Coordinatively unsaturated ruthenium complexes as efficient alkyneazide cycloaddition catalysts

Article abstract of DOI:10.1021/om2012425

The performance of 16-electron ruthenium complexes with the general formula Cp*Ru(L)X (in which L = phosphine or N-heterocyclic carbene ligand; X = Cl or OCH2CF3) was explored in azidealkyne cycloaddition reactions that afford the 1,2,3- triazole products

Full text of DOI:10.1021/om2012425

Article
pubs.acs.org/Organometallics
Coordinatively Unsaturated Ruthenium Complexes As Efficient
Alkyne−Azide Cycloaddition Catalysts
Marina Lamberti,†,‡ George C. Fortman,† Albert Poater,§,⊥ Julie Broggi,† Alexandra M. Z. Slawin,†
Luigi Cavallo,∥ and Steven P. Nolan*,†
†EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, U.K.
‡Dipartimento di Chimica e Biologia, Universita
̀
di Salerno, Via Ponte don Melillo, I-84084 Fisciano (SA), Italy
§Catalan Institute for Water Research (ICRA), H2O Building, Scientific and Technological Park of the University of Girona, Emili
Grahit 101, E-17003 Girona, Spain
⊥Institut de Química Computacional, Departament de Química, Universitat de Girona, Campus de Montilivi, E-17071 Girona, Spain
∥KAUST Catalyst Research Center, 4700 King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of
Saudi Arabia
S
* Supporting Information
ABSTRACT: The performance of 16-electron ruthenium complexes with the general
formula Cp*Ru(L)X (in which L = phosphine or N-heterocyclic carbene ligand; X = Cl or
OCH2CF3) was explored in azide−alkyne cycloaddition reactions that afford the 1,2,3-
triazole products. The scope of the Cp*Ru(PiPr3)Cl precatalyst was investigated for
terminal alkynes leading to new 1,5-disubstituted 1,2,3-triazoles in high yields. Mechanistic
studies were conducted and revealed a number of proposed intermediates. Cp*Ru-
1
(PiPr3)(η2-HCCPh)Cl was observed and characterized by H, 13C, and 31P NMR at
temperatures between 273 and 213 K. A rare example of N,N-κ2-phosphazide complex,
Cp*Ru(κ2-iPr3PN3Bn)Cl, was fully characterized, and a single-crystal X-ray diffraction
structure was obtained. DFT calculations describe a complete map of the catalytic
reactivity with phenylacetylene and/or benzylazide.
the Ru(II)-catalyzed approach (RuAAC) toward complemen-
tary regioisomers, the 1,5-disubstituted 1,2,3-triazoles.
The CuAAC reaction, considered as one of the most
powerful click reactions,7 has been the focus of significant
research activity. Much effort has been devoted to unravel its
mechanism,8 whereas only a few papers have appeared in the
literature regarding the RuAAC reaction.6,9
INTRODUCTION
■
While absent in natural products, the 1,2,3-triazoles are N-
heterocyclic compounds that constitute an important class of
organic substrates owing to their diverse uses, ranging from
industrial applications to a large number found in pharmaceut-
ical compounds.1 The Huisgen 1,3-dipolar cycloaddition of
alkynes (1) and azides (2) was the first reported direct route to
produce these interesting products.2 This thermal process,
known for more than a century, has a limited scope due to its
low regioselectivity and the required high reaction temper-
atures.3 More recently, catalytic processes to obtain exclusively
1,4- or 1,5-disubstitued regioisomers have been reported in the
literature, and a schematic representation of this transformation
is depicted in eq 1.
According to the proposed mechanism for RuAAC,6 the
catalytically active species is the neutral “Cp*RuCl” species,
produced by the displacement of spectator ligands from the 18-
electron ruthenium complexes, which then undergoes an
oxidative coupling of the azide and the alkyne to give a six-
membered ruthenacycle intermediate. Subsequent reductive
elimination releases the aromatic triazole product.
The extrusion of ligands to create coordinative unsaturation
at the metal center is obviously of central relevance. Within this
context, we proposed to investigate whether coordinatively
unsaturated 16-electron complexes Cp*Ru(L)Cl might exhibit
improved performance in this catalytic process and extend this
study to include other representative ligands, such as N-
heterocyclic carbenes (NHCs).10
In particular, Meldal4 and Sharpless5 independently reported
in 2002 the Cu(I)-catalyzed azide−alkyne cycloaddition
(CuAAC), which regioselectively leads to the 1,4-disubstituted
1,2,3-triazoles. Later, Fokin in collaboration with Jia6 reported
Received: December 14, 2011
Published: January 10, 2012
© 2012 American Chemical Society
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Stable coordinatively unsaturated ruthenium complexes
Cp*Ru(L)X, in which L represents a sterically demanding
phosphine or an NHC ligand and X represents a halide or an
alkoxide ligand, are well-known in the literature.11 Moreover,
the binding of these imidazole- and phosphine-based ligands to
the Cp*RuCl moiety was thoroughly investigated by
thermochemistry and structural studies.12 A linear correlation
between the experimental bond dissociation energies (BDEs)
RESULTS AND DISCUSSION
Catalytic Activity. Following literature procedures,11a,b,15
■
the chloro complexes 6a−f were obtained by mixing a solution
of the ligand L (5a−f, 4 equiv) in THF and the tetramer
[Cp*RuCl]4 (4) (1 equiv) at room temperature (eq 2),
whereas the alkoxo complex 7a was synthesized by reacting the
corresponding chloro complex 6a with Tl(OCH2CF3) (eq 3).16
Complexes 6 and 7 were employed as precatalysts for the
cycloaddition reaction of benzylazide and phenylacetylene as
model substrates. The results of this study are presented in
Table 1. For comparison, the analogous reaction catalyzed by
the [Cp*RuCl]4 (4) precursor is also reported. The reactions
were carried out in dichloromethane (DCM) at room
temperature with 1 mol % ruthenium catalyst. In all cases,
the 1,5-regioisomer was the only product. The metal-free
reactions (control reaction) conducted under the same
conditions gave <1% conversion (Table 1, entries 9 and 10).
Complexes 6a and 6b exhibited the best catalytic perform-
ance (Table 1, entries 1 and 2). Among the NHC-based
complexes, the highest conversion was obtained with complex
6c, which bears the IAd ligand, which is the most sterically
demanding among the explored NHC ligands (Table 1, entry 3).
Nevertheless, the obtained conversions and the %Vbur of the
examined L ligands did not show a linear correlation.
Therefore, the catalytic behavior of these ruthenium complexes
cannot simply be correlated with the steric requirements of L
ligands.
13
of this class of complexes and the %VBur (the percent of a
volume occupied by ligand atoms in a sphere centered about a
metal) of the corresponding ligands was found,14 suggesting
that the BDEs are significantly affected by the steric
requirements of the ligand.
In the present contribution, the activity of Cp*Ru(L)X
complexes 6a−f and 7a in which L is a NHC (Figure 1) ligand
Figure 1. NHC ligands used in this work.
or phosphine ligand and X is a chloride or an alkoxide group
(eqs 2 and 3) has been investigated as catalysts in the
The effect of the anionic ligand was also investigated. In
particular, in the aforementioned conditions, the alkoxo
complex, 7a, produced only traces of the expected 1,2,3-
triazole (Table 1, entry 7), which suggests that the chloride has
an important role in this catalytic process. Although the
[Cp*RuCl]4 precursor showed good conversion, the activities
of the 16-electron phosphine-based ruthenium complexes (6a
and 6b) proved higher.
The influence of the order of the addition of the substrates
on the catalytic activity was explored. For complex 6a, we found
that the addition of the alkyne prior to addition of the azide
caused a lowering of the conversion (6-fold), whereas adding
the azide before the alkyne did not show a significant difference
with respect to the addition of a mixture of the substrates to the
cycloaddition reaction of benzylazide with phenylacetylene to
afford the 1,2,3-triazole compound. The scope of the reaction
catalyzed by the Cp*Ru(PiPr3)Cl complex, which showed the
best activity among the examined catalysts, was explored for
both terminal and internal alkynes. Mechanistic studies,
performed by means of NMR experiments and DFT cal-
culations, allowed the description of both the catalyst activation
and the productive catalytic cycle.
Table 1. Catalytic Activity of 16-Electron Ruthenium Precatalysts in the Cycloaddition Reaction of Benzylazide and
a
Phenylacetylene
b
entry
[Ru]
conv [%]
1
2
Cp*Ru(PiPr3)Cl
Cp*Ru(PCy3)Cl
Cp*Ru(IAd)Cl
Cp*Ru(IPr)Cl
Cp*Ru(ICy)Cl
Cp*Ru(IMes)Cl
Cp*Ru(PiPr3)(OR)
[Cp*RuCl]4
6a
6b
6c
6d
6e
6f
89
87
67
58
8
3
4
5
6
4
c
7
7a
4
2
8
68
<1
<1
9
10
PiPr3
5a
a
b
c
Reaction conditions: 1 mol % [Ru]; DCM: 2 mL; azide/alkyne = 1:1.05. Conversion determined by GC, average of two runs. R = CH2CF3.
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solution of the catalyst. This behavior can be explained in light
of the observed reactivity of the catalyst with each substrate
(vide infra).
Scheme 1. Formation of 1,5-Disubstituted 1,2,3-Triazoles
Catalyzed by Complex 1
a
Table 2 shows the results of a solvent screening on the model
reaction catalyzed by 6a. The highest cycloaddition reaction
Table 2. Effect of Solvents on the Conversion (%) of the
a
Model Reaction
neat water iPrOH pentane toluene THF DMF dioxane DCM
9
9
16
22
49
65
70
75
89
a
Reaction conditions: catalyst 6a, 1 mol %; solvent, 2 mL; time, 40
min; room temperature; azide/alkyne = 1:1.05. Conversion
determined by GC, average of two runs.
efficiency was observed in coordinating solvents, such as
tetrahydrofuran, dimethylformamide, dioxane, and dichloro-
methane. Lower conversions were obtained in nonpolar
hydrocarbon solvents, such as pentane and toluene. Polar
protic solvents, including water and 2-propanol, led to very low
conversions as well. Presumably, a good balance of polarity and
coordinating ability makes dichloromethane the best perform-
ing solvent for this reaction.
Concentrations and catalyst loadings were examined,
showing that the highest efficiency is obtained at 1 mol %
and 2.5 mM of catalyst (Table 3). As discussed in the following
a
Table 3. Variation of Concentration and Loading of
Catalyst
Reaction times and isolated yields after flash chromatography are
a
reported for each triazole product. Reaction conditions: Catalyst 6a, 1
mol %; DCM, 2 mL; azide/alkyne = 1:1.05, 40 °C. bRoom
b
c
solvent (mL)
[Ru] (mol %)
conv (%)
temperature. 2 mol % catalyst 6a.
1.0
1.0
1.0
1.0
1.0
0.5
0.1
9
18
66
89
0.1
1
with 1,1-disubstituted propargylic alcohols and amines was
previously investigated with 18-electron ruthenium complexes
as precatalysts.6c By comparison, the 16-electron complex 6a
gave more rapid conversions operating under milder con-
ditions.
Because of the excellent activity observed with 1,1′-
disubstituted propargylic alcohols, we decided to investigate
the effect of the substituents on the α carbon and of the
position of the hydroxyl group relative to the triple bond.
Surprisingly, we observed that the cycloaddition reactions with
benzylazide and the alkynes, described in Figure 2, did not
2
c
2
98
2
52
6
2
a
Reaction conditions: catalyst 6a; solvent, DCM; time, 40 min; room
b
temperature; azide/alkyne = 1:1.05. Conversion determined by GC,
c
average of two runs. Reaction at 40 °C, 30 min.
mechanistic section, concentrations of the catalyst and
substrates play a significant role in defining the catalytic
efficiency. Finally, the reaction performed at 40 °C was found
to be faster than the one at room temperature, leading to
reaction completion within 30 min (98% conversion).
With the optimized conditions in hand, we extended the
scope of the RuAAC reaction to include different alkynes and
azides. Scheme 1 outlines the obtained 1,5-disubstituted 1,2,3-
triazoles with the corresponding reaction times and isolated
yields after flash chromatography. Whereas benzyl and alkyl
azides reached full conversions in short reaction times, the
cycloaddition of phenyl azides yielded a mixture of products, in
line with previous findings.6a Aryl and alkyl alkynes were found
to be suitable cycloaddition partners, as well as enynes. For aryl
alkynes, a significant effect of the substituents on the phenyl
ring was found (cf. 3f vs 3g). In particular, a better catalytic
performance was obtained with the alkyne bearing an electron-
donating substituent. Propargylic alcohols (triazoles 3h−3j)
were found to be extremely active at room temperature, as
apparent from the reaction solution turning orange in color and
boiling as these alkynes were added. The scope of the RuAAC
Figure 2. Unreactive alkynes in the cycloaddition reaction with
benzylazide, catalyzed by 6a.
proceed at all under the optimized conditions. Conversely,
increasing the catalyst loading and the reaction time led to the
conversion of 2-phenyl-3-butyn-2-ol to the corresponding
triazole in good yield (3k). These results suggest that
propargylic alcohols need a suitable substitution pattern to be
highly reactive in the cycloaddition reaction. Next, we turned
our attention to tertiary alkynes in which the hydroxyl group of
2-methyl-3-butyn-2-ol is replaced with different moieties.
Interestingly, 1,5-triazole products were obtained in excellent
yields and in very short reaction times in the case of 3,3-
dimethyl-1-butyne and 2-methyl-3-butyn-2-amine (3l and 3m),
suggesting that electron-donating groups on the carbon at the α
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position to the triple bond of the alkyne substrate promote
higher reactivity. The chemical nature of the atom in this
position also plays a crucial role in the activity, as the
trimethylsilylacetylene needed a longer reaction time and
higher catalyst loading to reach good conversion (3n).
The most reactive alkynes were also found able to react with
phenylazide to afford efficiently the corresponding 5-aryl 1,2,3-
triazoles (3o and 3p). Although a number of 1,5-disubstituted
triazoles from aryl azides and alkynes were previously
synthesized with ruthenium-based catalysts,6 complex 6a led
to complete conversions under milder conditions and very
short reaction times.
conducted under catalytic conditions but using 5 mol %
catalyst. A selected region of NMR spectra collected during this
experiment is shown in Figure 3.18
Next, we turned to the cycloaddition of internal alkynes. As
known in the literature, the CuAAC is limited to terminal
alkynes, while Ru catalysis has been extended to the more
challenging cycloaddition of internal alkynes.6,9,17 Table 4
Table 4. Formation of 1,4,5-Trisubstituted 1,2,3-Triazoles
a
Catalyzed by Complex 6a
1
Figure 3. Selected region of VT H NMR spectra of the reaction
mixture of complex 6a, benzylazide 2a (20 equiv), and phenyl-
acetylene 1a (20 equiv) in CD2Cl2.
The bottom spectrum in Figure 3, recorded at 203 K,
contains only complex 6a. The next two spectra are after the
addition of 20 equiv of the two substrates. Within 5 min after
substrate addition at 203 K, shifts assigned to the triazole (δ =
5.6 ppm) and an intermediate species (δ = 5.0 ppm) appear.
This intermediate is assigned as an η2-alkyne Ru complex (10)
(see below). The intensity of the chemical shifts assigned to the
intermediate and triazole continue to grow as the temperature
is increased from 213 to 233 K. Between 233 and 253 K,
intermediate 10 disappears. In the same range of temperatures,
1H and 31P NMR revealed the appearance of shifts denoting the
a
Reaction conditions: catalyst 6a, 5 mol % ; DCM, 2 mL; azide/alkyne
b
= 1:1.05; 3 h; 40 °C. Isolated yields after flash chromatography.
displays the results of our investigation with RuAAC and the
more challenging alkyne substrates. When diphenylacetylene
and benzylazide were added to a solution of catalyst 6a in
dichloromethane, the triazole 9a was obtained in good yield
after 3 h. The uncatalyzed reaction executed under the same
conditions did not proceed at all.
As observed for terminal alkynes, the activity of the internal
alkynes bearing hydroxyl groups on the carbon atoms in
position α to the triple bond strongly depends on the Cα
substituents. In this case, the secondary alcohol showed a good
reactivity (Table 4, 9b), and the primary and the tertiary ones
were found unreactive in the reaction with benzylazide.
An unsymmetrical alkyne was also tested (Table 4, 9c). The
regioisomer ratio and the regiochemistry of the products were
i
formation of free phosphine and of the phosphazide Pr3P
N3Bn (δ = 4.7 ppm).18 By the end of the reaction at 293 K,
both substrates were consumed. Unfortunately, the ultimate
fate of the Ru catalyst was unknown, as no assignable shifts
were observed. The presence of the phosphazide was constant
throughout substrate consumption. The formation of the
phosphazide is in line with the assumption that the neutral
Cp*RuCl is the catalytically active species.6c
The initial exploration of the reaction profile under variable
temperatures prompted further studies with each substrate. In
doing this we had hoped to gain more information about the
initiation of the precatalyst, formation of transient intermedi-
ates, and the nature of the active catalytic species.
1
Reaction of [Cp*Ru(PiPr3)Cl] (6a) with Phenyacetylene
(1a). The reaction of 6a with 1 equiv of HCCPh, carried out
at 203 K in CD2Cl2, led to the formation of η2-alkyne Ru
complex 10, as shown in eq 4. This species was characterized at
evaluated by comparison of H NMR with literature data. In
line with what we observed in the case of terminal alkynes,
complex 6a showed better catalytic performance with respect to
the 18-electron ruthenium complexes.9 On the other hand, no
significant differences were observed for the regiospecificity of
these different catalysts.
Mechanistic Studies. To gain mechanistic insights into the
RuAAC catalytic process, a number of variable-temperature
NMR experiments were performed. During the stoichiometric
reaction leading to the formation of the triazole 3a, no
intermediates were observed when reacting Cp*Ru(PiPr3)Cl
(6a) with 1 equiv of both phenylacetylene (1a) and benzylazide
(2a) at 223 K. To decrease the reaction rate, with the aim of
observing intermediate species, an NMR reaction was
the same temperature by 1H, 13C, and 31P NMR spectroscopy.19
In the 1H NMR spectrum, the signal of the Cp* methyl groups
and of the coordinated phosphine did not show significant
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change with respect to those observed for 6a. Most tellingly, a
doublet appeared at 4.96 ppm (3JPH = 7.7 Hz) for the acetylenic
proton of the phenylacetylene. The splitting of this signal was
At 293 K, the reaction mixture consisted of 6a, species 11,
and free PiPr3. Subsequently, complex 11 was synthesized at
room temperature by mixing complex 6a with an excess of
phenylacetylene, and its structure was assigned on the basis of
lH and 13C NMR spectroscopy.
As well-known in the literature, the CpRuCl fragment is an
active species in the cyclotrimerization of alkynes.21 On the
basis of DFT calculations, the first intermediate of this class of
reaction was proposed to be the metallacyclopentatriene
generated through oxidative coupling of two alkyne ligands.
Confirming this hypothesis, some stable metallacycles were
characterized by NMR spectroscopy and/or X-ray diffraction
study.22,23 Specifically, the crystal structure of a cationic species
similar to complex 1123 induced us to hypothesize that the
phenyl substituents are in the α position of the metallacycle.
Moreover, the stability of the different substitution patterns was
evaluated by computational calculations (vide infra).
1
reduced to a singlet when executing H{31P} NMR experi-
ments, confirming the presence of proton−phosphorus
coupling. In the 31P{1H} NMR spectrum only one resonance
was present at 38.54 ppm. Finally, in the 13C NMR spectrum,
the aliphatic carbons of the phenylacetylene were found at
2
72.62 ppm (CCH, JPC= 2.0 Hz) and 87.48 ppm (C
CH), and the quaternary nature of this carbon was
confirmed by DEPT experiments. All spectroscopic data of
the new ruthenium species were consistent with the
formation of the η2-phenylacetylene complex 10, shown in
eq 4.
The evolution of complex 10 was followed by variable-
20
1
temperature H and 31P NMR experiments. A selected range
of 1H NMR spectra are shown in Figure 4, in the range 213 to
The 1H NMR spectrum of the species 11 showed one signal
for the methyl groups of the Cp* and three resonances in the
aromatic region. A singlet at 7.27 ppm, accounting for two
protons, indicated the formation of a symmetrical metallacycle
in which the hydrogen atoms are magnetically equivalent.
Moreover, the appearance of 13C resonances at 262.6 and 155.2
ppm, assignable to Cα and Cβ of the metallacycle, are the most
indicative signals of the formation of the metallacyclopenta-
triene. The 13C NMR data are consistent with those reported
by Jia et al., who proposed the production of complex 11
through the reaction of Cp*RuCl(COD) in the presence of 5
equiv of phenylacetylene.23
The addition of 20 equiv of benzylazide to a solution
containing metallacycle 11 (prepared by mixing complex 6a
with 20 equiv of phenylacetylene) gave only 3% conversion to
the triazole 3a at room temperature, strongly suggesting that
complex 11 is not an effective intermediate in the catalytic cycle
of the RuAAC. Accordingly, the ruthenacyclopentatriene,
obtained by reaction of [Cp*RuCl]4 and 1,6-diyne, was
reported to be unreactive with phenylethylazide.6c
The previous experiments allowed for the demonstration of
the proposed mechanism shown in Scheme 2. Complex 6a
reacts with phenylacetylene at 203 K, and the alkyne−metal π
1
Figure 4. Selected region of variable-temperature H NMR spectra of
the reaction mixture of complex 6a and phenylacetylene (1 equiv) in
CD2Cl2 (the signal denoted with * indicates protio impurities). The
temperature for each spectrum is shown on the left. The first spectrum
shows only the η2-phenylacetylene complex 10. The sequence for the
conversion of 10 to species 11 can be seen as the temperature
increases.
Scheme 2. Proposed Reactivity of Complex 6a with
Phenylacetylene at Various Temperatures and the
Subsequent Reactivity with Benzylazide
293 K. Upon warming, species 10 evolved to complex 6a by
releasing phenylacetylene, and the conversion was complete at
273 K. Concurrently, at temperatures greater than 263 K, 31P
spectra revealed the formation of free phosphine. This
1
coincided with the evolution of the reaction monitored by H
NMR spectroscopy, which showed the formation of the new
1
species 11 (see eq 5). According to the H NMR spectrum,
species 11 coordinates 2 equiv of phenylacetylene, while
releasing 1 equiv of free phosphine.
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complex 10 is exclusively formed, but at temperatures closer to
273 K it is converted into complex 11. On the other hand,
upon warming the solution of 10 in the presence of
benzylazide, the formation of the triazole 3a is favored with
respect to the formation of complex 11.
In light of these experimental results, the detrimental
lowering of the conversion observed for the cycloaddition
reaction when the alkyne is first added to a solution of complex
6a can be explained keeping in mind that the metallacycle 11,
which is favored at room temperature in the absence of the
azide, is not catalytically active in the cycloaddition reaction.
Reaction of [Cp*Ru(PiPr3)Cl] (6a) with Benzylazide
(2a). The reaction of 6a with 1 equiv of benzylazide, carried out
at room temperature in dichloromethane-d2, led to the
formation of two new species, 12 and 13, as shown in eq 6.
Additionally, free phosphine and unreacted complex 6a were
observed in the reaction mixture.
Figure 5. ORTEP representation of the bound phosphazide complex
Cp*Ru(κ2-iPr3PN3Bn)Cl (12). Selected bond lengths and angles:
Ru1−N1 2.281(2) Å, Ru1−N3 2.108(2) Å, P1−N1 1.648(2) Å, N1−
Ru1−N3 57.11°.
The minor product, species 13, also showed an AB pattern
(JHH = 14.32 Hz) for the CH2 protons of benzylazide, the signal
of the CH3 of Cp* shifted toward lower field, and the
concomitant formation of 1 equiv of free phosphine was
observed. According to the signal intensity ratio, species 13
contains 2 equiv of azide. Confirmation of the formation of 13
was obtained through independent synthesis via the reaction of
the ruthenium precursor [Cp*RuCl]4 (4) with 8 equiv of
benzylazide.
We propose that species 12 is a phosphazide complex
generated by either the net insertion of azide into the bound
phosphine or the reaction of a preformed phosphazide with the
ruthenium complex, whereas species 13 is a tetraazametallacy-
clopentene complex generated by reaction of complex 6a with 2
equiv of benzylazide, with the extrusion of 1 equiv of molecular
nitrogen. Similar complexes have been previously reported in
the literature.25−27
In the Staudinger reaction,24 involving a tertiary phosphine
and an organic azide, the initial product is a phosphazide, which
predominantly produces a phosphimine with expulsion of
dinitrogen. In a similar manner, organic azides can react with
complexes having phosphines as ligands, leading to phospha-
zide complexes.25,26 Another reported reaction between organic
azides and phosphine complexes involves the formation of
tetraazametallacyclopentene complexes, which usually takes
place via transient metal imido intermediates.26,27
The 1H NMR spectrum of species 12 showed an AB pattern
(JHH = 11.44 Hz) for the CH2 protons of benzylazide. The
signals for the coordinated phosphine shifted toward lower field
with respect to the same signal in complex 6a, while the signal
of the CH3 of Cp* shifted toward higher field. Signal intensities
indicated that species 12 contains 1 equiv of benzylazide. In the
31P NMR spectrum a signal at 58.12 ppm appeared. In
preparative scale reactions, complex 12 could be isolated by
precipitation of the crude product from a mixture of toluene
and hexane.
Gratifyingly, we were also able to obtain single crystals
suitable for X-ray diffraction studies.28 Figure 5 shows an
ORTEP representation of complex 12. To the authors'
knowledge, this is a unique example of a Ru(II)-(κ2-
phosphazide) complex. Danopoulos and Hursthouse reported
an octahedral Ru(III)-(κ2-phosphazide) complex.26 In totality,
there are only a handful of transition metal bound phosphazide
complexes reported to date.25
The reactivity of 6a with benzylazide was also examined
under catalytic conditions (5 mol % of catalyst). Variable-
1
temperature H NMR spectra of the reaction of Cp*Ru(PiPr3)
Cl with excess benzylazide are shown in Figure 6. The first
spectrum at 233 K is a solution containing only Cp*Ru(PiPr3)-
Cl. Upon the addition of 20 equiv of benzylazide, slow
formation of both complexes 12 and 13 was observed.
Warming the solution to 273 K showed full conversion of 6a
to 12 and 13. Additionally, at this temperature, a chemical shift
at δ = 4.8 ppm begins to appear. This signal is assigned to the
i
unbound phosphazide Pr3PN3Bn.
The top spectrum in Figure 6 corresponds to the addition of
20 equiv of phenylacetylene. Immediate formation of triazole
3a was observed. Interestingly, the signals attributable to
1
species 13 were still present in the H NMR spectrum, while
the chemical shifts assigned to 12 disappeared. This suggests
that complex 13 is inactive in catalysis and that 12 is a transient
intermediate in the reaction cycle.
Catalysis reactions utilizing independently synthesized
complexes 12 and 13, which were carried out under identical
conditions to those described in Table 1, confirmed the
observations in the variable-temperature experiments. Reac-
tions in which complex 13 was utilized showed <1% conversion
of 1a and 2a to 3a, while reactions employing complex 12
Cp*Ru(κ2-iPr3PN3Bn)Cl is formally a d6, 18-electron
complex. It is best viewed as a classical three-leg piano stool
type complex. The N1−Ru1−N3 bite angle is 57.11(7)°. The
phosphazide is somewhat tilted in its coordination. The Ru1−
N1 bond length is 2.281 Å, while the Ru1−N2 bond length is
2.108 Å. These bond lengths and angles are similar to those
found in the Ru(III) complex described by Danopoulos and
Hursthouse.26
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Reaction of Cp*RuCl(PiPr3) with Phenylacetylene. As
shown in Scheme 3, the reaction of Cp*Ru(PiPr3)Cl with
excess phenyacetylene is predicted to result in the production
of metallacycle 11 as initially predicted by Jia et al.23 Reaction
pathways leading to three potential isomers of complex (11,
11′, and 11″; see Scheme 3) were considered. Independent of
the conformational isomer formed, the reaction initiates with
η2-coordination of one molecule of phenylacetylene to 6a,
leading to 10. η2-Coordination of the phenylacetylene is
predicted to be exothermic by 15.2 kcal/mol through a
transition state located at 6.1 kcal/mol. Dissociation of PiPr3
from 10, leading to 14, costs only 8.7 kcal/mol, while
coordination of a second phenylacetylene molecule leads to
15, 10.7 kcal/mol below 6a + free phenylacetylene.
As cycloaddition is initiated, 15 is the branching point
leading to formation of 11, 11′, and 11″. The most stable of the
conformational isomers was calculated to be the 1,3
regioisomer 11′, 52.4 kcal/mol below 6a + free phenyl-
acetylene, followed by the 1,4 regioisomer 11, only 0.4 kcal/
mol higher in energy, while the 2,3 regioisomer 11″ is predicted
to be less stable than 11′ by 4.1 kcal/mol. Focusing on their
formation, calculations indicate that 11″ can be reached only via
a single concerted step, through a transition state at 9.4 kcal/
mol. A single reaction pathway also leads to 11′, but in this case
this is a two-step pathway with an intermediate, pre-11′, at 34.9
kcal/mol below 6a + free phenylacetylene, which is formed first
through a transition state at 7.9 kcal/mol. Intermediate pre-11′
is characterized by a strong π-coordination between the C2
atom of the formed ring and the Ru center, leading to a rather
strained structure. Dissociation of the C2 atom, through a
transition state at 30.6 kcal/mol, releases this strain, and the
system collapses into regioisomer 11′.
Finally, for 11 we found that both the concerted and the two-
step pathways are possible. The concerted transition state, at
15.6 kcal/mol, is quite high in energy, which rules out this
possibility with respect to the two-step pathway. In fact, the first
transition state of the two-step pathway, leading to intermediate
pre-11 at 30.8 kcal/mol below 6a + free phenylacetylene, is at
−3.5 kcal/mol, and the opening of the strained pre-11 structure
presents a negligible barrier in the gas phase and becomes
barrierless when solvent effects are included. In agreement with
previous insights, this analysis indicates that 11 should be the
regioisomer formed preferentially, since branching from 15
through the two-step pathway toward 11, with a transition state
at −3.5 kcal/mol, is highly preferred over any other reactivity.
As a final remark, we were not able to find a two-step pathway
leading to 11″, probably due to steric congestion around the
Ph-substituted C2 and C3 atoms in the putative pre-11″
intermediate, which makes the potential energy surface too flat
to locate.
1
Figure 6. Selected region of variable-temperature H NMR spectra of
the reaction mixture of complex 6a and benzylazide (20 equiv) in
CD2Cl2 (the signal denoted with * indicates protio impurities).
resulted in 92% conversion in 40 min at room temperature.
The latter is similar to the activity found for complex 6a (89%
conversion; see Table 1). Although this complex displays
similar activity to that of 6a, DFT computations suggest that
complex 12 may play only a fleeting role in the catalytic cycle
(vide infra).
Density Functional Theory (DFT) Results. DFT static
calculations were performed at the GGA level with the
Gaussian03 package,29 using the BP86 functional of Becke
and Perdew.30 All energies reported correspond to free energies
(kcal/mol). Following the experimental strategy, computational
efforts were applied to the reaction of 6a with phenylacetylene
(Scheme 3), then on the reactivity of 6a with benzylazide
Scheme 3. Free Energies (kcal/mol) Corresponding to
Intermediates and Transition States in the Reaction of 6a
a
with Phenylacetylene
Reaction of Cp*RuCl(PiPr3) with Benzylazide. DFT
computations detailing the reactivity of 6a with benzylazide
are shown in Scheme 4. The reaction starts with coordination
of benzylazide to 6a through the terminal N atom, leading to
16 with an energy gain of 11.4 kcal/mol. Dissociation of PiPr3
from 16, leading to 17, costs 14.6 kcal/mol. We also
investigated if benzylazide could react with PiPr3 to form the
phosphazide species 12, which lies 12.4 kcal/mol below 6a +
benzylazide. Specifically, we examined formation of 12 via the
pathways 6a → 21 → 12 and 6a → 16′ → 21 → 12. The
former pathway requires overcoming two barriers of 17.2 and
26.8 kcal/mol, respectively. To reach intermediate 21 according
to the second pathway requires overcoming two barriers, of 3.3
a
Values in red above the arrows correspond to the energy of the
transition states connecting the structures left and right of the arrow.
(Scheme 4), and finally we report on the reaction of 6a in the
presence of both phenylacetylene and benzylazide (Scheme 5).
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a
Scheme 4. Energetics (kcal/mol) of the Reactivity of 6a + Benzylazide
a
All values correspond to free energies (values in red above the arrows correspond to the energy of the transition states connecting the structures left
and right of the arrow).
Scheme 5. Free Energies (kcal/mol) Computed for Species
Involved in Catalyst Activation
release of PiPr3 from 23. On the other hand, species 13 can also
be reached from 17″ if an additional benzylazide molecule
coordinates first to the Ru center, leading to intermediate 22,
with an energy gain of 4.6 kcal/mol. N2 release is then
concerted with formation of the tetraazametallacylopentene
ring, through a transition state at 23.9 kcal/mol, leading again
to 13. This indicates that N2 dissociation can occur either
before the latter ring is formed, through intermediate 24, or
concomittantly with ring formation, through intermediate 22,
since the rate-limiting transition states, at 24.7 and 23.9 kcal/
mol, are very close in energy. However, 13 can also be reached
from 17 by coordination of the second azide molecule through
the internal N atom, leading to 18, from which a N2 molecule
can be released through a transition state at 21.8 kcal/mol, and
collapsing into intermediate 19. Cyclization through inter-
mediate 20 finally leads to 13. The latter species displays similar
N−N bond distances (1.318, 1.318, and 1.325 Å, respectively),
thus delocalizing the electronic density of the previous N−N
double bonds.
Reaction of Cp*RuCl(PiPr3) with Phenylacetylene and
Benzylazide. Gleaning information from the computations
detailing individual reactions of phenylacetylene and benzyla-
zide with 6a discussed above made clear that three potential
pathways exist for catalyst activation. Shown in Scheme 5, in
the presence of both phenylacetylene and benzylazide binding
of benzylazide provides the lowest activation energy pathway.
Ligation of the terminal nitrogen (16, ΔG⧧ = 2.0 kcal/mol) is
favored over that of the binding of the internal nitrogen (16′)
by 1.3 kcal/mol. Although formation of Cp*RuCl(η2-HCCPh)-
(PiPr3) (10) proceeds through a transition state located at 6.1
kcal/mol higher than that of the starting material, formation of
complex 10 was calculated to be more stable than the
corresponding azide complexes 16 and 16′. Additionally,
comparing the phosphine dissociation pathways between 10,
16, and 16′ it is evident that only 10 favors phosphine
dissociation over that of the bound substrate. In other words,
both complexes 16 and 16′ are predicted to possess lower
energy pathways involving dissociation of the azide over that of
the phosphine. In contrast, phosphine dissociation from 10 is
endergonic by 8.7 kcal/mol, while acetylene dissociation is
calculated to proceed through a transition state of 21.3 kcal/
mol, thus trapping the stable intermediate 10 in an energy well.
and 18.4 kcal/mol, respectively. This indicates that formation of
21, precursor of 12, can occur along both the 6a → 21 and 6a
→ 16′ → 21 pathways. Nevertheless, calculations suggest that
in the presence of the alkyne formation of the experimentally
characterized species 12 is not favored, and thus it probably
plays an incidental role in the 6a → 3a transformation.
Returning to the PiPr3 free intermediate 17, benzylazide
coordination can occur in a variety of modes. The first involves
a N1, N3 coordination of the azide moiety, structure 17′ at 16.3
kcal/mol above 6a + benzylazide. Due to the high energy of
17′, we also considered an alternative coordination of the azide
through the internal N atom, i.e., structure 17″ at 10.2 kcal/mol
above 6a + benzylazide. Intermediate 17″ can dissociate N2
through a transition state at 24.7 kcal/mol, leading to species
24, 13.4 kcal/mol below 6a + benzylazide. Then, reaction of 24
with another free benzylazide molecule, through a transition
state at −9.4 kcal/mol, leads to the very stable tetraazametalla-
cylopentene species 13, 54.7 kcal/mol below 6a + benzylazide.
Species 24 can also be reached from species 16′, through
species 23. This is achieved by releasing first a N2 molecule
from 16′ by overcoming a barrier of 16.4 kcal/mol followed by
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This coincides with experimental results, as complex 10 was
observed by NMR spectrometry at low temperatures even
when azide addition to 6a precluded acetylene addition.
Once again, due to the nature of the substrates, several
possible scenarios were examined for the steps following
formation of complex 14. Shown in Scheme 6 are the potential
Scheme 6. Free Energy of Potential Pathways Leading from
Cp*RuCl(η2-HCCPh)(PiPr3) (14) in the Presence of Both
a
Phenylacetylene and Benzylazide
Figure 7. Free energies (kcal/mol) of triazole formation beginning
from complex 25. All free energies in kcal/mol are relative to
Cp*RuCl(PiPr3) + HCCPh + N3CH2Ph = 0.0 kcal/mol. Values in red
above the arrows correspond to the energy of the transition states
connecting the structures left and right of the arrow.
moiety rotates down into an orientation in which it is nearly
coplanar with the CC of the bound acetylene, as shown in
Figure 8. Oxidative coupling facilitates the second C−N bond
formation and occurs through a transition state at −16.2 kcal/
mol, which corresponds to a free energy barrier of 18.1 kcal/
mol from 26, in agreement with previous insights into this
reaction.6c,9b This process leads to a previously unidentified
intermediate, 27, in which the triazole is coordinated to the Ru
metal center through a matallacyclopropane. Dissociation of the
1-C of the triazole through intermediate 27−28 is accompanied
by an increase in CC bonding characteristics denoted by a
shortening of the C−C bond from 1.433 Å in complex 27 to
1.395 Å in complex 28, as well as the shortening of the C1−N5
bond of the triazole, decreasing from 1.399 Å to 1.271 Å. Only
a relatively small energy barrier exists for the isomerization of
the Ru−C-based triazole complex 27 to the more stable Ru−N-
based triazole bond in complex 28. The coordinated triazole-Ru
complex was calculated to be 66.0 kcal/mol below 6a + free
phenylacetylene and benzylazide.
Dissociation of the coordinated triazole from complex 28 was
calculated to be aided by the η2 coordination of the second
molecule of phenylacetylene, corresponding to a free energy
barrier of 5.7 kcal/mol. Ultimately this results in the formation
of complex 29. Coordination of phenylacetylene to 28 is
predicted to be exothermic by 13.4 kcal/mol. Regeneration of
complex 14 from 29 through triazole dissociation requires a
free energy barrier of 13.1 kcal/mol, only slightly larger than
the barrier associated with dissociation of PiPr3 from complex
10 (ΔG⧧ = 8.7 kcal/mol).
a
All energies relative to 6a + N3Bn + HCCPh. Energies in red
represent transition-state free energies; energies in blue, those of
intermediates.
pathways forward in the presence of both phenylacetylene and
benzylazide. Coordination of a second molecule of phenyl-
acetylene, ultimately leading to deactivation of the catalyst
through formation of complex 11, was calculated to have the
highest energy barrier (ΔG⧧ = 11 kcal/mol). Azide
coordination barriers were calculated to be much lower, with
ligation of the internal nitrogen predicted to ultimately possess
the lowest barrier (ΔΔG⧧ = 2.0 kcal/mol) than terminal N
coordination of the azide. Internal N-coordination of a
molecule of azide is favored over a second molecule of
phenylacetylene by 7.7 kcal/mol.
Lin, Jia, Fokin, et al. have previously performed computations
detailing the mechanistic aspects of triazole formation from the
model complex CpRuCl(η2-HCCMe)(α-N-N3Me), similar to
complex 25.6c Our efforts using complete molecules support
those initially found using the model complex. Although slight
differences in the calculated free energies are present, these are
suspected to mainly be the result of a combination of increased
sterics of the substrates and possibly stabilization of
intermediates through conjugation with the aryl rings or phenyl
acetylene and benzylazide.
Figure 7 shows calculated free energies of the species
involved in triazole formation once both azide and acetylene
substrates have been coordinated to the Ru metal center.
Graphical representations of these species as determined by
DFT calculations are shown in Figure 8. Triazole formation
from 25 is rather a dynamic process. Initiation of C−N bond
formation between the azide with the alkyne occurs through a
transition state at −4.3 kcal/mol (ΔG⧧ = 0.3 kcal/mol), and the
system collapses into intermediate 26, 34.3 kcal/mol below 6a
+ free phenylacetylene and benzylazide. The C−N bond
distance is calculated to be 1.446 Å. At this point the azide
Overall, our analysis suggests that catalyst activation should
proceed through coordination of phenylacetylene over that of
benzylazide coordination. Rationalization of this stems from
complex 10 {Cp*RuCl(η2-HCCPh)(PiPr3)} acting as an
energy well in which phosphine dissociation is favored over
substrate dissociation. Furthermore, our calculations suggest
that pathways leading to catalyst deactivation, through
formation of either complex 11 or 13, should be competitive
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Figure 8. Selected structural parameters (in Å) calculated for the species involved in RuAAC. Larger graphics are placed in the Supporting
Information.
with triazole formation under the circumstances where either
the acetylene or azide substrate is present in a large excess
relative to the other. The overall mechanism determined herein
has been found to be consistent with previous analysis6c,9b and
supports the energy profile reported by Fokin et al., which was
obtained through the utilization of a model system.
CONCLUSIONS
■
The behavior of the 16-electron ruthenium complexes
Cp*Ru(L)X (L = PiPr3, PCy3, IAd, IPr, ICy, IMes; X = Cl,
OCH2CF3) was examined in the RuAAC reaction. The
phosphines were found to result in more efficient catalysts
over the corresponding NHC complexes. Use of the catalyst
Cp*Ru(PiPr3)(OCH2CF3) resulted in only 2% conversion, in
stark contrast to Cp*Ru(PiPr3)Cl, which was found to be the
optimal catalyst within the study. Additionally, Cp*Ru(PiPr3)Cl
displayed improved performance with respect to the 18-
electron ruthenium catalysts,6 allowing the production of
several triazole products under milder conditions and shorter
reaction times. Moreover, a number of new 1,5-disubstitued
1,2,3-triazoles were produced with high yields.
As already reported for the 18-electron ruthenium catalysts,
complex 6a showed a high reactivity with 1,1-disubstituted
propargylic alcohols. Interestingly, we found that, in general,
electron-donating groups on the carbon at the α position to the
triple bond of the alkyne substrate promote high reactivity. As a
matter of fact, these properly substituted alkynes were found to
be extremely active in the reaction with benzyl- and phenyl-
azide.
RuACC Mechanism. Uniting computational and experimen-
tal investigations, the overall proposed mechanism for triazole
formation mediated by the Cp*RuCl moiety through activation
of the precatalyst Cp*RuCl(PiPr3) is shown in Scheme 7. Initial
side-on coordination of phenylacetylene leads to the exper-
imentally observed Cp*RuCl(η2-HCCPh)(PiPr3) (10). Com-
putations suggest that dissociation of the phosphine from 10 is
favored over phenylacetylene dissociation. Ligation of benzy-
lazide through the internal nitrogen leads to formation of
complex 25. Nucleophilic attack of the terminal acetylene CH
on the terminal nitrogen of the azide proceeds through a nearly
barrierless process (ΔG⧧ = 0.3 kcal/mol). C−N oxidative
coupling in complex 26 results in cyclization, ultimately leading
to N-bound triazole complex 28. Following formation of Ru-
triazole complex 28, catalyst regeneration begins with
coordination of an additional molecule of phenylacetylene.
Release of free triazole from complex 29 results in restoration
of the Cp*RuCl(η2-HCCPh) species. Triazole formation is
predicted to be exothermic by 68.9 kcal/mol and likely drives
the reaction.
Mechanistic studies revealed possible pitfalls in the catalytic
cycle along with the identification of Cp*Ru(η2-HCCPh)-
(PiPr3)Cl (10) and bound phosphazide complex Cp*Ru(κ2-
N3Bn)(PiPr3)Cl (12). Single crystals suitable for XRD
unambiguously clarified the atom connectivity in the latter
complex.
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Avance II 400 MHz spectrometer. Solvents were of puriss. grade and
used as received. Spectra were referenced to CD2Cl2 at c 5.32 (13C, δ
54.00) or CDCl3 at δ 7.26 (13C, δ 77.23) ppm. Gas chromatography
(GC) was performed on an Agilent 6890N gas chromatograph.
General Procedure for the [3+2] Cycloaddition of Azides
and Terminal Alkynes. In a vial fitted with a screw cap, azide (0.5
mmol) and alkyne (0.52 mmol) were added to a solution of catalyst 1
(1 mol %) in organic solvent. The solution was stirred at a given
temperature for a period of time indicated in Scheme 2. The reaction
was monitored by GC analysis of aliquots. In most cases the azide was
completely consumed at the end of the reaction. The solvent was
removed under vacuum, and the product was purified by silica gel
chromatography. The unreacted alkyne and traces of side products
were first eluted out with hexane, followed by 1:1 hexane/ether. The
pure 1,5-disubstituted triazole product was then obtained by elution
with ether or ethyl acetate.
Scheme 7. Proposed Precatalyst Activation and Subsequent
Catalytic Cycle in the RuAAC of Benzylazide with
Phenylacetylene
a
Computational Details. The DFT static calculations were
performed at the GGA level with the Gaussian03 package,29 using
the BP86 functional of Becke and Perdew.30 The electronic
configuration of the molecular systems was described with the
standard split-valence basis set with a polarization function of Ahlrichs
and co-workers for H, C, N, O, P, and Cl (SVP keyword in
Gaussian03).31 For Ru we used the small-core, quasi-relativistic
Stuttgart/Dresden effective core potential, with an associated
(8s7p6d)/[6s5p3d] valence basis set contracted according to a
(311111/22111/411) scheme (standard SDD keywords in Gaus-
sian03).32 The geometry optimizations were performed without
symmetry constraints, and the characterization of the located
stationary points was performed by analytical frequency calculations.
Solvent effects including contributions of non-electrostatic terms have
been estimated by single-point calculations on the gas phase optimized
structures,33 based on the polarizable continuous solvation model
using CH2Cl2 as the solvent.34
ASSOCIATED CONTENT
* Supporting Information
■
S
Analytical and spectral characterization data, Cartesian
coordinates and 3D view for all DFT-optimized structures,
and an extension of Scheme 4. This material is available free of
charge via the Internet at http://pubs.acs.org.
a
Numbers in blue coorespond to free energies (kcal/mol) of
AUTHOR INFORMATION
Corresponding Author
*E-mail: snolan@st-andrews.ac.uk.
intermediates, and numbers in red correspond to free energies
(kcal/mol) of the corresponding transition states.
■
Experimental results and DFT computations are in agree-
ment and suggest that acetylene binding precedes azide
coordination. Catalyst initiation was proposed to occur through
the formation Cp*Ru(η2-HCCPh)(PiPr3)Cl (10) followed by
phosphine loss. DFT computations calculate coordination of a
molecule of N3Bn to Cp*Ru(η2-HCCPh)Cl through the
internal nitrogen to be favored over coordination of a second
molecule of HCCPh by 7.7 kcal/mol. DFT calculations also
resulted in locating the previously unidentified intermediate 27,
in which the formed triazole is bound to the Ru metal center in
a C−Ru−C metallacyclopropane fashion, which ultimately
isomerizes to the N-bound triazole Ru species 28.
ACKNOWLEDGMENTS
S.P.N. would like to thank the ERC (Advanced Researcher
Award FUNCAT) for financial support. A.P. thanks the
■
́
Spanish MICINN for a Ramon y Cajal contract (ref RYC-
2009-05226) and the European Commission for a Career
Integration Grant (CIG09-GA-2011-293900). L.C. and A.P.
thank the HPC team of Enea (www.enea.it) for using the
ENEA-GRID and the HPC facilities CRESCO (www.cresco.
enea.it) in Portici, Italy. M.L. acknowledges Salerno Province
and the University of Salerno for supporting her stay at the
University of St Andrews (International Mobility Scholarship
2009). S.P.N. is a Royal Society Wolfson Research Merit Award
holder.
EXPERIMENTAL SECTION
■
General Considerations. All reagents and solvents were
purchased from commercial suppliers and used as received. The
catalysts were synthesized in an MBraun glovebox containing dry
argon and less than 1 ppm oxygen according to previously described
procedures. Complexes 1−7 were synthesized according to previously
described procedures.10,14,15 Flash column chromatography was
REFERENCES
■
(1) (a) Gilchrist, T. L.; Gymer, G. E. Adv. Heterocycl. Chem. 1974, 16,
33−85. (b) Finley, K. T. Triazoles: 1,2,3. In The Chemistry of
Heterocyclic Compounds; Weissberger, A., Taylor, C. E., Eds.; John
Wiley & Sons: New York, 1980. (c) Katritzky, A. R.; Zhang, Y.; Singh,
S. K. Heterocyles 2003, 60, 1225−1239. (d) Krivopalov, V. P.; Shkurko,
O. P. Russ. Chem. Rev. 2005, 74, 339−379. For therapeutic activities,
performed on silica gel 60 (230−400 mesh). H, 13C, and 31P NMR
1
spectra were recorded on either a Bruker Avance 300 MHz or Bruker
766
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Article
see: (e) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med.
Chem. 1986, 29, 2262−2267. (f) Alvarez, R.; Velazquez, S.; San-Felix,
A.; Aquaro, S.; De Clercq, E.; Perno, C. F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185−4194. (g) Chen, M. D.;
Lu, S. J.; Yuag, G. P.; Yang, S. Y.; Du, X. L. Heterocycl. Commun. 2000,
6, 421−426. (h) Genin, M. J.; Allwine, D. A.; Anderson, D. J.;
Barbachyn, M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega,
K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford,
C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi,
B. H. J. Med. Chem. 2000, 43, 953−970.
(15) (a) Jafarpour, L.; Stevens, E. D.; Nolan, S. P. J. Organomet.
Chem. 2000, 606, 49−54. (b) Huang, J.; Stevens, E. D.; Nolan, S. P.;
Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674−2678.
(16) Johnson, T. J.; Folting, K.; Strieb, W. E.; Martin, J. D.; Huffman,
J. C.; Jackson, S. A.; Eisenstein, O.; Caulton, K. G. Inorg. Chem. 1995,
34, 488−499.
(17) Tam, A.; Arnold, U.; Soellner, M. B.; Raines, R. T. J. Am. Chem.
Soc. 2007, 129, 12670−12671.
1
(18) Complete H spectra and accompanying 31P NMR spectra are
given in Supporting Information Figures S1 and S2.
(19) See Supporting Information for NMR spectra characterization
of η2-HCCPh Ru complex 10.
(2) (a) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565−598.
(b) Huisgen, R. 1,3-Dipolar Cycloadditional Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984.
1
(20) Complete H spectra and accompanying 31P NMR spectra are
given in Supporting Information Figures S3 and S4.
(3) Wang, Q.; Chittaboina, S.; Barnhill, H. N. Lett. Org. Chem. 2005,
(21) Kirchner, K.; Calhorda, M. J.; Schmid, R.; Veiros, L. F. J. Am.
Chem. Soc. 2003, 125, 11721−11729 , and reference therein.
(22) (a) Albers, M. O.; de Waal, D. J. A.; Liles, D. C.; Robinson, D.
J.; Singleton, E.; Wiege, M. B. J. Chem. Soc., Chem. Commun. 1986,
1680−1682. (b) Campion, B. K.; Heyn, R. H.; Don Tilley, T.
Organometallics 1990, 9, 1106−1112.
2, 293−301.
(4) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057−3064.
(5) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596−2599.
(6) (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,
15998−15999. (b) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org.
Lett. 2007, 9, 5337−5339. (c) 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, 8923−8930.
(23) Zhang, L.; Sung, H. H.-Y.; Williams, I. D.; Lin, Z.; Jia, G.
Organometallics 2008, 27, 5122−5129.
(24) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646.
(25) (a) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.;
Piangiolino, C. Coord. Chem. Rev. 2006, 250, 1234−1253.
(b) Bebbington, M. W. P.; Bourissou, D. Coord. Chem. Rev. 2009,
253, 1248−1261. (c) Hillhouse, G. L.; Goeden, G. V.; Haymore, B. L.
Inorg. Chem. 1982, 21, 2064−2071. (d) Fortman, G. C.; Captain, B.;
Hoff, C. D. Organometallics 2009, 28, 3587−3590. (e) Liu, B.; Cui, D.
Dalton Trans. 2009, 550−556.
(7) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004−2021.
(8) (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952−
3015. (b) Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V. J.
Am. Chem. Soc. 2005, 127, 13444−13445. (c) Rodionov, V. O.;
Presolski, S. I.; Díaz, D.; Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc.
2007, 129, 12705−12712. (d) Dutta, B.; Curchod, B. F. E.;
Campomanes, P.; Solari, E.; Scopelliti, R.; Rothlisberger, U.; Severin,
K. Chem.Eur. J. 2010, 16, 8400−8409.
(26) Danopoulos, A. A.; Hay-Motherwell, R. S.; Wilkinson, G.;
Cafferkey, S. M.; Sweet T. K. N. Hursthouse, M. B. J. Chem. Soc.,
Dalton Trans. 1997, 3177−3184.
(27) Michelman, R. I.; Bergman, R. G.; Andersen, R. A.
Organometallics 1993, 12, 2741−2751.
(28) CCDC 820903 (17) contains the supplementary crystallo-
graphic data for this contribution. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(29) Frisch, M. J.;et al. Gaussian03; Gaussian, Inc.: Pittsburgh, PA,
2003.
(30) (a) Becke, A. Phys. Rev. A 1988, 38, 3098−3100. (b) Perdew, J.
P. Phys. Rev. B 1986, 33, 8822−8824. (c) Perdew, J. P. Phys. Rev. B
1986, 34, 7406−7406.
(31) Schaefer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97,
2571−2577.
(32) Kuechle, W.; Dolg, M.; Stoll, H.; Preuss, H. J. Chem. Phys. 1994,
100, 7535−7542.
(33) (a) Poater, A.; Ragone, F.; Correa, A.; Cavallo, L. J. Am. Chem.
Soc. 2009, 131, 9000−9006. (b) Poater, A.; Cavallo, L. J. Mol. Catal. A
2010, 324, 75−79. (c) Bosson, J.; Poater, A.; Cavallo, L.; Nolan, S. P. J.
Am. Chem. Soc. 2010, 132, 13146−13149. (d) Nun, P.; Gaillard, S.;
Poater, A.; Cavallo, L.; Nolan, S. P. Org. Biomol. Chem. 2011, 9, 101−
104. (e) Poater, A.; Ragone, F.; Correa, A.; Szadkowska, A.;
Barbasiewicz, M.; Grela, K.; Cavallo, L. Chem.Eur. J. 2011, 16,
14354−14364. (f) Mariz, R.; Poater, A.; Gatti, M.; Drinkel, E.; Burgi, J.
J.; Luan, X. J.; Blumentritt, S.; Linden, A.; Cavallo, L.; Dorta, R.
Chem.Eur. J. 2010, 16, 14335−14347. (g) Poater, A.; Ragone, F.;
Mariz, R.; Dorta, R.; Cavallo, L. Chem.Eur. J. 2010, 16, 14348−
14353.
(9) (a) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71,
8680−8683. (b) Hou, D.-R.; Kuan, T.-C.; Li, Y.-K.; Lee, R.; Huang,
K.-W. Tetrahedron 2010, 66, 9415−9420. (c) Zhang, C. T.; Zhang, X.;
Qing, F.-L. Tetrahedron Lett. 2008, 49, 3927−3930. (d) Oppilliart, S.;
Mousseau, G.; Zhang, L.; Jia, G.; Thuery, P.; Rousseau, B.; Cintrat, J.
C. Tetrahedron 2007, 63, 8094−8098. (e) Yamamoto, Y.; Kinpara, K.;
Nishiyama, H.; Itoh, K. Adv. Synth. Catal. 2005, 347, 1913−1916.
(10) NHC-copper complexeswere found highly efficient catalysts for
the CuAAC reaction. See,for example: Díez- Gonzal
Angew. Chem., Int. Ed. 2008, 47, 8881−8884.
́
ez, S.; Nolan, S. P.
(11) (a) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 2370−2375. (b) Campion, B. K.; Heyn, R.
H.; Tilley, T. D. J. Chem. Soc., Chem. Commun. 1988, 278−280.
(c) Johnson, T. J.; Folting, K.; Streib, W. E.; Martin, J. D.; Huffman, J.
C.; Jackson, S. A.; Eisenstein, O.; Caulton, K. G. Inorg. Chem. 1995, 34,
488−499.
(12) (a) Luo, L.; Nolan, S. P. Organometallics 1994, 13, 4781−4786.
(b) Li, C.; Luo, L.; Nolan, S. P.; Marshall, W.; Fagan, P. J.
Organometallics 1996, 15, 3456−3462.
(13) (a) Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone, F.;
Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009, 1759−1766.
(b) Jacobsen, H.; Correa, A.; Poater, A.; Costabile, C.; Cavallo, L.
Coord. Chem. Rev. 2009, 253, 687−703. (c) Poater, A.; Ragone, F.;
Giudice, S.; Costabile, C.; Dorta, R.; Nolan, S. P.; Cavallo, L.
Organometallics 2008, 27, 2679−2681. (d) Ragone, F.; Poater, A.;
Cavallo, L. J. Am. Chem. Soc. 2010, 132, 4249−4258. (e) Poater, A.;
Cavallo, L. Dalton Trans. 2009, 8878−8883. (f) Clavier, H.; Nolan, S.
P. Chem. Commun. 2010, 46, 841−861. (g) Luan, X.; Mariz, R.; Gatti,
M.; Costabile, C.; Poater, A.; Cavallo, L.; Linden, A.; Dorta, R. J. Am.
Chem. Soc. 2008, 130, 6848−6858. (h) Credendino, R.; Poater, A.;
Ragone, F.; Cavallo, L. Catal. Sci. Technol. 2011, 1, 1287−1297.
(14) Hiller, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo,
L.; Nolan, S. P. Organometallics 2003, 22, 4322−4326.
(34) (a) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027−2094.
(b) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995−2001.
767
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