An efficient synthesis of thiazolo and thiadiazolo quinoxaline derivatives in ionic liquid

Article abstract of DOI:10.1155/2012/865414

A series of 3-substitutedphenyl-1-thia-tetrazopentaleno[1,2-b] naphthalene 4 (a-d) and 2-substitutedphenyl-1-thia-pentazopentaleno[1,2-b] naphthalene 5 (a-d) were synthesized via., the reaction of 2-aminothiazoles 2 (a-d) and 2-aminothiadiazoles 3 (a-d) with 2,3-dichloro quinoxaline 1 in ionic liquid without using any catalyst. This protocol has the advantages of easier workup, milder reaction conditions, high yields, and environmentally benign procedure over traditional methods. The synthesized compounds 4 (a-d) and 5 (a-d) tested for their anti-fungal activity and these compounds were characterized by IR, NMR and Mass spectral analysis.

Full text of DOI:10.1155/2012/865414

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(2), 893-898
An Efficient Synthesis of Thiazolo and Thiadiazolo
Quinoxaline Derivatives in Ionic Liquid
B. PRASANNA*, B. SRINIVAS, Y. JAGANNADHAM and SUMANGALA RAO
Research Centre, Department of Chemistry
Chaitanya PG College, Warangal-506 001, India
prasschem@gmail.com
Received 21 July 2011; Accepted 5 September 2011
Abstract:
A series of 3-substitutedphenyl-1-thia-tetrazopentaleno[1,2-b]
naphthalene 4(a-d) and 2-substitutedphenyl-1-thia-pentazopentaleno[1,2-b]
naphthalene 5(a-d) were synthesized via., the reaction of 2-aminothiazoles
2(a-d) and 2-aminothiadiazoles 3(a-d) with 2,3-dichloro quinoxaline 1 in ionic
liquid without using any catalyst. This protocol has the advantages of easier
workup, milder reaction conditions, high yields, and environmentally benign
procedure over traditional methods. The synthesized compounds 4(a-d) and
5(a-d) tested for their anti-fungal activity and these compounds were
characterized by IR, NMR and Mass spectral analysis.
Keywords: Aminothiazoles, Aminothiadiazoles, Dichloroquinoxaline.
Introduction
Compounds containing the quinoxaline nucleus exhibit abroad spectrum of biological
activity such as, anti-viral1, antiinflammatory, antiprotozoal2, antihelminthic3, anticancer4,
antimalarial5, and antidepressant activities6. Some of the antibiotics such as levomycin,
actinoleutin, and echinomycin also contain a quinoxaline scaffold and these are known to
inhibit the growth of gram positive bacteria7 and are active against various transplantable
tumours8. Besides the biological activities, quinoxalines are also used in the synthesis of
organic semiconductors, dyes9, and electroluminescent materials10. Some of quinoxalines
exhibit potent central nervous system (CNS) activities such as analgesic and anti-
inflammatory activities11. Few of azolopyrimidoquinaxalines, pyrimidoquinazolines
exhibited good antioxidants, anti-inflammatory, and analgesic activities12-15. Furthermore,
organic compounds bearing thiazolopyrimidines and pyridothiazolo quinoxaline nuclei were
found to possess potent anticancer activities16. These biological applications and
development of new route to heterocyclic systems in ionic liquid prompted us to synthesize
some new heterocyclic derivatives having phenylthiazoles, thiadiazoles, and quinoxaline
moieties starting from 2, 3-dichloro quinoxaline in ionic liquid without using any catalyst
and search of better anti-fungal activity. (Schemes 1 & 2).

B. PRASANNA et al.
894
Experimental
Melting points were measured in open capillary on Buchi melting point B-540 apparatus and were
uncorrected. IR spectra were recorded on Simadzu FTIR-8400 spectrometer using KBr pellets. 1H
NMR (300 MHz) spectra recorded in DMSO-d6 on a Bruker AVANCE 300 instrument with the
TMS as an internal standard. All the chemical shifts values were recorded as δ ppm. Mass spectra
(EI-MS) were taken on Perkin Elmer (SCIEX API-2000, ESI) at 12.5 eV. CHNS analysis
was carried out on Carlo Erba E A 1108 automatic analyzer. The progress of each reaction
was monitored and purity of the compounds was checked by thin layer chromatography.
R
R
[bmim]BF4
80oC
N
N
N
N
N
N
Cl
Cl
S
N
+
H2N
S
4 (a-d)
2 (a-d)
1
Scheme 1
R
N
S
N
N
N
N
N
N
[bmim]BF4
80oC
1
H2N
+
S
R
3 (a-d)
5 (a-d)
R=H, Cl, Br, CH3
Scheme 2
General Procedure for the Synthesis of 3-Substitutedphenyl-1-thia-
tetrazopentaleno-[1,2-b]naphthalene 4(a-d) and 2-substituted phenyl-1-thia-
pentazopentaleno[1,2-b] naphthalene 5(a-d)
A dry 50 mL flask was charged with 2, 3-dichloroquinoxaline17-18 1 (1 mmol) and substituted
2-aminothiazoles 2(a-d) (1mmol)/2-aminothiadiazoles 3(a-d) (1 mmol) and ionic liquid
[bmim] BF4 (2 mL). Then the reaction mixture was stirred for 1.5 h to 2.5 h to complete the
reaction (monitored by TLC) at 80oC. The reaction mixture was cooled to room temperature
and poured into 10 mL of water. The solid product collected by filtration and re-crystallized
from methanol to give pure compounds 4(a-d) and 5(a-d). The filtration was washed with
acetic ester for several times concentrated under reduced pressure at 100 oC for several hours to
give reusable solvent. A similar procedure was used in preparing all the compounds.
Spectral Data of the Synthesized Compounds 4(a-d) and 5(a-d)
3-Phenyl -1-thia-3a,4 ,9 ,10-tetrazopentaleno[1,2-b]naphthalene (4a)
Mp: 240-2420C; IR (KBr): υ (cm-1) 1612 (C=N); 1H NMR (300 MHz, DMSO-d6): δ 7.12 (s,
1H, CH), 7.22-7.40 (m, 5H, Ar-H) 7.48-7.52 (dd, 1H, quin-H), 7.80 ( dd, 1H, quin-H), 8.12
(dd, 2H, quin-H). EI-MS: 303 [M+1]+. Anal.Calcd for C17H10N4S: C, 67.53; H, 3.33; N,
18.53%. Found: C, 67.56; H, 3.31; N, 18.51%.

An Efficient Synthesis of Thiazolo and Thiadiazolo Quinoxaline 895
3-(4-Chlorophenyl)-1-thia-3a,4,9,10-tetrazopentaleno[1,2-b]naphthalene(4b)
1
Mp: 232-2330C; IR (KBr): υ (cm-1) 1618 (C=N); H NMR (300 MHz; DMSO-d6): δ 7.02-
7.18 (m, 4H, Ar-H), 7.20 (s, 1H, CH), 7.42 (dd, 1H, quin-H), 7.80( dd, 1H, quin-H), 8.12-
8.14 (dd, 2H, quin-H). EI-MS: 338 [M+1] +. Anal. Calcd for C17H9ClN4S: C, 60.62; H, 2.69,
N, 16.64%. Found: C, 60.64, H, 2.67, N, 16.62%.
3-(4-Bromophenyl)-1-thia-3a,4,9,10-tetrazopentaleno[1,2-b]naphthalene(4c)
1
Mp: 238-2400C; IR(KBr): υ (cm-1) 1610 (C=N); H NMR (300 MHz, DMSO-d6): δ 7.16-
7.34 (m, 4H, Ar-H), 7.20 (s, 1H, CH), 7.54 (dd, 1H, quin-H), 7.86 ( dd, 1H, quin-H), 8.14-
8.18 (dd, 2H, quin-H). EI-MS: 382 [M+1] +. Anal. Calcd for C17H9BrN4S: C, 53.56; H, 2.38;
N, 14.70%. Found: C, 53.54; H, 2.40; N, 14.72%.
3-p-Tolyl-1-thia-3a,4,9,10-tetrazopentaleno[1,2-b]naphthalene (4d)
Mp: 245-2470C; IR (KBr): υ (cm-1 ) 1610 (C=N); 1H NMR (300 MHz, DMSO-d6): δ 2.32 (s,
3H,CH3 ), 7.04-7.18 (dd, 2H, Ar-H), 7.24-7.26 (dd, 2H, Ar-H), 7.14 (s, 1H, CH), 7.60-7.64(
dd, 2H, quin-H), 8.17-8.19 (dd, 2H, quin-H). EI-MS: 317 [M+1]+. Anal. Calcd for
C18H12N4S: C, 68.33; H, 3.82; N, 17.71%. Found: C, 68.31; H, 3.80; N, 17.69%.
2-Phenyl-1-thia-3,3a,4,9,10-pentazopentaleno[1,2-b]naphthalene (5a)
1
Mp: 246-2480C; IR (KBr): υ (cm-1) 1612 (C=N); H NMR (300 MHz, DMSO-d6): δ 7.34-
7.64 (m, 5H, Ar-H), 7.72-7.74 (dd, 2H, quin-H), 8.14-8.16 (dd, 2H, quin-H). EI-MS: 304
[M+1] +. Anal. Calcd for C16H9N5S: C, 63.32; H, 2.99; N, 23.09%. Found: C, 63.32; H, 2.97;
N, 23.11%.
2-(4-Chlorophenyl)-1-thia-3,3a,4,9,10-pentazopentaleno[1,2-b]naphthalene (5b)
1
Mp: 250-2510C; IR (KBr): υ (cm-1) 1618 (C=N); H NMR (300 MHz, DMSO-d6): δ 7.38-
7.42 (dd, 2H, Ar-H), 7.74-7.76 (dd, 2H, Ar-H), 7.82 (dd, 2H, quin-H), 8.20-8.22(dd, 2H,
quin-H). EI-MS: 339 [M+1] +. Anal. Calcd for C16H8ClN5S: C, 56.89; H, 2.39; N, 20.73%.
Found: C, 56.87, H, 2.41, N, 20.71%.
2-(4-Bromophenyl)-1-thia-3,3a,4, 9,10-pentazopentaleno[1,2-b]naphthalene (5c)
1
Mp: 258-2600C; IR (KBr): υ (cm-1) 1620 (C=N); H NMR (300 MHz; DMSO-d6): δ 7.32-
7.36 (dd, 2H, Ar-H), 7.70-7.72 (dd, 2H, Ar-H), 7.84-7.86 (dd, 2H, quin-H), 8.18-8.20
(dd, 2H, quin-H). EI-MS: 383 [M+1] +. Anal.Calcd for C16 H8BrN5S; C, 50.28; H, 2.11;N,
18.32%. Found: C, 50.26; H, 2.13; N, 18.30%.
2-(p-Tolyl)-1-thia-3,3a,4, 9,10-pentazo pentaleno[1,2-b]naphthalene (5d)
1
Mp: 242-2440C; I R (K Br): υ (cm-1) 1610 (C=N); H NMR (300 MHz; DMSO-d6): δ 2.34
(s, 3H, CH3 ), 7.12-7.16 (dd, 2H, Ar-H), 7.54-7.60 (dd, 2H, Ar-H), 7.72-7.78 (dd, 2H, quin-
H), 8.12-8.16 (dd, 2H, quin-H). EI-MS: 318 [M+1] +. Anal. Calcd for C17 H11N5 S: C, 64.34;
H, 3.49; N, 22.07%. Found: C, 64.32; H, 3.51; N, 22.06%.
Antifungal Activity
The antifungal activity19 was assayed by sabouraud dextrose agar media plate disc diffusion
method at the concentration of 50 μg per disk. All the synthesized compounds were tested in
vitro for their antifungal activity against microorganisms such as Candida albicans,
Microsporium gypsum and microsporium canis. Each test compound was dissolved in
dimethylsulphoxide (DMSO) to get a concentration of 10 mg/mL. The disc (6 mm in diameter
was impregnated with 5 μ L of each test solution to get 50 μg/mL; air dried and placed on
the sabouraud dextrose agar media, previously seeded with 0.2 mL of broth culture of each
organism for 18 h. The plates were incubated at 220C for 48 h and the inhibition zones were

B. PRASANNA et al.
896
measured in mm. Discs impregnated with DMSO were used as a control and flucanazole
disc as antifungal reference standard.
Results and Discussion
Choosing an appropriate solvent is of crucial importance for the successful organic
synthesis, Room temperature ionic liquids, especially those based on 1-alkyl-3-
methylimidazoliumcations have shown great promise as an attractive alternative to
conventional organic solvents and more attention has been currently focused on organic
reactions prompted by ionic liquids20. They are nonvolatile, recyclable, non explosive, easily
operable, and thermally robust 21. To search for the optimal reaction solvent, the reaction of
2,3-dichloroquinoxaline 1 with substituted 2-aminothiazoles 2(a-d) and substituted
2-aminothiadiazoles 3(a-d) were examined using ionic liquid such as [bmim]BF4 and
conventional reaction solvent such as acetic acid at different reaction temperatures. The
results are summarized Table 1. It can be seen from Table 1 that the best result was obtained
when the reaction was carried out in [bmim] BF4 at 80oC. It was chosen as solvent for the
reactions as it is environmentally friendly and the toxic organic reagents can be avoided,
Under these optimized reaction conditions a series of 3-substituted phenyl-1-thia-
tetrazopentaleno-[1,2-b]-naphthalene 4(a-d) and 2-substituted phenyl-1-thia-pentazo-
pentaleno-[1,2-b]-naphthalene 5 (a-d) were synthesized.
The IR spectra of compounds 4(a-d) and 5(a-d), show absorption bands within the υ
1620-1604 cm-1 region. They are due to symmetric vibration of C=N group. The absence of
the absorption band corresponding to amino stretching frequency of the compound
substituted 2-aminothiazoles 2(a-d) and 2-aminothiadiazoles 3(a-d) clearly confirm the
formation of compound 4(a-d) and 5(a-d).
Antifungal Activity
The antifungal activity was determined by the disc diffusion method at the concentration of
50 per disk. All the synthesized compounds were tested in vitro for their antifungal activity
against microorganisms such as Candida albicans, Microsporium gypsum, and Microsporium
canis, using flucanazole as standard antifungal. The compounds 4b and 5b were highly active.
Compounds 4a and 5a were inactive, while rest of the compounds showed moderate activity.
Table 1. Results of anti-fungal activity.
Zone of Inhibition
C.albicans M.gypsum M.canis
Compounds
4a
-
-
-
4b
4c
4d
5a
+++
++
++
-
+++
++
++
-
+++
++
++
-
5b
5c
5d
+++
++
++
+++
+++
++
++
+++
+++
++
++
+++
Flucanazole
Inactive (inhibition zone < 6 mm); slightly active= ‘+’
(inhibition zone 7-9 mm); moderately active = ‘++‘
(inhibition zone 10-13 mm ); highly active = ;+++’
(inhibition zone > 14 mm).

An Efficient Synthesis of Thiazolo and Thiadiazolo Quinoxaline 897
Table 1. Solvent and temperature optimization for the synthesis of 4(a-d) and 5(a-d).
Yield, %/Time, h
Entry
R
a[bmim]VBF4
92/1.8
93/1.5
95/1.5
89/2.2
91/2.1
93/2
bAcOH
62/16
65/14
67/14
58/17
60/15
62/14
64/15
57/16
4a
4b
4c
4d
5a
5b
5c
5d
H
Cl
Br
Me
H
Cl
Br
Me
94/2
90/2.5
a reaction temperature at 80oC, b reaction temperature at reflux.
Conclusion
We developed an efficient and economical safe and environmentally benign procedure for
synthesis of 3-substituted phenyl-1-thia-tetrazopentaleno-[1,2-b]-naphthalene 4(a-d) and
2-substituted phenyl-1-thia-pentazopentaleno-[1,2-b]-naphthalene 5(a-d) through the
reaction of 2-aminothiazoles 2(a-d) and 2-aminothiadiazoles 3(a-d) with 2,3-dichloro
quinoxaline 1 in ionic liquid [bmim]BF4 without using any catalyst. A series of the
synthesized compounds 4(a-d) and 5(a-d) were tested for antifungal activity, the compounds
4b and 5b were found highly active against Candida albicans, microsporium gypsum and
microsporium canis when compared to Flucanazole as standard antifungal agent.
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