Synthesis and physiological evaluation of new N-nitroso-2,6-dicarbethoxy-3, 5-diaryltetrahydro-1,4-thiazine-1,1-dioxides

Article abstract of DOI:10.1007/s00044-011-9729-7

A series of new N-nitroso-2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4- thiazine-1,1-dioxides 4a-r were synthesized and evaluated for antibacterial and antifungal activity. Most of them registered significant antibacterial and antifungal activity. The newly synthesized compounds have been characterized on the basis of elemental analysis, infrared, and nuclear magnetic resonance spectroscopic data. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9729-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2056–2063
DOI 10.1007/s00044-011-9729-7
ORIGINAL RESEARCH
Synthesis and physiological evaluation of new N-nitroso-2,6-
dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides
•
Naushad Edayadulla Penugonda Ramesh
Received: 27 December 2010 / Accepted: 21 June 2011 / Published online: 10 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of new N-nitroso-2,6-dicarbethoxy-
3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides 4a–r were
synthesized and evaluated for antibacterial and antifungal
activity. Most of them registered significant antibacterial
and antifungal activity. The newly synthesized compounds
have been characterized on the basis of elemental analysis,
infrared, and nuclear magnetic resonance spectroscopic
data.
Among the nitrogen heterocyclic compounds, N-nitroso
compounds are important because, they are the most ver-
satile chemical carcinogens known, serving as models for
almost every kind of human cancers (Lijinsky, 1992;
Pablo, 2009; Dennie et al., 2010; Yet Hua et al., 2011).
Therefore, we anticipated that the molecules containing
the hybrid structure resulting from the incorporation of
N-nitroso group into tetrahydrothiazine-1,1-dioxide core
might exhibit useful biological activity.
Keywords Thiazine ꢀ Antibacterial activity ꢀ
N-nitroso compounds
Tetrahydro-1,4-thiazine-1,1-dioxides exhibit a wide
range of biological activities (Srivastava et al., 2004;
Moriyama et al., 2004). Baliah and Rangarajan (1954) first
reported an elegant method of preparation of 3,5-diaryl-
tetrahydro-1,4-thiazine-1,1-dioxides by condensing sul-
phonyl diacetic acid with arylaldehydes in the presence of
ammonium acetate in acetic acid/ethanol as solvent.
Pandiarajan and Christopher Newton (1994) studied the
conformational behaviour of some substituted 1,4-thiazine-
1,1-dioxides by 1H nuclear magnetic resonance (NMR) and
13C NMR spectroscopic techniques.
Introduction
Heterocycles play an important role in biochemical pro-
cesses because the side groups of the most typical and
essential constituents of living cells, DNA and RNA are
based on aromatic heterocycles (Balaban et al., 2004).
Many organosulphur compounds exhibit diverse pharma-
cological activities of various types. Clinically useful
organosulphur compounds fall under aryl sulphonic
acid derivatives, phenothiazines, benzothiazipines and
1,2,4-benzothiadiazines. Another medicinally important
sulphur- and nitrogen-containing heterocyclic system is
tetrahydro-1,4-thiazine. Derivatives of tetrahydro-1,4-thia-
zine are associated with diverse pharmacological activities
(Katritzky, 1985; Barbachyn et al., 1996; Kumazawa et al.,
1997; Sundari et al., 2007; Muhammad et al., 2009).
In our present study, the required 2,6-dicarbethoxy-3,5-
diaryltetrahydro-1,4-thiazine-1,1-dioxides were prepared in
high yield by a modification of the procedure described by
Baliah and Rangarajan (1954) using water as reaction
medium in place of acetic acid for the first time. Direct
nitrosation with HNO2 afforded the N-nitroso compounds
4a–r (Scheme 1).
Results and discussions
N. Edayadulla ꢀ P. Ramesh (&)
All the synthesized compounds 4a–r answered positive
tests for nitrogen and sulphur and all of them have been
characterized by their spectroscopic data (IR, 1H NMR and
13C NMR). The IR spectrum of the 4a (a representative
Department of Natural Products Chemistry,
School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, Tamil Nadu, India
e-mail: npc_ramesh@yahoo.co.in
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Med Chem Res (2012) 21:2056–2063
2057
Scheme 1 Protocol for
synthesis of the title compounds
(4a–r)
example) displayed a band at 1039 cm-1 for N–N stretch-
ing and the presence of N=O group is evident from a band at
1446 cm-1 (Looney et al., 1957). The stretching bands at
1332 cm-1 (S=O unsymmetrical stretch) and 1121 cm-1
(S=O symmetrical stretch) revealed the presence of sul-
phone moiety (Silverstein et al., 1983).
The NMR (1H and 13C NMR) spectra of the synthesized
compounds 4a–r bear close resemblance in their spectral
characteristics. The 1H NMR spectrum of 4a (a representa-
tive example) displayed a triplet for six protons at d 1.03 and
a four-proton quartet at d 4.08 for methyl and methylene
groups of two ethoxycarbonyl groups, respectively. Of the
pair of doublets each integrating for two protons, the one at d
4.21(J = 10.2 Hz) is assigned to the enantiotopic protons,
H-2 & H-6 while the other one at d 4.70 (J = 10.5 Hz) is due
to the enantiotopic protons, H-3 & H-5. The magnitude of
the coupling constant is consistent with trans diaxial ori-
entation of H-2 & H-6 and H-3 & H-5 and suggests that the
heterocyclic ring adopts a rigid chair conformation. The
complex multiplet due to ten protons in the region d 7.44–
7.93 is associated with the aromatic protons of two phenyl
groups at C-3 and C-5. The 13C NMR spectrum of 4a reg-
istered only two signals for heterocyclic ring carbons at d
66.92 (C-3/C-5) and 73.78 (C-2/C-6) revealing high degree
of symmetry in the molecule. A comparison of the spec-
troscopic data (IR, 1H NMR and 13C NMR) of 4a with that of
3a disclosed that the 1H NMR spectrum of the former (4a)
was identical with that of the latter (3a) in all respects but for
the absence of one-proton broad signal (d 2.10) of the latter
due to NH proton. Thus, based on the above spectroscopic
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data, compound 4a has been characterized as N-nitroso-2,6-
dicarbethoxy-3,5-diphenyltetrahydro-1,4-thiazine-1,1-
dioxide.
Table 1 Antimicrobial activity of compounds 4a–r
Compound Zone of inhibition in mm at 10 lg/ml
no.
S.
aureus
S.
pyogenes coli
E.
P.
aeruginosa albicans
C.
In vitro antibacterial and antifungal activity
4a
11 (0.61) 15 (0.75) 12 (0.71) 13 (0.76)
9 (0.50) 10 (0.50) 13 (0.76) 12 (0.71)
11 (0.61) 8 (0.40) 14 (0.82) 10 (0.59)
10 (0.56) 10 (0.50) 13 (0.76) 12 (0.71)
12 (0.67) 9 (0.45) 14 (0.82) 15 (0.88)
13 (0.72) 17 (0.85) 17 (1.0) 11 (0.65)
11 (0.61) 13 (0.65) 12 (0.71) 18 (1.11)
13 (0.69)
16 (0.84)
15 (0.79)
16 (0.84)
13 (0.69)
12 (0.63)
13 (0.69)
11 (0.58)
14 (0.74)
20 (1.11)
14 (0.74)
12 (0.63)
15 (0.79)
11 (0.58)
10 (0.53)
18 (0.95)
15 (0.79)
14 (0.74)
–
4b
Biochemical studies help to test the efficacy and existing
toxicity of the compounds that possess antimicrobial
properties. In search of new antimicrobial compounds, we
have synthesized, a series of N-nitroso-2,6-dicarbehoxy-
3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide, 4a–r and
screened them for their in vitro antibacterial and antifungal
activity using disc diffusion method (Barry, 1976;
Chandrasekaran et al., 2005). Antibacterial activity of the
compounds 4a–r has been evaluated against microbial
strains of two Gram-positive (Staphylococcus aureus
MTCC 96 & Streptococcus pyogenes MTCC 389), two
Gram-negative bacteria (Pseudomonas aeruginosa ATCC
2853 & Escherichia coli MTCC 722), and one fungi
(Candida albicans MTCC 227). Amikacin (the antibacte-
rial drug) and nystatin (the antifungal drug) were used as
standards for comparison. The activity was measured as a
function of zone of inhibition in mm and the results were
compared with those of the reference drug by measuring
their zone of inhibition and activity index (Table 1).
4c
4d
4e
4f
4g
4h
11 (0.61) 17 (0.85) 17 (1.0)
9 (0.53)
4i
12 (0.67) 11 (0.55) 15 (0.88) 10 (0.59)
17 (0.94) 15 (0.75) 13 (0.76) 14 (0.82)
15 (0.83) 9 (0.45) 14 (0.82) 13 (0.76)
13 (0.72) 11 (0.55) 10 (0.59) 9 (0.53)
14 (0.78) 8 (0.40) 12 (0.71) 11 (0.65)
13 (0.72) 14 (0.70) 11 (0.65) 12 (0.71)
9 (0.50 11 (0.55) 8 (0.47) 12 (0.71)
14 (0.78) 12 (0.60) 9 (0.53) 10 (0.59)
8 (0.44) 9 (0.45) 12 (0.71) 11 (0.65)
12 (0.67) 8 (0.40) 13 (0.76) 11 (0.65)
4j
4k
4l
4m
4n
4o
4p
4q
4r
Amikacin
Nystatin
18
–
20
–
17
–
17
–
19
Zone of growth inhibition (mm) (activity index)
The antibacterial screening data revealed that all the
tested compounds showed moderate to good antibacterial
activity as compared to that of the standard. Compounds 4j,
4k, 4m and 4p showed significant inhibition in the order
4j [ 4k [ 4m = 4p against S. aureus, whereas com-
pounds 4f, 4h, 4a and 4j showed significant inhibition in
the order 4f = 4h [ 4a = 4j against S. pyogenes, com-
pounds 4g, 4e and 4j registered significant activity against
P. aeruginosa in the order 4g [ 4e [ 4j; of these, 4g
showed greater activity than that of the standard; 4f, 4h, 4i
4c, 4e, 4k showed significant inhibition in the order
4f = 4h [ 4i [ 4c = 4e = 4k against E. coli; of these 4f
and 4h registered comparable activity to that of the stan-
dard. Of all compounds of this series, 4j showed most
significant activity against Gram-positive strains and 4e
against Gram-negative strains. Compound 4g registered
excellent inhibitory activity against P. aeruginosa. Overall,
antibacterial activity of the synthesized compounds 4a–r is
significant as compared to that of the standard (amikacin).
Screening of above compounds at a concentration of
10 lg/ml for antifungal activity by the same methodology
was carried out against the fungal strain, Candida albicans
using nystatin as a control. Substitution by thiophen-2-yl
(4j) group results in an increase in activity and the activity
index is greater than one. Compounds 4j, 4p, 4d, 4b, 4c,
4m and 4q have emerged as moderately effective anti-
fungal agents against C. albicans. Overall, the antifungal
(Activity index) = Inhibition zone of the compound/Inhibition zone
of the standard drug
activity of synthesized compounds is significant as com-
pared to that of the nystatin. The results of antimicrobial
activity of the tested compounds are listed in Table 1.
Acute toxicity studies (LD50 determination)
Acute toxicity studies were undertaken to assess the lethal
dose 50 (LD50) of the compound. LD50 of a synthetic drug
is determined as per OECD (Organization for Economic
Co-operation and Development) guidelines. The observed
values of LD50 revealed that the active compounds were
non-toxic to mice even at a dose of 300 mg/kg.
Experimental section
General procedures
Melting points were recorded in open capillary tube and are
uncorrected. IR spectra were recorded in KBr on a 8400S
Shimadzu FT-IR Spectrophotometer and NMR spectra were
scanned on a Bruker 300 MHz Spectrometer in CDCl3/
DMSO-d6 using TMS as internal standard. The chemical
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Med Chem Res (2012) 21:2056–2063
2059
shifts are cited in d-scale. Elemental analyses were carried
out on Perkin-Elmer 2400 Series-II instrument. Purity of
synthesized compounds was checked by TLC using silica
gel-G and spots were detected in an iodine chamber.
(7 ml) containing conc. hydrochloric acid (1 ml) and water
(1 ml), solid sodium nitrite (0.03 mol) was added in por-
tions during 0.5 h and the stirring was continued for
another 0.5 h. After the completion of the reaction, the
organic layer was washed with water and dried over
anhydrous calcium chloride. The products 4a–r that
obtained on removal of the solvent were crystallized from
ethanol–ethyl acetate mixture (1:2 v/v).
Synthesis of diethyl 2,20-sulphonyldiacetate, 2 (Kwan
et al., 1989)
To a stirred solution of diethyl 2,20-thiodiacetate 1 (1.0 mol)
in methanol (20 ml) containing a pinch of selenium dioxide,
30% H2O2 (10 ml) was added dropwise and stirring con-
tinued while maintaining the temperature of the reaction
mixture at 20°C for about 2 h. The contents were extracted
with dichloromethane (3 9 25 ml) and removal of the sol-
vent afforded diethyl 2,20-sulphonyldiacetate 2 as thick oil.
Yield: 88%; 1H NMR (300 MHZ, CDCl3): d 1.36 (t, 6H,
–OCH2CH3), 4.32 (q, 4H, –OCH2CH3), 4.39 (s, 4H, CH2).
N-nitroso-2,6-dicarbethoxy-3,5-diphenyltetrahydro-1,4-
thiazine-1,1-dioxide (4a)
Colourless solid; m.p. 163°C (aq. alcohol); yield: 81%;
IR (KBr) mmax (cm-1): 1734 (ester C=O), 1332 (S=O
unsym. str.), 1121 (S=O sym. str.), 1446 (N=O), 1039
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.03 (t, 6H,
–OCH2CH3), 4.08 (q, 4H, –OCH2CH3), 4.21 (d, 2H,
J = 10.2 Hz, H-2/H-6), 4.70 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.44–7.93 (m, 10H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 18.56 (OCH2CH3), 66.92 (C-3, C-5),
67.49 (OCH2CH3), 73.78 (C-2, C-6), 127.26, 128.56,
133.47, 148.44 (ipso carbon), 153.12, 165.79 (C=O of
ester). Anal. calcd.for C22H24N2O7S: C, 57.38; H, 5.25; N,
6.08%. Found C, 57.18; H, 5.18; N, 5.88%.
General procedure for the synthesis of 2,6-
dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-
dioxides (3a–r)
A mixture of diethyl 2,20-sulphonyldiacetate 2 (0.01 mol),
aromatic aldehydes a–r (0.02 mol), ammonium acetate
(0.02 mol) and a few drops of alcohol were made as a
homogeneous paste. Then it was stirred with 10 ml of water
at room temperature for about 3 h and left overnight. The
reaction mixture was diluted with excess of water. The solid
that separated was filtered, washed with water and dried;
crystallization from aqueous alcohol gave pure 2,6-dicar-
bethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides,
3a–r.
N-nitroso-2,6-dicarbethoxy-3,5-bis(2-
chlorophenyl)tetrahydro-1,4-thiazine-1,1- dioxide (4b)
Creamy white solid; m.p.182°C (aq. alcohol); yield:78%.
IR (KBr) mmax (cm-1): 1736 (ester C=O), 1321 (S=O
unsym. str.), 1124 (S=O sym. str.), 1453 (N=O), 1044
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.04 (t, 6H,
2,6-dicarbethoxy-3,5-diphenyltetrahydro-1,4-thiazine-1,1-
dioxide (3a)
–OCH2CH3), 4.11 (q, 4H, –OCH2CH3), 4.28 (d, 2H,
J = 10.2 Hz, H-2/H-6), 4.72 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.77–8.11 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 19.08 (OCH2CH3), 66.25 (C-3, C-5),
67.42 (OCH2CH3), 74.52 (C-2, C-6), 128.90, 128.63,
135.12, 150.06 (ipso carbon), 165.06 (C=O of ester). Anal.
calcd.for C22H22Cl2N2O7S: C, 49.91; H, 4.19; N, 5.29%.
Found C, 49.72; H, 4.08; N, 5.18%.
Colourless solid; m.p. 183–184°C (aq. alcohol); yield: 92%.
IR (KBr) mmax (cm-1): 3328 (NH str.), 1730 (ester C=O),
1323 (S=O unsym. str.), 1129 (S=O sym. str.). H NMR
1
(300 MHZ, CDCl3): d 1.02 (t, 6H, –OCH2CH3), 2.10 (s,
1H, NH) 4.08 (q, 4H, –OCH2CH3), 4.22 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.72 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.24–7.44 (m, 10H, Ar-H). 13C NMR (75 MHz): d
13.72 (OCH2CH3), 61.94 (C-3, C-5), 62.49 (OCH2CH3),
72.69 (C-2, C-6), 127.87, 128.78, 129.12, 130.33, 137.70
(ipso carbon), 161.09 (C=O of ester).
N-nitroso-2,6-dicarbethoxy-3,5-bis(3-
chlorophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4c)
Colourless solid; m.p. 127°C (aq. alcohol); yield: 79%.
IR (KBr) mmax (cm-1): 1738 (ester C=O), 1326 (S=O
unsym. str.), 1118 (S=O sym. str.), 1448 (N=O), 1039
General procedure for the synthesis of N-nitroso-2,6-
dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-
dioxide (4a–r)
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.03 (t, 6H,
–OCH2CH3), 4.10 (q, 4H, –OCH2CH3), 4.25 (d, 2H,
J = 10.2 Hz, H-2/H-6), 4.78 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.72–8.11 (m, 8H, Ar-H). 13C NMR (75 MHz,
To a stirred solution of 2,6-dicarbethoxy-3,5-diaryltetrahy-
dro-1,4-thiazine-1,1-dioxides3a–r(0.03 mol)inchloroform
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Med Chem Res (2012) 21:2056–2063
CDCl3 ? DMSO): d 19.68 (OCH2CH3), 66.12 (C-3, C-5),
67.33 (OCH2CH3), 74.49 (C-2, C-6), 129.07, 129.75,
135.23, 149.51 (ipso carbon), 164.48 (C=O of ester). Anal.
calcd.for C22H22Cl2N2O7S: C, 49.91; H, 4.19; N, 5.29%.
Found C, 49.69; H, 4.12; N, 5.11%.
calcd.for C22H22N4O11S: C, 48.00; H, 4.03; N, 10.18%.
Found C, 47.95; H, 3.95; N, 10.12%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(4-
methoxyphenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4g)
N-nitroso-2,6-dicarbethoxy-3,5-bis(4-
chlorophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4d)
Colourless solid; m.p. 139°C (aq. alcohol); yield: 72%.
IR (KBr) mmax (cm-1): 1745 (ester C=O), 1328 (S=O
unsym. str.), 1114 (S=O sym. str.), 1451 (N=O), 1042
1
Colourless solid; m.p. 196°C (aq. alcohol); yield: 82%.
IR (KBr) mmax (cm-1): 1726 (ester C=O), 1328 (S=O
unsym. str.), 1122 (S=O sym. str.), 1436 (N=O), 1044 (N–N
str.). 1H NMR (300 MHZ, CDCl3): d 1.04 (t, 6H,
–OCH2CH3), 4.12 (q, 4H, –OCH2CH3), 4.27 (d, 2H,
J = 10.2 Hz, H-2/H-6), 4.71 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.69-8.18 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 19.12 (OCH2CH3), 67.02 (C-3, C-5),
67.48 (OCH2CH3), 73.88 (C-2, C-6), 129.10, 129.72,
134.12, 149.12 (ipso carbon), 164.80 (C=O of ester). Anal.
calcd.for C22H22Cl2N2O7S: C, 49.91; H, 4.19; N, 5.29%.
Found C, 49.74; H, 4.07; N, 5.19%.
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.04 (t, 6H,
–OCH2CH3), 3.74 (s, 6H, –OCH3) 4.08 (q, 4H, –OCH2CH3),
4.21 (d, 2H, J = 10.2 Hz, H-2/H-6), 4.73 (d, 2H,
J = 10.5 Hz, H-3/H-5), 7.63-8.39 (m, 8H, Ar-H). 13C
NMR (75 MHz, CDCl3 ? DMSO): d 18.79 (OCH2CH3),
66.00 (OCH3), 67.25 (C-3, C-5), 67.43 (OCH2CH3), 74.81
(C-2, C-6), 128.42, 128.63, 134.09, 149.83 (ipso carbon),
152.49, 166.34 (C=O of ester). Anal. calcd.for
C24H28N2O9S: C, 55.38; H, 5.42; N, 5.38%. Found C,
55.26; H, 5.25; N, 5.32%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(4-
methylphenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4h)
N-nitroso-2,6-dicarbethoxy-3,5-bis(3-
nitrophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4e)
Colourless solid; m.p. 145°C (aq. alcohol); yield: 76%.
IR (KBr) mmax (cm-1): 1732 (ester C=O), 1324 (S=O
unsym. str.), 1122 (S=O sym. str.), 1448 (N=O), 1046
Pale yellow solid; m.p. 166°C (aq. alcohol); yield: 80%.
IR (KBr) mmax (cm-1): 1738 (ester C=O), 1323 (S=O
unsym. str.), 1132 (S=O sym. str.), 1453 (N=O), 1046
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.05 (t, 6H,
1
–OCH2CH3), 2.30 (s, 6H, CH3), 4.10 (q, 4H, –OCH2CH3),
4.27 (d, 2H, J = 10.5 Hz, H-2/H-6), 4.88 (d, 2H,
J = 10.5 Hz, H-3/H-5), 7.66–8.18 (m, 8H, Ar-H). 13C
NMR (75 MHz, CDCl3 ? DMSO): d 18.54 (OCH2CH3),
23.32 (CH3), 67.94 (C-3, C-5), 68.33 (OCH2CH3), 74.82
(C-2, C-6), 127.75, 128.17, 133.12, 148.51 (ipso carbon),
164.89 (C=O of ester). Anal. calcd.for C24H28N2O7S: C,
59.00; H, 5.78; N, 5.73%. Found C, 58.91; H, 5.65; N,
5.62%.
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.08 (t, 6H,
–OCH2CH3), 4.14 (q, 4H, –OCH2CH3), 4.31 (d, 2H,
J = 10.2 Hz, H-2/H-6), 4.81 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.81–8.22 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 19.68 (OCH2CH3), 66.94 (C-3, C-5),
67.12 (OCH2CH3), 74.52 (C-2, C-6), 128.88, 129.10,
134.78, 148.18 (ipso carbon), 165.19 (C=O of ester). Anal.
calcd.for C22H22N4O11S: C, 48.00; H, 4.03; N, 10.18%.
Found C, 47.91; H, 3.99; N, 10.10%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(phur-2-yl)tetrahydro-
1,4-thiazine-1,1-dioxide (4i)
N-nitroso-2,6-dicarbethoxy-3,5-bis(4-
nitrophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4f)
Pale brown solid; m.p. 167°C (aq. alcohol); yield: 69%.
IR (KBr) mmax (cm-1): 1736 (ester C=O), 1330 (S=O
unsym. str.), 1118 (S=O sym. str.), 1454 (N=O), 1042
Pale yellow solid; m.p. 203°C (aq. alcohol); yield: 83%.
IR (KBr) mmax (cm-1): 1734 (ester C=O), 1328 (S=O
unsym. str.), 1122 (S=O sym. str.), 1450 (N=O), 1038
1
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.11 (t, 6H,
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.07 (t, 6H,
–OCH2CH3), 4.12 (q, 4H, –OCH2CH3), 4.32 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.81 (d, 2H, J = 10.5 Hz, H-3/H-
5), 6.56–7.42 (m, 6H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 18.11 (OCH2CH3), 66.23 (C-3, C-5),
67.11 (OCH2CH3), 73.12 (C-2, C-6), 112.14, 114.23,
141.58, 150.12 (ipso carbon), 164.77 (C=O of ester). Anal.
–OCH2CH3), 4.13 (q, 4H, –OCH2CH3), 4.30 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.81 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.78–8.16 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 20.09 (OCH2CH3), 67.01 (C-3, C-5),
67.86 (OCH2CH3), 74.19 (C-2, C-6), 128.90, 129.75,
136.06, 150.51 (ipso carbon), 166.06 (C=O of ester). Anal.
123

Med Chem Res (2012) 21:2056–2063
2061
calcd.for C18H20N2O9S: C, 49.09; H, 4.58; N, 6.36%.
Found C, 49.01; H, 4.47; N, 6.29%.
calcd.for C20H22N4O7S: C, 51.94; H, 4.79; N, 12.11%.
Found C, 51.81; H, 4.67; N, 12.04%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(pyridin-3-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4m)
N-nitroso-2,6-dicarbethoxy-3,5-bis(thiophen-2-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4j)
Pale brown solid; m.p. 198–200°C (aq. alcohol); yield:
83%.
Colourless solid; m.p. 156–157°C (aq. alcohol); yield:
74%.
IR (KBr) mmax (cm-1): 1732 (ester C=O), 1326 (S=O
unsym. str.), 1130 (S=O sym. str.), 1450 (N=O), 1038
IR (KBr) mmax (cm-1): 1730 (ester C=O), 1326 (S=O
unsym. str.), 1124 (S=O sym. str.), 1450 (N=O), 1034
1
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.03 (t, 3H,
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.13 (t, 6H,
–OCH2CH3), 4.09 (q, 2H, –OCH2CH3), 4.27 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.79 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.29–8.12 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 18.84 (OCH2CH3), 65.67 (C-3, C-5),
66.98 (OCH2CH3), 73.55 (C-2, C-6), 128.33, 129.34,
144.78 (ipso carbon), 166.78 (C=O of ester). Anal.
calcd.for C20H22N4O7S: C, 51.94; H, 4.79; N, 12.11%.
Found C, 51.79; H, 4.77; N, 12.01%.
–OCH2CH3), 4.19 (q, 4H, –OCH2CH3), 4.30 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.83 (d, 2H, J = 10.5 Hz, H-3/H-
5), 6.66–7.39 (m, 6H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 18.07 (OCH2CH3), 66.12 (C-3, C-5),
67.26 (OCH2CH3), 74.08 (C-2, C-6), 125.52, 126.12,
141.26 (ipso carbon), 164.18 (C=O of ester). Anal.
calcd.for C18H20N2O7S3: C, 45.75; H, 4.27; N, 5.93%.
Found C, 45.59; H, 4.22; N, 5.79%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(1H pyrrole-2-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4n)
N-nitroso-2,6-dicarbethoxy-3,5-bis(thiophen-3-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4k)
Pale grey solid; m.p. 129°C (aq. alcohol); yield: 77%.
IR (KBr) mmax (cm-1):1737 (ester C=O), 1328 (S=O
unsym. str.), 1120 (S=O sym. str.), 1444 (N=O), 1046
Colourless solid; m.p. 168°C (aq. alcohol); yield: 80%.
IR (KBr) mmax (cm-1): 1739 (ester C=O), 1334 (S=O
unsym. str.), 1120 (S=O sym. str.), 1448 (N=O), 1040
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.03 (t, 6H,
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.03 (t, 6H,
–OCH2CH3), 2.1 (broad s, 1H, NH) 4.12 (q, 4H,
–OCH2CH3), 4.27 (d, 2H, J = 10.5 Hz, H-2/H6), 4.80 (d,
2H, J = 10.5 Hz, H-3/H-5), 6.25–6.59 (m, 6H, Ar-H). 13C
NMR (75 MHz, CDCl3 ? DMSO): d 19.12 (OCH2CH3),
66.12 (C-3, C-5), 67.11 (OCH2CH3), 73.54 (C-2, C-6),
111.21, 115.22, 126.2, 141.81 (ipso carbon), 164.06 (C=O
of ester). Anal. calcd.for C18H22N4O7S: C, 49.31; H, 5.06;
N, 12.78%. Found C, 49.21; H, 4.97; N, 12.63%.
–OCH2CH3), 4.15 (q, 4H, –OCH2CH3), 4.28 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.78 (d, 2H, J = 10.5 Hz, H-3/H-
5), 6.72–7.28 (m, 6H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 18.67 (OCH2CH3), 65.77 (C-3, C-5),
67.22 (OCH2CH3), 73.86 (C-2, C-6), 126.21, 126.76,
140.21 (ipso carbon), 165.11 (C=O of ester). Anal.
calcd.for C18H20N2O7S3: C, 45.75; H, 4.27; N, 5.93%.
Found C, 45.66; H, 4.17; N, 5.84%.
N-nitroso-2,6-dicarbethoxy-3,5-bis(1,3-benzodioxol-6-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4o)
N-nitroso-2,6-dicarbethoxy-3,5-bis(pyridin-2-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4l)
Pale yellow solid; m.p. 216–218°C (aq. alcohol); yield:
81%.
Pale brown solid; m.p. 108–110°C (aq. alcohol); yield:
85%.
IR (KBr) mmax (cm-1): 1738 (ester C=O), 1312 (S=O
unsym. str.), 1130 (S=O sym. str.), 1442 (N=O), 1038
IR (KBr) mmax (cm-1): 1732 (ester C=O), 1328 (S=O
unsym. str.), 1128 (S=O sym. str.), 1454 (N=O), 1044 (N–N
str.). 1H NMR (300 MHZ, CDCl3): d 1.11 (t, 6H,
–OCH2CH3), 4.22 (q, 4H, –OCH2CH3), 4.31 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.84 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.31–8.28 (m, 8H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 17.68 (OCH2CH3), 66.14 (C-3, C-5),
67.12 (OCH2CH3), 74.12 (C-2, C-6), 127.90, 128.75,
129.12, 144.51 (ipso carbon), 166.33 (C=O of ester). Anal.
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.05 (t, 6H,
–OCH2CH3), 4.12 (q, 4H, –OCH2CH3), 4.31 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.82 (d, 2H, J = 10.5 Hz, H-3/H-
5), 6.04 (s, 4H, –OCH2O–), 6.89–7.69 (m, 6H, Ar-H). 13C
NMR (75 MHz, CDCl3 ? DMSO): d 18.68 (OCH2CH3),
65.86 (C-3, C-5), 67.12 (OCH2CH3), 74.11 (C-2, C-6),
101.2 (–OCH2O–), 125.32, 129.85, 148.12 (ipso carbon),
165.11 (C=O of ester). Anal. calcd.for C24H24N2O11S: C,
123

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Med Chem Res (2012) 21:2056–2063
52.55; H, 4.41; N, 5.11%. Found C, 52.38; H, 4.36; N,
5.02%.
53.79; H, 5.56; N, 4.82%. Found C, 53.68; H, 5.39; N,
4.69%.
Acknowledgment The authors thank the Department of Science
and Technology, New Delhi for providing a high resolution NMR
spectrometer under IRHPA programme and Bose Clinical Laboratory,
Madurai for antimicrobial screening.
N-nitroso-2,6-dicarbethoxy-3,5-bis(2-chloroquinolin-3-
yl)tetrahydro-1,4-thiazine-1,1-dioxide (4p)
Pale yellow solid; m.p. 228°C (aq. alcohol); yield: 93%.
IR (KBr) mmax (cm-1): 1741 (ester C=O), 1333 (S=O
unsym. str.), 1122 (S=O sym. str.), 1446 (N=O), 1038
References
1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.05 (t, 6H,
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–OCH2CH3), 4.12 (q, 4H, –OCH2CH3), 4.24 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.71(d, 2H, J = 10.5 Hz, H-3/H-
5), 7.67–8.16 (m, 10H, Ar-H). 13C NMR (75 MHz,
CDCl3 ? DMSO): d 19.09 (OCH2CH3), 65.27 (C-3, C-5),
67.32 (OCH2CH3), 73.12 (C-2, C-6), 129.11, 129.87,
132.34, 139.11, 143.12, 152.33, 166.22 (C=O of ester).
Anal. calcd.for C28H24Cl2N4O7S: C, 53.26; H, 3.83; N,
8.87%. Found C, 53.18; H, 3.76; N, 8.79%.
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N-nitroso-2,6-dicarbethoxy-3,5-bis(1H-indol-2-
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Creamy white solid; m.p. 164°C (aq. alcohol); yield: 77%.
IR (KBr) mmax (cm-1): 1738 (ester C=O), 1340 (S=O
unsym. str.), 1132 (S=O sym. str.), 1456 (N=O), 1048
1
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(N–N str.). H NMR (300 MHZ, CDCl3): d 1.07 (t, 6H,
–OCH2CH3), 4.12 (q, 4H, –OCH2CH3), 4.29 (d, 2H,
J = 10.5 Hz, H-2/H-6), 4.88 (d, 2H, J = 10.5 Hz, H-3/H-
5), 7.12–7.78 (m, 10H, Ar-H), 11.02 (s, 2H, indole-NH).
13C NMR (75 MHz, CDCl3 ? DMSO):
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d
18.22
(OCH2CH3), 66.11 (C-3, C-5), 67.18 (OCH2CH3), 74.11
(C-2, C-6), 114.11, 115.12,116.78, 122.12, 129.90, 130.12,
131.12, 139.18 165.18 (C=O of ester). Anal. calcd.for
C26H26N4O7S: C, 57.98; H, 4.87; N, 10.40%. Found C,
57.88; H, 4.69; N, 10.22%.
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dimethoxyphenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4r)
Colourless solid; m.p. 158°C (aq. alcohol); yield: 84%.
IR (KBr) mmax (cm-1): 1732 (ester C=O), 1327 (S=O
unsym. str.), 1125 (S=O sym. str.), 1449 (N=O), 1033
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1
(N–N str.). H NMR (300 MHZ, CDCl3): d 1.09 (t, 6H,
–OCH2CH3), 3.84 (s, 6H, –OCH3), 3.88 (s, 6H, –OCH3),
4.12 (q, 4H, –OCH2CH3), 4.31 (d, 2H, J = 10.5 Hz, H-2/
H-6), 4.84 (d, 2H, J = 10.5 Hz, H-3/H-5), 7.69–8.09 (m,
6H, Ar-H). 13C NMR (75 MHz, CDCl3 ? DMSO): d 18.11
(OCH2CH3), 60.12, 60.16, 65.12 (C-3, C-5), 67.12
(OCH2CH3), 72.11 (C-2, C-6), 114.12,116.12, 129.12,
131.34, 132.98, 140.34 (ipso carbon), 151.09, 152.66,
166.04 (C=O of ester). Anal. calcd.for C26H24N2O11S: C,
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123