Suzuki-Miyaura cross-coupling of potassium trifluoroboratohomoenolates

Article abstract of DOI:10.1021/ol800357c

Ketone-, ester-, and amide-containing potassium trifluoroboratohomoenolates were prepared in good to excellent yields from the corresponding unsaturated carbonyl compounds. They were shown to be effective coupling partners in the Suzuki-Miyaura reaction with a variety of electrophiles including electron-rich and electron-poor aryl bromides and -chlorides.

Full text of DOI:10.1021/ol800357c

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1795-1798
Suzuki-Miyaura Cross-Coupling of
Potassium Trifluoroboratohomoenolates
Gary A. Molander* and Daniel E. Petrillo
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received February 16, 2008
ABSTRACT
Ketone-, ester-, and amide-containing potassium trifluoroboratohomoenolates were prepared in good to excellent yields from the corresponding
unsaturated carbonyl compounds. They were shown to be effective coupling partners in the Suzuki-Miyaura reaction with a variety of electrophiles
including electron-rich and electron-poor aryl bromides and -chlorides.
Homoenolates1 or their equivalents are important synthetic
reagents, and when employed as nucleophiles in synthetic
schemes they exhibit “umpolung” reactivity.2 Previous
methods to generate homoenolates have relied most heavily
on the Lewis acid-mediated cleavage of 1-alkoxy-1-siloxy-
cyclopropanes, generating the air- and moisture-sensitive
titanium3 and zinc4 homoenolates. These useful organome-
tallic compounds have been shown to participate in aldol-
type reactions,3a copper-mediated conjugate additions,4 and
palladium-catalyzed cross-coupling reactions.4
One limitation of commonly used homoenolates is that
primarily ꢀ-metallo esters have been employed; the corre-
sponding ꢀ-metallo ketones often react irreversibly to form
metallocyclopropanoxides.5 The limited examples of carbon-
carbon bond-forming reactions involving ketone homoeno-
lates include the palladium-catalyzed cross-coupling of zinc
homoenolates with acid chlorides6 and the coupling of in
situ generated palladium homoenolates with aryl triflates.7
Although ꢀ-stannyl ketones have been prepared,8 to the best
of our knowledge there are no examples of their use in a
Migita-Stille cross-coupling.
Organoboron reagents are versatile synthetic reagents that
participate in many selective carbon-carbon bond-forming
reactions.9 They are known for their functional group
tolerance and exhibit minimal toxicity. Potassium organo-
trifluoroborates have recently been shown to exhibit increased
chemical and physical stability compared to other organo-
metallic species.10 In some cases, they have demonstrated
enhanced reactivity compared to other organoborons.11
(6) Tamaru, Y.; Ochia, H.; Nakamura, T.; Yoshida, Z. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1157.
(7) (a) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1988, 110, 3296. (b) Fujimura, T.; Aoki, S.; Nakamura, E. J. Org.
Chem. 1991, 56, 2809.
(8) (a) Burley, J. W.; Hutton, R. E.; Oakes, V. J. Chem. Soc., Chem.
Commun. 1976, 803. (b) Nakahira, H,; Ryu, I.; Ogawa, A.; Kambe, N.;
Sonoda, N. Organometallics 1990, 9, 277.
(1) Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic Synthesis;
Trost, B., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2p 441.
(2) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(3) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1977, 99, 7360.
(b) Nakamura, E. Kuwajima, I. J. Am. Chem. Soc. 1983, 105, 652.
(4) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am.
Chem. Soc. 1987, 109, 8056.
(9) Zaidlewicz, M.; Brown, H. C. Organic Syntheses Via Boranes;
Aldrich Chemical Co.: Milwaukee, 2002.
(10) For reviews of organotrifluoroborates, see: (a) Darses, S.; Genet, J.-P.
Chem. ReV. 2008, 108, 288. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res.
2007, 40, 275. (c) Stefani, H. A.; Cellia, R.; Vieira, A. Tetrahedron 2007,
63, 3623. (d) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49.
(11) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4, 3827.
(5) Shiner, C. S.; Berks, A. H.; Fisher, A. M. J. Am. Chem. Soc. 1988,
110, 957.
10.1021/ol800357c CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

Boron homoenolates can be prepared by a number of
methods, including alkylation of a halomethyl boronate
species12 as well as the 1,4-addition of diboron species to
unsaturated ketones and esters (Scheme 1).13 Although these
species can be utilized in a number of synthetic applica-
tions,14 their use in the Suzuki-Miyaura cross-coupling15 is
limited to a single example.16
Table 2. Cross-Coupling of Electron-Poor Bromidesa
Scheme 1. Preparation of Boron Homoenolates
As part of a research program in functionalized organoboron
reagents10b,d we prepared several potassium trifluoroborato-
homoenolates via the conjugate addition of bis(pinacolato)-
diboron to unsaturated carbonyl compounds according to the
conditions of Yun and co-workers.13c Conversion to the
potassium organotrifluoroborate salt was accomplished using
KHF2 (Table 1). The trifluoroboratohomoenolates thus pre-
Table 1. Preparation of Trifluoroboratohomoenolatesa
a Conditions: 2.5% Pd(OAc)2, 5% RuPhos, K2CO3 (3 equiv), toluene/
water, 85 °C, 18 h.
The tert-butyl ester substituted trifluoroborate 5 was also
prepared via alkylation of the lithium enolate of tert-butyl acetate
with iodomethylpinacol boronate.12a The resulting pinacolbo-
ronate was converted to the potassium trifluoroborate through
treatment with KHF2 to give 5 in moderate yield (eq 1).
We utilized trifluoroboratohomoenolate 2 in conjunction
with p-bromobenzonitrile to determine optimal conditions
a Conditions: (1) 3% CuCl, 3% DPEPhos, 9% NaOt-Bu, THF/MeOH,
3 h; (2) KHF2, MeCN, 0 °C, 3 h.
(13) (a) Lawson, Y. G.; Lesley, M. J. G.; Marder, T. B.; Norman, N. C.;
Rice, C. R. Chem. Commun. 1997, 2051. (b) Takahashi, K.; Ishiyama, T.;
Miyaura, N. Chem. Lett. 2000, 982. (c) Mun, S.; Lee, J.-E.; Yun, J. Org.
Lett. 2006, 8, 4887.
(14) (a) Curtis, A. D. M.; Whiting, A. Tetrahedron Lett. 1991, 32, 1507.
(b) Mears, R. J.; Whiting, A. Tetrahedron 1993, 49, 177. (c) Curtis,
A. D. M.; Whiting, A. Tetrahedron 1993, 49, 187. (d) Mears, R. J.; Sailes,
H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc., Perkin Trans. 2000, 1, 3250.
(15) (a) Suzuki, A.; Brown, H. C. Organic Syntheses Via Boranes:
Volume 3 Suzuki Coupling: Aldrich Chemical Co.: Milwaukee, 2003. (b)
Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (c) Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457.
pared were all nonhygroscopic, free-flowing powders or crystal-
line solids that were indefinitely stable to the atmosphere.
(12) (a) Whiting, A. Tetrahedron Lett. 1991, 32, 1503. (b) Matteson,
D. S.; Majundar, D. J. Am. Chem. Soc. 1980, 102, 7590. (c) Matteson,
D. S.; Cheng, T.-C. J. Org. Chem. 1968, 33, 3055.
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Org. Lett., Vol. 10, No. 9, 2008

Table 3. Cross-Coupling of Electron-Rich Aryl Bromidesa
Table 4. Cross-Coupling of Other Electrophilesa
a Conditions: 2.5% Pd(OAc)2, 5% RuPhos, K2CO3 (3 equiv), toluene/
water, 85 °C, 18 -24 h.
a Conditions: 2.5% Pd(OAc)2, 5% RuPhos, K2CO3 (3 equiv), toluene/
water, 85 °C, 24 h.
products in good to excellent yield (Table 2). Many common
functional groups were tolerated in the reaction mixture
including an aldehyde, an ester, ketones, and nitriles. A nitro
substituent, which is often reduced by alkyl organoboron
compounds,18 was also tolerated, giving the coupled product
10 in excellent yield.
Electrophiles containing an electron-donating group are
often difficult coupling partners in the Suzuki-Miyaura
reaction. Potassium trifluoroboratoketone 2 was shown to
cross-couple to several electron-rich aryl bromides in good
yield (Table 3). In addition, a sterically hindered aryl bromide
(entry 5) also underwent the cross-coupling reaction ef-
fectively.
To demonstrate the scope of the cross-coupling reaction,
other common electrophiles were investigated (Table 4). Both
an electron-poor (entry 1) and an electron-rich (entry 2) aryl
chloride were shown to take part in the cross-coupling
reaction. A heteroaromatic bromide (entry 3) and an aryl
triflate (entry 4) also gave a good yield of the cross-coupled
products. Additionally, an alkenyl bromide (entry 5) par-
ticipated in this reaction.
We then chose to examine the behavior of other potassium
trifluoroboratohomoenolates. The ester homoenolate 5 de-
rived from tert-butyl acrylate underwent cross-coupling to
provide the product 21 in 70% yield (eq 3). Preliminary
results indicate that the corresponding methyl and ethyl esters
for cross-coupling. Screening several common catalyst/ligand
combinations, we found that the combination of 2.5 mol %
Pd(OAc)2/5 mol % RuPhos (2-dicyclohexylphosphino-2′,6′-
diisopropoxy-l,l′-biphenyl) in the presence of three equiva-
lents of K2CO3 in toluene/H2O led to an 88% isolated yield
of coupled product 7 after heating at 85 °C for 18 h (Table
2, entry 1). To the best of our knowledge, this is the first
example of a cross-coupling reaction of a ketone homoeno-
late with an aryl halide.
Interestingly, there was little to no formation of the corre-
sponding unsaturated products. These could result from ꢀ-hy-
dride elimination of the presumed palladium(II) homoenolate
intermediate to form an alkyl vinyl ketone, which could then
undergo a Heck reaction. This elimination is a known reaction
pathway for palladium homoenolates (eq 2).17
The conditions developed were shown to be general for a
variety of electron-poor aryl bromides, providing the coupled
(16) Scherer, S.; Meudt, A.; Nerdinger, S., Lehnemann, B.; Jagusch,
T.; Snieckus, V. Method for producing alkyl-substituted aromatic and
heteroaromatic compounds by cross-coupling alkyl boronic acids with aryl-
or heteroaryl halogenides or sulfonates under Pd catalysis in the presence
of a ligand. Sep 21, 2006, WO 2006/097221.
(17) Ryu, I.; Matsumoto, K.; Ando, M.; Murai, S.; Sonoda, N.
Tetrahedron Lett. 1980, 21, 4283.
(18) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 4, 221.
Org. Lett., Vol. 10, No. 9, 2008
1797

are not effective partners in this process, perhaps owing to
competitive ester hydrolysis during the course of the reaction.
Pleasingly, the amide-containing homoenolate 6, derived
from dimethyl acrylamide, also participated in the Suzuki-
Miyaura cross-coupling reaction under the general conditions
to provide 22 in moderate yield. As is the case with ketone
homoenolate coupling, this amide homoenolate cross-
coupling is unprecedented, and its scope is currently being
investigated.
carbonyl compounds, and they represent the most versatile
metallohomoenolates for cross-coupling yet introduced. As
examples, the methods developed allow the cross-coupling
of ketone and amide homoenolates, both previously unreal-
ized cross-coupling partners. Efforts toward the preparation
of more complex potassium trifluoroboratohomoenolates and
their use in other synthetically important reactions are
currently underway.
Acknowledgment. We thank the NIH-General Medical
Sciences, Merck Research Laboratories, and Amgen for their
generous support of our program. BASF is thanked for their
donation of bis(pinacolato)diboron. Johnson Matthey and
Frontier Scientific are thanked for their donation of palladium
catalysts. We are grateful to Dr. Rakesh Kohli (University
of Pennsylvania) for obtaining HRMS data.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have prepared a variety of potassium
trifluoroboratohomoenolates and shown that they are effective
coupling partners in the Suzuki-Miyaura reaction. These
novel coupling reagents are easily synthesized from the
conjugate addition of bis(pinacolato)diboron to unsaturated
OL800357C
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Org. Lett., Vol. 10, No. 9, 2008