Synthesis and biological applications of some novel spiro heterocycles containing 1,3,4-thiadiazine, thiazole, and oxazole derivatives

Article abstract of DOI:10.1002/jhet.956

2-Ethoxy carbonylcyclopentanone (1) has been brominated to yield 2-bromo-2-ethoxy carbonylcyclopentanone (2) which on further reaction with substituted thiosemicarbazones, thiocarbohydrazones, thiocarbamides and carbamides has furnished 1-thia-3,4-diaza-5

Full text of DOI:10.1002/jhet.956

January 2013
Synthesis and Biological Applications of Some Novel Spiro
Heterocycles Containing 1,3,4-Thiadiazine, Thiazole,
and Oxazole Derivatives
155
*
Vijay V. Dabholkar and Nitin V. Bhusari
Department of Chemistry, Organic Research Laboratory, University of Mumbai, K.C. College, Churchgate,
400 020, Mumbai
*
E-mail: vijaydabholkar@gmail.com
Received December 11, 2010
DOI 10.1002/jhet.956
View this article online at wileyonlinelibrary.com.
2-Ethoxy carbonylcyclopentanone (1) has been brominated to yield 2-bromo-2-ethoxy carbonylcyclo-
pentanone (2) which on further reaction with substituted thiosemicarbazones, thiocarbohydrazones, thio-
carbamides and carbamides has furnished 1-thia-3,4-diaza-5,7-dioxo-2-[(substituted benzylidine)-amino]
spiro[4.5]dec-2-ene (3a–e), 1-thia-3,4-diaza-5,7-dioxo-2-[(substituted benzylidine)-hydrazino] spiro[4.5]
dec-2-ene (4a–e), 1-thia-3-aza-2-(substituted imino)-4,6-dioxo-spiro[4.4]nonane (5a–f) and 1-oxa-3-aza-2-
(substituted imino)-4,6-dioxo-spiro[4.4]nonane (6a–g) respectively. The structures of the compounds have
been elucidated on the basis of spectral analysis.
J. Heterocyclic Chem., 50, 155 (2013).
INTRODUCTION
Spiro compounds containing sulfur and nitrogen are of
great interest due to their physiological and biological
activities [9, 10]. Spiro compounds are also known to
possess various biological activities e.g., anti-inflammatory
[11], fungistatic [12], and bacteriostatic [13].
Thus, keeping in view the chemistry of 1,3,4-thiadiazines,
oxazoles, and thiazoles, their derivatives have been synthesized
by conventional methods.
In recent years, interest in 1,3,4-thiadiazines has
increased in connection with a high biological activity
and broad spectral action of their derivatives. New methods
have been developed for the synthesis of 1,3,4-thiadiazines
and condensed heterosystems based on these compounds.
Thiadiazines display biological activities, such as anti-
microbial [1, 2], antiirradiation [3, 4], and antiparasitic
[5]. The compounds bearing thiadiazine nucleus are a
versatile pharmacophore, which exhibits a wide variety
of biological activities.
RESULTS AND DISCUSSION
1,3,4-Thiadiazines represent the most widely studied
class of compounds among the six theoretically possible
thiadiazine isomers, they are of interest in a chemical sense
because they are labile compounds which are capable of
undergoing intramolecular rearrangements to give thiazole
and pyrazole derivatives.
The five-membered heterocycles, oxazoles, and thiazoles
have gained importance because of their varied physiological
activities. Fused oxazoles [6] and thiazoles [7, 8] have been
found to exhibit antihelmintic, insecticidal, sedative,
tranquilizer, antiepileptic, antitubercular, and parasiticidal
activities.
The synthesis of 2-bromo-2-ethoxy carbonylcyclopentanone
(2) was achieved from 2-ethoxy carbonylcyclopentanone (1)
which was synthesized using reported procedure [14]. The title
compounds 2-amino-6-cyclopentanone-1,3,4-thiadiazine
(3a–e) and 2-hydrazino-6-cyclopentanone-1,3,4-thiadia-
zine (4a–e), 1-thia-3-aza-2-imino-4,6-dioxo-spiro[4.4]
nonane (5a–f) and 1-oxa-3-aza-2-imino-4,6-dioxo-spiro
[4.4] nonane (6a–g) were synthesized by reacting bromo
compound (2) with substituted thiosemicarbohydrazones
[15], thiocarbohydrazones [16], thiocarbamides, and
carbamides, respectively, in the presence of potassium
hydroxide using ethanol as a solvent (Scheme 1).
© 2013 HeteroCorporation

156
V. V. Dabholkar and N. V. Bhusari
Vol 50
Scheme 1. Pathway of synthesis of compound 3, 4, 5, and 6.
by separating funnel, and purified by distillation to give 2-
bromo-2-ethoxy carbonylcyclopentanone, yield 86%. Boiling
point is 108–110°C.
Further, the newly synthesized representative compounds
were screened for their antimicrobial activity, which
shows a significant activity against gram-positive as well as
gram-negative bacteria. The activity data of these compounds
are given in Table 2.
1-Thia-3,4-diaza-5,7-dioxo-2-[(substituted benzylidine)-amino]
spiro[4.5]dec-2-ene (3a–e). A mixture of bromo compound 2
(0.01 mol), substituted thiosemicarbazone (0.01 mol), and a KOH
(0.02 mol) in ethanol (20 mL) were refluxed for about 4–5 h.
Progress of the reaction was monitored by TLC. After completion of
reaction, the contents were poured into crushed ice. The solid
obtained was filtered off, washed with water and purified by
recrystallization from ethanol to get 3a–e.
EXPERIMENTAL
Melting points of all the compounds were determined in open-
ended capillary tubes on an electro thermal apparatus and were
uncorrected. The progress of the reaction was monitored by thin
layer chromatography (TLC) on silica gel coated aluminium
plates (Merck) as adsorbent and UV light as visualizing agent.
IR spectra (KBr) were recorded on Perkin-Elmer spectrometer
1-Thia-3,4-diaza-5,7-dioxo-2-[(2′hydroxy-benzylidine)-amino]
spiro [4.5]dec-2-ene (3b). Yield: 58%; mp = 104–109°C: Anal.
Calcd. for C14H13N3O3S: C, 55.45; H, 4.29; N, 13.86. Found C,
55.35; H, 4.32; N, 13.95%. IR (cm−1): 3408 (OH), 2205 (C═N),
1
1
in the spectral range of 4000–400 cm−1. H-NMR spectra were
2185 (C═N), 1725 (C═O), 1628 (C═O), H-NMR (DMSO-d6,
recorded on Varian 500 MHz NMR spectrometer using CDCl3/
DMSO-d6 as solvent and TMS as an internal standard (chemical
shifts in δ ppm).
δ/ppm): 1.16 (t, 2H, CH2), 1.50 (m, 2H, CH2), 2.26 (t, 2H, CH2),
4.04 (s, 1H, OH), 6.86–8.08 (m, 4H, Ar–H), 8.35 (s, 1H, CH),
11.36 (s, 1H, NH). 13C-NMR (DMSO-d6, δ/ppm): 39.78–40.33
(CH2 × 3), 116.04 (Spiro-C), 119.24–131.07 (Ar–C), 139.62
(HC═N), 156.43 (C═N), 170.42 (C═O), 173.40 (C═O).
2-Bromo-2-ethoxy carbonylcyclopentanone (2). 2-Ethoxy
carbonylcyclopentanone (0.01 mol) was dissolved in
a
minimum quantity of carbon tetrachloride (10 mL). A solution
of bromine (0.01 mol) in carbon tetrachloride was added drop
wise with continuous stirring in the presence of UV light. The
progress of reaction was monitored by TLC. The reaction
mixture was washed with water and the product was separated
1-Thia-3,4-diaza-5,7-dioxo-2-[(4′methoxy-benzylidine)-amino]
spiro [4.5]dec-2-ene (3e). Yield: 64%; mp = 88–89°C: Anal. Calcd.
for C15H15N3O3S: C, 56.78; H, 4.73; N, 13.25. Found C, 56.82; H,
4.69; N, 13.28%. IR (cm−1): 2198 (C═N), 2156 (C═N), 1730
1
(C═O), 1635 (C═O), H-NMR (DMSO-d6, δ/ppm): 1.16 (t, 2H,
Journal of Heterocyclic Chemistry
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January 2013
Synthesis and Biological Applications of Some Novel Spiro Heterocycles Containing
1,3,4-Thiadiazine, Thiazole, and Oxazole Derivatives
157
Table 1
CH2), 1.49 (m, 2H, CH2), 2.23 (t, 2H, CH2), 3.77 (s, 3H, OCH3),
6.95–8.09 (m, 4H, Ar–H), 8.35 (s, 1H, CH), 11.29 (s, 1H, NH).
13C-NMR (DMSO-d6, δ/ppm): 39.78–40.33 (CH2 × 3), 55.31
(OCH3), 100.12 (Spiro-C), 114.19–147.42 (Ar–C), 142.27
(HC═N), 160.71 (C═N), 177.60 (C═O), 180.16 (C═O). The
physical data of the compounds 3a–e is given in Table 1.
Physical data of synthesized compounds (3a–e), (4a–e), (5a–f), and
(6a–g).
Mol.
formula
Yield
(%)
Compds
R
mp (°C)
1-Thia-3,4-diaza-5,7-dioxo-2-[(substituted benzyl dine)-
hydrazine]spiro[4.5]dec-2-ene (4a–e). The 2-bromo-2-ethoxy
carbonylcyclopentanone 2 (0.01 mol), was dissolved in a
minimum quantity of ethanol (20 mL) containing KOH (0.02 mol) as
a catalyst. An equimolar quantity of substituted thiocarbohydrazone
(0.01 mol) was added to it and the reaction mixture was refluxed for
about 4–5 h. Progress of the reaction was monitored by TLC. After
completion of reaction, the contents were poured into crushed ice.
The solid obtained was filtered off, washed with water and purified
by recrystallization from ethanol to get 4a–e.
1-Thia-3,4-diaza-5,7-dioxo-2-[(2′-hydroxy-benzyl dine)-
hydrazine]spiro[4.5]dec-2-ene (4b). Yield: 76%; mp = 93–97°C:
Anal. Calcd for C14H14N4O3S: C, 52.83; H, 4.40; N, 17.61. Found
C, 52.89; H, 4.42; N,17.58%. IR (cm−1): 3395 (OH), 1721 (C═O),
1622 (C═O), 1533 (C═N).1H-NMR (DMSO-d6, δ/ppm): 0.66 (t,
2H, CH2), 0.97 (m, 2H, CH2), 1.57 (t, 2H, CH2), 4.96 (s, 1H, OH),
6.00–6.8 (m, 4H, Ar–H), 8.58 (s, 1H, CH), 9.28 (s, 1H, NH), 10.52
(s, 1H, NH). 13C-NMR (DMSO-d6, δ/ppm): 38.66–40.32
(CH2 × 3), 53.68 (N═CH), 105.59 (Spiro-C), 114.19–147.42
(Ar–C and HC═N), 154.39 (C═N), 170.42 (C═O), 173.43 (C═O).
1-Thia-3,4-diaza-5,7-dioxo-2-[(4′-hydroxy-3′methoxy-
benzyldine)-hydrazine]spiro[4.5]dec-2-ene (4d). Yield:
64%; mp = 92–95°C: Anal. Calcd. for C15H16N4O4S: C,
51.72; H, 4.60; N, 16.09. Found C, 51.62; H, 4.62; N, 16.14%.
IR (cm−1): 3422 (OH), 1625 (C═O), 1548 (C═N). 1H-NMR
(DMSO-d6, δ/ppm): 1.16 (t, 2H, CH2), 1.50 (m, 2H, CH2), 2.26
(t, 2H, CH2), 3.81 (s, 3H, OCH3), 4.02 (s, 1H, OH), 6.90–7.90
(m, 3H, Ar–H), 8.58 (s, 1H, CH), 9.28 (s, 1H, NH), 10.4 (s, 1H,
NH). 13C-NMR (DMSO-d6, δ/ppm): 35.14–40.32 (CH2 × 3), 56.45
(N═CH), 98.60 (Spiro-C), 115.10–131.72 (Ar–C and HC═N),
152.67 (C═N), 179.55 (C═O), 195.10 (C═O). The physical data
of the compounds 4a–e are given in Table 1.
3a
3b
3c
3d
H
o‐OH
p‐Cl
p‐OCH3-
m‐OH
p‐OCH3
H
o‐OH
p‐Cl
m‐OCH3-
p‐OH
p‐OCH3
p‐OCH3-
C6H4
p‐CH3-
C6H4
p‐Cl-
C6H4
m‐Cl-
C6H4
H
C6H5
p‐OCH3-
C6H4
p‐CH3-
C6H4
o‐OCH3-
C6H4
o‐NO2-
C6H4
C
14H13N3O2S
61
58
l72
74
103–105
104–109
96–98
C14H13N3O3S
C14H12N3O2SC
C15H15N3O4S
84–87
3e
4a
4b
4c
4d
C15H15N3O3S
C14H14N4O2S
C14H14N4O3S
C14H13N4O2SCl
C15H16N4O4S
64
78
76
81
64
88–91
107–110
93–97
106–109
92–95
4e
5a
C15H16N4O3S
C14H14N2O3S
65
72
85–89
116–121
5b
5c
5d
C14H14N2O2S
60
68
54
105–111
106–110
91–92
C13H11N2O2SCl
C13H11N2O2SCl
5e
5f
6a
C7H8N2O2S
C13H12N2O2S
C14H14N2O4
78
81
58
88–91
74–77
105–107
6b
6c
6d
6e
C14H14N2O3
C14H14N2O4
C13H11N3O5
C13H11N2O3Cl
55
67
72
51
63–65
101–103
84–87
o‐Cl-
C6H4
H
C6H5
72–75
6f
6g
C7H8N2O3
C13H12N2O3
81
84
72–76
84–87
Table 2
Antimicrobial activities of some newly synthesized compounds.
Inhibition zone (mm)
Gram‐negative
Gram‐positive
Fungi
Yeast
Compounds
E. coli
P. putide
B. subtilis
S. lactis
A. niger
P. sp.
C. albicans
3a
3c
4b
4c
5a
5b
6d
6f
17
16
15
18
19
18
19
20
24
15
16
14
19
17
16
18
19
20
18
17
18
19
16
17
16
18
19
21
21
19
20
19
18
20
19
22
12
10
8
10
10
8
8
10
9
0
8
14
5
5
5
5
4
4
0
5
14
8
11
13
0
7
24
Ampicilin®
E. coli = Escherichia coli; P. putide = Pseudomonas putide; B. subtilis = Bacillus subtilis; S. lactis = Sterptococcus lactis; A. niger = Aspergillus niger; P.
sp. = Penicillium sp.; C. albicans = Candida albicans. The sensitivity of microorganisms to the tested compounds is identified in the following mannera:
Highly sensitive = inhibition zone: 15–20 mm; moderately sensitive = inhibition zone: 10–15 mm; slightly sensitive = inhibition zone: 5–10 mm; not
sensitive = inhibition zone: 0 mm.
aEach result represents the average of triplicate readings.
Journal of Heterocyclic Chemistry
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V. V. Dabholkar and N. V. Bhusari
Vol 50
1-Thia-3-aza-2-imino-4,6-dioxo-spiro[4.4]nonane (5a–f). A
Streptococcus lactis; (c) Fungi: Aspergillus niger,
Penicillium sp.; (d) Yeast – Candida albicans. The prelimi-
nary screening of the investigated compounds was performed
using the filter paper disc-diffusion method [17]. The
compounds were tested at a concentration of 100 μg/mL.
The zone of inhibition was measured in mm and compared
with reference standard ampicillin trihydrate (100 μg/mL).
The compounds tested displayed good activity towards
gram-positive bacteria, but were less active against gram-
negative bacteria. The results of antibacterial screening
studies are reported in Table 2.
mixture of 2-bromo-2-ethoxy carbonylcyclopentanone 2
(0.01 mol) and substituted thiocarbamide (0.01 mol) was
added to a solution of KOH (0.02 mol) in ethanol (20 mL).
The reaction mixture was refluxed for about 7–8 h. Progress of
the reaction was monitored by TLC. After completion of
reaction, the contents were poured into ice-cold dilute HCl.
The resulting solid obtained was filtered off, washed several
times with water and purified by recrystallization from ethanol
to get 5a–f.
1-Thia-3-aza-2-(4′methylphenyl)-imino-4,6-dioxo-spiro
[4.4]nonane (5b). Yield: 60%; mp = 105–111°C: Anal. Calcd.
for C14H14N2O2S: C, 61.31; H, 5.11; N, 10.22. Found C,
61.22; H, 5.22; N, 10.26%. IR (cm−1): 1732 (C═O), 1626
(C═O), 1533 (C═N). 1H-NMR (DMSO-d6, δ/ppm): 1.18
(t, 2H, CH2), 1.22 (m, 2H, CH2), 1.86 (t, 2H, CH2), 2.28
(s, 3H, CH3), 4.09 (s, 1H, NH), 7.20–7.78 (m, 4H, Ar–H).
13C-NMR (DMSO-d6, δ/ppm): 23.42 (CH3) 35.14–40.32 (CH2 × 3),
101.62 (Spiro-C), 129.37–138.51 (Ar–C), 153.06 (C═N), 186.26
(C═O), 187.99 (C═O). The physical data of the compounds
5a–f are given in Table 1.
Acknowledgments. The authors are thankful to the principal
Ms. Manju J Nichani and Management of K.C. College, Churchgate,
Mumbai for constant encouragement and providing necessary
facilities. Authors are also thankful to Director, Institute of science,
Mumbai for providing spectral datas.
1-Oxa-3-aza-2-imino-4,6-dioxo-spiro[4.4]nonane (6a–g). To
a solution of 2-bromo-2-ethoxy carbonylcyclopentanone 2
(0.01 mol) and substituted carbamide (0.01 mol) in ethanol
(20 mL), KOH (0.02 mol) was added as catalyst. The
reaction mixture was refluxed for about 7–8 h. Progress of
the reaction was monitored by TLC. After completion of
reaction, the contents were poured into ice-cold dilute HCl.
The resulting solid obtained was filtered off, washed several
times with water, and purified by recrystallization from
ethanol to get 6a–g.
1-Oxa-3-aza-2-(4′-methoxyphenyl)-imino-4,6-dioxo-spiro
[4.4]nonane (6a). Yield: 58%; mp = 105–107°C: Anal. Calcd.
for C14H14N2O4: C, 61.31; H, 5.11; N, 10.22. Found C, 61.38;
H, 5.18; N, 10.26%. IR (cm−1): 1715 (C═O), 1626 (C═O),
and 1551 (C═N). 1H-NMR (DMSO-d6, δ/ppm): 1.16 (t, 2H,
CH2), 1.31 (m, 2H, CH2), 1.88 (t, 2H, CH2), 3.67 (s, 3H,
OCH3), 5.69 (s, 1H, NH), and 6.71–7.20 (m, 4H, Ar–H). 13C-
NMR (DMSO-d6, δ/ppm): 35.14–40.32 (CH2 × 3), 55.34
(OCH3), 104.14 (Spiro-C), 125.41–141.08 (Ar–C), 155.66
(C═N), 185.04 (C═O), and 195.78(C═O). The physical data
of the compounds 6a–g are given in Table 1.
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ANTIMICROBIAL EVALUATION
The newly synthesized representative compounds were
tested for their antimicrobial activity against the following
microorganisms: (a) gram-negative – Escherichia coli,
Pseudomonas putide; (b) Gram-positive – Bacillus subtilis,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet