Substituted potassium internal vinyltrifluoroborates: Preparation and use in Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2012.03.119

A collection of substituted potassium internal vinyltrifluoroborates was prepared and utilized in palladium-catalyzed cross-coupling reactions with aryl and heteroaryl halides. The cross-coupling reactions proceeded readily with Pd(PPh₃)₄ as a catalyst in toluene/H₂O under reflux in the presence of Cs₂CO₃. The process is regiospecific with regard to the internal vinyltrifluoroborate starting material and tolerates a variety of functional groups. This unique collection of substituted internal vinyltrifluoroborates can be readily utilized in research pharmaceutical applications.

Full text of DOI:10.1016/j.tetlet.2012.03.119

Tetrahedron Letters 53 (2012) 2847–2849
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Substituted potassium internal vinyltrifluoroborates: preparation and use in
Suzuki–Miyaura cross-coupling reactions
⇑
Shivanand K. Math , Homayoun H. Mokri, James B. LaMunyon, Dustin R. Cefalo, Charles A. Testa
Frontier Scientific, Inc., PO Box 31, Logan, UT 84323-0031, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A collection of substituted potassium internal vinyltrifluoroborates was prepared and utilized in
palladium-catalyzed cross-coupling reactions with aryl and heteroaryl halides. The cross-coupling
reactions proceeded readily with Pd(PPh3)4 as a catalyst in toluene/H2O under reflux in the presence of
Cs2CO3. The process is regiospecific with regard to the internal vinyltrifluoroborate starting material
and tolerates a variety of functional groups. This unique collection of substituted internal vinyltrifluorob-
orates can be readily utilized in research pharmaceutical applications.
Received 3 February 2012
Revised 27 March 2012
Accepted 28 March 2012
Available online 4 April 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Substituted potassium internal
vinyltrifluoroborates
Suzuki–Miyaura
Cross-coupling
Aryl bromides
Heteroaryl bromides
Organoborons have long been used in synthetic organic chemis-
try to construct C–C, C–O, C–N, and C–S bonds via metal-mediated
cross-coupling reactions.1 Thus, organoborons are very valuable to
synthetic chemists as key intermediates in the synthesis of more
complex molecules. Substituted potassium internal vinyltrifluo-
roborates provide a systematic collection of a particular class of
compounds that can carry a nitrogen or oxygen heteroatom at
the allylic carbon center. These substituted internal vinyltrifluo-
roborates can be valuable in synthetic manipulations, as in olefin
metathesis, to generate complex C@C bonds in molecules.2 In gen-
eral, the olefin moiety in a molecule is useful as a point of synthetic
manipulation. One example is the functionalization of the olefin by
hydroboration, reduction, epoxidation, cyclopropanation, dihydr-
oxylation, ozonolysis, polymerization, and other reactions well
known in the field (Scheme 1).3
Other organometallic reagents suffer from limitations that limit
their utility. Organozinc reagents are prepared and immediately
used as they cannot be stored for long periods of time.4 Organotin
reagents are toxic and also pose difficulty in removing the tin-
containing byproducts.5 On the other hand, organoboron byprod-
ucts are nontoxic and can be easily removed during standard
reaction work up. Among the organoboron derivatives, trifluorob-
orates have several advantages over boronic acids and boronates.6
Boronic acids can form cyclic trimers resulting in boroxines which
are difficult to quantify. Organoboronates can potentially
Metathesis
Epoxidation
BF3K
X
Hydroboration
Hydroxylation
X=N,O
Polymerization
Scheme 1. Applications of substituted potassium internal vinyltrifluoroborates.
hydrolyze, making them difficult to purify and also afford byprod-
ucts in the cross-coupling reactions that need to be separated.
Organotrifluoroborates, however, are readily prepared from a
variety of organoborons in situ with inexpensive KHF2. They are
monomeric, crystalline solids, air-stable, and can be stored for
longer periods of time. It is known that vinylboronic acid and
vinylboronates are unstable,7 whereas internal vinyltrifluorobo-
rates are quite stable and work well in cross-coupling reactions.8
Related materials have been reported, yet all suffer from signif-
icant limitations. Terminal olefin-boron derivatives (b-boroalk-
enes) have been easily obtained by established methods such as
hydroboration.9 However, the preparation of the internal vinylbo-
ron derivatives (a-boroalkenes) regiospecifically has been difficult,
and particularly problematic when the allylic nitrogen atom exists
as a free amine. The inherent ability to complex between the amine
nitrogen and sp2-boron makes them difficult to isolate. Markovni-
kov vinylboranes have been reported with simple alkyl
⇑
Corresponding author. Tel.: +1 435 753 1901; fax: +1 435 753 6731.
E-mail address: smath@frontiersci.com (S.K. Math).
substituents on the
a-carbon, with all lacking a free amine at the
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.119

2848
S. K. Math et al. / Tetrahedron Letters 53 (2012) 2847–2849
Table 1
to prepare internal vinylboron derivatives with a nitrogen atom
from free amine at the allylic position. To the best of our knowl-
edge there are no methods or suppliers of such vinylboron deriva-
tives that are regiospecifically pure with a diverse selection of
systematic substituents at the allylic center. The substituted potas-
sium internal vinyltrifluoroborates described in this report repre-
sent new reagents to address many of the limitations of previous
reported reagents.
A key distinction of the work described in this letter when com-
pared to previously reported related chemistry describes the use of
free amines of internal vinyl boronates in cross-coupling reactions.
To address this unmet need, we developed a method to generate a
regiospecific collection of functionally complex internal vinyltriflu-
oroborates as potassium salts, featuring amine and ether function-
alities in the allylic position, as air-stable crystalline products
(Table 1). These substituted potassium internal vinyltrifluorobo-
rates are prepared from corresponding vinyl bromides that are
either known in the literature or commercially available, and the
reactions can be performed from gram to multigram scale.11 This
approach enables chemists to generate a collection of systemati-
cally substituted potassium internal vinyltrifluoroborates which
are expected to be valuable additions for research and pharmaceu-
tical applications.
Preparation of substituted potassium internal vinyltrifluoroboratea
tert-BuLi, (i-PrO)BPin
BF3K
Br
X
X
KHF2, THF
X=N, O
1
2
Entry Potassium internal
vinyltrifluoroborates
Product Isolated yield
(%)
BF3K
N
N
1
2
2a
2b
43
34
BF3K
BF3K
N
3
4
5
2c
2d
2e
41
39
45
O
BF3K
O
BF3K
O
a
Treated with 2 equiv of tert-BuLi, 1 equiv of (i-PrO)BPin and 3 equiv of KHF2.
allylic position.10 Transition metal catalyzed hydroboration
approaches utilizing terminal alkynes also have limitations of
isolation and regioselectivity. There is currently no general method
To establish their absolute structures, stability, and reactivity,
these internal vinyltrifluoroborates were used in Suzuki–Miyaura
Table 2
Reactions of substituted potassium internal vinyltrifluoroborates with aryl and heteroaryl bromidesa
Br
BF3K
Ar/HetAr
Pd(0)
X2
X
X
+
R
X1
X1, X2 = C, N
R= F, OMe, CN, CHO, -C(=O)CH3
2
3
X = N
Entry
1
Vinyltrifluoroborates
Ar/HetArBr
Product
Yieldb (%)
80
BF3K
N
Br
2a
3a
3b
CN
2a
BF3K
N
2b
2
3
88
2b
BF3K
N
O
2c
3c
67
2c
4
5
6
2a
2b
2c
3d
3e
3f
80c
87d
72
O
Br
Br
7
8
2a
2b
3g
3h
71
F
80c
9
2c
3i
73
CHO
10
11
12
2a
2b
2c
3j
3k
3l
64
88
70
Br
Br
N
N
CHO
OMe
13
14
15
2a
2b
2c
3m
3n
3o
85
71
88
N
16
17
18
2a
2b
2c
3p
3q
3r
72
Br
73d
77e
N
a
b
c
Heated to reflux with 9 mol% Pd(PPh3)4, Cs2CO3, toluene/H2O (10:1), for 16 h.
Isolated yield.
Reaction time 24 h.
Reaction time 36 h.
Reaction time 56 h.
d
e

S. K. Math et al. / Tetrahedron Letters 53 (2012) 2847–2849
2849
cross-coupling reactions as shown in Table 2. A variety of aryl and
Supplementary data
heteroaryl bromides bearing electron-rich and electron-poor func-
tional groups were employed to determine their applicability in
Suzuki–Miyaura cross-coupling reactions.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.119.
The application of metal-mediated arylation with the aryl and
heteroaryl bromide substrates requires careful optimization of cat-
alyst, ligand, base, solvent, and reaction temperature. Several pal-
ladium catalysts including PdCl2(dppf), Pd(PPh3)4, and Pd(OAc)2
were used with methanol, THF, H2O, and toluene as solvents with
Cs2CO3, tert-butylamine, and PPh3 as bases and ligands. The best
coupling results were achieved with Pd(PPh3)4 as catalyst in
toluene-H2O (10:1) under reflux in the presence of Cs2CO3, and
the reactions proceeded regiospecifically.
In summary, the substituted potassium internal vinyltrifluorob-
orates were most conveniently prepared in one pot by in situ lith-
iation of commercially available, inexpensive substituted vinyl
bromides, quenched with isopropoxy-pinacol-borate, and treated
with KHF2. Palladium catalyzed cross-coupling reactions of substi-
tuted potassium internal vinyltrifluoroborates with aryl and het-
eroaryl halides proceed with clean retention of configuration
with respect to both coupling partners and were achieved in good
yields tolerating a variety of functional groups. The substituted
potassium internal vinyltrifluoroborates generated are air-stable
monomeric solids that are easily isolated and purified, thus making
them highly attractive intermediates for numerous synthetic
applications.
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Acknowledgments
We thank Professor Glenn D. Prestwich for his guidance on
this project and Dr. Kuanchiang Chen for helpful scientific
discussions.