Molander and Jean-Ge´rard
SCHEME 1
FIGURE 1. DPEPhos ligand.
nesium bromide, and the resulting allylic alcohols 1a-c were
then oxidized using IBX to give ketones 2a-c in good to
excellent yields18,19 (Scheme 1).
The value of organoboron cross-coupling reagents has been
widely described in the literature. In addition to their functional
group tolerance, they also exhibit low toxicity. Boron homoeno-
lates can be prepared either by alkylation of a halomethyl
boronate11a,12 or by 1,4-addition of bis(pinacolato)diboron to
R,ꢀ-unsaturated carbonyl derivatives.11b,c,13 Surprisingly, outside
of our first report,14 only a single example using boron
homoenolates in Suzuki-Miyaura cross-coupling reaction has
been reported in the literature, and this involved the transforma-
tion of ester homoenolates.4c
With these R,ꢀ-unsaturated ketones in hand, organoboron
reagents were then prepared according to the conditions of Yun
and co-workers13a by using a combination of CuCl, DPEPhos
(Figure 1), and NaOt-Bu. The resulting pinacolboronates were
subsequently converted to the corresponding potassium orga-
notrifluoroborates by quenching with KHF2 (Strategy A, eq 2,
Table 1). The aliphatic trifluoroboratoketohomoenolates were
obtained in good yields.
Potassium organotrifluoroborates represent a novel class of
organoborons that possess physical and chemical properties that
make them attractive alternatives to the classic boronic acids
and boronate esters for use in organic synthesis. The organo-
trifluoroborates are crystalline compounds that are indefinitely
stable to moisture and air.15 Their monomeric form, coupled
with their lower tendency to protodeboronate as compared to
boronic acids,16 permits the use of stoichiometric amounts of
these nucleophiles for cross-coupling reactions.17 We recently
reported an efficient synthesis of various potassium trifluorobo-
ratohomoenolates and showed that they are effective coupling
partners in the Suzuki-Miyaura reaction.14 To the best of our
knowledge, this was the first example of the cross-coupling of
ketone- and amide-containing homoenolates.
Unfortunately, we could not prepare the aryl ketone deriva-
tives using this procedure, and an alternative route was
investigated. Using commercially available aromatic ketones,
a deprotonation by LHMDS followed by the addition of
iodomethylpinacolboronate12c and quenching with KHF2 led to
the desired aromatic trifluoroboratoketohomoenolates in good
yields (Strategy B, eq 3, Table 1). Purification of the different
trifluoroboratohomoenolates prepared by either method was
accomplished using either Soxhlet extraction or filtration/hot
filtration in acetone,20 depending on their solubilities.
To expand the scope of this method, we prepared a larger
variety of ketone homoenolates derived from both aromatic and
aliphatic ketones. Herein, we report the preparation of several
potassium trifluoroboratoketohomoenolates and their coupling
with a wide variety of aryl and heteroaryl chlorides.
Results and Discussion
Initially, we prepared an array of potassium trifluorobora-
toketohomoenolates using two different procedures. First,
aliphatic trifluoroboratoketohomoenolates were generated via
the conjugate addition of bis(pinacolato)diboron to unsaturated
ketones as reported by Yun and co-workers.13a The starting R,ꢀ-
unsaturated ketones were prepared via the following sequence:
commercially available aldehydes were treated with vinylmag-
With the requisite trifluoroboratohomoenolates in hand,
Suzuki cross-coupling reactions were next examined. A pre-
liminary study had shown that a trifluoroboratoketohomoenolate
cross-coupled in good yields with aryl bromides and selected
aryl chlorides.14 These results prompted us to expand the study,
using the more stable and less expensive aryl chlorides as the
coupling partner to examine the scope of this method. On the
basis of the optimized conditions previously reported,14 we
initially conducted the cross-coupling of trifluoroboratohomoeno-
late 3a with electron-poor aryl chlorides (Table 2) in the
presence of Pd(OAc)2 (2.5 mol %) and RuPhos (Figure 2, 5
mol %) using K2CO3 as a base and a mixture of toluene/H2O
as the solvent system. All of the electrophiles gave rise to the
(11) (a) Mears, R. J.; Sailes, H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc.,
Perkin Trans. 1 2000, 3250. (b) Lawson, Y. G.; Lesley, M. J. G.; Marder, T. B.;
Norman, N. C.; Rice, C. R. Chem. Commun. 1997, 2051. (c) Takahashi, K.;
Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982. (d) Ito, H.; Yamanaka, H.;
Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821. (e) Kabalka, G. W.;
Das, B. C.; Das, S. Tetrahedron Lett. 2002, 43, 2323.
(12) (a) Matteson, D. S.; Cheng, T.-C. J. Org. Chem. 1968, 33, 3055. (b)
Matteson, D. S.; Beedle, D. S. Tetrahedron Lett. 1987, 4499. (c) Whiting, A.
Tetrahedron Lett. 1991, 32, 1503.
(13) (a) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887. (b) Hirano,
K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5031.
(14) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795.
(15) For reviews of organotrifluoroborate salts, see: (a) Darses, S.; Geneˆt,
J.-P. Chem. ReV. 2008, 108, 288. (b) Molander, G. A.; Figueroa, R. Aldrichimica
Acta 2005, 38, 49. (c) Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2003, 4313.
(d) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (e) Stefani, H. A.;
Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
(18) Depending on the commercial source, vinylmagnesium bromide permit-
ted the formation of the R,ꢀ-unsaturated ketones in quantitative yield over the
two steps.
(16) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(17) Molander, G. A.; Jean-Ge´rard, L. J. Org. Chem. 2007, 72, 8422. (b)
Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008, 73,
2052. (c) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135.
(19) Nicolaou, K. C.; Lim, Y. H.; Piper, J. L.; Papageorgiou, C. D. J. Am.
Chem. Soc. 2007, 129, 4001.
(20) See Supporting Information for details of all of the purification
procedures.
1298 J. Org. Chem. Vol. 74, No. 3, 2009