Synthesis of novel anti-bacterial 2,1-benzothiazine 2,2-dioxides derived from methyl anthranilate

Article abstract of DOI:10.4067/S0717-97072011000100001

A convenient ultrasound assisted synthesis of new anti-bacterial N-benzylidene-N'-(1-methyl-2, 2-dioxo-2,3-dihydro-1H-2?6-benzo[c][1,2]thiazin-4- ylidene)-hydrazines from methyl anthranilate is reported. Methyl anthranilate was reacted with methane sulfon

Full text of DOI:10.4067/S0717-97072011000100001

J. Chil. Chem. Soc., 56, Nº 1 (2011)
SYNTHESIS OF NOVEL ANTI-BACTERIAL 2,1-BENZOTHIAZINE 2,2-DIOXIDES DERIVED
FROM METHYL ANTHRANILATE
MUHAMMAD SHAFIQ1, MUHAMMAD ZIA-UR-REHMAN2*, ISLAM ULLAH KHAN1,
MUHAMMAD NADEEM ARSHAD1, SIRAJ AHMED KHAN3
1Materials Chemistry Laboratory, Department of Chemistry, Government College University; Lahore-54000, Pakistan
2Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore-54600, Pakistan
3Microbiology Laboratories, Qarshi Research International, Hattar, Pakistan
(Received: October 14, 2010 - Accepted: January 26, 2011)
ABSTRACT
A convenient ultrasound assisted synthesis of new anti-bacterial N-benzylidene-N’-(1-methyl-2, 2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-
hydrazines from methyl anthranilate is reported. Methyl anthranilate was reacted with methane sulfonyl chloride, followed by N-alkylation and subsequent base
catalyzed cyclization. Hydrazinolysis of the cyclized products followed by their ultrasound mediated condensations with different benzaldehydes yielded the title
compounds. Some of these compounds showed good anti-bacterial activity against Pseudomonas aeruginosa, Salmonella typhimurium and Staphylococcus aureus.
Key Words: 2,1-Benzothiazine 2,2-dioxides, Schiff bases, Anti-bacterial activity, Methyl anthranilate.
INTRODUCTION
Sulfonamides are well known for their enormous potential as
pharmaceutical and agricultural agents due to their versatile nature of biological
activities1 while cyclic sulfonamides are important as chiral auxiliaries2,3 and
therapeutic compounds4,5. Among these, benzothiazines, due to their diverse
biological activities are gaining much attention since the very first synthesis
by Braun et al6. Many of the benzothiazine based drugs e.g., Piroxicam®,
Droxicam® and Lornoxicam® (Fig 1) are now-a-days in the market due to their
effective role as analgesic and anti-inflammatory agents.
Figure 2: 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives
Carbohydrazides are becoming popular day by day in the field of drug
development due to their easy cyclization and condensations9. Up till now,
a large number of such compounds have been synthesized with significant
antimicrobialactivities10,11. In continuation of our on-going research on various
biologically active benzothiazine derivatives12-14, synthesis of N-benzylidene-
N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-
hydrazines has been carried out to get a series of possible biologically active
Figure 1: Examples of some benzothiazine based drugs
compounds. Besides, characterization of the newly synthesized compounds
through spectroscopic techniques and single crystal X-ray analysis, these were
2,1-Benzothiazine 2,2-dioxides are now becoming important and are being
also subjected to the preliminary evaluation for their anti-bacterial potential
reported in literature due to their applications in the synthesis of medicinally
due to their carbohydrazide functionalities10,11
.
important natural products and new chiral ligands for catalysis and molecular
recognition7. Among these, 3,4-dihydro-2,1-benzothiazine 2,2-dioxide
derivatives have been reported to possess potent biological activities such as
lipoxygenase inhibition and are being used as drugs for treating heart diseases8
(Fig. 2).
Figure 3: Synthesis of N-benzylidene-N’-(1-methyl-2, 2-dioxo-2,3-
dihydro-1H-2λ6- benzo[c][1,2]thiazin-4-ylidene)-hydrazines
e-mail: rehman_pcsir@hotmail.com
527

J. Chil. Chem. Soc., 56, Nº 1 (2011)
and ethanol (200 ml) was allowed to react at 45oC in an ultrasound reaction bath
for a period of 35 minutes. After completion of the reaction, excess hydrazine
and solvent were removed under vacuum. The crude product obtained was
washed with water and dried. Light brown solid; Yield: 88%; M.p. 139-141oC.
1H NMR (CDCl3) δ: 3.37 (s, 3H, N-CH3), 4.50 (s, 2H, CH2), 5.21 (s, 2H, NH2),
6.88-7.92 (m, 4H, ArH). IR (KBr): 3410, 1680, 1384, 1160 cm-1; MS m/z:
225.03 [M+]; Anal. calcd for C9H11N3SO2: C, 48.00; H, 4.89; N, 18.67; Found:
C, 48.01; H, 4.90; N, 18.68.
EXPERIMENTAL
All the chemicals were purchased from E. Merck, BDH or Fluka and used
without purification. However, solvents were purified through distillation. H
1
NMR spectra were recorded on a Bruker DPX-400 instrument at 400 MHz.
Chemical shifts are reported in ppm referenced to the residual solvent signal.
Melting points were recorded on an electrothermal (Griffin 1090) apparatus
and are reported as uncorrected. IR spectra were recorded on a Perkin Elmer
1600-FT spectrometer. Mass spectra were taken on a Jeol SX-102 instrument.
Ultrasonic mediated reactions were carried out in Clifton Ultrasonic Bath (2 x
T2A, 300W, DU-4) made by Nickel Electro Ltd, Weston-S-Mare Somerset,
England.
(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-hydrazine (5b):
Yellow needle like crystalline compound was prepared using procedure
employed for 5a. Yield: 74%; M.p. 178-179 ºC; 1H NMR (CDCl3) δ: 3.39 (s,
3H, NCH3), 4.46 (s, 2H, CH2), 5.15 (s, 2H, NH2), 6.92-8.10 (m, 3H, ArH). IR
(KBr): 3415, 1685, 1380, 1155 cm-1; MS m/z: 303 [M+], 305 [M++2]; Anal.
calcd for C H N3SO2Br: C, 35.53; H, 3.29; N, 13.82; Found: C, 35.50; H,
3.32; N, 13.9791.0
N-(2-Acetylphenyl)methanesulfonamide (2a):
A mixture of methanesulfonyl chloride (0.55g; 4.8 mmoles), methyl
anthranilate (0.72g; 4.8 mmoles) and dichloromethane (30 ml) was allowed
to react in an ultrasonic bath at 40oC for a period of 30 minutes till the
completion of reaction (as indicated by TLC). The contents were washed twice
with water and dried. Evaporation of the solvent under vacuum followed by
recrystallization of the crude product from ethanol afforded white crystalline
solid. Yield: 90%. M.p. 88-89ºC (Lit M.p. 89-90oC)15; IR (KBr) cm-1: 3248,
3049, 1740, 1342, 1244.
General procedure for the synthesis of N-benzylidene-N’-(1-methyl-
2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazines
(6a-o)
(Using thermal conditions):
A
mixture of (1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-hydrazine (5a) or (6-bromo-1-methyl-2,2-dioxo-2,3-
dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (5b) (2.0 mmol),
corresponding aromatic aldehyde (2.0 mmol), methanol (50 ml) and glacial
acetic acid (2 drops) was refluxed till completion of the reaction (for yields,
reaction conditions & reaction times, see Table 1). The contents were cooled
to 5oC in an ice bath, filtered and the solids were washed with cold methanol to
get the pure compound.
N-(2-Acetyl-4-bromophenyl)methanesulfonamide (2b):
A mixture of methanesulfonyl chloride (0.55 g; 4.8 mmol), 1-(2-amino-
5-bromophenyl)ethanone (1.10 g; 4.8 mmoles) and dichloromethane (10 ml)
was allowed to react in an ultrasonic bath at 40oC for a period of 3.5 hours till
the completion of reaction (as indicated by TLC). The contents were washed
twice with water and dried. Evaporation of the solvent under vacuum and
recrystallization of the crude product from ethanol afforded white crystalline
solid. Yield: 82%. M.p. 92-93 ºC. 1H NMR (MeOD) δ: 2.70 (s, 3H, SCH3), 3.50
(s, 3H, OCH3), 5.21 (s, 1H, NH), 8.10 (s, 1H, ArH), 7.52-7.70 (dd, 2H, ArH);
IR (KBr) cm-1: 3250, 3050, 2950, 1740, 1345. MS m/z: 307(M+), 309(M++2).
N-(2-Acetylphenyl)-N-methylmethanesulfonamide (3a):
A mixture of N-(acetylphenyl)methanesulfonamide (2a) (7.56 g; 33.0
mmoles), dimethylformamide (25.0 ml) and sodium hydride (1.58 g; 66.0
mmoles) was stirred for 45 minutes followed by the addition of methyl iodide
(9.37 g; 66.0 mmoles). The contents were stirred at room temperature for a
further period of 85 minutes and were poured into ice cold hydrochloric acid
(3N) which was extracted with dichloromethane. Solvent was evaporated
under reduced pressure to get the product. Yield: 62.0%; M.p. 55ºC (Lit. M.p.
55-56oC)16; IR (KBr) cm-1: 3246, 3044, 1706, 1342.
(Using ultrasonic waves):
A
mixture of (1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-hydrazine (5a) or (6-bromo-1-methyl-2,2-dioxo-2,3-
dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (5b) (2.0 mmol),
corresponding aromatic aldehydes (2.0 mmol), methanol (50 ml) and glacial
acetic acid (2 drops) taken in a loosely screw capped test tube was immersed in
an ultrasonic reaction bath (for yields, reaction conditions and reaction times,
see Table 1). The contents were cooled and washed with cold methanol to get
the pure compound.
N-(2-Chloro-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6a):
Yellow crystals; M.p. 296-298ºC. 1H NMR (CDCl3) δ: 3.42 (s, 3H,
N-CH3), 4.86 (s, 2H, CH2), 7.12-8.20 (m, 8H, ArH), 8.59 (s, 1H, NCH). IR
(KBr): 3508, 1640, 1419, 1328, 1148 cm-1; MS m/z: 347 [M+], 349 [M++2];
Anal. calcd for C H14N3SO2Cl: C, 55.25; H, 4.03; N, 12.09; Found: C, 55.26;
H, 4.03; N, 12.061.6
N-(2-Acetyl-4-bromophenyl)-N-methylmethanesulfonamide (3b):
A mixture of N-(2-acetyl-4-bromophenyl)methanesulfonamide (2b) (10.16
g; 33.0 mmoles), dimethylformamide (25.0 ml) and sodium hydride (1.58 g;
66.0 mmoles) was stirred for 45 minutes followed by the addition of methyl
iodide (9.37 g; 66.0 mmoles). The contents were stirred at room temperature
for a further period of 15 hours and were poured into ice cold hydrochloric
acid (3N) which was extracted with dichloromethane. Solvent was evaporated
under reduced pressure to get the product. Yield: 67.0%; M.p. 64-65 ºC. (Lit.
M.p. 64oC)17; IR (KBr) cm-1: 3242, 3043, 1732, 1337.
N-(3-Chloro-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6b):
1
Yellow powder; M.p. 198-200 ºC. H NMR (CDCl3) δ: 3.38 (s, 3H,
N-CH3), 4.85 (s, 2H, CH2), 7.12-7.70 (m, 8H, ArH), 8.56 (s, 1H, NCH). IR
(KBr): 3518, 1632, 1426, 1312, 1155 cm-1; MS m/z: 347 [M+], 349 [M++2];
Anal. calcd for C H14N3SO2Cl: C, 55.25; H, 4.03; N, 12.09; Found: C, 55.24;
H, 4.05; N, 12.101.6
1-Methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-one
(4a):
N-(4-Chloro-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6c):
To a suspension of n-hexane washed sodium hydride (2.30 g; 96.0
mmoles) in dry DMF (30 ml),
a solution of N-(2-acetylphenyl)-N-
Yellow crystals; M.p. 203-204ºC. 1H NMR (CDCl3) δ: 3.40 (s, 3H,
N-CH3), 4.84 (s, 2H, CH2), 7.12-7.80 (m, 8H, ArH), 8.58 (s, 1H, NCH). IR
(KBr): 3522, 1636, 1428, 1342, 1165 cm-1; MS m/z: 347 [M+], 349 [M++2];
Anal. calcd for C16H14N3SO2Cl: C, 55.25; H, 4.03; N, 12.09; Found: C, 55.23;
H, 4.08; N, 12.12. Details of crystal data and structure refinement have been
provided in Table 2 & Fig. 4. Supplementary crystallographic data have been
deposited with the CCDC number 804082. These data can be obtained free
of charge from Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
methylmethanesulfonamide (3a) (11.66 g; 48.0 mmoles) in dry DMF (70 ml)
was added and stirred at room temperature for 1.5 hours. After completion
of the reaction (as indicated by TLC), the contents were poured into cold
hydrochloric acid (3N) to get the precipitates which were dried at room
temperature to get the title compound. Yield: 91 %; M.p. 118-119ºC (Lit M.p.
120oC)18; IR (KBr) cm-1: 3250, 3052, 1734, 1680, 1342.
6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-one (4b):
To a suspension of n-hexane washed sodium hydride (2.30 g; 96.0
mmoles) in dry DMF (30 ml), solution of N-(2-acetyl-4-bromophenyl)-N-
methylmethanesulfonamide (3b) (13.92 g; 48.0 mmoles) in dry DMF (70 ml)
was added and stirred at room temperature for 3.5 hours. After completion of
the reaction (as indicated by TLC), contents were poured into cold hydrochloric
acid (3N) to get the precipitates which were dried at room temperature to get
the title compound. Yield: 90 %; M.p. 108-109 ºC (Lit M.p. 110oC)19; IR (KBr)
cm-1: 3254, 3055, 1739, 1690, 1342.
N-(2-Methyl-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6d):
1
Greenish yellow crystals; M.p. 148-150ºC. H NMR (CDCl3) δ: 2.42 (s,
3H, Ar-CH3), 3.38 (s, 3H, N-CH3), 4.88 (s, 2H, CH2), 7.12-8.02 (m, 8H, ArH),
8.47 (s, 1H, NCH). IR (KBr): 3507, 1608, 1453, 1336, 1155 cm-1; MS m/z:
327 [M+]; Anal. calcd for C17H17N3SO2: C, 62.39; H, 5.20; N, 12.84; Found: C,
62.38; H, 5.21; N, 12.85.
N-(4-Methyl-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6e):
(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-
ylidene)-hydrazine (5a):
1
A
mixture of 1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
Yellow crystals; M.p. 189-190ºC. H NMR (CDCl3) δ: 2.43 (s, 3H, Ar-
CH3), 3.37 (s, 3H, N-CH3), 4.85 (s, 2H, CH2), 7.10-7.74 (m, 8H, ArH), 8.57 (s,
thiazin-4-one (4a) (10.60 g; 50.0 mmoles), hydrazine hydrate (85%) (5.0 ml)
528

J. Chil. Chem. Soc., 56, Nº 1 (2011)
1H, NCH). IR (KBr): 3515, 1610, 1445, 1325, 1150 cm-1; MS m/z: 327 [M+];
Anal. calcd for C17H17N3SO2: C, 62.39; H, 5.20; N, 12.84; Found: C, 62.41; H,
5.24; N, 12.81.
[M+], 407 [M++2]; Anal. calcd for C17H16N3SO2Br: C, 50.25; H, 3.94; N, 10.34;
Found: C, 50.28; H, 3.95; N, 10.31
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N’-(4-nitro-benzylidene)-hydrazine (6k):
Yellow needle like crystals; M.p. 244-246ºC. 1H NMR (CDCl ) δ: 3.40 (s,
3H, N-CH3), 4.87 (s, 2H, CH2), 7.10-7.82 (m, 7H, ArH), 8.56 (s,31H, NCH).
IR (KBr): 3509, 1642, 1413, 1315, 1145 cm-1; MS m/z: 436 [M+], 438[M++2];
Anal. calcd for C H13N4SO4Br: C, 43.94; H, 2.97; N, 12.81; Found: C, 43.92;
H, 2.98; N, 12.841.6
N-(2-Nitro-benzylidene)-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-
benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6f):
Yellow crystalline powder; M.p. 292-295ºC. 1H NMR (CDCl3) δ: 3.38 (s,
3H, N-CH3), 4.86 (s, 2H, CH2), 7.10-7.85 (m, 8H, ArH), 8.53 (s, 1H, NCH).
IR (KBr): 3518, 1638, 1426, 1345, 1160 cm-1 .MS m/z: 358.09 [M+]; Anal.
calcd for C16H14N4SO4: C, 53.63; H, 3.91; N, 15.64; Found: C, 53.60; H, 3.93;
N, 15.66.
N-Anthracen-9-yl-methylene-N-(6-Bromo-1-methyl-2,2-dioxo-2,3-
dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6l):
Dark orange thin crystals; M.p. 215-218 ºC. 1H NMR (CDCl3) δ: 3.44 (s,
3H, N-CH3), 4.85 (s, 2H, CH2), 7.05-8.25 (m, 12H, ArH), 8.52 (s, 1H, NCH).
IR (KBr): 3528, 1621, 1415, 1336, 1152 cm-1; MS m/z: 491 [M+], 493 [M++2];
Anal. calcd for C24H18N3SO2Br: C, 58.54; H, 3.66; N, 8.54; Found: C, 58.51;
H, 3.64; N, 8.57.
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N-(3-chloro-benzylidene)-hydrazine (6g):
Yellow powder, M.p. 197-198ºC. 1H NMR (CDCl3) δ: 3.38 (s, 3H,
N-CH3), 4.84 (s, 2H, CH2), 6.99-7.87 (m, 7H, ArH), 8.58 (s, 1H, NCH). IR
(KBr): 3518, 1636, 1416, 1333, 1146 cm-1; MS m/z: 425 [M+], 427 [M++2], 429
[M++4]; Anal. calcd for C16H13N3SO2BrCl: C, 45.02; H, 3.05; N, 9.85; Found:
C, 45.00; H, 3.04; N, 9.87.
4-[(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-hydrazonomethyl]-phenol (6m):
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N-(4-chloro-benzylidene)-hydrazine (6h):
Yellow crystalline powder; M.p. 210-211ºC. 1H NMR (CDCl3) δ: 3.38 (s,
3H, N-CH3), 4.84 (s, 2H, CH2), 6.99-7.80 (m, 7H, ArH), 8.59 (s, 1H, NCH). IR
(KBr): 3510, 1625, 1426, 1340, 1150 cm-1; MS m/z: 425 [M+], 427 [M++2], 429
[M++4]. Anal. calcd for C16H13N3SO2BrCl: C, 45.02; H, 3.05; N, 9.85; Found:
C, 44.99; H, 3.03; N, 9.83.
Yellow powder; M.p. 209-210ºC. 1H NMR (CDCl3) δ: 3.41 (s, 3H, NCH3),
4.94 (s, 2H, CH2), 7.03-8.08 (m, 7H, ArH), 8.62 (s, 1H, NCH), 9.98 (s, 1H,
ArOH). IR (KBr): 3495, 1629, 1438, 1332, 1145 cm-1; MS m/z: 407 [M+], 409
[M++2]; Anal. calcd for C17H16N3SO3Br: C, 47.05; H, 3.43; N, 10.29; Found:
C, 47.04; H, 3.45; N, 10.31.
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N’-(3,4-dimethoxy-benzylidene)-hydrazine (6n):
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N-(4-fluoro-benzylidene)-hydrazine (6i):
Yellow crystalline powder; M.p. 196-198ºC. 1H NMR (CDCl3) δ: 3.37 (s,
3H, N-CH3), 4.84 (s, 2H, CH2), 6.98-7.86 (m, 7H, ArH), 8.58 (s, 1H, NCH).
IR (KBr): 3530, 1618, 1412, 1340, 1153 cm-1; MS m/z: 409 [M+], 411 [M++2];
Anal. calcd for C16H13N3SO2BrF: C, 46.83; H, 3.17; N, 10.24; Found: C, 46.80;
H, 3.21; N, 10.27.
1
Light orange crystalline powder; M.p. 225-227ºC. H NMR (CDCl3) δ:
3.08 (s, 6H, Ar-OCH3), 3.36 (s, 3H, N-CH3), 4.89 (s, 2H, CH2), 6.72-7.73 (m,
6H, ArH), 8.56 (s, 1H, NCH). IR (KBr): 3505, 1615, 1401, 1355, 1145 cm-1;
MS m/z: 451 [M+], 453 [M++2]; Anal. calcd for C18H18N3SO4Br: C, 47.79; H,
3.98; N, 9.29; Found: C, 47.82; H, 4.00; N, 9.32.
4-[(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-hydrazonomethyl]-2-methoxy-phenol (6o):
Yellow crystalline solid; M.p. 252-253ºC. 1H NMR (CDCl3) δ: 3.10 (s, 3H,
Ar-OCH3), 3.32 (s, 3H, N-CH ), 4.90 (s, 2H, CH2), 6.96-8.02 (m, 6H, ArH),
8.58 (s, 1H, NCH), 9.56 (s, 1H3, OH). IR (KBr): 3503, 1615, 1410, 1350, 1148
cm-1; MS m/z: 437 [M+], 439 [M++2]; Anal. calcd for C17H16N3SO4Br: C, 46.58;
H, 3.65; N, 9.59; Found: C, 46.55; H, 3.67; N, 9.57.
N-(6-Bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]
thiazin-4-ylidene)-N-(4-methyl-benzylidene)-hydrazine (6j):
Yellow needle like crystals; M.p. 184-185ºC. 1H NMR (CDCl3) δ: 2.43 (s,
3H, Ar-CH3), 3.37 (s, 3H, N-CH3), 4.86 (s, 2H, CH2), 6.98-7.75 (m, 7H, ArH),
8.59 (s, 1H, NCH). IR (KBr): 3515, 1640, 1417, 1336, 1155 cm-1; MS m/z: 405
Table 1: Reaction parameters and yields for the synthesis of 6a-o.
Ultrasonic
Reaction conditions
Entry Reactant Product
Thermal Reaction Conditions
Yield (%)
Yield (%)
1
2
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
6a
6b
6c
6d
6e
6f
Reflux:60 minutes
Reflux:60 minutes
Reflux:60 minutes
Reflux:125 minutes
Reflux:90 minutes
Reflux:35 minutes
Reflux:60 minutes
Reflux:60 minutes
Reflux:45 minutes
Reflux:100 minutes
Reflux:110 minutes
Reflux:80 minutes
Reflux:90 minutes
Reflux:70 minutes
Reflux:40 minutes
76.0
77.5
75.7
80.5
79.1
75.8
76.3
76.6
82.9
78.8
84.1
80.4
79.2
84.1
82.9
35oC; 2.0 minutes
30oC; 2.5 minutes
30oC; 2.0 minutes
30oC; 2.0 minutes
35oC; 2.5 minutes
30oC; 2.5 minutes
35oC; 3.0 minutes
35oC; 2.5 minutes
30oC; 2.0 minutes
40oC; 3.0 minutes
35oC; 3.0 minutes
35oC; 3.0 minutes
35oC; 2.5 minutes
40oC; 3.0 minutes
40oC; 2.5 minutes
94.4
92.6
93.2
95.2
94.8
90.8
91.8
92.6
93.0
93.0
91.2
89.6
95.4
92.6
93.2
3
4
5
6
7
6g
6h
6i
8
9
10
11
12
13
14
15
6j
6k
6l
6m
6n
6o
X-RAY CRYSTALLOGRAPHY
X-ray data were collected at 296 K on a Bruker KAPPA APEX II diffractometer using Mo Kα X-ray (0.71073 Å) source and a graphite monochromator.
The unit cell dimensions were obtained from least–squares fit to setting angles of about 25 reflections. Multi-scan absorption corrections were applied. SAINT20
was used for the cell refinement and data reduction, while SHELXS-9721 was used for structure solution and refinement. ORTEP-3 for Windows22, PLATON23
and WinGX24 were used for molecular graphics. In the refinement procedure, all the non-hydrogen atoms were refined with anisotropic displacement parameters.
529

J. Chil. Chem. Soc., 56, Nº 1 (2011)
The aromatic and aliphatic hydrogen atoms were positioned geometrically and
treated as riding atom over their parent carbon atoms. Details of crystal data and
structure refinement have been provided in Table 2 & Fig. 4. Supplementary
crystallographic data have been deposited with the CCDC number 804082.
These data can be obtained free of charge from Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
with methane sulfonyl chloride may be attributed to the presence of bromine on
the ring making amino group relatively weaker nucleophile. Similar behavior
was shown by the un/ bromo substituted intermediates (2a-b) in subsequent
N-alkylation. However, cyclization of ring had no such effect, which may be
due to generation of carbanion at methyl group of the sulfonamide. Its attack
on to the electrophilic carbon of the carbonyl group is independent of the
presence or absence of an electron withdrawing group on the benzene ring.
In the next step, 1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-
4-ones (4a) and 6-bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2 λ6-benzo[c]
[1,2]thiazin-4-one (4b) were reacted with hydrazine hydrate to get 1-methyl-
2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (5a)
and 6-bromo 1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-
ylidene)-hydrazine (5b) respectively. These were further reacted with different
aldehydes in ultrasonic bath to get the title compounds (6a-o) in excellent
yields (See Table 1).
It was observed that using ultrasonic waves, reaction times have been
considerably reduced with improved yields (for comparison of yields, reaction
conditions and reaction times, see Table 1). All of the synthesized compounds
are characterized through spectroscopic techniques. In order to determine the
stereochemistry (E or Z configuration), (as it could not be revealed through 1H
NMR spectroscopy) a single crystal of N-(4-chloro-benzylidene)-N’-(1-methyl-
2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-ylidene)-hydrazine (6c)
was grown in methanol and studied by X-ray crystallography. In the crystal
structure of the subjected molecule, C=N linkage adopts an E configuration
and the non-planer thiazine ring (C1/C6/C7/C8/N1/S1) with the r.m.s deviation
of 0.2334Å assumes the envelop shape. The two aromatic rings i.e. fused
benzene and chlorophenyl rings form the dihedral angles of 10.19 (0.24)o and
10.56 (0.24)o respectively with respect to the thiazine ring. The structure is
stabilized by the weak hydrogen bonding (C---H…O) interactions. The crystal
structure indicates E configuration of C=N bond for this specific compound. It
is assumed that rest of the compounds too have same (E) configuration which
is in consistent with literature studies14.
ANTI-BACTERIAL ASSAY:
Anti-bacterial assay of the synthesized compounds (dissolved in
dimethylformamide) was carried out by Agar Well Diffusion method25
against the human pathogenic bacteria. Suspensions of five strains of bacteria
i.e., Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa,
Staphylococcus aureus, and Salmonella typhimurium were adjusted with
sterile saline to a concentration of 1.0 x 105 colony forming unit (CFU)/ml.
The inocula were prepared daily and stored at +4°C until use. Dilutions of the
inocula were cultured on solid medium to verify the absence of contamination
and to check the validity of the inoculum. The compounds under investigation
were applied to the wells of 6 mm diameter at 1 mg per ml of DMF in addition
to 0 (control) and the standards, ampicillin & ciprofloxacin. The plates were
incubated at 370C for 24 hours and zone of inhibition was measured as an
average of three values.
RESULTS AND DISCUSSION
1-Methyl-2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c][1,2]thiazin-4-one (4a)
and 6-bromo-1-methyl-2,2-dioxo-2,3-dihydro-1H-2 λ6-benzo[c][1,2]thiazin-4-
one (4b) were synthesized by condensation of methane sulfonyl chloride with
methyl anthranilate and 5-bromo methyl anthranilate respectively followed by
N-methylation using methyl iodide. Sulfonamide formation between methyl
anthranilate and methane sulfonyl chloride was carried out under the influence
of ultrasonic waves and the reaction was completed in far less time (40 minutes)
than synthesized by literature procedure in diethyl ether (3.5 hours). However,
synthesis of bromo derivative (4b) took relatively longer time (3.5 hours) even at
elevated temperature (60-70oC). Poor reactivity of 5-bromo methyl anthranilate
Table 2: Crystal data and structure refinement for compound 6c
Structural formula
C16H14N3O2SCl
Cell Volume
1577.52(26) Å3
Formula weight
Crystal system
Space group
T (K)
347.80
Monoclinic
P121/n 1
296(2) K
8.3157(27)
12.8986(39)
14.7873(42)
90.00
Z
4
1.46
Calculated density/(g.cm-3)
Absorption coefficient/ mm-1
Crystal size (mm3)
0.3877
0.29×0.17×0.19
16179/3955
2.1-28.5
A (Å)
Reflection collected/unique
Range for data collection (°)
Goodness-of-fit on F2
F(000)
B (Å)
C (Å)
0.876
D (°)
719.9
D (°)
95.962(15)
90.00
Absorption correction
Refinement method
Multi-Scan
Full-matrix least squares on F2
D (°)
Anti-bacterial activities of the compounds under investigation are presented
in Table 3 in comparison with reference drugs Ampicillin and Ciprofloxacin.
assay revealed that most of the derivatives are active against pseudomonas
aeruginosa and some are active against Salmonella typhimurium; however, 6i
was found the only active compound against E. coli. Moreover, the results
also showed that amongst these synthesized compounds 6a, 6b, 6h, 6i and 6j
has shown good activities. From the results, it is evident that Pseudomonas
aeruginosa is the most sensitive bacterial species for these compounds, while
E. coli and Enterococcus faecalis were found as the most resistant species.
These compounds are mainly active against Gram negative bacteria such as
Pseudomonas aeruginosa and Salmonella typhimurium while they have shown
negligible activities against Gram positive bacteria.
Figure 4: ORTEP diagram for 6c with the 50% probability level of the
thermal ellipsoids
530

J. Chil. Chem. Soc., 56, Nº 1 (2011)
Table 3: Anti-bacterial Activity of Tested Compounds (Zone of inhibition in mm).
Pseudomonas
aeruginosa
Salmonella
typhimurium
Enterococcus
faecalis
Staphylococcus
aureus
Compound
Escherichia coli
6a
8.55
10.10
-
-
-
11.12
9.87
8.89
-
-
12.53
6b
-
-
-
6c
-
-
-
6d
-
-
-
-
6e
9.33
9.30
-
-
-
-
6f
-
-
-
12.84
6g
-
-
-
-
6h
11.47
10.27
-
-
9.84
-
-
-
6i
9.61
-
-
6j
-
9.98
-
9.98
-
6l
6m
8.95
9.15
9.30
-
-
-
-
-
-
8.09
-
-
6n
-
-
-
Ampicillin
Ciprofloxacin
19.47
31.40
25.06
25.0
30.54
21.6
30.95
20.54
23.93
8. Y. Misu, H.Togo, Org. Biomol. Chem. 1, 1342-1346 (2003).
9. S. Rollas, S. G. Küçükgüzel, Molecules, 12, 1910-1939 (2007).
10. C. Loncle, J. M. Brunel, N. Vidal, M. Dherbomez, Y. Letourneux, Eur. J.
Med. Chem. 39, 1067-1071 (2004).
11. S. N. Khattab, Molecules, 10, 1218-1228 (2005).
12. M. Zia-ur-Rehman, J. A. Choudary, S. Ahmad, Bull. Korean Chem. Soc.
26, 1771 (2005).
CONCLUSION
Synthesis of N-benzylidene-N’-(1-methyl-2,2-dioxo-2,3-dihydro-1H-
2λ6-benzo[c][1,2] thiazin-4-ylidene)-hydrazines and their evaluation for anti-
bacterial potential is reported. Some of the synthesized compounds have shown
good anti-bacterial activity and this study may be useful to synthesize more
biologically active compounds through further derivatization.
13. M. Zia-ur-Rehman, J. A. Choudary, S. Ahmad, H. L. Siddiqui, Chem.
Pharm. Bull. (Japan), 54, 1175 (2006).
14. M. Ahmad, H. L. Siddiqui, M. Zia-ur-Rehman, M. Parvez, Eur. J. Med.
Chem. 45, 698 (2010).
15. M. Shafiq, M. N. Tahir, I. U. Khan, M. N. Arshad, M. H. Khan, Acta Cryst.
E, 65, o955 (2009).
16. M. N. Tahir, M. Shafiq, I. U. Khan, W. A. Siddiqui, M. N. Arshad, Acta
Cryst. E, 64, o557 (2008).
ACKNOWLEDGEMENTS
MuhammadShafiq gratefullyacknowledgesHigherEducationCommision,
Islamabad Pakistan for research scholarship under its indigenous PhD
Scholarship 5000 Scheme. Assistance of M/s Qarshi Research International,
Hattar, Pakistan to M. Shafiq is also greatly acknowledged for the provision of
facilities of anti-bacterial assay.
17. M. Shafiq, M. N. Tahir, I. U. Khan, M. N. Arshad, M. N. Asghar, Acta
Cryst. E, 65, o1182 (2009).
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