Palladium-catalyzed α-vinylation of carbonyl compounds

Article abstract of DOI:10.1021/ol7019839

A mild, general, catalytic system for the α-vinylation of carbonyl compounds has been developed. By employing [Pd(P¹Bu ₃)Br]₂ as catalyst and LHMDS as base, vinyl bromides, vinyl triflates, and vinyl tosylates couple with 3-methyioxindole in satisfactory yields. The same catalytic system is extended to the α-vinylation of ketones and esters.

Full text of DOI:10.1021/ol7019839

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4343-4346
Palladium-Catalyzed
Carbonyl Compounds
r-Vinylation of
Jinkun Huang,* Emilio Bunel, and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center DriVe, Thousand Oaks,
California 91320
jhuang@amgen.com
Received August 14, 2007
ABSTRACT
A mild, general, catalytic system for the
and LHMDS as base, vinyl bromides, vinyl triflates, and vinyl tosylates couple with 3-methyloxindole in satisfactory yields. The same catalytic
system is extended to the -vinylation of ketones and esters.
r
-vinylation of carbonyl compounds has been developed. By employing [Pd(PtBu3)Br]2 as catalyst
r
In 1997, Buchwald,1 Hartwig,2 and Miura3 concurrently
reported the palladium-catalyzed R-arylation of ketones that
opened a new avenue for simple and useful construction of
molecules that were traditionally difficult to synthesize.4 In
parallel with advancements in transition metal mediated
C-C, C-N, C-O, C-S, and C-P bond formations in the
past decade, the R-arylation reaction has been expanded to
a variety of nucleophilic coupling partners such as ketones,5
esters,6 amides,7 nitriles,8 aldehydes,9 nitroalkanes,10 sul-
fones,11 and lactones.12 In this process, an enolate or a related
anion generated under basic conditions undergoes coupling
with an aryl halide in the presence of a palladium or nickel
catalyst. In the development of these R-arylation reactions,
it was found that the ligand plays a critical role in the success
of the coupling reaction and a great deal of effort has been
placed in tuning the electronic and steric properties of the
ligand bound to the transition metal centers. While many
reports have appeared detailing substrate scope expansion
of the enolate coupling partner, the electrophilic component
is generally limited to aryl halides or aryl triflates. Expansion
of the electrophilic coupling partner to include olefinic
halides and triflates would allow ready access to the
corresponding vinyl carbonyl compounds. Buchwald has
recently reported an elegant asymmetric R-vinylation of
ketone enolates; however, the substrate scope is limited.13
Other examples for this useful transformation are scarce.12b
The importance of a general R-vinylation reaction of enolates
stems not only from the frequent appearance of C-C double
bonds in natural products and biologically active compounds,
(1) Paluki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(2) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(3) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. 1997, 36, 1740.
(4) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(5) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(b) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1999, 40, 5345. (c) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2000, 122, 1360.
(6) (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) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465.
(d) Jørgensen, M.; Lee, S.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 12557.
(7) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(8) (a) Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 2239. (b) Culkin, D. A.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 9330.
(11) Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R. Tetrahedron
Lett. 2002, 43, 2539.
(12) (a) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
3500. (b) Liu, X.; Hartwig, J. F. Org. Lett. 2003, 5, 1915.
(13) Chieffi, A.; Kamikawa, K.; A° hman, A.; Fox, J. M.; Buchwald, S.
L. Org. Lett. 2001, 3, 1897.
(9) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2002, 43, 101.
(10) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106.
10.1021/ol7019839 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/22/2007

but also from the rich and well-studied chemistry of olefins
that enables efficient synthesis of complex structures.
Therefore the development of R-vinylation reactions is very
attractive, as an addition to the related transition metal-
catalyzed reactions such as Heck, Suzuki, Negishi, and Stille
couplings, where use of vinyl coupling partners has been
broadly used in the synthesis of natural products.14
Table 1. Catalyst Evaluation
In conjunction with one of our programs, development of
an effective R-vinylation reaction of carbonyl compounds
was desirable as a synthetic strategy. Herein, we report our
results on the successful R-vinylation of 3-methyloxindole
and the related ketones and esters.
entry
Pd-source
ligand
n/a
n/a
n/a
XantPhos
S-Phos
X-Phos
Q-Phos
IPr-HCl
BINAP
S-MOP
S-MOP*
yield (%)a,b
1
2
3
4
5
6
7
8
9
[PtBu3PdBr]2
(PhPtBu2)2PdCl2
(DTBPF)2PdCl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
94
55
72
<5
<5
<5
83
9
Oxindole 1 was selected as the model substrate due to the
presence of the structural motif in many biologically
important compounds.15 To our surprise, direct arylation of
1 has not been studied, although indirect synthesis of
N-methyloxindole has been reported via intramolecular or
stepwise intermolecular arylation.16 To develop a useful
R-vinylation reaction, we examined the coupling of 1 with
1-cyclohexenyl triflate 2 under various conditions. Two
features of this reaction were notable: (i) Although vinyl
triflates are easily prepared from the corresponding ketones,17
use of vinyl triflates in R-vinylation of enolates has not been
reported. (ii) Substrate 1 contains both C and N nucleophiles
which may result in the formation of mixed C-C and C-N
vinylated products when subjected to the reaction conditions.
To the best of our knowledge, there is no literature precedent
for R-arylation of an amide with a free N-H bond.
Initially, the model reaction was screened at 80 °C in
toluene with either Pd2(dba)3/ligand combination or a
preformed palladium complex18 as the catalyst, with lithium
hexamethyldisilazine (LHMDS) as base to generate the
enolate in situ.
20
34
32
10
11
Pd2(dba)3
a HPLC assay yield. b Reaction conditions: To a mixture of 1 (1.0 equiv),
Pd source (5 mol % Pd), and ligand (5-10 mol %) in toluene was added
LHMDS (2.5 equiv). The mixture was stirred for 5 min followed by addition
of 2 (1.5 equiv). The dark solution was heated to 80 °C for 24 h and analyzed
by HPLC.
successfully used in related palladium-catalyzed couplings,
including R-arylations, were less effective for the R-vinyl-
ation of 1. Interestingly, no instances of C-N coupling
product were observed.21
Having identified [Pd(PtBu3)Br]2 as the optimal catalyst,
the effects of solvent and base were next examined. With
LHMDS as base, reactions in toluene or xylene proceeded
smoothly, but those performed in dioxane, THF, DME, or
DMF occurred with lower yields. With toluene as solvent,
reactions carried out with LHMDS or NaHMDS as a base
gave the best yields, while those with Cs2CO3, K2CO3,
A few sterically hindered and electron-rich mono- and bis-
phosphines (Figure 1 and Table 1) were found effective,
(14) For a review of palladium-catalyzed couplings of vinyl compounds,
see: Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; Wiley-
VCH: Weinheim, Germany, 1996; pp 565-631.
(15) (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216. (b)
Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148. (c) Tang, Y.-Q.;
Sattler, I.; Thiericke, R.; Grabley, S.; Feng, S.-Z. Eur. J. Org. Chem. 2001,
261. (d) Suzuki, H.; Morita, H.; Shiro, M.; Kobayahsi, J. Tetrahedron 2004,
60, 2489. (e) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 3353.
(16) Lee, S.; Hartwig, J. J. Org. Chem. 2001, 66, 3402.
(17) Willis, M. C.; Brace, G. N.; Holmes, I. P. Synthesis 2005, 3229.
(18) The choosen catalysts have been shown successful in other coupling
reactions, see: (a) Hamada, T.; Chieffi, A.; A° hman, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 1261. (b) Guram, A. S.; King, A. O.; Allen, J.
G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. B.; Faul, M. M.; Larsen,
R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787. (c) Viciu,
M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053. (d) Hama,
T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976. (e)
Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (f) Wu, L.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
Figure 1. Selected ligand structures.
(19) For experimental/characterization details, see the Supporting Infor-
mation.
(20) (a) Dura-Vila, V.; Mingos, D. M. P.; Vilar, R.; White, A. J. P.;
Williams, D. J. J. Organomet. Chem. 2000, 600, 198. (b) Stambuli, J. P.;
Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746. (c)
Commercially available from Johnson Matthey.
(21) For examples of N-vinylation, see: (a) Movassaghi, M.; Ondrus,
A. E. J. Org. Chem. 2005, 70, 8638. (b) Klapars, A.; Campos, K. R.; Chen,
C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 1185.
providing 55-94% yields of the coupled product 3 (Table
1, entries 1, 2, 3, and 7).19 The reaction catalyzed by the
dimeric Pd(I) complex [Pd(PtBu3)Br]220 afforded the highest
yield of 94% (Table 1, entry 1). Other ligands that have been
4344
Org. Lett., Vol. 9, No. 21, 2007

K3PO4, NaOtBu, or KOtBu showed lower or negligible
conversions.
With the optimal conditions in hand, we examined the
scope of this reaction by coupling of a variety of vinyl
bromides and triflates with 1 (Table 2). Reaction of vinyl
Recently, vinyl tosylates have been used in coupling
reactions as organic halide equivalents due to the fact that
they are easy to prepare and generally are stable crystalline
compounds. However, they are also difficult coupling
partners and few studies have been reported with these
compounds.21b To our delight, the current conditions provided
a 65% yield for the reaction of 1,2-dihydro-3-naphthyl
tosylate with 3-methyloxindole 1 (Scheme 1).
Table 2. Substrate Scope for R-Vinylation of 1
Scheme 1
To explore the generality of the current process, we
extended the R-vinylation reaction to other related carbonyl
compounds (Table 3). With use of the optimized reaction
conditions described above, both cyclic and acyclic ketone
enolates were shown to react with vinyl bromides and
triflates, providing â,γ-unsaturated ketones in 48-95% yield.
Again the electron-deficient vinyl trifluoromethyl group was
introduced in 62-65% yield (Table 3, entry 2). Tetrasub-
stituted vinyl triflate or bromide was effective in this
coupling, though lower yields of 48% and 66%, respectively,
were obtained (Table 3, entries 3b, 6a, and 7). R-Vinylations
of methylene and methyl groups were moderate (56-81%)
in the cases studied (Table 3, entries 5, 6, and 7). The
R-vinylation reaction of the ethyl ester of N-Boc-piperidine-
4-carboxylic acid was also successful under these conditions
(Table 3, entries 8 and 9).
Although asymmetric catalysis has been emerging as an
important tool in modern organic synthesis, enantioselective
R-arylation has yet to be established as a general method.
The reported asymmetric protocols are highly substrate-
dependent with little generality.13,19a,23
We screened a range of chiral ligands under our optimal
conditions for R-vinylation of 1 with 1-cyclohexenyl triflate
2. Preliminary results showed that some chiral ligands
mediated the asymmetric coupling reaction albeit in low yield
of product 3. One of the promising ligands was MOP* 24
(Figure 1 and Table 1), which gave 31% ee at 80 °C (48 h,
a Isolated yield. b Reaction conditions: To a mixture of 1 (1.0 equiv)
and [PtBu3PdBr]2 (2.5 mol %) in toluene was added LHMDS (2.5 equiv).
The resulting mixture was stirred for 5 min followed by addition of vinyl
bromide, triflate, or tosylate (1.5 equiv).
bromides or triflates gave 56-89% yields (Table 2, entries
1-7), while terminal vinyl bromides coupled with 1 afforded
an 84-85% yield of product with complete retention of
olefin geometry (Table 2, entries 2 and 3). Hindered tri- or
tetrasubstituted vinyl bromides or triflates also coupled
smoothly to give the desired product in 70-85% yield (Table
2, entries 4, 6, and 7). Coupling of 1-trifluoromethyl-2-
bromopropene with 1 proceeded smoothly to afford 56%
yield of the desired vinylation product (Table 2, entry 5).22
(22) Fluorinated organic compounds constitute important targets in many
research fields due to the electronic and biological properties of fluoride
compounds, and introduction of a trifluoromethyl group in a mild manner
is often challenging. Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, UK, 2006.
(23) For more examples, see: (a) A° hman, A.; Wolfe, J. P.; Troutman,
M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.
(b) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500.
(c) Hartwig also disclosed the palladium-catalyzed arylation of amides using
Evans’ auxiliary and moderate to excellent diastereoselectivities were
obtained: Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
(24) Provided by Prof. Stephen L. Buchwald. Also see ref 13.
Org. Lett., Vol. 9, No. 21, 2007
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Table 3. Vinylation of Ketones and Esters
a Isolated yield. b Reaction conditions: To a mixture of ketone or ester (1.0 equiv) and [PtBu3PdBr]2 (2.5 mol %) in toluene was added LHMDS (2.5
equiv). The resulting mixture was stirred for 5 min followed by addition of vinyl bromide or triflate (1.5 equiv).
yield 35%) and 40% ee at 40 °C (96 h, yield 38%),
respectively.25
Acknowledgment. We thank Professor Stephen Buch-
wald at MIT for his helpful discussion and a sample of
S-MOP* and Drs. Eric Bercot and Xiang Wang for their
valuable comments during the preparation of this manuscript.
J.H. thanks Troy Soukup and Jenny Chen for analytical
support.
In conclusion, we have developed a mild catalytic system
for the R-vinylation of 3-methyloxindole 1, as well as a
variety of ketones and esters with exclusive C-C bond
formation. The reaction affords good yields of products with
use of commercially available reagents, making this an
attractive method to introduce the C-C double bond into
organic molecules. Further mechanistic studies are required
to optimize the asymmetric R-vinylation reaction
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) The parent MOP gave similar yield but no enantioselectivity.
Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
OL7019839
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Org. Lett., Vol. 9, No. 21, 2007