ORGANIC
LETTERS
2013
Vol. 15, No. 3
632–635
Solvent-Free Synthesis of r‑Amino
Nitrile-Derived Ureas
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Pilar Ventosa-Andres, Juan A. Gonzalez-Vera, M. Teresa Garcıa-Lopez, and
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ꢀ
´
Rosario Herranz*
´ ꢀ
Instituto de Quımica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
Received December 17, 2012
ABSTRACT
An efficient and environmentally friendly methodology for the solvent-free synthesis of R-amino nitrile derived ureas from R-amino acid based
amino nitriles has been developed. At room temperature no epimerization was observed in the resulting ureas, but under microwave heating,
epimerization occurred at the chiral center bearing the cyano group.
R-Amino nitriles are versatile intermediates for the
synthesis of multiple building blocks.1 In particular,
R-amino acid derived amino nitriles have shown high
potential for molecular diversity generation.2 Thus, we
have shown their utility in the synthesis of pseudopeptides3
and diverse chiral heterocyclic compounds.4
Among R-amino nitrile derivatives, N-acyl-amino-
nitriles have proven to be important molecules for the
search of inhibitors of therapeutically important peptidases,5
such as dipeptidyl peptidase IV,6 prolyl oligopeptidases,7
and cysteine cathepsins.8 More concretely, several R-amino
nitrile derived ureas have been patented as inhibitors of
cholesteryl ester transfer protein9 and diverse enzymes,10
agents for neurological disorders,11 pesticides,12 or
fungicides.13 On the other hand, R-amino nitrile derived
ureas are intermediates in the synthesis of diverse phar-
macologically active hydantoin derivatives from R-amino
nitriles,14 although these intermediates have not been
isolated and characterized. Therefore, the development
of simple and versatile methods for the synthesis and
identification of N-(cyanomethyl)ureas is an important
goal in synthetic organic chemistry, in particular, envi-
ronmentally friendly solvent-free procedures.
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(b) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947–6983.
In the context of a medicinal chemistry project focused on
the search for modulators of proteinÀprotein interactions,
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(2) Gonzalez-Vera, J. A.; Garcıa-Lopez, M. T.; Herranz, R. Mini-
´
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ꢀ
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~
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r
10.1021/ol303452r
Published on Web 01/15/2013
2013 American Chemical Society