Palladium-Catalyzed Direct α-Arylation of Ketones. Rate Acceleration by Sterically Hindered Chelating Ligands and Reductive Elimination from a Transition Metal Enolate Complex

Full text of DOI:10.1021/ja9727880

12382
J. Am. Chem. Soc. 1997, 119, 12382-12383
Table 1. Palladium-Catalyzed a-Arylation of Ketones
Palladium-Catalyzed Direct r-Arylation of Ketones.
Rate Acceleration by Sterically Hindered Chelating
Ligands and Reductive Elimination from a
Transition Metal Enolate Complex
Blake C. Hamann and John F. Hartwig*
Department of Chemistry, Yale UniVersity
P.O. Box 208107
New HaVen, Connecticut 06520-8107
ReceiVed August 11, 1997
The palladium-catalyzed coupling to form C-C bonds
between aryl and vinyl halides or triflates and a carbon
nucleophile is one of the most widely used transition-metal-
catalyzed reactions.1-3 However, cross-coupling reactions
involving ketone enolates as the nucleophile are limited, and
typically occur in modest yields.4 Further, many transition
metal-catalyzed approaches to ketone arylation using preformed
main group enol ethers4-14 or using bismuth or lead reagents15,16
have been investigated, and each has its drawbacks.13 The
simple direct reaction of an aryl halide and a ketone with base
in the presence of a transition metal catalyst has not been
reported. Given the success of our recent palladium-catalyzed
chemistry that produces aryl amines from aryl halides, amines,
and an appropriate base,17,18 and the similar pKa values of
arylamines and ketones,19 it seems likely that our amination
procedures could be extended to the direct arylation of ketones.
We report here our initial results on the arylation of ketones to
form secondary, tertiary, and quaternary carbon centers, along
with independent generation of the palladium enolate intermedi-
ate and the unusual direct observation of its C-C bond-forming
reductive elimination.
a Procedures: (A) 7.5 mol % Pd(DBA)2, 9 mol % DTPF, 2.2 equiv
of KN(SiMe3)2, refluxing THF, 0.75 h: (B) 7.5 mol % Pd(DBA)2, 9.0
mol % DPPF, 2.2 equiv of KN(SiMe3)2, refluxing THF, 2 h; (C) 10
mol % Pd(DBA)2, 15 mol % DTPF, 1.2 equiv of KN(SiMe3)2, refluxing
THF, 5 h; (D) 7.5 mol % Pd(DBA)2, 9.0 mol % DTPF, 2.2 equiv of
NaO-t-Bu, refluxing THF, 0.75 h. b Yields are for pure isolated product
and are an average of 2 runs on a 1 mmol scale.
The catalytic chemistry we report is shown in a general form
in eq 1, and specific examples and the yields of isolated pure
products are provided in Table 1. This chemistry resulted from
an attempt to conduct palladium-catalyzed aminations of aryl
halides in acetone solvent. The reaction procedure is simple,
or electron rich aryl halides were more selective for mono-
arylation when KN(SiMe3)2 was used. With electron poor aryl
halides, NaO-t-Bu gave good selectivity and did not lead to
direct decomposition of the aryl halide.
DPPF-ligated palladium complexes (DPPF ) bis(diphen-
ylphosphino)ferrocene) were active catalysts for this transforma-
tion. However, we also surveyed a combination of several
DPPF derivatives as ligands for the palladium catalysts and
(15) Barton, D. H. R.; Finet, J. P.; Khamsi, J.; Pichon, C. Tetrahedron
Lett. 1986, 27, 3619-3522.
and although conducted under N2 with solvents distilled under
N2, the reaction is not highly air-sensitive. The addition of the
ketone, typically used directly from a commercial source, to a
combination of Pd(DBA)2 and ligand, solvent, and either KN-
(SiMe3)2 or NaO-t-Bu base generated the aryl ketone in high
yields after heating in refluxing THF for several hours and after
silica gel chromatography. Reactions involving electron neutral
(16) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J. J.
Chem. Soc., Perkin Trans. 1 1992, 1365-1375.
(17) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-3612.
Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-7218.
Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1348-1350. Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J.
Am. Chem. Soc. 1996, 118, 7215-7216.
(18) For reviews, see: Hartwig, J. F. Synlett 1996, 329-340. Hartwig,
(1) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(2) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(3) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348.
(4) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem. Soc.
Jpn. 1984, 57, 242-246.
J. F. Angew. Chem., Int. Ed. Engl. In press.
(19) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(20) Kumobayashi, H.; Taketomi, H.; Akutagawa, S. Jpn. Kokai Tokkyo
Koho 80 02,627; 80 02,627, 1980.
(21) 1,1′-Bis[bis(2-methylphenyl)phosphino]ferrocene. Ferrocene (2.280
g, 12.26 mmol) was mixed with 2.1 equiv of n-butyllithium (2.66 M in
hexanes, 9.68 mL, 25.74 mmol), 2.1 equiv of TMEDA (3.88 mL, 25.74
mmol), and hexane (50 mL) in an oven dried flask fitted with a condenser,
addition funnel, and an N2 inlet. The reaction was heated to reflux for 5 h
before being cooled to -40 °C. A solution of bis(2-methylphenyl)-
chlorophosphine (6.400 g, 25.73 mmol) in THF (15 mL) was added
dropwise to the reaction over 10 min. The reaction was allowed to warm
slowly to room temperature and stirred for 12 h. The crude reaction was
concentrated to approximately 20% of its original volume, and the yellow
solids were filtered. The solids were then washed with 1 M HCl (20 mL),
H2O (20 mL), ethanol (20 mL), and ether (20 mL). The solids were dried
(5) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J. Org.
Chem. 1991, 56, 261-263.
(6) De Kimpe, N.; Zi-Peng, Y.; Schamp, N. Bull. Soc. Chim. Belg. 1989,
98, 481-496.
(7) Durandetti, M.; Ne´de´lec, J.-Y.; Pe´richon, J. J. Org. Chem. 1996, 61,
1748-1755.
(8) Fauvarque, J. F.; Jutand, A. J. Organomet. Chem. 1979, 177, 273-
281.
(9) Kosugi, M.; Suzuki, M.; Hagiwara, I.; Goto, K.; Saitoh, K.; Migita,
T. Chem. Lett. 1982, 939-940.
(10) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831-6833.
(11) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181-187.
(12) Millard, A. A.; Rathke, M. W. J. Org. Chem. 1977, 99, 4833-
4835.
1
under vacuum to give 6.214 g of product (83% yield). H NMR (CDCl3):
δ 7.17-6.96 (m, 16H), 4.25 (bs, 4H), 4.06 (bs, 4H), 2.46 (s, 12H); 13C-
{1H} NMR (CDCl3): δ 141.64 (d, J ) 26.3 Hz), 137.51 (d, J ) 10.6 Hz),
133.29, 129.41 (d, J ) 5.1 Hz), 128.4, 125.50, 76.52, 74.15 (d, J ) 15.1
Hz), 72.13 (d, J ) 3.0 Hz), 21.29 (d, J ) 21.6 Hz); 31P{1H} NMR:
(CDCl3): δ -36.81. Anal. Calcd. for C38H36FeP2: C, 74.76; H, 5.94.
Found: C, 74.31; H, 6.08.
(13) A list of approaches to ketone arylation is given in ref 6 of the
following: Stewart, J. D.; Fields, S. C.; Kochhar, K. S.; Pinnick, H. W. J.
Org. Chem. 1987, 52, 2110-2113.
(14) Shibata, I.; Baba, A. Org. Prep. Proc. Int. 1994, 26, 85-100.
S0002-7863(97)02788-1 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 50, 1997 12383
found that the sterically hindered chelating ligand 1,1′-bis(di-
o-tolylphosphino)ferrocene20,21 (DTPF) gave faster reaction rates
and higher yields than did DPPF. For example, on a small scale,
the reaction of phenyl bromide with acetophenone was complete
after 40 min for reactions involving DTPF, while aryl halide
remained in identical reactions involving either DPPF or BINAP.
As shown in entries 1 and 2, the final yields were also 10-
25% higher when using DTPF than when using DPPF.
Although DTPF is not commercially available, it is trivial to
prepare by methods analogous to those used to prepare DPPF,22
and we readily prepared multigram quantities in high yield.
Thus, we used this ligand for the majority of our studies,
although useful yields were observed when using DPPF.
As one can see from Table 1, this chemistry is general for
alkyl aryl ketones. Aryl iodides (entry 3) and aryl bromides
are both accommodated in the coupling process. Sterically
hindered (entry 5), electron poor (entry 7), and electron rich
(entry 8) aryl halides are all viable substrates. Both aryl and
heteroaryl ketones give moderate to good yields. We have not
extensively studied this chemistry for dialkyl ketones, but entry
12 shows that this class of ketones can participate in the coupling
process.
Scheme 1
Scheme 2
Bu)Br26 cleanly generated a new complex that was isolated in
45% yield, as a solid containing roughly 10% of Pd(0)-DPPF,
but was definitively characterized by 31P{1H} and H NMR
1
It is unusual for the coupling chemistry to occur with ketones
that would generate palladium-enolate intermediates bearing
â-hydrogens. Transmetalation of tin reagents typically requires
an open coordination site in the palladium square plane for rapid
reactions,23,24 and therefore, monodentate phosphines are the
best ligands for reactions with tin enolates. However, mono-
dentate ligands allow for â-hydrogen elimination since they can
dissociate to generate the open coordination site required for
this competing side reaction.25 In our case, the use of alkali
enolates allows for the transmetalation to occur rapidly for
complexes containing chelating phosphines and, therefore,
allows for the use of chelating phosphines that retard â-hydrogen
elimination relative to reductive elimination.
As a result, it seemed likely that our chemistry involving
DPPF and its derivatives could occur in high yields for enolates
that bear â-hydrogens. Indeed, this chemistry was conducted
successfully with ethyl phenyl ketone using a catalyst combina-
tion of Pd(DBA)2 and either DPPF or DTPF (entry 2).
Considering the instability of tertiary alkyl complexes toward
decomposition by either â-hydrogen elimination or M-C bond
homolysis, it is remarkable that these enolate arylations occur
intermolecularly to form quaternary centers in useful yields.
Reaction of bromobenzene with isobutyrophenone catalyzed by
10 mol % Pd(DBA)2 and DTPF in the presence of KN(TMS)2
gave the arylation product in 55% yield. The yield using DPPF
was a substantially lower by GC, and the reaction with this
catalyst was not pursued. Stereoselective enolate couplings with
chiral bidentate ligands should be possible in future studies.
A likely catalytic cycle is shown in Scheme 1. No DBA is
observed by GC during these reactions. It is consumed in the
reaction medium and is unlikely to participate in these reactions,
except in the initial stages. Oxidative addition of the aryl halide
to a (DPPF)Pd(0) complex, followed by reaction of the aryl
halide with the alkali enolate would form the enolate aryl
complex. C-C bond-forming reductive elimination would
occur to form the product, but such a reductive elimination
involving an enolate complex is uncommon.
spectroscopies. Two new doublets (δ 20.0, 18.7; JPP ) 25.5
Hz) were observed by 31P NMR spectroscopy, and a new tert-
butyl group was observed, along with a new set of DPPF Cp
1
resonances. Most important, a H resonance with intensity of
two hydrogens was observed at δ 3.40. This signal was a single
resonance (confirmed at different magnetic fields) that was a
virtual triplet (JHP ) 10.7), showing coupling to the two
phosphine ligands that was confirmed by 1H{31P} NMR
spectroscopy. This resonance is, therefore, due to a metal-bound
methylene and indicates that the enolate is C-bound. This
complex underwent reductive elimination at room temperature
to form the R-aryl ketone in 74-87% yield (1H NMR with
internal standard) with a half-life of 2 h at room temperature or
with complete consumption of enolate after 1 h at 50 °C. This
rapid reductive elimination prevented the isolation of the enolate
complex in pure form at this time but did demonstrate that this
complex is most likely the C-C bond-forming intermediate in
the catalysis.
A number of mechanistic questions need to be addressed in
the future. The product ketone contains R-hydrogens, and it is
not clear whether the high selectivity for monoarylation results
from steric or electronic effects. Furthermore, the origin of the
rate acceleration by DTPF relative to DPPF is not clear; neither
nor are the reactions that lead to catalyst deactivation. These
issues, as well as broadening the scope of the carbonyl substrates
will be the subject of future studies.
Acknowledgment. This work was generously supported by Boe-
hringer Ingelheim. We also gratefully acknowledge support from a
National Science Foundation Young Investigator Award, a DuPont
Young Faculty Award, a Union Carbide Innovative Recognition Award,
a Dreyfus Foundation New Faculty Award, and a Camille Dreyfus
Teacher-Scholar Award. J.F.H. is a fellow of the Alfred P. Sloan
Foundation. We thank Johnson-Matthey Alpha/Aesar for a loan of
palladium chloride.
Supporting Information Available: A representative procedure
for the ketone arylation process, literature references to the aryl ketone
1
products, and H NMR, 13C NMR, and mass spectra of the arylation
Thus, we conducted some initial studies shown in Scheme 2
to observe directly the enolate aryl complex that would undergo
this unusual stoichiometric reaction. Indeed, reaction of the
potassium enolate of acetophenone with (DPPF)Pd(p-C6H4-t-
products (42 pages). See any current masthead page for ordering and
Internet access information.
Note Added in Proof: An example of a related ketone
arylation appeared after submission of this manuscript (Satoh,
T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740-1741), and Buchwald has reported
related chemistry that uses BINAP as ligand (Palucki, M.;
Buchwald, S. J. J. Am. Chem. Soc. In press).
(22) de Lang, R.-J.; van Soolingen, J.; Verkruijsse, H. D.; Brandsma, L.
Synth. Commun. 1995, 25, 2989-2991.
(23) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598.
(24) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(25) Whitesides, G. M.; Gaasch, J. F.; Stedronsky, E. R. J. Am. Chem.
Soc. 1972, 94, 5258-5270.
(26) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-
8245.
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