Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf

Article abstract of DOI:10.1021/ol902155e

The mixed ligand system 10 mol % NICl₂(dppp) with 5 mol % dppf was discovered to be an extremely efficient catalyst for the neopentylglycolborylation of a diversity of electron-rich and electron-deficient aryl chlorides. Optimization showed tha

Full text of DOI:10.1021/ol902155e

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4974-4977
Neopentylglycolborylation of Aryl
Chlorides Catalyzed by the Mixed
Ligand System NiCl2(dppp)/dppf
Costel Moldoveanu, Daniela A. Wilson, Christopher J. Wilson, Patrick Corcoran,
Brad M. Rosen, and Virgil Percec*
Roy & Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
percec@sas.upenn.edu
Received September 17, 2009
ABSTRACT
The mixed ligand system 10 mol % NiCl2(dppp) with 5 mol % dppf was discovered to be an extremely efficient catalyst for the
neopentylglycolborylation of a diversity of electron-rich and electron-deficient aryl chlorides. Optimization showed that 5 mol % catalyst with
10% dppf was even more efficient. These results highlight the complexity of the relationship between catalyst and coligand in Ni catalysis and
the benefit of combinations of mixed ligand in catalyst design.
Interest in boronic acids as synthetic intermediates for cross-
coupling, as medicinal agents, and as components of supramo-
lecular assemblies and functional materials1 served to amplify
the necessity for more efficient and robust methods for the
synthesis of arylboronic acids and esters. Arylboronic acids and
esters are often synthesized from their corresponding aryl halides
via hard-metalation approaches.2 Pd-catalyzed Miyaura bory-
lation3 provides milder conditions that are tolerated by a greater
diversity of functional groups on the substrate. Most frequently,
Pd-catalyzed borylation of aryl bromides, iodides, and triflates
employs tetraalkoxydiboron3a,4 and pinacolborane3b,5 as a
boron source.
architectures6 and their precursors.7 Inspired by an earlier
publication wherein Ni-catalyzed pinacolborylation of two
aryl bromides was reported,8 we developed an efficient two-
step, one-pot NiCl2(dppp)/dppp-catalyzed neopentylglycol-
(4) (a) Brotherton, R. J.; McCloskey, J. L.; Petterson, L. L.; Steinberg,
H. J. Am. Chem. Soc. 1960, 82, 6243. (b) Lawlor, F. J.; Norman, N. C.;
Picket, N. L.; Robins, E. G.; Nguyen, P.; Lesley, G.; Marder, T. B.;
Ashmore, J. A.; Green, J. C. Inorg. Chem. 1998, 37, 5282. (c) Ishiyama,
T.; Murata, M.; Ahiko, T.-A.; Miyaura, N.; Hart, D. J. Org. Synth. 2000,
77, 176.
(5) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57,
3482.
(6) (a) Percec, V.; Zhao, M.; Bae, J.-Y.; Hill, D. H. Macromolecules
1996, 29, 3727. (b) Percec, V.; Holerca, M. N.; Nummelin, S.; Morrrison,
J. J.; Glodde, M.; Smidrkal, J.; Peterca, M.; Rosen, B. M.; Uchida, S.;
Balagurusamy, V. S. K.; Sienkowska, M. J.; Heiney, P. A. Chem.sEur. J.
2006, 12, 5731. (c) Percec, V.; Won, B. C.; Peterca, M.; Heiney, P. A.
J. Am. Chem. Soc. 2007, 129, 11265.
Our laboratory is involved in the development of Ni-
catalyzed approaches to the synthesis of complex molecular
(1) (a) Niu, W.; O’Sullivan, C.; Rambo, B. M.; Smith, M. D.; Lavigne,
J. J. Chem. Commun. 2005, 4342. (b) Jamese, T. D.; Shinkai, S. Top. Curr.
Chem. 2002, 218, 159.
(7) (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995,
60, 176. (b) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
1060. (c) Percec, V.; Bae, J.-Y.; Hill, D. H.; Zhao, M. J. Org. Chem. 1995,
60, 1066. (d) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
6895. (e) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org.
Chem. 2004, 69, 3447.
(2) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany,
2005.
(3) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458.
(8) Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000,
76, 1257.
10.1021/ol902155e CCC: $40.75
Published on Web 10/02/2009
 2009 American Chemical Society

borylation of aryl bromides and iodides9 and their sequential
Ni-catalyzed9a or complementary Pd-catalyzed9b cross-
coupling. Both approaches9 relied on the development of a
novel and cost-effective borylating reagent, neopentylgly-
colborane. As demonstrated for some applications of pina-
colborane,5 this reagent is prepared in situ and used without
purification or isolation. Arylneopentylglycolboronate esters
are typically easier to purify and hydrolyze than arylpina-
colboronate esters. Additionally, they enhance the diversity
of boronate esters that can be installed catalytically. Recent
work has demonstrated that bis(2-di-tert-butylphosphinophe-
nyl) ether10 or Buchwald-type ligands11,12 activate Pd for
the pinacolborylation of aryl chlorides,10,11 tosylates,12 and
mesylates.12
Table 1. Neopentylglycolborylation of Aryl Chlorides:
Screening for Optimum Combination of Catalyst and Ligand
Atom-inefficient bis(pinacolato)diboron10,11b as a boron
source was more general for aryl chlorides than more cost-
effective pinacolborane.11a Ni(II) catalysts containing con-
ventional ligands are more reactive toward aryl chlorides7e
than the corresponding Pd(II) catalysts. Herein, a general
method for the Ni-catalyzed neopentylglycolborylation of
aryl chlorides is reported. Ni-catalyzed neopentylglycolbo-
rylation of aryl bromides and iodides is performed using
2-10% NiCl2(dppp)/dppp as a catalytic system.9 The use
of dppp coligand suppresses deborylation. This catalytic
system was not sufficiently reactive with aryl chlorides (Table
1, entries 7 and 8). NiCl2(PPh3)/PPh3, NiCl2(dppe)/dppe,
NiCl2(PCy3)/PCy3, NiCl2(dppf)/(dppf), Ni(COD)2/PCy3, and
Ni(COD)2/PPh3 exhibited similarly poor yields (Table 1.
entries 1-6, 9, and 10). However, NiCl2(dppf)/(dppf)
exhibited improved reactivity (Table 1, entries 9 and 11).
Previously, it was shown that NiCl2(dppe) with PPh3 coligand
was the most general and solvent-independent catalytic
system for the Ni-catalyzed cross-coupling of aryl iodides,
bromides, chlorides, mesylates, and tosylates with arylboronic
acids.7e Application of mixed ligand systems to Ni-catalyzed
neopentylglycolborylation reiterated their enhanced perfor-
mance (Table 1, entries 12-19).
NiCl2(dppp)/PPh3 and NiCl2(PPh3)2/dppp showed signifi-
cantly improved activity for the electron-deficient methyl
4-chlorobenzoate (Table 1, entries 12-14) but were not as
effective for electron-rich substrates (Table 1, entries 15, 17,
and 18). The use of NiCl2(dppf) with dppp as coligand did
not improve catalytic activity (Table 1, entry 19), suggesting
that the reactivity enhancement provided by dppf is through
its role as coligand. A variety of catalytic systems employing
dppf as coligand were investigated (Table 2), including:
NiCl2(PPh3)2/dppf, NiCl2(dppe)/dppf, NiCl2(dppb)/dppf, and
NiCl2(dppp)/dppf. Of these catalytic systems, the combina-
tion of NiCl2(dppp), the optimal catalyst for Ni-catalyzed
borylation of aryl bromides and iodides,9 with dppf as
a Conversion calculated from GC. b Yield determined by GC. c Reaction
performed at 90 °C. d Reaction performed at 80 °C.
coligand provided the most efficient catalytic system for both
electron-rich and electron-deficient aryl chlorides (Table 2,
entries 5-8). Unlike the mixed NiCl2(dppe)/PPh3 that served
as a universal catalyst for the Ni-catalyzed cross-coupling
of arylboronic acids with aryl halides and pseudohalides,7
NiCl2(dppp)/dppf as catalyst for neopentylglycolborylation
is very sensitive to solvent conditions. Toluene is the most
effective solvent, while the use of anisole and dioxane
resulted in significantly diminished yields (Table 2, entries
9 and 10).
(9) (a) Rosen, B. M.; Huang, C.; Percec, V. Org. Lett. 2008, 10, 2597.
(b) Wilson, D. A.; Wilson, C. J.; Rosen, B. M.; Percec, V. Org. Lett. 2008,
10, 4879. (c) Knochel, P. Synfacts 2009, 2, 191.
(10) Murata, M.; Sambommatsu, T.; Watanabe, S.; Masuda, Y. Synlett
2006, 1867.
(11) (a) Billingsely, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2007, 46, 5359. (b) Billingsley, K. L.; Buchwald, S. L. J. Org.
Chem. 2008, 73, 5589
.
(12) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11,
3954
.
Org. Lett., Vol. 11, No. 21, 2009
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Table 2. Neopentylglycolboryaltion of Aryl Chlorides:
Screening for Optimum Combination of Catalyst and Solvent
with dppf
Table 3. Neopentylglycolborylation of Aryl Chlorides
Containing Additional Electron-Withdrawing Substituents
a Conversion calculated from GC. b Yield determined by GC. Isolated
yield in parentheses. c Diborylated product. d 1:1 Mono/diborylated products.
e Selective borylation of bromide. f Monoborylated product.
compatible with Ni-catalyzed neopentylglycolborylation
(Table 4, entry 1). NiCl2(dppp)/dppf-catalyzed neopentylg-
lycolborylation of electron-rich, dichlorinated substrates
provided monoborylation in the para-position, leaving the
ortho-position untouched (Table 4, entries 5 and 6). This
selectivity can be harnessed for sequential functionalization
reactions.
a Conversion calculated from GC. b Yield determined by GC. Isolated
yields in parentheses. c Reaction performed at 80 °C. d 0.1 equiv of ligand.
e Anisole used as solvent. f Dioxane used as solvent.
Application of the NiCl2(dppp)/dppf mixed ligand catalytic
system to monochlorinated, electron-deficient arenes was
extremely effective and resulted in excellent yields (Table
2, entries 5 and 6; Table 3, entries 1, 3, and 5). Diverse
functional groups such as cyano, sulfonyl, keto, and car-
boxylic ester groups were tolerated. NiCl2(dppp)/dppf-
catalyzed neopentylglycolborylation of dichlorinated, electron-
deficient arenes was also possible, but the results were
variable. 4,4′-Sulfonyl bis(chlorobenzene) and p-dichlo-
robenzene produced the diborylated product in excellent yield
(Table 3, entries 2 and 4), while in another case, a 1:1 mixture
of mono- and diborylated products (Table 3, entry 6) was
observed. NiCl2(dppp)/dppf-catalyzed neopentylglycolbory-
lation of 1-bromo-4-chlorobenzene demonstrated completely
selective borylation of the bromide (Table 3, entry 7),
demonstrating that this catalytic system is likely a universal
catalyst for the borylation of aryl halides.
As the NiCl2(dppp)/dppf-catalyzed neopentylglycolbory-
lation of aryl chlorides bearing sensitive electrophilic groups
is of great general utility, optimization with the substrate
methyl 4-chlorobenzoate was performed (Table 5). Using
10 mol % NiCl2(dppp), reduction of the amount of dppf from
10 to 5 mol % resulted in a modest increase in conversion.
Reduction in temperature from 100 to 90 °C resulted in only
a slight decrease in yield (Table 5, entry 10), while at 80 or
60 °C a significant decrease in conversion and yield was
observed (Table 5, entries 11 and 12). At 10 mol % catalyst,
optimal yields were achieved for a 1:1 or 2:1 ratio of
NiCl2(dppp) to dppf coligand. Suprisingly, reducing the
catalyst level to 5 mol % required a 1:2 ratio for complete
conversion and optimal yield in about 3 times shorter reaction
time (Table 5, entry 3). A decrease in dppf concentration
increased the reaction time (Table 5, entries 4-6). Further
reduction of catalyst loading level to 3 mol % required a
1:2.67 ratio of NiCl2(dppp) to dppf for optimal results (Table
5, entries 6-8). Below 3 mol % catalyst loading, only poor
yields could be achieved (Table 5, entry 9). The increasing
demand of coligand when lower catalyst loading levels are
NiCl2(dppp)/dppf was also an extremely competent catalyst
for the neopentylglycolborylation of monochlorinated, electron-
rich arenes (Table 4, entries 1-4, 7, and 8) as well as
heteroaryl or polyaryl chlorides (Table 4, entries 9 and 10).
It is remarkable that 4-chlorophenol, which forms an
electron-rich phenolate under the reaction conditions, is
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Org. Lett., Vol. 11, No. 21, 2009

Table 4. Neopentylglycolborylation of Aryl Chlorides with
Electron-Donating Substituents
Table 5. Neopentylglycolborylation of Aryl Chlorides:
Optimization of Reaction Conditions
catalyst
(%)
ligand
(%)
temp
(°C)
time
(h)
convna/yieldb
(%)
no.
1
NiCl2(dppp)
(10)
NiCl2(dppp)
(10)
NiCl2(dppp)
(5)
NiCl2(dppp)
(5)
NiCl2(dppp)
(5)
NiCl2(dppp)
(3)
NiCl2(dppp)
(3)
NiCl2(dppp)
(3)
NiCl2(dppp)
(1)
NiCl2(dppp)
(10)
NiCl2(dppp)
(10)
NiCl2(dppp)
(10)
dppf
(10)
dppf
(5)
dppf
(10)
dppf
(5)
dppf
(3)
dppf
(3)
dppf
(6)
dppf
(8)
dppf
(2)
dppf
(5)
100
100
100
100
100
100
100
100
100
90
19
20
7.5
19
19
19
19
20
26
24
24
24
97/95
100/95
100/100
100/91
88/86
83/82
92/91
95/95
38/17
97/94
85/81
29/25
2
3
4
5
6
7
8
9
10
11
12
dppf
(5)
dppf
(5)
80
60
a Conversion calculated from GC. b Yield determined by GC.
of mixed ligand discovery strategy and highly active Ni
catalysts is expected to provide the borylation of even more
challenging substrates.
a Conversion calculated from GC. b Yield determined by GC. Isolated
yields in parentheses. c Monoborylated in para position.
Acknowledgment. Financial support by the NSF (DMR-
0548559) and by the P. Roy Vagelos Chair at Penn is
gratefully acknowledged. We also thank Professor G. A.
Molander of the University of Pennsylvania for reading the
final version of the manuscript and for constructive sugges-
tions.
employed highlights the complex relationship between
catalyst and coligand in Ni-catalyzed borylation.
The discovery of NiCl2(dppp)/dppf for neopentylglycol-
borylation significantly expands the scope of cost-effective
Ni-catalyzed borylation to the more abundant and more
economical aryl chlorides and reinforces the discovery
process via the investigation of libraries.13 The combination
Supporting Information Available: Experimental pro-
cedures and spectral data for isolated products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) (a) Percec, V. Nature 2003, 424, 135. (b) Peterca, M.; Percec, V.;
Imam, R. M.; Leowanawat, P.; Morimitsu, K.; Heiney, P. A. J. Am. Chem.
Soc. 2008, 130, 14840.
OL902155E
Org. Lett., Vol. 11, No. 21, 2009
4977