Synthesis of 7-chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-4H-1,4-benzothiazines as antimicrobial agents

Article abstract of DOI:10.1016/j.bmc.2006.04.009

7-Chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-4H-1,4-benzothiazines have been synthesized by 2-amino-5-fluoro/5-trifluoromethyl/5-chloro-3-trifluoromethyl benzenethiols condensed with β-diketone/β-ketoesters in the presence of DMSO involving oxidative cyclization. Pharmacological activities have also been included.

Full text of DOI:10.1016/j.bmc.2006.04.009

Bioorganic & Medicinal Chemistry 14 (2006) 5678–5682
Synthesis of 7-chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-
4H-1,4-benzothiazines as antimicrobial agents
Bhawani Singh Rathore* and M. Kumar
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 16 December 2005; revised 8 April 2006; accepted 11 April 2006
Available online 2 May 2006
Abstract—7-Chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-4H-1,4-benzothiazines have been synthesized by 2-amino-5-fluoro/
5-trifluoromethyl/5-chloro-3-trifluoromethyl benzenethiols condensed with b-diketone/b-ketoesters in the presence of DMSO
involving oxidative cyclization. Pharmacological activities have also been included.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as 2a–c in chloroform. 4-Fluoro/4-trifluoromethyl/4-
chloro-2-trifluoromethylphenylthioureas were obtained
by the action of ammonium thiocyanate on 4-fluoro/tri-
fluoromethyl/4-chloro-2-trifluoromethyl anilines 1a–c.
4H-1,4-Benzothiazines are structural analogs of 10H-
phenothiazines.1–3 4H-1,4-Benzothiazines possess a wide
spectrum of biological and pharmacological activities
due to presence of a fold along the nitrogen and sulfur
axis, which is considered to be responsible as one of the
structural features to impart their activities. They are
used as antihistaminics,4 antipsychotics,5 antiemetics,6
neuroleptics,7 tranquilizers,8 sedatives,9 etc. Significant
activity against cancer has also been shown by phenothi-
azines.10–12 With the aim of developing a new class of
effective drugs embracing certain characteristic structural
features for effective drug–receptor interaction, we
have synthesized 7-chloro-5-trifluoromethyl/5-fluoro/5-
trifluoromethyl-4H-1,4-benzothiazines to make them
available for screening of wide ranging pharmacological
and biological activities.
7-Chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-
4H-1,4-benzothiazines 10a–m have been synthesized by
the condensation and oxidative cyclization of 2-amino-
5-fluoro/trifluoromethyl/5-chloro-3-trifluoromethylben-
zenethiols13 5a–c with active methylene compounds
in the presence of dimethylsulfoxide. The reaction is
considered to proceed through the formation of an
enaminoketone intermediate (Scheme 1).
In IR spectra, the synthesized 2-amino-5-fluoro/5-trifluo-
romethyl/5-chloro-3-trifluoromethyl-benzenethiols 5a–c
exhibit two sharp bands in the region 3483–3410 cmÀ1
and 3362–3310 cmÀ1 due to the asymmetric and symmet-
ric stretching vibrations of the primary amino group.
2. Results and discussion
In the region 2587–2550 cmÀ1 a weak absorption band is
observed due to S–H stretching vibrations. In com-
pound 5b strong absorption band is observed in the
region 1165 cmÀ1 due to C–F stretching. In compounds
5a, c two bands are observed in the region 1345–
1340 cmÀ1 and 1183–1180 cmÀ1 due to asymmetric and
symmetric C–F stretching vibrations of CF3 group.
The absorption band at 724 cmÀ1 is observed in
compound 5a due to C–Cl stretching vibrations.
2-Amino-5-fluoro/5-trifluoromethyl/5-chloro-3-trifluoro-
methyl-benzenethiols 5a–c were obtained by the hydro-
lytic cleavage of 6-fluoro/6-trifluoromethyl/6-chloro-4-
trifluoromethyl-2-aminobenzothiazoles 3a–c, which in
turn were prepared by the bromination of 4-fluoro/4-tri-
fluoromethyl/4-chloro-2-trifluoromethyl-phenylthioure-
IR spectra of 2-aminobenzenethiols 5a–c exhibit a
multiplet in the region d 8.48–6.53 ppm due to aromatic
protons. The broad signal observed in the region d 4.95–
3.61 ppm is attributed to –NH2 protons. The singlet
Keywords: 4H-1,4-Benzothiazines; b-Diketone/b-ketoesters; 2-Amino-
benzenethiols.
*
Corresponding author. E-mail: bhawani_bog@yahoo.com
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.04.009

B. S. Rathore, M. Kumar / Bioorg. Med. Chem. 14 (2006) 5678–5682
5679
R1
R1
S
NH2.HCl
NH C NH2
NH4SCN
H2O
R2
R2
2a-c
1a-c
Br2
R1
CHCl3
R1
N
S
NH2
S-K+
KOH
H2O
C NH2
R2
R2
3a-c
4a-c
Glacial
AcOH
R1
R1
NH2
NH2
SH
DMSO
R2
R2
S
S
R2
5a-c
NH2
R1
O
OH
CH C R4
7b
6a
R3
C
OH
O
R3 C CH C R4
7a
R1
R1
NH2
NH2
R2
R2
S
S
R2
R2
S
O
C
O
R3
S
C
R4
N
H
R4
N
H
R3
R1
R1
8
9
X
R1
R1
H
N
H
N
R4
COR3
R3
COR4
R2
S
R2
S
10a-m
11a-m
Scheme 1.
observed at d 1.27–1.23 ppm can be assigned to –SH
proton.
N–H stretching vibrations. In the region 1740–
1610 cmÀ1, an intense band is observed due to C@O
stretching vibrations. In the regions 1327–1120 cmÀ1
and 1187–1026 cmÀ1 two sharp bands are observed
due to asymmetric and symmetric C–F stretching vibra-
tions of CF3 group 10d–m. In the regions 1485–
In all the 7-chloro-5-trifluoromethyl/7-fluoro/7-trifluo-
romethyl-4H-1,4-benzothiazines 10a–m a sharp intense
band is observed in the region 3465–3248 cmÀ1 due to

5680
B. S. Rathore, M. Kumar / Bioorg. Med. Chem. 14 (2006) 5678–5682
1433 cmÀ1 and 1383–1350 cmÀ1 two sharp bands are ob-
served due to asymmetric and symmetric C–H deforma-
tion vibrations of CH3 group in compounds 10c, j, m.
An absorption band in the region 640–569 cmÀ1 is
attributed to C–Br stretching vibrations in compounds
10b, g, k. Compounds 10a, e, h, i–m containing chlorine
atom exhibit absorption band in the region 790–
752 cmÀ1 due to C–Cl stretching vibrations. Com-
pounds 10a, b, c show an absorption band in the region
1070–1050 cmÀ1 due to C–F stretching vibrations.
compounds 10a, d, e, g, i, k, and l show moderate activ-
ity compounds 10f and m shows weak activity as com-
pared to references. The standard drugs used for
references were chloramphenicol (30 lg/ml) and griseo-
fulvin (30 lg/ml).
5. Experimental
Melting points of all the synthesized compounds are
uncorrected. The purity of synthesized compounds was
checked by thin-layer chromatography. The IR spectra
have been recorded on FT IR spectrophotometer Mag-
A single sharp peak observed in the region d 10.43–
8.62 ppm in all 4H-1,4-benzothiazines 10a–m is due to
N–H proton. Allylic proton (–C@C–CH3) at C-3 in all
4H-1,4-benzothiazines appear in the region d 2.79–
2.21 ppm. Aromatic protons show multiplet in the re-
gion d 8.64–6.11 ppm. In compounds 10c, j a triplet is
observed in the region d 1.44–1.28 ppm due to CH3 pro-
tons of –C2H5(p) and a quartet observed in the region d
2.67–2.31 ppm is due to CH2 protons of –C2H5(p) group
at C-2. 13C NMR spectra of 10c, f and i as representative
and 19F NMR of 10a–m have also been recorded. In
mass spectra of 7-chloro-5-trifluoromethyl/5-fluoro/5-
1
na IR 550 Nicolet using KBr discs. H NMR and 13C
NMR spectra were scanned at 90 MHz/300 MHz on
Jeol FX 90Q FT NMR spectrophotometer in DMSO-
d6/CDCl3 using TMS as an internal standard. 19F
NMR spectra were scanned with respect to hexafluoro-
benzene with 19F signal at d162.9 ppm.
5.1. Preparation of 4-chloro-2-trifluoromethyl-/4-fluoro-/
4-trifluoromethyl-phenylthioureas (2a–c)
trifluoromethyl-4H-1,4-benzothiazines
molecular ion peak is in accordance to their molecular
weight.
10a–m,
the
4-Chloro-2-trifluoromethyl-/4-fluoro-/4-trifluoromethyl-
anilines (I; 0.1 mol), hydrochloric acid (9 ml), and water
(25 ml) were taken and refluxed for 30 min in a round-
bottomed flask. The contents were cooled down to room
temperature and then ammonium thiocyanate (0.1 mol)
was added. The reaction mixture was again refluxed for
4 h. The solid obtained was cooled down, filtered,
washed well with water, dried, and crystallized from
ethanol.
3. Pharmacological activity
All the synthesized compounds (10a–m) were screened
for antibacterial activity14,15 against Bacillus subtilis
(A), Bacillus mega (B) (Gram +ve), Escherichia coli
(C), Aspergillus arogens (D) (Gram Àve), and antifungal
activity against Aspergillus awamori (E) at a concentra-
tion of 30 lg/ml using CHCl3 as a solvent by standard
method. After 24 h of incubation at 37 °C, the zones
of inhibition were measured in millimeter (Table 1).
5.2. Preparation of 2-amino-6-chloro-4-trifluoromethyl-/
2-amino-6-fluoro-/2-amino-6-trifluoromethyl-benzothiaz-
oles (3a–c)
In a round-bottomed flask equipped with a mechanical
stirrer and a dropping funnel, 4-chloro-2-trifluorometh-
yl-/4-fluoro-/4-trifluoromethyl-phenylthioureas (II; 0.1 mol)
and chloroform (100 ml) were taken. A solution of bro-
mine (0.1 mol) in chloroform (100 ml) was added with
stirring for a period of two hours. Temperature of reac-
tion mixture remains below 5 °C during the reaction.
4. Conclusion
It has been noted that all the compounds 10b, c, h, and j
show strong activities against microbes, whereas
Table 1. Pharmacological data of substituted 4H-1,4-benzothiazines 10a–m
Compound
R1
R2
R3
R4
Antimicrobial and antifungal activity
(zones of inhibition in mm)
A
B
C
D
E
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
F
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
–C6H4Cl (m)
–C6H4Br (m)
–C6H4C2H5 (p)
–C6H5
16
20
18
15
16
15
16
19
16
18
17
16
14
14
18
16
13
14
13
19
17
15
16
19
17
15
15
19
16
14
17
16
18
18
16
17
21
17
16
19
21
18
15
19
18
20
19
18
19
20
20
18
14
17
15
14
16
14
20
18
16
17
18
18
15
H
F
H
F
H
CF3
CF3
CF3
CF3
CF3
Cl
H
–C6H4Cl (m)
–C6H5
H
H
–C6H4Br (p)
–C6H4Cl (p)
–C6H5
H
CF3
CF3
CF3
CF3
CF3
10j
Cl
Cl
–C6H4C2H5 (p)
–C6H4Br (p)
–C6H5
10k
10l
Cl
Cl
10m
–C6H4CH3 (o)

B. S. Rathore, M. Kumar / Bioorg. Med. Chem. 14 (2006) 5678–5682
5681
1
Stirring was continued for a period of 4 h. After the
addition of bromine, contents of round-bottomed flask
were refluxed for about 4 h till the evolution of HBr
ceased. Chloroform was removed by filtration and
resulting solid was treated with SO2 water and filtered.
The filtrate was neutralized with aqueous ammonia
solution. The precipitate was filtered, washed well with
water, and crystallized from ethanol.
1180 (CF3), 724 (C–Cl); H NMR (DMSO-d6, d, ppm)
4.95 (2H, s, NH2), 8.48–6.49 (3H, m, Ar), 1.24 (1H, s,
SH).
5.4.4. 2-(3-Chlorobenzoyl)-3-methyl-7-fluoro-4H-1,4-ben-
zothiazine (10a). C16H11ClFNOS; mp 155; yield 53.9%;
found: C, 60.07; H, 3.48; N, 4.37; Calcd: C, 60.09; H,
3.47; N, 4.38; IR KBr (m cmÀ1) 3250 (N–H), 1740
(˜C@O), 1040 (C–F), 1471–1350 (C–H of CH3), 752
(C–Cl); 1H NMR (DMSO-d6, d, ppm) 9.16 (1H, s,
NH), 8.15–6.40 (7H, m, Ar), 2.60 (3H, s, CH3); 19F
NMR (DMSO-d6, d, ppm) À113.2 (F at C7).
5.3. Synthesis of 2-amino-5-fluoro/5-trifluoromethyl-/5-
chloro-3-trifluoromethyl benzenethiols (5a–c)
2-Amino-6-fluoro-/trifluoromethyl-/6-chloro-4-trifluoro-
methyl-benzothiazoles obtained, KOH (5 times by
weight of thiazole) and water (10 times by weight of thi-
azole) were taken in a R.B. flask and refluxed until evo-
lution of ammonia ceased. The reaction mixture was
cooled, filtered and distilled with cold water. The filtrate
was neutralized by acetic acid (5N) with vigorous stir-
ring. During neutralization the temperature of mixture
was maintained below 10 °C by adding ice otherwise a
decomposed greenish mass is obtained instead of desired
2-aminobenzenethiol. The resulting mixture was extract-
ed 2 or 3 times with ether, ether was evaporated and yel-
low solid obtained was crystallized from ethanol.
5.4.5. 2-(3-Bromobenzoyl)-3-methyl-7-fluoro-4H-1,4-ben-
zothiazine (10b). C16H11BrFNOS; mp 160; yield 84.36%;
found: C, 52.75; H, 3.05; N, 3.83; Calcd: C, 52.76; H,
3.04; N, 3.85; IR KBr (m cmÀ1) 3248 (N–H), 1620
(˜C@O), 1070 (C–F), 1485–1378 (C–H of CH3), 630
(C–Br); 1H NMR (DMSO-d6, d, ppm) 9.26 (1H, s,
NH), 8.08–6.59 (7H, m, Ar), 2.59 (3H, s, CH3); 19F
NMR (DMSO-d6, d, ppm) À112.8 (F at C7).
5.4.6. 2-(4-Ethylbenzoyl)-3-methyl-7-fluoro-4H-1,4-ben-
zothiazine (10c). C18H16FNOS; mp 110; yield 55.07%;
found: C, 68.98; H, 5.13; N, 4.48; Calcd: C, 68.99; H,
5.15; N, 4.47; IR KBr (m cmÀ1) 3280 (N–H), 1610
(˜C@O), 1050 (C–F), 1485–1385 (C–H of CH3); 1H
NMR (DMSO-d6, d, ppm) 9.36 (1H, s, NH), 8.37–6.72
(7H, m, Ar), 2.79 (3H, s, CH3), 2.67–2.31 (2H, q,
CH2), 1.14–1.44 (3H, t, CH3); 13C NMR (DMSO-d6,
d, ppm) 15.8 (CH3), 16.5 (CH2CH3), 28.6 (CH2CH3),
117.9–140.2 (14 aromatic carbons), 152.8 (C–F), 178.9
(C@O); 19F NMR (DMSO-d6, d, ppm) À109.75 (F at
C7).
5.4. Preparation of 7-chloro-5-trifluoromethyl/7-fluoro/7-
trifluoromethyl-4H-1,4-benzothiazines (10a–m)
In a R.B. flask 2-amino-5-fluoro/5-trifluoromethyl/5-
chloro-3-trifluoromethyl benzenethiol (0.01 mol) was
added to a stirred suspension of b-diketone/b-ketoester
(0.01 mol) in dimethylsulfoxide (5 ml). The resulting
mixture was refluxed for about 30–40 min, concentrated
and cooled. The solid separated out was filtered, washed
well with petroleum ether, and crystallized from metha-
nol/acetone (Scheme 1).
5.4.7. 2-Benzoyl-3-methyl-7-trifluoromethyl-4H-1,4-ben-
zothiazine (10d). C17H12F3NOS; mp 230; yield 68.59%;
found: C, 60.88; H, 3.62; N, 4.16; Calcd: C, 60.89; H,
3.61; N, 4.18; IR KBr (m cmÀ1) 3390 (N–H), 1620
(˜C@O), 1125–1080 (C–F), 1433–1383 (C–H of CH3);
1H NMR (DMSO-d6, d, ppm) 10.00 (1H, s, NH),
8.64–6.76 (8H, m, Ar), 2.25 (3H, s, CH3); 19F NMR
(DMSO-d6, d, ppm) À55.6 (F at C7).
Physical, IR, and NMR data of the 2-amino-5-fluoro/
5-trifluoromethyl/5-chloro-3-trifluoromethyl-benzenethi-
ols 5a–c and 7-chloro-5-trifluoromethyl/7-fluoro/7-tri-
fluoromethyl-4H-1,4-benzothiazines 10a–m are as
follows:
5.4.1.
2-Amino-5-chloro-3-trifluoromethylbenzenethiol
5.4.8.
2-(3-Chlorobenzoyl)-3-methyl-7-trifluoromethyl-
(5a). C7H5ClF3NS; mp 186; yield 53.0%; found: C,
36.93; H, 2.21; N, 6.17; Calcd: C, 36.89; H, 2.25; N,
6.10; IR KBr (m cmÀ1) 3483, 3362 (NH2), 2587 (SH),
1345, 1183 (CF3), 724 (C–Cl); H NMR (DMSO-d6, d,
ppm) 3.62 (2H, s, NH2), 8.49–6.91 (2H, m, Ar), 1.29
(1H, s, SH).
4H-1,4-benzothiazine (10e). C17H11ClF3NOS; mp 190;
yield 78.48%; found: C, 55.23; H, 2.99; N, 3.77; Calcd:
C, 55.22; H, 3.00; N, 3.79; IR KBr (m cmÀ1) 3370 (N–
H), 1625 (˜C@O), 1120–1070 (C–F), 1466–1390 (C–H
1
1
of CH3); H NMR (DMSO-d6, d, ppm) 9.33 (1H, s,
NH), 8.48–6.12 (7H, m, Ar), 2.55 (3H, s, CH3); 19F
NMR (DMSO-d6, d, ppm) À54.7 (F at C7).
5.4.2. 2-Amino-5-fluorobenzenethiol (5b). C6H6FNS; mp
98; yield 55.0%; found: C, 50.32; H, 4.23; N, 9.79; Calcd:
C, 50.20; H, 4.22; N, 9.77; IR KBr (m cmÀ1) 3410, 3310
(NH2), 2540 (SH), 1065 (CF); H NMR (DMSO-d6, d,
ppm) 4.15 (2H, s, NH2), 7.32–6.53 (3H, m, Ar), 1.23
(1H, s, SH).
5.4.9. 2-Benzoyl-3-phenyl-7-trifluoromethyl-4H-1,4-ben-
zothiazine (10f). C22H14F3NOS; mp 130; yield 69.55%;
found: C, 66.50; H, 3.53; N, 3.51; Calcd: C, 66.49; H,
3.55; N, 3.52; IR KBr (m cmÀ1) 3396 (N–H), 1689
(˜C@O), 1327–1026 (C–F); 1H NMR (DMSO-d6) d
8.64 (1H, s, NH), 8.17–6.11 (13H, m, Ar); 13C NMR
(DMSO-d6, d, ppm) 108.4 (C–CF3), 118.4 (CCF3),
107.9–143.2 (20 aromatic carbons), 178.2 (C@O); 19F
NMR (DMSO-d6) À53.57 (F at C7).
1
5.4.3.
2-Amino-5-trifluoromethylbenzenethiol
(5c).
C7H6F3NS; mp 198; yield 49.0%; found: C, 43.51; H,
3.11; N, 7.25; Calcd: C, 42.98; H, 3.10; N, 7.23; IR
KBr (m cmÀ1) 3470, 3360 (NH2), 2550 (SH), 1340,

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B. S. Rathore, M. Kumar / Bioorg. Med. Chem. 14 (2006) 5678–5682
5.4.10. 2-(4-Bromobenzoyl)-3-methyl-7-trifluoromethyl-
4H-1,4-benzothiazine (10g). C17H11BrF3NOS; mp 168;
yield 74.16%; found: C, 49.27; H, 2.69; N, 3.36; Calcd:
C, 49.29; H, 2.68; N, 3.38; IR KBr (m cmÀ1) 3465 (N–
H), 1690 (˜C@O), 1250–1140 (C–F), 1475–1375 (C–H
of CH3), 569 (C–Br); 1H NMR (DMSO-d6, d, ppm)
9.43 (1H, s, NH), 8.19–6.11 (7H, m, Ar), 2.36 (3H, s,
CH3); 19F NMR (DMSO-d6, d, ppm) À53.7 (F at C7).
(12H, m, Ar); 19F NMR (DMSO-d6, d, ppm) À136.39
(F at C5).
5.4.16. 2-(4-Methylbenzoyl)-7-chloro-3-methyl-5-trifluo-
romethyl-4H-1,4-benzothiazine (10m). C18H13ClF3NO2S;
mp 102; yield 74.76%; found: C, 54.05; H, 3.30; N, 3.49;
Calcd: C, 54.07; H, 3.28; N, 3.50; IR KBr (m cmÀ1) 3370
(N–H), 1735 (˜C@O), 1240–1130 (C–F), 1483–1366 (C–
1
H of CH3), 755 (C–Cl); H NMR (DMSO-d6, d, ppm)
5.4.11. 2-(4-Chlorobenzoyl)-3-methyl-7-trifluoromethyl-
4H-1,4-benzothiazine (10h). C17H11ClF3NOS; mp 180;
yield 81.97%; found: C, 55.20; H, 2.98; N, 3.80; Calcd:
C, 55.22; H, 3.00; N, 3.79; IR KBr (m cmÀ1) 3293 (N–
H), 1689 (˜C@O), 1260–1125 (C–F), 1466–1383 (C–H
of CH3), 793 (C–Cl); 1H NMR (DMSO-d6, d, ppm)
9.38 (1H, s, NH), 8.47–6.19 (7H, m, Ar), 2.31 (3H, s,
CH3); 19F NMR (DMSO-d6, d, ppm) À55.8 (F at C7).
9.1 (1H, s, NH), 7.67–6.4 (7H, m, Ar), 2.1 (3H, s,
CH3), 1.14 (3H, s, CH3); 19F NMR (DMSO-d6, d,
ppm) À124.42 (F at C5).
Acknowledgment
CDRI, Lucknow, is acknowledged for providing NMR
and mass spectra.
5.4.12.
2-Benzoyl-7-chloro-3-methyl-5-trifluoromethyl-
4H-1,4-benzothiazine (10i). C17H11ClF3NOS; mp 167;
yield 47.39%; found: C, 55.21; H, 3.01; N, 3.76; Calcd:
C, 55.22; H, 3.00; N, 3.79; IR KBr (m cmÀ1) 3410 (N–
H), 1675 (˜C@O), 1210–1140 (C–F), 1479–1371 (C–H
References and notes
1. Gupta, R. R. Phenothiazines and 1,4-Benzothiazines-
Chemical and Biomedical Aspects; Elsevier: Amsterdam,
1988.
2. Keyzer, H.; Eckert, G. M.; Forrest, I. S.; Gupta, R. R.;
Gutmann, F.; Molnar, J. Thiazines and Structurally
Related Compounds, In Proceedings of the Sixth Interna-
tional Conference on Phenothiazines and Structurally
Related Psychotropic Compounds, Pasadena, CA, Sep-
tember 11–14, 1990; Krieger Publishers: Malabar, FL,
USA, 1992.
3. Gordon, M. Psychopharmacological Agents; Vol. II,
Medicinal Chemistry, Vol. 4-II; Academic Press: New
York, 1967; p 119.
4. Sugimoto, Y.; Tarumi, T.; Zhao, Q. E.; Fujii, Y.; Kamei,
C. Methods Find Exp. Clin. Pharmacol. 1998, 20, 457;
Chem. Abstr. 1999, 130, 75926.
1
of CH3); H NMR (DMSO-d6, d, ppm) 10.43 (1H, s,
NH), 8.35–6.83 (7H, m, Ar), 2.6 (3H, s, CH3); 13C
NMR (DMSO-d6, d, ppm) 16.9 (CH3), 107.8 (C–CF3),
118.9 (C–CF3), 117.9–138.6 (14 aromatic carbons),
124.8 (C–Cl), 180.2 (C@O); 19F NMR (DMSO-d6, d,
ppm) À115.37 (F at C5).
5.4.13. 2-(4-Ethylbenzoyl)-7-chloro-3-methyl-5-trifluoro-
methyl-4H-1,4-benzothiazine (10j). C19H15ClF3NOS;
mp 110; yield 93.25%; found: C, 57.34; H, 3.81; N,
3.51; Calcd: C, 57.36; H, 3.80; N, 3.52; IR KBr (m
cmÀ1) 3420 (N–H), 1680 (˜C@O), 1255–1187 (C–F),
1483–1383 (C–H of CH3), 790 (C–Cl); 1H NMR
(DMSO-d6, d, ppm) 9.13 (1H, s, NH), 8.40–6.91 (6H,
m, Ar), 2.66 (3H, s, CH3), 2.64–2.34 (2H, q, CH3),
1.25–1.28 (3H, t, CH3); 19F NMR (DMSO-d6, d, ppm)
À118.68 (F at C5).
5. David, J.; Wager, E. J. Psychopharmacol. 1998, 12, 283;
Chem. Abstr. 1999, 130, 119446.
6. Williams, P. I.; Smith, M. Eur. J. Anaesthesiol. 1999, 16,
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7. Platonov, I. A. Vop. Med. Khim. 1995, 41, 27; Chem.
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8. El-said, M. K. Pharmazie 1981, 36, 678.
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437; Chem. Abstr. 1983, 99, 16444.
10. Safa, A. R. Chimia 1999, 53, 299; Chem. Abstr. 1999, 131,
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11. Motohashi, N.; Sasaki, Y.; Wakabayashi, Y.; Sakagami,
H.; Molnar, J.; Kurihara, J. J. Anticancer Res. 1992, 12,
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Jaipur, India, 2004.
14. Carrod, L. P.; Grady, F. D. Antibiotic and Chemotherapy,
3rd ed.; Churchill Livingston: Edinburgh, 1972.
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Butterworth: London, 1980.
5.4.14. 2-(4-Bromobenzoyl)-7-chloro-3-methyl-5-trifluoro-
methyl-4H-1,4-benzothiazine (10k). C17H10BrClF3NOS;
mp 109; yield 67.25%; found: C, 45.49; H, 2.28; N, 3.10;
Calcd: C, 45.51; H, 2.25; N, 3.12; IR KBr (m cmÀ1) 3465
(N–H), 1225 (˜C@O), 1260–1180 (C–F), 1467–1384
(C–H of CH3), 640 (C–Br), 787 (C–Cl); 1H NMR
(DMSO-d6, d, ppm) 8.62 (1H, s, NH), 8.24–6.97 (6H, m,
Ar), 2.22 (3H, s, CH3); 19F NMR (DMSO-d6, d, ppm)
À53.7 (F at C5).
5.4.15.
2-Benzoyl-7-chloro-3-phenyl-5-trifluoromethyl-
4H-1,4-benzothiazine (10l). C22H13ClF3NOS; mp 140;
yield 60.65%; found: C, 61.18; H, 3.01; N, 3.22; Calcd:
C, 61.19; H, 3.03; N, 3.24; IR KBr (m cmÀ1) 3360 (N–
H), 1615 (˜C@O), 1316–1170 (C–F), 760 (C–Cl); 1H
NMR (DMSO-d6, d, ppm) 9.04 (1H, s, NH), 8.27–6.88