Au(i)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide pyrazolo[1,5-a]pyridines

Article abstract of DOI:10.1039/c2ob25973g

Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated adducts were further converted to 6-arylpyrazolo[1,5

Full text of DOI:10.1039/c2ob25973g

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Volume 10 | Number 33 | 7 September 2012 | Pages 6609–6804
ISSN 1477-0520
PAPER
Ming-Jung Wu et al.
Au(I)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to
provide pyrazolo[1,5-a]pyridines

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PAPER
Au(I)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide
pyrazolo[1,5-a]pyridines†
Hung-Chou Wu,b Chia-Wen Yang,a Long-Chih Hwangb and Ming-Jung Wu*a
Received 21st May 2012, Accepted 27th June 2012
DOI: 10.1039/c2ob25973g
Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and
iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated
adducts were further converted to 6-arylpyrazolo[1,5-a]pyridines via Suzuki–Miyaura coupling reaction
and 6-cyanopyrazolo[1,5-a]pyridine by Ullmann condensation reaction. One of the cyclization adducts,
2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine, was converted to a p38 kinase inhibitor, 2-(4-fluorophenyl)-3-
(4-pyridinyl)pyrazolo[1,5-a]pyridine, in two steps.
cyclization11 of enynylpyrazoles and iodine-mediated cycliza-
Introduction
tion12 of enynylpyrazoles to provide iodinated pyrazolo[1,5-a]-
The pyrazolo[1,5-a]pyridine substructure exists widely in mo-
lecules of pharmaceutical interest. For instance, the 3-carboxy-
lated pyrazolo[1,5-a]pyridines have been shown to be potent and
selective 5HT3-antagonists,1 the 2,3-disubstituted pyrazolo[1,5-a]-
pyridines were evaluated as potent p38 kinase inhibitors
and showed good anti-inflammatory activity,2 a series of
aminomethyl-substituted pyrazolo[1,5-a]pyridines were reported
as high affinity D4 receptor ligands,3 8,9-dihydrofuro[3,2-c]-
pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2)
ligands were discovered recently4 and other substituted pyrazolo-
[1,5-a]-pyridines were shown to exhibit anti-herpetic activity.5
Due to the broad spectrum of biological activities of pyrazolo-
[1,5-a]pyridines, the development of an efficient method to con-
struct these heterocycles has become an important issue. The
general methods are the regioselective [3 + 2] cycloaddition of
N-aminopyridines with alkenes6 or alkynes,7 the thermal cycliza-
tion of pyridinyl aziridines2a,8 and the synthesis of pyrazolo[1,5-a]-
quinolines via multicomponent reaction.9 Recently, we reported
a new synthetic method to provide pyrazolo[1,5-a]pyridines by
the reaction of enediynones with hydrazine mediated by copper
chloride.10 However the drawbacks of this method are that a stoi-
chiometric amount of copper chloride, high reaction temperature
and long reaction time are required. In continuation of our study
on the synthesis of pyrazolo[1,5-a]pyridines, a more efficient
synthesis of pyrazolo[1,5-a]pyridines by the gold-catalyzed
pyridines is reported herein.
Results and discussion
The enediynones 1a–w were prepared according to our previous
report.10 Treatment of 1a–w with two equivalents of hydrazine
in acetonitrile at 60 °C for 30 minutes gave enynylpyrazoles
2a–w in 75–95% yields, respectively. (Table 1).
Our investigation on the cyclization of enynylpyrazoles to
provide pyrazolo[1,5-a]pyridines was performed by screening of
various transition metal catalysts, such as palladium, platinum,
copper, silver, zinc and gold. The results are summarized in
Table 2. The results shown palladium catalysts (PdCl2 and
Pd(OAc)2 are not efficient at catalyzing this cyclization reaction
(Table 2, entries 1 and 2). 10 mol% of CuCl was employed in
this study and only a trace amount of 3d was obtained. Using
one equivalent of CuCl and stirring the reaction mixture for
48 hours, compound 3d was obtained in 45% yield and 36%
yield of starting material was recovered (Table 2, entry 3).
10 mol% of silver carbonate and zinc trifluoroacetate are able to
promote this cyclization reaction to give the desired product in
70% and 80% yields, respectively (Table 2, entries 4 and 5).
However, these reactions required refluxing temperature and long
reaction time (three days). Platinum dichloride was also found to
be an efficient catalyst in this reaction (Table 2, entry 6). Finally,
gold catalysts were found to be the most powerful catalyst in this
cyclization reaction. For instance, treatment of 2d with 3 mol%
of chloroauric acid (HAuCl4) in THF at room temperature for
5 hours gave 2-phenyl-7-pentylpyrazolo[1,5-a]pyridine (3d) in
90% yield (Table 2, entry 7). Using the combination of 3 mol%
of Ph3PAuCl with 10 mol% of AgSbF6 as the catalyst in THF
gave 3d in almost quantitative yield (Table 2, entry 8). Other
aDepartment of Chemistry, National Sun Yat-sen University, Kaohsiung,
Taiwan. E-mail: mijuwu@faculty.nsysu.edu.tw; Fax: (+886)-7-5253909
bDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung, Taiwan
†Electronic supplementary information (ESI) available: Representative
experimental procedure and spectroscopic data for all newly synthesized
products. CCDC 883588 and 883589. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2ob25973g
6640 | Org. Biomol. Chem., 2012, 10, 6640–6648
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solvents, such as dichloromethane and 1,4-dioxane, gave the
product 3d in lower yields (Table 2, entries 9 and 10).
With the optimized reaction conditions in hand, cyclization of
other enynylpyrazoles 2a–c and 2e–w bearing different substi-
tuents on the alkyne terminus and pyrazole ring were also
carried out and the results are summarized in Table 3. With the
exception of compound 2f, the reactions gave the pyrazolo[1,5-a]-
pyridines all in good chemical yields. The low yield (46%) of
7-t-butylpyrazolo[1,5-a]pyridine 3f obtained by cyclization of 2f
could be due to the steric hindrance caused by the tert-butyl
group affecting the cyclization reaction. Compound 2e bearing a
less bulky substituent, an isobutyl group, at the alkyne terminus
provides pyrazolo[1,5-a]pyridine 3e in a slightly lower yield
(86%) than compounds 2b–d bearing a straight chain alkyl
group. It was also found that the electron density on the aryl
group at the alkyne terminus has little effect on this cyclization
reaction. Cyclization of compounds 2g–p under the optimized
reaction conditions gave the desired products 3g–p in excellent
yields (92–98%). We also investigated the effect of the substitu-
ent on the aryl group at the 3-position of the pyrazole ring and
found compounds bearing either an electron-donating group,
such as 2q–t, or an electron-withdrawing group, such as 2u and
2v, at the para-position of phenyl ring gave the pyrazolo[1,5-a]-
pyridines 3q–v all in good chemical yields (90–97%). Com-
pound 2w bearing methyl group at the 3-position of the pyrazolo
ring was also converted to the pyrazolo[1,5-a]pyridine 3w in
good yield.
After successfully developing the gold-catalyzed cyclization
of enynyl pyrazoles to provide pyrazolo[1,5-a]pyridines, we then
turn our attention to the iodine-mediated cyclization reaction to
prepare the iodinated pyrazolo[1,5-a]pyridines. Further func-
tional group transformation would allow us to prepare various
multi-substituted pyrazolo[1,5-a]pyridines. Thus, treatment of 2a
with two equivalents of iodine in CH2Cl2 at room temperature
for four hours gave 4a in 97% yield. Compounds 2b–o and
2q–w were also subjected to this cyclization reaction to give the
iodinated products 4b–o and 4q–w in 60–99% yields (Table 4).
The results indicated that this cyclization reaction proceeded
very smoothly under the described reaction conditions. Com-
pound 2f bearing a tert-butyl group at the alkyne terminus also
produced the cyclization product 4f in good yield (72%). Com-
pounds 4n–o and 4t–v bearing an electron-withdrawing group at
the alkyne terminus or on the phenyl ring of the pyrazole ring
Table 1 Synthesis of enynylpyrazoles
Entry Enediynones
Products/yields (%)
1
2
3
4
5
6
7
8
1a, R = H; R′ = Ph
1b, R = C6H13; R′ = Ph
1c, R = C4H9; R′ = Ph
1d, R = C5H11; R′ = Ph
1e, R = iso-butyl; R′ = Ph
1f, R = tert-butyl; R′ = Ph
1g, R = Ph; R′ = Ph
1h, R = o-CH3C6H4; R′ = Ph
1i, R = m-CH3C6H4; R′ = Ph
1j, R = p-CH3C6H4; R′ = Ph
1k, R = o-CH3OC6H4; R′ = Ph
1l, R = m-CH3OC6H4; R′ = Ph
1m, R = p-OCH3C6H4; R′ = Ph
1n, R = p-NO2C6H4; R′ = Ph
1o, R = p-CNC6H4; R′ = Ph
1p, R = o-SCH3C6H4; R′ = Ph
1q, R = C6H13; R′ = p-CH3OC6H4
1r, R = Ph; R′ = p-CH3OC6H4
2a/93
2b/94
2c/93
2d/95
2e/92
2f/88
2g/82
2h/86
2i/89
2j/84
2k/83
2l/86
2m/86
2n/80
2o/80
2p/80
2q/75
2r/78
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1s, R = p-CH3OC6H4; R′ = p-CH3OC6H4 2s/76
1t, R = p-CNC6H4; R′ = p-CH3OC6H4
1u, R = C6H13; R′ = p-CF3C6H4
1v, R = H; R′ = p-FC6H4
2t/78
2u/76
2v/87
2w/90
1w, R = C5H11; R′ = CH3
Table 2 Optimization of reaction conditions
Entry
Catalysts
Equiv.
Solvent
Temp.
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
PdCl2
Pd(OAc)2
CuCl
Ag2CO3
Zn(C2F3O2)2·xH2O
PtCl2
HAuCl4
PPh3AuCl/AgSbF6
PPh3AuCl/AgSbF6
PPh3AuCl/AgSbF6
10 mol%
10 mol%
100 mol%
10 mol%
10 mol%
10 mol%
3 mol%
3 mol%/10 mol%
3 mol%/10 mol%
3 mol%/10 mol%
CH3CN
THF
CH3CN
CH3CN
CH3CN
CH3CN
THF
THF
CH2Cl2
1,4-dioxane
Reflux
r.t.
r.t.
Reflux
Reflux
Reflux
r.t.
r.t.
r.t.
r.t.
24
24
48
72
24
24
5
5
5
5
20
11
45
70
80
77
90
99
68
86
10
This journal is © The Royal Society of Chemistry 2012
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Table 3 Synthesis of pyrazolo[1,5-a]pyridines under optimized
reaction conditions
Table 4 Synthesis of 6-iodopyrazolo[1,5-a]pyridines by iodine-
mediated cyclization
Entry Enynylpyrazoles
Products/yields (%)
Entry Enynylpyrazoles
Products/yields (%)
1
2
3
4
5
6
7
8
2a, R = H; R′ = Ph
2b, R = C6H13; R′ = Ph
2c, R = C4H9; R′ = Ph
2d, R = C5H11; R′ = Ph
2e, R = iso-butyl; R′ = Ph
2f, R = tert-butyl; R′ = Ph
2g, R = Ph; R′ = Ph
2h, R = o-CH3C6H4; R′ = Ph
2i, R = m-CH3C6H4; R′ = Ph
2j, R = p-CH3C6H4; R′ = Ph
2k, R = o-CH3OC6H4; R′ = Ph
2l, R = m-CH3OC6H4; R′ = Ph
2m, R = p-CH3OC6H4; R′ = Ph
2n, R = p-NO2C6H4; R′ = Ph
2o, R = p-CNC6H4; R′ = Ph
2p, R = o-CH3SC6H4; R′ = Ph
2q, R = C6H13; R′ = p-CH3OC6H4
2r, R = Ph; R′ = p-CH3OC6H4
3a/98
3b/99
3c/99
1
2
3
4
5
6
7
8
2a, R = H; R′ = Ph
2b, R = C6H13; R′ = Ph
2c, R = C4H9; R′ = Ph
2d, R = C5H11; R′ = Ph
2e, R = iso-butyl; R′ = Ph
2f, R = tert-butyl; R′ = Ph
2g, R = Ph; R′ = Ph
2h, R = o-CH3C6H4; R′ = Ph
2i, R = m-CH3C6H4; R′ = Ph
2j, R = p-CH3C6H4; R′ = Ph
2k, R = o-OCH3C6H4; R′ = Ph
2l, R = m-OCH3C6H4; R′ = Ph
2m, R = p-OCH3C6H4; R′ = Ph
2n, R = p-NO2C6H4; R′ = Ph
2o, R = p-CNC6H4; R′ = Ph
2q, R = C6H13; R′ = p-CH3OC6H4
2r, R = Ph; R′ = p-CH3OC6H4
4a/97
4b/98
4c/99
4d/99
4e/86
4f/72
4g/99
4h/92
4i/90
4j/99
4k/94
4l/95
4m/98
4n/68
4o/60
4q/88
4r/85
3d/99 (75)a
3e/86 (75)
3f/46b (13)
3g/97 (69)
3h/98 (61)
3i/94 (46)
3j/96 (63)
3k/95 (73)
3l/94 (45)
3m/98 (73)
3n/94 (45)
3o/92
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
10
11
12
13
14
15
16
17
18
19
20
21
22
3p/92
3q/91 (74)
3r/96 (67)
2s, R = p-OCH3C6H4; R′ = p-CH3OC6H4 4s/78
2s, R = p-CH3OC6H4; R′ = p-CH3OC6H4 3s/90 (71)
2t, R = p-CNC6H4; R′ = p-CH3OC6H4
2u, R = C6H13; R′ = p-CF3C6H4
2v, R = H; R′ = p-FC6H4
4t/68
4u/64
4v/82
4w/90
2t, R = p-CNC6H4; R′ = p-CH3OC6H4
2u, R = C6H13; R′ = p-CF3C6H4
2v, R = H; R′ = p-FC6H4
3t/97 (44)
3u/95 (42)
3v/90
2w, R = C5H11; R′ = CH3
2w, R = C5H11, R′ = CH3
3w/92
a Values in parentheses are the yields obtained by one-pot reaction
reported previously.10 b 40% of starting material was recovered.
of the 6-arylated pyrazolo[1,5-a]pyridines except the electron
poor boronic acids (Table 5, entries 5, 6 and 7). An iodinated
pyrazolo[1,5-a]pyridine 4v was also coupled with copper
cyanide15 to give the cyano substituted adduct 7 in 42% yield
(eqn (1))
gave the products in slightly lower yields. The lower yields of
product formation could be due to the lower electron density of
the triple bond that will affect the coordination of the iodonium
ion to the triple bond to mediate the cyclization reaction. The
electron-withdrawing groups on the phenyl ring would also
reduce the electron density and nucleophilicity of the pyrazole
ring affecting the cyclization reaction.
The proposed mechanisms for the formation of pyrazolo[1,5-a]-
pyridines 3 and iodinated products 4 are shown in Scheme 1.
First of all, the gold catalyst could coordinate to the triple bond
to form a complex I-1 that could then undergo 6-endo-dig hydro-
amination to give intermediate I-2.13 After removal of a proton
from I-2, the gold compound I-3 would undergo protonation to
give the product 3 and regenerate the gold catalyst to continue
the reaction cycle. On the other hand, iodine could coordinate
the triple bond to form II-1, then iodonium amination could gen-
erate the intermediate II-2. Removal of the proton by iodide
would give the product 4.
To demonstrate the synthetic utility of the iodinated pyrazolo-
[1,5-a]pyridines, some of these products were converted to
6-aryl substituted pyrazolo[1,5-a]pyridines by Suzuki–Miyaura
cross-coupling reactions14 of 4 with arylboronic acids 5 using
Pd(OAc)2 as the catalyst. The results are summarized in Table 5.
All the reactions proceed very smoothly to give a high yield
ð1Þ
On the other hand, compound 3v was converted to a p38
kinase inhibitor 9 in two steps (Scheme 2). Treatment of 3v with
one equivalent of N-bromosuccinimide in DMF at room temp-
erature for 90 minutes gave 8 in 85% yield. Compound 8 was
then coupled with 4-pyridinylboronic acid (5f) using
Pd(PPh3)2Cl2 and Na2CO3 as the base according to the literature
procedure,2 but the final product 9 was obtained in only 12%
yield. A significant amount (52%) of starting material 8 was
recovered. To optimize the reaction conditions, the catalyst was
replaced by Pd(OAc)2 and the base was changed to K2CO3. Stir-
ring the reaction mixture of 8 and 5f in DMF at 120 °C for
8 hours, the final product 9 was then obtained in 32% yield and
the amount of the recovered starting material 8 was reduced to
36% yield.
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Scheme 1 Proposed mechanisms for the formation of pyrazolo[1,5-a]pyridines 3 and iodinated products 4.
Table 5 Suzuki–Miyaura coupling reactions of 4 with aryl boronic acids
Entry
Compounds
Arylboronic acids
Time (h)
Products/yields (%)
1
2
3
4
5
6
7
8
9
4b, R1 = C6H13
4b, R1 = C6H13
5a, R2 = H
5b, R2 = OMe
5a, R2 = H
5b, R2 = OMe
5c, R2 = NO2
5d, R2 = F
5e, R2 = Cl
5a, R2 = H
5
8
8
6a/90
6b/87
6c/85
6d/70
6e/20a
6f/32a
6g/43a
6h/95
6i/73
4i, R1 = m-CH3C6H4
4i, R1 = m-CH3C6H4
4i, R1 = m-CH3C6H4
4i, R1 = m-CH3C6H4
4i, R1 = m-CH3C6H4
4k, R1 = o-CH3OC6H4
4k, R1 = o-CH3OC6H4
8
24
24
24
8
5b, R2 = OMe
8
a Entries 5, 6 and 7 also obtained compound 3i in 15, 13 and 12% yields, respectively.
inhibitor. Since pyrazolo[1,5-a]pyridines are important hetero-
cycles in both pharmaceutical science and material chemistry, we
believe the synthetic methods described here would have a
strong impact on these areas.
Experimental section
General considerations
Solvents were purified and dried by standard procedures. Flash
column chromatography was performed using 230–400 mesh
silica according to standard techniques. Melting points: Barn-
stead melting point apparatus. MS were run on SHIMADZU
QP2010 by EI (70 ev). 1H NMR spectra were measured on
500 MHz spectrometers. Natural abundance 13C NMR spectra
were measured using pulse Fourier transform, on a 500 MHz
NMR spectrometer operating at 125 MHz. 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 reference peak for 1H is δ 7.26 of
CDCl3, and for 13C it is the central peak at δ 77.0.
Scheme 2 Synthesis of p38 kinase inhibitor.
Conclusions
We have developed an efficient synthetic method to convert
enynylpyrazoles to pyrazolo[1,5-a]pyridines and 6-iodopyra-
zolo[1,5-a]pyridines by gold-catalyzed cyclization and iodine-
mediated cyclization reactions, respectively. The 6-iodopyrazolo-
[1,5-a]pyridines were further converted to 6-arylpyrazolo[1,5-a]-
pyridines by Suzuki–Miyaura cross-coupling reaction. We have
also demonstrated synthetic utility by preparing a p38 kinase
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1
General procedure for the synthesis of enynylpyrazoles 2
acetate = 5 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 8.46
(dd, J = 7.0, 1.0 Hz, 1H), 7.94 (m, 2H), 7.50 (d, J = 8.5 Hz,
1H), 7.16–7.09 (m, 3H), 6.73 (m, 2H); 13C NMR (CDCl3,
125 MHz): δ 163.9 (d, J = 246.1 Hz), 152.6, 141.6, 129.4 (d,
J = 3.3 Hz), 128.4, 128.1 (d, J = 8.2 Hz), 123.5, 117.8; MS (EI)
212 (M+, 100), 211 (M+ − H+, 100); HRMS (EI) calcd for
C13H9FN2 212.0750, found 212.0752.
Hydrazine monohydrate (0.3 mmol) was added to a solution of
enediynones (1) (0.15 mmol) in CH3CN (5 ml). The reaction
mixture was stirred at 60 °C for 30 minutes. After cooling to
room temperature, the solution was filtered through MgSO4 and
celite on cotton plug and washed with ethyl acetate. After
removal of solvent, the residue was purified by column
chromatography (silica gel) to give the products (2a–w).
Characterization data of 2 can be found in the ESI.†
2-Methyl-7-pentylpyrazolo[1,5-a]pyridine
(3w). Colorless
liquid; Rf = 0.48 (n-hexane–ethyl acetate = 20 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 7.31 (d, J = 8.5 Hz, 1H),
7.01 (dd, J = 9.0, 7.0 Hz, 1H), 6.51 (d, J = 7.0 Hz, 1H), 6.29
(s, 1H), 3.12 (t, J = 7.5 Hz, 2H), 2.52 (s, 3H), 1.85 (m, J =
7.5 Hz, 2H), 1.45–1.41 (m, 4H), 0.92 (t, J = 7.5 Hz, 3H);
13C NMR (CDCl3, 125 MHz): δ 150.8, 141.6, 141.5, 123.0,
114.5, 108.4, 96.1, 31.5, 30.7, 25.7, 22.5, 14.1, 13.9; MS (EI)
202 (M+, 35), 173 (20), 159 (23), 146 (100); HRMS (EI) calcd
for C13H18N2 202.1470, found 202.1470.
General procedure for the synthesis of pyrazolo[1,5-a]pyridines 3
Chloro(triphenylphosphine)gold(I) (0.0045 mmol) and silver
hexafluoroantimonate(V) (0.015 mmol) were added to a solution
of enynylpyrazoles (2) (0.15 mmol) in THF at room temperature
for 5 hours. The reaction mixture was directly passed through
celite and washed with ethyl acetate. After removal of solvent,
the residue was purified by column chromatography (silica gel)
to give the products (3a–w). Data of most compounds 3 were
found in the paper was reported.10
General procedure for the synthesis of 6-iodo-pyrazolo[1,5-a]-
pyridines 4
2-Phenylpyrazolo[1,5-a]pyridine (3a). Characterization data
was consistent with that reported in the literature:6c white solid;
m.p.: 110–112 °C; Rf = 0.56 (n-hexane–ethyl acetate = 10 : 1 as
Iodine (0.3 mmol) was added to a solution of enynylpyrazoles
(2) (0.15 mmol) in CH2Cl2 at room temperature for 4 hours. The
reaction mixture was then quenched with saturated Na2S2O3(aq)
(10.0 mL) and water (10.0 mL). The resulting solution was
extracted with CH2Cl2. The combined organic extracts were
dried over anhydrous MgSO4. After filtration and removal of
solvent, the residue was purified by column chromatography
(silica gel) to give the products (4a–w).
1
eluent); H NMR (CDCl3, 500 MHz): δ 8.49 (d, J = 7.0 Hz,
1H), 7.98 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 7.46 (t,
J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz,
1H), 6.80 (s, 1H), 6.73 (td, J = 7.0, 5.0 Hz, 1H); 13C NMR
(CDCl3, 125 MHz): δ 153.5, 141.5, 133.1, 128.7(2C), 128.4,
128.3, 126.4(2C), 123.4, 117.8, 111.6, 93.6 ppm; MS (EI)
194 (M+, 100), 193 (M+, 94); HRMS (EI) calcd for C13H10N2
194.0844, found 194.0843.
6-Iodo-2-phenylpyrazolo[1,5-a]pyridine (4a). Brown liquid;
1
Rf = 0.58 (n-hexane–ethyl acetate = 10 : 1 as eluent); H NMR
(CDCl3, 500 MHz): δ 7.73 (d, J = 7.0 Hz, 2H), 7.42 (t, J =
7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H),
6.77 (s, 1H), 6.39 (d, J = 11.5 Hz, 1H), 5.98 (dd, J = 11.5,
2.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 149.2, 142.9,
131.8, 131.2, 128.8(2C), 128.3, 125.7(2C), 121.3, 104.6, 93.0,
82.9; MS (EI) 320 (M+, 23), 254 (15), 194 (100); HRMS (EI)
calcd for C13H9N2I 319.9810, found 319.9810.
4-(2-Phenylpyrazolo[1,5-a]pyridin-7-yl)benzonitrile (3o). Yellow
solid; m.p.: 184–186 °C; Rf = 0.46 (n-hexane–ethyl acetate = 10 : 1
as eluent); H NMR (CDCl3, 500 MHz): δ 8.20 (d, J = 8.0 Hz,
1
2H), 7.94 (d, J = 7.2 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.59
(dd, J = 8.8, 1.2 Hz, 1H), 7.45–7.33 (m, 4H), 7.20 (dd, J = 9.2,
7.2 Hz, 1H), 6.93 (s, 1H), 6.87 (dd, J = 7.2, 1.6 Hz, 1H);
13C NMR (CDCl3, 125 MHz): 153.1, 142.7, 138.1, 138.0,
132.0(2C), 129.0(2C), 128.6(2C), 128.5, 126.5(2C), 123.3,
118.6, 118.2, 113.2, 112.7, 94.4; MS (EI) 295 (M+, 100),
294 (M+ − H+, 67); HRMS (EI) calcd for C20H13N3 295.1109,
found 295.1110.
7-Hexyl-6-iodo-2-phenylpyrazolo[1,5-a]pyridine (4b). Beige
solid; m.p.: 52–54 °C; Rf = 0.68 n-hexane–ethyl acetate = 10 : 1
1
as eluent); H NMR (CDCl3, 500 MHz): δ 8.00 (d, J = 7.0 Hz,
2H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.36 (d,
J = 9.5 Hz, 1H), 7.14 (d, J = 9.5 Hz, 1H), 6.79 (s, 1H), 3.48 (t,
J = 8.0 Hz, 2H), 1.82 (m, J = 7.0 Hz, 2H), 1.57–1.36 (m, 6H),
0.93 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ 152.6,
143.5, 141.2, 133.1, 132.7, 128.6(2C), 128.3, 126.5(2C), 116.1,
94.4, 78.1, 34.9, 31.4, 29.2, 25.6, 22.5, 14.0; MS (EI) 404 (M+,
44), 334 (100), 207(16); HRMS (EI) calcd for C19H21N2I
404.0749, found 404.0747.
7-(2-(Methylthio)phenyl)-2-phenylpyrazolo[1,5-a]pyridine (3p).
Yellow solid; m.p.: 144–146 °C; Rf = 0.54 (n-hexane–ethyl
1
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.90
(d, J = 6.8 Hz, 2H), 7.57 (dd, J = 8.8, 1.2 Hz, 1H), 7.50–7.27
(m, 7 Hz), 7.17 (dd, J = 8.8, 1.2 Hz, 1H), 6.89 (s, 1H), 6.75 (dd,
J = 6.8, 1.2 Hz, 1H), 2.37 (s, 3H); 13C NMR (CDCl3,
125 MHz): 142.0, 139.2, 139.1, 133.9, 133.5, 130.5, 129.6,
128.4(2C), 128.0, 127.7, 126.6(2C), 125.3, 122.9, 117.2, 113.3,
93.9, 17.2; MS (EI) 316 (M+, 68), 269 (100); HRMS (EI) calcd
for C20H16SN2 316.1034, found 316.1033.
7-Butyl-6-iodo-2-phenylpyrazolo[1,5-a]pyridine
(4c). Beige
solid; m.p.: 48–50 °C; Rf = 0.71 n-hexane–ethyl acetate = 10 : 1
1
as eluent); H NMR (CDCl3, 500 MHz): δ 8.01 (d, J = 7.5 Hz,
2H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.36 (d,
J = 9.5 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.80 (s, 1H), 3.50
(t, J = 8.0 Hz, 2H), 1.81 (q, J = 7.0 Hz, 2H), 1.57 (m, J =
7.5 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridine (3v). Characteri-
zation data was consistent with that reported in the literature:6c
yellow solid; m.p.: 144–146 °C; Rf = 0.44 (n-hexane–ethyl
6644 | Org. Biomol. Chem., 2012, 10, 6640–6648
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125 MHz): δ 152.6, 143.5, 141.2, 133.1, 132.7, 128.6(2C),
128.3, 126.5(2C), 116.1, 94.4, 78.2, 34.6, 27.9, 22.7, 13.9; MS
(EI) 376 (M+, 100), 334 (100), 207(30); HRMS (EI) calcd for
C17H17N2I 376.0436, found 376.0434.
2H), 7.52 (d, J = 9.0 Hz, 1H), 7.48–7.27 (m, 8H), 6.86 (s, 1H),
2.47 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 153.1, 142.1,
141.5, 138.0, 135.8, 133.0, 132.8, 130.6, 130.1, 128.5(2C),
128.4, 128.3, 127.1, 126.5(2C), 117.5, 94.6, 79.5, 21.5; MS (EI)
410 (M+,100), 409 (M+ − H+, 67), 283 (14); HRMS (EI) calcd
for C20H15N2I 410.0280, found 410.0279.
6-Iodo-7-pentyl-2-phenylpyrazolo[1,5-a]pyridine (4d). Beige
solid; m.p.: 50–52 °C; Rf = 0.70 n-hexane–ethyl acetate = 10 : 1
1
6-Iodo-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyridine (4j). Brown
solid; m.p.: 138–140 °C; Rf = 0.53 (n-hexane–ethyl acetate =
as eluent); H NMR (CDCl3, 500 MHz): δ 8.00 (d, J = 7.5 Hz,
2H), 7.46 (t, J = 7.5 Hz, 2H), 8.37 (t, J = 8.0 Hz, 2H), 7.15 (d,
J = 9.0 Hz, 1H), 6.8 (s, 1H), 3.48 (t, J = 8.0 Hz, 2H), 1.84 (m,
J = 7.5 Hz, 2H), 1.53 (m, J = 7.0 Hz, 2H), 1.45 (m, J = 6.0 Hz,
2H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ
152.7, 143.6, 141.2, 133.2, 132.8, 128.7, 128.4, 126.5, 116.2,
94.4, 78.2, 34.9, 31.7, 25.4, 22.3, 14.0; MS (EI) 390 (M+, 23),
334 (100), 207(8); HRMS (EI) calcd for C18H19N2I 390.0593,
found 390.0595.
1
10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.84 (d, J =
7.5 Hz, 2H), 7.52 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H),
7.38–7.28 (m, 7H), 2.50 (s, 3H); 13C NMR (CDCl3, 125 MHz):
δ 153.1, 142.0, 141.5, 139.3, 133.0, 132.9, 132.8, 130.0(2C),
129.1(2C), 128.4(2C), 128.3, 126.5(2C), 117.5, 94.6, 79.5, 21.6;
MS (EI) 410 (M+, 100), 409 (M+ − H+, 99); HRMS (EI) calcd
for C20H15N2I 410.0280, found 410.0281.
6-Iodo-7-(2-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyridine
(4k). Yellow solid; m.p.: 182–184 °C; Rf = 0.51 (n-hexane–
ethyl acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz):
δ 7.82 (d, J = 7.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.50 (d, J =
9.0 Hz, 1H), 7.36–7.27 (m, 4H), 7.15 (dd, J = 7.5, 1.0 Hz, 1H),
7.0 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 3.77 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 157.2, 152.9, 141.2, 140.1, 133.1, 132.4,
131.3, 131.0, 128.4(2C), 128.2, 126.5(2C), 125.5, 120.7, 117.5,
111.7, 94.4, 80.6, 55.9; MS (EI) 426 (M+, 36), 395 (100);
HRMS (EI) calcd for C20H15ON2I 426.0229, found 426.0229.
6-Iodo-7-isobutyl-2-phenylpyrazolo[1,5-a]pyridine (4e). Brown
liquid; Rf = 0.66 (n-hexane–ethyl acetate = 10 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 8.00 (d, J = 7.5 Hz, 2H), 7.45 (t,
J = 7.0 Hz, 2H), 7.39–7.35 (m, 2H), 7.15 (d, J = 9.5 Hz, 1H),
6.79 (s, 1H), 3.41 (d, J = 7.0 Hz, 2H), 2.61 (m, J = 6.5 Hz, 1H),
1.08 (d, J = 7.0 Hz, 6H); 13C NMR (CDCl3, 125 MHz): δ 152.4,
142.7, 141.2, 133.1, 132.9, 128.6(2C), 128.3, 126.4(2C), 116.2,
94.3, 79.5, 42.9, 26.9, 22.6(2C); MS (EI) 376 (M+, 34),
334 (100), 207(14); HRMS (EI) calcd for C17H17N2I 376.0436,
found 376.0438.
1
6-Iodo-7-(3-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyridine
(4l). Yellow solid; m.p.: 136–138 °C; Rf = 0.47 (n-hexane–ethyl
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.85
7-tert-Butyl-6-iodo-2-phenylpyrazolo[1,5-a]pyridine (4f). Brown
liquid; Rf = 0.61 (n-hexane–ethyl acetate = 10 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 8.00 (d, J = 8.5 Hz, 2H), 7.36
(d, J = 9.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz,
1H), 7.04 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 1.93 (s, 9H);
13C NMR (CDCl3, 125 MHz): δ 150.3, 146.4, 142.3, 139.0,
133.2, 128.6(2C), 128.2, 126.3(2C), 116.5, 93.4, 71.5, 39.5,
31.0(3C); MS (EI) 376 (M+, 43), 334 (100); HRMS (EI) calcd
for C17H17N2I 376.0437, found 376.0439.
1
(d, J = 7.0 Hz, 2H), 7.52 (d, J = 9.5 Hz, 1H), 7.49 (t, J = 7.5 Hz,
1H), 7.37 (t, J = 8.0 Hz, 2H), 7.32–7.28 (m, 2H), 7.13 (dt, J =
7.5, 1.0 Hz, 1H), 7.10–7.08 (m, 2H), 6.87 (s, 1H), 3.88 (s, 1H);
13C NMR (CDCl3, 125 MHz): δ 159.4, 153.1, 141.7, 141.5,
137.0, 132.9, 132.8, 129.5, 128.5(2C), 128.3, 126.5(2C), 122.4,
117.6, 115.5, 115.3, 94.6, 79.3, 55.3; MS (EI) 426 (M+, 36), 425
(M+ − H+, 67); HRMS (EI) calcd for C20H15ON2I 426.0229,
found 426.0229.
6-Iodo-2,7-diphenylpyrazolo[1,5-a]pyridine
(4g). Brown
liquid; Rf = 0.54 (n-hexane–ethyl acetate = 10 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 7.83 (d, J = 7.5 Hz, 2H),
7.59–7.51 (m, 6H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz,
2H), 6.87 (s, 1H); 13C NMR (CDCl3, 125 MHz): δ 153.1, 141.9,
141.5, 135.9, 133.0, 132.7, 130.1(2C), 129.4, 128.5(2C),
128.4(2C), 128.3, 126.5(2C), 117.6, 94.6, 79.4; MS (EI) 396
(M+,100), 395 (M+ − H+, 73); HRMS (EI) calcd for C19H13N2I
396.0124, found 396.0122.
6-Iodo-7-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyridine
(4m). Yellow solid; m.p.: 188–200 °C; Rf = 0.48 (n-hexane–
ethyl acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ
1
7.84 (d, J = 7.0 Hz, 2H), 7.52–7.49 (m, 3H), 7.36 (t, J = 8.0 Hz,
2H), 7.32–7.25 (m, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.86 (s, 1H),
3.92 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 160.2, 153.0,
141.8, 141.5, 131.1, 132.9, 131.7(2C), 128.5(2C), 128.3, 128.1,
126.5(2C), 117.4, 113.7(2C), 94.6, 79.8, 55.2; MS (EI) 426
(M+,100), 425 (M+
C20H15ON2I 426.0229, found 426.0228.
−
H+, 61); HRMS (EI) calcd for
6-Iodo-2-phenyl-7-o-tolylpyrazolo[1,5-a]pyridine (4h). Brown
solid; m.p.: 118–120 °C; Rf = 0.54 (n-hexane–ethyl acetate =
1
10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.82 (d, J =
6-Iodo-7-(4-nitrophenyl)-2-phenylpyrazolo[1,5-a]pyridine (4n).
Brown solid; m.p.: 196–198 °C, Rf = 0.44 (n-hexane–ethyl
9.5 Hz, 2H), 7.52 (d, J = 10.5 Hz, 1H), 7.48–7.28 (m, 8H), 6.87
(s, 1H), 2.08 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 153.4,
142.2, 141.2, 137.0, 136.2, 132.8, 132.4, 130.1, 129.8, 128.4
(2C), 128.3, 126.5(2C), 126.0, 117.6, 94.6, 80.0, 19.0; MS (EI)
410 (M+,100), 409 (M+ − H+, 88); HRMS (EI) calcd for
C20H15N2I 410.0280, found 410.0281.
1
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 8.43
(d, J = 8.5 Hz, 2H), 7.80 (d, J = 7.0 Hz, 2H), 7.76 (d, J =
8.5 Hz, 2H), 7.54 (d, J = 9.0 Hz, 1H), 7.38–7.31 (m, 4H),
6.91 (s, 1H); 13C NMR (CDCl3, 125 MHz): δ 153.5, 148.3,
141.9, 141.4, 139.4, 132.9, 132.3, 131.7(2C), 128.7, 128.6(2C),
126.5(2C), 123.8(2C), 118.6, 95.1, 78.9; MS (EI) 441 (M+,100),
440 (M+ − H+, 32); HRMS (EI) calcd for C19H12O2N3I
440.9974, found 440.997.
6-Iodo-2-phenyl-7-m-tolylpyrazolo[1,5-a]pyridine (4i). Brown
solid; m.p.: 78–80 °C; Rf = 0.52 (n-hexane–ethyl acetate = 10 : 1
1
as eluent); H NMR (CDCl3, 500 MHz): δ 7.84 (d, J = 7.0 Hz,
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4-(6-Iodo-2-phenylpyrazolo[1,5-a]pyridin-7-yl)benzonitrile (4o).
Yellow solid; m.p.: 182–184 °C; Rf = 0.46 (n-hexane–ethyl
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.87
9.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 3.48 (t, J =
8.0 Hz, 2H), 1.81 (m, J = 7.5 Hz, 2H), 1.54 (m, J = 8.0 Hz, 2H),
1.45–1.36 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
1
(d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.0 Hz, 2H), 7.68 (d, J =
8.0 Hz, 2H), 7.53 (d, J = 9.5 Hz, 1H), 7.39–7.31 (m, 4H), 6.89
(s, 1H); 13C NMR (CDCl3, 125 MHz): δ 153.4, 141.4, 140.1,
139.7, 132.9, 132.4, 132.3(2C), 131.3(2C), 128.7, 128.6(2C),
126.5(2C), 118.6, 118.5, 113.3, 95.0, 78.9; MS (EI) 421
(M+,100), 420 (M+ − H+, 52); HRMS (EI) calcd for C20H12N3I
421.0076, found 421.0076.
125 MHz): 151.1, 143.6, 141.3, 136.6, 133.1, 130.2 (q, JC–F
=
31.8 Hz), 126.6(2C), 125.6 (q, JC–F = 4.1 Hz, 2C), 116.3, 94.9,
78.9, 34.8, 29.2, 25.6, 22.5, 14.1; MS (EI) 472 (M+, 94), 402
(100), 275 (44); HRMS (EI) calcd for C20H20N2F3I 472.0623,
found 472.0625.
2-(4-Fluorophenyl)-6-iodopyrazolo[1,5-a]pyridine (4v). Yellow
liquid; Rf = 0.33 (n-hexane–ethyl acetate = 3 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 7.69 (dd, J = 8.5, 5.5 Hz, 2H),
7.21 (d, J = 2.0 Hz, 1H), 7.09 (t, J = 8.5 Hz, 2H), 6.71 (s, 1H),
6.34 (d, J = 12.0 Hz, 1H), 5.96 (dd, J = 12.0, 2.0 Hz, 1H);
13C NMR (CDCl3, 125 MHz): δ 163.7 (d, J = 246.5 Hz), 149.1,
142.1, 132.1, 127.8 (d, J = 2.7 Hz), 127.6 (d, J = 8.3 Hz), 120.6,
115.8 (d, J = 21.3 Hz), 104.5, 92.8, 83.1; MS (EI) 337 (M+,
100), 336 (M+ − H+, 95); HRMS (EI) calcd for C13H8N2FI
337.9716, found 337.9714.
7-Hexyl-6-iodo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (4q).
Brown liquid; Rf = 0.58 (n-hexane–ethyl acetate = 10 : 1 as
1
eluent); H NMR (CDCl3, 500 MHz): δ 7.92 (d, J = 9.0 Hz,
2H), 7.34 (d, J = 9.5 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 6.71 (s,
1H), 3.87 (s, 3H), 3.46 (t, J = 8.0 Hz, 2H), 1.81 (q, J = 7.5 Hz,
2H), 1.54 (q, J = 7.0 Hz, 2H), 1.40 (m, 4H), 0.93 (t, J = 7.0 Hz,
3H); 13C NMR (CDCl3, 125 MHz): 159.9, 152.5, 143.4, 141.2,
132.7, 127.7(2C), 125.8, 115.9, 114.1(2C), 93.7, 77.8, 55.3,
34.8, 31.4, 29.2, 25.6, 22.5, 14.1; MS (EI) 434 (M+, 31), 364
(100); HRMS (EI) calcd for C20H23ON2I 434.0855, found
434.0854.
6-Iodo-2-methyl-7-pentylpyrazolo[1,5-a]pyridine (4w). Yellow
liquid; Rf = 0.52 (n-hexane–ethyl acetate = 20 : 1 as eluent);
1H NMR (CDCl3, 500 MHz): δ 7.30 (d, J = 9.0 Hz, 1H), 7.03
(d, J = 9.0 Hz, 1H), 6.27 (s, 1H), 3.38 (t, J = 7.5 Hz, 1H), 2.48
(s, 3H), 1.75 (m, J = 7.5 Hz, 2H), 2.48 (s, 3H), 1.75 (m, J =
7.5 Hz, 2H), 1.51–1.37 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): δ 151.2, 143.0, 140.7, 132.4, 115.4,
97.0, 77.3, 34.8, 31.6, 25.6, 22.4, 14.0; MS (EI) 328 (M+, 12),
272 (100); HRMS (EI) calcd for C13H17IN2 328.0436, found
328.0436.
6-Iodo-2-(4-methoxyphenyl)-7-phenylpyrazolo[1,5-a]pyridine
(4r). Yellow solid; m.p.: 180–182 °C, Rf = 0.52 (n-hexane–ethyl
1
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.75
(d, J = 9.0 Hz, 2H), 7.58–7.49 (m, 6H), 7.26 (d, J = 9.5 Hz,
1H), 6.89 (d, J = 9 Hz, 2H), 6.78 (s, 1H), 3.81 (s, 3H);
13C NMR (CDCl3, 125 MHz):159.8, 153.0, 141.8, 141.5, 136.0,
132.9, 130.1(2C), 129.3, 128.3(2C), 127.8(2C), 125.5, 117.4,
113.9(2C), 94.0, 79.0, 55.2; MS (EI) 426 (M+, 100), 425
(M+ − H+, 46); HRMS (EI) calcd for C20H15ON2I 426.0229,
found 426.0227.
7-Hexyl-2,6-diphenylpyrazolo[1,5-a]pyridine (6a). Green liquid;
1
Rf = 0.52 (n-hexane–ethyl acetate = 10 : 1 as eluent); H NMR
(CDCl3, 500 MHz): δ 8.06 (d, J = 8.0 Hz, 2H), 7.49–7.36 (m,
9H), 7.06 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 3.19 (t, J = 8.0 Hz),
1.89 (m, 7.0 Hz, 2H), 1.31–0.127 (m, 6H), 0.89 (t, J = 6.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): 152.7, 141.1, 139.9, 139.4,
133.8, 129.6 (2C), 128.6 (2C), 128.3 (2C), 128.1, 127.2,
126.4 (2C), 124.7, 114.5, 93.4, 31.2, 29.2, 28.5, 26.6, 22.4,
14.0; MS (EI) 354 (M+, 30), 284 (100), 283 (59); HRMS (EI)
calcd for C25H26N2 354.2096, found 354.2097.
6-Iodo-2,7-bis(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (4s).
Beige solid; m.p.: 192–194 °C, Rf = 0.55 (n-hexane–ethyl
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.77
(d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.24 (d, J =
9.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H),
6.77 (s, 1H), 3.92 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3,
125 MHz): 160.1, 159.8, 152.9, 141.7, 141.6, 133.0, 131.7(2C),
128.2, 127.8(2C), 125.6 117.2, 113.9(2C), 113.6(2C), 94.0,
79.3, 55.2; MS (EI) 456 (M+, 44), 85(56), 71 (75); HRMS (EI)
calcd for C21H17O2N2I 456.0335, found 456.0336.
1
7-Hexyl-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyridine
(6b). Brown liquid; Rf = 0.66 (n-hexane–ethyl acetate = 30 : 1 as
1
eluent); H NMR (CDCl3, 500 MHz): δ 8.05 (d, J = 7.0 Hz,
4-(6-Iodo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl)-
benzonitrile (4t). Yellow solid; m.p.: 188–190 °C; Rf = 0.46
(n-hexane–ethyl acetate = 10 : 1 as eluent); 1H NMR (CDCl3,
500 MHz): δ 7.86 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H),
7.68 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 9.5 Hz, 1H), 7.32 (d, J =
9.5 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.81 (s, 1H), 3.82 (s, 3H);
13C NMR (CDCl3, 125 MHz): δ 160.1, 153.3, 141.4, 140.2,
139.6, 132.8, 132.3(2C), 131.3(2C), 127.8(2C), 125.1, 118.5,
118.3, 114.0, 94.3, 78.4, 55.2; MS (EI) 451 (M+, 100), 450
(M+ − H+, 67); HRMS (EI) calcd for C21H14ON3I 451.0182,
found 451.0181.
2H), 7.48–7.29 (m, 6H), 7.04 (d, J = 9.0 Hz, 1H), 7.00 (d, J =
8.5 Hz, 2H), 6.83 (s, 1H), 3.88 (s, 3H), 3.18 (t, J = 7.5 Hz, 2H),
1.87 (m, J = 7.5 Hz, 2H), 1.40–1.25 (m, 6H), 0.88 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ 158.8, 152.6,
141.0, 139.9, 133.8, 131.8, 130.6, 128.6, 128.0, 126.7, 126.4,
124.3, 114.4, 113.7, 93.3, 55.3, 31.2, 29.2, 28.5, 26.6, 22.5,
14.0; MS (EI) 384 (M+, 27), 314 (72), 214 (77), 202 (68);
HRMS (EI) calcd for C26H28N2O 384.2202, found 384.2200.
2,6-Diphenyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine (6c). White
solid; m.p.: 166–168 °C; Rf = 0.60 (n-hexane–ethyl acetate =
30 : 1 as eluent); 1H NMR (CDCl3, 500 MHz): δ 7.87 (d, J = 7.5 Hz,
2H), 7.61 (d, J = 9.0 Hz, 1H), 7.36–7.09 (m, 13H), 6.89 (s, 1H),
2.11 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 153.3, 141.1,
138.7, 138.3, 138.0, 133.5, 132.7, 131.0, 129.7, 129.5, 128.7,
128.4, 128.1, 127.9, 126.7, 126.5, 126.4, 125.6, 125.5, 116.5,
7-Hexyl-6-iodo-2-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]-
pyridine (4u). Brown liquid; Rf
acetate = 10 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 8.10
(d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.39 (d, J =
= 0.50 (n-hexane–ethyl
1
6646 | Org. Biomol. Chem., 2012, 10, 6640–6648
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93.6, 19.6; MS (EI) 360 (M+, 68), 345 (100); HRMS (EI) calcd
for C26H20N2 360.1626, found 360.1628.
7-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo-
[1,5-a]pyridine (6i). White solid; m.p.: 212–214 °C; Rf = 0.60
(n-hexane–ethyl acetate = 30 : 1 as eluent); 1H NMR (CDCl3,
500 MHz): δ 7.88 (d, J = 7.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 1H),
7.39–7.20 (m, 6H), 7.12 (d, J = 8.5 Hz, 2H), 6.95 (m, 2H), 6.86
(s, 1H), 6.75 (d, J = 8.5 Hz, 2H), 3.76 (s, 3H), 3.64 (s, 3H);
13C NMR (CDCl3, 125 MHz): δ 158.3, 158.2, 152.7, 141.0,
135.2, 133.8, 132.0, 131.5, 130.4, 130.1, 128.4, 127.9, 126.5,
122.6, 120.5, 116.3, 113.2, 111.4, 93.4, 55.7, 55.1; MS (EI)
406 (M+, 12), 375 (21), 284 (11), 149 (21); HRMS (EI) calcd
for C27H22N2O2 406.1681, found 406.1679.
6-(4-Methoxyphenyl)-2-phenyl-7-(m-tolyl)pyrazolo[1,5-a]-
pyridine (6d). White solid; m.p.: 206–208 °C; Rf = 0.55 (n-hexane–
1
ethyl acetate = 30 : 1 as eluent); H NMR (CDCl3, 500 MHz):
δ 7.87 (d, J = 7.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.38–7.25
(m, 5H), 7.14 (d, J = 4.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 6.89
(s, 1H), 6.74 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 158.3, 153.2, 141.0, 137.6, 133.5, 132.8,
131.0, 130.5, 129.7, 128.6, 128.4, 128.0, 126.6, 125.5, 125.2,
116.4, 113.4, 93.5, 53.1, 19.6; MS (EI) 390 (M+, 82), 375 (81),
345 (100); HRMS (EI) calcd for C27H22N2O 390.1732, found
390.1729.
2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (7).
Characterization data was consistent with that reported in
the literature2a: brown solid; m.p.: 128–130 °C; Rf = 0.32
(n-hexane–ethyl acetate = 2 : 1 as eluent);1H NMR (CDCl3,
500 MHz): δ 8.73 (s, 1H), 7.91 (dd, J = 9.0, 5.5 Hz, 2H),
7.31–7.27 (m, 2H), 7.14 (t, J = 8.5 Hz, 2H), 6.74 (s, 1H); 13C
NMR (CDCl3, 125 MHz): δ 164.1 (d, J = 246.5 Hz), 152.8,
140.2, 135.5, 131.4, 128.8 (d, J = 3.1 Hz), 128.2 (d, J = 32.5
Hz), 118.5, 115.8 (d, J = 21.5 Hz), 94.2, 73.8, 29.6; MS (EI)
237 (M+, 100), 236 (M+ − H+, 99); HRMS (EI) calcd for
C14H8N3F 237.0702, found 237.0704.
6-(4-Nitrophenyl)-2-phenyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine
(6e). Yellow solid; m.p.: 238–240 °C; Rf = 0.38 (n-hexane–ethyl
1
acetate = 5 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 8.37
(d, J = 9.0 Hz, 1H), 8.06 (d, J = 7.5 Hz, 2H), 7.79 (d, J =
9.0 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.39–7.25 (m, 6H), 7.13
(t, J = 7.5 H, 1H), 6.95 (, 1H), 2.13 (s, 3H); 13C NMR (CDCl3,
125 MHz): δ 154.1, 141.3, 138.7, 138.3, 133.1, 131.8, 130.8,
130.2, 130.1, 129.4, 128.5, 128.4, 128.3, 126.5, 125.9, 125.2,
124.3, 123.2, 117.1, 94.2, 19.6; MS (EI) 405 (M+, 100), 404
(M+ − H+, 87); HRMS (EI) calcd for C26H19N3O2 405.1477,
found 405.1478.
3-Bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (8). Charac-
terization data was consistent with that reported in the litera-
ture2a: tan solid; Rf = 0.45 (n-hexane–ethyl acetate = 5 : 1 as
1
eluent); H NMR (CDCl3, 500 MHz): δ 8.43 (d, J = 7.0 Hz,
6-(4-Fluorophenyl)-2-phenyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine
(6f). Beige solid; m.p.: 208–210 °C; Rf = 0.56 (n-hexane–ethyl
1H), 8.04 (dd, J = 8.5, 5.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H),
7.23–7.16 (m, 3H), 6.83 (t, J = 6.5 Hz, 1H); 13C NMR (CDCl3,
125 MHz): δ 164.1 (d, J = 247.4 Hz), 149.4, 139.9, 130.2 (d,
J = 8.3 Hz), 128.6, 128.0 (d, J = 3.1 Hz), 124.4, 116.9, 115.5 (d,
J = 21.5 Hz), 112.7, 81.9; MS (EI) 292 (M + 2, 100), 290 (M+,
100), 211 (83); HRMS (EI) calcd for C12H8BrFN2 289.9855,
found 289.9854.
1
acetate = 30 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.87
(d, J = 7.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.37 (t, J = 7.5 Hz,
2H), 7.32–7.23 (m, 4H), 7.15–7.07 (m, 4H), 6.90–6.87 (m, 3H),
2.11 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 162.6 (d, J =
245.1 Hz), 153.5, 141.1, 138.2, 138.0, 134.7 (d, J = 3.6 Hz),
133.4, 132.5, 131.0 (d, J = 7.4 Hz), 130.9, 129.8, 128.8, 128.4,
128.1, 126.5 (d, J = 75.6 Hz), 125.6, 124.5, 116.6, 115.0 (d, J =
21.0 Hz), 93.7, 19.6; MS (EI) 378 (M+, 100), 379 (M + 1, 30);
HRMS (EI) calcd for C26H19N2F 378.1532, found 378.1534.
2-(4-Fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (9).
White solid; m.p.: 136–138 °C; Rf = 0.48 (n-hexane–ethyl
1
acetate = 5 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 8.57
(brs, 2H), 8.50 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H),
7.53 (m, 2H), 7.26–7.19 (m, 3H), 7.05 (t, J = 8.5 Hz, 2H), 6.85
(dt, J = 7.0, 1.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 163.9
(d, J = 247.5 Hz), 150.8, 150.1, 141.1, 139.4, 130.7 (d, J =
8.3 Hz), 128.6, 128.4 (d, J = 3.1 Hz), 125.0, 124.0, 116.5, 115.6
(d, J = 21.5 Hz), 112.8, 107.1; MS (EI) 290 (M + 1, 30), 289
(M+, 100); (HRMS (EI) calcd for C18H12N3F 289.1015, found
289.1014.
6-(4-Chlorophenyl)-2-phenyl-7-(m-tolyl)pyrazolo[1,5-a]pyridine
(6g). Beige solid; m.p.: 182–184 °C; Rf = 0.62 (n-hexane–ethyl
acetate = 30 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.91
(d, J = 8.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 1H), 7.39 (t, J = 7.5 Hz,
2H), 7.33–7.19 (m, 8H), 7.09 (d, J = 8.5 Hz, 2H), 6.90 (s, 1H),
2.32 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 153.2, 141.5,
138.1, 137.6, 137.5, 133.3, 132.6, 132.0, 131.8, 131.2, 129.5,
128.9, 128.4, 128.1, 127.8, 126.5, 124.0, 116.5, 93.8, 21.4; MS
(EI) 394 (M+, 100), 396 (M + 2, 52); HRMS (EI) calcd for
C26H19N2Cl 394.1237, found 394.1235.
1
Acknowledgements
7-(2-Methoxyphenyl)-2,6-diphenylpyrazolo[1,5-a]pyridine (6h).
White solid; m.p.: 172–174 °C; Rf = 0.58 (n-hexane–ethyl
acetate = 30 : 1 as eluent); H NMR (CDCl3, 500 MHz): δ 7.89
We thank the National Science Council of Republic of China for
financial support of this program.
1
(d, J = 7.5 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.38–7.17 (m,
11H), 6.95–6.91 (m, 2H), 6.88 (s, 1H), 3.61 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 158.1, 152.8, 141.2, 139.2, 133.7, 132.1,
130.3, 129.4, 128.4, 127.9, 127.7, 126.6, 126.4, 126.2, 126.0,
122.4, 120.4, 116.4, 111.3, 93.4, 55.6; 376 (M+, 97), 359 (67),
345 (100), HRMS (EI) calcd for C18H20N2O 376.1576, found
376.1579.
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This journal is © The Royal Society of Chemistry 2012