Aqueous hydrofluoric acid catalyzed facile synthesis of 2,3,6-substituted quinoxalines

Article abstract of DOI:10.1002/jhet.1753

A versatile synthetic route for the preparation of 2,3,6-trisubstituted quinoxalines in excellent yield is developed from θ-diamines and 1,2-dicarbonyl compounds in which aqueous hydrofluoric acid was employed as the medium and catalyst. Other salient features of this protocol include milder conditions, absence of coupling agents, and easy workup procedures.

Full text of DOI:10.1002/jhet.1753

Month 2014
Aqueous Hydrofluoric Acid Catalyzed Facile Synthesis of 2,3,6-
Substituted Quinoxalines
*
A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, K. Raju, P. V. S. S. Srinivas, P. Shanthan Rao, and B. Narsaiah
Fluoroorganics Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
*
E-mail: shanthanpp1954@gmail.com
Received March 1, 2012
DOI 10.1002/jhet.1753
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A versatile synthetic route for the preparation of 2,3,6-trisubstituted quinoxalines in excellent yield is devel-
oped from θ-diamines and 1,2-dicarbonyl compounds in which aqueous hydrofluoric acid was employed as the
medium and catalyst. Other salient features of this protocol include milder conditions, absence of coupling
agents, and easy workup procedures.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
of quinoxalines, benzoxazoles, and benzimidazoles [23].
Most of the existing methodologies suffer from disadvantages
such as usage of volatile organic solvents, complex product
isolation procedures, expensive and detrimental metal precur-
sors, and harsh reaction conditions, and they are not environ-
mentally benign processes. The ongoing program of our
interest is the use of anhydrous hydrogen fluoride as a
fluorinating agent [24] in the presence of metal oxide catalysts
to prepare HFC-134a, a CFC substitute. Several commercial
processes are available for various refrigerants [25],
halon substitutes [26], and fluoromonomer [27]. The applica-
tions of hydrofluoric acid (HF) is known for intramolecular
Diels–Alder reactions [28] and for fluorination of
1,3-dicarbonyl compounds [29]. However, there is no
example of quinoxaline synthesis using aqueous HF (aq. HF).
Quinoxalines are important class of nitrogen containing
heterocyclics because of their broad spectrum of biological
activity. Quinoxaline compounds received considerable
interest from the pharmaceutical industry because of their
therapeutic properties such as antibacterial [1], antimalarial
[2], antifungal [3], antithrombotic [4], anticancer [5], and
antikinase inhibition agents [6]. Several other applications
of quinoxalines are reported as dyes [7], organic semicon-
ductors [8], building blocks for the synthesis of cavitands
[9], dehydroannulenes [10] and for DNA cleaving agents
[11]. Drug formulations containing quinoxaline ring systems
such as Lamprene are currently available (Figure 1).
In the past few years, a number of synthetic strategies have
been developed for the synthesis of substituted quinoxalines.
The conventional method of preparation of quinoxalines is
the condensation of θ-phenylene diamine with 1,2-dicarbonyl
compounds in refluxing ethanol or acetic acid [12]. In order to
improve the yields, research effort has been focused on find-
ing new catalysts such as I2 [13], Montmorillonite K-10 [14],
H6P2W18O62.24H2O [15], InCl3 [16], MnCl2 [17], Zn/L-pro-
line [18], and zeolites [19], with microwave [20] and solid
phase synthesis [21]. Furthermore, other synthetic methods
for quinoxalines such as oxidative coupling epoxides and
ene-1,2-diamines catalyzed by Bi(O), Pd(OAc)2, RuCl2
(PPh3)3TEMPO, and MnO2 have been reported [22].
Telvekar et al. used glycerol as solvent for the preparation
RESULTS AND DISCUSSION
The purpose of our study is to explore the scope of aq. HF
in organic synthesis for the preparation of important class of
quinoxaline heterocycles. For our initially explored studies,
we carried out the reaction between 4-nitro-1,2-diamino-
benzene and symmetrical 1,2-diketones using commercially
available aqueous HF (40%) as solvent medium to afford
the desired 6-nitro-2,3-diphenyl quinoxaline 3 (Scheme 1).
A mixture of 4-nitro-1,2-diaminobenzene (0.1 mol) and
symmetrical 1,2-diketone (0.1 mol) in aq. HF (50 mL) was
charged into a polypropelene bottle and stirred at ambient
© 2014 HeteroCorporation

A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, K. Raju, P. V. S. S. Srinivas,
P. Shanthan Rao, and B. Narsaiah
Vol 000
Further, the reaction of 4-chloro-θ-phenylene diamine with
ethyl 3,3,3-trifluoro-2-oxopropanoate in aq. HF medium
furnished two positional isomers in 45:55 ratio. They are
separated by column chromatography and characterized as
3-trifluoromethyl-7-chloro-1,2-dihydroquinoxaline-2-one
(20a) and 3-trifluoromethyl-6-chloro-1,2-dihydroquinoxaline-
2-one (21a). Ethylpyruvate and ethyl benzoyl pyruvate afforded
the corresponding quinoxalines (20b,c and 21b,c; Scheme 3).
In a typical reaction of 1,2-diketone with 1,2-diamine, the
role of HF may be explained as the hydrogen of HF
may form a weak hydrogen bonding with the oxygen of the
1,2-diketone, and the resulting slight drift of p-electrons of
carbonyl function towards oxygen facilitates the carbonyl
carbon to become more electrophilic in nature. The reaction
initiation takes place by attacking the lone pair electrons of
amine function onto the carbonyl carbon to give the
corresponding hydroxyl form, which was followed by
dehydration that furnishes azomethine function. Similarly,
the other amine also follows the same pathway to form
quinoxaline derivatives as depicted in Scheme 4.
Although the aq. HF is a weak acid (pKa 3.17), the
yields of quinoxalines are found to be excellent at ambient
temperature. As a comparative study, the condensation of
diamine and 1,2-dicarbonyl compounds was carried out
in the presence of aq. hydrochloric acid (pKa 7) solution.
The quinoxaline product was formed, but the reaction
was very slow and the diamine was consumed over a
period of 6–8 h. The same reaction was conducted in etha-
nolic gadalonium chloride solution (Scheme 3). The prog-
ress of the reaction is very slow, and the completion of the
reaction was observed in 12 h with constant stirring. Gada-
lonium chloride is a Lewis acid and was not used earlier for
the preparation of quinoxalines. The comparative results
are included in Table 1.
Figure 1. Clofazimine.
temperature for a period of 1 h. The progress of the reaction
was periodically monitored by thin-layer chromatography
(TLC) and continued for another 30 min till the diamine
spot disappeared. The reaction mixture was poured onto
crushed ice, and the resulted solid was filtered. The solid
was sequentially washed with water and then sodium
bicarbonate solution and dried. The product was character-
ized as 6-nitro-2,3-disubstituted quinoxaline (Table 1). The
scope of this condensation reaction was evaluated by using
parent and substituted θ-phenylene diamines and different
1,2-diketones, and the results are tabulated in Table 1. The
reaction of 4-chloro-θ-phenylene diamine with isatin is much
faster, and the corresponding quinoxaline (Table 1, entry 17)
is formed in 1 h.
The reaction was also extended to aliphatic diamine with
different benzils furnished dihydropyrazine derivatives
(Scheme 2; Table 1, entries 18 and 19).
Scheme 1. General procedure for the synthesis of 6-substituted 2,3-diaryl/alkyl quinoxalines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014 Aqueous Hydrofluoric Acid Catalyzed Facile Synthesis of 2,3,6-Substituted Quinoxalines
Table 1
Synthesis of quinoxaline derivatives by using aq. HF.
Time
aq. HF (min)
Isolated yield (%)
S. no.
Compound
GdCl3 (h)
aq. HF (%)
GdCl3 (%)
1
2
3
4
5
6
7
8
Quinoxaline
60
45
40
30
60
40
40
30
60
45
40
90
30
30
30
30
60
10
10
6
6
6
5
6
6
6
12
10
8
8
6
6
5
8
5
6
1
98
98
95
95
98
98
96
95
98
98
98
96
96
98
96
98
95
98
98
98
98
98
98
98
98
98
95
98
98
96
95
96
96
95
98
95
98
98
6-Chloroquinoxaline
6-Fluoroquinoxaline
6-Nitroquinoxaline
2,3-Dimethylquinoxaline
6-Chloro-2,3dimethylquinoxaline
6-Fluoro-2,3dimethylquinoxaline
6-Nitro-2,3dimethylquinoxaline
2,3Diphenylquinoxaline
6-Chloro-2,3diphenylquinoxaline
9
10
11
12
13
14
15
16
17
18
19
6-Fluoro-2,3diphenylquinoxaline
6-Nitro-2,3diphenylquinoxaline
2,3-Bis(4-fluorophenyl)6-nitroquinoxaline
6-Chloro-2,3-bis(4-fluorophenyl)quinoxaline
6-Nitro-2,3-bis(4-(trifluoromethyl)phenyl)quinoxaline
6-Chloro-2,3-bis(4-(trifluoromethyl)phenyl)quinoxaline
3-Chloro6h-indolo[2,3-b]quinoxaline
5,6-Diphenyl2,3-dihydropyrazine
2,3-Bis(4-fluorophenyl)5,6-dihydropyrazine
0.5
Scheme 2. Synthesis of 5,6-substituted 2,3-dihydropyrazine by using aq. HF.
Scheme 3. Synthesis of substituted quinoxaline-2-one by using aq. HF.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, K. Raju, P. V. S. S. Srinivas,
P. Shanthan Rao, and B. Narsaiah
Vol 000
Scheme 4. Mechanism for the formation of quinoxaline from diamine and diketone with aq. HF.
The aqueous solution was extracted with ethyl acetate, and the
organic layer was separated. The latter was dried on sodium
sulfate, and the solvent was filtered and distilled. The separated
solid was purified by recrystallization using aq. ethanol (50%) to
give the title compounds.
CONCLUSION
In summary, we have demonstrated a simple, conve-
nient, and efficient protocol for the preparation of substi-
tuted quinoxalines using aq. HF (40%) as the medium.
The advantage of the present method lies in using inexpen-
sive aq. HF as solvent medium, milder reaction conditions,
and very good yields.
Spectral
data
for
6-chloro-2,3-bis(4-fluorophenyl)
White colored solid, mp
quinoxaline (Table 1, entry 14).
133.7, IR (KBr, cmÀ1): 3051, 3039 (Ar C–H) 1673 (N═C–Ar);
1H NMR (300 MHz; CDCl3): d 7.00–7.12 (4H, m), 7.46–7.55
(4H, m), 7.72 (1H, dd), 8.08 (1H, d, J = 7.97 Hz ), 8.16 (1H, s);
13C NMR (75 MHz; CDCl3): d 162.9, 162.7, 154.2, 153.8,
142.9, 142.3, 140.3, 132.2, 130.8, 129.1, 128.6, 128.2, 128.0,
126.3, 125.2, 124.6, 123.5, 122.7, 121.6, 116.0; 19F NMR
(282 MHz, CDCl3): d À118.80 (m, 1F); MS–EI m/z: 352 (M),
354 (M + 2); HRMS Calcd: 352.06 Observed: 352.08; Anal.
Calcd for C20H11ClF2N2: C, 68.09; H, 3.14; N, 7.94. Found:
C, 68.07; H, 3.12; N, 7.95.
EXPERIMENTAL
Melting points were recorded on Cassia Siamia (VMP-AM) melt-
ing point apparatus and were uncorrected. IR spectra were recorded
on a Perkin-Elmer FT-IR 240-C spectrophotometer using KBr
1
optics. H NMR spectra were recorded on Bruker AV 300 MHz
and Unity 400 MHz spectrometer in CDCl3 using TMS as an internal
standard. Electron impact (EI) and chemical ionization mass spectra
were recorded on a VG 7070H instrument at 70 eV. All reactions
were monitored by TLC on precoated silica gel 60 mesh; spots
were visualized with UV light. Carbon, hydrogen, nitrogen (CHN)
analyses were recorded on a Vario EL analyzer.
Spectral data for 6-chloro-2,3-bis((4-trifluoromethyl)
phenyl)quinoxaline (Table 1, entry 16).
Yellow colored
solid, mp135-137, IR (KBr, cmÀ1): 3041 (Ar C–H), 1650
1
(N═C–Ar), 889 (C–F); H NMR (300 MHz; CDCl3): d 7.48–
7.56 (8H, m), 8.09 (1H, d, J = 8.61 Hz), 8.17 (1H, dd), 8.39
(1H, s); 13C NMR (75 MHz; CDCl3): d 154.2, 153.3, 145.0,
142.9, 142.3, 140.3, 136.3, 132.2, 131.0, 130.8, 128.6, 128.4,
128.0, 127.2, 126.3, 126.0, 125.2, 124.9, 124.5, 124.3, 122.7,
116.1; 19F NMR (282 MHz, CDCl3): d À62.29 (s, 3F); MS–EI
m/z: 452 (M), 454 (M + 2); HRMS Calcd: 452.05 Observed:
452.07; Anal. Calcd for C22H11ClF6N2: C, 58.36; H, 2.45; N,
6.19. Found: C, 58.38; H, 2.43; N, 6.17.
General procedure for the synthesis of quinoxalines
Method 1. A mixture of diamine (0.1 mol), benzil (0.1 mol),
and 50 mL of aq. HF (40%) was placed in polypropylene bottle
and stirred for specified time (Table 1) at ambient temperature.
The progress of the reaction was monitored by TLC. After
completion of the reaction, the contents of the bottle were
slowly poured in water and neutralized with NaOH. The
separated solid was filtered, washed with sodium bicarbonate
solution followed by water, and oven dried. The product was
purified by recrystallization in 50% aqueous ethanol to give the
corresponding quinoxaline.
Spectral data for 6-nitro-2,3-bis((4-trifluoromethyl) phenyl)
quinoxaline (Table 1, entry 15).
Yellow colored solid, mp
177, IR (KBr, cmÀ1): 3041 (Ar C–H), 1640 (N═C–Ar), 869
1
(C–F); H NMR (300 MHz; CDCl3): d 7.64–7.76 (8H, m), 8.15
Method 2.
Diamine (0.1 mol) and diketone (0.1mol) were
(1H, d, J = 8.87 Hz), 8.35 (1H, dd), 8.60 (1H, partially split
singlet); 13C NMR (75 MHz; CDCl3): d 155.4, 154.1, 144.1,
143.2, 141.9, 139.6, 133.3, 130.7, 130.4, 128.2, 128.0, 127.9,
127.7, 127.2, 127.0, 126.3, 126.0, 124.3, 122.7, 124.2, 124.0,
116.2; 19F NMR (282 MHz, CDCl3): d À62.35 (s, 3F); MS–EI
m/z: 463 (M), 394 (M–CF3); HRMS Calcd: 463.08 Observed:
taken in a round bottom flask containing 10mL of ethanol.
Gadalonium (III) chloride hexahydrate (0.01 mol%) was added to
the mixture, and the contents were refluxed for specified time
(Table 1). The progress of the reaction was checked by TLC. The
ethanol was evaporated, and the residue was treated with water.
Journal of Heterocyclic Chemistry
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Month 2014 Aqueous Hydrofluoric Acid Catalyzed Facile Synthesis of 2,3,6-Substituted Quinoxalines
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Acknowledgments. Authors are thankful to Dr. J. S. Yadav,
Director, IICT, for his constant encouragement and authors
(A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, and K. Raju)
are thankful to the Council of Scientific and Industrial Research
(CSIR), India, for providing financial assistance in the form of
Senior Research Fellowship.
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