Synthesis of mono- and binuclear Cu(II) complexes bearing unsymmetrical bipyridine-pyrazole-amine ligand and their applications in azide-alkyne cycloaddition

Article abstract of DOI:10.1021/acs.organomet.7b00154

Mono- and binuclear Cu(II) complexes bearing an unsymmetrical bipyridine-pyrazole-amine ligand were synthesized and characterized using X-ray diffraction. The mononuclear complex could be converted to the corresponding binuclear complexes under basic conditions due to the lability of the pyrazolyl N-H. Both complexes proved to be effective catalysts for azide-alkyne cycloaddition to form triazoles, with the binuclear complex exhibiting higher catalytic activity than the corresponding mononuclear one. The binuclear complex was effective at catalyst loadings as low as 0.0125 mol %, making it one of the most active catalysts for this reaction to date. Therefore, this catalyst was applied in the synthesis of potentially biologically active molecules. At 0.1-0.3 mol % catalyst loading, three precursors of Sorafenib analogs were synthesized in excellent yields. A one-pot variant of the reaction, generating the azide in situ, could also be performed using the binuclear complex as the catalyst. The transition metal complex bearing an unsymmetrical ligand may exhibit excellent catalytic activity, which represents a direction for developing new highly active catalysts.

Full text of DOI:10.1021/acs.organomet.7b00154

Article
pubs.acs.org/Organometallics
Synthesis of Mono- and Binuclear Cu(II) Complexes Bearing
Unsymmetrical Bipyridine−Pyrazole−Amine Ligand and Their
Applications in Azide−Alkyne Cycloaddition
Wenjing Ye,* Xiao Xiao, Lan Wang, Shicheng Hou, and Chun Hu*
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education,
Shenyang, 110016 Liaoning, China
S
* Supporting Information
ABSTRACT: Mono- and binuclear Cu(II) complexes bearing
an unsymmetrical bipyridine−pyrazole−amine ligand were
synthesized and characterized using X-ray diffraction. The
mononuclear complex could be converted to the corresponding
binuclear complexes under basic conditions due to the lability of
the pyrazolyl N−H. Both complexes proved to be effective
catalysts for azide−alkyne cycloaddition to form triazoles, with
the binuclear complex exhibiting higher catalytic activity than
the corresponding mononuclear one. The binuclear complex
was effective at catalyst loadings as low as 0.0125 mol %, making
it one of the most active catalysts for this reaction to date.
Therefore, this catalyst was applied in the synthesis of
potentially biologically active molecules. At 0.1−0.3 mol %
catalyst loading, three precursors of Sorafenib analogs were synthesized in excellent yields. A one-pot variant of the reaction,
generating the azide in situ, could also be performed using the binuclear complex as the catalyst. The transition metal complex
bearing an unsymmetrical ligand may exhibit excellent catalytic activity, which represents a direction for developing new highly
active catalysts.
remarkably improve the effectiveness of various organometallic
catalysts. Unsymmetrical systems utilizing a variety of
heteroatoms and different coordinating abilities are known.8
For example, P/S,9 P/O,10 P/N,11 N/O,12 and C/S13 systems
bearing a dissociable group have been employed in catalytic
applications. Nevertheless, the use of unsymmetrical N-
heterocyclic ligands bearing a convertible group in catalytic
organic chemistry is still an underexplored area.14
We have been interested in developing unsymmetrical N-
heterocyclic ligands, in particular, ligands bearing a convertible
group, and the corresponding highly effective catalyst system
for application in homogeneous catalysis. Recently, we have
reported versatile unsymmetrical pyridyl-based NNN ligands
bearing a convertible group (either benzimidazolyl or
pyrazolyl) and their exceptionally active Ru(II) complexes for
transfer hydrogenation (TH) and asymmetric transfer hydro-
genation (ATH) of ketones (Scheme 1).15 Mechanistic studies
demonstrate that the NH moiety of the benzimidazolyl and
pyrazolyl moieties is convertible in the presence of a base such
as NEt3, resulting in excellent catalytic activity of the Ru(II)−
NNN complexes due to easy in situ generation of coordinatively
unsaturated 16-electron Ru(II) precatalysts.
INTRODUCTION
■
Development of ligands bearing donors other than phosphorus
has attracted much recent attention in the fields of coordination
chemistry, homogeneous catalysis, and organic synthesis. As an
alternative to phosphorus ligands, N-heterocyclic ligands have
many potential advantages: (i) ease of synthesis, (ii) higher
stability and lower toxicity, and (iii) excellent σ-donor
properties.1 Over the last few decades, a large number of N-
heterocyclic ligand scaffolds with symmetrical backbones have
been developed, and their potential applications have been
demonstrated. For example, NNN tridentate pincer ligands
such as PyBOX,2 2,6-bis-(imino)pyridines,3 and terpyridines,4
as well as “scorpionate” N3-tripodal neutral ligands such as
hydrotris(1-pyrazolyl)methane HC(pz)3, Tpm,5 and poly-
(pyrazolyl) borates.6 In contrast, a series of unsymmetrical
ligands (termed “hemilabile ligands” by Jeffrey and Rauchfuss in
1979)7 comprised substitutionally labile and substitutionally
inert groups have also been reported. The inert group in the
ligand is anchored to the transition metal center, stabilizing the
catalyst. The labile group is always a weakly coordinating one,
being easily dissociated or converted. This can help generate a
vacant site on the transition metal center for substrate binding.
Furthermore, the wider variability in the structure of unsym-
metrical ligands allows for a wider scope for altering the
electronic and steric environment around the catalytic metal
center. These characteristics have enabled hemilabile ligands to
Received: February 28, 2017
© XXXX American Chemical Society
A
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bipyridine−pyrazole−amine ligand, which showed excellent
catalytic activity for the 1,3-dipolar cycloaddition reaction
between alkynes and azides (Scheme 2).22 Herein, we report
the continued development of this system for the CuAAC
reaction. Both mononuclear Cu complex 3 and binuclear Cu
complex 4 were successfully synthesized and used as catalysts
for the 1,3-dipolar cycloaddition reaction between alkynes and
azides.
Scheme 1. Ligands Bearing an NH Group
RESULTS AND DISCUSSION
■
Synthesis and Spectroscopic Characterization. Bipyr-
idine−pyrazole−amine ligand 1 was synthesized using our
previously reported methods.22 This ligand provides a
convenient scaffold for the synthesis of mononuclear and
binuclear Cu complexes due to the presence of the NH group
in the pyrazole. At first, Cu(CH3CN)4PF6 was chosen as the Cu
precursor and reacted with ligand 1 under N2 to obtain a Cu(I)
complex. However, the resulting product was easily oxidized by
air and ultimately Cu(II) complex 2 was generated.22,23 Herein,
we directly employed a Cu(II) precursor, such as CuBr2, which
was reacted with ligand 1 in MeOH under air at room
temperature for 16 h, affording mononuclear Cu(II) complex 3
in 48% yield after recrystallization from MeOH−hexane−Et2O
(1:1:3) using the “layering” approach. As we expected,
mononuclear complex 3 could be converted to binuclear
complex 4 in the presence of NEt3 via loss of a HBr molecule,
due to the existence of a convertible NH in the pyrazolyl group.
After two recrystallizations from MeOH−hexane−Et2O (1:1:3)
using the “layering” approach, crystals of complex 4 suitable for
X-ray diffraction were obtained in 76% yield. Complexes 3 and
4 were air-stable, but attempts to determine their structure by
1H and 13C NMR spectroscopy were unsuccessful, possibly due
to the paramagnetic nature of the Cu(II) center.23
The molecular structures of complexes 3 and 4 were
confirmed by X-ray crystallographic studies, as shown in
Figures 1 and 2, respectively. Mononuclear complex 3 adopts a
square-pyramidal geometry with a tridentate κ3-coordination
mode of the N-heterocyclic ligand, which coordinates to the
Cu(II) center through an amino nitrogen and two pyridyl
nitrogen atoms. The bond to the amine N atom (2.075(11) Å)
is longer than those to the pyridine N atoms (1.973(11) and
1.976(10) Å), denoting a weaker interaction with the Cu(II)
center. The fourth and fifth coordination sites are occupied by
two bromide anions. The Br1 anion occupies the apex of the
The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition
reaction between alkynes and azides (CuAAC) for constructing
triazole cycles is the archetypal “click chemistry”, which was
reported independently by Sharpless16 and Meldal.17 This
triazole synthesis has been widely applied in medicinal,
bioorganic, and materials chemistry, as well as many other
research areas over the past decade.18 Over the past 10 years,
numerous efficient catalytic methods have been developed for
accelerating the catalytic process and decreasing the amount of
metal catalyst needed, for example, the use of ligands or direct
use of air- and moisture-stable Cu(I) salts as catalysts.19 The
most widely applied catalytic systems for CuAAC are based on
symmetrical polydentate nitrogen ligands such as the tris-
(benzyltriazolylmethyl) amine (TBTA) system introduced by
Sharpless and co-workers19j (Scheme 1). However, Finn and
co-workers20 recently found that hybrid tripodal ligands bearing
combinations of different heterocyclic fragments (mixed
ligands) are more active than their symmetrical analogs. Very
recently, Semakin and co-workers21 reported that “mixed”
oxime−triazole ligands, TzβOx2 and Tz2 Ox, demonstrated an
β
approximately 10-fold enhanced acceleration effect in compar-
ison to that shown by TBTA, using 0.1 mol % of the Cu/L
catalytic system (Scheme 1).
In a recent preliminary communication, we explored the
activity of binuclear Cu complex 2, bearing an unsymmetrical
a
Scheme 2. Synthesis of Mono- and Binuclear Cu Complexes
a
Reaction conditions: (i) Cu(CH3CN)4PF6, MeOH, rt, in air, 16 h, 71%.22 (ii) CuBr2, MeOH, rt, in air, 16 h, 48%. (iii) 1.5 equiv of NEt3, MeOH, rt,
in air, 20 h, 76%.
B
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In dinuclear bis-(pyrazolato)-bridged Cu(II) compound 4,
the geometry around each Cu(II) center is distorted trigonal-
bipyramidal (τ = 0.89) with a crystallographically imposed
inversion symmetry passing through the two bridging
pyrazolato groups. The axial positions of the trigonal bipyramid
are occupied by amino nitrogen N3 and nitrogen N2A in the
pyrazolato bridge of the other ligand with an N2A−Cu1−N3
angle of 177.5(2)°. N1, N4, and N5 atoms occupy three
vertexes of the basal plane, in which the bond angles around the
Cu1 atom are 110.8(2), 117.5(2), and 124.4(2)°, respectively.
The Cu(II)−nitrogen bond lengths range from 1.942(5) to
2.141(6) Å, with the shortest bond being between Cu1 and
N2A of the pyrazolato, attributed to its covalent nature.
Performance of Mononuclear Complex 3 and
Binuclear Complex 4 in CuAAC Reactions. In our recent
research, binuclear Cu complex 2 was applied as a catalyst for
the 1,3-dipolar cycloaddition reaction between alkynes and
azides. As reported in the preliminary communication,
screening of reaction conditions revealed that MeOH was the
most suitable solvent and that the ultimate catalyst loading
leading to complete conversion of the reactants was 0.1 mol %,
with a reaction time of 16 h (Table 1, entry 1).22 Considering
Figure 1. Molecular structure of 3. Selected bond lengths (Å) and
angles (deg): Br(1)−Cu(1), 2.614(2); Br(2)−Cu(1), 2.429(2);
Cu(1)−N(2), 1.973(11); Cu(1)−N(3), 1.976(10); Cu(1)−N(1),
2.075(11); N(2)−Cu(1)−N(3), 163.1(5); N(2)−Cu(1)−N(1),
80.6(5); N(3)−Cu(1)−N(1), 82.7(5); N(2)−Cu(1)−Br(2),
94.1(3); N(3)−Cu(1)−Br(2), 98.1(3); N(1)−Cu(1)−Br(2),
145.6(3); N(2)−Cu(1)−Br(1), 96.9(4); N(3)−Cu(1)−Br(1),
91.3(4); N(1)−Cu(1)−Br(1), 109.6(3); Br(2)−Cu(1)−Br(1),
104.74(8).
Table 1. Optimization of the Reaction Conditions for
a
CuAAC
entry cat. (mol %) NaAsc (mol %) NEt3 (mol %) isolated yield (%)
bc
,
1
2
3
4
5
6
7
8
9
2 (0.1)
1
1
1
1
1
99
93
27
99
29
N.R.
17
92
98
3 (0.05)
3 (0.025)
3 (0.025)
3 (0.01)
3 (0.025)
3 (0.025)
3 (0.025)
4 (0.0125)
1
1
1
1
1
Figure 2. Molecular structure of 4 with the H2O molecule and
bromide anion omitted for clarity. Selected bond lengths (Å) and
angles (deg): Cu(1)−N(2)#1, 1.942(5); Cu(1)−N(1), 2.009(5);
Cu(1)−N(3), 2.067(5); Cu(1)−N(4), 2.093(5); Cu(1)−N(5),
2.141(6); N(2)#1−Cu(1)−N(1), 98.9(2); N(2)#1−Cu(1)−N(3),
177.5(2); N(1)−Cu(1)−N(3), 82.0(2); N(2)#1−Cu(1)−N(4),
100.5(2); N(1)−Cu(1)−N(4), 124.4(2); N(3)−Cu(1)−N(4),
80.8(2); N(2)#1−Cu(1)−N(5), 97.6(2); N(1)−Cu(1)−N(5),
117.5(2); N(3)−Cu(1)−N(5), 80.0(2); N(4)−Cu(1)−N(5),
110.8(2).
d
e
1
1
1
a
Reaction conditions: 1.0 mmol of phenylacetylene, 1.0 mmol of
b
c
benzyl azide, 1 mL of MeOH, N2, 25 °C, 16 h. Ref 22. MeOH = 1.5
mL. Under air. t-BuOH/H2O (1:1) as solvents.
d
e
the structural similarity of complexes 2−4, we chose MeOH as
the solvent for exploring the application of complexes 3 and 4.
Mononuclear complex 3 demonstrated slightly better activity
than that of binuclear complex 2, reaching 93% yield at 0.05
mol % catalyst loading (Table 1, entry 2). When the amount of
catalyst 3 was decreased to 0.025 mol %, only 27% yield was
obtained (Table 1, entry 3). However, we were delighted to see
a dramatic acceleration upon addition of 1 mol % NEt3, giving
99% yield (Table 1, entry 4). Further decreasing the catalyst
loading led to the incomplete conversion of the reactants,
giving 29% yield with 0.01 mol % catalyst loading (Table 1,
entry 5). The cycloaddition reaction did not take place in the
absence of sodium L-ascorbate, indicating that the active species
was a Cu(I) complex (Table 1, entry 6).26 The reaction was
also performed under air, and the triazole product was obtained
in an isolated yield of only 17%, possibly because the resulting
active Cu(I) species was oxidized to inactive Cu(I) species by
air (Table 1, entry 7). When the solvent was changed to t-
BuOH/H2O, the reaction between phenylacetylene and benzyl
square-pyramid, and the four vertexes of the base are occupied
by Br1, N1, N2, and N3 atoms. The angles around the Cu(II)
atom in the basal plane vary from 80.6(5) to 98.1(3)°,
indicating a distorted square-pyramid geometry, which can be
quantitatively identified using the parameter τ = 0.29, as defined
by Addison et al. (τ = 1 for the trigonal bipyramid and 0 for the
square pyramid).24 Surprisingly, the N4 atom of the pyrazolyl is
not coordinated to the Cu(II) center but remains dissociated.
Changing the reaction temperature from room temperature to
reflux, we still obtained complex 3 with an uncoordinated
pyrazolyl arm, rather than the desired complex in which the
bipyridine−pyrazole−amine ligand presented a κ4-coordination
mode. Nicasio and co-workers recently reported a similar Cu(I)
complex bearing a tris-(pyrazolyl-methyl)amine ligand, which in
the solid-state structure presented a κ3-coordination mode with
an uncoordinated pyrazolyl arm.25 However, in solution, it
existed in an equilibrium between κ3- and κ4-coordinate species.
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a
Table 2. 1,3-Dipolar Cycloaddition Reaction of Various Alkynes and Azides Catalyzed by Mononuclear Complex 3
a
Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl azide, cat. 3 (0.025 mol %), 1 mol % sodium L-ascorbate, 1 mol % NEt3, 1.0 mL of
b
MeOH, N2, 25 °C, 16 h. 0.05 mol % cat. 3.
azide afforded the triazole product in 92% yield (Table 1, entry
8). Binuclear Cu complex 4 showed the best catalytic activity at
half the catalyst loading (0.0125 mol %), with the cycloaddition
reaction giving the desired product in 98% yield (Table 1, entry
9). It exhibited higher activity than did complex 2, possibly due
to the effect of Br− anion. Bertrand recently demonstrated the
Janus-face role of the anion ligand in the CuAAC catalytic
process.27 It is worth mentioning that when complexes 3 and 4
were used as catalysts the amount of the solvent varied from 1.5
to 1 mL as these two complexes exhibited greater solubility in
MeOH than did complex 2 (Table 1, entries 2−9).
With the optimized conditions in hand, the scope of the
cycloaddition was explored (Tables 2 and 3). A broad variety of
alkynes (5a−q) and azides (6a−h), both equipped with various
functional moieties such as arenes with electron-withdrawing or
-donating substituents, heterocycles, alcohols, alkanes, and
esters were successfully employed. As expected, most alkynes
reacted with the azides to give nearly quantitative yields of the
1,4-disubstituted triazole products. The reactions of fluoro-
substituted phenylacetylenes (5b−d) with benzyl azide 6a
afforded the corresponding 1,4-disubstituted triazoles in 97, 97,
and 99% yields, respectively (Table 2, entries 2−4). Similar
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propargyl alcohol 5m with benzyl azide 6a afforded
corresponding 1,4-disubstituted triazole 7m in 97% yield
(Table 2, entry 13). Interestingly, the more hindered alcohol,
5n, also exhibited excellent reactivity, giving 1,4-disubstituted
triazole 7n in 96% yield (Table 2, entry 14). Aliphatic alkynes
5o and 5p displayed moderate reactivity, both giving yields of
71% with 0.05 mol % catalyst loading (Table 2, entries 15 and
Table 3. 1,3-Dipolar Cycloaddition Reaction of Various
Alkynes and Azides Catalyzed by Binuclear Complex 4
a
̀
16). Pericas et al. have previously demonstrated that these two
substrates exhibit lower reactivity and require longer reaction
times for complete conversion using their catalyst in this
reaction.19e Unfortunately, the reaction of ethyl propiolate 5q
with benzyl azide 6a gave a complex mixture of products, and
we were unable to isolate the expected products, perhaps
because of the presence of NEt3 (Table 2, entry 17). The
reaction of the internal alkyne diphenylacetylene with benzyl
azide was also investigated: No products were obtained, and the
reactants were recycled. CuAAC reactions between phenyl-
acetylene 5a and fluoro- or methyl-substituted azides (6b and
6c) were also investigated at 0.05 mol % catalyst loading,
affording corresponding 1,4-disubstituted triazoles 7q and 7r in
99% yield (Table 2, entries 18 and 19). To further explore the
scope of the reaction, a range of aryl-substituted azides (6d−h)
were reacted with phenylacetylene 5a under the optimized
conditions. However, these azides were generally less reactive
than benzyl azide 6a, and the reactions required a higher
catalyst loading of 0.05 mol % for completion. Nevertheless, the
various phenyl azides, bearing electron-withdrawing or
-donating substituents (6d−g), could be converted to the
corresponding triazole products in 96−99% yields (Table 2,
entries 20−23). m-Nitrophenyl azide 6h displayed excellent
reactivity, giving corresponding triazole 7w in an isolated yield
of 99% (Table 2, entry 24).
To investigate the effect of NEt3 upon this CuAAC reaction,
we added NEt3 to a methanolic solution of mononuclear
complex 3 and successfully obtained the binuclear complex 4,
which possessed the same cationic structure as complex 2.
Next, we examined the catalytic activity of binuclear complex 4
for the CuAAC reaction with half the catalyst loading based on
complex 3 for maintaining a constant amount of Cu, because
complex 4 was a dimer of complex 3. As we expected, complex
4 showed catalytic activity nearly identical with that of the
combined system of mononuclear complex 3 and NEt3 for
most substrates (Table 3, entries 1−4 and 7−9, and Table 2,
entries 1, 7, 11, 14, and 19−21). We hypothesized that complex
3 can be considered as a precursor to complex 4 and that their
similar catalytic activity is presumably due to the in situ
formation of 4 from 3 under basic conditions (NEt3 as a
base).15b Using complex 4 as a catalyst, aliphatic and ester-
substituted alkynes (5o, 5p, and 5q) exhibited better reactivity
than that with complex 3, giving 95, 85, and 65% yields,
respectively (Table 3, entries 5, 6, and 10). In the combined
system of catalyst 3 and NEt3, the basic conditions may cause
some side reactions, leading to lower yields of the desired
triazole products and producing other unknown products.
Surprisingly, binuclear complex 4 displayed higher catalytic
activity than binuclear complex 2 and mononuclear complex 3
in the CuAAC reaction, promoting the quantitative formation
of triazole products 7 from most substrates at extremely low
loading (0.0125−0.025 mol %). To expand the application of
this highly effective catalyst, it was also used for the synthesis of
complicated molecules, as shown in Scheme 3. Diazotization of
amine 11 (an intermediate in the synthesis of Sorafenib (BAY
43−9006), the first oral multikinase inhibitor),28 and
a
Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl azide,
cat. 4 (0.025 mol %), sodium L-ascorbate 1 mol %, MeOH 1.0 mL, N2,
25 °C, 16 h. 0.0125 mol % Cat. 4.
b
results were obtained with chloro- and bromo-substituted
phenylacetylene substrates (5e−g), affording 1,4-disubstituted
triazoles in 97−99% yields (Table 2, entries 5−7). The
reactions of phenylacetylenes bearing electron-donating sub-
stituents (5h−j) with benzyl azide 6a also gave satisfactory
results, producing 1,4-disubstituted triazoles in 97−98% yields
(Table 2, entries 8−10). Heterocycle-substituted alkynes 5k
and 5l also showed excellent reactivity and were completely
converted to the desired triazole products in 99% yields but
required a catalyst loading of 0.05 mol % (Table 2, entries 11
and 12). The presence of unprotected OH groups in the
substrates did not inhibit catalyst 3; this is not entirely
surprising as similar behavior was previously observed with
complex 2.22 Using 0.05 mol % catalyst, the reaction of
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loading at 25 °C, giving the corresponding triazole 7a in 52%
yield in 16 h. After the amount of catalyst and reaction
temperature were increased, triazole 7a was obtained in 97%
isolated yield within 24 h (Table 4, entry 1). Therefore, using
0.1 mol % catalyst loading at 50 °C for 24 h as the optimal
reaction conditions, the reactions of a wide variety of alkynes
equipped with various functional moieties (like arenes,
heterocycles, alcohols, and alkanes) with benzyl bromide and
sodium azide have been developed, giving the corresponding
triazole products in good-to-excellent yields. Halogenated
phenylacetylenes showed slightly lower reactivity, giving the
corresponding triazoles in 89−94% yields (Table 4, entries 2−
7). The reaction of methyl-substituted phenylacetylenes 5h and
5i afforded the corresponding triazoles in 90 and 92% yields,
respectively (Table 4, entries 8 and 9). This methodology could
be extended to heterocyclic alkynes such as commercially
available 2-ethynylpyridine 5k and 2-ethynylthiophene 5l to
afford the desirable heterocycle-functionalized triazoles in 90
and 89% yields, respectively (Table 4, entries 10 and 11). This
one-pot method was also applicable to alkyne substrates with
an alcohol group. The reaction of alcoholic alkynes 5m and 5n
afforded triazoles 7m and 7n in 92% yield (Table 4, entries 12
and 13). Unsurprisingly, alkyl-substituted alkyne 5o showed
only moderate reactivity, giving triazole 7o in 65% yield (Table
4, entry 14). The scope of the benzyl reaction partner was also
investigated. Electron-poor p-fluorobenzyl bromide 13b and
electron-rich p-methylbenzyl bromide 13c reacted smoothly to
afford corresponding triazoles 7q and 7r in 97 and 90% yields,
respectively (Table 4, entries 15 and 16).
Scheme 3. Application of Catalyst 4 in the Synthesis of
Complicated Molecules
a
a
Conditions: (i) HCl/NaNO2, 1.2 equiv of NaN3, EtOAc, rt, 3 h; (ii)
0.1 mol % cat. 4 for 8 and 9, 0.3 mol % cat. 4 for 10, Na L-ascorbate,
MeOH, 25 °C, 16 h.
subsequent substitution with sodium azide (NaN3) gave azide
6i. With 0.1 mol % catalyst loading at 25 °C, the cycloaddition
reaction of 6i with alkynes 5a and 5g gave corresponding
triazole products 8 and 9 in 96 and 94% isolated yields in 16 h,
respectively. It is worth mentioning that triazole 9 was obtained
in high purity and nearly quantitative yield after a simple
filtration and methanol wash, without the use of column
chromatography, due to its extremely poor solubility in
methanol. Since resulting triazole 9 bears a bromo substituent,
it is primed for further functionalization. Ester analog 6j was
synthesized following the same method as amide 6i and was
then reacted with phenylacetylene 5a to give corresponding
triazole 10 in 91% isolated yield. This reaction required a
higher catalyst loading of 0.3 mol %. From these precursors, we
hope to synthesize a range of Sorafenib analogs and assess their
bioactivity.
Performance of Binuclear Complex 4 in One-Pot
CuAAC Reactions. Organic azides, especially those of low
molecular weight, are known to be generally unstable and
potentially explosive. In order to avoid the isolation and
purification processes for organic azides in these types of
cycloaddition reaction, one-pot synthesis of triazoles were
developed, using aromatic or alkyl halides and sodium azide for
direct cycloaddition with alkynes.29 Various copper catalysts
such as Cu2O,30 CuI,31 CuSO4,32 CuBr(PPh3)3,33 and other
heterogeneous catalysts34 have been used in this reaction.
Furthermore, one-pot triazole preparation from N-sulfonylazir-
idines,35 amines,36 boronic acids,37 or diaryliodonium salts38
has also been performed via in situ preparation of azides.
Considering the extraordinary catalytic activity of binuclear
complex 4 in the CuAAC reaction, we decided to evaluate our
catalytic system for the one-pot CuAAC reaction of alkyl
halides, sodium azide, and alkynes, as shown in Table 4. First,
we completed the one-pot reaction of phenylacetylene with
benzyl bromide and sodium azide with 0.05 mol % catalyst
The results obtained above for the one-pot method show
that the established protocol was very effective for most
alkynes, although the results were not as good as those for
direct cycloaddition between alkynes and azides. The NaBr
formed from the reaction of the starting bromide with NaN3
might inhibit the cycloaddition reaction.33 As far as we know,
these results represent one of the lowest catalyst loadings used
so far for this three-component transformation.39
Mechanistic Considerations. Initially, a stepwise catalytic
cycle was proposed, which proceeded via a six-membered
copper-containing intermediate.16,40 Further studies demon-
strated a second-order dependence on catalyst concentration
for both ligand-free41 and most ligand-containing42 CuAAC
reactions. Compared to the already reported monocopper
intermediate, the dinuclear Cu(I) intermediate participates in
the rate-determining step, leading to a further drop in the
activation barrier.43 Several binuclear Cu complex catalysts
showed superior catalytic activity.19g,k,44 Bertrand et al. reported
that although mono- and bis-copper complexes promote the
CuAAC reaction the pathway involving the dinuclear species
was kinetically favored, and they successfully isolated a hitherto
never-mentioned bis(metalated) triazole complex.45 On the
basis of these findings and the results of catalytic activities, we
propose a bimetallic mechanism for CuAAC reactions catalyzed
by 3 or 4 (Scheme 4). In the presence of NEt3, the catalytic
activity of mononuclear complex 3 is equivalent to that of the
binuclear complex 4 (see Tables 2 vs 3); therefore, the CuAAC
reaction can be initiated directly from 4 or in situ generated 4
by deprotonation of 2 equiv of 3. Next, as in most Cu(II)
catalytic systems, 4 is reduced in situ to the active Cu(I) species
A by sodium L-ascorbate, but we were unable to confirm the
structure of A due to its extreme lability in air. The starting
alkyne then reacts with A to form binuclear acetylide−copper
complex B, displacing one of the pyridyl coordinating groups
F
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Article
Table 4. One-Pot 1,3-Dipolar Cycloaddition of Various Alkynes and Benzyl Bromides with Sodium Azide, Catalyzed by the
a
Binuclear Complex 4
a
Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl bromide, 1.0 mmol of NaN3, cat. 4 (0.1 mol %), 2 mol % sodium L-ascorbate, 1.0 mL
of MeOH, N2, 50 °C, 24 h.
(L). The subsequent nucleophilic attack of the acetylide carbon
to the “external” nitrogen atom of the azide generates copper-
triazolide E through one of two possible transition states, C or
D. In transition state C, the acetylide and the azide are
coordinated to the same Cu atom (Cub) and the second Cu
atom (Cua) π-coordinates to the acetylide, leading to a further
drop in the activation barrier.43b−d However, because Cua and
Cub are bridged by two pyrazolato groups, the distance between
them may not be close enough to allow both of them to
interact with the same acetylide. Thus, it is also possible that
the reaction proceeds through transition state D, in which one
Cu center binds the acetylide fragment and the other Cu center
binds the azide fragment, synergistically providing a cyclic
transition state for the reaction between the terminal azide
nitrogen and the positively charged secondary carbon of the
acetylide. This possibility has been suggested by Bock et al.43a
and Meldal et al.,26 and is supported by mechanistic studies
performed by Rodionov et al.41 In the last step, protonation of
E and recoordination of ligand L afford the triazole product and
regenerate the active catalyst A. Hence, we cannot rule out that
ligand L is exchanged with the acetylide.
CONCLUSION
■
In conclusion, we have developed two novel copper complexes
bearing an unsymmetrical bipyridine−pyrazole−amine ligand,
mononuclear complex 3 and binuclear complex 4, and applied
them as catalysts for the CuAAC reaction. Owing to the
convertibility of NH in the pyrazolyl group of ligand 1, complex
4 could be obtained through the loss of HBr from complex 3 in
the presence of triethylamine. Binuclear complex 4 showed a
higher catalytic activity than that of mononuclear complex 3;
however, when triethylamine was added to the reaction system,
complex 3 exhibited catalytic activity equivalent with that of
complex 4, suggesting that binuclear complex 4 forms in situ by
deprotonation of 3. Using sodium L-ascorbate as a reducing
agent and MeOH as a solvent, 1,3-dipolar cycloaddition
reactions between various alkynes and azides were catalyzed
by complexes 3 and 4, and the corresponding 1,4-disubstituted
triazoles were obtained in good-to-excellent yields. Binuclear
complex 4 exhibited surprisingly high catalytic activity and
could promote the CuAAC reaction at a catalyst loading as low
as 0.0125 mol %, which is one of the lowest catalyst loadings
used in this reaction to date. As is widely known, click
chemistry is often applied in medicinal, bioorganic, and
G
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Article
a
N-((1H-Pyrazol-3-yl)methyl)-1-(pyridin-2-yl)-N-(pyridin-2-
ylmethyl)methanamine·CuBr2 (3). To a MeOH (10 mL) solution
of ligand 1 (2.15 mmol, 0.600 g) was added with stirring an equimolar
amount of CuBr2 (2.15 mmol, 0.480 g) in MeOH (10 mL). The
solution was stirred at rt for 24 h in air. The final green solution was
concentrated under reduced pressure to 5 mL and then layered with
hexane (5 mL) and Et2O (15 mL) for recrystallization at 2−8 °C to
give 3 as green crystals (0.519 g, 48% yield), which were suitable for X-
ray diffraction. Mp: >200 °C dec. HRMS Calcd for C16H18CuBr2N5
M: 499.9147; Found for C16H18CuBr2N5 M: 499.9141.
Scheme 4. Proposed Mechanism
N-((1H-Pyrazol-3-yl)methyl)-1-(pyridin-2-yl)-N-(pyridin-2-
ylmethyl)methanamine·CuBr (4). To a MeOH (20 mL) solution of
complex 3 (0.46 mmol, 0.233 g) was added with stirring the base NEt3
(1.5 equiv, 0.7 mmol, 0.070 g). The solution was stirred at rt for 20 h
in air. The final green solution was concentrated under reduced
pressure to 5 mL and then layered with hexane (5 mL) and Et2O (15
mL) for recrystallization at 2−8 °C to give green crystals as the target
complexes and white crystals as NEt3·HBr together. Then, the green
crystals were picked from the mixture and recrystallize through
layering method (V(MeOH):V(hexane):V(Et2O) = 1:1:3) for a
second time. Complex 4 was obtained as green crystals suitable for
X-ray diffraction (0.150 g, 76% yield). Mp: >200 °C dec. HRMS Calcd
for C32H32BrCu2N10 [M
−
Br−]+: 761.0587; Found for
C32H32BrCu2N10 [M − Br−]+: 761.0590.
4-(4-Azidophenoxy)-N-methylpicolinamide (6i).48 To a 0 °C
solution of 4-(4-aminophenoxy)-N-methyl-picolinamide (11) (0.520
g, 2.14 mmol) in EtOAc (10 mL) was added concentrated
hydrochloride (0.9 mL), followed by addition of a solution of
NaNO2 (0.177 g, 2.6 mmol) in 2.5 mL of H2O consecutive dropwise
addition over a period of 10 min with stirring. After the mixture was
stirred for a further 1 h, a solution of NaN3 (0.169 g, 2.6 mmol) in
H2O (2.5 mL) was added to the above reaction mixture with stirring.
The reaction mixture was warmed to room temperature and stirred for
3 h. The aqueous layer was separated, and the organic layer was
washed with water (5 mL × 4) up to pH = 6. Then, the solution was
dried over Na2SO4, filtered, and concentrated in vacuo to give 6i
(0.336 g, 61%, brown solid), which was used for the next step without
a
L: pyridyl or tertiary amino group. L′: pyrazolato group. Partially
coordinating groups are omitted for clarity.
materials chemistry. Low catalyst loading could significantly
reduce the negative impact of residual metals. Furthermore, this
method was found to be equally effective and straightforward
for the preparation of potentially biologically active com-
pounds. Several new triazoles, which are precursors to
Sorafenib analogs, were obtained in 91−96% isolated yields
through a CuAAC reaction catalyzed by binuclear complex 4. A
one-pot synthesis of 1,4-disubstituted triazoles via a three-
component reaction between terminal alkynes, organic
bromides, and sodium azide could be also achieved using
binuclear complex 4 as a catalyst to give the desired products in
good-to-excellent yields. The isolation and purification of
organic azides were avoided in this procedure, as they were
prepared in situ. Transition metal complexes bearing unsym-
metrical ligands can exhibit excellent catalytic activity, which
represents a direction for developing new highly active catalysts.
Future work will focus on developing the application of this
catalyst to the synthesis of a series of potentially biologically
active compounds bearing a triazole group, and the bioactivity
of these compounds.
1
further purification. H NMR (600 MHz, d6-DMSO) δ 8.77 (d, 1H, J
= 4.3 Hz, NH), 8.51 (d, 1H, J = 5.5 Hz, aromatic CH), 7.39 (d, 2H, J =
2.0 Hz, aromatic CH), 7.29−7.23 (m, 4H, aromatic CH), 7.15−7.14
(m, 1H, aromatic CH), 2.79 (d, 3H, J = 4.7 Hz, CH3).
Methyl 4-(4-Azidophenoxy)picolinate (6j). To a 0 °C solution
of methyl 4-(4 minophenoxy)-picolinate (12)49 (0.560 g, 2.29 mmol)
in EtOAc (50 mL) was added concentrated hydrochloride (0.9 mL),
followed by addition of a solution of NaNO2 (0.190 g, 2.75 mmol) in
2.5 mL of H2O by consecutive dropwise addition over a period of 10
min with stirring. After the mixture was stirred for a further 1 h, a
solution of NaN3 (0.179 g, 2.75 mmol) in H2O (2.5 mL) was added to
the above reaction mixture with stirring. The reaction mixture was
warmed to room temperature and stirred for 3 h. The aqueous layer
was extracted by using ethyl acetate (15 mL × 3), and then the organic
layers were combined, washed with brine (15 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to give 6j (0.600 g, 97%, gray solid),
which was used for the next step without further purification. Mp:
1
108−110 °C. H NMR (600 MHz, d6-DMSO) δ 8.64 (d, 1H, J = 4.8
EXPERIMENTAL SECTION
Hz, aromatic CH), 7.51 (s, 1H, aromatic CH), 7.31−7.26 (m, 5H,
aromatic CH), 3.87 (s, 3H, CH3). 13C NMR (150 MHz, d6-DMSO) δ
166.3, 163.7, 150.5, 149.9, 148.0, 137.4, 122.6, 121.3, 115.3, 112.9,
53.0. HRMS Calcd for C13H10N4O3 M: 270.0753; Found for
C13H10N4O3 M: 270.0755.
■
1
General Remarks. H and 13C{1H} NMR spectra were recorded
on a Bruker DRX-600 spectrometer and all chemical shift values refer
to TMS = 0.00 ppm, CDCl3 ((1H), 7.26 ppm; (13C), 77.16 ppm), or
d6-DMSO ((1H), 2.50 ppm; (13C), 39.52 ppm). HRMS analysis was
carried out on an Agilent 6500 Q-TOF mass spectrometer (Version
Q-TOF B.05.01). All the chemical reagents were purchased from
commercial sources. All the solvents were purified according to the
routine methods before used. Azides 6b,c and 6d−h were respectively
prepared through methods reported for the syntheses of 6a46 and 6d47
and subsequently applied in the 1,3-dipolar cycloaddition reaction.
(Caution: Low-molecular-weight carbon azides used in this study are
potentially explosive. Appropriate protection measures (lab coat, gloves,
and goggles) should always be used when handling these compounds.)
General Procedure for 3-Catalyzed 1,3-Dipolar Cycloaddi-
tion Reactions. Under N2 atmosphere, a mixture of alkyne (1.0
mmol), azide (1.0 mmol), Na ascorbate (0.01 mmol, 1 mol %), NEt3
(0.01 mmol, 1 mol %), and 0.25 × 10−3 M solution of catalyst 3 in
MeOH (1.0 mL, 0.025 mol %) was stirred in a 10 mL Schlenk tube at
25 °C for 16 h. Evaporation of the solvents followed by purification by
short column chromatography on silica gel provided the desired 1,4-
disubstituted triazole product. The unreacted alkyne and azide were
first eluted out with petroleum ether (PE), and the pure 1,4-
H
DOI: 10.1021/acs.organomet.7b00154
Organometallics XXXX, XXX, XXX−XXX

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Article
disubstituted triazole product was then obtained by elution with 1:3
PE/ethyl acetate.
Details of X-ray crystallography for 3 and 4, experimental
procedures, analytical data of triazholes, and copies of
NMR spectra (PDF)
General Procedure for 4-Catalyzed 1,3-Dipolar Cycloaddi-
tion Reactions. Under N2 atmosphere, a mixture of alkyne (1.0
mmol), azide (1.0 mmol), Na ascorbate (0.01 mmol, 1 mol %), and
0.125 × 10−3 M solution of catalyst 4 in MeOH (1.0 mL, 0.0125 mol
%) was stirred in a 10 mL Schlenk tube at 25 °C for 16 h. Evaporation
of the solvents followed by purification by short column chromatog-
raphy on silica gel provided the desired 1,4-disubstituted triazole
product. The unreacted alkyne and azide were first eluted out with PE,
and the pure 1,4-disubstituted triazole product was then obtained by
elution with 1:3 PE/ethyl acetate or pure ethyl acetate.
Accession Codes
CCDC 1444291 and 1444292 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
General Procedure for One-Pot Cu-Catalyzed 1,3-Dipolar
Cycloaddition Reactions. Under N2 atmosphere, a mixture of
alkyne (1.0 mmol), benzyl bromide (1.0 mmol), NaN3 (1.0 mmol),
Na ascorbate (0.02 mmol, 2 mol %), and 1.0 × 10−3 M solution of
catalyst 4 in MeOH (1.0 mL, 0.1 mol %) was stirred in a 10 mL
Schlenk tube at 50 °C for 24 h. Evaporation of the solvents followed
by purification by short column chromatography on silica gel provided
the desired 1,4-disubstituted triazole product. The unreacted alkyne
and azide were first eluted out with PE, and the pure 1,4-disubstituted
triazole product was then obtained by elution with 3:1 PE/ethyl
acetate.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: yewenjing@syphu.edu.cn.
*E-mail: chunhu@syphu.edu.cn.
ORCID
Wenjing Ye: 0000-0002-1222-8489
Notes
The authors declare no competing financial interest.
■
N-Methyl-4-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)-
1
ACKNOWLEDGMENTS
picolina-mide (8). Yield: 96%, white powder. Mp: 208−209 °C. H
■
NMR (600 MHz, d6-DMSO) δ 9.34 (s, 1H, triazole-H), 8.81 (d, 1H, J
= 4.6 Hz, NH), 8.57 (d, 1H, J = 5.5 Hz, aromatic CH), 8.10 (d, 2H, J =
8.8 Hz, aromatic CH), 7.96 (d, 2H, J = 7.4 Hz, aromatic CH), 7.52−
7.50 (m, 5H, aromatic CH), 7.40 (t, 1H, J = 7.4 Hz, aromatic CH),
7.26 (dd, 1H, J1 = 5.3 Hz, J2 = 2.3 Hz, aromatic CH), 2.81 (d, 3H, J =
4.7 Hz, CH3). 13C NMR (150 MHz, d6-DMSO) δ 165.6, 164.2, 153.8,
153.1, 151.1, 147.9, 134.6, 130.7, 129.5, 128.8, 125.8, 122.9, 120.3,
115.0, 109.8, 26.50. HRMS Calcd for C21H17N5O2 M: 371.1382;
Found for C21H17N5O2 M: 371.1386.
This work was supported by the NNSFC (21502120), China
Postdoctoral Science Foundation (2013M541254), and Scien-
tific Research Fund of Liaoning Provincial Education Depart-
ment (L2015525).
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DOI: 10.1021/acs.organomet.7b00154
Organometallics XXXX, XXX, XXX−XXX