RuH2(CO)(PPh3)3 catalyzed selective formation of 1,4-disubstituted triazoles from cycloaddition of alkynes and organic azides

Article abstract of DOI:10.1021/jo3008572

The ruthenium hydride complex RuH₂(CO)(PPh₃) ₃ was found to be an effective catalyst for the cycloaddition reactions of terminal alkynes and azides. In the presence of RuH ₂(CO)(PPh₃)₃, var

Full text of DOI:10.1021/jo3008572

Note
pubs.acs.org/joc
RuH2(CO)(PPh3)3 Catalyzed Selective Formation of 1,4-Disubstituted
Triazoles from Cycloaddition of Alkynes and Organic Azides
Pei Nian Liu,*,† Hai Xiao Siyang,† Li Zhang,‡ Sunny Kai San Tse,‡ and Guochen Jia*,‡
†Shanghai Key Laboratory of Functional Materials Chemistry and Institute of Fine Chemicals, East China University of Science and
Technology, Meilong Road 130, Shanghai, China
‡Department of Chemistry, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, P. R. China
S
* Supporting Information
ABSTRACT: The ruthenium hydride complex RuH2(CO)-
(PPh3)3 was found to be an effective catalyst for the
cycloaddition reactions of terminal alkynes and azides. In the
presence of RuH2(CO)(PPh3)3, various azides reacted with a
range of terminal alkynes to produce 1,4-disubstituted 1,2,3-
triazoles with 100% selectivity and moderate to excellent
yields.
uisgen’s 1,3-dipolar cycloaddition of azides and alkynes is
Ru(OAc)2(PPh3)2, can catalyze the cycloaddition of benzyl
azide and phenylacetylene to give selectively 1,4-substituted
triazole regioisomer in low yields. RuH2(CO)(PPh3)3 (1) is the
most active one.9 Encouraged by the observation, we have
optimized the reaction catalyzed by RuH2(CO)(PPh3)3 using
the cycloaddition of benzyl azide and phenylacetylene as the
prototype reaction. In the screening experiments, a mixture of
benzyl azide (2a) and phenylacetylene (3a) in THF was heated
at 80 °C for 2 h in the presence of 5 mol % of RuH2(CO)(PPh3)3.
H
the most straightforward route to give 1,2,3-triazoles1
and was thoroughly studied in the 1950−1970s.2 The
cycloaddition is highly exothermic, but it often proceeds very
slowly even at elevated temperature (80−120 °C for 12−24 h)3
because of the high activation barrier (ca. 25−26 kcal/mol for
reaction of methyl azide with propyne).4 As another distinct
disadvantage, the cycloaddition of azide and unsymmetrically
substituted alkyne usually affords a mixture of regioisomers.
The discovery of Cu(I)-catalyzed azide−alkyne cycloaddition
(CuAAC) yielding selectively 1,4-disubstituted 1,2,3-triazoles is
a very important advance in the chemistry of 1,2,3-triazoles.5 As
the most powerful Click reaction which fosters the area of Click
chemistry, CuAAC has been successfully applied in wide areas
including organic synthesis, chemical biology, drug develop-
ment, and materials sciences.6 However, effective noncopper
catalysts for the cycloaddition of alkynes and azides are still
very rare.7 Very recently, charcoal impregnated with zinc was
described as an effective catalyst for the cycloaddition of
arylazides and alkynes to afford the 1,4-disubstituted 1,2,3-
triazoles.8
1
The resulting reaction mixture was then analyzed by H NMR
with PhSiMe3 as the internal standard, and the results are given
in Table 1. The reaction of 2a and 3a catalyzed by complex 1
carried out in hexane gave low conversion due to the poor
solubility of the catalyst (Table 1, entry 1). The protic solvent
CH3OH has a negative effect on the reaction, and only 43% yield
was obtained (Table 1, entry 2). In aprotic solvents such as
CH3NO2, CH3CN, 1,2-dichloroethane (DCE), DMSO, and
dioxane, the reaction worked well to afford the triazole product
4a in 67−76% yields (Table 1, entries 3−7). When the
reactions were performed in benzene and THF, the 1,4-
disubstituted 1,2,3-triazole 4a was obtained in 79% yield (Table
1, entries 8 and 9). If the ratio of 2a to 3a was changed from 1:2
to 1:1, 1:1.1, or 2:1, the reaction yield was decreased slightly
(Table 1, entries 10−12). It is noted that the catalytic reaction
could not proceed at room temperature, however. Different
from the RuAAC via the ruthenacycle intermediate, which
controls the regioselectivity to afford the 1,5-disubstituted
1,2,3-triazoles,9 the current reaction affording regioselectively
the 1,4-disubstituted 1,2,3-triazoles undergoes the mechanism
via the ruthenium acetylide as the key intermediate, which is
proved by the experimental fact that the ruthenium complex
Ru(CO)(CCBu-t)2(PPh3)3 is also the effective catalyst for
Recently, we9 and others10 developed a facile cycloaddition
of a wide range of azides and terminal alkynes with penta-
methylcyclopentadienyl ruthenium chloride complexes as the
effective catalysts for azide−alkyne cycloaddition (RuAAC),
which complementarily affords the 1,5-disubstituted 1,2,3-triazoles
with high regioselectivity. Applications of this RuAAC, although
not as widely as those of CuAAC, have also been reported
in the literature.11 As a successive endeavor to explore the
ruthenium-catalyzed “Click reaction”, we report herein that
ruthenium complex RuH2(CO)(PPh3)3 can catalyze the
cycloaddition of a range of azides and alkynes to afford 1,4-
disubstituted 1,2,3-triazoles with 100% selectivity.
We have previously briefly mentioned that ruthenium(II)
complexes lacking cyclopentadienyl ligands, such as
RuCl2(PPh3)3, RuHCl(CO)(PPh3)3, RuH2(CO)(PPh3)3, and
Received: May 2, 2012
Published: June 6, 2012
© 2012 American Chemical Society
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Note
(Table 2, entries 13 and 14). The reactions of the aliphatic
azides 2d−2f with 3a also proceeded smoothly to produce the
products 4o−4q in good yields (Table 2, entries 15−17). It is
noteworthy that a very low yield of 9% was obtained in the
cycloaddition reaction of p-tolylazide with phenylacetylene and
that the cycloaddition of azides with internal alkynes failed
to afford the products under the typical reaction conditions.
In general, aryl azides are less stable than their aliphatic
counterparts and are prone to react with the ruthenium catalyst
to form the ruthenium imido complexes, which is proposed to
be the main reason for the reactivity decrease in the RuAAC.9
Podophyllotoxin and its derivatives exhibit pronounced bio-
logical activity mainly as antineoplastic drugs and antiviral
agents.12 As an application of the 1,4-RuAAC in natural product
derivation, the podophyllotoxin-based azide 2g reacted with
phenylacetylene 3a in toluene in the presence of 10 mol % of
complex 1 to give the triazole product 4r in 74% yield (Table 2,
entry 18). It is noteworthy that in current investigated substrate
scope, the cycloaddition of azides with alkynes catalyzed by
RuH2(CO)(PPh3)3 has demonstrated 100% selectivity to afford
the 1,4-disubstituted 1,2,3-triazoles, and no 1,5-disubstituted
1,2,3-triazoles could be detected. The current RuAAC affords
the same products with CuAAC, but the ruthenium catalyst
RuH2CO(PPh3)3 has more versatile catalytic ability compared
with Cu+ catalyst used in CuAAC. RuH2(CO)(PPh3)3 has been
described to be the effective catalyst for multiple reactions
including C−C coupling, C−H activation, C−O bond cleavage,
transfer hydrogenation, cycloaddition and hydrogen transfer
reactions, etc. So, the ruthenium catalyst might act as the
bifunctional or multifunctional catalyst to fulfill more trans-
formations accompanying the RuAAC in one pot. For example,
the reaction of 2a and 3f in the presence of 1,4-butanediol was
carried out with RuH2(CO)(PPh3)3 as the catalyst, and the
compound 4s was obtained as the product of both RuAAC and
transfer hydrogenation (Table 2, entry 19). In contrast, the
reactions using CuSO4/sodium ascorbate, CuI, or CuBr(PPh3)3
as the catalysts under similar conditions only produced the
cycloaddition product 4f, and no 4s was detected. As the
possible advantage compared with the traditional CuAAC, more
one-pot reactions or tandem reactions based on this RuAAC
might be exploited with the ruthenium complex as the catalyst in
the future.
Table 1. Cycloaddition of Benzyl Azide and Phenylacetylene
Catalyzed by RuH2(CO)(PPh3)3
a
b
c
entry
solvent
2a:3a
conv (%)
yield (%)
1
2
3
4
5
6
7
8
9
hexane
CH3OH
CH3NO2
CH3CN
DCE
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1.1
1:1
2:1
38
100
100
100
100
100
99
<5
43
67
69
71
75
76
79
DMSO
dioxane
benzene
THF
97
d
100
100
100
100
79 (82)
73
e
10
THF
f
11
THF
76
g
12
THF
74
a
General reaction conditions: 2a (0.5 mmol), 3a (1.0 mmol),
RuH2(CO)(PPh3)3 (0.025 mmol), 80 °C, 2 h, 0.5 mL of solvent
b
was added unless otherwise noted. The conversions were estimated
1
on the basis of the integration of triazole and unreacted azide in H
c
1
NMR spectra. Based on azide (2a) used, determined by H NMR
d
integration using PhSiMe3 as the internal standard. The yield in the
parentheses is the isolate yield. 2a (0.5 mmol) and 3a (0.55 mmol)
were used. 2a (0.5 mmol) and 3a (0.5 mmol) were used. 2a
(1.0 mmol) and 3a (0.5 mmol) were used.
e
f
g
this cycloaddition to produce regioselectively the 1,4-disub-
stituted 1,2,3-triazoles.
Subsequently, the cycloaddition reactions of various azides
and a series of alkynes were examined in THF at 80 °C (oil
bath temperature), using 5 mol % RuH2(CO)(PPh3)3 (1) as
the catalyst (Table 2). The triazole products were isolated after
1
2 h, and their structures are fully consistent with their H,
13C{1H} NMR, and HRMS data. The reactions of benzyl azide
2a with aromatic alkynes 3a−3g all proceeded to selectively
afford the 1,4-substituted triazole products (Table 2, entries 1−7).
In most of the reactions, the expected triazoles were obtained in
81−87% isolated yields. The reaction of 2a with 3d bearing the
coordinating NH2 group gave a slightly lower yield of 70% (Table
2, entry 4). The presence of electron-withdrawing groups such as
acetyl or ester groups in the arylacetylene has a negative effect, and
the product yields are 59 and 62%, respectively (Table 2, entries 6
and 7). The cycloaddition of 2a with ferrocenyl acetylene 3h
proceeded smoothly, giving the corresponding triazole in 82%
yield (Table 2, entry 8). When alkenyl alkyne 3i was used as the
substrate, its cycloaddition with 2a gave the product 4i in 69%
yield (Table 2, entry 9). Aliphatic alkynes containing an OH or
CN group also showed good reactivities with 2a, and the yields of
the products 4j and 4k are comparable to those from the reactions
of aromatic alkynes (Table 2, entries 10 and 11). The reaction of
2a with the alkyne 3l having a more sterically hindered cyclohexyl
group produced the triazole product 4l with a slightly decreased
yield of 61% (Table 2, entry 12). We noted that the reaction of 2a
with the sterically hindered tert-butylacetylene afforded the triazole
product in a very low yield (11%).
In summary, the catalytic activity of RuH2(CO)(PPh3)3 has
been evaluated for the cycloaddition of terminal alkynes and azides
to give selectively 1,4-disubstituted 1,2,3-triazoles. With
RuH2(CO)(PPh3)3 as the catalyst, various azides readily reacted
with a range of terminal alkynes to produce 1,4-disubstituted 1,2,3-
triazoles with 100% selectivity and moderate to excellent yields.
This is the first report describing a catalytic system of noncopper
metal complexes for the cycloaddition of azides with terminal
alkynes to selectively produce 1,4-disubstituted 1,2,3-triazoles. The
current results together with those mediated by pentamethylcy-
clopentadienyl ruthenium chloride complexes (which afford the
1,5-disubstituted 1,2,3-triazoles) provide an interesting example of
dramatic ligand effect on the selectivity of catalytic reactions.
Further investigations for the reaction mechanism and the possible
one-pot or tandem reactions based on this RuAAC are undergoing
in our laboratories.
We also explored the scope of azides in the cycloaddition
reactions. The azides 2b and 2c bearing a methyl or iodine
group in the aromatic ring also readily reacted with phenyl-
acetylene 3a to afford the corresponding 1,4-substituted
triazoles 4m and 4n in 76 and 81% yields, respectively
EXPERIMENTAL SECTION
All manipulations were carried out under a nitrogen atmosphere using
standard Schlenk techniques, unless otherwise stated. Solvents were
distilled under nitrogen from sodium-benzophenone (hexane, diethyl
■
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Note
a
Table 2. Cycloaddition of Azides and Various Alkynes Using Complex 1 as the Catalyst
a
b
Reaction conditions: azide (0.5 mmol), alkyne (1.0 mmol), RuH2CO(PPh3)3 (0.025 mmol), 80 °C, 2 h, 0.5 mL of THF unless noted. Isolated
c
d
yields. Reaction conditions: azide (0.5 mmol), alkyne (1.0 mmol), RuH2CO(PPh3)3 (0.050 mmol), 80 °C, 6 h, 0.5 mL of toluene. Reaction
conditions: azide (0.5 mmol), alkyne (1.0 mmol), 1,4-butanediol (4.0 mmol), RuH2CO(PPh3)3 (0.025 mmol), 120 °C, 48 h, 0.5 mL of toluene.
ether, THF, benzene) or calcium hydride (dichloroethane). The
organic azides 2a−2f,13 2g,14 alkynes 3f, 3g,15 and RuH2(CO)(PPh3)3
(1)16 were prepared according to literature methods. Chemical shifts
(δ, ppm) in the 1H NMR spectra were recorded using TMS as internal
standard. Chemical shifts in 13C{1H} NMR spectra were internally
referenced to CHCl3 (δ = 77.0 ppm).
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Note
Typical Procedure for the Cycloaddition of Alkyne with
Azide. To a mixture of azide (0.5 mmol), alkyne (1.0 mmol), and
THF (0.5 mL) was added the catalyst RuH2(CO)(PPh3)3 (23.4 mg,
0.025 mmol). The resulting solution was stirred at 80 °C for 2 h. The
solvent was evaporated under reduced pressure, and the residue was
passed through flash column chromatography on silica gel to afford the
desired product. 4f, 4g, 4o, and 4s are new compounds, and the other
products 4a−4e, 4h−4n, 4p−4r are known compounds.
(0.174 g, 1.0 mmol) following typical procedure: 0.095 g (62% yield)
of product was obtained as amorphous solid after column
chromatography (eluent = petroleum ether/ethyl acetate 5:1 v/v);
1
mp 124−126 °C; H NMR (400 MHz, CDCl3, 25 °C) δ 8.08 (d, J =
8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.39−7.41 (m,
3H), 7.32−7.34 (m, 2H), 5.60 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.41
(t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 166.3,
147.2, 134.7, 134.4, 130.2, 129.9, 129.3, 128.9, 128.2, 125.4, 120.4,
61.1, 54.4, 14.4; HRMS (ESI, TOF) calcd for C18H18N3O2 [M + H]+
308.1399, found 308.1394.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (4a).8a The compound
was prepared from 2a (0.067 g, 0.5 mmol) and 3a (0.102 g, 1.0 mmol)
following typical procedure: 0.096 g (82% yield) of product was
obtained after column chromatography (eluent = petroleum ether/
ethyl acetate 3:1 v/v); mp 127−129 °C (lit. 126−128 °C);8a 1H NMR
(400 MHz, CDCl3, 25 °C) δ 7.79 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H),
7.28−7.40 (m, 8H), 5.55 (s, 2H); 13C NMR (100.6 MHz, CDCl3,
25 °C) δ 148.1, 134.6, 130.4, 129.1, 128.7, 128.1, 128.0, 125.6, 119.5,
54.1; MS (+CI) m/z (%) 236.13 (M + H+, 100).
1-Benzyl-4-ferrocenyl-1,2,3-triazole (4h).18 The compound
was prepared from 2a (0.067 g, 0.5 mmol) and 3h (0.211 g, 1.0 mmol)
following typical procedure: 0.141 g (82% yield) of product was
obtained after column chromatography (eluent = CH2Cl2); mp 151−
153 °C (lit. 145−147 °C);18 1H NMR (400 MHz, CDCl3, 25 °C)
δ 7.27−7.38 (m, 6H), 5.52 (s, 2H), 4.69 (s, 2H), 4.28 (s, 2H), 4.06 (s,
5H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 147.2, 134.9, 129.0,
128.6, 127.8, 118.7, 75.4, 69.5, 68.6, 66.6, 54.0; MS (+CI) m/z (%)
344.21 (M + H+, 100).
1-Benzyl-4-p-tolyl-1H-1,2,3-triazole (4b).17 The compound was
prepared from 2a (0.067 g, 0.5 mmol) and 3b (0.116 g, 1.0 mmol)
following typical procedure: 0.105 g (84% yield) of product was
obtained after column chromatography (eluent = petroleum ether/
ethyl acetate 4:1 v/v); mp 151−153 °C (lit. 155−157 °C);17 1H NMR
(400 MHz, CDCl3, 25 °C) δ 7.67 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H),
7.24−7.37 (m, 5H), 7.18 (d, J = 8.0 Hz, 2H), 5.52 (s, 2H), 2.34 (s,
3H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 148.1, 137.9, 134.7,
129.4, 129.0, 128.6, 127.9, 127.6, 125.5, 119.1, 54.0, 21.1; MS (+CI)
m/z (%) 249.98 (M + H+, 100).
1-Benzyl-4-cyclohexenyl-1H-1,2,3-triazole (4i).19 The com-
pound was prepared from 2a (0.067 g, 0.5 mmol) and 3i (0.106 g, 1.0
mmol) following typical procedure: 0.083 g (69% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 5:1 v/v); mp 83−85 °C (lit. 87−89 °C);19 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.35−7.37 (m, 3H), 7.24−7.29 (m,
3H), 6.47−6.50 (m, 1H), 5.47 (s, 2H), 2.32−2.35 (m, 2H), 2.15−2.17
(m, 2H), 1.71−1.74 (m, 2H), 1.62−1.66 (m, 2H); 13C NMR (100.6
MHz, CDCl3, 25 °C) δ 149.7, 134.8, 128.8, 128.4, 127.7, 127.1, 124.8,
118.2, 53.8, 26.2, 25.1, 22.3, 22.0; MS (+CI) m/z (%) 240.18 (M +
H+, 100).
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (4c).17 The
compound was prepared from 2a (0.067 g, 0.5 mmol) and 3c (0.132 g,
1.0 mmol) following typical procedure: 0.115 g (87% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 4:1 v/v); mp 140−142 °C (lit. 144−146 °C);17 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.70−7.72 (m, 2H), 7.58 (s, 1H),
7.34−7.37 (m, 3H), 7.28−7.30 (m, 2H), 6.91−6.93 (m, 2H), 5.53 (s,
2H), 3.81 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 159.2,
148.0, 134.7, 129.0, 128.6, 128.0, 126.9, 123.2, 118.7, 114.1, 55.2, 54.1;
MS (+CI) m/z (%) 266.13 (M + H+, 100).
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)butan-1-ol (4j).20 The com-
pound was prepared from 2a (0.067 g, 0.5 mmol) and 3j (0.098 g,
1.0 mmol) following typical procedure: 0.097 g (84% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 3:1 v/v); mp 77−79 °C (lit. 80 °C);20 1H NMR
(400 MHz, CDCl3, 25 °C) δ 7.35−7.36 (m, 3H), 7.24−7.26 (m, 3H),
5.47 (s, 2H), 3.64 (t, J = 6.4 Hz, 2H), 2.84 (s, 1H), 2.71 (t, J = 7.6 Hz,
2H), 1.69−1.77 (m, 2H), 1.57−1.64 (m, 2H); 13C NMR (100.6 MHz,
CDCl3, 25 °C) δ 148.4, 134.7, 129.0, 128.6, 127.9, 120.7, 62.0, 53.9,
32.1, 25.4, 25.1; MS (+CI) m/z (%) 232.14 (M + H+, 100).
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)butanenitrile (4k).21 The
compound was prepared from 2a (0.067 g, 0.5 mmol) and 3k
(0.093 g, 1.0 mmol) following typical procedure: 0.080 g (71% yield)
of product was obtained after column chromatography (eluent =
petroleum ether/ethyl acetate 4:1 v/v); mp 59−61 °C; 1H NMR (400
MHz, CDCl3, 25 °C) δ 7.36−7.38 (m, 3H), 7.26−7.29 (m, 3H), 5.48
(s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1.98−2.05
(m, 2H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 145.7, 134.5, 128.7,
128.3, 127.6, 121.0, 119.1, 53.6, 24.5, 23.9, 16.1; MS (+CI) m/z (%)
227.13 (M + H+, 100).
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)benzenamine (4d).17 The
compound was prepared from 2a (0.067 g, 0.5 mmol) and 3d
(0.117 g, 1.0 mmol) following typical procedure: 0.088 g (70% yield)
of product was obtained after column chromatography (eluent =
CH2Cl2/CH3OH 25:1 v/v); mp 177−179 °C (lit. 182−185 °C);17 1H
NMR (400 MHz, CD3CN, 25 °C) δ 7.90 (s, 1H), 7.54 (d, J = 8.8 Hz,
2H), 7.32−7.39 (m, 5H), 6.68 (d, J = 8.4 Hz, 2H), 5.54 (s, 2H), 4.28
(br, 2H); 13C NMR (100.6 MHz, CD3CN, 25 °C) δ 149.1, 137.1,
129.9, 129.3, 128.9, 127.5, 121.0, 120.0, 118.3, 115.5, 54.5; MS (+CI)
m/z (%) 251.13 (M + H+, 100).
1-Benzyl-4-(4-fluorophenyl)-1H-1,2,3-triazole (4e).8a The
compound was prepared from 2a (0.067 g, 0.5 mmol) and 3e
(0.120 g, 1.0 mmol) following typical procedure: 0.103 g (81% yield)
of product was obtained after column chromatography (eluent =
petroleum ether/ethyl acetate 5:1 v/v); mp 108−110 °C (lit. 106−
108 °C);8a 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.73−7.77 (m, 2H),
7.64 (s, 1H), 7.26−7.37 (m, 5H), 7.04−7.08 (m, 2H), 5.54 (s, 2H);
13C NMR (100.6 MHz, CDCl3, 25 °C) δ 163.7, 161.3, 147.2, 134.5,
1-Benzyl-4-cyclohexyl-1H-1,2,3-triazole (4l).20 The compound
was prepared from 2a (0.067 g, 0.5 mmol) and 3l (0.108 g, 1.0 mmol)
following typical procedure: 0.074 g (61% yield) of product was
obtained after column chromatography (eluent = petroleum ether/
ethyl acetate 5:1 v/v); mp 109−111 °C (lit. 106 °C);20 1H NMR (400
MHz, CDCl3, 25 °C) δ 7.25−7.38 (m, 5H), 7.14 (s, 1H), 5.49 (s, 2H),
2.71−2.78 (m, 1H), 1.20−2.04 (m, 10H); 13C NMR (100.6 MHz,
CDCl3, 25 °C) δ 154.2, 135.0, 129.0, 128.6, 128.0, 119.2, 54.0, 35.3,
33.0, 26.1, 26.0; MS (ESI) m/z (%) 242.17 (M + H+, 100).
1-(4-Methyl-benzyl)-4-phenyl-1H-1,2,3-triazole (4m).21 The
compound was prepared from 2b (0.074 g, 0.5 mmol) and 3a
(0.102 g, 1.0 mmol) following typical procedure: 0.095 g (76% yield)
of product was obtained after column chromatography (eluent =
petroleum ether/ethyl acetate 3:1 v/v); mp 103−105 °C (lit. 105−106
°C);21 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.76−7.79 (m, 2H),
7.63 (s, 1H), 7.39 (t, J = 3.6 Hz, 2H), 7.27−7.36 (m, 1H), 7.16−7.20
(m, 4H), 5.50 (s, 2H), 2.34 (s, 3H); 13C NMR (100.6 MHz, CDCl3,
25 °C) δ 148.0, 138.6, 131.6, 130.5, 129.7, 128.7, 128.0, 125.6, 119.4,
53.9, 21.1; MS (ESI) m/z (%) 250.04 (M + H+, 100).
129.0, 128.7, 127.9, 127.4, 127.3, 126.7, 119.3, 115.8, 115.5, 54.1; MS
(+CI) m/z (%) 254.10 (M + H+, 100).
1-(4-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl)ethanone (4f).
The compound was prepared from 2a (0.067 g, 0.5 mmol) and 3f
(0.144 g, 1.0 mmol) following typical procedure: 0.082 g (59% yield)
of product was obtained as amorphous solid after column
chromatography (eluent = petroleum ether/ethyl acetate 5:1 v/v);
1
mp 160−162 °C; H NMR (400 MHz, CDCl3, 25 °C) δ 8.00 (d, J =
8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.39−7.42 (m,
3H), 7.33−7.34 (m, 2H), 5.60 (s, 2H), 2.62 (s, 3H); 13C NMR (100.6
MHz, CDCl3, 25 °C) δ 197.6, 147.1, 136.5, 135.0, 134.4, 129.3, 129.0,
128.9, 128.2, 125.6, 120.4, 54.4, 26.6; HRMS (ESI, TOF) calcd for
C17H16N3O [M + H]+ 278.1293, found 278.1292.
Ethyl 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)benzoate (4g). The
compound was prepared from 2a (0.067 g, 0.5 mmol) and 3g
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The Journal of Organic Chemistry
Note
1-(4-Iodobenzyl)-4-phenyl-1H-1,2,3-triazole (4n).22 The com-
pound was prepared from 2c (0.129 g, 0.5 mmol) and 3a (0.102 g,
1.0 mmol) following typical procedure: 0.146 g (81% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 3:1 v/v); mp 156−158 °C (lit. 154−156 °C);22 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.80 (d, J = 1.6 Hz, 2H), 7.70−
7.78 (m, 2H), 7.66 (s, 1H), 7.38−7.42 (m, 2H), 7.30−7.34 (m, 1H),
7.04 (d, J = 8.4 Hz, 2H), 5.50 (s, 2H);13C NMR (100.6 MHz, CDCl3,
25 °C) δ 148.4, 138.2, 134.3, 130.3, 129.8, 128.8, 128.2, 125.7, 119.4,
53.6; MS (ESI) m/z (%) 362.02 (M + H+, 100).
146.0, 134.7, 129.6, 129.2, 128.8, 128.1, 125.9, 125.8, 119.5, 70.0, 54.2,
25.2; HRMS (EI, TOF) calcd for C17H17N3O [M]+ 279.1366, found
279.1373.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H spectra for products 4a−s, 13C NMR spectra for
new compounds 4f, 4g, 4o, and 4s. This material is available
free of charge via the Internet at http://pubs.acs.org.
1-(4-Methoxyphenethyl)-4-phenyl-1H-1,2,3-triazole (4o).
The compound was prepared from 2d (0.089 g, 0.5 mmol) and 3a
(0.102 g, 1.0 mmol) following typical procedure: 0.109 g (78% yield)
of product was obtained as amorphous solid after column
chromatography (eluent = petroleum ether/ethyl acetate 4:1 v/v);
mp 134−136 °C;1H NMR (400 MHz, CDCl3, 25 °C) δ 7.77 (d, J =
7.3 Hz, 2H), 7.47 (s, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz,
1H), 7.04 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.60 (t, J = 7.2
Hz, 2H), 3.78 (s, 3H), 3.19 (t, J = 7.2 Hz, 2H);13C NMR (100.6 MHz,
CDCl3, 25 °C) δ 158.7, 147.5, 130.7, 129.8, 129.0, 128.8, 128.1, 125.7,
120.0, 114.2, 65.9, 55.3, 52.0, 36.0, 29.7, 15.3; HRMS (ESI, TOF)
calcd for C17H17N3O [M + H]+ 280.1444, found 280.1440.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liupn@ecust.edu.cn; chjiag@ust.hk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Hong Kong Research Grant
Council (Projects No. HKUST 601709, HKUST 601408, and
HKU1/CRF/08), the National Natural Science Foundation of
China (Projects No. 21172069, 21190033, and 20902020),
the Innovation Program of Shanghai Municipal Education
Commission (Project No. 12ZZ050), and the Fundamental
Research Funds for the Central Universities.
1-(n-Dodecyl)-4-(phenyl)-1H-1,2,3-triazole (4p).18 The com-
pound was prepared from 2e (0.106 g, 0.5 mmol) and 3a (0.102 g,
1.0 mmol) following typical procedure: 0.124 g (79% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 10:1 v/v); mp 90−92 °C (lit. 90−92 °C);18 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.84 (d, J = 1.3 Hz, 2H), 7.74 (s,
1H), 7.31−7.44 (m, 3H), 4.40 (t, J = 10.0 Hz, 2H), 1.91−1.97 (m,
2H), 1.26−1.35 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100.6
MHz, CDCl3, 25 °C) δ 147.7, 130.8, 128.8, 128.0, 125.7, 119.3, 50.5,
31.9, 30.4, 29.6, 29.5, 29.4, 29.3, 29.0, 26.5, 22.7, 14.1; MS (ESI) m/z
(%) 314.26 (M + H+, 100).
REFERENCES
■
(1) (a) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1, pp 559. (b) Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles
and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley: New
York, 2002.
1-Cyclohexyl-4-phenyl-1H-1,2,3-triazole (4q).23 The com-
pound was prepared from 2f (0.063 g, 0.5 mmol) and 3a (0.102 g,
1.0 mmol) following typical procedure: 0.085 g (75% yield) of product
was obtained after column chromatography (eluent = petroleum
ether/ethyl acetate 6:1 v/v); mp 105−107 °C (lit. 106−110 °C);23 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.82−7.84 (m, 2H), 7.78 (s, 1H),
7.41 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 4.43−4.51 (m, 1H),
2.23 (q, J1 = 12.8 Hz, J2 = 2.8 Hz, 2H), 1.90−1.95 (m, 2H), 1.73−1.83
(m, 3H), 1.41−1.51 (m, 2H), 1.26−1.33 (m, 1H); 13C NMR (100.6
MHz, CDCl3, 25 °C) δ 147.2, 130.8, 128.7, 127.9, 125.5, 117.3, 60.0,
33.5, 25.1, 25.0; MS (+CI) m/z (%) 228.14 (M + H+, 100).
(2) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565.
(3) Reactions involving activated alkynes or strained alkynes can be
accomplished under relatively mild conditions. See: Jewett, J. C.;
Bertozzi, C. R. Chem. Soc. Rev. 2010, 39, 1272.
(4) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(5) (a) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(6) (a) Theme issue on Click chemistry: Chem. Soc. Rev. 2010, (4),
39. For additional reviews, see: (b) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc.
Rev. 2007, 36, 1249 and the references therein. (d) Tron, G. C.; Pirali,
T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med.
Res. Rev. 2008, 28, 278. (e) Lutz, J.-F.; Zarafshani, Z. Adv. Drug
Delivery Rev. 2008, 60, 958. (f) Fokin, V. V. ACS Chem. Biol. 2007, 2,
775. (g) Johnson, J. A.; Koberstein, J. T.; Finn, M. G.; Turro, N. J.
Macromol. Rapid Commun. 2008, 29, 1052. (h) Wu, P.; Fokin, V. V.
Aldrichimica Acta 2007, 40, 7.
(7) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(8) (a) Zn/C catalyzed reactions: Meng, X.; Xu, X.; Gao, T.; Chen,
B. Eur. J. Org. Chem. 2010, 5409. (b) NMe4OH catalyzed reactions:
Kwok, S. W.; Fosing, J. R.; Fraser, R.; Rodionov, V. O.; Fokin, V. V.
Org. Lett. 2010, 12, 4217.
(9) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998. (b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.;
Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
8923. (c) Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
(d) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.; Thuer
Rousseau, B.; Cintrat, J. C. Tetrahedron 2007, 63, 8094.
(10) Other studies on RuAAC: (a) Hou, D. R.; Kuan, T. C.; Li, Y. K.;
Lee, R.; Huang, K. W. Tetrahedron Lett. 2010, 66, 9415. (b) Yap, A.
H.; Weinreb, S. M. Tetrahedron Lett. 2006, 47, 3035. (c) Majireck, M.
4β-(4-Phenyl-1,2,3-triazole)-1-podophyllotoxin (4r).24 The
compound was prepared from 2g (0.220 g, 0.5 mmol) and 3a
(0.102 g, 1.0 mmol) following typical procedure: 0.200 g (74% yield)
of product was obtained after column chromatography (eluent =
chloroform/ethyl acetate 2:1 v/v); mp 168−170 °C (lit. 155−
157 °C);24 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.78−7.81 (m, 2H),
7.33−7.44 (m, 4H), 6.68 (d, J = 4.4 Hz, 2H), 6.34 (s, 2H), 6.16 (d, J =
5.0 Hz, 1H), 6.01−6.04 (m, 2H), 4.80 (d, J = 5.0 Hz, 1H), 4.44−4.48
(m, 1H), 3.83 (s, 3H), 3.78(s, 6H), 3.37−3.42 (m, 1H), 3.22−3.31 (m,
1H), 3.10 (dd, J1 = 5.0 Hz, J2 = 14.3 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3, 25 °C) δ 173.1, 152.8, 149.5, 148.2, 148.0, 137.6, 134.2, 133.3,
129.8, 128.9, 128.6, 125.8, 124.7, 119.8, 110.6, 108.9, 108.2, 102.0,
67.5, 60.8, 58.7, 56.4, 43.7, 41.8, 37.2; MS (ESI) m/z (%) 542.19 (M +
H+, 100).
1-(4-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl)ethanol (4s). To a
mixture of azide (0.067 g, 0.5 mmol), alkyne (0.144 g, 1.0 mmol), 1,4-
butanediol (0.361 g, 4 mmol), and toluene (0.5 mL) was added the
catalyst RuH2(CO)(PPh3)3 (23.4 mg, 0.025 mmol). The resulting
solution was refluxed for 48 h. The solvent was evaporated under
reduced pressure, and the residue was passed through flash column
chromatography on silica gel (eluent = petroleum ether/ethyl acetate
2:1 v/v) to afford the desired product as pale yellow amorphous solid:
64 mg (46% yield); mp 108−111 °C; 1H NMR (400 MHz, CDCl3, 25
°C) δ 7.78 (d, J = 7.7 Hz, 2H), 7.65 (s, 1H), 7.30−7.42 (m, 7H), 5.58
(s, 2H), 4.92 (q, J1 = 6.2 Hz, J2 = 12.6 Hz, 1H), 1.90 (s, 1H), 6.44 (d,
J = 6.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C) δ 148.0,
́
y, P.;
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Note
M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680. (d) Johansson, J. R.;
Lincoln, P.; Norden, B.; Kann, N. J. Org. Chem. 2011, 76, 2355.
(11) For recent applications of RuAAC, see: (a) Empting, M.;
Avrutina, O.; Meusinger, R.; Fabritz, S.; Reinwarth, M.; Biesalski, M.;
Voigt, S.; Buntkowsky, G.; Kolmar, H. Angew. Chem., Int. Ed. 2011, 50,
5207. (b) Chardon, E.; Puleo, G. L.; Dahm, G.; Guihard, G.;
Bellemin,-Laponnaz, S. Chem. Commun. 2011, 47, 5864. (c) Isidro,-
Llobet, A.; Murillo, T.; Bello, P.; Cilibrizzi, A.; Hodgkinson, J. T.;
Galloway, W. R. J. D.; Bender, A.; Welch, M.; Spring, D. R. Proc. Natl.
Acad. Sci. U. S. A. 2011, 108, 6793. (d) Poecke, S. V.; Negri, A.; Gago,
F.; Daele, I. V.; Solaroli, N.; Karlsson, A.; Balzarini, J.; Calenbergh, S.
V. J. Med. Chem. 2010, 53, 2902. (e) Krause, M. R.; Goddard, R.;
Kubik, S. Chem. Commun. 2010, 46, 5307. (f) Horne, W. S.; Olsen, C.
A.; Beierle, J. M.; Montero, A.; Ghadiri, M. R. Angew. Chem., Int. Ed.
2009, 48, 4718. (g) Chemama, M.; Fonvielle, M.; Arthur, M.; Valery, J.
M.; Etheve-Quelquejeu, M. Chem.Eur. J. 2009, 15, 1929. (h) Kelly,
A. W.; Wei, J.; Kesavan, K.; Marie, J.-C.; Windmon, N.; Young, D. W.;
Maucaurelle, L. A. Org. Lett. 2009, 11, 2257.
(12) (a) Yousefzadi, M.; Sharifi, M.; Behmanesh, M.; Moyano, E.;
Bonfill, M.; Cusido, R. M.; Palazon, J. Eng. Life Sci. 2010, 10, 281.
(b) Garcia, E. S.; Azambuja, P. Toxicon 2004, 44, 431.
(13) Asano, K.; Matsubara, S. Org. Lett. 2010, 12, 4988.
(14) Zhou, X.-M.; Wang, Z.-Q.; Chang, J.-Y.; Chen, H.-X.; Cheng, Y.-
C.; Lee, K.-H. J. Med. Chem. 1991, 34, 3346.
(15) (a) Dash, B. P.; Satapathy, R.; Gaillard, E. R.; Norton, K. M.;
Maguire, J. A.; Chug, N.; Hosmane, N. S. Inorg. Chem. 2011, 50, 5485.
́ ́
(b) Lopez-Perez, J. L.; Olmo, E.; Pascual-Teresa, B.; Abad, A.;
Feliciano, A. S. Bioorg. Med. Chem. Lett. 2004, 14, 1283.
(16) Ahmad, N.; Levison, J. J.; Robinson, S. D.; Uttley, M. F.;
Wonchoba, E. R.; Parshall, G. W. Inorg. Synth. 1974, 15, 45.
̋ ́
(17) Lorincz, K.; Kele, P.; Novak, Z. Synthesis 2009, 3527.
(18) Wang, D.; Li, N.; Zhao, M.; Shi, W.; Ma, C.; Chen, B. Green
Chem. 2010, 12, 2120.
(19) Zhou, Y.; Lecourt, T.; Micouin, L. Angew. Chem., Int. Ed. 2010,
49, 2607.
(20) Chassaing, S.; Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.;
Sommer, J. Chem.Eur. J. 2008, 14, 6713.
́ ́ ́
(21) Gonzalez, J.; Perez, V. M.; Jimenez, D. O.; Lopez-Valdez, G.;
Corona, D.; Cuevas-Yanez, E. Tetrahedron Lett. 2011, 3514.
̃
́
(22) Gonda, Z.; Novak, Z. Dalton Trans. 2010, 39, 726.
(23) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Eur. J. Org. Chem.
2010, 1875.
(24) Shi, J. F.; Wang, Y. G. Chin. J. Org. Chem. 2003, 11, 1244.
5849
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