Ureas as safe carbonyl sources for the synthesis of carbamates with deep eutectic solvents (DESs) as efficient and recyclable solvent/catalyst systems

Article abstract of DOI:10.1039/c8nj02624f

A simple, efficient and eco-friendly one-pot synthesis of primary, N-mono- and N-disubstituted carbamates is developed from ureas. The corresponding carbamates were produced at 120 °C, within 18 h, and in the presence of a deep eutectic solvent as a recyclable catalytic system. The catalyst can be reused for several runs without any reduction in its activity. To demonstrate the utility of this approach, a wide variety of alcohols and phenols were studied to find a vast range of carbamate derivatives in moderate to high yields.

Full text of DOI:10.1039/c8nj02624f

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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ARTICLE
Ureas as Safe Carbonyl Sources for the Synthesis of Carbamates
with Deep Eutectic Solvents (DESs) as Efficient and Recyclable
Solvent/Catalyst Systems
Received 00th January 20xx,
Accepted 00th January 20xx
Iman Dindarloo Inaloo*a and Sahar Majnooni b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple, efficient and eco-friendly one-pot synthesis of primary, N-mono- and N-disubstituted carbamates is developed
from ureas. Corresponding carbamates were produced at 120 °C, within 18 h, and in the presence of the deep eutectic
solvent as a recyclable catalytic system. The catalyst can be reused for several runs without any reduction in activity. To
demonstrate the utility of this approach, a wide variety of alcohols and phenols were studied to find a vast range of
carbamate derivatives in moderate to high yields.
The classic and traditional approach for the synthesis of
carbamates from amines and alcohols usually entails the use
of toxic phosgene5 or its derivatives in which corresponding
carbamates such as methyl chloroformate,6 ethyl
Introduction
Carbamates and their derivatives are important chemicals
that widely used in drug designing and medicinal chemistry
(i.e., flupirtine, retigabine, albendazole and physostigmine are
carbamate-based drugs),1 agricultural chemistry (as herbicides,
pesticides, bactericides, and antiviral agents),2 cosmetics and
the synthesis of organic and polymer compounds.3 Some
important carbamate derivatives with biological activities are
depicted in Figure 1.1-3 One of the most common applications
of these structures in organic synthesis is the protection of
amino groups as well as amino acids in the multi-step synthesis
of multifunctional targets and structurally complicates natural
products like peptides.4
chloroformate,7 1,1,1-trichloromethylformate (diphosgene)8
and trichloroacetyl chloride9 can be observed. One of the
phosgene drawbacks is the production of large amounts of
corrosive HCl as the by-product in the conversion.10 Also,
chloride impurities will be found in the final products and the
purification of which is so difficult and a costly process.5-10 In
the view of environment protection and social safety, the
development of non-phosgene processes is highly desired.11
Therefore, to avoid the use of these extremely toxic, corrosive
and hazardous reagents, many efforts have been carried out to
develop alternatives.12-16 For this purpose, several effective
methods that apply the series of new reagents including
16
isocyanates,12 azides,13 carbonates,14 CO15 and CO2
have
been studied. Generally, the carbonylation with CO2, CO and
carbonates must be catalyzed by transitional metal complexes
16
such as ones bearing Pd, Pt, Ru, Rh, Ir, Au, Al etc.15,
Furthermore, these methodologies need to tolerate high
temperatures and pressures, long reaction time, and high
molar ratios of carbonylation agents.15, 16 Furthermore, the
mixture of CO and O2 often involves the rigorous safety
issues.15 Although, the alternative reagents allow the synthesis
of carbamates on
a small scale, unfortunately, these
methodologies are not suitable for the synthesis of large
quantities of product and do not present desired
performance.15, 16
In the past decades, scientists have emphasized on the use
of nontoxic carbonylation agents for the synthesis of the broad
range of organic compounds.17 Urea and many of its
derivatives are important classes of natural, low price and
nontoxic carbonylation agents which have attracted much
attention in recent years.18 Up to now, only a few reports
investigated the synthesis of carbamates through the
Figure 1. Some biologically active carbamates.
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treatment of ureas with alcohols.19 Unfortunately, in most corresponding carbamate is prepared in lower yiVeieldwsAr(tiTclaebOlnelin1e
DOI: 10.1039/C8NJ02624F
cases, the reactions proceed at the relatively high entries 3, 4). Furthermore, increasing the amount of urea
temperatures, low reactivity of phenols and in the presence of content compared to alcohol did not increase yields (Table 1
unrecoverable catalysts. However, an eco-friendly, mild, better entries 5, 6). Next, we examined the effect of changing the
yielding and practical approach are still under attention to amounts of [ChCl][ZnCl2]2 as the catalyst. Finally, It was found
constructing this synthetic, pharmaceutical and industrial that the reaction of A1 (2 mmol) and B1 (1 mmol) in the
important scaffolds.19
presence of 3.0 cm3 of [ChCl][ZnCl2]2 gave the highest yield of
The most common pollutants in the industrial and 1-propyl phenylcarbamate, at 120 oC within 18 h (Table 1 entry
laboratory scale processes are due to the usage of volatile 2).
organic solvents, especially halogenated solvents.20 From the
Table 1. Optimization of reaction parameters for the synthesis
of 1-propyl phenylcarbamate( 1).
economic and environmental point of view, according to the
advantages of deep eutectic solvents (DESs) such as being non-
hazardous, non-toxic, stable, non-flammable, and inexpensive
nature, they are very good and effective alternatives for
organic solvents.21 DESs have been known as preferable
alternative solvents/catalysts for organic synthesis that led to a
spectacular resurgence of interest.22
In recent years, as part of our ongoing research program
searching for the new, green and applicable synthesis of
carbamates,23 we have reported numerous highly active and
selective methods. In this effort, we develop a green, eco-
friendly, mild, and highly efficient method for the one-pot
synthesis of primary, N-mono- and N-disubstituted carbamates
using ureas as safe carbonyl source with choline chloride:Zinc
(II) chloride ([ChCl][ZnCl2]2) as a recoverable catalyst and
solvent (Scheme 1).
C
Molar ratio
A1:B1
[ChCl][ZnCl2]2
[cm3]
Temp Tim
Yield (%)a
Entry
[oC]
[h]
C1
0
D1
0
1
2
2 : 1
2 : 1
1 : 1
1.5 : 1
2.5 : 1
3 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
--
3
3
3
3
3
1
2
4
5
3
3
3
3
3
3
3
3
120
120
120
120
120
120
120
120
120
120
80
18
18
18
18
18
18
18
18
18
18
18
18
18
18
6
83
51
70
82
83
53
66
74
71
43
58
62
51
58
72
7
trace
21
3
4
14
5
trace
trace
trace
trace
11
6
7
8
9
10
11
12
13
14
15
16
17
18
13
trace
trace
16
100
140
160
120
120
120
120
Scheme 1. Primary, N-mono- and N-disubstituted carbamates
synthesis (C) via ureas.
23
trace
trace
11
12
24
30
Results and discussion
65
17
a Isolated yield.
We initiated our studies by investigating various reaction
conditions for the synthesis of primary, N-mono- and
N-disubstituted carbamates. Then, we postulated that the
main difficulty in this methodology is the low reactivity of
urea. On the other hand, it was envisioned that under more
efficient reaction conditions, one-pot synthesis of desired
products starting from N,N'-diarylurea would be beneficial.
In the next step of our investigation, the catalytic activities of a
wide range of commonly available DESs were checked out in
the model reaction under the optimized conditions and the
results are summarized in Table 2.
Based on the results presented in Table 2, when choline
chloride and metal chlorides based DESs including AlCl3, LaCl3,
MnCl2 and CaCl2 were used as catalyst no catalytic activity was
observed. Also, the usage of DESs such as [ChCl][ZnCl2],
[ChCl][FeCl3]2, [ChCl][SnCl2]2, [ChCl][NiCl2]2 [ChCl][CuCl2]2,
Therefore, N, N′‐diphenylurea (A1) and 1-propanol (B1) in the
presence of [ChCl][ZnCl2]2, were chosen as the model
substrates for the optimization of reaction conditions. Various
reaction parameters including the reaction time, temperature
and molar ratios of reagents were investigated to improve the
amount of the desired carbamate in the model reaction and
results are summarized in Table 1.
[ChCl][CoCl2]2,
[ChCl]2[Zn(NO3)2], [(BMIM)Cl][TiCl4] (BMIM
methylimidazolium) and [BTMAC][ZnCl2]2 (BTMAC
[ChCl][CrCl3]2,
[ChCl][ZnCl2][SnCl2],
=
1‐butyl‐3‐
=
According to these data, the presence of [ChCl][ZnCl2]2 is
necessary for the reaction progress and the best result
obtained when the molar ratio of urea:alcohol (2:1) was
applied in this reaction (Table 1 entries 1, 2). Decreasing the
amount of urea content than alcohol resulted in an increased
carbonate production as a side product. As a result, the
Benzyltrimethylammonium chloride) as catalyst, was led to the
synthesis of desired products in lower yields. Unfortunately,
during the usage of [ChCl][ZnCl2]3 as catalyst, a large quantity
of dipropyl carbonate as the side product has been formed and
detected. These results indicate the low selectivity of catalyst
for the formation of desired carbamates in the model reaction.
2 | J. Name., 2012, 00, 1-3
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Table 2. Results of 1-propyl phenylcarbamate (C1) from
ARTICLE
nucleophilicity of alcohols plays a serious role in the efficiency
View Article Online
1-propanol (B1) and N, N
′
‐diphenylurea (A1) over different
DOI: 10.1039/C8NJ02624F
of the reaction.
DESs.a
Table 3. Synthesis of N-monosubstituted carbamates (C1–20
)
from alcohols or phenols by N, N′-diphenylurea in the presence
of [ChCl][ZnCl2]2.a
Entry
DES
Yield (%)b
C1
62
83
74
43
56
0
39
38
41
0
54
0
0
72
68
47
0
D1
trace
trace
14
trace
trace
0
trace
trace
trace
0
trace
0
[ChCl][ZnCl2]
[ChCl][ZnCl2]2
[ChCl][ZnCl2]3
[ChCl][FeCl3]2
[ChCl][SnCl2]2
[ChCl][AlCl3]2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C2, 81 %b
C5, 72 %b
C3, 85 %b
C6, 73 %b
C1, 83 %b
C4, 80 %b
[ChCl][NiCl2]2
[ChCl][CuCl2]2
[ChCl][CoCl2]2
[ChCl][LaCl3]2
[ChCl][CrCl3]2
[ChCl][MnCl2]2
[ChCl][CaCl2]2
[ChCl][ZnCl2][SnCl2]
[ChCl]2[Zn(NO3)2]
[(BMIM)Cl][TiCl4]
[(BMIM)Cl][AlCl3]
[BTMAC][ZnCl2]2
C7, 76 %b
C10, 85 %b
C13, 20 %b
C16, 45 %b
C9, 64 %b
C8, 70 %b
C11, 23 %b
C14, 40 %b
0
trace
trace
trace
0
C12, 18 %b
70
trace
C15, 43 %b
C18, 39 %b
a Reaction conditions: 1-propanol (1 mmol), N, N
(2 mmol), DES (3 cm3), 120 oC, 18 h.
b Isolated yield.
′
‐diphenylurea
C17, 48 %b
Having determined the optimal reaction conditions, the scopes
of proposed one-pot methodology for the synthesis of
N-monosubstituted carbamates with varies alcohol and phenol
derivatives were investigated. Experimentally, it was found
that primary and secondary alcohols present good to excellent
yields of carbamates (Table 3, entries C1-8 and C10). It was
noticed that reaction with tertiary alcohols lead to the
formation of the desired carbamate in lower yields (Table 3,
entry C9). The steric hindrance seems to be the main reason
and causes low product yields. Interestingly, in the case of
L-(-)-menthol, the reaction can produce the corresponding
L-(-)-menthyl phenylcarbamate without any epimerization
(Table 3, entry C8). Unfortunately, the reaction of allyl alcohol,
benzyl alcohols and phenol under the same conditions
afforded the corresponding carbamates in low yields, even
with increasing the reaction time and temperature (Table 3,
entries C11-24). In addition, phenol nucleophiles containing an
electron donating group provided desired carbamates in low
yields (Table 3, entries C15-18). Moreover, when phenols
containing an electron withdrawing group were used as the
nucleophile, the amounts of wanted products were so
insignificant and the purification of which using experimental
methods like column chromatography and thin-layer
chromatography were unsuccessful (Table 3, entries C19-20).
These results showed that along with the steric hindrance, the
C19, traceb
C20, traceb
a
Reaction conditions: alcohols or phenols (1 mmol),
N, N′-diphenylurea (2 mmol), [ChCl][ZnCl2]2 (3 cm3), 120 oC, 18 h.
b Isolated yield.
In the next step, we explored the scope and limitations of
carbamates synthesis by employing various ureas. Therefore, a
range of commercially available N, N'-disubstituted ureas and
N, N'-tetrasubstituted ureas including aromatic and aliphatic
substitutes were applied in reaction and the results are
summarized in Table 4.
Under optimized conditions, N, N'-diphenyl ureas with both
electron donating and electron withdrawing substituents
underwent the conversion efficiently. However, N, N'-diphenyl
ureas bearing electron-withdrawing groups had slightly higher
yields than those with electron-donating moieties (Table 3,
entries C21-29). Importantly, good to excellent yields were
obtained when N, N'-dialkylureas were treated with primary,
secondary and tertiary aliphatic substrates (Table 3, entries
C31-34). However, N, N'-tetrasubstituted ureas such as 1,1,3,3-
tetraethylurea, 1,1,3,3-tetrabenzylurea, 1,3-dibenzyl-1,3-
diethylurea, 1,1,3,3-tetraphenylurea and also 1,3-dibenzylurea
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gave desired carbamates in moderate yields (Table 3, entries 3,3-diphenylurea and 1-ethyl-3-phenylurea gave the carbonate
View Article Online
DOI: 10.1039/C8NJ02624F
C35-38). In these cases, due to the more activity of product in more yield, other results were the same. The steric
N, N'-tetrasubstituted ureas rather than N, N'-disubstituted hindrance of applied ureas as well as the leaving strength of
ureas in this reaction conditions, the amount of carbonate side amines, probably resulted in this observations.
product was increased.
Table 5. Investigation of the reaction between 1-propanol and
various substituted of ureas.a
Table 4. Synthesis of N-mono- and N-disubstituted carbamates
(
C21–38) from 1-propanol by various ureas in the presence of
[ChCl][ZnCl2]2.a
Entry
R
Yield (%)b
R1
H
R2
H
R3
R4
1
2
3
4
5
6
7
H
H
E=F=58, D=0
E=0, F=74, D=0
E=0, F=80, D=0
E=0, F=69, D=0
E=0, F=73, D=0
E=17, F= 47, D=12
E=9, F= 54, D= 17
C21, 80 %b
D, trace
C22, 82 %b
D, trace
C23, 84 %b
D, trace
Phenyl
H
H
H
H
H
Phenyl Phenyl
Ethyl
Ethyl
H
Ethyl
H
H
H
H
H
C24, 78 %b
D, trace
Phenyl
Ethyl
H
C26, 89 %b
D, trace
C25, 88 %b
D, trace
Phenyl Phenyl
Ethyl
Ethyl
a Reaction conditions: 1-propanol (1 mmol), N, N
(2 mmol), DES (3 cm3), 120 oC, 18 h.
b Isolated yield.
′‐diphenylurea
C28, 88 %b
D, trace
C27, 86 %b
D, trace
C29, 87 %b
D, trace
Next, we decided to apply the reaction in the synthesis of
thiocarbamate and selenocarbamate. For this purpose, the
reaction of 1-pentanol with 1,3-diphenylthiourea or 1,3-
diphenylselenourea have been tested under the optimized
conditions and the results are summarized in Table 6.
Unfortunately, these tests were unsuccessful for the synthesis
of desired products and starting materials were only observed.
These results show that the [ChCl][ZnCl2]2 is unable to activate
thiocarbonyl and selenocarbonyl groups.
C30, 77 %b
D, trace
C31, 74 %b
D, trace
C32, 78 %b
D, trace
C35, 63 %b
D, 13 % b
C34, 60 %b
D, 16%b
C33, 76 %b
D, 10 %b
Table 6. Investigation of the reaction between 1-propanol and
N, N- diphenyl substituted of ureas, thioureas and
selenoureas.a
C38, 41 %b
D, 23 %b
C37, 45 %b
D, 00 % b
C36, 50 %b
D, 24 %b
a
Reaction conditions: 1-propanol (1 mmol), ureas (2 mmol),
[ChCl][ZnCl2]2 (3 cm3), 120 oC, 18 h.
Entry
1
X
Product structure
Yield (%)b
83
b Isolated yield.
O
Subsequently, the chemo selectivity of this approach was also
studied by the reaction of 1-propanol and different ureas.
Chemo selective formation of the of the propyl carbamate was
carried out by the reaction of 1-propanol with urea (Table 5,
2
3
S
0
entry
(Table 5, entry
diethylurea (Table 5, entry
1
), 1-phenylurea (Table 5, entry
),1-ethylurea (Table 5, entry
) in good yields with no formation
2
), 1,1-diphenylurea
Se
0
3
4
) and 1,1-
4
a
Reaction
conditions:
1-propanol
(1
mmol),
of carbonate and N-mono- and N-disubstituted carbamates by
products. However, using 1-ethyl-3-phenylurea undergoes the
produces unequal amount of 1-propyl phenylcarbamate and 1-
propyl propylcarbamate along with a remarkable amount of
dipropyl carbonate were obtained. Although using 1,1-diethyl-
N, N′‐diphenylurea, thiourea or selenourea (2 mmol), DES (3
cm3), 120 oC, 18 h.
b Isolated yield.
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The recyclability and reusability are important features of
catalysts which especially signify both economic and
environmental viewpoints in the industrial and chemical
processes. Therefore, the recyclability of [ChCl][ZnCl2]2 as a
deep eutectic solvent and the catalytic system was
investigated in the model reaction. After the completion of the
reaction, all products and remaining precursors were extracted
with diethyl ether (3 × 10 mL). Then, DES was separated from
Determination of the purity of the substrate and monitoring of the
reactions was accomplished by thin-layer chromatography (TLC) on
a silica-gel polygram SILG/UV 254 plates.
View Article Online
DOI: 10.1039/C8NJ02624F
Preparation of [ChCl][ZnCl]2 as deep eutectic solvent:24
For the preparation of this deep eutectic solvent, a mixture
of choline chloride (10 mmol, 1.39 g) and zinc(II) chloride (20
the ethereal solution, dried by evaporation at 70 oC under mmol, 2.72 g) was heated to 100 oC until a clear colorless
vacuum condition for 30 min and reused in the model reaction
for the next runs. As illustrated in Figure 2, the efficiency of
DES was found to be notable even after five cycles with the
lowest decrease in the activity of which.
liquid appeared, then allowed to cool at room temperature
and used without further purification.
General procedure for the preparation of primary, N-mono- and
N-disubstituted carbamates derivatives (C1-33):
Alcohol or phenol (1.0 mmol) was treated with ureas (2.0
mmol) in the presence of [ChCl][ZnCl2]2 (3 cm3) at 120 oC under
solvent-free magnetic stirring for 18 h. The progress of the
reaction was monitored by TLC. After the completion of the
reaction, the mixture was cooled down to room temperature.
The reaction mixture was separated from DES by multiple
dilutions using diethyl ether (3 × 10 mL). Then, all starting
materials were washed with H2O (2 × 15 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated to afford
final products. Finally, obtained crude was purified by
recrystallization from the CH2Cl2 or chromatograph using ethyl
acetate /petroleum ether (1/9). The purity and identity of the
1
product were confirmed by FT-IR, H NMR, 13C NMR, and MS.
Figure 2. Reuse of [ChCl][ZnCl2]2 catalyst in the synthesis of
The recovered catalyst was activated by heating under
reduced vacuum at 70 oC for 30 min and reused for next
cycles.
1-propyl phenylcarbamate.
Conclusions
In summary, we reported a green, efficient, inexpensive
and operationally simple process for the one-pot synthesis of
N-mono- and N-disubstituted carbamates. Remarkably, the
current method has many important highlights such as (i)
usage of ureas as an inexpensive and natural carbonyl source;
(ii) application of [ChCl][ZnCl2]2 as recoverable catalyst and
solvent system that proved to be a safe and eco-friendly
reaction medium and (iii) convenient and very simple
separation and purification process. In view of the potential
applicability of carbamates in drug design and the synthesis of
natural and bioactive molecules, it is significant that this
phosgene-free methodology can be widely used for
carbamate-based marketed drugs and opens the new avenue
for further research in this area.
Acknowledgments
Authors gratefully acknowledge the financial support of this
work by the research council of Shiraz University.
Notes and references
1
(a) A. K. Ghosh, M. Brindisi, J. Med. Chem., 2015, 58, 2895-
2940; (b) S. Ray, D. Chaturvedi, Drugs Future, 2004, 29, 343-
357; (c) J. P. Alexander, B. F. Cravatt, Chem. Biol., 2005, 12
,
1179-1187; (d) H. A. Friedel, A. Fitton, Drugs, 1993, 45, 548-
569; (e) A. D. Wickenden, W. Yu, A. Zou, T. Jegla, P. K.
Wagoner, Mol. Pharmacol., 2000, 58, 591-600; (f) A. G.
Saimot, A. C. Cremieux, J. M. Hay, A. Meulemans, M. D.
Giovanangeli, B. Delaitre, J. P. Coulaud, Lancet, 1983, 322
652-656; (g) B. H. Peters, H. S. Levin, Ann. Neurol., 1979,
,
,
6
219-221.
2
(a) K. R. Wilson, K. L. Hill, (1969). U.S. Patent No. 3,434,822.
Washington, DC: U.S. Patent and Trademark Office; (b) J. A.
Ocampo, J. M. Barea, Plant Soil, 1985, 85, 375-383; (c) D.
Liu, W. Chen, J. Wei, X. Li, Z. Wang, X. Jiang, Anal. Chem.,
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Chemosphere, 2011, 82, 291-307; (e) J. W. Pullen, R. P.
Neighbors, C. F. Clark, O. L. Hoffmann, A. C. Meunier,
(1960). U.S. Patent No. 2,951,786. Washington, DC: U.S.
Patent and Trademark Office; (f) S. Ray, S. R. Pathak, D.
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M. Roberti, G. Gentilomi, Farmaco, 2000, 55, 35-39.
Experimental
General experimental:
All chemicals were purchased from the Merck, Flucka and
Aldrich Chemical Companies in high purity. The products were
characterized by comparison of their spectral and physical data
such as NMR, FT-IR, MS, CHNS and melting point with the literature.
1H and 13C NMR spectra were recorded with Bruker Avance DPX
250MHz instruments with Me4Si or solvent resonance as the
internal standard. Fourier transform infrared (FTIR) spectra were
3
(a) B. Husár, R. Liska, Chem. Soc. Rev., 2012, 41, 2395-2405;
(b) W. E. Catlin, (1942). U.S. Patent No. 2,284,637.
obtained using
a Shimadzu FT-IR 8300 spectrophotometer.
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