Palladium-Catalyzed Regioselective Arylation of Pyrazolo[1,5-a]pyridines via C-H Activation and Synthetic Applications on P38 Kinase Inhibitors

Article abstract of DOI:10.1021/acs.organomet.5b00988

A direct arylation of pyrazolo[1,5-a]pyridines with aryl iodides selectively occurring at the C-3 and C-7 positions via palladium-catalyzed C-H activation is described. In these reactions, (a) cesium(I) fluoride and (b) silver(I) carbonate were employed a

Full text of DOI:10.1021/acs.organomet.5b00988

Article
pubs.acs.org/Organometallics
Palladium-Catalyzed Regioselective Arylation of
Pyrazolo[1,5‑a]pyridines via C−H Activation and Synthetic
Applications on P38 Kinase Inhibitors
Hung-Chou Wu,†,§ Jean-Ho Chu,*,‡ Chin-Wei Li,‡,§ Long-Chih Hwang,† and Ming-Jung Wu*,†,‡
†Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan 804
‡Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan 804
S
* Supporting Information
ABSTRACT: A direct arylation of pyrazolo[1,5-a]pyridines with
aryl iodides selectively occurring at the C-3 and C-7 positions via
palladium-catalyzed C−H activation is described. In these
reactions, (a) cesium(I) fluoride and (b) silver(I) carbonate
were employed as the additive to afford 3- and 7-arylated
pyrazolo[1,5-a]pyridines, respectively, in modest to good yields.
These reactions showed good compatibility with functional
groups, and the catalytic mechanisms of these reactions were
proposed. Finally, the synthetic application on the potent p38
kinase inhibitors was demonstrated.
2-phenylpyrazolo[1,5-a]pyrimidines,12 in which aryl bromides,
INTRODUCTION
■
Pd(OAc)2, PtBu3·HBF4, and K2CO3 were employed as reaction
Heterocycles containing nitrogen atoms are key motifs in
reagents and toluene was the solvent that eventually provided
natural products and pharmaceutical compounds because of
3-arylated-5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidines.
their potent bioactivities.1 Among them, pyridines and their
Meanwhile, the use of PPh3 and Cs2CO3 instead of PtBu3·HBF4
derivatives are recognized as the most important family of
and K2CO3 was able to generate 7-diarylated-5-methyl-2-
compounds.2 Therefore, developing more efficient and
phenylpyrazolo[1,5-a]pyrimidines as major products. On the
convenient strategies to approach these molecular architectures
other hand, in 2015, Bedford and co-workers reported the
is becoming highly critical for organic chemists.
palladium(II)-catalyzed direct regioselective C-3 and C-7
Pyrazolo[1,5-a]pyridine has been known as an important
arylation of pyrazolo[1,5-a]pyrimidines.13 In the study, the
skeleton in a class of biologically active compounds, such as p38
authors found that a phosphine ligand, 2-dicyclohexylphosphi-
no-2′,6′-dimethoxybiphenyl (SPhos, 20 mol %), is very critical
for the formation of 7-arylated-pyrazolo[1,5-a]pyrimidines,
whereas 3-arylated-pyrazolo[1,5-a]pyrimidines are easy to
synthesize without the use of an SPhos ligand.
kinase inhibitors,3 5HT3-antagonists,4 dopamine D4,5 and
MT1/MT2 melatonin receptor ligands.6 In 2011 and 2012,
we reported the copper-mediated and gold(I)-catalyzed
cyclizations of enediynones and enynylpyrazoles, respectively,
to afford pyrazolo[1,5-a]pyridines.7 After that, we went onto
In this article, we present a palladium-catalyzed direct C-3/C-
the development of more efficient and convenient method-
7 arylation of pyrazolo[1,5-a]pyridines with aryl iodides via C−
ologies for the synthesis of pyrazolo[1,5-a]pyridine derivatives,
H activation and finally demonstrate the simple synthesis of
especially in the aryl-substituted pyrazolo[1,5-a]pyridines.
In the literature, the arylation of pyrazolo[1,5-a]pyridines is
potent p38 kinase inhibitors based on the developed method-
ology.
usually achieved by the conventional methods, such as
halogenation and subsequent C−C coupling,8 but this is still
RESULTS AND DISCUSSION
■
not good enough in terms of synthetic efficiency. Recently, the
For the direct C-3 arylation of pyrazolo[1,5-a]pyridines 1, it
direct C−H functionalization has received great attention due
to its remarkable efficiency in organic synthesis.9,10 To date, the
synthetic strategy via C−H activation has been widely applied
to synthesize various organic compounds, especially in the aryl-
substituted heterocycles.11 However, only rare studies on the
direct arylation of pyrazolo[1,5-a]pyridine analogues were
reported.12,13 For instance, in 2013, Berteina-Raboin and co-
workers demonstrated the direct C-3 arylation of 5,7-dimethyl-
was examined by the reaction of 1a with 2a (phenyl iodide) in
the presence of 5 mol % palladium(II) acetate (see Table 1). In
the beginning, triphenylphosphine (Ph3P) was employed as the
ligand without any additives, and the reaction was heated in
Received: December 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
In view of this, we then concentrated on the use of CsF as
the additive and further studied the solvent effects of the
reaction on the influence of reactivity (entries 13−15, Table 1).
However, the product yield of 3a was not obviously improved
in the variation of solvents; oppositely, poor results were
observed (trace−15%). Thus, we turned to examine other
phosphine ligands, but unfortunately the product yield of 3a
was still not improved as anticipated (entries 16−21, Table 1).
Nevertheless, these above results drove us to remove the
phosphine ligand from the reaction and to only use CsF as the
additive. Delightfully, the product yield of 3a was potentially
increased to 68% yield (from 54% yield) with a reduction of
reaction time (30 h, entry 22, Table 1). Finally, we screened a
series of fluoride salts (entries 23−26, Table 1) and other
additives (entries 27−31, Table 1), but the experimental results
showed that CsF was still the best additive for the reaction.
With the optimized reaction conditions in hand (5 mol %
Pd(OAc)2, 4 equiv of aryl iodide,14a 2 equiv of CsF in DMF at
140 °C14b for 30 h), we subsequently carried out the direct C-3
arylation of 1a with a variety of aryl iodides 2 to afford 3-
arylpyrazolo[1,5-a]pyridines 3 in modest to good yields. The
experimental results are summarized in Table 2. In addition to
the reaction of 1a with 2a leading to product 3a (68%, entry 1,
Table 2), we also carried out the reaction of 1a with 2b−g,
bearing a methoxy or methyl substituent at the para-, meta-,
and ortho-position, respectively, to provide the anticipated
products 3b−g in 50−85% yields (entries 2−7, Table 2). In the
above reactions, we found that the reaction of 1a with meta-
methylphenyl iodide (2c)/meta-methoxyphenyl iodide (2f)
usually gave higher product yields (85% for 3c and 65% for 3f,
entries 3 and 6, Table 2) than that of ortho- and para-
substituted cases (51% for 3b and 50% for 3d, entries 2 and 4,
Table 2; 68% for 3g and 72% for 3i, entries 5 and 7, Table 2).
Moreover, dimethoxy-substituted aryl iodides, such as 2,4-
dimethoxyphenyl iodide (2h) and 2,6-dimethoxyphenyl iodide
(2i), were also explored in the reaction, and that gave products
3h and 3i in 40% and 51% yield, respectively (entries 8 and 9,
Table 2). When aryl iodides 2j−l, bearing a nitro group at the
para-, meta-, and ortho-position, respectively, were employed as
the coupling reagents, products 3j−l were isolated in 68−82%
yields (entries 10−12, Table 2). Among these, the product
yield of 3k (68%) was found to be lower than that of product 3j
(74%) and 3l (82%). These results seem to indicate that the
substituent position (i.e., inductive effects) potentially
influences the direct C-3 arylation of pyrazolo[1,5-a]pyridine
(1a).
Table 1. Optimization of the Direct C-3 Arylation of
Pyrazolo[1,5-a]pyridines 1
a
entry
ligand
additive
Ph-I (2a) (equiv)
t (h)
yield (%)
1
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
L1
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
72
72
72
72
72
72
72
72
72
72
48
48
48
48
48
48
48
48
48
48
48
30
30
30
30
30
30
30
30
30
30
trace
47
2
Cs2CO3
CsF
3
40
4
K2CO3
K3PO4
KOAc
Na2CO3
NaOAc
KF
32
5
27
6
24
7
20
8
25
9
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
K2HPO4
Cs2CO3
CsF
trace
40
54
b
CsF
trace
c
CsF
8
c
CsF
15
CsF
43
40
39
36
32
29
68
35
34
26
19
38
30
24
18
26
L2
CsF
L3
CsF
L4
CsF
L5
CsF
L6
CsF
CsF
KF
AgF
e
TBAF
CuF2
Cs2CO3
K2CO3
Na2CO3
KOAc
NaOAc
a
Product yields were determined as an average of three runs by
b,c,d
isolation.
1,4-Dioxane, toluene, and dimethylacetamide were used
e
as the solvent, respectively. TBAF = tetrabutylammonium fluoride. L1
= (o-tolyl)3P, L2 = Ph2PCl, L3 = (4-MeO-C6H4)3P, L4 = (2-furyl)3P,
L5 = Ph2PSiMe3, L6 = (C6F5)3P.
Furthemore, the reaction of 1a with halogen-substituted
phenyl iodides 2m−o could afford the anticipated products
3m−o in 61−81% yields (entries 13−15, Table 2).
Interestingly, an unexpected product, 3o-I (23%), was isolated
in the reaction of 1a with para-bromophenyl iodide (2o) (entry
15, Table 2). This indicates that the reaction can also take place
when aryl bromides are employed as the coupling reagents
under the reaction conditions, although its reactivity is
relatively poorer than that of aryl iodides.15 Herein, the
structure of 3n was secured by X-ray crystallography as shown
in Figure 1.16 Finally, we explored the reaction of 1a with
pyridinyl iodides 2p−r, and it smoothly gave the corresponding
products 3p−r in 44−60% yields (entries 16−18, Table 2).
Proposed Mechanism for the Direct C-3 Arylation of
Pyrazolo[1,5-a]pyridine (1a). In order to gain insight into
the reaction, we presented a possible mechanism as shown in
Figure 2. First, palladium(II) ion is reduced to palladium(0) in
dimethylformamide (DMF) at 140 °C for 72 h. The
experimental results showed that only a trace amount of 3-
phenylpyrazolo[1,5-a]pyridine (3a) was detected (entry 1,
Table 1). Subsequently, various additives were added to the
above reaction (entries 2−10, Table 1), and we found that both
cesium carbonate (Cs2CO3) and cesium fluoride (CsF) were
able to increase the product yield of 3a to 40−47% yields
(entries 2 and 3, Table 1). On the basis of these results, we
attempted to increase the used amount of phenyl iodide (2a)
(up to 4 equiv) and concurrently reduce the reaction time
(down to 48 h) toward the two cases of Cs2CO3 and CsF to
optimize the reaction conditions. According to the exper-
imental results, product 3a was eventually generated in 40%
and 54% yield, respectively (entries 11 and 12, Table 1). In the
above tuning of reaction conditions, we found that the product
yield of 3a was slightly decreased when Cs2CO3 was used, but
increased when Cs2CO3 was replaced by CsF.
B
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 2. Direct C-3 Arylation of 1a with 2
a
Product yields were determined as an average of three runs by isolation.
C
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
During the course of the investigation, we serendipitously
isolated 12% yield of 3,7-diphenylpyrazolo[1,5-a]pyridine (5)
from the reaction of 1a with 2a, whereas the anticipated
product 3a was isolated in 36% yield when the reaction
additive, cesium(I) fluoride, was replaced by silver(I) carbonate.
In view of the findings, we subsequently turned to evaluate
the possibility of the direct C-7 selective arylation of 1a through
the screening of other additives, but the C-3-arylated
compound (i.e., 3a) was still generated as a major product
accompanying a few C-7 arylated products (i.e., 6a). This result
indicated that the reactivity of the C-3 position of pyrazolo[1,5-
a]pyridine (1a) is still prior to that of the C-7 position in terms
of structural consideration. Thus, we turned to tagging a
CO2Me group at the C-3 position of 1a to prevent the
formation of 3-phenylpyrazolo[1,5-a]pyridine (3a). Prelimi-
narily, the reaction of methyl pyrazolo[1,5-a]pyridine-3-
carboxylate (1c) with phenyl iodides (2a) was carried out
with 5 mol % Pd(OAc)2 and 1.5 equiv of Ag2CO3 in DMF at
140 °C for 48 h and gave 7-phenylpyrazolo[1,5-a]pyridine (6a)
in 20% yield (entry 1, Table 3). The structure of 6a was further
Figure 1. ORTEP drawings of compound 3n.16 All hydrogen atoms
are omitted for clarity.
Table 3. Optimization for the Direct C-7 Arylation of Methyl
Pyrozolo[1,5-a]pyridine-3-carboxylate (1c)
a
entry Ph-I (2a) (equiv)
additive (equiv)
Ag2CO3 (1.5)
yield (%)
Figure 2. Proposed mechanism for the direct C-3 arylation of 1a.
1
2
3
4
5
6
7
8
9
2
2
3
3
3
3
3
3
3
20
33
31
25
43
75
43
29
17
Ag2CO3 (1.5) + BnBu3NCl (0.1)
Ag2CO3 (2) + BnBu3NCl (0.1)
Ag2CO3 (3) + BnBu3NCl (0.2)
Ag2CO3 (2) + DMSO (4)
Ag2CO3 (3) + DMSO (4)
AgOAc (2) + DMSO (4)
the presence of cesium(I) fluoride at 140 °C.17 Subsequently,
palladium(0) ion insertion into the carbon(sp2)−iodine bond
of aryl iodides 2 led to the formation of aryl palladium(II)
complex (A), and then complex A reacts with the zwitterion
form of 1a to generate intermediate B by a release of an iodine
anion.18 Intermediate B is rapidly transformed into inter-
mediate C through intramolecular electron transfer by a release
of hydrogen iodide. Eventually, the desired product 3 is given
through reductive elimination of intermediate C, and the
released palladium(II) ion is reduced to palladium(0) ion and
continues the catalytic cycle.
In addition to 1a, the direct C-3 arylation of another starting
substrate, 2-phenylpyrazolo[1,5-a]pyridine (1b), was also
explored under the aforementioned reaction conditions.
Three aryl iodides, 2a, 2e, and 2j, were introduced to the
above reaction and eventually provided the anticipated
products, 2,3-diarylpyrazolo[1,5-a]pyridines 4a,e,j, in 59%,
52%, and 64% yields, respectively (see Scheme 1).
AgOAc (3) + DMSO (4)
AgOAc (3) + BnBu3NCl (0.2)
a
Product yields were determined as an average of three runs by
isolation.
secured by X-ray crystallography as shown in Figure 3.16
Subsequently, the reaction conditions were optimized as shown
in Table 3. Initially, 0.1 and 0.2 equiv of an ammonium salt,
benzyltributylammonium chloride (BnBu3NCl), was added to
the above reaction. However, the product yield of 6a was not
obviously improved (only 25−33% yields were observed) even
Scheme 1. Direct C-3 Arylation of Substrate 1b
Figure 3. ORTEP drawing of compound 6a.16 All hydrogen atoms
were omitted for clarity.
D
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 4. Direct C-7 Arylation of 1c
a
Product yields were determined as an average of three runs by isolation.
E
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
when the used amount of silver(I) carbonate and phenyl iodide
(2a) were increased to 3 equiv (entries 2−4, Table 3). Finally,
we found that the addition of DMSO19 was able to increase the
product yield of 6a (43%, entry 5, Table 3), especially
combining both 3 equiv of Ag2CO3 and 4 equiv of DMSO,
where 75% yield of 6a was obtained (entry 6, Table 3). On the
other hand, we also used AgOAc with either DMSO or
BnBu3NCl in the reaction, but the product yield of 6a was not
improved (entries 7−9, Table 3).
With the optimized reaction conditions in hand (5 mol %
Pd(OAc)2, 3 equiv of Ag2CO3, and 4 equiv of DMSO in DMF
at 140 °C for 48 h), we subsequently carried out the direct C-7
arylation of 1c with a variety of aryl iodides 2 to afford the
desired products 6.20 The experimental results are summarized
in Table 4. In addition to the reaction of 1c with 2a leading to
product 6a (75%, entry 1, Table 4), the reaction of 1c with 2b−
r was subsequently carried out to give products 6b−r in 20−
87% yields (entries 2−18, Table 4). Among these, the reaction
of 1c with 2b−d, bearing a methyl substituent on the phenyl
ring at the para-, meta-, and ortho-position, produced the
anticipated compounds 6b−d in 82%, 80%, and 87% yield,
respectively (entries 2−4, Table 4). Then, the reaction of 1c
with 2e−g, bearing a methoxy substituent on the phenyl ring at
the para-, meta-, and ortho-position, gave the anticipated
products 6e−g in 72%, 62%, and 60% yield, respectively
(entries 5−7, Table 4). On the other hand, dimethoxy-
substituted aryl iodides 2h and 2i were also involved in the
reaction, which led to products 6h and 6i in 45% and 20%
yield, respectively (entries 8 and 9, Table 4).
Figure 4. ORTEP drawing of complex D.16 All hydrogen atoms were
omitted for clarity.
Proposed Mechanism for the Direct C-7 Arylation of
3-Methylcarboxylpyrazolo[1,5-a]pyridine (1c). Based on
the isolation of complex D, a possible reaction mechanism for
the direct C-7 arylation of 1c was presented as shown in Figure
5. First, palladium(II) ion is reduced to palladium(0) ion in the
In order to evaluate the substituent electronic effects on the
influence of this reaction, we further carried out the reaction of
1c with 2j−l, bearing a nitro substituent on the phenyl ring at
the para-, meta-, and ortho-position. The experimental results
showed that products 6j, 6k, and 6l were generated in 20% and
trace yields, repectively (entries 10−12, Table 4).21 In view of
the above results, we believe that the substituent electronic
effects indeed influence the reactivity for the direct C-7
arylation of 1c. In other words, the aryl iodide 2, bearing an
electron-withdrawing group (e.g., −NO2), usually resulted in a
lower product yield of 6 than that of an electron-donating
group (e.g., −OMe). Meanwhile, the steric hindrance caused
from the ortho-substituent seems to slightly influence the
reactivity of the reaction, especially in the methoxy-substituted
cases. Moreover, the substituent position seems not to show
obvious influence on the para-, meta-, and ortho-substituted aryl
iodides 2 in the reaction.
On the other hand, halogen-substituted aryl iodides 2m−o
were also employed into the reaction, and the anticipated
products 6m−o were generated in moderate yields (63−76%,
entries 13−15, Table 4). Finally, the reaction of 1c with 4-, 3-,
and 2-iodopyridines 2p−r were carried out to afford products
6p−r in 50−70% yields (entries 16−18, Table 4).
In order to gain insight into the direct C-7 arylation of 1c
with 2, we attempted to synthesize and isolate the possible
palladium intermediate. Herein, a stoichiometric reaction of 1c
with Pd(OAc)2 in dichloromethane was carried out, and
eventually a bis(3-methylcarboxylpyrazolo[1,5-a]pyridine)-
palladium(II) intermediate (D) was isolated and secured by
X-ray crystallography as shown in Figure 4.16
Figure 5. Proposed mechanism for the direct C-7 arylation of 1c.
presence of silver(I) carbonate at 140 °C.17 Subsequently, the
palladium(0) ion inserts into the carbon(sp2)−iodine bond of
aryl iodide 2 and generates aryl palladium(II) intermediate A.
Intermediate A is then coordinated with the nitrogen atom
located at the N-1 position of 1c and generates complex D′.22
Furthermore, complex D′ is transformed to intermediate E (a
concerted-metalation-deprotonation transition state)23 in the
presence of silver(I) carbonate, whereas silver(I) iodide is
released. Intermediate E is eventually converted to intermediate
F by a release of silver(I) hydrogen carbonate, and product 6 is
produced through reductive elimination of intermediate E,
which releases a palladium(0) ion and continues the next
catalytic cycle.
With 7-aryl-pyrazolo[1,5-a]pyridines 6 in hand, we sub-
sequently removed the CO2Me group by the treatment of an
F
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
acidic solution, sulfonic acid/water (1/1, v/v), under reflux
conditions. Finally, 7-arylpyrazolo[1,5-a]pyridines 7 were
obtained in 44−81% yields (see Scheme 2).
91% product ratio of 3a accompaning 3% and 6% product
ratios of 7a and 5 (70% total yield) was observed in the same
reaction under conditions B. When phenyl iodide instead of
phenyl bromide was employed as the coupling reagent in the
above reactions, a similar product distribution to that of phenyl
bromide was observed, and the product ratio of 3a, 7a, and 5
was determined to be 86:8:6 (37% total yield) for conditions A
and 88:1:11 (57% total yield) for conditions B (see Scheme
3a). Finally, we carried out the reaction of methyl pyrozolo[1,5-
a]pyridine-3-carboxylate (1c) with Ph−X (X = Br and I) under
conditions A, and that smoothly gives a single product, 6a, in
63% yield (X = Br) and 43% yield (X = I), respectively (see
Scheme 3b).
Scheme 2. Removal of the CO2Me Group of Compound 6
In addition, we are able to selectively synthesize 3,7-diaryl-
substituted pyrazolo[1,5-a]pyridines 8a and 5 by the reaction of
3a with 2h/6a with 2a in 73% and 75% yield, respectively,
based on the developed methodologies (see Scheme 4).
Scheme 4. Direct C-3/C-7 Arylation of Substrates 3a and 6a
On the other hand, in order to evaluate Bedford’s reaction
conditions13 on the direct C-3 and C-7 arylation of pyrazolo-
[1,5-a]pyridines 1, we carried out the reaction of pyrazolo[1,5-
a]pyridine (1a) with 3 and 1 equiv of phenyl bromide/iodide,
respectively, under their conditions A (10 mol % Pd(OAc)2, 20
mol % SPhos, 1 equiv of Cs2CO3, and 1 equiv of LiCl heated at
150 °C for 18 h in toluene) to synthesize 7-phenylpyrazolo[1,5-
a]pyridines 7a and conditions B (10 mol % Pd(OAc)2, 1 equiv
of K2CO3, and 1 equiv of LiCl heated at 120 °C for 18 h in 1,4-
dioxane) to synthesize 3-phenylpyrazolo[1,5-a]pyridines 3a.
According to the experimental results (see Scheme 3), only a
5% product ratio of 7a was observed in the reaction of 1a with
phenyl bromide under conditions A, whereas 76% and 19%
product ratios of 3a and 5 (3,7-diphenylpyrazolo[1,5-a]-
pyridine) were determined, respectively, and the reaction
total yield was determined to be 85%. Moreover, we found that
Finally, in order to demonstrate the synthetic applications of
the presented methodology, the syntheses of p38 kinase
inhibitor 9a24 and its analogue 9b were then carried out
through the direct C-3 arylation of 1d with 2p and 2s,
respectively. The experimental results showed that 62% yield of
9a and 50% yield of 9b were eventually obtained (see Scheme
5). Moreover, other potent p38 kinase inhibitors, such as 10a−
Scheme 3. Evaluation of Bedford’s Reaction Conditions13 on
the Direct C-3/C-7 Arylation of 1
Scheme 5. Synthesis of p38 Kinase Inhibitors 9 and 10
Directed from the Reaction of 1d with 2p,s
c, can be easily prepared by the reaction of 9b with various
amines in 42−70% yields based on the reported reaction
conditions.3a
CONCLUSION
■
We have successfully developed a convenient and efficient
strategy for the synthesis of 3- and 7-aryl-substituted pyrazolo-
[1,5-a]pyridines via palladium-catalyzed C−H bond activation
G
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
50 mg, 0.20 mmol), and the reaction was heated under reflux for 3 h.
After cooling to room temperature, sodium hydroxide solution (50%
w/w in water) was added to the reaction while maintaining the
temperature below 35 °C using an ice bath and until the solution was
basic, as determined by litmus paper. Finally, the basic solution was
extracted by ethyl acetate (5 mL × 3). The organic layers were
combined, dried over Mg2SO4, filtered, and evaporated under vacuum.
The residue was purified by flash chromatography on silica gel using n-
hexane/ethyl acetate (20/1 to 5/1) as the eluent to give product 7. All
product yields are listed as follows. 7a: 76% (29 mg, 0.15 mmol); 7c:
81% (31 mg, 0.15 mmol); 7d: 80% (31 mg, 0.15 mmol); 7e: 78% (31
mg, 0.14 mmol); 7g: 77% (31 mg, 0.14 mmol); 7j: 64% (26 mg, 0.11
mmol); 7o: 70% (30 mg, 0.11 mmol); 7r: 44% (18 mg, 0.09 mmol).
Characterization Data of Compounds 3−10. 3-
Phenylpyrazolo[1,5-a]pyridine (3a): pale yellow solid; mp 120−122
°C; Rf = 0.55 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500
MHz) δ 8.50 (d, J = 7.0 Hz, 1 H), 8.15 (s, 1 H), 7.83 (d, J = 9.0 Hz, 1
H), 7.61 (dd, J = 8.0, 1.0 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.30 (t, J
= 7.5 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 6.80 (td, J = 7.0, 1.0 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ 140.3, 136.9, 133.1, 129.0, 128.9,
127.0, 126.2, 123.9, 117.4, 112.8, 112.0; HRMS (EI-magnetic sector)
m/z [M+] calcd for C13H10N2 194.0844, found 194.0847.
and C−C bond coupling. Possible catalytic mechanisms were
presented to give an insightful understanding on these
reactions. The synthesis of potent p38 kinase inhibitors based
on the developed methodologies was demonstrated. Finally, we
believe that the developed methodologies can further be used
as useful synthetic tools in the field of pharmaceutical synthesis.
EXPERIMENTAL SECTION
General Procedures. Solvents and reagents were purchased from
commercial suppliers and used without purification. H NMR spectra
■
1
were measured on 300, 400, 500, and 600 MHz NMR spectrometers.
Natural abundance 13C NMR spectra were measured by using 300,
400, 500, and 600 MHz NMR spectrometers operating at 75, 100, 125,
and 150 MHz, respectively. Chemical shifts are given in parts per
million (ppm) and coupling constant J in hertz (Hz) for both nuclei,
with the solvent (usually CDCl3) peak as an internal standard. The
1
reference peak for H is δ 7.26 of chloroform and for 13C it is the
central peak at δ 77.0. Low- and high-resolution mass spectrometry
was majorly obtained by the following ionization method and mass
analyzer type: EI-magnetic sector. Melting points were measured by
using open capillary tubes and are uncorrected.
3-(p-Tolyl)pyrazolo[1,5-a]pyridine (3b): yellow solid; mp 100−102
°C; Rf = 0.54 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500
MHz) δ 8.48 (d, J = 7.0 Hz, 1 H), 8.12 (s, 1 H), 7.79 (d, J = 8.5 Hz, 1
H), 7.49 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H), 7.15 (m, 1 H),
6.77 (t, J = 7.0 Hz, 1 H), 2.40 (s, 3 H); 13C NMR (CDCl3, 125 MHz)
δ 140.2, 136.8, 135.9, 130.1, 129.6, 128.9, 126.9, 123.6, 117.5, 112.8,
111.8, 21.1; HRMS (EI-magnetic sector) m/z [M+] calcd for
C14H12N2 208.1000, found 208.1003.
3-(m-Tolyl)pyrazolo[1,5-a]pyridine (3c): brown oil; Rf = 0.58 (n-
hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 8.49 (d,
J = 7.0 Hz, 1 H), 8.15 (s, 1 H), 7.82 (d, J = 9.0 Hz, 1 H), 7.42 (d, J =
9.5 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.16−7.11 (m, 2 H), 6.76 (td, J
= 7.0, 1.0 Hz, 1 H), 2.43 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
140.2, 138.4, 136.8, 132.9, 128.8, 128.7, 127.6, 126.9, 124.0, 123.6,
117.4, 112.8, 111.8, 21.4; HRMS (EI-magnetic sector) m/z [M+] calcd
for C14H12N2 208.1000, found 208.0997.
3-(o-Tolyl)pyrazolo[1,5-a]pyridine (3d): brown oil; Rf = 0.56 (n-
hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 8.50 (d,
J = 7.0 Hz, 1 H), 8.01 (s, 1 H), 7.44 (d, J = 9.0 Hz, 1 H), 7.37−7.27
(m, 4 H), 7.09 (m, 1 H), 6.76 (td, J = 6.5, 1.0 Hz, 1 H), 2.33 (s, 3 H);
13C NMR (CDCl3, 125 MHz) δ 141.4, 137.6, 136.5, 131.8, 130.4,
130.3, 128.6, 127.0, 125.7, 123.2, 117.4, 111.9, 111.7, 20.4; HRMS (EI-
magnetic sector) m/z [M+] calcd for C14H12N2 208.1000, found
208.0997.
General Procedure for the Syntheses of 3 and 4. Pd(OAc)2
(4.7 mg, 0.021 mmol) and CsF (127 mg. 0.840 mmol) were added to
a well-stirred solution of pyrazolo[1,5-a]pyridines 1 (1a: 50 mg, 0.42
mmol; 1b: 81 mg, 0.42 mmol) and aryl iodides 2 (4 equiv) in N,N-
dimethylformamide (5 mL), and then the reaction was heated at 140
°C for 30 h. After cooling to room temperature, the reaction mixture
was quenched with water (20 mL). The resulting solution was
extracted with ethyl acetate (2 × 5 mL). Finally, the organic layers
were combined, dried over MgSO4, filtered, and evaporated under
vacuum. The residue was purified by flash chromatography on silica gel
using n-hexane/ethyl acetate (20/1 to 5/1) as the eluent to give
products 3 and 4. All product yields are listed as follows. 3a: 68% (55
mg, 0.29 mmol); 3b: 68% (60 mg, 0.29 mmol); 3c: 85% (74 mg, 0.36
mmol); 3d: 72% (62 mg, 0.30 mmol); 3e: 51% (48 mg, 0.21 mmol);
3f: 65% (60 mg, 0.27 mmol); 3g: 50% (47 mg, 0.21 mmol); 3h: 40%
(43 mg, 0.17 mmol); 3i: 51% (53 mg, 0.21 mmol); 3j: 74% (74 mg,
0.31 mmol); 3k: 68% (68 mg, 0.28 mmol); 3l: 82% (81 mg, 0.34
mmol); 3m: 75% (68 mg, 0.32 mmol); 3n: 61% (59 mg, 0.26 mmol);
3o-Br: 58% (66 mg, 0.24 mmol); 3o-I: 23% (32 mg, 0.10 mmol); 3p:
50% (41 mg, 0.21 mmol); 3q: 60% (49 mg, 0.25 mmol); 3r: 44% (35
mg, 0.18 mmol); 4a: 59% (68 mg, 0.25 mmol); 4e: 52% (66 mg, 0.22
mmol); 4j: 64% (85 mg, 0.27 mmol).
General Procedure for the Syntheses of 6. Pd(OAc)2 (3.1 mg,
0.014 mmol) and Ag2CO3 (154 mg, 0.560 mmol) were added to a
mixture of 3-methylcarboxylpyrazolo[1,5-a]pyridine 1c (50 mg, 0.28
mmol) and aryl iodides 2 (3 equiv) in N,N-dimethylformamide (5
mL), 4 equiv of dimethyl sulfoxide (79 μL, 1.1 mmol) was injected
into the above solution, and the reaction was then well-stirred and
heated at 140 °C for 48 h. After cooling to room temperature, the
reaction mixture was quenched with water (20 mL). The resulting
solution was extracted with ethyl acetate (2 × 5 mL). Finally, the
organic layers were combined, dried over MgSO4, filtered, and
evaporated under vacuum. The residue was purified by the flash
chromatography on silica gel using n-hexane/ethyl acetate (30/1 to 5/
1) as the eluent to give product 6. All product yields are listed as
follows. 6a: 75% (53 mg, 0.21 mmol); 6b: 82% (61 mg, 0.23 mmol);
6c: 80% (59 mg, 0.22 mmol); 6d: 87% (69 mg, 0.24 mmol); 6e: 72%
(56 mg, 0.20 mmol); 6f: 67% (52 mg, 0.18 mmol); 6g: 60% (48 mg,
0.17 mmol); 6h: 40% (36 mg, 0.12 mmol); 6i: 25% (22 mg, 0.07
mmol); 6j: 20% (18 mg, 0.06 mmol); 6k: trace; 6l: trace; 6m: 68% (53
mg, 0.19 mmol); 6n: 70% (55 mg, 0.19 mmol); 6o: 68% (63 mg, 0.19
mmol); 6p: 52% (36 mg, 0.15 mmol); 6q: 63% (46 mg, 0.18 mmol);
6r: 52% (38 mg, 0.15 mmol).
3-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridine (3e): yellow solid;
1
mp 76−78 °C; Rf = 0.52 (n-hexane/ethyl acetate = 10/1); H NMR
(CDCl3, 500 MHz) δ 8.48 (d, J = 7.0 Hz, 1 H), 8.08 (s, 1 H), 7.75 (d,
J = 9.0 Hz, 1 H), 7.51 (dt, J = 9.0, 2.0 Hz, 2 H), 7.13 (m, 1 H), 7.01
(dt, J = 9.0, 2.0 Hz, 2 H), 6.76 (td, J = 7.0, 1.0 Hz, 1 H), 3.85 (s, 3 H);
13C NMR (CDCl3, 125 MHz) δ 158.2, 140.0, 136.7, 128.8, 128.2,
125.5, 123.5, 117.3, 114.4, 112.6, 111.8, 55.3; HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H12N2O 224.0950, found 224.0953.
3-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridine (3f): brown oil; Rf =
0.55 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ
8.50, (d, J = 7.0 Hz, 1 H), 8.14 (s, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 7.37
(t, J = 8.0 Hz, 1 H), 7.20−7.13 (m, 3 H), 6.86 (m, 1 H), 6.79 (td, J =
7.0, 1.0 Hz, 1 H), 3.88 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
160.0, 140.4, 136.9, 134.5, 129.9, 129.0, 123.9, 119.5, 117.5, 112.8,
112.7, 112.0, 111.4, 55.2; HRMS (EI-magnetic sector) m/z [M+] calcd
for C14H12N2O 224.0950, found 224.0949.
3-(2-Methoxyphenyl)pyrazolo[1,5-a]pyridine (3g): brown oil; Rf =
0.54 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ
8.49 (d, J = 7.0 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d, J = 9.0 Hz, 1 H), 7.49
(dd, J = 7.5, 1.5 Hz, 1 H), 7.32 (td, J = 8.0, 1.5 Hz, 1 H), 7.14−7.02
(m, 3 H), 6.77 (td, J = 7.0, 1.0 Hz, 1 H), 3.87 (s, 3 H); 13C NMR
(CDCl3, 125 MHz) δ 156.3, 142.1, 137.6, 129.9, 128.7, 127.7, 123.2,
121.8, 120.8, 118.4, 111.7, 111.1, 108.7, 55.3; HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H12N2O 224.0950, found 224.0951.
General Procedure for the Syntheses of 7.25 Sulfuric acid
(50% v/v in water; 2.0 mL, 4.1 mmol) was added to 7-aryl-3-
methylcarboxylpyrazolo[1,5-a]pyridine 6 (6a: 50 mg, 0.20 mmol; 6c:
50 mg, 0.19 mmol; 6d: 50 mg, 0.19 mmol; 6e: 50 mg, 0.18 mmol; 6g:
50 mg, 0.18 mmol; 6j: 50 mg, 0.17 mmol; 6o: 50 mg, 0.15 mmol; 6r:
H
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
3-(2,4-Dimethoxyphenyl)pyrazolo[1,5-a]pyridine (3h): brown oil;
Rf = 0.48 (n-hexane/ethyl acetate = 5/1); 1H NMR (CDCl3, 500
MHz) δ 8.47 (d, J = 7.0 Hz, 1 H), 8.12 (s, 1 H), 7.60 (d, J = 9.0 Hz, 1
H), 7.37 (d, J = 8.5 Hz, 1 H), 7.09 (dd, J = 9.0, 9.0 Hz, 1 H), 6.74 (td,
J = 6.5, 1.0 Hz, 1 H), 6.61−6.58 (m, 2 H), 3.87 (s, 3 H), 3.84 (s, 3 H);
13C NMR (CDCl3, 125 MHz) δ 159.8, 157.4, 141.8, 137.4, 130.4,
128.6, 122.9, 118.3, 114.5, 111.5, 108.5, 104.6, 99.0, 55.4; HRMS (EI-
magnetic sector) m/z [M+] calcd for C15H14N2O2 254.1055, found
254.1057.
123.6, 117.5, 112.1, 111.6; HRMS (EI-magnetic sector) m/z [M+]
calcd for C13H9N2Br 271.9949, found 271.9950.
3-(4-Iodophenyl)pyrazolo[1,5-a]pyridine (3o-I): white solid; mp
1
156−158 °C; Rf = 0.54 (n-hexane/ethyl acetate = 10/1); H NMR
(CDCl3, 500 MHz) δ 8.50 (d, J = 7.0 Hz, 1 H), 8.12 (s, 1 H), 7.76 (d,
J = 9.0 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H),
7.20 (t, J = 8.0 Hz, 1 H), 6.81 (td, J = 6.5, 1.0 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 140.2, 137.9, 136.8, 132.0, 129.1, 128.4, 124.3,
119.8, 117.1, 112.1, 111.6; HRMS (EI-magnetic sector) m/z [M+]
calcd for C13H9N2I 319.9810, found 319.9810.
3-(2,6-Dimethoxyphenyl)pyrazolo[1,5-a]pyridine (3i): yellow oil;
1
3-(Pyridin-4-yl)pyrazolo[1,5-a]pyridine (3p): brown solid; mp 71−
Rf = 0.54 (n-hexane/ethyl acetate = 10/1); H NMR (CDCl3, 500
1
72 °C; Rf = 0.60 (n-hexane/ethyl acetate = 1/1); H NMR (CDCl3,
MHz) δ 8.46 (d, J = 7.0 Hz, 1 H), 8.11 (s, 1 H), 7.34 (d, J = 9.0 Hz, 1
H), 7.29 (t, J = 8.5 Hz, 1 H), 7.05 (m, 1 H), 6.73 (td, J = 6.5, 1.0 Hz, 1
H), 6.70 (d, J = 8.5 Hz, 2 H), 3.79 (s, 6 H); 13C NMR (CDCl3, 125
MHz) δ 158.2, 140.0, 136.7, 128.8, 128.2, 125.5, 123.5, 117.3, 114.4,
112.6, 111.8, 55.3; HRMS (EI-magnetic sector) m/z [M+] calcd for
C15H14N2O2 254.1055, found 254.1055.
600 MHz) δ 8.63 (d, J = 6.0 Hz, 2 H), 8.55 (ddd, J = 7.2, 1.2, 1.2 Hz, 1
H), 8.27 (s, 1 H), 7.89 (ddd, J = 9.0, 1.2, 1.2 Hz, 1 H), 7.53 (dd, J =
4.8, 1.5 Hz, 2 H), 7.31 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 6.89 (ddd, J =
6.6, 6.6, 1.2 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 150.1 (CH),
141.2 (Cq), 141.0 (CH), 135.5 (Cq), 129.6 (CH), 125.5 (CH), 121.0
(CH), 117.3 (CH), 112.8 (CH), 109.9 (Cq); HRMS (EI-magnetic
sector) m/z [M+] calcd for C12H9N3 195.0796, found 195.0798.
3-(Pyridin-3-yl)pyrazolo[1,5-a]pyridine (3q): brown oil; Rf = 0.46
3-(4-Nitrophenyl)pyrazolo[1,5-a]pyridine (3j): orange solid; mp
1
188−190 °C; Rf = 0.42 (n-hexane/ethyl acetate = 10/1); H NMR
(CDCl3, 500 MHz) δ 8.56 (d, J = 7.0 Hz, 1 H), 8.32 (d, J = 7.0 Hz, 2
H), 8.25 (s, 1 H), 7.88 (d, J = 9.0 Hz, 1 H), 7.75 (dt, J = 9.0, 2.0 Hz, 2
H), 7.33 (m, 1 H), 6.91 (td, J = 6.5, 1.0 Hz, 1 H); 13C NMR (CDCl3,
125 MHz) δ 145.5, 141.0, 140.2, 137.3, 129.5, 126.6, 125,.7, 124.5,
117.1, 112.9, 110.4; HRMS (EI-magnetic sector) m/z [M+] calcd for
C13H9N3O2 239.0695, found 239.0696.
1
(n-hexane/ethyl acetate = 5/1); H NMR (CDCl3, 500 MHz) δ 8.88
(d, J = 2.0 Hz, 1 H), 8.52−8.51 (m, 2 H), 8.16 (s, 1 H), 7.87 (dt, J =
8.0, 1.5 Hz, 1 H), 7.79 (d, J = 9.0 Hz, 1 H), 7.36 (dd, J = 8.0, 5.0 Hz, 1
H), 7.23 (m, 1 H), 6.84 (td, J = 7.5, 1.0 Hz, 1 H); 13C NMR (CDCl3,
125 MHz) δ 147.9, 147.2, 140.3, 137.1, 134.0, 129.3, 129.2, 124.7,
123.7, 116.9, 109.1; HRMS (EI-magnetic sector) m/z [M+] calcd for
C12H9N3 195.0796, found 195.0799.
3-(3-Nitrophenyl)pyrazolo[1,5-a]pyridine (3k): yellow solid; mp
1
131−132 °C; Rf = 0.44 (n-hexane/ethyl acetate = 2/1); H NMR
3-(Pyridin-2-yl)pyrazolo[1,5-a]pyridine (3r): yellow solid; mp 58−
(CDCl3, 400 MHz) δ 8.55 (d, J = 6.8 Hz, 1 H), 8.46 (dd, J = 2.0, 2.0
Hz, 1 H), 8.23 (s, 1 H), 8.13 (dd, J = 8.4, 2.0, 0.8 Hz, 1 H), 7.92 (d, J =
9.2 Hz, 1 H), 7.86 (d, J = 9.2 Hz, 1 H), 7.62 (dd, J = 8.0, 8.0 Hz, 1 H),
7.30 (ddd, J = 8.8, 6.8, 0.8 Hz, 1 H), 6.89 (ddd, J = 6.8, 6.8, 0.8 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ 148.9 (Cq), 140.6 (CH), 137.2
(Cq), 135.1 (Cq), 132.6 (CH), 129.9 (CH), 129.4 (CH), 125.2 (CH),
121.2 (CH), 120.8 (CH), 116.9 (CH), 112.7 (CH), 110.5 (Cq);
HRMS (EI-magnetic sector) m/z [M+] calcd for C13H9N3O2
239.0695, found 239.0695.
1
60 °C; Rf = 0.46 (n-hexane/ethyl acetate = 5/1); H NMR (CDCl3,
500 MHz) δ 8.64 (dd, J = 4.5, 0.5 Hz, 1 H), 8.54 (d, J = 9.0 Hz, 1 H),
8.50 (d, J = 7.0 Hz, 1 H), 8.38 (s, 1 H), 7.69 (td, J = 8.0, 1.5 Hz, 1 H),
7.63 (d, J = 8.0 Hz, 1 H), 7.27 (m, 1 H), 7.09 (m, 1 H), 6.85 (td, J =
7.0, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 153.2, 149.5, 138.1,
136.3, 128.8, 124.9, 120.1, 120.0, 119.7, 112.7, 112.0; HRMS (EI-
magnetic sector) m/z [M+] calcd for C12H9N3 195.0796, found
195.0797.
2,3-Diphenylpyrazolo[1,5-a]pyridine (4a): yellow solid; mp 134−
136 °C; Rf = 0.53 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3,
500 MHz) δ 8.51 (d, J = 7.0 Hz, 1 H), 7.63−7.61 (m, 2 H), 7.57 (d, J
= 9.0 Hz, 1 H), 7.41−7.28 (m, 8 H), 7.11 (m, 1 H), 6.78 (td, J = 6.5,
1.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 150.9, 139.5, 133.1,
33.0, 129.8, 128.8, 128.6, 128.4, 128.3, 128.0, 126.5, 123.6, 117.1,
112.1, 110.2; HRMS (EI-magnetic sector) m/z [M+] calcd for
C19H14N2 270.1157, found 270.1154.
3-(4-Methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyridine (4e): white
solid; mp 118−120 °C; Rf = 0.55 (n-hexane/ethyl acetate = 10/1); 1H
NMR (CDCl3, 500 MHz) δ 8.49 (d, J = 7.0 Hz, 1 H), 7.64 (dd, J =
7.5, 2.0 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.35−7.28 (m, 5 H), 7.09
(t, J = 7.5 Hz, 1 H), 6.95 (d, J = 8.5, Hz, 2 H), 6.77 (td, J = 6.5, 1.0 Hz,
1 H), 3.85 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 158.4, 150.7,
139.6, 133.1, 131.0, 128.8, 128.4, 128.3, 127.9, 125.2, 123.4, 117.2,
114.1, 112.0, 109.8, 55.2; HRMS (EI-magnetic sector) m/z [M+] calcd
for C20H16N2O 300.1263, found 300.1260.
3-(4-Nitrophenyl)-2-phenylpyrazolo[1,5-a]pyridine (4j): yellow
solid; mp 190−192 °C; Rf = 0.43 (n-hexane/ethyl acetate = 10/1);
1H NMR (CDCl3, 500 MHz) δ 8.55 (d, J = 7.0 Hz, 1 H), 8.23 (d, J =
9.0 Hz, 2 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.56−7.50 (m, 4 H), 7.38−
7.36 (m, 3 H), 7.25 (m, 1 H), 6.88 (td, J = 6.5, 1.0 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 151.9, 146.0, 140.4, 139.4, 132.2, 129.9,
129.0, 128.8, 128.6, 128.2, 125.2, 124.0, 116.5, 112.9, 108.0; HRMS
(EI-magnetic sector) m/z [M+] calcd for C19H13N3O2 315.1008, found
315.1010.
3,7-Diphenylpyrazolo[1,5-a]pyridine (5): colorless solid; mp 136−
138 °C; Rf = 0.53 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3,
500 MHz) δ 8.19 (s, 1 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.85 (dd, J = 9.0,
1.5 Hz, 1 H) 7.64 (d, J = 8.0 Hz, 2 H), 7.57−7.47 (m, 5 H), 7.34−7.25
(m, 2 H), 6.87 (dd, J = 7.0, 1.0 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 140.8, 140.1, 137.9, 133.6, 133.3, 129.4, 129.1, 128.9, 128.4,
127.2, 126.2, 124.1, 116.3, 113.1, 112.8; HRMS (EI-magnetic sector)
m/z [M+] calcd for C19H14N2 270.1157, found 270.1158.
3-(2-Nitrophenyl)pyrazolo[1,5-a]pyridine (3l): orange solid; mp
78−80 °C; Rf = 0.44 (n-hexane/ethyl acetate = 10/1); 1H NMR
(CDCl3, 500 MHz) δ 8.47 (d, J = 7.0 Hz, 1 H), 8.02 (s, 1 H), 7.88
(dd, J = 8.5, 1.0 Hz, 1 H), 7.60 (td, J = 7.5, 1.0 Hz, 1 H), 7.52 (dd, J =
7.5, 1.0 Hz, 1 H), 7.43 (td, J = 8.5, 1.5 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1
H), 7.14 (m, 1 H), 6.79 (td, J = 6.5, 1.0 Hz, 1 H); 13C NMR (CDCl3,
125 MHz) δ 149.1, 141.1, 137.7, 132.3, 132.2, 128.9, 127.5, 126.8,
124.6, 124.4, 116.5, 112.3, 107.2; HRMS (EI-magnetic sector) m/z
[M+] calcd for C13H9N3O2 239.0695, found 239.0695.
3-(4-Fluorophenyl)pyrazolo[1,5-a]pyridine (3m): yellow, viscous
1
liquid; Rf = 0.45 (n-hexane/ethyl acetate = 3/1); H NMR (CDCl3,
400 MHz) δ 8.50 (d, J = 7.2 Hz, 1 H), 8.10 (s, 1 H), 7.76 (d, J = 9.2
Hz, 1 H), 7.52−7.57 (m, 2 H), 7.12−7.21 (m, 3 H), 6.80 (ddd, J = 6.8,
6.8, 1.2 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 161.5 (d, JC−F
=
159.6 Hz, Cq), 140.1 (CH), 136.9 (Cq), 129.1 (d, JC−F = 2.5 Hz, Cq),
128.6 (d, JC−F = 6.3 Hz, CH × 2), 124.1 (CH), 117.2 (CH), 115.9 (d,
JC−F = 16.8 Hz, CH × 2), 112.0 (CH), 112.0 (Cq); HRMS (EI-
magnetic sector) m/z [M+] calcd for C13H9N2F 212.0750, found
212.0748.
3-(4-Chlorophenyl)pyrazolo[1,5-a]pyridine (3n): white solid; mp
1
144−146 °C; Rf = 0.51 (n-hexane/ethyl acetate = 10/1); H NMR
(CDCl3, 500 MHz) δ 8.50 (d, J = 7.0 Hz, 1 H), 8.12 (s, 1 H), 7.77 (d,
J = 9.0 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H),
7.20 (t, J = 8.0 Hz, 1 H), 6.81 (td, J = 7.0, 1.0 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 140.3, 136.9, 131.9, 131.6, 129.1, 128.1, 124.2,
117.2, 112.1, 111.7; HRMS (EI-magnetic sector) m/z [M+] calcd for
C13H9N235Cl 228.0454, found 228.0454.
3-(4-Bromophenyl)pyrazolo[1,5-a]pyridine (3o-Br): white solid;
mp 150−152 °C; Rf = 0.56 (n-hexane/ethyl acetate = 10/1); 1H NMR
(CDCl3, 500 MHz) δ 8.50 (d, J = 7.0 Hz, 1 H), 8.12 (s, 1 H), 7.77 (d,
J = 9.0 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.43 (d, J = 8.5 Hz, 2 H),
7.20 (t, J = 8.0 Hz, 1 H), 6.81 (td, J = 6.5, 1.0 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 140.2, 137.9, 136.8, 132.1, 129.6, 128.9, 126.9,
I
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Methyl-7-phenylpyrazolo[1,5-a]pyridine-3-carboxylate (6a): col-
orless solid; mp 120−122 °C; Rf = 0.51 (n-hexane/ethyl acetate = 5/
1); 1H NMR (CDCl3, 500 MHz) δ 8.42 (s, 1 H), 8.21 (dd, J = 9.0, 1.5
Hz, 1 H), 7.85 (dd, J = 8.0, 1.5 Hz, 2 H), 7.55−7.46 (m, 4 H), 6.99
(dd, J = 7.0, 1.5 Hz, 1 H), 3.93 (s, 3 H); 13C NMR (CDCl3, 125 MHz)
δ 163.8, 144.2, 141.8, 141.3, 132.7, 129.7, 129.2, 128.4, 127.5, 117.7,
114.4, 103.6, 51.1; HRMS (EI-magnetic sector) m/z [M+] calcd for
C15H12N2O2 252.0899, found 252.0900.
Methyl-7-(p-tolyl)pyrazolo[1,5-a]pyridine-3-carboxylate (6b):
white solid; mp 134−135 °C; Rf = 0.63 (n-hexane/ethyl acetate =
3/1); 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1 H), 8.19 (dd, J = 9.0,
1.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.48 (dd, J = 8.5, 8.5 Hz, 1 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.00 (dd, J = 7.0, 1.0 Hz, 1 H), 3.93 (s, 3 H),
2.44 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 164.0 (Cq), 144.4
(CH), 141.9 (Cq), 141.6 (Cq), 140.1 (Cq), 130.0 (Cq), 129.2 (CH ×
4), 127.6 (CH), 117.6 (CH), 114.2 (CH), 103.6 (Cq), 51.2 (CH3),
21.4 (CH3); HRMS (EI-magnetic sector) m/z [M+] calcd for
C16H14N2O2 266.1055, found 266.1053.
(Cq), 139.1 (Cq), 131.6 (CH), 127.3 (CH), 117.6 (CH), 115.4 (CH),
115.0 (Cq), 104.8 (CH), 103.3 (Cq), 99.1 (CH), 55.7 (CH3), 55.5
(CH3), 51.1 (CH3); HRMS (EI-magnetic sector) m/z [M+] calcd for
C17H16N2O4 312.1110, found 312.1111.
Methyl-7-(2,6-dimethoxyphenyl)pyrazolo[1,5-a]pyridine-3-car-
boxylate (6i): pale yellow solid; mp 133−134 °C; Rf = 0.39 (n-hexane/
1
ethyl acetate = 1/1); H NMR (CDCl3, 500 MHz) δ 8.34 (s, 1 H),
8.19 (dd, J = 9.0, 1.0 Hz, 1 H), 7.43−7.50 (m, 2 H), 6.92 (dd, J = 7.0,
1.0 Hz, 1 H), 6.70 (d, J = 8.5 Hz, 2 H), 3.91 (s, 3 H), 3.69 (s, 6 H);
13C NMR (CDCl3, 125 MHz) δ 164.2 (Cq), 158.5 (CH), 144.2 (CH),
141.6 (Cq), 135.6 (CH), 131.6 (CH), 127.3 (CH), 117.6 (CH), 116.4
(CH), 110.9 (Cq), 104.2 (CH × 2), 103.2 (Cq), 55.9 (CH3), 51.1
(CH3); HRMS (EI-magnetic sector) m/z [M+] calcd for C17H16N2O4
312.1110, found 312.1111.
Methyl-7-(4-nitrophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6j): yellow solid; mp 128−130 °C; Rf = 0.44 (n-hexane/ethyl acetate
= 5/1); 1H NMR (CDCl3, 500 MHz) δ 8.42−8.39 (m, 3 H), 8.30 (dd,
J = 9.0, 1.5 Hz, 1 H), 8.09 (d, J = 9.0 Hz, 2 H), 7.54 (dd, J = 9.0, 7.0
Hz, 1 H), 7.10 (dd, J = 7.0, 1.5 Hz, 1 H), 3.95 (s, 3 H); 13C NMR
(CDCl3, 125 MHz) δ 163.7, 148.3, 144.4, 141.8, 138.9, 138.8, 130.4,
127.3, 123.7, 119.4, 115.2, 104.3, 51.3; HRMS (EI-magnetic sector)
m/z [M+] calcd for C15H11N3O4 297.0750, found 297.0748.
Methyl-7-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6m): pale yellow solid; mp 201−202 °C; Rf = 0.53 (n-hexane/ethyl
acetate = 3/1); 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1 H), 8.22 (d,
J = 9.0 Hz, 1 H), 7.86 (dd, J = 8.5, 5.5 Hz, 2 H), 7.49 (dd, J = 7.5, 7.5
Hz, 1 H), 7.22−7.27 (m, 2 H), 6.99 (d, J = 7.0 Hz, 1 H), 3.94 (s, 3 H);
13C NMR (CDCl3, 125 MHz) δ 163.9 (Cq), 163.5 (d, JC−F = 249.1
Methyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine-3-carboxylate (6c):
white solid; mp 108−110 °C; Rf = 0.51 (n-hexane/ethyl acetate =
1
5/1); H NMR (CDCl3, 500 MHz) δ 8.40 (s, 1 H), 8.15 (d, J = 9.0
Hz, 1 H), 7.61−7.60 (m, 2 H), 7.43−7.37 (m, 2 H), 7.29 (d, J = 7.5
Hz, 1 H), 6.94 (d, J = 6.5 Hz, 1 H), 3.91 (s, 3 H), 2.42 (s, 3 H); 13C
NMR (CDCl3, 125 MHz) δ 163.3, 144.0, 141.6, 137.9, 132.5, 130.3,
129.6, 128.1, 127.3, 126.2, 117.3, 114.2, 103.3, 50.9, 21.2; HRMS (EI-
magnetic sector) m/z [M+] calcd for C16H14N2O2 266.1055, found
266.1056.
Methyl-7-(o-tolyl)pyrazolo[1,5-a]pyridine-3-carboxylate (6d): yel-
1
low oil; Rf = 0.52 (n-hexane/ethyl acetate = 5/1); H NMR (CDCl3,
Hz, Cq), 144.4 (CH), 141.9 (Cq), 140.4 (Cq), 131.4 (d, JC−F = 8.8
Hz, CH), 128.9 (d, JC−F = 3.3 Hz, Cq), 127.5 (CH), 118.0 (CH),
115.7 (d, JC−F = 21.5 Hz, CH), 114.4 (CH), 103.9 (Cq), 51.2 (CH3);
HRMS (EI-magnetic sector) m/z [M+] calcd for C15H11N2O2F
270.0805, found 270.0807.
500 MHz) δ 8.39 (s, 1 H), 8.24 (dd, J = 9.0, 1.5 Hz, 1 H), 7.50 (dd, J =
9.0, 7.0 Hz, 1 H), 7.45−7.32 (m, 4 H), 6.89 (dd, J = 7.0, 1.0 Hz, 1 H),
3.93 (s, 3 H), 2.08 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 163.8,
144.6, 141.6, 141.3, 137.3, 132.8, 130.2, 129.8, 129.6, 127.2, 125.9,
117.8, 114.7, 103.5, 51.1, 19.4; HRMS (EI-magnetic sector) m/z [M+]
calcd for C16H14N2O2 266.1055, found 266.1052.
Methyl-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxy-
late (6e): white solid; mp 130−132 °C; Rf = 0.51 (n-hexane/ethyl
acetate = 5/1); 1H NMR (CDCl3, 500 MHz) δ 8.40 (s, 1 H), 8.15 (dd,
J = 9.0, 1.0 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 2 H), 7.45 (dd, J = 9.0, 7.0
Hz, 1 H), 7.05 (d, J = 9.0 Hz, 2 H), 6.96 (dd, J = 7.0, 1.0 Hz, 1 H),
3.92 (s, 3 H), 3.87 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 163.9,
160.6, 144.2, 141.8, 141.2, 130.7, 127.5, 125.0, 117.1, 113.9, 113.8,
103.4, 55.3, 51.1; HRMS (EI-magnetic sector) m/z [M+] calcd for
C16H14N2O3 282.1004, found 282.1003.
Methyl-7-(4-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6n): white solid; mp 169−170 °C; Rf = 0.55 (n-hexane/ethyl acetate =
3/1); 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1 H), 8.23 (dd, J = 9.0,
1.5 Hz, 1 H), 7.82 (d, J = 8.5 Hz, 2 H), 7.48−7.53 (m, 3 H), 7.01 (dd,
J = 7.0, 1.0 Hz, 1 H), 3.94 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
163.9 (Cq), 144.4 (CH), 141.9 (Cq), 140.3 (Cq), 136.0 (Cq), 131.2
(Cq), 130.7 (CH × 2), 128.8 (CH × 2), 127.5 (CH), 118.2 (CH),
114.5 (CH), 103.9 (Cq), 51.3 (CH3); HRMS (EI-magnetic sector) m/
z [M+] calcd for C15H11N2O235Cl 286.0509, found 286.0510.
Methyl-7-(4-bromophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6o): yellow solid; mp 186−188 °C; Rf = 0.50 (n-hexane/ethyl acetate
Methyl-7-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxy-
1
= 5/1); H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1 H), 8.23 (dd, J =
late (6f): white solid; mp 95−96 °C; Rf = 0.48 (n-hexane/ethyl acetate
9.0, 1.0 Hz, 1 H), 7.75−7.47 (m, 5 H), 7.01 (dd, J = 7.0, 1.0 Hz, 1 H),
3.93 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 163.8, 144.3, 141.8,
140.2, 131.7, 131.6, 130.9, 127.5, 124.2, 118.2, 114.4, 103.9, 51.2;
HRMS (EI-magnetic sector) m/z [M+] calcd for C15H11N2O279Br
330.0004, found 330.0006.
1
= 3/1); H NMR (CDCl3, 300 MHz) δ 8.42 (s, 1 H), 8.21 (dd, J =
9.0, 1.0 Hz, 1 H), 7.39−7.51 (m, 4 H), 7.06 (ddd, J = 9.0, 2.5, 1.0 Hz,
1 H), 7.02 (dd, J = 7.0, 1.0 Hz, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H); 13C
NMR (CDCl3, 125 MHz) δ 164.0 (Cq), 159.5 (Cq), 144.4 (CH),
141.9 (Cq), 141.3 (Cq), 134.1 (Cq), 129.6 (CH), 127.5 (CH), 121.7
(CH), 117.9 (CH), 115.4 (CH), 114.5 (CH), 114.0 (CH), 103.7
(Cq), 55.4 (CH3), 51.2 (CH3); HRMS (EI-magnetic sector) m/z
[M+] calcd for C16H14N2O3 282.1004, found 282.1003.
Methyl-7-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6p): white solid; mp 163−164 °C; Rf = 0.39 (n-hexane/ethyl acetate =
1
1/2); H NMR (CDCl3, 500 MHz) δ 8.82 (bs, 2 H), 8.44 (s, 1 H),
8.30 (dd, J = 9.0, 1.0 Hz, 1 H), 7.84 (d, J = 6.0 Hz, 2 H), 7.53 (dd, J =
9.0, 9.0 Hz, 1 H), 7.11 (dd, J = 7.0, 1.0 Hz, 1 H), 3.95 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 163.7 (Cq), 150.2 (CH), 144.4 (CH),
141.9 (Cq), 140.3 (Cq), 138.6 (Cq), 127.3 (CH), 123.5 (CH), 119.5
(CH), 115.1 (CH), 104.3 (Cq), 51.4 (CH3); HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H11N3O2 253.0851, found 253.0850.
Methyl-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6q): white solid; mp 159−160 °C; Rf = 0.42 (n-hexane/ethyl acetate =
Methyl-7-(2-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxy-
late (6g): white solid; mp 98−100 °C; Rf = 0.58 (n-hexane/ethyl
acetate = 5/1); 1H NMR (CDCl3, 500 MHz) δ 8.37 (s, 1 H), 8.21 (dd,
J = 8.5, 1.0 Hz, 1 H), 7.49−7.42 (m, 3 H), 7.11 (td, J = 7.5, 1.0 Hz, 1
H), 7.07 (d, J = 8.0 Hz, 1 H), 6.96 (dd, J = 7.0, 1.0 Hz, 1 H), 3.92 (s, 3
H), 3.75 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 164.0, 157.4, 144.2,
141.4, 139.2, 131.3, 130.8, 127.2, 122.3, 120.6, 117.8, 115.2, 111.4,
103.3, 55.6, 51.1; HRMS (EI-magnetic sector) m/z [M+] calcd for
C16H14N2O3 282.1004, found 282.1006.
1
1/2); H NMR (CDCl3, 500 MHz) δ 9.03 (s, 1 H), 8.75 (d, J = 3.5
Hz, 1 H), 8.41 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.26 (d, J = 9.0 Hz, 1
H), 7.48−7.54 (m, 2 H), 7.07 (d, J = 7.0 Hz, 1 H), 3.94 (s, 3 H); 13C
NMR (CDCl3, 125 MHz) δ 163.8 (Cq), 150.6 (CH), 149.6 (CH),
144.4 (CH), 141.8 (Cq), 138.1 (Cq), 137.1 (CH), 129.0 (Cq), 127.4
(CH), 123.1 (Cq), 118.8 (CH), 114.7 (CH), 104.2 (Cq), 51.3 (CH3);
HRMS (EI-magnetic sector) m/z [M+] calcd for C14H11N3O2
253.0851, found 253.0850.
Methyl-7-(2,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridine-3-car-
boxylate (6h): pale yellow solid; mp 114−115 °C; Rf = 0.44 (n-
hexane/ethyl acetate = 2/1); 1H NMR (CDCl3, 500 MHz) δ 8.36 (s, 1
H), 8.18 (dd, J = 9.0, 1.0 Hz, 1 H), 7.46 (dd, J = 9.0, 7.0 Hz, 1 H), 7.37
(d, J = 8.0 Hz, 1 H), 6.94 (dd, J = 7.0, 1.0 Hz, 1 H), 6.62−6.64 (m, 2
H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.73 (s, 3 H); 13C NMR (CDCl3, 125
MHz) δ 164.1 (Cq), 162.4 (Cq), 158.6 (Cq), 144.2 (CH), 141.5
J
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate
(6r): white solid; mp 132−134 °C; Rf = 0.44 (n-hexane/ethyl acetate =
10/1); 1H NMR (CDCl3, 500 MHz) δ 8.80 (m, 1 H), 8.58 (d, J = 8.0
Hz, 1 H), 8.46 (s, 1 H), 8.29 (dd, J = 9.0, 1.5 Hz, 1 H), 7.90 (td, J =
7.5, 1.5 Hz, 1 H), 7.65 (dd, J = 7.0, 1.5 Hz, 1 H), 7.56 (dd, J = 9.0, 7.5
Hz, 1 H), 7.41 (ddd, J = 7.5, 5.0, 1.0 Hz, 1 H), 3.94 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 163.9, 150.3, 149.8, 144.2, 142.0, 139.5, 136.4,
127.5, 125.2, 124.2, 119.0, 115.7, 103.8, 51.2; HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H11N3O2 253.0851, found 253.0849.
Dimethyl [7,7′-bipyrazolo[1,5-a]pyridine]-3,3′-dicarboxylate (6s):
white solid; mp >250 °C (dec); Rf = 0.45 (n-hexane/ethyl acetate = 1/
7.66−7.64 (m, 2 H), 7.58 (dd, J = 8.5, 1.0 Hz, 1 H), 7.18 (dd, J = 9.0,
7.0 Hz, 1 H), 6.80), dd, J = 7.0, 1.0 Hz, 1 H), 6.62 (d, J = 2.5 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 141.4, 141.1, 139.3, 132.5, 131.6,
130.7, 123.5, 123.2, 117.5, 112.3, 97.3; HRMS (EI-magnetic sector)
m/z [M+] calcd for C13H9N2Br 271.9949, found 271.9951.
7-(Pyridin-2-yl)pyrazolo[1,5-a]pyridine (7r): orange oil; Rf = 0.48
(n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 8.73
(d, J = 4.5 Hz, 1 H), 8.63 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 2.0 Hz, 1
H), 7.80 (td, J = 7.5, 2.0 Hz, 1 H), 7.56 (dd, J = 9.0, 1.0 Hz, 1 H), 7.44
(dd, J = 7.0, 1.0 Hz, 1 H), 7.30−7.27 (m, 1 H), 7.18 (dd, J = 9.0, 7.0
Hz, 1 H), 6.59 (d, J = 2.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
150.8, 149.4, 141.2, 140.9, 138.4, 136.0, 124.5, 123.5, 123.0, 118.2,
113.6, 97.1; HRMS (EI-magnetic sector) m/z [M+] calcd for C12H9N3
195.0796, found 195.0795.
1
1); H NMR (CDCl3, 500 MHz) δ 8.40 (dd, J = 9.0, 1.5 Hz, 2 H),
8.34 (s, 2 H), 7.57 (dd, J = 9.0, 7.0 Hz, 2 H), 7.30 (dd, J = 7.0, 1.0 Hz,
2 H), 3.93 (s, 6 H); 13C NMR (CDCl3, 125 MHz) δ 163.7 (Cq × 2),
144.6 (CH × 2), 141.3 (Cq × 2), 133.0 (Cq × 2), 126.7 (CH × 2),
120.8 (CH × 2), 116.5 (CH × 2), 104.6 (Cq × 2), 51.6 (CH3 × 2);
HRMS (ESI-positive) m/z [MH+] calcd for C18H15N4O4 351.1093,
found 351.1089.
7-Phenylpyrazolo[1,5-a]pyridine (7a): yellow oil; Rf = 0.55 (n-
hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 8.00 (d,
J = 2.5 Hz, 1 H), 7.90 (dt, J = 8.5, 2.0 Hz, 2 H), 7.57−7.47 (m, 4 H),
7.19 (dd, J = 9.0, 7.0 Hz, 1 H), 6.82 (dd, J = 7.0, 1.0 Hz, 1 H), 6.62 (d,
J = 2.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 141.3, 141.1, 140.5,
133.7, 129.3, 129.0, 128.3, 123.3, 117.0, 112.4, 97.1; HRMS (EI-
magnetic sector) m/z [M+] calcd for C13H10N2 194.0844; found
194.0841.
7-(m-Tolyl)pyrazolo[1,5-a]pyridine (7c): brown oil; Rf = 0.58 (n-
hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 7.99 (d,
J = 2.0 Hz, 1 H), 7.68 (m, 2 H), 7.55 (dd, J = 9.0, 1.0 Hz, 1 H), 7.42 (t,
J = 8.0 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.18 (dd, J = 9.0, 7.0 Hz, 1
H), 6.80 (dd, J = 7.0, 1.0 Hz, 1 H), 6.61 (d, J = 2.0 Hz, 1 H), 2.45 (s, 3
H); 13C NMR (CDCl3, 125 MHz) δ 141.3, 141.1, 140.7, 138.0, 133.7,
130.1, 129.6, 128.3, 126.2, 123.3, 116.9, 112.3, 97.0, 21.5; HRMS (EI-
magnetic sector) m/z [M+] calcd for C14H12N2 208.1000, found
208.1002.
7-(o-Tolyl)pyrazolo[1,5-a]pyridine (7d): brown oil; Rf = 0.56 (n-
hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ 7.97 (d,
J = 2.0 Hz, 1 H), 7.60 (dd, J = 9.0, 1.0 Hz, 1 H), 7.44−7.32 (m, 4 H),
7.20 (dd, J = 9.0, 7.0 Hz, 1 H), 6.71 (dd, J = 6.5, 1.0 Hz, 1 H), 6.61 (d,
J = 2.5 Hz, 1 H), 2.12 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 141.7,
140.7, 140.5, 137.4, 133.8, 130.1, 129.6, 129.4, 125.8, 123.0, 117.0,
112.6, 96.9, 19.4; HRMS (EI-magnetic sector) m/z [M+] calcd for
C14H12N2 208.1000, found 208.1002.
3-Phenyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine (8a): yellow solid; mp
1
140−142 °C; Rf = 0.53 (n-hexane/ethyl acetate = 10/1); H NMR
(CDCl3, 500 MHz) δ 8.19 (s, 1 H), 7.84 (dd, J = 9.0, 1.0 Hz, 1 H),
7.71−7.64 (m, 4 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 1 H),
7.34−7.24 (m, 3 H), 6.85 (dd, J = 6.5, 1.0 Hz, 1 H), 2.48 (s, 3 H); 13C
NMR (CDCl3, 125 MHz) δ 141.0, 140.0, 138.0, 137.9, 133.5, 133.3,
130.2, 129.7, 128.9(2C),128.3, 127.2(2C), 126.2, 126.1, 124.1, 116.1,
113.0, 112.8, 21.5; HRMS (EI-magnetic sector) m/z [M+] calcd for
C20H16N2 284.1313, found 284.1312.
2-(4-Fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (9a):
characterization data were consistent with those reported in the
literature;7b white solid; mp 136−138 °C; Rf = 0.48 (n-hexane/ethyl
acetate = 5/1); 1H NMR (CDCl3, 500 MHz) δ 8.57 (bs, 2 H), 8.50 (d,
J = 7.0 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 7.53 (m, 2 H), 7.26−7.19
(m, 3 H), 7.05 (t, J = 8.5 Hz, 2 H), 6.85 (dt, J = 7.0, 1.0 Hz, 1 H).
2-(4-Fluorophenyl)-3-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]-
pyridine (9b): characterization data were consistent with those
reported in the literature;3a brown solid; mp 168−170 °C; Rf = 0.52
1
(n-hexane/ethyl acetate = 5/1); H NMR (300 MHz, CDCl3) δ 8.52
(d, J = 6.9 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 7.66 (d, J = 9.3 Hz, 1
H), 7.56−7.51 (m, 2 H), 7.30−7.26 (m, 1 H), 7.15−7.06 (m, 3 H),
6.91 (m, 2 H).
4-(2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethyl-
pyridin-2-amine (10a): characterization data were consistent with
those reported in the literature;3a brown solid; mp 158−160 °C; Rf =
1
0.60 (n-hexane/ethyl acetate = 5/1); H NMR (300 MHz, CDCl3) δ
8.49 (d, J = 7.2 Hz, 1 H), 8.17 (d, J = 5.4 Hz, 1 H), 7.65−7.59 (m, 3
H), 7.20−7.15 (m, 1 H), 7.05 (t, J = 9.0 Hz, 2 H), 6.83 (t, J = 6.9 Hz, 1
H), 6.55 (d, J = 5.1 Hz, 1 H), 6.46 (s, 1 H), 3.03 (s, 6 H).
4-(2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-N-phenyl-
pyridin-2-amine (10b): characterization data were consistent with
those reported in the literature;3a brown solid; mp 177−178 °C; Rf =
0.46 (n-hexane/ethyl acetate = 5/1); 1H NMR (300 MHz, acetone-d6)
δ 8.66 (d, J = 7.2 Hz, 1 H), 8.22 (m, 2 H), 7.78−7.62 (m, 5 H), 7.36
(m, 1 H), 7.27−7.19 (m, 4 H), 7.02 (td, J = 6.9, 1.2 Hz, 1 H), 6.87 (t, J
= 7.5 Hz, 1 H), 6.87 (s, 1 H), 6.79 (dd, J = 5.4, 1.5 Hz, 1 H).
4-(2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-N-benzyl-
pyridin-2-amine (10c): characterization data were consistent with
those reported in the literature;3a brown solid; mp 158−160 °C; Rf =
0.55 (n-hexane/ethyl acetate = 5/1); 1H NMR (300 Mz, acetone-d6) δ
8.60 (d, J = 6.9 Hz, 1 H), 8.01 (d, J = 5.1 Hz, 1 H), 7.66 (m, 2 H), 7.50
(d, J = 9.0 Hz, 1 H), 7.39- 7.13 (m, 7 H), 6.96 (t, J = 6.9 Hz, 1 H),
6.53 (s, 1 H), 6.46 (d, J = 5.1 Hz, 1 H), 6.32 (m, 1 H), 4.58 (d, J = 6.0
Hz, 2 H).
7-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridine (7e): brown oil; Rf =
0.52 (n-hexane/ethyl acetate = 10/1); 1H NMR (CDCl3, 500 MHz) δ
7.99 (d, J = 2.5 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 2 H), 7.52 (dd, J = 9.0,
1.0 Hz, 1 H), 7.16 (dd, J = 8.5, 7.0 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 2 H),
6.78 (dd, J = 7.0, 1.0 Hz, 1 H), 6.60 (d, J = 2.0 Hz, 1 H), 3.99 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 160.3, 141.2, 141.1, 140.3, 130.4,
126.1, 123.3, 116.5, 113.8, 111.8, 96.9, 55.3; HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H12N2O 224.0950, found 224.0952.
7-(2-Methoxyphenyl)pyrazolo[1,5-a]pyridine (7g): yellow solid;
mp 124−126 °C; Rf = 0.50 (n-hexane/ethyl acetate = 10/1); 1H NMR
(CDCl3, 500 MHz) δ 7.94 (d, J = 2.5 Hz, 1 H), 7.57 (dd, J = 8.5, 1.0
Hz, 1 H), 7.50−7.45 (m, 2 H), 7.19−7.06 (m, 3 H), 6.76 (dd, J = 7.0,
1.0 Hz, 1 H), 6.58 (d, J = 2.0 Hz, 1 H), 3.76 (s, 3 H); 13C NMR
(CDCl3, 125 MHz) δ 157.4, 141.3, 140.6, 138.1, 130.9, 130.8, 123.2,
122.9, 120.6, 117.0, 113.1, 111.4, 96.7, 55.7; HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H12N2O 224.0950, found 224.0951.
7-(4-Nitrophenyl)pyrazolo[1,5-a]pyridine (7j): orange solid; mp
ASSOCIATED CONTENT
■
1
138−140 °C; Rf = 0.45 (n-hexane/ethyl acetate = 10/1); H NMR
S
* Supporting Information
(CDCl3, 500 MHz) δ 8.38−8.35 (m, 2 H), 8.14 (d, J = 9.0 Hz, 2 H),
7.99 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 9.0, 1.0 Hz, 1 H), 7.23 (dd, J =
9.0, 7.0 Hz, 1 H), 6.91 (dd, J = 7.0, 1.0 Hz, 1 H), 6.67 (d, J = 2.0 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ 148.0, 141.6, 139.8, 138.0, 130.0,
128.3, 124.3, 123.6, 123.1, 118.7, 113.4, 97.8; HRMS (EI-magnetic
sector) m/z [M+] calcd for C13H9N3O2 239.0695, found 239.0697.
7-(4-Bromophenyl)pyrazolo[1,5-a]pyridine (7o): yellow solid; mp
68−70 °C; Rf = 0.54 (n-hexane/ethyl acetate = 10/1); 1H NMR
(CDCl3, 500 MHz) δ 7.98 (d, J = 2.0 Hz, 1 H), 7.80−7.78 (m, 2 H),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00988.
1
1H and 13C NMR spectra of new compounds and H
NMR of known compounds (PDF)
CIF file giving X-ray crystallographic data for compound
3n (CIF)
K
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
CIF file giving X-ray crystallographic data for compound
Article
2013, 52, 11726−11743. (f) Mousseau, J. J.; Charette, A. B. Acc. Chem.
Res. 2013, 46, 412−424. (g) Arockian, P. B.; Bruneau, C.; Dixneuf, P.
H. Chem. Rev. 2012, 112, 5879−5918. (h) Hartwig, J. F. Acc. Chem.
Res. 2012, 45, 864−873. (i) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215−1292. (j) Ackerman, L. Chem. Rev. 2011, 111, 1315−
1345. (k) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−
1169. (l) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624−655. (m) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082−
1146. (n) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094−5115.
(10) (a) Chu, J.-H.; Chen, S.-T.; Chiang, M.-F.; Wu, M.-J.
Organometallics 2015, 34, 953−966. (b) Chu, J.-H.; Hsu, W.-T.; Wu,
Y.-H.; Chiang, M.-F.; Hsu, N.-H.; Huang, H.-P.; Wu, M.-J. J. Org.
Chem. 2014, 79, 11395−11408. (c) Chu, J.-H.; Huang, H.-P.; Shu, W.-
T.; Chen, S.-T.; Wu, M.-J. Organometallics 2014, 33, 1190−1204.
(d) Chu, J.-H.; Wu, C.-C.; Chang, D.-H.; Lee, Y.-M.; Wu, M.-J.
Organometallics 2013, 32, 272−282. (e) Chu, J.-H.; Lin, P.-S.; Lee, Y.-
M.; Shen, W.-T.; Wu, M.-J. Chem. - Eur. J. 2011, 17, 13613−13620.
(f) Chu, J.-H.; Lin, P.-S.; Wu, M.-J. Organometallics 2010, 29, 4058−
4065. (g) Chu, J.-H.; Tsai, S.-L.; Wu, M.-J. Synthesis 2009, 22, 3757−
3764. (h) Chu, J.-H.; Chen, C.-C.; Wu, M.-J. Organometallics 2008, 27,
5173−5176.
6a (CIF)
CIF file giving X-ray crystallographic data for complex D
(CIF)
Text file of all computed molecule Cartesian coordinates
in a format for convenient visualization (XYZ)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: j_hchu@yahoo.com.tw.
*E-mail: mijuwu@faculty.nsysu.edu.tw.
■
Author Contributions
§H.-C. Wu and C.-W. Li equally contributed to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China for financial support of this program (MOST
104-2113-M-110-012-MY2) and Mr. Min-Yuan Hung for his
technical support and services in GC-MS, Center for Research
Resources and Development of Kaohsiung Medical University
(Taiwan).
(11) Selected references for direct C−H functionalization of
heterocyclic compounds: (a) Kazzouli, S. E.; Koubachi, J.; Brahmia,
N. E.; Guillaumet, G. RSC Adv. 2015, 5, 15292−15327. (b) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068−5083.
(c) Yan, T.; Chen, L.; Bruneau, C.; Dixneuf, P.; Doucet, H. J. Org.
Chem. 2013, 78, 4177−4183. (d) Meng, G.; Niu, H. Y.; Qu, G. R.;
Fossey, J. S.; Liu, J. P.; Guo, H. M. Chem. Commun. 2012, 48, 9601−
9603. (e) Min, M.; Hong, S. Chem. Commun. 2012, 48, 9613−9615.
(f) Yan, T.; Chen, L.; Bruneau, C.; Dixneuf, P.; Doucet, H. J. Org.
Chem. 2012, 77, 7659−7664. (g) Kirchberg, S.; Tani, S.; Ueda, K.;
Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011, 50,
2387−2391. (h) Roy, D.; Mom, S.; Beauperin, M.; Doucet, H.; Hierso,
J.-C. Angew. Chem., Int. Ed. 2010, 49, 6650−6654.
REFERENCES
■
(1) (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R.
Heterocycles in Life and Society; John Wiley & Sons, Ltd: West Sussex,
1997. (b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles:
Structures, Reactions, Synthesis, and Applications, 2nd ed.; Wiley-VCH:
Weinheim, 2003.
(2) (a) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
Dev. 2005, 9, 253−258. (b) Carey, J. S.; Laffan, L.; Thompson, C.;
Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337−2347.
(3) (a) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.;
Peckham, G. E.; Veal, J. M.; Cheung, M. P.; Harris, A. S.; Chamberlain,
D.; Peel, M. R. Org. Lett. 2005, 7, 4753−4756. (b) Cheung, M. P.;
Harris, A. S.; Badiang, J. G.; Peckham, G. E.; Chamberlain, S. D.;
Alberti, M. J.; Jung, D. K.; Bramson, N. H.; Epperly, A. H.; Stimpson,
S. A.; Peel, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 5428−5430.
(4) Hansen, J. B.; Weis, J.; Suzdak, P. D.; Eskesen, K. Bioorg. Med.
Chem. Lett. 1994, 4, 695−698.
(12) Bassoude, I.; Berteina-Raboin, S.; Massip, S.; Leger, J.-M.; Jarry,
C.; Essassi, E. M.; Guillaumet, G. Eur. J. Org. Chem. 2012, 13, 2572−
2578.
(13) Bedford, R. B.; Durrant, S. J.; Montgomery, M. Angew. Chem.,
Int. Ed. 2015, 54, 8787−8790.
(14) (a) The amount of aryl iodide can be reduced to 3 equivalents
for the reaction, but the product yield of 3 is usually decreased by 10−
15% compared to 4 equivalents used of aryl iodide. (b) The reaction
can be carried out at lower reaction temperatures (e.g., 100−130 °C),
but that would prolong the reaction time (up to 3 days) while lowering
product yields of 3..
(15) In addition to aryl iodides/bromides, we also carried out the
direct C-3 and C-7 arylation of 1a,c with phenyl tosylates/mesylates,
respectively, under our optimal reaction conditions. However,
according to the experimental results, only a trace amount of desired
C-3-arylated product 3a was detected by GC-MS, but no C-7-arylated
product 6a was found. Moreover, most of the starting materials (e.g.,
1a,c and phenyl tosylates/mesylates) were recovered in the above
reactions. Regarding the employment of aryl tosylates/mesylates as the
coupling reagent in the direct arylation of heteroarenes, see:
(a) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed.
2009, 48, 201−204. (b) Ackermann, L.; Fenner, S. Chem. Commun.
2011, 47, 430−432.
(16) Copies of the deposited crystallographic data CCDC-1439753
(3n), CCDC-1439754 (6a), and CCDC-1439755 (D) can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(17) Palladium(II) ions can be reduced to palladium(0) ions at a
higher reaction temperature in the presence of salt additives; see:
Oestreich, M. The Mizororki-Heck Reaction; John-Wiley & Sons, Ltd:
Chichester, 2009; pp 1−43.
(18) The mechanistic proposal for the reaction of intermediate A
with the zwitterionic form of 1a leading to intermediate B is supported
(5) (a) Lanig, H.; Utz, W.; Gmeiner, P. J. Med. Chem. 2001, 44,
1151−1157. (b) Lober, S.; Hubner, H.; Utz, W.; Gmeiner, P. J. Med.
̈
Chem. 2001, 44, 2691−2694. (c) Bettinetti, L.; Schlotter, K.; Hubner,
̈
H.; Gmeiner, P. J. Med. Chem. 2002, 45, 4594−4597. (d) Bettinetti, L.;
Lober, S.; Hubner, H.; Gmeiner, P. J. Comb. Chem. 2005, 7, 309−316.
̈
̈
(e) Elsner, J.; Boeckler, F.; Heinemann, F. W.; Hubner, H.; Gmeiner,
̈
P. J. Med. Chem. 2005, 48, 5771−5779. (f) Prante, O.; Tietze, R.;
Hocke, C.; Lober, S.; Hubner, H.; Kuwert, T.; Gmeiner, P. J. Med.
̈
̈
Chem. 2008, 51, 1800−1810.
(6) Koike, T.; Takai, T.; Hoashi, Y.; Nakayama, M.; Kosugi, Y.;
Nakashima, M.; Yoshikubo, S. I.; Hirai, K.; Uchikawa, O. J. Med. Chem.
2011, 54, 4207−4218.
(7) (a) Wu, H.-C.; Hwang, L.-C.; Wu, M.-J. Org. Biomol. Chem. 2011,
9, 670−672. (b) Wu, H.-C.; Yang, C.-W.; Hwang, L.-C.; Wu, M.-J.
Org. Biomol. Chem. 2012, 10, 6640−6648.
(8) (a) Bethel, P. A.; Campbell, A. D.; Goldberg, F. W.; Kemmitt, P.
D.; Lamont, G. M.; Suleman, A. Tetrahedron 2012, 68, 5434−5444.
(b) Aboul-Fadl, T.; Lober, S.; Gmeiner, P. Synthesis 2000, 12, 1727−
̈
1732.
(9) Selected reviews: (a) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014,
47, 1208−1219. (b) Franzoni, I.; Mazet, C. Org. Biomol. Chem. 2014,
12, 233−241. (c) Zhang, X.-S.; Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5,
2146−2159. (d) Wu, Y.; Wang, J.; Mao, F.; Kwong, F. Y. Chem. - Asian
J. 2014, 9, 26−47. (e) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed.
L
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
by the substituent electronic effects of the direct C-3 arylation of 1a;
see entries 2−7 and 10−12 in Table 2.
(19) DMSO was found to prohibit the catalyst decomposition and
metal aggregation; see: (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2007, 129, 11904−11905. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2009, 131, 9651−9653 and ref 10e.
(20) When the reaction conditions of direct C-3 arylation of 1a (i.e.,
the catalytic system of Pd(OAc)2/CsF) was applied to the direct C-7
arylation of 1c, the experimental results showed that no product 6 was
formed, whereas most of starting materials were recovered.
(21) In the reaction of 1c with an alternative of 3-nitrophenyl iodide
(2k) and 2-nitrophenyl iodide (2l), we serendipitously isolated an
approximately 10−20% yield of dimethyl [7,7′-bipyrazolo[1,5-a]
pyridine]-3,3′-dicarboxylate (6s), in which only trace amounts of
products 6k and 6l were detected by GC-MS. Most of the starting
substrate 1c was recovered after the reaction.
(22) Based on the findings of compound 6s (refer to ref 21), we
suspect that the poor reactivity of palladium(0) ion and nitro-
substituted phenyl iodides (e.g., 2k and 2l) might provide the
opportunity to form complex D in the course of the reaction and
eventually transform it to the dimeric product (i.e., 6s) via a concerted
metalation−deprotonation process in the presence of silver(I)
carbonate. Moreover, this result also supports the proposal of
intermediate D′, E, and F for the direct C-7 aryaltion of 1c with
aryl iodide 2.
(23) For the concerted metalation−deprotonation mechanism, see
the following selected references: (a) Gorelsky, S. I. Coord. Chem. Rev.
2013, 257, 135−164. (b) Livendahl, M.; Echavarren, A. M. Isr. J. Chem.
́
2010, 50, 630−651. (c) Liegault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou,
K. J. Org. Chem. 2010, 75, 1047−1060. (d) Fagnou, K. Top. Curr.
Chem. 2009, 292, 35−56.
(24) Cheung, M.; Harris, P. A.; Badiang, J. G.; Peckham, G. E.;
Chamberlain, S. D.; Alberti, M. J.; Jung, D. K.; Harris, S. S.; Bramson,
N. H.; Epperly, A. H.; Stimpson, S. A.; Peel, M. R. Bioorg. Med. Chem.
Lett. 2008, 18, 5428−5430.
(25) The experimental procedure was operated by the literature
reported; see: Bethel, P. A.; Campbell, A. D.; Goldberg, F. W.;
Kemmitt, P. D.; Lamont, G. M.; Suleman, A. Tetrahedron 2012, 68,
5434−5444.
M
DOI: 10.1021/acs.organomet.5b00988
Organometallics XXXX, XXX, XXX−XXX