Copper(II) triflate as a double catalyst for the one-pot click synthesis of 1,4-disubstituted 1,2,3-triazoles from benzylic acetates

Article abstract of DOI:10.1055/s-2007-986638

Copper(II) triflate doubly catalyzed the substitution of benzylic acetates by TMSN₃ and the subsequent 1,3-dipolar addition with an alkyne in one pot. This procedure afforded the preparation of 1,4-disubstituted 1,2,3-triazoles in good yields starting from the easily accessible acetates without isolating an organic azide using a single catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986638

2436
LETTER
Copper(II) Triflate as a Double Catalyst for the One-Pot Click Synthesis of
1,4-Disubstituted 1,2,3-Triazoles from Benzylic Acetates
C
opper(II) Tr
i
h
flate as
a
D
o
i
uble Ca
n
talyst for the
-
O
ne-Po
i
t
Click
c
Synthesishi Fukuzawa,* Eiji Shimizu, Satoshi Kikuchi
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
Fax +81(3)38171895; E-mail: fukuzawa@chem.chuo-u.ac.jp
Received 19 June 2007
acetylene in one pot without isolation of the azides.
Abstract: Copper(II) triflate doubly catalyzed the substitution of
Table 1 summarizes the results of the one-pot (two-step)
benzylic acetates by TMSN3 and the subsequent 1,3-dipolar addi-
tion with an alkyne in one pot. This procedure afforded the prepara-
tion of 1,4-disubstituted 1,2,3-triazoles in good yields starting from
click reaction of 1 with phenylacetylene.7 The preceding
displacement reaction was carried out using a 1:1.5 molar
the easily accessible acetates without isolating an organic azide ratio of 1 to TMSN3 (1.5 equiv),8 and a catalytic amount
using a single catalyst.
of Cu(OTf)2 (10 mol%) at room temperature in dichloro-
methane. After the reaction was completed, i.e., disap-
pearance of the acetate 1 (ca. 12 h), then phenylacetylene
and the additive (0.1–1.1 equiv) were added to the mixture
and the following reaction was carried out for 1 hour. Af-
ter the usual workup, identification and determination of
the product were carried out using GC-MS. The product 2
was fully characterized by a spectroscopic method and
confirmed by comparison to the authentic sample sepa-
rately prepared by Sharpless’s click reaction.2 No additive
left the azide unchanged, Cu(OTf)2 itself hardly cata-
lyzing the following 1,3-dipolar cycloaddition (entry 1).
When ascorbic acid, sodium ascorbate, or potassium fer-
rocyanate was added to the mixture in order to reduce the
Cu(II) species to the Cu(I) species, which could work as a
catalyst for the following cycloaddition reaction, the cor-
responding 1,4-disubstituted 1,2,3-triazole 2 was obtained
in low yields (entries 2 and 3) using the former two addi-
tives. The addition of CuI and CuCl as a Cu(I) salt itself
resulted in no reaction and a low yield, respectively (en-
tries 5 and 6). The addition of diisopropyl ethyl amine
(DIPEA) as an additive remarkably improved the yield of
the triazole 2; compound 2 was obtained in an 81% yield
(entry 7) and any unreacted azide was scarcely contained
in the final products.9 The addition of 2,6-lutidine as an
tertiary amine was not so effective as DIPEA, producing
a low yield of 2 (entry 8).10
Key words: triazole, copper(II) triflate, click reaction
‘Click chemistry’ has recently drawn much attention as a
powerful and efficient way to synthesize the desired com-
pounds in high yields using a simple and benign proce-
dure.1 The Huisgen 1,3-dipolar cycloaddition of azide and
alkynes is the most intensively studied click reaction
which yields 1,2,3-triazoles in high yields by just mixing
the starting compounds and Cu(I) catalyst in an aqueous
solvent.2 The starting organic azides are usually prepared
and isolated by the substitution reaction of the organic
halides by sodium azide. As some organic azides can be
explosive and need to be handled with care, a procedure
without isolating the azide should be preferable. The im-
proved click syntheses of 1,2,3-triazoles without isolation
of organic azides have been reported, in which the three-
component reaction of an organic halide, sodium azide,
and an alkyne is carried out in one pot.3 This procedure
would be more useful if the starting organic halides could
be replaced by more easily accessible compounds, such as
alcohols and their derivatives. The one-pot method em-
ploys an acetate as the starting compound, but it is first
converted into the corresponding halide, then the azide in
situ.4 We now report the Cu(OTf)2 doubly catalyzed one-
pot procedure for the synthesis of a 1,4-disubstituted
1,2,3-triazole using the corresponding acetate as a precur-
sor of an azide which undergoes cyloaddition with an
alkyne.
We separately confirmed that the 1,3-dipolar cycloaddi-
tion of the isolated azide with phenylacetylene proceeded
to give 2 in the presence of both the amine and a catalytic
amount of Cu(OTf)2 (10 mol%), but did not proceed in the
absence of either the amine or Cu(OTf)2; the amine itself
did not catalyze the cycloaddition. The use of other Cu(I)
and Cu(II) salts, such as CuOTf·C6H6 and CuSO4·5H2O,
was ineffective for the preceding displacement reaction.
While Sc(OTf)3 could catalyze the substitution reaction of
1 with TMSN3, it could not catalyze the cycloaddition:
The cycloaddition could not be catalyzed by a Lewis acid,
and a copper(II) catalyst should be required for the reac-
tion. Dichloromethane was the choice of solvents; the
preceding reaction did not proceed in THF, diethyl ether,
DMF, or DMSO, and 2 was hardly obtained in MeCN and
We previously reported the substitution of 1-ferrocenyl-
ethyl acetate by azidotrimethylsilane (TMSN3) in the
presence of a Lewis acid, such as Cu(OTf)2 and Sc(OTf)3,
in the synthetic studies of the chiral ferrocenyl diamine.5
The extension of the reaction to 1-phenylethyl acetate (1)
successfully produced the corresponding azide in a quan-
titative amount.6 We tried the subsequent click reaction of
the azide generated in situ from the acetate with phenyl-
SYNLETT 2007, No. 15, pp 2436–2438
1
7
.0
9
.2
0
0
7
Advanced online publication: 28.08.2007
DOI: 10.1055/s-2007-986638; Art ID: U05807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper(II) Triflate as a Double Catalyst for a One-Pot Click Synthesis
2437
Table 2 The One-Pot Click Synthesis of 1,4-Substituted 1,2,3-Tri-
azoles Doubly Catalyzed by Cu(OTf)2
Table 1 The One-Pot Reaction of 1-Phenylethyl Acetate, TMSN3,
and Phenylacetylene Catalyzed by Cu(OTf)2
a
a
OAc
OAc
TMSN3, Cu(OTf)2
TMSN3, Cu(OTf)2
CH2Cl2, r.t., 12 h
CH2Cl2, r.t., 12 h
N
N
Ph
Ph
N
N
N
then additive,
Ph
Ph
then DIPEA,
N
R
R
r.t., 1 h
r.t., 1 h
2
1
1
2
Entry
Additive
Yield of 2 (%)b
Entry
1
R in 1
H
Yield of 2 (%)b
1
2
3
4
5
6
7
8
None
0
24
26
0
81 (71)c
85 (81)c
75
Ascorbic acid
Sodium ascorbate
K4Fe(CN)6·3H2O
CuI
2
o-Me
m-Me
p-Me
o-Cl
p-Cl
p-F
3
4
83 (80)c
11
0
5
CuCl
29
81
47
6
61
DIPEAc
7
78
2,6-Lutidined
8
p-NO2
0
a Compound 1 (0.5 mmol), TMSN3 (0.75 mmol), Cu(OTf)2 (0.05
mmol), CH2Cl2 (1 mL), r.t., 12 h, then phenylacetylene (0.6 mmol),
additive (0.05 mmol), r.t., 1 h.
9
1-Naphthyl
94 (84)c
53
10
11d
12e
2-Naphthyl
b Determined by GC-MS.
c DIPEA (0.55 mmol).
H
H
70c
d 2,6-Lutidine (0.75 mmol).
65d
a Compound 1 (0.5 mmol), TMSN3 (0.75 mmol), Cu(OTf)2 (0.05
mmol), CH2Cl2 (1 mL), r.t., 12 h, then phenylacetylene (0.6 mmol),
DIPEA (0.55 mmol), r.t., 1 h.
toluene although the production of a small amount of the
azide was observed.
b Determined by GC-MS.
c Isolated yield.
This one-pot reaction is interesting and useful because
Cu(OTf)2 doubly catalyzed the preceding displacement
reaction and the following cycloaddition reaction without
any additional metal catalyst. Furthermore, the reaction
can completely be carried out at room temperature. Thus,
the reaction was applied to the aromatic substituted
benzylic acetates, and these results are summarized in
Table 2.11 The sequential reaction with the o-, m, and
p-methylphenyl derivatives gave the corresponding 1,4-
disubstituted 1,2,3-triazoles in good yields (entries 2–4).
For the reaction, the intermediate azide was hardly ob-
served; most of the azide was consumed and transformed
into the triazole. The p-halogeno-substituted (Cl, F) ben-
zylic triazoles were obtained in good yields (entries 6 and
7), but the reaction with o-chlorophenyl derivative gave
d 1-Hexyne was used as the alkyne.
e 2-Methyl-3-butyn-2-ol was used as the alkyne.
the corresponding triazole in low yields, the starting ace-
tate being recovered mostly (entry 5). The p-nitro-substi-
tuted triazoles were not obtained, as no azide was
produced in the first reaction (entry 8). The reaction with
the 1- and 2-naphthyl derivatives proceeded to give the
corresponding 2 in good to excellent yields (entries 9 and
10). This process could be applied to alkynes other than
phenylacetylene, such as 1-hexyne and 2-methyl-3-butyn-
2-ol with the corresponding 4-alkyl-substituted triazole
being obtained in good yields (entries 11 and 12).
The reaction could not be applied to the benzyl and allyl
acetates since the substitution by TMSN3 did not proceed
in the presence of Cu(OTf)2. However, the sequential
reaction with 1-phenylallyl 3 and cinnamyl acetate 4 pro-
ceeded to give the same products, the 1,4-disubstituted
cinnamyl triazole 5 in moderate yields (30–50%,
Scheme 1).12
Ph
OAc
N
N
N
TMSN3, Cu(OTf)2
CH2Cl2, r.t., 12 h
3
then DIPEA,
Ph
r.t., 1 h
OAc
5
In conclusion, this procedure allowed the preparation of
1,4-disubstituted 1,2,3-triazoles in good yields starting
from easily accessible acetates without isolating the
organic azide using Cu(OTf)2 as a double catalyst.
4
Scheme 1
Synlett 2007, No. 15, 2436–2438 © Thieme Stuttgart · New York

2438
S.-i. Fukuzawa et al.
LETTER
extracted with EtOAc (3 × 15 mL). The combined extracts
were washed with brine, dried over MgSO4, filtered, and the
solvent was removed using a rotary evaporator that left a
yellow residue. The GC-MS analysis revealed the presence
of 2 of which the yield was determined by GC using
biphenyl as the internal standard. The product 2 was isolated
by preparative TLC (hexane–EtOAc, 4:1); yield, 89 mg,
71%. 1H NMR (300 MHz, CDCl3): d = 2.00 (d, 3 H, J = 7.1
Hz), 5.86 (q, 1 H, J = 7.1 Hz), 7.30–7.50 (m, 8 H), 7.63 (s, 1
H), 7.80 (d, 2 H, J = 7.3 Hz). 13C NMR (CDCl3): d = 21.2,
60.1, 118.4, 125.6, 126.4, 128.0, 128.5, 128.7, 128.9, 130.6,
139.8, 147.6. IR (KBr): n = 3092, 1483, 1459, 1421, 1373,
1349, 1304, 1218, 1175, 1155, 1074, 1038, 1025, 993, 973,
913 cm–1. Anal. Calcd for C16H15N3: C, 77.08; H, 6.06; N,
16.85. Found: C, 76.86; H, 6.14; N, 17.01.
Acknowledgment
This work was financially supported by a Chuo University Grant for
Special Research.
References and Notes
(1) For reviews, see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2001, 40, 2004. (b) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51. (c) Gil, M. V.; Arévalo, M. J.; López, Synthesis
2007, 1589.
(2) Rostovsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(3) For examples of one-pot reactions, see: (a) Feldman, A. K.;
Colasson, B.; Fokin, V. V. Org. Lett 2004, 6, 3897.
(b) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett 2004, 6, 4223. (c) Molander, G. A.;
Ham, J. Org. Lett 2006, 8, 2767. (d) Kacprzak, K. Synlett
2005, 943. (e) Beckmann, H. S. G.; Wittmann, V. Org. Lett
2007, 9, 1.
(8) Azidotrimethylsilane has been used as a nitrogen source in
the palladium-catalyzed 1,2,3-triazole synthesis. See:
(a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahedron
Lett. 2002, 43, 9707. (b) Kamijo, S.; Jin, T.; Huo, Z.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786.
(c) Kamijo, S.; Jin, T.; Yamamoto, Y. Tetrahedron Lett.
2004, 45, 689.
(9) It has been reported that the addition of DIPEA often
improves the yield of 1,2,3-triazole by the Cu(I)-catalyzed
click reaction. For examples, see: (a) Tornø, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2003, 125, 9372. (c) Meng, J.-C.; Fokin, V. V.; Finn,
M. G. Tetrahedron Lett. 2005, 46, 4543. (d) Reddy, K. R.;
Rajgopal, K.; Kantam, M. L. Synlett 2006, 957. (e) See also
ref. 2.
(10) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46,
1730.
(11) Small amounts of 1,4,5-trisubstituted triazoles were detected
by GC-MS analyses (ca. 5%), but these were not isolated.
For the synthesis of the 1,4,5-trisubstituted triazoles, see:
Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A. Jr.
Tetrahedron 2006, 62, 66405.
(4) Chittaboina, S.; Xie, F.; Wang, Q. Tetrahedron Lett. 2005,
46, 2331.
(5) Fukuzawa, S.-i.; Suzuki, T. Eur. J. Org. Chem. 2006, 1012.
(6) The Cu(OTf)2-catalyzed reaction of (R)-1-phenylethyl
acetate (95% ee) with TMSN3 under the conditions gave the
racemate 1-phenylethyl azide. This result suggests that the
substitution reaction proceeds with SN1-type reaction.
(7) The reaction must be carried out in two steps. Mixing of
three components, i.e., compound 1, phenylacetylene, and
TMSN3, in the presence of the Cu catalyst and additive
(DIPEA) in CH2Cl2 (1 mL) did not afford 2, along with
recovering the starting compounds. A typical experimental
procedure is as follows: In a 20 mL Schlenk tube containing
a magnetic stirring bar were charged Cu(OTf)2 (18 mg, 0.05
mmol) and dry CH2Cl2 (1 mL) under a slight pressure of
nitrogen. A mixture of 1-phenylethyl acetate (1, 82 mg, 0.5
mmol) and TMSN3 (86 mg, 1.5 mmol) was then added using
a syringe through the septum with stirring at r.t. The reaction
was monitored by TLC and after the starting acetate had
almost disappeared (12 h), phenylacetylene 2 (62 mg, 0.6
mmol) was then added to the mixture followed by DIPEA
(95 mL, 0.55 mmol). The mixture was stirred at r.t. for an
additional 1 h. The reaction was quenched with H2O, and
(12) For a click reaction with allylic acetates, see:
(a) Chandrasekhar, S.; Basu, D.; Rambabu, C. Tetrahedron
Lett. 2006, 47, 3059. (b) Sreedhar, B.; Reddy, P. S.; Kumar,
N. S. Tetrahedron Lett. 2006, 47, 3055.
Synlett 2007, No. 15, 2436–2438 © Thieme Stuttgart · New York

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