Pd-Catalyzed
R
-Arylation of Zinc Amide Enolates
A R T I C L E S
of amides, with one exception,57 has been limited to reactions
of lactams or intramolecular reactions of acyclic amides.24,57-63
The R-arylation of amides requires a stronger base to generate
the enolate than the R-arylation of ketones and esters, and the
use of this strong base has several significant drawbacks. For
example, the need for a strong base limits the scope of coupling
reactions to electron-neutral or electron-rich aryl halides and
aryl halides that lack protic or electrophilic functionality. In
addition, the strongly basic conditions lead to catalyst decom-
position, and the coupling of amides has required higher loadings
of palladium than the coupling of ketone or ester enolates.
Further, the R-aryl amide product quenches the starting enolate,
and products from diarylation have been formed. Finally, the
strongly basic conditions prevent asymmetric R-arylations that
would form tertiary stereocenters.
To overcome these problems, a reaction that occurs with
enolates that are less basic than alkali metal enolates of amides
must be developed. Although zinc enolates of amides are not
common reagents, they can be formed from the R-bromo
amide64 or by quenching of an alkali metal amide enolate with
zinc halide.65,66 Considering the greater functional group toler-
ance of the coupling of aryl and alkyl zinc reagents67-69 than
that of the coupling of aryl and alkyl magnesium or lithium
reagents,70,71 we anticipated that the coupling of zinc enolates
of amides could address the problem of functional group
tolerance of the coupling of amide enolates.
the solid state, and the zinc is bound to the oxygen of one enolate
and the carbon of another.72,73 Although the structures of the
zinc enolates of propionates and isobutyrates are not known
from X-ray diffraction, NMR data suggests that the zinc ion of
these zinc enolates is also bound to carbon.74,75
A few limited examples of palladium-catalyzed R-arylations
of zinc enolates have been reported. We first reported in
communication form several examples of the coupling of aryl
bromides with zinc enolates of amides formed from the
corresponding R-halo amides.76 These reactions were conducted
with isolated zinc amides, which can be cumbersome to
manipulate, and the reported reactions were limited to those of
N,N-diethylacetamide and N,N-diethylpropionamide. Recently,
Cossy and co-workers reported the palladium-catalyzed coupling
of aryl bromides with zinc enolates of δ-lactams generated in
situ.63,77-79 The scope of these reported reactions was limited
to this class of cyclic amide and to aryl halides that lacked
potentially reactive protic or electrophilic functional groups, such
as cyano, nitro, ester, keto, hydroxyl, and amino groups.
Here, we present a full account of the scope and limitations
of a mild, more general palladium-catalyzed coupling of zinc
enolates of amides that are generated in situ from R-bromo
amides or from quenching of the alkali metal amide. The scope
of these reactions now encompasses the coupling of acyclic
acetamides, propionamides, isobutyramides, and morpholine
amides with aryl halides that are electron-rich or electron-poor
and that contain typically reactive, protic and electrophilic
functional groups.
Little structural data is available on zinc enolates of amides,
but the structures of zinc enolates of esters have been revealed
by several methods. As determined by X-ray diffraction of the
bromozinc enolate of tert-butyl and ethyl acetate bound by two
tetrahydrofuran (THF) molecules, the enolates are dimeric in
Results and Discussion
1. Arylation of Reformatsky Reagents of Amides. A.
r-Arylation of Isolated Refomatsky Reagents. Our initial
studies of palladium-catalyzed R-arylation of zinc enolates of
amides were performed using isolated Reformatsky reagents.76
Although this reaction requires the conversion of an amide to
an R-bromo amide or the synthesis of the R-bromo amide from
the appropriate acid bromide, the use of isolated Reformatsky
reagents allowed us to eliminate the effects that could arise from
formation of the enolate in situ.
The catalyst and temperatures needed for reactions of
Reformatsky reagents of amides were much different from those
needed for the R-arylation of alkali metal amide enolates.24
Unlike the reactions of alkali metal amide enolates, the
R-arylation of zinc enolates occurred in low yields with
palladium catalysts ligated by 1,1′-binaphthalene-2,2′-diylbis-
(diphenylphosphine) (BINAP) or carbene ligands. Instead, the
reaction occurred in the presence of the palladium catalyst
generated from Pd(dba)2 (dba ) 1,5-diphenyl-1,4-pentadien-3-
one) and 1,2,3,4,5-pentaphenyl-1′-di-tert-butylphosphinofer-
rocene (Q-phos)80-82 or in the presence of the dinuclear
(43) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 15168.
(44) Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 1261.
(45) Cao, H.; Yu, J. M.; Wearing, X. Y. Z.; Zhang, C. C.; Liu, X. X.; Deschamps,
J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013.
(46) Churruca, F.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron Lett.
2003, 44, 5925.
(47) Nguyen, H. N.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11818.
(48) Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S.
P. Org. Lett. 2003, 5, 1479.
(49) Churruca, F.; SanMartin, R.; Carril, M.; Tellitu, I.; Dominguez, E.
Tetrahedron 2004, 60, 2393.
(50) Churruca, F.; SanMartin, R.; Tellitu, I.; Dominguez, E. Eur. J. Org. Chem.
2005, 2481.
(51) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410.
(52) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(53) Jorgensen, M.; Lee, S.; Liu, X. X.; Wolkowski, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 12557.
(54) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
(55) Liu, X. X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
(56) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett. 2004,
45, 4261.
(57) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
63, 6546.
(58) Freund, R.; Mederski, W. W. K. R. HelV. Chim. Acta 2000, 83, 1247.
(59) Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631.
(60) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(61) Zhang, T. Y.; Zhang, H. B. Tetrahedron Lett. 2002, 43, 193.
(62) Zhang, T. Y.; Zhang, H. B. Tetrahedron Lett. 2002, 43, 1363.
(63) de Filippis, A.; Pardo, D. G.; Cossy, J. Tetrahedron 2004, 60, 9757.
(64) Poller, R. C.; Silver, D. J. Organomet. Chem. 1978, 157, 247.
(65) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J. Am.
Chem. Soc. 1973, 95, 3310.
(72) Dekker, J.; Boersma, J.; Vanderkerk, G. J. M. Chem. Commun. 1983, 553.
(73) Dekker, J.; Budzelaar, P. H. M.; Boersma, J.; Vanderkerk, G. J. M.; Spek,
A. L. Organometallics 1984, 3, 1403.
(74) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron Lett. 1982, 23, 3945.
(75) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron 1984, 40, 2781.
(76) Hama, T.; Liu, X. X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176.
(66) Bertrand, J.; Gorrichon, L.; Maroni, P.; Meyer, R.; Viteva, L. Tetrahedron
Lett. 1982, 23, 1901.
(67) Negishi, E. J. Organomet. Chem. 2002, 653, 34.
(68) Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis,
1st ed.; John Wiley & Sons: Hoboken, NJ, 2002; Vol. 1.
(69) Negishi, E. Xingzhong, Z.; Tan, Z; Qian, M.; Hu, Q.; Huang, Z. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 815.
(70) Tamao, K. J. Organomet. Chem. 2002, 653, 23.
(71) Murahashi, S. I. J. Organomet. Chem. 2002, 653, 27.
(77) Cossy, J.; de Filippis, A.; Pardo, D. G. Org. Lett. 2003, 5, 3037.
(78) Cossy, J.; de Filippis, A.; Pardo, D. G. Synlett 2003, 2171.
(79) de Filippis, A.; Pardo, D. G.; Cossy, J. Synthesis 2004, 2930.
(80) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000,
122, 10718.
(81) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002,
67, 5553.
(82) Available from STREM Chemicals, Inc., catalog no. 312959-24-3.
9
J. AM. CHEM. SOC. VOL. 128, NO. 15, 2006 4977