commonly synthesized by reaction of an amine with
phosgene14 or carbamates.15 Use of phosgene or phosgene
surrogates14,16 is still regarded as the traditional method
for the formation of ureas, at least in industry. This
approach is particularly efficient for symmetrical ureas.
However, in the case of nonsymmetrical ureas, the
synthetic efficiency is limited by the formation of symmet-
rical urea side products. Another method of choice for
urea formation is the coupling of an alkyl or aryl carba-
mate with an amine.15 In this case, the reaction is re-
versible and may not reach completion.17 Herein we
report a very convenient method for the synthesis of un-
symmetrical ureas based on isopropenyl carbamates.
Upon reaction with an amine, isopropenyl carbamate
liberates acetone enol, which quickly tautomerizes to
acetone and enables the reaction to go to completion. The
method works well, is extremely clean and is ideal for
the rapid synthesis of compound libraries, because simple
evaporation of all volatiles yields the product in a high
level of purity.
Practical Synthesis of Unsymmetrical
Ureas from Isopropenyl Carbamates
Isabelle Gallou,* Magnus Eriksson, Xingzhong Zeng,
Chris Senanayake, and Vittorio Farina
Department of Chemical Development,
Boehringer Ingelheim Pharmaceutical, Inc.,
900 Ridgebury Road, Ridgefield, Connecticut, 06877
Received April 15, 2005
A very convenient method for the synthesis of unsym-
metrical ureas is described, based on isopropenyl carbam-
ates. The synthetic efficiency of traditional methods for urea
formation, such as use of phosgene or alkyl and aryl
carbamates, is limited by the formation of symmetrical urea
side products or reaction reversibility. Isopropenyl carbam-
ates react with amines cleanly and irreversibly and give
unsymmetrical ureas in high yield and purity. This method
is ideal for the rapid synthesis of compound libraries.
We initially compared the triphosgene and the “acti-
vated carbamate” routes to the isopropenyl carbamate
reaction for the synthesis of unsymmetrical urea 1, to
gauge the efficiency of our method vs that of well-
established procedures (Scheme 1).
Addition of 1-naphthylamine to isocyanate 3, formed
in situ by reaction of amine 2 with triphosgene,16 led to
(4) The plethora of methods to prepare ureas include reaction of an
amine with carbonates,5 N,N′-carbonyldiimidazole,6 1,1′-carbonylbis-
benzotriazole,7 S,S-dimethylthiocarbonate,8 S-methylthiocarbamates,9
formamides,10 and isocyanates.11 Ureas have also been prepared by
metal-catalyzed carbonylation of amines using carbon monoxide12 or
carbon dioxide.13
Ureas are frequently encountered subunits of synthetic
targets with a wide range of applications in agrochemi-
cals, petrochemicals, and pharmaceuticals. Used as hair
dyes, additives in hydrocarbon fuels, detergents, and
polymers, corrosion inhibitors, and more, ureas have also
been shown to display significant biological activities as
plant growth regulators.1 Recently, potent urea-contain-
ing HIV-1 protease inhibitors2 and p-38 MAP kinase
inhibitors3 have been disclosed. Despite the growing
number of synthetic methodologies,4-13 ureas are most
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10.1021/jo0507643 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/27/2005
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J. Org. Chem. 2005, 70, 6960-6963