Chromatography-Free Multicomponent Synthesis of Thioureas Enabled by Aqueous Solution of Elemental Sulfur

Article abstract of DOI:10.1002/open.202000250

The development of a new three-component chromatography-free reaction of isocyanides, amines and elemental sulfur allowed us the straightforward synthesis of thioureas in water. Considering a large pool of organic and inorganic bases, we first optimized the preparation of aqueous polysulfide solution from elemental sulfur. Using polysulfide solution, we were able to omit the otherwise mandatory chromatography, and to isolate the crystalline products directly from the reaction mixture by a simple filtration, retaining the sulfur in the solution phase. A wide range of thioureas synthesized in this way confirmed the reasonable substrate and functional group tolerance of our protocol.

Full text of DOI:10.1002/open.202000250

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Chromatography-Free Multicomponent Synthesis of
Thioureas Enabled by Aqueous Solution of Elemental Sulfur
András Gy. Németh,[a] Renáta Szabó,[a] Attila Domján,[b] György M. Keserű,*[a] and
Péter Ábrányi-Balogh*[a]
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The development of a new three-component chromatography-
free reaction of isocyanides, amines and elemental sulfur
allowed us the straightforward synthesis of thioureas in water.
Considering a large pool of organic and inorganic bases, we
first optimized the preparation of aqueous polysulfide solution
from elemental sulfur. Using polysulfide solution, we were able
to omit the otherwise mandatory chromatography, and to
isolate the crystalline products directly from the reaction
mixture by a simple filtration, retaining the sulfur in the solution
phase. A wide range of thioureas synthesized in this way
confirmed the reasonable substrate and functional group
tolerance of our protocol.
1. Introduction
Recently a couple of innovative, multicomponent and one-pot
procedures have been published for the use of elemental sulfur
in synthetic procedures.[20–26] Numerous methods rely on the
known transformation of isocyanides to isothiocyanates with
elemental sulfur in the presence of base or various metal
catalysts,[19,27–35] which is utilized in particular for the synthesis of
thioureas (Scheme 1). Zhou et al. developed a cobalt-catalyzed
method for the synthesis of thioureas starting from isocyanides,
elemental sulfur, aliphatic and aromatic amines under oxidative
conditions.[36] The one-pot procedure of Tan et al. offers the
in situ synthesis of isocyanides from amines and chloroform in
the presence of potassium tert-butoxide, followed by the
addition of sulfur and various amines.[37] It should be noted that
the above mentioned methods require catalyst and organic
solvents. The most practical way was introduced by Nguyen
et al. who developed a solvent- and catalyst-free method
starting from isocyanides, elemental sulfur and aliphatic
amines.[38] As a limitation of this method, the preparation of
biaryl thioureas is not available due to the reduced nucleophilic
behavior of aromatic amines under the applied conditions.
Moreover, the excess of sulfur make chromatography indispen-
sable as crystallization from an organic solvent is not suitable
for the removal of S8.
Since the introduction of the 12 principles in green
chemistry, considerable efforts have been made to the develop-
ment of environmentally friendly and sustainable organic
processes. A major aspect of green chemistry is to use safer
solvents and to reduce the environmental impact of the
chemical reactions.[39,40] Chromatographic purification produces
large waste of organic solvents and dischargeable static phase,
therefore, developing new reaction pathways and improving
existing methods to avoid chromatography remains an impor-
tant issue[40–46] from both environmental and economic points
of view. The replacement of organic solvents with water as a
non-toxic, abundant and cheap solvent has generated signifi-
cant attention. Notably, its features of accelerating reactions
and simplifying the isolation of the products are regarded as
main advantages of its application in organic reactions.[47–50] In
continuation of our interest in green chemistry,[51] multicompo-
Sulfur–containing compounds are widely used as biologically
active molecules[1] and functional organic materials.[2,3] Thiour-
eas, in particular, are important pharmaceutical and agro-
chemical intermediates and active ingredients represented by
the marketed drug thiocarlide,[4] algicides,[5] fungicides[6] and the
insecticide chloromethiuron.[7] In addition, they are key syn-
thetic precursors of nitrogen and sulfur containing compounds,
especially pharmacologically relevant heterocycles.[8–12] Notably,
in the last two decades thioureas were also applied as highly
selective and efficient organocatalysts.[13–16] Given the wide
utility of thioureas, their clean and efficient synthesis is of high
interest.
Elemental sulfur is a bench-stable environmentally benign,
inexpensive and nontoxic reagent for sulfuration offering an
atom-economical and safe alternative to incorporate the sulfur
atom into products.[17] Certain nucleophiles, such as aliphatic
amines are able to generate trisulfur radical anions[18] and open-
chain ionic polysulfide anions from elemental sulfur,[19] the
former existing only under inert conditions. These transforma-
tions are responsible for the activation of elemental sulfur,
which can then be used as efficient sulfurating reagent.[17]
[a] A. G. Németh, R. Szabó, Prof. G. M. Keserű, Dr. P. Ábrányi-Balogh
Medicinal Chemistry Research Group
Research Centre for Natural Sciences
Magyar tudósok krt. 2
1117 Budapest (Hungary)
E-mail: abranyi-balogh.peter@ttk.hu
keseru.gyorgy@ttk.hu
[b] Dr. A. Domján
NMR Research Laboratory
Research Centre for Natural Sciences
Magyar tudósok krt. 2
1117 Budapest (Hungary)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202000250
© 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Com-
mercial NoDerivs License, which permits use and distribution in any med-
ium, provided the original work is properly cited, the use is non-commercial
and no modifications or adaptations are made.
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Scheme 1. Synthetic methods for the elemental sulfur based multicomponent synthesis of thioureas.
nent reactions[52–54] and reactions involving sulfur[19,55] we aimed
to develop an environmentally friendly synthesis for diverse
thioureas, including challenging biaryl derivatives. We envi-
sioned the preparation of aqueous solutions of polysulfide
anions to use it as a novel agent for the incorporation of sulfur
atom. The main advantages of this reagent would be an
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environmentally friendly, atom economical access to thio
compounds in water with easy work-up and purification by
avoiding chromatography. As the first step in this direction,
here we report the development of a chromatography-free
multicomponent synthesis of thioureas in polysulfide anion
containing aqueous solutions.
amidines DBU, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (MTBD), we successfully prepared
more concentrated, 0.4 M solutions of elemental sulfur in the
presence of only 2.5 equivalents of the base (entries 5–10,
Table 1). In the case of Et3N, N-ethylpiperidine and quinine the
addition of 50% acetonitrile or tetrahydrofuran (THF) was
necessary in order to keep the solution homogeneous (entries
12–14, Table 1), however, the maximal concentration was
limited to 0.15 M of sulfur for 0.25 M of quinine (entry 14,
Table 1). Although we achieved higher sulfur concentration in
some cases, we have standardized the amount of base and
elemental sulfur in 1.0 M and 0.4 M, respectively due to
practical considerations (versatility, comparability and easy
handling). These target concentrations were achieved by multi-
ple bases that provided considerable flexibility for developing
synthetic applications.
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2. Results and Discussion
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Our first objective was to prepare polysulfide anion containing
aqueous solutions from elemental sulfur using different bases
(Table 1). Optimizing the conditions, we applied 0.05 M elemen-
tal sulfur in the presence of 20 equivalents of bases including
NaOH, diisopropylamine (DIPA) and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) in water. Although sonication at room temper-
°
°
ature or at 40 C and 60 C failed to result in the homogeneous
solution, vigorous stirring enabled the complete dissolution of
Polysulfide solutions were investigated by NMR in D2O.
1
Figure 1 shows the stacked H-NMR spectra obtained for the
°
the solid at 60 C. Encouraged by the results, we have screened
polysulfide solutions containing 0.1 M, 0.4 M and 1.0 M sulfur
together with 1.0 M PMDTA in D2O, respectively. Dissolving
sulfur in 0.1:1 ratio with the base (Fig 1B), chemical shifts are
shifted lower and the signals of the methyl groups 1’ and 4’
became merged at 2.08 ppm. Increasing the ratio of sulfur to
0.4:1 (Fig 1 C) and 1:1 (Fig 1D) the chemical shift of the methyl
groups 1‘ show a 0.13 and then a 0.14 ppm positive shift, while
the methyl group 4’ is moving only 0.10 and further 0.09 ppm
upwards. The signals of the ethylene groups shifts upwards as
well and start to merge around 10% sulfur content indicating
that the chemical difference between the carbons 2 and 3
fades. Performing the experiments in the presence of CF3COOD
instead of sulfur, we had similar observations, proving quaterni-
zation of the nitrogen atoms (see ESI Figure S1). These
observations indicate that both types of nitrogen atoms are
involved in the nucleophilic attack on sulfur, though the
terminal nitrogen atoms participate more in the transformation.
In fact, the activation energy of ammonium ion formation is
very low,[67] and thus we suppose a dynamic equilibrium
a number of bases in water (see ESI Table S1) and finally found
14 bases suitable for the preparation of homogenous poly-
sulfide anion containing aqueous solutions in various concen-
trations (Table 1). Our goal was to reach a sulfur concentration
of at least 0.1 M that is perfectly suited for synthetic
purposes.[25,56–65] Generally, inorganic bases did not provide the
appropriate concentration, as in the case of NaOH, Na2S and
tetrabutylammonium hydroxide (TBAOH) we could reach a
concentration of only 0.05 M elemental sulfur in the presence
of 20 equivalents of base (entries 1–3, Table 1). Although Wang
et al. claimed to dissolve 0.05 M sulfur and 0.34 M disodium
disulfide in water at 70 C in 15 minutes,[66] this method was not
°
reproducible in our hands. Employing 1.0 M piperidine or 1,4-
diazabicyclo[2.2.2]octane (DABCO) in water provided a 0.05 M
and 0.1 M solution of sulfur, respectively (entries 4 and 11,
Table 1). Considering further organic bases, such as DIPA,
N,N,N’,N’’,N’’-pentamethyldiethylenetriamine (PMDTA) or the
Table 1. Suitable bases for the preparation of aqueous polysulfide
solution.
Entry[a,b]
Base
Solvent
Base/S8 concentration [c]
1
2
3
4
5
6
7
8
NaOH
Na2S
TBAOH
Piperidine
DBU
DBN
TBD
MTBD
PMDTA
DIPA
DABCO
Et3N
N-ethylpiperidine
Quinine
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water:MeCN
Water:MeCN
Water:THF
1.0 M/0.05 M
1.0 M/0.05 M
1.0 M/0.05 M
1.0 M/0.05 M
1.0 M/0.4 M
1.0 M/0.4 M
1.0 M/0.4 M
1.0 M/0.4 M
1.0 M/0.4 M
1.0 M/0.4 M
1.0 M/0.1 M
1.0 M/0.4 M
1.0 M/0.4 M
0.25 M/0.15 M
9[d,e]
10[e]
11[e]
12[e,f]
13[e,f]
14[e,g]
[a] For the full list of bases, see the supporting information (Table S1). [b]
°
Conditions: 60 C, water, vigorous stirring. [c] Concentration of base and
Figure 1. Stack plot of the 1H-NMR spectra of PMDTA and polysulfide
solutions made of PMDTA and sulfur in D2O in different amine:sulfur ratios;
Spectrum „A”: PMDTA; Spectrum „B”: PMDTA:S 1:0.1; Spectrum „C”: PMDTA:S
1:0.4; Spectrum „D”: PMDTA:S 1:1.
°
sulfur respectively. [d] 70 C was employed. [e] Overnight stirring was
employed. [f] 50% acetonitrile was used as co-solvent. [g] 50% THF was
used as co-solvent.
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between the quaternization of the terminal and the middle
nitrogens.
halobenzenes[73–75] and esters.[76] As a result of the preparation
of the polysulfide solution, we observed the ring opening
transformation of DBU.[73–76] Figure 2 shows the stacked spectra
of DBU (Figure 2A), 1-(3-aminopropyl)azepan-2-one (Figure 2B)
and the polysulfide solution prepared from 0.4 M sulfur and
1.0 M DBU (Figure 2C). Comparing these spectra and the
highlighted atoms, no change in the chemical shift of the
opened DBU can be observed. The protons at the position 7, 1’
and 3’ are located at the same chemical shift in the neat and
polysulfide solution (Figure 2B and 2 C). The corresponding
protons of DBU at the position 2, 11 and 9, respectively,
however, moving upwards from 3.58, 3.54 and 3.34 ppm to
3.64, 3.59 and 3.39 ppm, respectively after the preparation of
the polysulfide solution (Figure 2A and 2B). These findings
suggest that the quaternization, thus the interaction of sulfur
happens with DBU and the presence of 1-(3-aminopropyl)
azepan-2-one is a result of the known hydrolysis of DBU
(Scheme 2).[73–76] Therefore, we envisioned the reaction of the
polysulfide solution of amidines (3) with isocyanides (1) in order
to generate caprolactam and pyrimidinone substituted thiour-
eas. We found this reaction suitable for the validation of the
aqueous polysulfide solution to prepare isothiocyanate from
isocyanide followed by the transformation to thiourea in a one-
pot, multicomponent manner. Accordingly, a polysulfide sol-
ution has been made from DBU (3a, 1.0 M) and sulfur (0.4 M)
1
2
3
4
5
6
7
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9
The nucleophilicity of DBU and related amidines DBN, TBD
and MTBD has been used in their reactions with aldehydes,[68]
carbonates,[69]
imidazolides,[70]
methyl-pyrazoles[71]
and
benzoxazinones[72] as electrophiles leading to caprolactams or
substituted tetrahydropyrimidinones. Notably, cyclic amidines
undergo ring-opening in the presence of water yielding amino-
propyl lactams and pyrimidinones that readily react with
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°
stirring vigorously at 60 C for 1 hour and cooling to room
Figure 2. Stack plot of the 1H-NMR spectra of DBU (spectrum „A”), 1-(3-
aminopropyl)-azepan-2-one (spectrum „B”) and the polysulfide solution
made of 1.0 M DBU and 0.4 M sulfur (spectrum „C”) in D2O.
temperature. Then, 0.2 mmol of 2,6-dimethylphenyl isocyanide
(1a, 0.2 M) was added to 1 mL polysulfide solution which
provided the corresponding thiourea 4aa in 55% yield at room
temperature after 5 hours (Table 2, entry 1). Notably, the
product precipitated from water, thus it could be separated
easily by filtration. The excess of the base and polysulfide
anions could be removed by washing the solid with water i.e.
no chromatographic purification was necessary. Next, we
optimized the conditions of this reaction isolating the products
after the full consumption of the isocyanide monitored by TLC
°
°
and HPLC-MS. Raising the temperature to 40 C and 60 C the
reaction time decreased to 2 hours and 0.5 hour, resulting in
4aa in 74% and 96% yields, respectively (Table 2, entries 2, 3).
°
Scheme 2. Proposed interaction of DBU with elemental sulfur.
Reducing the excess of sulfur to 1.5 equivalents at 60 C
Table 2. Optimization of the reaction conditions for the synthesis of thioureas.
Entry
T
Time
[h]
Molar excess of
1a/2/3a
Yield[a,b]
[%]
°
[ C]
1
2
3
RT
40
60
60
60
60
60
5
2
0.5
0.5
0.5
0.5
0.5
1/2/5
1/2/5
1/2/5
1/1.5/5
1/2/4
1/2/3
1/2/5
55
74
96
85
93
76
91
4[c]
5[d]
6[e]
7[f]
[a] Reaction conditions: 1a (0.2 mmol), polysulfide solution in water (1 mL, 1.0 M DBU (3a)/0.4 M S8 (2)), temperature, time. [b] Isolated yields. [c] Polysulfide
solution in water (1 mL, 1.0 M DBU (3a)/0.3 M S8 (2)). [d] Polysulfide solution in water (1 mL, 0.8 M DBU (3a)/0.4 M S8 (2)). [e] Polysulfide solution in water
(1 mL, 0.6 M DBU (3a)/0.4 M S8 (2)). [f] Performed at a 0.5 mmol scale.
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decreased the yield (85%, Table 2, entry 4). When the excess of
the base was reduced to 4 equivalents (0.8 M) no significant
change in the yield was observed (93%, Table 2 entry 5),
however, further decreasing to 3 equivalents (0.6 M) reduced
the yield significantly (76%, Table 2, entry 6). Finally, with the
optimized conditions in hand (Table 2, entry 3), scaling up the
reaction to 0.5 mmol provided 4aa in 91% yield (Table 2,
entry 7).
(3a–d) and isocyanides (1a–e) to investigate the scope and
limitation of the method developed. Using 2,6-dimethylphenyl
isocyanide (1a) with the polysulfide containing aqueous
1
2
3
4
5
6
7
8
9
°
solutions made of DBN (3b) and MTBD (3c) at 60 C provided
thioureas 4ab and 4ac in excellent, 92% and 99% yields,
respectively (Scheme 3). Applying TBD (3d) as base, the desired
thiourea (4ad) was obtained in 62% yield after 2 hours. The
adamantyl derivative 4ba was isolated in 70% yield after
4 hours. Next, we applied heterocyclic thioureas containing
indole, quinoline or pyridine ring 4ca–4ea in 72%, 50% and
The optimized conditions scaled to 0.5 mmol (Table 2,
entry 7) were applied to a structurally diverse set of amidines
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Scheme 3. Substrate scope for amidines and isocyanides. [a] Reaction conditions: 1 (0.5 mmol), polysulfide solution (1.0 M base (3)/0.4 M S8 (2), 2.5 mL),
°
reaction time in parentheses, 60 C, water.
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67% yields, respectively (Scheme 3). Notably, the aromatic
bromine on the pyridine ring (1e) was well tolerated.
1
2
Considering bases resistant to acylating agents such as
DABCO, PMDTA, Et3N, N-ethylpiperidine and quinine (Table 1),
the reaction was envisaged to provide virtually any desired
thioureas. Since DABCO enables the preparation of only 0.1 M
solution of sulfur and the latter three bases require co solvents,
the generality of the reaction was investigated using PMDTA
(1.0 M) and sulfur (0.4 M, Table 1, entry 9) with various isocya-
3
4
5
6
7
8
9
°
nides and benzylamine at 80 C (5a, Scheme 4). Applying
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aromatic 2,6-dimethylphenyl- (1a), 4-fluorophenyl- (1f) and 4-
methoxyphenyl isocyanide (1g), the formation of thioureas
6aa, 6fa and 6ga was observed in excellent yields (89%, 85%
and 96%, respectively on Scheme 4). The cyclohexyl and tert-
butyl derivatives 6ha and 6ia were obtained in slightly lower
but still reasonable yields of 81% and 89%, respectively.
Importantly, the formed thioureas crushed out of water and
were separated by filtration, no further purification was
necessary.
Next, we evaluated the scope of aliphatic and aromatic
amines. Aqueous ammonia (5b), and primary amines, like
hexylamine, allylamine, (S)-(-)-1-phenylethylamine, trypt-
amine and cyclohexylamine (5c-g) reacted well leading to
the formation of the corresponding thioureas (6ab–6ag) in
good to excellent yields (77–91%, Scheme 5), in the case of
°
6ab and 6ad at 80 C. Sterically more challenging tert-
butylamine (6ai) and morpholine (6aj) derivatives were both
°
isolated in 74 % yield after 0.5 h at 80 C, applying
3
equivalents of amine. 1-Adamantylamine (5h) was used in 3
equivalents for 1 hour at 80 C, providing the desired thiourea
°
6ah in 83% yield. Employing phenylhydrazine (5k) and L-
tryptophan (5l) in the reaction led to the formation of the
thiosemicarbazide 6ak and thiourea 6al in good yields (78%
and 66%, respectively), the latter being isolated in a two-step
crystallization procedure (see experimental section). Next, we
have aimed to investigate the synthesis of biaryl thioureas.
As we mentioned in the introduction, the preparation of
biaryl derivatives has been only accomplished in the
presence of a catalyst or in organic solvents under inert
conditions.[36,37] The practical, catalyst- and solvent-free
Scheme 5. Substrate scope for amines. [a] Reaction conditions: 1
(0.50 mmol), 5 (0.75 mmol), polysulfide solution (1.0 M PMDTA/0.4 M S8 (2),
°
°
2.5 mL), 60 C, 0.5 hour, water. [b] 10 equivalents of aq. 25% NH3. [c] 80 C
and 3 equivalents of 5. [d] 1 hour reaction time. [e] In the case of anilines, 3
°
equivalents of 5, 80 C.
method of Nguyen et al., however, is not suitable for the
synthesis of these compounds.[38] Using the polysulfide
solution made of PMDTA (1.0 M) and sulfur (0.4 M, Table 1,
entry 9) in the presence of 3 equivalents of aniline (5m) and
°
2,6-dimethylphenyl isocyanide (1a) at 80 C eventually led to
full conversion of the isocyanide in 0.5 hour. After removing
the excess of polysulfide anions and the base with water, the
excess of the aniline was washed away with 1.0 M aq. HCl
providing the thiourea 6am in 74% yield. The 2-methyl (5n)
and 4-methyl (5o) derivatives reacted in 1 hour providing the
corresponding thioureas 6 an and 6ao in 74% and 81%
yields, respectively. However, the 2,6-dimethyl- (5p), 4-meth-
oxy- (5q), 3,4,5-trimethoxy- (5r) and 4-hydroxy aniline (5v)
reacted faster, giving the thioureas 6ap–6aq and 6av in only
0.5 hour in good yields (79%, 69%, 62 % and 73% respec-
tively, Scheme 5). Halogens (Cl, Br, I) were generally well
Scheme 4. Substrate scope for isocyanides. [a] Reaction conditions: 1
(0.50 mmol), 5a (0.75 mmol), polysulfide solution (1.0 M PMDTA/0.4 M S8 (2),
°
2.5 mL), 80 C, 0.5 hour, water. [b] 2 hours reaction time.
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tolerated in the reaction, the thioureas 6as–6au were
obtained in 76 %, 77% and 63% yields, respectively. Hence,
this simple approach was used efficiently for the preparation
of challenging biaryl thioureas starting from 2,6-dimethyl
isocyanide, aqueous polysulfide solution and the correspond-
ing anilines.
Next, as an eye-catching example, we have synthesized
the marketed drug thiocarlide (Isoxyl®).[4] At first, 1-(isopenty-
loxy)-4-nitrobenzene (9) was prepared from the commercially
synthesis of thiocarlide starting from 4-(isopentyloxy)aniline
(10) than that of published procedures using carbon
disulfide[77] (53%) or thiophosgene[78] (50%).
1
2
3
4
5
6
7
8
9
3. Conclusions
In summary, we have prepared aqueous solutions of polysulfide
anions from elemental sulfur with a pool of organic and
inorganic bases. The resulting aqueous solutions were used
efficiently for the chromatography-free synthesis of thioureas in
a multicomponent reaction in good to excellent yields. This
approach enables the easy isolation of the desired products by
a simple filtration, and thus, introduces an environmentally
benign synthesis of thioureas. The methodology has been
validated in a wide range of synthesis scenarios including
lactam-, tetrahidropyrimidin-2-one and other, disubstituted
thioureas, highlighting biaryl derivatives and the marketed
drug, thiocarlide.
available 4-nitrophenol
7 with isopentyl-bromide (8) in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
refluxing DMF in the presence of NaOH in 70% yield
(Scheme 6). Then, the reduction of the nitro group by
catalytic hydrogenation and the subsequent transformation
of amine 10 provided the formamide 11 in quantitative yield.
The formal dehydration of 11 led to the corresponding
isocyanide 12 in 73% yield. In the reaction of isocyanide 12,
amine 10 and the aqueous polysulfide solution made of
PMDTA (1.0 M) and sulfur (0.4 M, Table 1, entry 9) led to
°
thiocarlide (13) in full conversion after 0.5 hour at 60 C
(Scheme 7). Compound 13 precipitated from water, enabling
the separation by filtration. The excess of the polysulfide
anions, the base and the amine was removed by washing Experimental Section
with water and with 0.5 M aq. HCl resulting in an isolated
yield of 84%. In conclusion, our method (Scheme 9) have
provided better overall yield (61% for 4 steps) for the
General
All melting points were determined on a Jasco SRS OptiMelt
apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded in DMSO-d6 or CDCl3 solution at room temperature, on a
1
Varian Unity Inova 500 spectrometer (500 and 125 MHz for H and
APT NMR spectra, respectively), with the residual solvent signal as
the lock and TMS 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
device equipped with a Reprospher 100 C18 (5 μm; 100×3 mm)
column and 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). Flow rate
was set to 1.5 mL/min. The initial condition was 5% B eluent,
followed by a linear gradient to 100% B eluent by 1.5 min, from 1.5
to 4.0 min 100% B eluent was retained; and from 4.0 to 4.5 min
back to initial condition with 5% B eluent and retained 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 are known, purchased or synthetically feasible and
>95% pure.
Scheme 6. Synthesis of the key intermediates 10 and 12 for the preparation
of thiocarlide. [a] Reaction conditions: (i): NaOH, DMF, reflux, 3 hours; (ii): H2,
10% Pd/C, EtOAc, rt; (iii): HCOOH, (CH3CO)2O, THF, RT; (iv): POCl3, Et3N, THF,
RT.
General Procedure for the Preparation of Aqueous Solutions
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 μL, 2.5 mmol) and water
°
(2.13 mL) and stirred vigorously at 60 C until the complete
dissolution of sulfur.
3.1. General Procedure for the Synthesis of Thioureas
Isocyanide (1a–i, 0.5 mmol) was added to the aqueous solution of
sulfur and the appropriate base (3a–d or PMDTA, 2.5 mL, 1.0 M
°
Scheme 7. Synthesis of thiocarlide in the three component reaction applying
polysulfide solution in water and known literature methods.
base, 0.4 M sulfur) and stirred vigorously at 60 or 80 C until the
total consumption of the isocyanide monitored by HPLC-MS
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Table 3. Preparation of polysulfide solutions according to the general procedure.
1
2
3
Amine
Sulfur
[mg, mmol]
Amine
[μL or mg,
mmol]
Water
[mL]
T
°
[ C]
4
5
6
7
8
9
1,5-Diazabicyclo[4.3.0]non-5-ene
1,5,7-Triazabicyclo[4.4.0]dec-5-ene
7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene
N,N,N‘,N‘,N“-pentamethyldiethylenetriamine
1,4-Diazabicyclo[2.2.2]octane
Triethylamine
32, 1.00
32, 1.00
32, 1.00
32, 1.00
8, 0.25
32, 1.00
16, 0.50
12, 0.38
310, 2.50
348, 2.50
360, 2.50
522, 2.50
280, 2.50
348, 2.50
343, 2.50
203, 0.63
2.19
2.50
2.17
1.98
60
60
60
70
60
60
60
60
2.50
2.16[a]
2.16[a]
2.50[b]
N-ethylpiperidine
Quinine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[a] 1:1 mixture of water and acetonitrile. [b] 1:1 mixture of water and THF.
(between 0.5 and 4 hours). Afterwards, the product was filtered and
washed with water and in the case of poorly water soluble amines
with 0.5 or 1.0 M aq. HCl, then water providing thioureas 4 and 6 in
50–99% yield.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C20H34N3OS 364.2417;
found 364.2408.
1-(2-(1H-Indol-3-yl)ethyl)-3-(3-(2-oxoazepan-1-yl)propyl)thiourea
1
(4ca): Yellow gum; H-NMR: (500 MHz, CDCl3) δ 8.63 (bs, 1H), 7.56
1-(2,6-Dimethylphenyl)-3-(3-(2-oxoazepan-1-yl)propyl)thiourea
(d, J=7.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.08
(t, J=7.8 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.13 (bs, 1H), 3.68 (bs, 2H),
3.51 (bs, 2H), 3.34À 3.26 (m, 4H), 3.00 (t, J=6.6 Hz, 2H), 2.48 (t, J=
5.5 Hz, 2H), 1.70À 1.59 (m, 8H) ppm; 13C-NMR: (125 MHz, CDCl3) δ
177.3, 136.5, 132.6, 132.1, 127.2, 122.6, 122.1, 119.4, 118.6, 111.3,
49.7, 45.2, 41.0, 37.1, 29.9, 28.3, 26.6, 24.7, 23.4 ppm; HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C20H29N4OS 373.2056; found 373.2074.
(4aa): White solid, m.p. 163–164 C (water); 1H-NMR: (500 MHz,
°
CDCl3) δ 7.25 (bs, 1H), 7.21–7.14 (m, 3H), 6.38 (bs, 1H), 3.57 (t, 2H,
J=6.0 Hz), 3.29–3.27 (m, 4H), 2.41À 2.38 (m, 2H), 2.27 (s, 6H),
1.77À 1.60 (m, 8H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 176.3 (C),
137.2 (C), 128.8 (CH), 110.0 (C), 49.8 (CH2), 45.2 (CH2), 41.9 (CH2),
37.1 (CH2), 29.9 (CH2), 28.6 (CH2), 27.5 (CH2), 23.4 (CH2), 18.1 (CH3)
ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C18H28N3OS
334.1947; found 334.1960.
1-(3-(2-Oxoazepan-1-yl)propyl)-3-(quinolin-3-yl)thiourea
(4da):
1
°
Beige crystals, m.p. 134–135 C (water); H-NMR: (500 MHz, CDCl3) δ
9.18 (bs, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.85
(bs, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.43 (d, J=
7.7 Hz, 1H), 3.62 (d, J=5.4 Hz, 2H), 3.36 (t, J=6.1 Hz, 2H), 3.26 (t, J=
4.5 Hz, 2H), 2.39 (t, J=5.4 Hz, 2H), 1.77 (m, 2H), 1.64 (d, J=5.2 Hz,
2H), 1.55 (d, J=4.4 Hz, 4H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 181.0
(C), 177.1 (C), 147.6 (CH), 145.7 (C), 131.7 (C), 129.0 (CH), 128.8 (CH),
128.2 (bs, CH), 128.0 (C), 127.8 (CH), 127.1 (CH), 49.8 (CH2), 45.6
(CH2), 41.6 (CH2), 37.1 (CH2), 29.8 (CH2), 28.4 (CH2), 26.8 (CH2), 23.3
(CH2) ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C19H25N4OS
357.1743; found 357.1736.
1-(2,6-Dimethylphenyl)-3-(3-(2-oxopyrrolidin-1-yl)propyl)thiourea
(4ab): White solid, m.p. 154–155 C (water); 1H-NMR: (500 MHz,
°
CDCl3) δ 7.27 (bs, 1H), 7.22À 7.14 (m, 3H), 6.32 (bs, 1H), 3.54 (bs, 2H),
3.36 (t, 2H, J=7.0 Hz), 3.18 (bs, 2H), 2.32À 2.24 (m, 2H), 2.27 (s, 6H),
2.01À 1.95 (m, 2H), 1.79À 1.76 (m, 2H) ppm; 13C-NMR: (125 MHz,
CDCl3) δ 175.6 (C), 137.3 (C), 128.8 (CH), 47.3 (CH2), 41.7 (CH2), 39.5
(CH2), 30.8 (CH2), 26.7 (CH2), 18.1 (CH3), 17.9 (CH2) ppm; HRMS (ESI/
Q-TOF) m/z: [M+H]+ Calcd. for C16H24N3OS 306.1634; found
306.1651.
1-(2,6-Dimethylphenyl)-3-(3-(3-methyl-2-oxotetrahydropyrimidin-
°
1(2H)-yl)propyl)thiourea (4ac): Yellow crystals, m.p. 156–157 C
(water); H-NMR: (500 MHz, DMSO-d6) δ 8.67 (bs, 1H), 7.05 (m, 3H),
1-(6-Bromopyridin-3-yl)-3-(3-(2-oxoazepan-1-yl)propyl)thiourea
1
(4ea): White solid, m.p. 182–183 C (water); 1H-NMR: (500 MHz,
°
6.11 (bs, 1H), 3.77À 3.74 (m, 2H), 3.26À 3.20 (m, 7H), 3.10À 3.08 (m,
2H), 2.13 (s, 6H), 1.82À 1.77 (m, 4H) ppm; 13C-NMR: (125 MHz,
DMSO-d6) δ 180.8 (C), 155.8 (C), 139.1 (C), 136.9 (C), 127.9 (CH),
126.8 (CH), 45.3 (CH2), 44.5 (CH2), 25.7 (CH2), 22.6 (CH2), 18.5 (CH3)
ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C17H28N4OS
335.1900; found 335.1920.
DMSO-d6) δ 9.77 (bs, 1H), 8.40 (d, J=2.7 Hz, 1H), 8.01 (bs, 1H), 7.94
(d, J=6.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 3.36À 3.30 (m, 6H), 2.42 (t,
J=5.6 Hz, 2H), 1.72À 1.54 (m, 8H) ppm; 13C-NMR: (125 MHz, DMSO-
d6) δ 181.2 (C), 175.3 (C), 145.1 (CH), 136.9 (C), 135.2 (C), 134.1 (CH),
127.7 (CH), 49.0 (CH2), 45.4 (CH2), 42.0 (CH2), 37.0 (CH2), 29.7 (CH2),
28.8 (CH2), 27.5 (CH2), 23.5 (CH2) ppm; HRMS (ESI/Q-TOF) m/z: [M+
H]+ Calcd. for C15H22BrN4OS 385.0692; found 385.0699.
1-(2,6-Dimethylphenyl)-3-(3-(2-oxotetrahydropyrimidin-1(2H)-yl)
propyl)thiourea (4ad): White solid, m.p. 142–143 C (water); 1H-
1-Benzyl-3-(2,6-dimethylphenyl)thiourea (6aa): White solid 106–
°
1
°
NMR: (500 MHz, CDCl3) δ 7.27 (bs, 1H), 7.18À 7.11 (m, 3H), 6.67 (bs,
1H), 4.50 (bs, 1H), 3.59À 3.56 (m, 2H), 3.20À 3.18 (m, 6H), 2.25 (s, 6H),
1.88À 1.86 (m, 2H), 1.76À 1.71 (m, 2H) ppm; 13C-NMR: (125 MHz,
CDCl3) δ 156.6 (C), 150.7 (C), 144.6 (C), 137.3 (C), 128.7 (CH), 45.3
(CH2), 44.3 (CH2), 41.9 (CH2), 40.3 (CH2), 27.0 (CH2), 22.1 (CH2), 18.1
(CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C16H25N4OS
321.1743; found 321.1759.
107 C (water); H-NMR: (500 MHz, CDCl3) δ 7.53 (bs, 1H), 7.33À 7.26
(m, 5H), 7.20À 7.12 (m, 3H), 5.64 (bs, 1H), 4.87 (d, J=5.3 Hz, 2H),
2.28 (s, 6H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 181.4 (C), 137.7 (C,
bs), 137.3 (C), 129.0 (CH), 128.7 (CH), 127.6 (CH), 127.5 (CH), 49.2
(CH2), 18.1 (CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C16H19N2S 271.1263; found 271.1261.
1-Benzyl-3-(4-fluorophenyl)thiourea (6fa): Brown solid, m.p. 112–
[79]
113 C (water; ref. 106À 108 C); 1H-NMR: (500 MHz, DMSO-d6,
ref.[79]) δ 9.54 (bs, 1H), 8.13 (bs, 1H), 7.44À 7.41 (m, 2H), 7.34À 7.33
(m, 4H), 7.27À 7.24 (m, 1H), 7.16 (t, J=8.8 Hz, 2H), 4.73 (d, J=5.4 Hz,
2H) ppm.
°
°
1-((3s,5s,7s)-Adamantan-1-yl)-3-(3-(2-oxoazepan-1-yl)propyl)thi-
ourea (4ba): Yellow gum; 1H-NMR: (500 MHz, CDCl3) δ 7.22 (bs, 1H),
5.90 (bs, 1H), 3.61À 3.57 (m, 2H), 3.37 (t, J=5.8 Hz, 2H), 3.32 (t, J=
4.7 Hz, 2H), 2.51 (t, J=5.7 Hz, 2H), 2.09 (bs, 3 H), 2.02 (bs, 6H),
1.73À 1.62 (m, 14H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 179.7, 177.0,
53.8, 49.9, 45.6, 41.9, 41.6, 37.2, 35.9, 30.0, 29.5, 28.7, 27.2, 23.5 ppm;
1-Benzyl-3-(4-methoxyphenyl)thiourea (6ga): Brown solid, m.p.
[80]
1
[80]
°
°
90–91 C (water; ref. 113–114 C); H-NMR: (500 MHz, CDCl3, ref.
)
δ 7.82 (bs, 1H), 7.34À 7.27 (m, 5H), 7.16 (d, J=8.6 Hz, 2H), 6.91 (d,
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J=8.6 Hz, 2H), 6.09 (bs, 1H), 4.87 (d, J=5.2 Hz, 2H), 3.80 (s, 3H)
ppm.
18.1 ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C19H27N2S
315.1889; found 315.1889.
1
2
3
4
5
°
1-Benzyl-3-cyclohexylthiourea (6ha): Beige solid, m.p. 108–109 C
1-(tert-Butyl)-3-(2,6-dimethylphenyl)thiourea (6ai): White solid,
(water; ref.[81] 89–90 C); 1H-NMR: (500 MHz, CDCl3, ref.[82]
)
δ
m.p. 123–124 C (water); H-NMR: (500 MHz, CDCl3) δ 7.19À 7.11 (m,
1
°
°
7.34À 7.30 (m, 5H), 6.16 (bs, 1H), 5.79 (bs, 1H), 4.62 (bs, 2H), 3.85 (bs,
1H), 1.95À 1.93 (m, 2H), 1.65À 1.56 (m, 3H), 1.34À 1.13 (m, 5H) ppm;
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C14H21N2S 249.1419;
found 249.1419.
4H), 5.27 (bs, 1H), 2.25 (s, 6H), 1.43 (s, 9H) ppm; 13C-NMR: (125 MHz,
CDCl3) δ 137.1, 128.9 (bs), 128.8 (bs), 110.0, 53.6, 28.9 (bs), 18.1 (bs)
ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C13H21N2S
237.1419; found 237.1419.
6
7
8
9
°
1-Benzyl-3-(tert-butyl)thiourea (6ia): White solid, m.p. 93–94 C
N-(2,6-Dimethylphenyl)morpholine-4-carbothioamide (6aj): White
[88]
1
(water; ref.[83] 94 C); 1H-NMR: (500 MHz, CDCl3, mixture of E/Z
solid, m.p. 163–164 C (water; ref. 138–140 C); H-NMR: (500 MHz,
CDCl3, ref.[88]) δ 7.15À 7.08 (m, 3H), 6.84 (bs, 1H), 3.84 (t, J=4.4 Hz,
2H), 3.73 (t, J=5.1 Hz, 2H), 2.25 (s, 6H) ppm.
°
°
°
isomers, ref[83]) δ 7.38À 7.30 (m, 5H), 6.01 (bs, 1H), 5.86 (bs, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
4.78À 4.77 (m, 2H), 1.39 (s, 9H) ppm.
1-(2,6-Dimethylphenyl)thiourea (6ab): White solid, m.p. 184–
N-(2,6-Dimethylphenyl)-2-phenylhydrazine-1-carbothioamide
[84]
1
185 C (water; ref. 205–207 C); H-NMR: (500 MHz, CDCl3, mixture
of E/Z isomers ref.[85]) δ 7.77 (bs, 1H), 7.22À 7.19 (m, 1H), 7.15À 7.13
(m, 2H), 6.23 (bs, 1H), 5.33 (bs, 1H), 2.30 (s, 6H) ppm; HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C9H13N2S 181.0793; found 181.0799.
(6ak): White solid, m.p. 194–195 C (water); 1H-NMR: (500 MHz,
°
°
°
DMSO-d6, mixture of E/Z isomers) δ 9.53 (bs, 1H), 9.40 (bs, 1H), 8.07
(bs, 1H), 7.23 (t, J=7.1 Hz, 2H), 7.07À 7.03 (m, 3H), 6.82 (m, 3H), 2.19
((two signals: 2.23 (s), 2.14 (s)), 6H), ppm; 13C-NMR: (125 MHz, CDCl3)
δ 136.8, 129.2, 127.9 (bs), 127.0 (bs), 120.0 (bs), 113.4, 18.5 ppm;
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C15H18N3S 272.1215;
found 272.1221.
1-(2,6-Dimethylphenyl)-3-hexylthiourea (6ac): White solid, m.p.
92–93 C (water); 1H-NMR: (500 MHz, CDCl3)
δ 7.39 (bs, 1H),
°
7.21À 7.18 (m, 1H), 7.14À 7.13 (m, 2H), 5.32 (bs, 1H), 3.57 (q, J=
6.7 Hz, 2H), 2.26 (s, 6H), 1.49À 1.46 (m, 2H), 1.23 (m, 6H), 0.84 (t, J=
6.9 Hz, 2H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 180.9 (C), 137.4 (C),
129.0 (CH), 128.9 (CH), 45.3 (CH2), 31.3 (CH2), 29.2 (CH2), 26.4 (CH2),
22.5 (CH2), 18.0 (CH3), 13.9 (CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+
H]+ Calcd. for C15H25N2S 265.1732; found 265.1736.
((2,6-Dimethylphenyl)carbamothioyl)-L-tryptophan (6al): After
complete consumption of the isocyanide, the reaction mixture was
acidified with 10% aq. HCl and the precipitate was filtered. Next,
the crude product was treated with 1.0 M aq. NaOH at room
temperature for 0.5 h and the mixture was filtered. Then, the
product was precipitated with 10% aq. HCl and filtered to provide
1-Allyl-3-(2,6-dimethylphenyl)thiourea (6ad): Beige solid, m.p. 64–
°
the thiourea 6al in 66% yield. Yellow solid, m.p. 120–121 C (water);
[86]
1
°
°
65 C (water; ref. 75 C); H-NMR: (500 MHz, CDCl3) δ 7.78 (bs, 1H),
7.18À 7.12 (m, 3H), 5.83À 5.78 (m, 1H), 5.38 (bs, 1H), 5.08À 5.06 (m,
2H), 4.23 (m, 2H), 2.26 (s, 6H) ppm; 13C-NMR: (125 MHz, CDCl3) δ
181.1 (C), 137.3 (C), 133.6 (CH), 129.0 (bs, CH), 116.7 (CH2), 47.5
(CH2), 18.1 (CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C12H17N2S 221.1106; found 221.1114.
1H-NMR: (500 MHz, CDCl3, mixture of E/Z isomers) δ 8.06 (s, 1H),
7.82 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.14 (t,
J=7.4 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H),
6.93À 6.89 (m, 2H), 6.72 (s, 1H), 5.63 (d, J=6.2 Hz, 1H), 5.35 (d, J=
5.8 Hz, 1H), 3.35 (dd, J1 =14.7 Hz, J2 =4.8 Hz, 1H), 3.21 (dd, J1 =
14.9 Hz, J2 =6.4 Hz, 1H), 2.06 (s, 3H), 1.84 (s, 3H) ppm; 13C-NMR:
(125 MHz, CDCl3) δ 180.7 (C), 176.0 (C), 137.2 (C), 137.0 (C), 136.0
(C), 132.1 (C), 128.9 (CH), 128.7 (CH), 127.3 (C), 122.8 (CH), 122.2
(CH), 120.0 (CH), 118.1 (CH), 111.2 (CH), 109.1 (C), 57.8 (CH), 27.0
(CH2), 17.7 (CH3), 17.6 (CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+
Calcd. for C20H22N3O2S 368.1427; found 368.1430.
(S)-1-(2,6-Dimethylphenyl)-3-(1-phenylethyl)thiourea (6ae): White
1
°
solid, m.p. 117–118 C (water); H-NMR: (500 MHz, CDCl3, mixture of
E/Z isomers) δ 7.56 (bs, 1H), 7.30À 7.11 (m, 8H), 5.75 (bs, 1H), 5.48
(bs, 1H), 2.24 ((two signals: 2.30 (s), 2.17 (s)) 6H), 1.48 ((two signals:
1.48 (s), 1.47 (s)) 3H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 180.3, 142.4,
137.3, 132.7, 129.0 (bs), 128.6 (bs), 127.4 (bs), 126.0, 53.8, 21.2 (bs),
18.0 ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C17H21N2S
285.1419; found 285.1426.
1-(2,6-Dimethylphenyl)-3-phenylthiourea (6am): White solid, m.p.
[89]
1
°
°
170–171 C (water; ref. 203–205 C); H-NMR: (500 MHz, DMSO-d6,
ref.[90]) δ 9.87 (bs, 1H), 8.98 (bs, 1H), 7.52À 7.09 (m, 8H), 2.22 (s, 6H)
ppm.
1-(2-(1H-indol-3-yl)ethyl)-3-(2,6-dimethylphenyl)thiourea
(6af):
[87]
184–186 C); 1H-NMR:
°
°
Beige solid, m.p. 174–175 C (water; ref.
1-(2,6-Dimethylphenyl)-3-(o–tolyl)thiourea (6an): White solid, m.p.
(500 MHz, CDCl3, ref[87]) δ 7.93 (bs, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.33
(d, J=8.1 Hz, 1H), 7.22À 7.11 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 7.02 (d,
J=7.5 Hz, 2H), 6.78 (s, 1H), 5.41 (bs, 1H), 3.91 (q, J=6.4 Hz, 2H), 2.99
(q, J=6.8 Hz, 2H), 2.08 (s, 6H) ppm; 13C-NMR: (125 MHz, CDCl3) δ
137.4, 136.6, 132.8, 129.1, 127.2, 122.5, 122.1, 119.8, 118.8, 112.5,
111.3, 45.4, 25.0, 18.0 ppm.
205–206 C (water); 1H-NMR: (500 MHz, DMSO-d6) δ 9.40 (bs, 1H),
°
8.63 (bs, 1H), 7.28À 7.05 (m, 7H), 2.29À 2.19 (m, 9H) ppm; 13C-NMR:
(125 MHz, DMSO-d6) δ 137.2 (bs), 136.6. (bs), 136.4 (bs), 130.5 (bs),
128.3 (bs), 128.1, 127.7, 127.5 (bs), 126.4 (bs), 120.0, 18.0, 17.7 ppm;
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C16H19N2S 271.1263;
found 271.1272.
1-Cyclohexyl-3-(2,6-dimethylphenyl)thiourea (6ag): White solid,
1-(2,6-Dimethylphenyl)-3-(p–tolyl)thiourea (6ao): White solid, m.p.
1
°
m.p. 124–125 C (water); H-NMR: (500 MHz, CDCl3) δ 7.41 (bs, 1H),
156–157 C (water); 1H-NMR: (500 MHz, DMSO-d6) δ 9.75 (bs, 1H),
°
7.20À 7.12 (m, 3H), 5.14 (bs, 1H), 4.24 (bs, 1H), 2.25 (s, 6H),
1.99À 1.97 (m, 2H), 1.60À 1.58 (m, 3H), 1.39À 1.34 (m, 2H), 1.07À 0.97
(m, 3H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 179.5, 137.3, 129.0 (bs),
128.9 (bs), 110.0, 53.6, 32.8, 25.4, 24.7, 18.0 ppm; HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd. for C15H23N2S 263.1576; found 263.1579.
8.84 (bs, 1H), 7.34À 7.08 (m, 7H), 2.28 (s, 3H), 2.21 (s, 6H) ppm; 13C-
NMR: (125 MHz, DMSO-d6) δ 180.2, 137.2 (bs), 136.8, 136.3, 133.7,
129.2 (bs), 128.8, 128.1, 127.6 (bs), 126.7 (bs), 123.9, 123.6 (bs), 20.5,
18.1 ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C16H19N2S
271.1263; found 217.1268.
1-((1S,3R,5S)-Adamantan-1-yl)-3-(2,6-dimethylphenyl)thiourea
1,3-bis(2,6-Dimethylphenyl)thiourea (6ap): White solid, m.p. 203–
(6ah): White solid, m.p. 145–146 C (water); 1H-NMR: (500 MHz,
°
[91]
1
°
°
204 C (water; ref. 230–232 C); H-NMR: (500 MHz, CDCl3) δ 8.13
(bs, 1H), 7.25À 7.19 (m, 3H), 7.11À 7.03 (m, 3H), 6.49 (bs, 1H), 2.45 (s,
3H), 2.24 (s, 6H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 180.9 (C), 137.7
(C), 136.5 (C), 135.7 (C), 133.2 (C), 129.3 (CH), 129.1 (CH), 128.3 (CH),
CDCl3) δ 7.19À 7.11 (m, 3H), 7.03 (bs, 1H), 5.16 (bs, 1H), 2.26 (s, 6H),
2.12 (s, 6H), 2.06 (s, 3H), 1.64 (s, 6H) ppm; 13C-NMR: (125 MHz, CDCl3)
δ 137.2, 128.9 (bs), 128.8 (bs), 110.0, 54.1, 41.6 (bs), 36.2, 29.5,
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128.1 (CH), 18.7 (CH3), 18.3 (CH3) ppm; HRMS (ESI/Q-TOF) m/z: [M+
1.86À 1.78 (m, 1H), 1.64 (q, J=6.8 Hz, 2H), 0.95 (d, J=6.6 Hz, 6H)
1
2
3
4
5
6
7
8
9
H]+ Calcd. for C17H21N2S 285.1419; found 285.1422.
ppm.
1-(2,6-Dimethylphenyl)-3-(4-methoxyphenyl)thiourea (6aq): Yel-
Synthesis of N-(4-(isopentyloxy)phenyl)formamide (11): To formic
1
°
°
low solid, m.p. 147–148 C (water); H-NMR: (500 MHz, DMSO-d6) δ
acid (1.66 mL, 44 mmol) at 0 C acetic anhydride (3.40 mL, 36 mmol)
°
9.64 (bs, 1H), 8.73 (bs, 1H), 7.31 (m, 2H), 7.07 (m, 3H), 6.91 (m, 2H),
3.74 (s, 3H), 2.20 (s, 6H) ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 181.0,
157.1, 136.8, 128.0 (bs), 114.5 (bs), 55.7, 18.5 ppm; HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd. for C16H19N2OS 287.1212; found 287.1217.
was added, then the mixture was heated up to 60 C for 2 h. After
°
cooling to 0 C the reaction mixture was diluted with tetrahydrofur-
an (15 mL) and the solution of the amine 10 (1.79 g, 10 mmol) in
tetrahydrofuran (15 mL) was added carefully. After the complete
consumption of the amine followed by TLC, the volatiles were
evaporated providing 11 in quantitative yield (2.07 g). Yellow oil;
1H-NMR: (500 MHz, CDCl3, mixture of E/Z isomers) δ 8.51 (d, J=
11.5 Hz, 0.46H), 8.35 (d, J=1.7 Hz, 0.54H), 7.44 (m, 1H), 7.03 (m, 1H),
6.91À 6.87 (m, 2H), 4.00À 3.97 (m, 2H), 1.88À 1.81 (m, 1H), 1.71À 1.66
(m, 2H), 0.99À 0.97 (m, 6H) ppm; 13C-NMR: (125 MHz, CDCl3) δ 158.6,
129.6, 121.9, 121.7, 117.0, 115.53, 114.9, 110.0, 66.7, 38.0, 25.1,
22.6 ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C12H18NO2
208.1332; found 208.1332.
1-(2,6-Dimethylphenyl)-3-(3,4,5-trimethoxyphenyl)thiourea (6ar):
1
°
White solid, m.p. 170–171 C (water); H-NMR: (500 MHz, DMSO-d6)
δ 9.78 (bs, 1H), 8.89 (bs, 1H), 7.08 (m, 3H), 6.82 (s, 2H), 3.76 (s, 6H),
3.65 (s, 3H), 2.21 (s, 6H) ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 179.8,
152.8 (bs), 137.4 (bs), 136.3, 134.6, 127.6 (bs), 126.7 (bs), 101.2 (bs),
60.0, 55.8, 18.1 ppm; HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for
C18H23N2O3S 347.1423; found 347.1435
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1-(4-Chlorophenyl)-3-(2,6-dimethylphenyl)thiourea (6as): Off
1
°
white solid 136–137 C (water); H-NMR: (500 MHz, DMSO-d6) δ 9.93
Synthesis of 1-isocyano-4-(isopentyloxy)benzene (12): To a
solution of formamide 11 (1.66 g, 8 mmol) in tetrahydrofuran
(10 mL) and triethylamine (8.92 mL, 64 mmol) was added
(bs, 1H), 9.02 (bs, 1H), 7.55À 7.27 (m, 4H), 7.09À 7.06 (m, 3H), 2.20 (s,
6H) ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 180.3, 138.3, 136.3, 128.5
(bs), 128.3, 127.7 (bs), 126.8 (bs), 125.3, 124.7 (bs), 18.0 ppm; HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd. for C15H16ClN2S 291.0717; found
291.0725.
°
phosphoryl chloride (1.50 mL, 16 mmol) dropwise at 0 C. The
resulted mixture was stirred under reflux until the consumption
of 11 followed by TLC. Afterwards, aqueous sodium hydro-
gencarbonate (20 mL) was added slowly under ice cooling, then
the reaction mixture was extracted with dichloromethane (2 ×
20 mL) and the organic layer was washed with brine (20 mL).
Evaporation of the solvent followed by purification by flash
column chromatography in hexane-ethyl acetate on aluminium
oxide led to 12 in 73% yield (1.10 g). Green oil; 1H-NMR:
(500 MHz, CDCl3, ref.[93]) δ 7.28 (d, J=8.9 Hz, 2H), 6.85 (d, J=
9.0 Hz, 2H), 3.99 (t, J= 6.7 Hz, 2H), 1.86À 1.78 (m, 1H), 1.68 (q, J=
6.7 Hz, 2H), 0.97 (d, J=6.7 Hz, 6H) ppm.
1-(4-Bromophenyl)-3-(2,6-dimethylphenyl)thiourea (6at): Off
1
°
white solid 128–129 C (water); H-NMR: (500 MHz, DMSO-d6) δ 9.91
(bs, 1H), 9.04 (bs, 1H), 7.52À 7.45 (m, 5H), 7.09 (m, 3H), 2.21 (s, 3H)
ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 180.8 (C), 139.2 (C), 136.8 (C),
131.7 (CH), 126.1 (CH), 117.0 (C), 18.5 (CH3) ppm; HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd. for C15H16BrN2S 335.0212; found 335.0212.
1-(4-Iodophenyl)-3-(2,6-dimethylphenyl)thiourea (6au): Off white
1
°
solid 159–160 C (water); H-NMR: (500 MHz, DMSO-d6) δ 9.93 (bs,
1H), 9.07 (bs, 1H), 7.66 (m, 2H), 7.40À 7.34 (m, 2H), 7.09 (m, 3H), 2.20
(s, 6H) ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 180.2, 139.2, 137.1 (bs),
137.0, 136.2, 127.6 (bs), 126.8 (bs), 125.6, 125.1 (bs), 18.0 ppm;
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd. for C15H16IN2S 383.0073;
found 383.0073.
Synthesis of 1,3-bis(4-(isopentyloxy)phenyl)thiourea (Isoxyl®, thi-
ocarlide, 13): 1-Isocyano-4-(isopentyloxy)benzene (12, 95 mg,
0.5 mmol) and 4-(isopentyloxy)aniline (11, 134 mg, 0.75 mmol) was
added to the aqueous solution of sulfur and PMDTA (2.5 mL, 1.0 M
°
PMDTA, 0.4 M sulfur) and stirred vigorously at 60 C for 0.5 hour.
1-(2,6-Dimethylphenyl)-3-(4-hydroxyphenyl)thiourea (6av): White
After filtration of the reaction mixture, the solid was washed with
water, then with 0.5 M hydrochloric acid, and finally with water to
provide 13 in 84% yield (168 mg). Pale yellow solid, m.p. 136–
1
°
solid, m.p. 165–166 C (water); H-NMR: (500 MHz, DMSO-d6) δ 9.51
(bs, 1H), 9.33 (bs, 1H), 8.62 (bs, 1H), 7.16À 7.06 (m, 4H), 6.74 (s, 2H),
2.19 (s, 6H) ppm; 13C-NMR: (125 MHz, DMSO-d6) δ 180.4, 155.0,
136.4, 127.5 (bs), 126.5 (bs), 115.3 (bs), 18.0 ppm; HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd. for C15H17N2OS 273.1056; found 273.1062.
137 C (water; ref.[78] 139–141 C, dichloromethane); 1H-NMR:
(500 MHz, DMSO-d6, ref.[78]) δ 9.39 (bs, 2H), 7.30 (d, J=8.4 Hz, 4H),
6.88 (d, J=8.5 Hz, 4H), 3.97 (t, J=6.4 Hz, 4H), 1.81À 1.75 (m, 2H),
1.60 (q, J=6.4 Hz, 4H), 0.93 (d, J=6.5 Hz, 12H) ppm.
°
°
Synthesis of 1-(isopentyloxy)-4-nitrobenzene (9): To the mixture
of 4-nitrophenol (7, 4.17 g, 30 mmol), dimethylformamide (80 mL)
and NaOH (3.60 g, 90 mmol), 1-bromo-3-methylbutane (8, 13.59 g,
90 mmol) was added, and the resulted mixture was refluxed for
3 hours. The solvent was evaporated and the residue was
partitioned between diethyl ether (20 mL) and 1.0 M hydrochloric
acid. The aqueous phase was extracted with diethyl ether (2×
20 mL), and the organic phases were combined. Evaporation of the
solvent, followed by flash column chromatography on silica gel in
hexane-ethyl acetate provided 9 in 70% yield (4.42 g). Brown oil;
1H-NMR: (500 MHz, CDCl3, ref.[92]) δ 8.18À 8.15 (m, 2H), 6.94À 6.91 (m,
2H), 4.07 (t, J=6.7 Hz, 2H), 1.86À 1.80 (m, 1H), 1.70 (q, J=6.7 Hz,
2H), 0.97 (d, J=6.7 Hz, 6H) ppm.
Acknowledgements
Krisztina Németh and Pál Szabó for the HRMS measurements. P.
Ábrányi-Balogh was supported by the Hungarian Science Founda-
tion OTKA (PD124598) grant.
Conflict of Interest
Synthesis of 4-(isopentyloxy)aniline (10): To the solution of 1-
(isopentyloxy)-4-nitrobenzene (9, 4.19 g, 20 mmol) in ethyl acetate
(80 mL), 10% Pd/C (0.2 mmol) was added and the resulting mixture
was stirred under a hydrogen atmosphere of 4–7 bar for 1 hour.
The reaction mixture was filtered through celite and the evapo-
ration of the solvent provided 10 in quantitative yield (3.59 g).
Brown oil; 1H-NMR: (500 MHz, CDCl3, ref.[92]) δ 6.74 (d, J=8.8 Hz, 2H),
6.64 (d, J=8.8 Hz, 2H), 3.92 (t, J=6.7 Hz, 2H), 3.40 (bs, 2H),
The authors declare no conflict of interest.
Keywords: sulfur
·
thiourea
·
chromatography-free
·
multicomponent reactions · water
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[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–
10274.
[45] S. Tortoioli, A. Friedli, A. Prud’homme, S. Richard-Bildstein, P. Kohler, S.
Abele, G. Vilé, Green Chem. 2020, 22.
[46] P. B. Thakur, H. M. Meshram, RSC Adv. 2014, 4, 5343–5350.
[47] C. J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68–82.
[48] A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725–748.
[49] R. Breslow, Acc. Chem. Res. 1991, 24, 159–164.
[50] M. B. Gawande, V. D. B. Bonifácio, R. Luque, P. S. Branco, R. S. Varma,
Chem. Soc. Rev. 2013, 42, 5522–5551.
[51] P. Ábrányi-Balogh, T. Földesi, A. Grün, B. Volk, G. Keglevich, M. Milen,
1
2
3
4
5
6
7
8
9
[2] W. Cao, F. Dai, R. Hu, B. Z. Tang, J. Am. Chem. Soc. 2020, 142, 978–986.
[3] L. Chen, P. Xia, T. Du, Y. Deng, Y. Xiao, Org. Lett. 2019, 21, 5529–5532.
[4] B. Phetsuksiri, M. Jackson, H. Scherman, M. McNeil, G. S. Besra, A. R.
Baulard, R. A. Slayden, A. E. DeBarber, C. E. Barry, M. S. Baird, et al., J.
Biol. Chem. 2003, 278, 53123–53130.
[5] S. Xiao, L. Wei, Z. Hong, L. Rao, Y. Ren, J. Wan, L. Feng, Bioorg. Med.
Chem. 2019, 27, 805–812.
[6] J. Wu, Q. Shi, Z. Chen, M. He, L. Jin, D. Hu, Molecules. 2012, 17, 5139–
5150.
[7] C. R. Worthing, R. J. Hance, British Crop Protection Council., The Pesticide
Manual: A World Compendium, British Crop Protection Council 1991.
[8] K. Biswas, M. F. Greaney, Org. Lett. 2011, 13, 4946–4949.
[9] J. Zhao, H. Huang, W. Wu, H. Chen, H. Jiang, Org. Lett. 2013, 15, 2604–
2607.
[10] R. A. Batey, D. A. Powell, Org. Lett. 2000, 2, 3237–3240.
[11] S. M. Ghodse, V. N. Telvekar, Tetrahedron Lett. 2015, 56, 472–474.
[12] M. R. Maddani, K. R. Prabhu, J. Org. Chem. 2010, 75, 2327–2332.
[13] B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7, 1967–1969.
[14] Á. Madarász, Z. Dósa, S. Varga, T. Soós, A. Csámpai, I. Pápai, ACS Catal.
2016, 6, 4379–4387.
[15] P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296.
[16] T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672–
12673.
[17] T. B. Nguyen, Adv. Synth. Catal. 2017, 359, 1066–1130.
[18] T. Chivers, P. J. W. Elder, Chem. Soc. Rev. 2013, 42, 5996–6005.
[19] A. G. Németh, G. M. Keserű, P. Ábrányi-Balogh, Beilstein J. Org. Chem.
2019, 15, 1523–1533.
[20] T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit, Angew. Chem.
Int. Ed. 2014, 53, 13808–13812; Angew. Chem. 2014, 126, 14028–14032.
[21] H. Xie, J. Cai, Z. Wang, H. Huang, G.-J. Deng, Org. Lett. 2016, 18, 2196–
2199.
Tetrahedron Lett. 2016, 57, 1953–1957.
[52] M. Milen, P. Ábrányi-Balogh, A. Dancsó, D. Frigyes, L. Pongó, G.
Keglevich, Tetrahedron Lett. 2013, 54, 5430–5433.
[53] P. Ábrányi-Balogh, A. Dancsó, D. Frigyes, B. Volk, G. Keglevich, M. Milen,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Tetrahedron. 2014, 70, 5711–5719.
[54] V. Varga, M. Milen, P. Ábrányi-Balogh, Tetrahedron Lett. 2018, 59, 3683–
3689.
[55] P. Ábrányi-Balogh, B. Volk, M. Milen, Tetrahedron Lett. 2018, 617–619.
[56] E. Davis, J. Am. Chem. Soc. 1962, 84, 2085–2090.
[57] T. A. Tikhonova, K. A. Lyssenko, I. V. Zavarzin, Y. A. Volkova, J. Org. Chem.
2019, 84, 15817–15826.
[58] P. Yu, Y. Wang, Z. Zeng, Y. Chen, J. Org. Chem. 2019, 84, 14883–14891.
[59] J. Liu, Y. Zhang, Y. Yue, Z. Wang, H. Shao, K. Zhuo, Q. Lv, Z. Zhang, J.
Org. Chem. 2019, 84, 12946–12959.
[60] L. Gan, Y. Gao, L. Wei, J.-P. Wan, J. Org. Chem. 2019, 84, 1064–1069.
[61] M. Wu, Y. Jiang, Z. An, Z. Qi, R. Yan, Adv. Synth. Catal. 2018, 360, 4236–
4240.
[62] S. Shi, J. Chen, S. Zhuo, Z. Wu, M. Fang, G. Tang, Y. Zhao, Adv. Synth.
Catal. 2019, 361, 3210–3216.
[63] M. Kozlov, A. Kozlov, A. Komkov, K. Lyssenko, I. Zavarzin, Y. Volkova,
Adv. Synth. Catal. 2019, 361, 2904–2915.
[64] X. Zhang, Z. Shi, C. Shao, J. Zhao, D. Wang, G. Zhang, L. Li, Eur. J. Org.
Chem. 2017, 2017, 1884–1888.
[65] Y. Zhang, Y. Liu, J. Zhang, R. Gu, S. Han, Tetrahedron Lett. 2019, 60,
151289.
[66] Z. Wang, C. Zhang, H. Wang, Y. Xiong, X. Yang, Y. Shi, A. L. Rogach,
Angew. Chem. Int. Ed. 2020, 59, 1–7.
[22] Y. Liao, Y. Peng, H. Qi, G. J. Deng, H. Gong, C. J. Li, Chem. Commun.
2015, 51, 1031–1034.
[23] J. Chen, G. Li, Y. Xie, Y. Liao, F. Xiao, G.-J. Deng, Org. Lett. 2015, 17,
5870–5873.
[67] J. W. Thomson, K. Nagashima, P. M. Macdonald, G. A. Ozin, J. Am. Chem.
[24] Z. Chen, P. Liang, F. Xu, Z. Deng, L. Long, G. Luo, M. Ye, J. Org. Chem.
2019, 84, 12639–12647.
[25] M. Kozlov, A. Komkov, T. Losev, A. Tyurin, A. Dmitrenok, I. Zavarzin, Y.
Volkova, J. Org. Chem. 2019, 84, 11533–11541.
[26] T. Szabó, M. Milen, Chem. Heterocycl. Compd. 2019, 55, 126–128.
[27] J. H. Boyer, V. T. Ramakrishnan, J. Org. Chem. 1972, 37, 1360–1364.
[28] A. Zajdlik, Z. Wang, J. L. Hickey, A. Aman, A. D. Schimmer, A. K. Yudin,
Angew. Chem. Int. Ed. 2013, 52, 8411–8415; Angew. Chem. 2013, 125,
8569–8573.
[29] W. Adam, R. M. Bargon, S. G. Bosio, W. A. Schenk, D. Stalke, J. Org. Chem.
2002, 67, 7037–7041.
[30] M. Arisawa, M. Ashikawa, A. Suwa, M. Yamaguchi, Tetrahedron Lett.
2005, 46, 1727–1729.
[31] W. S. Farrell, P. Y. Zavalij, L. R. Sita, Organometallics. 2016, 35, 2361–
2366.
[32] S. Chakrabarty, S. Choudhary, A. Doshi, F.-Q. Liu, R. Mohan, M. P.
Ravindra, D. Shah, X. Yang, F. F. Fleming, Adv. Synth. Catal. 2014, 356,
2135–2196.
[33] V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Y. Kukushkin, Chem. Rev.
2015, 115, 2698–2779.
[34] S. ichi Fujiwara, T. Shin-Ike, K. Okada, M. Aoki, N. Kambe, N. Sonoda,
Tetrahedron Lett. 1992, 33, 7021–7024.
[35] W. Feng, X. G. Zhang, Chem. Commun. 2019, 55, 1144–1147.
[36] T.-H. Zhu, X.-P. Xu, J.-J. Cao, T.-Q. Wei, S.-Y. Wang, S.-J. Ji, Adv. Synth.
Catal. 2014, 356, 509–518.
[37] W. Tan, J. Wei, X. Jiang, Org. Lett. 2017, 19, 2166–2169.
[38] T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Synth. 2014, 46, 3172–3179.
[39] P. Anastas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301–312.
[40] E. A. Peterson, B. Dillon, I. Raheem, P. Richardson, D. Richter, R. Schmidt,
H. F. Sneddon, Green Chem. 2014, 16, 4060–4075.
[41] P. S. W. Leung, Y. Teng, P. H. Toy, Org. Lett. 2010, 12, 4996–4999.
[42] Z. Kaleta, G. Tárkányi, Á. Gömöry, F. Kálmán, T. Nagy, T. Soós, Org. Lett.
2006, 8, 1093–1095.
Soc. 2011, 133, 5036–5041.
[68] D. Peixoto, G. Malta, H. Cruz, S. Barroso, A. L. Carvalho, L. M. Ferreira,
P. S. Branco, J. Org. Chem. 2019, 84, 3793–3800.
[69] M. Vangala, G. P. Shinde, Beilstein J. Org. Chem. 2016, 12, 2086–2092.
[70] R. Nirmala, T. Ponpandian, B. R. Venkatraman, S. Rajagopal, Tetrahedron
Lett. 2013, 54, 5181–5184.
[71] H. Lammers, P. Cohen-Fernandes, C. L. Habraken, Tetrahedron. 1994, 50,
865–870.
[72] S. B. Baravkar, A. Roy, R. L. Gawade, V. G. Puranik, G. J. Sanjayan, Synth.
Commun. 2014, 44, 2955–2960.
[73] N. A. Isley, R. T. H. Linstadt, S. M. Kelly, F. Gallou, B. H. Lipshutz, Org. Lett.
2015, 17, 4734–4737.
[74] R. S. Gonçalves, P. V. Abdelnur, V. G. Santos, R. C. Simas, M. N. Eberlin, A.
Magalhães, E. R. Pérez González, Amino Acids. 2011, 40, 197–204.
[75] B. Gierczyk, G. Schroeder, B. Brzezinski, J. Org. Chem. 2003, 68, 3139–
3144.
[76] O. A. Shemyakina, O. G. Volostnykh, A. V. Stepanov, A. G. Mal’Kina, I. A.
Ushakov, B. A. Trofimov, Synth. 2018, 50, 853–858.
[77] V. Bhowruth, A. K. Brown, R. C. Reynolds, G. D. Coxon, S. P. Mackay, D. E.
Minnikin, G. S. Besra, Bioorg. Med. Chem. Lett. 2006, 16, 4743–4747.
[78] J. R. Brown, E. J. North, J. G. Hurdle, C. Morisseau, J. S. Scarborough, D.
Sun, J. Korduláková, M. S. Scherman, V. Jones, A. Grzegorzewicz, et al.,
Bioorg. Med. Chem. 2011, 19, 5585–5595.
[79] R. Pingaew, V. Prachayasittikul, N. Anuwongcharoen, S. Prachayasittikul,
S. Ruchirawat, V. Prachayasittikul, Bioorg. Chem. 2018, 79, 171–178.
[80] K. Inamoto, C. Hasegawa, J. Kawasaki, K. Hiroya, T. Doi, Adv. Synth. Catal.
2010, 352, 2643–2655.
[81] T. T. Li, X. H. Song, M. S. Wang, N. Ma, RSC Adv. 2014, 4, 40054–40060.
[82] P. K. Mohanta, S. Dhar, S. K. Samal, H. Ila, H. Junjappa, Tetrahedron.
2000, 56, 629–637.
[83] R. Custelcean, M. G. Gorbunova, P. V. Bonnesen, Chem. Eur. J. 2005, 11,
1459–1466.
[84] B. Loev, P. E. Bender, H. Bowman, A. Helt, R. Mclean, T. Jen, J. Med.
Chem. 1972, 15, 1024–1027.
[85] M. E. Jung, B. T. Chamberlain, C. L. C. Ho, E. J. Gillespie, K. A. Bradley, ACS
[43] P. A. Byrne, K. V. Rajendran, J. Muldoon, D. G. Gilheany, Org. Biomol.
Chem. 2012, 10, 3531–3537.
[44] R. K. Orr, J. M. M. C. Dunn, A. Nolting, A. M. Hyde, E. R. Ashley, J. Leone,
E. Sirota, J. A. Jurica, A. Gibson, C. Wise, et al., Green Chem. 2018, 20,
2519–2525.
Med. Chem. Lett. 2014, 5, 363–367.
ChemistryOpen 2021, 10, 16–27
www.chemistryopen.org
26
© 2020 The Authors. Published by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/open.202000250
ChemistryOpen
[86] H. Martin, D. Dürr, A. Hubele, O. Rohr, J. Rufener, G. Pissiotas, Verfahren
Und Mittel Zur Förderung Der Fruchtabszission, Patent number CH560003
(A5), 1975.
[87] Kanwal, M. Khan, Arshia, K. M. Khan, S. Parveen, M. Shaikh, N. Fatima,
M. I. Choudhary, Bioorg. Chem. 2019, 83, 595–610.
[88] B. V. Varun, K. R. Prabhu, RSC Adv. 2013, 3, 3079–3087.
[89] T. Jen, H. Hoeven Van, W. Groves, R. A. McLean, B. Loev, J. Med. Chem.
1975, 18, 90–99.
[90] L. Krasovskiy, Arkady, E. Szuromi, Thioguanidine Group IV Transition
Metal Catalysts and Polymerization Systems, Patent number US
2019/0263949 A1, 2019
[91] S. Sakai, T. Fujinami, T. Aizawa, Bull. Chem. Soc. Jpn. 1977, 50, 425–428.
[92] A. Liav, S. K. Angala, P. J. Brennan, Synth. Commun. 2008, 38, 1176–1183.
[93] K. K. Kenichi Eguchi, Akira Ohira, Yoshikazu Kitano, Marine Sessile
Organism-Repelling Composition, Patent number US 2018/0072657 A1,
2018.
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