Electronic effects of ruthenium-catalyzed [3+2]-cycloaddition of alkynes and azides

Article abstract of DOI:10.1016/j.tet.2010.09.099

A combined experimental and theoretical study of ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) reactions is presented and various electronic analyses were conducted to provide a basis in understanding the observed regioselectivity of the 1,2,3-triazole products. Computational studies using density functional theory (DFT) and atoms in molecules quantum theory (AIM) further yield fresh details on the electronic factors that determine the regioselectivity in the RuAAC. It is found that the formation of 1,2,3-triazole products is irreversible and from the Hammett study, the pathway involving a vinyl cationic intermediate is ruled out. The electronic effect favors the formation of 5-electron-donating-group substituted-1,2,3-trizoles.

Full text of DOI:10.1016/j.tet.2010.09.099

Tetrahedron 66 (2010) 9415e9420
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electronic effects of ruthenium-catalyzed [3þ2]-cycloaddition of alkynes
and azides
,
a
a
b
,
,c,
*
Duen-Ren Hou a , Ting-Chun Kuan , Yu-Kai Li , Richmond Lee c, Kuo-Wei Huang b
*
a Department of Chemistry, National Central University, 300 Jhong-Da Rd. Jhong-Li, Taoyuan 32001, Taiwan
b Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
c KAUST Catalysis Center and Division of Chemical and Life Sciences and Engineering, 4700 King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2010
Received in revised form 7 September 2010
Accepted 28 September 2010
A combined experimental and theoretical study of ruthenium-catalyzed azide-alkyne cycloaddition
(RuAAC) reactions is presented and various electronic analyses were conducted to provide a basis in
understanding the observed regioselectivity of the 1,2,3-triazole products. Computational studies using
density functional theory (DFT) and atoms in molecules quantum theory (AIM) further yield fresh details
on the electronic factors that determine the regioselectivity in the RuAAC. It is found that the formation
of 1,2,3-triazole products is irreversible and from the Hammett study, the pathway involving a vinyl
cationic intermediate is ruled out. The electronic effect favors the formation of 5-electron-donating-
group substituted-1,2,3-trizoles.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we report experimental and computational studies to elu-
cidate the electronic contribution from the alkyne moiety on the
Synthesis of 1,2,3-triazoles has recently attracted much atten-
tion mainly due to the development of the copper(I) catalyzed
azide/alkyne cycloaddition (CuAAC) and for valuable applications in
medicinal chemistry, biological systems, and materials sciences.1e7
The CuAAC methodology, however, is only feasible with terminal
alkynes, potentially limiting its scope. The Fokin and Jia groups
have demonstrated that ruthenium based catalysts, such as CpRuCl
regioselectivity of RuAAC reactions.
2. Results and discussion
2.1. Effect of the substituent
The Hammett equation has been recognized as one of the most
useful methodologies to study and explain the mechanisms of
a wide range of different reactions.6 In order to analyze the elec-
tronic effects in the RuAAC reactions, we prepared a number of
para-substituted diarylacetylenes by one-pot Sonogashira coupling
reactions to compare their reactivities.16 The competition experi-
ments between diphenylacetylene and its disubstituted analogues
in the RuAAC reactions were performed by heating the reaction
mixture of benzyl azide, 5 equiv of diphenylacetylene, 5 equiv of the
bis-para-substituted diaryl alkynes, and 5 mol% of CpRuCl(PPh3)2 at
80 ꢀC for 3 h. The results of relative reactivities are summarized in
Table 1. It was observed that the electron-rich alkynes are more
reactive than the electron-deficient species. The Hammett plot of
(PPh3)2 and Cp RuCl(PPh3)2, are capable of promoting the cyclo-
*
addition of azides and alkynes.8 In contrast to the Cu-catalyzed
systems, both terminal and internal alkynes are good substrates for
the Ru-catalyzed azide-alkyne cycloaddition (RuAAC). Weinreb
et al. further explored these reactions with unsymmetrical internal
alkynes and found interesting regioselectivity.9,10 Recently, Lin et al.
published their further findings on these reactions together with
DFT calculations that rationalized the selectivity circumstantially
and suggested that the ‘Cp( )RuCl’ core is the catalytically active
*
center and the reductive elimination of the triazole product is rate-
determining.11 Since RuAAC offers the most direct synthetic
methodology to prepare 1,4,5-trisubstituted 1,2,3-triazoles, a better
understanding of the factors that influence the regioselectivity
would lead to the design and development of useful synthetic
routes to prepare highly attractive trisubstituted triazoles.12e15
log krel versus
s
generates a reaction constant of ꢁ0.79 (Fig. 1) with
a slightly lower correlation coefficient (R2¼0.79), which could be
attributed to the fact that both para-substituents can contribute to
influence the stability of the reaction intermediate, albeit un-
equally. Even so, the relatively small reaction constant un-
equivocally rules out the pathway involving
a vinyl cation
* Corresponding authors. E-mail addresses: drhou@ncu.edu.tw (D.-R. Hou),
hkw@kaust.edu.sa (K.-W. Huang).
intermediate.17 This observation is consistent with the reported
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.099

9416
D.-R. Hou et al. / Tetrahedron 66 (2010) 9415e9420
Table 1
that the formation of 1,2,3-triazole is irreversible under the re-
action conditions of these RuAAC reactions.
Electronic influence of X substituent on relative activity
Ph
Ph
Diaryl alkynes 4 and 5, both with electronically opposite, para-
substituents, provide an excellent platform to examine and eluci-
date the electronic effect on the regiochemistry of the RuAAC
reactions by minimizing steric considerations (Scheme 2). Indeed,
it was found that two sets of the regioisomers of triazole (6a, 6b,
and 7a, 7b) were generated with moderate ratios (4.1:1 and 2.9:1,
respectively). The triazoles 6a and 7a, with the 4-electron deficient
and 5-electron rich aryls, were identified as the major isomers
according to a series of H,H-COSY and NOE spectroscopic analyses.
Since the observed regioselectivity in these two RuAAC reactions is
mainly due to the electronic factors,10,11 the results suggest that the
formation of 5-electron-donating-group substituted-1,2,3-trizoles
is more favorable.
5 equiv.
+
5 mol% CpRuCl(PPh3)2
C6H6, 80 oC, 3 h
N3CH2Ph
1 equiv.
+
X
X
2 5 equiv.
N
N
NCH2Ph
N
N
NCH2Ph
Ph
+
Ph
1
3
X
X
,
b
Entry
Alkyne
X
Product
Relative activitya
s
2.2. Density functional theory studies
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
F
Cl
Br
OMe
CO2Me
CN
3a
3b
3c
3d
3e
3f
1.50
1.22
1.12
2.00
0.38
0.48
0.06
0.23
0.23
Informative DFT calculations on the RuAAC reaction using
methylazide and propyne as model reactants with the ‘CpRuCl’ core
have been previously reported by Lin et al.11 In this work, we fo-
cused on the RuAAC reaction of alkyne 4 with ethyl 2-azidoacetate
(for modeling butyl 2-azidoacetate) to understand the electronic
interactions in the transition states that could result in the ob-
served regioselectivity. Triazole products 6a and 6b were found to
be more stable than the starting materials by 44.8 and 43.6 kcal/
mol, respectively, with 6a more favorable than 6b by 1.2 kcal/mol.
These data are in good agreement with the observation that the
RuAAC reaction is irreversible under the above-mentioned reaction
conditions, and thus suggest that the observed regioselectivity is
a result of kinetic preference.
ꢁ0.27
0.45
0.66
a
The ratio of 3/1; determined from the integration of the 1H NMR (500 MHz)
spectrum of the crude product.
b
Average of two runs.
All transition states and intermediates located have similar ge-
ometries to the structures reported in the literature.11 It was found
that the relative energy of the transition state for the CeN bond
formation of the major product 6a is 0.6 kcal/mol lower than that of
6b (
D
Gz¼18.4 vs 19.0 kcal/mol, see Supporting information), and
the calculated overall activation barrier for the formation of 6a is
1.0 kcal/mol lower than that for 6b. As the DFT calculation results
are consistent with the experimental findings, we further analyzed
the molecular orbital of the transition state to identify the in-
teractions in the CeN bond formation process. It was found that the
electronic interactions mainly involve the electron donation from
Fig. 1. Hammett plot of log krel versus s.
properties of ‘Cp
Ruþ’ cationic complexes, which are totally inactive
*
one of the alkynyl carbons to the
p orbital of the terminal N]N
*
to catalyze the cycloaddition reactions of alkynes and azides.11
The reversibility of RuAAC was examined by heating the solu-
tion of the alkyne 2d (X¼OMe), triazole 3e, and CpRuCl(PPh3)2 in
benzene at reflux for 16 h. No apparent reaction was observed as
the starting materials were recovered and the formation of the
cycloadduct 3d was not detected (Scheme 1). These results indicate
group of the azide moiety (Fig. 2).10 This observation provides
a plausible explanation for the lower overall activation energy
barrier for the cyclization leading to triazole 6a, since the carbon at
b carbon of the C^C moiety (referenced to the 4-methoxy-
phenyl ring) is more electron-donating than the
electron-donation from the methoxy group.
the
a carbon due to the
This bond formation process was further probed with Bader’s
atom in molecule (AIM) quantum theory by using AIM2000 soft-
ware for the topological analysis.18,19 The AIM-based theory ana-
lyzes interactions between atoms via the topological mapping of
electron density. The relief of the electron density displays different
characteristic points called critical points, which are important for
the understanding of the interactions that transpire within the
CpRuCl(PPh3)2
N
5 mol%
2d
N
NCH2Ph
+
No reaction
(X = OMe)
C6H6, 80 oC, 16 h
(p-C6H4CO2Me)
(p-C6H4CO2Me)
3e
Scheme 1. Reversibility of RuAAC of 3e to 3d.
N
N
N
NCH2CO2Bu
N
NCH2CO2Bu
N3CH2CO2Bu
CpRuCl(PPh3)2
5 mol%
MeO
Y
+
6a : 6b = 4.1 : 1
7a : 7b = 2.9 : 1
80oC
C6H6,
4, Y = CO2Me
5, Y = CN
MeO
Y
Y
OMe
6a, Y = CO2Me
6b, Y = CO2Me
7b, Y = CN
7a, Y = CN
Scheme 2. Electronic factors influencing regiochemistry of RuACC.

D.-R. Hou et al. / Tetrahedron 66 (2010) 9415e9420
9417
the electron-rich alkynes are more reactive and the formation of
5-electron-donating-group substituted 1,2,3-trizoles is also more
favorable. These insightful findings will be helpful for the de-
velopment of the next generation of catalysts with enhanced
selectivities and substrate scope.
4. Experimental section
4.1. Materials
All purchased chemicals were used without further purification.
THF was distilled from sodium benzophenone ketyl. 1H and 13C
NMR spectra were obtained on 200, 300 or 500 MHz spectrometers
and referenced to TMS or residual CHCl3. Analytical TLC was carried
out using aluminum-backed 0.2 mm silica gel 60 F254 plates. Puri-
fication or separation of product was carried out with flash column
chromatography using 230e400 mesh silica gel. Microwave-assis-
ted reactions were performed in a CEM Discover single mode mi-
crowave reactor, equipped with vertically-focused IR temperature
sensor. Controlled temperature, power and time setting was used in
all reactions. Synthesis of benzyl azide and 2f,21 1,8 2a to 2e,16 4,16
and 5,22 followed literature protocols.
Fig. 2. HOMO of the transition state for the cyclization of 6a formation.
molecule. Herein, we mainly focus on the bond critical points
(BCPs) and ring critical points (RCPs). BCP is a point of maximum
charge density found between a pair of nuclei while RCP is a point
of minimum density found within a ring surface.9 AIM analysis of
the transition state for the cyclization shows a BCP between the
b
carbon and terminal N of the azide, indicating a CeN bond is
being formed. The
b carbon and azide form a nearly planar geom-
etry with a CeNeNeN dihedral angle of ꢁ3.4o. Enclosed within the
transition state is an RCP. As reported by Palusiak and Krygowski, an
RCP can be treated as an indicator of aromaticity and the estimation
of
clization reaction site in this transition state structure therefore
implies the delocalization of -electrons within this transient cyclic
p
-electron delocalization.20 The generation of an RCP at the cy-
4.1.1. Benzyl azide. A solution of benzyl bromide (500.0 mg,
2.92 mmol), sodium azide (285.0 mg, 4.38 mmol), water (4 mL),
and acetone (6 mL) was heated to reflux for 14 h. The acetone was
removed under vacuum and the remaining mixture was extracted
with ether (20 mLꢂ2). The combined organic layer was dried over
Na2SO4, filtered, and concentrated to give the title compound
(311.0 mg, 2.34 mmol, 80%) as a light yellow liquid. 1H NMR (CDCl3,
p
structure from the alkynyl to azido-group (Fig. 3). Both the BCP and
RCP descriptors confirm the observed orbital interaction between
the alkyne and azide groups in the transition state.
300 MHz)
75 MHz)
d
4.33 (s, 2H), 7.29e7.40 (m, 5H); 13C NMR (CDCl3,
54.8, 128.2, 128.3, 128.8, 135.3.
d
4.1.2. Butyl 2-azidoacetate15. A solution of butyl 2-bromoacetate
(941.0 mg, 4.87 mmol), sodium azide (475.0 mg, 7.31 mmol), water
(6.4 mL), and acetone (9.6 mL) was heated to reflux for 14 h. The
acetone was removed under vacuum and the remaining mixture
was extracted with ether (20 mLꢂ2). The combined organic layer
was dried over Na2SO4, filtered, and concentrated to give the title
compound (708.4 mg, 4.51 mmol, 92%). 1H NMR (CDCl3, 500 MHz)
d
0.92 (t, J¼4.7 Hz, 3H), 1.35e1.39 (m, 2H), 1.60e1.66 (m, 2H), 3.84
(s, 2H), 4.18 (t, J¼6.6 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
d 13.4, 18.8,
30.3, 50.1, 65.5, 168.2.
4.1.3. 1,2-Bis(4-fluorophenyl)ethyne (2a). 4-Fluoro-1-iodobenzene
(177.6 mg, 0.8 mmol), dichlorobis(triphenylphosphine)palladium
(II) (33.7 mg, 0.048 mmol), and copper(I) iodide (15.2 mg,
0.08 mmol) were charged into a reaction tube. DMF (4 mL), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 731 mg, 718
mL, 4.8 mmol),
water (5.8 L, 0.3 mmol), and trimethylsilylacetylene (57
m
mL,
0.4 mmol) were added to the tube sequentially. The reaction tube
was sealed, heated to 120 ꢀC in the microwave for 45 min. After
cooling to room temperature, water was added (50 mL) and
extracted with ether (50 mL). The organic layer was neutralized
with hydrochloric acid (1 N), washed with satd NaCl(aq) (30 mL),
dried over Na2SO4, filtered, and concentrated. The crude product
was further purified by column chromatography (SiO2, hexanes; Rf
0.20) to give 2a (58 mg, 0.27 mmol, 68%) as a colorless solid. 1H
Fig. 3. Inset showing the zoom-in area of AIM analysis of the cyclization transition
state. BCPs are red dots with bond path drawn through connecting a pair of nuclei.
RCPs are yellow dots. The dotted line connects BCP associated with the RCP. For in-
terpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article.
3. Conclusion
In summary, our combined experimental and theoretical studies
on the RuAAC reactions with internal alkynes provide clear evi-
dence of electronic factors influencing regioselectivity. The RuAAC
reactions for the formation of 1,2,3-triazole are irreversible under
these experimental conditions and the Hammett studies reveal that
the involvement of vinyl cation intermediates is not plausible. Our
calculations suggest that the CeN bond formation is a process of
nucleophilic attack by the alkynyl carbon onto nitrogen. As a result,
NMR (CDCl3, 300 MHz)
NMR (CDCl3, 75 MHz)
d
6.99e7.07 (m, 4H), 7.45e7.52 (m, 4H); 13
87.9, 115.8, 119.1, 133.5, 160.8.
C
d
4.1.4. 1,2-Bis(4-chlorophenyl)ethyne (2b). Starting with 4-chloro-1-
iodobenzene (131 mg, 0.55 mmol), dichlorobis(triphenylphosphine)
palladium(II) (23.2 mg, 0.033 mmol), CuI (10.5 mg, 0.055 mmol),
DBU (494
mL, 3.3 mmol), and trimethylsilylacetylene (39 mL,
0.275 mmol), compound 2b (34 mg, 0.14 mmol, 50%) was produced

9418
D.-R. Hou et al. / Tetrahedron 66 (2010) 9415e9420
as a light yellow solid. (SiO2, hexanes; Rf 0.30) 1H NMR (CDCl3,
(20 mL), dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2, EtOAc/hex-
anes, 1:7; Rf 0.55) to give 2e (22.3 mg, 0.098 mmol, 24%). 1H NMR
(CDCl3, 300 MHz)
d 91.5, 112.3, 118.2, 127.0, 132.1, 132.2.
300 MHz)
d
7.31 (d, J¼8.7 Hz, 4H), 7.43 (d, J¼8.7 Hz, 4H); 13C NMR
(CDCl3, 75 MHz) d 89.2, 121.4, 128.8, 132.8, 134.5.
d
7.59e7.67 (m, 8H); 13C NMR (CDCl3, 75 MHz)
4.1.5. 1,2-Bis(4-bromophenyl)ethyne (2c). Starting with 4-bromo-1-
iodobenzene (1.13 g, 4.0 mmol), dichlorobis(triphenylphosphine)
palladium(II) (168.5 mg, 0.24 mmol), CuI (76 mg, 0.40 mmol), DBU
4.1.9. Methyl 4-[2-(4-methoxyphenyl)ethynyl]benzoate (4). Methyl
4-iodobenzoate (200 mg, 0.763 mmol), dichlorobis(triphenyl-
phosphine)palladium(II) (32.1 mg, 0.046 mmol) and copper(I) io-
dide (14.5 mg, 0.076 mmol) were put into a reaction tube. DMF
(3.0 mL), triethylamine (0.64 mL, 4.6 mmol), and trimethylsilyla-
(3.6 mL, 24 mmol), and trimethylsilylacetylene (285
mL, 2.0 mmol),
compound 2c (378 mg, 1.12 mmol, 57%) was produced as a colorless
solid. (SiO2, hexanes; Rf 0.30). 1H NMR (CDCl3, 300 MHz)
d 7.35 (d,
J¼8.1 Hz, 4H), 7.47 (d, J¼8.1 Hz, 4H); 13C NMR (CDCl3, 75 MHz)
d
89.4, 121.9, 122.8, 131.7, 133.0.
cetylene (54.3 mL, 0.76 mmol) were added to the tube sequentially.
The reaction tube was sealed, heated to 120 ꢀC in the microwave
oven and held for 5 min. 4-Iodoanisole (178 mg, 0.763 mmol),
4.1.6. 1,2-Bis(4-methoxyphenyl)ethyne (2d). Starting with 4-iodoa-
nisole (187.2 mg, 0.8 mmol), dichlorobis(triphenylphosphine)pal-
ladium(II) (33.7 mg, 0.048 mmol), CuI (15.2 mg, 0.08 mmol), DBU
DBU (1.36 mL, 9.2 mmol), and water (5.5 mL, 0.3 mmol) were
added to the reaction. The reaction mixture was reheated to
120 ꢀC and held for another 15 min. After cooling to room tem-
perature, the reaction mixture was added to water (30 mL) and
extracted with diethyl ether (50 mL). The organic layer was neu-
tralized with hydrochloric acid (1 N), washed with satd NaCl(aq)
(30 mL), dried over Na2SO4, filtered, and concentrated. The crude
product was further purified by column chromatography (SiO2,
hexanes; Rf 0.30) to give 4 (68.7 mg, 0.26 mmol, 34%). 1H NMR
(718
mL,
4.8 mmol),
and
trimethylsilylacetylene
(57 mL,
0.40 mmol), compound 2d (66.6 mg, 0.28 mmol, 70%) was pro-
duced as a light yellow solid. (SiO2, EtOAc/hexanes,1:20; Rf 0.33). 1H
NMR (CDCl3, 300 MHz)
d
6.86 (d, J¼8.4 Hz, 4H), 7.45 (d, J¼8.4 Hz,
55.2, 87.9, 113.9, 115.6, 132.8, 159.3.
4H); 13C NMR (CDCl3, 75 MHz)
d
4.1.7. Dimethyl 4,40-(1,2-ethyndiyl)bisbenzoate (2e). Methyl 4-
iodobenzoate (124.7 mg, 0.476 mmol), dichlorobis(triphenylphos-
phine)palladium(II) (20 mg, 0.029 mmol), and copper(I) iodide
(9.0 mg, 0.048 mmol) were put into a reaction tube. DMF (2.4 mL),
triethylamine (0.4 mL, 2.85 mmol), and trimethylsilylacetylene
(CDCl3, 300 MHz)
7.44e7.47 (m, 2H), 7.52e7.55 (m, 2H), 7.97e7.99 (m, 2H); 13C NMR
(CDCl3, 75 MHz) 55.1, 55.3, 87.8, 92.6, 114.1, 114.8, 128.4, 129.1,
d 3.81 (s, 3H), d3.90 (s, 3H), 6.85e6.88 (m, 2H),
d
129.5, 131.3, 133.2, 156.0.166.6.
(71.2 mL, 0.5 mmol) were added to the tube sequentially. The re-
action tube was sealed, heated to 120 ꢀC in the microwave oven,
and held for 5 min. Another equivalent of methyl 4-iodobenzoate
(125.0 mg, 0.476 mmol), DBU (854 mL, 5.7 mmol), and water (3.4 mL,
4.1.10. 4-(4-Methoxyphenylethynyl)benzonitrile (5). 4-Iodoanisole
(200 mg, 0.85 mmol), dichlorobis(triphenylphosphine)palladium
(II) (35.9 mg, 0.051 mmol) and copper(I) iodide (16.0 mg,
0.085 mmol) were put into a reaction tube. DMF (3.0 mL), trie-
0.19 mmol) were added to the reaction. The reaction mixture was
reheated to 120 ꢀC and held for another 15 min. After cooling to
room temperature, the reaction mixture was added to water
(30 mL) and extracted with diethyl ether (50 mL). The organic layer
was neutralized with hydrochloric acid (1 N), washed with satd
NaCl(aq) (30 mL), dried over Na2SO4, filtered, and concentrated. The
crude product was further purified by column chromatography
(SiO2, EtOAc/hexanes, 1:9; Rf 0.50) to give 2e (28 mg, 0.095 mmol,
thylamine (360
(133
mL, 2.56 mmol), and trimethylsilylacetylene
m
L, 0.94 mmol) were added to the tube sequentially. The re-
action tube was sealed, heated to 120 ꢀC in the microwave oven and
held for 5 min. 4-Bromobenzonitrile (155 mg, 0.85 mmol), DBU
(1.52 mL, 10.2 mmol), and water (6.0 mL, 0.34 mmol) were added to
the reaction. The reaction mixture was reheated to 120 ꢀC and held
for another 15 min. After cooling to room temperature, the reaction
mixture was added to water (30 mL) and extracted with diethyl
ether (50 mL). The organic layer was neutralized with hydrochloric
acid (1 N), washed with satd NaCl(aq) (30 mL), dried over Na2SO4,
filtered, and concentrated. The crude product was further purified
by column chromatography (SiO2, hexanes; Rf 0.30) to give 5
19%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz)
d 3.91 (s, 6H),
7.58 (d, J¼8.4 Hz, 4H), 8.02 (d, J¼8.1 Hz, 4H); 13C NMR (CDCl3,
75 MHz)
d 52.3, 91.3, 127.2, 129.5, 130.2, 131.6, 166.3.
4.1.8. 4,40-(1,2-Ethynediyl)bisbenzonitrile (2f). Trimethylsilylacetylene
(137 L, 0.96 mmol) was added to a solution of 4-bromobenzonitrile
m
(30.0 mg, 0.13 mmol, 15%). 1H NMR(CDCl3, 300 MHz)
d 3.82 (s, 3H),
(145.6 mg, 0.8 mmol), dichlorobis(triphenylphosphine)palladium(II)
(28 mg, 0.04 mmol), copper(I) iodide (15.2 mg, 0.08 mmol), and
6.87 (d, J¼9.0 Hz, 2H), 7.46 (d, J¼8.7 Hz, 2H), 7.53e7.60 (m, 4H); 13C
NMR(CDCl3, 75 MHz)
d 55.3, 86.7, 94.1, 111.0, 114.2, 118.6, 128.6,
triethylamine (333
mL, 2.4 mmol) in benzene (4 mL). The reaction
130.4, 131.8, 132.0, 133.3, 160.3.
mixture was heated to reflux (70 ꢀC) for 16 h, quenched with water
(20 mL) and extracted with ether (50 mL). The organic layer was
washed with satd NH4Cl(aq) (20 mL), hydrochloric acid (1 N, 20 mL),
satd NaCl(aq) (20 mL) dried over Na2SO4, filtered, and concentrated.
The crude intermediate was redissolved in CH2Cl2 (5 mL) and meth-
anol (5 mL), and potassium carbonate (1.1 g, 8 mmol) was added to
the solution. After stirring at room temperature for 1 h, the reaction
mixture was added to water (20 mL) and extracted with CH2Cl2
(20 mL). The organic layer was dried over Na2SO4, filtered, and con-
centrated. The crude product was purified by column chromatogra-
phy (SiO2, EtOAc/hexanes, 1:7; Rf 0.70) to give 4-ethynylbenzonitrile
(52.6 mg, 0.413 mmol, 52%). Dichlorobis(triphenylphosphine)palla-
dium(II) (14.5 mg, 0.02 mmol), CuI (7.9 mg, 0.041 mmol), triethyl-
4.1.11. 1-Benzyl-4,5-diphenyl-1H-1,2,3-triazole (1). A solution of
benzyl azide (30 mg, 0.23 mmol), diphenylacetylene (48.2 mg,
0.27 mmol), and CpRuCl(PPh3)2 (8.2 mg, 0.011 mmol) in anhydrous
benzene (10 mL) was refluxed under nitrogen for 3 h. The reaction
mixture was concentrated and purified by column chromatography
(SiO2, EtOAc/hexanes, 1:4) to give 1 (53.7 mg, 0.17 mmol, 77%) as
a light yellow oil. 1H NMR (CDCl3, 300 MHz)
7.00e7.26 (m, 10H), 7.37e7.55 (m, 5H); 13C NMR (CDCl3, 75 MHz)
52.0, 126.7, 127.4, 127.6, 127.8, 128.0, 128.4, 128.6, 129.1, 129.6,
d 5.39 (s, 2H),
d
130.0, 130.9, 133.8, 135.3, 144.5.
4.1.12. 1-Benzyl-4,5-bis(4-fluorophenyl)-1H-1,2,3-triazole
(3a). A
amine (172
m
L, 1.24 mmol), and 4-bromobenzonitrile (75.3 mg,
solution of benzyl azide (10.0 mg, 0.075 mmol), 2a (17.6 mg,
0.083 mmol), and CpRuCl(PPh3)2 (2.7 mg, 0.004 mmol) in anhydrous
benzene (2 mL) was refluxed under nitrogen for 3 h. The reaction
mixture was concentrated and purified by column chromatography
(SiO2, EtOAc/hexanes, 1:5, Rf 0.51) to give 3a (15.0 mg, 0.043 mmol,
0.413 mmol) were added to the solution of 4-ethynylbenzonitrile in
benzene (2 mL). The reaction mixture was heated to reflux for 16 h
and diluted with ether (50 mL). The organic solution was washed
with water (20 mL), hydrochloric acid (1 N, 20 mL), satd NaCl(aq)

D.-R. Hou et al. / Tetrahedron 66 (2010) 9415e9420
9419
57%) as a light yellow oil. 1H NMR (CDCl3, 500 MHz)
6.91e7.10 (m, 8H), 7.25e7.50 (m, 5H); 13C NMR (CDCl3, 125 MHz)
d
5.38 (s, 2H),
d
5.42 (s, 2H), 6.94e7.27 (m, 7H), 7.52e7.73 (m, 6H); 13C NMR
(CDCl3, 75 MHz)
d 52.7, 111.7, 114.3, 127.0, 127.3, 128.7, 129.0, 130.7,
d
52.2,115.6,116.6,123.6,126.9,127.4,128.3,128.4,128.5,128.9,132.0,
132.0, 132.5, 133.0, 134.4, 134.6, 143.4; HRMS-FAB (m/z): [MþH]þ
135.1, 144.0, 162.5, 163.4; HRMS-FAB (m/z): [MþH]þ calcd for
calcd for (C23H16N5), 362.1406; found 362.1400.
(C21H16N3F2), 348.1312; found 348.1317.
4.2. Reversibility of RuAAC
4.1.13. 1-Benzyl-4,5-bis(4-chlorophenyl)-1H-1,2,3-triazole
(3b). A
solution of benzyl azide (10 mg, 0.075 mmol), 2b (20.0 mg,
0.083 mmol), and CpRuCl(PPh3)2 (2.7 mg, 0.004 mmol) in anhy-
drous benzene (2 mL) was refluxed under nitrogen for 3 h. The
reaction mixture was concentrated and purified by column chro-
matography (SiO2, EtOAc/hexanes, 1:3, Rf 0.45) to give 3b (16.7 mg,
0.044 mmol, 58%) as a light yellow oil. 1H NMR(CDCl3, 500 MHz)
A solution of alkyne 2d (7.9 mg, 0.033 mmol), triazole 3e (15 mg,
0.033 mmol), and CpRuCl(PPh3)2 (1.2 mg, 0.0017 mmol) in benzene
(2.0 mL) was refluxed for 16 h under nitrogen. The solvent was
removed under vacuum and analyzed with 1H NMR spectroscopy.
Only the starting materials remain.
d
5.38 (s, 2H), 6.99e7.05 (m, 4H), 7.20e7.27 (m, 5H), 7.36e7.45 (m,
4H); 13C NMR (CDCl3, 125 MHz)
d
52.2, 125.9, 127.3, 127.9, 128.3,
4.3. Competition studies between diphenylacetylene and 1,
2-bis(4-substituted phenyl)ethyne (2)
128.7, 128.8, 129.1, 129.6, 131.3, 132.8, 133.8, 135.0, 136.2, 143.8;
HRMS-FAB (m/z): [MþH]þ calcd for (C21H16N3Cl2), 380.0721; found
380.0719.
CpRuCl(PPh3)2 (1.5 mg, 0.002 mmol), benzyl azide (5.3 mg,
0.04 mmol), diphenylacetylene (35.6 mg, 0.2 mmol), and
2
(0.2 mmol) were added into benzene (2 mL). The mixture was
refluxed under nitrogen for 3 h, and concentrated. The crude
mixture was analyzed by 1H NMR, and the ratio of the two products
was determined by the integration of their benzylic hydrogens.
Two independent reactions were performed to obtain the ratio.
4.1.14. 1-Benzyl-4,5-bis(4-bromophenyl)-1H-1,2,3-triazole
(3c). A
solution of benzyl azide (10.5 mg, 0.079 mmol), 2c (29.0 mg,
0.087 mmol), and CpRuCl(PPh3)2 (2.9 mg, 0.004 mmol) in anhy-
drous benzene (2 mL) was refluxed under nitrogen for 3 h. The
reaction mixture was concentrated and purified by column chro-
matography (SiO2, EtOAc/hexanes, 1:5, Rf 0.46) to give 3c (17.6 mg,
0.038 mmol, 50%) as a light yellow oil. 1H NMR (CDCl3, 500 MHz)
4.4. Studies on the regioselectivity of RuAAC
d
5.38 (s, 2H), 6.94e7.02 (m, 4H), 7.25e7.38 (m, 7H), 7.52e7.55 (m,
2H); 13C NMR (CDCl3, 125 MHz)
d
52.2, 122.0, 124.4, 126.4, 127.4,
A solution of butyl 2-azidoacetate (10.0 mg, 0.063 mmol), 4
(18.6 mg, 0.07 mmol), and CpRuCl(PPh3)2 (2.3 mg, 0.003 mmol) in
anhydrous benzene (2 mL) was refluxed under nitrogen for 3 h.
Solvent was removed under vacuum, and the reaction mixture was
filtered with a short silica gel plug (eluted with 1:1 ethyl acetate/
hexanes) and concentrated to give the mixture (20.0 mg, 74%) of 6a
and 6b. The ratio of 6a and 6b and their identity was determined by
1H NMR (CDCl3, 300 MHz), H,H-COSYand NOESY. Compound 6a: 1H
128.2, 128.4, 128.8, 129.5, 131.5, 131.7, 132.6, 132.7, 135.0, 143.8;
HRMS-FAB (m/z): [MþH]þ calcd for (C21H16N3Br2), 467.9711; found
467.9704.
4.1.15. 1-Benzyl-4,5-bis(4-methoxyphenyl)-1H-1,2,3-triazole (3d). A
solution of benzyl azide (10.0 mg, 0.075 mmol), 2d (19.7 mg,
0.083 mmol), and CpRuCl(PPh3)2 (2.7 mg, 0.004 mmol) in anhy-
drous benzene (2 mL) was refluxed under nitrogen for 3 h. The
reaction mixture was concentrated and purified by column chro-
matography (SiO2, EtOAc/hexanes, 1:3 Rf 0.40) to give 3d (27.3 mg,
0.073 mmol, 97%) as a light yellow oil. 1H NMR (CDCl3, 300 MHz)
NMR (CDCl3, 300 MHz)
d
0.84e0.89 (t, J¼7.5 Hz, 3H), 1.20e1.33 (m,
2H), 1.49e1.59 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.09e4.13 (t,
J¼6.9 Hz, 2H), 4.96 (s, 2H), 6.97e7.00 (d, J¼9.0 Hz, 2H), 7.20e7.23
(d, J¼8.7 Hz, 2H), 7.62e7.65 (d, J¼8.7 Hz, 2H), 7.90e7.99 (d,
d
3.75 (s, 3H), 3.84 (s, 3H), 5.36 (s, 2H), 6.77e6.92 (m, 4H), 7.01e7.49
J¼8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
d 13.1, 18.9, 30.4, 49.1, 52.0,
(m, 9H); 13C NMR (CDCl3, 75 MHz)
d
51.8, 55.2, 55.3, 113.8, 114.6,
55.4, 66.0.114.0, 115.0, 118.5, 126.4, 128.2, 129.8, 130.4, 131.1, 135.3,
119.7, 123.7, 127.4, 127.9, 128.0, 128.6, 131.4, 132.9, 135.6, 144.3, 159.1,
160.4; HRMS-FAB (m/z): [MþH]þ calcd for (C23H22N3O2), 372.1712;
found 372.1708.
143.2, 161.0, 166.8. Compound 6b: 1H NMR (CDCl3, 300 MHz)
d
0.84e0.89 (t, J¼7.5 Hz, 3H), 1.20e1.33 (m, 2H), 1.49e1.59 (m, 2H),
3.75 (s, 3H), 3.93 (s, 3H), 4.09e4.13 (t, J¼6.9 Hz, 2H), 4.97 (s, 2H),
6.77e6.80 (d, J¼9.0 Hz, 2H), 7.39e7.43 (m, 4H), 8.10e8.13 (d,
J¼8.4 Hz, 2H); HRMS-APCI (m/z): [MþH]þ calcd for (C23H25N3O5)
424.1872; found 424.1865.
4.1.16. 1-Benzyl-4,5-bis[4-(methylcarboxylate)phenyl]-1H-1,2,3-tri-
azole (3e). A solution of benzyl azide (4.0 mg, 0.031 mmol), 2e
(9.0 mg, 0.031 mmol), and CpRuCl(PPh3)2 (1.1 mg, 0.002 mmol) in
anhydrous benzene (2 mL) was refluxed under nitrogen for 3 h. The
reaction mixture was concentrated and purified by column chro-
matography (SiO2, EtOAc/hexanes, 1:5 Rf 0.23) to give 3e (8.0 mg,
0.019 mmol, 62%) as a light brown oil. 1H NMR (CDCl3, 300 MHz)
A solution of butyl 2-azidoacetate (10.6 mg, 0.068 mmol), 5
(17.5 mg, 0.075 mmol), and CpRuCl(PPh3)2 (2.4 mg, 0.003 mmol) in
anhydrous benzene (2 mL) was refluxed under nitrogen for 3 h. The
solvent was removed under vacuum, and the reaction mixture was
filtered with a short silica gel plug (eluted with 1:3 ethyl acetate/
hexanes) and concentrated to give the mixture (20.4 mg, 79%) of 7a
and 7b. The ratio of 7a and 7b and their identity was determined
with 1H NMR (CDCl3, 300 MHz), H,H-COSY and NOESY. Compound
d
3.92 (s, 3H), 3.94 (s, 3H), 5.68 (s, 2H), 7.25e7.38 (m, 5H), 7.51e7.54
(m, 2H), 8.05e8.13 (m, 4H), 8.22e8.25 (m, 2H); 13C NMR (CDCl3,
125 MHz) 52.1, 52.4, 53.2, 125.4, 125.9, 127.9, 128.6, 128.9, 129.5,
d
129.7, 129.8, 130.0, 131.1, 131.4, 134.2134.3, 147.5, 165.0, 166.6;
HRMS-FAB (m/z): [M]þ calcd for (C25H21N3O4), 427.1532; found
427.1532.
7a: 1H NMR (CDCl3, 300 MHz)
d
0.86 (t, J¼7.2 Hz, 3H), 1.21e1.33 (m,
2H), 1.50e1.59 (m, 2H), 3.86 (s, 3H), 4.11e4.14 (m, 2H), 4.95 (s, 2H),
7.00 (d, J¼8.7 Hz, 2H), 7.22 (d, J¼11.1 Hz, 2H), 7.52 (d, J¼8.4 Hz, 2H),
7.68 (d, J¼8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
d 13.5, 18.9, 30.3,
4.1.17. 1-Benzyl-4,5-bis[4-cyanophenyl]-1H-1,2,3-triazole (3f). A so-
lution of benzyl azide (10.0 mg, 0.075 mmol), 2f (18.9 mg,
0.083 mmol), and CpRuCl(PPh3)2 (2.7 mg, 0.004 mmol) in anhy-
drous benzene (2 mL) was refluxed under nitrogen for 3 h. The
reaction mixture was concentrated and purified by column chro-
matography (SiO2, EtOAc/hexanes, 1:3; Rf 0.25) to give 3e (17.5 mg,
0.049 mmol, 61%) as a light brown oil. 1H NMR (CDCl3, 300 MHz)
49.1, 55.4, 66.1, 111.0, 115.2, 118.1, 126.8, 128.4, 130.8, 131.0, 132.9,
133.1, 135.7, 142.4, 166.4. Compound 7b: 1H NMR (CDCl3, 300 MHz)
d
0.84e0.89 (t, J¼7.2 Hz, 3H), 1.21e1.33 (m, 2H), 1.50e1.59 (m, 2H),
3.76 (s, 3H), 4.11e4.14 (m, 2H), 4.98 (s, 2H), 6.80 (d, J¼8.7 Hz, 2H),
7.36e7.38 (d, J¼8.4 Hz, 2H), 7.46 (d, J¼8.1 Hz, 2H), 7.74 (d, J¼7.8 Hz,
2H); HRMS-APCI (m/z): [MþH]þ calcd for (C22H23N4O3), 390.1692;
found 390.1691.

9420
D.-R. Hou et al. / Tetrahedron 66 (2010) 9415e9420
13. Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9,
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employing the Gaussian 03 program.23 B3LYP theory was ap-
plied,24,25 LANL2DZ ECP basis set was used for Ru atom,26-28 and
a 6-31G(d) Pople basis set for the rest of the atoms.29e31 See the
Supporting information for a summary of Cartesian coordinates
and thermodynamic data. For atoms in molecules quantum theory
(AIM), the wavefunction was generated with a Gaussian 09 pack-
age.32 B3LYP theory was applied, all electron Well-tempered basis
set (WTBS) was used for Ru,33,34 and a 6-31G(d) Pople basis set was
used for the rest of the atoms. The wavefunction output was ana-
lyzed with AIM2000 software for topological interpretation. WTBS
was obtained from an EMSL basis set library.35
Lett. 2009, 19, 891e893.
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Acknowledgements
We acknowledge the financial support from NSC (95-2113-M-
008-007-MY3) to D.-R.H., from National University of Singapore
(R-143-000-346-133 and R-143-000-376-112) and KAUST (400000
0076) to K.-W.H. R.L. is grateful for a Provost fellowship from
KAUST. We are indebted to Dr. Dodi Heryadi of KAUST Super-
computing Laboratory for advice on computational chemistry and
€
to Prof. Jorg Eppinger for useful discussions.
24. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
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Supplementary data
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Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.09.099.
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