Synthesis of 7-chloro-9-trifluoromethyl-/7-fluorophenothiazines

Article abstract of DOI:10.1002/hc.20235

Synthesis of 7-chloro-9-trifluoromethyl-/7-fluorophenothiazines is reported by Smiles rearrangement of 5-chloro-3-trifluoromethyl-/5-fluoro-2-formamido- 2′-nitrodiphenyl sulfides. The later were obtained by the formylation of 2-amino-5-chloro-7-trifluorom

Full text of DOI:10.1002/hc.20235

Heteroatom Chemistry
Volume 18, Number 1, 2007
Synthesis of 7-Chloro-9-trifluoromethyl-/7-
fluorophenothiazines
Bhawani Singh Rathore, V. Gupta, R. R. Gupta, and M. Kumar
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 18 November 2004; revised 18 January 2006
phenothiazines with certain structural specificity, in-
ABSTRACT: Synthesis of 7-chloro-9-trifluoromethyl-
cluding thiazine moiety for effective drug–receptor
/7-fluorophenothiazines is reported by Smiles rear-
interactions. Synthesized phenothiazines have been
rangement of 5-chloro-3-trifluoromethyl-/5-fluoro-2-
1
characterized by their IR, H NMR, and mass spec-
formamido-2ꢀ-nitrodiphenyl sulfides. The later were
tral studies.
obtained by the formylation of 2-amino-5-chloro-
7-trifluoromethyl-/5-fluoro-2ꢀ-nitrodiphenyl sulfides,
which were prepared by the condensation of 2-amino-
EXPERIMENTAL
5-fluoro-/5-chloro-3-trifluoromethyl
benzenethiols
Melting points of all the substituted phenothiazines
are uncorrected. The purity of all the synthesized
compounds has been checked by thin-layer chro-
matography. Their structures have been assigned by
elemental and spectral studies. The infrared spec-
tra were recorded on FT-IR spectrometer MAGNA
IR 550 NICOLET using potassium bromide discs.
1H NMR spectra were recorded on FT NMR Bruker
DRX-300 MHz in DMSO-d6 using TMS as an internal
standard. Mass spectra have been recorded on Jeol
D-300 (EI).
with o-halonitrobenzenes. 1-Nitrophenothiazines
have also been synthesized by the condensation of
2-aminobenzenethiols with o-halonitrobenzenes,
ꢁ
C
involving Smiles rearrangement in situ.
2007
Wiley Periodicals, Inc. Heteroatom Chem 18:81–
86, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20235
INTRODUCTION
Phenothiazines and their analogues, nitrogen and
sulfur, containing heterocycles, particularly with thi-
azine ring system, are well known for their pharma-
cological activities due to their structural specificity.
They have been used as antihistaminics [1], anal-
gesics [2], antiemetics [3], diuretics [4], neurolep-
tics [5], sedatives [6], tuberculostatics [7], tranquil-
izers [8], etc. Significant anticancer activities have
also been shown by phenothiazines [9–11]. In view
of such a wide spectrum of medicinal and biolog-
ical applications of phenothiazines [12], it is con-
sidered worthwhile to synthesize hitherto unknown
Synthesis of Phenothiazines
Synthesis of phenothiazines involves the following
three steps.
Preparation of 2-Amino-2ꢀ-nitrodiphenyl Sul-
fides IIIa–d. Substituted 2-aminobenzenethiol I
(0.01 mol) was dissolved in ethanol (20 mL) in a
50 mL round bottom flask and halonitrobenzene II
(0.01 mol) dissolved in 10 mL ethanol containing an-
hydrous sodium acetate (0.01 mol) was added. The
contents of reaction mixture were refluxed for 4 h
with stirring, concentrated and cooled in an ice bath
overnight. The solid separated out was filtered and
washed well with 30% ethanol solution. The product
Correspondence to: M. Kumar; e-mail: bhawani bog@yahoo.
com; bhawanisr@hotmail.com.
c
ꢁ
2007 Wiley Periodicals, Inc.
81

82 Rathore et al.
TABLE 1 Physical Data of Compounds III–V
% Found/(Calcd)
H
Compo-
unds
M.p. Yield
R 1 R 2 R 3 R 4 R 5 R 6 ( ◦C)
(%)
Molecular Formula
C
N
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
Vj
Vk
Vl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
CF3 Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Cl
H
H
H
Cl
148 37.2
80 74.5
95 25.4
89 22.2
194 52.3
72 57.5
82 44.6
89 43.5
230 26.6
C13H7Cl F3N2O2S
40.74/(40.75) 1.85/(1.84) 7.30/(7.31)
C13H7Br2ClF N O S 36.50/(36.51) 1.66/(1.65) 6.56/(6.55)
3
2
2
C13H8ClF3N2O2S
C13H7Cl F N O S
C14H7Cl2F3N2O2S
44.76/(44.77) 2.29/(2.31) 8.04/(8.03)
40.71/(40.75) 1.83/(1.84) 7.30/(7.31)
40.87/(40.89) 1.73/(1.72) 6.80/(6.81)
H
Cl
Br
H
3
2
3
C14H7Br2ClF N O S 36.91/(36.90) 1.54/(1.55) 6.14/(6.15)
3
2
3
C14H8ClF3N2O3S
C14H7Cl F N O3S
C13H6Cl22F33N2S
44.63/(44.63) 2.12/(2.14) 7.42/(7.44)
40.87/(40.89) 1.73/(1.72) 6.80/(6.81)
46.43/(46.45) 1.81/(1.80) 4.16/(4.17)
41.00/(41.02) 1.60/(1.59) 3.67/(3.68)
51.73/(51.75) 2.36/(2.34) 4.63/(4.64)
46.44/(46.45) 1.78/(1.80) 4.15/(4.17)
39.85/(39.86) 1.30/(1.29) 10.72/(10.73)
H
Cl
Br
H
H
NO2
H
Cl
Cl
NO2
H
Cl
Cl
180 21.23 C13H6BrClF3NS
106 29.9
120 22.3
C13H7ClF3NS
C13H6Cl2F3NS
C13H5ClF3N3O4S
C13H4Br2ClF3N2O2S 30.93/(30.95) 0.79/(0.80) 5.53/(5.55)
C13H5Cl F N O S
NO2 170 75.4
CF3 Cl Br
CF3 Cl
CF3 Cl
Br NO2 108 68.7
H
H
H
Br
H
H
H
H
H
NO2 148 72.1
NO2 140 76.21 C13H5Cl2F3N2O2S
NO2 198 80.9
40.92/(40.96) 1.34/(1.32) 7.33/(7.35)
40.95/(40.96) 1.31/(1.32) 7.34/(7.35)
46.89/(46.91) 1.96/(1.97) 13.65/(13.68)
34.30/(34.31) 1.21/(1.20) 6.65/(6.67)
48.57/(48.58) 2.10/(2.04) 9.41/(9.44)
48.59/(48.58) 2.03/(2.04) 9.43/(9.44)
2
3
2
2
H
H
H
H
F
F
F
F
C12H6FN3O4S
Br NO2 104 76.63 C12H5Br2FN2O2S
H
H
NO2 220 68.3
NO2 214 65.1
C12H6ClFN2O2S
C12H6ClFN2O2S
was recrystallized from methanol. Physical data of
all synthesized compounds are shown in Table 1.
stituted 2-aminobenzenethiol I (0.01 mol), ethanol
(20 mL), and sodium hydroxide (0.01 mol) contained
in a round-bottomed flask (50 mL) fitted with reflux
condenser. The color of the solution changed imme-
diately. The contents were refluxed for 2 h, concen-
trated, cooled, and filtered. The separated solid was
washed well with hot water and finally with 30%
hot alcohol. The compounds were crystallized from
methanol/acetone. Physical and analytical data of
synthesized compounds are shown in Table 1.
Preparation of 2-Formamido-2ꢀ-nitrodiphenyl Sul-
fides IVa–d. The diphenyl sulfides IIIa–d (0.01 mol)
obtained in the first step were refluxed for 4 h in 90%
formic acid (20 mL). The contents were poured in a
beaker containing crushed ice. The solid separated
out was filtered, washed well with water, and crys-
tallized from benzene. Physical data of synthesized
2-formamido-2ꢀ-nitrodiphenyl sulfides are shown in
Table 1.
RESULTS AND DISCUSSION
In the present investigation, 7-chloro-9-trifluoro-
methyl-/7-fluorophenothiazines Va–l have been syn-
thesized by Smiles rearrangement [13–16] of
2-formamido-2ꢀ-nitrodiphenyl sulfides IVa–d, which
were prepared by the formylation of corresponding
2-amino-2ꢀ-nitrodiphenyl sulfides IIIa–d. The 2-
amino-2ꢀ-nitrodiphenyl sulfides IIIa–d were pre-
pared by the condensation of 2-amniobenzenethiols
I with o-halonitrobenzenes II.
A single-step synthesis of 1-nitrophenothiazines
has been achieved by the condensation of 2-
aminobenzenethiols I with halonitrobenzenes in the
presence of NaOH, involving Smiles rearrangement
and ring closure occurring in situ due to com-
bined resonance and inductive effect of nitro group
(Scheme 1).
Preparation of Phenothiazines Va–d. To an alco-
holic solution of potassium hydroxide (0.2 g in 5 mL
ethanol), a solution of formyl derivative IVa–d (0.01
mol) in acetone (15 mL) was added. The contents of
round bottom flask were heated for 30 min under re-
flux. A second lot of potassium hydroxide (0.2 g in 5
mL ethanol) was added to the reaction mixture and
refluxed for 2 h. The contents of round bottom flask
was then poured into a beaker containing crushed
ice and filtered. The residue obtained was washed
well with water, finally with 30% ethanol and crys-
tallized from benzene. Physical data of synthesized
phenothiazines are shown in Table 1.
Preparation of Substituted
1-Nitrophenothiazines Ve–l
The infrared spectral data of synthesized
An alcoholic solution of reactive halonitrobenzene II
(0.01 mol) was added to a stirred suspension of sub-
2-amino-2ꢀ-nitrodiphenyl
sulfides
IIIa–d,
2-
form-amido-2ꢀ-nitrodiphenyl sulfides IVa–d, and
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 7-Chloro-9-trifluoromethyl-/7-fluorophenothiazines 83
SCHEME 1 Synthesis of phenothiazines via Smiles rearrangement.
phenothiazines Va–l are shown in Tables 2 and 3,
respectively.
tions. The intense absorption band observed in the
region 1692–1666 cm−1 is due to >C O stretching
vibrations. Asymmetric and symmetric stretching vi-
brations of NO2 group are observed in the regions
1567–1533 and 1380–1376 cm−1, respectively. The
absorption bands observed in the regions 1383–
1333− and 1361–1267 cm−1 are due to asymmet-
ric and symmetric C F stretching vibrations of
CF3 group. The absorption band in the region
767–708 cm−1 is observed due to C Cl stretching vi-
brations, while the absorption band at 567 cm−1 ap-
pears due to C Br stretching vibrations.
All the synthesized phenothiazines Va–l exhibit
an absorption band in the region 3492–3316 cm−1
due to N H stretching vibrations. Two sharp ab-
sorption bands in the region 1384–1367 and 1276–
1267 cm−1 are assigned to C F stretching vibrations
in CF3 group. A sharp band observed in the region
Synthesized 2-amino-2ꢀ-nitrodiphenyl sulfides
IIIa–d exhibit absorption bands in the regions 3490–
3444 and 3383–3333 cm−1 due to asymmetric and
symmetric vibrations of NH2 group. Two bands ob-
served in the regions 1570–1539 and 1383–1329 cm−1
are due to asymmetric and symmetric stretching vi-
brations of NO2 group. Asymmetric and symmet-
ric C F stretching vibrations of CF3 group occur in
the regions 1391–1317 and 1287–1282 cm−1, respec-
tively. The absorption band observed in the region
717–667 cm−1 is due to C Cl stretching vibrations,
while the absorption band at 575 cm−1 is due to
C–Br stretching vibrations.
Synthesized 2-formamido-2ꢀ-nitrodiphenyl sul-
fides IVa–d exhibit an absorption band in the re-
gion 3433–3383 cm−1 due to N H stretching vibra-
Heteroatom Chemistry DOI 10.1002/hc

84 Rathore et al.
TABLE 2 Infrared Spectral Data of Compounds IIIa–d and IVa–d (in cm−1
)
Compounds
A
B
C
D
E
F
G
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
3467, 3333
3483, 3383
3490, 3381
3444, 3381
–
–
–
–
–
–
1533, 1383
1545, 1355
1543, 1334
1570, 1329
1533, 1316
1558, 1342
1567, 1380
1556, 1347
1366, 1287
1317, 1283
1391, 1287
1381, 1282
1383, 1250
1367, 1260
1333, 1267
1370, 1254
717
683
667
690
767
708
733
715
–
575
–
–
–
567
–
–
–
–
–
–
–
–
3433
3417
3383
3415
1667
1666
1692
1690
A, asymmetric and symmetric stretching vibrations of primary amino group; B, N H stretching vibrations; C, C O stretching vibrations; D,
asymmetric and symmetric stretching vibrations of nitro group; E, C F stretching vibrations of CF3 group; F, C Cl stretching vibrations; G,
C
Br stretching vibrations.
737–722 cm−1 is due to C Cl stretching vibrations
and the absorption band observed at 585–567 cm−1
is due to C Br stretching vibrations.
band in the region 587–575 cm−1 due to C Br stretch-
ing vibrations, while compounds Vi–l exhibit strong
absorption band in the region 1097–1067 cm−1 due
to C F stretching vibrations.
NMR spectra of phenothiazines show a singlet in
the region δ 9.53–8.20 ppm due to NH proton. All the
phenothiazines Va–l exhibit a multiplet in the region
δ 7.88–6.71 ppm due to aromatic protons. NMR data
of these compounds are shown in Table 4.
All the synthesized 1-nitrophenothiazines Va–
l exhibit a sharp peak in the region δ 10.30–8.71
ppm due to N–H proton and peaks in the region δ
8.57–5.3 ppm due to aromatic protons. But phenoth-
iazines without NO2 group at 1-position exhibit a
peak due to NH proton in the δ 9.93–8.20 ppm re-
gion (Table 4). This shifting towards downfield in
1-nitrophenothiazines Ve–l is attributed to intramo-
lecular hydrogen bonding ( N H· · ·O N ) (Fig. 1).
In mass spectra of all phenothiazines, molecu-
lar ion peaks are in accordance with their molecular
weights. 1-Nitrophenothiazines undergo fragmenta-
tion with the loss of OH radical by Mc-Lafferty
IR spectra of synthesized 1-nitrophenothiazines
Ve–l exhibit a broad band in the region 3406–3316
cm−1 (Table 3) corresponding to the N H stretch-
ing vibrations, which appears at 3492–3428 cm−1 in
phenothiazines having no nitro group at 1-position.
This large shifting of N–H stretching vibrations to a
lower frequency region in 1-nitrophenothiazines is
attributed to the formation of six-membered chelate
of high stability through strong intramolecular hy-
drogen bonding ( N H· · ·O N ).
All 1-nitrophenothiazines exhibit two sharp and
intense bands in the region 1580–1475 and 1358–
1233 cm−1 due to asymmetric and symmetric vibra-
tions of the aromatic nitro group. Compounds Ve–h
exhibit two bands in the region 1366–1316 and 1166–
1133 cm−1 due to asymmetric and symmetric stretch-
ing vibrations of CF3 group, while the band due to
C Cl stretching vibrations was observed between
816 and 725 cm−1. Compounds Vf–j exhibit a sharp
TABLE 3 Infrared Spectral Data of Compounds Va–l (in cm−1
)
Compounds
A
B
C
D
E
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
3467
3492
3428
3387
3358
3383
3365
3367
3316
3406
3376
3383
1384, 1267
1367, 1275
1383, 1276
1373, 1260
1325, 1166
1333, 1150
1366, 1133
1316, 1158
1083
717
725
737
722
733
683
816
725
–
–
567
–
–
–
575
–
–
–
585
–
–
–
–
–
1516, 1308
1541, 1383
1566, 1233
1566, 1358
1580, 1350
1566, 1350
1483, 1316
1475, 1308
Vj
Vk
Vl
1067
1097
1092
–
708
758
–
A, N H stretching vibrations; B, C F stretching vibrations of CF3 group; C, C Cl stretching vibrations; D, C Br stretching vibrations; E,
asymmetric and symmetric vibrations of NO2 group.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 7-Chloro-9-trifluoromethyl-/7-fluorophenothiazines 85
TABLE 4 1H NMR Spectral Data of Compounds Va–l (in ppm on FT NMR Bruker DRX-300 MHz in DMSO-d6 300 MHz)
Compounds
ꢀ (ppm)
Hydrogen
Multiplicity
Assignment
Va
Vb
Vc
Vd
Ve
Vf
7.80–7.39
9.93
7.67–6.72
8.86
7.88–6.73
8.78
7.76–6.71
8.20
7.57–6.77
9.11
7.37–6.43
8.73
7.85–6.62
9.50
7.85–6.77
9.32
7.51–6.25
8.65
7.54–6.19
9.07
7.32–6.30
10.30
7.64–6.19
9.13
6
1
6
1
7
1
6
1
5
1
4
1
5
1
5
1
6
1
5
1
6
1
6
1
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Multiplet
Singlet
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Aromatic protons
N H proton
Vg
Vh
Vi
Vj
Vk
Vl
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FIGURE 1
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SCHEME 2
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ACKNOWLEDGMENT
CDRI, Lucknow, is gratefully acknowledged for pro-
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