesis.6,7
The mechanismstudies revealthatboth ringproduct(3)and chain
product (4e6) share the 5-cuprated 1,2,3-triazole (7) as a common
intermediate. But, the electron-withdrawing substituents on 7 seri-
ously reduce the stability of 7 and cause its NeN bondcleavage to give
ring-opening product (Scheme 2).8 Therefore, although the ring-
product 3 have been used as important intermediates9 or latent diazo
precursors10 inorganic synthesis, its efficient synthesis by CuAAC was
rarely described in literature.8a,11 However, the mechanism studies
[Cu(I)]
+
Chang's conditions
Nu
R1SO2N3
chain-product
Nu-H
N
2
Nu-H = amines for 4; alcoholes for 5; water for 6
Scheme 1.
also clearly indicated that the distribution of ring and chain products
depended upon the competitive reactions between the protonation
and ring-opening of 7. Thus, highly efficient synthesis of the ring-
product 3 might be expected by developing a highly efficient pro-
tonation reagent or procedure.
[Cu]
H
H+
R
SO2R1
R
SO2R1
[Cu]
1
N
N
N
+
R
R SO2N3
protonation
N
N
N
1
2
7
3
Nu-H
Nu
R
R
[Cu]
N
H+
-[Cu], -N2
Nu-H
R
.
N
SO2R1
N+
N
H
SO2R1
SO2R1
-N
4-6
* Corresponding authors. Tel.: þ86 10 6279 5380; fax: þ86 10 6277 1149; e-mail
addresses: wangxinyan@mail.tsinghua.edu.cn (X. Wang), yfh@mail.tsinghua.edu.cn
(Y. Hu).
Scheme 2.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.017

Y. Liu et al. / Tetrahedron 67 (2011) 6294e6299
6295
2. Results and discussion
Similar to CuSO4$5H2O/NaAsc, both the catalysts CuOAc and
Cu(OAc)2$H2O lost their catalytic activity within 2 h and gave 3a as
a major product in low conversions (entries 3 and 4). However,
when the same reactions proceeded under N2, higher conversions
were obtained and CuOAc catalyzed reaction could finish within 4 h
(entries 5 and 6). By the addition of some ligands, such as PPh3,
DMAP, DIPEA, HOCH2CH2OH, HOCH2CH2NH2 or H2NCH2CH2NH2,
no significant improvements were observed for both conversion
and selectivity. To our delight, when 2-aminophenol (8a) was used
as a ligand, both CuOAc and Cu(OAc)2$H2O gave similarly good
results even without the protection of N2 (entries 7 and 8). To our
surprising, when the mixture of 1a (1.1 equiv), 2a (1 equiv),
Cu(OAc)2$H2O (0.1 equiv), and 2-aminophenol (8a, 0.1 equiv) in
EtOH was heated at 50 ꢀC for 1 h, 3a was obtained as a major
product in 68% yield (entries 9). Thus, the combination of
Cu(OAc)2$H2O/8a (entry 8) may be an efficient catalytic system
with high selectivity for the ring product and with two advantages
by comparing with the entries 5e7. (a) In entry 8, the cheap and
chemically stable Cu(OAc)2$H2O was used as a copper source. But,
CuOAc was used in entries 5 and 7, which is around 50 times more
expensive than Cu(OAc)2$H2O and chemically unstable for storage.
(b) In entry 8, Cu(I) species may be generated from the redox be-
tween Cu(II) and 2-aminophenol (8a). But, the Cu(I) species was
confirmed to be generated from the Cu(II) promoted oxidative
coupling of phenylacetylene (1a) in entry 6, by which the large
amounts of acetylene was wasted and the amount of Cu(I) largely
depended upon the reactivity of individual acetylenes.
In 2007, Straub12 reported that the CeCu bond in 5-cuprated
1,2,3-triazole (as a coordination compound) can be protonated by
HOAc within few minutes. Very recently, we reported a novel
copper(I) acetate catalyzed CuAAC reaction,13 in which the CeCu
bond can be protonated within 5 min by the in situ formed HOAc.
As shown in Scheme 3, this efficient protonation was indirectly
proved by an isotopic labeling experiment. This result strongly
encouraged us to develop a copper(I) acetate catalyzed CuAAC for
efficient synthesis of the ring-product 3 from the electron-deficient
sulfonyl azides (2).
H
H2O, t-BuOH/H2O (1:2 by v/v)
or t-BuOH, rt, 5 h
no reaction
Ph
Ph
Bn
Bn
N
X
PhC CCu (1.0 equiv)
N
N
N
+
D
DOAc (1.0 equiv)
C6H12, rt, 5 min
BnN3 (1.1 equiv)
N
98% yield and 97% D
N
Scheme 3.
Thus, a group of control experiments were designed for CuAAC
between phenylacetylene (1a) and p-tolenesulfonyl azide (2a). To
clearly identify the ring-chain selectivity of the catalysts, EtOH was
used as a solvent (Table 1). As was expected, by using the popular
catalytic system CuI/Et3N, the chain-product 5a was obtained as
a major product in 86% yield (entry 1). When the other popular
catalytic system CuSO4$5H2O/NaAsc was used, its catalyzed re-
action stopped automatically within 2 h. Although it gave a very
low conversion, the ring-product 3a was the major product (entry
2). This is a very exciting result because the in situ formed HAsc
behaves as a vinylogous carboxylic acid having pKa values of 4.10
and 11.79, respectively (pKa value of acetic acid is 4.76). In-
terestingly, no H2O involved product was detected even H2O was
a necessary co-solvent in this reaction.
Then, different solvents were scanned to find their effects on the
catalytic activity of Cu(OAc)2$H2O/8a. As shown in Table 2, the ring-
product 3a was obtained in excellent yields in all non-protonic
solvents (entries 1e5) and the best result was obtained in MeCN
(entry 5). The chemoselectivity of Cu(OAc)2$H2O/8a was so good
that 3a was formed as a single product even the reaction proceeded
in H2O (entry 6). We found that it was a two-phase reaction and the
organic layer was surrounded by H2O. Therefore, it actually is also
a solvent-free reaction and the reactants could contact with H2O
only on the interface.
Table 2
Effects of solvents on the catalytic activity of Cu(OAc)2$H2O/8aa
Cu(OAc)2.H2O (0.1 equiv)
8a (0.1 equiv), solvent, rt
Table 1
1a
+
2a
3a
Yield of 3ab (%)
Effects of the catalysts on the ring-chain selectivitya
H
Entry
Solvent
Time (h)
Ph
Ph
SO2Tol
SO2Tol
Ph
1
2
3
4
5
6
PhMe
EtOAc
CH2Cl2
THF
MeCN
H2O
14
14
5
2
1
88
93
91
95
95
86
3a
N
N
1a
N
[Cu]-catalyst, EtOH, rt
+
+
OEt
TolSO2N3
2a
1.2
5a
N
a
The mixture of 1a (1.1 mmol), 2a (1.0 mmol), Cu(OAc)2$H2O (0.1 mmol), and 8a
(0.1 mmol) in solvent (1 mL) was stirred at room temperature.
Entry Cu(I) Catalyst (0.1 equiv) Time (h) Yield of 3ab (%) Yield of 5ab (%)
b
The isolated yields were obtained.
1
CuI/Et3N
CuSO4$5H2O/NaAsc
CuOAc
Cu(OAc)2$H2O
CuOAc
Cu(OAc)2$H2O
CuOAc/8a
3
24
24
24
4
16
2
2
5
38
42
40
74
71
76
77
68
86
3
5
6
8
3
3
3
17
2c
3
Next, the effects of ratios of Cu(OAc)2$H2O/8a on the catalytic
activity were tested. As shown in Table 3, although the 1:2 ratio of
copper source/ligand usually was employed in the ligand-mediated
CuAAC in literature, the worst result was obtained with the 1:2
ratio of Cu(OAc)2$H2O/8a (entry 2). This may be caused by the fact
that a stable 1:2 coordination product was formed (Chart 1),14 by
which the reduction of Cu(II) and the catalytic cycle of the in situ
formed Cu(I) may be retarded. On the contrary, the 2:1 ratio of
Cu(OAc)2$H2O/8a showed the highest catalytic activity (entry 4).
This result suggested that the ligand 8a may be used to dissociate
Cu(II) from the stable dinuclear ‘paddle-wheel’ coordination
structure in Cu(OAc)2$H2O (Chart 1) or dissociate Cu(I) from the
coordination of MeCN, which has been proved to retard the
4
5d
6d
7
8
Cu(OAc)2$H2O/8a
Cu(OAc)2$H2O/8a
9e
1
a
The mixture of 1a (1.1 mmol), 2a (1.0 mmol), and catalyst (0.1 mmol) in EtOH
(1 mL) was stirred at room temperature.
b
The isolated yields were obtained.
The mixture of EtOH/H2O (1:1) was used as a solvent for the reason of the sol-
c
ubility of CuSO4$5H2O and NaAsc.
d
The reaction was protected under N2.
The reaction was proceeded at 50 ꢀC.
e

6296
Y. Liu et al. / Tetrahedron 67 (2011) 6294e6299
Table 3
benzenediamines 11aec or excess amount of 8a. (b) It was a re-
Effects of the ratio of Cu(OAc)2$H2O/8a on the catalytic activitya
ductant to reduce Cu(II) into Cu(I) in situ through the formation of
1,2- or 1,4-quinones. This may be the reason that 8b and 10b had
low or no promotion activity because they could not be converted
into quinones.
Cu(OAc)2.H2O (0.1 equiv)
8a, MeCN, rt, 20-360 min
1a
2a
+
3a
Yield of 3ab (%)
Finally, 8a was chosen as the ligand for our purpose because it is
a nonhygroscopic crystal and Cu(OAc)2$H2O/8a (2:1 by mole) in
MeCN was chosen as the standard conditions. To generalize this
method, different alkynes (1aeg) and sulfonyl azides (2aec) were
tested under the standard conditions. As shown in Scheme 5, they
all gave the desired 1-sulfonyl-1,2,3-triazoles (3aei) in excellent
yields within minutes. Since the method was performed under
extremely mild conditions, many sensitive functional groups stayed
intact, such as tertiary alcohol (3c), benzyl ether (3d), and N-Boc
protective group (3e). When benzenesulfonyl azide (2b) or meth-
ansulfonyl azide (2c) was used as a substrate, 3h or 3i was obtained
in 91% or 92% yield, respectively.
Entry
Cu(OAc)2$H2O/8a (by mole)
Time (min)
1
2
3
4
5
1:3
1:2
1:1
2:1
3:1
360
360
60
20
90
74
52
95
95
87
a
The mixture of 1a (1.1 mmol), 2a (1.0 mmol), Cu(OAc)2$H2O (0.1 mmol), and 8a
in MeCN (1 mL) was stirred at room temperature.
b
The isolated yields were obtained.
Me
Me
H
O
Cu
O
O
H2
N
O
O
O
O
H
Cu
H
O
Cu
O
O
H
Cu(OAc)2.H2O (0.1 equiv)
8a (0.05 equiv)
MeCN, 20-50 min, rt
45-96%
N
O
O
Me
H2
R
SO2R1
Me
N
N N
3a-3i
R1SO2N3
R
+
.
A stable coordination product from
Cu(OAc)2 H2O as a dinuclear coordination
.
1:2 ratio of Cu(OAc)2 H2O and 8a
compound with stable "paddle-wheel" structure
1a-1g
2a-2c
Chart 1.
Ph
SO2Tol
SO2Tol
4-MeOC6H4
SO2Tol
N
N
N
N
N
N N
HO
catalytic cycle of Cu(I) in our previous works.13bThus, the real cat-
alyst may be a copper coordination compound with mixed ligands
including 8a, acetate anion and/or MeCN.
N
N
a
3a (20 min, 95%)
from 1a and 2a
3b (30 min, 96%)
from 1b and 2a
3c (30 min, 92%)
from 1c and 2a
n
To further understand the relationship between structure and
promotion activity of 8a, three aminophenol isomers 8aec were
tested as shown in Scheme 4. To our surprise, 8c showed the same
excellent promotion activity as 8a. Since 8c is not a chelating ligand,
therefore the monodentate ligands aniline (9a) and phenol (9b)
were tested. As was expected, 9a had the similar promotion activity
as 8b, while 9b almost had no promotion activity. This result seems
that the hydroxyl group had less importance than amine group, but
it was not true when benzenediols (10aec) and benzenediamines
(11aec) were evaluated. For example, although 10b in fact was
inert, the promotion activity of 10a and 10c was as high as that of 8a
and 8c. On the contrary, none of 11aec showed satisfying pro-
motion activity.
SO2Tol
Bu
SO2Tol
N
N N
SO2Tol
N
N
N
N
BocHN
BnO
N
N
3d (30 min, 90%)
from 1d and 2a
3e (30 min, 94%)
from 1e and 2a
3f (30 min, 95%)
from 1f and 2a
MeO2C
SO2Tol
Ph
SO2Ph
Ph
SO2Me
N
N N
N
N
N
N
N
N
b
3g (50 min, 45%)
from 1g and 2a
3h (20 min, 91%)
from 1a and 2b
3i (20 min, 92%)
from 1a and 2c
aThe isolated yields were obtained. bThe reaction proceeded at 0 oC.
Scheme 5.
It is very noteworthy that ethyl 1-(toluene-4-sulfonyl)-1H-
[1,2,3]triazole-4-carboxylate (3g, Scheme 5) can be synthesized in
45% yield when methyl propynoate (1g) was used as a substrate at
0 ꢀC. This is the first example that [1,2,3]triazole bearing two strong
electron-withdrawing groups was prepared by CuAAC. In further
studies on 1g, we found that its reaction with 2a was very sensitive
to the nucleophiles and the chain-product 6b was produced as
a single product in the presence of EtOH. As shown in Scheme 6,
when the mixture of 1a, 1g, and 2a in MeCN/EtOH was treated by
Cu(OAc)2$H2O/8a, a highly ring-chain selectivity was achieved to
give the corresponding ring-product 3a and chain-product 6b in
excellent yields.
Cu(OAc)2.H2O (0.1 equiv)
8-11 (0.05 equiv), MeCN, rt
1a
+
2a
3a
OH
OH
NH2
NH2
NH2
OH
NH2
a
c
c
c
8a (20 min, 95%)
HO NH2
9a (30 min, 81%) 10a (30 min, 93%)
11a (60 min, 62%)
OH
HO
OH
H2N
NH2
Ph
SO2Tol
TolSO2N3 (2a, 2 equiv)
Cu(OAc)2.H2O (0.2 equiv)
8a (0.1 equiv), MeCN
N
b
b
Ph
8b (30 min, 84%)
9b (12 h, 10%)
10b (12 h, 7%)
11b (45 min, 43%)
N
N
1a (1 equiv)
3a (93%)
NH2
OH
NH2
EtOH (1.1 equiv), rt, 40 min
+
+
HO
HO
H2N
11c (45 min, 46%)
SO2Tol
OEt
O
N
8c (30 min, 96%)
10c (30 min, 92%)
MeO2C
1g (1 equiv)
aThe isolated yields were obtained for all examples. bThe reaction was
quenched at 12 h. cThe time is that reactant 2a was exhausted.
MeO
6b (90%)
Scheme 6.
Scheme 4.
Based on the results in Table 3 and Scheme 4, we proposed that
a satisfying ligand in Cu(OAc)2$H2O catalyzed CuAAC may play dual
roles. (a) It was a ligand to loosely coordinate with Cu(II) or Cu(I)
species, because unsatisfying results were obtained by using
It is well-known that active methylene compounds are the
versatile synthones in organic synthesis, therefore, CuAAC reaction
between sulfonyl azids and propynoates may afford a practical
method for the preparation a series of structurally novel active

Y. Liu et al. / Tetrahedron 67 (2011) 6294e6299
6297
methylene compounds. Thus, the reaction between propynoates
4. Experimental section
4.1. General
(1gei) and sulfonyl azids (2aec) catalyzed by Cu(OAc)2$H2O/8a
was studied in alcohols and H2O. As shown in Scheme 7, after the
mixture of 1g, 2a, Cu(OAc)2$H2O/8 in EtOH was stirred at room
temperature for 15 min, the desired chain-product 6b was
obtained in 95% yield. It is clear to observe that the size of pro-
pynoate had no negative effect on the reaction efficiency (see
samples: 6bed). However, the size of nucleophile showed signif-
icant effect on the reaction time (see samples: 6eei) and the
preparation of 6i took for 100 min in t-BuOH. When H2O was used
as a solvent, the corresponding N-Ts amides 6l and 6m were
obtained in excellent yields.
All melting points were determined on a Yanaco melting
point apparatus and are uncorrected. IR spectra were recorded
on a Nicolet FT-IR 5DX spectrometer with KBr. The 1H NMR and
13H NMR spectra were recorded on a JEOL JNM-ECA 300 spec-
trometer in CDCl3 with TMS as internal reference. The J values
are given in hertz. MS (EI) were recorded on a VG-ZAB-MS
spectrometer with 70 eV. Elementary analysis data were
obtained on a PerkineElmer-241C apparatus. PE is petroleum
ether (60e90ꢀ).
Cu(OAc)2.H2O (0.1 equiv)
SO2R1
8a (0.05 equiv)
4.2. A Typical procedure for the preparation of ring-product
4-phenyl-1-(toluene-4-sulfonyl)-1H-[1,2,3]triazole (3a)
O
N
R2OH, 10-100 min, rt
90-97%
R1SO2N3
RO2C
1g-1i
+
RO
O
OR2
2a-2c
6b-6m
To a stirred solution of phenylacetylene (1a, 112 mg, 1.1 mmol),
4-methylbenzenesulfonyl azide (2a, 197 mg, 1 mmol), and 2-
aminophenol (8a, 5.5 mg, 0.05 mmol) in MeCN (1 mL) was added
Cu(OAc)2$H2O (20 mg, 0.1 mmol) at room temperature. After 2a
was exhausted (ca. 20 min, monitored by TLC), the solvent was
removed off in vacuum. The residue was purified by chromatog-
raphy (silica gel, 10% EtOAc in PE) to give desired product 3a as
a colorless solid (284 mg, 95%), mp 104e105 ꢀC (EtOAc/PE) (lit.11a
SO2Tol
SO2Tol
SO2Tol
O
N
O
N
N
t
MeO
OEt
EtO
OEt
BuO
OEt
a
6b (15 min, 95%)
6c (10 min, 97%)
from 1h and 2a in EtOH
6d (15 min, 94%)
from 1g and 2a in EtOH
from 1i and 2a in EtOH
SO2Tol
SO2Tol
SO2Tol
O
N
O
N
O
N
n
O Pr
i
EtO
OMe
EtO
EtO
O Pr
105.2e107 ꢀC, lit.8a 107e108 ꢀC). 1H NMR
8.03e8.00 (m, 2H), 7.84e7.80 (m, 2H), 7.42e7.36 (m, 5H), 2.43 (s,
3H); 13C NMR
147.5, 133.2, 130.6 (2C), 129.2 (2C), 129.1 (2C), 129.0,
d 8.32 (s, 1H),
6e (15 min, 90%)
from 1h and 2a in MeOH
6f (10 min, 96%)
from 1h and 2a in n-PrOH
6g (20 min, 94%)
from 1h and 2a in i-PrOH
d
SO2Tol
SO2Tol
SO2Ph
O
N
O
N
O
N
128.8 (2C), 126.2 (2C), 119.1, 22.0.
By the similar procedure for the preparation of 3a, products
3bei were prepared.
n
O Bu
t
EtO
EtO
O Bu
EtO
OEt
6h (10 min, 95%)
from 1h and 2a in n-BuOH
6i (100 min, 90%)
from 1h and 2a in t-PrOH
6j (10 min, 96%)
from 1h and 2b in EtOH
SO2Me
O
NHSO2Tol
O
O
NHSO2Me
O
O
N
4.2.1. 4-(4-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-[1,2,3]tri-
azole (3b).10c It is a white solid, mp 100e101 ꢀC (EtOAc/PE). 1H NMR
EtO
EtO
EtO
OEt
6k (10 min, 94%)
6l (90 min, 92%)
from 1h and 2a in H2O
6m (90 min, 91%)
from 1h and 2c in H2O
d
8.22 (s, 1H), 8.02 (d, J¼8.6 Hz, 2H), 7.75 (d, J¼8.6 Hz, 2H), 7.38 (d,
from 1h and 2C in EtOH
J¼7.7 Hz, 2H), 6.95 (d, J¼8.8 Hz, 2H), 3.84 (s, 3H), 2.44 (s, 3H); 13C
aThe isolated yields were obtained for all products.
NMR
d 160.0, 147.1, 132.9, 130.3 (2C), 128.4 (2C), 127.2 (3C), 121.2,
118.0, 114.2 (2C), 55.1, 21.6.
Scheme 7.
4.2.2. 2-[1-(Toluene-4-sulfonyl)-1H-[1,2,3]triazol-4-yl]-propan-2-ol
3. Conclusion
(3c). It is a yellowish solid, mp 120e122 ꢀC (EtOAc/PE) (lit.8a
122e123 ꢀC). 1H NMR
d
8.04e7.98 (m, 3H), 7.40e7.37 (m, 2H),
2.64 (s, 1H), 2.45 (s, 3H), 1.61 (s, 6H); 13C NMR
155.1, 147.3, 132.9,
130.4 (2C), 128.7 (2C), 119.1, 68.5, 30.1 (2C), 21.8.
By using electron-deficient sulfonyl azids as substrates, CuAAC
tends to yield chain products in the presence of nucleophiles.
Since the mechanism studies proved that the ring and chain
products share 5-cuprated 1,2,3-triazole (7) as a common in-
termediate, therefore, it is expected to obtain the ring product by
a highly competitive protonation of 7. We found that the in situ
formed HOAc in CuOAc catalyzed CuAAC was a super protonation
reagent for 5-cuprated 1,2,3-triazole (7), by which the ring product
can be obtained as a major product even by using EtOH as a sol-
vent. We also found that CuOAc could be replaced by
Cu(OAc)2$H2O as a highly active catalyst in the presence of 2-
aminophenol (8a). Since the best catalytic result was obtained
with the 2:1 ratio of Cu(OAc)2$H2O/2-aminophenol (8a), this
strange phenomenon was further studied to reveal that 2-
aminophenol (8a) played dual roles as both ligand and re-
ductant. Finally, the combination of Cu(OAc)2$H2O/2-aminophenol
(8a) was developed as a highly efficient and controlling catalytic
system for CuAAC. By using this catalytic system, sulfonyl azids
reacted with normal alkynes or propynoates to selectively give the
ring products or the chain products, respectively. This catalytic
system characterized to use cheap and chemically stable
Cu(OAc)2$H2O as copper source and all examples were made in
excellent yields within minutes.
d
4.2.3. 4-Benzyloxymethyl-1-(toluene-4-sulfonyl)-1H-[1,2,3]triazole
(3d). It is a gray white solid, mp 80e81 ꢀC (EtOAc/PE) (lit.11a
85.1e86.7 ꢀC). 1H NMR
d
8.10 (s, 1H), 7.99 (d, J¼8.3 Hz, 2H),
7.39e7.33 (m, 7H), 4.66 (s, 2H), 4.60 (s, 2H), 2.45 (s, 3H); 13C NMR
147.3, 145.0, 137.2, 132.8, 130.3 (2C), 128.6 (2C), 128.4 (2C), 127.9,
d
127.8 (2C), 122.2, 72.9, 63.0, 21.7.
4.2.4. [1-(Toluene-4-sulfonyl)-1H-[1,2,3]triazol-4-ylmethyl]-carba-
mic acid tert-butyl ester (3e). It is a yellowish solid, mp 111e113 ꢀC
(EtOAc/PE) (lit.8a 117e118 ꢀC). 1H NMR
d
8.08 (s, 1H), 8.00e7.97 (m,
2H), 7.40e7.37 (m, 2H), 5.07 (s, 1H), 4.40e4.38 (m, 2H), 2.45 (s, 3H),
1.43 (s, 9H); 13C NMR
155.7, 147.3, 145.4, 132.8, 130.4 (2C), 128.6
d
(2C), 121.7, 79.9, 35.7, 28.2 (3C), 21.7.
4.2.5. 4-Butyl-1-(toluene-4-sulfonyl)-1H-[1,2,3]triazole (3f). It is
a yellowish oil. IR
7.98 (d, J¼8.6 Hz, 2H), 7.91 (s,1H), 7.37 (d, J¼8.6 Hz, 2H), 2.73e2.68
n ;
3472, 3134, 2963, 1606, 1455 cmꢁ1 1H NMR
d
(m, 2H), 2.43 (s, 3H), 1.66e1.61 (m, 2H), 1.39e1.32 (m, 2H), 0.90 (t,
J¼7.2 Hz, 3H); 13C NMR
d 148.1, 146.9, 133.0, 130.2 (2C), 128.3 (2C),
120.2, 30.7, 24.8, 21.9, 21.5, 13.5; MS m/z (%) 172 (100), 91 (71). Anal.

6298
Y. Liu et al. / Tetrahedron 67 (2011) 6294e6299
Calcd. For C13H17N3O2S: C, 55.89; H, 6.13; N, 15.04. Found: C, 56.11;
H, 6.02; N, 15.18.
299 (Mþ, 6), 91 (100). Anal. Calcd. For C13H17NO5S: C, 52.16; H, 5.72;
N, 4.68. Found: C, 52.43; H, 5.57; N, 4.71.
4.2.6. 1-(Toluene-4-sulfonyl)-1H-[1,2,3]triazole-4-carboxylic
acid
4.3.4. 3-Propoxy-3-(toluene-4-sulfonylimino)-propionic acid ethyl
ester (6f). It is a yellow oil. IR
methyl ester (3g). It is a white solid, mp 110e112 ꢀC (lit.15
n ;
3469, 3196, 1743, 1613, 1320 cmꢁ1
115e117 ꢀC). 1H NMR
d
8.63 (s, 1H), 8.02 (d, J¼8.6 Hz, 2H), 3.95 (s,
1H NMR
d
7.81 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.3 Hz, 2H), 4.20e4.13
3H), 2.47 (s, 3H); 13C NMR
128.8 (2C), 127.4, 52.5, 21.8.
d
159.9, 148.1, 139.0, 132.1, 130.6 (2C),
(m, 4H), 3.95 (s, 2H), 2.40 (s, 3H), 1.70e1.63 (m, 2H), 1.26 (t,
J¼7.2 Hz, 3H), 0.91 (t, J¼7.2 Hz, 3H); 13C NMR
d 167.6, 165.8, 143.2,
138.2, 129.1 (2C), 126.5 (2C), 70.5, 61.4, 39.7, 21.2, 21.1, 13.7, 9.9. MS
m/z (%) 286 (22), 172 (18), 155 (100). Anal. Calcd. For C15H21NO5S: C,
55.03; H, 6.47; N, 4.28. Found: C, 55.28; H, 6.36; N, 4.32.
4.2.7. 1-Benzenesulfonyl-4-phenyl-1H-[1,2,3]triazole
a white solid, mp 105e107 ꢀC (EtOAc/PE) (lit.7n 105e107 ꢀC).1H NMR
8.33 (s, 1H), 8.17e8.15 (m, 2H), 7.84e7.82 (m, 2H), 7.74e7.73 (m,
1H), 7.64e7.61 (m, 2H), 7.44e7.41 (m, 3H); 13C NMR
147.4, 136.2,
135.7,129.8 (2C),129.1,129.0 (2C),128.7,128.6 (3C),126.1 (2C),119.0.
(3h). It
is
d
d
4.3.5. 3-Isopropoxy-3-(toluene-4-sulfonylimino)-propionic acid ethyl
ester (6g). It is a yellowish oil. IR
1318 cmꢁ1; 1H NMR
7.81 (d, J¼8.3 Hz, 2H), 7.30 (d, J¼8.3 Hz, 2H),
5.14e5.10 (m, 1H), 4.22e4.15 (m, 2H), 3.91 (s, 2H), 2.42 (s, 3H),
1.28e1.23 (m, 9H); 13C NMR
166.8, 165.8, 143.1, 138.3, 129.0 (2C),
n 3469, 3196, 1743, 1612,
d
4.2.8. 1-Methanesulfonyl-4-phenyl-1H-[1,2,3]triazole
a white solid, mp 87e89 ꢀC (EtOAc/PE) (lit.11c 86e87 ꢀC). 1H NMR
8.31 (s, 1H), 7.88e7.85 (m, 2H), 7.47e7.41 (m, 3H), 3.57 (s, 3H); 13
NMR 147.4, 129.3, 129.1 (2C), 128.6, 126.1 (2C), 118.9, 42.6.
(3i). It
is
d
d
C
126.3 (2C), 72.7, 61.2, 39.9, 21.1, 20.7 (2C), 13.6; MS m/z (%) 286 (9),
172 (11),155 (84), 91 (100). Anal. Calcd. For C15H21NO5S: C, 55.03; H,
6.47; N, 4.28. Found: C, 55.31; H, 6.40; N, 4.34.
d
4.3. A Typical procedure for the preparation of chain-product
3-ethoxy-3-(toluene-4-sulfonylimino)-propionic acid methyl
ester (6b)
4.3.6. 3-Butoxy-3-(toluene-4-sulfonylimino)-propionic acid ethyl ester
(6h). It is a yellowish oil. IR
NMR
7.81 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.3 Hz, 2H), 4.20e4.15 (m,
n
3196, 2962, 1744, 1618, 1323 cmꢁ1; 1H
d
4H), 3.94 (s, 2H), 2.40 (s, 3H), 1.64e1.60 (m, 2H), 1.36e1.33 (m, 2H),
To a stirred solution of methyl propynoate (1g, 93 mg, 1.1 mmol),
4-methylbenzenesulfonyl azide (2a, 197 mg, 1 mmol), and 2-
aminophenol (8a, 5.5 mg, 0.05 mmol) in EtOH (1 mL) was added
Cu(OAc)2$H2O (20 mg, 0.1 mmol) at room temperature. After 2a
was exhausted (ca. 15 min, monitored by TLC), the solvent was
removed off in vacuum. The residue was purified by chromatog-
raphy (silica gel, 10% EtOAc in PE) to give desired product 6b as
1.25 (t, J¼7.2 Hz, 3H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR
d 167.5, 165.7,
143.1, 138.1, 129.0 (2C), 126.4 (2C), 68.7, 61.3, 39.6, 29.6, 21.1, 18.5,
13.6, 13.2; MS m/z (%) 286 (22), 172 (19), 155 (100). Anal. Calcd.
For C16H23NO5S: C, 56.29; H, 6.79; N, 4.10. Found: C, 56.48; H,
6.62; N, 4.35.
4.3.7. 3-tert-Butoxy-3-(toluene-4-sulfonylimino)-propionic
ethyl ester (6i). It is a yellow oil. IR 3529, 3068, 1724, 1597,
1349 cmꢁ1; 1H NMR
7.80 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.3 Hz, 2H),
acid
a white solid (284 mg, 95%). It is a colorless oil. IR
n
2982,1737,1595,
n
1462 cmꢁ1; 1H NMR
d
8.02 (d, J¼8.6 Hz, 2H), 7.32e7.27 (m, 2H), 4.24
d
(q, J¼6.9 Hz, 2H), 3.95 (s, 2H), 3.75 (s, 3H), 2.43 (s, 3H), 1.28 (t,
4.18 (q, J¼7.2 Hz, 2H), 3.86 (s, 2H), 2.41 (s, 3H), 1.46 (s, 9H), 1.26 (t,
J¼6.9 Hz, 2H); 13C NMR
d
167.5, 166.7, 143.5, 138.3, 129.3 (2C), 126.8
J¼7.2 Hz, 3H); 13C NMR
d 166.3, 166.0, 143.0, 138.6, 129.2 (2C), 126.3
(2C), 65.3, 52.6, 39.7, 21.5, 13.4; MS m/z (%) 299 (Mþ, 3.9), 155 (100).
Anal. Calcd. For C13H17NO5S: C, 52.16; H, 5.72; N, 4.68. Found: C,
52.41; H, 5.57; N, 4.71.
(2C), 86.1, 61.3, 40.8, 27.4 (3C), 21.3, 13.8; MS m/z (%) 171 (27), 155
(55), 108 (80), 91 (100). Anal. Calcd. For C16H23NO5S: C, 56.29; H,
6.79; N, 4.10. Found: C, 56.47; H, 6.86; N, 4.01.
By the similar procedure for the preparation of 6b, products
6cek were prepared. When H2O was used as a solvent, 6lem were
prepared.
4.3.8. 3-Benzenesulfonylimino-3-ethoxy-propionic acid ethyl ester
(6j). It is a yellowish oil. IR
NMR 7.96e7.93 (m, 2H), 7.56e7.50 (m, 3H), 4.26e4.20 (m, 4H),
3.95 (s, 2H), 1.30e1.28 (m, 6H); 13C NMR
167.7, 165.8, 141.0, 132.5,
n
3467, 3065, 1742, 1614, 1324 cmꢁ1; 1H
d
4.3.1. 3-Ethoxy-3-(toluene-4-sulfonylimino)-propionic acid ethyl ester
d
(6c). It is a colorless oil. IR
7.82 (d, J¼8.3 Hz, 2H), 7.30 (d, J¼8.3 Hz, 2H), 4.24e4.19 (m, 4H),
3.93 (s, 2H), 2.42 (s, 3H), 1.29e1.24 (m, 6H); 13C NMR
167.8, 166.3,
n
2989, 1742, 1599, 1450 cmꢁ1; 1H NMR
128.5 (2C), 126.4 (2C), 65.1, 61.4, 39.8, 13.7, 13.2; MS m/z (%) 299
(Mþ, 0.9), 254 (24), 77 (100). Anal. Calcd. For C13H17NO5S: C, 52.16;
H, 5.72; N, 4.68. Found: C, 52.28; H, 5.92; N, 4.47.
d
d
143.6,138.5,129.5 (2C),126.9 (2C), 65.4, 61.8, 40.1, 21.6, 14.1, 13.6. MS
m/z (%) 313 (Mþ, 2.3), 155 (100). Anal. Calcd. For C14H19NO5S: C,
53.66; H, 6.11; N, 4.47. Found: C, 53.43; H, 6.02; N, 4.69.
4.3.9. 3-Ethoxy-3-methanesulfonylimino-propionic acid ethyl ester
(6k). It is a yellowish oil. IR
NMR 4.41e4.18 (m, 4H), 3.86 (s, 2H), 3.07 (s, 3H), 1.50e1.22 (m,
6H); 13C NMR
d 168.2, 166.2, 65.2, 61.6, 42.3, 39.9, 13.9, 13.4; MS m/z
n
3468, 2987, 1743, 1622, 1308 cmꢁ1; 1H
d
4.3.2. 3-Ethoxy-3-(toluene-4-sulfonylimino)-propionic acid butyl
ester (6d). It is a colorless oil. IR
n
2980, 1740, 1604, 1439 cmꢁ1; 1H
(%) 237 (Mþ, 0.7), 86 (100). Anal. Calcd. For C8H15NO5S: C, 40.50; H,
6.37; N, 5.90. Found: C, 40.78; H, 6.42; N, 5.76.
NMR
d
7.82 (d, J¼8.3 Hz, 2H), 7.31e7.27 (m, 2H), 4.22 (q, J¼6.9 Hz,
2H), 3.85 (s, 2H), 2.42 (s, 3H), 1.47 (s, 9H), 1.28 (t, J¼7.2 Hz, 2H); 13C
NMR
d
168.0, 165.1, 143.2, 138.4, 129.2 (2C), 126.6 (2C), 82.3, 65.0,
4.3.10. 3-Oxo-3-(toluene-4-sulfonylamino)-propionic acid ethyl ester
41.1, 27.7 (3C), 21.3, 13.4; MS m/z (%) 312 (12), 171 (23), 155 (100).
Anal. Calcd. For C16H23NO5S: C, 56.29; H, 6.79; N, 4.10. Found: C,
56.46; H, 6.61; N, 4.23.
(6l). Mp 97e99 ꢀC (lit.15 97e98 ꢀC). 1H NMR
d 10.07 (s, 1H), 7.96 (d,
J¼8.3 Hz, 2H), 7.33 (d, J¼8.3 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 3.35 (s,
2H), 2.43 (s, 3H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR
d 167.4, 163.7, 144.9,
135.1, 129.3 (2C), 128.1 (2C), 61.9, 41.8, 21.3, 13.6.
4.3.3. 3-Methoxy-3-(toluene-4-sulfonylimino)-propionic acid ethyl
ester (6e). It is a white solid, mp 40e42 ꢀC (EtOAc/PE). IR
n
3449,
4.3.11. 3-Methanesulfonylamino-3-oxo-propionic acid ethyl ester
(6m). It is a yellowish solid, mp 57e59 ꢀC (EtOAc/PE). IR
3196,
3091, 1740, 1620, 1156 cmꢁ1; 1H NMR
d
7.83 (d, J¼8.3 Hz, 2H), 7.30
n
(d, J¼8.3 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 3.95 (s, 2H), 3.80 (s, 3H),
3030, 1738, 1691, 1348 cmꢁ1 1H NMR
; d 9.97 (s, 1H), 4.26 (q,
2.42 (s, 3H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR
d
168.0, 165.8, 143.3,
J¼7.2 Hz, 2H), 3.47 (s, 2H), 3.32 (s, 3H), 1.32 (t, J¼7.2 Hz, 3H); 13C
138.0, 129.1 (2C), 126.5 (2C), 61.4, 55.7, 39.5, 21.2, 13.7; MS m/z (%)
NMR d
167.7, 164.9, 62.2, 41.7, 41.2, 13.8; MS m/z (%) 209 (Mþ, 1), 80

Y. Liu et al. / Tetrahedron 67 (2011) 6294e6299
6299
2010, 20, 541e545; (c) Shang, Y.; Ju, K.; He, X.; Hu, J.; Yu, S.; Zhang, M.; Liao, K.;
Wang, L.; Zhang, P. J. Org. Chem. 2010, 75, 5743e5745; (d) Song, W.; Lu, W.;
Wang, J.; Lu, P.; Wang, Y. J. Org. Chem. 2010, 75, 3481e3483; (e) Yao, W.; Pan, L.;
Zhang, Y.; Wang, G.; Wang, X.; Ma, C. Angew. Chem., Int. Ed. 2010, 49,
9210e9214; (f) Shen, Y.; Cui, S.; Wang, J.; Chen, X.; Lu, P.; Wang, Y. Adv. Synth.
Catal. 2010, 352, 1139e1144; (g) Lu, W.; Song, W. Z.; Hong, D.; Lu, P.; Wang, Y. G.
Adv. Synth. Catal. 2009, 351, 1768e1772; (h) Shang, Y.; He, X.; Hu, J.; Wu, J.;
Zhang, M.; Yu, S.; Zhang, Q. Adv. Synth. Catal. 2009, 351, 2709e2713; (i) Cui, S.;
Wang, J.; Wang, Y. G. Tetrahedron 2008, 64, 487e492; (j) Cui, S.; Wang, J.; Wang,
Y. G. Org. Lett. 2008, 10, 1267e1269; (k) Cui, S.; Wang, J.; Wang, Y. G. Org. Lett.
2007, 9, 5023e5025; (l) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9,
1585e1587; (m) Mandal, S.; Gauniyal, H. M.; Pramanik, K.; Mukhopadhyay, B. J.
Org. Chem. 2007, 72, 9753e9756; (n) Cassidy, M. P.; Raushel, J.; Fokin, V. V.
Angew. Chem., Int. Ed. 2006, 45, 3154e3157; (o) Whiting, M.; Fokin, V. V. Angew.
Chem., Int. Ed. 2006, 45, 3157e3161; (p) Cui, S.; Lin, X. F.; Wang, Y. G. Org. Lett.
2006, 8, 4517e4520.
(100). Anal. Calcd. For C6H11NO5S: C, 34.44; H, 5.30; N, 6.69. Found:
C, 34.62; H, 5.38; N, 6.44.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21072112).
Supplementary data
Supplementary data (1H and 13C NMR spectra for products 3aei
and 6bem) associated with this article can be found in the online
version at doi:10.1016/j.tet.2011.06.017.
8. (a) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. J. Org.
Chem. 2008, 73, 5520e5528; (b) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.;
Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1730e1733.
9. (a) Keith, J. M. J. Org. Chem. 2010, 75, 2722e2725; (b) Yamauchi, M.; Miura, T.;
Murakami, M. Heterocycles 2010, 80, 177e181.
10. (a) Grimster, N. P.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132,
2510e2511; (b) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V.
J. Am. Chem. Soc. 2009, 131, 18034e18035; (c) Miura, T.; Yamauchi, M.;
Murakami, M. Chem. Commun. 2009, 1470e1471; (d) Horneff, T.; Chuprakov,
S.; Chernyak, N.;
References and notes
1. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596e2599.
2. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057e3064.
3. For reviews, see: (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302e1315;
(b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952e3015; (c) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51e68.
4. Bae, I.; Han, H.; Chang, S. J. Am. Soc. Chem. 2005, 127, 2038e2039.
5. (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8,1347e1350; (b)
Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046e16047.
6. For more Chang’s works, see: (a) Yoo, E. J.; Park, S. H.; Lee, S. H.; Chang, S. Org.
Lett. 2009, 11, 1155e1158; (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47,
2836e2839; (c) Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49,
1745e1749; (d) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163e1166; (e) Kim, J.;
Lee, Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454e9457; (f) Cho, S. H.;
Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1897e1900.
Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972e14974.
11. (a) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952e4955; (b) Cano, I.; Nicasio,
ꢀ
M. C.; Perez, P. J. Org. Biomol. Chem. 2010, 8, 536e538; (c) Wang, F.; Fu, H.; Jiang,
Y.; Zhao, Y. Adv. Synth. Catal. 2008, 350, 1830e1834.
12. Nolte, C.; Mayer, P.; Straub, B. F. Angew. Chem., Int. Ed. 2007, 46, 2101e2103.
13. (a) Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. J. Org. Chem. 2010, 75,
7002e7005; (b) Shao, C.; Cheng, G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv. Synth.
Catal. 2010, 352, 1587e1592.
14. Ainsdough, E. W.; Bingham, A. G.; Brodie, A. M.; Englebretsen, D. R.; Husbands,
J. M. J. Chem. Res., Synop. 1988, 60e61.
15. Huisgen, R.; Knorr, R.; Moebius, L.; Szeimies, G. Chem. Ber. 1965, 98,
4014e4021.
7. For selected references, see: (a) Jin, H.; Xu, X.; Gao, J.; Zhong, J.; Wang, Y. Adv.
Synth. Catal. 2010, 352, 347e350; (b) Lee, M. Y.; Kim, M. H.; Kim, J.; Kim, S. H.;
Kim, B. T.; Jeong, I. H.; Chang, S.; Kim, S. H.; Chang, S.-Y. Bioorg. Med. Chem. Lett.