The 2-(10H-phenothiazinyl) -1,3-dithiol-2-yliu

Dalila Belei

Elena Bicu

Laura Gabriela Sarbu

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REV. CHIM. (Bucharest) ♦ 65 ♦ No. 2 ♦ 2014 http://www.revistadechimie.ro 249
Synthesis of Mesoionic [2-(10H-phenothiazinyl)-1,3-
dithiolium]phenolates
LAURA GABRIELA SARBU1, ELENA BICU1, DALILA BELEI1*
1 “Al. I. Cuza” University of Iasi, Department of Chemistry, 11 Carol I Blvd., 700506, Iasi, Romania
The 2-(10H-phenothiazinyl)-1,3-dithiol-2-ylium salts have been synthesized by the
heterocyclocondensation of the corresponding hydroxyphenacyl dithiocarbamates. The superacidic
mixture of P2O5 : H2SO4 (1:10) has been developed as a novel dehydration agent, which is extremely
efficient for the products that are prone to nucleophilic attack, especially hydrolysis.  The treatment of
1,3-dithiol-2-ylium salts with a saturated aqueous solution of NaHCO3  has provided the corresponding
mesoionic phenolates.
Keywords: phenothiazines, dithiocarbamates, dithiolium salts, mesoionic compounds
Synthetic and biosynthetic heterocycles have
widespread therapeutic uses, such as antibacterial,
antifungal, antimycobacterial, trypanocidal, anti-HIV
activity, antitubercular, antimalarial, herbicidal, analgesic,
antiinflammatory, muscle relaxants, anticonvulsant,
anticancer and lipid peroxidation inhibitor, hypnotics,
antidepressant, and antitumoral agents [1-5]. Between
them, sulfur and nitrogen-containing heterocyclic
compounds have maintained the continuous interest of
researchers [6-15]. Phenothiazine derivatives are an
important class of organic compounds due to their varied
biological and chemical properties. Phenothiazines and
related compounds have shown diverse biological activities
[16, 17]. A slight variation in the substitution pattern on the
phenothiazine often causes a marked difference in
activities and therefore phenothiazines with various
substituents are being synthesized and tested for activities
in search of better medicinal agents. An important
modification of the parent phenothiazine structure has been
carried out by the introduction of a substituent at the
thiazine nitrogen atom.
On the other hand, 1,3-dithiolium systems are well
known for the reactivity of the C(2)-position towards
nucleophiles [18]. Besides the synthetic interest for these
reactions, it should be noted that the nucleophilic addition
of the purinic bases of DNA to the model compounds was
postulated as the Maxam-Gilbert mechanism for the
biological activity of electrophilic substrates [19]. Moreover,
1,3-dithiolium salts are well-known precursors of
tetrathiafulvalenes (TTF), which in turn are notable π-
electron donors in organic metals [20]. Although
tetrathiafulvalenes are well-known electron donor
systems, a variety of acceptor units have been investigated,
special attention being paid to cationic systems [21]. Of
special interest are systems where the donor moiety is
linked through a  π- or  σ-bonded bridge to the acceptor
moiety [22-26]. Heteroatoms may act as auxiliary donors
or acceptors and improve the overall polarizability of the
chromophore. In this context, investigations on a series of
(1,3-dithiolium-2-yl)phenolates showed that 1,3-dithiolium
ions can also serve as an acceptor moiety in intramolecular
charge-transfer systems [27]. Prompted by these facts,
we decided to investigate the synthesis of a combined
system with a direct link between the 1,3-dithiolium and
phenothiazine moieties.
* email:dalila@uaic.ro
Experimental part
Analysis methods
Melting points were obtained on a Mel-Temp II apparatus
and are uncorrected. IR spectra were recorded on a Bruker
Tensor 27 instrument. NMR spectra were recorded on a
Bruker DPX-300 spectrometer. Chemical shifts are reported
in ppm downfield from TMS. Elemental analyses (C, H, N,
and halogen) were conducted using the CE440 Elemental
Analyser; the results were found to be in good agreement
(± 0.25%) with the calculated values.
Synthesis
Scheme 1. The synthesis of 10H-phenothiazinyl carbodithioates 3
2-(2-Hydroxyphenyl)-2-oxoethyl-10H-phenothiazinyl-10-
carbodithioate (3a)
General procedure
To a solution of ω-bromo-2-hydroxyacetophenone 2a
(2.15 g, 0.01 mol) in acetone (50 mL) a solution of lithium
10H-phenothiazine-10-carbodithioate 1 (2.18 g, 0.01 mol)
dissolved in acetone/water (50 mL, 1:1) was added. The
mixture was heated under refluxed for 10 min, then cooled
and poured into cold water (200 mL). The precipitate was
filtered, dried off and recrystallized from dioxane (10 mL/
g). Yield 3.42 g (85%). Analytical and spectral data of
carbodithioates 3a-d are presented in table 1.
4-(2-Hydroxyphenyl)-2-(10H-phenothiazinyl)-1,3-dithiol-2-
ylium hydrogen sulphate (4a)
General procedure
To a mixture of P2O5 : H2SO4 (1:10, 10 mL) carbodithioate
3a (2.04 g, 5 mmol) was added under stiring at 0oC. The
 REV. CHIM. (Bucharest) ♦ 65♦ No.2 ♦ 2014http://www.revistadechimie.ro250
reaction mixture was stirred at room temperature for 30
min and then poured in cold water (100 mL). The
precipitate was filtered, dried off and recrystallized from
MeCN (100mL/g). Yield 1.95 g (80%). Analytical and
spectral data of 1,3-dithiolium perchlorates 4 are presented
in table 2.
2-[2-(10H-Phenothiazinyl)-1,3-di thiol -2-y l ium-4-
yl]phenolate (5a)
General procedure
To a saturated aqueous solution of sodium hydrogen-
carbonate (50 mL) 1,3-dithiolium hydrogen sulphate 4a
(0.49 g, 1 mmol) was added. Carbon dioxide evolved and
the reaction mixture became yellow. After 2 h under
vigorous stirring at room temperature, the orange-red solid
was filtered off, washed with water, and dried.
Recrystallization from DMF-AcOMe afforded the pure
product. Yield 0.37 g (99%). Analytical and spectral data of
1,3-dithiolium phenolates 5 are presented in table 3.
Results and discussions
The synthesis of phenothiazinyl carbodithioates 3a-d has
been accomplished by treatment of lithium 10H-
phenothiazinyl-10-carbodithioate (1) with various
substituted ω-bromo-2-hydroxyacetophenones 2a-d
(scheme 1).ω-Bromo-2-hydroxyacetophenones were
synthesized according to the literature procedures. Thus,
compound 2a was obtained by Fries rearrangement of the
corresponding ester [28], while compounds 2b and 2d by
regioselective bromination of 2-hydroxyacetophenone [29,
30], and 2-hydroxypropiophenone [31], respectively.
The synthesis of 2-dialkylamino-1,3-dithiolium salts is
well-known in the literature [32, 33]. The most used method
consists in heterocyclocondensation of the corresponding
dithiocarbamates [34-38]. However, special experimental
conditions must be used for sensitive precursors. Typical
cyclization agents have failed to provide the desired 1,3-
dithiolium salts with the phenothiazine moiety at the 2
position. Even in the presence of a gentle cyclization agent,
a mixture of MeSO3H : P2O5 (10:1) [39],
 decomposition of
the substrate has occurred. Although the cyclization
reaction takes place, the presence of the aromatic amine
moiety at the 2-position of the 1,3-dithiol-2-ylium ring
increases the sensibility towards nucleophiles, especially
water. Most likely, hydrolysis occurs during the work-up.
This type of reaction is known to trigger the ring opening,
followed by decomposition of the substrate. In order to
minimize the side reactions, we decided to considerable
increase the hydrophilic properties of the cyclization agent
by using a freshly prepared mixture of P2O5 : H2SO4 (1:10).
Rather surprisingly, a literature survey revealed that this
mixture was not previously used as a dehydrating agent.
With this novel cyclization reagent we successfully
synthesized 1,3-dithiol-2-ylium salts 4 a-d as hydrogen
sulfates in good yields (75-85%,  scheme 2).
The cyclization of 10H-phenothiazinyl carbodithioates 3
to the corresponding 1,3-dithiol-2-ylium salts was
accompanied by significant changes in the spectral
features. The IR spectra revealed the disappearance of the
carbonyl absorption band from the region of 1625 - 1635
cm-1 and the appearance of a very strong and broad band
due to the hydrogen sulphate anion (ca. 1150 cm-1). Nuclear
magnetic resonance spectra also indicated that the
heterocyclocondensation has occurred through the
disappearance of the signal for aliphatic hydrogens (4.7 -
4.9 ppm) and the appearance of a new signal at lower
field (ca. 8.3 ppm) for the C(5) proton of 1,3-dithiolium
ring. Consequently, due to the positive charge associated
to a part of the 1,3-dithiolium ring, the signal corresponding
to the C(2) atom appears at a very low field, around 190
ppm.
The treatment of these compounds with an aqueous
solution of NaHCO3 leads to the corresponding phenolates
5a-d (scheme 2). These compounds were isolated as
orange-red crystalline products that present the features
Table 1
ANALYTICAL AND SPECTRAL DATA
OF DITHIOCARBAMATES 3
Scheme 2. Cyclization of 10H-phenothiazinyl
carbodithioates 3. (i) P2O5 / H2SO4 (1:10), 0 °C;
(ii) NaHCO3 (aq.)
REV. CHIM. (Bucharest) ♦ 65 ♦ No. 2 ♦ 2014 http://www.revistadechimie.ro 251
of mesoionic compounds [40]. Recently, the comparative
study of UV-Vis absorption spectra of 2-, 3-, and 4-[2-
(pyrrolidin-1-yl)-1,3-dithiol-2-ylium-4-yl]phenolates has
shown that the color of these zwitterionic compounds is
due to a charge transfer between electron-rich and
electron-deficient regions of the molecules and not to the
contribution of quinoid structures in the ground states [27].
Usually, the intramolecular charge-transfer UV-Vis
absorption of such chromophores results from a charge
transfer from the HOMO of the donor part to the LUMO of
the acceptor part. Most likely, the bathochromic shift
recorded for mesoionic phenolates 5 is a consequence of
an extended delocalization over the acceptor part.  The
presence of a hydroxy substituent in the ortho-position
induces an extended delocalization of the negative charge
up to the C(5) atom of the dithiolium ring (scheme 3).
Conclusions
In conclusion, a new method for heterocyclo-
condensation of 10H-phenothiazine-10-carbodithioates
has been accomplished using a superacidic mixture of
P2O5 : H2SO4 (1:10). The resulting 1,3-dithiolium salts have
been converted to the corresponding mesoionic phenolates
under mild basic conditions.
Acknowledgments : This work was supported by a grant of the
Romanian National Authority for Scientific Research, CNDI– UEFISCDI,
project number 51/2012.
Table 2
ANALYTICAL AND SPECTRAL DATA OF
1,3-DITHIOLIUM PERCHLORATES 4
Table 3
ANALYTICAL AND SPECTRAL DATA OF
MESOIONIC 1,3-DITHIOLIUM
PHENOLATES 5
Scheme 3. Mesoionic phenolates 5
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Manuscript received: 17.09.2013


Synthesis of Mesoionic [2-(10H-phenothiazinyl)-1,3- dithiolium]phenolates

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Synthesis of Mesoionic [2-(10H-phenothiazinyl)-1,3- dithiolium]phenolates

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