Synthesis of 2-Arylpyrazolo[1,5- a ]pyridines by Suzuki-Miyaura Cross-Coupling Reaction

Article abstract of DOI:10.1055/s-0034-1381025

Convenient access to a variety of 2-arylated pyrazolo[1,5-a]pyridine via pyrazolo[1,5-a]pyridine-2-yl triflate using the Suzuki-MiyauraA AA cross-coupling reaction is described. Fifteen 2-arylpyrazolo[1,5-a]pyridine derivatives were synthesized in 52-95% yields.

Full text of DOI:10.1055/s-0034-1381025

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3221–3230
paper
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Synthesis
Synthesis of 2-Arylpyrazolo[1,5-a]pyridines by Suzuki–Miyaura
Cross-Coupling Reaction
Kentaro Umei
Yosuke Nishigaya
Megumi Kamiya
Yasushi Kohno
Shigeki Seto*
PdCl2(PPh3)2
2 M Na2CO3, DME
90 °C
2
2
Ar B(OH)2
OTf
Ar
+
N
N
N
N
R
R
15 examples
52–95% yield
Watarase Research Center, Discovery Research Headquarters,
Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi,
Shimotsuga-gun, Tochigi 329-0114, Japan
shigeki.seto@mb.kyorin-pharm.co.jp
Received: 30.04.2015
Accepted after revision: 18.05.2015
Published online: 16.07.2015
es to the 2-arylpyrazolo[1,5-a]pyridine scaffold have been
reported. Predominant among these, particularly for 3-sub-
stituted 2-arylpyrazolo[1,5-a]pyridines, is the construction
of the pyrazolopyridine ring via 1,3-dipolar cycloaddition
of a 1-aminopyridinium salt with an arylpropynoate
(Scheme 1,A).1,7 However, these reactions typically afforded
a regioisomeric mixture of 6-substituted and 4-substituted
2-arylpyrazolo[1,5-a]pyridines, thus necessitating a chro-
matographic separation step. In addition, the removal of
the alkoxycarbonyl group at the 3-position on the pyrazo-
lo[1,5-a]pyridine ring under acidic and thermal conditions
is required for the synthesis of 1. Other common approach-
es include intramolecular cycloaddition methods using any
of several intermediates, such as phenacylpyridines8 or
ethynylpyridines (Scheme 1,B).9 Along these lines, Charette
and co-workers recently reported an alkenylation/cycliza-
tion reaction between N-iminopyridinium ylides and alke-
nyl iodides.8c However, these approaches usually require
multiple steps for the introduction of the C2 aryl moiety,
including complicated steps to construct the pyrazole ring.
These drawbacks in synthesis have limited the versatility of
the 2-arylpyrazolo[1,5-a]pyridine scaffold, especially 6-
substituted ones such as 1, and also limited their medicinal
potential.
DOI: 10.1055/s-0034-1381025; Art ID: ss-2015-f0285-op
Abstract Convenient access to a variety of 2-arylated pyrazolo[1,5-
a]pyridine via pyrazolo[1,5-a]pyridine-2-yl triflate using the Suzuki–
Miyaura cross-coupling reaction is described. Fifteen 2-arylpyrazo-
lo[1,5-a]pyridine derivatives were synthesized in 52–95% yields.
Key words Suzuki–Miyaura cross-coupling reaction, 2-arylpyrazo-
lo[1,5-a]pyridine, triflate, regioselectivity, medicinal chemistry
The 2-arylpyrazolo[1,5-a]pyridine moiety is an import-
ant pharmacophore in medicinal chemistry with respect to
drug discovery. For instance, several biologically active
compounds contain this moiety, such as poly(ADP-ri-
bose)polymerase (PARP) inhibitor,1 RNA polymerase inhibi-
tor,2 AKT inhibitor,3 adenosine A1 antagonist,4 and EP1 an-
tagonist (Figure 1).5
As part of our drug discovery program on EP1 antago-
nists for the treatment of overactive bladder syndrome,5,6
we searched for a rapid and efficient synthetic access to a
variety of 2-arylated pyrazolo[1,5-a]pyridines, especially 6-
substituted 2-arylpyrazolo[1,5-a]pyridines such as those
with the structure 1 (Figure 1). Several synthetic approach-
O
N
N
N
CO2H
2
Ar
6
N
N
R
N
N
1
N
N
Cl
MeO
adenosine antagonist
Figure 1 Structures of bioactive molecules and 6-substituted 2-arylpyrazolo[1,5-a]pyridine 1
6
EP1 antagonist
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A. 1,3-dipolar cycloaddition approaches
R1O2C
R
4
CO2R1
Ar
CO2R1
Ar
X–
base
+
+
6
N+
N
N
N
N
Ar
R
R
NH2
B. intramolecular cycloaddition approaches
Ar
2
Ar
Ar
6
N
or
N
R
N
O
R
N
1
R
C. this work: Suzuki–Miyaura cross-coupling approaches
ArBH(OH)2
OH
X
+
N
N
N
N
R
R
4
2 R = Cl
or
3 R = OTf
Scheme 1 Synthetic strategies for 1
In this context, we were interested in developing a rapid
and efficient method for the synthesis of 6-substituted 2-
arylpyrazolo[1,5-a]pyridines 1 to install diverse aryl groups
at the C2 position on the pyrazolo[1,5-a]pyridine core by
using the Suzuki–Miyaura cross-coupling reaction10
(Scheme 1,C). To the best of our knowledge, only one exam-
ple of the Suzuki–Miyaura cross-coupling reaction between
ethyl 2-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]quino-
line-3-carboxylate and phenylboronic acid has been report-
ed, but without a description of the substrate generality of
this transformation.11 However, the reaction afforded the
coupling product in a low yield of 46%, which contained an
unwanted carboxylate group at C3 that must be remove in
two steps for the synthesis of 1. Thus, a need remains for
the development of a new facile procedure for the construc-
tion of 1 by the Suzuki–Miyaura cross-coupling reaction.
Herein, we report the synthesis of 1 by the Suzuki–
Miyaura cross-coupling reaction under mild conditions in
good to moderate yields. The reaction begins with either 2-
chloride 2 or 2-triflate 3, which could be accessed from 2-
hydroxide 412 (Scheme 1,C).
First, the reaction of 2-chloropyrazolo[1,5-a]pyridine
(2a) with phenylboronic acid was chosen as a model reac-
tion to confirm the feasibility of our concept, since the syn-
thesis of 2a from the hydroxide 4a has already been report-
ed13 (Scheme 2). When we carried out the Suzuki–Miyaura
PhB(OH)2, SPhos
K3PO4, Pd(OAc)2
THF, 80 °C, 10 h
POCl3, 145 °C, 6 h in
a sealed tube
OH
Cl
N
N
N
N
N
N
69%
23%
1a
4a
2a
N
N
Cl
PhB(OH)2, SPhos
K3PO4, Pd(OAc)2
THF, 80 °C, 10 h
1b (0%)
POCl3, 145 °C, 6 h in
a sealed tube
OH
Cl
Cl
N
N
N
N
N
N
Cl
Cl
12%
5 (85%)
4b
2b
N
N
6 (10%)
Scheme 2 Suzuki coupling reaction of 2-chloropyrazolo[1,5-a]pyridines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3221–3230

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Synthesis
coupling reaction of 2a and phenylboronic acid in the pres-
ence of palladium(II) acetate (20 mmol%), 2-(dicyclohexyl-
phosphino)-2′,6′-dimethoxybiphenyl (SPhos, 20 mmol%),
and tripotassium phosphate (3 equiv) in tetrahydrofuran at
80 °C, the expected coupling product 1a was only obtained
in 23% yield, although the reaction did not proceed at all
under the standard Suzuki–Miyaura coupling reaction con-
ditions, which include the presence of dichlorobis(triphen-
ylphosphine)palladium(II) (10 mmol%) and sodium carbon-
ate (3 equiv) in 1,2-dimethoxyethane–water at 90 °C. This
result prompted us to synthesize 6-chloro-2-phenylpyrazo-
lo[1,5-a]pyridine (1b), which was obtained from 6-chloro-
2-hydroxypyrazolo[1,5-a]pyridine (4b) by the same strate-
gy. However, the chlorination reaction of 4b with phos-
phoryl chloride at 145 °C in a sealed tube provided 2b in
only 12% yield. Furthermore, the Suzuki coupling reaction
between 2b and phenylboronic acid did not provide the de-
sired product, 1b, but proceeded to provide undesired 2-
chloro-6-phenylpyrazolo[1,5-a]pyridine (5) in 85% yield
and the double-coupling product 6 in 10% yield. To improve
the reactivity of the Suzuki coupling reaction, we attempt-
ed to synthesize 2-bromopyrazolo[1,5-a]pyridine by the
treatment of 4a with phosphoryl bromide in toluene at re-
flux temperature for five hours; unfortunately, only starting
material was recovered.
(entry 1). Both electron-withdrawing and electron-donat-
ing groups on the triflate part at C6 position, 3b and 3c, re-
spectively, are tolerated in this reaction (entries 2 and 3). To
our delight, the reaction of 3b provided the desired 6-
chloro-2-phenylpyrazolo[1,5-a]pyridine (1b) in 90% yield
in a regioselective manner without producing the unde-
sired 6-phenyl coupling product. We next investigated the
reactions with a variety of arylboronic acids and found that
the reactions provided the corresponding coupled products
in good to moderate yields (entries 4–15). Sterically hin-
dered arylboronic acids with ortho substituents (Cl, CF3,
OMe) do not limit this reaction (entries 5, 9, and 11). Nota-
bly, heteroarylboronic acids are also good substrates for this
reaction (entries 12–15).
Table 1 Suzuki Coupling Reactions of Triflates
ArB(OH)2
PdCl2(PPh3)2
OTf
Ar
N
N
2 M Na2CO3, DME
90 °C, 7 h
N
N
R
R
3a–c
1a–o
Product
Entry
1
Substrate
3a
R
Ar
Yield (%)
93
H
Ph
1a
1b
1c
1d
1e
1f
2
3b
Cl
OMe
H
Ph
90
We next studied the synthesis of triflates 3 as an alter-
native to chlorides 2, since (hetero)aryl triflates are valu-
able substrates for a number of metal-catalyzed cross-cou-
pling reactions10 (Scheme 3). Triflation of the alcohol 4a
with N-phenyltrifluoromethanesulfonimide14 provided the
corresponding triflate 3a in quantitative yield. Fortunately,
this reaction was compatible with electron-withdrawing
and electron-donating substituents such as chloro and
methoxy at C6, and afforded the desired products 3b and 3c
in good yields.
3
3c
Ph
92
4
3a
4-ClC6H4
2-ClC6H4
4-FC6H4
2-FC6H4
4-F3CC6H4
2-F3CC6H4
4-MeOC6H4
2-MeOC6H4
2-furyl
88
5
3a
H
87
6
3b
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
90
7
3b
1g
1h
1i
89
8
3b
95
9
3b
83
10
11
12
13
14
15
3b
1j
93
3b
1k
1l
92
NaH, Tf2NPh, THF–DMF
r.t., 1 h
3b
80a
52a
54a
55a
OH
OTf
3b
3-furyl
1m
1n
1o
N
N
N
N
R
R
3b
2-thienyl
3-thienyl
4a: R = H
4b: R = Cl
4c: R = OMe
3a: R = H (99%)
3b: R = Cl (95%)
3c: R = OMe (97%)
3b
a 80 °C, 1 h.
Scheme 3 Preparation of triflates 3a–c
Having a facile route to triflates 3 in hand, we next di-
rected our attention to the palladium-catalyzed Suzuki–
Miyaura cross-coupling reactions of triflates 3a–c with a
variety of arylboronic acids (Table 1). Fortunately, the reac-
tion proceeded very well under the standard Suzuki–
Miyaura coupling reaction conditions; that is, the reaction
of 3a with phenylboronic acid (1.5 equiv) in the presence of
dichlorobis(triphenylphosphine)palladium(II) (10 mol%)
and sodium carbonate (3 equiv) in 1,2-dimethoxyethane at
90 °C afforded the desired coupled product 1a in 93% yield
Accomplishing the synthesis of our target, 2-arylpyrazo-
lo[1,5-a]pyridines 1, by the Suzuki–Miyaura cross-coupling
reaction prompted us to attempt other palladium coupling
reactions. Hence we attempted the reaction of triflate 3a
with carbon monoxide in the presence of palladium(II) ace-
tate (10 mol%), 1,3-bis(diphenylphosphino)propane (dppp)
(10 mol%), and triethylamine (3 equiv) in ethanol–N,N-di-
methylformamide at 60 °C, and afforded the desired cou-
pled product 7 in 83% yield (Scheme 4). Additionally, the re-
action of 3a with ethyl acrylate in the presence of palladi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3221–3230

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Synthesis
um(II) acetate (10 mol%) and triethylamine (3 equiv) in
N,N-dimethylformamide at 80 °C provided the desired cou-
pling product 8 in 65% yield.
ence of palladium(II) acetate (20 mmol%), SPhos (20
mmol%), and tripotassium phosphate (3 equiv), in tetrahy-
drofuran at 80 °C (Scheme 5).
Finally, we examined the synthesis of the EP1 antagonist
as an example of further transformations of 6-substituted
2-arylpyrazolo[1,5-a]pyridines 1 (Scheme 6). One- (path A)
or five-step (path B) C3-alkylation of 1b to 10, followed by
hydrolysis afforded the desired EP1 antagonist.
In summary, we have accomplished a concise and versa-
tile approach to the synthesis of 2-arylpyrazolo[1,5-a]pyri-
dines 1 using the Suzuki–Miyaura cross-coupling reaction
between the triflates 3 and arylboronic acids. This new
method allows new substitution patterns on the C2 aryl
unit and can be applied to diversity-oriented synthesis in
drug discovery programs.
CO, Pd(OAc)2
dppp, Et3N
EtOH–DMF, 60 °C, 10 h
CO2Et
N
83%
N
7
OTf
N
N
3a
CH2=CHCO2Et
Pd(OAc)2, dppp, Et3N
DMF, 80 °C, 10 h
CO2Et
N
N
65%
8
Scheme 4 Palladium-catalyzed cross-coupling reactions
Melting points were determined with a OptiMelt and are uncorrect-
ed. 1H and 13C NMR spectra were measured in CDCl3 or DMSO-d6 with
TMS and the solvent peak as internal standards, on a Jeol ECA-400
(400 MHz) spectrometer. Mass spectra (MS) were obtained on a Hita-
chi M-2000 mass spectrometer. Column chromatography was carried
out on Merck silica gel 60. Analytical TLC was performed on Merck
precoated silica gel 60F254 plates, and the compounds were visualized
by UV illumination (254 nm) or by heating after spraying with phos-
phomolybdic acid in EtOH.
PhB(OH)2, SPhos
K3PO4, Pd(OAc)2
THF, 80 °C, 10 h
N
N
94%
N
N
Cl
1b
6
Scheme 5 Arylation of C6
With the regioselective C2 Suzuki–Miyaura cross-cou-
pling conditions to 1b obtained (Table 1, entry 2), we next
examined the introduction of a phenyl group at the C6 po-
sition of 1b by the Suzuki–Miyaura cross-coupling reaction.
Although the double-coupling product 6 can be synthesized
from 2b or 3b in one pot, stepwise introduction of aryl
groups at C2 and C6 positions could be more useful method
for the generation of structurally diverse compounds. This
reaction afforded desired coupling product 6 in 94% yield
by the reaction of 1b with phenylboronic acid in the pres-
2,6-Dichloropyrazolo[1,5-a]pyridine (2b)
A solution of 6-chloropyrazolo[1,5-a]pyridin-2-ol (4a, 169 mg, 1.00
mmol) in POCl3 (4 mL) was heated at 145 °C for 6 h in a sealed tube.
The mixture was cooled to r.t., then it was poured into ice-water and
stirred at r.t. for 1 h. The mixture was extracted with CH2Cl2 and the
organic layer was dried (Na2SO4), and then concentrated in vacuo. The
crude material was purified by flash column chromatography (silica
gel, hexane–EtOAc, 20:1) to give 2b as a colorless solid; yield: 22.9 mg
(12%); mp 72.0–75.0 °C.
OHC
N
CO2Me
9
path A
TFA, TESH, CH2Cl2, r.t., 5 h
45%
N
CO2Me
N
N
N
N
Cl
Cl
1) i) n-BuLi, THF, –78 °C, 0.5 h
ii) TMSCl, r.t., 1 h (92%)
1b
10
path B
2) NBS, MeCN, r.t., 1 h (93%)
3) i) n-BuLi, THF, –78 °C, 0.5 h
ii) 9, r.t., 1 h (53%)
2 M KOH, MeOH
r.t., 6 h
N
CO2H
4) TBAF, THF, 0 °C, 1 h (75%)
5) TFA, TESH, r.t., 1 h (quant.)
90%
N
N
Cl
EP1 antagonist
Scheme 6 Synthesis of the EP1 antagonist
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IR (ATR): 3144, 3078, 1901, 1744, 1633, 1572, 1527, 1510, 1438, 1365,
1315, 1247, 1110, 1072 cm–1
IR (ATR): 2984, 2659, 1639, 1544, 1519, 1368, 1303, 1247, 1150, 1068,
.
1032 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.47 (s, 1 H), 7.14 (dd, J = 9.7, 1.8 Hz, 1
H), 7.39 (d, J = 9.7 Hz, 1 H), 8.40 (d, J = 1.8 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.13 (dd, J = 9.1, 1.8 Hz, 1 H), 7.40
(d, J = 9.1 Hz, 1 H), 8.65 (d, J = 1.8 Hz, 1 H), 10.62 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 96.6, 117.4, 120.3, 126.2, 126.5, 139.8,
13C NMR (100 MHz, DMSO-d6): δ = 81.0, 115.8, 116.5, 124.6, 126.3,
144.1.
139.5, 164.4.
LRMS (FI): m/z = 185 [M]+.
LRMS (EI): m/z = 168 [M]+.
HRMS (FI): m/z [M]+ calcd for C7H4Cl2N2: 185.97515; found:
HRMS (EI): m/z [M]+ calcd for C7H5ClN2O: 168.00904; found:
185.97558.
168.00930.
2-Chloro-6-phenylpyrazolo[1,5-a]pyridine (5) and 2,6-Diphenyl-
pyrazolo[1,5-a]pyridine (6)
6-Methoxy-2-hydroxypyrazolo[1,5-a]pyridine (4c)
Following the typical procedure for 4b using 2-amino-6-methoxypyr-
azolo[1,5-a]pyridine (300 mg, 1.84 mmol) and 50% aq H2SO4 (10 mL)
gave 4c as a pale yellow solid; yield: 190 mg (63%); mp 166–168 °C.
IR (ATR): 1524, 1355, 1312, 1289, 1234, 1161, 1037, 1020 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 5.64 (s, 1 H), 6.90 (td,
J = 7.9, 2.4 Hz, 1 H), 7.28 (d, J = 9.7 Hz, 1 H), 8.05 (d, J = 2.4 Hz, 1 H),
10.15 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 56.1, 79.2, 111.5, 115.9, 118.2,
137.1, 146.9, 163.1.
LRMS (EI): m/z = 164 [M]+.
To a solution of 2,6-dichloropyrazolo[1,5-a]pyridine (2b, 16.8 mg,
89.8 μmol) in THF (1 mL) was added phenylboronic acid (24.0 mg,
0.197 mmol), Pd(OAc)2 (4.1 mg, 18 μmol), SPhos (7.5 mg, 18 μmol),
and K3PO4 (57.2 mg, 0.269 mmol) at r.t. The mixture was stirred un-
der argon at 80 °C for 10 h. The mixture was cooled to r.t., and then
passed through a Celite pad and concentrated in vacuo. The crude
material was purified by flash column chromatography (silica gel,
hexane–EtOAc, 10:1) to give 2-chloro-6-phenylpyrazolo[1,5-a]pyri-
dine (5) (17.5 mg, 85%) and 2,6-diphenylpyrazolo[1,5-a]pyridine (6)
(2.5 mg, 10%).
.
HRMS (EI): m/z [M]+ calcd for C8H8N2O2: 164.05858; found:
164.05925.
2-Chloro-6-phenylpyrazolo[1,5-a]pyridine (5)
Colorless solid; mp 56.0–58.0 °C.
IR (ATR): 3142, 3060, 3032, 2924, 1638, 1538, 1519, 1489, 1454, 1428,
Pyrazolo[1,5-a]pyridin-2-yl Trifluoromethanesulfonate (3a); Typi-
cal Procedure
1400, 1365, 1321, 1255, 1104 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.45 (s, 1 H), 7.36–7.59 (m, 7 H), 8.55
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 95.6, 117.0, 125.1, 125.6, 126.5, 126.8,
128.1, 129.2, 136.8, 140.4, 143.8.
LRMS (ESI): m/z = 229 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H10ClN2: 229.05325; found:
To a solution of 4a (3.10 g, 23.1 mmol) in THF (17 mL) and DMF (17
mL) was added NaH (1.0 g, 25.4 mmol, 60% dispersion in oil) and
Tf2NPh (9.90 g, 27.7 mmol) at 0 °C. The mixture was stirred for 1 h,
then it was added to ice-water and extracted with EtOAc. The organic
layer was washed with brine and dried (Na2SO4). The mixture was
concentrated in vacuo. The crude material was purified by flash col-
umn chromatography (silica gel, hexane–EtOAc, 10:1) to give 3a as a
colorless solid; yield: 6.10 g, 99%); mp 37–38 °C.
229.05360.
IR (ATR): 1639, 1520, 1481, 1428, 1340, 1243, 1208, 1127, 1026.
2,6-Diphenylpyrazolo[1,5-a]pyridine (6)
1H NMR (400 MHz, CDCl3): δ = 6.37 (s, 1 H), 6.89 (td, J = 7.3, 1.2 Hz, 1
H), 7.22–7.25 (m, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 8.37 (dt, J = 7.3, 1.2 Hz,
1 H).
Colorless solid; mp 134–137 °C.
IR (ATR): 3056, 2924, 1635, 1598, 1545, 1462, 1442, 1387, 1319, 1246,
1108, 1079, 1027 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 86.6, 113.2, 118.2, 118.7 (d, J = 321.4
1H NMR (400 MHz, CDCl3): δ = 6.83 (s, 1 H), 7.35–7.43 (m, 3 H), 7.43–
7.53 (m, 4 H), 7.53–7.65 (m, 3 H), 7.98 (d, J = 8.5 Hz, 2 H), 8.72 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 93.7, 117.8, 124.1, 125.9, 126.2, 126.5,
126.7, 127.8, 128.5, 128.8, 129.2, 133.1, 137.3, 140.6, 154.0.
LRMS (ESI): m/z = 271 [M + H]+.
Hz), 125.2, 128.8, 141.3, 154.6.
LRMS (FI): m/z = 266 [M]+.
HRMS (FI): m/z [M]+ calcd for C8H5F3N2O3S: 265.99730; found:
265.99738.
HRMS (ESI): m/z [M + H]+ calcd for C19H15N2: 271.12352; found:
271.12395.
6-Chloropyrazolo[1,5-a]pyridin-2-yl Trifluoromethanesulfonate
(3b)
Following the typical procedure for 3a using 4b (1.59 g, 9.43 mmol) in
THF (10 mL) and DMF (10 mL), NaH (414 mg, 10.4 mmol, 60% disper-
sion in oil), and Tf2NPh (3.89 g, 10.4 mmol) gave 3b as a pale yellow
oil; yield: 2.68 g (95%).
6-Chloro-2-hydroxypyrazolo[1,5-a]pyridine (4b); Typical Proce-
dure
A mixture of 2-amino-6-chloropyrazolo[1,5-a]pyridine (250 mg, 1.49
mmol) and 50% aq H2SO4 (7.5 mL) was stirred at 100 °C for 2 h. The
mixture was cooled to r.t., then it was poured into sat. aq NaHCO3 to
adjust to pH 11. The mixture was extracted with EtOAc and the com-
bined extracts were dried (Na2SO4). The mixture was concentrated in
vacuo to give 4b as a yellow solid; yield: 196 mg (78%); mp 193–
198 °C.
IR (ATR): 1640, 1520, 1464, 1426, 1392, 1338, 1206, 1128, 1018 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.42 (s, 1 H), 7.24 (dd, J = 9.7, 1.8 Hz, 1
H), 7.47 (d, J = 9.7 Hz, 1 H), 8.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 87.6, 118.4, 118.7 (d, J = 321.4 Hz),
121.5, 127.0, 129.6, 139.6, 154.8.
LRMS (EI): m/z = 300 [M + H]+.
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HRMS (EI): m/z [M]+ calcd for C8H4ClF3N2O3S: 299.95832; found:
6-Methoxy-2-phenylpyrazolo[1,5-a]pyridine (1c)
299.95784.
Following the typical procedure for 1a using 3c (50.0 mg, 0.169
mmol) in DME (0.8 mL), phenylboronic acid (30.5 mg, 0.250 mmol), 2
M aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7 mg, 16.7
μmol) gave 1c as a pale red solid; yield: 35.0 mg (92%); mp 84–85 °C.
6-Methoxypyrazolo[1,5-a]pyridin-2-ylTrifluoromethanesulfonate
(3c)
Following the typical procedure for 3a using 4c (175 mg, 1.07 mmol)
in THF (0.8 mL) and DMF (0.8 mL), NaH (52 mg, 1.3 mmol, 60% disper-
sion in oil), and Tf2NPh (460 mg, 1.29 mmol) gave 3c as a pale yellow
oil; yield: 308 mg (97%).
IR (ATR): 3048, 2929, 2837, 1713, 1645, 1517, 1466, 1379, 1323, 1280,
1198, 1157, 1128, 1025, 941, 852, 818, 756, 694, 603, 508, 421 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.74 (s, 1 H), 6.92 (dd, J =
9.7, 1.8 Hz, 1 H), 7.34 (tt, J = 7.3, 1.8 Hz, 1 H), 7.40 (d, J = 9.7 Hz, 1 H),
7.44 (t, J = 7.3 Hz, 2 H), 7.91–7.94 (m, 2 H), 8.09 (d, J = 1.8 Hz, 1 H).
IR (ATR): 1533, 1475, 1424, 1291, 1201, 1134, 1018 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 6.31 (s, 1 H), 7.05 (dd, J =
9.7, 2.4 Hz, 1 H), 7.38 (d, J = 9.7 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 56.0, 93.6, 110.9, 117.8, 118.9, 126.1,
128.1, 128.7, 133.4, 137.9, 149.2, 152.7.
13C NMR (100 MHz, CDCl3): δ = 56.1, 86.5, 111.2, 118.0, 118.8 (d, J =
LRMS (EI): m/z = 224 [M]+.
322.4 Hz), 120.8, 137.3, 149.9, 153.5.
LRMS (ESI): m/z = 297 [M + H]+.
HRMS (EI): m/z [M]+ calcd for C14H12N2O: 224.0950; found: 224.0933.
HRMS (ESI): m/z [M + H]+ calcd for C9H8F3N2O4S: 297.01569; found:
2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridine (1d)
297.01604.
Following the typical procedure for 1a using 3a (50.0 mg, 0.188
mmol) in DME (1 mL), 4-chlorophenylboronic acid (44.9 mg, 0.287
mmol), 2 M aq Na2CO3 (0.3 mL, 0.6 mmol), and PdCl2(PPh3)2 (14.0 mg,
19.9 μmol) gave 1d as a colorless solid; yield: 37.9 mg (88%); mp 103–
2-Phenylpyrazolo[1,5-a]pyridine (1a); Typical Procedure
To a solution of 3a (50.0 mg, 0.188 mmol) in DME (1 mL) was added
phenylboronic acid (35.0 mg, 0.287 mmol), 2 M aq Na2CO3 (0.3 mL,
0.6 mmol), and PdCl2(PPh3)2 (14.0 mg, 19.9 μmol) at r.t. The mixture
was stirred at 90 °C for 4 h, then it was cooled to r.t., diluted with
EtOAc, and washed with water and brine. The organic layer was dried
(Na2SO4), and then concentrated in vacuo. The crude material was pu-
rified by flash column chromatography (silica gel, hexane–EtOAc,
10:1) to give 1a as a colorless solid; yield: 34.0 mg (93%); mp 99–
104 °C.
1
105 °C. H NMR spectroscopic data are identical to those reported in
the literature.15
IR (ATR): 3073, 3032, 2160, 1899, 1776, 1634, 1599, 1508, 1423, 1333,
1255, 1185, 1089, 1012, 946, 833, 772, 727, 636, 599, 509, 470 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.74 (d, J = 6.7 Hz, 1 H), 6.76 (s, 1 H),
7.10 (t, J = 8.5 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 1 H),
7.90 (d, J = 8.5 Hz, 2 H), 8.46 (d, J = 6.7 Hz, 1 H).
LRMS (EI): m/z = 228 [M]+.
HRMS (EI): m/z [M]+ calcd for C13H9ClN2: 228.0454; found: 228.0453.
IR (ATR): 3123, 3076, 3034, 1891, 1767, 1634, 1514, 1471, 1456, 1421,
1333, 1257, 1191, 1146, 1082, 1011, 947, 910, 838, 782, 759, 736,
683, 564, 506, 430 cm–1
.
2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridine (1e)
1H NMR (400 MHz, CDCl3): δ = 6.72 (td, J = 7.3, 1.2 Hz, 1 H), 6.79 (s, 1
H), 7.05–7.11 (m, 1 H), 7.18–7.21 (m, 2 H), 7.34–7.39 (m, 1 H), 7.44–
7.49 (m, 1 H), 7.97 (d, J = 7.3 Hz, 2 H), 8.47 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 93.7, 111.7, 117.9, 123.4, 126.5, 128.4,
128.5, 128.7, 133.2, 141.6, 153.5.
LRMS (EI): m/z = 194 [M]+.
HRMS (EI): m/z [M]+ calcd for C13H10N2: 194.0844; found: 194.0883.
Following the typical procedure for 1a using 3a (500 mg, 1.88 mmol)
in DME (6.3 mL), 2-chlorophenylboronic acid (441 mg, 2.82 mmol), 2
M aq Na2CO3 (2.8 mL, 5.63 mmol), and PdCl2(PPh3)2 (132 mg, 0.19
mmol) gave 1e as a yellow oil; yield: 371 mg (87%). 1H NMR spectro-
scopic data are identical to those reported in the literature.8c,16
IR (ATR): 2958, 1713, 1636, 1519, 1460, 1413, 1331, 1249, 1163, 1048,
949, 850, 758, 731, 653, 564, 516, 463 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.77 (td, J = 6.7, 1.2 Hz, 1 H), 7.03 (s, 1
H), 7.10–7.14 (m, 1 H), 7.28–7.39 (m, 2 H), 7.50 (dd, J = 7.9, 1.2 Hz, 1
H), 7.56 (d, J = 9.1 Hz, 1 H), 7.91 (dd, J = 7.9, 1.8 Hz, 1 H), 8.49 (d, J = 6.7
Hz, 1 H).
LRMS (EI): m/z = 228 [M]+.
HRMS (EI): m/z [M]+ calcd for C13H9ClN2: 228.0454; found: 228.0440.
6-Chloro-2-phenylpyrazolo[1,5-a]pyridine (1b)
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), phenylboronic acid (30.5 mg, 0.250 mmol), 2 M
aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7 mg, 16.7 μmol)
gave 1b as a yellow solid; yield: 34.0 mg (90%); mp 117–120 °C. 1H
NMR spectroscopic data are identical to those reported in the litera-
ture.8c
6-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1f)
IR (ATR): 3068, 2557, 2164, 1947, 1898, 1756, 1697, 1634, 1534, 1506,
1461, 1379, 1309, 1194, 1131, 1060, 949, 854, 806, 755, 682, 576,
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 4-fluorophenylboronic acid (35.0 mg, 0.250
mmol), 2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7
mg, 16.7 μmol) gave 1f as a colorless solid; yield: 37.0 mg (90%); mp
96–102 °C.
505, 423 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H), 7.08 (dd, J = 9.1, 1.8 Hz, 1
H), 7.38 (t, J = 7.3 Hz, 1 H), 7.46 (t, J = 7.3 Hz, 3 H), 7.94 (d, J = 7.3 Hz, 2
H), 8.52 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 94.5, 118.1, 119.7, 125.0, 126.5, 126.6,
128.6, 128.8, 132.8, 140.0, 154.2.
LRMS (EI): m/z = 228 [M]+.
HRMS (EI): m/z [M]+ calcd for C13H9ClN2: 228.0454; found: 228.0461.
IR (ATR): 3085, 1632, 1600, 1508, 1456, 1222, 1156, 1092, 1014, 949,
940, 803, 764, 642, 576, 518 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.76 (s, 1 H), 7.08 (dd, J = 9.4, 1.5 Hz, 1
H), 7.14 (t, J = 8.5 Hz, 2 H), 7.46 (d, J = 9.1 Hz, 1 H), 7.91 (dd, J = 8.5, 5.4
Hz, 2 H), 8.50 (s, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 115.7 (d, J = 21.9 Hz), 118.0, 119.8,
125.2, 126.6, 128.2 (d, J = 8.6 Hz), 129.0 (d, J =3.8 Hz), 140.1, 153.3,
163.1 (d, J = 248.0 Hz).
13C NMR (100 MHz, CDCl3): δ = 98.6 (d, J = 2.9 Hz), 118.3, 120.2, 124.0
(d, J = 273.7 Hz), 125.1, 126.3 (d, J = 5.7 Hz), 126.5, 128.2, 128.7 (d, J =
30.5 Hz), 131.6, 132.4, 132.5 (d, J = 13.4 Hz), 139.1, 152.3.
LRMS (FI): m/z = 246 [M]+.
LRMS (ESI): m/z = 297 [M + H]+.
HRMS (FI): m/z [M]+ calcd for C13H8ClFN2: 246.0360; found: 246.0363.
HRMS (ESI): m/z [M + H]+ calcd for C14H9ClF3N2: 297.0406; found:
297.0407.
6-Chloro-2-(2-fluorophenyl)pyrazolo[1,5-a]pyridine (1g)
6-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (1j)
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 2-fluorophenylboronic acid (35.0 mg, 0.250
mmol), 2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7
mg, 16.7 μmol) gave 1g as a colorless solid; yield: 36.5 mg (89%); mp
142–146 °C.
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 4-methoxyphenylboronic acid (38.0 mg, 0.250
mmol), 2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7
mg, 16.7 μmol) gave 1j as a colorless solid; yield: 40.0 mg (93%); mp
132–137 °C.
IR (ATR): 3094, 1892, 1669, 1582, 1507, 1466, 1443, 1380, 1310, 1215
cm–1
.
IR (ATR): 3089, 2933, 2836, 2552, 1901, 1610, 1521, 1464, 1436 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.01 (d, J = 3.6 Hz, 1 H), 7.09 (dd, J = 9.4,
1.5 Hz, 1 H), 7.18 (dd, J = 11.2, 8.2 Hz, 1 H), 7.24 (t, J = 7.7 Hz, 1 H),
7.32–7.38 (m, 1 H), 7.50 (d, J = 9.4 Hz, 1 H), 8.14 (td, J = 7.7, 1.5 Hz, 1
H), 8.54 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.72 (s, 1 H), 6.98 (d, J =
9.1 Hz, 2 H), 7.04 (dd, J = 9.7, 1.8 Hz, 1 H), 7.41 (d, J = 9.7 Hz, 1 H), 7.86
(d, J = 9.1 Hz, 2 H), 8.49 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 55.3, 93.8, 114.2, 117.8, 119.3, 124.9,
13C NMR (100 MHz, CDCl3): δ = 98.3 (d, J = 10.6 Hz), 116.2 (d, J = 22.0
Hz), 118.4, 120.1, 120.7 (d, J = 11.4 Hz), 124.4 (d, J = 2.9 Hz), 124.9,
126.5, 129.0 (d, J = 2.9 Hz), 130.0 (d, J = 8.6 Hz), 139.7 (d, J = 2.9 Hz),
148.6, 160.6 (d, J = 250.8 Hz).
125.5, 126.5, 127.7, 140.0, 154.1, 160.1.
LRMS (ESI): m/z = 259 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClFN2O: 259.0638; found:
259.0639.
LRMS (FI): m/z = 246 [M]+.
HRMS (FI): m/z [M]+ calcd for C13H8ClFN2: 246.0360; found: 246.0366.
6-Chloro-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyridine (1k)
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 2-methoxyphenylboronic acid (38.0 mg, 0.250
mmol), 2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and PdCl2(PPh3)2 (11.7
mg, 16.7 μmol) gave 1k as a colorless solid; yield: 39.5 mg (92%); mp
85–88 °C.
6-Chloro-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine
(1h)
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 4-(trifluoromethyl)phenylboronic acid (47.5
mg, 0.250 mmol),
PdCl2(PPh3)2 (11.7 mg, 16.7 μmol) gave 1h as a colorless solid; yield:
46.6 mg (95%); mp 128–133 °C.
IR (ATR): 3079, 1617, 1426, 1322 cm–1
1H NMR (400 MHz, CDCl3): δ = 6.87 (s, 1 H), 7.12 (dd, J = 9.1, 1.8 Hz, 1
H), 7.50 (d, J = 9.1 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 2 H), 8.05 (d, J = 7.9 Hz,
2 H), 8.53 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 95.0, 118.3, 120.4, 125.3, 124.2 (d, J =
271.8 Hz), 125.7 (d, J = 3.8 Hz), 126.6, 126.7, 130.3 (d, J = 32.4 Hz),
136.2, 140.1, 152.5.
2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and
IR (ATR): 3167, 3053, 2963, 2833, 1912, 1634, 1581, 1510, 1474, 1445,
1379 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.95 (s, 3 H), 7.04–7.08 (m, 4 H), 7.34–
7.38 (m, 1 H), 7.46 (d, J = 9.1 Hz, 1 H), 8.07 (dd, J = 7.9, 1.8 Hz, 1 H),
8.53 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 55.6, 98.9, 111.4, 118.2, 119.5, 121.0,
121.6, 124.4, 126.4, 129.4, 129.7, 139.4, 151.0, 157.3.
LRMS (FI): m/z = 258 [M]+.
HRMS (FI): m/z [M]+ calcd for C14H11ClN2O: 258.0560; found:
.
258.0562.
LRMS (ESI): m/z = 297 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H9ClF3N2: 297.0406; found:
297.0405.
6-Chloro-2-(furan-2-yl)pyrazolo[1,5-a]pyridine (1l)
Following the typical procedure for 1a using 3b (400 mg, 1.33 mmol)
in DME (2.7 mL), (furan-2-yl)boronic acid (194 mg, 1.73 mmol), 2 M
aq Na2CO3 (2.0 mL, 4.00 mmol), and PdCl2(PPh3)2 (187 mg, 0.266
mmol) at 80 °C for 1 h gave 1l as a colorless solid; yield: 230 mg
(80%); mp 99.0–102 °C.
6-Chloro-2-[2-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine
(1i)
Following the typical procedure for 1a using 3b (50.0 mg, 0.166
mmol) in DME (1 mL), 2-(trifluoromethyl)phenylboronic acid (47.5
IR (ATR): 3135, 3095, 1616, 1526, 1510, 1447, 1378, 1306, 1222, 1189,
mg, 0.250 mmol),
2 M aq Na2CO3 (0.25 mL, 0.5 mmol), and
1086, 1016, 927, 894, 800, 749, 700, 596, 572, 436 cm–1
.
PdCl2(PPh3)2 (11.7 mg, 16.7 μmol) gave 1i as a yellow solid; yield: 40.8
mg (83%); mp 71.0–74.0 °C.
1H NMR (400 MHz, CDCl3): δ = 6.51 (dd, J = 3.6, 1.8 Hz, 1 H), 6.72 (s, 1
H), 6.84 (d, J = 3.6 Hz, 1 H), 7.06 (dd, J = 9.7, 1.8 Hz, 1 H), 7.42 (d, J = 9.7
Hz, 1 H), 7.52 (d, J = 1.8 Hz, 1 H), 8.47 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 94.7, 117.9, 119.6, 122.3, 125.1, 126.2,
126.3, 126.5, 134.6, 139.8, 150.3.
IR (ATR): 3141, 3080, 3014, 1837, 1633, 1582, 1535, 1509, 1445 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.75 (s, 1 H), 7.13 (dd, J = 9.7, 1.8 Hz, 1
H), 7.49–7.55 (m, 2 H), 7.62 (t, J = 7.3 Hz, 1 H), 7.72 (d, J = 7.3 Hz, 1 H),
7.80 (d, J = 7.3 Hz, 1 H), 8.53 (s, 1 H).
LRMS (EI): m/z = 218 [M]+.
HRMS (EI): m/z [M]+ calcd for C11H7ClN2O: 218.02469; found:
218.02399.
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6-Chloro-2-(furan-3-yl)pyrazolo[1,5-a]pyridine (1m)
stirred under a CO atmosphere at 60 °C for 10 h. The mixture was
cooled to r.t., and then passed through a Celite pad and concentrated
in vacuo. The crude material was purified by flash column chroma-
tography (silica gel, hexane–EtOAc, 1:1) to give 7 as a pale yellow sol-
id; yield: 31.6 mg (83%); mp 43.0–46.0 °C.
Following the typical procedure for 1a using 3b (400 mg, 1.33 mmol)
in DME (2.7 mL), (furan-3-yl)boronic acid (194 mg, 1.73 mmol), 2 M
aq Na2CO3 (2.0 mL, 4.00 mmol), and PdCl2(PPh3)2 (187 mg, 0.266
mmol) at 80 °C for 1 h gave 1m as a colorless solid; yield: 152 mg
(52%); mp 86.0–89.0 °C.
IR (ATR): 3089, 2981, 1717, 1636, 1516, 1498, 1486, 1404, 1329, 1241,
1197, 1100, 1025 cm–1
.
IR (ATR): 3152, 3083, 1616, 1562, 1507, 1402, 1308, 1154, 1068, 1014,
989, 873, 808, 795, 765, 702, 597, 574, 493 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.3 Hz, 3 H), 4.48 (q, J = 7.3
Hz, 2 H), 6.88 (dd, J = 7.9, 7.3 Hz, 1 H), 7.08 (s, 1 H), 7.17 (dd, J = 9.1,
7.9 Hz, 1 H), 7.59 (d, J = 9.1 Hz, 1 H), 8.53 (d, J = 7.3 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 6.60 (s, 1 H), 6.84 (s, 1 H), 7.07 (dd, J =
9.1, 1.8 Hz, 1 H), 7.42 (d, J = 9.1 Hz, 1 H), 7.50 (t, J = 1.8 Hz, 1 H), 7.93
(s, 1 H), 8.48 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.4, 61.4, 100.2, 114.1, 119.2, 124.0,
13C NMR (100 MHz, CDCl3): δ = 94.7, 109.1, 117.7, 119.4, 119.5, 125.1,
126.5, 139.7, 140.3, 143.6, 147.6.
129.0, 140.9, 145.0, 162.8.
LRMS (ESI): m/z = 191 [M + H]+.
LRMS (EI): m/z = 218 [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C10H11N2O2: 191.08205; found:
HRMS (EI): m/z [M]+ calcd for C11H7ClN2O: 218.02469; found:
191.08183.
218.02495.
Ethyl (E)-3-(Pyrazolo[1,5-a]pyridin-2-yl)acrylate (8)
6-Chloro-2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine (1n)
To a solution of 3a (53.3 mg, 0.200 mmol) in DMF (1 mL) was added
ethyl acrylate (0.22 mL, 2.0 mmol), Pd(OAc)2 (22.5 mg, 0.100 mmol),
dppp (45.5 mg, 0.110 mmol), and Et3N (56 μL, 0.40 mmol) at r.t. The
mixture was stirred under argon at 80 °C for 10 h. The mixture was
cooled to r.t., and then passed through a Celite pad and then concen-
trated in vacuo. The crude material was purified by flash column
chromatography (silica gel, hexane–EtOAc, 3:1) to give 8 as a pale yel-
low solid; yield: 28.0 mg (65%); mp 56.0–59.0 °C.
Following the typical procedure for 1a using 3b (400 mg, 1.33 mmol)
in DME (2.7 mL), (thiophen-2-yl)boronic acid (187 mg, 1.46 mmol), 2
M aq Na2CO3 (2.0 mL, 4.00 mmol), and PdCl2(PPh3)2 (187 mg, 0.270
mmol) at 80 °C for 1 h gave 1n as a colorless solid; yield: 170 mg
(54%); mp 85.0–88.0 °C.
IR (ATR): 3087, 1630, 1560, 1506, 1475, 1389, 1303, 1215, 1130, 1066,
927, 850, 799, 758, 686, 569 cm–1
.
IR (ATR): 2984, 2931, 1712, 1646, 1633, 1609, 1514, 1475, 1402, 1348,
1H NMR (400 MHz, CDCl3): δ = 6.71 (s, 1 H), 7.07 (dd, J = 9.7, 1.8 Hz, 1
H), 7.11 (d, J = 4.8, 3.6 Hz, 1 H), 7.34 (dd, J = 4.8, 1.2 Hz, 1 H), 7.41 (d,
J = 9.7 Hz, 1 H), 7.50 (d, J = 3.6, 1.2 Hz, 1 H), 8.48 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 94.3, 117.8, 119.7, 125.2, 125.3, 125.9,
126.5, 127.7, 135.8, 139.9, 149.3.
LRMS (EI): m/z = 234 [M]+.
HRMS (EI): m/z [M]+ calcd for C11H7ClN2S: 234.00185; found:
1298, 1271, 1243, 1172, 1163, 1033 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.3 Hz, 3 H), 4.27 (q, J = 7.3
Hz, 2 H), 6.67 (d, J = 15.8 Hz, 1 H), 6.70 (s, 1 H), 6.78 (t, J = 7.9 Hz, 1 H),
7.11 (t, J = 7.9 Hz, 1 H), 7.50 (d, J = 7.9 Hz, 1 H), 7.79 (d, J = 15.8 Hz, 1
H), 8.41 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 60.6, 96.6, 112.8, 118.4, 121.3,
123.8, 128.5, 136.4, 141.3, 149.5, 166.7.
234.00124.
LRMS (ESI): m/z = 217 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O2: 217.09770; found:
217.09813.
6-Chloro-2-(thiophen-3-yl)pyrazolo[1,5-a]pyridine (1o)
Following the typical procedure for 1a using 3b (800 mg, 2.66 mmol)
in DMF (4.0 mL), (thiophen-3-yl)boronic acid (375 mg, 2.93 mmol), 2
M aq Na2CO3 (4.0 mL, 8.00 mmol), and PdCl2(PPh3)2 (373 mg, 0.530
mmol) at 80 °C for 1 h gave 1o as a colorless solid; yield: 312 mg
(55%); mp 120–123 °C.
2,6-Diphenylpyrazolo[1,5-a]pyridine (6)
To a solution of 1b (68.7 mg, 0.300 mmol) in THF (3 mL) was added
phenylboronic acid (55.0 mg, 0.451 mmol), Pd(OAc)2 (13.7 mg, 61.0
μmol), SPhos (25.0 mg, 60.9 μmol), and K3PO4 (191 mg, 0.900 mmol)
at r.t. The mixture was stirred under argon at 80 °C for 10 h. The mix-
ture was cooled to r.t., and then passed through a Celite pad and then
concentrated in vacuo. The crude material was purified by flash col-
umn chromatography (silica gel, hexane–EtOAc, 10:1) to give 6 as a
colorless solid; yield: 76.5 mg (94%); mp 134–137 °C.
IR (ATR): 3082, 1631, 1562, 1508, 1478, 1341, 1307, 1071, 853, 790,
762, 701, 573 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.70 (s, 1 H), 7.07 (dd, J = 9.7, 1.5 Hz, 1
H), 7.24 (dd, J = 4.8, 3.0 Hz, 1 H), 7.44 (d, J = 9.7 Hz, 1 H), 7.57 (dd, J =
4.8, 1.2 Hz, 1 H), 7.76 (dd, J =3.0, 1.2 Hz, 1 H), 8.49 (d, J = 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 94.1, 107.7, 111.6, 118.0, 119.9, 125.3,
126.6, 139.6, 142.8, 146.3, 148.2.
LRMS (EI): m/z = 234 [M]+.
HRMS (EI): m/z [M]+ calcd for C11H7ClN2S: 234.00185; found:
IR (ATR): 3056, 2924, 1635, 1598, 1545, 1462, 1442, 1387, 1319, 1246,
1108, 1079, 1027 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.83 (s, 1 H), 7.35–7.43 (m, 3 H), 7.43–
7.53 (m, 4 H), 7.53–7.65 (m, 3 H), 7.98 (d, J = 8.5 Hz, 2 H), 8.72 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 93.7, 117.8, 124.1, 125.9, 126.2, 126.5,
234.00147.
126.7, 127.8, 128.5, 128.8, 129.2, 133.1, 137.3, 140.6, 154.0.
Ethyl Pyrazolo[1,5-a]pyridine-2-carboxylate (7)
LRMS (ESI): m/z = 271 [M + H]+.
To a solution of 3a (53.3 mg, 0.200 mmol) in DMF (0.5 mL) and EtOH
(0.5 mL) was added Pd(OAc)2 (22.5 mg, 0.100 mmol), dppp (45.5 mg,
0.110 mmol), and Et3N (56 μL, 0.40 mmol) at r.t. The mixture was
HRMS (ESI): m/z [M + H]+ calcd for C19H15N2: 271.12352; found:
271.12395.
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Synthesis
Methyl 6-[(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)meth-
yl]picolinate (10) by Path A
1H NMR (400 MHz, CDCl3): δ = 0.61 (s, 9 H), 7.11 (d, J = 9.1 Hz, 1 H),
7.42 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 9.1 Hz, 1 H), 7.49 (t, J = 7.3 Hz, 2 H),
8.11 (d, J = 7.3 Hz, 2 H).
To a stirred solution of 1b (229 mg, 1.00 mmol) and methyl 6-
formylpyridine-2-carboxylate (248 mg, 1.50 mmol) in CH2Cl2 (10 mL)
was added TFA (0.16 mL, 2.09 mmol) and TESH (0.48 mL, 3.01 mmol),
and the mixture was stirred at r.t. for 5 h. The mixture was quenched
by the addition of sat. aq NaHCO3 to adjust to pH 11, then it was ex-
tracted with EtOAc and the combined extracts were dried (Na2SO4).
The crude material was purified by flash column chromatography
(silica gel, hexane–EtOAc, 4:1) to give 10 as yellow oil; yield: 170 mg
(45%).
IR (ATR): 3060, 2960, 2903, 1938, 1887, 1792, 1733, 1607, 1527, 1480,
1454, 1382, 1302, 1237, 1146, 1105, 1014, 955, 842, 763, 679, 642,
594, 519, 470, 434 cm–1
.
LRMS (ESI): m/z = 379 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H17BrClN2Si: 379.00329; found:
379.00418.
Methyl 6-[(6-Chloro-2-phenyl-7-(trimethylsilyl)pyrazolo[1,5-
a]pyridin-3-yl)(hydroxy)methyl]picolinate
IR (ATR): 3448, 3065, 2950, 1721, 1630, 1586, 1533, 1460, 1435, 1317,
1289, 1242, 1136, 1075, 993, 918, 835, 754, 699, 674, 576, 498, 417
cm–1
.
To a stirred solution of 3-bromo-6-chloro-2-phenyl-7-(trimethylsi-
lyl)pyrazolo[1,5-a]pyridine (530 mg, 1.40 mmol) in THF (3.5 mL) was
added 2.6 M BuLi in hexane (0.60 mL, 1.67 mmol) at –78 °C, and the
mixture was stirred at –78 °C for 0.5 h. A solution of methyl 6-
formylpyridine-2-carboxylate (461 mg, 2.79 mmol) in THF (3.5 mL)
was added to the mixture at –78 °C, and then then it was warmed to
r.t. and stirred for 1 h. The mixture was quenched by the addition of
sat. aq NH4Cl, then it was extracted with EtOAc, and the combined ex-
tracts were dried (Na2SO4). The crude material was purified by flash
column chromatography (silica gel, hexane–EtOAc, 2:1) to give the ti-
tle compound as a yellow oil; yield: 345 mg (53%).
1H NMR (400 MHz, CDCl3): δ = 4.03 (s, 3 H), 4.54 (s, 2 H), 7.04 (dd, J =
9.7, 1.8 Hz, 1 H), 7.09 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 9.7 Hz, 1 H), 7.38–
7.46 (m, 3 H), 7.65 (t, J = 7.9 Hz, 1 H), 7.68–7.72 (m, 2 H), 7.96 (d, J =
7.9 Hz, 1 H), 8.52 (d, J = 1.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 32.5, 52.9, 105.3, 117.4, 120.1, 123.0,
124.6, 125.4, 126.5, 128.4, 128.5, 128.7, 132.7, 137.7, 138.8, 147.5,
153.2, 160.8, 165.8.
LRMS (EI): m/z = 377 [M]+.
HRMS (EI): m/z [M]+ calcd for C21H16ClN3O2: 377.0931; found:
IR (ATR): 3421, 2953, 2899, 1721, 1586, 1490, 1457, 1438, 1356, 1314,
1246, 1217, 1137, 1043, 961, 892, 839, 761, 701, 635, 605, 487, 420
377.0932.
cm–1
.
Methyl 6-[(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)meth-
yl]picolinate (10) by Path B
1H NMR (400 MHz, CDCl3): δ = 0.59 (s, 9 H), 4.05 (s, 3 H), 5.34 (d, J =
3.0 Hz, 1 H), 6.28 (d, J = 3.0 Hz, 1 H), 6.87 (d, J = 9.7 Hz, 1 H), 6.99 (d, J =
9.7 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 7.37–7.48 (m, 3 H), 7.71 (t, J = 7.9
Hz, 1 H), 7.83–7.87 (m, 2 H), 8.07 (d, J = 7.9 Hz, 1 H).
LRMS (EI): m/z = 465 [M]+.
HRMS (EI): m/z [M]+ calcd for C24H24ClN3O3Si: 465.1275; found:
6-Chloro-2-phenyl-7-(trimethylsilyl)pyrazolo[1,5-a]pyridine
To a stirred solution of 1b (689 mg, 3.01 mmol) in THF (15 mL) was
added 2.6 M BuLi in hexane (1.4 mL, 3.62 mmol) at –78 °C, and the
mixture was stirred at –78 °C for 0.5 h. TMSCl (1.9 mL, 15.1 mmol)
was added to the mixture at –78 °C, and then then it was warmed to
r.t. and stirred for 1 h. The mixture was quenched by the addition of
sat. aq NH4Cl, then it was extracted with EtOAc, and the combined ex-
tracts were dried (Na2SO4). The crude material was purified by flash
column chromatography (silica gel, hexane–EtOAc, 4:1) to give the ti-
tle compound as a yellow solid; yield: 830 mg (92%); mp 91–92 °C.
465.1251.
Methyl 6-[(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)(hy-
droxy)methyl]picolinate
To a stirred solution of methyl 6-[(6-chloro-2-phenyl-7-(trimethylsi-
lyl)pyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl]picolinate (216 mg,
0.55 mmol) in THF (5.5 mL) was added 1 M TBAF in THF (1.10 mL,
1.10 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The
mixture was quenched by the addition of sat. aq NH4Cl, then it was
extracted with EtOAc and the combined extracts were dried (Na2SO4).
The crude material was purified by flash column chromatography
(silica gel, hexane–EtOAc, 2:1) to give the title compound as a yellow
oil; yield: 162 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 0.63 (s, 9 H), 6.78 (s, 1 H), 7.00 (d, J =
9.1 Hz, 1 H), 7.36 (tt, J = 7.3, 1.2 Hz, 1 H), 7.40–7.47 (m, 3 H), 7.94–7.97
(m, 2 H).
IR (ATR): 3067, 2954, 2896, 1612, 1535, 1457, 1379, 1279, 1245, 1182,
1108, 1081, 969, 878, 848, 777, 697, 637, 555, 482, 421 cm–1
.
LRMS (EI): m/z = 300 [M]+.
HRMS (EI): m/z [M]+ calcd for C16H17ClN2Si: 300.0850; found:
IR (ATR): 3386, 3062, 2951, 2245, 1723, 1632, 1587, 1515, 1460, 1437,
1317, 1294, 1215, 1137, 1076, 1029, 890, 836, 755, 730, 701, 669,
300.0841.
573, 492, 407 cm–1
.
3-Bromo-6-chloro-2-phenyl-7-(trimethylsilyl)pyrazolo[1,5-a]pyr-
idine
1H NMR (400 MHz, CDCl3): δ = 4.03 (s, 3 H), 5.37 (br s, 1 H), 6.23 (s, 1
H), 6.95 (dd, J = 9.7, 1.8 Hz, 1 H), 7.12 (d, J = 9.7 Hz, 1 H), 7.20 (d, J = 7.9
Hz, 1 H), 7.39–7.49 (m, 3 H), 7.71 (t, J = 7.9 Hz, 1 H), 7.79–7.83 (m, 2
H), 8.02 (d, J = 7.9 Hz, 1 H), 8.50 (d, J = 1.8 Hz, 1 H).
LRMS (EI): m/z = 393 [M]+.
HRMS (EI): m/z [M]+ calcd for C21H16ClN3O3: 393.0880; found:
To a stirred solution of 6-chloro-2-phenyl-7-(trimethylsilyl)pyrazo-
lo[1,5-a]pyridine (830 mg, 2.76 mmol) in MeCN (14 mL) was added
NBS (589 mg, 3.31 mmol) at r.t., and the mixture was stirred at r.t. for
1 h. The mixture was quenched by the addition of sat. aq NaHCO3,
then it was extracted with EtOAc and the combined extracts were
dried (Na2SO4). The crude material was purified by flash column
chromatography (silica gel, hexane–EtOAc, 4:1) to give the title com-
pound as a yellow solid; yield: 970 mg (93%); mp 96–97 °C.
393.0869.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3221–3230

3230
K. Umei et al.
Paper
Synthesis
Methyl 6-[(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)meth-
yl]picolinate (10)
(2) Bravi, G.; Cheasty, A. G.; Corfield, J. A.; Grimes, R. M.; Harrison,
D.; Hartley, C. D.; Howes, P. D.; Medhurst, K. J.; Meeson, M. L.;
Mordaunt, J. E. WO 2007039146, 2007.
(3) Kettle, J. G.; Brown, S.; Crafter, C.; Davies, B. R.; Dudley, P.;
Fairley, G.; Faulder, P.; Fillery, S.; Greenwood, H.; Hawkins, J.;
James, M.; Johnson, K.; Lane, C. D.; Pass, M.; Pink, J. H.; Plant, H.;
Cosulich, S. C. J. Med. Chem. 2012, 55, 1261.
(4) Satake, N.; Zhou, Q.; Sato, N.; Matsuo, M.; Sawada, T.; Shibata, S.
Pharmacology 1992, 44, 206.
(5) Seto, S.; Umei, K.; Nishigaya, Y.; Tanioka, A.; Tatani, K.; Kondo,
A.; Kondo, T.; Kawamura, N. WO 2012102297, 2012.
(6) Wang, X.; Momota, Y.; Yanase, H.; Narumiya, S.; Maruyama, T.;
Kawatani, M. Biomed. Res. 2008, 29, 105.
To a stirred solution of methyl 6-[(6-chloro-2-phenylpyrazolo[1,5-
a]pyridin-3-yl)(hydroxy)methyl]picolinate (100 mg, 0.254 mmol) in
CH2Cl2 (1.3 mL) was added TFA (0.20 mL, 3.05 mmol) and TESH (0.20
mL, 1.52 mmol), and the mixture was stirred at r.t. for 1 h. The mix-
ture was quenched by the addition of sat. aq NaHCO3 to adjust to pH
11. The mixture was extracted with EtOAc and the combined extracts
were dried (Na2SO4). The crude material was purified by flash column
chromatography (silica gel, hexane–EtOAc, 4:1) to give 10 as yellow
oil; yield: 97.0 mg (quant.). 1H NMR spectroscopic data are identical
with those of 10 prepared using path A.
(7) (a) Anderson, P. L.; Hasak, J. P.; Kahle, A. D.; Paolella, N. A.;
Shapiro, M. J. J. Heterocycl. Chem. 1981, 18, 1149. (b) Miki, Y.;
Uragi, M.; Takemura, S.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1
1985, 379. (c) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J.
G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.;
Chamberlain, S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753. (d) Elsner,
J.; Boeckler, F.; Davidson, K.; Sugden, D.; Gmeiner, P. Bioorg.
Med. Chem. 2006, 14, 1949.
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Chem. Lett. 2008, 18, 1157. (b) Johns, B. A.; Gudmundsson, K. S.;
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M. R. Tetrahedron 2003, 59, 9001. (c) Mousseau, J. J.; Bull, J. A.;
Ladd, C. L.; Fortier, A.; Sustac, R. D.; Charette, A. B. J. Org. Chem.
2011, 76, 8243.
(9) (a) Tsuchiya, T.; Sashida, H. J. Chem. Soc., Chem. Commun. 1980,
1109. (b) Hoashi, Y.; Takai, T.; Kotani, E.; Koike, T. Tetrahedron
Lett. 2013, 54, 2199. (c) Takahashi, Y.; Hibi, S.; Hoshino, Y.;
Kikuchi, K.; Shin, K.; Murata-Tai, K.; Fujisawa, M.; Ino, M.;
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70, 2766.
6-[(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)methyl]picolic
Acid (EP1 Antagonist)
To a ice-cooled solution of 10 (90.0 mg, 0.24 mmol) in MeOH (1.2 mL)
was added 2 M aq KOH (0.60 mL, 1.19 mmol) and the mixture was
stirred at r.t. for 6 h. The reaction was quenched by the addition of 1
M HCl. A precipitate formed and it was collected by filtration and
then dried to give the title compound as a colorless solid; yield: 79.0
mg (90%); mp 173–174 °C.
IR (ATR): 3071, 2927, 2528, 1948, 1759, 1703, 1591, 1518, 1463, 1432,
1331, 1248, 1226, 1144, 1079, 995, 927, 829, 810, 752, 694, 661, 570,
482, 414 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 4.44 (s, 2 H), 7.26 (dd, J = 9.1, 1.8
Hz, 1 H), 7.31 (dd, J = 7.3, 1.8 Hz, 1 H), 7.37–7.47 (m, 3 H), 7.75 (d, J =
9.1 Hz, 1 H), 7.81–7.86 (m, 4 H), 9.03 (d, J = 1.8 Hz, 1 H), 13.08 (br s, 1
H).
13C NMR (100 MHz, DMSO-d6): δ = 31.4, 105.7, 117.9, 119.3, 122.4,
124.3, 125.4, 126.6, 128.3, 128.3, 128.6, 132.6, 138.1, 138.5, 147.9,
151.9, 160.1, 166.1.
LRMS (ESI): m/z = 364 [M + H]+
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3O2: 364.08528; found:
(12) Nishigaya, Y.; Umei, K.; Yamamoto, E.; Kohno, Y.; Seto, S. Tetra-
hedron Lett. 2014, 55, 5963.
364.08547.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1381025.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(15) Ding, S.; Yan, Y.; Jiao, N. Chem. Commun. 2013, 49, 4250.
(16) Mousseau, J. J.; Fortier, A.; Charette, A. B. Org. Lett. 2010, 12,
516.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3221–3230