Synthesis of Novel Drug-Like Small Molecules Based on Quinoxaline Containing Amino Substitution at C-2

Article abstract of DOI:10.1002/jhet.2177

A series of novel "drug-like" small molecules based on quinoxaline containing amino substitution at C-2 were synthesized. All these molecules were prepared either via the reaction of 2-phenyl-3-(piperazin-1-yl)quinoxaline with acyl bromides or benzyl bromides or various carboxylic acids or via the reaction of 2-chloro-3-phenylquinoxaline with various amines. The structures of these novel compounds were confirmed by spectral analysis. The strategy used is simple and efficient and afforded good yields of quinoxaline derivatives.

Full text of DOI:10.1002/jhet.2177

May 2016
Synthesis of Novel Drug-Like Small Molecules Based on Quinoxaline
Containing Amino Substitution at C-2
K. Raghavendra Rao,a,b Akula Raghunadh,a Ramamohan Mekala,a Suresh Babu Meruva,a K. Ravi Ganesh,a T. Krishna,a
a
b
c
*
Dipak Kalita, Eppakayala Laxminarayana, and Manojit Pal
aTechnology Development Centre, Custom Pharmaceutical Services, Dr Reddy’s Laboratories Ltd, Miyapur, Hyderabad,
500 049, India
bDepartment of Physics and Chemistry, Mahatma Gandhi Institute of Technology, Chaitanya Bharati, Gandipet,
Hyderabad, 500 075 Andhra Pradesh, India
cDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500 046, India
*
E-mail: manojitpal@rediffmail.com
Additional Supporting Information may be found in the online version of this article.
Received July 7, 2013
DOI 10.1002/jhet.2177
Published online 30 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel “drug-like” small molecules based on quinoxaline containing amino substitution at C-2
were synthesized. All these molecules were prepared either via the reaction of 2-phenyl-3-(piperazin-1-yl)
quinoxaline with acyl bromides or benzyl bromides or various carboxylic acids or via the reaction of 2-
chloro-3-phenylquinoxaline with various amines. The structures of these novel compounds were confirmed
by spectral analysis. The strategy used is simple and efficient and afforded good yields of quinoxaline derivatives.
J. Heterocyclic Chem., 53, 901 (2016).
INTRODUCTION
antagonistic activities as is exemplified by the discovery
of TZB-30878 as an orally bioavailable agent for irritable
bowel syndrome [13]. 2-Amino-substituted quinoxalines
on the other hand have been reported as interleukin-8 recep-
tor antagonists for the potential treatment of chemokine-
mediated diseases [14]. These observations and our interest
on quinoxalines [15–19] prompted us to devote our efforts
toward the synthesis of novel quinoxaline derivatives (C,
D, E, and F) containing amino substitution at C-2 (Fig. 1)
of potential biological significance. In continuation of our
interest in bioactive molecules [20–24], we now report
our results on the library generation based on the scaffolds
C–F by using efficient chemistry methodologies (Scheme 1).
Generation of a library of novel “drug-like” small mole-
cules is of considerable importance as this can lead to the
identification of preliminary hits required by pharmaceuti-
cal industries either via high throughput or traditional
screen against various pharmacological targets.
Quinoxaline, an important class of fused N-heterocycle,
has attracted considerable interest in the area of synthetic
and medicinal chemistry [1,2] due to their broad-spectrum
biological activities such as antiviral [3], antibacterial [4],
anti-inflammatory [5], antiprotozoal [6], anticancer [7]
(colon cancer therapies) [8], antidepressant [9], and anti-
HIV [6], and as kinase inhibitors [10,11]. In particular,
quinoxaline moiety has been found to be an integral part
of several antibiotics such as echinomycin, levomycin,
and actinoleutin that inhibit the growth of Gram-positive
bacteria and showed activities against various transplant-
able tumors [12]. It is therefore evident that quinoxaline
represents an attractive template for the design and discov-
ery of potential new drugs. Moreover, the quinoxaline ring
has been described as a bioisostere of quinoline, naphtha-
lene, benzothiophene, and several other aromatic rings
such as pyridine and pyrazine. A quinoxaline equivalent
of bioactive molecules containing all these moieties there-
fore has high probability to show relevant pharmacological
properties useful for the discovery of new chemical entities
in a particular therapeutic area. Quinoxalines or analogues
of quinoline derivatives possessing a piperizine ring at C-2
have shown remarkable 5-HT1A agonistic and 5-HT3
RESULTS AND DISCUSSION
The key starting materials, that is, 2-chloro-3-
phenylquinoxaline (3) and 2-phenyl-3-(piperazin-1-yl)
quinoxaline (4) required for our synthesis, were prepared
via a known method [13] as shown in Scheme 1.
We then prepared the 2-(4-(3-phenylquinoxalin-2-yl)
piperazin-1-yl)ethanone derivatives 5 (or C, Fig. 2) by
treating compound 4 with various acyl bromides in the
presence of basic alumina in MeCN at room temperature
for 10–12 h (Scheme 2). The alumina, most commonly
used to perform surface chemistry [25], is basic in nature
and possesses a large surface area and highly porous
exteriors available to substrates. Unlike clays and zeolites,
the basic alumina does not contain accessible channels or
© 2015 HeteroCorporation

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K. R. Rao, A. Raghunadh, R. Mekala, S. B. Meruva, K. R. Ganesh,
T. Krishna, D. Kalita, E. Laxminarayana, and M. Pal
Vol 53
Figure 1. Novel quinoxaline derivatives (C–F) containing amino substitution at C-2. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
Scheme 1. Preparation of starting material 3 and 4.
Figure 2. Library generation based on the drug-like scaffolds C–F. [Color figure can be viewed in the online issue, which is available at www.
interscience.wiley.com.]
Scheme 2. Preparation of 1-(4-(3-phenylquinoxalin-2-yl)piperazin-1-yl)ethanone derivatives 5.
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Synthesis of Novel Drug-Like Small Molecules Based on Quinoxaline
903
Scheme 4. Preparation of N-acyl/aryl derivatives 7.
cavities. While as a heterogeneous catalyst it has attracted
considerable attention in the organic synthesis, its use has
not been explored extensively to date. The present example
of alumina-mediated N-alkylation of a secondary amine 4
is not common in the literature. Nevertheless, the desired
N-alkylated products 5 were obtained in 83–92% yield
under mild conditions, demonstrating the potential of this
methodology.
The 2-(4-benzylpiperazin-1-yl)-3-phenylquinoxaline de-
rivatives 6 (or D, Fig. 2) were prepared by treating
compound 4 with a number of benzyl bromides in the pres-
ence of TEA in MeCN at room temperature for 10–12 h
(Scheme 3). The reaction proceeded smoothly affording
the desired products 6 in 83–93% yield.
The N-acyl/aryl derivatives 7 (or E, Fig. 2) were pre-
pared by reacting compound 4 with various carboxylic
acids in the presence of 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC) and TEA in DMF at room
temperature for 8–10 h (Scheme 4). The aryl, heteroaryl,
and aliphatic carboxylic acids were used in these reactions
to afford the desired products 7 in 78–82% yield.
The 2-anilino-3-phenyl quinoxaline derivatives 8 (or F,
Fig. 2) were prepared by reacting the chloro compound 3
with various amines at 100–110°C for 8–10 h in the
absence of any solvent (Scheme 5). Both aryl and alkylaryl
amines participated well in these reactions affording the
desired products in high yields.
Scheme 5. Preparation of 2-anilino-3-phenyl quinoxaline derivatives 8.
All the compounds synthesized were well characterized
by spectral (1H and 13C NMR, MS, and HRMS) data. For
example, compound 5 showed the NCH2CO signal as a
singlet in the range 3.9–4.0 δ in the 1H NMR and carbonyl
signal in the range 195–197 ppm in the 13C NMR spectra.
Compound 6 showed the CH2 signal as a singlet near 3.5 δ.
Compound 7 showed the CO signal in the range
160–172 ppm in the 13C NMR spectra. Satisfactory
HRMS data were also obtained for all these compounds,
that is, 5–8, indicating the formation of the desired
quinoxaline derivatives.
CONCLUSIONS
Scheme 3. Preparation of 2-(4-benzylpiperazin-1-yl)-3-phenylquino-
xaline derivatives 6.
In conclusion, we have explored quinoxaline as a template
for the generation of a library of novel drug-like small mole-
cules of potential biological significance. These molecules
were designed by introducing an amino substituent at C-2 of
the quinoxaline ring. All these molecules were prepared either
via the reaction of 2-phenyl-3-(piperazin-1-yl)quinoxaline
with acyl bromides or benzyl bromides or various carboxylic
acids or via the reaction of 2-chloro-3-phenylquinoxaline with
various amines. The structures of these novel compounds
were confirmed by spectral analysis. The strategy used for
the present synthesis is simple and efficient and afforded good
yields of the desired quinoxaline derivatives. It is therefore
amenable for the generation of diversity-based small mole-
cules related to the quinoxaline framework of potential phar-
macological interest.
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K. R. Rao, A. Raghunadh, R. Mekala, S. B. Meruva, K. R. Ganesh,
T. Krishna, D. Kalita, E. Laxminarayana, and M. Pal
Vol 53
Yellow color solid; mp: 145–147°C, yield: 90%; 1H NMR
(400 MHz, DMSO-d6) δ: 2.50 (t, J = 2.0 Hz, 4H, 2 × CH2), 3.2
(t, J = 2.2 Hz, 4H, 2 × CH2), 4.05 (s, 2H, N–CH2), 7.52–7.68
(m, 8H, ArH), 7.92–8.00 (m, 6H, ArH), 8.12 (d, J = 8 Hz, 1H,
ArH), 8.69 (d, J = 7.8 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ: 48.4 (N–CH2, 2 × CH2), 52.9 (N–CH2, 2 × CH2), 64.5
(CH2), 123.8, 126.3, 126.8, 126.9, 127.7 (2 x CH), 128.3,
128.5, 128.7 (3 × CH), 128.7, 129.2, 129.5 (2 × CH), 129.8,
132.4,133.2, 135.6, 138.5, 139.5, 140.3, 148.2, 154.0 (N═C–N),
196.2 (C═O); MS: m/z (%) = 459.2 (M + 1). HRMS: [MH]+
459.2203, calculated mass: 459.2185, molecular formula: C30H27N4O.
1-Phenyl-2-(4-(3-phenylquinoxalin-2-yl) piperazin-1-yl) ethanone
(5c).
EXPERIMENTAL
All the reactants and reagents were used as received from
commercial sources without further purification or prepared as de-
scribed in the literature. Reactions were stirred using Teflon-coated
magnetic stirring bars (IKA India Private Limited, Bangalore,
India). TLC plates were visualized by UV light or by treatment with
a spray of Pancaldi reagent {(NH4)6MoO4, Ce(SO4)2, H2SO4,
H2O}. Chromatographic purification of products was carried out
by flash column chromatography on silica gel (230–400 mesh).
Melting points were determined using an electrothermal melting
point apparatus and are uncorrected. NMR spectra were measured
in CDCl3, acetone, DMSO-d6 (all with TMS as internal standard)
on a Varian Gemini 400-MHz FT NMR spectrometer magnetic
resonance spectrometer (California, USA). Chemical shifts (δ) are
reported in parts per million, and coupling constants (J) are in
Hertz. The following abbreviations were used to explain the
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; and m,
multiplet. Mass spectra were recorded on an HP-5989A quadrapole
mass spectrometer (Agilent Technologies, Texas, USA).
General procedure for the synthesis of compound 5.
A
mixture of 2-phenyl-3-(piperazin-1-yl)quinoxaline (4, 1.0 equiv),
acyl bromide (1.0 equiv), and basic alumina (0.5 w/w) in
acetonitrile (5 mL) was stirred at room temperature for 10–12 h.
The progress of the reaction was monitored by TLC. After
completion of the reaction, the mass was filtered and washed
with acetonitrile (1 mL). Filtrates were collected, combined, and
concentrated under reduced pressure. The crude product isolated
was purified by column chromatography using EtOAc/n-hexane
(20:80) on 230–400 silica gel.
Yellow color solid; mp: 130–133°C, yield: 94%; 1H NMR
(400 MHz, DMSO-d6) δ: 2.50 (t, J = 2.0 Hz, 4H, 2 × CH2), 3.2
(t, J = 2.2 Hz, 4H, 2 × CH2), 3.89 (s, 2H, N–CH2), 7.49–7.56
(m, 6H, ArH), 7.58–7.63 (m, 2H, ArH), 7.78 (d, J = 7.6 Hz, 1H,
ArH), 7.91–7.98 (m, 5H, ArH); 13C NMR (100 MHz, DMSO-
d6) δ: 48.2 (N–CH2, 2 × CH2), 51.8 (N–CH2, 2 × CH2), 63.4
(CH2), 126.4, 126.5, 127.6 (2 × CH), 128.0 (2 × CH), 128.3
(3 × CH), 128.5 (2 × CH), 129.3, 129.8, 133.2, 135.8, 137.8,
138.9, 139.6, 147.7, 153.6 (N═C–N), 196.8 (C═O); MS: m/z
(%) = 409.3 (M + 1). HRMS: [MH]+ 409.2047, calculated mass:
409.2028, molecular formula: C26H25N4O.
1-([1, 1′-Biphenyl]-4-yl)-2-(4-(3-phenylquinoxalin-2-yl) piperazin-1-yl)
ethanone (5a).
2-(4-(3-Phenylquinoxalin-2-yl)piperazin-1-yl)-1-(4-(trifluoro-
methyl)phenyl)ethanone (5d).
Yellow color solid; mp: 164–168°C, yield: 92%; 1H NMR
(400MHz, DMSO-d6) δ: 2.50 (t, J = 2.0 Hz, 4H, 2 × CH2), 3.2
(t, J = 2.1 Hz, 4H, 2 × CH2), 3.91 (s, 2H, N–CH2), 7.48–7.55
(m, 7H, ArH), 7.73–7.82 (m, 6H, ArH), 7.96–7.98 (m, 3H, ArH),
8.08 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (100MHz, CDCl3) δ:
48.5 (N–CH2, 2 × CH2), 52.5 (N–CH2, 2 × CH2), 64.6 (CH2),
126.3, 126.9, 127.1 (2 × CH), 127.2 (2× CH), 127.7 (2× CH),
128.2, 128.7 (4× CH), 128.9 (2× CH), 129.2, 129.5, 134.6, 138.5,
139.3, 139.7, 140.3, 145.9, 148.2, 156.0, 158.6 (N═C–N), 195.0
(C═O); MS: m/z (%) = 485.3 (M + 1). HRMS: [MH]+ 485.2357,
calculated mass: 485.2341, molecular formula: C32H29N4O.
1-(Naphthalen-1-yl)-2-(4-(3-phenylquinoxalin-2-yl)piperazin-
1-yl)ethanone (5b).
Brown color syrup; yield: 83%;1H NMR (400 MHz, DMSO-
d6) δ: 2.60 (t, J = 2.0 Hz, 4H, 2 × CH2), 3.2 (t, J = 2.2 Hz, 4H,
2 × CH2), 3.90 (s, 2H, N–CH2), 7.51–7.58 (m, 5H, ArH), 7.60–
7.70 (m, 2H, ArH), 7.87–7.97 (m, 4H, ArH), 8.01–8.17 (m, 2H,
ArH); 13C NMR (100 MHz, CDCl3) δ: 48.3 (N–CH2, 2 × CH2),
52.7 (N–CH2, 2 × CH2), 64.7 (CH2), 125.0, 125.5, 126.4, 126.9,
127.0 (2 × CH), 127.3 (2 × CH), 127.7 (2 × CH), 128.7 (2 × CH),
128.8 (2 × CH), 129.0, 129.3, 130.0, 130.3, 147.80, 152.9,
171.2 (N═C–N), 195.9 (C═O); MS: m/z (%) = 477.2 (M + 1).
HRMS: [MH]+ 477.1990, calculated mass: 477.1902, molecular
formula: C27H24N4OF3.
General procedure for the synthesis of compound 6.
A
mixture of 2-phenyl-3-(piperazin-1-yl)quinoxaline (4, 1.0 equiv),
alkyl bromide (1.0 equiv), and TEA (2.0 equiv) in acetonitrile
(5 mL) was stirred at room temperature for 10–12 h. The
progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was concentrated under
reduced pressure. The crude product isolated was purified by
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Synthesis of Novel Drug-Like Small Molecules Based on Quinoxaline
905
column chromatography using EtOAc/n-hexane (20:80) on
2-Phenyl-3-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)
230–400 silica gel.
quinoxaline (6d).
4-((4-(3-Phenylquinoxalin-2-yl)piperazin-1-yl)methyl)benzonitrile
(6a).
1
Brown color syrup; yield: 86%; H NMR (400 MHz, CDCl3)
δ: 2.45 (t, J = 4.8 Hz, 4H, 2 × CH2), 3.30 (t, J = 5.0 Hz, 4H,
2 × CH2), 3.51 (s, 2H, CH2), 7.13 (d, J = 8.0 Hz, 2H, ArH),
7.44–7.51 (m, 6H, ArH), 7.60 (t, J = 7.0 Hz, 1H, ArH), 7.80
(d, J = 7.0 Hz, 1H, ArH), 7.95–7.97 (m, 3H, ArH); 13C NMR
(100 MHz, CDCl3) δ: 48.6 (N–CH2, 2 × CH2), 52.5 (N–CH2,
2 × CH2), 62.0, 119.3 (2 × CH), 120.7 (2 × CH), 121.7, 126.3,
126.9, 127.8 (2 × CH), 128.7 (2 × CH), 129.2, 129.5, 130.2
(2 × CH), 136.8, 138.5, 139.5,140.3, 148.2, 154.1; MS: m/z
(%) = 465.20 (M + 1). HRMS: [MH]+ 465.1917, calculated mass:
465.1902, molecular formula: C26H24N4OF3.
Yellow color solid; mp: 140–143°C, yield: 83%; 1H NMR
(400 MHz, CDCl3) δ: 2.46 (t, J = 2.0 Hz, 4H, 2 × CH2), 3.3
(t, J = 2.2 Hz, 4H, 2 × CH2), 3.56 (s, 2H), 7.42–7.63 (m, 9H,
ArH), 7.81 (d, J = 6.8 Hz, 1H, ArH), 7.95–7.99 (m, 3H, ArH);
13C NMR (100 MHz, CDCl3) δ: 48.6 (N–CH2, 2 × CH2), 52.6
(N–CH2, 2 × CH2), 62.3 (CH2), 110.9, 118.9, 126.4, 126.9,
127.8 (2 × CH), 128.7 (2 × CH), 129.2 (2 × CH), 129.4 (2 × CH),
129.6 (2 × CH), 132.1 (2 × CH), 138.6, 139.5, 140.3, 148.2,
154.0; MS: m/z (%) = 406.20 (M + 1). HRMS: [MH]+ 406.2043,
calculated mass: 406.2032, molecular formula: C26H24N5.
2-(4-(4-(tert-Butyl) benzyl) piperazin-1-yl)-3-phenylquinoxaline
(6b).
2-(4-(3,4-Dimethylbenzyl)piperazin-1-yl)-3-phenylquinoxaline
(6e).
Yellow color solid; mp: 165–167°C, yield: 85%; 1H NMR
(400 MHz, CDCl3) δ: 2.22–2.31 (m, 6H, 2 × CH3), 2.44
(t, J = 2.8 Hz, 4H, 2 × CH2), 3.32 (t, J = 2.2 Hz, 4H, 2 × CH2),
3.43 (s, 2H, CH2), 7.95–7.97 (m, 2H, ArH), 7.10 (d, J = 6.8 Hz,
1H, ArH), 7.57–7.61 (m, 4H, ArH), 7.43–7.50 (m, 1H, ArH),
7.80 (d, J = 7.6 Hz, 1H, ArH), 7.95–7.97 (m, 3H, ArH); 13C
NMR (100 MHz, CDCl3) δ: 19.2 (CH3), 21.0 (CH3), 48.5
(N–CH2, 2 × CH2), 52.3 (N–CH2, 2 × CH2), 60.4 (CH2), 126.1,
126.2, 126.8, 127.7 (2× CH), 128.6 (4 × CH), 129.2, 129.4,
129.9, 131.1 (2× CH), 137.3,138.5, 139.5, 140.3, 148.3, 154.1;
MS: m/z (%) = 409.30 (M+ 1). HRMS: [MH]+ 409.2394, calcu-
lated mass: 409.2392, molecular formula: C27H29N4.
Pale yellow solid; mp: 128–130°C, yield: 93%; 1H NMR
(400 MHz, CDCl3) δ: 1.30 (s, 9H, 3 × CH3), 2.45 (t, J = 2.1 Hz,
4H, 2 × CH2), 3.3 (t, J = 2.2 Hz, 4H, 2 × CH2), 3.49 (s, 2H,
CH2), 7.22–7.32 (m, 2H, ArH), 7.45–7.50 (m, 7H, ArH), 7.82
(d, J = 7.8 Hz, 1H, ArH), 7.95–7.97 (m, 3H, ArH); 13C NMR
(100 MHz, CDCl3) δ: 31.3 (3 × CH3), 34.4, 48.6 (N–CH2,
2 × CH2), 52.6 (N–CH2, 2 × CH2), 62.5 (CH2), 125.5 (2 × CH),
126.2, 126.8, 127.8 (2 × CH), 128.7 (4 × CH), 128.8 (2 × CH),
129.2, 129.5, 138.5, 139.6, 140.4, 148.2, 150.0, 154.2; MS: m/z
(%) = 437.3 (M + 1). HRMS: [MH]+ 437.2715, calculated mass:
437.2705, molecular formula: C29H33N4.
General procedure for the synthesis of compound 7.
A
mixture of 2-phenyl-3-(piperazin-1-yl) quinoxaline (4, 1.0 equiv),
appropriate carboxylic acid (1.0 equiv), EDC (1.5 equiv), and TEA
(2.0 equiv) in DMF (5 mL) was stirred at room temperature for
8–10 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, water (25 mL) followed by EtOAc
(25 mL) was added to the reaction mass. The separated organic layer
was collected, washed with water (25 mL), and concentrated under
reduced pressure. The crude product was purified by column
chromatography using EtOAc/n-hexane (20:80) on 230–400 silica gel.
2-(5-Methoxy-1H-indol-3-yl)-1-(4-(3-phenylquinoxalin-2-yl)
piperazin-1-yl)ethanone (7a).
2-(4-(4-Methoxybenzyl) piperazin-1-yl)-3-phenylquinoxaline
(6c).
Yellow color solid; mp: 144–146°C, yield: 90%; 1H NMR
(400 MHz, CDCl3) δ: 2.44 (s, 4H, 2 × CH2), 3.3 (s, 4H,
2 × CH2), 3.46 (s, 2H, CH2), 3.79 (s, 3H, OCH3), 6.83
(d, J = 7.8 Hz, 2H, ArH), 6.85–7.23 (m, 2H, ArH), 7.40–7.50
(m, 5H, ArH), 7.82, (d, J = 8.0 Hz, 1H, ArH), 7.65–7.97 (m, 3H,
ArH); 13C NMR (100 MHz, CDCl3) δ 48.5 (N–CH2, 2 × CH2),
52.4 (N–CH2, 2 × CH2), 55.2 (CH3), 62.2 (CH2), 113.7 (2 × CH),
126.1, 126.9, 127.8 (2 × CH), 128.6 (2 × CH), 128.7, 129.1,
129.4, 129.7, 130.2 (2 × CH), 138.5, 139.6, 140.4, 148.1, 156.0,
158.9; MS: m/z (%) = 411.20 (M + 1). HRMS: [MH]+ 411.2196,
calculated mass: 411.2185, molecular formula: C26H27N4O.
Yellow color solid; mp: 110–112°C, yield: 84%; 1H NMR
(400 MHz, CDCl3) δ: 3.14 (t, J= 4.8 Hz, 2H, CH2), 3.22
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K. R. Rao, A. Raghunadh, R. Mekala, S. B. Meruva, K. R. Ganesh,
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(t, J= 5.0 Hz, 2H, CH2), 3.51 (t, J= 4.6 Hz, 2H, CH2), 3.67
(t, J= 4.6 Hz, 2H, CH2), 3.80 (s, 2H), 3.85 (s, 3H, OCH3), 6.85 (dd,
J= 2.4 Hz,1H, ArH), 7.05 (s, 2H, ArH), 7.25 (s, 1H, NH), 7.45–7.64
(m, 5H, ArH), 7.81 (dd, J= 1.2 Hz, 1H, ArH), 7.93–7.99 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) δ: 41.1 (CH2), 45.5 (N–CH2,
2×CH2), 48.6 (N–CH2, 2×CH2), 55.8 (CH3), 100.3, 108.6, 111.9,
112.5, 122.9, 126.8, 126.9, 127.3 (2 × CH), 127.7 (2 × CH), 128.7,
128.8, 129.4, 129.7, 131.3, 138.7, 139.0, 140.0, 148.2, 153.7, 154.1,
170.2; MS: m/z (%) = 478.30 (M + 1). HRMS: [MH]+ 478.2231,
calculated mass: 478.2243, molecular formula: C29H28N5O2.
Furan-2-yl (4-(3-phenylquinoxalin-2-yl) piperazin-1-yl)
methanone (7b).
Yellow color syrup; yield: 82%; H NMR (400 MHz, CDCl3)
δ: 0.72–0.88 (m, 2H, CH2), 1.09–1.33 (m, 2H, CH2), 1.68–1.73
(m, 1H, CH), 3.27 (t, J = 4 Hz, 4H, 2 × CH2), 3.63 (t, J = 5 Hz,
4H, 2 × CH2), 7.46–7.55 (m, 4H, ArH), 7.61–7.64 (m, 2H,
ArH), 7.82 (d, J = 6.8 Hz, 1H, ArH), 8.00–8.01 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3) δ: 7.3 (2 × CH), 10.9, 44.8
(N–CH2, 2 × CH2), 48.5 (N–CH2, 2 × CH2), 126.6, 126.9, 127.7
(2× CH), 128.6, 128.7 (2× CH), 129.3, 129.6, 138.6, 139.04,
140.0, 148.0, 153.7, 172.2; MS: m/z (%) = 359.10 (M + 1).
HRMS: [MH]+ 359.1884, calculated mass: 359.1872, molecular
formula: C22H23N4O.
(4-(tert-Butyl)phenyl)(4-(3-phenylquinoxalin-2-yl)piperazin-
1-yl)methanone (7e).
1
Brown color syrup; yield: 89%; H NMR (400 MHz, CDCl3)
δ: 3.36 (t, J = 4.8 Hz, 4H, 2 × CH2), 3.89 (t, J = 5.0 Hz, 4H,
2 × CH2), 6.47 (dd, J = 2.0 Hz, 1H, ArH), 6.55 (m, 1H, ArH),
7.0 (d, J = 7.6 Hz, 1H, ArH), 7.28–7.29 (m, 1H, ArH), 7.54–
7.56 (m, 4H, ArH), 7.61–7.66 (m, 1H, ArH), 7.85 (d, J = 6.8 Hz,
1H, ArH), 8.0–8.02 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3)
δ: 44.8 (N–CH2, 2 × CH2), 48.7 (N–CH2, 2 × CH2), 111.3, 111.8,
116.9, 118.8, 126.7, 126.9, 127.8 (2 × CH), 128.6 (2 × CH),
129.7, 138.9, 140.0, 146.6, 147.5, 148.1, 153.7, 159.3, 161.3;
MS: m/z (%) = 385.20 (M + 1). HRMS: [MH]+ 385.1679, calcu-
lated mass: 385.1665, molecular formula: C23H21N4O2.
1-(4-(3-Phenylquinoxalin-2-yl)piperazin-1-yl)-2-(thiophen-2-yl)
ethanone (7c).
1
Yellow color syrup; yield: 86%; H NMR (400 MHz, CDCl3)
δ: 1.31 (s, 9H, 3 × CH3), 3.29–3.31 (m, 8H, 4 × CH2), 7.27–7.31
(m, 3H, ArH), 7.33–7.55 (m, 7H, ArH), 7.8 (d, J = 7.8 Hz, 1H,
ArH), 7.99–8.01 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3) δ:
31.0 (3 × CH3), 34.6, 43.2 (N–CH2, 2 × CH2), 48.8 (N–CH2,
2 × CH2), 113.8, 126.7, 126.8 (2 × CH), 126.9, 127.7 (2 × CH),
128.1, 128.6 (2 × CH), 128.7, 129.0 (2 × CH), 132.4, 138.9,
140.02, 152.9, 153.7, 154.6, 167.1, 170.6; MS: m/z
(%) = 451.30 (M + 1). HRMS: [MH]+ 451.2504, calculated mass:
451.2498, molecular formula: C29H31N4O.
(4-Fluorophenyl)(4-(3-phenylquinoxalin-2-yl)piperazin-1-yl)
methanone (7f).
Yellow color solid; mp: 128–130°C, yield: 92%; 1H NMR
(400MHz, CDCl3) δ: 3.23 (t, J = 5.0 Hz, 4H, 2 × CH2), 3.54
(t, J = 5.2Hz, 2H, CH2), 3.65 (t, J = 5.2 Hz, 2H, CH2), 3.90 (s, 2H,
CH2), 6.88–6.94 (m, 2H, ArH), 7.18–7.19 (m, 1H, ArH), 7.47–
7.51 (m, 4H, ArH), 7.61–7.63 (m, 1H, ArH), 7.81 (d, J = 7.0 Hz,
1H, ArH), 7.95–8.00 (m, 3H, ArH); 13C NMR (100 MHz, CDCl3)
δ:34.9 (CH2), 45.4 (N–CH2, 2 × CH2), 48.4 (N–CH2, 2 × CH2),
124.6, 125.9, 126.7, 126.8 (2 × CH), 127.6 (2× CH), 128.3, 128.6,
128.7 (2× CH), 129.6, 136.1, 138.6, 138.9, 139.9, 147.9, 153.5,
168.4; MS: m/z (%) = 415.20 (M + 1). HRMS: [MH]+ 415.1612,
calculated mass: 415.1593, molecular formula: C24H23N4OS.
Cyclopropyl-(4-(3-phenylquinoxalin-2-yl)piperazin-1-yl)methanone
(7d).
Yellow color solid; mp: 185–188°C, yield: 78%; 1H NMR
(400 MHz, CDCl3) δ: 3.25 (s, 4H, 2 × CH2), 3.51 (s, 4H,
2 × CH2), 7.08–7.10 (m, 3H, ArH), 7.38–7.52 (m, 7H, ArH), 7.8
(d, J = 7.8 Hz, 1H, ArH), 8.02–8.11 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3) δ: 43.3 (N–CH2, 2 × CH2), 48.7 (N–CH2,
2 × CH2), 115.12 (2 × CH), 126.3, 126.4, 126.8, 126.9, 127.7
(2 × CH), 128.3 (2 × CH), 128.6, 128.7, 129.3, 129.3, 129.4,
129.7, 139.9, 148.1, 153.6, 164.2, 169.6; MS: m/z (%) = 413.10
(M + 1). HRMS: [MH]+ 413.1766, calculated mass: 413.1778,
molecular formula: C25H22N4OF.
General procedure for the synthesis of compound 8.
A
mixture of 2-chloro-3-phenylquinoxaline (3, 1.0 equiv) and
appropriate amine (1.0 equiv) was heated to 100–110°C for
8–10 h. The progress of the reaction was monitored by TLC.
After completion of the reaction, the crude isolated was purified
by column chromatography using EtOAc/n-hexane(20:80) on
230–400 silica gel.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Novel Drug-Like Small Molecules Based on Quinoxaline
907
N-(4-(tert-Butyl)phenyl)-3-phenylquinoxalin-2-amine (8a).
126.2, 126.2, 126.4, 126.8 (2 × CH), 128.6, 128.9, 129.7
(2 × CH), 130.2 (2 × CH), 136.0, 137.9, 140.3, 142.4, 146.6,
146.9; MS: m/z (%) = 366.10 (M + 1). HRMS: [MH]+ 366.1206,
calculated mass: 366.1218, molecular formula: C21H15N3F3.
N-(4-Methoxybenzyl)-3-phenylquinoxalin-2-amine (8d).
Yellow color solid; mp: 120–125°C, yield: 90%; 1H NMR
(400 MHz, CDCl3) δ: 1.33 (s, 9H, 3 × CH3), 7.00 (s, 1H, NH),
7.39 (d, J = 8.8 Hz, 2H, ArH), 7.44–7.56 (m, 1H, ArH), 7.57–7.64
(m, 4H, ArH), 7.69 (d, J = 8.2 Hz, 2H, ArH), 7.69–7.78 (m, 2H,
ArH), 7.85 (d, J = 7.6 Hz, 1H, ArH), 7.94–7.96 (m, 1H, ArH);
13C NMR (100 MHz, CDCl3) δ: 31.4 (3 × CH3), 34.3, 119.2
(2 × CH), 125.4, 125.7, 126.6 (2 × CH), 128.6, 128.7 (2 × CH),
129.5 (2 × CH), 129.8, 129.9, 136.4, 136.5, 137.6, 140.8,
146.0, 146.9, 147.2; MS: m/z (%) = 354.20(M + 1). HRMS:
[MH]+ 354.1961, calculated mass: 354.1961, molecular
Formula: C24H24N3.
1
Brown color syrup; yield: 92%; H NMR (400 MHz, CDCl3)
δ: 3.78 (s, 3H, OCH3), 4.71 (d, J = 6.0 Hz, 2H, CH2), 5.3
(s, 1H, NH), 6.86 (d, J = 5.0 Hz, 2H, ArH), 7.28 (d, J = 8.0 Hz,
2H, ArH), 7.39–7.47 (m, 1H, ArH), 7.48–7.57 (m, 4H, ArH),
7.69–7.77 (m, 3H, ArH), 7.93 (d, J = 8.0 Hz, 1H, ArH); 13C
NMR (100 MHz, CDCl3) δ: 44.7, 55.1, 113.9, 114.2, 124.4
(2 × CH), 125.9 (2 × CH), 128.3 (2 × CH), 128.7, 129.2, 129.6
(2 × CH), 130.8, 131.8, 136.6, 137.1, 141.5, 146.4, 149.8,
158.8. MS: m/z (%) = 342.20 (M + 1). HRMS: [MH]+ 342.1602,
calculated mass: 342.1606, molecular formula: C22H20N3O.
3-Phenyl-N-(4-(trifluoro methoxy)phenyl) quinoxalin-2-amine
(8b).
Acknowledgments. The author (KRR) thanks Dr. Upadhya
Timmanna for his encouragement and the Department of
Chemistry, JNTU, Hyderabad, for support.
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Yellow color solid; mp: 154–156°C, yield: 80%; 1H NMR
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Yellow color solid; mp: 182–184°C, yield: 82%; 1H NMR
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