Facile and efficient regioselective synthesis of 1-(3′-substituted quinoxalin-2′-yl)-3-aryl/heteroaryl-5-methylpyrazoles

Article abstract of DOI:10.1080/00397911.2012.674168

This report describes an efficient and practical approach for regioselective synthesis of 1-(3′-substituted quinoxalin-2′-yl)-3- aryl/heteroaryl-5-methylpyrazoles (3a-j). Reaction of 2-chloro-3-substituted quinoxalines (1) with 3(5)-methyl-5(3)-aryl-1H-pyrazoles (2) in the presence of sodium hydride furnished the title compounds in excellent yields with good levels of regioselectivity. The present protocol is superior to the existing method, which yielded a mixture of regioisomeric pyrazoles (I, II) and triazolo[4,3-a]quinoxalines (III). Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.674168

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A Facile and Efficient Regioselective Synthesis of 1-
(3′-Substitutedquinoxalin-2′-yl)-3-Aryl/Heteroaryl-5-
Methylpyrazoles
Ranjana Aggarwal a , Eakta Masan a & Garima Sumran a
a Department of Chemistry, Kurukshetra University, Kurukshetra, India
Accepted author version posted online: 02 Jan 2013.
To cite this article: Ranjana Aggarwal , Eakta Masan & Garima Sumran (2013): A Facile and Efficient Regioselective Synthesis
of 1-(3′-Substitutedquinoxalin-2′-yl)-3-Aryl/Heteroaryl-5-Methylpyrazoles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.674168
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A FACILE AND EFFICIENT REGIOSELECTIVE SYNTHESIS OF 1-(3'-
SUBSTITUTEDQUINOXALIN-2'-YL)-3-ARYL/HETEROARYL-5-
METHYLPYRAZOLES
Ranjana Aggarwal1,, Eakta Masan1, Garima Sumran1
1Department of Chemistry, Kurukshetra University, Kurukshetra, India
Address correspondence to Dr. Ranjana Aggarwal, Department of Chemistry,
Kurukshetra University, Kurukshetra-136119, India. E-mail: ranjana67in@yahoo.com
Abstract
This report describes an efficient and practical approach for regioselective synthesis of 1-
(3'-substitutedquinoxalin-2'-yl)-3-aryl/heteroaryl-5-methylpyrazoles (3a-j). Reaction of
2-chloro-3-substitutedquinoxalines (1) with 3(5)-methyl-5(3)-aryl-1H-pyrazoles (2) in
presence of sodium hydride furnished the title compounds in excellent yields exhibiting
high level of regioselectivity. The present protocol is superior to the existing method
which yielded a mixture of regioisomeric pyrazoles (I, II) and triazolo[4,3-a]quinoxalines
(III).
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: 2-Chloro-3-substitutedquinoxalines; 3(5)-methyl-5(3)-aryl-1H-pyrazoles;
regioselective synthesis; 1-(3'-substitutedquinoxalin-2'-yl)-3-aryl/heteroaryl-5-
methylpyrazoles
INTRODUCTION
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Pyrazoles and their derivatives exhibit many diverse type of pharmaceutical activities
such as herbicidal,[1] cholecystokinin 1 (CCK 1) receptor antagonist[2] besides being
selective monoamine oxidase[3] and human complement component (C1s) inhibitors.[4]
The introduction of celecoxib, a COX-2 inhibitor, for the treatment of chronic
inflammatory diseases like rheumatoid and osteoarthritis has stimulated further interest in
the pyrazole chemistry.[5] Recently, there has been a growing interest in developing
general and versatile synthetic methods for the synthesis of this heterocyclic nucleus. In
addition, quinoxaline ring has attracted considerable attention as a result of their
pharmacological properties. Several potentially useful antibiotics e.g. echinomycin,
levomycin, actinoleutin based on this pharmacophore have been developed in recent
years,[6,7] but there is still an ample scope for further exploration of this system.
Therefore, it was thought of interest to synthesize some pharmacologically active
pyrazole derivatives bearing quinoxaline nucleus.
Synthetic routes available for the construction of pyrazole include 1,3-dipolar
intermolecular [2+3] cycloadditions of diazoalkanes to alkynes,[8] oxidation of
pyrazolines[9–11] and cyclocondensation of hydrazines with 1,3-difunctionalized
compounds which include β-keto esters, aldehydes, nitriles, substituted α,β-unsaturated
ketones and β-diketones[12–14] etc. A 1,3-diketone is the classical 3-atom synthon which
has a wide scope not only because of its ready availability but also because one carbonyl
of the starting diketone may be replaced by an acetal, a hemiacetal, a chlorovinyl group
and a dihalide. Although very frequently used, unsymmetrical 1,3-diketones and
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hydrazines suffer not only from the drawback of regioselectivity but some reports also
mention the formation of isomeric diazepines and triazepines.[15–18]
Recently, we have undertaken the study of reaction of 2-hydrazino-3-methylquinoxaline
with several aryl/heteroaryl-1,3-diketones[19] and it was observed that the reaction
furnished a mixture of three products namely: regioisomeric 1-(3'-methylquinoxalin-2'-
yl)-3-methyl-5-substitutedpyrazole I, 1-(3'-methylquinoxalin-2'-yl)-5-methyl-3-
substitutedpyrazole II and an unexpected 1,4-dimethyl-s-triazolo[4,3-a]quinoxaline III
(Scheme 1).
Intrigued by the formation of a mixture of products, we intended to develop an efficient
alternative synthesis involving nucleophilic aromatic substitution (SNAr) which is a
versatile approach to prepare a wide range of functionalized heterocycles.[20] We wish to
report here a regioselective synthesis of 1-(3'-substitutedquinoxalin-2'-yl)-3-
aryl/heteroaryl-5-methylpyrazoles involving the reaction of 2-chloro-3-
substitutedquinoxaline with sodium salt of 3(5)-methyl-5(3)-aryl/heteroaryl-1H-pyrazole.
RESULTS AND DISCUSSION
3(5)-Methyl-5(3)-phenyl-1H-pyrazole (2a), obtained by condensation of hydrazine
hydrate with benzoylacetone, on treatment with equimolar amount of 2-chloro-3-
methylquinoxaline (1a) in presence of NaH in N,N-dimethylformamide (DMF) under
reflux led to the formation of 1-(3'-methylquinoxalin-2'-yl)-5-methyl-3-phenylpyrazole
(3a) as the exclusive product (on the basis of TLC and NMR of crude reaction mixture).
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The compound was found to be identical in all respects (mixed mp, co-TLC and 1H NMR
spectrum) with the product obtained by the reaction of an equimolar amount of 2-
hydrazino-3-methylquinoxaline with phenyl-1,3-butanedione in THF under reflux.[19]
Success of this reaction encouraged us to examine the generality of this reaction by
reacting 2-chloro-3-methyl/phenylquinoxalines (1a-b) with sodium salts of a variey of
3(5)-methyl-5(3)-aryl/heteroaryl-1H-pyrazoles (2) in DMF (Scheme 2) under similar
reaction conditions. Except in case of reaction of 1a with 2b and 1b with 2a (where
formation of small amount of 3-methyl isomers 4b and 4f was observed), 5-methyl
isomer (3a-j) was formed as an exclusive isomer in all the cases as shown in Table 1. The
known products 3a-e and 4b were identified by comparison of mps with those reported in
the literature.[19] The structure of new compounds 3f-j and 4f was confirmed from their
spectral data (IR, 1H NMR and HRMS) and elemental analysis.
The IR spectra of compounds 3f-j and 4f showed the disappearance of a band due to -NH
stretch in the range 3100-3400 cm-1 which was present in 3(5)-methyl-5(3)-
aryl/heteroaryl-1H-pyrazoles 2, indicating that nucleophilic substitution has occurred.
High resolution 1H NMR spectrum of 3f showed the singlet of 5-methyl at δ 2.14
appeared as a doublet due to allylic coupling with C4-H having coupling constant of 4J=
0.68 Hz. Similarly, a singlet of one proton intensity appeared as a quartet rather than a
singlet at δ 6.48 ppm (4J= 0.68 Hz) for pyrazole 4-H and it was characterized as 1-(3'-
phenylquinoxalin-2'-yl)-5-methyl-3-phenylpyrazole. Similarly, in 1H NMR spectra of 3g-
j a sharp singlet for three protons (CH3) appeared upfield at δ 2.04-2.17 probably due to
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shielding of methyl protons due to phenyl ring at position 3' of quinoxaline ring and a
singlet of one proton intensity at 6.34-6.54 for pyrazole 4-H, besides the aromatic
protons of quinoxaline. However, 1H NMR spectra of 4f revealed CH3 protons resonating
as a singlet at δ 2.49 (C3-CH3) and a characteristic signal for one proton as a sharp singlet
at 6.19 which was assigned to C4-H of the pyrazole ring, alongwith aromatic protons.
It is evident from the results given in Table 1 that 5-methylpyrazole is the
exclusive/major isomer in all such cases. Ratio of the two products 3 and 4 depends on
the tautomeric equilibrium of the 3(5)-methyl-5(3)-aryl/heteroaryl-1H-pyrazoles (2). As
the 5-methyl isomer 3a-j is predominant than 3-isomer 4b,f this indicates that the ratio of
equilibrium between tautomers of 2 may be more towards 3-aryl/heteroaryl-5-methyl-1H-
pyrazoles.
Finally, the present approach is significant as this alternative route not only eliminates the
formation of triazoloquinoxaline III but also provides the 5-methyl isomer as the
exclusive/major product which otherwise was a minor product in the reaction of 2-
hydrazino-3-methylquinoxaline with 1,3-diketones.
EXPERIMENTAL SECTION
General Procedure
Melting points were determined in open capillaries and are uncorrected. The IR spectra
were recorded on a Buck Scientific IR M-500 spectrophotometer in KBr pellets (νmax in
cm-1). Low and high resolution 1H NMR spectra were recorded in CDCl3 on a Bruker
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instrument at 300 MHz and 400 MHz respectively. 13C NMR spectra was recorded in
CDCl3 on a Bruker instrument at 50 MHz and 75 MHz; chemical shifts are expressed as δ
values with units of ppm, downfield from TMS (δ 0.0) as an internal standard. Coupling
constants (J) are given in Hertz (Hz). All the compounds gave satisfactory elemental
analyses. The reactions were monitored by the TLC carried out on pre-coated silica gel
glass plates. Isolation of product was accomplished via crystallization in ethanol in those
reactions where a single product was obtained. Wherever, a mixture of products was
obtained, separation was done by column chromatography using silica gel (100-200
mesh) and ethyl acetate- pet. ether as eluent.
The starting materials 2-chloro-3-methylquinoxaline (1a) and 2-chloro-3-
phenylquinoxaline (1b) were prepared via the chlorination of 2-hydroxy-3-
methylquinoxaline and 2-hydroxy-3-phenylquinoxaline, respectively, with phosphorus
oxychloride.[21] 3(5)-Methyl-5(3)-aryl/heteroaryl-1H-pyrazoles (2a-e) were prepared
according to the literature procedure.[22]
Synthesis Of 1-(3'-Methylquinoxalin-2'-Yl)-5-Methyl-3-Phenylpyrazole (3a)
A solution of 3(5)-methyl-5(3)-phenyl-1H-pyrazole (2a) (790 mg, 5 mmol) in anhydrous
N,N-dimethylformamide (20 ml) was refluxed with a suspension of sodium hydride (240
mg, 10 mmol) for 30 minutes. Subsequently, 2-chloro-3-methylquinoxaline (1a) (890 mg,
5 mmol) was added slowly and the reaction mixture was heated at 150 C for 13 hr.
After distilling the excess of N,N-dimethylformamide, the residue was poured into water
(50 ml) and extracted with DCM (3 x 20 ml). The combined extracts were dried over
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anhydrous Na2SO4 and DCM was distilled off. The crude solid thus obtained was
recrystallised in ethanol to obtain 3a as a crystalline solid.
mp 130-132 C (Lit[19] mp 132 C), yield 71%.
All other compounds were synthesized according to the procedure mentioned for 3a
using 2-chloro-3-substitutedquinoxaline (1) with different 3(5)-methyl-5(3)-aryl-1H-
pyrazoles (2). Column chromatographic workup using ethyl acetate- pet. ether as eluent,
was performed for reaction between 1a and 2b which afforded 3b in the initial fractions
followed by 4b in the next fractions. Similarly, a mixture of 3f and 4f, obtained by
reaction between 1b with 2a was also separated by column chromatography.
The Characterization Data For 3f: 3f: 1-(3'-Phenylquinoxalin-2'-Yl)-5-Methyl-3-
Phenylpyrazole
mp 110-112 °C; yield 68.4%; IR (cm-1): 3063, 1597, 1443, 1366; 1H NMR (CDCl3, δ, 400
MHz): 2.14 (d, 3H, 4J= 0.68 Hz, C5-CH3), 6.48 (q, 1H, 4J= 0.68 Hz, C4-H), 7.30-7.39 (m,
6H, C3'-Ph, Pha- 4H), 7.48-7.50 (m, 2H, Pha- 2H, 6H), 7.70-7.72 (m, 2H, Pha- 3H, 5H),
7.81-7.88 (m, 2H, quinox-6'H, 7'H), 8.18-8.19 (m, 1H, quinox-5'H ), 8.20-8.21 (m, 1H,
quinox-8'H); 13C NMR (CDCl3, δ, 75 MHz): 11.68, 104.90, 126.03, 127.58, 128.05,
128.39, 128.50, 128.54, 129.17, 129.30, 129.49, 130.05, 130.21, 130.30, 140.17, 141.87,
143.40, 144.87, 151.34, 152.83. HRMS (m/z) (Ir, %): 363.1603 (M+ +1) (33); Anal.
Calcd. for C24H18N4: C, 79.54; H, 5.01; N, 15.46 %. Found: C, 79.70; H, 4.91; N, 15.70
%.
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Complete experimental and spectral details are available online in the Supplementary
Materials.
ACKNOWLEDGEMENTS
We are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi,
India for providing financial assistance to Eakta. We also thank the Mass Spectrometry
Facility, University of California, San Francisco, USA for running the mass spectra.
Thanks are also due to SAIF, CDRI, Lucknow for elemental analysis.
SUPPLEMENTARY DATA
Supplementary data associated with this article can be found in the online version.
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Table 1 Ratio of the products calculated from 1H NMR of the crude reaction mixture
(Yield %)
3,4
a
b
c
R
R'
(3a-j) 5-isomer
100 %
(4b,f) 3-isomer
CH3 C6H5
Nil
CH3 4-CH3C6H4
90 %
10 %
Nil
CH3 4-OCH3C6H4 100 %
d
e
CH3 4-ClC6H4
CH3 2-Thienyl
C6H5 C6H5
100 %
100 %
70 %
Nil
Nil
f
30 %
Nil
g
h
i
C6H5 4-CH3C6H4
100 %
C6H5 4-OCH3C6H4 100 %
Nil
C6H5 4-ClC6H4
C6H5 2-Thienyl
100 %
100 %
Nil
j
Nil
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Scheme 1 Synthesis of regioisomeric pyrazoles I, II and triazole III.
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Scheme 2 Synthesis of compounds 3a-j and 4b,f.
H
H
N
R
N
N
N
N
+
CH3
R'
R'
H3C
N
Cl
2a-e
1a-b
NaH/DMF
150 oC
N
N
R
N
N
R
N
+
N
N
N
CH3
R'
R'
3-Isomer
H3C
5-Isomer
Exclusive/Major
Negligible/Minor
3a-j
4b,f
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