Unprecedented "in water" imidazole carbonylation: Paradigm shift for preparation of urea and carbamate

Article abstract of DOI:10.1021/ol301009d

The first "In Water" imidazolecarbonylation of amine is described. A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates. Use of an anhydrous solvent and an inert atmosphere could be avoided. Product precipitate out from the reaction mixture and can be obtained in high purity by filtration, resulting in a simple and scalable method.

Full text of DOI:10.1021/ol301009d

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2814–2817
Unprecedented “In Water” Imidazole
Carbonylation: Paradigm Shift for
Preparation of Urea and Carbamate
Kamlesh J. Padiya,*,† Sandip Gavade,‡ Bhavana Kardile,† Manojkumar Tiwari,‡
Swapnil Bajare,† Madhav Mane,‡ Vivek Gaware,‡ Shaji Varghese,‡ Dipak Harel,‡ and
Suresh Kurhade‡
Department of Medicinal Chemistry, Nycomed Pharma Pvt. Ltd., 29-31 Suren Road,
Andheri east, Mumbai-400 092, India
kamleshpadiya@lupinpharma.com
Received April 20, 2012
ABSTRACT
The first “In Water” imidazolecarbonylation of amine is described. A one pot reaction of carbonylimidazolide in water with a nucleophile provides
an efficient and general method for the preparation of urea, carbamates and thiocarbamates. Use of an anhydrous solvent and an inert atmosphere
could be avoided. Product precipitate out from the reaction mixture and can be obtained in high purity by filtration, resulting in a simple and
scalable method.
Water is the most economic and eco-friendly solvent
available in nature. However, it is not a popular choice of
solvent for chemists,1 as most organic substances have
Scheme 1. “In Water” Reaction of Amine and CDI
poor solubility and many of the reagents are unstable in
water. Recently the concepts of “On Water”2 and “In
water”3 synthesis have achieved a great deal of attention
for their high efficiency and ease of process. Herein we
report a general and versatile method for preparing urea,
Urea and carbamate are important functional groups
carbamates, and thiocarbamates in an aqueous media.
found in pharmaceutical candidates,4 agrochemicals, and
material science.5 Although a number of methodologies,
such as oxidative carbonylation of amines6 and dialkyl
† Current address, Department of Medicinal Chemistry, Lupn Research
Park, Genesis Square, Hinjewadi Phase-II, Pune-411057, India
‡ Nycomed Pharma Pvt. Ltd.
(1) For general review, see: (a) Organic Synthesis in Water; Grieco,
P. A., Ed.; Springer: New York, 1997. (b) Clean Solvents: alternative Media
for Chemical Reactions and Processing; Abraham, M. A., Moens, L., Eds.;
ACS Symposium Series 819; American Chemical Society: Washington, DC,
2002. (c) Organic Reactions in Water; Lindstroem, U. M., Ed.; Blackwell:
Oxford, U.K., 2007.
(2) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
(3) (a) Shapiro, N.; Vigalok, A. Angew. Chem., Int. Ed. 2008, 47,
2849. (b) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 8,
3259.
(4) (a) Gallou, I. Org. Prep. Proc. Int. 2007, 39, 355. (b) McMorris,
T. C.; Chimmani, R.; Alisala, K.; Staake, M. D.; Banda, G.; Kelner,
M. J. J. Med. Chem. 2010, 53, 1109. (c) Maier, T.; Beckers, T.; Baer, T.;
Vennemann, M.; Gekler, V.; Zimmermann, A.; Gimmnich, P.; Padiya,
K.; Joshi, H.; Joshi, U.; Makhija, M.; Harel, D. U.S. Patent
20110021494. (d) Feng, Y.; Lograsso, P.; Schroeter, T.; Yin, Y. U.S.
Patent 200899642.
(5) (a) Kim, J.; Riju, D.; Rudolf., Z. J. Colloid Interface Sci. 2011,
359, 428.
(6) Diaz, D. J.; Darko, A. K.; White, L. M. Eur. J. Org. Chem. 2007,
4453.
r
10.1021/ol301009d
Published on Web 05/18/2012
2012 American Chemical Society

Table 1. Reaction of Amine with CDI in Watera
Table 3. Preparation of Carbamate by in Situ Generation of
Carbonylimidazole in Watera
a To the solution of amine (10 mmol) in water at 0 °C was added 1,10-
carbonyldiimidazole (12 mmol) in solid form. The reaction mixture was
stirred at 0 °C and monitored by TLC. b Isolated yield. c Reactions carried
out at rt gave similar results. d Starting amine recovered unchanged.
a CDI (12 mmol) was added to the solution of amine (10 mmol) in
water at 0 °C and monitored by TLC. The reaction mixture was then
warmed up to room temperature. Phenol or thiophenol (12 mmol) was
added. The reaction mixture was stirred at room temperature and was
monitored by TLC. b Isolated yield. c Thiophenol was used as a nucleo-
phile to react with carbonylimidazolide.
Table 2. Effect of Solvent on Preparation of Carbonylimidazo-
lide of Tetrahydroquinoline
based exchange processes,7 have been developed recently
for the synthesis of ureas and carbamates which are
environmentaly more benign, a standard method for rapid
library generation of urea and carbamate involves use of a
transfer reagent such as phosgene, triphosgene,4b 1,10-
carbonylimidazole,4b carbonylimidazolium salt,8 chloro-
formates, or some carbamoyl cation equivalent such as
entry
solvent
water
time
yield (%)
1
2
10 min
7 h
94
30
90
53
78
50
33
79
50
55
MeOH
tert-butanol
DMSO
DMF
3
75 min
80 min
40 min
16 h
4
5
6
dioxane
THF
7
90 min
90 min
65 min
16 h
(7) (a) Han, C.; Porco, J. A., Jr. Org. Lett. 2007, 9, 1517. (b) Leung,
M. K.; Lai, J. L.; Lau, K. H.; Yu, H. H.; Hsiao, H. J. J. Org. Chem. 1996,
61, 4175. (c) For general review on chemistry of dialkyl carbonates, see:
Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706. (d) Belfadhel, H. A.;
Brack, H.; Godoy-Lopez, R.; Willemse, D. J. P. M. U.S. Patent
20100113819.
8
CH3CN
CH2Cl2
toluene
9
10
Org. Lett., Vol. 14, No. 11, 2012
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Table 4. Preparation of Urea by in Situ Generation of Carbonylimidazole in Watera
a CDI (12 mmol) was added to the solution of amine (10 mmol) in water at 0 °C and monitored by TLC. The reaction mixture was then warmed up to room
temperature. The second amine (12 mmol) was added. The reaction mixture was stirred at room temperature and was monitored by TLC. b Isolated yield.
isocyanates4b or carbamoylchlorides. There are significant
drawbacks associated with many of these reagents. Carba-
moylchlorides and isocyanates have limited commercial
availability, whereas phosgene and triphosgene are
highly toxic and highly moisture sensitive making the
process more tedious. Among these 1,10-carbonyldiimida-
zole (CDI) is comparatively mild and the most widely used
reagent. However, CDI is moisture sensitive and is re-
ported to react with water with evolution of carbon
dioxide.9 We observed a complete decomposition of CDI
to imidazole in 10 min at 0 °C. CDI is known to react with
amines to give N-substituted 1H-imidazole-1-carbonyl-
(carbonylimidazolide), which can be converted to urea,
carbamate, or thiocarbamate. Preferred solvents for such
conversions are CH2Cl2, THF, or CH3CN preferably
under anhydrous conditions.9 We have investigated the
same reaction in water and found that CDI, though un-
stable in water, rapidly reacts with amine to give good yields
of respective imidazole-N-carboxamides (N-substituted
carbonylimidazolide) (Scheme 1). CDI mediated amidation
of unprotected R-amino acids10 and, recently, a solvent-free
CDI mediated amidation are reported.11 However, to the
best of our knowledge, there is no precedence for the
preparation or reaction of carbonylimidazolide in water.
CDI on treatment with the solution of benzylamine in
water at room temperature yielded symmetric urea. The
same reaction when carried out at low temperature (0 °C)
gave N-benzylcarbonylimidazolide (entry 2, Table 1) as a
sole product. Both, primary and secondary amines under-
go “In Water” imidazocarbonylation to give the corre-
sponding carbonylimidazolide. This method was used to
make a number of carbonylimidazolides (Table 1). In most
cases the product precipitates out from the reaction mixture.
The product could be isolated in pure form by just filtration.
It has been observed that an aromatic amine with a deac-
tivated ring does not undergo this reaction even at elevated
temperature (entries 9 and 10, Table 1). This could be
attributed to the low nucleophilicity of such amines.
The effect of solvent in the preparation of carbonylimi-
dazolide was studied by reacting tetrahydroisoquinoline
with CDI. As shown in Table 2, the reaction goes to
completion within 10 min with water as a solvent, which
is comparatively much faster than the reaction in other
solvents.
(8) (a) Grzyb, J. A.; Shen, M.; Ishii, Y.; Chi, W.; Brown, R. S.; Batey,
R. A. Tetrahedron 2005, 61, 7153. (b) Review on carbamate preparation:
Chaturvedi, D. Curr. Org. Chem. 2011, 15, 1593
(9) (a) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley: Chichester, 2005; Vol. 2, pp 1006ꢀ1010. (b) NMR of CDI
in D2O shaw complete decomposition of CDI at 0 °C in 10 min.
(10) Sharma, R. K.; Jain, R. Synlett 2007, 603.
Carbonylimidazolides obtained from primary amines
are less reactive as compared to CDI and do not undergo
(11) Verma, S. K.; Ghorpade, R.; Pratap, A.; Kaushik, M. P. Tetra-
hedron Lett. 2012, 53, 2373.
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Org. Lett., Vol. 14, No. 11, 2012

further substitution to yield symmetric urea at low tem-
peratures. Carbonylimidazolides obtained from secondary
amines are very stable and does not react further to give
urea, carbamate, or thiocarbamate. The method is there-
fore not suitable for the preparation of tetrasubstituted
ureas, and carbamates or thiocarbamates derived from
secondary amines. Adamantylamine under similar condi-
tions does not react with CDI to yield any product.
In water, hydrogen bonding of imidazole rings and the
carbonyl group of CDI with a water molecule makes the
carbonyl carbon highly electrophilic. Electron densities in
imidazole rings are reduced because of H-bonding, thereby
increasing the nucleofugality of the imidazole group. In
addition to this, the nucleophilic reactivity of amine is very
high in water compared to organic solvents.12 These
together explain the very high reaction rate of amine with
CDI in water as compared to the rate of decomposition of
CDI in water due to the nucleophilic attack by the water
molecule.
thiocarbamate (Table 3), and urea (Table 4). Alcohols, thiols,
and electron-deficient amines such as nitrobenzene do not
react with carbonylimidazolide under similar conditions.
In summary, we have developed an “in water” imidazo-
lecarbonylation reaction that provides a highly efficient
and general method for preparing ureas, carbamates, and
thiocarbamates, which essentially removes the usage of
anhydrous solvent and an inert atmosphere. The product
precipitates out from the reaction mixture and can be
obtained in high purity by filtration, making the method
simple and scalable. Water isaninexpensive, nontoxic, and
environmentally benign solvent. In addition, unique reac-
tivities observed in water can be regarded as a paradigm
shift where highly moisture sensitive reagent 1,10-carbo-
nyldiimidazole undergoes “in water” reaction. The results
discussed are unprecedented and add value to the current
knowledge of organic reactions in water.
Supporting Information Available. Experimental pro-
cedure and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Carbonylimidazolide derived from the primary amine
reactsinsituwith anucleophile suchasphenol, thiophenol,
and amine to give the corresponding carbamate (Table 3),
(12) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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