An isocyanide based multi-component reaction under catalyst- and solvent-free conditions for the synthesis of unsymmetrical thioureas

Article abstract of DOI:10.1016/j.tetlet.2016.11.082

A new and efficient method for the synthesis of thiourea derivatives by a sequential one-pot, three-component reaction between aromatic isocyanides, amines, and 1,2-di-tert-butyldisulfane (DTBS) was developed and 27 different examples were synthesized in good to excellent yields. DTBS was identified as an effective sulfur surrogate without the use of both catalysts and solvents. This protocol does not employ any transition metal catalyst or special experimental setup.

Full text of DOI:10.1016/j.tetlet.2016.11.082

DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.082
TETL 48368
Reference:
Tetrahedron Letters
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Accepted Date:
16 September 2016
28 October 2016
19 November 2016
Please cite this article as: Singh, K., Sharma, S., An isocyanide based multi-component reaction under catalyst- and
solvent-free conditions for the synthesis of unsymmetrical thioureas, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.11.082
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An isocyanide based multi-component reaction under catalyst-
and solvent-free conditions for the synthesis of unsymmetrical
thioureas
Karandeep Singh,a,b Siddharth Sharmaa*
aDepartment of Chemistry, Mohanlal Sukhadia University, Udaipur, India, 313001.
bDepartment of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev
University, Amritsar, India, 143005.
Abstract: A new and efficient method for the synthesis of thiourea derivatives by a
sequential one-pot, three-component reaction between aromatic isocyanides, amines, and 1,2-
di-tert-butyldisulfane (DTBS) was developed and 27 different examples were synthesized in
good to excellent yields. DTBS was identified as an effective sulfur surrogate without the use
of both catalysts and solvents. This protocol does not employ any transition metal catalyst or
special experimental setup.
٭Corresponding author. Address: Department of Chemistry, Mohanlal Sukhadia University, Udaipur,
India, 313001. E-mail address: sidorg19@gmail.com
Catalyst- and solvent-free approaches towards organic synthesis have attracted an immense
interest from the organic chemistry community over recent decades.1-2 The avoidance of
catalysts and solvents in well established chemical processes, or the replacement of toxic
solvents with more environmentally-benign solvents, has become a major focus in the
pharmaceutical industry. Also, multicomponent reactions (MCRs) have become an effective
approach for rapid assembly of complex molecules from simple precursors in a one-pot
procedure via the formation of carbon-carbon and carbon-heteroatom bonds.3 These domino-
type reactions involve multiple intermediate reactions where the product of the first is the
starting substrate for the subsequent and can also incorporate “green chemistry” values such
as atom economy, time, and labour economies.
Thiourea containing molecules have been reported to possess a plethora of biological
properties such as anti-bacterial, anti-fungal, anti-inflammatory and anti-cancer.4 In addition,
they are used as supramolecular assemblies, and anion sensing.5 On the other hand, the area
of organocatalysts has been dominated by the cinchona-thiourea based catalysts for variety of
organocatalytic transformations.6 These intrinsic qualities of thioureas, in combination with

the avalanche of research on their use in the synthesis of various heterocyclic scaffolds, make
them privileged building blocks for synthetic chemists.7 Consequently, a great deal of effort
have been focused on the development of newer synthetic strategies for this important
building block. Until now, one of the most common methods for the synthesis of thiourea has
been the reaction of primary or secondary amines with isothiocyanates.8 Recently, Kaupp and
co-workers developed a solvent-free thiourea synthesis involving gas phase reaction of
amines and isothiocyanates, and subsequently, Li and Wang used microwave irradiation for
the synthesis of thiourea using similar synthetic substrates.9 Similarly, Liu et al. developed
microwave assisted one-pot synthesis of symmetrical diaryl-substituted thioureas from
arylamines and carbondisulphide.10 Mane et al. developed unsymmetrical N,N′-diphenyl
urea in aqueous medium under base and catalyst free condition from corresponding
substituted isocyanate and amines.11 Other methods, include the reaction of primary amines
or secondary amines with thiophosgene, dithiocarbamates, unsubstituted thiourea.12 These
reported methods have their own disadvantages including the use of toxic reagents
(thiophosgene & hydrogen sulphide), harsh reaction conditions, and/or are limited to the
synthesis of symmetrical thiourea derivatives. Undoubtedly, taking into account the atom and
step economy, the development of a catalyst- and solvent-free MCR would be highly
desirable, as a part of our interest towards the development of newer isocyanide-based
organic synthesis,13 herein, we report a straightforward protocol to access thiourea derivatives
from the multicomponent reaction of aryl isocyanide, amine, and DTBS. DTBS has been
used as sulfur surrogate for transferring sulfur to isocyanide, which is otherwise reported to
be very sluggish with elemental sulphur.14
Isocyanides 3 (Scheme 1) are privileged divalent carbon nucleophiles for the wide range of
multi-component reactions. Whereas DTBS (1) is known to decompose readily at high
temperature into the corresponding radical 2.15 We envisioned that the radical 2 might be
attacked by isocyanide 316 to generate an intermediate radical 4 which should undergo de-
tert-butylation, followed by the reaction of intermediate 2-methylpropane-2-thiol 6 and
isothiocyanate 5 to generate substituted tert-butyl phenylcarbamodithioate 7. Reaction of
intermediate 7 with amine 8 resulted in thiourea 9 (Scheme 1). In this one-pot assembly, two
independent reactions should occur sequentially: reaction of isocyanide 3 with DTBS 1 to
produce 7, and a substitution reaction of 7 with amines 8 to generate thiourea derivatives
through a cascade process.

Scheme 1. Proposed synthesis of thiourea 9 through a coupling of DTBS 1, isocyanide 3 with
amines 8.
Table 1. Optimization of reaction condition for the synthesis of 9a.a
Entry
Temperature (°C)
Solvent
None
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
25
24
24
12
6
0
80
None
trace
46
87
23c
83
0
100
120
120
140
80
None
None
None
1
None
6
MeOH
24
110
Toluene
24
31
b
c
aReaction condition: 1 (5 mmol), 3a (1 mmol), 8a (1.2 mmol). Isolated Yield. Microwave heating at 120 °C for
1 h using 300 W power.

Figure 1. Formation of thiourea derivatives (9) from DTBS (1), isocyanides (3), and amines
(8).a
aThe reactions were carried out at 120°C using 1 (5 mmol), 3 (1 mmol), 8 (1.2 mmol). Yields refer to the
isolated yields. All the reactions were heated for 5 h for 120 °C and 1 h at 60 °C after the addition of amines.
In order to check the feasibility of the concept, the reaction of phenyl isocyanide 3a with
piperidine 8a and DTBS 1 under catalyst- and solvent-free conditions at various temperatures
was first investigated (Table 1). When the reaction was performed at 25°C, no desired
product was formed (entry 1). On the other hand, at 80°C for 24 h, product 9a was obtained
in trace (Table 1, entry 2). The desired product was obtained in increased yield with reduced
reaction time at 120°C for 6 h in 87% isolated yield (Table 1, entry 4). The reaction under
microwave irradiation lowered the yield to only 23% (Table 1, entry 5). Increasing the

reaction temperature to 140 °C for 6 h failed to improve the reaction yield (Table 1, entry 6).
No reaction product was obtained in such as MeOH, though toluene as the reaction solvent
afforded product in 31% (Table 1, entry 8). Thus the conditions shown for the entry-4 in
Table 1, gave the best yield and were selected for further syntheses of different derivatives.
The structure of 9a was consistent with its spectroscopic data. Since the reaction is selective,
the product formed exclusively and no column purification is required and the pure thiourea
derivatives were isolated by simple filtration.
The results of a study into the scope and limitations of the methodology with a variety of
different isocyanides 3 and amines 8 are shown in Figure 1. Aromatic isocyanides 3a-3e were
17
obtained by formylation of aromatic amines followed by dehydration using POCl3.
A
number of aromatic isocyanides derived from aromatic amines bearing electron withdrawing
functional group gave very high yields (9 99%) of desired thiourea derivatives (Figure 1,
9d, 9m, 9t, 9u, 9v, 9y, 9z,).18 Aromatic isocyanides derived from electron rich aromatic
amines, gave relatively lower yields (56 81%) of the thiourea derivatives (Figure 1, 9b, 9c,
9k, 9l, 9q, 9r, 9w, 9x). Having explored the scope of aromatic isocyanides for novel multi-
component reaction, we attempted to explore the scope of structurally diverse amines
including aliphatic, benzylic and aromatic amines, to afford the corresponding unsymmetrical
thiourea. Gratifyingly the conditions optimized for various aromatic isocyanides and
secondary aliphatic amine, provided equally significant isolated yields for aromatic amines
without any further optimization (Figure 1, 9e-9i, 9s-9w). No obvious electronic effects of the
aromatic amines were observed, and the products were obtained in good to excellent yields.
To further illustrate the versatility of the developed protocol, the optically active thiourea
based organocatalyst (11) was also synthesized (Scheme 2) by the reaction of 1, 3a and
cinchonamine (10). Related cinchona-thiourea derivatives are known to be well suited for
various organocatalytic enantioselective transformations. In order to expand the synthetic
scope of our strategy, a gram-scale synthesis of 9a (82%) was performed under the standard
conditions (Scheme 3).
Scheme 2. Synthesis of organocatalyst under catalyst- and solvent-free condition.

Scheme 3. Gram scale synthesis of 9a.
Scheme 4. Mechanistic investigations for thiourea synthesis.
With the scope of the process established, a series of experiments (Scheme 4) were
conducted, with the aim of understanding the mechanism. Isocyanide 3a was treated
with DTBS
1 and piperidine 8a in the presence of radical scavenger TEMPO under the
standard condition. No reaction was observed due to radical quenching experiment,
thus indicating the involvement of possible radical intermediates (Scheme 4a).

Subsequently, tert-butyl phenylcarbamodithioate 7a (intermediate) was observed as
sole product from the reaction of 3a and 5 equiv. of , (Scheme 4b), whereas use of 1
equiv. of DTBS ( ) gave mixture of phenylisothiocyanate (5a) and tert-butyl
phenylcarbamodithioate (7a) as depicted in Scheme 4c. Formation of compounds 5a
and 7a can be explained by a plausible mechanism depicted in scheme . On the other
1
1
1
hand, the expected product was isolated in quantitative yield (Scheme 4d) for the
reaction of tert-butyl phenylcarbamodithioate (7a) and piperidine (8a). This finding
implied that 7a and phenylisothiocyanate (5a) are probably key intermediates during
the thiourea synthesis. Product 9a could not be obtained from for the reaction of
isocyanide (3a), amine (8a) and 1,2-diphenyldisulfane (12) indicating the importance
of tert-butyl group in the sufur insertion for the synthesis of thiourea (Scheme 4e).
In summary, we have developed an efficient procedure for the synthesis of
unsymmetrical thiourea under catalyst- and solvent-free condition. This one-pot, three-
component reaction between aromatic isocyanide, amines and DTBS afforded the
products in high yields.
Acknowledgements
SS is grateful to the DST-INSPIRE Project (IFA-CH-116), New Delhi, for research
support and Funding.
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18. General procedure for thiourea synthesis (Figure 1). To a 10 mL round bottom flask were
added isocyanide 3a (103 mg, 1.0 equiv.) and DTBS (5 mmol, 890 mg). Round bottomed flask
was filled with N2. The above reaction mixture was allowed to stir at 120 °C for 5 h and
monitored by TLC. After complete consumption of isocyanide 3a, the reaction mixture was
cooled down to 60 °C and piperidine 8a (100 mg, 1.2 equiv.) was added and further stir for 1
h, the reaction mixture was precipitated. The resulting precipitate was filtered and washed with
cold ether to obtain pure product 9a. N-Phenylpiperidine-1-carbothioamide (9a). White solid
1
(191 mg, 87% yield); Rf = 0.52 (ethyl acetate/hexanes = 35:65); melting point: 96 °C. H
NMR (500 MHz, CDCl3) δ 1.66 (s, 6H), 3.76-3.78 (m, 4H), 7.09 (t, J = 8 Hz, 2H),7.13 (d, J =
13
7.5 Hz, 1H), 7.17 (s, 1H), 7.30 (t, J = 7.5 Hz, 2H); C NMR (125 MHz, CDCl3) δ 24.2, 25.6,
50.1, 122.7, 124.9, 129.2, 140.5, 183.0.

 We have developed a straightforward method to access unsymmetrical thioureas.
 Total 27 compounds were synthesized using multicomponent reaction.
 DTBS was identified as sulfur surrogate for transferring sulfur to isocyanide.
 Optically active thiourea based organocatalyst was also synthesized.
 A series of experiments were conducted with the aim of understand the mechanism.

Graphical Abstract
Leave this area blank for abstract info.
An isocyanide based multi-component reaction under
catalyst- and solvent-free conditions for
the synthesis of unsymmetrical thioureas
Karandeep Singh, Siddharth Sharma*