Halogen-Free Synthesis of Carbamates from CO2 and Amines Using Titanium Alkoxides

Article abstract of DOI:10.1002/asia.201700465

A direct synthesis of carbamates from amines and carbon dioxide in the presence of Ti(OR)₄ (R=nBu (1), Me (2), Et (3), nPr (4)) was investigated. Aniline was reacted with titanium n-butoxide (1) in the presence of carbon dioxide (5 MPa) to give the corresponding n-butyl N-phenylcarbamate (BPC) in nearly quantitative yield (99 %) within 20 min. Furthermore, 1 could be regenerated upon reaction with n-butanol during water removal. The recovered 1 could then be reused in a subsequent reaction.

Full text of DOI:10.1002/asia.201700465

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Halogen-free synthesis of carbamates from CO2 and amines
using titanium alkoxides
Authors: Jun-Chul Choi, Hao-Yu Yuan, Norihisa Fukaya, Syun-ya
Onozawa, Qiao Zhang, Seong Jib Choi, and Hiroyuki Yasuda
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using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Asian J. 10.1002/asia.201700465
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Chemistry - An Asian Journal
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COMMUNICATION
Halogen-free synthesis of carbamates from CO
titanium alkoxides
2
and amines using
Jun-Chul Choi,*[a,b] Hao-Yu Yuan, Norihisa Fukaya, Syun-ya Onozawa, Qiao Zhang, Seong Jib
[b]
[a]
[a]
[a]
Choi, [a] and Hiroyuki Yasuda[a]
Abstract: The direct synthesis of carbamates from amines and
synthesizing N-arylcarbamates.[2b] Two routes to arylcarbamate
syntheses directly from CO are shown in Scheme 1: a) using
n
carbon dioxide in the presence of Ti(OR)
4
(R = Bu (1), Me (2), Et (3),
2
n
organic halides;[8] b) using tin alkoxides.[9] However, this process
can still be improved due to the toxicity of the organotin
compounds, which are used in excess amounts. Hence, the use
of a metal alkoxide that is less toxic and more active compared to
tin alkoxide would be desirable. And such metal of choice could
be titanium which is nontoxic, very abundant, and relatively
inexpensive. Titanium alkoxides are widely used in organic
synthesis and materials science.[10] In this paper, we report a
highly efficient synthetic method of obtaining carbamates through
Pr (4)) was investigated. Aniline was reacted with the titanium n-
butoxide (1) in the presence of carbon dioxide (5 MPa) to give the
corresponding n-butyl N-phenylcarbamate (BPC) in nearly
quantitative yield (99%) within 20 min. Furthermore, 1 could be
regenerated upon reaction with n-butanol during water removal. The
recovered 1 could then be reused in a subsequent reaction.
Organic carbamates are widely used in agriculture,
pharmaceuticals, cosmetics, and in the synthesis of
polyurethanes.[2] The industrial production of polyurethanes relies
on isocyanates, which are synthesized through the thermolysis of
organic carbamates (eq.1);[ however, the historical synthetic
route to carbamates is based on the highly toxic and corrosive
phosgene. Thus, this process is far from being sustainable and is
not an environmentally friendly synthesis of carbamates.
the reaction of CO
2
and amines using a reusable titanium
alkoxide (Scheme 1).
3]
base
a) RNH2 + CO2 + R'X
RNHCOOR' + HX(base)
b) RNH2 + CO2 + Bu Sn(OR')
RNHCOOR'
2
2
(
R'X and Sn environmentally unfriendly)

RNHCOOR'
R = aryl, alkyl)
RNCO
(1)
-
R'OH
This work
c) RNH + CO
(
2
2
+ Ti(OR')
4
RNHCOOR'
Ti(OR') (OH)
+
On the other hand, carbamates could be obtained from
reactions between amines and dimethyl carbonate (DMC) as a
substitute for phosgene;[ however, DMC is synthesized from
methanol through a multi-step high energy-consuming procedure,
which encourages us to find a greener carbon source.
n
4-n
(
R = aryl, alkyl)
R'OH (Easy conversion)
4]
(
Ti environmentally friendly)
Scheme 1. Synthesis of carbamate using CO
2
as a carbon source.
Carbon dioxide (CO
phosgene because CO
2
) is a very attractive substitute for
is safe, inexpensive, and renewable.[
4]
2
Our group has successfully synthesized N-alkylcarbamate using
n
Initially, the reactions of aniline (0.8 mmol) and Ti(O Bu)
4
(1)
nickel or tin complexes directly from CO
2
, alkylamine, and alcohol
in the presence of acetals as a dehydrating agent;[ however, N-
6]
(0.8 mmol) under a pressure of CO (5 MPa) were carried out in
2
a stainless-steel autoclave (10 mL) at 180 °C. The formation of
butyl N-phenylcarbamate (BPC) as the major product and N,N’-
diphenylurea (DPU) as the by-product was detected by HPLC
arylcarbamate is not formed under such conditions due to the
formation of imines by a reaction of arylamine and acetals.[7] In
the polyurethane industry, over 90% of products possess aryl
groups, which has encouraged us to seek novel approaches to
(
Table 1). The products were obtained in common organic
solvents, such as diethyl ether, 1,4-dioxane, tetrahydrofuran, and
acetonitrile (Table 1, entries 2–5); however, the products did not
form notably in butanol (Table 1, entry 1). The reaction mixture
was analyzed by GC-MS, which provided peaks at m/z =57 (-
[
a]
b]
Prof. Drs J.-C. Choi, N. Fukaya, S. Onozawa, Q. Zhang, S. J. Choi,
H. Yasuda,
National Institute of Advanced Industrial Science and Technology
4 9 4 9 2 4 9
C H ), 73 (-OC H ), and 118 (HOCO C H ), consistent with the
(AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-
formation of dibutyl carbonate (DBC). As a result of the above
solvent screening, we found that the highest yield of BPC (84%)
was achieved using acetonitrile solvent. The yield of BPC
gradually increased as the concentration of 1 increased (Table 1,
entries 5–9). In particular, the reaction of aniline with two
equimolar amounts of 1 provided a total yield up to 100% (99%
BPC, 1% DPU; Table 1, entry 9).
8565 (Japan)
E-mail: junchul.choi@aist.go.jp
Tel: (+81) 029 861 9283.
Prof. Dr. J.-C. Choi, H.-Y. Yuan
[
Graduate School of Pure and Applied Sciences, University of
Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8573 (Japan)
A relevant patent has already been applied for; see ref. 1.
Supporting information for this article is given via a link at the end of
the document.
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conditions provided ethyl N-phenylcarbamate in 90% yield (Table
2, entry 3). The process involved in regenerating the metal
alkoxide from a metal oxide or hydroxide in the presence of a
dehydrating agent is known.[9, 11] Ono et al. reported the synthesis
, and 1.[a]
2
Table 1. n-Butyl N-phenylcarbamate synthesis from aniline, CO
2
CO (5 MPa)
1 (x equiv.)
H
H
H
N
n
NH
2
N
O Bu
N
of Ti(OEt)
4 2
(3) from a reaction of titanium dioxide hydrate (TiO -
Solvent, 180 oC, t
+
O
O
H
2
O) using diethyl carbonate (DEC) as the dehydrating agent
BPC
DPU
over 16 h at 260 °C;[
11b]
however, DEC must be synthesized
Entry
Solvent
t
(
x
Conv.
(%)
BPC
DPU
(%)
separately, resulting in a multiple-step reaction process.
[
b]
[b]
[b]
min)
(equiv.)
(%)
trace
67
1
2
3
4
5
6
7
8
9
n-BuOH
20
20
20
20
20
20
20
20
20
5
1.0
1.0
1.0
1.0
1.0
0.3
0.5
1.5
2.0
1.0
1.0
1.0
5
0
2
1
1
1
1
1
1
1
1
2
2
Table 2. The effect of the titanium alkoxides.[a]
Diethyl ether
1,4-dioxane
THF
72
79
66
88
36
59
98
100
80
89
92
73
66
Entry
R
Conv.[b]
Yield (%)[b]
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
84
1
2
3
4
nBu (1)
Me (2)
Et (3)
88
86
91
91
84
85
90
85
35
59
97
nPr (4)
99
10
11
12
64
[
a] Reaction conditions: aniline (0.8 mmol), Ti(OR)
4
3
(0.8 mmol), CH CN (3
1
2
mL), CO (5 MPa). [b] Determined by HPLC or H NMR.
30
60
81
80
[
(
a] Reaction conditions: aniline (0.8 mmol), 1 (0.8 mmol), solvent (3 mL), CO
5 MPa). [b] Determined by HPLC.
2
The experimental results obtained from the reuse studies
are listed in Table 3. The Ti-containg residues were recovered
from the reaction mixture, and 1 was regenerated upon reaction
with n-BuOH. These results revealed that 1 could be reused
through a sixth run without losing its activity.
Table 3. Recycling of 1 for the n-butyl N-phenyl carbamate synthesis.[a]
Recycle
time
Fresh
(1)
2
3
4
5
6
BPC
84 (79)
84 (78)
83 (80)
83 (80)
83 (79)
82 (78)
[
b]
(%)
[
a] Reaction conditions: aniline (2.7 mmol), 1 (2.7 mmol), CH
3
CN (10 mL),
o
CO
2
(5 MPa), 180 C, 20 min. [b] Determined by HPLC, and isolated yields
are given in parentheses.
Figure 1. The effect of the CO
2
pressure. Reaction conditions: aniline (0.8
o
3
mmol), 1 (0.8 mmol), CH CN (3 mL), 180 C, 20 min.
Figure 1 shows the effects of the CO
reaction of aniline, CO , and 1. The yield of BPC increased as the
CO pressure increased. On the other hand, the yield of DPU
decreased slightly as the CO pressure increased.
2
pressure on the
2
2
2
The effects of the titanium alkoxides were examined, and
the results are summarized in Table 2. Our synthetic method was
applied to a variety of titanium alkoxides in an effort to synthesize
N-phenylcarbamates. In particular, the use of 3 under the reaction
Scheme 2. The synthesis of dicarbamates (isolated yields are given).
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We next applied our method to the synthesis of the
corresponding dicarbamates (Scheme 2). First of all, 2,4-
diaminotoluene (TDA) could be converted to the corresponding
dibutyl toluene-2,4-dicarbamate in 64% yield (Scheme 2a). Use
of 4,4’-methylenedianiline (MDA) resulted in an 92% yield of the
corresponding dibutyl diphenyl methane-4,4’-dicarbamate
emphasized that the process is environmentally benign and
economical and involves a readily available phosgene alternative.
(
Scheme 2b).
As summarized in Table 4, our synthetic method was
successfully applied to a variety of arylamines substituted with an
electron-withdrawing or an electron-donating group to give the
corresponding N-arylcarbamates (Table 4, entries 1-7). Note that
2
the arylamines with p-CN and p-NO groups gave poor results
(
Table 4, entries 8 and 9). In addition, the reaction of alkyl- and
cycloalkylamines to give the corresponding N-alkylcarbamates
proceeds in excellent yield (Table 4, entries 10-12).
Table 4. The reaction of amines, CO
2
, and 1.[a]
Scheme 3. Possible reaction mechanism underlying the synthesis of
carbamates.
Experimental Section
Entry
R
Conv. (%)[b]
Yield (%)[b]
100 (94)
93 (85)
75 (70)
92 (83)
84 (80)
95 (84)
85 (75)
68 (60)
59 (54)
94 (88)
88 (82)
94 (85)
General information
1
2
3
4
5
6
7
8
9
p-MeOC
6
H
4
100
93
78
95
88
96
85
68
59
96
89
96
All manipulations were conducted under an atmosphere of purified
n
m-MeOC
o-MeOC
p-MeC
6
H
4
argon or nitrogen. The starting compounds Ti(OR)
4
(R = Bu (1), Me (2),
n
Et (3), and Pr (4)) were purchased from Aldrich Co. CO
2
was purchased
6 4
H
from Showa Tansan Co., Kawasaki, (purity > 99.99%) and was used
without further purification.
6
H
4
1
The reaction products were analysed by NMR, HPLC, and GC-MS. H
and 13C{ H} NMR spectra were measured on a Bruker AVANCE-III high-
1
6 5
C H
1
resolution spectrometer (400 MHz for H). HPLC analyses were conducted
using Shim-pack VP-ODS columns from GL Science mounted on a
Shimadzu Prominence HPLC equipped with a refractive index detector
(RID). All volatile products were characterized by GC-MS using a
Shimadzu GC-2010 gas chromatograph connected to a GCMS-QP 2010
plus mass spectrometer.
p-FC
p-MeCO
p-NCC
p-O NC
6 4
H
2
C
6 4
H
6
H
4
2
6 4
H
A typical procedure for synthesizing carbamates
Amine (0.8 mmol), Ti(OR)
4
(0.8 mmol), and CH
3
CN (3 mL) were
10
11
12
cyclo-Hex
n-Hex
3
added to a stainless-steel autoclave (10 cm inner volume) at room
temperature under a N atmosphere. The pressure was then adjusted to 5
2
MPa at 180 °C, and the autoclave was heated for 20 min. After cooling to
room temperature, toluene (85 mg) was added to the mixture as an internal
standard to determine the product yield using HPLC. The solvent was
removed at room temperature under reduced pressure. Isolated material
was purified by distillation or column chromatography. All of the isolated
products were characterized by 1H NMR, 13C{ H} NMR, and GC-MS.
Results are comparable with authentic materials and literature.[13]
Tert-Bu
[
(
a] Reaction conditions: amine (0.8 mmol), 1 (0.8 mmol), CH
3
CN (3 mL), CO
2
5 MPa), 180 C, 20 min. [b] Determined by HPLC or 1H NMR, and isolated
o
1
yields are given in parentheses.
Recycling of 4 for the butyl N-phenylcarbamate synthesis
n
A reaction mixture of aniline (252 mg, 2.7 mmol), Ti(O Bu)
4
(1) (0.92
A possible reaction mechanism underlying the carbamates
g, 2.7 mmol), and CH
3
CN (10 mL) were added to a stainless-steel
2
synthesis comprised 3 steps (Scheme 3). In step 1, CO inserted
autoclave (20 cm3 inner volume) at room temperature under a N
2
n
[12]
into the Ti-O Bu bond of 1, followed step 2 by the reaction of
the carbonate complex 1a with amines. In the final step 3, 1 was
regenerated from Ti-containing residues, which indicates that only
atmosphere. The pressure was then adjusted to 5 MPa at 180 °C, and the
autoclave was heated for 20 min. After cooling to room temperature,
toluene (85 mg) was added to the mixture as an internal standard to
determine the yield of products using HPLC.
2
amines, CO , and n-butanol were consumed during the entire
The products were separated from the reaction mixture by vacuum
sublimation at 100 °C. After sublimation, the residues were refluxed in n-
BuOH (30 ml) for 24 h. The water was removed by azeotropic distillation.[
After cooling to room temperature, n-BuOH was removed under vacuum
process, and the only by-product was water.
In summary, we successfully synthesized carbamates from
2
CO , amines, and titanium alkoxides through a halogen-free
process. Titanium n-butoxide (1) could be easily regenerated and
reused without losing its activity. Furthermore, our method could
be applied to the synthesis of dicarbamates. It should be
14]
to yield a yellowish liquid of 1 (recovery of 1; 99% after each run).
n
A reaction mixture of aniline (223 mg, 2.4 mmol), recycled Ti(O Bu)
4
(
3
1) (0.82 g, 2.4 mmol), and CH CN (10 mL) were added to a stainless-steel
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autoclave (20 cm3 inner volume) at room temperature under a N
atmosphere. The pressure was then adjusted to 5 MPa at 180 °C, and the
autoclave was heated for 20 min. All other reactions were conducted in a
similar manner
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Acknowledgements
This research was supported in part by a grant from the New
Energy and Industrial Technology Development Organization
(
NEDO) of Japan.
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2
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Keywords: Halogen-free • Carbon dioxide • Carbamates •
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Jun-Chul Choi,* Hao-yu Yuan, Norihisa
Fukaya, Syun-ya Onozawa, Qiao Zhang,
Seong Jib Choi, and Hiroyuki Yasuda
Page No. – Page No.
Halogen-free synthesis of carbamates
2
from CO and amines using titanium
alkoxides
A new efficient method of synthesizing carbamates directly from CO
Ti(OR’) through a halogen-free process was developed. Ti(OR’)
regenerated upon reaction with alcohol during water removal. The recovered Ti(OR’)
could then be reused in a subsequent reaction. This indicates that only CO , amines,
2
, amines, and
4
4
could be
4
2
and alcohol were consumed in the entire process, and the only by-product was water.
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