Palladium-catalyzed α-arylation of ketones

Full text of DOI:10.1021/ja972593s

11108
J. Am. Chem. Soc. 1997, 119, 11108-11109
Scheme 1
Palladium-Catalyzed r-Arylation of Ketones
Michael Palucki† and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed July 30, 1997
to the corresponding ketone. It was during this latter study that
we unexpectedly observed small amounts of R-aryl ketone
products. For example, GC analysis of the crude reaction
mixture of the attempted Pd-catalyzed coupling of 1-bromo-4-
tert-butylbenzene with cyclohexanol showed that tert-butyl-
benzene was the major product along with small amounts of
2-(4-tert-butylphenyl)cyclohexanone (2%), Scheme 1.8
Realizing the need for a general method for the synthesis of
R-aryl ketones, we began to focus on optimizing the formation
of this product. After some experimentation, we found that the
combination of Pd2(dba)3 and Tol-BINAP or BINAP in the
presence of NaO-t-Bu effectively catalyzes the desired coupling
reaction, eq 1.9 We found that 3 mol % Pd and 3.6 mol %
The synthesis of R-aryl ketones has received much attention
over the past two decades.1 A number of stoichiometric
arylating reagents have been successfully developed for this
purpose; however, their utility is decreased because each
synthesis of an R-aryl ketone requires the synthesis of a different
arylating reagent.2,3 In contrast, the direct coupling of aryl
halides with ketones would provide a convenient method for
the synthesis of R-aryl ketones. Semmelhack et al. have
demonstrated that Ni(COD)2 (COD ) cyclooctadiene) catalyzes
the intramolecular coupling of an aryl iodide with a ketone
enolate.4 While there are reports of Pd- or Ni-catalyzed
intermolecular coupling reactions that afford R-aryl ketones,
these methods require the use of stoichiometric amounts of tin
reagents and/or the use of enol ether, enamine, or R-chloro
ketone derivatives instead of the ketone.5,6 Thus, a general
method which utilizes readily available starting materials and
affords products in high regioselectivity has not been realized.
Herein, we describe a novel Pd-catalyzed method for the direct
cross coupling of aryl halides with ketones.
We have previously shown that a mixture of Pd2(dba)3 (dba
) dibenzylidene acetone) and Tol-BINAP catalyzes the coupling
of sodium alkoxides (generated in situ by reaction of the alcohol
with NaH) with electron-deficient aryl bromides to form aryl
ethers.7 In addition, we found that reaction of electron neutral
or electron-rich aryl bromides with sodium alkoxides (generated
from primary or secondary alcohols) provides the reduced arene
as the major product with concomitant oxidation of the alcohol
ligand were sufficient to obtain complete conversion of starting
aryl bromide. Under the conditions employed, R-aryl ketones
were not formed in the absence of catalyst. A broad study on
the generality of this reaction was undertaken, and the results
are shown in Table 1.10,11
As illustrated in Table 1, the Pd-catalyzed arylation of ketones
provides a general method for obtaining a wide variety of R-aryl
ketones. The mild reaction conditions are compatible with a
wide variety of functional groups including nitriles, ethers,
imines, amides, aryl chlorides, and acetals. Reaction times are
typically 4-12 h using 3 mol % palladium and 3.6 mol %
ligand. Reaction of 2-bromo-p-xylene with 3′,4′-(methylene-
dioxy)acetophenone required 5 mol % Pd and 18 h for complete
conversion of the starting aryl halide (entry 12).12
† National Institutes of Health Postdoctoral Fellow (1996-7). Current
address: Merck & Co., Inc., P.O. Box 2000, RY55-228, Rahway, NJ 07065-
0900.
(1) Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P. Tetrahedron 1988,
44, 3039-3071.
(2) (a) Morgan, J.; Pinhey, J. T.; Rowe, B. A. J. Chem. Soc., Perkin
Trans. 1 1997, 1005-1008. (b) Ryan, J. H.; Stang, P. J. Tetrahedron Lett.
1997, 38, 5061-5064. (c) Barton, D. H. R.; Finet, J.-P.; Giannotti, C.;
Halley, F. J. Chem. Soc., Perkin Trans. 1 1987, 241-249. (d) Mino, T.;
Matsuda, T.; Maruhashi, K.; Yamashita, M. Organometallics 1997, 16,
3241-3242. (e) Dell’erba, C.; Novi. M.; Petrillo, G.; Tavani, C. Tetrahedron
1993, 49, 235-242. (f) Rathke, M. W.; Vogiazoglou, D. J. Org. Chem.
1987, 52, 3697-3698.
(3) Arylation of ketones via SRN1 aromatic substitution has been
succussfully employed, see: Norris, R. K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon
Press: New York, 1991; Vol. 4, Chapter 2.2 and references cited therein.
(4) Semmelhack, M. F.; Chong. B. P.; Stauffer, R. D.; Rogerson, T. D.;
Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507-2516.
(5) (a) Durandetti, M.; Sibille, S.; Ne´de´lec J.-Y.; Pe´richon, J. Synth.
Commun. 1994, 24, 145-151. (b) Sakakura, T.; Hara, M.; Tanaka, M. J.
Chem. Soc., Perkin Trans. 1 1994, 283-288. (c) Negishi, E.-i.; Akiyoshi,
K. Chem. Lett. 1987, 1007-1010. (d) Kosugi, M.; Hagiwara, I.; Sumiya,
T.; Migita, T. Bull. Chem. Soc. Jpn. 1984, 57, 242-246. (e) Kuwajima, I.;
Urabe. H. J. Am. Chem. Soc. 1982, 104, 6831-6833. (f) Heck, R. F. J.
Am. Chem. Soc. 1968, 90, 5535-5538.
The regioselectivity of the Pd-catalyzed arylation of ketones
is quite remarkable. Ketones containing R,R′-hydrogens are
(8) Palucki. M.; Buchwald. S. L. Unpublished results.
(9) Tol-BINAP ) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl, BINAP
) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
(10) Representative procedure: In a fume hood, an oven-dried Schlenk
tube containing a stir bar was charged with Pd2(dba)3 (6.9 mg, 0.0075
mmol), Tol-BINAP (12.2 mg, 0.018 mmol), and NaO-t-Bu (65 mg, 0.65
mmol). The Schlenk tube was evacuated and back filled with argon. THF
(2 mL) was added followed by 2-(3-bromophenyl)-1,3-dioxolane (76 µL,
0.5 mmol), 3-methyl-2-butanone (64 µL, 0.60 mmol), and additional THF
(1 mL). The resulting red mixture was heated under argon in a 70 °C oil
bath until the starting halide had been consumed as judged by GC analysis.
The Schlenk tube was cooled to room temperature, and diethyl ether (25
mL) and H2O (25 mL) were added. The aqueous layer was separated and
extracted with diethyl ether (25 mL). The organic layers were combined,
washed with brine (40 mL), dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography on silica gel to
give 90 mg (76% yield) of a colorless oil.
(6) For examples of Pd- or Ni-catalyzed coupling of aryl halides with
esters or ester equivalents, see: (a) Galarini, R.; Musco, A.; Pontellini, R.
J. Mol. Catal. 1992, 72, L11-L13. (b) Carfagna, C.; Musco, A.; Sallese,
G.; Santi, R.; Fiorani, T. J. Org. Chem. 1991, 56, 261-263. (c) Orsini, F.;
Pelizzoni, F.; Vallarino, L. M. J. Organomet. Chem. 1989, 367, 375-382.
(d) Fauvarque, J. F.; Jutand, A. J. Organomet. Chem. 1979, 177, 273-
281. (e) Millard, A. A.; Rathke, M. W. J. Am. Chem. Soc. 1977, 99, 4833-
4835. For examples of Pd-catalyzed intramolecular coupling of aryl halides
with â-dicarbonyl compounds, see: Ciufolini, M. A.; Browne, M. E.
Tetrahedron Lett. 1987, 28, 171-174. Ciufolini, M. A.; Qi, H.-B.; Browne,
M. E. J. Org. Chem. 1988, 53, 4149-4151.
(11) Other ligands examined in the Pd-catalyzed coupling of cyclohex-
anone with 1-bromo-4-tert-butylbenzene include tri-o-tolylphosphine, 1,2-
bis(diphenylphosphino)ethane (DPPE), 1,2-bis(diphenylphosphino)propane
(DPPP), and 1,1′-bis(diphenylphosphino)ferrocene (DPPF). The use of DPPF
provided the desired product in 50% yield (GC); however, tert-butylbenzene
was formed in 25% yield (GC). Use of Tol-BINAP afforded >90% yield
(GC, uncorrected for response factors) of the desired product and <1%
yield (GC) of tert-butylbenzene.
(12) The reaction of 4-chloroacetophenone and of 4-methoxyacetophe-
none with 2-bromo-p-xylene proceeded to only ca. 90% conversion of the
starting aryl halide using 5 mol % Pd and 6 mol % ligand. The reaction of
2-bromo-p-xylene with 3-methyl-2-butanone using 7 mol % Pd and 8.4
mol % ligand gave complete conversion of the starting aryl halide, but the
isolated product was <95% pure.
(7) (a) Palucki, M.; Wolfe. J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333-10334. (b) Palucki. M.; Wolfe. J. P.; Buchwald. S. L. J.
Am. Chem. Soc. 1997, 119, 3395-3396.
S0002-7863(97)02593-6 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 45, 1997 11109
Table 1. Palladium-Catalyzed Coupling of Aryl Bromides with
Scheme 2
Ketonesa
gave, after 14 h, <2% of the desired 2,6-dimethyl-2-(4-tert-
butylphenyl)cyclohexanone.13
Although little mechanistic information has been obtained
about the Pd-catalyzed arylation of ketones, we believe that the
reaction proceeds via the mechanism shown in Scheme 2.
Oxidative addition of the Pd(0)Ln with the aryl bromide affords
the Pd(II) organometallic intermediate A. Ligand substitution
of the bromide by the sodium enolate provides the Pd(II)
organometallic intermediate B or C. Given the high degree of
regioselectivity of arylation, we believe that deprotonation of
the ketone occurs prior to coordination to the Pd center. Finally,
reductive elimination from intermediate B or C provides the
R-aryl ketone and regenerates the Pd(0)Ln catalyst. That C does
not decompose via a â-hydride elimination pathway (in cases
where both R-carbons are substituted) further attests to the ability
of BINAP and Tol-BINAP to render such complexes 4-coor-
dinate.14
In summary, we have developed a general method for the
direct synthesis of R-aryl ketones from ketones and aryl
bromides.15,16 This process displays good functional group
tolerance and high regioselectivity. Efforts to extend the
substrate scope to other classes of substrates such as esters and
amides and to develop an asymmetric variant are currently under
progress.
a Reaction conditions are as follows: 1.0 equiv of ArBr, 1.2 or 2.0
equiv of ketone, 1.3 equiv of NaOt-Bu, 1.5 mol % of Pd2(dba)3, 3.6
mol % of ligand in THF (ArBr ) 0.17 M), 70 °C. b Yields refer to the
average of isolated yields for two runs. c Isolated as a 20:1 mixture of
regioisomers. d Isolated as a 16:1 mixture of regioisomers. e Reaction
performed using 5 mol % Pd and 6 mol % BINAP.
preferentially arylated at the least-hindered side (methyl >
methylene . methine). For example, NMR analysis of the
crude reaction mixture of the coupling of 2-(3-bromophenyl)-
1,3-dioxolane with 3-methyl-2-butanone showed no evidence
of arylation at the methine carbon and a 13:1 mixture of
monoarylation:diarylation of the methyl ketone (entry 1).
Likewise, NMR analysis of the crude reaction mixture of the
coupling of 4-bromobiphenyl with 2-methyl-3-pentanone re-
vealed that coupling occurred exclusively at the methylene
carbon (entry 3). Coupling of 1,1-diphenylacetone to 2-(3-
bromophenyl)-1,3-dioxolane (entry 2) or N,N-diethyl-p-bromo-
benzamide (entry 9) occured exclusively at the methyl group
despite the significantly greater acidity of the methine proton.
Further examples illustrating the high degree of regioselec-
tivity can be seen in the reaction of N-(diphenylmethylene)-4-
bromoaniline with 2-hexanone (entry 6). Although the degree
of regioselectivity (arylation of methyl vs methylene) decreased
slightly upon increasing the relative concentration of ketone,
the amount of diarylation of the methyl ketone decreased from
9% to 3%, as determined by NMR analysis of the crude reaction
mixture. Diarylation was observed only for methyl ketones
which are relatively unhindered at the R′-position. Thus, no
diarylation was observed for 1,1-diphenylacetone (entries 2 and
9), 3-methyl-2-butanone (entry 1), and pinacolone (entries 5 and
10). In addition, no diarylation was observed in the coupling
of 2-bromo-p-xylene with 3′,4′-(methylenedioxy)acetophenone,
presumably because of the steric hindrance provided by the
o-methyl group (entry 12). Arylation of methine carbons was
not observed under these conditions. Attempts at coupling
1-bromo-4-tert-butylbenzene with 2,6-dimethylcyclohexanone
Acknowledgment. Financial support from the National Science
Foundation, the National Institutes of Health (postdoctoral fellowship
to M.P.) and Pfizer are gratefully acknowledged. We thank Joseph P.
Sadighi for providing N-(diphenylmethylene)-4-bromoaniline.
Supporting Information Available: Details of experimental
procedures and spectroscopic and analytical data (7 pages). See any
current masthead page for ordering and Internet access instructions.
Note Added in Proof. Hamann and Hartwig have independ-
ently discovered and conducted a study of the catalytic arylation
of ketones.16a In addition, Miura and co-workers have reported
the catalytic conversion of 1,3-diphenylacetone to 1,1,3,3-
tetraphenylacetone via a similar transformation.16b
JA972593S
(13) Determined by GC and GC/MS analysis of the crude reaction
mixture.
(14) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215-7216.
(15) After completion of this work, an abstract describing similar work
appeared: Hamann, B. C.; Hartwig, J. F. Abstracts of Papers, 214th ACS
National Meeting of the American Chemical Society, Division of Inorganic
Chemistry, Las Vegas, NV, September 7-11, 1997; American Chemical
Society: Washington, DC, 1997; INORG 444.
(16) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. In press. (b)
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew Chem., Int. Ed.
Engl. 1997, 36, 1740-1742.