A novel and efficient strategy for the synthesis of various carbamates using carbamoyl chlorides under solvent-free and grinding conditions using microwave irradiation

Article abstract of DOI:10.1016/j.cclet.2012.06.025

We present an efficient, fast and simple strategy of generating the intermediate carbamoyl chlorides from secondary amines using stoichiometric amounts of bis(trichloromethyl)carbonate (BTC) in solution and solvent-free conditions with excellent yields. The results obtained showed the yield increasing on whether a base was used. Finally, an efficient and rapid synthesis of variety carbamate derivatives was developed by the reaction with a high variety of different alcohols, phenols, diols and this intermediate at room temperature with grinding and in solvent-free conditions under microwave irradiation. The presence of various safe bases is shown to be effective in reducing the reaction times, increasing the yields and easing purification. The present method does not involve any hazardous phosgene.

Full text of DOI:10.1016/j.cclet.2012.06.025

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 883–886
www.elsevier.com/locate/cclet
A novel and efficient strategy for the synthesis of various carbamates
using carbamoyl chlorides under solvent-free and grinding
conditions using microwave irradiation
a
a
Hassan Zare a, Mohammad Mehdi Ghanbari b, , Marzieh Jamali , Abdollah Aboodi
*
a Department of Chemistry, Firoozabad Branch, Islamic Azad University, Firoozabad, Iran
b Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
Received 17 February 2012
Available online 4 July 2012
Abstract
We present an efficient, fast and simple strategy of generating the intermediate carbamoyl chlorides from secondary amines
using stoichiometric amounts of bis(trichloromethyl)carbonate (BTC) in solution and solvent-free conditions with excellent yields.
The results obtained showed the yield increasing on whether a base was used. Finally, an efficient and rapid synthesis of variety
carbamate derivatives was developed by the reaction with a high variety of different alcohols, phenols, diols and this intermediate at
room temperature with grinding and in solvent-free conditions under microwave irradiation. The presence of various safe bases is
shown to be effective in reducing the reaction times, increasing the yields and easing purification. The present method does not
involve any hazardous phosgene.
# 2012 Mohammad Mehdi Ghanbari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Bis(trichloromethyl)carbonate; Carbamoyl chloride; Carbamate; Microwave irradiation; Solvent-free; Grinding
Carbamoyl chlorides are starting material for production the various classes of compounds such as carbamates and
urea derivatives [1]. They are to be employed to synthesize various compounds in pharmaceutical, medical,
agrochemical, and polymer chemistry, which possess biologically desirable properties such as superior inhibitors of
TryR or HIV, anticancer, anticonvulsants, antibacterials, antiepileptics, and enzyme inhibitors. They are also useful
chemical intermediates for many industrial products such as fine chemicals, cosmetics, and pesticides [2–6]. Typically,
aliphatic and aromatic carbamoyl chlorides are generated from amines reacting with phosgene or phosgene
equivalents [7]. Carbamoyl chlorides and carbamates are generated by other processes, such as, the oxidative and
reductive carbonylation of amines with CO or CO2 in the presence of transition metal catalysts, even with
photocatalysis [8]. These routes were always suffered from the hazards in using of carbon monoxide and phosgene
under high pressure. Also, these routes were limited due to low yields, longer reaction times, stringent conditions, and
use of expensive reagents. Another approach to the preparations of carbamates is using the reaction of urea with
symmetrical carbonates [9]. This process can be used only when the two components (urea and carbonate) are either
* Corresponding author.
E-mail address: M.Mehdi.Ghanbari@Gmail.com (M.M. Ghanbari).
1001-8417/$ – see front matter # 2012 Mohammad Mehdi Ghanbari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.025

[(Scheme_1)TD$FIG]
884
H. Zare et al. / Chinese Chemical Letters 23 (2012) 883–886
R'
H
N
O
CCl3
CCl3
Base
N
Cl
O
+
Solvent or solvent-free
R
R'
R
O
O
3
1
2
Ph
Ph
N
N
Ph
+ R"ONa
Cl
Ph
O
O
OR"
4
3e
5
Scheme 1. Synthesis of compounds 3, 5.
both aliphatic or both aromatic [2], which limits the possible number of accessible products. All these facts prompted
us to find a new nontoxic method and to employ safe bases for the synthesis of the carbamoyl chlorides in a solvent-
free environment. As a solution to these problems, we envisaged the use of BTC. This capable compound has replaced
its gaseous congener, phosgene and diphosgene, in terms of its lower vapor pressure, reactivity, higher stability and
safe handling [10]. As part of our current studies on the development of new compounds, [11–15] we now report a
novel and efficient synthesis of carbamoyl chlorides 3 and carbamates 5 (Scheme 1).
1. Experimental
Amines 1, bis(trichloromethyl)carbonate 2, alcohols, phenols and diols were obtained from Merck and were used
without further purification. Alkoxides and phenoxides 4 were prepared by known methods [16]. Melting points
(uncorrected) were measured on an Electrothermal 9100 apparatus. The microwave oven used for this work was an
ETHOS-MR (800 W, 180 8C) operating at 2450 MHz. Elemental analyses for C, H, N and S were performed using a
Heraeus CHN-O-Rapid analyzer. The experimental data were in good agreement with the calculated values. 1H and
13C NMR spectra (CDCl3) were measured with a Bruker DRX-300 Avance spectrometer. IR spectra were recorded on
a Bruker tensor FT-IR 27 spectrometer. Mass spectra were recorded on a Hewleet-Packard 5993C spectrometer.
2. Results and discussion
The reaction of stoichiometric amounts of BTC with diphenyl amine in various solvents and solvent-free conditions
was revisited and it was shown that the formation of carbamoyl chlorides in high yields required careful adjustments of
experimentalconditionsandtheuse ofthe base asanHClscavenger. Weinvestigatedcomparativelytheactivitiesofsome
representatives of various bases which are nonvolatile, noncorrosive, and very popularly studied recently in green
catalysis, diphenyl carbamoyl chloride synthesis from BTC and diphenyl amine, and the results are listed in Table 1.
Given the fact that some carbamoyl chlorides are unstable and best used without any purification, we searched for a
cleaner and more efficient approach to synthesis them. BTC appeared as a good reagent for generating carbamoyl
chlorides but this reagent used in the presence of triethylamine [17] or pyridine [18]. The disadvantages of these routes
are always suffered from the byproducts [19]. Herein, we describe the approach to the synthesis of various carbamoyl
chlorides as a single product by the reaction of stoichiometric amounts of BTC with secondary amines in solvents and
Table 1
Chlorocarbonylation of diphenyl amine using BTC in solvent (I) and in solvent free condition (II): influence of the added base.
Base
Time (min)
I
Yield (%)
I
II
II
NaOH
30
60
5
90
60
72
75
70
96
65
80
85
75
CaCO3
CaHCO3
Na2CO3
None
20
20
20
30
45
40
180

H. Zare et al. / Chinese Chemical Letters 23 (2012) 883–886
885
Table 2
Synthesis of various carbamoyl chlorides 3a–f.
Substrate
Product
R
R0
Solvent
Time
(min)
Yieldb (%)
Mp (8C)
I
II
I
II
Found
Reporteda
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
Me
Me
CH2Cl2
10
10
20
20
30
30
2
2
5
5
5
7
80
85
95
92
90
85
88
92
99
98
96
90
White oil
White oil
86–88
White oil
White oil
87–90
n-Pr
Ph
n-Pr
Me
CH2Cl2
Benzene-xylene
Benzene-xylene
Benzene-xylene
Benzene-xylene
Ph
Et
56–58
–
Ph
Ph
81–83
83–85
Benzyl
Benzyl
White oil
White oil
a
1
All the products were characterized on the basis of their IR, H NMR and 13C NMR spectral analysis and compared with the literature data
[19,20].
b
Isolated yields.
solvent-free conditions using NaOH with temperature and time control in excellent yields (see the supporting
information and Table 2).
The advantage procedure is there can be use a broad spectrum of variety aromatic or aliphatic alcohols and diols to
react with carbamoyl chloride to the synthesis respective carbamates. The data obtained will help to establish a scale of
entering groups that will extend our knowledge on the reactivity of alcohols with carbamoyl chlorides for the synthesis
of carbamates. The reaction of carbamoyl chlorides with alcohols under solvent-free conditions at room temperature
on microwave and grinding generated carbamates in moderate purity and high yields (Table 3).
Although we have not yet established experimental proof for the mechanism of the formation of compounds 3 and
5, a plausible mechanism was proposed as shown in Scheme 2. It is reasonable to assume that carbamoyl chlorides 3
results from the initial addition amines to the BTC and subsequent deprotonation of the intermediate, followed by
rearrangement of 6, to from the carbamoyl chlorides 3. These compounds undergo a substitution reaction to produce
the final products 5 (Scheme 2).
Table 3
Synthesis of carbamates and hydroxyl carbamates using carbamoyl chloride and corresponding alcohols in solvent (I), and by grinding in solvent free
condition (II), and under microwave-irradiated condition (III).
Substrate
Product
R00
Time (h)
I
Yield (%)
Mp (8C)
II
III
I
II
III
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Me
0.01
0.05
8
0.005
0.009
0.21
0.26
0.25
0.10
0.17
0.14
0.13
0.18
0.15
0.25
0.31
0.28
0.21
0.30
0.26
0.37
0.31
0.34
0.38
0.002
0.004
0.14
0.17
0.16
0.07
0.11
0.09
0.08
0.12
0.10
0.16
0.21
0.19
0.14
0.20
0.17
0.24
0.21
0.22
0.25
97
95
80
75
76
80
75
78
91
90
93
85
81
76
83
75
78
73
76
73
69
99
99
76
69
71
82
77
80
93
92
95
87
83
78
85
77
80
75
80
77
71
99
99
90
85
87
92
86
88
99
98
99
96
93
89
96
87
90
85
88
84
80
58
Et
70
n-Propyl
214
sec-Butyl
10
9.5
4
Oil
t-Butyl
Oil
Benzyl
108
4g
4h
4i
5g
5h
5i
4-t-Bu benzyl
4-Methoxy benzyl
C6H5
6.5
5.5
5
140
121
105
4j
5j
4-CH3 C6H4
7
82
4k
4l
5k
5l
4-CH3O C6H4
4-Cl C6H4
6
102–103
104–106
113
9.5
12
11
8
4m
4n
4o
4p
4q
4r
5o
5q
5r
5m
5n
5o
5p
5q
5r
6o
6q
6r
4-NO2 C6H4
3-NO2 C6H4
84
CH2CH2OH
67–68
Oil
CH2CH2CH2OH
CH2CH OHCH3
3-Hydroxynaphthalen-2-olate
CH2CH2OCON(C6H5)2
CH2CH(CH3)OCON(C6H5)2
Naphtalen-2-yl diphenyl carbamate
11.5
10
14
12
13
14.5
106
162
160
202–205
208

[(Scheme_2)TD$FIG]
886
H. Zare et al. / Chinese Chemical Letters 23 (2012) 883–886
R'
N
OH
C
Base
Cl
Cl
1 + 2
OCl 3
3
+
R
Cl
O
7
6
Ph
N
Cl
5
+ R''ONa
Ph
O
Scheme 2. A plausible mechanism for the formation of compounds 3, 5.
3. Conclusion
The reaction of BTC, amines and NaOH provides a simple one-pot entry into the synthesis of carbamoyl chloride of
potential synthetic interest. Carbamoyl chlorides 3a–f can be considered as potentially useful synthetic intermediates.
The advantages that can be the reaction performed under neutral conditions and the starting materials and reagents can
be mixed without any activation or modification.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.06.025.
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