A simple and efficient one-step synthesis of 2,4,10a-triaryl-1,10a-dihydro- 2H-pyrazino[2,1-b][1,3] benzothiazoles catalyzed by p-toluene sulfonic acid

Article abstract of DOI:10.1080/10426500601013190

A series of 2,4,10a-triaryl-1,10a-dihydro-2H-pyrazino[2,1-b][1,3] benzothiazoles were prepared in good yields by the reaction of 2-[(2-oxo-2-arylethyl) anilino]-1-aryl-1-ethanones with 2-aminothiophenol in the presence of p-toluenesulfonic acid under solv

Full text of DOI:10.1080/10426500601013190

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A Simple and Efficient One-
Step Synthesis of 2,4,10a-
Triaryl-1,10a-Dihydro-2H-
Pyrazino[2,1-b][1,3]
Benzothiazoles Catalyzed by p-
Toluene Sulfonic Acid
a
a
G. Ravindran , S. Muthusubramanian , S. Selvaraj
a
a
&
S. Perumal
a
Department of Organic Chemistry, School of
Chemistry , Madurai Kamaraj University , Madurai,
India
Published online: 30 Jan 2007.
To cite this article: G. Ravindran , S. Muthusubramanian , S. Selvaraj & S.
Perumal (2007) A Simple and Efficient One-Step Synthesis of 2,4,10a-Triaryl-1,10a-
Dihydro-2H-Pyrazino[2,1-b][1,3] Benzothiazoles Catalyzed by p-Toluene Sulfonic
Acid, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:3, 509-515, DOI:
10.1080/10426500601013190
To link to this article: http://dx.doi.org/10.1080/10426500601013190
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Phosphorus, Sulfur, and Silicon, 182:509–515, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601013190
A Simple and Efficient One-Step Synthesis of
2
,4,10a-Triaryl-1,10a-Dihydro-2H-Pyrazino[2,1-b][1,3]
Benzothiazoles Catalyzed by p-Toluene Sulfonic Acid
G. Ravindran
S. Muthusubramanian
S. Selvaraj
S. Perumal
Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai, India
A
series of 2,4,10a-triaryl-1,10a-dihydro-2H-pyrazino[2,1-b][1,3]benzothiazoles
were prepared in good yields by the reaction of 2-[(2-oxo-2-arylethyl) anilino]-1-
aryl-1-ethanones with 2-aminothiophenol in the presence of p-toluenesulfonic acid
1
13
under solventless conditions. The products were characterized by H NMR and
C
NMR spectroscopy.
Keywords Benzothiazole; pyrazine; p-toluenesulfonic acid; microwave irradiation
INTRODUCTION
Benzothiazole and pyrazine units assume importance, as they are
found in many biologically active compounds. Pyrazines are found
1
in the luminescent chromophores of certain marine organisms ; in
cephalostatins isolated from Cephalodiscus Gilehrist, which are pow-
2
3
erful anticancer agents; in the fungal metabolite aspergillic acid;
4
and in foods as potent flavor compounds. Moreover, several fun-
gal metabolites such as glyantripine, fumiquinazolines F and G,
5
6,7
8
,9
10,11
fiscalin B,
and N-acetylardeemin,
and some spiro compounds
such as fumiquinazoline C, spiroquinazoline,12 and alantrypinone
6,7
13
contain a pyrazino[2,1-b]moiety. Heterocycles containing a thiazole
Received June 26, 2006; accepted July 27, 2006.
The authors thank Department of Science and Technology, New Delhi for assistance
under the Intensified Research in High Priority Area, program for the Nuclear Magnetic
Resonance facility.
Address correspondence to S. Muthusubramanian, Department of Organic Chem-
istry, School of Chemistry, Madurai Kamaraj University, Madurai, 625 021 India. E-mail:
muthumanian2001@yahoo.com
509

5
10
G. Ravindran et al.
X
X
O
Heat or
NH
SH
2
Y
microwave
N
S
N
+
N
Y
P-TsOH
O
X
X
1
2
SCHEME 1
moiety are present in many natural products such as bleomycin,
1
4
1
5
16
17
epothilone A, lyngbyabellin A and dolastatin 10. Benzothiazole
1
8
derivatives have been shown to possess antimicrobial properties and
1
9
have found applications in industry as antioxidants and vulcanization
2
0
accelerators. The previously discussed bioapplications of these two
classes of heterocycles prompted us to synthesize 2,4,10a-triaryl-1,10a-
dihydro-2H-pyrazino[2,1-b][1,3]benzothiazoles (Scheme 1) comprising
of both pyrazine and benzothiazole rings under solventless conditions,
and the results are presented in this article. The development of simple,
efficient, and environmentally benign chemical processes or methodolo-
gies to obtain organic compounds from readily available reagents is one
of the major challenges for chemists in organic synthesis, and a solvent-
less reaction to offer target molecules is one such process.
RESULTS AND DISCUSSION
A simple protocol has been developed that allowed the crucial dialky-
lation of anilines with phenacyl bromides to give diphenacyl anilines
1
efficiently under solvent-free conditions. It was found that by simple
mixing of phenacylbromide, aniline, and potassium carbonate in a ratio
:1:1 and by leaving the mixture for 3 h at r.t., compound 1 was obtained
2
2
1
in good yields with adequate purities for the next stage. This solvent-
free synthetic method assumes considerable interest because of the eco-
nomical and environmental concerns associated with organic solvents.
Slurry obtained by the addition of 1.5 mmol of 2-[(2-oxo-2-arylethyl)
anilino]-1-aryl-1-ethanone 1 with 1.5 mmol of 2-aminothiophenol and
a catalytic amount of p-toluenesulfonic acid were heated over a water
bath for 15–20 min. The progress of the reaction was monitored by TLC,
and the product formed in relatively good yield was found to be 2,4,
10a-triaryl-1,10a-dihydro-2H-pyrazino[2,1-b][1,3]benzothiazole 2. The

Pyrazino Benzothiazoles
511
TABLE I Physical Data of 2,4,10a-Triaryl-1, 10a-dihydro-2H-
pyrazino[2,1-b] [1,3] benzothiazoles 2
Thermal
Microwave
◦
Entry
X
Y
Time (min)
Yield (%)
Time (min)
Yield (%)
M.Pt. ( C)
2a
2b
2c
2d
2e
2f
H
Cl
Me
H
Cl
H
H
H
Me
Me
Me
20
16
19
19
15
16
80
81
82
79
80
81
8
7
5
8
6
5
86
89
86
85
86
89
194
238
232
189
225
222
Me
reaction of 2-aminothiophenol with a differently substituted 1 thus
led to several hitherto unreported 2,4,10a-triaryl-1,10a-dihydro-2H-
pyrazino[2,1-b][1,3]benzothiazoles 2 as a single product in good yield,
as summarized in Table I (Scheme 1). There was no significant differ-
ence in reaction time or yield with different substituents in the tertiary
amines employed. Microwave irradiation of the original reaction
mixture was found to improve the yield with reduced reaction time
(
Table I).
The proton and carbon NMR data of the fused benzothiazoles 2 are
in consonance with the structure of the products. Compound 2b exhib-
ited doublets at 4.04 and 4.40 ppm each with a coupling constant of
1
2 Hz corresponding to the diastereotopic methylenic protons. The up-
field multiplet around 6.2 ppm can be assigned to the peri hydrogen
ortho to the nitrogen in the benzothiazole unit. The mechanism of the
Ar
S
Ar
.
.
HS
O
..
NH
N
..
N
Ar
H2N
-H O
2
Ar
O
1
O
Ar
S
N
Ar
S
.
.
N
N
N
H
-
H O
2
Ar
H
H
HO
Ar
2
SCHEME 2

5
12
G. Ravindran et al.
formation of the product is formulated in Scheme 2, and a similar ad-
dition of 1,5-diketone to 1,2-diamine leading to a fused heterocycle of
type 2 has already been reported.2
2
CONCLUSION
This article thus describes an ecofriendly, simple, and efficient
methodology for the synthesis of 2,4,10a-triaryl-1,10a-dihydro-2H-
pyrazino[2,1-b][1,3]benzothiazoles, which have two biologically impor-
tant heterocycles fused together.
EXPERIMENTAL
All chemicals were of reagent grade and were used without further pu-
rification. Melting points were measured on a melting point apparatus
and are uncorrected. NMR spectra were recorded on a Bruker 300 MHz
(
Ultrashield) spectrometer. Chemical shifts are reported in ppm rela-
tive to tetramethylsilane as an internal standard. The reactions were
routinely monitored by TLC on silica-gel plates. A domestic microwave
oven (LG) was used for irradiation, and the reactions were carried out
in 520 Watts of power.
General Procedure for the Preparation of 2,4,10a-Triaryl-1,10a-
dihydro-2H-pyrazino[2,1-b][1,3]benzothiazole
A mixture of 2-[(2-oxo-2-arylethyl)anilino]-1-aryl-1-ethanone 1 (0.50 g,
1
.5 mmol), 2-aminothiophenol (0.20 g, 1.5 mmol), and a catalytic
amount of p-toluenesulfonic acid was heated on a water bath for about
5–20 min. The reaction mixture was treated with water and then ex-
1
tracted with dichloromethane. The organic layer was washed with wa-
ter repeatedly, dried over anhydrous calcium chloride, and evaporated
to give the crude product. Purification of the product was performed
by column chromatography on silica gel using a petroleum ether-ethyl
acetate [97:3(v/v)] mixture as an eluent.
Irradiation of the previously discussed reaction mixture in a mi-
crowave (600 W) reduced the reaction time to 5 min with an improved
yield up to 85%.
2
,4,10a-Triphenyl-1,10a-dihydro-2H-pyrazino[2,1-b][1,3]-
benzothiazole (2a)
1
Colorless solid from ethanol. H (CDCl3): 4.05 (d, 1H), 4.46 (d, 1H),
.25 (m, 1H), 6.71 (s, 1H), 6.78–6.85 (m, 4H), 6.93–7.0 (m, 1H), 7.06–
.1 (m, 1H), 7.19–7.25 (m, 6H), 7.32–7.40 (m, 2H), 7.52–7.61 (m, 4H).
6
7

Pyrazino Benzothiazoles
513
13C (CDCl3): 52.3, 76.2, 114.1, 117.4, 118.0, 119.7, 121.4, 122.2, 122.4,
124.2, 124.4, 126.1, 126.3, 127.1, 128.5, 128.6, 129.3, 129.8, 132.1, 137.4,
139.0, 146.1, 147.2; Anal. calcd. for C28H22N2S: C, 80.35; H, 5.30; N,
6.69; found: C, 80.31; H, 5.31; N, 6.65.
4
,10a-Bis(4-chlorophenyl)-2-phenyl-1,10a-dihydro-2H-
pyrazino[2,1-b][1,3]benzothiazole (2b)
1
Pale yellow solid from ethanol. H (CDCl3): 4.04 (d, 1H), 4.40 (d, 1H),
6
7
7
1
.22 (m, 1H), 6.68 (s, 1H), 6.80–6.88 (m, 4H), 7.0–7.10 (m, 2H), 7.18–
1
3
.22 (m, 2H), 7.28–7.35 (m, 4H), 7.45–7.54 (m, 4H). C (CDCl3): 52.1,
5.6, 114.1, 116.6, 117.5, 120.1, 121.8, 122.6, 122.7, 124.2, 125.1, 126.3,
28.5, 129.0, 129.5, 130.0, 131.7, 134.5, 135.6, 137.4, 145.7, 146.7. Anal.
calcd. for C28H20Cl2N2S: C, 68.99; H, 4.14; N, 5.75; found: C, 69.01; H,
.16; N, 5.72.
4
4
,10a-Bis(4-methylphenyl)-2-phenyl-1,10a-dihydro-2H-
pyrazino[2,1- b][1,3]benzothiazole (2c)
1
White solid from ethanol. H (CDCl3): 2.24 (s, 3H), 2.36 (s, 3H), 4.0
(
4
(
d, 1H), 4.41 (d, 1H), 6.24–6.26 (m, 1H), 6.67 (s, 1H), 6.73–6.86 (m,
H), 6.91–7.1 (m, 5H), 7.12–7.18 (m, 2H), 7.23–7.30 (m, 1H), 7.40–7.50
m, 4H). C (CDCl3): 21.4, 21.5, 52.1, 76.2, 113.9, 117.1, 118.0, 119.0,
1
3
1
1
21.2, 122.0, 122.3, 124.1, 124.4, 126.1, 127.0, 129.3, 129.8, 130.0, 134.5,
36.0, 138.3, 146.0, 147.3. Anal. calcd. for C30H26N2S: C, 80.68; H, 5.87;
N, 6.27; found: C, 80.66; H, 5.86; N, 6.25.
2
-(4-methylphenyl)-4,10a-diphenyl-1,10a-dihydro-2H-
pyrazino[2,1-b][1,3]benzothiazole (2d)
1
White solid from ethanol. H (CDCl3): 2.27 (s, 3H), 4.05 (d, 1H), 4.41
(
3
(
d, 1H), 6.22–6.28 (m, 1H), 6.67 (s, 1H), 6.72–6.82 (m, 2H), 7.01–7.1 (m,
H), 7.14–7.21 (m, 4H), 7.30–7.38 (m, 3H), 7.47–7.50 (m, 1H), 7.51–7.60
m, 4H). C (CDCl3): 21.0, 52.5, 76.1, 114.1, 117.3, 120.2, 121.4, 122.4,
1
3
1
1
24.1, 124.4, 126.1, 127.1, 128.0, 128.5, 128.7, 129.3, 129.5, 130.4, 131.8,
37.5, 139.0, 144.0, 147.4. Anal. calcd. for C29H24N2S: C, 80.52; H, 5.59;
N, 6.48; found: C, 80.49; H, 5.60; N, 6.45.
4
2
,10a-Bis(4-Chlorophenyl)-2-(4-methylphenyl)-1,10a-dihydro-
H-pyrazino[2,1-b][1,3]benzothiazole (2e)
1
Pale yellow solid from ethanol. H (CDCl3): 2.30 (s, 3H), 4.0 (d, 1H),
4.40 (d, 1H), 6.21–6.28 (m, 1H), 6.67 (s, 1H), 6.70–6.72 (m, 2H), 6.79–
6.86 (m, 2H), 7.05–7.12 (m, 3H), 7.18–7.21 (m, 2H), 7.28–7.31 (m, 2H),
7
.42–7.50 (m, 4H). 13C (CDCl3): 21.0, 52.3, 75.6, 114.1, 116.0, 117.7,
120.6, 121.7, 122.6, 124.1, 125.0, 126.3, 128.6, 128.8, 129.4, 130.5, 131.2,

5
14
G. Ravindran et al.
1
32.3, 134.4, 135.7, 137.5, 143.6, 146.8. Anal. calcd. for C29H22Cl2N2S:
C, 69.46; H, 4.42; N, 5.59; found: C, 69.51; H, 4.45; N, 5.57.
2
,4,10a-Tris(4-methylphenyl)-1,10a-dihydro-2H-pyrazino[2,1-
b][1,3]benzothiazole (2f)
1
White solid from ethanol. H (CDCl3): 2.24 (s, 3H), 2.30 (s, 3H), 2.35
s, 3H), 4.01 (d, 1H), 4.4 (d, 1H), 6.24–6.30 (m, 1H), 6.65 (s, 1H), 6.70–
(
6
.82 (m, 4H), 7.0–7.10 (m, 5H), 7.11–7.18 (m, 2H), 7.42–7.50 (m, 4H).
C (CDCl3): 20.96, 21.44, 21.50, 52.3, 76.2, 114.0, 117.3, 119.3, 121.2,
22.4, 124.0, 124.4, 126.0, 127.1, 129.3, 130.0, 130.3, 131.4, 132.2, 134.7,
35.8, 136.1, 138.2, 144.0, 147.4: Anal. calcd. for C31H28N2S: C, 80.83;
1
3
1
1
H, 6.13; N, 6.08; found: C, 80.85; H, 6.12; N, 6.11.
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