Thiourea-Mediated Regioselective Synthesis of Symmetrical and

Unsymmetrical Diversied Thioethers

Pitchai Manivel,

Kamalakannan Prabakaran,

Varadhan Krishnakumar,

Fazlur-Rahman Nawaz Khan,*

,
and Thandavarayan Maiyalagan

Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT-University,
Vellore 632 014, Tamil Nadu India

Materials Science and Engineering Program The University of Texas at Austin, Austin, Texas 78712, United States
*S Supporting Information
ABSTRACT: An ecient and simple thiourea-mediated regioselective synthesis of symmetrical and unsymmetrical diversied
thioethers is reported. The regioselective reaction avoids byproduct formation and oers simplied methodology, wider
applicability, and easy workability and an environmentally friendly approach toward symmetrical and unsymmetrical thioethers.
The mechanism of formation of thiols and symmetrical and unsymmetrical thioethers involving a sulfur surrogate is described.
1. INTRODUCTION
Organo sulfur compounds, especially thiols, play a signicant
role because of the presence of a sulfur atom, a reactive center
of variable valency, and form an important part in many
chemical transformations and biochemical processes as
metabolic products.
1
Organosulfur compounds such as thiols
and thioethers are versatile intermediates for synthetic
transformations.
2
The photochemical reactions of aryl halides
with thiourea aord aryl methyl suldes, diaryl suldes, diaryl
disuldes, and arylthiols.
3
Several methodologies in the
regioselective synthesis of thioethers are known;
4
however,
they suer from regiocontrol, side product formation of
disuldes by self-oxidation, etc. For example, there are reports
on thioether preparations utilizing thiourea, such as the reaction
of pyrrole with iodine or potassium triiodide and thiourea with
the formation of isothiouranium iodides, which react with
halides to oer thioethers; however, this required a two-step
reaction and also the involvement of additives such as hydrazine
hydrates to avoid side products.
5
Similarly, photoinduced
reactions of aryl halides and a thiourea anion aord arene
thiolate ions in dimethyl sulfoxide (DMSO), which upon
subsequent aliphatic nucleophilic substitution yield aryl methyl
suldes, also with the formation of disuldes; this reaction again
required the initiator t-BuOK, irradiation for 3 h to form a
thiolate anion, and subsequent reaction with aryl halides
3a
to
aord a mixture of products including dehalogenated arenes,
disuldes, etc. There is a report on thioethers from the
chlorodipicolinates utilizing thiourea; these reactions exclu-
sively provide symmetrical thioethers.
3b
In order to overcome
these drawbacks, an eort was made to develop an ecient
methodology for the regioselective synthesis of symmetrical
and unsymmetrical thioether, which is reported. It is evident
that the amount of thiourea plays an important role in the
regioselective control of thiol formation of symmetrical and
unsymmetrical thioethers (Scheme 1).
2. EXPERIMENTAL SECTION
2.1. Methods and Materials. Melting points were
measured on a open-capillary melting point apparatus and are
uncorrected. The purity of the compounds was checked using
precoated thin-layer chromatography (TLC) plates (Merck,
60F-254). IR spectra (KBr, in cm
1
) were recorded on a
PerkinElmer BX series Fourier transform infrared (FTIR)
spectrophotometer.
1
H NMR (400 MHz) and
13
C NMR (100
MHz) spectra were recorded on a Bruker 400 MHz
spectrometer in CDCl
3
or DMSO (with tetramethylsilane for
1
H NMR and DMSO for
13
C NMR as internal references).
Liquid chromatographymass spectrometry (LCMS) anal-
yses were performed with a LCMS Agilent 1100 series ion trap.
2.2. General Preparation of 1-Chloroisoquinolines
1a1l. 3-Arylisoquinolinone (15 g, 0.068 mol) and phosphoryl
chloride (90 mL) were mixed. The mixture was reuxed
overnight under a nitrogen atmosphere in an oil bath until TLC
showed completion of the reaction. Then the reaction mixture
was added to ice-cold water, and it was extracted with ethyl
acetate. The extract was dried over anhydrous sodium sulfate.
Removal of the solvent under vacuum gave a crude product,
which was further puried by column chromatography on silica
gel (230400 mesh) with ethyl acetatehexane (2%) as the
eluent to aord the pure products 1-chloro-3-phenylisoquino-
line (1a) in 92% yield, which are characterized by their
1
H and
13
C NMR spectra and compared with reports in the
literature.
6,7
2.3. General Procedure for the Synthesis of 3-
Substituted Isoquinoline-1-thiols 3a3l. 1-Chloro-3-aryli-
soquinoline (1; 2.04 mmol, 1.0 equiv) and thiourea (2; 1.938
mmol, 0.95 equiv) were mixed in an absolute ethanol solvent
(10 mL, 20 vol) at ambient temperature under a nitrogen
Received: January 11, 2014
Revised: March 29, 2014
Accepted: April 14, 2014
Published: April 14, 2014
Article
pubs.acs.org/IECR
2014 American Chemical Society 7866 dx.doi.org/10.1021/ie500119p | Ind. Eng. Chem. Res. 2014, 53, 78667870
atmosphere. The resulting mixture was reuxed for 6 h. The
reaction progress was monitored by TLC. Usually all reaction
completed in a 612 h period; upon completion, the reaction
mixture was cooled to ambient temperature, and the product
slowly crystallized and was ltered o, washed with 5 mL of
petroleum ether, and dried under reduced pressure over a
period of 1 h. In some cases, the solid was not formed at this
stage; under such circumstances, ethanol was completely
stripped o and 10 mL of petroleum ether was added. Solid
precipitates were ltered and dried under reduced pressure over
a period of 1 h. A yellow crystalline solid was obtained in all
cases with high purity and good yield (7991%).
2.4. General Procedure for the Synthesis of Sym-
metrical Thioethers 4a4k. Chloro compounds 1 (2.04
mmol, 1.0 equiv) and thiourea 2 (1.02 mmol, 0.5 equiv) were
mixed in an absolute ethanol solvent (10 mL, 20 vol) at
ambient temperature under a nitrogen atmosphere. The
resulting mixture was reuxed for 6 h. The reaction progress
was monitored by TLC. Usually all reaction completed in a 6
8 h period; upon completion, the reaction mixture was cooled
to ambient temperature, and the product slowly crystallized and
was ltered o, washed with 5 mL of petroleum ether, and
dried under reduced pressure over a period of 1 h. A yellow
crystalline solid was obtained in all cases with high purity and
good yield (7995%).
2.5. General Procedure for the Synthesis of Unsym-
metrical Thioethers 6a6e. Chloro compounds 1a (2.04
mmol, 1.0 equiv) and thiourea 2 (1.938 mmol, 0.95 equiv)
were mixed in an absolute ethanol solvent (10 mL, 20 vol) at
ambient temperature under a nitrogen atmosphere. The
resulting mixture was reuxed for 6 h. The reaction progress
was monitored by TLC. After 6 h, the reaction mixture was
cooled to ambient temperature. At ambient temperature, R
1
Cl
(5; 2.04 mmol) was added, and reux was continued for a
period of 68 h. Upon completion, the reaction mixture was
cooled to ambient temperature, and the product slowly
crystallized and was ltered o, washed with 5 mL of petroleum
ether, and dried under reduced pressure over a period of 1 h. A
yellow crystalline solid was obtained in all cases with high
purity and good yield (8491%).
3. RESULTS AND DISCUSSION
In a continuation of our research in isoquinolines,
6
initially 3-
substituted chloroisoquinolines
7
were similarly derived from
homophthalic acid, which were when thionated with equimolar
thiourea in ethanol and aorded thiols (Scheme 2) successfully
in 6 h with good yield.
Optimization of the reaction conditions was carried out with
thionation of 1-chloro-3-(4-chlorophenyl)isoquinoline 1b and
Scheme 1. Synthesis of Symmetrical and Unsymmetrical Thioethers and 3-Arylisoquinoline-1-thiols
Scheme 2. Synthesis of 3-Arylisoquinoline-1-thiol 3b
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thiourea 2 as the model reaction (Scheme 2 and Table 1). As
shown in Table 1, the reaction proceeds with equimolar
thiourea, with an excellent product yield. However, higher
concentration reduced the yields (Table 1, entries 57)
because of the formation of a disulde byproduct (515%).
With the optimized conditions in hand, varoius isoquinoline
thiols were prepared from their corresponding chloro
compounds (Scheme 2 and Table1; see Table 1s in the
Supporting Information, SI) in good yield without the
formation of a thiol dimer.
Interestingly, lesser loading of thiourea produced lesser yields
of thiols (Table 1, entries 14) because of the formation of
symmetrical thioether as a byproduct in the reaction. It is
envisioned that symmetrical thioether could be obtained in
excellent yield by reduced loading (50%) of thiourea.
In the further screening of thiourea 2, loading gave exciting
results, as shown in Table 2. The results illustrated that the
formation of symmetrical thioether can be achieved by varying
the concentration of thiourea. The increase in the concen-
tration of thiourea proportionally increased symmetrical
thioether 4b (Table 2, entries 13), and the optimized amount
of 0.5 equiv produced higher yield. It should be noted that in
this concentration range no thiol formation is observed (entries
13) and that thiol product is seen to form at above 0.5 equiv
of thiourea. Thus, an optimized amount of 0.5 equiv of the
thiourea concentration is necessary for the regioselective
synthesis of symmetrical thioethers in good yield and purity.
In our continued interest in symmetrical thioether, we
generalized this approach to some commercially available N-
heteroaryl chlorides 1m1w, and the yields are shown in
Scheme 3 and Table 2s in the SI.
The interesting results prompted us to extend the method-
ology to unsymmetrical thioethers by adopting a one-pot
synthesis. Initially, the thiols were obtained with an optimum
amount of thiourea in an ethanol solvent reuxed for 6 h and
by avoiding their isolation; the desired unsymmetrical
thioethers 6 were obtained in good yield by reuxing further
with the other chloro derivatives 5. Under optimized
conditions, diversied unsymmetrical thioethers were obtained,
as summarized in Scheme 4 and Table 3s in the SI.
Table 1. Optimization of the Thiourea Concentration in the
Reaction of 1b
a
entry thiourea (mol equiv) yield
b
(%)
1 0.70 50
2 0.85 74
3 0.90 80
4 0.95 90
5 1.00 84
c
6 1.05 79
d
7 1.10 72
e
8 1.15 68
f
a
Reaction conditions: 1b (2.04 mmol), ethanol (10 mL), reux 12 h.
b
Isolated yields.
c
Disulde byproduct yield: 5%.
d
Disulde byproduct
yield: 10%.
e
Disulde byproduct yield: 12%.
f
Disulde byproduct
yield: 15%.
Table 2. Optimization of the Thiourea Concentration in the
Reaction of 1b
a
yield
b
(%)
entry thiourea (mol equiv), 2 product 3b product 4b
1 0.204 nil 20
2 0.408 nil 36
3 0.5 nil 88
3 0.612 10 40
4 0.816 60 32
5 1.020 84 15
6 1.2 79 12
a
Reaction conditions: 1b (2.04 mmol), ethanol (10 mL), reux 6 h.
b
LCMS yields.
Scheme 3. Synthesis of Symmetrical Thioethers 4
Scheme 4. Synthesis of Unsymmetrical Thioethers 6
Industrial & Engineering Chemistry Research Article
dx.doi.org/10.1021/ie500119p | Ind. Eng. Chem. Res. 2014, 53, 78667870 7868
The products of all three regioselective reactions were
isolated and puried by recrystallization in an ethanol/
petroleum ether solvent mixture. All of the pure compounds
were identied by various spectral techniques such as FTIR,
1
H
and
13
C NMR, LCMS, and CHN analysis.
The proposed mechanism of the reaction is depicted in
Scheme 5. The chloro compounds undergo an aromatic
nucleophilic substitution (S
N
Ar) reaction using thiourea as
the sulfur source to form an isothiouronium salt. This salt
further gets converted to thiol in the presence of water (derived
from 99.9% absolute ethanol). The mechanism explains clearly
that the reaction takes place to produce initially thiol, which
further gets converted to symmetric thioethers and unsym-
metrical thioethers in the presence of dierent concentrations
of thiourea and halo derivative similarly.
4. CONCLUSION
In conclusion, an ecient and facile regioselective synthesis of
3-substituted isoquinoline-1-thiols and symmetrical and unsym-
metrical thioethers is reported. The regioselective reactions
avoid byproduct formation and oer simplied methodology,
wider applicability, and easy workability and an environmentally
friendly approach (avoid the intermediate foul-smelling thiol
isolation) toward symmetrical and unsymmetrical thioethers.

ASSOCIATED CONTENT
*S Supporting Information
Spectral values and
1
H and
13
C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author
*E-mail: nawaz_f@yahoo.co.in.
Notes
The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
The authors express their gratitude to the Indian Institute of
Science, SAIF, Bangalore, and IIT Madras for their support of
NMR, LCMS, and IR facilities.

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