Selective formation of 1,4-disubstituted triazoles from ruthenium-catalyzed cycloaddition of terminal alkynes and organic azides: Scope and reaction mechanism

Article abstract of DOI:10.1021/om300513w

The catalytic activity of a series of ruthenium complexes lacking cyclopentadienyl ligands has been evaluated for the cycloaddition of terminal alkynes and azides to give selectively 1,4-disubstituted 1,2,3-triazoles. The complex RuH(η²-BH

Full text of DOI:10.1021/om300513w

Article
pubs.acs.org/Organometallics
Selective Formation of 1,4-Disubstituted Triazoles from Ruthenium-
Catalyzed Cycloaddition of Terminal Alkynes and Organic Azides:
Scope and Reaction Mechanism
Pei Nian Liu,†,‡ Juan Li,† Fu Hai Su,† Kun Dong Ju,‡ Li Zhang,† Chuan Shi,† Herman H. Y. Sung,†
Ian D. Williams,† Valery V. Fokin,§,* Zhenyang Lin,*,† and Guochen Jia*,†
†Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's
Republic of China
‡Shanghai Key Laboratory of Functional Materials Chemistry and Institute of Fine Chemicals, East China University of Science and
Technology, Meilong Road 130, Shanghai, People's Republic of China
§The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: The catalytic activity of a series of ruthenium
complexes lacking cyclopentadienyl ligands has been evaluated
for the cycloaddition of terminal alkynes and azides to give
selectively 1,4-disubstituted 1,2,3-triazoles. The complex
RuH(η2-BH4)(CO)(PCy3)2 was found to be an effective
catalyst for the cycloaddition reactions. In the presence of
RuH(η2-BH4)(CO)(PCy3)2, primary and secondary azides
reacted with a range of terminal alkynes containing various
functionalities to selectively produce 1,4-disubstituted 1,2,3-
triazoles. The ruthenium-catalyzed azide−alkyne cycloaddition
appears to proceed via a Ru−acetylide species as the key
intermediate, which undergoes formal cycloaddition with an azide to give a ruthenium triazolide complex. The 1,4-disubstituted
1,2,3-triazole product is generated by metathesis of the triazolide complex with a terminal alkyne. In support of the reaction
mechanism, the acetylide complex Ru(CCCMe3)2(CO)(PPh3)3 reacts cleanly with benzyl azide to give a ruthenium triazolide
complex, which reacts with excess tert-butylacetylene in the presence of PPh3 to give 4-tert-butyl-1-benzyl-1,2,3-triazole and the
diacetylide complex Ru(CCCMe3)2(CO)(PPh3)3. The mechanism is also supported by DFT calculations.
disclosed that (pentamethylcyclopentadienyl)ruthenium chlor-
ide complexes can effectively catalyze the facile cycloaddition of
a wide range of azides and terminal alkynes (RuAAC) to afford
regioselectively the complementary 1,5-disubstituted 1,2,3-
triazoles. The system can also promote cycloaddition reactions
of internal alkynes and azides. Applications of RuAAC,
although not as widely as those of CuAAC, have also appeared
in the literature.10
It is generally accepted that CuAAC involves copper−
acetylide species as the key intermediates.4,11,12 Since many
transition-metal complexes can react with terminal alkynes to
give acetylide complexes, one might expect that metal
complexes other than those of copper could also catalyze
azide−alkyne cycloaddition to yield selectively 1,4-disubstituted
1,2,3-triazoles. However, previous efforts in searching for
efficient catalytic systems of noncopper metal complexes for
the transformation have so far met with unsatisfactory results.11
Recently, Meng et al. reported that charcoal impregnated with
zinc was able to promote the cycloaddition of aryl azides and
INTRODUCTION
■
1,3-Dipolar cycloaddition of azides and alkynes represents the
most direct route to 1,2,3-triazoles.1 The thermal cycloaddition
reaction has been known for more than a century and was
thoroughly studied by Huisgen and co-workers in the 1950s−
1970s.2 Although the reaction is highly exothermic, the
cycloaddition involving unactivated substrates is often very
slow, even at elevated temperature (80−120 °C for 12−24 h),3
due to the high activation barrier (ca. 25−26 kcal/mol for
reaction of methyl azide with propyne).4 Moreover, a mixture
of regioisomers is usually formed when an unsymmetrically
substituted alkyne is involved.
The reaction rate and regiochemistry of the cycloaddition
reaction can be drastically altered by metal catalysts. In 2002,
the Meldal5 and Fokin and Sharpless6 groups independently
reported Cu(I)-catalyzed azide−alkyne cycloaddition
(CuAAC) to yield selectively 1,4-disubstituted 1,2,3-triazoles
under mild conditions. As perhaps the most powerful click
reaction to date, a wide range of applications of this reaction
have been described in recent years, especially in the areas of
organic synthesis, chemical biology, drug development, and
materials sciences.7 More recently, we8 and others9 have
Received: June 9, 2012
Published: June 26, 2012
© 2012 American Chemical Society
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alkynes to give the corresponding 1,4-disubstituted 1,2,3-
triazoles.13
azide). The resulting reaction mixture or the isolated product
was then analyzed by 1H NMR. Results of the catalytic
reactions are given in Table 1.
During the course of our effort to develop ruthenium-
mediated cycloaddition of azides and alkynes, we interestingly
found that ruthenium(II) complexes lacking cyclopentadienyl
ligands, such as RuH2(CO)(PPh3)3, can catalyze the cyclo-
addition of terminal acetylenes and azides to give selectively
1,4-substituted triazole regioisomers,14 rather than 1,5-disub-
stituted 1,2,3-triazoles as in the case of the Cp*RuCl system. In
this paper, we will report the results of our detailed study on
the reactions catalyzed by a variety of ruthenium(II) complexes
lacking cyclopentadienyl ligands, including the scope of the
catalytic reactions and mechanistic aspects. Through isolation
and characterization of active reaction intermediates and DFT
studies, we have been able to elucidate the reaction mechanism
of the click reaction.
The tricarbonyl Ru(0) complex Ru(CO)3(PPh3)2 (1) is
completely inactive (entry 1). Other complexes show varied
activities, depending on the ligand environment around the
metal center, all giving selectively 1,4-disubstituted triazole 12a.
The catalytic activity of the dicarbonyl Ru(0) complex
Ru(CO)2(PPh3)3 (2) is very poor, and the reaction only has
a conversion of the azide at ca. 26% after the reaction mixture
was refluxed in THF for 4 h (entry 2). The Ru(II) chloro
complex RuHCl(CO)(PPh3)3 (3) is marginally active (entry
3). The dihydride complex RuH2(CO)(PPh3)3 (4) is more
active; 99% conversion of the azide was achieved in 2 h, and the
expected triazole 12a was obtained in 79% yield (entry 4).14
The acetylide complexes RuH(CCCMe3)(CO)(PPh3)3 (5)
and Ru(CCCMe3)2(CO)(PPh3)3 (6) have catalytic activity
similar to that of RuH2(CO)(PPh3)3 (entries 5 and 6), giving
1,4-disubstituted 1,2,3-triazole in ca. 63% yield after the
reaction mixture was refluxed in THF for 1.5 h.
RESULTS AND DISCUSSION
Selection of Catalysts. In our effort to find efficient
ruthenium catalysts for the cycloaddition of azides and terminal
■
Interestingly, when PPh3 in RuHCl(CO)(PPh3)3 is replaced
with the bulkier and more electron-rich ligand PCy3, the
catalytic reactivity increased significantly. Thus, RuHCl(CO)-
(PCy3)2 (7) is much more effective than RuHCl(CO)(PPh3)3,
giving 1,4-disubstituted 1,2,3-triazole in ca. 51% yield after the
reaction mixture was refluxed in THF for 1 h (entry 7). The
most effective catalytic precursor found in this study is the
hydride complex RuH(η2-BH4)(CO)(PCy3)2 (8). In the
presence of 5 mol % of the complex, the reaction is completed
within 1 h to give product 12a in 89% yield (entry 8).
Reduction in the loading of 8 from 5 to 2 mol % does not affect
the yield of the product (entry 10). The reaction works well in
aprotic solvents such as THF, benzene, CH3CN, and dioxane
and the protic solvent CH3OH (entries 10−14). When the
ratio of 10a to 11a was changed from 2 to 1.5, the reaction
yield was affected negatively (entry 15). It is noted that the
catalytic reaction could not proceed at room temperature,
however. The diacetylide complex Ru(CCPh)2(CO)(PCy3)2
(9) has a catalytic activity similar to that of RuH(η2-
BH4)(CO)(PCy3)2 (8) (entries 9 and 16). The result is
expected, because RuH(η2-BH4)(CO)(PCy3)2 (8) can react
with terminal alkyne to give the diacetylide complex Ru(C
CPh)2(CO)(PCy3)2 (9), as described in Scheme 1.
Scheme 1. Structures of Complexes 1−9
alkynes to give selectively 1,4-disubstituted 1,2,3-triazoles, the
catalytic properties of several ruthenium complexes lacking
cyclopentadienyl ligands were examined. The structures of
these ruthenium complexes are shown in Scheme 1. Most of
the complexes (1−7) are known. The new complexes RuH(η2-
BH4)(CO)(PCy3)2 (8) and Ru(CCPh)2(CO)(PCy3)2 (9)
can be readily prepared from RuHCl(CO)(PCy3)2 (7).
Treatment of 7 with NaBH4 produced 8, which was converted
to 9 upon treatment with 5 equiv of HCCPh. It is possible
that the reaction of 8 with NaBH4 to give 9 may give boron-
containing coproducts, although our attempts to identify
boron-containing coproducts were unsuccessful. Excess HC
CPh is crucial for the success in the preparation of complex 9.
For example, the reaction of RuH(BH4)(CO)(PCy3)2 with 3
equiv of HCCPh produced a complicated mixture, including
unreacted 8, and complex 9 could not be detected by in situ
NMR in this case.
Scope of Catalytic Reactions. The most active catalysts
are RuH(η2-BH4)(CO)(PCy3)2 (8) and Ru(CCPh)2(CO)-
(PCy3)2 (9). The hydride complex 8 has an activity similar to
that of 9 and can be prepared more conveniently. Moreover,
the reactions of the various alkynes and azides catalyzed by
complex 9 will inevitably produce the byproduct triazole 12a.
Therefore, complex 8 was used in our subsequent investigations
on the scope of the cycloaddition reactions. These reactions
were carried out in THF using 2 mol % of the hydride complex
8 as the catalytic precursor. The products were isolated after a
mixture of an azide and an alkyne was heated at 80 °C (oil bath
temperature) for 1.5 h. The structures of the triazole products
1
are fully consistent with their H and 13C{1H} NMR and
HRMS data. In addition, the structure of 12l has been
confirmed by single-crystal X-ray diffraction studies (see the
Supporting Information).
The results of the catalytic reactions are shown in Table 2.
The hydride complex 8 efficiently catalyzed the cycloaddition
of benzyl azide (10a) with aryl- and heteroarylacetylenes
(entries 1−5). The presence of a coordinating amine or pyridyl
The catalytic properties of these ruthenium complexes were
investigated using the cycloaddition of benzyl azide and
phenylacetylene as the prototypical reaction. In the screening
experiments, a mixture of benzyl azide (10a) and phenyl-
acetylene (11a) (1/1.5 or 1/2 equiv) in THF was heated at 80
°C for a period of time in the presence of 5 mol % of a
ruthenium complex (with respect to the limiting reagent benzyl
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a
Table 1. Cycloaddition of Benzyl Azide and Phenylacetylene Catalyzed by Ruthenium Complexes
b
c
entry
cat.
solvent
S/C
time (h)
conversn (%)
yield (%)
d
1
Ru(CO)3(PPh3)2 (1)
THF
20
4
0
26
0
d
e
2
Ru(CO)2(PPh3)3 (2)
THF
20
4
ND
31
3
RuHCl(CO)(PPh3)3 (3)
THF
20
20
20
20
20
20
2
51
f
4
RuH2(CO)(PPh3)3 (4)
THF
2
99
79
5
RuH(CCCMe3)(CO)(PPh3)3 (5)
THF
1.5
1.5
1
100
100
100
100
100
100
100
100
100
100
97
63
63
51
89
92
89
87
83
88
88
81
95
6
Ru(CCCMe3)2(CO)(PPh3)3 (6)
THF
7
RuHCl(CO)(PCy3)2 (7)
THF
8
RuH(η2-BH4)(CO)(PCy3)2) (8)
THF
1
d
9
Ru(CCPh)2(CO)(PCy3)2 (9)
THF
20
1
10
11
12
13
14
15
16
8
THF
50
50
50
50
50
1.5
1.5
1.5
1.5
1.5
1.5
1.5
8
CH3CN
dioxane
CH3OH
benzene
THF
8
8
8
d
8
50
Ru(CCPh)2(CO)(PCy3)2 (9)
THF
50
100
a
b
General reaction conditions: 10a (0.5 mmol), 11a (1.0 mmol), 80 °C, 0.5 mL of solvent was added unless otherwise noted. The conversions were
c
estimated on the basis of the integration of triazole and unreacted azide in 1H NMR spectra. On the basis of azide (10a) used, determined by 1H
d
e
f
NMR integration using PhSiMe3 as the internal standard. 10a (0.5 mmol) and 11a (0.75 mmol) were used. ND = not determined. A similar result
was obtained when the reaction was carried out in 2.5 mL of THF.
group at the meta position does not affect the reactivity
appreciably, and the products 12d,e were obtained in 72% and
86% yields, respectively (entries 4 and 5). However, 2-
ethynylpyridine whose N atom is in the position ortho to the
alkyne group, could not react with benzyl azide to afford the
corresponding product. The cycloaddition of 10a with
polyaromatic alkynes, such as naphthalenylacetylene (11f),
phenanthrenylacetylene (11g), and ferrocenylacetylene (11h),
proceeded smoothly, giving the corresponding triazoles in 87−
93% yields (entries 6−8). The reaction of 10a with the alkenyl
alkyne 11i gave the product 12i in 62% yield (entry 9).
Aliphatic alkynes containing an OH or CN group also readily
reacted with 10a, and the yields of the products 12j,k are
comparable to those from the reactions of aromatic alkynes
(entries 10 and 11). The reaction of benzyl azide with 3-butyn-
1-ol, which has a shorter linker between the alkyne and
hydroxyl functional groups, afforded the cycloaddition product
in 30% yield only.
In all of the above examples, the reactions only produce 1,4-
disubstituted triazoles. Interestingly, the reaction of 10a with
the alkynes 11l,m, substituted with a strong electron-with-
drawing sulfonyl or carboxyl group, afforded respectively the
1,4-disubstituted 1,2,3-triazoles 12l,m in 72% and 71% yields
(entries 12 and 13) together with a minor amount of the
corresponding 1,5-disubstituted 1,2,3-triazole products (in 24%
and 21% isolated yields, respectively). When cyclohexyl azide
(10b) was allowed to react with phenylacetylene (11a), the
triazole product 12n was obtained in excellent yield (92%, entry
14). However, when sterically hindered tert-butylacetylene was
allowed to react with 10a, the product 4-tert-butyl-1-benzyl-1H-
1,2,3-triazole (12o) was obtained in a low yield of 24% (entry
15). Low yields (less than 15%) were also observed in the
cycloaddition reactions of phenyl azide or p-tolyl azide with
phenylacetylene (entry 16). Finally, the hydride complex 8
failed to catalyze the cycloaddition of azides and internal
alkynes under the typical reaction conditions.
The results shown in Table 1 clearly indicate the potential
value of the Ru-AAC, even though the advantage of using the
ruthenium catalyst in place of a conventional copper catalyst
was not demonstrated at this stage.
Mechanism Considerations. It is generally believed that
CuAAC involves Cu−acetylide species of varying nuclearity as
the key intermediate, which reacts with an azide to give a
Cu(triazolyl) intermediate. The 1,4-disubstituted 1,2,3-triazole
product is generated by protolysis of the Cu−C(triazolyl)
bond. The mechanism is supported by DFT calculations.15
A
mononuclear NHC copper triazolide complex has been isolated
from the reaction of azidodi-4-tolylmethane with a copper
NHC acetylide in a previous study.16 The triazolide complex
reacts quantitatively with acetic acid to give the expected
triazole product. The selectivity of the reactions catalyzed by
ruthenium complexes in the present study is the same as that of
CuAAC. Therefore, a catalytic cycle involving ruthenium
acetylide can be similarly proposed to explain the regiose-
lectivity.
In agreement with the involvement of ruthenium acetylide
species in the catalytic reactions, we found that ruthenium
acetylide complexes such as RuH(CCCMe3)(CO)(PPh3)3
(5), Ru(CCCMe3)2(CO)(PPh3)3 (6), and Ru(C
CPh)2(CO)(PCy3)2 (9) are all catalytically active. Since
reactions of ruthenium hydride complexes with terminal
alkynes to give acetylide complexes are well precedented, it is
reasonable to assume that acetylide species are generated in situ
and involved in reactions using hydride complexes such as
RuH(η2-BH4)(CO)(PCy3)2 (8), RuH2(CO)(PPh3)3 (4),
RuHCl(CO)(PCy3)2 (7), and RuHCl(CO)(PPh3)3 (3). In
fact, Wakatsuki et al have reported that RuH2(CO)(PPh3)3
reacts with excess HCCCMe3 to give first RuH(C
CCMe3)(CO)(PPh3)3 (5) and then Ru(CCCMe3)2(CO)-
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a
Table 2. Cycloaddition of Azides and Various Alkynes Using Complex 8 as the Catalyst
a
b
Reaction conditions: azide (0.5 mmol), alkyne (1.0 mmol), catalyst 8 (0.01 mmol), 80 °C, 1.5 h, 0.5 mL of THF unless otherwise noted. Isolated
c
d
e
yields. 0.025 mmol of catalyst 8 was used. 24% yield of 1,5-product was isolated. 21% yield of 1,5-product was isolated.
similar to that of RuH2(CO)(PPh3)3, and Ru(CCPh)2(CO)-
Scheme 2. Proposed Catalytic Cycle of 1,4-RuAAC
(PCy3)2 has a catalytic activity similar to that of RuH(η2-
BH4)(CO)(PCy3)2.
On the basis of the above observations, we propose that the
active species in the reactions catalyzed by RuH2(CO)(PPh3)3
(4), RuH(CCCMe3)(CO)(PPh3)3 (5), Ru(C
CCMe3)2(CO)(PPh3)3 (6), and RuH(η2-BH4)(CO)(PCy3)2
(8) are bis-acetylide complexes of the type Ru(CCR)2(CO)-
(PR′3)2 (13). A plausible catalytic cycle is illustrated in Scheme
2 using benzyl azide as the substrate. The diacetylide undergoes
a formal cycloaddition reaction with an azide to give the
Ru(triazolyl) complex 14. Metathesis of the Ru−C bond with a
terminal alkyne gives the 1,4-disubstituted 1,2,3-triazole
product and regenerates the acetylide species 13.
Model Stoichiometric Reactions. In an effort to detect
the active species involved in the reaction catalyzed by RuH(η2-
BH4)(CO)(PCy3)2 (8), we have examined the 31P NMR
spectrum of the reaction mixture of phenylacetylene and benzyl
azide (in 2/1 molar ratio) in benzene-d6 catalyzed by complex 8
(5 mol %). The in situ 31P{1H} NMR spectrum of the reaction
mixture (after heating at 80 °C for 30 min) indicates that 8 has
been consumed completely and the mixture contains at least
four phosphorus-containing species. Unfortunately, it is difficult
to separate/isolate or identify these phosphorus-containing
species from the mixture. In another approach to get reaction
(PPh3)3 (6), which can dissociate a PPh3 ligand readily in
solution.17 We have demonstrated that the five-coordinate bis-
alkynyl complex Ru(CCPh)2(CO)(PCy3)2 (9) was pro-
duced from the reaction of HCCPh with RuH(η2-BH4)-
(CO)(PCy3)2 (8). It has also been reported that the five-
coordinate bis-alkynyl complexes M(CCPh)2(CO)(PiPr3)2
(M = Os, Ru) were produced from the reactions of HCCPh
with MH(η2-BH4)(CO)(PiPr3)2.18 Furthermore, we have found
experimentally that RuH(CCCMe3)(CO)(PPh3)3 (5) and
Ru(CCCMe3)2(CO)(PPh3)3 (6) have a catalytic activity
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Scheme 3. Reaction of Complex 6 with Benzyl Azide To Form Complex 15, Which Further Reacts with tert-Butylacetylene To
Give Complex 6
Table 3. Crystal Data and Structure Refinement Details for
15·2C6H6
Table 4. Selected Bond Lengths (Å) and Angles (deg) in 15
Bond Distances
empirical formula
C68H67N3OP2Ru
1105.26
Ru(1)−C(20)
Ru(1)−C(1)
Ru(1)−P(2)
C(1)−C(2)
N(1)−N(2)
N(3)−C(1)
C(2)−C(3)
C(15)−C(16)
1.790(2)
2.125(2)
2.4146(7)
1.395(3)
1.309(2)
1.367(2)
1.500(3)
1.487(3)
Ru(1)−C(14)
Ru(1)−P(1)
O(1)−C(20)
N(1)−C(2)
N(2)−N(3)
N(3)−C(7)
C(14)−C(15)
2.061(2)
2.3734(6)
1.161(3)
1.362(3)
1.363(2)
1.459(3)
1.196(3)
formula wt
wavelength
0.710 73 Å
triclinic
cryst syst
space group
P1
̅
unit cell dimens
a
10.9419(14) Å
12.9169(17) Å
21.300(3) Å
b
c
Bond Angles
α
84.167(2)°
76.817(2)°
C(20)−Ru(1)−
97.38(9)
C(20)−Ru(1)−C(1)
98.19(9)
β
C(14)
γ
80.056(2)°
C(14)−Ru(1)−C(1)
C(14)−Ru(1)−P(1)
C(20)−Ru(1)−P(2)
C(1)−Ru(1)−P(2)
N(3)−C(1)−Ru(1)
164.13(8)
87.98(6)
92.61(7)
97.15(6)
C(20)−Ru(1)−P(1)
C(1)−Ru(1)−P(1)
C(14)−Ru(1)−P(2)
P(1)−Ru(1)−P(2)
86.21(7)
89.99(6)
V
2881.0(7) Å3
Z
2
85.18(6)
calcd density
1.274 Mg/m3
0.20 × 0.18 × 0.15 mm3
1.60−26.00°
172.853(19)
123.57(15)
175.4(2)
cryst size
135.25(15) C(2)−C(1)−Ru(1)
θ range for data collecn
no. of rflns collected
no. of indep rflns
completeness to θ = 25.00°
no. of data/restraints/params
goodness of fit on F2
final R indices (I > 2σ(I))
largest diff peak and hole
O(1)−C(20)−Ru(1) 178.2(2)
C(15)−C(14)−
Ru(1)
28 136
C(14)−C(15)−
177.9(3)
N(3)−C(1)−C(2)
100.89(17)
11 189 (R(int) = 0.0363)
99.1%
C(16)
N(2)−N(3)−C(1)
N(2)−N(1)−C(2)
113.14(17) N(1)−N(2)−N(3)
108.60(17) N(1)−C(2)−C(1)
106.46(16)
110.92(19)
11 189/0/682
0.993
R1 = 0.0358, wR2 = 0.0716
0.532 and −0.265 e Å−3
intermediates involved in the catalytic reaction, we have
collected the in situ 31P{1H} NMR spectra of the reaction of
the complex Ru(CCPh)2(CO)(PCy3)2 (9) with benzyl
azide. The 31P NMR showed that the signal of complex 9
disappeared after heating at 80 °C for 30 min, and the mixture
contained several phosphorus-containing species, including
those with the same 31P chemical shifts as those generated in
the catalytic reactions. When a mixture of complex 9 (0.005
mmol) and benzyl azide (0.01 mmol) in benzene (0.2 mL) was
stirred at room temperature for 5 min under N2, the ESI-
HRMS of the reaction mixture (diluted with methanol) showed
an ion peak at m/z 1026.5156 (see the Supporting
Information), which is assignable to the [M + H]+ peak of
the expected intermediate, the triazolide complex Ru(C
CPh)[(C2N3)(CH2Ph)Ph](CO)(PCy3)2 (14′).
Figure 1. ORTEP diagram of complex 15. The hydrogen atoms on Ph
and CCCMe3 are omitted for clarity.
Solid evidence for the involvement of acetylide and triazolide
species in the catalytic reactions comes from the isolation and
characterization of the related species from the reaction of the
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Figure 2. Energy profile calculated for the reaction mechanism proposed in Scheme 2 for the ruthenium-catalyzed cycloaddition of alkynes with
azides. The relative free energies and electronic energies (in parentheses) are given in kcal/mol.
acetylide complex Ru(CCCMe3)2(CO)(PPh3)3 (6)17 with
benzyl azide. In CH2Cl2, benzyl azide reacted readily with the
complex Ru(CCCMe3)2(CO)(PPh3)3 (6) to afford the
ruthenium triazolide complex 15. The reaction is essentially
complete at room temperature in 70 min (Scheme 3). Further
reaction of complex 15 with benzyl azide to afford a ditriazolide
complex was not observed. It is noted that triazolide complexes
have been previously isolated from reactions of azides with
NHC copper(I)16 and gold(I) (Cu-catalyzed)19 acetylide
complexes.
group at 4.38 ppm, all as singlets. The 13C{1H} spectrum
exhibited resonances of the tertiary carbons of Bu at 31.5 and
t
30.1 ppm and resonances of the methyl groups at 32.0 and 28.4
ppm. The methylene resonance of the benzyl group of the
triazolyl ligand was observed at 53.6 ppm, and the resonances
of the two carbon atoms of the alkynyl group appear at 67.8
(singlet) and 101.9 ppm (triplet). A triplet signal of the CO
ligand was observed at 208.3 ppm. The 31P{1H} NMR
spectrum displayed only a singlet at 33.8 ppm, as expected.
The mass spectrum of complex 15 showed an ion peak of the
cation (15 + H+) at m/z 950.2937 (calcd 950.3055).
The triazole product could be generated by a metathesis
reaction of the triazolide complex with a terminal alkyne. To
test this idea, we have treated complexes 15 with excess of tert-
butylacetylene in the presence of PPh3. When complex 15 was
allowed to react with tert-butylacetylene and PPh3 in deuterated
benzene at 80 °C for 80 min, complex 6 was produced along
with the triazole product 12o, which was isolated in 95% yield
(Scheme 3). The reaction of complex 15 with excessive tert-
butylacetylene and PPh3 became complicated when the
reaction time was prolonged, likely due to further reaction of
complex 6 with tert-butylacetylene. If PPh3 was not added to
the reaction mixture, the reaction gave a mixture of
phosphorus-containing products, which could not be separated
and identified, and complex 6 was not produced, as indicated
by in situ NMR.
The structure of complex 15 has been confirmed by X-ray
diffraction. A brown single crystal suitable for a single-crystal X-
ray diffraction study was obtained by slow diffusion of hexane
into the benzene solution of complex 15. The crystal data and
refinement details are given in Table 3, and selected bond
lengths and bond angles of complex 15 are shown in Table 4.
Figure 1 shows the X-ray structure of complex 15. The
coordination geometry of 15 is a distorted octahedron with two
trans-disposed PPh3 ligands. The triazolyl ligand and the
alkynyl ligand are trans to each other. The Ru−C(triazolyl)
bond length (2.125(2) Å) is slightly longer than the Ru−
C(vinyl) bond in RuCl(PhCCHPh)(CO)(PPh3)2 (2.03 (1)
Å).20 Another interesting feature of the structure is that it
contains an agostic Ru···H−C interaction involving one of the
hydrogens of the CMe3 group of the triazolyl ligand with a
Ru···H distance of 2.0998 Å.
1
The H, 13C{1H}, and 31P{1H} NMR and MS spectroscopic
The triazolide complex 15 was found to be an active catalyst
for cycloaddition of 10a with 11a, giving 99% of conversion of
the azide and 67% yield of 12a after a reaction mixture in the
presence of 2 mol % of the complex was refluxed in THF for
1
data are in agreement with the solid-state structure. The H
t
NMR spectrum of complex 15 shows the Bu resonances at
1.13 and 0.63 ppm and the methylene resonance of the benzyl
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Figure 3. Selected structural parameters (Å) calculated for important species shown in Figure 2.
1.5 h. The observation confirms the intermediacy of triazolide
complexes in the catalytic cycle.
(PMe3)2 (20) with methyl azide to give azide-coordinated
complex 16, in which the azide coordinates to the metal center
via the alkylated nitrogen atom. Figure 2 gives the energy
profile calculated for the proposed mechanism. Figure 3 gives
the structures calculated for those species involved. The
reaction of Ru(CCMe)2(CO)(PMe3)2 (20) with methyl
azide to give 16 was calculated to be thermodynamically
favorable by 1.0 kcal/mol. From 16, oxidative coupling of the
coordinated methyl azide and one of the acetylide ligands leads
to the formation of the six-membered ruthenium vinylidene
intermediate 17. An amide migration in 17 can then occur to
give the ruthenium triazolide complex 18 via the transition state
TS17‑18. The overall barrier leading to the formation of 18 via
16 is 10.5 kcal/mol. Finally, the ruthenium triazolide complex
18 undergoes a metathesis reaction with propyne via the four-
centered transition state TS19‑20 (Figure 3) to give the 1,4-
dimethyl-1,2,3-triazole product and to regenerate the catalyst
precursor complex. Four-centered transition states were also
found in metathesis reactions of many other late-transition-
DFT Studies. The experimental observations strongly
suggest that ruthenium acetylide intermediates are involved in
the catalytic cycles. However, several questions could not be
easily defined experimentally. For example, does the coupling of
an acetylide ligand and an azide involve coordinated azide or
free azide? Is triazole released through direct metathesis or
oxidation addition of C−H bond of alkynes? Why is 1,4-
disubstituted triazole formed preferentially? To answer these
questions, density functional theory (DFT) calculations were
carried out.
We first examined the energetics associated with the
mechanism proposed in Scheme 2, which gives the 1,4-
disubstituted triazole products observed experimentally. In the
theoretical study, PMe3 was used as the model phosphine and
methyl azide and propyne were used as the model organic
substrates. We first studied the reaction pathway starting with
the reaction of the model complex Ru(CCMe)2(CO)-
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Figure 4. Energy profile calculated for the path that can lead to the formation of 1,5-dimethyl-1,2,3-triazole. The relative free energies and electronic
energies (in parentheses) are given in kcal/mol.
intermediate 17 (Figures 2 and 3). The Lewis structure drawn
for 17 shown in Figure 2 indicates that the NN bond
conjugates well with the CC bond. The existence of such an
intermediate lends stability to the immediately followed
transition state TS17‑18. When the acetylide−methyl azide
coupling from 16A is considered, no corresponding inter-
mediate can be located. If it existed, the corresponding
intermediate would have the Lewis structure 17A shown in
Figure 5. Structure of 17A.
Figure 5. One can see that the NN bond in 17A does not
metal complexes.21 The rate-determining step is the metathesis
reaction, consistent with the experimental result that complex
15, theoretically modeled by 18, can be isolated.
conjugate with the CC bond, explaining its instability found
in the calculations.
We also calculated the paths involving direct coupling
(cycloaddition) between one of the acetylide ligands and free
methyl azide. The calculation results are shown in Figures 6 and
7. As expected, the two direct coupling paths have similar
reaction barriers (ca. 29.6 kcal/mol). However, they are all
higher than those calculated via methyl azide coordinated
intermediates (10.5 kcal/mol in Figure 2 and 21.5 kcal/mol in
Figure 4). The results clearly indicated that the two direct
coupling paths to give triazolide intermediates are much more
difficult than the paths via methyl azide coordinated
intermediates and that the reaction pathway shown in Figure
2 is the most favorable one.
Overall, the reaction pathway shown in Figure 2 is similar to
that proposed for the Cu catalysis. However, there are subtle
differences in the computed reaction profiles of the two
systems. The reaction barrier (6.1 kcal/mol) for the formation
of the six-membered ruthenium vinylidene intermediate 17
from acetylide complex 16 is significantly lower than that for
the corresponding step in the copper system (17 kcal/mol for
mononuclear copper acetylide and 10.5−12.9 kcal/mol for
dinuclear copper complexes).15a The reaction barrier (7.0 kcal/
mol) for the formation of ruthenium triazolide complex 18
We then studied the reaction pathway involving complex
16A, in which the azide coordinates to the metal center via the
terminal nitrogen atom. When methyl azide coordinates to the
metal center via the terminal nitrogen atom, one would expect
that the reactions would afford the 1,5-disubstituted triazole
products. Figure 4 gives the energy profile calculated for the
coupling between the terminal N coordinated methyl azide
ligand and one of the acetylide ligands in 16A. The terminal N
coordinated complex 16A is less stable than the methyl bonded
N coordinated complex 16 by 4.6 kcal/mol. The overall barrier
leading to the formation of 18A via 16A is 21.5 kcal/mol,
significantly higher than that leading to the formation of 18 via
16 (10.5 kcal/mol). These results are consistent with the
experimental observation that 1,5-disubstituted triazole prod-
ucts were not observed.
Two factors contribute to the preference for the acetylide−
methyl azide coupling from 16 over from 16A. 16 is more
stable than 16A, since the methyl-bonded nitrogen in the
methyl azide binds better with the metal center than the
terminal nitrogen does. The acetylide−methyl azide coupling
from 16 initially gives the metal-containing six-membered-ring
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Figure 6. Energy profiles calculated for direct coupling between the acetylide ligand and methyl azide that can lead to the formation of 1,4-dimethyl-
1,2,3-triazole (a) and 1,5-dimethyl-1,2,3-triazole (b). The relative free energies and electronic energies (in parentheses) are given in kcal/mol.
from 17 is significantly higher than that for the corresponding
step in the copper system (3.2 kcal/mol for mononuclear
copper acetylide).15a Furthermore, we propose that the triazole
product is formed from the metathesis reaction of the
ruthenium triazolide complex 18 with alkyne, while the 1,2,3-
triazole product was thought to be generated by protolysis of
cupper triazolide complexes.4,11,12
to the metal center via the internal nitrogen atom. The
ruthenium triazolide complex undergoes a metathesis reaction
with a terminal alkyne via a four-centered transition state to
give the 1,4-disubstituted 1,2,3-triazole product and to
regenerate the catalyst precursor complex. The metathesis
reaction appears to be the rate-determining step.
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
ether, THF, benzene) or calcium hydride (dichloromethane). The
organic azides 10a,b,22 Ru(CO)3(PPh3)2 (1),23 Ru(CO)2(PPh3)3
(2),24 RuHCl(CO)(PPh3)3 (3),25 RuH2(CO)(PPh3)3 (4),25 RuH-
(CO)(CCBu-t)(PPh3)3 (5),17 Ru(CO)(CCBu-t)2(PPh3)3 (6),17
and RuHCl(CO)(PCy3)2 (7)26 were prepared according to literature
methods. Alkynes 11a−m and other chemicals were purchased from
Aldrich. Elemental analyses were performed by M-H-W Laboratories
(Phoenix, AZ). Mass spectra were collected on a MALDI Micro MX
mass spectrometer (MALDI) or an API QSTAR XLSystem (ESI) or
GCT Premier mass spectrometer (CI). 1H, 13C{1H}, and 31P{1H}
NMR spectra were collected on a Bruker AV 400 MHz NMR
CONCLUSION
■
The catalytic activity of a series of ruthenium complexes lacking
cyclopentadienyl ligands has been evaluated for the cyclo-
addition of terminal alkynes and azides to give selectively 1,4-
disubstituted 1,2,3-triazoles. Complexes such as RuH(η2-
BH4)(CO)(PCy3)2 and Ru(CCPh)2(CO)(PCy3)2 were
found to be the most effective catalysts for the cycloaddition
reactions. In the presence of RuH(η2-BH4)(CO)(PCy3)2,
primary and secondary azides reacted with a range of terminal
alkynes to produce selectively 1,4-disubstituted 1,2,3-triazoles.
Both experimental and computational studies indicate that the
Ru-catalyzed reactions of azides with terminal alkynes involve
Ru−acetylide species as the key intermediate, which undergoes
formal cycloaddition with azide to give a Ru(triazolyl) complex
through an alkyne/azide species in which the azide coordinates
1
spectrometer or a Bruker ARX 300 MHz NMR spectrometer. H and
13C NMR chemical shifts are relative to TMS or residue of deuterium
solvents, and 13P NMR chemical shifts are relative to 85% H3PO4.
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Figure 7. Selected structural parameters (Å) calculated for the transition states shown in Figures 4 and 6.
Single-crystal X-ray analysis was performed on an Oxford Xcalibur PD
X-ray diffractometer.
Preparation of 15. To a solution of complex 6 (200 mg, 0.186
mmol) in CH2Cl2 (15 mL) was added benzyl azide (148 mg, 1.12
mmol). The mixture was stirred at room temperature for 70 min. The
solution was concentrated to 1 mL, and hexane (10 mL) was added to
give a precipitate. After filtration, the solid was washed with hexane
and dried under vacuum to afford a brown solid. Yield: 113 mg, 64%.
31P{1H} NMR (162.0 MHz, C6D6, 25 °C): δ 33.8 (s). 1H NMR (400.1
MHz, C6D6, 25 °C): δ 0.63 (s, 9H), 1.13 (s, 9H), 4.38 (s, 2H), 7.00−
7.06 (m, 22H), 7.60−7.66 (m, 13H). 13C{1H} NMR (100.6 MHz,
C6D6, 25 °C): δ 28.4, 30.1, 31.5, 32.0, 53.6, 67.8, 101.9, 127.3, 127.8,
128.1, 128.3, 130.2, 131.6, 132.4, 132.5, 133.2, 133.4, 133.6, 133.8,
134.9, 135.0, 137.6, 152.4, 159.2, 208.3. HRMS (+ESI): calcd for
C56H56N3OP2Ru+ 950.2937, found 950.3055 [M + H]+. Anal. Calcd
for C56H55N3OP2Ru + H2O: C, 69.55; H, 5.94; N, 4.35. Found: C,
69.14; H, 5.66; N, 4.31.
Preparation of RuH(CO)(PCy3)2(η2-H2BH2) (8). To a solution of
RuHCl(CO)(PCy3)2 (7; 0.200 g, 0.27 mmol) in benzene (10 mL) was
added NaBH4 (0.100 g, 2.7 mmol). The mixture was stirred at room
temperature for 48 h and then filtered. The volume of the filtrate was
reduced to ca. 1 mL, and then Et2O (1 mL) and hexane (2 mL) were
added to give a precipitate. The solid was collected by filtration and
washed with THF (1 mL) and hexane (2 mL). The resulting solid was
recrystallized using a mixed solvent of CH2Cl2 and hexane. The yellow
solid was dried under vacuum. Yield: 0.120 g, 63%. 31P{1H} NMR
1
(162.0 MHz, CD2Cl2, 25 °C): δ 50.2 (s). H NMR (400.1 MHz,
CD2Cl2, 25 °C): δ −14.8 (t, J = 18.0 Hz, 1H, Ru-H), −7.99 (br, 1H,
Ru-η2-H2BH2), −5.06 (br, 1H, Ru-η2-H2BH2), 1.25−2.12 (m, 66H,
Cy-H), 3.65 (br, 2H, Ru-η2-H2BH2). 13C{1H} NMR (100.6 MHz,
CD2Cl2, 25 °C): δ 27.2, 28.3, 30.3, 30.9, 36.4, 205.3. HRMS (MALDI,
CHCA): calcd for C37H70BOP2Ru+ 705.4033, found 705.4844 [M −
H−]+. Anal. Calcd for C37H71BOP2Ru·0.3CH2Cl2: C, 61.26; H, 9.87.
Found: C, 61.21; H, 9.52.
Preparation of Ru(CO)(CCPh)2(PCy3)2 (9). HCCPh (0.144
g, 1.41 mmol) was added to a suspension of RuH(CO)(η2-
H2BH2)(PCy3)2 (0.200 g, 0.28 mmol) in 10 mL of benzene. The
mixture was refluxed for 15 h. The resulting suspension was cooled to
room temperature, the volume of the reaction mixture was reduced to
ca. 1 mL, and then methanol (1 mL) was added to give a precipitate.
The solid was collected by filtration, washed with methanol, and dried
under vacuum to give a dark red microcrystalline solid. Yield: 200 mg,
79%. 31P{1H} NMR (162.0 MHz, CD2Cl2): δ 43.3 (s). 1H NMR
(400.1 MHz, CD2Cl2): δ 1.19−1.31 (m, 20H), 1.48−1.57 (m, 16H),
1.78−1.81 (m, 12H), 2.05−2.09 (m, 12H), 2.84−2.91 (m, 6H), 7.07
(t, J = 7.2 Hz, 2H), 7.21 (t, J = 7.6 Hz, 4H), 7.29 (d, J = 7.6 Hz, 4H).
13C{1H} NMR (100.6 MHz, CD2Cl2, 25 °C): δ 26.9, 28.4, 30.4, 35.7,
121.7, 124.7, 128.3, 129.8, 130.4, 207.1. HRMS (+ESI): calcd for
C53H77OP2Ru+ 893.4493, found 893.4495 [M + H]+. Anal. Calcd for
C53H76OP2Ru: C, 71.35; H, 8.59. Found: C, 71.27; H, 8.62..
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 8 (0.01 mmol). The resulting
solution was stirred at 80 °C for 1.5 h. The solvent was evaporated
under reduced pressure, and the residue was passed through a flash
column of silica gel to afford the desired product. The products 12a−
f,h−k,m−p are known compounds;27 12g,l are new compounds, and
their spectroscopic data are listed as follows.
1
1-Benzyl-4-(phenanthren-1-yl)-1H-1,2,3-triazole (12g). H NMR
(400.1 MHz, CDCl3, 25 °C): δ 5.63 (s, PhCH2, 2H), 7.34−7.42 (m,
5H), 7.55−7.59 (m, 2H), 7.62−7.67 (m, 2H), 7.74 (s, 1H), 7.85 (d, J
= 6.8 Hz, 1H), 7.93 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 8.4
Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H). 13C{1H} NMR (100.6 MHz,
CDCl3, 25 °C): δ 54.3, 122.5, 122.7, 122.9, 126.1, 126.6, 126.8, 126.9,
127.1, 128.1, 128.3, 128.8, 129.2, 130.0, 130.3, 130.6, 131.2, 134.6,
+
147.2. HRMS (+CI): calcd for C23H18N3 336.1495, found 336.1447
[M + H]+.
1-Benzyl-4-tosyl-1H-1,2,3-triazole (12l). 1H NMR (400.1 MHz,
CDCl3, 25 °C): δ 2.39 (s, Ar-CH3, 3H), 5.52 (s, PhCH2, 2H), 7.27−
7.32 (m, 4H), 7.37 (t, J = 2.8 Hz, 3H), 7.92 (d, J = 8.4 Hz, 2H), 8.04
(s, triazole-H, 1H). 13C{1H} NMR (100.6 MHz, CDCl3, 25 °C): δ
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21.5, 54.7, 125.6, 128.0, 128.5, 129.2, 129.3, 129.9, 133.0, 137.0, 145.0,
149.4. HRMS (+CI): calcd for C16H16N3O2S+ 314.0958, found
314.0965 [M + H]+.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chjiag@ust.hk (G.J.); fokin@scripps.edu (V.V.F.);
chzlin@ust.hk (Z.L.).
■
Crystallographic Details. Crystals of complex 15 suitable for an
X-ray analysis were obtained by slow diffusion of hexane into a
benzene solution of the complex. The crystal was mounted on a glass
fiber, and the diffraction intensity data were collected with a Bruker
CCD diffractometer with monochromated Mo Kα radiation (λ =
0.710 73 Å) at 173 K. Lattice determination and data collection were
carried out using SMART v.5.625 software. Data reduction and
absorption correction were performed using SAINT v 6.26 and
SADABS v 2.03. Structure solution and refinement were performed
using the SHELXTL v.6.10 software package. The structure was solved
by direct methods and refined by full-matrix least squares on F2. All
non-hydrogen atoms were refined anisotropically. The hydrogen
atoms were introduced at their geometric positions and refined as
riding atoms.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Hong Kong Research Grant
Council (Project Nos. HKUST 601306, HKUST 601408, and
HKU1/CRF/08), the National Natural Science Foundation of
China (Project Nos. 21172069 and 21190033), the Innovation
Program of Shanghai Municipal Education Commission
(Project No. 12ZZ050), and the Fundamental Research
Funds for the Central Universities.
Computational Details. Density functional theory calculations at
the Becke3LYP (B3LYP)28 level have been used to perform the
geometry optimizations for all species studied here. Frequency
calculations at the same level of theory have also been performed to
identify all stationary points as minima (zero imaginary frequency) or
transition states (one imaginary frequency). An intrinsic reaction
coordinate (IRC)29 analysis was carried out to confirm that all
stationary points are smoothly connected to each other. The Gibbs
free energy at 298.15 K was obtained on the basis of frequency
calculations. The Ru and P atoms were described using the LANL2DZ
basis set including a double-valence basis set with the Hay and Wadt
effective core potential (ECP).30 An additional f polarization shell was
added for Ru, with an exponent of 1.235.31 In the case of P, a d
polarization shell was added, with an exponent of 0.387.32 The 6-
31G33 basis set was used for other atoms. All calculations were
performed with the use of the Gaussian 03 packages.34
REFERENCES
■
(1) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
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(2) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
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that are likely to play a key role in weakly bound complexes.35
Therefore, we used single-point B3LYP-D3 energies,36 which include a
dispersion energy correction, for the energy curve shown in Figure 2.
A detailed comparison of the B3LYP and B3LYP-D3 results is given in
the Supporting Information.
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Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
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The results presented were obtained with a basis set of a double-ζ
quality described above. To test the basis set dependence of the
results, we carried out single-point energy calculations for selected
species shown in Figure 2 using a better basis set having a triple-ζ
quality for all atoms. On the basis of the LanL2DZ basis set, we split
the d-type valence orbitals to get a triple-ζ representation of the 4d
electrons for Ru. Similarly, we split the p-type valence orbitals to get a
triple-ζ representation of the 3p electrons for P. f and d polarization
shells were also added for Ru and P, respectively, as described above.
The 6-311G basis set was used for other atoms. The results of these
additional single-point calculations show that the use of the better
basis set does not change the shape of the potential energy curve given
in Figure 2 and that both basis sets give the same conclusion. For
example, the electronic energies of 16, TS16‑17, 17, TS17‑18, 18, and
TS19‑20 relative to 20 + MeN3 are −16.2, −13.0, −14.1, −8.9, −57.1,
and −39.7 kcal/mol, respectively, using the double-ζ quality basis set.
Using the triple-ζ quality basis set, the relative electronic energies are
−15.4, −9.5, −10.2, −4.6, −52.4, and −32.7 kcal/mol, respectively.
(d) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.; Thuer
Rousseau, B.; Cintrat, J. C. Tetrahedron 2007, 63, 8094.
́
y, P.;
(9) 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.
M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680. (d) Recently, a
simple one-pot RuAAC reaction starting from an alkyl halide, sodium
azide, and an alkyne to give 1,5-disubstituted 1H-1,2,3-triazoles was
reported: Johansson, J. R.; Lincoln, P.; Norden, B.; Kann, N. J. Org.
Chem. 2011, 76, 2355.
(10) For recent applications of RuAAC, see for example: (a) Empting,
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ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and CIF files giving experimental
procedures, compound characterization data, X-ray crystallo-
graphic data, and details of computational studies. This material
is available free of charge via the Internet at http://pubs.acs.org.
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