Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines

Article abstract of DOI:10.1080/714040982

Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines is reported by Smiles rearrangement of 5-ethoxy- and 5-fluoro-2-formamido-2′- nitrodiphenylsulfides. The later were obtained by the formylation of 2-amino-5-ethoxy 15-fluoro-2′-nitrodiphenylsulfides which were prepared by the condensation of 2-amino-5-ethoxy/5-fluoro-benzenethiols with o-halonitrobenzenes.

Full text of DOI:10.1080/714040982

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines
Thandi Lal Kachhee a , Vandana Gupta a , D. C. Gautam a & R. R. Gupta a
a University of Rajasthan, Jaipur, India
Published online: 18 Jun 2010.
To cite this article: Thandi Lal Kachhee , Vandana Gupta , D. C. Gautam & R. R. Gupta (2003) Synthesis of 7-ethoxy- and 7-
fluoro-phenothiazines, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:12, 2671-2678, DOI: 10.1080/714040982
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Phosphorus, Sulfur, and Silicon, 178:2671–2678, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390252308
SYNTHESIS OF 7-ETHOXY- AND
7-FLUORO-PHENOTHIAZINES
Thandi Lal Kachhee, Vandana Gupta, D. C. Gautam,
and R. R. Gupta
University of Rajasthan, Jaipur, India
(Received February 6, 2003; accepted June 24, 2003)
Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines is reported by
Smiles rearrangement of 5-ethoxy- and 5-fluoro-2-formamido-2ꢁ-
nitrodiphenylsulfides. The later were obtained by the formylation of 2-
amino-5-ethoxy/5-fluoro-2ꢁ-nitrodiphenylsulfides which were prepared
by the condensation of 2-amino-5-ethoxy/5-fluoro-benzenethiols with
o-halonitrobenzenes.
Phenothiazines, have been used as tranquilizer, antihistaminics,1
neuroleptics,2 antiemetics,3−5 diuretics,6,7 sedatives,8 tuberculosta-
tics,9 analgesics,10 and soon. Phenothiazines have also shown anti-
cancer activities.11−14 Therefore, it is considered worthwhile to synthe-
size hitherto unknown phenothiazines in order to make them available
for biomedical investigations.15 Synthesized phenothiazines have been
characterized by IR, 1H NMR, and mass spectral analysis.
RESULTS AND DISCUSSION
In the present investigation, 7-ethoxy/7-flouro-phenothiazines [Va–
d] have been synthesized by Smiles rearrangement16,17 of 5-ethoxy-
and 5-fluoro-2-formamido-2ꢁ-nitrodiphenyl sulfides [IVa–d] in alcoholic
potassium hydroxide solution. The formyl derivatives were pre-
pared by the formylation of resultant diphenylsulfides [IIIa–d] ob-
tained by the condensation of 2-aminobenzenethiols18−21 [I] with
Authors express sincere thanks to CDRI, Lucknow to provide NMR and mass spectra.
Address correspondence to R. R. Gupta, Department of Chemistry, University of
Rajasthan, Jaipur 302004, India.
2671

2672
T. L. Kachhee et al.
o-halonitrobenzenes [II] in ethanolic sodium acetate solution. 2-
Aminobenzenethiols, required in the synthesis of phenothiazines, have
been prepared by the hydrolytic cleavage of 2-aminobenzothiazoles
which were prepared by the action of ammonium thiocyanate22 and
bromine on p-phenitidine and 4-fluoro-2-methyl aniline.
A single-step synthesis of nitrophenothiazines have been achieved by
the condensation of 2-aminobenzenethiol [I] with halonitrobenzene [II]
containing nitro groups at both ortho positions to halogen atom in the
presence of NaOH involving Smiles rearrangement and ring closure
occurs in situ due to combined resonance and inductive effect of two
nitro groups (Scheme 1).
The IR spectra of all the synthesized diphenylsulfides [IIIa–d] ex-
hibit two peaks in the region 3400–3340 cm−1 and 3320–3260 cm−1
due to asymmetric and symmetric vibrations of the primary amino
group. Two peaks observed in the region 1580–1510 cm−1 and 1370–
1330 cm−1 are attributed to the asymmetric and symmetric vibra-
tions of nitro group respectively. The two bands in the regions 1260–
1240 cm−1 and 1060–1020 cm−1 appear in all diphenylsulfides having
OC2H5 group due to C O C asymmetric and symmetric vibrations
respectively. In compound [IIId] two sharp peaks observed at 1360–
1350 cm−1 and 1170–1120 cm−1 can be assigned to C F stretching
vibrations. All the synthesized diphenylsulfides exhibits a single sharp
peak at 810–760 cm−1 due to C Cl stretching vibrations. The peak in
the region 1490–1420 cm−1 and 1370–1290 cm−1 are due to asymmet-
ric and symmetric C H deformation vibrations of CH3 group in com-
pound [IIId]. The IR spectra of all 2-formamido-diphenylsulfides re-
semble the spectra of their parent diphenylsulfides. However a single
peak is observed in the region 3310–3260 cm−1 due to N H stretch-
ing vibrations and an additional peak in the region 1640–1610 cm−1
is obtained due to C O stretching vibrations. Two bands obtained
in the region 1580–1530 cm−1 and 1350–1320 cm−1 can be assigned
to asymmetric and symmetric vibration of nitro group respectively.
Compound [IVd] shows two peaks at 1370–1320 cm−1 and 1160–
1150 cm−1 due to C F stretching vibrations. The two sharp peaks
at 1250–1230 cm−1 and 1070–1040 cm−1 obtained in all compounds
[IVa–d] can be attributed to C O C asymmetric and symmetric vi-
brations due to OC2H5 group respectively. All compounds [IVa–d] ex-
hibits a single sharp peak at 800–760 cm−1 due to C Cl stretching
vibrations.
The IR spectra of all phenothiazines exhibits a sharp peak in the
region 3430–3280 cm−1 due to N H stretching vibrations. Phenoth-
iazines [Va–d] containing no nitro group at 1-position exhibit this band
in the region 3340–3240 cm−1 while in 1-nitrophenothiazines [Ve–h]

Phenothiazines
2673
SCHEME 1 Synthesis of phenothiazines via Smiles rearrangement.

2674
T. L. Kachhee et al.
FIGURE 1
it appears at 3380–3290 cm−1. The shift to a lower frequency region
in 1-nitrophenothiazines suggests a six membered chelation of high
stability through a strong ( NH O N) hydrogen bonding (Figure 1).
1-Nitropheno-thiazines exhibits two peaks of medium intensity in the
region 1500–1570 cm−1 and 1390–1320 cm−1 due to asymmetric and
symmetric vibrations of aromatic nitro groups. The peaks in the re-
gion 1280–1250 cm−1 and 1070–1020 cm−1 are due to asymmetric and
symmetric C O C deformation vibrations of OC2H5 group. The two
peaks in the region 1470–1430 cm−1 and 1350–1290 cm−1 are due to
asymmetric and symmetric C H deformation vibrations of CH3 group.
A single sharp peak in the region 790–720 cm−1 in compounds [Va–
d, Vf and Vh] is due to C Cl stretching vibrations. In compounds
[Ve and Vg] two sharp peaks are observed in the region 1350–1340
cm−1 and 1170–1120 cm−1 are due to C F stretching vibrations of CF3
group.
In NMR spectra phenothiazines without a nitro group at 1-position
exhibit a single peak in the region δ 9.214–8.81 due to N H proton
which is shifted to δ 9.68–9.35 in 1-nitrophenothiazines. The shifting
of this peak towards down field in 1-nitrophenothiazines is ascribed
to intramolecular hydrogen bonding (as NH O N) which has been
also suggested by infrared spectra. All the synthesized phenothiazines
exhibit multiplets in the region δ 8.48–6.64 due to aromatic protons. A
singlet is observed in region δ 2.038–2.20 due to CH3 protons at C9. A
quartet in the region δ 2.96–2.21 and triplet centred in the region δ 1.62–
0.82 are observed due to methylene and methyl protons of ethoxy group
respectively.
Molecular ion peaks are in accordance with their molecular weights.
1-Nitrophenothiazines have exhibited the characteristics of an aro-
matic nitro group10 in the fragmentation besides the other fragmen-
tations caused by different substituents. Moieties M+-30, M+-46 and
M+-47 are observed with variable intensity in 1-nitrophenothiazines
and are ascribed to the loss of NO, NO2 and HNO2 respectively.
1-Nitrophenothiazines exhibit a peak at M+-17 which is assigned to
the loss of OH. radical by Mc-Lafferty rearrangement23−25 as shown in
(Scheme 2).

Phenothiazines
2675
SCHEME 2
EXPERIMENTAL
All the melting points are uncorrected. The purity was checked by
thin layer chromatography and characterized by spectral studies. The
infrared spectra were recorded on FT-IR spectrometer. MAGNA-IR
1
550, NICOLET using potassium bromide discs. H NMR spectra were
recorded on Brucker WM-400 (400 MHz FT-NMR) spectrometers (chem-
ical shift are in δ ppm using TMS as internal standard), the mass spec-
tra were recorded on Jeol D-300 spectrometer using electron ionization
technique. Physical data of synthesized compounds are summarized in
Table I.
Preparation of 2-Amino-5-ethoxy/5-fluoro-
2ꢀ -nitrodiphenylsulfides (IIIa–d)
2-Amino-5-ethoxy/ 5-fluorobenzenethiol [I, 0.01 mmol] was dissolved in
ethanol (20 ml) containing anhydrous sodium acetate (0.01 mmol) and
halonitrobenzene26(II; 0.01 mmol) in ethanol (10 ml) was added. The
reaction mixture was refluxed for 4 h, concentrated, and cooled in an
ice bath overnight. The solid separated out was filtered and washed
with 30% ethanol. Crystallization from methanol afforded the desired
product. Physical data are recorded in Table I.
Preparation of 5-Ethoxy/5-fluoro-2-formamido-
2ꢀ -nitrodiphenylsulfides (IVa–d)
A mixture of diphenylsulfide (IIIa–c, 0.01 mmol) and 90% formic
acid (20 ml) was refluxed for 4 h. The contents were poured into a
beaker containing crushed ice. The solid separated out was filtered and
washed with water until the filtrate was neutral and crystallized from
benzene/methanol.

2676

Phenothiazines
2677
Preparation of 7-Ethoxy and 7-Fluoro-
phenothiazines (Va–d)
To the refluxing solution of formyl derivatives (IVa–d; 0.01 mmol) in
acetone (15 ml) was added an alcoholic solution of potassium hydroxide
(0.2 g in 5 ml ethanol). The contents were heated for .5 h. A second por-
tion of potassium hydroxide (0.2 mmol in 5 ml ethanol) was added to the
reaction mixture and refluxed for 2 h. The contents were poured into
a beaker containing crushed ice. The solid separate out was filtered,
washed with cold water, and finally washed with 30% ethanol. Crystal-
lization from methanol/benzene afforded phenothiazines. The physical
data of synthesized phenothiazines are tabulated in Table I.
Preparation of 1-Nitrophenothiazines (Ve–h)
To a stirred suspension of halonitrobenzene (2, 0.01 mmol), 2-amino-5-
ethoxybenzenethiol (I, 0.01 mmol), sodium hydroxide (0.01 mmol) and
absolute ethanol (20 ml) was refluxed for 2 h. The reaction mixture was
concentrated on water bath, cooled down, and filtered. The solid sepa-
rated out was washed with hot water and 30% ethanol. The crystalliza-
tion from methanol/acetone afforded 1/9-nitrophenothiazines. Physical
data are included in Table I.
REFERENCES
[1] Y. Sugimoto, T. Tarumi, Q. E. Zhao, Y. Fujji, and C. Kamei, Methods Find. Exp. Clin.
Pharmacol., 20(6), 457–462 (1998); Chem. Abstr., 130, 75926 (1999).
[2] E. N. Makareeva, E. L. Lozovskaya, and I. I. Saphezhinskii, Biofizika, 43(2), 181–
185 (1998); Chem. Abstr., 131, 84963 (1999).
[3] P. I. Williams, and M. Smith, Eur. J. Anaestheiol, 16(9), 639–645 (1999); Chem.
Abstr., 131, 332076 (1999).
[4] K. Mystakidou, S. Befon, C. Liossi, and L. Vlachos, Cancer, 83(6), 1214–1223 (1998);
Chem. Abstr., 130, 32919 (1999).
[5] S. Singh, P. K. Peshin, and D. Krishnamurthy, Indian, Vet. J., 71(10), 983–987 (1994);
Chem. Abstr., 122, 96226 (1995).
[6] V. V. Vorontsov, I. M. Lerner, and E. I. Shchelkuno, Farmocal. Toksikol., 43(1), 81
(1980); Chem. Abstr., 92, 157547 (1980).
[7] Bristol-Myres Co. Belg., 838, 243 (1976); Chem. Abstr., 87, 23310 (1977).
[8] H. V. Petts and B. J. Pleuvry, Br. J. Anaesth., 55, 437 (1983); Chem. Abstr., 99, 16444
(1983).
[9] R. L. Gupta, S. Jain, V. Talwar, H. C. Gupta, and P. S. Murthy, Indian J. Clin.
Biochem., 13(2), 92–97 (1998); Chem. Abstr., 130, 346919 (1999).
[10] G. Acs, M. Palkovits, and P. M. Blumberg, J. Pharmacol. Exp. Ther., 274(3), 1090–
1098 (1995); Chem. Abstr., 123, 235739 (1995).
[11] R. R. Gupta, ed., Phenothiazines and 1,4-Benzothiazines-Chemical and Biomedical
Aspects (Elsevier, Amsterdam, 1988).

2678
T. L. Kachhee et al.
[12] M. Gordon, in Medicinal Chemistry, edited by M. Gordon, Academic Press, New
York, (1967), vol. 2, p. 119.
[13] H. Keyzer, G. M. Eckert, I. S. Forrest, et al., eds., Thiazines and Structurally
Related Compounds, Proceedings of Sixth International Conference on Phenoth-
iazines and Structurally Related Psychotropic Compounds, Pasadena, California,
September 11–14 1990, (Krieger Publishing, Malabar, FL, 1992).
[14] A. R. Safa, Chimia, 53(6), 299 (1999); Chem. Abstr., 131, 193907 (1999).
[15] C. Bodea and I. Silberg, Advances in Heterocyclic Chemistry, edited by A. R.
Katritzky and A. J. Boulton (Academic Press, New York and London, 1968),
vol. 9.
[16] C. F. Weight and S. Smiles, J. Chem. Soc., 340 (1935).
[17] A. A. Levy, H. C. Rains, and S. Smiles, J. Chem. Soc., 3264 (1931).
[18] R. R. Gupta, S. K. Jain, N. K. Goswami, and G. S. Kalwania, Heterocycles, 14, 831
(1980).
[19] E. Ongini, E. Bonizzoni, N. Ferri, S. Milani, and M. Trampus, J. Phamacol. Exp.
Ther., 266(2), 726–731 (1993); Chem. Abstr., 119, 262286 (1993).
[20] B. L. Roth, S. Tandra, L. H. Burgess, D. R. Sibley, and H. Y. Mettzer, Psychophar-
macology, 120(3), 365–368 (1995); Chem. Abstr., 123, 24661 (1995).
[21] M. Sansone, M. Battaglia, and F. Pavona, Pharmacol. Biochem. Behav., 62(4), 613–
618 (1999); Chem. Abstr., 131, 626 (1999).
[22] R. Adams, Organic Reactions, 3, 259 (1957).
[23] F. W. Mc-Lafferty, Anal. Chem., 31, 82 (1959).
[24] F. W. Mc-Lafferty, Interpretation of Mass Spectra (New York, W. A. Benjamin, 1973),
2nd ed.
[25] F. W. Mc-Lafferty, Mass Spectrometry of Organic Ions, (New York, Academic Press,
1963).
[26] R. S. Rathore, M. Jain, A. Gupta, V. Saraswat, V. Gupta, and R. R. Gupta, Pharmazie,
47, 1945 (1992).