Continuous-flow synthesis of thioureas, enabled by aqueous polysulfide solution

Article abstract of DOI:10.3390/molecules26020303

We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the utility of the convenient continuous-flow application of sulfur.

Full text of DOI:10.3390/molecules26020303

molecules
Article
Continuous-Flow Synthesis of Thioureas, Enabled by Aqueous
Polysulfide Solution
1,
András Gy. Németh 1, Renáta Szabó 1, György Orsy 2, István M. Mándity 2 , György M. Keseru˝
*
and
Péter Ábrányi-Balogh 1,
*
1
2
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, H-1117 Budapest, Hungary;
nemeth.andras.gyorgy@ttk.hu (A.G.N.); szaboreni287@gmail.com (R.S.)
Lendület Artificial Transporters Research Group, Research Centre for Natural Sciences,
H-1117 Budapest, Hungary; orsy.gyorgy@ttk.hu (G.O.); mandity.istvan@ttk.mta.hu (I.M.M.)
Correspondence: keseru.gyorgy@ttk.hu (G.M.K.); abranyi-balogh.peter@ttk.hu (P.Á.-B.)
*
Abstract: We have developed the continuous-flow synthesis of thioureas in a multicomponent
reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution
enabled the application of sulfur under homogeneous and mild conditions. The crystallized products
were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the
mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the
utility of the convenient continuous-flow application of sulfur.
Keywords: continuous flow; sulfur; aqueous polysulfide solution; thiourea; multicomponent reaction
1. Introduction
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
In the last two decades, continuous-flow (CF) synthesis has become a powerful and
versatile tool in synthetic organic chemistry. The enhanced mixing properties, heat, and
mass transfer of CF systems lead to more precise regulation of the reaction conditions, and
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Németh, A.G.; Szabó, R.;
Orsy, G.; Mándity, I.M.; Keseru˝, G.M.;
Ábrányi-Balogh, P. Continuous-Flow
Synthesis of Thioureas, Enabled by
Aqueous Polysulfide Solution.
thus, better reproducibility and selectivity can be realized than in batch processes [
tably, CF chemistry has been used in hazardous reactions (nitration, halogenation, reaction
with organolithium reagents and azides, etc.) [ ] and in synthetic methods requiring a
high temperature and pressure [ ], as well. In addition, it enables cleaner reaction pro-
1,2]. No-
3,4
5–7
Molecules 2021, 26, 303. https://
doi.org/10.3390/molecules26020303
files with better product–side-product ratios, and reaction pathways that could hardly be
realized in batch processes (e.g., use of highly reactive peptidyl donors) [8–10]. Moreover,
CF techniques are suitable for multistep [11–14] and automated synthetic processes, which
is a rapidly growing field in modern organic chemistry [15–17].
Received: 15 December 2020
Accepted: 7 January 2021
Published: 8 January 2021
Sulfur-containing compounds are widely known as biologically active molecules [18
]
and functional organic materials [19,20]. Thioureas, in particular, are used as pharmaceu-
tical and agrochemical intermediates or active ingredients represented by the marketed
drug thiocarlide [21], and by algicides [22], fungicides [23], and the insecticide chlorome-
thiuron [24]. In addition, they are key intermediates of nitrogen- and sulfur-containing
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional clai-
ms in published maps and institutio-
nal affiliations.
compounds, especially pharmacologically relevant heterocycles [25
last two decades, thioureas were also applied as highly selective and efficient organocat-
alysts [30 34] (Scheme 1). Given the wide utility of thioureas, their clean and efficient
synthesis is of high interest.
–29]. Notably, in the
–
Copyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 303. https://doi.org/10.3390/molecules26020303
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 303
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Scheme 1. Examples of important thioureas.
Elemental sulfur is a bench-stable, environmentally benign, inexpensive, and nontoxic
reagent for sulfuration, and offers an atom-economical and safe alternative to incorporate
the sulfur atom into products [35]. In the last two decades, the uses of elemental sulfur
in chemical reactions have emerged greatly, leading to, in particular, many innovative,
multicomponent, and one-pot procedures [36
–42]. Notably, a handful of thiourea syntheses
have been developed as well [34 43 45]. Most synthetic methods require chromatographic
,
–
purification and apply sulfur in solid form, which makes the transfer of these reactions into
CF processes inconvenient. Nonethel◦ess, Shavel et al. realized the continuous production
of Cu2ZnSnS4 nanoparticles at 300 C, starting from metal complexes and sulfur [46].
Organic reactions, however, require milder conditions to provide selectivity and maintain
the stability of the compounds. Recently, we prepared aqueous polysulfide solutions
from elemental sulfur with organic and inorganic bases and used it efficiently for the
mild multicomponent preparation of thioureas starting from isocyanides and amidines
or amines [47]. Herein, as a model study, we report the CF synthesis of thioureas using
elemental sulfur under homogeneous conditions.
2. Results
First, we performed the model reaction of 2,6-dimethylphenyl isocyanide (
polysulfide solution made of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, ) and elemental
sulfur. In this reaction, the base ( ) opened the S8-crown, resulting in polysulfide anions.
1) and the
3
3
These become the reactive agents attacking the isocyanide, leading to isothiocyanates in
situ, which was able to acylate a nucleophilic amine in its close surroundings. In this model
reaction, the open form of DBU acted as the corresponding nucleophile [47–51]. We applied
two HPLC pumps to provide the feed for the solution of the isocyanide in acetonitrile
(0.2 M), and the aqueous polysulfide solution containing DBU (1.0 M for the base, 0.4 M for
the sulfur). The two inputs met in a T-mixer right before the heated reactor oven, and the
output was collected in a flask (Figure 1).

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Figure 1. Image of the experimental setup.
◦
Applying a residence time of 26 s at 60 C enabled a conversion of 36% for the
isocyanide, monitored by HPLC–MS at 190 nm (Table 1, Entry 1). This was improved to
50% by a longer residence time of 66 s (Entry 2), and to 62% by maintaining the reaction
◦
temperature at 80 C (Entry 3). Eventually, increasing the residence time gradually to
6.5 min enabled the practically full conversion of
the appearance of side products, and thus, kept the reaction temperature at 80 C. We
removed the acetonitrile in vacuo, and the product crystallized from water. We were able
1
(Entries 4–7). At 100 ◦C, we observed
◦
to isolate the pure thiourea
4 in 88% yield by simple filtration, while the excess of DBU and
polysulfide anions were washed away by water (Table 1).
Table 1. Optimization of the reaction conditions for the synthesis of thioureas 4 under CF conditions.
H
H
N
time
NC
N
N
N
S8
temperature
N
2
S
O
0.4 M in H2O
4
3
1
0.2 M in MeCN
1.0 M in H
2O
◦
Entry a
T [ C]
Flow Rate [mL min
]
Residence Time
HPLC Conversion 4/1 b,c [%]
−1
1
2
3
4
5
6
7
60
60
80
80
80
80
80
1.0
0.4
0.4
0.2
0.6
0.4
0.3
26 s
36/64
50/50
62/38
84/16
93/7
98/2
99/1 (88)
1 min 6 s
1 min 6 s
2 min 12 s
3 min 16 s
4 min 54 s
6 min 32 s
a
Reaction conditions: isocyanide
UV–VIS absorbance at 190 nm; c Isolated yield in parentheses for 0.5 mmol scale.
1 (0.2 M in acetonitrile), polysulfide solution (1.0 M 3
, 0.4 M sulfur in water); b Conversion is based on
With the optimized reaction conditions in hand, we planned to investigate the scope
and limitations of the reaction. First, we applied different amidine type bases ( and
10) and isocyanides of a broad structural diversity ( and 5–8) using the same experi-
mental setup (Figure 1, Table 2). Using together with the polysulfide solutions made
of commercially available amidines 1,5-diazabicyclo[4.3.0]non-5-ene (DBN, ) and 1,5,7-
9
1
1
9
triazabicyclo[4.4.0]dec-5-ene (TBD, 10), we isolated the thiourea 11 in 90% yield and the
tetrahydropyrimidin-2(1H)-one derivative 12 in 56% yield (Entries 1 and 2). The pyridine
and the quinoline-containing thioureas 13 and 14 were isolated in 67% and 68% yields,
respectively (Entries 3 and 4). The aliphatic phenethyl isocyanide
7 and 2-(indole-3-yl)ethyl
isocyanide provided the corresponding products (15 and 16) in slightly lower 40% and
8
54% yields, respectively (Entries 5 and 6). Notably, after the removal of the acetonitrile in
vacuo, all thioureas crystallized from water and were isolated by simple filtration.

Molecules 2021, 26, 303
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Table 2. Scope of isocyanides and amidines.
80 °C
N
H
H
NC
t
min
R 6.5
S8
R1
N
N
N
R1
N
2
S
O
0.4 M in H2O
3,9,10
1.0 M in H2O
1,5-8
0.2 M in acetonitrile
11-16
Entry a
Isocyanide
Amine
Product
Yield [%] b
H
H
N
N
N
N
1
90
56
N
O
9
S
NC
11
1
N
H
H
1
N
N
N
NH
2
3
N
N
H
S
O
10
12
NC
H
N
H
N
N
67
68
Br
N
5
S
O
Br
N
13
NC
H
H
N
N
N
4
N
6
7
S
O
N
N
14
N
3
NC
H
N
H
N
N
5
6
40
54
S
O
15
H
H
NC
N
N
N
HN
8
S
O
HN
16
a
Reaction conditions: isocyanide 1a–e (0.2 M in acetonitrile), polysulfide solution (1.0 M 3b,c, 0.4 M sulfur in water); b 0.5 mmol scale.
Considering bases resistant to acylating agents, the reaction may provide virtually
any desired thiourea. Recently, we used N,N,N0,N”,N”-pentamethyldiethylenetriamine
(PMDTA)-based aqueous polysulfide solution for the synthesis of versatile thiourea deriva-
tives [47]. Following the extension of the reaction, we applied this aqueous polysulfide
solution in the reaction with
1 and benzylamine 19 in the continuous stream. This re-
sulted in the formation of thiourea 26 in excellent, 96% yield, with an extended 42 min
of residence time, which was necessary for the complete conversion of the isocyanide
(Table 3, Entry 1). In this setup, the solution of the isocyanide and the amine in acetonitrile
provided one feed, and the other feed contained the aqueous polysulfide solution. The
3-isocyano quinoline
yield (Entry 2). Next, we applied aliphatic isocyanides
the thioureas 28 29, and 30 in moderate yields (49%, 42%, and 42%, respectively, En-
6
reacted well, leading to the formation of the thiourea 27 in 92%
7
,
17, and 18, which provided
,
tries 3–5). These results clearly indicate the convenience of aromatic isocyanides over
aliphatic ones. The phenylethylamine and morpholine derivatives 31 and 32 were isolated
in 96% and 76% yields, respectively (Entries 6 and 7). Notably, due to the precipitation
of the product from the water–acetonitrile mixture, in the case of aniline 22, we applied
2-methyltetrahydrofuran as a co-solvent and isolated the biaryl thiourea 33 in 70% yield
(Entry 8). After the removal of the polysulfide solution by filtration, the aniline was washed
away with 1.0 M aq. HCl. The 4-methyl and the halogen-substituted biaryl thioureas 34–36
were isolated in 79%, 39%, and 36% yields, respectively (entries 9–11), showing favor of the
reaction to the electron donor substrates.

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Table 3. Scope of isocyanides and amines for the synthesis of thioureas 26–36.
80 °C
H
H
t
R 42 min
NH2
NC
N
N
S8
R2
R1
R1
R2
PMDTA
2
S
1.0 M in H
2O
0.4 M in H2O
19-25
0.3 0.6 M
in MeCN
26-36
1,6,7,17,18
0.2 M in MeCN
or
Entry a
Isocyanide
Amine
Product
Yield [%] d
H
N
H
N
NC
1
96
92
49
S
1
26
H
N
H
NC
N
2
3
N
S
6
7
N
27
28
NH2
H
N
H
N
NC
19
S
NC
H
N
H
N
4
5
6
42
42
96
17
S
29
H
H
NC
N
N
18
S
30
H
H
NC
N
N
H2N
S
1
20
31
O
H
O
N
N
7 b
76
HN
21
S
32 b
H
N
H
H2N
N
8 b,c
70
79
39
S
22
33 b,c
NC
H
H
H2N
N
N
9 b
1
S
23
34 b
H
H
H2N
N
N
10 b
S
Cl
24
b
Cl
35
36
H
N
H
N
H2N
11 b
36
S
Br
25
b
Br
a
Reaction conditions: isocyanide 1,6,7,17,18 and amine 19–25 (0.2 M isocyanide and 0.3 M amine in acetonitrile), polysulfide solution
(1.0 M PMDTA and 0.4 M sulfur in water); b 0.6 M for the amine in acetonitrile; c 2-Methyltetrahydrofuran was used as a co-solvent instead
of MeCN; d 0.5 mmol scale.

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3. Materials and Methods
3.1. General
All melting points were determined on a Jasco SRS OptiMelt apparatus and are
1
uncorrected. H-NMR and 13C-NMR spectra were recorded in DMSO-d6 or CDCl3 solution
at room temperature, on a Varian Unity Inova 500 spectrometer (Bruker Corp., Oxford, UK)
(500 and 125 MHz for 1H-NMR and APT-NMR spectra, respectively), with the residual
solvent signal as the lock and TMS (tetramethylsilane) as the internal standard. Chemical
shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. HPLC–MS
measurements were performed using a Shimadzu LCMS-2020 (Shimadzu Corp., Kyoto,
Japan) device, equipped with a Reprospher (Altmann Analytik Corp., München, Germany)
100 C18 (5
µ
m; 100
×
3 mm) column and a positive/negative double ion source (DUIS )
±
with a quadrupole MS analyzer in a range of 50–1000 m/z. The samples were eluted with
gradient elution, using eluent A (0.1% formic acid in water) and eluent B (0.1% formic
acid in acetonitrile). The flow rate was set to 1.5 mL/min. The initial condition was 5%
eluent B, followed by a linear gradient to 100% eluent B by 1.5 min; from 1.5 to 4.0 min,
100% eluent B was retained; and from 4 to 4.5 min, it went back by a linear gradient to
5% eluent B, which was retained from 4.5 to 5 min. The column temperature was kept at
room temperature, and the injection volume was 1–10 µL. The purity of the compounds
was assessed by HPLC with UV detection at 215 and 254 nm; all starting compounds were
known, purchased, or synthetically feasible, and >95% pure. In the CF system, the stream
of the solution of the starting materials was provided by HPLC pumps (JASCO model
PU–2080), and the tubing (BGB, 1/16” OD
×
0.50 mm or 1.00 mm ID, 10 m) was placed
in a Carlo Erba HRGC 5300 oven. Compounds not precedented in the literature were
characterized by 1H-NMR and 13C-NMR, HRMS and if were obtained in solid form by
melting point. For known compounds 1H-NMR spectra and melting points were measured.
All spectra and data is available in the Supplementary Materials.
3.2. General Procedure for the Preparation of the Aqueous Solution of Polysulfide Anions
Sulfur (32 mg, 1.0 mmol) was added to a mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene
◦
(373
µ
L, 2.5 mmol) and water (2.13 mL), and stirred vigorously at 60 C until the complete
dissolution of the sulfur (Table 4).
Table 4. Preparation of polysulfide solutions, according to the general procedure.
◦
Amine
Sulfur [mg, mmol]
Amine [µL or mg, mmol]
373 µL, 2.50
Water [mL]
2.13
T [ C]
1,8-diazabicyclo[5.4.0]undec-7-ene
1,5-Diazabicyclo[4.3.0]non-5-ene
1,5,7-Triazabicyclo[4.4.0]dec-5-ene
60
60
60
310 µL, 2.50
2.19
348 mg, 2.50
2.50
32, 1.00
7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-
5-ene
360 µL, 2.50
522 µL, 2.50
2.17
1.98
60
70
0
N,N,N ,N”,N”-
Pentamethyldiethylenetriamine
3.3. General Procedure for the CF Synthesis of Thioureas 11–16
Isocyanide ( ; 3.0 mmol) was dissolved in MeCN, then filtered through a 0.45
pore-sized syringe filter to provide Feed A (0.2 M in MeCN). The aqueous solution of sulfur
and the appropriate amidine (
1,
5–
8
µm
3, 9, 10) was used for Feed B (1.0 M base, 0.4 M sulfur). Feeds
A and B were pumped into a T-mixer at room temperature at flow rates of 0.15 mL min−1
each. The mixture passed through a reaction coil at 80 ◦C in 6.5 min, then collected in an
Erlenmeyer flask. Altogether, 0.5 mmol of product was collected (calculated on the used
isocyanide), the acetonitrile was evaporated in vacuo, and the product was filtered and
washed with water to provide thioureas 11–16.

Molecules 2021, 26, 303
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3.4. General Procedure for the CF Synthesis of Thioureas 26–36
Isocyanide ( 17 18; 3.0 mmol) and amine (19 25, 4.5 or 9.0 mmol) was dissolved
in MeCN, then filtered through a 0.45 m pore-sized syringe filter to provide Feed A (0.2 M
1
,
6,
7
,
,
–
µ
isocyanide and 0.3 or 0.6 M amine in MeCN). The aqueous polysulfide solution made of
PMDTA and elemental sulfur was used for Feed B (1.0 M PMDTA, 0.4 M sulfur). Feeds A
and B were pumped into a T-mixer at room temperature at flow rates of 0.10 mL min−1
each. The mixture passed through a reaction coil at 80 ◦C in 42 min, then collected in an
Erlenmeyer flask. Altogether, 0.5 mmol of product was collected (calculated on the used
isocyanide), the acetonitrile was evaporated in vacuo, and the product was filtered and
washed with water to provide thioureas 26–36.
4. Conclusions
Starting from our former batch procedure, we developed a new continuous-flow
synthesis of thioureas by the multicomponent reaction of aqueous polysulfide solution,
isocyanides, and amidines or amines. We have shown the convenient continuous-flow
application of elemental sulfur and explored the scope and limitations of the procedure.
Notably, the products were isolated by simple filtration, and no further purification was
necessary. We believe that this approach widens the synthetic toolbox for the development
of new methods using polysulfide solution for the incorporation of sulfur into organic
molecules.
Supplementary Materials: The following are available online: general procedures for the iso-
cyanides, characterization data, and NMR spectra.
Author Contributions: Conceptualization, A.G.N. and P.Á.-B.; investigation, A.G.N. and R.S.; super-
vision, G.O., I.M.M., G.M.K., P.Á.-B.; writing—original draft preparation, A.G.N.; writing—review
and editing, G.O., I.M.M., G.M.K., P.Á.-B. All authors have read and agreed to the published version
of the manuscript.
Funding: This research was funded by Hungarian Science Foundation OTKA, grant number
PD124598.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data supporting this study is available in the manuscript and the
Supplementary Materials.
Acknowledgments: Krisztina Németh and Pál Szabó for the HRMS measurements.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available upon request from the corresponding
authors.
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