The syntheses of new cyclopenta[d][1,3]thiazine derivatives and their use as antimicrobial agents

Article abstract of DOI:10.1080/10426500500366947

Cyclopentanone (1) was exploited as a starting material for the syntheses of hitherto unknown cyclopenta[d][1,3]thiazine derivatives. Copyright Taylor & Francis Group, LLC.

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The Syntheses of New
Cyclopenta[d][1,3]thiazine
Derivatives and Their Use as
Antimicrobial Agents
M. S. A. El-Gaby a , N. M. Saleh b , J. A. Micky b , Y.
A. Ammar b & H. S. A. Mohamed b
a Department of Chemistry, Al-Azhar, University at
Assiut, Assiut, Egypt
b Department of Chemistry, Al-Azhar University, Nasr
City, Cairo, Egypt
Version of record first published: 01 Feb 2007.
To cite this article: M. S. A. El-Gaby , N. M. Saleh , J. A. Micky , Y. A. Ammar & H.
S. A. Mohamed (2006): The Syntheses of New Cyclopenta[d][1,3]thiazine Derivatives
and Their Use as Antimicrobial Agents, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:7, 1655-1663
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Phosphorus, Sulfur, and Silicon, 181:1655–1663, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500366947
The Syntheses of New Cyclopenta[d][1,3]thiazine
Derivatives and Their Use as Antimicrobial Agents
M. S. A. El-Gaby
Department of Chemistry, Al-Azhar University at Assiut, Assiut, Egypt
N. M. Saleh
J. A. Micky
Y. A. Ammar
H. S. A. Mohamed
Department of Chemistry, Al-Azhar University, Nasr City, Cairo, Egypt
Cyclopentanone (1) was exploited as a starting material for the syntheses of hitherto
unknown cyclopenta[d][1,3]thiazine derivatives.
Keywords Cyclopentanone; thiazine and cyclopenta[d][1,3]thiazine derivatives
INTRODUCTION
1,3-thiazine derivatives are reported to show antibacterial,1
antimycobacterial,2 antiviral,3 and pesticide4 agents. In addition,
4,6,6-trimethyl-2-mercaptothiazine (A) is slightly active in producing
hyperplasia of the thyroid and an impairment of the ability to fix admin-
istered I in rats.5 Further, 2-aminothiazines increase the survival time
in mice irradiated with X-rays.6 Also, arylthiazines have bactericidal,
fungicidal, and algicidal properties that are useful in agriculture, spin-
ning mixtures, and manufacturing papers and paints.7 Cephalosporins
(B) have a 3,6-dihydro-2H-1,3-thiazine nucleus (Scheme 1).8 In con-
tinuation with our work on the synthesis of some novel heterocyclic
compounds from readily available starting materials,9−13 we report
herein on the synthesis of novel cyclopenta[d][1,3]thiazine derivatives
from cyclopentanones.
Received July 14, 2005; accepted August 29, 2005.
Address correspondence to M. S. A. El-Gaby, Al-Azhar University at Assiut, Depart-
ment of Chemistry, Faculty of Science, Assiut, 71524 Egypt. E-mail: m elgaby@hotmail.
com
1655

1656
M. S. A. El-Gaby et al.
SCHEME 1
RESULTS AND DISCUSSION
The 2-oxo-1,3-thiazine derivative was prepared by the acid-catalyzed
reaction of chalcone with thiourea.14 Lorand and Szabo15,16 inves-
tigated the reaction of 2-arylidene cyclohexanones and 2-arylidene-
1-tetralones with thiourea under acidic conditions and synthe-
sized 1,3-thiazines and 3,1-benzothiazines. The reaction of 2-
arylidenecycloalkanones, 2-arylidene-1-tetralones, and 2-arylidene-1-
benzosuberones with thiourea in the presence of sodium ethoxide or
sodium hydroxide gave pyrimidines.17,18 In the present article, the
reaction of cyclopentanone with aromatic aldehyde in the presence
of thiourea or urea under acidic and alkaline reaction conditions
was investigated. Thus, three possible structures can be formulated,
(2), (3), and (4), when cyclopentanone (1) was condensed with aro-
matic aldehyde and thiourea in ethanol in the presence of concen-
trated hydrochloric acid at a reflux temperature (Scheme 2). The cy-
clopenta[d][1,3]thiazines (4a–h) were confirmed as the only product on
1
the basis of analytical and spectroscopic data. The H NMR spectrum
of compound (4a) in DMSO-d6 revealed a signal at δ = 5.8 ppm for
an thiazine-H in addition to two methylene, methylidene aromatic, and
two NH protons. Also, the mass spectrum of compound (4g; C28H22N2S)
showed a molecular ion peak at m/z = 418, which is the base peak in
the spectrum. Also, the following fragments were found in the mass
spectrum of (4g) at m/z: 419 (M+1; 29.2%), 420 (M+2; 10.5%), 386 (M-
sulphur; 4.3%), 359 (M-HNCS; 5.3%), 291 (M-naphthyl group; 63.1%),
232 (7.9%), 164 (14.5%), 141 (C10H7CH2; 96%), 127 (naphthyl; 32%),
217 (23.8%), 105 (1.5%), 92 (2.6%), and 77 (11.8%).
The formation of thiazine derivatives (4a–h) was assumed to proceed
according to the following mechanism (Scheme 3):
The structure of thiazine derivatives (4a–h) was established via the
following synthetic routes:
1. by ternary condensation of cyclopentanone (1), aromatic aldehyde,
and thiourea (1:2:1 molar ratio) in refluxing ethanol in the presence
of potassium hydroxide; and

Cyclopenta[d][1,3]thiazine Derivatives
1657
SCHEME 2
2. through the cyclocondensation of 2,5-diarylidene cyclopentanones
(5)19 with thiourea in an ethanolic solution in the presence of con-
centrated hydrochloric acid at a reflux temperature (Scheme 4).
The treatment of compound (4c) with chloroacetyl chloride in
dimethyl-formamide in the presence of anhydrous potassium carbonate
gave the corresponding 2-(dichloroacetyl)amino-4-(4-methylphenyl)-7-
(4-methyl-phenyl)methylidene-4,5,6,7-tetrahydrocyclopenta[d][1,3]th-
iazine (7). Condensed imidazole (6) was discarded on the basis of
analytical and spectral data. The infrared spectrum of compound
(7) exhibited νC
at 1725 cm−1 in addition to CH-aliph. The 1H
O
NMR spectrum in DMSO-d6 was characterized by the presence of a
N(COCH2Cl)2 moiety in addition to two methylenes, methylidene,
thiazine, and aromatic protons. In a similar manner, diacetylamino

1658
M. S. A. El-Gaby et al.
SCHEME 3
derivatives (8) were achieved by heating compound (4c) in acetic
anhydride (Scheme 5).
Antimicrobial Activity
All synthesized compounds were screened in vitro for their antimi-
crobial activities against two strains of bacteria, Staphylococcus au-
reus and Bacillus cereus, and two strains of fungi, Aspergillus funiga-
tus and Candida albicans, by agar diffusion techniques.20 The tested
SCHEME 4

Cyclopenta[d][1,3]thiazine Derivatives
1659
SCHEME 5
compounds were dissolved in N,N-dimethylformamide (DMF) to get a
solution of 1000 µg mL−1 concentration. The bacteria and fungi cul-
tures were maintained on nutrient agar and Czapek’s Dox agar media,
respectively. The agar media were incubated with different microor-
ganisms that were culture tested. After 24 h of incubation at 30◦C for
bacteria and 48 h of incubation at 28◦C for fungi, the diameter of the
inhibition zone (mm) was measured. Chloramphenicol and fungicide
Terbinafin were used as references.
The results indicated that most of the tested compounds exhibit mild
to strong activities. However, none of the tested compounds showed
superior activity over the reference (Table I).
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded (KBr) on a
Perkin Elmer 1650 spectrophotometer. 1H NMR spectra were recorded

1660
M. S. A. El-Gaby et al.
TABLE I Antimicrobial Activity of the Synthesized
Compounds and Inhibition Zones
Compound
no.
Staphylococcus
aureus
Bacillus
cereus
Aspergillus
funigatus
Candida
albicans
4a
4b
4c
4d
4e
4f
4g
4h
++
++
++
+
+
+
+
+
+ + +
+
+
++
+
++
+
+
+
++
+
++
+ + +
+
+
+
+
++
+
+
+
++
+
+
+
7
8
++
+ + +
+
+
+ + +
+ + ++
+
+
Reference
+ + ++
+ + ++
+ + ++
+: Less active (2–5 mm), ++: Moderately active (6–14 mm), + + +: Highly
active (15–20 mm).
on a Varian Gemini spectrometer 200 (200 MHz), using DMSO-d6
as a solvent and TMS as internal standard. Chemical shifts are ex-
pressed as δ ppm units. Mass spectra were recorded on a gas chro-
matographic GC-MS gp 1000 Ex Shimadzu instrument at 70 eV. Mi-
croanalytical data were obtained from the Microanalytical Data Unit
at Cairo University, Egypt. Physical data for synthesized compounds
are given in Table II. Also, the infrared spectral data are collected in
Table III.
2-Amino-4-aryl-7-arylmethylidene-4,5,6,7-
tetrahydrocyclopenta-[d][1,3]thiazines (4a–h): General
Procedure
Method A
A mixture of cyclopentanone 1 (0.01 mole), thiourea (0.01 mole), aro-
matic aldehyde (0.02 mole) in ethanol (30 mL), and concentrated hy-
drochloric acid (37%; 3 mL) was refluxed for 3 h. The solid product,
which separated on heating, was collected and recrystallized to give 4.
Method B
A mixture of 2,5-diarylidenecyclopentanone 5 (0.01 mole), thiourea
(0.01 mole) in ethanol (30 mL), and concentrated hydrochloric acid (37%;
3 mL) was refluxed for 3 h. The solid product, which separated on heat-
ing, was collected to give 4.

Cyclopenta[d][1,3]thiazine Derivatives
1661
TABLE II Physical Data for the Synthesized Compounds
Elemental analyses
C% H% N%
Compound
no.
M.P.
(◦C)
Yield (%)
(Color)
Molecular formula
(Mol. Wt.)
Solvent
Dioxane
4a
4b
4c
4d
4e
4f
4g
4h
7
140–141
168–169
170–172
230–233
306–308
246–248
240–243
258–259
138–139
166–168
88
(Brown)
83
(Red)
89
(Orange)
86
(Brown)
79
(Brown)
85
(Red)
80
(Yellow)
84
(Orange)
79
C20H16Cl2N2S
(387.40)
62.00 4.16 7.23
62.10 4.20 7.20
62.00 4.16 7.23
62.30 4.20 7.20
76.26 6.40 8.08
76.30 6.30 8.10
50.21 3.79 5.85
50.20 3.80 5.90
68.55 5.18 7.99
68.50 5.20 8.00
62.81 4.74 7.32
62.80 4.70 7.30
80.34 5.29 6.69
80.30 5.30 6.70
80.34 5.29 6.69
80.30 5.30 6.80
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Benzene
Benzene
C
20H16Cl2N2S
(387.40)
C22H22N2S
(346.49)
C
20H18Br2N2S
(478.44)
C
20H18N2O2S
(350.44)
C
20H18N2O4S
(382.44)
C
28H22N2S
(418.56)
C28H22N2S
(418.56)
C
26H24Cl2N2O2S 62.51 4.84 5.61
(Brown)
70
(Brown)
(499.53)
26H26N2O2S
(430.57)
62.50 4.90 5.60
72.53 6.87 6.50
72.60 6.90 6.51
8
C
Method C
A mixture of cyclopentanone 1 (0.01 mole), thiourea (0.01 mole), aro-
matic aldehyde (0.02 mole), and potassium hydroxide (0.12 mole) in
ethanol (30 mL) was refluxed for 3 h. The solid product, which sepa-
rated on heating, was collected to give 4.
TABLE III Infrared Spectra of the Synthesized Compounds
Compound
no.
ν
max/cm−1
4a
4b
4c
4d
4e
4f
4g
4h
7
3398, 3171 (2NH), 3062 (CH-arom.), 2949 (CH-aliph.), 1545 (C C)
3394, 3201 (2NH), 3085 (CH-arom.), 2923 (CH-aliph.), 1558 (C C)
3384, 3173 (2NH), 3019 (CH-arom.), 2920 (CH-aliph.), 1544 (C C)
3386, 3189 (2NH), 3085 (CH-arom.), 2916 (CH-aliph.), 1555 (C C)
3307, 3200 (NH/OH), 3079 (CH-arom.), 3950 (CH-aliph.), 1559 (C C)
3243 (broad; NH/OH), 3030 (CH-arom.), 1560 (C C)
3388, 3195 (2NH), 3062 (CH-arom.), 2922 (CH-aliph.), 1542 (C C)
3419, 3180 (2NH), 3092 (CH-arom.), 2993, 2914 (CH-aliph.), 1561 (C C)
3021 (CH-arom.), 2921 (CH-aliph.), 1725 (C O)
8
3021 (CH-arom.), 2922 (CH-aliph.), 1716 (C O)

1662
M. S. A. El-Gaby et al.
1H NMR spectrum (4a; DMSO-d6) (δ/ppm): 2.14, 2.91 (2s, 4H, 2CH2),
5.80 (s, 1H, thiazine-H), 6.72 (s, 1H, methylidene-H), 6.93–7.59 (m, 8H,
Ar-H), 9.39, 10.50 (2s, 2H, 2NH; exchangeable with D2O).
1H NMR spectrum (4b; DMSO-d6) (δ/ppm): 2.16, 2.85 (2s, 4H, 2CH2),
5.29 (s, 1H, thiazine-H), 6.96 (s, 1H, methylidene-H), 7.29–7.54 (m, 8H,
Ar-H), 9.08. 10.17 (2s, 2H, 2NH; exchangeable with D2O).
Compounds (4c–h) insoluble in DMSO-d6.
In the mass spectrum of compound (4h), a molecular ion peak was
observed at m/z = 418, which is the base peak in the spectrum.
2-(Dichloroacetyl)amino-4-(4-methylphenyl)-7-(4-
methylphenyl)-methylidene-4,5,6,7-
tetrahydrocyclopenta[d][1,3]thiazine (7)
To a solution of compound 4c (0.01 mole) and chloroacetyl chloride
(0.02 mole) in N,N-dimethylformamide (10 mL), anhydrous potassium
carbonate (2 g) was added and refluxed for 1 h. It then was allowed
to cool and was poured into cold water (50 mL). The solid product was
collected and recrystallized to give 7.
1H NMR spectrum (7; DMSO-d6) (δ/ppm): 1.25, 1.40 (2s, 6H, 2CH3),
2.27–2.34 (m, 4H, 2CH2), 3.99 (s, 4H, 2CH2CO), 4.28 (s, 1H, thiazine-H),
7.08–7.36 (m, 9H, Ar-H + methylidene-H).
2-(Diacetyl)amino-4-(4-methylphenyl)-7-(4-
methylphenyl)methyl-idene-4,5,6,7-
tetrahydrocyclopenta[d][1,3]thiazine (8)
A sample of compound 4c (0.01 mole) in acetic anhydride (10 mL) was
refluxed for 30 min and then allowed to cool. The solid product was
collected and recrystallized to give 8.
1H NMR spectrum (8; DMSO-d6) (δ/ppm): 1.92 (s, 6H, 2CH3), 2.22–
2.28 (m, 4H, 2CH2), 2.34 (s, 6H, 2COCH3), 5.20 (s, 1H, thiazine-H),
6.60–7.84 (m, 9H, Ar-H + methylidene-H).
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