Polyethylene glycol-enhanced chemoselective synthesis of organic carbamates from amines, CO2, and alkyl halides

Article abstract of DOI:10.1080/00397911.2010.517890

An efficient and environmentally benign method for the synthesis of organic carbamates was developed. Amines, CO₂, and alkyl halides underwent a three-component reaction with the aid of K₂CO₃ and polyethylene glycol (PEG, MW=400), affording the organic carbamates under ambient conditions. PEG could presumably act as a solvent and phase-transfer catalyst (PTC). Notably, the presence of PEG could also depress the alkylation of both the amine and the carbamate, thus resulting in enhanced selectivity toward the target carbamate. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2010.517890

1
Synthetic Communications , 41: 3298–3307, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517890
POLYETHYLENE GLYCOL–ENHANCED
CHEMOSELECTIVE SYNTHESIS OF ORGANIC
CARBAMATES FROM AMINES, CO , AND ALKYL
2
HALIDES
De-Lin Kong, Liang-Nian He, and Jin-Quan Wang
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai
University, Tianjin, China
GRAPHICAL ABSTRACT
Abstract An efficient and environmentally benign method for the synthesis of organic car-
2
bamates was developed. Amines, CO , and alkyl halides underwent a three-component reac-
tion with the aid of K CO
2
3
and polyethylene glycol (PEG, MW ¼ 400), affording the
organic carbamates under ambient conditions. PEG could presumably act as a solvent
and phase-transfer catalyst (PTC). Notably, the presence of PEG could also depress the
alkylation of both the amine and the carbamate, thus resulting in enhanced selectivity
toward the target carbamate.
Supplemental materials are available for this article. Go to the publisher’s online edition
1
of Synthetic Communications to view the free supplemental file.
Keywords Amine; carbon dioxide; organic carbamate; polyethylene glycol; potassium
carbonate
INTRODUCTION
Organic carbamates have extensive applications in the pharmaceutical
[
industry and agriculture, and they have been widely used as key intermediates
1]
[2]
[
3]
or protecting groups in synthetic chemistry. The conventional synthesis of organic
carbamates involves using highly toxic phosgene as a carbonylating agent, and
organic solvents are required, causing environmental problems. Therefore, much
effort has been directed toward developing alternative routes to the synthesis of
carbamates using CO as a carbonyl reagent in place of phosgene.
2
Carbon dioxide is able to react with an amine to form an ammonium carba-
mate and subsequently with an alkyl halide in conjunction with a base, forming
[4]
an organic carbamate, or sequentially with the amine in the presence of both a
Received December 30, 2009.
Address correspondence to Liang-Nian He, State Key Laboratory and Institute of
Elemento-organic Chemistry, Nankai University, Tianjin 300071, China. E-mail: heln@nankai.edu.cn
3
298

SYNTHESIS OF ORGANIC CARBAMATES
3299
2
Scheme 1. Cyclic PEG-improved synthesis of carbamates from amines, CO , and alkyl halides.
[
5]
dehydrating reagent and a base to produce a urea. In the former case, the major
challenge would be to control a competitive side reaction, the alkylation of the amine
with the alkyl halide. In this context, a Phase-Transfer Catelyst (PTC) such as crown
[
6]
ether and quaternary ammonium salt and a strong base like Cs CO
[
or an organic
base have been successfully used to promote the synthesis of organic carbamates.
2
3
7]
[
8]
On the other hand, high CO pressure is necessary when K CO is used as a base.
2
2
3
It is worth mentioning that carbamates can also be prepared by employing a
three-component reaction of amines, CO , and alcohols, although an excessive dehy-
2
[9]
drating agent is required.
PEG and its derivatives are commonly known to be inexpensive, thermally
stable, toxicologically innocuous, and environmentally benign and have almost neg-
[
10–15]
ligible vapor pressure for chemical reactions and PTCs.
[
Notably, PEG, like a
whereby it could act as
14]
crown ether, is able to coordinate with metal cations,
an excellent PTC as well as a cosolvent=additive for a number of organic reac-
[
14,15]
tions.
pared from biomass-based starting materials such as lactic acid.
Using K CO as a base for the carbamate synthesis would be promising from
In addition, unlike most volatile organic solvents, PEG can be also pre-
[
12]
2
3
economic and environmental points of view. However, high CO pressure is required
2
[
8]
in the current process, thus limiting its application. With our continuous effort to
develop the environmentally benign method for the PEG-promoted organic syn-
[
thesis, we herein report a PEG400-enhanced synthesis of organic carbamates with
16]
high chemoselectivity from amines, CO , and alkyl halides under room temperature
2
and atmospheric pressure utilizing K CO as a base (Scheme 1). PEG in this study
2
3
probably could serve as both a solvent and PTC and also activate the carbamic anion
so that PEG could depress the alkylation and enhance the selectivity toward the
target product.
RESULTS AND DISCUSSION
In the preliminary study, the reactions were conducted with dibutylamine,
-bromobutane, PEG400, a base, and CO (1 atm) at rt for 24 h to furnish the
2
1
organic carbamate along with the formation of tributylamine, the alkylation product
of dibutylamine. The results are summarized in Table 1. As easily seen, the yield and
selectivity of the carbamate were strongly dependent on the base. K CO showed
2
3
excellent activity and selectivity, even better than Cs CO under otherwise identical
2
3
reaction conditions (entries 1–7). In addition, several organic bases were also exam-
ined for this reaction, but all displayed poor activities (entries 8–11). As a conse-
quence, K CO was chosen as a model base for further investigation in terms of
2
3
availability, environmentally friendly workup, and economical considerations.

3300
D.-L. KONG, L.-N. HE, AND J.-Q. WANG
a
Table 1. Screening bases
b
Yield of
carbamate (%)
b
Yield of
tributylamine (%)
b
Conv. (%)
Entry
Base
1
2
3
4
5
6
7
8
9
LiOH
NaOH
Na CO
10.6
10.8
16.0
12.0
51.0
67.1
82.0
24.0
9.2
9.2
10.7
14.0
9.3
Trace
Trace
1.7
2
3
Ca(OH)
KOH
2
2.3
33.6
65.4
66.4
6.0
12.6
2.1
K
2
CO
CO
3
Cs
DABCO
Et
n-Pr
Pyridine
2
3
13.9
16.5
1.9
c
3
N
6.9
1
0
1
3
N
17.1
32.3
15.0
1.4
1.5
25.5
1
a
Reaction conditions: dibutylamine (2 mmol), 1-bromobutane (4 mmol),
2
PEG400 (10 mL), base (4 mmol), CO (1 atm), and biphenyl (60 mg, as inter-
nal standard), rt, 24 h.
b
Determined by GC using biphenyl as internal standard.
,4-Diazabicyclo[2.2.2]octane.
c
1
The solvent effect was evaluated as shown in Table 2. Dimethylformamide
DMF), a commonly used solvent, gave high conversion but poor selectivity (entry
, Table 2). As anticipated, PEG400 showed good activity and the best selectivity to
(
2
the target carbamate among the examined solvents (entry 1 vs. 2–7). This is under-
þ
standable because PEG is able to coordinate with the metal ion (e.g., K ), thereby
[
16]
increasing in reactivity of the carbonate anion. However, ethylene glycol was inac-
tive (entry 7), and triethylene glycol (MW150) PEG200 displayed poor results
a
Table 2. Solvent effect
b
Yield of
carbamate (%)
b
Yield of
tributylamine (%)
b
Conv. (%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
PEG400
DMF
CH CN
67.1
84.8
12.7
34.3
Trace
Trace
Trace
8.6
65.4
46.8
6.3
2.1
34.5
5.3
3
c
NMP
Toluene
THF
4.9
23.1
Trace
Trace
Trace
6.7
Trace
Trace
Trace
0.5
Ethylene glycol
Triethylene glycol
PEG200
15.7
41.4
49.4
9.9
5.8
3.8
1
1
0
1
PEG600
PEG1000
37.6
4.2
d
42.0
a
Reactions were conducted with dibutylamine (2 mmol), 1-bromobutane (4 mmol),
solvent (10 mL), K CO (4 mmol), CO (1 atm), and biphenyl (60 mg, as internal
standard) at rt for 24 h.
2
3
2
b
Determined by GC using biphenyl as internal standard.
N-Methylpyrrolidone.
c
d
3
73 K for 6 h.

SYNTHESIS OF ORGANIC CARBAMATES
3301
(entries 8, 9), hinting at a requirement for a minimum molecular weight of PEG for
complexation activity of more than 200 g=mol.
[
15b]
PEG600 also gave poor results
because of the viscosity and mass-transfer rate (entry 10). PEG1000 showed poor sel-
ectivity at 373 K and was solid at room temperature (entry 11). Accordingly, PEG’s
effect on the activity could probably be ascribed to the ease of forming
þ
ꢁ
þ
[4]
[
PEG could increase the solubility of the ammonium carbamate salt and also improve
R NH ꢀ PEG] [O CNR ] from [R NH ] and PEG (Scheme 1). In other words,
2
2
2
2
2
2
[
4]
the nucleophilicity of the carbamic anion, thus leading to enhanced activity of the
reaction. On the other hand, PEG’s effect on the selectivity could presumably be due
to PEG increasing the thermodynamic stability of [R NH ] , which could depress
2
the N-alkylation of the amine. Moreover, the product could be readily separated
by a diethyl ether extraction.
Subsequently, the reaction conditions were optimized with the K CO =PEG
þ
2
[5]
2
3
system (Table 3). It was found that the reaction proceeded rapidly within the first
2 h under ambient conditions (entries 1–4, Table 3). Good yields up to 85.2%
1
and excellent selectivity could be achieved within 48 h. In other words, the reaction
time of 48 h is required for completing the reaction (entries 5–7). Additionally, the
reaction temperature had a great influence on the reaction. The formation of the car-
þ
ꢁ [5,17]
bamate is likely correlated with the stability of [R NH ꢀ PEG] [O CNR ] .
2
2
2
2
Indeed, higher temperatures favored the conversion of the amine at the expense of
the selectivity toward organic carbamates (entries 3, 8, and 9), so PEG1000 gave
poor selectivity at 373 K (Table 2, entry 11). Consequently, the suitable temperature
could be 293 K in view of both activity and selectivity.
On the other hand, greater CO pressure up to 6 MPa could slightly decrease
2
yield of organic carbamate (entries 2 and 10–12). It is understandable that high
CO pressure could decrease the polarity of the reaction medium and also dilute
2
[
18i]
the concentration of the ammonium carbamate salt.
In addition, the amine could
a
Table 3. Dependence of carbamate yield on reaction conditions
b
b
Yield of
carbamate
(%)
Yield of
tributylamine
(%)
b
Temp.
(K)
Time Pressure
(h)
Conv.
(%)
Entry
(MPa)
1
2
3
4
5
6
7
8
9
293
293
293
293
293
293
293
323
373
293
293
293
4
6
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
2
12.8
26.8
41.5
67.1
87.8
95.8
97.3
91.8
98.2
16.8
13.8
13.6
12.2
24.9
40.8
65.4
85.2
92.6
95.6
59.9
29.0
16.5
13.6
13.0
Trace
Trace
1.1
12
24
48
72
96
12
12
6
2.1
2.4
2.6
2.6
26.8
61.8
Trace
Trace
Trace
1
1
1
0
1
2
6
4
6
6
a
Reactions were conducted with dibutylamine (2 mmol), 1-bromobutane (4 mmol),
PEG400 (10 mL), biphenyl (60 mg, as internal standard), and K CO (4 mmol).
2
3
b
Determined by GC using biphenyl as internal standard.

3302
D.-L. KONG, L.-N. HE, AND J.-Q. WANG
a
Table 4. Synthesis of various carbamates
b
Yield of
carbamate (%)
b
Conv. (%)
Entry
Amine
Halide
1
2
3
4
5
6
7
8
9
n-Bu
2
2
2
2
2
2
2
2
NH
MeI
EtBr
39.9
79.1
36.1
82.2
87.8
53.4
59.1
91.9
94.2
57.3
90.4
56.5
31.3
74.4
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
NH
NH
NH
NH
NH
NH
NH
n-BuOH
n-BuCl
n-BuBr
AllBr
29.1
77.0
85.2 (57.7)
49.7
51.6
n-OctBr
BnCl
88.0 (60.6)
93.0
54.2
CyNH
n-BuNH
Et NH
PhNH
2
n-BuBr
n-BuBr
n-BuBr
n-BuBr
1
1
1
0
1
2
2
2
86.8
2
53.9
a
Reactions were conducted with amine (2 mmol), halide (4 mmol), PEG400 (10 mL), biphenyl (60 mg, as
internal standard), K CO (4 mmol), and CO (1 atm), at rt for 48 h.
2
3
2
b
Conversion and yield were determined by GC using biphenyl as internal standard. Data in parentheses
refer to the isolated yield.
be converted to less O-nucleophilic species such as carbamic acid and dimeric car-
[
bamic acid, thus leading to lower yield of carbamate. Accordingly, the optimized
4]
reaction conditions could be 293 K, ambient pressure of CO , and 48 h.
2
To demonstrate the utility and generality of this approach, we examined the
reactions of various amines and alkyl halides with CO under the optimized reaction
2
conditions. The results are summarized in Table 4. It was found that aliphatic sec-
ondary amines gave better results than the primary ones (entries 5, 10, and 11). This
might be explained by a slightly increased nucleophilicity of the amine group. Inter-
estingly, the synthesis of the carbamate from aromatic amine was also proved to be
operative (entry 12). On the other hand, the yield of carbamates also depended on
the activity of the halides. In this regard, benzyl chloride gave the best result among
the halides used in this work (entries 1, 2, and 4–8). The methyl iodide showed the
poorest activity, probably being attributed to its instability under the reaction con-
ditions. The halides with different alkyl chains gave rise to relatively different reac-
tivity (entries 2, 5, and 7), presumably owing to the electronic effect. It is noteworthy
that alcohol could also react with the amine and CO to form carbamate without the
2
need of any dehydrating agents though low activity (entry 3).
CONCLUSIONS
In conclusion, we have developed a PEG-promoted three-component reaction
of amines, CO , and halides under ambient conditions for the chemoselective syn-
2
thesis of carbamates, which required no additional PTC or ligands. Notably, this
protocol is able to effectively depress common side reactions such as N-alkylation
of both the amine and the carbamate. In this reaction, PEG400 mainly plays an irre-
placeable role in three possible ways, including (1) forming an adduct of
þ
ꢁ
[
R NH ꢀ PEG] [O CNR ] to increase the solubility of the ammonium carbamate
2
2
2
2

SYNTHESIS OF ORGANIC CARBAMATES
3303
þ
ꢁ
2
salt; (2) lowering the interaction of [R NH ꢀ PEG] with [O CNR ] and improving
2
2
2
ꢁ
2
the reactivity of [O CNR ] , thus depressing N-alkylation of the amine; and (3)
2
weakening the electrostatic interactions between the ion pairs of K CO to increase
2
3
the reactivity of the carbonate anion. Moreover, the protocol worked well for vari-
ous aliphatic and aromatic amines and halides.
EXPERIMENTAL
Carbon dioxide with a purity of 99.99% was commercially available. All of the
other reagents used in this work were of analytical grade and were used as received
1
without further purification. H NMR and C NMR spectra were recorded on a
13
Bruker 400-MHz instrument at 100.4 MHz respectively in CDCl . Chemical shifts
3
(d) are given in parts per million (ppm) relative to tetramethylsilane (TMS). The
solvent signals were used as references, and the chemical shifts were converted to
the TMS scale (CDCl : d 77.0 ppm; residual CHCl in CDCl : d 7.26 ppm). The
3
C
3
3
H
products were characterized by comparison of their spectral data with those of auth-
entic samples. Gas Chromatographic (GC) analyses were performed on a Shimadzu
GC-2014 instrument, equipped with a capillary column (RTX-5, 30 m ꢂ 0.25 mm)
using a flame ionization detector.
General Procedure for the Reaction of Amines, Halides, and CO2
Potassium carbonate (0.55 g, 4 mmol, 2 equiv.) and biphenyl (60 mg) as internal
standard were added to dibutylamine (0.32 mL, 2 mmol) in PEG400 (10 mL) for
analysis. Carbon dioxide gas (1 atm) was introduced into the reaction mixture and
stirred for 2 h. Then 1-bromobutane (0.4 mL, 4 mmol, 2 equiv.) was added into the
suspension. The reaction proceeded at an ambient temperature with CO for a cer-
2
tain time. The yield of carbamate and the conversion of dibutylamine were estimated
by GC using biphenyl as an internal standard. In the case of di-n-butylamine, the
calibration equation with the correlation coefficient of 0.99825 was obtained as
y ¼ 1.34311 þ 0.09895; the calibration equation for butyl dibutylcarbamate was
determined to be y ¼ 0.64977 þ 0.04468 and the correlation coefficient was 0.99954.
The calibration equation with the correlation coefficient of 0.99928 was found to be
y ¼ 1.32519 þ 0.0587 for tri-n-butylamine. The reaction mixture was extracted with
diethyl ether (20 mL), and the organic layer was washed with water (10 mL) and
brine (30 mL) and dried over anhydrous sodium sulfate. Evaporation of solvent
followed by column chromatography afforded the carbamate. The products were
further identified by NMR (see Supplementary Information, available online), which
[
19]
are consistent with those reported in the literature and are in good agreement with
the assigned structures.
Characterization Data
1
Butyl dibutylcarbamate. H NMR (CDC13, 400 MHz) d ¼ 4.03 (t,
1
3
l
J ¼ 6.6 Hz, 2H), 3.16 (br, 4H), 1.59–1.23 (m, 12H), 0.90 (t, J ¼ 7.3 Hz, 3H). C f Hg
NMR (CDCl , 100.6 MHz) d ¼ 156.7, 64.9, 47.0, 30.9, 30.6, 19.9, 19.1, 13.7, 13.6.
3

3304
D.-L. KONG, L.-N. HE, AND J.-Q. WANG
1
Butyl diethylcarbamate. H NMR (CDC13, 400 MHz) d ¼ 4.04 (t,
J ¼ 6.5 Hz, 2H), 3.36 (d, 4H), 1.62–1.55 (m, 2H), 1.39–1.33 (m, 2H), 1.08 (t,
1
3
1
J ¼ 7.2 Hz, 6H), 0.90 (t, J ¼ 7.3 Hz, 3H). C f Hg NMR (CDCl , 100.6 MHz)
3
d ¼ 156.4, 65.0, 41.4, 30.9, 19.0, 13.6.
1
Butyl phenylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 7.05–7.41 (m,
3
5
0
1
H), 6.67 (br, N-H), 4.17–4.20(t, 2H), 1.64–1.71 (m, 2H), 1.39–1.48 (m, 2H),
1
3
1
.95–0.99 (t, 3H). C f Hg NMR (CDCl , 100.6 MHz) d ¼ 153.7, 138.0, 129.0,
3
23.3, 118.6, 65.1, 30.9, 19.0, 13.7.
1
Butyl cyclohexylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 4.70 (br,
3
N-H), 4.00 (2H), 3.40 (1H), 1.87 (2H), 1.65 (2H), 1.53 (3H), 1.31 (4H), 1.10 (3H),
.88 (3H). C f Hg NMR (CDC1 , 100.6 MHz) d ¼ 156.0, 64.4, 49.7, 33.3, 31.0,
1
3
l
0
2
3
5.3, 24.6, 18.9, 13.6.
1
Butyl butylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 4.71 (br, N-H),
3
1
3
l
4
1
.03 (2H), 3.15 (2H), 1.56–1.33 (m, 8H), 0.90–0.89 (6H). C f Hg NMR (CDC1 ,
3
00.6 MHz) d ¼ 156.9, 64.8, 40.7, 32.0, 31.0, 19.8, 19.0, 13.6.
1
Octyl dibutylcarbamate. H NMR (CDC13, 400 MHz) d ¼ 4.00 (t,
J ¼ 6.6 Hz, 2H), 3.15 (br, 4H), 1.41–1.59 (m, 6H), 1.18–1.31 (m, 14H), 0.81–0.90
1
3
1
(
2
m, 9H). C f Hg NMR (CDCl , 100.6 MHz) d ¼ 156.4, 65.0, 47.0, 31.7, 29.1,
3
9.0, 25.9, 22.5, 20.0, 13.9, 13.7.
Methyl dibutylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 53.65 (s, 3H),
1
3
1
3
1
3
(
.14 (m, 4H), 1.48 (m, 4H), 1.24–1.31 (m, 4H), 0.88–0.92 (t, 3H). C f Hg NMR
CDCl , 100.6 MHz) d ¼ 156.8, 52.2, 46.6, 30.5, 20.0, 13.8.
3
1
Ethyl dibutylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 4.05–4.10 (m,
3
2
0
1
H), 3.15 (m, 4H), 1.44–1.47 (m, 4H), 1.24–1.28 (m, 4H), 1.19–1.22 (t, 3H),
.86–0.90 (t, 3H). C f Hg NMR (CDCl , 100.6 MHz) d ¼ 156.3, 60.7, 46.9, 30.6,
1
3
1
3
9.9, 14.6, 13.7.
1
Allyl dibutylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 5.89–5.96 (m,
3
1
1
H), 5.16–5.30 (m, 2H), 4.56–4.58 (m, 2H), 3.20–3.22 (m, 4H), 1.47–1.54 (m, 4H),
1
3
1
.28–1.34 (m, 4H), 0.90–0.93 (t, 6H). C f Hg NMR (CDCl , 100.6 MHz)
3
d ¼ 156.0, 133.4, 116.7, 65.6, 47.2, 30.7, 20.0, 13.8.
1
Benzenyl dibutylcarbamate. H NMR (CDC1 , 400 MHz) d ¼ 7.30–7.36
3
(
0
1
m, 5H), 5.13 (s, 2H), 3.23–3.24 (m, 4H), 1.51 (m, 4H), 1.26–1.34 (m, 4H),
1
3
1
.91–0.95 (m, 6H). C f Hg NMR (CDCl , 100.6 MHz) d ¼ 156.1, 137.1, 128.3,
3
27.7, 127.6, 66.7, 46.6, 30.2, 20.0, 13.8.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China
Grant Nos. 20421202, 20672054 and 20872073), the 111 Project (B06005), and
(
the Committee of Science and Technology of Tianjin is gratefully acknowledged.

SYNTHESIS OF ORGANIC CARBAMATES
3305
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1
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2
3
. For selected examples using carbamates as key intermediates or as protecting groups, see
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2
of crownethers. Tetrahedron 1992, 48, 1515–1530.
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4
5
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