BMIm HCO3: an ionic liquid with carboxylating properties. Synthesis of carbamate esters from amines

Article abstract of DOI:10.1039/c6nj02705a

1-Butyl-3-methylimidazolium hydrogen carbonate (BMIm HCO₃) was used as an ionic liquid with carboxylating properties able to convert, in the presence of an alkyl halide, amines into the corresponding carbamate esters. Moderate to good yields of

Full text of DOI:10.1039/c6nj02705a

NJC
View Article Online
View Journal
LETTER
BMIm HCO3: an ionic liquid with carboxylating
properties. Synthesis of carbamate esters from
amines†
Cite this:DOI: 10.1039/c6nj02705a
Received (in Nottingham, UK)
29th August 2016,
A. Di Nicola, A. Arcadi and L. Rossi*
Accepted 11th October 2016
DOI: 10.1039/c6nj02705a
www.rsc.org/njc
1-Butyl-3-methylimidazolium hydrogen carbonate (BMIm HCO3) room-temperature ionic liquids (RTILs), because of their low
was used as an ionic liquid with carboxylating properties able to vapor pressure, chemical and thermal stability, solvating ability,
convert, in the presence of an alkyl halide, amines into the corres- non-flammability, and ability to act as catalysts, have been
ponding carbamate esters. Moderate to good yields of carbamates frequently used as ‘‘green’’ reaction media in clean organic
were obtained according to the nature of the amine and the synthetic processes as substitutes for conventional toxic and
alkylating agent.
volatile solvents.8 Recently we used ionic liquids as valuable
substitutes of the classical solvent-supporting electrolyte systems
Organic carbamates1 are a class of compounds of great interest (SSES) in carbon dioxide mediated electrochemical synthesis of
in different fields of organic synthesis; they found wide use as carbamates.9
synthetic intermediates and biologically active compounds
Starting from these considerations and making use of our
(anticancer, antibacterial, antimalarial, antidiabetic, antioxidant, previous experience, we decided to develop a new method for the
anti-inflammatory, antitubercular, antiprogestational, anti-HIV, synthesis of organic carbamates that made use of an ionic liquid
anticoagulant, antiestrogenic compounds). They are also largely that can act both as a solvent and as a carboxylating reagent.
used as agrochemicals (herbicides, pesticides, insecticides, In order to achieve this target, we assumed to use an ionic liquid
fungicides), pharmaceuticals and in synthetic chemistry. Their having a hydrogen carbonate ion as an anion.
use as protective groups2 for the amine function of amino acids
or pesticides3 is probably the most extensive application.
Herein, we report a simple and safe methodology for the
synthesis of alkyl and aryl carbamates by reaction of amines with
In recent years many synthetic routes have been proposed to butylmethylimidazolium hydrogen carbonate (BMIm HCO3).
replace the ‘‘classical syntheses’’ involving the use of toxic and
harmful reagents such as phosgene and isocyanates.4
Imidazolium hydrogen carbonates were recently used as cata-
lysts in the carbonylation reaction of amines to formamides,10
Our research group proposed, in the last few years, several in the conversion of CO2 to cyclic carbonates from epoxides,11
syntheses of organic carbamates based on safe methodologies in the conversion of nitriles to amides,12 as stable precursors of
using carbon dioxide or a reagent derived from carbon dioxide N-heterocyclic carbenes13 or as intermediates in the synthesis
itself. In particular, we proposed the synthesis of carbamate esters of several halide-free ILs.14
by reaction of aliphatic and aromatic amines with carboxylating
At first, we synthesized BMIm HCO3 through the classical
reagents such as tetraethylammonium carbonate (TEAC)5 or anion metathesis reaction of BMIm halides with alkali metal
tetraethylammonium hydrogen carbonate (TEAHC)6 or mediated hydrogen carbonates14 or carbonates.10,15 The unsatisfactory
by electrochemical methodologies.7
results obtained in terms of product purity led us to develop a
The growing demand for environment friendly technologies new procedure for the synthesis of desired IL using ion-exchange
operating in accordance with the principles of green chemistry resins.16 The synthesis of BMIm HCO3, based on the use of an
prompted us to develop new clean, safe and sustainable method- ion-exchange resin, was set up. DowexTM MonosphereTM 550A, a
ologies for the synthesis of organic carbamates. In recent years, strong base anion exchange resin in the OH form, was chosen to
perform a double anion substitution. First, the resin was treated
with an aqueous solution of sodium hydrogen carbonate
Department of Physical and Chemical Sciences, University of L’Aquila,
(1.0 mol LÀ1) in order to switch hydroxide with hydrogen carbonate
Via Vetoio snc. Coppito I-67100, L’Aquila, Italy. E-mail: leucio.rossi@univaq.it;
À
anions. Then, treatment of the resin in the HCO3 form with a
Tel: +39 0862 434246
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj02705a methanol solution of butylmethylimidazolium chloride (BMIm Cl)
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016
New J. Chem.

View Article Online
Letter
NJC
affords very good yield of carbamate as amines 1e–f do. Reaction
with secondary amines 1g–h (entries 7 and 8) gave very good
reaction yields of carbamates too, but in the case of N-methyl-
cyclohexylamine (1h), several difficulties in the extraction and
purification of product 3h were encountered and only 20% yields
of an isolated product was obtained. Less basic substrates such
as anilines gave, as expected, poor yields of carbamates (entries 9
and 10). Change of the alkylating reagent does not substantially
affect the reaction yields; benzyl bromide 2b reacts with cyclo-
hexylamine only in moderate yields (48% entry 11) while reaction
with 3-phenylpropyl bromide 2c affords the corresponding
carbamate in 70% yield (entry 12).
Fig. 1 Synthesis of BMim HCO3 starting from DowexTM MonosphereTM
550A.
The reaction is supposed to proceed through the formation
of the imidazolium carbamate by reaction of the amine with
BMIm HCO3. Then, the addition of the alkyl halide leads to the
formation of the alkyl carbamate.
Scheme 1 Reaction of cyclohexylamine with BMIm HCO3.
In order to investigate the effect of the ‘‘onium’’ cation
structure on the carboxylation reaction, tetrabutyl phosphonium
hydrogen carbonate (TBP HCO3) was synthesized using the same
procedure as that used for BMIm HCO3. In a test reaction carried
out using amine 1a and ethyl iodide 2a carbamate 3a was obtained
with reaction yields of 80% showing that the nature of the
‘‘onium’’ cation does not affect the outcome of the reaction.
In conclusion, we propose a new clean and safe methodology
for the synthesis of organic carbamates starting from amines,
BMIm HCO3 and an alkylating reagent. The method avoids the
use of any volatile and/or toxic solvent or catalyst. The synthesis
was carried out under mild reaction conditions and carbamates
were isolated in moderate to high yields. The reaction was
carried out in a medium with the twofold function of the solvent
and reagent. In addition, a new procedure for the synthesis
of BMIm HCO3 starting from an anionic resin was projected
and set-up.
allows the second anionic switch and the synthesis of the desired
ionic liquid. BMIm HCO3 was collected, dried and used, according
to the scheme proposed in Fig. 1. The resin in the Cl form was
then treated with NaOH 8%w/w and recycled.
To test the effectiveness of BMIm HCO3 as a carboxylating
agent, cyclohexylamine was used as a model compound, while
ethyl iodide was used as the alkylating reagent according to the
general scheme.
As reported in Scheme 1, the reaction was firstly carried out
by mixing 1.0 mmol of cyclohexylamine with 0.5 mL of BMIm
HCO3. The reaction was conducted at different reaction times
at room temperature, after that, an excess of ethyl iodide was
added to the reaction mixture that was stirred for 2 hours and
then worked up.
The results reported in Table 1 show that the best reaction
yields are obtained when the reaction was carried out at 55 1C
for 5 h (entry 6).
In order to verify the feasibility of the reaction, several experi-
ments were carried out using different amines and alkylating
reagents under the optimized reaction conditions. The results are
reported in Table 2.
Reaction yields are very good when primary amines react
with ethyl iodide (entries 1–7); cyclic primary amines (entries 1–3)
afford carbamates in very good yields. Also benzylic amine (entry 4)
Experimental
General
All commercially available reagents were used without further
purification unless otherwise stated. Reactions were monitored
by analytical thin-layer chromatography (TLC) using silica gel
60 F254 precoated glass plates (0.25 mm thickness) and visualized
using UV light, iodide, and a molybdate reagent.
Table 1 Reaction of cyclohexylamine with BMIm HCO3 under different
Flash column chromatography was performed on a silica gel
(230–400 mesh). 1H NMR and 13C NMR were recorded on a 400 MHz
reaction conditionsa
1
Yieldb (%)
nuclear magnetic resonance spectrometer (400 MHz for H NMR
Entry
T (1C)
t (h)
and 100 MHz for 13C NMR).
1
2
3
4
5
6
7
25
25
25
25
25
45
55
2
3
4
5
6
5
5
15
22
30
35
39
78
81
Synthesis of BMIm HCO3
An 8%w/w solution of sodium hydroxide (200 ml) was percolated
through a column filled in with DOWEXTM MONOSPHERETM
550A (OH) (60 g; capacity 1.1 eq. per L). The resin was then washed
a
1.0 mmol of cyclohexylamine was added to 0.5 mL of BMIm HCO3. with water until neutrality. Then a 1.0 M solution of sodium
The mixture was stirred at the desired temperature for the appropriate
hydrogen carbonate (300 ml) was passedÀthrough the column,
time, after that 3.0 mol of EtI were added. The reaction with EtI is
until the exchange of OHÀ ions to HCO3 (pH was monitored
usually completed in 2 h. Lower yields were obtained when the reaction
b
is worked up in minor times. Reaction yields refer to isolated products. during the switch). The column was then washed thoroughly
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016

View Article Online
NJC
Letter
Table 2 Synthesis of carbamates by reaction of amines with BMIm HCO3
with anhydrous methanol to remove any traces of water. An
anhydrous methanol solution of 1-buthyl-3-methyl imidazolium
chloride (5.0 g; 29 mmol) was passed through the column to
exchange the chloride ions with hydrogen carbonate ions. The
solvent was then evaporated under reduced pressure and the
product was collected and dried in vacuo for 3 hours at room
temperature.
and alkylating reagentsa
Alkyl
halide
Yieldb
(%)
Entry Amine
1
Carbamate
CH3CH2I
2a
81
81
83
Colorless oil. 1H NMR (400 MHz, CDCl3) d 0.95 (t, J = 7.3 Hz,
3H); 1.34–1.41 (m, 2H); 1.83–1.90 (m, 2H); 4.12 (s, 3H); 4.29
(t, J = 7.4 Hz, 2H); 7.28 (s, 1H); 7.54 (s, 1H); 10.52 (s, 1H).
13C NMR (100 MHz, CDCl3) d ppm 13.4; 19.4; 32.1; 36.4; 49.8;
121.5; 123.2; 137.3.11
2
3
2a
2a
General procedure for the synthesis of carbamates 3
A solution of amine 1 (1.0 mmol) and BMIm HCO3 (0.5 ml) was
stirred at 55 1C for 5 hours, then alkyl halide 2 was added
(3.0 mmol) at room temperature for 2 hours. The crude reaction
mixture was then extracted with diethyl ether (5 Â 5 ml) and
dried under reduced pressure. The residue was, in the case,
purified by flash column chromatography.
4
5
6
2a
2a
2a
72
73
70
3-Phenylpropyl cycloethylcarbamate (3l)
1
White solid (183 mg, 70%; mp 57–59 1C). H NMR (400 MHz,
CDCl3): d 1.11–1.25 (m, 4H); 1.33–1.42 (m, 2H); 1.60–1.76 (m, 4H);
1.90–2.00 (m, 2H, OCH2CH2CH2); 2.71(t, J = 7.0 Hz, 2H,
OCH2CH2CH2); 3.50–3.53 (m, 1H, CHNH); 4.11 (t, J = 6.9 Hz, 2H,
OCH2CH2); 4.72 (br, s, 1H, NH); 7.20–7.33 (m, 5H). 13C (100 MHz,
CDCl3): d 155.9; 141.5; 128.4; 128.3; 125.9; 64.0; 49.8; 33.5; 32.2;
30.8; 25.5; 24.9. MS m/z 41, 65, 91, 118, 261 (M+); IR (KBr): 3326,
2936, 2854, 1685, 1536 cmÀ1
.
7
2a
82
Anal. calcd for C16H23NO2: C, 75.53; H, 8.87; N, 5.36. Found:
C, 75.35; H, 8.81; N, 5.35%.
8
9
2a
2a
20
17
Notes and references
1 (a) P. Adams and F. A. Baron, Chem. Rev., 1965, 65, 567;
(b) L. Rossi, Science of Synthesis: Houben-Weyl Methods
of Molecular Transformations, in Science of Synthesis,
ed. J. G. Knight, 2005, vol. 18, pp. 461–646.
2 P. G. M. Wuts, Greene’s Protective Groups in Organic Syn-
thesis, John Wiley & Sons, Inc., Hoboken, New Jersey, 2014,
pp. 907–989.
10
2a
26
3 R. P. Pohanish, Sittig’s Handbook of Pesticides and Agricultural
Chemicals, William Andrew, Inc., Waltham, USA, 2015.
4 (a) D. Chaturvedi, Tetrahedron, 2012, 6, 15; (b) D. Chaturvedi,
Curr. Org. Chem., 2011, 15, 1593.
5 M. A. Casadei, A. Inesi, F. Micheletti Moracci and L. Rossi,
Chem. Commun., 1996, 2575.
6 A. Inesi, V. Mucciante and L. Rossi, J. Org. Chem., 1998, 63, 1337.
7 (a) M. A. Casadei, F. Micheletti Moracci, G. Zappia, A. Inesi
and L. Rossi, J. Org. Chem., 1997, 62, 6754; (b) M. Feroci,
A. Inesi and L. Rossi, Tetrahedron Lett., 2000, 41, 963.
8 (a) J. Dupont, T. Itoh, D. Lozano and S. V. Malhotra, Environ-
mentally Friendly Syntheses Using Ionic Liquids, CRC Press,
Boca Raton, 2015; (b) in Handbook of Green Chemistry,
PhCH2Br
2b
11
1a
1a
48
70
Ph(CH2)3Br
2c
12
a
1.0 mmol of amine was added to 0.5 mL of BMIm HCO3. The reaction
was maintained at 55 1C for 5 h, then 3.0 mmol of the desired alkyl
halides were added. Reaction yields refer to an isolated product.
b
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016
New J. Chem.

View Article Online
Letter
NJC
`
Ionic Liquids, ed. P. Wasserscheid and A. Stark, WILEY-VCH 13 (a) M. Fevre, P. Coupillaud, K. Miqueu, J.-M. Sotiropoulos,
Verlag GmbH & Co. KGaA, Weinheim, 2010, vol. 6.
9 M. Feroci, M. Orsini, L. Rossi, G. Sotgiu and A. Inesi, J. Org.
Chem., 2007, 72, 200.
J. Vignolle and D. Taton, J. Org. Chem., 2012, 77, 10135;
`
(b) M. Fevre, J. Pinaud, A. Leteneur, Y. Gnanou, J. Vignolle,
D. Taton, K. Miqueu and J.-M. Sotiropoulos, J. Am. Chem.
Soc., 2012, 134, 6776.
10 Y.-S. Choi, Y. N. Shim, J. Lee, J. H. Yoon, C. S. Hong,
M. Cheong, H. S. Kim, H. G. Jang and J. S. Lee, Appl. Catal., 14 S. Koguchi and K. Nakamura, Synlett, 2013, 2305.
A, 2011, 404, 87.
15 Z. Deng, J. Guo, L. Qiu, Y. Zhou, L. Xia and F. Yan, Polym.
Chem., 2012, 3, 2436.
16 M. Zanatta, A.-L. Girard, N. M. Simon, G. Ebeling, H. K.
Stassen, P. R. Livotto, F. P. dos Santos and J. Dupont, Angew.
Chem., Int. Ed., 2014, 53, 12817.
11 A.-L. Girard, N. Simon, M. Zanatta, S. Marmitt, P. Gonçalves
and J. Dupont, Green Chem., 2014, 16, 2815.
12 P. K. Verma, U. Sharma, M. Bala, N. Kumar and B. Singh,
RSC Adv., 2013, 3, 895.
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016