Synthesis of pyrazolo[1,5-a]quinolines from 1-aryl-5-styrylpyrazoles via intramolecular Friedel-Crafts reaction/aerobic oxidation

Article abstract of DOI:10.1002/bkcs.10225

Various pyrazolo[1,5-a]quinolines were synthesized via the intramolecular Friedel-Crafts reaction of 1-aryl- 5-styrylpyrazoles and the following base-catalyzed aerobic oxidation process. The required 1-aryl-5- styrylpyrazoles were readily prepared from th

Full text of DOI:10.1002/bkcs.10225

Article
DOI: 10.1002/bkcs.10225
BULLETIN OF THE
H. R. Moon et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles via
Intramolecular Friedel-Crafts Reaction/Aerobic Oxidation
*
Hye Ran Moon, Jin Yu, Ko Hoon Kim, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757,
Korea. *E-mail: kimjn@chonnam.ac.kr
Received November 29, 2014, Accepted December 16, 2014, Published online March 17, 2015
Various pyrazolo[1,5-a]quinolines were synthesized via the intramolecular Friedel-Crafts reaction of 1-aryl-
5-styrylpyrazoles and the following base-catalyzed aerobic oxidation process. The required 1-aryl-5-
styrylpyrazoles were readily prepared from the corresponding conjugated dienones and arylhydrazines in a
one-pot process.
Keywords: Pyrazolo[1,5-a]quinolines, Friedel-Crafts reaction, Conjugated dienones, 5-Styrylpyrazoles,
Aerobic oxidation
Introduction
Results and Discussion
Fused aza-heterocycles such as pyrazolo[1,5-a]pyridines and
pyrazolo[1,5-a]quinolines have received much attention due
to their interesting biological activities.1,2 As an example,
some pyrazolo[1,5-a]quinoline derivatives showed dopamine
D4 antagonistic and GPR109a agonistic activities.1a,b Thus,
numerous synthetic methods of pyrazolo[1,5-a]quinolines
have been developed.2 Recently, Yokomatsu and coworkers
have reported the synthesis of pyrazolo[1,5-a]quinolines via
a combination of aromatic nucleophilic substitution (SNAr)
and Knoevenagel condensation reactions.2a,b Charette and
coworkers developed a palladium-catalyzed alkenylation of
N-iminoquinolinium ylide with alkenyl iodide and the follow-
ing silver-mediated cyclization process.2c,d Miura and cowor-
kers reported a rhodium-catalyzed oxidative coupling reaction
of 1-phenylpyrazoles and internal alkynes.2e Shi and cowor-
kers reported a 1,3-dipolar cycloaddition of isoquinolinium
imides and acetylene dicarboxylate.2f However, most of these
methods required an inconvenient multi-step process, thus
development of an efficient synthetic method of pyrazolo
[1,5-a]quinolines is highly required.
Very recently, we reported an efficient one-pot synthesis of
pyrazoles by the reaction of α,β-enones and arylhydrazine
hydrochlorides in 1,2-dichlorobenzene (ODCB) under O2 bal-
loon atmosphere.3 As a continuing study, we envisaged that
pyrazolo[1,5-a]quinoline 4a could be synthesized from conju-
gated dienone 1a via a sequential preparation of 1-phenyl-5-
styrylpyrazole 2a, an acid-catalyzed intramolecular Friedel-
Crafts (IMFC) reaction to form 3a, and a base-catalyzed aer-
obic oxidation to4a, as shown inScheme1. The preparation of
pyrazole 2a was carried out in reasonable yield (68%) in a one-
pot reaction from dienone 1a, which was prepared from cinna-
maldehyde and acetophenone by the Knoevenagel condensa-
tion reaction, and phenylhydrazine hydrochloride in ODCB
under O2 balloon atmosphere according to our recent paper.3
To our delight, polyphosphoric acid (PPA)-catalyzed IMFC
reaction of 2a (100 ꢀC, 2 h) produced dihydropyrazolo[1,5-
a]quinoline 3a in good yield (94%).4,5 The corresponding
five-membered ring compound 5a was not formed in the reac-
tion. The reason can be ascribed to the stability of the benzylic
carbocation I rather than the secondary carbocation II. The
Ph
Cs2CO3, DMF
1
N
N
130 oC, 24 h
N
PPA
100 oC, 2 h
N
N
2
N
5a
Ph
Ph
Ph
Ph
Ph
O
2 balloon
Ph
5
2a (68%)
3a (94%)
4a (88%)
PhNHNH2HCl
ODCB, 130 o
C
Ph
Ph
N
N
O
2 balloon, 4 h
O
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
5a (not formed)
II
Ph
Ph
I
1a
Scheme 1.
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Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
KOREAN CHEMICAL SOCIETY
carbocation II would be less stable due to the presence of an
electron-withdrawing C N double bond of pyrazole ring.
Base-catalyzed aerobic oxidation of 3a in DMF under an O2
balloon atmosphere (130 ꢀC, 24 h) afforded 2,5-diphenylpyr-
azolo[1,5-a]quinoline (4a) in good yield (88%).6
Encouraged by the successful synthesis of pyrazolo[1,5-a]
quinoline 4a, some representative dienones 1b–e were pre-
pared by the Knoevenagel condensation of cinnamaldehydes
and appropriate ketones.7 As shown in Table 1, various 5-styr-
ylpyrazoles8 2b–g were prepared in good to moderate yields
(64–71%) by the reaction of 1a–e and appropriate arylhydra-
zine hydrochlorides. The pyrazole 2h was prepared in a rea-
sonable yield (40%) from the Baylis–Hillman adduct 1f7h of
cinnamaldehyde according to the reported method.9
(100 ꢀC, 2 h), and the yields of 3b–h were high (87–93%) irre-
spective of the substituents at the 1,3,4,5-positions of the start-
ing pyrazoles 2b–h. The compounds 3e and 3f were obtained
as inseparable diastereomeric mixture (3:1) in the IMFC reac-
tions of 2e and 2f (entries 5 and 6). The synthesis of 4b–h was
carried out in DMF (130 ꢀC, 24 h) in the presence of Cs2CO3
under O2 balloon atmosphere. The yields of 4b–h were high in
all entries (86–95%).
The reaction of conjugated dienone 1g and phenylhydra-
zine hydrochloride under the standard condition (ODCB,
130 ꢀC) produced 2i in low yield. Thus, 5-(2-propenyl)pyra-
zole 2i was prepared in moderate yield (62%) by using I2 in
refluxing EtOH according to the reported method.10 The
IMFC reaction of 2i in PPA at 100 ꢀC was sluggish, and the
reaction was carried out at 140 ꢀC for 6 h to obtain 3i in good
yield (90%), as shown in Scheme 2. The Friedel-Crafts cycli-
zation could produce a mixture of five- and six-membered
rings; however, six-membered ring compound 3i was formed
With these pyrazoles 2b–h, the synthesis of
dihydropyrazolo[1,5-a]quinolines 3b–h and pyrazolo[1,5-a]
quinolines 4b–h were carried out, and the results are summar-
ized in Table 2. The synthesis of 3b–h was carried out in PPA
Table 1. Synthesis of 5-styrylpyrazoles 2a–h.
Entry
1
Dienone 1
Conditionsa
Pyrazole 2 (%)
O
Ph
PhNHNH2HCl (4 h)
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
1a
1a
2a (68)
Ar1
N
2
3
p-CIPhNHNH2HCl (4 h)
p-MePhNHNH2HCl (4 h)
N
2b (70)b
Ar2
1a
N
N
2c (64)c
Ph
O
O
4
5
PhNHNH2HCl (4 h)
PhNHNH2HCl (6 h)
N
N
Ph
Ph
Me
Ph
1b
1c
1d
2d (66)
Ph
N
N
N
2e (71)
Ph
O
6
PhNHNH2HCl (6 h)
N
Ph
Me
Ph
Me
2f (67)
O
Ph
7
8
PhNHNH2HCl (3 h)
PhNHNH2HCl (3 h)
N
N
Ph
Ph
S
1e
S
2g (65)
Ph
OH
O
N
N
Ph
Me
Ph
Me
1f
Me
2h (40)
a All reactions were carried out in ODCB under O2 balloon atmosphere at 130 ꢀC.
b Ar1 is p-chlorophenyl.
c Ar2 is p-tolyl.
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Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
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Table 2. Synthesis of pyrazolo[1,5-a]quinolines.
ineffective in the presence of 1, 8-diazabicyclo [5.4.0]
undec-7-ene (DBU) in DMF (130 ꢀC, 10 h).
Entry Pyrazole 2
Compound 3 (%)a
Product 4 (%)b
N-Benzyl-5-styrylpyrazole 2j was prepared from 1a and
benzylhydrazine dihydrochloride in moderate yield (58%)
in the presence of I2 in EtOH for 10 h.10 The reaction of 2j
in PPA at 100 ꢀC for 2 h afforded 2,9-diphenyl-3,3a-diaza-
benzo[f]azulene derivative 3j in good yield (74%), as shown
in Scheme 3.
2a
1
N
N
N
N
Ph
Ph
Ph
Cl
Ph
4a (88)
Cl
3a (94)
2b
2
N
N
N
As a last entry, 5-(2,2-diphenylvinyl)pyrazole 2k was pre-
pared from dienone 1h and phenylhydrazine hydrochloride in
moderate yield (59%). Treatmentof this pyrazole 2kwith PPA
afforded thedihydropyrazolo[1,5-a]quinolinederivative 3kin
good yield (93%), as shown in Scheme 4.
Insummary,variouspyrazolo[1,5-a]quinolinesweresynthe-
sized via the IMFC reaction of 1-aryl-5-styrylpyrazoles and
the following base-catalyzed aerobic oxidation process. The
required 1-aryl-5-styrylpyrazoles were readily prepared from
conjugated dienones and arylhydrazines in a one-pot process.
N
Ph
Ph
Ph
Ph
Me
Ph
4b (91)
Me
3b (93)
2c
3
N
N
N
N
Ph
Ph
Ph
3c (93)
4c (93)
2d
4
N
N
N
N
Me
Me
Ph
Ph
3d (91)
4d (88)
Experimental Section
2e
5
N
N
Typical Procedure for the Preparation of Pyrazole 2a. A
mixture of 1a (234 mg, 1.0 mmol) and phenylhydrazine
hydrochloride (174 mg, 1.2 mmol) in ODCB (1.0 mL) was
heated to 130 ꢀC under O2 balloon atmosphere for 4 h.3 After
the usual aqueous extractive workup and column chromato-
graphic purification process (hexanes/Et2O, 30:1) pyrazole
2a was obtained as a pale yellow solid, 219 mg (68%). Other
pyrazole derivatives were prepared similarly and the spectro-
scopic data are as follows.
N
N
Ph
Ph
Ph
Ph
3e (87)c
4e (88)
6
2f
N
N
N
N
Me
Me
Ph
Ph
3f (91)c
4f (86)
Compound 2a3: 68%; pale yellow solid, mp 138–140 ꢀC;
1
IR (KBr) 1596, 1499, 1458, 1362 cm−1; H NMR (CDCl3,
7
8
2g
2h
300 MHz) δ 6.92 (d, J = 16.2 Hz, 1H), 7.00 (s, 1H), 7.17 (d,
J = 16.2 Hz, 1H), 7.26–7.40 (m, 4H), 7.41–7.50 (m, 5H),
7.51–7.61 (m, 4H), 7.93 (d, J = 7.2 Hz, 2H); ESIMS m/z
323 [M + H]+.
N
N
N
N
S
S
Ph
Ph
3g (88)
4g (95)
Compound 2b: 70%; pale yellow solid, mp 150–152 ꢀC; IR
1
(KBr) 1495, 1459, 1434, 1363 cm−1; H NMR (CDCl3, 300
N
N
N
N
MHz) δ 6.87 (d, J = 16.5 Hz, 1H), 6.98 (s, 1H), 7.17 (d, J =
16.5 Hz, 1H), 7.27–7.41 (m, 4H), 7.41–7.49 (m, 4H),
7.49–7.56 (m, 4H), 7.91 (d, J = 7.8 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 101.51, 115.20, 125.79, 126.60, 126.68,
128.14, 128.50, 128.66, 128.83, 129.40, 132.60, 132.78,
133.71, 136.22, 138.09, 142.59, 152.29; ESIMS m/z 357 [M
+ H]+, 359 [M + H + 2]+. Anal. Calcd for C23H17ClN2: C,
77.41; H, 4.80; N, 7.85. Found: C, 77.75; H, 4.92; N, 7.59.
Compound 2c: 64%; pale yellow solid, mp 138–140 ꢀC; IR
(KBr) 1515, 1460, 1433 cm−1; 1H NMR (CDCl3, 300 MHz) δ
2.45 (s, 3H), 6.90 (d, J = 16.5 Hz, 1H), 6.98 (s, 1H), 7.15 (d, J
= 16.5 Hz, 1H), 7.25–7.39 (m, 6H), 7.39–7.50 (m, 6H), 7.92
(d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.16,
100.83, 115.77, 125.43, 125.78, 126.62, 127.89, 128.24,
128.59, 128.75, 129.78, 131.86, 133.10, 136.49, 137.09,
138.00, 142.49, 151.76; ESIMS m/z 337 [M + H]+.
Me
Me
Ph
Ph
3h (87)
4h (94)
a Conditions: 2, PPA, 100 ꢀC, 2 h.
b Conditions: 3, Cs2CO3 (2.0 equiv), DMF, 130 ꢀC, O2 balloon, 24 h.
c Diastereomeric mixture (3:1) by 1H NMR.
as a sole product presumably due to destabilization of the car-
bocationic intermediate II0, as compared with the secondary
carbocation I0, by the presence of an electron-withdrawing
C N double bond of pyrazole (vide supra). However, the
following aerobic oxidation was completely ineffective under
the standard condition employing Cs2CO3 even at elevated
temperature (140 ꢀC). The aerobic oxidation of 3i was also
Compound 2d8i: 66%; pale yellow oil; IR (film) 1596,
1499, 1458, 1362 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.29
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Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
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Cs2CO3
PhNHNH2HCl
(2.0 equiv)
Ph
O
PPA
140 oC, 6 h
DMF, 140 o
C
N
N
N
N
N
N
Me
I
2 (2.0 equiv)
Me
Me
Me
O2 balloon
Me
Me
EtOH, reflux, 2 h
Me
Me
1g
2i (62%)
3i (90%)
4i
Ph
Ph
N
N
N
N
Me
Me
Me
Me
I' (more stable)
II' (less stable)
Scheme 2.
Ph
PhCH2NHNH22HCl
(2.0 equiv)
3a
3
N
N N
N
PPA
100 oC, 2 h
Ph
1a
I2 (2.0 equiv)
EtOH, reflux, 10 h
Ph
Ph
1
9
Ph
2j (58%)
3j (74%)
Scheme 3.
PhNHNH2HCl
(2.0 equiv)
PPA
100 oC, 10 h
Ph
Ph
N
Ph
O
N
N
N
Ph
Ph
Ph
Ph
I2 (2.0 equiv)
EtOH, reflux, 10 h
Ph
Ph
Ph
3k (93%)
2k (59%)
1h
Scheme 4.
(s, 3H), 6.39 (s, 1H), 6.79 (d, J = 16.2 Hz, 1H), 6.97 (d, J =
16.2 Hz, 1H), 7.14–7.45 (m, 10H); ESIMS m/z 261 [M + H]+.
Compound 2e: 71%; pale yellow oil; IR (film) 1597, 1498,
1458, 1362 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.04 (s, 3H),
6.72 (s, 1H), 6.75 (s, 1H), 7.23–7.50 (m, 11H), 7.62 (d, J = 8.1
Hz, 2H), 7.92 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
δ 18.33, 104.45, 124.55, 125.75, 127.15, 127.44, 127.46,
127.90, 128.29, 128.59, 128.95, 129.07, 132.46, 133.08,
136.85, 140.74, 147.83, 151.58; ESIMS m/z 337 [M + H]+.
Anal. Calcd for C24H20N2: C, 85.68; H, 5.99; N, 8.33. Found:
C, 85.54; H, 6.12; N, 8.27.
Compound 2h: 40%; pale yellow solid, mp 58–60 ꢀC; IR
(KBr) 1597, 1502, 1366 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 2.24 (s, 3H), 2.32 (s, 3H), 6.85 (d, J = 16.5 Hz, 1H), 6.91
(d, J = 16.5 Hz, 1H), 7.23–7.51 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 9.76, 11.82, 113.93, 117.06, 125.01,
126.37, 127.18, 127.99, 128.71, 129.06, 131.91, 136.96,
137.35, 140.09, 148.80; ESIMS m/z 275 [M + H]+. Anal.
Calcd for C19H18N2: C, 83.18; H, 6.61; N, 10.21. Found: C,
83.31; H, 6.69; N, 9.98.
Compound 2i8h: 62%; colorless oil; IR (film) 1597, 1545,
1
1502, 1445, 1365 cm−1; H NMR (CDCl3, 300 MHz) δ 1.84
Compound 2f: 67%; pale yellow oil; IR (film) 1598, 1502,
1376, 1364 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.99 (s, 3H),
2.36(s, 3H), 6.22(s, 1H), 6.61(s, 1H), 7.20–7.46(m, 8H), 7.51
(d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.51,
18.28, 106.99, 124.39, 127.03, 127.09, 127.55, 128.23,
128.89, 128.98, 132.04, 136.93, 140.72, 147.16, 149.11;
ESIMS m/z 275 [M + H]+.
(dd, J = 4.8 and 1.2 Hz, 3H), 2.32 (s, 3H), 6.18–6.24 (m, 2H),
6.27 (s, 1H), 7.33–7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 13.50, 18.56, 103.21, 118.89, 125.30, 127.38, 128.95,
129.60, 139.66, 141.99, 149.17; ESIMS m/z 199 [M + H]+.
Compound 2j: 58%; white solid, mp 102–104 ꢀC; IR (KBr)
1495, 1454, 1436, 1317 cm−1; 1H NMR (CDCl3, 300 MHz) δ
5.52 (s, 2H), 6.87 (s, 1H), 6.88 (d, J = 15.9 Hz, 1H), 7.08 (d, J
= 15.9 Hz, 1H), 7.18–7.47 (m, 13H), 7.88 (d, J = 7.8 Hz, 2H);
13C NMR (CDCl3, 75 MHz) δ 53.48, 100.31, 114.45, 125.62,
126.56, 126.61, 127.69, 128.30, 128.60, 128.76, 128.81,
132.29, 133.35, 136.39, 137.09, 142.29, 150.86, one carbon
was overlapped; ESIMS m/z 337 [M + H]+.
Compound 2g8j: 65%; white solid, mp 138–140 ꢀC; IR
(KBr) 1595, 1499, 1399, 1374 cm−1; 1H NMR (CDCl3, 300
MHz) δ 6.86 (d, J = 16.2 Hz, 1H), 6.87 (s, 1H), 7.07 (dd, J
= 5.1 and 3.6 Hz, 1H), 7.13 (d, J = 16.2 Hz, 1H), 7.23–7.59
(m, 12H); 13C NMR (CDCl3, 75 MHz) δ 101.07, 115.37,
124.04, 124.79, 125.56, 126.66, 127.46, 128.04, 128.37,
128.76, 129.23, 132.36, 136.26, 136.30, 139.28, 142.50,
147.31; ESIMS m/z 329 [M + H]+.
Compound 2k: 59%; pale yellow solid, mp 135–137 ꢀC; IR
(KBr) 1597, 1498, 1458, 1361 cm−1; 1H NMR (CDCl3, 300
MHz) δ 5.74 (s, 1H), 6.81 (s, 1H), 7.22–7.54 (m, 16H),
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Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
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7.57–7.66 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 104.13,
114.76, 125.57, 125.65, 127.43, 127.75, 127.82, 128.06,
128.08, 128.33, 128.46, 128.92, 129.18, 129.69, 133.01,
139.70, 141.13, 141.60, 144.49, 151.40, one carbon was over-
lapped; ESIMS m/z 399 [M + H]+. Anal. Calcd for C29H22N2:
C, 87.41; H, 5.56; N, 7.03. Found: C, 87.29; H, 5.75; N, 6.88.
155.61, 124.69, 126.99, 127.96, 128.07, 128.65, 128.70,
128.72, 136.32, 137.88, 142.44, 150.17; ESIMS m/z 261
[M + H]+.
Compound 3e: 87% (major/minor, 3:1); white solid; IR
(KBr) 1490, 1474, 1457, 1368 cm−1; 1H NMR (major, CDCl3,
300 MHz) δ 1.30 (d, J = 6.6 Hz, 3H), 3.32–3.46 (m, 1H), 3.89
(d, J = 9.9 Hz, 1H), 6.52(s, 1H), 6.78–6.86(m, 1H), 7.03–7.48
Typical
Procedure
for
the
Preparation
of
1
Dihydropyrazolo[1,5-a]quinoline 3a. A mixture of 2a
(161 mg, 0.5 mmol) and PPA (0.5 mL) was heated to 100 ꢀ
C for 2 h. After the usual aqueous extractive workup and col-
umn chromatographic purification process (hexanes/Et2O,
20:1) compound 3a was obtained as a white solid, 152 mg
(94%). Other dihydropyrazolo[1,5-a]quinoline derivatives
were prepared similarly and the spectroscopic data are as
follows.
(m, 10H), 7.90–7.98 (m, 2H), 8.07–8.14 (m, 1H); H NMR
(minor, CDCl3, 300 MHz) δ 1.25 (d, J = 6.6 Hz, 3H),
3.54–3.66 (m, 1H), 4.10 (d, J = 6.3 Hz, 1H), 6.45 (d, J = 0.9
Hz, 1H), 6.78–6.86 (m, 1H), 7.03–7.48 (m, 10H), 7.90–7.98
(m, 2H), 8.07–8.14 (m, 1H); ESIMS m/z 337 [M + H]+. Anal.
Calcd for C24H20N2: C, 85.68; H, 5.99; N, 8.33. Found: C,
85.76; H, 6.13; N, 8.07.
Compound 3f: 91% (major/minor, 3:1); colorless oil; IR
(film) 1555, 1491, 1454, 1364 cm−1; 1H NMR (major, CDCl3,
300 MHz) δ 1.22 (d, J = 6.6 Hz, 3H), 2.37 (s, 3H), 3.22–3.36
(m, 1H), 3.82 (d, J = 9.9 Hz, 1H), 5.98 (s, 1H), 6.72–6.82
(m, 1H), 7.01 (t, J = 7.5 Hz, 1H), 7.10–7.40 (m, 6H), 7.91
Compound 3a: 94%; white solid, mp 60–62 ꢀC; IR (KBr)
1
1489, 1475, 1457, 1367 cm−1; H NMR (CDCl3, 300 MHz)
δ 3.27 (dd, J = 15.6 and 7.8 Hz, 1H), 3.38 (dd, J = 15.6 and
6.6 Hz, 1H), 4.30 (dd, J = 7.8 and 6.6 Hz, 1H), 6.45 (s, 1H),
6.73 (d, J = 7.5 Hz, 1H), 7.05–7.19 (m, 3H), 7.20–7.47 (m,
7H), 7.91 (d, J = 7.2 Hz, 2H), 8.10 (d, J = 7.8 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 29.73, 42.16, 102.13, 116.12,
125.19, 125.75, 127.08, 127.94, 127.98, 128.18, 128.60,
128.69, 128.78, 129.08, 133.21, 136.35, 138.42, 142.34,
152.26; ESIMS m/z 323 [M + H]+. Anal. Calcd for
C23H18N2: C, 85.68; H, 5.63; N, 8.69. Found: C, 85.71; H,
5.90; N, 8.54.
1
(d, J = 7.5 Hz, 1H); H NMR (minor, CDCl3, 300 MHz) δ
1.16 (d, J = 6.6 Hz, 3H), 2.37 (s, 3H), 3.45–3.57 (m, 1H),
4.04 (d, J = 6.0 Hz, 1H), 5.91 (s, 1H), 6.72–6.82 (m, 1H),
7.06 (t, J = 7.5 Hz, 1H), 7.10–7.40 (m, 6H), 7.94 (d, J = 7.5
Hz, 1H); ESIMS m/z 275 [M + H]+.
Compound 3g: 88%; white solid, mp 104–106 ꢀC; IR (KBr)
1588, 1488, 1475, 1378 cm−1; 1H NMR (CDCl3, 300 MHz) δ
3.25 (dd, J = 15.9 and 7.2 Hz, 1H), 3.37 (dd, J = 15.9 and 6.9
Hz, 1H), 4.30 (dd, J = 7.2 and 6.9 Hz, 1H), 6.36 (s, 1H), 6.98
(d, J = 7.5 Hz, 1H), 7.07 (dd, J = 5.1 and 3.6 Hz, 1H), 7.09 (d,
J = 7.5 Hz, 1H), 7.12–7.18 (m, 2H), 7.22–7.42 (m, 6H), 8.07
(d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 29.66,
42.05, 102.21, 116.21, 124.13, 124.82, 125.25, 127.09,
127.43, 127.94, 128.20, 128.65, 128.78, 128.96, 136.11,
136.60, 138.46, 142.24, 147.59; ESIMS m/z 329 [M + H]+.
Anal. CalcdforC21H16N2S:C, 76.80;H, 4.91;N, 8.53. Found:
C, 76.72; H, 4.87; N, 8.73.
Compound3b:93%; white solid, mp 131–133 ꢀC; IR (KBr)
1487, 1446, 1366 cm−1; 1H NMR (CDCl3, 300 MHz) δ 3.26
(dd, J = 15.9 and 8.1 Hz, 1H), 3.38 (dd, J = 15.9 and 6.6 Hz,
1H), 4.27 (dd, J = 8.1 and 6.6 Hz, 1H), 6.47 (s, 1H), 6.94 (s,
1H), 7.16 (d, J = 7.8 Hz, 2H), 7.26–7.48 (m, 7H), 7.90 (d, J
= 7.8 Hz, 2H), 8.03 (d, J = 8.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 29.59, 42.13, 102.37, 117.50, 125.76, 127.43,
127.93, 128.12, 128.21, 128.60, 128.65, 128.98, 130.48,
130.84, 132.95, 134.93, 138.29, 141.47, 152.57; ESIMS m/
z 357 [M + H]+, 359 [M + H + 2]+. Anal. Calcd for
C23H17ClN2: C, 77.41; H, 4.80; N, 7.85. Found: C, 77.74;
H, 4.92; N, 7.81.
Compound3h:87%; white solid, mp 111–113 ꢀC; IR (KBr)
1594, 1494, 1454, 1377 cm−1; 1H NMR (CDCl3, 300 MHz) δ
1.94 (s, 3H), 2.31 (s, 3H), 3.10 (dd, J = 15.6 and 9.0 Hz, 1H),
3.23 (dd, J = 15.6 and 6.3 Hz, 1H), 4.25 (dd, J = 9.0 and 6.3
Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H),
7.18 (d, J = 8.1 Hz, 2H), 7.24–7.37 (m, 4H), 7.90 (d, J = 8.1
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 7.54, 12.02, 28.49,
42.24, 111.79, 115.24, 124.27, 126.97, 127.98, 128.07,
128.56, 128.64, 128.71, 134.81, 136.45, 142.67, 149.48;
ESIMS m/z 275 [M + H]+.
Compound 3c: 93%; white solid, mp 117–119 ꢀC; IR (KBr)
1554, 1503, 1452, 1367 cm−1; 1H NMR (CDCl3, 300 MHz) δ
2.28 (s, 3H), 3.25 (dd, J = 15.9 and 7.2 Hz, 1H), 3.38 (dd, J =
15.9 and 6.6 Hz, 1H), 4.27 (dd, J = 7.2 and 6.6 Hz, 1H), 6.44
(s, 1H), 6.81 (s, 1H), 7.10–7.48 (m, 9H), 7.91 (d, J = 8.1 Hz,
2H), 8.00 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
21.03, 29.87, 42.20, 101.96, 116.03, 125.71, 127.01,
127.82, 127.91, 128.58, 128.75, 128.86, 129.22, 133.33,
134.17, 134.88, 138.06, 142.60, 151.95, one carbon was over-
lapped; ESIMS m/z 337 [M + H]+.
Compound 3d: 91%; pale yellow oil; IR (film) 1588, 1559,
1491, 1363 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H),
3.20 (dd, J = 15.6 and 8.1 Hz, 1H), 3.29 (dd, J = 15.6 and 6.3
Hz, 1H), 4.26 (dd, J = 8.1 and 6.3 Hz, 1H), 5.94 (s, 1H), 6.96
(d, J = 7.5 Hz, 1H), 7.07 (t, d = 7.5 Hz, 1H), 7.15 (d, J = 7.8
Hz, 2H), 7.22–7.39 (m, 4H), 7.95 (d, J = 7.8 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 13.84, 29.64, 42.20, 104.68,
Compound 3i: 90%; colorless oil; IR (film) 1589, 1560,
1
1492, 1363 cm−1; H NMR (CDCl3, 300 MHz) δ 1.26 (d, J
= 6.9 Hz, 3H), 2.35 (s, 3H), 2.68–2.80 (m, 1H), 3.00–3.16
(m, 2H), 5.96 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.25 (t, J =
7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.83, 20.10, 28.97,
30.59, 104.65, 115.58, 124.68, 126.86, 127.57, 130.91,
135.70, 138.31, 149.90; ESIMS m/z 199 [M + H]+.
Compound 3j: 74%; white solid, mp 143–145 ꢀC; IR (KBr)
1493, 1446, 1342 cm−1; 1H NMR (CDCl3, 300 MHz) δ 3.52
Bull. Korean Chem. Soc. 2015, Vol. 36, 1189–1195
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
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Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
KOREAN CHEMICAL SOCIETY
(d, J = 6.6 Hz, 2H), 4.69 (t, J = 6.6 Hz, 1H), 5.36 (d, J = 15.3
Hz, 1H), 5.56 (d, J = 15.3 Hz, 1H), 6.33 (s, 1H), 6.94–7.01 (m,
1H), 7.14–7.41 (m, 11H), 7.75 (d, J = 7.8 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 31.34, 45.87, 55.16, 103.43, 125.45,
126.78, 126.86, 127.41, 128.11, 128.52, 128.58, 128.60,
129.49, 129.99, 133.52, 133.79, 140.91, 142.80, 142.93,
149.72; ESIMS m/z 337 [M + H]+. Anal. Calcd for
C24H20N2: C, 85.68; H, 5.99; N, 8.33. Found: C, 85.80; H,
5.92; N, 8.17.
128.49, 128.69, 129.65, 130.67, 133.01, 133.52, 134.02,
136.90, 138.57, 138.84, 152.80; ESIMS m/z 335 [M + H]+.
Anal. Calcd for C24H18N2: C, 86.20; H, 5.43; N, 8.38. Found:
C, 85.98; H, 5.76; N, 8.41.
Compound 4d: 88%; white solid, mp 80–82 ꢀC; IR (KBr)
1608, 1483, 1408 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.58
(s, 3H), 6.40 (s, 1H), 7.29 (s, 1H), 7.33 (dd, J = 8.4 and 8.1
Hz, 1H), 7.42–7.55 (m, 5H), 7.65 (dd, J = 8.4 and 8.1 Hz,
1H), 7.72 (d, J = 8.1 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 14.15, 99.41, 115.41, 116.21,
122.21, 123.88, 127.19, 127.90, 128.45, 129.19, 129.64,
134.64, 136.83, 138.38, 138.74, 151.31; ESIMS m/z 259
[M + H]+. Anal. Calcd for C18H14N2: C, 83.69; H, 5.46; N,
10.84. Found: C, 83.87; H, 5.44; N, 10.59.
Compound3k:93%; white solid, mp 190–192 ꢀC; IR (KBr)
1486, 1366 cm−1; 1H NMR (CDCl3, 300 MHz) δ 3.86 (s, 2H),
6.43 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 7.07–7.17 (m, 5H),
7.19–7.33 (m, 7H), 7.35–7.47 (m, 3H), 7.85 (d, J = 8.4 Hz,
2H), 8.10 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
35.63, 51.76, 101.72, 116.49, 127.78, 125.67, 126.87,
127.88, 128.14, 128.38, 128.52, 128.83, 129.97, 132.87,
133.10, 136.39, 138.65, 144.42, 151.99; ESIMS m/z 399
[M + H]+. Anal. Calcd for C29H22N2: C, 87.41; H, 5.56; N,
7.03. Found: C, 87.33; H, 5.81; N, 6.87.
Typical Procedure for the Preparation of Pyrazolo[1,5-a]
quinolines 4a. A mixture of 3a (129 mg, 0.4 mmol) and
Cs2CO3 (261 mg, 2.0 equiv) in DMF (0.5 mL) was heated
to 130 ꢀC under O2 balloon atmosphere for 24 h. After the
usual aqueous extractive workup and column chromato-
graphic purification process (hexanes/Et2O, 20:1) compound
4a was obtained as a white solid, 113 mg (88%). Other
pyrazolo[1,5-a]quinoline derivatives were prepared similarly
and the spectroscopic data are as follows.
Compound 4e: 88%; white solid, mp 112–114 ꢀC; IR (KBr)
1600, 1543, 1467 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.29
(s, 3H), 6.94 (s, 1H), 7.27–7.64 (m, 11H), 8.10 (d, J = 8.4
Hz, 2H), 8.72 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 16.36, 95.92, 115.35, 123.24, 124.24, 124.33,
126.40, 127.23, 127.66, 128.13, 128.23, 128.52, 128.71,
130.20, 133.48, 133.52, 133.97, 137.35, 140.84,
152.84; ESIMS m/z 335 [M + H]+. Anal. Calcd for
C24H18N2: C, 86.20; H, 5.43; N, 8.38. Found: C, 86.54; H,
5.77; N, 8.29.
Compound 4f: 86%; white solid, mp 138–140 ꢀC; IR (KBr)
1598, 1542, 1482, 1299 cm−1; 1H NMR (CDCl3, 300 MHz) δ
2.21 (s, 3H), 2.59 (s, 3H), 6.42 (s, 1H), 7.20–7.32 (m, 4H),
7.42–7.60 (m, 4H), 8.55 (d, J = 8.1 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.19, 16.30, 98.55, 114.89, 122.92,
123.79, 123.92, 127.21, 127.59, 128.03, 128.48, 130.20,
133.28, 133.74, 137.45, 140.39, 151.06; ESIMS m/z 273
[M + H]+. Anal. Calcd for C19H16N2: C, 83.79; H, 5.92; N,
10.29. Found: C, 83.57; H, 6.03; N, 10.06.
Compound 4a: 88%; white solid, mp 104–106 ꢀC; IR
(KBr) 1606, 1463, 1454 cm−1; 1H NMR (CDCl3, 600 MHz)
δ 6.84 (s, 1H), 7.28–7.33 (m, 3H), 7.38–7.47 (m, 7H), 7.62
(dd, J = 8.4 and 7.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 8.01
(d, J = 7.8 Hz, 2H), 8.70 (d, J = 8.4 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 96.75, 115.89, 116.48, 122.65,
124.34, 126.43, 127.22, 128.00, 128.30, 128.51, 128.72,
129.30, 129.65, 133.42, 134.85, 137.10, 138.66, 138.84,
153.11; ESIMS m/z 321 [M + H]+. Anal. Calcd for
C23H16N2: C, 86.22; H, 5.03; N, 8.74. Found: C, 86.41; H,
5.37; N, 8.69.
Compound 4g: 95%; white solid, mp 132–134 ꢀC; IR
(KBr) 1607, 1561, 1477 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 6.80 (s, 1H), 7.14 (dd, J = 5.1 and 3.6 Hz, 1H), 7.34
(s, 1H), 7.34–7.40 (m, 2H), 7.44–7.56 (m, 5H), 7.57 (dd, J
= 3.6 and 1.2 Hz, 1H), 7.68 (dd, J = 8.4 and 8.1 Hz, 1H),
7.73 (d, J = 8.4 Hz, 1H), 8.73 (d, J = 8.4 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 96.64, 115.95, 116.19,
122.58, 124.38, 124.85, 125.49, 127.19, 127.62, 128.03,
128.50, 129.36, 129.62, 134.63, 136.67, 137.43, 138.54,
138.76, 148.33; ESIMS m/z 327 [M + H]+. Anal. Calcd for
C21H14N2S: C, 77.27; H, 4.32; N, 8.58. Found: C, 77.50; H,
4.31; N, 8.44.
Compound4b:91%; white solid, mp 190–192 ꢀC; IR (KBr)
1551, 1465, 1452, 1415 cm−1; 1H NMR (CDCl3, 300 MHz) δ
6.91 (s, 1H), 7.36–7.44 (m, 2H), 7.45–7.59 (m, 7H), 7.63 (dd,
J = 9.0 and 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 8.06 (d, J =
7.8 Hz, 2H), 8.71 (d, J = 9.0 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 97.16, 117.50, 117.64, 123.87, 126.42, 128.30,
128.48, 128.74, 128.76, 129.52, 130.14, 133.11, 133.29,
136.16, 137.93, 138.69, 153.42, two carbons were over-
lapped; ESIMS m/z 355 [M + H]+, 357 [M + H + 2]+. Anal.
Calcd for C23H15ClN2: C, 77.85; H, 4.26; N, 7.89. Found:
C, 77.81; H, 4.50; N, 7.74.
Compound4h:94%; white solid, mp 105–106 ꢀC; IR (KBr)
1630, 1493, 1481, 1444, 1333 cm−1; 1H NMR (CDCl3, 300
MHz) δ 2.25 (s, 3H), 2.51 (s, 3H), 7.21 (s, 1H), 7.30 (dd, J
= 8.4 and 8.1 Hz, 1H), 7.44–7.56 (m, 5H), 7.62 (dd, J = 8.4
and 8.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 7.53, 12.22,
106.91, 115.07, 115.28, 122.28, 123.60, 127.16, 127.81,
128.44, 129.02, 129.68, 134.73, 135.60, 136.06, 139.06,
149.86; ESIMS m/z 273 [M + H]+. Anal. Calcd for
C19H16N2: C, 83.79; H, 5.92; N, 10.29. Found: C, 83.68; H,
6.11; N, 10.13.
Compound 4c: 93%; white solid, mp 166–168 ꢀC; IR (KBr)
1621, 1562, 1456 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.43
(s, 3H), 6.89 (s, 1H), 7.35 (s, 1H), 7.38 (t, J = 7.5 Hz, 1H),
7.45–7.58 (m, 9H), 8.08 (d, J = 8.1 Hz, 2H), 8.67 (d, J = 9.3
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.37, 96.51,
115.76, 116.49, 122.61, 126.39, 126.74, 127.91, 128.20,
Bull. Korean Chem. Soc. 2015, Vol. 36, 1189–1195
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1194

BULLETIN OF THE
Article
Synthesis of Pyrazolo[1,5-a]quinolines from 1-Aryl-5-styrylpyrazoles
KOREAN CHEMICAL SOCIETY
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Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Educa-
tion, Science and Technology (2014R1A1A2053606). Spec-
troscopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
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Bull. Korean Chem. Soc. 2015, Vol. 36, 1189–1195
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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