Neopentylglycolborylation of ortho -substituted aryl halides catalyzed by NiCl2-Based mixed-ligand systems

Article abstract of DOI:10.1021/jo101023t

NiCl₂-based mixed-ligand systems were shown to be very effective catalysts for the neopentylglycolborylation of aryl iodides, bromides, and chlorides bearing electron-rich and electron-deficient ortho-substituents. Although NiCl₂-based single-ligand catalytic systems were able to mediate neopentylglycolborylation of selected substrates, they were not as effective for all substrates, highlighting the value of the mixed-ligand concept. Optimization of the Ni(II)-catalyzed neopentylglycolborylation of 2-iodoanisole and methyl 2-iodobenzoate demonstrated that, while the role of ligand and coligand in the conversion of Ni(II) precatalyst to Ni(0) active catalyst cannot be ignored, a mixed-ligand complex is likely present throughout the catalytic cycle. In addition, protodeborylation and hydrodehalogenation were demonstrated to be the predominant side reactions of Ni(II)-catalyzed borylation of ortho-substituted aryl halides containing the electron-deficient carboxylate substituents. Ni(II) complexes in the presence of H₂O and Ni(0) are responsible for the catalysis of these side reactions.

Full text of DOI:10.1021/jo101023t

pubs.acs.org/joc
Neopentylglycolborylation of ortho-Substituted Aryl Halides Catalyzed
by NiCl2-Based Mixed-Ligand Systems
Costel Moldoveanu, Daniela A. Wilson, Christopher J. Wilson, Pawaret Leowanawat,
Ana-Maria Resmerita, Chi Liu, 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 December 18, 2009
NiCl2-based mixed-ligand systems were shown to be very effective catalysts for the neopentylglycolbory-
lation of aryl iodides, bromides, and chlorides bearing electron-rich and electron-deficient ortho-
substituents. Although NiCl2-based single-ligand catalytic systems were able to mediate neopentylglycol-
borylation of selected substrates, they were not as effective for all substrates, highlighting the value of the
mixed-ligand concept. Optimization of the Ni(II)-catalyzed neopentylglycolborylation of 2-iodoanisole
and methyl 2-iodobenzoate demonstrated that, while the role of ligand and coligand in the conversion of
Ni(II) precatalyst to Ni(0) active catalyst cannot be ignored, a mixed-ligand complex is likely present
throughout the catalytic cycle. In addition, protodeborylation and hydrodehalogenation were demon-
strated to be the predominant side reactions of Ni(II)-catalyzed borylation of ortho-substituted aryl halides
containing the electron-deficient carboxylate substituents. Ni(II) complexes in the presence of H2O and
Ni(0) are responsible for the catalysis of these side reactions.
Introduction
groups and substitution patterns. The use of aryl Grignard or
aryllithium species generated from aryl halides is most exten-
sively employed in the synthesis of aryl boronic acids. However,
this pathway is typically less tolerant to electrophilic or protic
functionality than transition-metal-catalyzed approaches.1
Among transition-metal-catalyzed borylation techniques, di-
rect C-H borylation of aromatic compounds has attracted consi-
derable attention in recent years. This is mostly due to its high
atom-economy that results from the absence of arylhalide or
pseudohalide synthetic intermediates. In 1999, Hartwig demon-
strated the photochemical Cp*Re(CO)3-catalyzed (where Cp* is
1,2,3,4,5-pentamethylcyclopentadiene)11 and in 2000 the thermal
Cp*Rh(η4-C6Me6)-catalyzed12 direct aromatic C-H borylation
of benzene using bis(pinacolato)diboron (B2pin2)13,14 as the
The versatility of aryl boronic acids,1 boronate esters,1 and
potassium trifluoroborate salts,1-3 as synthetic precursors,4,5
catalysts,6 components in functional materials,7,8 and in medi-
cine9,10 has driven the development of efficient methods for
carbon-boron bond formation. The ultimate goal is to develop
an efficient and cost-effective method for the synthesis of
aryl-boron compounds that is tolerant toward all functional
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Published on Web 07/20/2010
DOI: 10.1021/jo101023t
r
2010 American Chemical Society

Moldoveanu et al.
JOCFeatured Article
demonstrated effective pinacolborylation of ortho-substituted
boron source. Later, Marder15 reported a (Cp*RhCl2)2 catalyst
for direct aromatic C-H borylation of benzene, and Smith16
elaborated a very selective catalytic system from (Ind)Ir(COD)
(where Ind is indenyl and COD is 1,5-cyclooctadiene) and biden-
date phosphine ligands, both employing pinacolborane (HBpin)
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42
pin39,40 or B2pin2 as boron sources. Additionally, a few
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reported the CuI-catalyzed pinacolborylation of aryl iodides.
This study includes four examples of ortho-substituted sub-
strates. Subsequently, Marder et al. reported a Cu(I)I/PBu3-
catalyzed borylation of aryl iodides and bromides utilizing
1.5 equiv of B2pin2 and bis(neopentylglycolato)diboron
(B2neop2).44b Good yields were obtained for the ortho-
methoxy and ortho-methyl-substituted substrates investi-
gated by Marder’s group. However, aryl chlorides do not
react under these conditions.
butylpyridine (dtbpy), for the direct C-H borylation of arenes
and heteroarenes using B2pin2
17-22
or HBpin23,24 as the boron
source. Direct C-H borylation exhibits regioselectivity domi-
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Certain functional groups have been shown to mediate
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of 1,4-dibromobenzene and 1,3,5-tribromobenzene to pro-
duce nonhalogenated boronic acid additives for flame-
retardant materials. Later, Mindiola developed a tridentate
Ni(II) complex capable of transferring catecholborane to
bromobenzene.62 Following these preliminary reports, in 2008,
we elaborated the first general approach to Ni-catalyzed
borylation56 using in situ generated pinacolborane and
neopentylglycolborane.37,63 The novel and extremely inexpen-
sive boron source, neopentylglycolborane,58c was prepared in
situ. In situ prepared neopentylglycolborane is not purified,
and therefore, the reaction mixture contains residual S(CH3)2.
The S(CH3)2 does not affect Ni(II) species involved in the
borylation but poisons the Pd(II)-catalyzed neopentylgly-
colborylation.56 This Ni-catalyzed neopentylglycolborylation
was successfully paired with sequential Ni-catalyzed56 or com-
plementary Pd-catalyzed57,64 cross-coupling, providing cost-
effective access to a diversity of useful biaryl compounds.
Although progress has been made to expand the scope of Ni-
catalyzed neopentylglycolborylation, many substrates remain a
challenge, including ortho-substituted aryl halides. In an earlier
communication, NiCl2(dppp)/dppp provided 100% conver-
sion of the starting material for the neopentylglycolborylation
of 2-bromotoluene.56 However, the isolated yield was not
determined.
The development of universal catalysts for the Ni(II)-
catalyzed Suzuki-Miyaura cross-coupling49 and effective
neopentylglycolborylation of aryl chlorides55 was achieved
through the use of the mixed-ligand catalysts NiCl2(dppp)/
PPh3 (dppp is 1,3-bis(diphenylphosphino)propane) and NiCl2-
(dppp)/dppf [where dppf is 1,10-bis(diphenylphosphino)-
ferrocene], respectively. In the previous studies and in the
current one, we define a Ni(II)-based mixed-ligand catalytic
system as having the following structure: Ni(II)X2(ligand-1)/
ligand-2 (where X is a halide or pseudohalide). In this report,
X = Cl. Herein, the Ni(II)-catalyzed neopentylglycolboryla-
tion of ortho-substituted aryl iodides, bromides, and chlor-
ides is investigated, and through the use of libraries of
mixed-ligand Ni(II) catalysts, efficient and general reaction
conditions are recommended.
TABLE 1. Neopentylglycolborylation of Methyl 2-Iodobenzoate. Pre-
liminary Screening for Optimum Combinations of Catalyst and Ligand
entry
catalyst (%)
ligand (%) time (h) convna/yieldb (%)
1
2
3
4
5
6
7
8
Ni(COD)2 (5)
Ni(COD)2 (5)
dppp (10)
P(Cy)3 (10)
dppp (5)
dppe (5)
dppe (5)
PPh3 (10)
dppf (10)
5
4
4
5
5
5
5
5
100/100 (88)
100/100 (96)
100/100 (82)
28/28 (27)c
100/100 (80)
100/100 (81)
100/100 (97)c
100/100 (78)
NiCl2(dppp) (5)
NiCl2(dppe) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(PPh3)2 (5) dppp (10)
aConversion determined by GC. bYield determined by GC. Isolated
yield in parentheses. cIsolated yield for trifluoroborate.
NiCl2(dppp)/dppp (Table 1, entry 3), the first catalyst devel-
oped for Ni-catalyzed neopentylglycolborylation,56 while origi-
nally thought to be ineffective for ortho-substituents, was found
to be effective for methyl 2-iodobenzoate. On the contrary,
NiCl2(dppe)/dppe [dppe is 1,2-bis(diphenylphosphino)ethane]
(Table 1, entry 4) provided significantly lower yields than
NiCl2(dppp)/dppp, demonstrating once again the limited utility
of dppe as ligand. However, the use of dppe as coligand to form
the mixed-ligand catalyst NiCl2(dppp)/dppe (Table 1, entry 5)
provided a marked improvement in yield. Interestingly, other
mixed-ligand systems NiCl2(dppp)/PPh3 and NiCl2(PPh3)2/
dppp (Table 1, entries 6 and 8) were also able to provide very
good yields. However, a mixture of 5 mol % of NiCl2(dppp)
with 10 mol % of dppf coligand, the most efficient catalytic
system discovered for the Ni(II)-catalyzed neopentylglycolbor-
ylation of para-substituted aryl chlorides55 and aryl mesylates,65
was also the most competent catalyst for this transformation
(Table 1, entry 7).
It should be noted that the ortho-borylated compounds are
almost exclusively viscous oils that, at the scale of these experi-
ments, are more difficult to isolate and purify than the related
crystalline meta- and para-borylated compounds.55-57,64 Their
isolation was improved by converting the ortho-boronate esters
to trifluoroborates.2,3 The conversion of aryl neopentylglycol-
boronates to aryltrifluoroborates was previously reported.56
For specifically noted entries in Tables 1, 9, 10, and 12, the
crude products were treated with KHF2 to produce the crystal-
line potassium trifluoroborates,66 and the resulting two-step
isolated yields reported were in many cases significantly higher
than the isolated yields of the one-step borylation.
Results and Discussion
Neopentylglycolborylation of Aryl Iodides. Preliminary
experiments screening the Ni(II)-catalyzed neopentylglycol-
borylation of ortho-substituted aryl halides started with the
aryl iodide methyl 2-iodobenzoate (Table 1) and a variety of
catalysts. Ni(COD)2/ligand catalytic system was shown pre-
viously to mediate the neopentylglycolborylation of all aryl
halides,57 and therefore, it was used to explore which aryl halide
substrates are expected to be reactive under suitable NiCl2-
based catalysis. Therefore, in this study, Ni(COD)2/ligand is
not considered a mixed-ligand catalytic system. Ni(COD)2/
PCy3 and Ni(COD)2/dppp (Table 1, entries 1 and 2) are very
effective for the ortho-neopentylglycolborylation of methyl
2-iodobenzoate, providing quantitative conversion and excel-
lent yield. However, Ni(II)Cl2-based catalysts are preferred on
the basis of easier handling and preparation.
Aryltrifluoroborates exhibit reactivity similar to that of
arylboronate esters.2,3 Therefore, this two-step Ni-catalyzed
trifluoroborylation serves as an effective solution to the
isolation of oil-forming ortho-substituted aryl boronates.
The mixed-ligand systems composed of 5 mol % of NiCl2-
(dppp) with 10 mol % of dppf, NiCl2(dppp)/PPh3, and
NiCl2(PPh3)2/dppp were universal and mediated the neo-
pentylglycolborylation of electron-deficient (Table 2 entries
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4489–4491.
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Moldoveanu et al.
JOCFeatured Article
TABLE 2. Neopentylglycolborylation of Aryl Iodides Containing Electron-Rich and Electron-Deficient ortho-Substituents
aConversion determined by GC. bYield determined by GC. Isolated yield in parentheses. cSelective monoborylated on iodide.
1, 2, and 8) and electron-rich (Table 2, entries 3-7 and 9) aryl
iodides in 71-97% yield. In the case of 2-bromo-1-iodoben-
zene (Table 1, entry 2), a mixture of monoborylated and
diborylated compounds was produced.
lower yields of 77 or 71% after 1 h, respectively. A similar study
of catalyst loading was performed for electron-deficient methyl
2-iodobenzoate (Table 4). Using 5% NiCl2(dppp) and 10%
dppf, a quantitative yield was obtained in 1 h (Table 4, entry 1).
At 3% NiCl2(dppp) and 6% dppf, the yield remained good
(80%) after 1 h (Table 4, entry 2). Further limiting catalyst
loading to 2% NiCl2(dppp) with 4% dppf, 1% NiCl2(dppp),
2% NiCl2(dppf), or 0.5% NiCl2(dppp) with 1% dppf provided
lower yields of 71, 61, and 8% after 1 h, respectively. However,
higher yields for lower catalyst loading could be achieved with
longer reaction times.
It is evident from the emergence of mixed-ligand catalysts
in Ni(II)-catalyzed neopentylglycolborylation that the role
of the catalyst and coligand is complex. A more comprehen-
sive screening for optimum combinations of Ni(II)-based
catalysts and mixed ligands for 2-iodoanisole (Table 5 and
Figure 1, left) and methyl 2-iodobenzoate (Table 6 and
Figure 1, right) utilizing a library of mixed-ligand systems
at a loading level of 1 mol % of catalyst, 2 mol % of coligand
(unless otherwise noted), and a reaction time of 2 h was
conducted. These experiments were also compared with the
catalyst Ni(COD)2 that was used as standard for Ni(0)
Screening for Optimum Combinations of Ni(II)-Based Cata-
lysts and Mixed Ligands for the Neopentylglycolborylation of
2-Iodoanisole and 2-Iodomethyl benzoate. In a previous report, it
was demonstrated that the catalyst loading level for the Ni(II)-
catalyzed neopentylglycolborylation of para-substituted aryl
iodides could be decreased to as low as 2 mol % without
significantly decreasing the isolated yield.57 As NiCl2(dppp)/
dppf has been identified as a universal catalyst for the neopentyl-
glycolborylation of ortho-aryl iodides, it is necessary to ascertain
the effect of catalyst loading on performance. The effect of
catalyst loading on the NiCl2(dppp)/dppf-catalyzed neopentyl-
glycolborylation of electron-rich 2-iodoanisole was investigated
(Table 3). Using 5% NiCl2(dppp) and 10% dppf, a quantitative
yield was obtained in 1 h (Table 3, entry 1). Even at 2%
NiCl2(dppp) and 4% dppf, the yield was as high as 91% after
1 h (Table 3, entry 3).
Decreasing catalyst loading to 1% NiCl2(dppp) with 2%
(dppf), or 0.5% NiCl2(dppp) with 1% dppf, provided slightly
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TABLE 3. Neopentylglycolborylation of 2-Iodoanisole. Screening for
Optimum Combinations of Catalyst and Mixed-Ligand Loading
product was obtained without coligand, suggesting that an
active catalyst was not generated or was not stable under these
conditions. NiCl2(dppp) as catalyst exhibited superior perfor-
mance to other catalysts under mixed-ligand conditions, with
maximum yield (100%) in the presence of dppf coligand. This
is the same Ni(II)-based mixed-ligand system that was most
efficient for the neopentylglycolborylation of aryl chlorides.55
Interestingly, while NiCl2(dppp) with no coligand achieved
86% yield in 2 h, the use of excess dppp as “coligand” resulted
in one of the lowest yields for NiCl2(dppp) as catalyst (42%). It
is possible that the resulting active Ni(0)(dppp)2 complex
readily adopts a relatively unstrained tetrahedral Ni(II)-bis-
chelate structure that decreases the reactivity of the Ni(0)
species toward oxidative addition.
entry
NiCl2(dppp) (%)
dppf (%)
yielda (%)
1
2
3
4
5
5
3
2
1
0.5
10
6
4
2
1
100
90
91
77
71
Likewise, for NiCl2(dppp), the use of other bidendate phos-
phine ligands such as dppe or dppb resulted in lower yields
(6-69%) while the use of monodendate ligands PCy3, PPh3, or
PTol3 produced higher yields (86-97%). For all Ni catalysts
composed of bidendate phosphine ligands, NiCl2(dppp),
NiCl2(dppe), NiCl2(dppb), and NiCl2(dppf), lower yields were
achieved when excess of ligand was employed as coligand than
any of the corresponding mixed-ligand combinations. There-
fore, it is not simply the concentration of ligand but also the
combination of the mixed ligand that enables the superior
catalytic performance. As reported previously55 and demon-
strated by the results from Table 5, reversing the ligand
combination from NiCl2(dppp)/dppf to NiCl2(dppf)/dppp
changes the reaction yield from 100 to 33%. All other combi-
nations of NiCl2(dppf) with various coligands resulted in even
lower yields (0-23%). This trend reiterates that the benefit of
dppf is achieved only as a coligand and that NiCl2(dppf) is not
an efficient catalyst. Therefore, at least in the case of bidentate
ligands, where ligand exchange is more limited, there will be a
notable difference when the precatalyst ligand and the coli-
gand are reversed. Like in the case of NiCl2(dppf), the remain-
ing catalysts composed of a bidentate phosphine ligand, NiCl2-
(dppe) and NiCl2(dppb), exhibited generally poor yields. For
NiCl2(dppe), the highest yields were achieved using bidentate
dppb as coligand (36%) or monodentate coligands such as
PCy3 (15%) or PTol3 (30%). For NiCl2(dppb) catalyst, opti-
mum yields (18-25%) were obtained using either PPh3 or
dppf as coligand.
aYield determined by GC.
TABLE 4. Neopentylglycolborylation of 2-Iodomethylbenzoate. Screening
for Optimum Combinations of Catalyst and Mixed-Ligand Loading
entry
NiCl2(dppp) (%)
dppf (%)
yielda (%)
1
2
3
4
5
5
3
2
1
0.5
10
6
4
2
1
100
80
71
61
8
aYield determined by GC.
TABLE 5. Neopentylglycolborylation of 2-Iodoanisole. Screening for
Optimum Combinations of Catalyst and Mixed Ligand
NiCl2(PPh3)2 was the only catalyst based on a monoden-
tate phosphine ligand that was investigated. The best yields
were achieved for NiCl2(PPh3)/dppp (97%), NiCl2(PPh3)2/
dppb (57%), or NiCl2(PPh3)2 /PPh3 (44%). Interestingly, ex-
tremely low yield was obtained for NiCl2(PPh3)2/dppf (12%),
despite the fact that dppf was the most efficient coligand for
NiCl2(dppp).
convn/yielda (%) for mixed ligands
no
ligand PCy3 PPh3 PTol3 dppf dppe dppp dppb
catalyst
NiCl2(PPh3)2 0/0 11/11 44/44 33/33 12/12 9/9 97/97 57/57
NiCl2(dppf)
0/0
6/6
5/5
6/6
NiCl2(dppe) 15/15 15/15 10/10 30/30
3/3
7/7
3/3 33/33 23/23
1/1 2/2 36/36
Switching the substrate to methyl 2-iodobenzoate (Table 6
and Figure 1, right) demonstrated similarities to the previous
substrate as well as some intriguing differences. While yields
were generally elevated as compared to 2-iodoanisole due to
the presence of an activating electron-withdrawing group,
NiCl2(dppp) was once again demonstrated to be a privileged
catalyst providing consistently the highest yields. Likewise,
the universal mixed-ligand catalyst NiCl2(dppp)/dppf pro-
vided quantitative yield. As before, NiCl2(dppf) and NiCl2-
(dppe) did not show good catalytic activity. Mixed- and
non-mixed-ligand systems derived from NiCl2(PPh3)2 also
provided very high yields, but unlike with 2-iodoanisole, the
mixed-ligand system NiCl2(PPh3)2/dppp was not as effective as
NiCl2(dppp) 86/86 86/86 97/97 95/95 100/100 6/6 42/42 69/69
NiCl2(dppb) 7/7 10/10 18/18 15/15 25/25 5/5 6/6 7/7
Ni(COD)2
0/0 12/12 42/42 5/5
51/51 2/2 97/97 46/46
84/84d
aDetermined by GC. dMixture of 0.01 equiv of dppp and 0.01 equiv of
dppf used as ligand.
species. In these experiments, 1,4-bis(diphenylphosphino)-
butane (dppb) and tri-p-tolylphosphine (PTol3) were inves-
tigated in addition to the ligands already mentioned.
Interestingly, for 2-iodoanisole, NiCl2(dppp) with no coli-
gand is still a competent catalyst, achieving 86% yield in 2 h.
The other catalysts were far less efficient in the absence of
coligand. For Ni(COD)2, NiCl2(dppf), and NiCl2(PPh3)2, no
5442 J. Org. Chem. Vol. 75, No. 16, 2010

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FIGURE 1. Three-dimensional representation of the effect of catalyst and mixed ligand on the yield of the Ni-catalyzed neopentylglycolbor-
ylation of 2-iodoanisole (left) and methyl 2-iodobenzoate (right).
TABLE 6. Neopentylglycolborylation of 2-Iodomethylbenzoate. Screening for Optimum Combinations of Catalyst and Mixed Ligand
convn/yielda (%) for mixed ligands
catalyst
no ligand
PCy3
PPh3
PTol3
dppf
dppe
dppp
dppb
NiCl2(PPh3)2
NiCl2(dppf)
NiCl2(dppe)
NiCl2(dppp)
NiCl2(dppb)
Ni(COD)2
99/99
9/9
5/5
100/92
100/83
2/2
96/96
10/10
21/21
100/100
100/100
100/100
89/89
20/20
3/3
100/100
100/100
100/100
100/100
16/16
5/5
100/100
100/100
100/100
71/71
5/5
2/2
100/100
72/72
43/34
1/1
0/0
0/0
7/7
0
51/51
7/7
3/3
59/59
85/66
21/21
100/89
2/2
8/8
61/61
100/89
100/100
0
aDetermined by GC.
other systems. Likewise, Ni(COD)2/dppp, which was very
effective for 2-iodoanisole, only provided 21% yield, while
Ni(COD)2 with PCy3, PPh3, PTol3, or dppb provided quanti-
tative yields (Table 6).
A high yield with dppb as a coligand was quite surprising,
and intriguingly, yields for the neopentylglycolborylation of
methyl 2-iodobenzoate using NiCl2(dppb) as catalyst with
and without coligands provided generally excellent yields. It
is interesting to note that for methyl 2-iodobenzoate some
catalyst systems provided a discrepancy between GC con-
version and yield, which as it will be described in a subse-
quent section can be the result of protodeborylation or
hydrodehalogenation side reactions.
It is apparent that the profile of catalytic activity changes
from substrate to substrate. Fortuitously, it seems that
NiCl2(dppp)-based catalysts and, in particular, the mixed-
ligand system NiCl2(dppp)/dppf are general catalysts for
providing excellent to quantitative yield. However, dppf is
a more expensive ligand and, in some scenarios, may be more
difficult to remove during purification than simpler phos-
phine ligands. If price and catalyst separation become re-
strictive, a full catalyst screening is likely to provide alternate
catalysts that, while not universal, will be equally attractive
for the substrate in question.
Neopentylglycolborylation of Aryl Bromides. Aryl bro-
mides exhibit different trends in reactivity than aryl iodides.
The mixed-ligand system NiCl2(dppp)/dppf is still capable of
mediating effective neopentylglycolborylation of electron-rich
and sterically small 2-bromotoluene (Table 7, entry 12) and
2-bromoanisole (Table 8, entry 5). However, for bulkier or
more electron-deficient ortho-substituents (Table 8, entries 1-4),
NiCl2(dppp)/dppf provides lower yields. For 2-bromotoluene,
the mixed-ligand system NiCl2(dppp)/PPh3 (Table 7, entries 6
and 7) and the single-ligand system NiCl2(dppp)/dppp
(Table 7, entry 4) provide comparable yields to the mixed-
ligand NiCl2(dppp)/(dppf) (Table 7, entry 12). As in the case of
aryl iodides, the model catalyst Ni(COD)2/PCy3 is relatively
adept at mediating the borylation of electron-deficient aryl
bromides (Table 7, entry 1) but is less reactive toward electron-
rich substrates (Table 7 entries 2 and 3).
The large discrepancy between the conversion and yield
of the NiCl2(dppp)/dppp-catalyzed neopentylglycolboryla-
tion of methyl 2-bromobenzoate suggests that the bulky
and electron-withdrawing ortho-carboxylates facilitate a side
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TABLE 7. Neopentylglycolborylation of ortho-Substituted Aryl Bromides. Preliminary Screening for Optimum Combinations of Catalyst and Mixed Ligand
aConversion calculated from GC. bYield determined by GC. Isolated yield in parentheses. cIsolated yield for trifluoroborate.
reaction, which can be attributed to either protodeborylation
or hydrodehalogenation.
the synthesis of thiophene-based precursors for cross-cou-
pling reactions (Table 8, entries 6-8) isof particularinterest.67
Therefore, we sought to investigate the neopentylglycolbor-
ylation of 2-bromothiophene. Excellent yield (93%) was
obtained in 17 h for the neopentylglycolborylation of 2-
bromothiophene (Table 8, entry 6) using 5 mol % of NiCl2-
(dppp)/10 mol % of dppf as catalyst. Under these conditions,
quantitative GC yield was obtained in 4.5 h using 5 mol % of
NiCl2(dppp)/10 mol % of dppf (Table 9, entry 1). Decreasing
the catalyst loading to 3 mol % of NiCl2(dppp)/6 mol % of
dppf (Table 9, entry 2) provided 97% yield in 4.5 h and
quantitative GC yield in 18 h. Further reduction in catalyst
loading level to 2 mol % of NiCl2(dppp)/4 mol % of dppf
As it will be described in a later section, protodeborylation
requires the presence of adventitious moisture and tends to
occur only at extended reaction times. As the present experi-
ments were conducted under rigorously dry conditions with
short reaction times, hydrodehalogenation of the starting
material is the most likely side reaction.
In addition to aryl neopentylglycolboronate esters, the
single-ligand system NiCl2(dppp)/dppp was able to mediate
the effective monoborylation of pseudo-ortho-substituted
2-bromothiophene (Table 8, entries 6 and 7) and the dibor-
ylation of 2,5-dibromothiophene (Table 8, entry 8) in up to
97 and 83% recovered yield, respectively.
In light of the interest in thiophene-based derivatives for
organic electronics, dendrimers, sensors, and other materials,
(67) Rosen, B. M.; Wilson, C. J.; Wilson, D. A.; Peterca, M.; Imam,
M. R.; Percec, V. Chem. Rev. 2009, 109, 6275–6540.
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TABLE 8. Neopentylglycolborylation of ortho-Substituted Aryl Bromides
c
aConversion calculated from GC. bYield determined by GC. Isolated yield in parentheses. Isolated yield for trifluoroborate. dMonoborylated/
hydrodehalogenated/diborylated (3/7/1) 2d, isolated yield for mixture mono- and hydrodehalogenated.
(Table 9, entry 3) or 1 mol % of NiCl2(dppp)/2 mol % of dppf
provided only 74 or 32% GC yield in 18 h, respectively.
Neopentylglycolborylation of Aryl Chlorides. In a previous
report, the mixed-ligand system NiCl2(dppp)/dppf was shown
to be far superior to other single-ligand and mixed-ligand
systems for the neopentylglycolborylation of aryl chlorides.55
This system was also explored for the neopentylglycolboryla-
tion of ortho-substituted aryl chlorides.
TABLE 9. Neopentylglycolborylation of 2-Bromothiophene. Screening
for Optimum Combinations of Catalyst and Mixed-Ligand Loading
For aryl chlorides, the steric bulk of the ortho-substituent
appears to have the most profound effect on reactivity
(Table 10). The highest yields were observed for aryl chlorides
with small ortho-substituents regardless of whether they are
electron-withdrawing or electron-donating, such as 2-chloro-
anisole (Table 10, entry 2), 1-chloro-2-fluorobenzene (Table 10,
entry 5), 1,2-dichlorobenzene (Table 10, entry 6), 2-chloroto-
luene (Table 10, entry 7), and 1-chloro-2-(trifluoromethyl)-
benzene (Table 10, entry 11).
yielda (%) at time (h)
entry
NiCl2(dppp) (%)
dppf (%)
2 h
4.5 h
18 h
1
2
3
4
5
3
2
1
10
6
4
98
91
67
26
100
97
67
26
100
100
74
2
32
aYield determined by GC.
Aryl chlorides with bulkier ortho-substituents such as 1-(ben-
zyloxy)-2-chlorobenzene (Table 10, entry 1), methyl 2-chloro-
benzoate (Table 10, entry 8), and (2-chlorophenyl)(phenyl)-
methanone (Table 10, entry 10) could only be borylated in low
yield.
in low yield. In addition to ortho-substituted phenyl halides,
NiCl2(dppp)/dppf was able to mediate the neopentylglycolbor-
ylation of heteroaryl halides to provide, for example, pseudo-
ortho-substituted 2-chlorothiophene (Table 10, entry 13) in
93% isolated yield.
Likewise, 2-chlorophenol, which most probably is deproto-
nated under these reaction conditions could only be borylated
In the previous section, the conditions for the Ni-catalyzed
neopentylglycolborylation of 2-bromothiophene were optimized.
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TABLE 10. Neopentylglycolborylation of ortho-Substituted Aryl Chlorides
aConversion determined by GC. bYield determined by GC. Isolated yield in parentheses. cMonoborylated and hydrodehalogenated/monoborylated
(1/15), isolated yield for mixture of mono- and hydrodehalogenated products. dIsolated yield for trifluoroborate.
Here, a similar optimization was performed on 2-chlorothio-
phene (Table 11). Using, 5 mol % of NiCl2(dppp)/10 mol %
of dppf, the neopentylglycolborylation of 2-chlorothiophene
(Table 11, entry 1) was more sluggish than for 2-bromothio-
phene, achieving quantitative GC yield only after 15 h.
Decreasing catalyst loading level to 3 mol % of NiCl2(dppp)/6
mol % of dppf (Table 11, entry 2) or 2 mol % of NiCl2-
(dppp)/4 mol % of dppf (Table 11, entry 3) provided 87 (38 h)
and 92% (43 h) GC yield, respectively. Further reduction in
catalyst loading level to 1 mol % of NiCl2(dppp)/2 mol % of
dppf provided 58% GC yield in 43 h.
Investigation of Protodeborylation and Hydrodehalogena-
tion Pathways Encountered during the Neopentylglycolbory-
lation of Aryl Halides with NiCl2-Based Mixed-Ligand
Catalytic Systems. As discussed in the previous sections,
the neopentylglycolborylation of aryl halides containing
methylcarboxylates sometimes results in a notable discre-
pancy between GC yield and GC conversion. This suggests
one or more side reactions. Fundamentally, four side reac-
tions are possible: (1) hydrodehalogenation of aryl halide, (2)
protodeborylation, (3) homocoupling of aryl halide, and (4)
homocoupling of neopentylglycolboronate ester (Scheme 1).
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TABLE 11. Neopentylglycolborylation of 2-Chlorothiophene. Screen-
ing for Minimum Catalyst and Mixed-Ligand Loading
SCHEME 1. Possible Side Reactions for Ni-Catalyzed
Borylation
yielda (%)
entry NiCl2(dppp) (%) dppf (%) 2 h 5 h 15 h 23 h 38 h
1
2
3
4
5
3
2
1
10
6
4
50
31
17
3
71
60
40
18
100
68
100
78
78
50
100
87
72b
92c
58c
2
45b
aYield determined from GC. bGC at 18 h. cGC at 43 h.
On the basis of the mechanism proposed for the Pd-catalyzed
borylation using pinacolborane,38a it is assumed that, for
Ni(II)-catalyzed borylation, borane/Et3N mediates activa-
tion of Ni(II)Cl2(Ligand) precatalyst to a Ni(0)(Ligand)
active catalyst. If the mechanism of Ni-catalyzed borylation
proceeds in a related way to the Pd-catalyzed mechanism, the
aryl halide oxidatively adds to the Ni(0) active catalyst.
Substitution of the Ni-halide bond with neopentylglycol-
borane followed by reductive elimination would produce the
expected aryl neopentylglycolboronate ester product. How-
ever, at this time, it is not possible to exclude that a single-
electron transfer (SET) mechanism could play some role in
this reaction.38b Kochi’s38b early work on Ni-catalyzed
homocoupling established that a SET chain reaction can
operate under certain reaction conditions. SET from Ni(0)/
Ni(II) to Ar-X could result in hydrodehalogenation by the
decomposition of the incipient radical anion into a radical
that will become hydrogenated by chain transfer, and a
halide anion, rather than through.
While the detailed mechanism of Ni(II)-catalyzed boryla-
tion is still uncertain, the discrepancy between conversion and
yield was preliminarily attributed to the protodeborylation of
the resulting boronate ester produced during the course of the
reaction. Other studies have demonstrated the relative in-
stability of electron-deficient ortho-boronic acids and esters
toward protodeborylation.1,44b In addition, Ni(II) salts have
been shown to be extremely effective at accelerating proto-
deboronation of arylboronic acids.68 An alternative explana-
tion for the difference between yield and conversion could be
provided by the direct hydrodehalogenation of the starting
aryl halide mediated via SET from the Ni(0) catalyst and/or
homocoupling side reactions. A model of protodeborylation
side reaction was performed where methyl 2-(5,5-dimethyl-
1,3,2-dioxaborinan-2-yl)benzoate was treated with 5 mol %
of NiCl2(dppp), Et3N, in toluene at 100 °C in the absence of
neopentylglycolborane and in the presence of 2 μL of H2O
(Figure 2a) or air (Figure 2b). Under these conditions, con-
tinuous protodeborylation was observed with time, achieving
in 22 h 93% protodeborylation in the presence of water
(Figure 2a) and 70% protodeborylation in the presence of
air (compound B) and 7-30% homocoupling byproduct
(compound C) (Figure 2b).
GC analysis of the NiCl2(dppp)/dppf-catalyzed neopentyl-
glycolborylation of methyl 2-bromobenzoate and methyl
2-chlorobenzoate (Figure 2c,d) reveals an increased rate of pro-
todeborylated/hydrodehalogenated byproduct formation and a
much lower rate for the formation of borylated product.
In the case of NiCl2(dppp)/dppf-catalyzed neopentylglycol-
borylation of methyl 2-bromobenzoate, the reaction reaches a
maximum at 360 min, where 50% loss of starting material is
observed corresponding to ∼70% GC yield. Starting at 180 min,
a major increase in the amount of hydrodehalogenated bypro-
duct (compound B) is seen, while a maximum in the GC yield is
observed. From 360 to 1440 min, the amount of product
(compound A) decreases from 20% (maximum yield recorded
at 360 min) to 10% GC yield, while the amount of hydrode-
halogenated byproduct (compound B) increases correspondingly
to 65%. These results demonstrate that during the most pro-
ductive time domain of the reaction, the first 360 min, the rates
of hydrodehalogenated byproduct and product formation are
comparable. From 120 to 480 min, hydrodehalogenation and
protodeborylation starts to compete with borylation, and from
480 min onward, protodeborylation is the most probable side
reaction since a decrease of the of the GC yield is observed while
the substrate consumption remains constant. NiCl2(dppp)/
dppf-catalyzed neopentylglycolborylation of methyl 2-chloro-
benzoate is considerably slower than that of the corresponding
bromide. In this case, the rate of protodeborylated/hydrodeha-
logenated byproduct formation is comparable with the rate of
neopentylglycolborylation. Further investigation of the occur-
rence of protodeborylation showed no side reaction in the
absence of Ni(II) catalyst when methyl 2-(5,5-dimethyl-1,3,2-
dioxaborinan-2-yl)benzoate was treated with Et3N in toluene at
100 °C for 24 h (Table 12, entry 1). Thus, Ni(II) species are
capable of mediating the protodeborylation of arylneopentyl-
glycolboronate esters with bulky, electron-deficient ortho-
methylcarboxylate substituents. When the electron-deficient
ortho-methylcarboxylate was replaced with the electron-
deficient ortho-trifluoromethyl or with the electron-rich ortho-
methoxy groups, no protodeborylation was observed under the
same conditions even after 24 h (Table 12, entries 12 and 13).
Also, when the electron-deficient ortho-methylcarboxylate
was replaced with a para-methylcarboxylate group, protode-
borylation was not observed even after 24 h (Table 12, entry
14). These experiments demonstrate that only the ortho-methyl-
carboxylates mediate the protodeborylation and suggest that
coordination of the Ni(II) catalyst by the carbonyl group of the
(68) Kuivila, H. G.; Reuwer, J. F.; Mongravite, J. A. J. Am. Chem. Soc.
1964, 86, 2666–2670.
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JOCFeatured Article
FIGURE 2. Evolution of starting material (compound A), protodeborylated product (compound B), and homocoupling byproduct (C) in the
NiCl2(dppp)-catalyzed protodeborylation of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate 2a performed in water (a) and air (b).
Evolution of starting material (compounds D and E), product (compound A), and protodeborylated side product (compound B) in the
NiCl2(dppp)/dppf-catalyzed neopentylglycolborylation of methyl 2-bromobenzoate (c) and methyl 2-chlorobenzoate (d).
carboxylate may have an important role in this reaction. This
hypothesis is strongly supported by experiments where the
methylcarboxylate unit in the para-position of the aryl group
or noncoordinating electron-withdrawing groups such as
-CF3 in the ortho-position do not mediate protodeborylation
(Table 12, entries 13 and 14).
The protodeboronation of arylboronic acids has been pre-
viously demonstrated to proceed through an acid- or base-
catalyzed A-SE2 mechanism in aqueous media.69 This process
is accelerated by some metal cations,70 such as Ni(II)68 and
Pd(II).71 Suzuki was the first to report the Pd-catalyzed homo-
coupling of arylboronic acids,72 while a more recent report
suggests that hydridic palladium nanoparticles generated in situ
from palladacycles mediate catalytic hydrodehalogenation of
aryl halides or protodeboronation of arylboronic esters.73 In the
related electrophilic displacement reaction of arylboronic acids
with hydrogen peroxide to generate phenols,74 chelation with
neopentylglycol did not have a catalytic effect.74c
ꢀ
(71) (a) Cammidge, A. N.; Crepy, K. V. L. J. Org. Chem. 2003, 68, 6832–
(69) (a) Kuivala, H. G.; Nahabedian, K. V. Chem. Ind. 1959, 1312–1313.
(b) Kuivala, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2159–
2163. (c) Kuivala, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83,
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TABLE 12. Investigation of the Protodeborylation under Different Reaction Conditions
aConversion calculated from GC. bYield determined by GC. Isolated yield in parentheses. cEquivalent to 20% molar ratio. dHomocoupling
byproduct. eWith 70% deuterium incorporation.
Furthermore, arylneopentyglycolboronates are relatively
stable to hydrolysis,53 and therefore, it is highly unlikely that
the currently observed protodeborylation proceeds through
an arylboronic acid intermediary.
Unfortunately, to the best of our knowledge, systematic
investigations of the protodeborylation of arylboronate
esters have not been reported in any prior publication. In
the current study, it is evident that Ni(II) species catalyze the
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TABLE 13. Investigation of the Hydrodehalogenation under Different Reaction Conditions
aConversion calculated from GC. bHydrodehalogenated:homocoupling products determined by GC, isolated yield in parentheses. cWith 1 equiv of
Ni(COD)2. dReaction temperature at 70 °C. eWith 14% deuterium incorporation.
protodeborylation of coordinating ortho-substituted aryl-
boronates such as methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-
2-yl)benzoate. The effects of catalyst, ligand, base, neopentyl-
glycolborane, and water or air as additives to the reaction
mixture were investigated.
elucidate the mechanism of Ni(II)Cl2-mediated protodeboryla-
tion. In addition, other Ni(II) species that are generated during
the catalytic process may also be capable of mediating proto-
deborylation.
This study demonstrates that, when the yield of the pro-
duct in Ni-catalyzed borylation of ortho-substituted carboxy-
lates is low, improved yields may be achieved by reducing the
reaction time of the borylation65 or adjusting reaction condi-
tions so as to minimize protodeborylation and hydrodehalo-
genation side reactions.
In light of Marder’s results with Cu(I)I-mediated boryla-
tion, the hydrodehalogenation of 2-iodomethylbenzoate was
investigated in the presence of either Ni(0) from Ni(COD)2
(Table 13, entries 1 and 2) or generated in situ by the reduction
of Ni(II) catalyst with Zn powder.48 Quantitative homocou-
pling of aryl halide was obtained as a byproduct in the pre-
sence of Ni(COD)2 catalyst in toluene, which is in agreement
with other experiments.48 However, Ni(0) generated in situ by
the reduction of NiCl2(dppp)/dppf with Zn powder in THF
mediates almost quantitative hydrodehalogenation. Addi-
tionally, when the same experiment was performed in THF-
d8, 14% deuterium incorporation into the hydrodehaloge-
nated product was observed. This suggests that a SET process
that results in an aryl radical may operate under some boryla-
tion conditions.
Addition of 20% water to the reaction mixture containing
both Ni(II) catalyst and the Et3N base mediates almost quanti-
tative protodeborylation in 18 h (Figure 2a), while in the
absence of the Ni(II) catalyst, no protodeborylation product
was observed (Table 12, entry 9). These experiments reiterate
the role of the Ni(II) species in mediating protodeborylation of
electron-deficient ortho-methylcarboxylate. Complete protode-
borylation of methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-
benzoate and 70% deuterium incorporation was observed after
addition of D2O in the reaction mixture (Table 12, entry 11). It
should be noted that, in the case of Cu(I)I-mediated borylation
reported by Marder et al,44b hydrodehalogenation was also
observed. In this study,44b the addition of H2O did not increase
the amount of hydrodehalogenated side product. Likewise, the
addition of D2O did not result in deuteration of the side product,
indicating that H2O does not mediate protodeborylation in
Cu(I)I-mediated borylation. On the other hand, reactions run in
THF-d6 resulted in 70% deuterium incorporation in the hydro-
dehalogenated side product. The mechanism outlined in their
report does not explain the hydrodehalogenation side reaction,
though Cu(0) nanoparticles were potentially implicated as the
active catalyst. While not mentioned by the original authors,44b
these results are consistent with a radical mechanism of hydro-
dehalogenation, which could arise from a SET process mediated
by either Cu(0) or Cu(I)I. Further work will be needed to
Comparison with Previous Methods for ortho-Borylation.
In this report, strategies for the Ni-catalyzed neopentylgly-
colborylation of ortho-substituted aryl chlorides, bromides,
and iodides were elaborated. The expensive Pd catalysts and
tetralkoxydiboron reagents were replaced with cost-effective
5450 J. Org. Chem. Vol. 75, No. 16, 2010

Moldoveanu et al.
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Ni catalysts and with the in situ prepared neopentylglycol-
borane. However, there are other methods in the literature
for ortho-borylation, which may be more suitable for certain
substrates.
catalysts from Ni(II)Cl2 precatalysts is highly dependent on
the ligand and coligand, but also that a mixed-ligand catalyst is
likely present in the active catalytic cycle. Additionally, it was
demonstrated that protodeborylation and hydrodehalogenation
are competitive side reactions of Ni-catalyzed neopentylglycol-
borylation of ortho-substituted derivatives containing carboxy-
lates as electron-deficient substituents and that Ni(II)Cl2(ligand)
in the presence of H2O and Ni(0), respectively, most probably
mediates these processes. Further mechanistic and theoretical
studies will be required to elucidate the structural benefits of
mixed-ligand systems in various stages of the catalytic cycle.
The ortho-directing substituents can be used to achieve
ortho-borylated products.26-31 Ir-, Re-, or Rh-catalyzed
direct C-H borylation typically provides para- or meta-
regioisomers, except in the presence of ortho-directing groups,
and therefore26-28 represents an effective method for the synthe-
sis of a limited pool of ortho-borylated arenes. Scattered exam-
ples of Pd-catalyzed borylation of ortho-substituted aryl halides
are available in the literature.33-42 Pd(0)-catalyzed bory-
lation of ortho-substituted aryl triflates using B2pin2 has been
demonstrated for a limited set of substrates.33,38a In these cases,
no isolated yields were reported, and consequently, a compar-
ison of efficacy cannot be made. Additionally, in the present
case of Ni-catalyzed borylation, aryl triflates were not investi-
gated due to the high costs of their preparation, which negates
the economic advantages of Ni catalysis. Pd-catalyzed boryla-
tion of ortho-substituted aryl iodides36,38a,75 and bromides41,43,75
typically provides comparable yields to the present Ni-catalyzed
approach, though in many cases with increased cost. Improved
yields for certain substrates via Ni-catalyzed neopentyl-
glycolborylation may be due to the decreased steric bulk of
neopentylglycolborane versus pinacolborane.43 The relatively
low loading levels of cost-effective Ni catalysts and simple
phosphine-containing ligands make Ni catalysis a particularly
attractive method for the synthesis of ortho-substituted bory-
lated derivatives starting from aryl iodides and selected aryl
bromides and heteroaryl bromides. Recently, Buchwald
reported a system for the Pd-catalyzed pinacolborylation of aryl
chlorides using dicyclohexyl[20,40,60-triisopropyl(1,10-biphenyl)-
2-yl]phosphine (XPhos) ligand and relatively high loading levels
Experimental Section
Preparation of Neopentylglycolborane. To a cooled solution
(0 °C) of neopentylglycol (10.0 mmol, 2.0 equiv) dissolved in
toluene (5 mL) was slowly added (CH3)2S BH3 (10.0 mmol,
3
2.0 equiv) via a syringe under nitrogen. After 30 min of stirring
at 0 °C, the reaction mixture was allowed to warm to 23 °C
and was left stirring at 23 °C until the gas evolution ceased
(60-90 min). Neopentylglycolborane was used directly without
further purification.
General Procedure for Neopentylglycolborylation. A Schlenk
tube charged with the aryl chloride (5.0 mmol, 1.0 equiv) (for
aryl chlorides, the reaction was conducted on 2.5 mmol scale),
Ni catalyst (for the exact amount of catalyst and coligand, see
Tables 1-8 in the text), (NiCl2(dppp), NiCl2(dppe), NiCl2-
(dppb), NiCl2(dppf), NiCl2(PPh3)2, Ni(COD)2) (0.5 mmol,
0.1-0.02 equiv), ligand (L: dppp, dppe, dppf, dppb, PPh3,
PCy3, PTol3) (0.5 mmol, 0.2-0.02 equiv), and a Teflon-coated
stir bar was evacuated three times for 10 min under high vacuum
and backfilled with N2. Toluene (5 mL) and Et3N (15.0 mmol,
3.0 equiv) were added to the reaction mixture at 23 °C. Freshly
prepared neopentylglycolborane (10.0 mmol, 2.0 equiv in 5 mL
of toluene) was added to the red colored suspension via syringe
at 23 °C. The reaction mixture was heated to 100 °C (for
NiCl2(PPh3)2 catalyst, the reactions were performed at 80 °C
to ensure catalyst stability), and the conversion was followed by
GC. After 1-40 h (reaction time depends on the type of the
chloro derivative and on the catalyst loading), maximum con-
version was determined by GC and the reaction mixture was
quenched via slow addition of a saturated aqueous ammonium
chloride solution (10 mL). The quenched reaction mixture was
washed three times with saturated aqueous ammonium chloride
solution and extracted with ethyl acetate (50 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated. The crude product was purified by silica gel
chromatography or by recrystallization.
42
of B2pin2 in dioxane, or using dicyclohexyl[20,60-dimethoxy-
(1,10-diphenyl)-2-yl]phosphine (SPhos) ligand, pinacolborane,
and triethylamine as solvent.40 The Buchwald systems deliver
superior performance in the borylation of many ortho-
substituted aryl chlorides but are more expensive than
the mixed-ligand systems reported here. In addition to Pd
and Ni, Zu, Ma,44a and Marder44b reported Cu-catalyzed
borylation of aryl halides which has been shown to be
effective for ortho-methoxy and ortho-methyl-substituted
aryl bromides and iodides but not for aryl chloride.
Conclusions
Methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (2a):43
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.9 (dd, J = 7.8, 0.8
Hz, 1H), 7.5 (m, 2H), 7.4 (dt, J = 7.8, 2.4 Hz, 1H), 3.9 (s, 3H), 3.80
(s, 4H), 1.1 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 169.4, 133.1,
132.3, 131.6, 129.0, 128.7, 72.9, 52.7, 32.2 22.4.
Efficient catalysts have been developed for the Ni-catalyzed
neopentylglycolborylation of ortho-substituted aryl iodides, bro-
mides, and chlorides. The mixed-ligand system NiCl2(dppp)/
dppf, previously developed for the Ni-catalyzed neopentylgly-
colborylation of a diverse array of aryl chlorides, and the mixed-
ligand system NiCl2(dppp)/PPh3 were shown to be effective
catalysts for the ortho-substituted aryl halides, demonstrating
once again the value of the mixed-ligand concept. Preliminary
experiments showed that electron-poor heterocycles such as
2-bromopyridines and pyrimidines were not successful in the
neopentylglycolborylation under the same reaction conditions.
Detailed optimization of the Ni-catalyzed neopentylglycolbor-
ylation of Ni-catalyzed borylation of 2-iodoanisole and methyl
2-iodobenzoate suggests that the generation of Ni(0) active
2-(2-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2b):
Yellowish crystals, mp 37-40 °C(lit.31 40 °C); 1H NMR (500 MHz,
CDCl3) δ 7.7 (dt, J = 6.8, 1.7 Hz, 1H), 7.4 (m, 1H), 7.1 (t, J = 7.3
Hz, 1H), 7.0 (t, J = 8.8 Hz, 1H), 3.8 (s, 4H), 1.0 (s, 6H); 13C NMR
(126 MHz, CDCl3) δ 168.4 (d, J = 250 Hz), 136.5 (d,
J = 8 Hz), 132.9 (d, J = 9 Hz), 123.8 (d, J = 3 Hz), 115.7 (d,
J = 24 Hz), 72.7, 32.1, 22.2.
2-(2-Bromophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2c):76
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.6 (dd, J = 7.3, 1.7
Hz, 1H), 7.5 (dd, J =7.9, 0.9 Hz, 1H), 7.3(dt, J = 7.6, 1.0 Hz, 1H),
7.2 (dt, J = 7.6, 1.8 Hz, 1H), 3.8 (s, 4H), 1.0 (s, 6H); 13C NMR
(75) Murata, M.; Oda, T.; Watanabe, S.; Masuda, Y. Synthesis 2007,
351–354.
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47, 2331–2335.
J. Org. Chem. Vol. 75, No. 16, 2010 5451

Moldoveanu et al.
JOCFeatured Article
(126 MHz, CDCl3) δ 135.7, 132.9, 131.4, 127.8, 126.6, 72.8, 32.2,
22.2.
2-(2-Chlorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2m):
Yellow crystals, mp 33-35 °C (lit.31 36 °C); 1H NMR (500 MHz,
CDCl3) δ 7.6 (dd, J = 7.4, 1.5 Hz, 1H), 7.3 (m, 2H), 7.2 (dt, J =
7.3, 1.3 Hz, 1H), 3.8 (s, 4H), 1.1 (s, 6H); 13C NMR (126 MHz,
CDCl3) δ 138.9, 135.8, 131.4, 129.8, 126.1, 72.9, 32.1, 22.2.
General Procedure for Aryl Trifluoroborate Synthesis. The
trifluoroborates were prepared from the corresponding crude
boronic esters according to literature procedures.66 In a nalgene
bottle were added a stir bar and the crude boronic ester (5 mmol,
1 equiv) dissolved in 12 mL of MeOH/H2O (2:1). KHF2 (15 mmol,
3 equiv) was added one portion over the reaction mixture, and the
reaction mixture was stirred at room temperature overnight. The
reaction mixture was transferred to a round-bottom flask and
concentrated by rotary evaporation. The crude product was recrys-
tallized from acetone to yield the corresponding trifluoroborate.
Potassium trifluoro(2-(methoxycarbonyl)phenyl)borate (3a):81
White powder, mp >250 °C; 1H NMR (500 MHz, DMSO-d6) δ
7.5 (d, J = 7.3 Hz, 1H), 7.2 (m, 2H), 7.1 (dt, J = 7.4, 1.2 Hz, 1H),
3.7 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 172.2, 136.6, 132.7,
128.2, 125.7, 124.8, 51.2.
1,2-Bis(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzene (2d): White
crystals, mp 55-58 °C; 1H NMR (500 MHz, CDCl3) δ 7.6 (dd, J =
5.4, 3.3 Hz, 2H), 7.3 (dd, J = 5.4, 3.3 Hz, 2H), 3.8 (s, 8H), 1.1 (s,
12H); 13C NMR (126 MHz, CDCl3) δ 132.5, 128.9, 72.9, 32.2, 22.3;
HRMS (ESþ) calcd for C16H24B2O4 (Mþ þ H) 303.1939, found
303.1947.
5,5-Dimethyl-2-(o-tolyl)-1,3,2-dioxaborinane (2e):77 Colorless
oil; 1H NMR (500 MHz, CDCl3) δ 7.7 (d, J = 7.3 Hz, 1H), 7.3
(dt, J = 7.4, 1.4 Hz, 1H), 7.1 (t, J = 7.5 Hz, 2H), 3.7 (s, 4H), 2.5 (s,
3H), 1.0 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 144.1, 135.0,
130.2, 130.1, 124.8, 72.4, 31.8, 22.6, 22.0.
2-(2-Methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2f):
1
White solid, mp 39-41 °C (lit.78 41 °C); H NMR (500 MHz,
CDCl3) δ 7.6 (dd, J = 7.2, 1.7 Hz, 1H), 7.4 (dt, J = 7.8, 1.8 Hz,
1H), 6.9 (dt, J = 7.3, 0.7 Hz, 1H), 6.9 (d, J = 8.3 Hz, 1H), 3.8 (s,
3H), 3.8 (s, 4H), 1.0 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
164.0, 136.1, 132.0, 120.6, 110.7, 72.8, 56.0, 32.1, 22.2.
5,5-Dimethyl-2-(2-(trifluoromethyl)phenyl)-1,3,2-dioxaborinane
(2h):79 Colorless oil;1H NMR(500 MHz, CDCl3) δ 7.7 (d, J = 7.1
Hz, 1H), 7.4 (m, 1H), 7.6 (d, J = 7.6 Hz, 1H), 7.5 (m, 2H), 3.8 (s,
4H), 1.1 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 134.2, 133.5 (d,
J = 31 Hz), 131.0, 129.6, 126.0 (d, J = 273 Hz), 125.6 (q, J =
5 Hz), 72.9, 32.1, 22.1.
Potassium trifluoro(2-methoxyphenyl)borate (3f): White pow-
der, mp >250 °C (lit.81 >230 °C); 1H NMR (500 MHz, DMSO-
d6) δ 7.3 (d, J = 6.6 Hz, 1H), 7.0 (d, J = 7.4 Hz, 1H), 6.7 (m, 2H),
3.6 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 162.5, 131.2,
126.6, 119.1, 109.6, 54.7.
5,5-Dimethyl-2-(thiophen-2-yl)-1,3,2-dioxaborinane (2i): White
Potassium (2,6-difluorophenyl)trifluoroborate (3g): White
1
1
crystals, mp 91-92 °C (lit.55 91-92 °C); H NMR (500 MHz,
powder, mp >250 °C (lit.66 >250 °C); H NMR (500 MHz,
CDCl3) δ 7.6 (dd, J = 3.5, 0.8 Hz, 1H), 7.6 (dd, J = 4.7, 0.8 Hz,
1H), 7.2 (dd, J = 4.7, 3.5 Hz, 1H), 3.8 (s, 4H), 1.0 (s, 6H); 13C
NMR (126 MHz, CDCl3) δ 136.0, 131.7, 128.4, 72.7, 32.4, 22.2.
2,5-Bis(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)thiophene (2j):
White crystals, mp 156-157 °C (lit.80 156.5-157.5 °C); 1H
NMR (500 MHz, CDCl3) δ 7.6 (s, 2H), 3.8 (s, 8H), 1.0 (s,
12H); 13C NMR (126 MHz, CDCl3) δ 136.6, 72.7, 32.4, 22.3.
2-(2-(Benzyloxy)phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2k):
DMSO-d6) δ 7.1 (m, 1H), 6.7 (m, 2H); 13C NMR (126 MHz,
DMSO-d6) δ 166.9 (dd, J = 242, 18 Hz), 127.6, 110.2 (dd, J =
31, 8 Hz).
Potassium trifluoro(2-(trifluoromethyl)phenyl)borate (3h):
1
White powder, mp 195-200 °C (lit.82 175-180 °C); H NMR
(500 MHz, DMSO-d6) δ 7.7 (d, J = 6.1 Hz, 1H), 7.5 (d, J = 7.5
Hz, 1H), 7.4 (t, J = 7.0 Hz, 1H), 7.2 (d, J = 7.2 Hz, 1H); 13
C
NMR (126 MHz, DMSO-d6) δ 134.1 (d, J = 3 Hz), 131.7 (d, J =
30 Hz), 129.8, 126.6 (d, J = 274 Hz), 125.4, 124.2 (q, J = 5 Hz).
1
White crystals, mp 79-81 °C; H NMR (500 MHz, CDCl3) δ
7.7 (dd, J = 7.3, 1.7 Hz, 1H), 7.5 (d, J = 7.2 Hz, 2H), 7.4 (m, 3H),
7.3 (t, J = 7.4 Hz, 1H), 7.0 (td, J = 7.3, 0.7 Hz, 1H), 6.9 (d, J = 8.3
Hz, 1H), 5.1 (s, 2H), 3.8 (s, 4H), 1.1 (s, 6H); 13C NMR (126 MHz,
CDCl3) δ 163.1, 138.1, 135.9, 131.9, 128.6, 127.7, 127.2, 121.7,
112.7, 72.8, 70.6, 32.1, 22.3; HRMS (CIþ) calcd for C18H21BO3
(Mþ) 296.1584, found 296.1601.
Acknowledgment. Financial support by the NSF (DMR-
0548559) and by the P. Roy Vagelos Chair at Penn is grate-
fully acknowledged. We also thank Professor G. A. Molander
of the University of Pennsylvania for constructive suggestions
and for reading the manuscript.
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Supporting Information Available: 1H NMR, 13C NMR,
and HRMS data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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