Preparation of carbamates from amines and alcohols under mild conditions

Article abstract of DOI:10.1016/S0040-4039(01)00991-1

The practical and mild preparation of carbamates in a two-component system is described. The smooth reaction of an alcohol with 1,1′-carbonyldiimidazole, followed by subsequent trapping with an amine represents a safe replacement for phosgene derivatives.

Full text of DOI:10.1016/S0040-4039(01)00991-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5227–5229
Preparation of carbamates from amines and alcohols
under mild conditions
David D’Addona and Christian G. Bochet*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Received 10 April 2001; revised 19 April 2001; accepted 11 June 2001
Abstract—The practical and mild preparation of carbamates in a two-component system is described. The smooth reaction of an
alcohol with 1,1%-carbonyldiimidazole, followed by subsequent trapping with an amine represents a safe replacement for phosgene
derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
amine function, we were faced with the issue of prepar-
ing numerous carbamates under especially mild condi-
tions. To date, the two general procedures for
preparing carbamates are either the reaction of amines
with a chloroformate,8 or of alcohols with an isocya-
nate.9 The preparation of chloroformates or isocyanate
frequently requires aggressive reagents and/or condi-
tions, and the use of triphosgene 3 consistently failed in
our hands. We describe here a convenient preparation
of carbamates under mild conditions, with very high
yields and no purification other than aqueous washing.
1. Introduction
Phosgene (1) is potentially a very versatile building
block for organic synthesis.1 It offers the possibility of
binding two nucleophilic units to the same carbon
atom, and such a two-component system is particularly
well suited for the combinatorial synthesis of carbon-
ates, ureas or carbamates (Scheme 1). Although phos-
gene is industrially produced and used, its gaseous
nature and extreme toxicity often prevent its use in
research laboratories. Safer substitutes have been pro-
posed. 1,1,1-Trichloromethyl chloroformate (diphos-
gene, 2)2 and bis(1,1,1-trichloromethyl)carbonate
(triphosgene, 3)3 are frequently used. A most interesting
study by React-IR monitoring has recently shown that
chloride ions could catalyze the depolymerization of 3
into 1,4 and it is now widely accepted that triphosgene
can replace phosgene in most cases. A much safer
substitute is 1,1%-carbonyldiimidazole, which cannot
form phosgene under reasonable conditions.5 On the
other hand, the higher pKa of imidazole makes this
species significantly less reactive than phosgene, allow-
ing clean successive reactions.6,7
2. Results and discussion
The reaction of an alcohol with 1,1%-carbonyldiimida-
zole is well known to give an imidazolide with the
release of one equivalent of imidazole, as has recently
been demonstrated in the synthesis of mixed carbon-
ates.10 We anticipated that this moderately reactive
intermediate would be easily trapped by an amine,
without requiring an additional base. We tested this
reaction with various benzylic alcohols and dodecyl-
amine (Scheme 2). In all cases, the yields were higher
than 85% (Table 1).
As part of our program directed towards the develop-
ment of new photolabile protecting groups for the
O
O
Cl
Cl
O
Cl
O
O
Cl
Cl
Cl
Cl
Cl
Cl
R2
R1
R1NH2
HOR2
+
+
Cl
Cl
Cl
O
O
O
N
H
O
X
X
1
2
3
Scheme 1.
Keywords: carbamates; phosgene; two-component system; protecting groups.
* Corresponding author. Fax: +41 22 328 7396; e-mail: christian.bochet@chiorg.unige.ch
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00991-1

5228
D. D’Addona, C. G. Bochet / Tetrahedron Letters 42 (2001) 5227–5229
1) CDI/CH2Cl2
2) n-C12H25NH2
R1
R4
R1
R4
R2
R3
R2
R3
H
N
OH
O
85-95%
C12H25
O
Scheme 2.
NO2
O
NO2
OH
1) CDI
H
N
2) 2 / NEt3
Cl
NHBoc
Cl
O
87%
1) CF3COOH
2) 2,4-(NO2)2C6H3CH2OH/CDI
79%
HCl.H2N
NHBoc
2
NO2
O
O
H
N
Cl
N
H
O
O
O2N
NO2
Scheme 3.
Table 1.
gave similar results as those obtained by separate
syntheses.
Entry
R1
R2
R3
R4
Yield (%)
The same procedure was also applied for the protection
of diamines, as shown in Scheme 3. The commercially
available hydrochloride 2 was condensed (as its free
base upon treatment with triethylamine) with the imi-
dazolide derived from 5-chloro-2-nitrobenzyl alcohol in
excellent yield. Liberation of the Boc group under
acidic conditions was followed by the condensation
with the 2,4-dinitrobenzyl alcohol and carbonyldiimida-
zole to give the desired bis carbamate. The overall yield
of the process was around 70%.
1
2
3
4
5
6
7
8
9
SO2Ph
SO2Ph
NO2
H
NO2
NO2
NO2
NO2
NO2
H
MeO
MeO
MeO
H
H
Cl
MeO
H
H
H
H
H
H
H
H
Me
H
H
100
88
94
95
94
91
89
89
83
MeO
MeO
NO2
NO2
H
MeO
Cl
Br
In conclusion, we could prepare a series of carbamates
by the simple successive mixing of an alcohol and
1,1%-carbonyldiimidazole, and an amine. Using our
standard protocol, only primary or benzylic alcohols
were found satisfactory, whereas the amine could be
primary or secondary. This method is well suited for
parallel or combinatorial synthesis. To illustrate this
feature, we prepared a small library of carbamates
using standard laboratory equipment.
In a typical procedure (Table 1, entry 1), carbonyldiim-
idazole (30 mg, 0.18 mmol) was suspended in anhy-
drous dichloromethane (0.5 ml) and the mixture was
cooled to 0°C. 5-Methoxy-2-phenylsulfonylbenzyl alco-
hol (50 mg, 0.18 mmol) was slowly added as a solution
in dichloromethane (0.5 ml). The mixture was stirred at
room temperature for 1 h. The amine was added (33
mg, 0.18 mmol) and the mixture was stirred at room
temperature for 6 h. Ethyl acetate was added, and the
mixture was washed four times with HCl 10%, and
once with brine. The organic layer was dried over
MgSO4, filtered and evaporated to give the pure carba-
mate as a white solid (90 mg, 100%).
Acknowledgements
This work was supported by the Swiss National Science
Foundation Grant 2100-57044.99, and by the Fonds
Fre´de´ric Firmenich et Philippe Chuit. The generous
support of Professor A. Alexakis is gratefully
acknowledged.
This coupling is not limited to primary benzylic alco-
hols or primary amines, as shown by the entry 7, and
by the virtually quantitative reaction between n-pen-
tanol, CDI and piperidine. On the other hand, more
hindered alcohols such as menthol or tert-butanol gave
complex mixtures of products. The two-component
nature of this procedure is clearly well suited for paral-
lel synthesis; some of the reactions were also checked
on small-scale experiments, in a 4×4 array of 8 mm test
tubes. Micro-workups and direct analysis by GC-MS
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