ORGANIC
LETTERS
2010
Vol. 12, No. 6
1340-1343
Parallel Synthesis of Ureas and
Carbamates from Amines and CO2
under Mild Conditions
Scott L. Peterson,* Sabrina M. Stucka, and Christopher J. Dinsmore
Department of Chemistry, Merck Research Laboratories, 33 AVenue Louis Pasteur,
Boston, Massachusetts 02115
Received February 1, 2010
ABSTRACT
A mild and efficient library synthesis technique has been developed for the synthesis of ureas and carbamates from carbamic acids derived
from the DBU-catalyzed reaction of amines and gaseous carbon dioxide. Carbamic acids derived from primary amines reacted with Mitsunobu
reagents to generate isocyanates in situ which were condensed with primary and secondary amines to afford the desired ureas. Similarly,
carbamic acids from secondary amines reacted with alcohols activated with Mitsunobu reagents to form carbamates.
The structure-activity relationships (SAR) of urea and
carbamate-containing bioactive compounds are often ex-
plored in the development of pharmaceutically active agents.1
Typically, efficient synthesis of the urea functional group is
achieved through the condensation of an amine with an
isocyanate2 or the coupling of amines with phosgene or a
phosgene equivalent.3 Given the limited number of com-
mercially available isocyanates and the toxicities related to
the use of phosgene, an alternative environmentally benign
and high-throughput synthesis technique for the construction
of ureas is desirable.
utilized for the synthesis of isocyanates,5 carbamates,6 and
ureas.7 However, while the potential versatility of this
chemistry is clear, the scope of amenable building blocks
has not been defined sufficiently to predict a successful
parallel synthesis approach. Here, we have optimized and
expanded the scope and efficiency of this reaction to be
amenable to library synthesis. This method allows for the
rapid SAR development of compounds containing ureas or
carbamates.
Initially, we investigated the parallel synthesis of unsym-
metrical disubstituted ureas. Using a Bohdan MiniBlock
The chemistry of carbamic acids derived from the reaction
of amines with carbon dioxide gas has been established4 and
(4) Hampe, E. M.; Rudkevich, D. M. Tetrahedron 2003, 59, 9619.
(5) (a) Horvath, M. J.; Saylik, D.; Elmes, P. S.; Jackson, W. R.; Lovel,
C. G.; Moody, K. Tetrahedron Lett. 1999, 40, 363. (b) Waldmann, T. E.;
McGhee, W. D. J. Chem. Soc., Chem. Commun. 1994, 957.
(6) Using alkyl halides as electrophiles: (a) McGhee, W.; Riley, D.;
Christ, K.; Pan, Y.; Parnas, B. J. Org. Chem. 1995, 60, 2820. (b) Hooker,
J. M.; Reibel, A. T.; Hill, S. M.; Schueller, M. J.; Fowler, J. S. Angew.
Chem., Int. Ed. 2009, 48, 3482. Using Mitsunobu’s reagents at elevated
temperature: Chaturvedi, D.; Mishra, N.; Mishra, V. Montash. Chem. 2007,
138, 57.
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10.1021/ol100259j 2010 American Chemical Society
Published on Web 02/22/2010