A domino protocol for the efficient synthesis of structurally diverse benzothiazolylquinoline-2,5-diones and their spiro analogues

Article abstract of DOI:10.1016/j.tetlet.2012.08.099

Structurally diverse benzothiazolylquinoline-2,5-diones and their spiro analogues have been synthesized by an environmentally benign efficient and convenient synthetic method involving sulfamic acid catalyzed one-pot four-component reaction of Meldrum aci

Full text of DOI:10.1016/j.tetlet.2012.08.099

Tetrahedron Letters 53 (2012) 6035–6038
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A domino protocol for the efficient synthesis of structurally diverse
benzothiazolylquinoline-2,5-diones and their spiro analogues
Anand Kumar Arya b, Sunil Kumar Gupta a, Mahendra Kumar a,
⇑
a Department of Chemistry, University of Rajasthan, Jaipur 302 055, India
b DESM, Regional Institute of Education (NCERT), Ajmer 305 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Structurally diverse benzothiazolylquinoline-2,5-diones and their spiro analogues have been synthesized
by an environmentally benign efficient and convenient synthetic method involving sulfamic acid cata-
lyzed one-pot four-component reaction of Meldrum acid, 2-aminobenzothiazoles, dimedone, and isat-
in/carbonyl compound.
Received 30 June 2012
Revised 22 August 2012
Accepted 24 August 2012
Available online 1 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent domino reaction
Dihydropyrimidobenzothiazolone
Benzothiazolyl-quinolinediones
Spirobenzothiazolylquinoline-2,5-dione
Multicomponent reactions have played a critical role in the
development of modern synthetic methodology for pharmaceuti-
cal and drug discovery research. Multicomponent reactions have
significant advantages over conventional step-by-step synthetic
methods not only from atom economy and environmentally
friendly view points, but also because of their straightforward
experimental procedures.1 Spiroheterocycles characterized by high
structural rigidity are often claimed as privileged templates in the
field of medicinal chemistry.2 Benzothiazole is also a privileged
heterosystem in drug research.3 The hybrid pharmacophores of
isatin-benzothiazoles have been reported to exhibit anti-breast
cancer activity.4 The quinoline-2,5-diones have been targets in
chemical research due their use as antitumor, antimalarial, anti-
bacterial, and antifungal drugs.5 Quinoline-2,5-diones have been
synthesized generally by modifying the N-containing moiety on
the ring.6 The spiro analogues of quinoline-2,5-diones have seldom
been reported. So far, only spiro[imidazolidine-4,40-quinoline]-2,5-
diones have been synthesized by a multistep synthesis and these
compounds were claimed to mimic the beta-turn motif.7 The re-
ported method is associated with some drawbacks such as moder-
ate yields, multistep procedures, harsh reaction conditions, and
prolonged reaction times. Therefore, the interest of developing a
simple, convenient, and efficient method for the synthesis of so
far unexplored quinoline-2,5-diones and their spiro analogues is
CH3
OCH3
N
N
S
CHO
H2N
O
O
Br
2
O
CH3
reflux
O
ethanol
OCH3
sulfamic acid
O
N
S
Br
1
3a
5
reflux
Step-I
ethanol
CH3
sulfamic acid
OCH3
N
H2N
Step-II
S
Br
2
reflux
O
O
ethanol
sulfamic acid
O
O
4
Scheme 1. Synthetic route of dihydropyrimidobenzothiazolone.
highly desirable and would be of great relevance to both synthetic
and medicinal chemists. In continuation of our research program
on the synthesis of therapeutically interesting heterocycles,8–14
we have presented a domino protocol for the efficient synthesis
⇑
Corresponding author. Tel.: +91 0141 2702720.
E-mail address: mahendrakpathak@gmail.com (M. Kumar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.099

6036
A. K. Arya et al. / Tetrahedron Letters 53 (2012) 6035–6038
R2
N
O
R1
S
reflux
CH3
O
O
N
O
O
R2
R1
ethanol
N
S
C
O
O
H2N
sulfamic acid
O
Br
O
CH3
3 (a-e)
1
2
6
Br
7 (a-e)
Scheme 2. Synthesis of benzothiazolyltetrahydroquinolinedione.
Table 1
Synthesized benzothiazolyltetrahydroquinolinediones 7 (a–e)
Compound
R1
R2
Time (min)
Yield (%)
Mp (°C)
7a
7b
7c
7d
7e
4-OCH3–C6H4
4-Cl–C6H4
C6H5
CH3
C6H5
H
H
H
CH3
CH3
12
10
15
23
18
93
92
90
89
92
265–267
271–274
261–265
255–258
261–265
Meldrum acid 1 (1 mmol), 2-amino-6-bromo-4-methylbenzothiazole 2 (1 mmol), aldehyde/ketone 3 (1 mmol),
dimedone 6 (1 mmol).
H
N
O
O
CH3
O
O
O
reflux
O
N
N
S
ethanol
O
O
H2N
sulfamic acid
S
N
N
Br
O
O
O
H
CH3
8
1
2
6
Br
9
Scheme 3. Synthesis of [benzothiazolyl]-spiro[tetrahydroquinoline-indoline]trione.
of structurally diverse benzothiazolylquinolinediones and their
spiro analogues. To the best of our knowledge, heterocycles
with such skeletal diversity have not been documented in the
literature.
The scope of the above reaction was further investigated by
using different aldehydes/ketones and it is particularly noteworthy
that the protocol15 can be applied to different aldehydes/ketones
including aliphatic and aromatic (Table 1).
When arylidene-Meldrum’s acid 4, obtained as a result of the
reaction of p-anisaldehyde 3a and Meldrum acid 1 in the first step,
was subjected to a reaction with 2-amino-6-bromo-4-methylben-
zothiazole 2 in refluxing ethanol in the presence of a catalytic
amount of sulfamic acid, 3,4-dihydropyrimidobenzothiazolone 5
was produced in good yield (60%, 55 min). But the sulfamic acid
catalyzed multicomponent reaction of Meldrum’s acid 1, p-anisal-
dehyde 3a, and 2-amino-6-bromo-4-methylbenzothiazole 2 in eth-
anol provided dihydropyrimidobenzothiazolone 5 in excellent
yield (94%, 15 min) (Scheme 1).
When the reaction was conducted using isatin 8 in place of
aldehyde/ketone 3 using the catalytic amount of sulfamic acid,
[benzothiazolyl]-spiro[tetrahydroquinoline-indoline]trione 9 was
obtained in excellent yield, 90% in 25 min (Scheme 3).
It was found that the catalyst, sulfamic acid, could be easily
quantitatively recovered after the reaction completed and
could be reused for at least four cycles without any loss of
activity.
The plausible mechanisms of this multicomponent domino
reaction process are proposed as shown in Scheme 4.
Surprisingly, when the multicomponent reaction was per-
formed with the four components Meldrum’s acid 1, 2-amino-6-
bromo-4-methylbenzothiazole 2, aldehydes/ketones 3, and
dimedone 6, the structurally diverse benzothiazolyltetrahydroqu-
inolinedione 7 was obtained in excellent yield (93%, 12 min)
(Scheme 2).
In conclusion, we have developed a domino protocol for the effi-
cient synthesis of structurally diverse benzothiazolylquinolinedi-
ones and their spiro analogues that serve as versatile scaffolds
for medicinal research. The simplicity of the method, ease of the
product isolation, and mild reaction conditions will make this syn-
thetic method useful on a preparative scale.

A. K. Arya et al. / Tetrahedron Letters 53 (2012) 6035–6038
6037
O
HO
O
H+
O
O
O
O
O
O
-H2O
O
O
O
Knoevenagel
reaction
NH
H
O
N
H
O
H
O
O
8
1
H
C
O
O
O
O
Knoevenagel
reaction
O
H+
H
N
NH
OCH3
O
O
O
H
3a
OCH3
O
O
O
H
O
O
O
O
O
H
O
O
6
O
O
CH3
I
N
S
H+
-H2O
O
O
NH2
4
Br
2
O
H
N
H
N
H
N
6
O
O
O
OCH3
O
O
O
O
O
O
-CO2
O
H+
O
O
O
O
O
N
-
O
O
H
N
HN
O
S
O
S
N
N
N
S
O
O
HO
CH3
CH3
CH3
H+
Br
Br
9
Br
OCH3
OCH3
OCH3
O
O
O
H+
-CO2
O
O
O
O
O
CH3
O
N
N
-
O
N
S
O
H
N
O
S
NH2
S
O
N
Br
2
CH3
II
CH3
Br
7a
Br
Scheme 4. Plausible mechanisms for the synthesis of benzothiazolyltetrahydroquinolinedione and [benzothiazolyl]-spiro[tetrahydroquinoline-indoline]trione.
LaBarbera, D. V.; Jamil, A.; Chapuis, J. C.; Skibo, E. B. J. Med. Chem. 2008, 51,
2492; (d) Morin, C.; Besset, T.; Moutet, J.-C.; Fayolle, M.; Brückner, M.; Limosin,
D.; Becker, K.; Davioud-Charvet, E. Org. Biomol. Chem. 2008, 6, 2731; (e) APan,
H. L.; Fletcher, T. L. J. Med. Chem. 1967, 10, 957; (f) Shaikh, I. A.; Johnson, F.;
Grollman, A. P. J. Med. Chem. 1986, 29, 1329.
References and notes
1. (a) Colombo, M.; Peretto, I. Drug Discovery Today 2008, 13, 667; (b) Zhu, J.;
Bienayme´, H. Multicomponent Reactions; Wiley-VCH: Weinheim, Germany,
2005.
6. (a) Tu, S.; Zhu, X.; Zhang, J.; Xu, J.; Zhang, Y.; Wang, Q.; Jia, R.; Jiang, B.; Zhang, J.;
Yao, C. Bioorg. Med. Chem. Lett. 2006, 16, 2925; (b) Strozher, F. M.; Lieldriedis, F.
I. Khim Geterotsikl. Soedin. 1993, 9, 1227.
7. Chianelli, D.; Kim, Y.-C.; Lvovskiyb, D.; Webb, T. R.Bioorg. Med. Chem. 2003, 11, 5059.
8. Arya, A. K.; Kumar, M. Green Chem. 2011, 13, 1332.
2. (a) Hilton, S. T.; Ho, T. C.; Pljevalijcic, G.; Jones, K. Org. Lett. 2000, 17, 2639; (b)
Chang, M. Y.; Pai, C. L.; Kung, Y. H. Tetrahedron Lett. 2005, 46, 8463.
3. (a) Kashiyama, E.; Hutchinson, I.; Chua, Mei-Sze; Stinson, S. F.; Phillips, L. R.;
Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J.
Med. Chem. 1999, 42, 4172; (b) Henriksen, G.; Yousefi, B. H.; Drzezga, A.;
Wester, H. J. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 75; (c) Yoshida, M.;
Hayakawa, I.; Hayashi, N.; Agatsuma, T.; Oda, Y.; Tanzawa, F.; Iwasaki, S.;
Koyama, K.; Furukaw, H.; Kurakata, S. Bioorg. Med. Chem. Lett. 2005, 15, 3328.
4. Solomon, V. R.; Hu, C.; Lee, H. Bioorg. Med. Chem. 2009, 17, 7585.
5. (a) Bolognese, A.; Correale, G.; Manfra, M.; Lavecchia, A.; Mazzoni, O.;
Novellino, E.; Barone, V. Tetrahedron 2004, 60, 8189; (b) Delfourne, E.; Darro,
F.; Bontemps-Subielos, N.; Decaestecker, C.; Bastide, J.; Frydman, A.; Kiss, R. J.
Med. Chem. 2001, 44, 3275; (c) Hargreaves, R. H. J.; David, C. L.; Whitesell, L. J.;
9. Arya, A. K.; Kumar, M. Mol. Divers. 2011, 15, 781.
10. Kumar, M.; Sharma, K.; Arya, A. K. Tetrahedron Lett. 2012, 56, 4604.
11. Kumar, M.; Sharma, K.; Samarth, R. M.; Kumar, A. Eur. J. Med. Chem. 2010, 45,
4467.
12. Gupta, R. R.; Kumar, M. Synthesis, Reactions and Properties of Phenothiazines’.
In Phenothiazines and 1,4-Benzothiazines. Chemical and Biomedical Aspect;
Elsevier: Amsterdam, 1988.
13. Rathor, B. S.; Kumar, M. Bioorg. Med. Chem. 2006, 14, 5678.

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A. K. Arya et al. / Tetrahedron Letters 53 (2012) 6035–6038
14. (a) Rathor, B. S.; Gupta, V.; Gupta, R. R.; Kumar, M. Heteroat. Chem. 2007, 18, 81;
(b) Kumar, M.; Sharma, K.; Sharma, D. K. Org. Med. Chem. Lett. 2012, 2, 10.
(6-Bromo-4-methylbenzothiazol-2-yl)-4-(phenyl)-7,7-dimethyl-3,4,7,8-tetrahydro-
6H-quinoline-2,5-dione (7c): Mp 261–265 °C, IR (KBr) 1692, 1678, 1585, 837
15. Representative
procedure:
A
mixture
of
1
2-amino-6-bromo-4-
(1 mmol), dimedone
and 645 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 0.99 (6H, s, CH3), 2.05–2.20 (2H, m,
.
methylbenzothiazole
2
(1 mmol), Meldrum acid
6
CH2), 2.21 (1H, m, COCH2), 2.27 (1H, m, COCH2), 2.35–2.41 (2H, m, CH2), 2.46
(3H, s, CH3), 2.67 (1H, m, NCOCH2), 2.83 (1H, m, NCOCH2), 4.35 (1H, s, CH),
6.83–7.21 (7H, m, ArH). 13C NMR (DMSO-d6) d (ppm): 18.4, 19.3, 26.6, 26.8,
29.3, 37.8, 44.9, 53.8, 116.8, 119.8, 123.1, 124.9, 125.8, 127.9, 128.0, 128.4,
129.2, 133.8, 140.3, 142.3, 147.8, 167.2, 174.1, 197.7. Anal. Calcd (%) for
(1 mmol), and aldehyde/ketone 3 or isatin 8 (1 mmol), in ethanol (5 mL) with
catalytic amount of sulfamic acid (0.2 mmol) was stirred on magnetic stirrer at
80 °C for 10–25 min. The progress of the reaction was monitored by TLC. After
completion of the reaction, the precipitated product was cooled to room
temperature. The precipitated product was then filtered and washed with
water and cooled ethanol to afford the pure product.
C
25H23BrN2O2S: C, 60.61; H, 4.68; N, 5.65. Found: C, 60.60; H, 4.71; N, 5.67.
(6-Bromo-4-methylbenzothiazol-2-yl)-4,4,7,7-tetramethyl-3,7,8-trihydro-6H-
4-(4-Methoxyphenyl)-3,4-dihydrobenzothiazolo[2,3-b]pyrimidin-2-one (5):
quinoline-2,5-dione (7d): Mp 255-258 °C, IR (KBr) 1701, 1673, 1583, 1326, 841
Mp 185–187 °C, IR (KBr) 1705, 1078, 810 and 621 cmꢀ1
.
1H NMR (DMSO-d6) d
and 651 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 0.97 (3H, s, CH3), 1.03 (3H, s, CH3),
.
(ppm) 2.42 (3H, s, CH3), 2.84 (1H, m, CH2), 2.96 (1H, m, CH2), 3.25 (3H, s, OCH3),
4.17 (1H, s, CH), 6.93–7.33 (6H, m, H-Ar). 13C NMR (DMSO-d6) d (ppm): 18.3,
42.2, 47.9, 56.6, 113.6, 114.0, 117.5, 118.4, 124.3, 128.3, 130.1, 130.3, 134.6,
143.8, 160.8, 163.8, 193.7. Anal. Calcd (%) for C18H15BrN2O2S: C, 53.61; H, 3.75;
N, 6.95. Found: C, 53.62; H, 3.73; N, 6.98.
2.07 (1H, m, COCH2), 2.18 (1H, m, COCH2), 2.35 (3H, s, CH3), 2.43 (1H, m, CH2),
2.45 (3H, s, CH3), 2.53 (3H, s, CH3), 2.57 (1H, m, CH2), 2.86 (1H, m, NCOCH2),
2.90 (1H, m, NCOCH2), 6.96-7.05 (2H, m, ArH). 13C NMR (DMSO-d6) d (ppm):
18.9, 19.6, 22.8, 23.2, 23.5, 26.7, 26.8, 43.7, 45.7, 54.2, 120.3, 123.0, 124.6,
129.0, 129.5, 133.8, 147.8, 166.5, 174.3, 197.7. Anal. Calcd (%) for
(6-Bromo-4-methylbenzothiazol-2-yl)-4-(4-methoxyphenyl)-7,7-dimethyl-3,4,7,
C21H23BrN2O2S: C, 56.38; H, 5.18; N, 6.26. Found: C, 56.37; H, 5.20; N, 6.25.
8-tetrahydro-6H-quinoline-2,5-dione (7a): Mp 265–267 °C, IR (KBr) 1685, 1656,
(6-Bromo-4-methylbenzothiazol-2-yl)-4-(phenyl)-4,7,7-trimethyl-3,7,8-trihydro-
1580, 1327, 1060, 835 and 613 cmꢀ1
.
1H NMR (DMSO-d6) d (ppm): 1.03 (3H, s,
6H-quinoline-2,5-dione (7e): Mp 261–265 °C, IR (KBr) 1698, 1665, 1565, 1343
CH3), 1.07 (3H, s, CH3), 2.15 (1H, m, COCH2), 2.29 (1H, m, COCH2), 2.38 (3H, s,
CH3), 2.43 (1H, m, CH2), 2.56 (1H, m, CH2), 2.83 (1H, m, NCOCH2), 2.91 (1H, m,
NCOCH2), 3.47 (3H, s, OCH3), 4.21 (1H, s, CH), 7.02–7.36 (6H, m, ArH). 13C NMR
(DMSO-d6) d (ppm): 18.1, 18.9, 26.3, 26.4, 29.3, 38.1, 45.4, 56.2, 67.8, 113.9,
114.3, 117.0, 119.7, 123.0, 124.7, 128.8, 129.1, 132.5, 133.5, 142.4, 147.7, 147.8,
153.9, 159.1, 173.9, 197.6. Anal. Calcd (%) for C26H25BrN2O3S: C, 59.43; H, 4.80;
N, 5.33. Found: C, 59.42; H, 4.81; N, 5.30.
and 815 cm-1 1H NMR (DMSO-d6) d (ppm): 1.02 (3H, s, CH3), 1.07 (3H, s, CH3),
.
2.17 (1H, m, COCH2), 2.27 (1H, m, COCH2), 2.40 (3H, s, CH3), 2.43 (1H, m, CH2),
2.54 (1H, m, CH2), 2.87 (1H, m, NCOCH2), 2.93 (1H, m, NCOCH2), 6.83–7.47 (7H,
m, ArH). 13C NMR (DMSO-d6) d (ppm): 18.7, 19.3, 26.3, 26.7, 29.5, 45.3, 43.9,
54.3, 120.3, 121.7, 123.0, 124.6, 125.7, 126.3, 126.7, 128.1, 128.5, 129.3, 133.5,
138.6, 147.7, 147.8, 148.7, 166.3, 174.7, 197.3. Anal. Calcd (%) for
C
26H25BrN2O2S: C, 61.30; H, 4.95; N, 5.50. Found: C, 61.32; H, 4.93; N, 5.49.
(6-Bromo-4-methylbenzothiazol-2-yl)-4-(4-chlorophenyl)-7,7-dimethyl-3,4,7,8-
(6-Bromo-4-methylbenzothiazol-2-yl)-7,7-dimethyl-7,8-dihydro-3H,6H-spiro-
tetrahydro-6H-quinoline-2,5-dione (7b): Mp 271–274 °C, IR (KBr) 1703, 1667,
[quinoline-4,3’-indoline]-2,2,’5-trione (9): Mp 278–280 °C, IR (KBr) 3327, 1708,
1315, 838, 790 and 710 cmꢀ1
.
1H NMR (DMSO-d6) d (ppm): 0.99 (3H, s, CH3),
1690, 1671, 1579, 1308, 813 and 620 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 0.99
.
1.04 (3H, s, CH3), 2.17 (1H, m, COCH2), 2.25 (1H, m, COCH2), 2.41 (3H, s, CH3),
2.46 (1H, m, CH2), 2.56 (1H, m, CH2), 2.79 (1H, m, NCOCH2), 2.92 (1H, m,
NCOCH2), 4.30 (1H, s, CH), 6.68–7.27 (6H, m, ArH). 13C NMR (DMSO-d6) d
(ppm): 18.9, 19.3, 26.3, 26.5, 29.3, 38.1, 45.1, 54.0, 116.9, 120.1, 122.8, 124.9,
128.8, 129.0, 129.1, 129.3, 129.7, 131.3, 133.6, 138.4, 142.3, 147.5, 167.4, 174.3,
197.3. Anal. Calcd (%) for C25H22BrClN2O2S: C, 56.67; H, 4.18; N, 5.29. Found: C,
56.66; H, 4.19; N, 5.29.
(3H, s, CH3), 1.01 (3H, s, CH3), 2.17 (1H, m, COCH2), 2.27 (1H, m, COCH2), 2.45
(3H, s, CH3), 2.51 (1H, m, CH2), 2.62 (1H, m, CH2), 2.81 (1H, m, NCOCH2), 2.93
(1H, m, NCOCH2), 6.83–7.28 (6H, m, ArH), 10.57 (1H, s, NH). 13C NMR (DMSO-
d6) d (ppm): 18.3, 19.3, 25.8, 26.1, 29.1, 37.6, 44.7, 47.8, 53.1, 117.1, 120.3,
121.1, 123.1, 124.3, 124.7, 127.3, 127.9, 133.2, 142.3, 142.5, 147.8, 167.3, 172.7,
174.6, 197.3. Anal. Calcd (%) for C26H22BrN3O3S: C, 58.21; H, 4.13; N, 7.83.
Found: C, 58.94; H, 4.81; N, 7.52.