Pd-catalyzed α-arylation of trimethylsilyl enol ethers with aryl bromides and chlorides: A synergistic effect of two metal fluorides as additives

Article abstract of DOI:10.1002/anie.200601887

(Chemical Equation Presented) The long-sought-after palladium-catalyzed coupling of silyl enol ethers, both cyclic and acyclic, with a wide range of aryl bromides and chlorides to form α-aryl ketones is realized. The key to effective activation of the silicon enolate was the use of two metal fluoride additives, which operate in a synergistic fashion.

Full text of DOI:10.1002/anie.200601887

Communications
Cross-Coupling
DOI: 10.1002/anie.200601887
Pd-Catalyzed a-Arylation of Trimethylsilyl Enol
Ethers with Aryl Bromides and Chlorides: A
Synergistic Effect of Two Metal Fluorides as
Additives**
Weiping Su, Steven Raders, John G. Verkade,*
Xuebin Liao, and John F. Hartwig*
Ketone enolates are among the most common nucleophiles in
organic chemistry, and transition-metal-catalyzed cross-coup
ling reactions are among the most commonly used catalytic
processes.[1] However, the combination of these two chem-
istries—cross-coupling of enolate nucleophiles—has been
developed only recently.[2–6] Moreover, coupling of silyl enol
ethers, which temper the high basicity and nucleophilicity of
alkali metal enolates,[7] is undeveloped.[8–11] The first example
of the cross-coupling of silyl enol ethers was reported in 1982
by Kuwajima and Urabe, and the reactions of related tin
enolates were reported by Kosugi and co-workers in 1984.[9]
The reactions of silyl enol ethers were limited to the enolates
of methyl ketones, and the activation of the silyl enol ether
was conducted with stoichiometric tributyltin fluoride. Over
the next twenty years, the scope and utility of the coupling of
silyl or stannyl enol ethers has advanced only slightly.[10–12]
The cross-coupling of silyl enol ethers offers several
advantages over the coupling of alkali-metal enolates of
ketones. The reduced basicity should improve functional-
group compatibility; the defined structure of the main-group
enolate could allow coupling at the more hindered site of a
ketone with two enolizable positions; and conditions for the
coupling of silyl enol ethers could ultimately allow the
development of enantioselective processes to form acidic
tertiary stereocenters.
[*] Dr. W. Su,[+] S. Raders, Prof. Dr. J. G. Verkade
Department of Chemistry
Gilman Hall, Iowa State University
Ames, IA 50011 (USA)
Fax: (+1)515-294-0105
E-mail: jverkade@iastate.edu
Dr. X. Liao, Prof.Dr. J. F. Hartwig
Department of Chemistry
Yale University, P.O. Box 208107
New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
E-mail: john.hartwig@yale.edu
[+] Current address:
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Fujian 350002 (P.R. China)
[**] J.G.V. gratefully acknowledges the National Science Foundation for
financial support of this investigation, and J.F.H. thanks the NIH
(NIGMS GM-58108). The authors thank Professor Robert Angelici
for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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We report two protocols for the coupling of several classes
of ketones with aryl bromides catalyzed by palladium and
PtBu3. These reactions are conducted in toluene as the solvent
with a combination of tributyltin fluoride and cesium fluoride
as additives, or in N,N-dimethylformamide (DMF) with a
combination of cesium fluoride and zinc fluoride as additives.
The success of these procedures, which tolerate a variety of
electrophilic functionalities and allow arylations at the more
hindered position of dialkyl ketones, results from a synergistic
effect[13] of two fluoride activators.
The reaction of 1.4 equivalents of 1 with 2 in THF
containing CsF as the additive afforded the desired product in
a high yield of 81% (entry 10), but the functional-group
tolerance of reactions with CsF alone was similar to that of
reactions of alkali-metal enolates. For example, reactions of 1
with 1-bromo-4-nitrobenzene and 4’-bromoacetophenone in
THF afforded only 40 and 10% yields, respectively [Eq.(1)].
One set of studies focused on the arylation of silyl enol
ethers formed by the addition of Grignard regents to a,b-
unsaturated ketones in the presence of CuBr·Me2S, chloro-
trimethylsilane, and hexamethylphosphoramide (HMPA;
Scheme 1).[14] Studies of the model reaction of 2-trimethyl-
In contrast, reactions conducted with a combination of
Bu3SnF and CsF as additives occurred in high yields (entry 4)
and with a broad scope (see below). Reactions conducted
with a catalytic amount of Bu3SnF (10 mol% based on the
silyl enol ether) and 1 equivalent of CsF afforded the desired
product in 67% yield (entry 9). Altering the ligand, palladium
precursor, and solvent did not further improve the reaction
(reactions in toluene and THF occurred in comparable
yields), but increasing the amount of the silyl enol ether and
additive (1.4:1.4:1.4:1 ratio of the two additives, enol 1, and
aryl halide 2) led to formation of the coupled product in 98%
yield (entry 8).
Table 2illustrates the scope of the reactions under the
conditions of entry 8 in Table 1 with Bu3SnF and CsF as the
additives. Both acyclic and cyclic silyl enol ethers smoothly
underwent coupling at 85–908C with a wide variety of aryl
bromides and chlorides to form a-arylated ketones in good-
to-excellent yields. These weakly basic conditions were
compatible with ester, nitro, cyano, and keto substituents.
Both sterically hindered aryl bromides and heterocyclic aryl
bromides, such as 3-bromothiophene, served as coupling
partners.
Scheme 1. Two approaches to a-arylated carbonyl compounds.
siloxy-4-phenyl-2-butene (1) with 1-bromo-4-tert-butylben-
zene (2) were examined with a variety of additives, ligands,
solvents, and palladium sources (Table 1). In the presence of
catalytic amounts of Pd(OAc)2 and PtBu3, the reaction
between 1.2equivalents of 1 with limiting 2 in toluene in
the absence of an additive did not afford the desired product
in appreciable amounts (entry 1). The same reactions con-
ducted with added Bu3SnF formed some arylated product, but
the yields were poor (entry 2). These reactions with added
CsF or ZnF2 (entries 3 and 4) formed the product in low yield,
and reactions conducted with the more soluble Me4NF
apparently caused only decomposition of silyl enol ether 1
(entry 6).
Table 1: Coupling of 1 with 2.[a]
The coupling between a vinyl bromide and a silyl enol
ether under these conditions was tested briefly [Eq. (2)].[15]
The combination of 3 mol% Pd(OAc)2 and 5.4 mol% PtBu3
catalyzed the coupling of a-bromostyrene with 1 in THF in
the presence of 1.4 equivalents of CsF and 0.7 equivalents of
Bu3SnF (based on the amount of silyl enol ether) in 66%
yield.
Entry
Additive (equiv)
Ratio of 1/2
Yield [%][b]
1
2
3
4
5
6
7
8
9
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1:1.2
1.4:1
1.4:1
1.4:1
1.4:1
0
34
18
Bu3SnF (1.2)
CsF (1.2)
Bu3SnF (1.2), CsF (1.2)
ZnF2 (1.2)
Me4NF (1.2)
Bu3SnF (1.2), CsF (1.2)
Bu3SnF (1.4), CsF (1.4)
Bu3SnF (0.14), CsF (1.4)
CsF (1.4)
81
38[c]
0
65
98
67
10
11
81[d]
93[d]
Bu3SnF (1.4), CsF (1.4)
Considering the stoichiometric amounts of tin reagent in
the couplings of Table 2and the toxicity of tin, other
combinations of metal fluorides were examined to promote
the couplings of silyl enol ethers. One of us recently reported
[a] Reactions were run at 858C with 0.5 mmol 2 (0.25m). [b] Yield of the
isolated product (average of two runs). [c] DMF was used as the solvent.
[d] THF was used as the solvent.
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Table 2: Scope of the arylation of a trimethylsilyl enol ether.[a]
palladium-catalyzed coupling of silyl enol ethers with bro-
moarenes.
Entry Silyl enol
ether
Halide
Products
Yield [%][b]
The results of experiments to develop reaction conditions
with the metal fluoride additives are provided in the
Supporting Information. Experiments on the coupling of 1
with 4-bromoacetophenone showed that conditions could be
developed for the coupling of silyl enol ethers with aryl
bromides in high yield and in the presence of the combination
of stoichiometric amounts of ZnF2 and either CsF or MnF2 as
additives. These reactions occurred in much higher yield in
the polar DMF than the less polar toluene and with [Pd(dba)2]
(dba = dibenzylideneacetone) as the precursor than Pd-
(OAc)2. Reactions carried out in DMF with [Pd(dba)2] and
PtBu3 as the catalyst with stoichiometric amounts of ZnF2 and
CsF occurred in lower yields than reactions with stoichio-
metric amounts of ZnF2 and 0.4 equivalents of CsF. Reactions
with stoichiometric ZnF2 and substoichiometric CsF as
additives occurred with high functional-group tolerance (see
below). However, this combination of metal fluorides led to
diarylation of the silyl enol ethers of methyl ketones. Selective
monoarylation of silyl enol ethers of ketones was achieved
instead when the reactions were carried out with the
combination of ZnF2 and MnF2 as additives.
1
2
3
4
89[c]
84
96
97
5
6
7
97
93
91
Several examples of the [Pd(dba)2]/PtBu3-catalyzed reac-
tions of silyl enol ethers promoted by catalytic CsF or MnF2
and stoichiometric ZnF2 are shown in Table 3. Most generally,
these data illustrate the same two beneficial effects of
conducting the coupling of silyl enol ethers in the presence
of these fluoride activators, as was observed from the use of
Bu3SnF and CsF as additives: The product from the reaction
of the silyl enol ether 2-siloxy-1-butene was formed by
monoarylation of the methyl group with aryl halides that
contained functionalities intolerant of the basic conditions of
the couplings of alkali-metal enolates, and reactions of the
more substituted silyl enol ethers of an alkyl ketone
regioselectively formed the product from arylation at the
more hindered enolizable position.
The first two examples (Table 3, entries 1 and 2) show that
similar yields for reactions of electron-neutral and ortho-
substituted bromoarenes are obtained for reactions contain-
ing tin fluoride as an additive. Entries 3 and 4 show that these
conditions allow the coupling of bromoarenes with function-
alities that are not tolerated by the basic alkali-metal enolates.
Hydrolysis of the silyl enol ether during the reaction of
bromophenol did limit the yield of entry 4, but substantial
quantities of coupled product were formed. Entries 5–7 show
examples of the selective monoarylation of the silyl enol ether
of 4-phenyl-2-butanone with bromoarenes that are intolerant
of alkali-metal enolates. Finally, entry 8 (Table 3) shows the
first coupling of an enolate of acetone without tin reagents.
Diarylation to form 1,1-diphenylacetone competed with the
monoarylation in this case, but the use of excess silyl enol
ether led to the formation of a-aryl acetone in good yield.
In summary, the combination of two metal fluorides
synergistically promotes the coupling of silyl enol ethers with
aryl bromides and chlorides. Two procedures are presented,
each with certain advantages: reactions containing CsF and
tributyltin fluoride occur in nonpolar solvents, whereas the
reactions containing either ZnF2/MnF2 or ZnF2/CsF occur
8
9
55
80[c]
80[c]
70[c]
84
10
11
12
13
77[c]
14
15
85
78
[a] Reactions were run under the conditions of entry 8 in Table 1 for 12–
20 h. [b] Yield of the isolated product (average of two runs). [c] Reaction
run at 908C.
that the combination of CsF and ZnF2 promotes the
asymmetric iridium-catalyzed allylation of silyl enol ethers
with allylic carbonates.[16] Thus, we investigated the combi-
nation of ZnF2 with other metal fluorides as promoters for the
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Table 3: Scope of the palladium-catalyzed arylation of trimethylsilyl enol
ethers in the presence of ZnF2 and CsF or MnF2.
[1] a) A. de Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 2004; b) E. Negishi, Hand-
book of Organopalladium Chemistry for Organic Synthesis,
Wiley, Hoboken, 2002.
Entry Silyl enol
ether
Halide
Product
Yield [%]
[2] a) D. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 2 34; b) M.
Miura, M. Nomura, Top. Curr. Chem. 2002, 219, 211.
1
2
3
89[a]
87[a]
90[a]
[3] a) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
11108; b) B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc. 1997,
119, 12382; c) M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc.
1999, 121, 1473; d) J. M. Fox, X. H. Huang, A. Chieffi, S. L.
Buchwald, J. Am. Chem. Soc. 2000, 122, 1360; e) T. Satoh, Y.
Kawamura, M. Miura, M. Nomura, Angew. Chem. 1997, 109,
1820; Angew. Chem. Int. Ed. Engl. 1997, 36, 1740; f) J. L.
Rutherford, M. P. Rainka, S. L. Buchwald, J. Am. Chem. Soc.
2002, 124, 15168; g) M. S. Viciu, R. F. Germaneau, S. P. Nolan,
Org. Lett. 2002, 4, 4053; h) D. SolØ, L. Vallverdffl, X. Solans, M.
Font-Bardia, J. Bonjoch, J. Am. Chem. Soc. 2003, 125, 1587; i) A.
Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Catal. 2002, 344, 209;
j) T. Satoh, Y. Kametani, Y. Terao, M. Miura, M Nomura,
Tetrahedron Lett. 1999, 40, 5345; k) Y. Terao, Y. Kametani, H.
Wahui, T. Satoh, M. Miura, M Momura, Tetrahedron 2001, 57,
5967.
[4] a) M. Jørgensen, S. Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J.
Am. Chem. Soc. 2002, 124, 12557; b) W. A. Moradi, S. L.
Buchwald, J. Am. Chem. Soc. 2001, 123, 7996; c) S. Lee, N. A.
Beare, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 8410.
[5] a) N. A. Beare, J. F. Hartwig, J. Org. Chem. 2002, 67, 541; b) S.
Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402; c) J. Cossy, A.
Filippis, D. G. Pardo, Org. Lett. 2003, 5, 3037.
4
5
6
53[a]
78[b]
71[b,c]
7
8
64[d,e]
68[f,g]
[6] T. Hamada, A. Chieffi, J. Ahman, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 1261.
[7] I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997, 97, 2063.
[8] I. Kuwajima, H. Urabe, J. Am. Chem. Soc. 1982, 104, 6831.
[9] M. Kosugi, I. Hagiwara, T. Sumiya, T. Migita, Bull. Chem. Soc.
Jpn. 1984, 57, 242.
[10] For a recent coupling of a diphenyl bisenol ether, see: J. Chae, J.
Yun, S. L. Buchwald, Org. Lett. 2004, 6, 4809.
[11] For coupling of silyl ketene acetals, see: a) T. Hama, X. Liu,
D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125, 11176;
b) X. Liu, J. F. Hartwig, J. Am. Chem. Soc. 2004, 126, 5182.
[12] For activation of silyl ketene acetals of an acetate, see: F.
Agnelli, G. A. Sulikowski, Tetrahedron Lett. 1998, 39, 8807.
[13] A synergistic effect of the combination of CsF and CuI as
additives has been observed in the promotion of Stille coupling
reactions; see: S. P. H. Mee, V. Lee, J. E. Baldwin, Angew. Chem.
2004, 116, 1152; Angew. Chem. Int. Ed. 2004, 43, 1132.
[14] S. Matsuzawa, Y. Horiguchi, E. Nakamura, I. Kuwajima,
Tetrahedron 1989, 45, 349.
[a] Reaction conditions: aryl halide (1.0 equiv), silyl enol ether
(1.4 equiv), zinc fluoride (1.4 equiv), cesium fluoride (0.4 equiv), [Pd-
(dba)2] (3 mol%), and PtBu3 (5.4 mol%), 858C; DMF (1 mL) was added
per 0.2 mmol of aryl halide. [b] Reaction conditions: aryl halide
(1.0 equiv), silyl enol ether (1.5 equiv), zinc fluoride (1.0 equiv),
manganese fluoride (0.4 equiv), [Pd(dba)2] (2 mol%), and PtBu3 (4
mol%), 708C; DMF (1 mL) was added per 0.2 mmol of aryl halide.
[c] The ratio of mono/diarylation was 5.5:1. [d] Reaction conditions: aryl
halide (1.0 equiv), silyl enol ether (1.5 equiv), zinc fluoride (1.4 equiv),
manganese fluoride (1.4 equiv), [Pd(dba)2] (3 mol%), and PtBu3
(5.4 mol%), 608C; DMF (1 mL) was added per 0.2 mmol of aryl
halide. [e] The ratio of mono/diarylation was 4:1. [f] Reaction conditions:
aryl halide (1.0 equiv), silyl enol ether (5.0 equiv), zinc fluoride
(1.4 equiv), manganese fluoride (1.4 equiv), [Pd(dba)2] (3 mol%), and
PtBu3 (5.4 mol%), 708C; DMF (2 mL) was added per 0.2 mmol of aryl
halide. [g] The ratio of mono/diarylation was 5.5:1.
[15] For the palladium-catalyzed intermolecular vinylation of
ketones, see: Ref. [6]; A. Chieffi, K. Kamikawa, J. Ahman,
J. M. Fox, S. L. Buchwald, Org. Lett. 2001, 3, 1897; for the
palladium-catalyzed intramolecular vinylation of ketones, see:
a) T. Wang, J. M. Cook, Org Lett. 2000, 2057; b) D. SolØ, E.
Peidrꢀ, J. Bonjoch, Org. Lett. 2000, 2, 2225; c) D. SolØ, F. Diaba,
J. Bonjoch, J. Org. Chem. 2003, 68, 5746; d) D. SolØ, X. Urbaneja,
J. Bonjoch, Adv. Synth. Catal. 2004, 346, 1646.
without tin. All the reactions appear to occur without
cleavage to form alkali-metal enolates, thus providing a
mild and selective methodology for the preparation of a-aryl
ketones. Studies to determine the origin of the synergistic
effect, which remains unclear at this time, will be the subject
of future studies.
[16] T. Graening, J. F. Hartwig, J. Am. Chem. Soc. 2005, 127, 17192.
Received: May 12, 2006
Published online: July 17, 2006
Keywords: additives · cross-coupling · enolates · fluorine ·
.
palladium
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