Selective monoarylation of acetate esters and aryl methyl ketones using aryl chlorides

Article abstract of DOI:10.1021/ol900295u

Simple, efficient procedures for the monoarylation of acetate esters and aryl methyl ketones using aryl chlorides are presented. Previously, no general method was available to ensure the highly selective monoarylation of these classes of substrates using

Full text of DOI:10.1021/ol900295u

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1773-1775
Selective Monoarylation of Acetate
Esters and Aryl Methyl Ketones Using
Aryl Chlorides
Mark R. Biscoe and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachussetts 02139
sbuchwal@mit.edu
Received February 11, 2009
ABSTRACT
Simple, efficient procedures for the monoarylation of acetate esters and aryl methyl ketones using aryl chlorides are presented. Previously,
no general method was available to ensure the highly selective monoarylation of these classes of substrates using aryl chlorides. Using
palladium precatalysts recently reported by our group, these reactions are easily accomplished under mild conditions that tolerate a wide
array of heterocyclic substrates.
It has been well demonstrated that the use of Pd-catalyzed
R-substitution reactions of carbonyl compounds can be an
effective strategy to achieve the arylation and vinylation of
enolates,1,2 often with excellent enantiomeric control.3
However, there are very few reported examples of the
selective monoarylation of enolates from acetate esters and
methyl ketones using aryl halides or sulfonates where the
enolate is not biased toward monoarylation by the presence
of an ortho substituent on the aryl halide or by the presence
of a pre-existing R-substituent on the enolate. Such R-ary-
lation reactions are typically unsuccessful as a result of the
instability of alkali ester enolates2d or the formation of
significant amounts of diarylated side products. To the best
of our knowledge, the few examples of the monoarylation
of tert-butyl acetate that have been demonstrated separately
by Hartwig2b,c and our group2a using aryl bromides constitute
the only examples of the direct monoarylation of acetate
esters. In one recent report, when alkali metal enolates of
acetate esters were employed with aryl chlorides, less than
10% of the desired R-arylated ester was observed (Scheme
1a).2d The corresponding zinc enolates were employed in
an attempt to circumvent this problem, but the only reported
examples utilized chlorobenzene and electron-deficient aryl
(1) For ketones, see: (a) Palucki, M.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Angew. Chem., Int. Ed. 1997, 36, 1740. (d) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 1473. (e) Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. (f) Nguyen, H. N.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (g) Culkin,
D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (h) Viciu, M. S.;
Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M; Nolan, S. P. Org. Lett.
2003, 5, 1479. (i) Navarro, O.; Marion, N.; Oonishi, Y.; Kelly, R. A.; Nolan,
S. P. J. Org. Chem. 2006, 71, 685. (j) Huang, J.; Bunel, E; Faul, M. M.
Org. Lett. 2007, 9, 4343. (k) Grasa, G. A.; Colacot, T. J. Org. Process Res.
DeV. 2008, 12, 522. (l) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso,
D.; Bell, A.; Nolan, S. P. J. Org. Chem. 2006, 71, 3816. (m) Carril, M.;
SanMartin, R.; Dominguez, E.; Tellitu, I. Tetrahedron 2007, 63, 690
.
(2) For esters, see: (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7996. (b) Lee, S.; Beare, N. A; Hartwig, J. F. J. Am. Chem.
Soc. 2001, 123, 8410. (c) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10,
(3) (a) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald,
S. L. Org. Lett. 2001, 3, 1897. (b) Hamada, T.; Chieffi, A.; Ahman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261. (c) Liao, X.; Weng,
Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.
1545. (d) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549
.
10.1021/ol900295u CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

efficiently promote the R-arylation of tert-butyl acetate.
Although 3 and 4 can both promote the R-arylation reaction,
the use of 4 is necessary to obtain selective monoarylation
of the acetate ester. Table 1 displays a series of monoarylated
Scheme 1
Table 1. Selective Monoarylation of tert-Butyl Acetate Using
Aryl and Heteroaryl Chloridesa
chlorides as substrates. With regards to the monoarylation
of aryl methyl ketones, there exist only a few reported
examples that employ aryl halides lacking an ortho
substituent.1e,i A recent report highlighted the difficulty of
preventing the formation of undesired diarylated products
when the enolates of methyl aryl ketones are employed in
cross-coupling reactions using aryl halides (Scheme 1b).1k
Previously, we reported a new class of palladium precata-
lyst for C-N cross-coupling reactions that is easily activated
without the need for exogenous additives and ensures the
formation of the corresponding monoligated active complex
of Pd(0) (Figure 1).4 These biarylmonophosphine-ligated
Figure 1. Formation of L1Pd(0) complexes bearing biarylphos-
phines.
a Reaction conditions: aryl chloride (0.5 mmol), tert-butyl acetate (0.75
mmol), 1 M LHMDS (1.5 mL, 1.5 mmol) at rt for 30 min. b Isolated yields
(average of two runs). c Reaction conducted at 0 °C. d 4 h reaction time.
e 14 h reaction time.
precatalysts intercept a competent catalytic cycle for C-N
bond formation at the amine complex and are activated after
deprotonation by the base intrinsically necessary for the
cross-coupling reaction. Since base is also required for the
R-arylation of carbonyl enolates, we have begun to inves-
tigate the use of these precatalysts as convenient Pd sources
for conducting such C-C cross-coupling reactions under
mild conditions.5 Herein we report simple, efficient proce-
dures to effect the R-arylation of acetate esters and aryl
methyl ketones with aryl chlorides using precatalysts bearing
biarylmonophosphine ligands. We believe that the success
of these reactions results largely from the high activity of
the L1Pd(0) species generated by our precatalysts and the
related ability to conduct the reactions under very mild
conditions.
tert-butyl acetates that were prepared from the direct R-ary-
lation of tert-butyl acetate. These reactions occur efficiently
using aryl and heteroaryl chlorides and tert-butyl acetate at
room temperature with 1 mol % 4 and a commercially
available solution of 1 M LHMDS in toluene. No solvent
other than that from the LHMDS solution is necessary. In
general, these reactions are complete in less than 30 min.
However, more difficult aryl chlorides (entries 9 and 10)
require longer reaction times. The electronic nature of the
aryl chloride had little effect on the success of the cross-
coupling reaction; reactions involving 4-chlorotoluene (entry
1) and 4-chlorodimethylaniline (entry 3) each proceeded
efficiently in less than 30 min. For reactions involving highly
reactive aryl chlorides (entries 5 and 7), the temperature had
to be reduced to 0 °C to preclude the formation of bisarylated
products. Even at 0 °C, these reactions were complete in
We have found that precatalysts bearing bulky biaryl-
monophosphine ligands 1 and 2 (3 and 4, respectively) can
(4) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
130, 6686.
(6) A water-mediated preactivation protocol that we recently reported
could also be used to access an active L1Pd(0) complex for use at room
temperature. See: Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L.
Org. Lett. 2008, 10, 3505.
(5) (a) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552. (b) Martin, R.; Buchwald, S. L. Org. Lett.
2008, 10, 4561.
1774
Org. Lett., Vol. 11, No. 8, 2009

approximately 30 min. Because our precatalysts are easily
activated well below 0 °C, they constitute powerful palladium
sources for such low-temperature cross-coupling reactions.6
We propose that our ability to monoarylate the lithium
enolate of tert-butyl acetate arises from a combination of
three factors: (1) the use of a bulky ligand that retards
subsequent bisarylation of the monoarylated product; (2) the
use of a precatalyst that rapidly forms a highly active L1Pd(0)
complex and results in the rapid conversion of the starting
material, preventing competitive background Claisen reac-
tions and the decompostition of potentially unstable metal
enolates;2d and (3) the use of low temperatures, which favors
monoarylation in these cross-coupling reactions. All three
of these reaction properties are readily accessed through the
use of precatalyst 4 as the palladium/ligand source. At
present, monodentate ligands provide better results than those
obtained with bidentate ones. However, it is possible that
bidentate ligands whose use provides similar (or better)
results may be discovered.
Table 2. Selective Monoarylation of Aryl and Heteroaryl
Acetyls Using Aryl and Heteroaryl Chloridesa
Although the use of t-BuXPhos (2) was required to achieve
the selective monoarylation of tert-butyl acetate using aryl
chlorides, XPhos (1) proved to be the optimal ligand for the
monoarylation of aryl methyl ketones (Table 2). Using pre-
catalyst 3 and KOt-Bu7 in toluene at 60 °C, the monoarylation
reactions are complete in less than 4 h. The reaction tolerates
a variety of heterocyclic moieties in both the aryl chloride and
the aryl methyl ketone. Previously, there have been few reported
examples of analogous Pd-catalyzed R-arylation reactions that
employ either heteroaryl methyl ketones (entries 2, 3, 5, 10) or
heteroaryl halides (entry 6). With this protocol, various acetyl
furans, acetyl thiophenes, and acetyl pyridines can be success-
fully monoarylated. Using precatalyst 3,8 monoarylation prod-
ucts can also be obtained in good yields where both heteroaryl
acetyls and heteroaryl chlorides are employed together (entries
7-9, 11). Efforts to arylate heteroaryl methyl ketones whose
heteroaryl groups possess two or more heteroatoms (e.g.,
thiazoles, imidazoles, pyrazines, and triazoles) were largely
unsuccessful. When the R-arylation of an aryl methyl ketone
is conducted in the presence of an acetamide group, complete
selectivity for the arylation of the ketone enolate is observed
over the amide enolate (entry 12). Again, the use of a bulky,
biarylphosphine ligand permits selective monoarylation, and the
use of a highly active Pd source permits the cross-coupling
reactions to be conducted under mild conditions.
a See Supporting Information for general procedures. b Isolated yields
(average of two runs).
precatalysts such as 3 and 4. Such precatalysts permit Pd
activation under mild reaction conditions and in the absence
of competitive residual ligands such as dba or PPh3 that are
typically used to stabilize Pd(0) precursors.
Acknowledgment. We thank the National Institutes of
Health (NIH) for support (GM-46059). M.R.B. thanks the
NIH for a postdoctoral fellowship (GM-F32-75685). We also
thank Merck, Boehringer Ingelheim, and Nippon Chemical
for unrestricted funds.
In summary, we have developed operationally simple,
efficient methods for the selective monoarylation of acetate
esters and aryl methyl ketones. These methods employ
readily activated precatalysts bearing bulky biarylmonophos-
phine ligands in order to effect monoarylation under mild
conditions. In each case, the reactions largely tolerate the
presence of heteroaromatic substituents. The success of these
reactions further demonstrates the advantages of conducting
Pd-catalyzed cross-coupling reactions using metallacyclic
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900295U
(7) It was found empirically that the use of NaOt-Bu resulted in the
formation of significantly greater amounts of diarylated products.
(8) Precatalyst 3 is currently available from Strem (item 46-0268). We
expect 4 to be available in the near future.
Org. Lett., Vol. 11, No. 8, 2009
1775