Synthesis of pyrazole derivatives 4(1H)-quinolone and 4-chloroquinoline by thermolysis of arylaminomethylene Meldrum's acid derivative

Article abstract of DOI:10.1081/SCC-120002520

Efficient syntheses of 4(1H)-quinolone 1 and 4-chloroquinoline 2 by thermolysis of arylaminomethylene Meldrum's acid derivative starting from 2-nitrophenyl acetic acid.

Full text of DOI:10.1081/SCC-120002520

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SYNTHESIS OF PYRAZOLE DERIVATIVES 4(1H)-
QUINOLONE AND 4-CHLOROQUINOLINE BY
THERMOLYSIS OF ARYLAMINOMETHYLENE MELDRUM's
ACID DERIVATIVE
Lizeng Peng a , Tao Zhang a , Ying Li a & Yulin Li a
a National Laboratory of Applied Organic Chemistry , Institute of Organic Chemistry ,
Lanzhou University , Lanzhou, Gansu, 730000, P.R. China
Published online: 16 Aug 2006.
To cite this article: Lizeng Peng , Tao Zhang , Ying Li & Yulin Li (2002) SYNTHESIS OF PYRAZOLE DERIVATIVES 4(1H)-
QUINOLONE AND 4-CHLOROQUINOLINE BY THERMOLYSIS OF ARYLAMINOMETHYLENE MELDRUM's ACID DERIVATIVE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:5, 785-791, DOI:
10.1081/SCC-120002520
To link to this article: http://dx.doi.org/10.1081/SCC-120002520
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SYNTHETIC COMMUNICATIONS, 32(5), 785–791 (2002)
SYNTHESIS OF PYRAZOLE
DERIVATIVES 4(1H)-QUINOLONE
AND 4-CHLOROQUINOLINE BY
THERMOLYSIS OF
ARYLAMINOMETHYLENE
MELDRUM’S ACID DERIVATIVE
*
Lizeng Peng, Tao Zhang, Ying Li, and Yulin Li
National Laboratory of Applied Organic Chemistry,
Institute of Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, P.R. China
ABSTRACT
Efficient syntheses of 4(1H)-quinolone 1 and 4-chloroquino-
line 2 by thermolysis of arylaminomethylene Meldrum’s acid
derivative starting from 2-nitrophenyl acetic acid.
The search for new immunomodulating drugs is an active area of
investigation in medicinal chemistry. Recently, the synthesis and immuno-
modulating effects of quinolines containing a pyrazole ring have been
described.1 Concerning our interest in the synthesis and chemistry of qui-
nolones, we have finished the synthesis of a novel type of pyrazole deriva-
tives 4(1H)-quinolone 1 and 4-chloroquinolone 2 that can be structurally
compared to analogous compounds of known immunomodulatory activity.1
*Corresponding author. E-mail: liyl@lzu.edu.cn
785
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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PENG ET AL.
Scheme 1. Reagents and conditions: a) 1. SOCl2, toluene, r.t.; 2. methyl acetoace-
tate, NaH, THF, r.t. b) MeONa, MeOH, r.t.; c) 1. 2-(6-methyl)pyridyl hydrazine (6),
MeOH, reflux; 2.MeONa, r.t.; d) 1. NaOH, H2O, 0.5 h; 2) AgNO3, 1 h; 3. Mel, THF,
reflux, 3 h; e) H2, Pd/C (10%), r.t.; f ) Meldrum’s acid, CH(OMe)3, reflux; g) Ph2O,
reflux, 40 min; h) POCl3, 80ꢀC, 2 h.
The synthesis involves the construction of B-C-D ring system and sub-
sequent quinolone cyclization as shown in Scheme 1. Condensation2 of
2-nitrophenyl acetyl chloride derived from acid 3 with methyl acetoacetate
was followed by deacetylation of resulting 4 with sodium methoxide to give
the corresponding ketoester 5, which was coupled3 with 2-(6-methyl)pyridyl
hydrazine 64 in boiling MeOH to give the desired pyrazole 7. Methylation5 of
silver alkoxide of 7 with methyl iodide afforded methoxy pyrazole 8 in
56% yield that was converted to amino compound 9 (98%) by catalytic

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787
hydrogenation in methanol. Condensation6 of 9 with one equivalent of
methoxymethylene Meldrum’s acid (prepared in situ by refluxing with
methylorthoformate) to give the desired arylaminomethylene Meldrum’s
acid derivative 10. Cyclization7 of 10 in boiling diphenyl ether and subsequent
recrystallization of the crude product from MeOH to afford quinolone 1.
Treatment8 of 1 with POCl3 at 80ꢀC furnished chloride 2 in good yield
(77%). The spectroscopic properties of synthetic products 1 and 2 were in
good agreement with their assigned structures respectively.
EXPERIMENTAL
Melting points were measured on a Kofler hot stage apparatus and
are uncorrected. IR spectra were recorded on a Nicolet 170 FT-IR spec-
l
trophotometer as a KBr discs. H NMR spectra were recorded on a Bruker
AM-400 instrument in a CDCl3 solution with TMS as an internal standard.
Low-resolution mass spectra were measured on an HP-5988 mass spectro-
meter and high-resolution mass spectra (HRMS) were determined on a
Bruker Daltonics APEXII 47e Fourier Transfer spectrometer with any of
EI, CI, FAB, SIMS or MALDI ionization methods. Purification of reagents
and solvents was effected according to standard methods. Prior to concentra-
tion under reduced pressure, all extracts were dried over anhydrous Na2SO4.
Flash column chromatography was performed on silica gel (200–300 mesh)
purchased from Qing Dao Marine Chemical Co (Qingdao, China).
Methyl 2-Nitrophenylacetyl Acetoacetate (4)
Methyl acetoacetate (4.53 ml, 42 mmol) in dry THF (50 ml) was added
dropwise to a stirred suspension of sodium hydride (60% suspension in oil,
1.96 g, 49 mmol) in THF (100 ml). The mixture was stirred for 2 h at room
temperature and was treated with 2-nitrophenyl acetyl chloride prepared
from 2-nitrophenyl acetic acid 3 (3.62 g, 20 mmol) and thionyl chloride
(1.53 ml, 21 mmol) in 100 ml of anhydrous toluene. The resulting mixture
was stirred for 16 h at room temperature. It was poured into water and
extracted with ether (3 ꢁ 100 ml). The combined organic phases was dried
and concentrated under reduced pressure. The residue was dissolved in
50 ml of methanol and allowed to stand in a freezer overnight to give 4 as
yellow crystals (3.57 g, 64%), m.p. 74–75ꢀC. IR (cmꢂ1): 2956, 2854, 1712,
l
1525, 1343, 1086, 790, 720; H NMR (400 MHz, CDCl3): d 2.41 (s, 3H,
COCH3); 3.85 (s, 3H, COOCH3); 4.52 (s, 2H, CH2); 7.34 (d, J ¼ 7.4 Hz,

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PENG ET AL.
1H, ArH); 7.50 (d, J ¼ 8.4 Hz, 1H, ArH); 7.6 (d, J ¼ 7.4 Hz, 1H, ArH); 8.12
(d, J ¼ 8.4 Hz, 1H, ArH); EIMS (70 eV): m/z (%) 279 (27) [Mþ].
Methyl 4-(2-Nitrophenyl)-3-oxobutyrate (5)
A solution of 4 (3.57g, 12.8 mmol) in MeOH (30 ml) was treated with
NaOMe (1.38 g, 25.6 mmol). After stirring for 2 h at r.t. the solvent was
evaporated under vacuum and the residue was purified by column chroma-
tography to give 5 (2.55 g, 84%). M.p. 54–55ꢀC (MeOH). IR (cmꢂ1): 2954,
2850, 1710, 1525, 1353, 801, 732; lH NMR (400 MHz, CDCl3): d 3.66 (s, 2H,
CH2); 3.78 (s, 3H, COOCH3): 4.25 (s, 2H, ArCH2); 7.32 (d, J ¼ 7.2 Hz, 1H,
ArH); 7.48 (d, J ¼ 8.2 Hz, 1H, ArH); 7.62 (d, J ¼ 7.2 Hz, 1H, ArH); 8.14
(d, J ¼ 8.2 Hz, 1H, ArH). EIMS (70 eV): m/z (%) 237(40) [M þ].
1-(6-Methyl-2-pyridyl)-3-[(nitrophenyl)-methyl)]-
1H-pyrazol-5-ol (7)
A mixture of 5 (2.55 g, 10.8 mmol), 6 (1.33 g, 10.8 mmol) in 20 ml of
anhydrous MeOH was stirred under reflux at Ar atmosphere for 3 h. The oil
bath was removed and MeONa (583 mg, 10.8 mmol) was added to the mix-
ture and stirring continued for 3 h. At 0ꢀC, AcOH (5 ml) was added slowly
at 0ꢀC and the precipitates was collected and dried to give 7 (2.68 g, 80%).
M.p. 121–122ꢀC. IR (cmꢂ1): 2867, 2697, 1602, 1525, 1479, 1398, 1353, 801,
753; lH NMR (400 MHz, CDCl3): d 2.53 (s, 3H, COCH3); 4.28 (s, 2H, CH2);
5.41 (s, 1H, CH); 6.97(d, J ¼ 7.5 Hz, 1H, ArH); 7.41 (d, J ¼ 8.0 Hz, 1H,
ArH); 7.44 (d, J ¼ 7.5 Hz, 1H, ArH); 7.53 (t, J ¼ 7.5 Hz, 1H, ArH); 7.62
(d, J ¼ 8.3 Hz, 1H, ArH); 7.73 (t, J ¼ 8.0 Hz, 1H, ArH); 7.96 (d, J ¼
8.3 Hz, 1H, ArH); EIMS (70 eV): m/z (%) 310 (100) [Mþ].
2-[[5-Methoxy-3-(2-nitrophenyl)-1H-pyrazol-1-yl]-
6-methyl]pyridine (8)
A mixture of 7 (2.68 g, 8.6 mmol) and NaOH (346 mg, 8.6 mmol) in
H2O (10 ml) was stirred for 0.5 h. The reaction mixture was treated with a
solution of AgNO3 (1.75 g, 10.3 mmol) in H2O (10 ml), and the resulting
mixture was stirred for 2 h at room temperature. After filtration of the
reaction mixture, the resulting solid residue was taken up in 40 ml of dry
THF and treated with 2 ml of MeI and brought to reflux for 3 h, filtered. The
filtrate was concentrated and purified by column chromatography to give 8

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PYRAZOLE DERIVATIVES
789
as foam (1.49 g, 56%). IR (cmꢂ1): 3410, 1601, 1574, 1526, 1456, 1350, 1101,
l
792; H NMR (400 MHz, CDCl3): d 2.61 (s, 3H, CH3; 3.89, (s, 3H, OCH3;
4.32 (s, 2H, CH2); 5.50 (s, 1H, CH); 7.07 (d, J ¼ 7.6 Hz, 1H, ArH); 7.37
(t, J ¼ 8.0 Hz, 1H, ArH); 7.40 (d, J ¼ 7.6 Hz, 1H, ArH); 7.50 (t, J ¼ 7.6 Hz,
1H, ArH); 7.52 (d, J ¼ 8.3 Hz, 1H, ArH); 7.66 (t, J ¼ 8.0 Hz, 1H, ArH); 7.96
(d, J ¼ 8.3 Hz, 1H, ArH); EIMS (70 eV): m/z (%) 324 (18) [Mþ].
2-[[5-Methoxy-1-(6-methyl-2-pyridyl)-1H-pyrazol-
3-yl]methyl]benzenamine (9)
A mixture of the compound 8 (1.49 g, 4.6 mmol), Pd/C (10%, 345 mg)
in MeOH (60 ml) was stirred with H2 (1 atm.) at r.t. for 4 h. The mixture was
filtered and the resulting filtrate was concentrated under reduced pressure to
leave the product, compound 9 as foam (1.33 g, 98%). The crude amino
product was used for the next operation without further purification. An
analytical sample was obtained by column chromatography. IR (cmꢂ1):
l
3349, 1598, 1572, 1497, 1454, 1149, 1010, 794, 749; H NMR (400 MHz,
CDCl3): d 2.59 (s, 3H,CH3); 3.82, (s, 3H, OCH3; 3.88 (s, 2H, CH2); 5.14
(br, 2H, CH2); 5.42 (s, 1H, CH); 6.63 (d, J ¼ 7.2 Hz, 1H, ArH); 6.72
(t, J ¼ 7.2 Hz, 1H, ArH); 7.04 (d, J ¼ 7.5 Hz, 1H, ArH); 7.06 (t, J ¼ 7.5 Hz,
1H, ArH); 7.15 (d, J ¼ 7.5 Hz, 1H, ArH); 7.39 (d, J ¼ 7.8 Hz, 1H, ArH); 7.63
(t, J ¼ 7.5 Hz, 1H, ArH); EIMS (70 eV) m/z (%): 294 (100) [Mþ]. (Found
(HRMS) (ESI): Mþ þ H, 295.1549. C17H18N4O þ H requires Mþ þ H
295.1553.)
1-[(40,40-Dimethyl-20,60-dioxo-30,50-dioxan-10-yl)methylene
amino]-2-[[5-methoxy-1-(6-methyl-2-pyridyl)-1H-pyrazol-
3-yl]methyl]benezenamine 10
A mixture of 710 mg (5 mmol) of Meldrum’s acid and methylorthofor-
mate (20 ml) was refluxed for 2 h. The amino compound 9 (1.33 g, 4.5 mmol)
was added and the heating continued for further 2 h. The solvent was
evaporated under reduced pressure and the residue purified by column
chromatography to give 10 (1.69 g, 79%). IR (cmꢂ1): 3161, 2991, 1729,
l
1682, 1622, 1594, 1438, 1271, 1202, 1144, 1012, 932, 797, 732; H NMR
(400 MHz, CDCl3): d 1.73 (s, 6H, 2 ꢁ OCH3); 2.59 (s, 3H, CH3); 3.91 (s,
3H, OCH3); 4.06 (s, 2H, CH2); 5.53 (s, 1H, CH); 7.05 (d, J ¼ 7.6 Hz, 1H,
ArH); 7.27 (t, J ¼ 7.6 Hz, 1H, ArH); 7.30 (d, J ¼ 7.6 Hz, 1H, ArH); 7.34 (t,
J ¼ 7.6 Hz, 1H, ArH); 7.39 (d, J ¼ 7.6 Hz, 1H, ArH); 7.50 (d, J ¼ 7.6 Hz, 1H,
ArH); 7.66 (t, J ¼ 7.6 Hz, 1H, ArH); 8.54 (d, J ¼ 14.1 Hz, 1H, NHCH );

ORDER
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790
PENG ET AL.
11.49 (d, J ¼ 14.1 Hz, 1H, NHCH); EIMS (70 eV) m/z (%): 476 (4) [Mþ].
(Found (HRMS) (ESI): Mþ þ H, 449.1818. C24H24N4O5 þ H requires
Mþ þ H 449.1819).
8-[[5-Methoxy-1-(6-methyl-2-pyridyl)-1H-pyrazole-3-
yl]methyl]-4(1H)-quinolone (1)
A suspension of the amino compound 10 (1.69 g, 3.56 mmol) in Ph2O
(20 ml) was heated under reflux for 40 min. After cooling, the mixture was
diluted with 120 ml of light petroleum ether. The resulting precipitate was
collected and recrystallized from MeOH to give 1 (690 mg, 69%). M.p.
223–224ꢀC. IR (cmꢂ1): 3237, 2927, 1725, 1569, 1522, 1455, 1199, 1147,
l
1013, 792, 732; H NMR (400 MHz, CDCl3): d 2.48 (s, 3H, CH3); 3.83 (s,
3H, OCH3); 4.16 (s, 2H, CH2); 5.69 (s, 1H, CH); 6.06 (d, J ¼ 7.5 Hz, 1H,
ArH); 7.20 (t, J ¼ 7.5 Hz, 1H, ArH); 7.26 (d, J ¼ 8.0 Hz, 1H, ArH); 7.34 (d,
J ¼ 8.0 Hz, 1H, ArH); 7.51 (d, J ¼ 7.5 Hz, 1H, ArH); 7.79 (t, J ¼ 7.5 Hz, 1H,
ArH); 7.85 (t, J ¼ 7.6 Hz, 1H, ArH); 8.01 (d, J ¼ 7.6 Hz, 1H, ArH); 11.27 (br,
s, 1H, NH); EIMS (70 eV): m/z (%) 346 (100) [Mþ]. (Found (HRMS) (ESI):
Mþ þ H, 347.1503. C20H18N4O2 þ H requires Mþ þ H 347.1503).
4-Chloro-8-[[5-methoxy-1-(6-methy-2-pyridyl)-
1H-pyrazol-3-yl]-methyl]-quinoline (2)
A suspension of 1 (200 mg , 0.57mmol) in POCl 3 (6 ml) was stirred
under reflux for 3 h. The reaction mixture was cooled and poured onto ice
(20 g), neutralized with sat aq. NaHCO3 and extracted with CH2Cl2
(2 ꢁ 50 ml). The combined organic extracts were washed with sat aq.
NaHCO3, brine, and dried. The solvent was evaporated under reduced
pressure and the residue purified by column chromatography to give 2
(120 mg, 77%). M.p. 127 – 128ꢀC. IR (cmꢂ1): 3391, 2926, 1593, 1572, 1492,
l
1455, 1386, 1143, 1013, 794; H NMR (400 MHz, CDCl3): d 2.63 (s, 3H,
CH3); 3.83 (s, 3H, OCH3); 4.71 (s, 2H, CH2); 5.43 (s, 1H, CH); 7.06
(d, J ¼ 7.5 Hz, 1H, ArH); 7.44 (t, J ¼ 8.0 Hz, 1H, ArH); 7.53 (d, J ¼ 4.8 Hz,
1H, ArH); 7.57 (t, J ¼ 8.0 Hz, 1H, ArH); 7.65 (t, J ¼ 8.0 Hz, 1H, ArH);
7.74 (d, J ¼ 8.0 Hz, 1H, ArH); 8.15 (t, J ¼ 8.0 Hz, 1H, ArH); 8.86 (d,
J ¼ 4.8 Hz, 1H, ArH); EIMS (70 eV) m/z (%): 364 (100) [Mþ], 366 (33)
[Mþ þ 2] (Found (HRMS) (ESI): Mþ þ H, 365.1172. C20H17CIN4O2 þ H
requires Mþ þ H 365.1164).

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Received in Japan November 17, 2000

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