A green, isocyanide-based three-component reaction approach for the synthesis of multisubstituted ureas and thioureas

Article abstract of DOI:10.1016/j.tetlet.2017.11.053

A one-pot, isocyanide based multicomponent protocol was presented starting from secondary amines towards (thio)urea derivatives and utilized for the construction of a diverse 27-membered chemical library. Following a green compatible microwave assisted condition, the formed N,N′-multisubstituted (thio)ureas were obtained in up to 85% yield.

Full text of DOI:10.1016/j.tetlet.2017.11.053

Accepted Manuscript
A green, isocyanide-based three-component reaction approach for the synthesis
of multisubstituted ureas and thioureas
Anikó Angyal, András Demjén, János Wölfling, László G. Puskás, Iván
Kanizsai
PII:
S0040-4039(17)31487-9
https://doi.org/10.1016/j.tetlet.2017.11.053
TETL 49496
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 October 2017
24 November 2017
28 November 2017
Please cite this article as: Angyal, A., Demjén, A., Wölfling, J., Puskás, L.G., Kanizsai, I., A green, isocyanide-
based three-component reaction approach for the synthesis of multisubstituted ureas and thioureas, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.053
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A green, isocyanide-based three-component
reaction approach for the synthesis of
multisubstituted ureas and thioureas
Leave this area blank for abstract info.
Anikó Angyal, András Demjén, János Wölfling, László G. Puskás, Iván Kanizsai∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
A green, isocyanide-based three-component reaction approach for the synthesis of
multisubstituted ureas and thioureas
Anikó Angyala,b, András Demjéna,b, János Wölflingb, László G. Puskása,c, Iván Kanizsaia,∗
aAVIDIN Ltd., Alsó Kikötő sor 11/D, Szeged, H-6726, Hungary
bDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary
cAVICOR Ltd., Alsó Kikötő sor 11/D, Szeged, H-6726, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
A one-pot, isocyanide based multicomponent protocol was presented starting from secondary
amines towards (thio)urea derivatives and utilized for the construction of a diverse 27-membered
chemical library. Following a green compatible microwave assisted condition, the formed N,N’-
multisubstituted (thio)ureas were obtained in up to 85% yield.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Isocyanide
Urea
Thiourea
N-chloro amine
1. Introduction
isocyanides with bromine affords isocyanide dibromide, which
can easily be converted into carbamate intermediates for the
addition of primary alcohols.11 Concerning the formation of
The formation of (un)symmetrical N,N’-multisubstituted
(thio)ureas is well-known in the synthetic toolbar. They can be
prepared easily from the corresponding amines upon treatment
with iso(thio)cyanates or (thio)phosgene.1-3 These conventional
transformations proceed well but they are associated with high
toxicity of the reagents. Therefore, recent efforts have focused on
development of less toxic and more elegant routes involving
catalysis and/or replacement of (thio)phosgene.
carbodiimide
and
carbodiimidium
salts,
the
simplest methods relied either on the assembly of isocyanides or
For novel urea synthetic approaches, most methods use
transition metal catalyzed direct oxidative carbonylation of an
amine with carbon dioxide or carbon monoxide4, in situ
formation of isocyanate5a,b, transformations of carbamoyl azides,
and carbamates as well as imidazole carbonylation of amines
towards the corresponding carbamides6a-g. On the other hand,
current synthetic strategies for the preparation of N,N’-substituted
thioureas are based on classic methods such as application of
thiophosgene7, isothiocyanates8 and carbon disulfide.9 Hence,
reactions of carbon disulfide as reactant with amines can afford a
wide range of symmetrical and unsymmetrical thioureas in
reasonable yields via a simple condensation in aqueous
medium.10
A less explored synthetic strategy involves isocyanide-based
redox reactions towards carbodiimides or carbamates as urea
precursors (Figure 1). The oxidative treatment of
Figure 1. Isocyanide-based synthetic strategies towards
(thio)ureas.
———
∗ Corresponding author. Tel.: +36-62/202107; fax: +36-62/202108; e-mail: i.kanizsai@avidinbiotech.com

2
Tetrahedron
on isocyanide insertion into primary or secondary amines under
The application of the alcohol-water solvent mixtures at a
temperature of 60 °C allowed shorter reactions. The yield in
methanol was similar to that found at room temperature (72%,
entry 11). The best isolated yield was accomplished in IPA (87%,
entry 12). Further attempts were also made in IPA at higher
temperatures to achieve improvements. Whereas a reaction at 80
°C (oil bath) proved to be less effective (73%, entry 13),
application of microwave irradiation provided optimal
conditions. Albeit, both 60 °C and 100 °C microwave
temperatures afforded similar yields (83 and 85%, entries 14 and
15), dramatic decreases in reaction times are a great advantage.
In accordance, further transformations were performed under
highly-efficient microwave-assisted conditions (100 °C, 10
minutes, 250 W max. power).
oxidative conditions.12-14 Of these, the work of Katriczky et al.
should be mentioned as the first application of benzotriazole-1-
carboximidoyl chlorides as N-chlorinated reactants with
isocyanides. In this method, these compounds were exploited as
precursors of stable synthetic equivalent intermediates for
isocyanide dichloride towards the synthesis of N,N’-di- and –tri-
substituted ureas. However, the applicability of this procedure is
limited: the success of the final amination step depends strongly
on the nucleophilicity of the amines.13 The second exclusive
example has disclosed isocyanide insertion into primary or
secondary amines under oxidative conditions. The use of tert-
butyl hydroperoxide (TBHP) and the presence of cobalt(II)
acetylacetonate with additional ultrasonication afforded
substituted ureas and thioureas. This method proceeded well with
primary amines, but it was less effective for the treatment of
secondary amines. Only two carbamides were represented in
yields of 51 and 96% and only a single one from thiourea species
with 21% yield. Other attempts led to traces of the products or no
conversion.14 Nevertheless, isocyanide-based transformations
have a larger share in thiourea syntheses in comparison with the
preparation of urea derivatives. Among others, a molybdenum-
complex as sulfur and amine transfer reagent for isocyanide
Table 1. Solvent and temperature scope (optimization)a
Isolated
yieldc (%)
Entry
Solvent
Temp. (°C)
Time (h)b
1
H2O
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
24
24
2
41
–
2
toluene
DCM
EtOAc
DMF
3
17
34
50
65
66
67
75
83
72
87
73
83
85
4
5
6
MeCN
7
1,4-dioxane rt
transformation towards thiourea and
a
selenium-induced
8
THF
MeOH
IPA
rt
isocyanide-to-isocyanate oxidation method were presented.15-19
Furthermore, a three-component reaction (3CR) was also
demonstrated by reacting isocyanides, aliphatic primary and
secondary amines and sulfur as oxidant.20
9
rt
10
11
12
13
14
15
rt
MeOH
IPA
IPA
60
60
80
60d
100d
2
1.5
0.5
0.17
IPA
IPA
Our aim was to develop a one-pot, facile and green 3CR
method to synthesize highly diverse N,N’-multisubstituted
carbamides and thiocarbamides from isocyanides and in situ
formed N-chlorinated secondary amines in the presence of water
or sodium sulfide as the third reactant.
aReaction conditions: morpholine (0.5 mmol), NaDCC (0.55 mmol), water
(0.5 mL), 90 min, rt, then solvent (1 ml), CyNC (0.5 mmol).
bWorked up when intermediate consumed.
cAfter recryst.
2. Results and discussion
dµW: 100 °C, 10 min, 250 W.
In a preliminary study, N-chloromorpholine A and cyclohexyl
isocyanide 2a were reacted. The required chlorination was
accomplished in situ in water by treating morpholine 1a with
sodium dichloroisocyanurate (NaDCC).21 After chlorination,
subsequent addition of the isocyanide furnished desired
compound 3a isolated in a yield of 41%. Since unreacted NaDCC
did not affect the formation and isolation of the target compound,
the one-pot approach was applied for the further attempts and
experiments.
With the optimal conditions in our hands, the transformation
of several secondary amines (1a˗i) such as heterocyclic (1a˗f),
aliphatic (1g) and benzylic derivatives (1h and 1i) was conducted
by cyclohexyl- (2a) t-butyl- (2b) 1,1,3,3-tetramethylbutyl (2c), 1-
pentyl (2d), benzyl (2e) and phenylethyl (2f) isocyanides,
affording the desired 3a-s ureas with up to 85% yields (Figure 2).
The applicability was limited for aliphatic isocyanides since
aromatic isocyanides gave only trace amounts of the
corresponding carbamides.22 The best isolated yield was found in
the reaction of N-chloromorpholine with cyclohexyl isocyanide
First, our efforts focused on finding both a suitable
water/solvent mixture and the optimal reaction temperature
(Scheme 1 and Table 1).
(3a,
85%),
whereas
N-Boc-piperazine
(1c)
and
decahydroquinoline (1e) as well as Walborsky’s isocyanide 2c
gave the lowest yields. Hence, no significant correlation could be
established regarding the amine type and reactivity.
Afterwards, our purpose was to exploit this optimal
microwave-assisted protocol for the synthesis of thiourea
derivatives with the use of sodium sulfide (Na2S) as the
nucleophilic partner. Unfortunately, the presence of water
prohibited the formation of thiourea and preferred the urea
synthesis. Thus, we slightly modified the reaction conditions and
the one-pot, two-step protocol has been carried out in dry 2-
propanol under argon atmosphere. Other efforts such as utilizing
in situ generated H2S from Na2S in combination with acids
(KH2PO4, sulfuric acid or acetic acid) or other sulfur-based
reactants like sodium thiosulfate (Na2S2O3) did not afford the
desired final product.
Scheme 1. Model reaction.
For optimization, water-alcohol, water-dipolar aprotic media
and biphasic systems (water with EtOAc, DCM and toluene)
were tested at ambient (entries 2–10) and elevated temperatures
(entries 11–15). In biphasic solvent mixtures (entries 2–4) no
conversion (toluene) or poor yields were obtained (17% in DCM
and 34% in EtOAc). Reactions carried out in dipolar-aprotic
solvents such as DMF, MeCN, 1,4-dioxane and THF, provided
moderate to good yields (50–67%, entries 5–8). Gratifyingly, the
use of MeOH and 2-propanol (IPA) greatly increased the isolated
yields (75% and 83%, Entries 9 and 10).

3
R3NC
2a-f
R1 R2
N
NaDCC
R1 R2
N
R1 R2
R3
N
H
H2O, rt, 90 min
IPA
N
H
O
3a-s
100°C, 10 min, 250W
Cl
1a-i
23-85%
O
NH
OH
NH
NH
O
NH
NH
NH
O
NH
O
NH
N
NH
1b
Boc
O
O
1a
1g
1h
1e
1f
1c
1d
1i
O
O
O
NC
O
O
NC
O
N
N
N
NH
O
N
N
O
O
N
N
N
N
H
N
N
O
O
H
H
H
N
H
O
O
N
O
Boc
N
N
Boc
H
2d
2a
3b 72%
3a 85%
46%
3g
3c
3e
3f
3d 71%
74%
45%
53%
NC
O
O
O
N
O
O
O
NC
N
N
H
N
N
H
N
N
N
N
N
H
N
N
H
H
H
N
OH
Boc
2e
2b
3h 23%
55%
3l 73%
3m
51%
3i
3j
55%
30%
3k
NC
CN
O
O
O
O
O
O
N
N
H
O
O
O
N
N
N
N
N
N
N
N
H
H
N
N
H
N
H
H
O
O
Boc
O
2c
2f
3n
3o
3r
3s
64%
47%
3p
3q
81%
43%
66%
79%
Figure 2. The prepared 3a˗s urea derivatives.
The absence of water is a requirement for the successful
thiourea transformation as depicted in the proposed reaction
mechanism (Scheme 2). Treatment of A with isocyanides
generates intermediate B, which forms easily the corresponding
isourea C in the presence of water stabilized towards the final
product E. Since the formation of C is strongly preferred, the
successful sulfur coupling and access to intermediate D require
dry conditions and inert atmosphere.
and 68%). Surprisingly, the thiocarbamide synthesis proceeded
well with aromatic isocyanide 2g and furnished product 4b in a
yield of 52%. In turn, t-butyl isocyanide 2b proved to be a less
effective isocyanide component under these conditions.
1. NaDCC, rt, 120 min
R2 R1
R1 R2
2. R3NC (2a-g), Na2S
N
N
H
R3
100°C, 10 min, 250W
dry IPA, Ar
27-68%
N
S
H
1a,b,c,d,h,i
4a-h
R1 R2
R3NC
H2O
R1 R2
N
R1 R2
N
Boc
N
H
R3
O
N
Cl
Cl
N
NH
O
H
NH
Ph
NH
NH
N
O
O
N
Ph
O
H
1c
1a
1b
1d
1h
1i
Na2S
NaCl
S
OMe
S
N
N
R1 R2
N
R1 R2
N
N
H
O
NC
2a
H
N
Na
O
4b
52%
R3
R3
4a
62%
S
NC
S
N
HO
N
2e
S
NC
N
N
N
H2O
work-up
N
O
H
H
2b
O
O
4d
27%
4c 49%
R1 R2
N
R1 R2
N
O
S
S
NC
S
NH
R3
O
NH
R3
N
N
NC
N
S
N
2f
H
H
2c
4e
30%
4f
47%
OMe
Scheme 2. Proposed reaction mechanism.
S
The chlorination of the selected amines 1a,b,c,d,h and 1i
underwent successfully in dry 2-propanol then the subsequent
addition of isocyanide and Na2S afforded the corresponding 4a-h
thiourea derivatives in acceptable yields of 27–68% (Figure 3).
The best yields have been achieved with morpholine (1a) (52, 62
N
N
H
NC
NC
N
N
H
4h
N
O
2g
2d
Boc
4g
50%
68%
Figure 3. The synthesized 4a˗h thiourea derivatives.

4
Tetrahedron
3. Conclusion
Supplementary data
In conclusion, we have developed a facile and green one-pot
Supplementary data (list of compounds along with their yield
1
three-component reaction for the synthesis of a 27-membered
N,N’-multisubstituted urea and thiourea library, based on the
reaction of in situ generated secondary N-chloro amines,
isocyanides and water or Na2S under dry conditions.
and copies of H NMR and 13C NMR spectra are included)
associated with this article can be found, in the online version, at
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5
Highlights
A green, isocyanide based multicomponent reaction
was developed.
Unstable N-chlorinated amines, isonitriles and
water or sulfide were used for the 3CR.
Water could be exploited as reactants and solvent
for the preparation of carbamides.