Acid-base jointly promoted copper(I)-catalyzed azide-alkyne cycloaddition

Article abstract of DOI:10.1021/jo200869a

In this novel acid-base jointly promoted CuAAC, the combination of CuI/DIPEA/HOAc was developed as a highly efficient catalytic system. The functions of DIPEA and HOAc have been assigned, and HOAc was recognized to accelerate the conversions of the C-Cu b

Full text of DOI:10.1021/jo200869a

NOTE
pubs.acs.org/joc
AcidÀBase Jointly Promoted Copper(I)-Catalyzed AzideÀAlkyne
Cycloaddition
Changwei Shao, Xinyan Wang,* Qun Zhang, Sheng Luo, Jichen Zhao, and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
S Supporting Information
b
ABSTRACT: In this novel acidÀbase jointly promoted CuAAC,
the combination of CuI/DIPEA/HOAc was developed as a
highly efficient catalytic system. The functions of DIPEA and
HOAc have been assigned, and HOAc was recognized to accel-
erate the conversions of the CÀCu bond-containing intermedi-
ates and buffer the basicity of DIPEA. As a result, all drawbacks
occurring in the popular catalytic system CuI/NR3 were over-
come easily.
opper(I)-catalyzed azideÀalkyne cycloaddition (CuAAC)
C
has been a prime example of “click chemistry” in the
literature1 since it was reported independently by the groups
of Sharpless2 and Meldal3 in 2002. Much progress has been made
in recent years toward better understanding the mechanism
of CuAAC. As shown in Figure 1, a three-step catalytic cycle
proposed by Sharpless has been widely accepted.2 The copper(I)
source has been recognized as one of major factors to influence
the efficiency of CuAAC.1e,g,h
It is well-known that CuI is the most often used copper(I)
source in catalytic organic reactions, and it also often was
used in CuAAC. However, CuI alone was an inefficient
catalyst for CuAAC. In most cases, it was used as a combina-
tion of CuI/NR3,4 in which the tertiary amine was an essential
additive.5,6 This results in CuI naturally occurring in a stable
polymeric structure that then must be dissociated by amines to
yield the “active” Cu(I) species for the formation of copper(I)
acetylide (2).
Figure 1. Three-step catalytic cycle for CuAAC.
Since the tertiary amine additive functions as both a ligand
and a base, it also promotes the coupling of copper(I) acetylide
(2) and the substitution of 5-cuprated 1,2,3-triazole (4) to yield
undesired byproduct. As shown in Figure 2, Sharpless2 has
observed that the byproduct diacetylenes, bis-triazoles,
and 5-hydroxytriazoles were formed when NEt3 or DIPEA
was used as an additive. Other 5-substituted byproducts7
were also reported recently by using different amine additives.
This may be the reason that the combination of CuSO4/NaAsc
(used in aqueous t-BuOH)2 is the most common catalytic
system for CuAAC rather than the combination of CuI/NR3
to date. However, CuI/NR3 is highly beneficial to be used
in nonaqueous or nonprotonic solvents, which is practically
important to a range of substrates because they may not
tolerate water or protonic solvents. Therefore, CuI/NR3 is still
widely employed in CuAAC despite using a large amount
of CuI (up to 2 equiv) and NR3 (up to 20 equiv) in many
cases.6
Figure 2. Byproduct formed from the CÀCu bond-containing
intermediates.
By carefully monitoring the CuAAC reactions catalyzed by
CuI/DIPEA, we observed two phenomena: (a) the intermediate
2 usually was formed very fast, but its conversion into product 5
often proceeded slowly; (b) the amounts of byproduct were
increased by prolonging the reaction time. These phenomena
clearly indicated that the byproducts were caused by inefficient
cycloaddition of 2 and protonation of 4. Therefore, a good
strategy to overcome these drawbacks may be to accelerate the
conversions of the CÀCu bond-containing intermediates 2 and
4. However, much less attention has been focused on these
Received: April 28, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200869a J. Org. Chem. 2011, 76, 6832–6836
|

The Journal of Organic Chemistry
NOTE
Scheme 1
Table 1. Effects of DIPEA and HOAc on CuAACa
CuI
DIPEA
(equiv)
HOAc
time
yield of 5ab
entry
(equiv)
(equiv)
(min)
(%)
1
2
3
4
5
0
0
0
180
180
180
150
3
trace
trace
trace
84
0.1
0.1
0.1
0.1
0
0
0
2.0
0
2.0
2.0
Scheme 2
2.0
96
a A mixture of 1a (2 mmol) and 3a (2.1 mmol) in toluene (2 mL) was
tested. b Isolated yields.
Table 2. Effects of the Ratios of DIPEA and HOAc on
CuAACa
CuI
DIPEA
(equiv)
HOAc
time
yield of 5ab
conversions and their influence on the efficiency of CuAAC in
literature.
entry
(equiv)
(equiv)
(min)
(%)
In 2007, Straub8 reported that the CÀCu bond in intermedi-
ate 4 could be protonated by HOAc within a few minutes.
Recently, we9,10 reported a highly efficient copper(I) acetate
catalyzed CuAAC in which both cycloaddition of 2 and proton-
ation of 4 could be promoted significantly by the in situ formed
HOAc. As shown in Scheme 1, the triazole 5a was obtained in 98%
yield within 5 min when the mixture of phenylethynylcopper(I)
(2a) and benzyl azide (3a) was treated with HOAc. This was not
the case when using other proton sources, such as H2O, t-BuOH,
PhCtCH, ammonia, or aqueous solution of NaOAc.
1
2
0.01
0.1
0
80
1
89
94
95
96
95
96
96
97
92
96
96
0.01
0.1
0.1
3
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.05
0.03
0.03
0.03
0.03
0.03
0.01
0.05
0.1
0.05
0.03
0.005
0.01
0.05
0.1
5
4
6
5
27
18
11
14
120
4
6
7
8
9
0.03
0.03
0.03
10
11
The results from Straub’s work and Scheme 1 strongly imply
that CuI/NR3-catalyzed CuAAC may be enhanced by simple
addition of HOAc. Thus, a novel acidÀbase jointly promoted
CuAAC was proposed as shown in Scheme 2, in which NR3
serves to dissociate the polymeric structure of CuI and accelerate
the formation of 2a. Then, 2a will be quickly converted into 5a by
our HOAc-promoted CuAAC pathway.9,10
2.5
a A mixture of 1a (2 mmol) and 3a (2.1 mmol) was tested. b Isolated
yields.
respectively (entry 4). The results in entries 4À8 indicated that
the 1:1 ratio of DIPEA and HOAc gave the best results by fixing
the amount of DIPEA at 0.03 equiv. The results in entries 9À11
indicated that the higher ratios of DIPEA and HOAc gave better
results by fixing the amount of HOAc at 0.03 equiv.
To further understand the relationship between structure
and promotion activity, different amines and carboxylic acids
were tested. As shown in Table 3, tertiary amine gave better results
than secondary and primary amines (entries 1À3). Although
HOAc, t-BuCO2H, and PhCO2H (entries 4À6) showed similar
promotion activity, TFA and TsOH had lower activity (entries 7
and 8) possibly because they are strong acids. Proline and
pyridine-2-carboxylic acid (entries 9 and 10) gave dissatisfied
results even though they have both amine and carboxylic acid
groups, which may be caused by their tight coordination with
Cu(I) ion.10,11
For safety reasons, the catalytic behavior of CuI/DIPEA/
HOAc in solvent was tested since CuAAC is a highly exothermic
reaction. As shown in Table 4, its catalytic efficiency was reduced
significantly in all tested polar solvents (entries 1À4). None-
theless, it showed excellentcatalytic efficiency innonpolarsolvents,
and the best results were obtained in cyclohexane (entry 5). The
results in entries 5À7 indicated that the 1:2:2 ratios (by mole) of
To confirm our hypothesis, a group of control experiments
were made as shown in Table 1. As was expected, no desired product
5a was detected without CuI when the mixture of phenylethyne
(1a, 1.0 equiv) and benzyl azide (3a, 1.05 equiv) in toluene was
stirred for 3 h (entry 1). Upon addition of CuI, no 5a was
detected either (entry 2). Upon additions of CuI and HOAc, the
same disappointing result was obtained (entry 3). However,
when CuI and DIPEA were added into the reaction, the
substrates were exhausted in 2.5 h to give 5a in 84% yield
(entry 4). To our delight, in the presence of CuI, DIPEA, and
HOAc, 5a was obtained in 96% yield within 3 min (entry 5).
Then, the neat conditions were used to quickly scan the effect
of the amount of CuI and the ratio of CuI/DIPEA/HOAc on the
reaction efficiency. As shown in Table 2, the amounts of CuI
could be reduced significantly under the neat conditions. In entry
1, the cycloaddition of 1a and 3a was finished in 80 min by using
0.01 equiv of CuI and 0.1 equiv of DIPEA. However, in the
presence of 0.1 equiv of HOAc, the same reaction was finished
within 1 min (entry 2). An excellent result was obtained even by
using 0.005, 0.03, and 0.03 equiv of CuI, DIPEA, and HOAc,
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The Journal of Organic Chemistry
NOTE
Table 3. Effects of Different Amines and Acids on CuAACa
Scheme 3
entry amine (0.03 equiv) acid (0.03 equiv) time (min) yield of 5ab (%)
1
2
BuNH2
Bu2NH
Bu3N
HOAc
14
8
90
91
96
96
96
97
92
67
23
31
HOAc
3
HOAc
HOAc
t-BuCO2H
PhCO2H
TFA
6
4
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
6
5
12
6
6
7
240
320
480
480
8
TsOH
9
L-proline
Py-2-CO2H
10
a A mixture of 1a (2 mmol) and 3a (2.1 mmol) was tested. b Isolated
yields.
Table 4. Effects of Solvents on CuAACa
Scheme 4
CuI
DIPEA
(equiv)
HOAc
time
yield of 5ab
entry (equiv)
(equiv) solvent (min)
(%)
1
2
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.04
0.02
0.02
0.02
0.02
0.02
0.03
0.01
0.02
0.02
0.04
0.08
0.02
0.02
0.02
0.02
0.02
0.03
0.01
0.02
0.02
0.04
0.08
H2O
60
60
60
60
12
13
20
32
50
28
30
51
85
96
96
95
94
87
96
96
EtOH
THF
3
4
MeCN
C6H12
C6H12
C6H12
PhCH3
CH2Cl2
5
6
7
8
9
10
CH2Cl2 13
CH2Cl2
11
2
a A mixture of 1a (2 mmol) and 3a (2.1 mmol) in different solvents
(2 mL) was tested. b Isolated yields.
120 min, no coupling or substituted byproduct were detected,
possibly because HOAc also has a capability to buffer the basicity
of DIPEA.
As shown in Scheme 4, the method has wide scope for
alkynes. Interestingly, ethyl propynoate (1g) showed lower
reactivity even through it is one of the best dipolarophiles in
many 1,3-dipolar cycloadditions. It is plausible that the ring of
intermediate 4g is more electron-deficient by substitution of
the carboxylate group. Therefore, the protonation of the CÀCu
bond on intermediate 4g may be retarded.
CuI/DIPEA/HOAc was good enough, and large excessive
amounts of DIPEA and HOAc were not necessary. The tests
in entries 9À11 indicated that an excellent result can be obtained
in CH2Cl2 (entry 10) by using 0.02 equiv of CuI. When
0.04 equiv of CuI was used, 5a was obtained in 96% yield for
2 min in CH2Cl2 (entry 11). Finally, entry 10 was assigned as our
standard conditions. In comparison with our previous proce-
dures,9,10 this procedure afforded two practical advantages for
CuAAC. (a) CuI was used as a copper(I) source to replace the
unstable and costly copper(I) acetate {[(MeCO2Cu)2]n} (around
30 times more expensive than CuI). (b) CH2Cl2 was used as a
solvent to replace the poor solvent cyclohexane or aqueous t-BuOH.
To generalize this method, CuAAC between PhCtCH (1a)
and different azides 3bÀl was tested under both standard and
neat conditions. As shown in Scheme 3, all tested azides gave
excellent results. In the cases of substrates 3aÀf, the electronic
and steric effects were observed clearly. As we mentioned in
our previous works,9,10 β-substituted azides (3k and l) usually
gave better results. Although the preparation of 5f took for
’ CONCLUSION
CuI/NR3-catalyzed CuAAC is highly beneficial for use in
nonaqueous or nonprotonic solvents, but it suffers from bypro-
duct formed by NR3-catalyzed coupling and substitution of
copper(I) acetylide (2) and 5-cuprated 1,2,3-triazole (4). In this
study, we showed that these drawbacks can be overcome easily by
addition of the catalytic amount of HOAc, which was recognized
to accelerate the conversions of the CÀCu bond-containing
intermediates 2 and 4, as well as to buffer the basicity of NR3.
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The Journal of Organic Chemistry
NOTE
Finally, the combination of CuI/DIPEA/HOAc was developed
as a highly efficient catalytic system for CuAAC. The success of
catalytic system CuI/DIPEA/HOAc provides a further evidence
for the strategy of carboxylic acids promoted CuAAC.
9.31 (s, 1H), 8.04À7.90 (m, 4H), 7.80À7.32 (m, 6H); 13C NMR
(DMSO-d6) δ 147.3, 136.6, 130.2, 129.9 (2C), 129.0 (2C), 128.7,
128.2, 125.3 (2C), 120.0 (2C), 119.6.
1-(2-Phenylethyl)-4-phenyl-1H-1,2,3-triazole (5h): white
1
solid; mp 141À142 °C (PEÀEtOAc) (lit.12 mp 139 °C); H NMR
δ 7.76À7.74 (m, 2H), 7.50 (s, 1H), 7.39À7.32 (m, 2H), 7.28À
7.21 (m, 4H), 7.08À7.04 (m, 2H), 4.53 (t, J = 7.2 Hz, 2H), 3.16
(t, J = 7.2 Hz, 2H); 13C NMR δ 147.1, 136.8, 130.5, 128.6 (4C), 128.4,
128.2, 127.8, 126.8, 125.4 (2C), 119.9, 51.3, 36.4.
’ EXPERIMENTAL SECTION
All spectra of 1H NMR (300 MHz) and 13C NMR (75 MHz) were
determined in CDCl3 using TMS as internal standard.
Typical preparation of 1-benzyl-4-phenyl-1H-[1,2,3]triazole
(5a) under Neat Conditions. To a mixture of CuI (1.9 mg, 0.01 mmol,
0.01 equiv), DIPEA (2.6 mg, 0.02 mmol, 0.02 equiv), and HOAc (1.2 mg,
0.02 mmol, 0.02 equiv) was added a mixture of phenylethyne (1a, 102 mg,
1 mmol) and benzyl azide (3a, 140 mg, 1.05 mmol) at room temperature.
The resultant mixture was then stirred until the reaction system had
solidified completely (ca. 3 min). After the crude product was diluted with
CH2Cl2 (5 mL), it was purified by a short chromatography column [silica
gel, 30% EtOAc in PE (60À90 °C)] to give 226 mg (96%) of 5a as an off-
white solid.
1-Cyclohexyl-4-phenyl-1H-1,2,3-triazole (5i): white solid; mp
1
108À109 °C (PEÀEtOAc) (lit.16 mp 105.8À110 °C); H NMR δ
7.85À7.81 (m, 3H), 7.38À7.35 (m, 2H), 7.32À7.24 (m, 1H),
4.42À4.37 (m, 1H), 2.18À2.11 (m, 2H), 1.84À1.65 (m, 5H),
1.45À1.17 (m, 3H); 13C NMR δ 146.8, 130.7, 128.4 (2C), 127.6,
125.3 (2C), 117.3, 59.8, 33.2 (2C), 24.8 (2C), 24.7.
1-Octyl-4-phenyl-1H-1,2,3-triazole (5j): white solid; mp
78À80 °C (PEÀEtOAc) (lit.15 mp 74À75 °C); 1H NMR δ
7.88À7.80 (m, 2H), 7.73 (s, 1H), 7.42À7.37 (m, 2H), 7.32À7.26
(m, 1H), 4.34 (t, J = 7.2 Hz, 2H), 1.93À1.86 (m, 2H), 1.40À1.24 (m,
10H), 0.86 (t, J = 5.9 Hz, 3H); 13C NMR δ 147.5, 130.7, 128.7 (2C),
127.9, 125.5 (2C), 119.4, 50.3, 31.6, 30.2, 28.9, 28.8, 26.1, 22.3, 13.8.
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)dihydrofuran-2(3H)-one
(5k): white solid; mp 140À141 °C (PEÀEtOAc); IR (KBr) ν 3453,
1780, 1446, 1295, 1166, 1005 cmÀ1; 1H NMR δ 8.81 (s, 1H), 7.88À7.85
(m, 2H), 7.49À7.44 (m, 2H), 7.39À7.31 (m, 1H), 5.98 (t, J = 22.9 Hz,
1H), 4.66À4.56 (m, 1H), 4.51À4.42 (m, 1H), 2.98À2.79 (m, 2H); 13C
NMR δ 172.3, 146.7, 130.3, 129.0 (2C), 128.1, 125.2 (2C), 121.7, 66.2,
57.8, 29.3; HRMS calcd for C12H11N3O2 229.0851, found 229.0859.
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (5l): white
A similar procedure was used for the preparation of 5bÀt (see
Schemes 3 and 4).
Typical Preparation of 1-Benzyl-4-phenyl-1H-[1,2,3]triazole
(5a) in CH2Cl2. To a mixture of CuI (3.8 mg, 0.02 mmol, 0.02 equiv),
DIPEA (5.2 mg, 0.04 mmol, 0.04 equiv), and HOAc (2.4 mg, 0.04 mmol,
0.04 equiv) in CH2Cl2 (1.0 mL) was added a mixture of phenylethyne (1a,
102 mg, 1 mmol) and benzyl azide (3a, 140 mg, 1.05 mmol) at room
temperature. The resultant mixture was stirred until the alkyne disappeared
(ca. 13 min). The reaction mixture was purified by a short chromatography
column [silica gel, 30% EtOAc in PE (60À90 °C)] to give 227 mg (96%) of
5a as an off-white solid.
1
solid; mp 91À92 °C (PEÀEtOAc) (lit.6 mp 94À95 °C); H NMR δ
A similar procedure was used for the preparation of 5bÀt (see
7.91 (s, 1H), 7.87À7.84 (m, 2H), 7.46À7.32 (m, 3H), 5.21 (s, 2H), 4.29
(q, J = 6.9 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR δ 166.2, 148.0,
130.3, 128.7 (2C), 128.1, 125.6 (2C), 121.1, 62.3, 50.8, 13.9.
1-Benzyl-4-(3-fluorophenyl)-1H-1,2,3-triazole (5m): yellow-
ish solid; mp 109À110 °C (PEÀEtOAc); IR (KBr) ν 3091, 1582,
1450, 1218, 11620, 853 cmÀ1. 1H NMR δ 7.77 (s, 1H), 7.53À7.50 (m,
2H), 7.35À7.23 (m, 6H), 5.98À5.89 (m, 1H), 5.48 (s, 2H); 13C NMR δ
162.8 (J = 243.8 Hz), 146.6, 134.3, 132.5 (J = 8.6 Hz), 130.1 (J = 8.6 Hz),
128.8 (2C), 128.4, 127.7 (2C), 121.0 (J = 2.2 Hz), 120.1, 114.5 (J = 20.8
Hz), 112.0 (J = 8.6 Hz), 53.8; HRMS calcd for C15H12FN3 253.1015,
found 253.1019.
Schemes 3 and 4).
1-Benzyl-4-phenyl-1H-1,2,3-triazole (5a): white solid; mp
1
127À128 °C (PEÀEtOAc) (lit.12 mp 129À129.5 °C); H NMR δ
7.82À7.75 (m, 2H), 7.67 (s, 1H), 7.41À7.20 (m, 8H), 5.49 (s, 2H); 13C
NMR δ 148.0, 134.6, 130.4, 128.9 (2C), 128.6 (2C), 128.5, 127.9, 127.8
(2C), 125.5 (2C), 119.6, 53.9.
1-(4-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (5b): white
1
solid; mp 93À95 °C (PE-EtOAc) (lit.13 mp 95À97 °C); H NMR
δ 7.79À7.76 (m, 2H), 7.64 (s, 1H), 7.40À7.23 (m, 3H), 7.19À7.16 (m,
4H), 5.46 (s, 2H), 2.32 (s, 3H); 13C NMR δ 147.9, 138.4, 131.5, 130.4,
129.6 (2C), 128.6 (2C), 127.9 (3C), 125.5 (2C), 119.4, 53.7, 21.0.
1-(2-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (5c): white
1-Benzyl-4-(4-methylphenyl)-1H-1,2,3-triazole (5n): white
solid; mp 153À155 °C (PEÀEtOAc) (lit.17 mp 155À157 °C); 1H NMR
δ 7.69À7.60 (m, 3H), 7.33À7.10 (m, 7H), 5.50 (s, 2H), 2.33 (s, 3H);
13C NMR δ 148.0, 137.7, 134.6, 129.3 (2C), 128.8 (2C), 128.4, 127.8
(2C), 127.6, 125.4 (2C), 119.2, 53.8, 21.0.
1
solid; mp 102À104 °C (PEÀEtOAc) (lit.13 mp 105À106 °C); H
NMR δ 7.81À7.78 (m, 3H), 7.62À7.58 (m, 1H), 7.40À7.10 (m, 6H),
5.66 (s, 2H); 13C NMR δ 147.9, 134.1, 133.1, 130.4, 130.2, 130.1, 128.7
(2C), 128.1, 128.0, 125.6 (2C), 123.0, 119.8, 53.7.
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (5o): white
solid; mp 143À145 °C (PEÀEtOAc) (lit.15 mp 143À144 °C); 1H NMR
δ 7.73À7.70 (m, 2H), 7.57 (s, 1H), 7.39À7.26 (m, 5H), 6.94À6.91
(m, 2H), 5.55 (s, 2H), 3.82 (s, 3H); 13C NMR δ 159.5, 148.1, 134.7,
129.1 (2C), 128.7, 128.0 (2C), 127.0 (2C), 123.2, 118.7, 114.2 (2C),
55.3, 54.1.
1-(3-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (5d): white
solid; mp 91À93 °C (PEÀEtOAc) (lit.13 mp 94À95 °C); 1H NMR δ
7.85À7.80 (m, 2H), 7.71 (s, 1H), 7.49À7.20 (m, 7H), 5.50 (s, 2H); 13C
NMR δ 148.2, 136.8, 131.8, 130.8, 130.6, 130.3, 128.7 (2C), 128.2,
126.4, 125.6 (2C), 122.9, 119.6, 53.3.
1-(4-Nitrobenzyl)-4-phenyl-1H-1,2,3-triazole (5e): yellow
1
solid; mp 158À159 °C (PEÀEtOAc) (lit.12 mp 156À157 °C); H
1-Benzyl-4-(prop-1-en-2-yl)-1H-1,2,3-triazole (5p): white
1
solid; mp 84À86 °C (PE/EtOAc) (lit.18 mp 91À91.5 °C); H NMR
NMR δ 8.20À8.18 (m, 2H), 7.82À7.79 (m, 3H), 7.43À7.34 (m, 5H),
5.67 (s, 2H); 13C NMR δ 148.5, 147.9, 141.7, 130.1, 128.8 (2C), 128.5
(2C), 128.4, 125.6 (2C), 124.2 (2C), 119.8, 53.0.
δ 7.49 (s, 1H), 7.41À7.22 (m, 5H), 5.68 (s, 1H), 5.51 (s, 2H),
5.11À5.06 (m, 1H), 2.10 (s, 3H); 13C NMR δ 149.2, 134.7, 133.5,
129.0 (2C), 128.6, 127.9 (2C), 119.4, 112.4, 54.0, 20.5.
4-Phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole (5f):14 white
1
solid; mp 80À82 °C (PEÀEtOAc); H NMR δ 7.81À7.78 (m, 2H),
1-Benzyl-4-butyl-1H-1,2,3-triazole (5q): white solid; mp
64À66 °C (PE/EtOAc) (lit.8 mp 61À62 °C); 1H NMR δ 7.33À7.20
(m, 6H), 5.44 (s, 2H), 2.67 (t, J = 7.9 Hz, 2H), 5.51.64À1.56
(m, 2H), 1.38À1.31 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H); 13C NMR δ
148.2, 134.7, 128.4 (2C), 127.9, 127.3 (2C), 120.3, 53.2, 31.0, 24.8,
21.8, 13.3.
7.64 (s, 1H), 7.38À7.28 (m, 8H), 5.86 (q, J = 7.2 Hz, 1H), 2.02 (d, J = 7.2
Hz, 3H); 13C NMR δ 147.7, 139.9, 130.6, 129.0 (2C), 128.7 (2C),
128.5, 128.0, 126.5 (2C), 125.6 (2C), 118.3, 60.2, 21.3.
1,4-Diphenyl-1H-1,2,3-triazole (5g): yellowish solid; mp
182À184 °C (PEÀDCM) (lit.15 mp 184À186 °C); 1H NMR δ
6835
dx.doi.org/10.1021/jo200869a |J. Org. Chem. 2011, 76, 6832–6836

The Journal of Organic Chemistry
NOTE
Ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (5r): yellow-
ish solid; mp 82À83 °C (PEÀEtOAc) (lit.15 mp 83À85 °C); 1H NMR
δ 8.13 (s, 1H), 7.36À7.30 (m, 5H), 5.60 (s, 2H), 4.36 (q, J = 7.2 Hz,
2H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR δ 160.3, 140.0, 133.7, 128.8
(2C), 128.5, 127.8 (2C), 127.2, 60.7, 53.9, 13.9.
Methyl (1-benzyl-1H-1,2,3-triazol-4-yl)methyl carbonate
(5s): yellowish solid; mp 60À62 °C (PEÀEtOAc); IR (KBr) ν 3070,
1750, 1450, 1260, 939 cmÀ1; 1H NMR δ 7.65 (s, 1H), 7.34À7.22 (m,
5H), 5.50 (s, 2H), 5.22 (s, 2H), 3.74 (s, 3H); 13C NMR δ 155.1, 142.1,
134.2, 128.7 (2C), 128.3, 127.7 (2C), 123.5, 60.5, 54.5, 53.7; HRMS
calcd for C12H13N3O3 247.0957, found 247.0960.
tert-Butyl (1-benzyl-1H-1,2,3-triazol-4-yl)methylcarbamate
(5t): yellowish solid; mp 80À82 °C (PEÀEtOAc) (lit.19 mp 100À
102 °C); 1H NMR δ 7.42 (s, 1H), 7.14À7.05 (m, 5H), 5.86 (t, J = 6.0
Hz, 1H), 5.28 (s, 2H), 4.18 (d, J = 6.0 Hz, 2H), 1.24 (s, 9H); 13C NMR δ
155.3, 145.4, 134.3, 128.3 (2C), 127.8, 127.3 (2C), 121.5, 78.5, 53.1, 34.5,
27.7 (3C).
R. E.; Pizzirani, D.; Schreiber, S. L. Org. Lett. 2006, 8, 2063. (i) Font, D.;
Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653. (j) Pirali, T.; Tron,
G. C.; Zhu, J. Org. Lett. 2006, 8, 4145. (k) Dondoni, A.; Marra, A. J. Org.
Chem. 2006, 71, 7546. (l) Goess, B. C.; Hannoush, R. N.; Chan, L. K.;
Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc. 2006, 128, 5391. (m)
Giguere, D.; Patnam, R.; Bellefleur, M.-A.; St-Pierre, C.; Satob, S.; Roy,
R. Chem. Commun. 2006, 2379. (n) Bodine, K. D.; Gin, D. Y.; Gin, M. S.
Org. Lett. 2005, 7, 4479. (o) Jang, H.; Fafarman, A.; Holub, J. M.;
Kirshenbaum, K. Org. Lett. 2005, 7, 1951. (p) van Maarseveen, J. H.;
Horne, W. S.; Ghadiri, M. R. Org. Lett. 2005, 7, 4503. (q) Billing, J. F.;
Nilsson, U. J. J. Org. Chem. 2005, 70, 4847. (r) Bodine, K. D.; Gin, D. Y.;
Gin, M. S. J. Am. Chem. Soc. 2004, 126, 1638. (s) Lo1ber, S.; Rodriguez-
Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753. (t) Horne, W. S.; Stout,
C. D.; Ghadiri, M. R. J. Am. Chem. Soc. 2003, 125, 9372. (u) Fazio, F.;
Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H. J. Am. Chem. Soc.
2002, 124, 14397.
(7) (a) Smith, N. W.; Polenz, B. P.; Johnson, S. B.; Dzyuba, S. V.
Tetrahedron Lett. 2010, 51, 550. (b) Gerard, B.; Ryan, J.; Beeler, A. B.;
Porco, J. A., Jr. Tetrahedron 2006, 62, 6405.
(8) Nolte, C.; Mayer, P.; Straub, B. F. Angew. Chem., Int. Ed. 2007,
46, 2101.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
(9) Shao, C.; Cheng, G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv. Synth.
Catal. 2010, 352, 1587.
(10) Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. J. Org.
S
b
tra for compounds 5aÀt. This material is available free of charge
via the Internet at http://pubs.acs.org.
Chem. 2010, 75, 7002.
(11) Xie, J.; Seto, C. T. Bioorg. Med. Chem. 2007, 15, 458.
(12) Sharghi, H.; Khalifeh, R.; Doroodmand, M. M. Adv. Synth.
Catal. 2009, 351, 207.
(13) Abu-Orabi, S. T.; Atfah, M. A.; Jibril, I.; Maríi, F. M.; Ali, A. A.-S.
J. Heterocycl. Chem. 1989, 26, 1461.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: +86-10-62795380. Fax: +86-10-62771149. E-mail:
xinyanwang@mail.tsinghua.edu.cn; yfh@mail.tsinghua.edu.cn.
(14) Sreedhar, B.; Reddy, P. S.; Krishna, V. R. Tetrahedron Lett.
2007, 48, 5831.
(15) Campbell-Verduyn, L. S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga,
P. H. Chem. Commun. 2009, 2139.
’ ACKNOWLEDGMENT
(16) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Eur. J. Org. Chem.
2010, 1875.
This work was supported by NNSFC (21072112).
(17) Loerincz, K.; Kele, P.; Novak, Z. Synthesis 2009, 3527.
(18) Moulin, F. Helv. Chim. Acta 1952, 35, 167.
’ REFERENCES
(19) Jlalia, L.; Beauvineau, C.; Beauvineau, S.; Onen, E.; Aufort, M.;
Beauvineau, A.; Khaba, E.; Herscovici, J.; Meganem, F.; Girard, C.
Molecules 2010, 15, 3087.
(1) For reviews, see: (a) Mamidyala, S. K.; Finn, M. G. Chem. Soc.
Rev. 2010, 39, 1252. (b) Hua, Y.; Flood, A. H. Chem. Soc. Rev. 2010,
39, 1262. (c) Le Droumaguet, C.; Wang, C.; Wang, Q. Chem. Soc. Rev.
2010, 39, 1233. (d) Hanni, K. D.; Leigh, D. A. Chem. Soc. Rev. 2010,
39, 1240. (e) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(f) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39, 1325.
(g) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (h) Bock,
V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(3) Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
(4) See: Tables 1 and 4 in ref 1g and references cited therein.
(5) For selected references for the reactions in protonic
solvents, see: (a) Jagasia, R.; Holub, J. M.; Bollinger, M.; Kirshenbaum,
K.; Finn, M. G. J. Org. Chem. 2009, 74, 2964. (b) Muthana, S.; Yu, H.;
Huang, S.; Chen, X. J. Am. Chem. Soc. 2007, 129, 11918. (c) Luo, S.; Xu,
H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P. J. Org. Chem. 2006, 71, 9244.
(6) For selected references for the reactions in nonprotonic
solvents, see: (a) Nahrwold, M.; Bogner, T.; Eissler, S.; Verma, S.;
Sewald, N. Org. Lett. 2010, 12, 1064. (b) Mwakwari, S. C.; Guerrant, W.;
Patil, V.; Khan, S. I.; Tekwani, B. L.; Gurard-Levin, Z. A.; Mrksich, M.;
Oyelere, A. K. J. Med. Chem. 2010, 53, 6100. (c) Shetti, V. S.; Ravikanth,
M. Eur. J. Org. Chem. 2010, 494. (d) Sai Sudhir, V.; Phani Kumar, N. Y.;
Chandrasekaran, S. Tetrahedron 2010, 66, 1327. (e) Gissibl, A.; Padie,
C.; Hager, M.; Jaroschik, F.; Rasappan, R.; Cuevas-Yanez, E.; Turrin, C.-
O.; Caminade, A.-M.; Majoral, J.-P.; Reiser, O. Org. Lett. 2007, 9, 2895.
(f) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith, S. C.;
Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559. (g) Franz, A. K.; Dreyfuss,
P. D.; Schreiber, S. L. J. Am. Chem. Soc. 2007, 129, 1020. (h) Looper,
6836
dx.doi.org/10.1021/jo200869a |J. Org. Chem. 2011, 76, 6832–6836