One-pot sequential Cu-catalyzed reduction and Pd-catalyzed arylation of silyl enol ethers

Article abstract of DOI:10.1021/ol048313c

(Chemical Equation Presented) Enantiomerically enriched β-substituted diphenylsilyl enol ethers, which can be prepared from Cu-catalyzed asymmetric conjugate reduction, are utilized in the Pd-catalyzed arylation of various aryl bromides. This new method p

Full text of DOI:10.1021/ol048313c

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4809-4812
One-Pot Sequential Cu-Catalyzed
Reduction and Pd-Catalyzed Arylation of
Silyl Enol Ethers
Junghyun Chae,† Jaesook Yun,‡ and Stephen L. Buchwald*,†
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139 and Department of Molecular Science
and Technology, Ajou UniVersity, Suwon, 443-749, Korea
sbuchwal@mit.edu
Received August 24, 2004
ABSTRACT
Enantiomerically enriched
â
-substituted diphenylsilyl enol ethers, which can be prepared from Cu-catalyzed asymmetric conjugate reduction,
-arylated cycloalkanones with
are utilized in the Pd-catalyzed arylation of various aryl bromides. This new method provides a simple route to
r
excellent levels of enantiomeric and diastereomeric purity. The isolation of the intermediate, diphenylsilyl enol ethers is not necessary; the
procedure can be carried out in one-pot.
The palladium-catalyzed R-arylation of ketones has provided
a general way to prepare R-arylated ketones.1 In particular,
the use of bulky, electron-rich phosphine ligands not only
increased the rate of R-arylation but also allowed the use of
aryl chlorides as substrates. The usual process, however, has
several drawbacks. For example, arylation generally occurs
preferentially at the less hindered of the two enolizable
R-positions. Thus, it is often necessary to block one R-carbon
in many instances to prevent multiple arylations of the
substrate.2 Another limitation is that for asymmetric ketone
arylations, tertiary stereogenic centers formed after arylation
at a methylene position contain a more acidic proton than
that in the starting material, and therefore the product under-
goes racemization under the reaction conditions. In many
instances, reactions involving ketones and/or aryl halides
bearing a base-sensitive functional group afford the desired
products in low yield. As a result of these limitations, cy-
clopentanones, for example, remain one of the most difficult
classes of ketones to arylate in affordable yield.1c,2 The
R-arylation of these ketones is potentially an attractive tool
for preparing R-aryl cyclopentanones, a structural motif that
often appears in natural products or important intermediates
in their synthesis.3 Thus, the Pd-catalyzed arylation of the
corresponding silyl enol ether of ketones, which appears to
overcome the disadvantages of direct ketone arylation, was
reexamined. Simple fluoride sources, which serve as silicon
activators, replace the need for a strong base.
† Massachusetts Institute of Technology.
‡ Ajou University.
(1) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 1918. (c) Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. (d) Hamann, B.
C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382. (e) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (f) Satoh, T.; Kawamura,
Y; Miura, M; Nomura, M. Angew, Chem., Int. Ed. Engl. 1997, 36, 1740.
(g) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1999, 40, 5345. (h) Terao, Y; Kametani, Y; Wakui, H; Satoh, T.;
Miura, M; Nomura, M. Tetrahedron 2001, 57, 5967. (i) Ehrentraut, A.;
Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344, 209. For a recent review
on Pd-catalyzed R-arylation of carbonyl compounds and nitriles, see: (j)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
Previously, Kuwajima described palladium-catalyzed cou-
pling reactions of silyl enol ethers with aryl halides to afford
(2) For examples where R′-protected cyclopentanones were used for
Pd-catalyzed arylation or vinylation, see: (a) Hamada, T.; Chieffi, A.;
Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261. (b) Chieffi,
A.; Kamikawa, K.; Ahman, J.; Fox, J. M., Buchwald, S. L. Org. Lett. 2001,
3, 1897.
(3) (a) Takano, S.; Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1990, 290. (b) Srikrishna, A.; Reddy, T. J.
Tetrahedron 1998, 54, 8133.
10.1021/ol048313c CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/23/2004

R-aryl ketones.4 In his report, trimethylsilyl enol ethers of
methyl ketones were coupled with aryl bromides using
catalytic PdCl2(o-Tolyl3P)2 in the presence of n-Bu3SnF as
an additive. The organotin enolate generated in situ from
the corresponding silyl enol ether was the proposed reactive
species. Similarly, the use of an organotin enolate for the
R-arylation of ketones was reported by Kosugi and Migita.5
In this case, the tributyltin enolates were generated in situ
from enol acetates. These methods, however, had poor
substrate scope, encompassing only methyl ketones. Thus,
internal ketones such as cycloalkanones were unreactive
under the reaction conditions. Additionally, the use of the
tin additive detracts from the attractiveness of the method.
In this report, we describe a room temperature, Pd-cat-
alyzed method for the arylation of silyl enol ethers of cyclo-
pentanones in the presence of CsF. We utilized enantiomeri-
cally enriched diphenylsilyl enol ethers 2, which can be
prepared from the Cu-catalyzed asymmetric conjugate reduc-
tion of cyclopentenones,6,7 as cyclopentanone enolate equiva-
lents. This protocol provides a new means to access various
R-arylated cyclopentanones with excellent levels of enan-
tiomeric and diastereomeric purity (Scheme 1). In addition,
reactive nucleophilic partners in Pd-catalyzed coupling
reactions8,9 drew our attention to the use of 2 in the Pd-cata-
lyzed arylation process (Scheme 1). We anticipated that under
the Pd-catalyzed coupling conditions, 2 would be approxi-
mately as reactive as those siloxanes reported8,9 and the
fluorodiphenyl siloxane 3, a possible transient intermediate
generated in situ, would be also reactive due to the increased
Lewis acidity of the silicon center.10
Initial experiments employing Kuwajima’s reaction condi-
tions revealed that the coupling reaction of the diphenylsilyl
enol ether dimer 2a and 4-tert-butylbromobenzene gave a
40% yield of arylated product. This result is in contrast to
Kuwajima’s findings, as he had reported that internal silyl
enol ethers are unreactive under these conditions. Our results
suggested that 2 is more reactive than the corresponding TMS
enol ether derivatives. Further optimization of the reaction
protocol by varying the phosphine ligand and the fluoride
source led to a procedure that allowed for the coupling
between 2a and 4-tert-butylbromobenzene in THF at room
temperature using Pd(OAc)2/5 in the presence of CsF in 93%
yield (Table 1, entry 2). Ligand 5, which has previously been
Table 1. Arylation of Diphenylsilyl Enol Ether
Scheme 1
this process can be carried out in a one-pot procedure without
the need for isolation of the intermediate, diphenylsilyl enol
ethers.
Arylation of Diphenylsilyl Enol Ethers. A recent report
describing the use of organosilanols or organosiloxanes as
a Reaction conditions: 1.0 equiv of monomeric diphenylsilyl enol ether
(0.5 equiv 2a), 1.1 equiv of CsF, 1.5 equiv of ArBr, 5 mol % Pd(OAc)2, 10
mol % 5 in THF (4 mL/mmol 2a). b Isolated yield (average of two
(4) For Pd-catalyzed coupling reactions of silyl enol ethers, see: (a)
Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831. (b) Kuwajima,
I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181. For Pd-catalyzed coupling
reactions of silyl ketene acetals, see: (c) Galarini, R.; Musco, A.; Pontellini,
R. J. Mol. Catal. 1992, 72, L11. (d) Agnelli, F.; Sulikowski, G. A.
Tetrahedron Lett. 1998, 39, 8807. (e) Hama, T.; Liu, X.; Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 123, 11176.
1
experiments) of product with >95% purity as determined by GC and H
NMR. c Major diastereomer was determined to be trans11 and the relative
stereochemistry of all other products was assigned by analogy. d Performed
with 2.0 equiv of ArBr. e Obtained after equilibration with K2CO3 in MeOH.
(5) (a) Kosugi, M.; Suzuki, M.; Hagiwara, I.; Goto, K.; Saitoh, K.; Migita,
T. Chem. Lett. 1982, 6, 939. (b) Kosugi, M.; Hagiwara, I.; Sumiya, T.;
Migita, T. J. Chem. Soc., Chem. Commun. 1983, 7, 344. (c) Kosugi, M.;
Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem. Soc. Jpn. 1984, 57, 242.
(6) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 6797. For other important Cu-catalyzed
conjugate reductions using silanes as the hydride source, see: (b) Appella,
D. H.; Moritani, Y.; Shintani, Y.; Ferreira, E. M.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9473. (c) Jurkauskas, V.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 2892. (d) Lipshutz, B. H.; Keithe, J. M.; Papa, P.;
Vivian, R. W.; Tetrahedron Lett. 1998, 39, 4627. (e) Lipshutz, B. H.;
Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789. (f) Lipshutz, B.
H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126, 8352. (g)
Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A.
Org. Lett. 2004, 6, 1273.
used for the direct R-arylation of ketones,1c was found to be
most effective for the arylation of diphenylsilyl enol ethers.
While the use of NaF, KF, TBAF on SiO2, TBAT (1.0 M in
THF), ZnF2, and TiCl4 gave poor results, CsF afforded good
(7) (a) Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3, 1129. For other
examples where the silyl enol ether intermediates were used in C-C bond
formations such as Aldol reaction, see: (b) Lipshutz, B. H.; Chrisman, W.;
Noson, K.; Papa, P.; Sclafani, J. A.; Vivian, R. W.; Keithe, J. M.
Tetrahedron 2000, 56, 2779.
4810
Org. Lett., Vol. 6, No. 26, 2004

yields of product while minimizing the amount of desilylated
byproduct. Employing THF as the solvent was also crucial;
the use of toluene led to a slower reaction rate even at ele-
vated temperatures. Although the potential competitive trans-
fer of the silicon-bound phenyl group8,9 during transmeta-
lation could diminish the amount of the desired coupling
product, the biaryl product was observed only at higher tem-
peratures. A range of substrates, including electron-neutral
(Table 1, entries 1-2), electron-rich (entries 3-4), and elec-
tron-poor (entry 5) aryl bromides along with ortho-substituted
aryl bromides (entry 6), were found to be compatible under
these conditions. The mild reaction conditions also tolerated
the presence of functional groups such as an ester (entry 5)
in the aryl bromide. It is noteworthy that the arylation
reaction is highly regioselective. Formation of regioisomers
or diarylated products could not be detected by GC analysis.
The arylated products were produced generally with a high
diastereomeric ratio (>95:5), with the trans isomer being
favored.11 The one exception was entry 6 where a diaster-
eomeric ratio of 92:8 was observed. This ratio was improved
to 97.5:2.5 after equilibration with K2CO3 in MeOH.
One-Pot Sequential Cu-Catalyzed Conjugate Reduction
and Pd-Catalyzed Silyl Enol Ether Arylation. Purification
of silyl enol ethers can be troublesome, and therefore the
development of a one-pot protocol was investigated. After
performing the asymmetric conjugate reduction following
the previously described procedure,6a we carried out the
arylation in the same reaction vessel after the addition of
Pd(OAc)2, ligand 5, CsF, aryl bromide, and THF. Two
important factors for the success of this one-pot protocol were
determined to be (1) the use of lower quantities of catalyst
in the reduction step and (2) the choice of solvent for each
step.
does 5, resulting in a low yield of arylated product. To
support this hypothesis, we examined the effect of changing
the ratio of the catalysts for the two steps of the reaction
sequence. We found that the yield of 4b increased as the
quantity of the CuCl/Tol-BINAP catalyst was reduced
relative to that of the Pd catalyst. It was determined that the
use of 1 mol % CuCl/(S)-Tol-BINAP in the reduction step
and 5 mol % Pd(OAc)2/10 mol % 5 in the arylation step
was optimal.
The choice of solvent affected both the enantioselectivity
of the reduction and the yield of the arylation step (Table
3). Since THF was proven to be effective for the arylation
Table 3. Solvent Effect
solvent
THF
tolueneb,c
eed
yield
THF/n-pentaneb,c
R
eed
yield
eed
yield
CH3
(CH2)2Ph
72%
76%
74%
80%
96%
95%
97%
95%
72%
75%
a After reduction, the solvent was removed in vacuo and the second
set of reagents were added followed by THF. b About 2/3 of solvent
was removed in vacuo. c T ) 78 °C. d Ee of 2 (3-substituted cyclopen-
tanone)14.
step, we began by examining the use of THF for the con-
jugate reduction step. The use of THF in both steps afforded
a high yield (74%) of the desired arylated product. However,
a significant decrease in the enantioselectivity of the reduc-
tion (∼70% ee) was seen. Reinvestigation into the appropri-
ate solvent system for the asymmetric conjugate reduction
revealed that the use of nonpolar solvents such as toluene
and n-pentane12 was necessary to maintain high enantiose-
lectivity. Initially, toluene, which we have previously used,6a
Our initial attempt to effect a one-pot reaction, using
equimolar amounts of CuCl/(S)-Tol-BINAP (5 mol %) and
Pd(OAc)2 (5 mol %), gave only a trace amount of the desired
coupling product 4b (Table 2). We felt that this disappointing
Table 2. Effect of the Relative Quantities of Catalysts
(8) (a) Mowery, M. E.; Deshong, P. J. Org. Chem. 1999, 64, 1684. (b)
Mowery, M. E.; Deshong, P. Org. Lett. 1999, 1, 2137. (c) Lam, P. Y. S.;
Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; Deshong, P.; Clark, C. G.
J. Am. Chem. Soc. 2000, 122, 7600. (d) Correia, R.; Deshong, P. J. Org.
Chem. 2001, 66, 7159. (e) Riggleman, S.; Deshong, P. J. Org. Chem. 2003,
68, 8106. (f) McElroy, W. T.; Deshong, P. Org. Lett. 2003, 5, 4779. (g)
Seganish, W. M.; Deshong, P. J. Org. Chem. 2004, 69, 1137.
CuCl:( S)-Tol-BINAP
Pd(OAc)2:5
yield (GC) of 4b
(9) (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835, and
references therein. (b) Kellemeyn, J. M.; Denmark, S. E. Org. Lett. 2003,
5, 3483. (c) Ober, M. H.; Denmark, S. E. Org. Lett. 2003, 5, 1357. (d)
Tymonko, S. A.; Denmark, S. E. J. Org. Chem. 2003, 68, 9151.
(10) For examples where fluorinated silanes are used in Pd-catalyzed
coupling reactions, see: (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1989,
54, 268. (b) Hatanaka, Y.; Goda, K.; Okahara, Y.; Hiyama, T. Tetrahedron
1994, 50, 8301. (c) Hatanaka, Y.; Ebina, Y.; Hiyama, T. J. Am. Chem.
Soc. 1991, 113, 7075. (d) Matsuhashi, H.; Asai, S.; Hirabayashi, K.;
Hatanaka, Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 1997, 70, 437.
(11) 1H NMR spectrum of trans-2-phenyl-3-methylcyclopentanone was
consistent with that previously reported: Baldwin, J. E.; Bonacorsi, S., Jr.
J. Am. Chem. Soc. 1993, 153, 10621.
5 mol %:5 mol %
3 mol %:3 mol %
1 mol %:1 mol %
5 mol %:10 mol %
5 mol %:10 mol %
5 mol %:10 mol %
trace
32%
74%
result was due to the presence of (S)-Tol-BINAP. While
screening phosphine ligands for the arylation of silyl enol
ethers, we found bisphosphine ligands such as Tol-BINAP
to be ineffective, and using them afforded low yields of the
arylated product. We believed that the Tol-BINAP in the
reaction mixture binds to Pd with a higher affinity than
(12) n-Pentane could be used in place of toluene in the conjugate
reduction of lactones. Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 11253.
Org. Lett., Vol. 6, No. 26, 2004
4811

underwent coupling with aryl bromides, providing compa-
rable yields to the reactions in which THF was used for both
steps.
Table 4. One-Pot Reaction
These optimized one-pot reaction conditions were applied
to the reaction of a variety of â-substituted cyclopentenones
(Table 4). Both methyl and phenethyl-substituted cyclopen-
tenones were reduced in high ee (97 and 95%, respectively),
and the resulting in situ-generated diphenylsilyl enol ethers
were coupled with various aryl bromides regioselectively in
good to moderate yields. This protocol could also be applied
to cyclohexenone substrates. Reduction of 3-methyl cyclo-
hexenone and the subsequent arylation of the corresponding
diphenylsilyl enol ether afforded the R-arylated cyclohex-
anone in moderate yields (Table 4, entries 9-10). In all cases,
a high level of diastereoselectivity (>90% de) was observed.
In conclusion, we have developed a protocol for the
Pd-catalyzed coupling of silyl enol ethers with aryl bromides.
Enantiomerically enriched â-substituted diphenylsilyl enol
ethers 2, which were prepared from Cu-catalyzed asymmetric
conjugate reduction, were coupled with various aryl bromides
using Pd/5 in the presence of CsF. This new method provides
a simple means to access R-arylated cycloalkanones with
two new tertiary stereogenic centers in excellent enantio-
and diastereoselectivity that are difficult to prepare via other
methods.
Acknowledgment. We thank the National Institutes of
Health (GM46059) for funding as well as Pfizer, Merck, and
Novartis for additional unrestricted support. We are grateful
to Engelhard for a gift of Pd(OAc)2. We thank Dr. Valdas
Jurkauskas for helpful discussions.
a 1a (n ) 1, R ) Me), 1b (n ) 1, R ) (CH2)2Ph), 1c (n ) 2, R ) Me).
b Reaction conditions: 1.0 equiv of enone 1, 1 mol % CuCl, 1 mol % (S)-
Tol-BINAP, 1 mol % NaOt-Bu, 0.51 equiv of Ph2SiH2 in THF/n-pentane
(1:1, 2 mL per mmol of enone 1) at -78 °C. After reduction, about 2/3 of
the solvent was removed in vacuo and 1.1 equiv of CsF, 1.5 equiv of ArBr,
5 mol % Pd(OAc)2, and 10 mol % ligand 5 were added followed by THF
(2 mL per mmol of enone). c Reduction was carried out at 0 °C.
d (S)-BIPHEMP was used in place of (S)-Tol-BINAP. e Yields are the
average of two isolated yields of >95% purity as determined by GC and
1H NMR. f Major diastereomer was determined to be trans.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048313C
was employed and removed in vacuo after the reduction was
completed. This left a gel-like crude material to which THF
and the remaining reaction components were added. How-
ever, the coupling with aryl bromides performed in this way
afforded product in poor yield. We subsequently found that
the use of a n-pentane/THF solvent (1:1) system afforded
the production of the silyl enol ether with high enantiose-
lectivity (95-97% ee). Additionally, n-pentane, in contrast
to toluene, was easily removed from the reaction mixture,
leaving the intermediate silyl enol ethers in THF.13 These
(13) After the asymmetric reduction was carried out in THF/n-pentane
(1:1), about 2/3 of the solvent was removed under vacuum and 2 in the
remaining THF was subsequently used in arylation by adding Pd(OAc)2,
5, ArBr, and additional THF. See Supporting Information for details. Later,
it was found that the slow addition of the cyclopentenone (5-6 h/mmol of
enone) to the suspension of CuCl, NaOt-Bu, and Ph2SiH2 in THF also gave
comparably high ee. However, the protocol using a THF/n-pentane cosolvent
system is preferred due to its experimental convenience.
(14) Ee of each product was determined by analyzing the ee of unarylated
3-substituted cyclopentanone by HPLC or the diastereomeric ketals of
unarylated 3-substituted cyclopentanone by NMR, and the absolute stereo-
chemistry at the C3 position of the product was assigned in accord with a
previous report.8a See Supporting Information for details.
4812
Org. Lett., Vol. 6, No. 26, 2004