Published on Web 10/05/2007
Pd-Catalyzed Amidations of Aryl Chlorides Using
Monodentate Biaryl Phosphine Ligands: A Kinetic,
Computational, and Synthetic Investigation
Takashi Ikawa, Timothy E. Barder, Mark R. Biscoe, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology, 77
Massachusetts AVenue, Cambridge, Massachusetts 02139
Abstract: We present results on the amidation of aryl halides and sulfonates utilizing a monodentate biaryl
phosphine-Pd catalyst. Our results are in accord with a previous report that suggests that the formation of
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κ -amidate complexes is deleterious to the effectiveness of a catalyst for this transformation and that their
formation can be prevented by the use of appropriate bidentate ligands. We now provide data that suggest
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that the use of certain monodentate ligands can also prevent the formation of the κ -amidate complexes
and thereby generate more stable catalysts for the amination of aryl chlorides. Furthermore, computational
studies shed light on the importance of the key feature(s) of the biaryl phosphines (a methyl group ortho
to the phosphorus center) that enable the coupling to occur. The use of ligands that possess a methyl
group ortho to the phosphorus center allows a variety of aryl and heteroaryl chlorides with various amides
to be coupled in high yield.
Introduction
reasonable rate of “transmetallation” to form the amidate
1
2
intermediate. Further complicating matters is that, in the catalytic
cycle for palladium-catalyzed amidation reactions, it is likely
that the formation of κ -amidate complex, e.g., complex 1,
where the amidate is bound to the palladium center at both the
oxygen and nitrogen atoms, inhibits reductive elimination and
therefore catalytic turnover. Recently, a study concerning Pd-
The copper- and palladium-catalyzed amidation of aryl
bromides and iodides have become well-established processes
in organic synthesis. However, largely absent from the literature
on Pd-catalyzed amidation reactions is the description of an
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efficient and general method for coupling aryl chlorides. It is
unlikely that this is due to the inability of phosphine-Pd catalysts
to oxidatively add to aryl chlorides, as numerous ligands, in
the past 10 years, have been shown to promote oxidative
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addition to even extremely hindered aryl chlorides. More likely,
a ligand has yet to be developed that is capable of promoting
oxidative addition to aryl chlorides and reductive elimination
of an amidate ligand from Pd(II) centers, while supporting a
(
1) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421-7428. (b) Jiang, L.; Job, G. E.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2003, 5, 3667-3669. (c) Huang, X.; Anderson,
K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
catalyzed amidation suggested that reductive elimination to form
the C-N bond of N-aryl amides can occur more readily from
complexes generated from bidentate phosphine ligands than
from monodentate phosphine ligands as a result of the inhibition
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003, 125, 6653-6655. (d) Klapars, A.; Parris, S.; Anderson, K. W.;
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529-3533. (e) Strieter, E.
R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
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120-4121.
(
2) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. (b) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048. (c) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653-6655. (d) Willis, M. C.; Brace, G. M.; Holmes,
I. P. Synthesis 2005, 3229-3234. (e) Klapars, A.; Campos, K. R.; Chen,
C.-y.; Volante, R. P. Org. Lett. 2005, 7, 1185-1188.
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of the formation of a κ -amidate complex. Since reports from
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c
2d,3c
our laboratory, as well as others,
on the Pd-catalyzed
amidation of aryl halides and sulfonates have demonstrated
monodentate biaryldialkyl phosphines as components of highly
active catalyst systems, we felt that it was important to
investigate the origin of the enhanced activity that is observed
with these particular monodentate ligands.
(
3) Pd-catalyzed intermolecular amidation of aryl chlorides: (a) Hartwig, J.
F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L.
M. J. Org. Chem. 1999, 64, 5575-5580. (b) Arterburn, J. B.; Rao, K. V.;
Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351-1354. (c) Ghosh, A.;
Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org. Lett. 2003, 5, 2207-
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210. (d) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433-2435.
Herein we present the first general catalytic system capable
of the facile amidation of aryl chlorides by utilizing a finely
(
e) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2005, 44, 1371-1375. (f) Shi, F.; Smith, M. R., III; Maleczka, R.
E., Jr. Org. Lett. 2006, 8, 1411-1414. Examples of the intramolecular
amidation of aryl chlorides: (g) Poondra, R. R.; Turner, N. J. Org. Lett.
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(5) For an example of a κ -bis(amidate) titanium complex, see: Zhang, Z.;
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005, 7, 863-866. (h) McLaughlin, M.; Palucki, M.; Davies, I. W. Org.
Schafer, L. L. Org. Lett. 2003, 5, 4733-4736.
Lett. 2006, 8, 3311-3314.
4) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(6) Fujita, K.-i.; Yamashita, M.; Puschman, F.; Alvarez-Falcon, M. M.;
Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 9044-9045.
(
10.1021/ja0717414 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 13001-13007
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