boration was developed to synthesize the relatively inacces-
sible 3,5-disubstiuted aryl boronic acids and aryltrifluorobo-
rates from 1,3-disubstituted arenes.12 Pd-catalyzed borations
of aryl halides and direct Ir-catalyzed C-H borations are
restrictively expensive due to the high cost of reagents and
catalyst and the difficult synthesis of alkoxydiborons.8
Our laboratory has focused on the development of Ni-
catalysts for Suzuki-Miyaura cross-coupling of aryl halides,
tosylates, and mesylates.13 The broad applicability of
NiCl2(dppe)13b for Suzuki-Miyaura cross-coupling and the
need for large quantities of boronic acid derived biaryls14
triggered the pursuit of a general method for Ni-catalyzed
dialkoxyborations. Ni-catalyzed pinacolborylation has been
reported once in the literature.15 Therein, the Pd borylation
was modified to use less expensive Ni and HBpin for the
bis- and tris-borylation. For the purpose of multiborylation,
10% NiCl2(dppp), 1.5 equiv of HBPin per halide, and 3.0
equiv of Et3N were suitable.15 Our investigation into Ni-
catalyzed monoborations used these conditions as a starting
point. Two significant modifications were incorporated at the
onset of this study. To reduce the cost and eliminate a
synthetic step, HBpin was prepared in situ by addition of
BH3·DMS to a toluene solution of pinacol and directly used
in the boration via cannulation without purification. While
the use of unpurified HBpin has been reported for hydrobo-
rations, prior distillation is standard for metal-catalyzed
coupling. To ensure high conversion while using in situ
formed HBpin, the starting equivalents of HBPin were
increased from 1.5 to 2.0. Optimizations of the initial
conditions were performed on electron-rich 4-bromoanisole
and later on electron-deficient methyl 4-bromobenzoate
(Table 1). The primary motivation for the two-substrate
optimization is that limited protiodeboration was observed
in electron-rich substrates, whereas extensive protiodebora-
tion was initially observed in electron-deficient substrates.
In an initial screen with 4-bromoanisole, it was revealed
that solvent choice is critical. Pinacolborylation proceeds in
toluene but did not proceed in dioxane. This is unusual
considering that Ni-catalyzed Suzuki-Miyaura cross-
coupling proceeds in both dioxane and toluene.13 Further,
dioxane is an acceptable solvent for Pd-catalyzed Miyaura
boration using HBpin.
Table 1. Pinacolborylation of Methyl 4-Bromobenzoate
HBpin
(equiv)
catalyst
(equiv)
temp convn byproduct
(°C)
(%)a
(%)a
2.0
2.0
2.0
1.5
2.0
2.0
2.0
2.0
a
NiCl2(dppp) (0.1)
NiCl2(dppp) (0.1)
NiCl2(dppp) (0.1)
NiCl2(dppp) (0.1)
NiCl2(dppp) (0.05)
NiCl2(dppe) (0.1)
NiCl2(PPh3)2 (0.1)
NiCl2(dppp)/dppp (0.1)
100
80
90
100
100
100
100
100
100
0
25
0
50
80
66
90
70
90
30
35
20
10
15
10
1
Conversion and byproduct percentage determined via H NMR.
quality of Et3N. Use of as received Et3N resulted in 66%
conversion after 18 h. Et3N distilled from CaH2 raised
conversion to 80%.
After conditions for 4-bromoanisole were optimized, effort
was focused on reduction of apparent protiodeboration in
methyl 4-bromobenzoate (Table 1). Methyl 4-bromobenzoate
was obtained with 100% conversion after 18 h at 100 °C.
Decreased reaction temperature did not reduce the amount
of protiodeboration but did have dramatic effects on conver-
sion. Below 80 °C no measurable conversion was observed,
and at 90 °C the reaction proceeded to only 50% conversion
in 18 h. As protiodeboration did not appear to be temperature
dependent, the potential for catalyst or borane loading levels
dependence was assessed. Reducing the catalyst from 10.0
mol % or the equiv of HBpin from 2.0 decreased conversion
and failed to reduce protiodeboration. Catalyst effects were
investigated. As determined previously15 for bis- and tris-
borylations, the most effective catalyst for monoborylations
is NiCl2(dppp). This catalyst achieved 100% conversion of
4-carbonyl-methoxyphenyl-1-bromide in 18 h. NiCl2(dppe)
resulted in 90% conversion, while the conversion for
NiCl2(PPh3)2 was 70%. The NiCl2(dppp) system can be
modified to improve the product distribution. Introduction
of an additional 1.0 equiv of dppp as a coligand reduced
byproduct formation from 25% to 7%. It is unclear why dppp
is superior to dppe or why increased dppp levels suppress
protiodeboration. The role of ligand is under experimental
and computational investigation.
In Pd-catalyzed coupling of dialkoxyboranes with aryl
halides, Et3N has been shown to be more efficient than Py,
DBU, KOAc, or even Hu¨nig’s base. Due to the superiority
of Et3N in Pd-catalyzed reactions and the likely similar
mechanism for Ni, Et3N was used without investigating other
bases. In order to develop the simplest procedure possible,
the purity requirements for each reagent were investigated.
It was found that the reaction was highly dependent on the
Optimized Ni-catalyzed pinacolborylation was tested on
an electron-deficient aryl bromide, two electron-rich aryl
bromides, and an aryl iodide resulting in 60-80% yield
(Table 2). More substrates were tested, but they proved to
be difficult to isolate. However, analysis of the crude reaction
mixture by NMR generally showed good to excellent
conversion for aryl bromides and aryl iodides but very limited
conversion for aryl chlorides. The high conversions hinted
at a promising reaction, but the frequent difficulties in
purification of the pinacol boronate esters, the incompatibility
of the purifiable pinacol boronate esters with NiCl2(dppe)
(12) Murphy, J. M.; Tzsachicke, C. C.; Hartwig, J. F. J. Org. Chem.
2007, 9, 757.
(13) (a) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
1060. (b) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org.
Chem. 2004, 69, 3447.
(14) Percec, V.; Holerca, M. N.; Nummelin, S.; Morrison, J. J.; Glodde,
M.; Smidrkal, J.; Peterca, M.; Rosen, B. M.; Uchida, S.; Balagurusamy,
V. S. K.; Sienkowska, M. J.; Heiney, P. A. Chem. Eur. J. 2006, 12, 5731.
(15) Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000,
76, 1257.
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Org. Lett., Vol. 10, No. 12, 2008