Utilization of potassium vinyltrifluoroborate in the development of a 1,2-dianion equivalent

Article abstract of DOI:10.1021/ol900822j

Previous studies of orthogonally reactive dibora species led to the discovery of a unique reactivity pattern associated with potassium vinyltrifluoroborate. Upon hydroboration, the vinyltrifluoroborate generates a 1,2-diboraethane, which is distinct from

Full text of DOI:10.1021/ol900822j

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2369-2372
Utilization of Potassium
Vinyltrifluoroborate in the Development
of a 1,2-Dianion Equivalent
Gary A. Molander* and Deidre L. Sandrock
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received April 15, 2009
ABSTRACT
Previous studies of orthogonally reactive dibora species led to the discovery of a unique reactivity pattern associated with potassium
vinyltrifluoroborate. Upon hydroboration, the vinyltrifluoroborate generates a 1,2-diboraethane, which is distinct from the 1,1-dibora intermediates
generated when traditional alkenyldialkylboron species undergo hydroboration. The 1,2-dianion equivalent thus generated can be envisioned
as a building block for the linkage of two different electrophiles via palladium-catalyzed Suzuki-Miyaura cross-couplings.
Orthogonally reactive boron species in dibora compounds
have been described as a means of generating functionalized
compounds efficiently in a bidirectional manner.1 We have
recently disclosed a strategy for creating boryl-substituted
trifluoroborates in situ and subsequently cross-coupling the
trialkylborane moiety chemoselectively to provide a func-
tionalized trifluororoborate.1a In a one-pot process, these
trifluoroborates can be further cross-coupled to increase
molecular complexity in a highly efficient manner.
hydroboration/cross-coupling sequence to generate a func-
tionalized trifluoroborate (eq 1). Hydroboration with 9-BBN
followed by Pd-catalyzed cross-coupling conditions provided
the desired phenethyltrifluoroborate derivative.
The selectivity seen in this transformation is a result of the
fluoride-hydroxyl exchange that must occur for an organotri-
fluoroborate to be activated for transmetalation.2 Because protic
media are necessary for the cross-coupling of organotri-
fluoroborates with most electrophilic species (e.g., halides,
triflates) and trialkylborane cross-coupling can be effected under
anhydrous conditions,3 selective conditions have been developed
that will allow reaction only at the tricoordinate boron.
During the course of our investigations, we examined the
ability of potassium vinyltrifluoroborate to undergo the
By contrast, hydroboration of vinyldialkylboranes provides
the 1,1-dibora compounds (eq 2).4 This reaction demonstrates
that a trifluoroborate inverts the polarity of the double bond.
The unique regioselectivity of the hydroboration of vinyl-
trifluoroborate can be exploited for the development of a 1,2-
dianion equivalent (Figure 1).
(1) (a) Molander, G. A.; Sandrock, D. L. J. Am. Chem. Soc. 2008, 130,
15792. (b) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem.
Soc. 2008, 130, 466.
A limited number of 1,2-dibora compounds have been
described in the literature.5 They have been generated via
(2) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302. (b)
Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2002, 42, 9099. (c) Batey,
R. A.; Thadani, A. N. Org. Lett. 2002, 4, 3827. (d) Hutton, C. A.; Yuen,
A. K. Tetrahedron Lett. 2005, 46, 7899.
(3) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9772. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9550.
10.1021/ol900822j CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

Table 1. One-Pot Generation/Cross-Coupling of a
1,2-Diboraethane with Aryl Electrophilesa
Figure 1
equivalent.
. Hydroborated intermediate as a 1,2-ethane dianion
the catalyzed diboration of ethene, the reductive coupling
of iodomethylpinacolborane with various metals, and the
hydrogenation of the alkynyl 1,2-dibora substrates. However,
each of these protocols utilizes chemically equivalent boron
species, effectively eliminating the possibility of selective
reaction at one boron center.
The 1,2-dibora intermediate from potassium vinyltri-
fluoroborate, on the other hand, can be differentially reacted
and therefore serves as a new linchpin building block for
the linkage of two different electrophilic partners. Herein
we report a comprehensive examination of the unique
applications of this protocol, demonstrating its utility as a
linker to connect aryl, heteroaryl, and alkenyl electrophiles,
generating a diverse library of ethyl-bridged subunits via
sequential processes.
Initially, we examined the scope and limitations of this
one-pot generation/cross-coupling of the 1,2-diboraethane
with a variety of aryl electrophiles (Table 1). After hydrobo-
ration of potassium vinyltrifluoroborate with 9-BBN in THF,
the resulting dibora intermediate was subjected to a variety
of electrophiles using the conditions previously optimized
for the chemoselective cross-coupling of the trialkylborane
moiety [2 mol % of Pd(OAc)2, 3 mol % of DavePhos,6 and
3 equiv of KF].1a After the reaction was stirred at rt
overnight, the solvent was removed in vacuo, and each was
subjected to conditions optimized for the cross-coupling of
primary alkyltrifluoroborates with aryl chlorides [4 mol %
of RuPhos,7 3 equiv of K2CO3, and 10:1 toluene/H2O (0.2
M)].8
A variety of chloride and bromide electrophiles were
tolerated under these conditions including those containing
ketones, aldehydes, nitriles, and esters. Specifically, all
combinations of electron-rich and electron-poor electrophiles
underwent reaction to generate the corresponding cross-
coupled products in good yield. The system also proved
tolerant of sterically hindered substrates, generating the
product in only slightly reduced yield (Table 1, entry 7).
Additionally, the reaction proved to be scaleable to 5 mmol
(Table 1, entry 4). Of note, the second cross-coupling step
of each example proceeded readily without the need of
additional Pd(OAc)2.
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv), and THF
(0.25 M) followed by Pd(OAc)2 (2 mol %), DavePhos (3 mol %), Ar1-X
(1.0 equiv), and KF (3 equiv), rt, overnight. After solvent removal, RuPhos
(4 mol %), Ar2-X (1.0 equiv), K2CO3 (3 equiv), and 10:1 toluene/H2O (0.25
M), 24 h, 80 °C. b Reaction scaled to 5 mmol.
1-Bromo-3,5-dimethoxybenzene was then chosen as a
model electrophile to probe the system’s tolerance of a
variety of heteroaryl halide substrates (Table 2). Again,
subjecting vinyltrifluoroborate to the hydroboration/cross-
coupling sequence with the optimized conditions, the fully
elaborated products were obtained in excellent yield over
the three-step process with pyridine, pyrimidine, isoquinoline,
furan, and thiophene derivatives.
Because of the ubiquity of heterocycles in many biologi-
cally active molecules, we also investigated whether two
heterocycles could be linked via this diboraethane subunit.
A literature search shows various conditions for the cross-
(4) (a) Colberg, J. C.; Rane, A.; Vaquer, J.; Soderquist, J. A. J. Am.
Chem. Soc. 1993, 115, 6065. (b) Wrackmeyer, B.; Schanz, H.-J. Collect.
Czech. Chem. Commun. 1997, 62, 1254.
(5) (a) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2008,
27, 1178. (b) Ali, H. A.; Goldberg, I.; Srebnik, M. Organometallics 2001,
20, 3962. (c) Eisch, J. J.; Kotowicz, B. W. Eur. J. Inorg. Chem. 1998, 761.
(d) Iverson, C. N.; Smith, M. R. Organometallics 1997, 16, 2757.
(6) 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.
(7) 2-Dicyclohexylphosphino-2′6′-diisopropoxy-1,1′-biphenyl.
(8) Dreher, S. D.; Lim, S.-E.; Sandrock, D. L.; Molander, G. A. J. Org.
Chem. 2009, DOI: 10.1021/jo900152n.
2370
Org. Lett., Vol. 11, No. 11, 2009

Table 2. One-Pot Generation/Cross-Coupling of a 1,2-Diboraethane
Table 3. One-Pot Generation/Cross-Coupling of a 1,2-Diboraethane
with 1-Bromo-3,5-dimethoxybenzene and Heteroaryl Halidesa
with 5-Chloro-2-furaldehyde and Various Aryl and Heteroaryl Halidesa
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv), and THF
(0.25 M) followed by Pd(OAc)2 (2 mol %), DavePhos (3 mol %), Ar-Br
(1.0 equiv), and KF (3 equiv), rt, overnight. After solvent removal, RuPhos
(4 mol %), HetAr-X (1.0 equiv), K2CO3 (3 equiv), and 10:1 toluene/H2O
(0.25 M), 24 h, 80 °C.
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv), and THF
(0.25 M) followed by Pd(OAc)2 (2 mol %), DavePhos (3 mol %), HetAr-
Cl (1.0 equiv), and KF (3 equiv), rt, overnight. After solvent removal,
RuPhos (4 mol %), Ar(HetAr)-X (1.0 equiv), K2CO3 (3 equiv), and 10:1
toluene/H2O (0.25 M), 24 h, 80 °C.
coupling of some heteroaryl halides to trialkylborane sub-
strates. However, most examples require conditions not
amenable to the system described herein (aqueous or
unsuitable reaction solvents).9
Although other heteroaryl electrophiles proceeded to a
limited extent with our optimized system, for the most part,
these conditions seemed restricted to the coupling of
5-chloro-2-furaldehyde as the first electrophilic partner.
Further investigations are currently underway to find more
general conditions for effecting anhydrous cross-couplings
of trialkylboranes with heteroaryl halides.
Using the Pd(OAc)2/DavePhos conditions and 5-chloro-
2-furaldehyde, we were able to generate a functionalized
trifluoroborate intermediate that could be cross-coupled with
various electron-rich and electron-poor aryl chlorides and
bromides (Table 3). A number of heteroaryl bromides worked
well in this reaction sequence, generating the desired
diheteroarylethane substrates in good yield.
Using conditions that were previously described for the cross-
coupling of primary alkyltrifluoroborates with alkenyl bro-
mides,10 the cross-coupling of the 1,2-diboraethane equivalent
with 1-bromo-3,5-dimethoxybenzene and a variety of alkenyl
bromides was demonstrated (Table 4). The functionalized
trifluoroborate intermediate was shown to cross-couple with
various alkenyl bromide electrophiles in good yield.
Interestingly, when 2-bromo-3-methylcyclopenten-2-one
was used as the electrophilic coupling partner, the desired
product was obtained in a 32% yield with an isomerized
byproduct in 44% yield (Table 4, entry 3). A similar
observation has been made previously for the cross-coupling
of 4-phenylbutyltrifluoroborate and potassium 2-phenyleth-
(10) Molander, G. A.; Ham, J.; Seapy, D. G. Tetrahedron 2007, 63,
768.
(11) (a) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538. (b) Fang,
Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (c) Yamada, Y. M. A.; Takeda,
K.; Takahashi, H.; Ikegami, S. J. Org. Chem. 2003, 68, 7733. (d) Abe, S.;
Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1992, 65, 2863.
(12) 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
(13) 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
(9) (a) Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.;
Medina, J. R.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2008, 130,
9218. (b) Valente, C.; Baglione, S.; Candito, D.; O’Brien, C. J.; Organ,
M. G. Chem. Commun. 2008, 735.
Org. Lett., Vol. 11, No. 11, 2009
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Table 4. One-Pot Generation/Cross-Coupling of a 1,2-Diboraethane
Table 5. One-Pot Generation/Cross-Coupling of a 1,2-Diboraethane
with 1-Bromo-3,5-dimethoxybenzene and Alkenyl Bromidesa
with Alkenyl Bromides and Various Aryl and Heteroaryl Halidesa
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv), and THF
(0.25 M), then Pd(OAc)2 (2 mol %), DavePhos (3 mol %), Ar-Br (1.0
equiv), and KF (3 equiv), rt, overnight. After solvent removal,
PdCl2(dppf)•CH2Cl2 (10 mol %), alkenyl bromide (1.0 equiv), Cs2CO3 (3
equiv), and 3:1 toluene/H2O (0.17 M), 24 h, 80 °C.
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv), and THF
(0.25 M) followed by Pd(OAc)2 (2 mol %), XPhos (3 mol %), alkenyl
bromide (1.0 equiv), and KF (3 equiv), rt, overnight. After solvent removal,
RuPhos (4 mol %), Ar(HetAr)-X (1.0 equiv), K2CO3 (3 equiv), and 10:1
toluene/H2O (0.25 M), 24 h, 80 °C.
yltrifluoroborate to this same bromide. This isomerization
is undoubtedly a result of a ꢀ-hydride elimination/reinsertion
process.10
reaction sequence, the cross-coupling of three different
alkenyl bromides as the first electrophilic partner with diverse
aryl and heteroaryl halides was demonstrated (Table 5).
The 1,2-diboraethane generated from the hydroboration of
potassium vinyltrifluoroborate allows sequential reactivity at
chemically inequivalent boron moieties. To the best of our
knowledge, this reagent is the only ethyl dianion equivalent to
be used in this context, and its unique reactivity pattern gives
rise to a new protocol for the multicomponent construction of
libraries of ethyl-linked subunits in a one-pot process.
Lastly the cross-coupling of the 1,2-diboraethane inter-
mediate first to an alkenyl bromide and then to various aryl
and heteroaryl electrophiles was investigated. There is limited
precedent for the anhydrous cross-coupling of trialkylboranes
to alkenyl bromides,9a,11 so a very brief ligand screen was
carried out to identify conditions capable of facilitating this
transformation. To screen reaction conditions for this step,
allylbenzene was subjected to hydroboration with 9-BBN (eq
3) and then to cross-coupling using 2 mol % of Pd(OAc)2,
3 mol % of a ligand (RuPhos, DavePhos, XPhos,12 and
SPhos13) and 3 equiv of KF.
Acknowledgment. We thank the NIH (General Medical
Sciences) and Merck Research Laboratories for their gener-
ous support of our program. The work was also generously
supported by a Novartis Graduate Research Fellowship to
D.L.S. We acknowledge Johnson Matthey for their donation
of palladium catalysts. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectral
data of all compounds synthesized. This material is available
free of charge via the Internet at http://pubs.acs.org.
For this system with 2-bromo-3-methylbut-2-ene as the
electrophile, XPhos emerged as the best ligand to promote
the transformation. Applying these new conditions to the
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Org. Lett., Vol. 11, No. 11, 2009