Palladium-catalyzed regiocontrolled α-arylation of trimethylsilyl enol ethers with aryl halides

Article abstract of DOI:10.1021/ol062093g

(Diagram presented) Inter- and intramolecular arylations of trimethylsilyl enol ethers with aryl halides are accomplished regiospecifically in the presence of a palladium catalyst and tributyltin fluoride in refluxing benzene or toluene. The optimal catalyst system called for the use of Pd ₂(dba)₃ and tri-tert-butylphosphine in ca. 1:2 ratio. Aryl iodides, bromides, and chlorides are all effective arylation partners in this reaction.

Full text of DOI:10.1021/ol062093g

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5725-5728
Palladium-Catalyzed Regiocontrolled
-Arylation of Trimethylsilyl Enol Ethers
with Aryl Halides
r
Tetsuo Iwama and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received August 24, 2006
ABSTRACT
Inter- and intramolecular arylations of trimethylsilyl enol ethers with aryl halides are accomplished regiospecifically in the presence of a
palladium catalyst and tributyltin fluoride in refluxing benzene or toluene. The optimal catalyst system called for the use of Pd2(dba)3 and
tri-tert-butylphosphine in ca. 1:2 ratio. Aryl iodides, bromides, and chlorides are all effective arylation partners in this reaction.
The direct introduction of an aryl unit at a nucleophilic
carbon is a transformation of central importance to complex
molecule synthesis.1 A synthetically useful subset of this class
of reactions is the arylation of ketones at the R-position.2
Such transformations are even more valuable in instances
where the arylating agent is adorned with substitutents. For
example, in connection with a route to Aspidosperma
alkaloids,3 we developed a diaryliodonium reagent for the
regiospecific o-nitrophenylation of an silyl enol ether,
wherein subsequent reduction of the nitro group yielded
indoles (e.g., eq 1).4 Our long-standing interest in transition
metal catalyzed arylation and vinylation of phenolates (eq
2)5 prompted us to examine procedures for the palladium-
catalyzed arylations of silyl enol ethers with aryl halides,
and we report our results below.6,7
(1) Abramovitch, R. A.; Barton, D. H. R.; Finet, J. P. Tetrahedron 1988,
44, 3039-3071.
(2) Selected examples of R-arylation of ketones that do not involve Pd
catalysis: (a) 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.
(b) Sakakura, T.; Hara, M.; Tanaka, M. J. Chem. Soc., Chem. Commun.
1985, 1545-1546. (c) Rathke, M. W.; Vogiazoglou, D. J. Org. Chem. 1987,
52, 3697-3698. (d) Negishi, E. I.; Akiyoshi, K. Chem. Lett. 1987, 1007-
1010. (e) Finet, J. P. Chem. ReV. 1989, 89, 1487-1501. (f) Chen, K.; Koser,
G. F. J. Org. Chem. 1991, 56, 5764-5767. (g) Morgan, J.; Pinhey, J. T.;
Rowe, B. A. J. Chem. Soc., Perkin Trans. 3 1997, 1005-1008. (h) Mino,
T.; Matsuda, T.; Maruhashi, K.; Yamashita, M. Organometallics 1997, 16,
3241-3242. (i) Ryan, J. H.; Stang, P. J. Tetrahedron Lett. 1997, 38, 5061-
5064. (j) Oxidative arylation of ketone enolate: Bhowmik, D. R.; Ven-
kateswaran, R. V. Tetrahedron Lett. 1999, 40, 7431-7433. (k) Deng, H.;
Konopelski, J. P. Org. Lett. 2001, 3, 3001-3004. (l) Ooi, T.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 10494-10495. (m) Koech, P. K.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 5350-5351. For a comprehensive listing
of methods for R-arylation of ketones, see ref 13d.
In pioneering work, Kuwajima and Urabe8 reported the
palladium-catalyzed R-arylation of silyl enol ethers of
ketones with aryl halides in the presence of Bu3SnF.9-11 The
advantage of this method over the palladium-catalyzed
arylation of ketones under basic conditions is that it enables
regiocontrol of the arylation rather than have it be controlled
by the inherent kinetic or, more commonly, thermodynamic
(3) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120,
13523-13524. (b) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 4628-4641.
10.1021/ol062093g CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/08/2006

reactivity of the ketone.12-15 Furthermore, one can hope to
exploit the rich chemistry of regioselective enolate formation
and parlay it into a regioselective arylation procedure.16
Unfortunately, as originally reported, the scope of this
reaction was rather limited, primarily to the arylation of the
kinetic enol silyl ethers of methyl ketones.8 Even the arylation
of cyclohexanone enol ether was reported to give <15% yield
of the R-arylation product. We examined modern variations
of this process and developed a general procedure for the
regiospecific inter- and intramolecular arylation of various
ketone enol silyl ethers.6,7
conditions were examined for the arylation of cyclohexanone
trimethylsilyl enol ether (2) with p-iodoanisole (eq 3).18,19
Of the reaction parameters examined, the combination that
afforded the cleanest reaction involved the use of 2.5 mol
% of Pd2(dba)3, 6 mol % of t-Bu3P, and 1 equiv of Bu3SnF
in refluxing benzene. However, the reaction was slow under
these conditions and reached only ∼50% completion after
20 h. On the other hand, it progressed well when the silyl
enol ether and tin fluoride were used in excess (2 equiv each),
and afforded arylated product 3a in 82% isolated yield (Table
1, entry 1).
In considering the results and probable mechanism of the
Kuwajima-Urabe arylation, the problematic steps appeared
to be either the transmetalation of the putative tin enolate to
the arylpalladium enolate or its reductive elimination to the
arylated ketone. Assuming the latter was the issue, the
expectation was that this step could be accelerated through
the use of the bulky ligand t-Bu3P.17 Numerous reaction
Table 1. Pd-Catalyzed Arylation of Trimethylsilyl Enol Ether
of Cyclohexanone with Various Aryl Halidesa
(4) (a) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org.
Lett. 1999, 1, 673-676. (b) The direct o-nitroarylation of enolates with
aryliodonium salts has also been reported: Rawal, V. H.; Takenaka, N.;
Iwama, T. Abstracts of Papers; 222nd National Meeting of the American
Chemical Society, Chicago, IL, August 26-30, 2001; American Chemical
Society: Washington, DC, 2001; ORGN-007 (for a detailed abstract, see
Chem. Abstr. AN 2001:640370). For a full discussion of this work, see:
Takenaka, N. Ph.D. Dissertation, University of Chicago, Chicago, IL, 2002.
For a related report, see: (c) Aggarwal, V. K.; Olofsson, B. Angew. Chem.,
Int. Ed. 2005, 44, 5516-5519.
(5) (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997,
62, 2-3. (b) Hennings, D. D.; Iwasa, S.; Rawal, V. H. Tetrahedron Lett.
1997, 38, 6379-6382. (c) Hennings, D. D.; Iwama, T.; Rawal, V. H. Org.
Lett. 1999, 1, 1205-1208. For application to complex molecule synthesis
see: (d) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7,
3421-3424.
(6) The contents of this paper were presented at the 222nd National
Meeting of the American Chemical Society: Rawal, V. H.; Iwama, T.
Abstracts of Papers; 222nd National Meeting of the American Chemical
Society, Chicago, IL, August 26-30, 2001; American Chemical Society:
Washington, DC, ORGN-606 (for a detailed abstract, see Chem. Abstr. AN
2001:640969). This work was also presented at the 33rd Great Lakes/Central
Regional Meeting of the American Chemical Society, Grand Rapids, MI,
June 11-13, 2001.
(7) A recent publication by Verkade, Hartwig, and co-workers, describing
the use of similar conditions, that appeared on the web prompts us to present
fully our previously reported work (ref 6) in this area. See: Su, W.; Raders,
S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem., Int. Ed. 2006,
45, 5852-5855.
entry
R
X
time (h)
product
% yielda
1
2
3b
4c
5
6
7
8
9
10
11
12
13
14
15
4-MeO
4-MeO
4-MeO
4-MeO
4-NMe2
H
4-NO2
4-NO2
4-NO2
4-MeO2C
3-MeO
2-MeO
2-Me
I
19
19
20
20
9
21
8
8
3a
3a
3a
3a
3b
3c
3d
3d
3d
3e
3f
82
78
64
64
54
75
70
71
61
62
53
71
70
55
25
Br
Br
Cl
Br
I
I
Br
Cl
Br
I
5
21
20
21
21
20
3.5
I
3g
3h
3h
3i
Br
Cl
Cl
2-Me
2-NO2
a Reactions were conducted with 1 equiv of the aryl halide 1 (0.25 M)
and 2 equiv of TMS enol ether 2. Yield is based on the aryl halide. b 2-
(Di-tert-butylphosphino)biphenyl (6 mol %) was used instead of t-Bu3P.
c Carried out in refluxing toluene.
(8) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831-6833.
(9) Other early examples of Pd-catalyzed R-arylation that go through
stannyl enolates: (a) Kosugi, M.; Sizuki, M.; Hagiwara, I.; Goto, K.; Saitho,
K.; Migita, T. Chem. Lett. 1982, 939-940. (b) Kosugi, M.; Hagiwara, I.;
Sumiya, T.; Migita, T. J. Chem. Soc., Chem. Commun. 1983, 344-345.
(c) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem. Soc. Jpn.
1984, 57, 242-246. (d) Sakakura, T.; Hara, M.; Tanaka, M. J. Chem. Soc.,
Perkin Trans. 1 1994, 283-288. Antimony enolate: (e) Kang, S. K.; Ryu,
H. C.; Hong, Y. T. J. Chem. Soc., Perkin Trans. 1 2000, 3350-3351.
(10) Pd-catalyzed arylations of silyl ketene acetals: (a) Carfagna, C.;
Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J. Org. Chem. 1991, 56, 261-
263. (b) Galarini, R.; Musco, A.; Pontellini, R.; Santi, R. J. Mol. Catal.
1992, 72, L11-L13. (c) Sakamoto, T.; Kondo, Y.; Masumoto, K.;
Yamanaka, H. Heterocycles 1993, 36, 2509-2512. (d) Sakamoto, T.;
Kondo, Y.; Masumoto, K.; Yamanaka, H. J. Chem. Soc., Perkin Trans. 1
1994, 235-236. (e) Agnelli, F.; Sulikowski, G. A. Tetrahedon Lett. 1998,
39, 8807-8810. (f) Lee, S.; Lee, W.-M.; Sulikowski, G. A. J. Org. Chem.
1999, 64, 4224-4225. (g) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004,
126, 5182-5192.
(11) For recent developments on Pd-catalyzed arylation of silyl enol
ethers or related species, see: (a) Hama, T.; Culkin, D. A.; Hartwig, J. F.
J. Am. Chem. Soc. 2006, 128, 4976-4985,and references cited therein. (b)
Chae, J.; Yun, J.; Buchwald, S. L. Org. Lett. 2004, 6, 4809-4812 and
references cited therein.
(12) Early examples of Ni-catalyzed R-arylation of enolates: (a) Refer-
ence 2a. (b) Millard, A. A.; Rathke, M. W. J. Am. Chem. Soc. 1977, 99,
4833-4835.
The standard conditions described above were utilized to
perform the arylation of 2 with various aryl halides, and the
results are summarized in Table 1.20,21 The arylation of 2
with p-bromoanisole under the same conditions afforded
cyclohexanone 3a in 78% yield (entry 2). Arylation product
3a was obtained in slightly lower yield when the bulky ligand
2-(di-tert-butylphosphino)biphenyl was used (entry 3). Even
the corresponding aryl chloride gave the arylated product in
good yield, provided the reaction was carried out at a slightly
higher temperature, in refluxing toluene (entry 4). By
contrast, the corresponding triflate was unreactive and was
1
recovered cleanly (by H NMR) after 18 h. Other electron-
rich aryl halides were also effective coupling partners (entries
5726
Org. Lett., Vol. 8, No. 25, 2006

6, 11-14). The successful use of o-chlorotoluene, in
particular, is noteworthy, since it is both electron-rich and
sterically encumbered. Aryl halides possessing an electron-
withdrawing group at the para position gave the respective
arylated products in good yields (entries 7-10). By com-
parison, o-nitro-substituted aryl halides (Cl, Br, I) were poor
arylating agents, and only o-chloronitrobenzene gave any of
the arylation product (entry 15). Some of the above arylations
were also carried out successfully in toluene at 80 °C instead
of refluxing benzene.
palladium enolate intermediates do not equilibrate to the
regioisomeric, less-hindered enolates. Norbornanone-derived
enol ether 6 reacted slowly with p-iodoanisole to produce
the expected arylation product (7) in 58% yield together with
recovered p-iodoanisole (entry 2). Also slow to react was
the acyclic enol ether 8.8 This reaction was carried out in
refluxing benzene, using p-bromoanisole as the arylating
agent, and examination of the reaction mixture by 1H NMR
after 9 h showed the presence of primarily unreacted 8. In
refluxing toluene, however, this arylation proceeded well and
afforded 9 in 70% yield (entry 3). When this reaction was
carried out with p-iodoanisole, it proceeded in low yield and
produced unindentified byproducts. A competition experi-
ment (eq 4) showed that the aryl iodide is consumed faster
To explore the generality of the arylation protocol,
additional TMS enol ethers were prepared and subjected to
standard arylation protocol (Table 2).16 Entry 1 highlights
Table 2. Intermolecular Pd-Catalyzed Arylation of Different
TMS Enol Ether Substratesa
than the bromide, consistent with the expected relative rates
of oxidative addition of Pd0 to aryl halides. These observa-
tions indicate that oxidative addition of Pd0 onto the aryl
halide is not the rate determining step in the reaction and
suggest that the Pd-intermediate formed from the aryl iodide
is less competent, due to either poor reactivity or stability,
than that from the aryl bromide at proceeding to the product.
(15) For early reports on Pd-catalyzed alkenylation of enolates, see: (a)
Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454-3455. (b) Piers, E.;
Renaud, J. J. Org. Chem. 1993, 58, 11-13. See also: (c) Yu, J. M.; Wang,
T.; Liu, X. X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X. B.; Cook, J.
M. J. Org. Chem. 2003, 68, 7565-7581 and references cited therein. (d)
Sole, D.; Urbaneja, X.; Bonjoch, J. AdV. Synth. Catal. 2004, 346, 1646-
1650 and references cited therein. (e) Chieffi, A.; Kamikawa, K.; Ahman,
J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897-1900.
(16) (a) Heathcock, C. H. Mod. Synth. Methods 1992, 6, 1-102. (b)
Kobayashi, S.; Manabe, K.; Ishitani, H.; Matsuo, J. I. In Science of Synthesis;
Bellus, D., et al., Eds.; Georg Thieme: Stuttgart, Germany, 2002; Vol. 9,
pp 317-369.
(17) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617-620. (b) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 1998, 39, 2367-2370. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 1998, 37, 3387-3388. (d) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F.
J. Am. Chem. Soc. 1999, 121, 2123-2132. See also ref 13g.
(18) This combination was selected as it was expected to be a challenging
arylation, since not only is the phenylation cyclohexanone reported to be
low yielding (ref 8), but the oxidative addition to the electron-rich
p-iodoanisole was expected to be slow.
(19) An extensive screening of reaction conditions was carried out. Pd
sources examined: PdCl2(Ph3P)2, PdCl2(o-Tol3P)2, PdCl2, Pd2(dba)3, Pd(OAc)2,
or PtCl2(PhCN)2. Phosphine ligands: BINAP, Tol-BINAP, t- Bu3P,
(t-BuCH2)3P, 2-(di-tert-butylphosphino)biphenyl, cHex3P, Ph3P, (o-Tol)3As,
Ph3As, and (i-PrO)3P. Fluoride sources: Bu3SnF, LiF, NaF, CsF, CuF2,
ZnF2, ZrF4, KF, ZnCl2, SnCl4, or Me4NF. Solvents: benzene, toluene, DMF,
or THF. Additives: LiCl, NaOAc and t-BuOK.
a Reactions were conducted with 1 equiv of the aryl halide (0.25 M), 2
equiv of TMS-enol ether, 2.5 mol % of Pd2(dba)3, 6 mol % of t-Bu3P, 2
equiv of Bu3SnF, PhH, reflux.
an important feature of the silyl enol ether arylation
method: arylations take place regiospecifically. Thus, aryl-
ation of enol ether 4, prepared easily and regiospecifically
by methylcuprate addition to 2-cyclohexenone,22 with p-
iodoanisole gave arylated product 5 as a single regio- and
stereoisomer in 72% yield.23 Evidently, the putative tin and
(13) For the Pd-catalyzed intermolecular arylation of carbonyl com-
pounds, see: (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 11108-11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382-12383. (c) Kawatsura, M; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473-1478. (d) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370. (e) Ehrentraut,
A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344, 209-217. (f) Marion,
N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.; Nolan, S. P. J.
Org. Chem. 2006, 71, 3816-3821 and references cited therein. (g)
Review: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-
245.
(14) Intramolecular R-arylation of enolates: (a) Muratake, H.; Natsume,
M.; Nakai, H. Tetrahedron 2004, 60, 11783-11803 and references cited
therein. (b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546-6553. (c) Sole, D.; Vallverdu, L.; Solans, X.; Font-
Bardia, M.; Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587-1594. (d)
Honda, T.; Sakamaki, Y. Tetrahedron Lett. 2005, 46, 6823-6825. (e)
Reference 5d.
(20) General procedure for Pd-catalyzed arylation: A mixture containing
TMS enol ether (1 mmol), aryl halide (0.5 mmol), 2.5 mol % of Pd2(dba)3
(11.4 mg), and Bu3SnF (309 mg, 1 mmol) under a nitrogen atmosphere
t
was treated with a solution of Bu3P (7.5 µL) in benzene (2 mL) at room
temperature. The resulting mixture was heated to reflux. After cooling to
room temperature, the reaction mixture was diluted with ether (20 mL)
(when the precipitate of tin residue was formed, it was removed by
decantation with ether), washed with 1 N aqueous NaOH twice (5 mL each)
followed by brine (2 × 5 mL), dried (MgSO4), and concentrated. The residue
was purified by flash column chromatography on silica gel.
Org. Lett., Vol. 8, No. 25, 2006
5727

The synthetic utility of this method was further developed
through the examination of substrates in which the arylation
would take place intramolecularly (Table 3).14 Treatment of
afforded arylation product 15 high yield (entry 3). All three
of the entries are noteworthy in that they produce a [3.3.1]-
bicyclic array. The final entry shows the construction of
tetrahydrofluorenone 17 through the intramolecular arylation
method. In this case the arylated product (17), assumed to
be cis, was formed in 46% yield along with 24% of the
recovered ketone.
Table 3. Intramolecular Pd-Catalyzed Arylation
A plausible mechanism for the Pd-catalyzed arylation of
TMS enol ethers is shown in Scheme 1. The starting TMS
Scheme 1
a Standard conditions: 0.25 M of TMS enol ether, 5 mol % of Pd2(dba)3,
12 mol % of t-Bu3P, 1 equiv of Bu3SnF, reflux. b 2.5 mol % of Pd2(dba)3
and 6 mol % of t-Bu3P were used. c Uncyclized ketone was isolated in 12%
yield. d Uncyclized ketone was isolated in 24% yield.
enol ether is expected to react with Bu3SnF to generate tin
enolate A, which is under equilibrium with R-stannyl ketone
B.8,24 The reaction of the tin enolate with Ar-Pd-X would
produce the transmetalation product, Pd-enolates C.9-11
Reductive elimination of C to give a CsC bond then gives
the arylation product and regenerates Pd0.
In summary, Pd-catalyzed arylation of TMS enol ethers
was achieved in both inter- and intramolecular manner by
use of Pd2(dba)3 and t-Bu3P in the presence of Bu3SnF.
Electron-poor and electron-rich aryl halides, including
iodides, bromides, and chlorides, participated in the present
arylation. The arylations proceeded regiospecificity and with
a range of substrates.
TMS enol ether 10 with 1 equiv of Bu3SnF, 5 mol % of
Pd2(dba)3, and 12 mol % of t-Bu3P in benzene furnished
[3.3.1] bicyclic product 11 in 62% yield together with 12%
of the uncyclized ketone, corresponding to the hydrolysis
product of 11. The arylative cyclization of 12 required higher
temperature (refluxing toluene) and gave 13 in 66% yield,
accompanied by the uncyclized ketone (12%). In both cases,
lower loadings of Pd2(dba)3 (2.5 mol %) and t-Bu3P (6 mol
%) resulted in slower reactions and increased amounts of
the ketone arising from hydrolysis of the starting material.
On the other hand, the reaction of 14 with 2.5 mol % of
Pd2(dba)3 and 6 mol % of t-Bu3P in refluxing benzene
Acknowledgment. We thank the National Institutes of
Health for financial suport of this work. We also thank Merck
& Co. for additional support.
(21) The success of this reaction is dependent on the quality of t-Bu3P.
Irreproducible results were obtained with one, newly purchased bottle of
t-Bu3P.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra of arylated compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Binkley, E. S.; Heathcock, C. H. J. Org. Chem. 1975, 40, 2156-
2160. (b) Dieter, R. K.; Dieter, J. W. J. Chem. Soc., Chem. Commun. 1983,
1378-1380.
(23) The product arising from the regioisomeric enolate was not detected
1
OL062093G
in the H NMR of the crude reaction mixture. Product 5 was assigned the
trans stereochemistry based on the coupling constant of the 2,3-vicinal
protons (J ) 11.5 Hz).
(24) Shibata, I.; Baba, A. Org. Prep. Proced. Int. 1994, 26, 85-100.
5728
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