One-pot, procedure for the preparation of some thiazino[2,3-b]quinoxaline derivatives

Article abstract of DOI:10.3184/174751914X13926569127947

An efficient and convenient synthesis of new thiazino[2,3-b]quinoxaline derivatives has been developed by employing a one-pot cyclo-condensation of several α-haloketones and 3-aminoquinoxaline-2-thiol in acetic acid. A similar reaction with 4-bromo-3-methyl-4,5-dihydro-1H-5-pyrazolone gave a new heterocyclic system, 3-methyl-1,4-dihydropyrazolo[4′,3′:5,6][1,4] thiazino[2,3-b]quinoxaline.

Full text of DOI:10.3184/174751914X13926569127947

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MARCH, 189–191
RESEARCH PAPER 189
One-pot, procedure for the preparation of some thiazino[2,3-b]quinoxaline
derivatives
Mehdi Bakavolia*, Hossein Eshghia, Hamid Azizollahia, Sattar Saberia and Faezeh Bazrafshanb
aDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, PO Box 91775-1436, Mashhad, Iran
bDepartment of Chemistry, Payame Noor University (PNU), PO Box 91735-433, Mashhad, Iran
An efficient and convenient synthesis of new thiazino[2,3-b]quinoxaline derivatives has been developed by employing a
one-pot cyclo-condensation of several α-haloketones and 3-aminoquinoxaline-2-thiol in acetic acid. A similar reaction with
4-bromo-3-methyl-4,5-dihydro-1H-5-pyrazolone gave a new heterocyclic system, 3-methyl-1,4-dihydropyrazolo[4′,3′:5,6][1,4]
thiazino[2,3-b]quinoxaline.
Keywords: quinoxaline; α-haloketones; synthesis; cyclo-condensation; thiazino[2,3-b]quinoxaline
Studies on the synthesis and chemistry of new quinoxalines
have attracted considerable attention in the past 10 years
because of their interesting chemical as well as biological
properties.1 Quinoxalines have anti-viral,2 anti-bacterial,3 anti-
inflammatory,4 anti-protozoal,5 anti-cancer,6 anti-depressant,7
anti-HIV activity8 and are also kinase inhibitors.9 They are
used in the agricultural area as fungicides, herbicides, and
insecticides.1 Furthermore quinoxaline units are present in
the structure of various antibiotics such as echinomycin,
levomycin and actinoleutin, which are known to inhibit
the growth of gram positive bacteria and are active against
various transplantable tumours.10,11 In addition, quinoxaline
derivatives are used in dyes,12 efficient electron luminescent
materials,13 organic semiconductors,14 chemically controllable
switches,15 building blocks for the synthesis of anion
receptors,16 cavitands17 and dehydroannulenes.18 They also
serve as useful rigid subunits in macrocyclic receptors in
molecular recognition.19 Some quinoxaline derivatives have
been synthesised using microwave irradiation.20 However,
recent synthetic methods have focused on techniques involving
alternative activation modes. Numerous methods are available
for the synthesis of quinoxaline derivatives which involve
condensation of 1,2-diamines with α-diketones,1 1,4-addition
of 1,2-diamines21 to diazenylbutenes,22 cyclisation–oxidation
of phenacyl bromides and oxidative coupling of epoxides with
ene-1,2-diamines.23–25 Since quinoxalines are biologically
important compounds, they have been the subject of our recent
investigations. We now report a convenient and straightforward
method for the synthesis of new thiazino[2,3-b]quinoxaline
derivatives and a new heterocyclic system, 3-methyl-1,4-
dihydropyrazolo[4′,3′:5,6][1,4]thiazino[2,3-b]quinoxaline.
Results and discussion
3-Aminoquinoxaline-2-thiol (1) was prepared according to the
literature procedure.26 We initially reacted this compound with
phenacyl bromide (2b) under different reaction conditions. The
excellent conversion of the starting materials (1 and 2b) into
their product 3b was achieved within two hours in refluxing
acetic acid (Scheme 1).
Under the optimised conditions, the cyclo-condensation of
a wide range of aryl α-haloketones carrying either electron-
donating or electron-withdrawing substituents on their aromatic
rings, with 3-aminoquinoxaline-2-thiol proceeded smoothly
and gave the corresponding thiazino[2,3-b]quinoxaline
derivatives (3b–g) in good to excellent yields. The phenacyl
bromides containing electron-withdrawing substituents tended
to react at higher rates with shorter reaction times (2e–g) in
comparison with those having electron-donating substituents
(2b–d) (Table 1).
O
X
H
R
(2a-g)
R
N
N
N
S
acetic acid / reflux
(3a-g)
3a: R=CH3, 3b: R=Ph, 3c: R=p-C6H4-Me
3d: R=p-C6H4-OMe, 3e: R=p-C6H4-Ph
3f: R=p-C6H4-Br, 3g: R=p-C6H4-NO2
N
N
NH2
H
S
H
O
N
(1)
N
H
H
r
B
N
N
N
N
4
( )
N
acetic acid / reflux
S
(5)
Scheme 1 General route for the synthesis of thiazino[2,3-b]quinoxaline.
* Correspondent. E-mail: mbakavoli@yahoo.com

190 JOURNAL OF CHEMICAL RESEARCH 2014
3‑Phenyl‑4H‑[1,4]thiazino[2,3‑b]quinoxaline (3b): Yield 92%; m.p.
230 °C; 1H NMR (400 MHz, CDCl3): δ 5.31 (s, 1H, CH), 7.78–7.66 (m,
9H, Ar), 12.26 (s, 1H, NH); 13C NMR (400 MHz, CDCl3) δ 108, 120.74,
125.95, 127.84, 128.56, 129.02, 130.68, 132.49, 132.97, 134.31, 135.78,
141.09, 147.17, 152.69; IR (KBr disc): ν 3187, 3020, 2974, 2869, 1648,
1598, 1121 cm–1.; MS (m/z) 277 (M+). Anal. calcd for C11H9N3S: C,
69.29; H, 4.00; N, 15.15; S, 11.56; found: C, 69.01; H, 3.87; N, 15.02; S,
11.00%.
The structural assignment of compounds 3a–g and 5 is based
upon spectroscopic and microanalytical data. For example,
the 1H NMR spectrum of 3-(4-methoxyphenyl)-4H-[1,4]
thiazino[2,3-b]quinoxaline (3e) showed two singlet peaks at δ
3.82 and 5.47 ppm belonging to methyl groups of the methoxy
and CH of thiazin ring, respectively. The multiplet signals in
the range of δ 6.94–7.72 ppm correspond to the aromatic ring
protons. The IR spectrum was devoid of the NH2 absorption
bands at ν 3264 and 3395 cm−1 of the precursor, but an
absorption band at ν 3199 cm−1 demonstrated the existence
of the NH group in the product 3e. The mass spectrum of 3e
showed a molecular ion signal at m/z 307 (M+) corresponding to
the molecular formula C17H13N3OS.
3‑(p‑Tolyl)‑4H‑[1,4]thiazino[2,3‑b]quinoxaline (3c): Yield 95%; m.p.
1
213 °C; H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H, CH3), 5.44 (s, 1H,
CH), 7.02–7.65 (m, 8H, Ar), 11.64 (s, 1H, NH); 13C NMR (400 MHz,
CDCl3): δ 20.19, 108.16, 121.74, 129.34, 129.87, 130.64, 130.99, 131.09,
134.51, 136.10, 136.54, 138.48, 140.19, 144.52, 151.35; IR (KBr disc):
ν 3214, 3048, 2916, 2864, 1697, 1621, 1121 cm–1.; MS (m/z) 291 (M+).
Anal. calcd for C17H13N3S: C, 70.08; H, 4.50; N, 14.42; S, 11.00; found:
C, 70.32; H, 4.88; N, 14.87; S, 11.66%.
Table 1 Synthesis of new thiazino[2,3-b]quinoxaline derivatives
3‑(4‑Methoxyphenyl)‑4H‑[1,4]thiazino[2,3‑b]quinoxaline (3d):
Yield 96%; m.p. 248 °C; H NMR (400 MHz, CDCl3): δ 3.82 (s, 3H,
Compound
R
Time/h
Yield/%
1
3a
3b
3c
3d
3e
3f
CH3
Ph
2.15
2
89
82
87
79
99
80
89
CH3), 5.47 (s, 1H, CH), 6.94–7.72 (m, 8H, Ar), 11.17 (s, 1H, NH); 13C
NMR (400 MHz, CDCl3): δ 55.45, 96.36, 114.71, 118.07, 123.58, 126.44,
127.72, 128.90, 131.35, 132.64, 135.45, 138.56, 143.46, 151.67, 161.17; IR
(KBr disc): ν 3199, 3035, 2929, 2839, 1633, 1604, 1137 cm–1.; MS (m/z)
307 (M+). Anal. calcd for C17H13N3OS: C, 66.43; H, 4.26; N, 13.67; S,
10.43; found: C, 66.12; H, 4.02; N, 13.27; S, 9.87%.
p-C6H4–Me
p-C6H4–OMe
p-C6H4–Ph
p-C6H4–Br
2.10
2.20
1.50
1.50
1.45
3g
p-C6H4–NO2
3-([1,1′-Biphenyl]-4-yl)-4H-[1,4]thiazino[2,3-b]quinoxalineꢀꢀꢀ(3e):
1
Yield 100%; m.p. 241 °C; H NMR (400 MHz, CDCl3): δ 5.47 (s, 1H,
CH), 7.22–7.66 (m, 13H, Ar), 12.21 (s, 1H, NH); 13C NMR (400 MHz,
CDCl3): δ 109.00, 122.65, 124.32, 126.41, 127.32, 127.98, 128.34,
128.61, 128.97, 129.53, 132.27, 133.98, 135.79, 139.45, 142.39, 134.21,
147.15, 154.28; IR (KBr disc): ν 3076, 2978, 2851, 1630, 1606,
1135 cm–1; MS (m/z) 353 (M+). Anal. calcd for C22H15N3S: C, 74.76; H,
4.28; N, 11.89; S, 9.07; found: C, 74.09; H, 4.02; N, 11.41; S, 8.77%.
3-(4-Bromophenyl)-4H-[1,4]thiazino[2,3-b]quinoxalineꢀꢀꢀ(3f):
Conclusion
In summary, we have successfully developed a simple and
efficient method for the synthesis of new thiazino[2,3-b]
quinoxaline derivatives from 3-aminoquinoxaline-2-thiol and
various α-haloketones using acetic acid. Similar reaction with
4-bromo-3-methyl-4,5-dihydro-1H-5-pyrazolone gave a new
heterocyclic system, 3-methyl-1,4-dihydropyrazolo [4′,3′:5,6]
[1,4] thiazino [2,3-b]quinoxaline.
1
Yield 96%; m.p. 229 °C; H NMR (400 MHz, CDCl3): δ 5.61 (s, 1H,
CH), 7.21–7.61 (m, 8H, Ar), 11.34 (s, 1H, NH); 13C NMR (400 MHz,
CDCl3): δ 100.96, 116.67, 117.58, 126.47, 129.83, 130.56, 131.15, 131.49,
132.36, 134.62, 135.24, 138.67, 142.36, 152.47; IR (KBr disc): ν 3197,
3033, 2917, 1668, 1636, 1135 cm–1.; MS (m/z) 356 (M+). Anal. calcd for
C16H10BrN3S: C, 53.94; H, 2.83;N, 11.80; S, 9.00; found: C, 53.46; H,
2.71; N, 11.18; S, 8.30%.
Experimental
Reactions were monitored by TLC and melting points were recorded
on an Electrothermal type 9100 melting point apparatus and are
uncorrected. FT-IR spectra were recorded using KBr disks on an
Avatar 370 FT-IR Thermo-Nicolet spectrometer. The 1H NMR
(400 MHz) spectra were recorded on a Bruker AC 400 spectrometer
using CDCl3 or DMSO as a solvent, chemical shifts have been
expressed in ppm downfield from TMS. The mass spectra were
scanned on a Varian Mat CH-7 at 70 eV. Elemental analysis was
performed on a Thermo Finnigan Flash EA microanalyser.
3‑(4‑Nitrophenyl)‑4H‑[1,4]thiazino[2,3‑b]quinoxaline (3g):
1
Yield 80%; m.p. 261 °C; H NMR (400 MHz, CDCl3): δ 5.38 (s, 1H),
7.48–7.65 (m, 8H), 11.87 (s, 1H); 13C NMR (400 MHz, CDCl3): δ
102.785, 120.56, 124.53, 126.95, 127.06, 128.25, 129.65, 131.53, 132.26,
134.98, 145.53, 146.34, 149.16, 105.42; IR (KBr disc): ν 3178, 3031,
2920, 2840, 1642, 1612, 1129 cm–1.; MS (m/z) 356 (M+). Anal. calcd for
C16H10N4O2S: C, 59.62; H, 3.13; N, 17.38; S, 9.95; found: C, 59.21; H,
3.03; N, 16.99; S, 9.37%.
Synthesis of 3‑aminoquinoxaline‑2‑thiol (1)
Compound (1) was prepared by the literature procedure. Yield
73%; m.p.>300 °C; H NMR (400 MHz, DMSO-d6): δ 7.02 (s, 2H,
NH2), 7.23–7.45 (m, 4H, Ar), 14.33 (s, 1H, SH); 13C NMR (400 MHz,
DMSO-d6): δ 115.9, 124.7,125.0, 126.5, 128.2, 136.5, 154.3, 168.2; IR
(KBr disc): ν 3395, 3264, 1450, 1359 cm–1.; MS (m/z) 177 (M+). Anal.
calcd for C8H7N3S: C, 54.22; H, 3.98; N, 23.71; S, 18.09; found: C,
54.02; H, 3.64; N, 23.36; S, 17.85%.
3-methyl-1,11-dihydropyrazolo[3′,4′:5,6][1,4]thiazino[2,3-b]
quinoxaline (5): Yield 89%; m.p. 306 °C; 1H NMR (400 MHz, CDCl3):
δ 2.05 (s, 3H), 7.26–7.39 (m, 4H, Ar), 10.35 (s, 1H, NH), 11.91 (s, 1H,
NH); 13C NMR (400 MHz, CDCl3): δ 19.32, 119.65, 125.46, 127.65,
128.37, 129.93, 131.24, 135.72, 139.74, 142.71, 145.26, 158.43; IR (KBr
disc): ν 3235, 3203, 3125, 3051, 2839, 1671, 1070 cm–1.; MS (m/z) 255
(M+). Anal. calcd for C12H9N5S: C, 56.45; H, 3.55; N, 27.43; S, 12.56;
found: C, 56.13; H, 3.00; N, 26.98; S, 12.013%.
1
Synthesis of compounds (3a–g and 5); general procedure
A mixture of 2-amino-3-quinoxalinethiol (0.177 g, 1 mmol) and the
appropriate α-haloketones (1 mmol) in glacial acetic acid (10 mL)
was heated under reflux for the appropriate time. The solvent was
evaporated under reduced pressure and the precipitate was collected
and recrystallised from ethanol.
Received 22 December 2013; accepted 27 January 2014
Paperꢀ1302358ꢀdoi:ꢀ10.3184/174751914X13926569127947
Publishedꢀonline:ꢀ7ꢀMarchꢀ2014
3‑Methyl‑4H‑[1,4]thiazino[2,3‑b]quinoxaline (3a): Yield 89%; m.p.
196 °C; 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 3H, CH3), 5.46 (s, 1H,
CH), 7.39–7.76 (m, 4H, Ar), 11.87 (s, 1H, NH); 13C NMR (400 MHz,
CDCl3): δ 16.57, 98.84, 128.31, 128.81, 128.97, 131.61, 133.71, 136.41,
139.62, 146.29, 147.67; IR (KBr disc): ν 3215, 3056, 2982, 2917, 1673,
1640, 1135 cm–1.; MS (m/z) 215 (M+). Anal. calcd for C11H9N3S: C, 61.37;
H, 4.21; N, 19.52; S, 14.89; found: C, 61.10; H, 4.11; N, 19.01; S, 14.16%.
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