Potential antimicrobial agents: Trifluoromethyl-10H-phenothiazines and ribofuranosides

Article abstract of DOI:10.1002/hc.10165

The zinc salts of substituted 2-amino benzenethiols, on condensation with 2-chloro-3-nitro-5-trifluoromethyl benzene, in presence of sodium acetate and ethanol and subsequent formylation gave the corresponding 2-formamido-substituted diphenylsulfides. From them substituted 2-trifluoromethyl-10H-phenothiazines have been synthesized via Smiles rearrangement. Ribofuranosides α- and β- anomers were synthesized by the condensation of phenothiazines with sugar in toluene in presence of SnCl₄ at 0°C and 155-160°C, respectively.

Full text of DOI:10.1002/hc.10165

Heteroatom Chemistry
Volume 14, Number 6, 2003
Potential Antimicrobial Agents:
Trifluoromethyl-10H-phenothiazines
and Ribofuranosides
Girwar Singh, Neeraj Kumar, Ashok K. Yadav, and A. K. Mishra
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 14 March 2002; revised 20 November 2002
ease AIDS [10] has attracted tremendous interest
ABSTRACT: The zinc salts of substituted 2-amino
in this area. A number of reviews regarding gen-
benzenethiols, on condensation with 2-chloro-3-nitro-
eral nucleoside chemistry [11,12], as well as aimed
5-trifluoromethyl benzene, in presence of sodium ac-
more specifically at AIDS [13,14], have been pub-
etate and ethanol and subsequent formylation gave the
lished previously while the opportunistic viral in-
corresponding 2-formamido-substituted diphenylsul-
fections associated with AIDS, such as those caused
fides. From them substituted 2-trifluoromethyl-10H-
by cytomegalovirus (CMV) and herpes simplex virus
phenothiazines have been synthesized via Smiles rear-
(HSV), have initiated additional research into new
rangement. Ribofuranosides ꢀ- and ꢁ- anomers were
nucleoside type antiviral agents. This area has been
synthesized by the condensation of phenothiazines
reviewed [15] and will not be induced. Throughout
with sugar in toluene in presence of SnCl4 at 0◦C
the literature, the location of each has been substi-
tuted under considerations described as ꢀ-anomer
when it lies below the plane of the ring system
and ꢁ-anomer when it lies above it. In view of the
above, we have attempted to prepare some new
fluoro-10H-phenothiazine derivatives, their ribofu-
ranosides, and have screened them for antimicrobial
activity, in the hope to obtain some potential medic-
inally important compounds.
◦
ꢀ
C
and 155–160 C, respectively. 2003 Wiley Periodicals,
Inc. Heteroatom Chem 14:481–486, 2003; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.10165
INTRODUCTION
During the past few years, an effort has been made
to synthesize the metabolites of important phe-
nothiazine derivatives, used as antipsychotic agents
[1,2], i.e., promazine, chloropromazine, prometh-
azine, fluphenazine, etc. Phenothiazines are associ-
ated with a large number of diverse activities, i.e.
analgesic [3], anticancer [4], antitumor [5], CNS-
depressant [6], antiasthemic [7], antibacterial [8].
Luo et al. [9] have reported phenothiazine nucleo-
sides as antihistamic and antidepressant. Further,
the importance of nucleosides against the viral dis-
RESULTS AND DISCUSSION
The zinc salts of 3,6-dimethoxy/3,6-dichloro/3-
phenoxy/3-chloro/2-amino benzenethiols (1a–d),
on condensation with 2-chloro-3-nitro-5-trifluoro-
methylbenzene (2), in presence of sodium acetate
and ethanol gave 2-amino-3,6-dimethoxy/3,6-
dichloro/3-phenoxy/3-chloro-2ꢁ-(3ꢁ-nitro-5ꢁ-trifluoro-
methyl)diphenylsulfides (3a–d). The formylation
of compounds
orded
3 with 95% formic acid, aff-
2-formamido-3,6-dimethoxy/3,6-dichloro/
3-phenoxy/3-chloro-2ꢁ-(3ꢁ-nitro-5ꢁ-trifluoromethyl)-
diphenylsulfides 4. Of the various ring-closure meth-
ods reported for the synthesis of nuclear substituted
Correspondence to: A. K. Mishra; e-mail: kishoreanant@yahoo.
com.
Contract grant sponsor: UGC Bhopal.
2003 Wiley Periodicals, Inc.
c
ꢀ
481

482 Singh et al.
phenothiazines, reaction of diphenylamines with
sulfur in the presence of catalyst and Smiles rear-
rangement of 2-aminophenyl-2ꢁ-nitrophenylsulfides
followed by ring closure with loss of nitrous acid are
quite versatile. Many substituted diphenylamines
did not react [16,17] and some halogeno-substituted
diphenylamines suffered dehalogenation [18–20].
However, use of dimethyl formamide in the pres-
ence of anhydrous potassium carbonate and copper
bronze was successful [19]. Zinc salts of the ben-
zenethiols in the presence of sodium hydroxide
in ethanol or methanol did not condense with
halogeno-nitrobenzenes. We have synthesized 6,9-
dimethoxy/6,9-dichloro/6-phenoxy/6-chloro-2-triflu-
oromethyl-10H-phenothiazines (5) [21] from
compound 4 with NaOH and ethanol via Smiles
rearrangement. The combined resonance and
inductive mechanisms enforced by the one nitro
and halogen atom as in compound 2 activated
the Smiles rearrangement as well as the ring clo-
sure to such an extent that both the processes
were instantaneous and in situ. Chloroacetylation
of compounds 5 with chloroacetyl chloride in
presence of benzene afforded 10-chloroacetyl-6,9-
dimethoxy/6,9-dichloro/6-phenoxy/6-chloro-2-triflu-
oromethyl-phenothiazines (6) (Scheme 1).
SCHEME 2
SnCl4 at 0◦C in 1,2-dichloroethane. The formation
of ꢀ-anomers is perhaps due to the coordination
at SnCl4 to OCOCH3 group of the sugar moiety,
thus permitting selective condensation of ꢀ-anomer
[24,25] (Scheme 3).
The structure of compounds 5a–d, 6a–d, and
8a–h have been established by elemental analysis
(Table 1), IR, 1H NMR (Table 2), and 13C NMR
(Table 3) spectral data. The m.p. and yield of all these
compounds are presented in Table 1.
IR Spectra
In the IR spectra of compounds 3, an absorption
band in the region 665–650 cm−1 was ascribed to
❍✟C S C✟❍ linkage, indicating its formation from
condensation of compounds 1 and 2. This band was
also observed in compounds 4–6 and 8 in the region
690–650 cm−1. An abosorption band due to primary
amino group appeared in the region 3460–3420 cm−1
in compounds 3. The band in compound 4 at 3380–
3130 cm−1 was due to ❍✟NH stretching vibrations. In
compounds 3 and 4, the strong absorption bands
in the regions 1590–1560 cm−1 and 1380–1320 cm−1
were due to asymmetric and symmetric stretching vi-
brations of nitro group. Formation of compounds 5
was confirmed by the presence of ❍✟NH group absorp-
tion in the region 3170–3150 cm−1 and the absence of
bands due to nitro and carbonyl group. Compounds
6 showed an absorption band in the region 1695–
1680 cm−1 due to ❍✟C O group. The synthesized com-
pounds showed C C ring vibrations in the region
Ribofuranosides 8a–d were prepared by the
reaction of compound 5 with ꢁ-D-ribofuranose-1-
acetate-2,3,5-tribenzoate (7) in toluene under vac-
uum at 160◦C. The formation of 8a–d (ꢁ-anomer)
may be due to the SN2-mechanism via neighboring
group participation and is in consonance with the
earlier report [22,23] (Scheme 2).
Ribofuranosides 8e–h were synthesized by con-
densing compound 5 with sugar 7 in presence of
SCHEME 1
SCHEME 3

Potential Antimicrobial Agents 483
TABLE 1 Data of Trifluoromethyl-10H-phenothiazines and Ribofuranosides
Calcd and Found Valuesa
Compound
R1
R2
Mol. Formula (Mol. Weight) m.p. (◦C) Yield (%)
C
H
N
5a
5b
5c
5d
6a
6b
6c
6d
8a
8b
8c
8d
8e
8f
OCH3
Cl
OC6H5
Cl
OCH3
Cl
OC6H5
Cl
OCH3
Cl
OC6H5
Cl
OCH3
Cl
OC6H5
Cl
OCH3 C15H12F3NO2S (313)
>350b
323
68
76
78
78
80
82
78
80
68
70
69
71
70
75
72
75
57.51 (57.47) 3.83 (3.79) 4.77 (4.75)
46.43 (46.41) 1.78 (1.75) 4.47 (4.46)
63.51 (63.47) 3.34 (3.30) 3.90 (3.86)
51.74 (51.70) 2.32 (2.29) 4.64 (4.61)
50.56 (50.51) 3.22 (3.18) 3.47 (3.43)
43.85 (43.81) 1.70 (1.66) 3.41 (3.39)
57.86 (57.82) 2.98 (2.96) 3.21 (3.18)
47.62 (47.48) 2.12 (2.08) 3.70 (3.66)
63.90 (63.87) 4.02 (4.01) 1.82 (1.78)
60.08 (60.04) 3.21 (3.18) 1.80 (1.76)
66.83 (66.82) 3.92 (3.88) 1.77 (1.73)
62.86 (62.83) 3.49 (3.46) 1.88 (1.84)
63.90 (63.87) 4.02 (4.01) 1.82 (1.78)
60.08 (60.04) 3.21 (3.18) 1.80 (1.76)
66.83 (66.82) 3.92 (3.88) 1.77 (1.73)
62.86 (62.83) 3.49 (3.46) 1.88 (1.84)
Cl
H
H
C13H6Cl2F3NS (336)
C19H12F3NOS (359)
C13H7ClF3NS (301.5)
325–327
>320b
OCH3 C17H13ClF3NO3S (403.5) 310–312
Cl
H
H
C15H7Cl3F3NOS (410.5)
C21H13ClF3NO2S (435.5)
C15H8Cl2F3NOS (378)
>300b
>360b
>310b
OCH3 C41H31F3NO9S (770)
130–132
120–121
135–137
140
140–142
130–131
145–147
Cl
H
H
C39H25Cl2F3NO7S (779)
C44 31
H
F3NO8S (790)
ClF3NO7S (744.5)
F3NO9S (770)
C39 26
H
OCH3 C41 31
H
Cl
H
H
C39 25
C44 31
C39H26ClF3NO7S (744.5) 148–190
H
Cl2F3NO7S (779)
8g
8h
H F3NO8S (790)
aFound values are given in parentheses.
bDecomposed.
1600–1580 cm−1 and C N ring vibrations in the re-
gion 1450–1420 cm−1. Compounds 3 and 4 showed
three sharp and strong bands in the region 1375–
1300 cm−1, 1270–1200 cm−1, and 1190–1110 cm−1
due to trifluoromethyl group. In compounds 8, the
band in the region δ 3350–3150 cm−1 due to ✟❍NH
completely vanished, suggesting the site of ribosyla-
tion at this position. In compounds 8, the position
of other groups (viz. C Cl and ❍✟C O) appeared in
the region 1730–1710 cm−1. Bands due to ✟❍C O C✟❍
linkage were observed in the region 1370–1020 cm−1
in compounds 8.
group. The NH signal has disappeared in compounds
8. Aromatic protons gave signals in the region
ꢁ
δ 7.20–8.50 for compounds 8. The C1 H protons of
sugar moiety caused a singlet in the region δ 6.42–
6.50, confirming the ꢁ-configuration of sugar [23].
The ꢀ-configuration of the ribofuranosides was con-
firmed by a doublet at δ 6.40–6.50 (J = 8 Hz) [24] due
ꢁ
ꢁ
ꢁ
to C1 H, C4 H, and C5 2H protons of sugar moi-
ety causing a multiplet in the region δ 4.35–4.85, and
ꢁ
ꢁ
protons at C2 H and C3 -H appeared in the region δ
5.30–5.90 as multiplet.
In the 19F NMR spectra of compounds 3, 4, and
8, signals were observed in the region δ −58.120 to
−59.250.
NMR Spectra
The 1H NMR spectra of compounds 3 showed a mul-
tiplet due to aromatic protons in the region δ 6.50–
8.20. A broad singlet in the region δ 5.10–5.40 was
attributed to NH2 protons in compounds 8. Methoxy
protons in compounds 3a, appeared as two singlets
at δ 3.70 and 3.95. Compounds 4 showed a multi-
plet due to aromatic protons in the region δ 6.70–
8.10. A broad hump in the region δ 8.15–8.25 was
attributed to NH protons in compounds 4a–d. Com-
pounds 5 showed a multiplet due to aromatic pro-
tons in the region δ 6.60–8.10. Methoxy protons in
compounds 5a, 6a, and 8e showed two singlets in the
region δ 3.80–3.95. Phenoxy groups in compounds
5c, 6c, 8c, and 8g showed a multiplet in the region
δ 6.50–7.30. Compounds 6 showed a multiplet in the
region δ 6.80–8.20 due to aromatic protons. A singlet
corresponding to two protons in the region δ 4.80–
4.95 was attributed due to protons of the chloroacetyl
Antimicrobial Activity
The synthesized compounds 5, 6, and 8 were
screened for their antimicrobial activity (according
to Bauer et al. [26]) against bacteria and fungi at
concentrations of 100 ꢂg/disc, using streptomycin
and mycostatin as reference compounds, respec-
tively. These compounds show moderate to fairly
good activity against organisms such as Escherichia
coli (gram −ve bacteria), Staphylococcus aureus
(gram +ve bacteria), and Aspergillus niger, Aspergillus
flavus, Fusarium oxysporium (fungi). Compound 5a
showed better activity against E. coli than other
compounds. Compound 6b showed significant ac-
tivity against S. aureus. Against A. niger, compound
6b showed better activity than compounds 6 and
8. Compound 8b showed better activity against A.
flavus. Against F. oxysporium, compounds 6a and

484 Singh et al.
TABLE 2 IR, 1H NMR, and 19F NMR Spectral Data of Trifluoromethyl-10H-phenothiazines and Ribofuranosides
Compound
IR (KBr, νmax cm−1 a
)
1H NMR (δ)b
19F NMR
−58.120
−58.190
−58.210
−58.205
−58.390
−58.320
−58.360
−58.220
−59.012
5a
5b
5c
5d
6a
6b
6c
6d
8a
3150 (s, NH), 1320, 1235, 1160 (s, CF3),
660 (s, C S C)
3160 (s, NH), 1350, 1275, 1150 (s, CF3),
650 (s, C S C), 765 (m, C Cl)
3170 (s, NH), 1340, 1250, 1150 (s, CF3),
670 (s, C S C)
6.80–8.00 (m, Ar H), 8.20 (s, ❍✟NH), 3.80,
3.90 (2s, 6H, 2 × OCH3)
6.70–8.02 (m, Ar H), 8.30 (s, ❍✟NH)
6.75–8.10 (m, Ar H), 8.25 (s, ❍✟NH),
6.50–7.10 (m, 5H, OC6H5)
3165 (s, NH), 1375, 1250, 1170 (s, CF3),
690 (s, C S C)
6.85–8.05 (m, Ar H), 8.15 (s, ❍✟NH)
1690 (s, C O), 1320, 1200, 1150 (s, CF3),
650 (s, C S C), 750 (m, C Cl)
1680 (s, C O), 1300, 1205, 1150 (s, CF3),
675 (s, C S C), 760 (m, C Cl)
1685 (s, C O), 1330, 1225, 1190 (s, CF3),
660 (s, C S C), 775 (m, C Cl)
1695 (s, C O), 1310, 1260, 1135 (s, CF3),
685 (s, C S C), 765 (m, C Cl)
1710 (s, C O), 1345 (s), 1030 (m)
(C O C) 1370, 1270, 1140 (s, CF3),
665 (s, C S C)
1720 (s, C O), 1350 (s), 1020 (m)
(C O C) 1345, 1260, 1130 (s, CF3),
670 (s, C S C)
1730 (s, C O), 1360 (s), 1040 (m)
(C O C) 1350, 1245, 1120 (s, CF3),
680 (s, C S C)
1725 (s, C O), 1370 (s), 1050 (m)
(C O C) 1360, 1240, 1130 (s, CF3),
685 (s, C S C)
1720 (s, C O), 1340 (s), 1020 (m)
(C O C) 1365, 1260, 1150 (s, CF3),
670 (s, C S C)
1710 (s, C O), 1360 (s), 1030 (m)
(C O C) 1370, 1250, 1135 (s, CF3),
675 (s, C S C)
1730 (s, C O), 1365 (s), 1060 (m)
(C O C) 1360, 1250, 1125 (s, CF3),
690 (s, C S C)
6.85–8.10 (m, Ar H), 3.82, 3.95 (2s, 6H,
2 × OCH3), 4.60 (s, CH2 of COCH2Cl)
6.80–8.20 (m, Ar H), 4.70 (s, CH2 of
COCH2Cl)
6.82–8.06 (m, Ar H), 6.65–7.20 (m, 5H,
OC6H5), 4.72 (s, CH of COCH2Cl)
6.90–8.10 (m, Ar H), 4.265 (s, CH2 of
COCH2Cl)
6.95–8.25 (m, Ar H), 3.85, 3.95 (2s, 6H,
ꢁ
2 × OCH3), 6.45 (C1 H of sugar)
ꢁ
8b
8c
8d
8e
8f
6.90–8.20 (m, Ar H), 6.42 (C1 H of
−59.140
−59.210
−59.220
−59.250
−59.205
−59.185
−59.198
sugar)
6.92–8.15 (m, Ar H), 6.80–7.20 (m, 5H,
ꢁ
OC6H5), 6.48 (C1 H of sugar)
ꢁ
6.95–8.20 (m, Ar H), 6.50 (C1 H of
sugar)
6.92–8.20 (m, Ar H), 3.80, 3.90 (2s, 6H,
ꢁ
2 × OCH3), 6.50 (d, C1 H of sugar,
J = 8 Hz)
ꢁ
6.95–8.10 (m, Ar H), 6.45 (d, C1
of sugar, J = 8 Hz)
H
8g
8h
6.90–8.15 (m, Ar H), 6.70–7.30 (m, 5H,
ꢁ
OC6H5), 6.48 (d, C1 H of sugar,
J = 8 Hz)
ꢁ
1715 (s, C O), 1350 (s), 1020 (m)
(C O C) 1375, 1210, 1110 (s, CF3),
685 (s, C S C)
6.98–8.08 (m, Ar H), 6.42 (d, C1 H of
sugar, J = 8 Hz)
as = sharp and strong, m = medium.
bs = singlet, d = doublet, m = multiplet.
TABLE 3
δ
13C of Ribofuranosides 8a--d in CH3OH
8a 8b 8c 8d
8a
8b
8c
8d
C-1
C-2
C-3
C-4
C-4a
C-5a
C-6
C-7
C-8
C-9
C-9a
115.4 116.8 115.9 116.6
132.3 133.4 132.8 132.5
122.5 122.9 122.2 122.8
127.6 128.2 128.3 128.4
119.5 120.1 119.8 120.3
118.6 118.9 118.4 118.7
126.7 127.1 126.9 127.3
122.6 122.8 122.4 122.2
126.5 126.8 126.2 126.7
116.4 116.4 116.9 116.8
143.5 143.8 143.2 143.6
C-1ꢁ
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C O
100.80
78.45
77.06
73.60
64.08
167.60
102.12
78.62
77.50
74.52
66.70
167.70
103.93
79.41
77.86
73.85
66.20
167.72
100.52
78.90
77.80
73.77
65.90
167.52
Ar(OBr) 126.50–136.52 125.28–136.42 127.06–136.52 125.72–136.86
C-10a 145.8 146.2 146.4 146.6

Potential Antimicrobial Agents 485
8a showed equal activity. ꢀ-Anomer ribofuranosides
showed better activity against all tested organisms.
Compound 8h showed better activity (1.20 and 1.21
against E. coli and F. oxysporium, respecitvely).
2-Formamido-3-chloro/3-phenoxy/3,6-
dimethoxy/3,6-dichloro-2ꢁ-(3ꢁ-nitro-5ꢁ-
trifluoromethyl)diphenylsulfides (4a–d)
A solution of 3 (0.05 mol) in 20 ml of 95% formic
acid was refluxed on a water bath. After 6 h the re-
sultant solution was poured onto crushed ice. The
solid obtained was filtered, washed with water, dried,
and recrystallized from ethanol. 4a: R1 = OCH3;
R2 = OCH3; m.p. = 160–162◦C; yield 70%; Calc. for
C16H13F3N2O5S (402) (Found): C, 47.76 (47.72); H,
3.23 (3.21); N, 6.96 (6.93); IR (KBr, νmax cm−1);
3150 ( NH); 1660 (C O); 1590, 1360 ( NO2); 1320,
1210, 1110 ( CF3); 685 (C S C); 1H NMR (δ): 6.85–
8.00 (Ar H), 8.20 (NH), 4.06 (OCH3). 4b: R1 = Cl;
R2 = Cl; m.p. = 150–152◦C; yield 77%; Calc. for
C14H7Cl2F3N2O3S (411) (Found): C, 40.87 (40.85); H,
1.70 (1.67); N, 6.81 (6.79); IR (KBr, νmax cm−1); 3160
(NH); 1690 (C O), 1590, 1340 ( NO2); 1350, 1250,
1170 ( CF3); 660 (C S C); 750 (C Cl); 1H NMR
(δ): 6.60–8.10 (Ar H), 8.15 (NH). 4c: R1 = OC6H5;
R2 = H; m.p. = 200–202◦C; yield 71%; Calc. for
C20H13F3N2O4S (434) (Found): C, 55.30 (55.28); H,
2.99 (2.96); N, 6.45 (6.44); IR (KBr, νmax cm−1): 3130
(NH); 1680 (C O); 1570, 1320 ( NO2); 1310, 1205,
EXPERIMENTAL
All the melting points were determined in open capil-
lary tubes and are uncorrected. The IR spectra were
recorded on a NICOLET-MEGNA FT-IR 550 spec-
trophotometer in KBr pellets. The NMR spectra were
scanned on a FX 90Q JEOL spectrometer (1H NMR
in CDCl3/DMSO-d6; 13C NMR spectra in CH3OH, us-
ing TMS as internal standard; 19F NMR spectra in
CDCl3, using hexafluorobenzene as internal stan-
dard). The purity of compounds were checked by
TLC using silica gel “G” as adsorbent and visualiza-
tion was accomplished by UV light/iodine. Zinc mer-
captide of 2-amino-benzenethiols were synthesized
by reported methods [27].
2-Amino-3-chloro/3-phenoxy/3,6-dimethoxy/
3,6-dichloro-2ꢁ-(3ꢁ-nitro-5ꢁ-trifluoromethyl)-
diphenylsulfides (3a–d)
1
1150 ( CF3); 665(C S C); H NMR (δ): 6.70–8.05
(Ar H), 8.25 (NH). 4d: R1 = Cl; R2 = H; m.p. = 187–
189◦C; yield 79%; Calc. for C14H8ClF3N2O3S (376.5)
(Found): C, 44.62 (44.58); H, 2.12 (2.09); N, 7.44
(7.42); IR (KBr, νmax cm−1): 3180 (NH); 1685 (C O);
1580, 1185 ( NO2); 1320, 1260, 1180 ( CF3); 675
(C S C); 760 (C Cl); 1H NMR (δ): 6.85–8.10 (Ar H),
8.20 (NH).
A mixture of 1 (0.005 mol), 2 (0.01 mol), and anhy-
drous sodium acetate (0.025 mol) in absolute ethanol
(15 ml) was refluxed for 7–8 h on a water bath. Af-
ter cooling, the resultant precipitate was filtered and
washed with warm water followed by ethanol. The
solid thus obtained was dried and recrystallized from
benzene. 3a: R1 = OCH3; R2 = OCH3; m.p. = 195◦C;
yield 65%; Calc. for C15H13F3N2O4S (374) (Found):
C, 48.13 (48.10); H, 3.47 (3.44); N, 7.49 (7.45); IR
(KBr, νmax cm−1): 3450 ( NH2); 1550, 1375 ( NO2);
1320, 1250, 1150 ( CF3); 650 (C S C); 1H NMR (δ):
6.50–7.30 (Ar H), 5.10 (NH2), 4.20 (OCH3). 3b: R1 =
Cl; R2 = Cl; m.p. = 180◦C; yield 78%; Calc. for
C13H7Cl2F3N2O2S (383) (Found): C, 40.73 (40.71);
H, 1.83 (1.80); N, 7.30 (7.28); IR (KBr, νmax cm−1):
3420 ( NH2); 1590, 1380 ( NO2); 1350, 1230, 1140
( CF3); 660 (C S C); 750 (C Cl); 1H NMR (δ): 6.60–
8.20 (Ar H), 5.40 (NH2). 3c: R1 = OC6H5, R2 = H;
m.p. = 175◦C; yield 72%; Calc. for C19H13F3N2O3S
(406) (Found): C, 56.16 (56.14); H, 3.20 (3.18); N,
6.90 (6.88); IR (KBr, νmax cm−1): 3460 ( NH2); 1560,
1340 ( NO2); 1350, 1220, 1120 ( CF3); 650 (C S C);
1H NMR (δ): 6.80–8.10 (Ar H), 5.25 (NH2). 3d:
R1 = Cl, R2 = H; m.p. = 185◦C; yield 73%; Calc. for
C13H8ClF3N2O2S (348.5) (Found): C, 44.76 (44.72);
H, 2.29 (2.27); N, 8.03 (8.01); IR (KBr, νmax cm−1);
3450 ( NH2); 1565, 1345 ( NO2); 1340, 1245, 1150
( CF3); 665 (C S C); 760 (C Cl); 1H NMR (δ); 6.60–
7.9 (Ar H), 5.30 (NH2).
6-Chloro/6-phenoxy/6,9-dimethoxy/6,9-dichloro-
2-trifluoromethyl-10H-phenothiazines (5a–d)
Alcoholic solution of sodium hydroxide (0.2 in 10 ml
absolute alcohol) was added to an alcoholic solution
(20 ml) of 4 (0.005 mol). The reaction mixture dark-
ened immediately. It was refluxed. After 30 min a
second portion of sodium hydroxide (0.2 g) in ab-
solute alcohol (10 ml) was added and refluxing was
continued for a further 2 h. The mixture was poured
onto crushed ice, and the solid was filtered, washed
with cold water, dried, and recrystallized from
benzene.
10-Chloroacetyl-6-chloro/6-phenoxy/6,9-
dimethoxy/6,9-dichloro-2-
trifluoromethylphenothiazines (6a–d)
A solution of chloroacetyl chloride (0.15 mol) in
dry benzene (50 ml) was added to a solution of
5 (0.1 mol) in 100 ml of dry benzene at room

486 Singh et al.
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temperature with constant stirring and then refluxed
for 4 h. After cooling, benzene was removed under
reduced pressure and the residue was chilled in ice.
The product was separated by filtration, dried, and
recrystallized from ethanol.
N-(2ꢁ,3ꢁ,5ꢁ-tri-O-Benzoyl-ꢁ-D-ribofuranosyl)-6-
chloro/6-phenoxy/6,9-dimethoxy/6,9-dichloro-2-
trifluoromethyl-10H-phenothiazines (8a–d)
Compound 5 (0.01 mol) and ꢁ-D-ribofuranose-1-
acetate-2,3,5-tribenzoate (7) (0.01 mol) in toluene
(30 ml) was stirred at 155–160◦C under vacuum for
15 min in absence of moisture. The vacuum was
broken and the reaction was protected from mois-
ture using a guard tube. Stirring was further contin-
ued for 10 h by applying vacuum for 5 min at ev-
ery hour. The viscous mass thus obtained was dis-
solved in methanol, boiled for 10 min, and cooled to
room temperature. The precipitate was filtered and
the filtrate was evaporated to dryness. The viscous
residue was dissolved in ether, filtered, concentrated,
and kept in refrigerator overnight to get crystalline
ribofuranosides.
N-(2ꢁ,3ꢁ,5ꢁ-tri-O-Benzoyl-ꢀ-D-ribofuranosyl)-6-
chloro/6-phenoxy/6,9-dimethoxy/6,9-dichloro-2-
trifluoromethyl-10H-phenothiazines (8e–h)
Compound 5 (0.01 mol) was refluxed with sugar 7
(0.01 mol) in 1,2-dichloroethane (20 ml) for 4 h un-
der anhydrous conditions. The mixture was cooled
to 0◦C and a solution of SnCl4 (1.6 ml) was added
dropwise with stirring. The completion of reaction
was judged by TLC (2–3 h). The mixture was then
poured on to saturated NaHCO3 solution, extracted
with chloroform, dried over anhydrous MgSO4, and
filtered. The removal of solvent gave ribofuranoside.
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ACKNOWLEDGMENT
Authors are thankful to the Head, Chemistry Depart-
ment, University of Rajasthan, Jaipur for providing
laboratory facilities.
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