Environmentally Benign Large-Scale Synthesis of a Precursor to Vortioxetine

Article abstract of DOI:10.1055/s-0040-1707823

An eco-friendly, high-yielding, and transition-metal-free synthesis of 2-[(2,4-dimethylphenyl)thio]aniline precursor to vortioxetine is reported. Vortioxetine, a multi-modal acting drug with high affinity for a range of serotonergic targets, is used for the treatment of major depressive disorder (MDD). The synthesis - applicable in multi-gram scale - involves the reaction of bis(2,4-dimethyl)iodonium bromide with commercial 2-aminophenyl disulfide, whereas its reaction with 2-aminothiophenol afforded the same product but in low to moderate yields. This method works equally well in deep eutectic solvents (DESs), based on choline chloride (ChCl).

Full text of DOI:10.1055/s-0040-1707823

SYNTHESIS
0
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8
1
1
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2
1
0
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–E
psp
A
en
S. A. Zisopoulou et al.
PSP
Synthesis
Environmentally Benign Large-Scale Synthesis of a Precursor to
Vortioxetine
Stavroula A. Zisopouloua
Anastasia E. Pafilia
Petros Gkizisb
Thanos Andreoub
Theoharis V. Koftisb
Alexandra Lithadiotib
Efstratios Neokosmidisb
John K. Gallos*a
Me
Me
Me
Me
NH2
NH2
I
KOtBu
I
S
Br
+
S
+
S
DMSO
or
DESs
Me
Me
Me
recyclable
Me
NH2
applicable in 20 g scale
99%
no chromatographic separation
a Department of Chemistry, Aristotle University of Thessaloniki,
Thessaloniki 54124, Greece
igallos@chem.auth.gr
b Pharmathen S.A. – R & D API Operations,
9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece
Received: 02.04.2020
Accepted after revision: 06.05.2020
Published online: 27.05.2020
In general, all syntheses start from a 1,2-disubstituted
benzene derivative with the generation of aromatic carbon–
heteroatom bond, usually through transition-metal-assisted
nucleophilic aromatic substitution. This is a major draw-
back for industrial production of vortioxetine making
urgent the development of environmentally more friendly
syntheses.
DOI: 10.1055/s-0040-1707823; Art ID: ss-2020-t0176-psp
Abstract An eco-friendly, high-yielding, and transition-metal-free syn-
thesis of 2-[(2,4-dimethylphenyl)thio]aniline precursor to vortioxetine
is reported. Vortioxetine, a multi-modal acting drug with high affinity
for a range of serotonergic targets, is used for the treatment of major
depressive disorder (MDD). The synthesis – applicable in multi-gram
scale – involves the reaction of bis(2,4-dimethyl)iodonium bromide
with commercial 2-aminophenyl disulfide, whereas its reaction with 2-
aminothiophenol afforded the same product but in low to moderate
yields. This method works equally well in deep eutectic solvents (DESs),
based on choline chloride (ChCl).
Recently, a number of elegant short preparations of vor-
tioxetine appeared in the literature. In 2015, Greaney et al.4
prepared this molecule by a tandem S- and N-addition to
benzyne, using 2-iodophenyl arylsulfonates as benzyne
precursors. However, the synthesis requires quite expensive
materials, low temperatures, and the use of CuCl as a cata-
lyst. In 2017, Diness et al.5 reported a general method for
transition-metal-free N-arylation of amines, also applicable
for the preparation of vortioxetine. Starting from 1,2-diflu-
orobenzene, the dimethylphenylsulfanyl group was intro-
duced by a direct SNAr reaction, followed by displacement
of the second fluorine atom with piperazine and LiHMDS in
refluxing THF. More recently, Biju et al.6 developed a
transition-metal-free thioamination of arynes using sulfon-
amides. Treatment of the benzyne generated in situ from 2-
(trimethylsilyl)phenyl triflate (using excess CsF) with N-
Boc-protected 1-[(2,4-dimethylphenyl)thio]piperazine in
DME as solvent, followed by deprotection led to the forma-
tion of vortioxetine. In 2020, Jafarpour et al.7 reported an
iodine-mediated oxidative cross-coupling reaction of aryl-
hydrazines and thiols for construction of thioethers in the
absence of any transition metals or photocatalysts and this
method was applied in the synthesis of the key structure of
vortioxetine.
Key words iodonium salts, vortioxetine, major depressive disorder,
green chemistry, deep eutectic solvents, hypervalent iodine
Vortioxetine (4), a multi-modal acting drug with high
affinity for a range of serotonergic targets, was first pre-
pared in 20071 and is now on the market for the treatment
of major depressive disorder (MDD). This is a prevalent dis-
ease that is considered by the World Health Organization
(WHO) to be one of the leading causes of disability world-
wide.2 The emergence of vortioxetine aroused the strong
interest of pharmaceutical companies and researchers, and
a large number of patents and publications regarding its
preparation appeared in the literature,3 as summarized in
Scheme 1.
H
N
H
N
Y
Me
NH2
Me
N
N
X
S
S
Z
or
From the existing data, it can be concluded that the
most difficult step is the formation of aromatic thioether.8
Looking for an eco-friendly method for large scale synthesis
of vortioxetine, our attention was turned to diaryl iodoni-
um salts,9 which recently gained growth interest as arylating
Me
1 (X, Y = halogen,
NO2, NH2, SH)
Me
2 (Z = F, Cl, I)
4
3
Scheme 1 General scheme summarizing the existing syntheses of
vortioxetine (4)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. A. Zisopoulou et al.
PSP
Synthesis
agents. For our purpose, they could be suitable reagents for
construction of the unsymmetrical sulfide 3, which then
could be readily converted to vortioxetine by the existing
methods.
According to our retrosynthetic analysis, compound 3
could be prepared from the symmetrical iodonium salt 5
(Scheme 2). We reasonably supposed that reaction of 5
with commercial 2-aminothiophenol (7) could afford the
desired target along with iodoxylene by-product 8, which
could be recycled to 5 by known procedures10 diminishing
thus mass wastage. Diaryl iodonium salts have been report-
ed in the literature11 to react with thiols and thioethers in
metal-free conditions to afford aryl sulfides.
phenyl disulfide side-product 9 as a hydrochloric salt and
then extracted with aqueous 9 N HCl. 1-Iodo-2,4-dimethyl-
benzene remained in the organic layer and the desired
product 2-[(2,4-dimethylphenyl)thio]aniline (3) was isolat-
ed from the aqueous phase by adjusting its pH to 7. Howev-
er, the yields of sulfide 3 were low to moderate, the best of
them being obtained under the conditions of Table 1 entry
1, making the method unsuitable for industrial production.
Searching in the literature,13 we found that unsymmet-
rical diaryl sulfides can be prepared by a potassium tert-
butoxide-mediated reaction of aryl disulfides14 with aryl
bromides. This finding prompted us to try the reaction of
iodonium bromide 5 with the commercial disulfide 9
(Scheme 3). Since, as reported,13 the reaction of aryl bro-
mides proceeds via a benzyne formation by the action of
potassium tert-butoxide to the aryl bromides, leading to the
formation of regioisomers, we excluded from the beginning
the use of iodide 8 or the respective bromide as starting
materials, hoping that such an undesirable pathway would
be avoided in the case of much more reactive iodonium
bromide 5.
Me
Me
Me
Me
NH2
I
S
Br
Me
Me
Me
Me
5
6
3
Scheme 2 Retrosynthesis of 3, the precursor to vortioxetine
To this end, we decided to use the iodonium bromide 5
(Table 1), as an easily accessible compound from inexpen-
sive starting materials.12 It was prepared according to the
literature, by reaction of m-xylene with NaIO4 in a glacial
AcOH/concd H2SO4 mixture and subsequent addition of
KBr, a process applicable in multi-gram scales. Then, we
investigated the reaction of iodonium bromide 5 with 2-
aminothiophenol (7; 2 equiv) and a base (2 equiv) at room
temperature in a solvent given in Table 1.
Me
Me
Me
Me
NH2
Br
NH2
KOtBu
I
I
S
+
S
+
S
DMSO
Me
Me
Me
Me
NH2
5
9
8
3
Scheme 3 Synthesis of the unsymmetrical sulfide 3 from iodonium
salt 5 and disulfide 9
To our satisfaction, when potassium tert-butoxide (1.25
equiv) was added portionwise to a DMSO solution of iodo-
nium bromide 5 (in a 10 g scale) and 9 (0.5 equiv; molar ra-
tio 5:9 = 2:1) and the resulting mixture was initially stirred
at 40–45 °C for 15 minutes and then heated at 80 °C for 3
hours, the desired product 3 was isolated in quantitative
yield (99%) (Scheme 3). Exactly the same were the results in
a 20 g scale. The iodoxylene by-product 8 formed can be re-
cycled to 5 by a known procedure.10
Interestingly, after experimentation, we found that
compound 3 can be isolated from the reaction mixture
without using any chromatographic method, as follows: the
mixture was poured into ethyl acetate and then extracted
with aqueous 9 N HCl. Iodoxylene 8 was obtained from the
organic layer, whereas 2-[(2,4-dimethylphenyl)thio]aniline
(3) was taken from the aqueous phase by adjusting its pH to
7, with addition of solid NaHCO3 and further extraction
with ethyl acetate (99%).
Table 1 Reaction of Iodonium Bromide 3 with 2-Aminothiophenol (7)
Me
Me
Me
NH2
Me
I
H2N
HS
S
I
Br
Me
base
+
+
solvent
Me
Me
Me
5
7
3
8
Entry
Solvent
Base
Time (h) 3 Yield (%) 8 Yield (%)
1
2
3
4
5
6
7
8
9
THF
NaH
NaH
NaH
0.5
2
57
45
50
28
47
30
32
30
20
99
99
86
73
92
93
95
93
99
toluene
DMSO
THF
2
NaOMe
NaOMe
NaOMe
NaOMe
NaOH
2
toluene
DMSO
MeOH
DMSO
toluene
4
2
12
2
In addition to the known methods of preparing vortiox-
etine (4) from 3, we tried another approach, involving con-
version of 3 to the fluoro analogue 10 (Scheme 4). Indeed,
conventional diazotization of the amino group in 3, fol-
lowed by treatment with HPF6 afforded the known fluoro
compound 10, which is known to give vortioxetine,5 upon
reaction with piperazine and LiHMDS in refluxing THF.
Et3N
12
The reaction progress was monitored by TLC and, as ex-
pected, the desired compound 3 and iodoxylene 8 were
formed and separated chromatographically from 2-amino-
phenyl disulfide side-product 9. Alternatively, the products
were extracted with ethyl acetate and the organic layer was
washed with aqueous 1.4 M HCl to remove the 2-amino-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

C
S. A. Zisopoulou et al.
PSP
Synthesis
H
N
with anisaldehyde in EtOH/H2SO4. Column chromatography was per-
formed with Merck silica gel 60 (0.063–0.200 mm). Melting points
were determined with a Kofler hot-stage microscope. 1H and 13C NMR
spectra were recorded at 500 MHz and 126 MHz, respectively. Chemi-
cal shift values are referenced against residual protons in the deuter-
ated solvents, and multiplicity (standard abbreviations). J-values are
reported in hertz (Hz).
Me
S
NH2
Me
F
Me
N
NaNO2/HCl
HPF6
S
ref. 5
S
Me
Me
Me
3
4
10
Scheme 4 Alternative approach to vortioxetine (4)
Bis(2,4-dimethyl)iodonium Bromide (5)
The synthesis of 2-[(2,4-dimethylphenyl)thio]aniline (3)
was also successful when the reaction was carried out in
deep eutectic solvents (DESs). Over the past decades an on-
going effort focuses in the replacement of hazardous vola-
tile organic solvents by alternatives, which do not emit
flammable or toxic vapors at a wide range of temperatures.
In 2001, Abbott et al.15 introduced DESs based on choline
chloride (ChCl), low cost mixtures with similar physical
properties and behavior to ionic liquids, as an alternative
medium. Type III eutectics employed for our purpose are
formed from choline chloride and hydrogen bond donors,
such as urea and glycerol. These liquids are simple to pre-
pare and unreactive with water and they appear to have
great interest due to the fact that they are considered more
eco-friendly and pose useful characteristics such as low va-
por pressure and the possibility of recycling.16 For our pur-
pose we used DES-urea, that is, the ionic compound of cho-
line chloride/urea (1:2), and DES-glycerol, that is, the ionic
compound of choline chloride/glycerol (1:2), both being
prepared according to the procedures disclosed in the liter-
ature.17
m-Xylene (128 mL, 1.04 mol) was dissolved in a mixture of concd
H2SO4 (133 mL) and glacial AcOH (933 mL) and the resulting mixture
was warmed up, with stirring, to 50–55 °C. While keeping the same
temperature, NaIO4 (85.6 g, 0.4 mol) was slowly added portionwise
over 1.5 h. The stirred mixture was kept at the same temperature 50–
55 °C for another 1.5 h, then cooled to r.t. and finally poured into
stirred ice/H2O (2 L). The resulting solid was filtered off, the cold fil-
trates were extracted with Et2O (4 × 800 mL) and the ethereal extracts
were discarded. A solution of KBr (80 g, 0.67 mol) in H2O (400 mL)
was added to the vigorously stirred aqueous solution and after 1 day,
the precipitated iodonium bromide 5 was collected by filtration and
repeatedly washed with cold H2O until the filtrates were neutral, and
dried in a vacuum desiccator to give the crude product (85.7 g) in 64%
yield (based on NaIO4) with spectral and physical data in agreement
to those reported in the literature;12 mp 167–169 °C (Lit.12 mp 167–
169 °C).
1H NMR (500 MHz, CDCl3):  = 7.86 (d, J = 8.2 Hz, 2 H), 7.09 (s, 2 H),
6.88 (d, J = 8.2 Hz, 2 H), 2.58 (s, 6 H), 2.26 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 142.16, 140.08, 136.43, 132.22,
129.53, 121.69, 25.49, 21.15.
Reaction of Bis(2,4-dimethyl)iodonium Bromide (5) with 2-Amino-
thiophenol (7)
The reactions between disulfide 9 and bis(2,4-dimethyl-
phenyl)iodonium bromide (5) in DESs was carried out in a
sealed tube by adding KOt-Bu portionwise at 40–45 °C and
then the mixture was heated at 80 °C for 3 hours. Products
3 and 8 were obtained upon addition of the resulting mix-
ture to water and extraction with ethyl acetate and separat-
ed as above.
In conclusion, we have developed an eco-friendly high
yielding and transition-metal-free synthesis of 2-[(2,4-di-
methylphenyl)thio]aniline precursor to vortioxetine, a
multi-modal acting drug with high affinity for a range of
serotonergic targets, which is now on the market for the
treatment of major depressive disorder. The synthesis –
applicable in multi-gram scale – involves the reaction of
bis(2,4-dimethyl)iodonium bromide, which is accessible
from m-xylene, with commercial 2-aminophenyl disulfide,
whereas its reaction with 2-aminothiophenol afforded the
same product but in low to moderate yields. This method
works equally well in deep eutectic solvents, based on cho-
line chloride.
A suspension of diarylodonium salt 5 (0.150 g, 0.36 mmol), NaH
(0.028 g, 0.72 mmol), and 2-aminothiophenol (7; 0.077 mL, 0.72
mmol) in anhyd THF (2.5 mL) was carefully flashed with argon and
stirred at r.t. for 0.5 h. Upon completion of the reaction (checked by
TLC), the mixture was poured into brine (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layers were extracted with
aq 1.4 M HCl (2 × 10 mL) to remove the 2-aminophenyl disulfide side-
product as a hydrochloric salt and then with aq 9 N HCl (2 × 10 mL). 1-
Iodo-2,4-dimethylbenzene (8) was obtained from the organic layer as
a pure product (0.083 g, 99%) after drying (Na2SO4) and evaporation of
the solvent. The pH of the aqueous phase was subsequently adjusted
to 7 with the addition of NaHCO3 and extracted with EtOAc (3 × 10
mL). The combined organic layers were dried (Na2SO4) and the solvent
was evaporated off to give 2-[(2,4-dimethylphenyl)thio]aniline (3;
0.047 g, 57%) in satisfactory purity. Alternatively, the solvent of the
initial EtOAc extractions was evaporated off and the residue was chro-
matographed on a silica gel column using hexane/EtOAc as the eluent
to give first 1-iodo-2,4-dimethylbenzene (8), followed by 2-amino-
phenyl disulfide (9), and lastly the desired 2-[(2,4-dimethyl-
phenyl)thio]aniline (3).
Reaction of Bis(2,4-dimethyl)iodonium Bromide (5) with 2-Amino-
phenyl Disulfide (9)
KOt-Bu (3.37 g, 30 mmol) was added portionwise to a solution of 2-
aminophenyl disulfide (9; 2.98 g, 12 mmol) and bis(2,4-dimethylphe-
nyl)iodonium bromide (5; 10 g, 23.9 mmol) in DMSO (50 mL), and the
mixture was stirred at 40–45 °C for 15 min and then heated at 80 °C.
The progress of the reaction was monitored by TLC. Upon completion
of the reaction (3 h), the mixture was cooled to r.t. and poured into
All reagents are commercially available and were used without fur-
ther purification. Solvents were dried by standard methods. The
progress of reactions was checked by TLC on Merck silica gel 60F254
glass plates (0.25 mm). The spots were visualized by heat staining
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

D
S. A. Zisopoulou et al.
PSP
Synthesis
EtOAc (200 mL). The organic layer was washed with brine (2 × 150
mL) and extracted with aq 9 N HCl (2 × 100 mL). The organic phase
was dried (MgSO4) and the solvent was evaporated to give 1-iodo-2,4-
dimethylbenzene (8) as a pure product (3.4 g, 62%). The pH of the
aqueous phase containing hydrochloric salt of 2-[(2,4-dimethylphe-
nyl)thio]aniline was adjusted to 7 with the addition of solid NaHCO3
and extracted with EtOAc (3 × 100 mL). The combined organic layers
were dried (Na2SO4) and evaporated to give 2-[(2,4-dimethylphe-
nyl)thio]aniline (3) as a pure product (5.4 g, 99%) with spectral and
physical data in agreement to those reported in the literature;18 mp
34–36 °C (Lit.18 mp 34–36 °C).
bromide (5; 100 mg, 239 mmol). The tube was sealed and the mixture
was heated at 80 °C. The progress of the reaction was monitored by
TLC. Upon completion of the reaction (3 h), the mixture was cooled to
r.t., poured into brine and extracted with EtOAc (2 × 10 mL). The com-
bined organic layers were washed with aq 9 N HCl (2 × 10 mL), dried
(Na2SO4) and the solvent was distilled off to afford 1-iodo-2,4-di-
methylbenzene (8; 26 mg) as a crude oily by-product. The pH of the
aqueous phase containing the hydrochloride salt of 2-[(2,4-dimethyl-
phenyl)thio]aniline was adjusted to 7 by the addition of solid NaHCO3
and extracted with EtOAc (2 × 10 mL).The combined organic layers
were dried (Na2SO4) and the solvent evaporated off to give 2-[(2,4-di-
methylphenyl)thio]aniline (3) as a pure product (48 mg, 88%).
1-Iodo-2,4-dimethylbenzene (8)
1H NMR (500 MHz, CDCl3):  = 7.66 (d, J = 8.0 Hz, 1 H), 7.06 (s, 1 H),
Choline Chloride-Glycerol (1:2) Based DES
6.70 (d, J = 7.9 Hz, 1 H), 2.39 (s, 3 H), 2.27 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 141.00, 138.64, 138.07, 130.76,
128.34, 97.01, 27.92, 20.85.
A mixture of choline chloride (6.98 g, 50 mmol) and urea (9.21 g, 100
mmol) was heated up to 80 °C for 60 min until a clear solution was
formed. The obtained DES was used without further purification.
Reaction of Bis(2,4-dimethyl)iodonium Bromide (5) with 2-Amino-
phenyl Disulfide (9) in DES-Glycerol
2-[(2,4-Dimethylphenyl)thio]aniline (3)
1H NMR (500 MHz, CDCl3):  = 7.36 (d, J = 7.7 Hz, 1 H), 7.21 (t, J = 7.6
Hz, 1 H), 7.01 (s, 1 H), 6.86 (d, J = 7.9 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H),
6.76 (t, J = 7.5 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 2.39 (s, 3 H), 2.27 (s, 3
H).
By using the same as above procedure, 1-iodo-2,4-dimethylbenzene
(8; 27 mg) and 2-[(2,4-dimethylphenyl)thio]aniline (3; 46 mg; 85%)
were obtained as pure products.
13C NMR (126 MHz, CDCl3):  = 148.38, 136.60, 135.79, 135.36,
131.74, 131.20, 130.48, 127.33, 126.60, 118.86, 115.34, 115.13, 20.82,
20.07.
Funding Information
This research was co-financed by the European Union and Greek
national funds through the Operational Program Competitiveness,
Entrepreneurship and Innovation, under the call RESEARCH – CREATE
– INNOVATE (project code: T1EDK-01161).()
(2,4-Dimethylphenyl)(2-fluorophenyl)sulfane (10)
To a cooled (5 °C), vigorously stirred solution of 2-[(2,4-dimethylphe-
nyl)thio]aniline (3; 0.1 g, 0.44 mmol) in H2O (1,3 mL) and concd HCl
(0.6 mL) was added a solution of NaNO2 (0.049 g, 0.572 mmol) in H2O
(1.2 mL) dropwise during 15 min. The mixture was stirred for another
30 min at the same temperature, then HPF6 (60% solution in H2O, 0.61
mL) was added and the mixture was heated to 100 °C for 12 h. Upon
completion of the reaction, the precipitated solid was filtered off,
washed with EtOAc and the organic layer was washed with brine (3
mL) and aq NaHCO3 (3 mL). The organic solution was dried (Na2SO4)
and the solvent evaporated to dryness to get a sticky residue, which
was purified by column chromatography on silica gel using hexane/
EtOAc (20:1) as the eluent to afford 10 (0.067 g, 65%) as an oil, with
NMR spectra identical to those reported in the literature.5
1H NMR (500 MHz, CDCl3):  = 7.27 (d, J = 7.8 Hz, 1 H), 7.17–7.12 (m, 1
H), 7.11 (d, J = 1.7 Hz, 1 H), 7.05 (ddd, J = 9.9, 8.2, 1.6 Hz, 1 H), 6.98
(ddd, J = 8.9, 7.8, 2.0 Hz, 2 H), 6.85 (td, J = 7.7, 1.9 Hz, 1 H), 2.35 (s, 3
H), 2.33 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 160.0 (d, J = 245.1 Hz), 141.0, 138.9,
134.4, 131.7, 130.2 (d, J = 1.9 Hz), 127.7, 127.6, 127.5 (d, J = 7.6 Hz),
124.5 (d, J = 3.7 Hz), 124.4, 115.5 (d, J = 21.7 Hz) 21.1, 20.4.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1702823.
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at 40–45 °C to a mixture of DES-urea (0.7 mL), 2-aminophenyl disul-
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

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S. A. Zisopoulou et al.
PSP
Synthesis
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