On the 3-aminophenothiazine synthesis

Article abstract of DOI:10.1081/SCC-120022480

Investigation of the key step of 3-aminophenothiazine (5) synthesis, that is thiation of N-(4-phenylaminophenyl)-phthalimid (3) was carried out. The best results were achieved using microwave irradiation, when 55% of the pure thiation product 3-phalimidophenothiazine (4) were isolated in 10-20 min reaction time.

Full text of DOI:10.1081/SCC-120022480

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On the 3-Aminophenothiazine Synthesis
Mária Mečiarová a , Štefan Toma a & Peter Magdolen a
a Comenius University, Faculty of Natural Sciences , Department of Organic Chemistry ,
Bratislava, Slovak Republic
Published online: 21 Aug 2006.
To cite this article: Mária Mečiarová , Štefan Toma & Peter Magdolen (2003) On the 3-Aminophenothiazine Synthesis,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:17,
3049-3054, DOI: 10.1081/SCC-120022480
To link to this article: http://dx.doi.org/10.1081/SCC-120022480
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 17, pp. 3049–3054, 2003
On the 3-Aminophenothiazine Synthesis
*
Maria Meciarova, Stefan Toma, and Peter Magdolen
Comenius University, Faculty of Natural Sciences,
Department of Organic Chemistry, Bratislava,
Slovak Republic
ABSTRACT
Investigation of the key step of 3-aminophenothiazine (5) synthesis,
that is thiation of N-(4-phenylaminophenyl)-phthalimid (3) was car-
ried out. The best results were achieved using microwave irradiation,
when 55% of the pure thiation product 3-phalimidophenothiazine (4)
were isolated in 10–20 min reaction time.
Key Words: Aminophenothiazine; Microwave irradiation.
Phenothiazines are well known as intermediates for pharmaceuticals,
they are active as insecticides as well as antioxidants. These compounds
are usually prepared by thiation of diphenylamines with octasulfur.[1]
*Correspondence: Stefan Toma, Comenius University, Faculty of Natural
Sciences, Department of Organic Chemistry, Mlynskadolina CH-2, SK-842-15.
Bratislava, Slovak Republic; Fax: þ421-2-60296690; E-mail: toma@fns.uniba.sk.
3049
DOI: 10.1081/SCC-120022480
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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Meciarova, Toma, and Magdolen
RESULTS AND DISCUSSION
The reaction course of 3-aminophenothiazine (5) is depicted in Sch. 1.
Synthesis of 3-aminophenothiazine (5) started with the protection of the
primary amino group of 4-aminodiphenylamine (1). Heating the reaction
mixture containing 4-aminodiphenylamine (1), phthaloic anhydride (2),
and sodium acetate in acetic acid to reflux for 2 h resulted in 92% yield of
N-(4-phenylaminophenyl)-phthalimid (3) (Lit.[2] 99%).
To prepare 3-phalimidophenothiazine (4), we first tried to repeat the
procedure desribed in literature.[2] N-(4-Phenylaminophenyl)-phthalimid
(3), octasulfur and diiodine were dissolved in 1,2-dichlorobenzene
and refluxed (180ꢀC) for 2 h. After cooling to room temperature, black
solid material was filtered off and crystallized from acetone/water (7:2)
mixture. 3-Phthalimidophenothiazine (4) was obtained in 10% yield
(Table 1, Entry 1) (Lit.[2] 30.8%).
In continuation, we tried to change the solvent. Decahydronaphtha-
lene (DecalinÕ) was used instead of 1,2-dichlorobenzene. Reaction
1
2
3
3
4
4
5
Scheme 1.

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3-Aminophenothiazine Synthesis
3051
Table 1. Results of thiation of N-(4-phenylaminophenyl)-phthalimid (3) by
different methods.
Conversion
of 3 (%)
Entry
Reaction conditions
1
1,2-Dichloromethane, thermal heating,
180ꢀC, 2 h
10a
2
3
4
5
DecalinÕ, thermal heating, 190ꢀC, 4 h
DecalinÕ, ultrasonic irradiation, 95ꢀC, 1 h
Nitrobenzene, thermal heating, 211ꢀC, 2h
Solvent-free, microwave irradiation, 420 W,
Tfinal ¼ 236ꢀC, 10 min
15
0
0b
100 (55c)
6
7
8
Solvent-free, microwave irradiation, 240 W,
Tfinal ¼ 228ꢀC, 20 min
100 (55c)
50
DecalinÕ, microwave irradiation, 360 W,
Tfinal ¼ 180ꢀC, 30 min
Solvent-free, thermal heating, 200ꢀC, 3 h
100 (50c)
aYield isolated by crystallization from acetone/water (7:2) mixture.
bYield detected by TLC.
cYields isolated by chromatography.
mixture was heated to reflux (190ꢀC) for 4 h. Conversion of N-(4-phenyl-
aminophenyl)-phthalimid (3) was after 4 h 15% only (Table 1, Entry 2),
what is probably due to the poor solubility of the reactants in the solvent.
To improve the solubilty of the reactants in DecalineÕ, the reaction
was performed under ultrasonic irradiation. An immersed horn
reactor (20 kHz, 300 W) was used as a source of ultrasonic irradiation.
The temperature of reaction mixture attained after 1 h of irradiation 95ꢀC
and just starting material N-(4-phenylaminophenyl)-phthalimid (3) was
detected in the reaction mixture by TLC (Table 1, Entry 3).
When nitrobenzene was used as a solvent and the reaction of
N-(4-phenylaminophenyl)-phthalimid (3) with octasulfur under diiodine
catalysis was performed at the temperature of its boiling point (211ꢀ) for
2 h, no product was detected (Table 1, Entry 4) in the reaction mixture
(TLC). Black tarry material was isolated, what is probably result of
strong oxidizing ability of the solvent.
Thiation of diphenylamine with octasulfur catalyzed by diiodine
was described[1], working under solvent-free conditions under microwave
irradiation. The yield of phenothiazine was 87% after 2 min of reaction.
We decided therefore to apply microwave irradiation to our reaction
mixture. The mixture of N-(4-phenylaminophenyl)-phthalimid (3),

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Meciarova, Toma, and Magdolen
octasulfur and diiodine was exposed to microwave irrradiation. Final
temperature attained in the reaction mixture was 228 and 236ꢀC, respec-
tively. Conversion of N-(4-phenylaminophenyl)-phthalimid (3) was 100%
after 10–20 min of irradiation (Table 1, Entries 5, 6). Yield of 3-phthali-
midophenothiazine (4) was 55% after column chromatography. In the
case when this reaction was performed under microwave irradiation with
DecalineÕ as a solvent, temperature of the reaction mixture was after
30 min irradiation 180ꢀC and the conversion of N-(4-phenylaminophe-
1
nyl)-phthalimid (3) was acccording to H NMR spectra 50%.
To achieve 100% conversion of N-(4-phenylaminophenyl)-phthali-
mid (3) in solvent-free thiation reaction without microwave irradiation,
it was necessary to heat the reaction mixture in oil bath under magnetic
stirring for 3 h. Yield of 3-phthalimidophenothiazine (4) was 50%
(Entry 8).
An attempt has been made on thiathion of N-phenylphenylene
diamine (1) with unprotected primary amino group. The reaction resulted
in formation of unidentified products of oxidation and polymerization
reactions.
Deprotection of the amino group was performed with hydrazine
hydrate solution in ethanol. Crude product was purified by column
chromatography and the yield of chromatographed product was 48%
(lit.[2] 42% after crystallization from toluene). Purification of the crude
product by crystallization from toluene resulted in thick oil material.
EXPERIMENTAL
1H NMR spectra were measured on Varian Gemini 2000 instrument,
working frequency 300 MHz and 75 MHz, respectively, with DMSO as
the solvent and tetramethylsilane as an internal standard. Melting points
were determined on a Kofler apparatus and are not corrected. All micro-
wave experiments were carried out in the SYNTHEWAVE 402,
PROLABO reactor.
Protection of Primary Amino Group
N-phenylphenylene diamine 1 (36.8 g, 0.2 mol), phthaloic anhydride
2 (29.6 g, 0.2 mol), anhydrous sodium acetate (26.2 g, 0.32 mol) were
refluxed in acetic acid (360 mL) for 2 h. Reaction mixture was then
cooled down to the room temperature and the yellow solid precipitated.

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3-Aminophenothiazine Synthesis
3053
The product N-(4-phenylaminophenyl)-phthalimid (3) was filtered off
with suction and washed with water and acetone.
N-(4-Phenylaminophenyl)-phthalimid (3). Yield 92%; m.p. 277–279ꢀC
(lit.[2] 273–274ꢀC); ꢀH (300 MHz, DMSO): 6.88 (t, J 7.2 Hz, 1H),
7.13–7.17 (m, 4H), 7.25–7.30 (m, 4H), 7.88–7.97 (m, 4H), 8.40 (s, NH).
Thiation of N-(4-Phenylaminophenyl)-phthalimide
N-(4-Phenylaminophenyl)-phthalimid 3 (15 g, 48 mmol), octasulfur
(7.5 g, 235 mmol), diiodine (0.75 g, 3 mmol) were ground together in a
mortar and the mixture was then microwave irradiated. The final tem-
perature was 228–236ꢀC. 100% conversion of N-(4-phenylaminophenyl)-
phthalimid (3) was achieved after 10–20 min of irradiation. Reaction
mixture was cooled down to room temperature and then dissolved in
DMSO (300 mL) in boiling water bath. DMSO solution was after cooling
poured in water (800 mL). Yellow solid, which precipitated from water,
was collected by filtration with suction, washed with ether and dried
under reduced pressure.
3-Phthalimidophenothiazine (4). Yield 55%; m.p. 258ꢀC (lit.[2]
255–257ꢀC); ꢀH (300 MHz, DMSO): 6.70–6.82 (m, 2H), 6.95 (dd, J 7.5 Hz,
1.2 Hz, 1H), 6.99–7.06 (m, 4H), 7.87–7.96 (m, 4H), 8.83 (s, NH).
Deprotection of Primary Aminogroup
3-Phthalimidophenothiazine 4 (10 g, 29 mmol), hydrazine hydrate
98–100% solution (2.76 mL, 55.3 mmol) were suspended in ethanol
(100 mL) under magnetical stirring and heating to 60–70ꢀC for 2.5 h.
After the reaction, precipitated phthaloyl hydrazide was filtered
off. Ethanol from fitrate was evaporated under reduced pressure and
the solid portion was dissolved in diethyl ether. Undissolved particles
were filtered off and ether was evaporated from the filtrate. Crude
product was purified by column chromatography on Al2O3 and 1:1 mix-
ture of toluene/ethyl acetate with 5% of triethylamine was used as the
eluent.
3-Aminophenothiazine (5). Yield 48%; m.p. 140–142ꢀC (lit.[2]
139–141ꢀC); ꢀH (300 MHz, DMSO): 4.78 (s, NH2), 6.28–6.35 (m, 2H),
6.60 (dd, J 8.0 Hz, 1.2 Hz, 1H), 6.70–6.75 (m, 2H), 6.92–7.02 (m, 2H), 8.14
(s, NH); ꢀC (75 MHz, DMSO): 111.59, 113.15, 113.81, 115.07, 116.73,
119.55, 120.44, 126.13, 127.15, 131.64, 137.40, 143.69.

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3054
Meciarova, Toma, and Magdolen
ACKNOWLEDGMENTS
Our thanks are due to Dr. Eva Solcaniova from Comenius
University, Faculty of Natural Sciences, Institute of Chemistry for
NMR measurements, and to the Slovak Grant Agency VEGA for the
financial support ( Grant No. 1/7348/20).
REFERENCES
1. Villemin, D.; Vlieghe, X. Sulfur Lett. 1998, 21, 191.
2. Skorodumov, V.A.; Zhuravlev, S.V.; Panova E.D. Chimia
Geterocycl. Soed. 1967, 88.
Received in the Netherlands November 11, 2002