ORGANIC
LETTERS
2011
Vol. 13, No. 11
2818–2821
A Simple Copper-Catalyzed Synthesis of
Tertiary Acyclic Amides
Emilie Racine,† Florian Monnier,*,† Jean-Pierre Vors,‡ and Marc Taillefer*,†
ꢀ
Ecole Nationale Superieure de Chimie de Montpellier, Institut Charles Gerhardt, CNRS
UMR 5253, AM2N, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 05, and Bayer
CropScience SA, Rue Pierre Baizet, 69005 Lyon, France
florian.monnier@enscm.fr; marc.taillefer@enscm.fr
Received March 21, 2011
ABSTRACT
The N-arylation of aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, has been accomplished using a simple and
cheap copper catalytic system. The corresponding tertiary acyclic amides, which can be found in numerous biologically active compounds, have
been obtained in good to excellent yields.
Copper-catalyzed N-arylation of amides has been
known for over a century as the Goldberg reaction;1
however, its development continues to be extensively
investigated because improvements are still needed,
particularly concerning the scope of the reaction.2
Thus, the discovery of a general catalytic method allow-
ing the intermolecular N-arylation of secondary acyclic
amides,3 which are known to be poor nucleophilic
partners,4 is still challenging. For this reaction, only few
isolated examples involving either palladium or copper as
catalysts have been described until recently.4 This point
wasoutlinedina veryrecent workbased on anefficient cat-
alytic system with palladium/monophosphine (JackiePhos)
resulting in the synthesis of tertiary amides from aryl
halides and secondary amides.5 It is worth noting that
the latter, classically obtained by acylation reactions, are
found in numerous biologically active compounds and
intermediates in total synthesis.5
† Institut Charles Gerhardt.
‡ Bayer CropScience SA.
We report herein a Cu-catalyzed general method for
access to tertiary amides via intermolecular N-arylation of
secondary amides avoiding the use of palladium and so-
phisticated phosphine ligands. This system allows the
transformation, in an economical and ecological way, of
already existing secondary amides in tertiary ones with
an easy modulation of the aromatic component. It thus
constitutes an interesting method facilitating structureꢀ
activity relationship studies of these important targets in
life sciences.
First, a set of experiments was carried out using N-phenyl-
benzamide 1 (benzanilide) and iodobenzene 2 as model
substrates. These two coupling partners were reacted
in DMF at 130 °C in the presence of cesium carbonate as the
base, a catalytic amount of Cu2O (5%) as the copper
(1) (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (b)
Goldberg, I. Ber. Dtsch. Chem. Ges. 1907, 40, 4541.
(2) For recent reviews, see: (a) Monnier, F.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 6954. (b) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054.
(3) In this paper, we used the frequently encountered classification
for amides RCONR0R00: R0 = R00 = H for primary amides, R0 = H and
R00¼ H for secondary amides, R0 and R00¼ H for tertiary amides. It is
worth noting that following the IUPAC rules all these amides categories
correspond in fact to primary amides differently N,N-substituted,
(RCO)2NR0 and (RCO)3N being respectively secondary and tertiary
amides.
(4) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (b) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (c) Klapars, A.;
Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421. (d) Lange, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.; Osnaburg,
S. J. M.; Verveer, P. C.; Kruse, C. G.; Feenstra, R. W. Tetrahedron Lett.
2002, 43, 1101. (e) Deng, W.; Wang, Y. F.; Zou, Y.; Liu, L.; Guo, Q. X.
Tetrahedron Lett. 2004, 45, 2311. (f) Ikawa, T.; Barder, T. E.; Biscoe,
M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001. (g) Mino, T.;
Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614. (h)
Chen, W.; Li, J.; Fang, D.; Feng, C.; Zhang, C. Org. Lett. 2008, 10, 4565.
(i) Wang, C.; Liu, L.; Wang, W.; Ma, D.-S.; Zhang, H. Molecules 2010,
15, 1154.
(5) Hick, J. D.; Hyde, A. M.; Martinez Cuezva, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 16720 and references cited therein.
r
10.1021/ol200750p
Published on Web 05/06/2011
2011 American Chemical Society