Zero-valent metals accelerate the neopentylglycolborylation of aryl halides catalyzed by NiCl2-based mixed-ligand systems

Article abstract of DOI:10.1021/jo101718v

The highly active mixed-ligand catalytic system NiCl₂(dppp)/dppf combined with the reducing effect of zerovalent Zn and of other metals was used to demonstrate a method for the dramatic acceleration of the rate and for the enhancement of the yi

Full text of DOI:10.1021/jo101718v

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Zero-Valent Metals Accelerate the Neopentylglycolborylation of
Aryl Halides Catalyzed by NiCl2-Based Mixed-Ligand Systems
Pawaret Leowanawat, Ana-Maria Resmerita, Costel Moldoveanu, Chi Liu, Na Zhang,
Daniela A. Wilson, Lisa M. Hoang, Brad M. Rosen, and Virgil Percec*
Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
percec@sas.upenn.edu
Received August 31, 2010
The highly active mixed-ligand catalytic system NiCl2(dppp)/dppf combined with the reducing effect of
zerovalent Zn and of other metals was used to demonstrate a method for the dramatic acceleration of the
rate and for the enhancement of the yield of Ni-catalyzed neopentylglycolborylation of aryl halides. A
diversity of electron-rich and electron-deficient aryl iodides, bromides, and chlorides were efficiently
neopentylglycolborylated, typically in 1 h or less. This acceleration is particularly remarkable for the
generally less reactive aryl bromides and chlorides and for all ortho-substituted aryl halides. By accelerating
the rate of borylation and reducing its reaction time to complete conversion, pathways leading to
protodeborylated or hydrodehalogenated side products have a reduced impact on the outcome of the
overall reaction. Although Zn powder was the reducing agent of choice, compatibility of this technique
with more readily recoverable Zn chips, as well as other metals such as Mn, Mg, Fe, Al, and Ca, has
demonstrated the broad scope of this synthetic method.
Introduction
reactive organolithium or Grignard reagents have been and
continue to be the subject of intense investigations. Arenes can
be directly, regioselectively borylated via Re,12 Rh,13,14 or Ir15-21
Boronic acids,1 esters,1 and trifluoroborate salts2-4 are crucial
intermediates for Suzuki-Miyaura coupling reactions5 provid-
ing synthetic precursors for the medical6 and material science7,8
but can also serve as catalysts,9 sensors,10 or as therapeutics.11
Not surprisingly, the development of efficient transition-metal-
catalyzed techniques that completely obviate the need for highly
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Published on Web 10/27/2010
DOI: 10.1021/jo101718v
r
2010 American Chemical Society

Leowanawat et al.
JOCArticle
catalysis. Alternatively, Pd-catalyzed Miyaura borylation22-29
of aryl halides and triflates has proven to be an effective
regiospecific strategy. Often, these techniques involve the use
of relatively expensive tetraalkoxydiborons such as bis-
(pinacolato)diboron,30,31 though recent interest has focused
on the use of more practical dialkoxyboranes, such as
pinacolborane.32,33 Due in large part to the high cost of
Pd, alternative methods for the borylation of aryl halides
using less expensive metals such as Cu are seeing increasing
use.34-36 Analogous chemistry employing Ni-catalysis holds
similar promise for process economy as well as for the ability
to employ less reactive electrophiles.37-41
In 2000, the possibility of Ni-catalyzed borylation was
demonstrated.42 Meanwhile, we developed a novel borylat-
ing reagent, neopentylglycolborane, which can be prepared
in situ43 from neopentylglycol and borane-dimethyl sulfide.
This reagent facilitated the development of Ni-catalyzed neo-
pentylglycolborylation as an effective strategy for the prepara-
tion of aryl boronate esters. The resulting arylneopentylgly-
colboronate esters have been harnessed in the sequential44 or
one-pot cross-coupling45 with aryl halides44,45a and aryl sulfo-
nates49 to form a diversity of substituted biaryls. The Ni-
catalyzed borylation/cross-coupling strategy enabled the
expeditious synthesis of building blocks for the construction
of self-organizable supramolecular dendrimers.46,47 The first
catalyst for this neopentylglycolborylation was the single-
ligand 1:1 complex of NiCl2(dppp) and dppp, NiCl2(dppp)/
dppp, which was effective for aryl iodide and bromide
substrates.44,45a However, it was later discovered that
mixed-ligand systems, in particular NiCl2(dppp)/dppf, were
significantly more efficient for the catalytic neopentylglycol-
borylation of aryl chlorides48 and of the less reactive aryl
sulfonates.49 While some aryl mesylates and tosylates were
successfully neopentylglycolborylated in high yield with
NiCl2(dppp)/dppf without any additives, the addition of
zerovalent Zn metal provided for very broad substrate
compatibility and greatly accelerated the reaction, typically
generating excellent yields within 1-2 h.49 Recently, it was
shown that NiCl2(dppp)/dppf, as well as other mixed-ligand
Ni complexes, are also superior catalysts for the neopentyl-
glycolborylation of ortho-substituted aryl halides.50 ortho-
Substituted aryl iodide substrates typically reached maxi-
mum yield within a few hours. However, aryl bromides and
chlorides usually required extended reaction times, often
exceeding 24 h. In some cases, this longer reaction time
allows for competitive protodeborylation that diminishes
the yield of the reaction and generates mixtures of products.
Herein, we explore the application of zerovalent metal
activation to the acceleration of neopentylglycolborylation
of aryl halides, including of the less reactive ortho-substituted
aryl iodides, bromides, and chlorides.
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Results and Discussion
Zero-Valent Metals Accelerate the Ni-Catalyzed Neopen-
tylglycolborylation of Aryl Halides. The use of Zn as an
accelerant for Ni-catalyzed borylation of aryl mesylates49
was inspired by our earlier work38a-e where Zn was used as a
(38) For select examples employing aryl sulfonates and sulfamates, see:
(a) Percec, V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895–6903. (b)
Percec, V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060–1065. (c)
Percec, V.; Bae, J. Y.; Zhao, M. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1066–
1069. (d) Percec, V.; Bae, J. Y.; Zhao, M. Y.; Hill, D. H. J. Org. Chem. 1995,
60, 176–185. (e) Percec, V.; Bae, J. Y.; Zhao, M. Y.; Hill, D. H. Macro-
molecules 1995, 28, 6726–6734. (f) Zim, D.; Monteiro, A. L. Org. Lett. 2001,
3, 3049–3051. (g) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J.
Org. Chem. 2004, 69, 3447–3452. (h) Macklin, T. K.; Snieckus, V. Org. Lett.
2005, 7, 2519–2522.
(39) For examples employing aryl fluorides, see: (a) Bohm, V. P. W.;
Grstotmayr, C. W. K.; Weskamp, T.; Hermann, W. A. Angew. Chem., Int.
Ed. 2001, 39, 1602–1604. (b) Mongin, F.; Mojovic, L.; Guillamet, B.;
Trecourt, F.; Queguiner, G. J. Org. Chem. 2002, 67, 8991–8994. (c) Ramnial,
T.; Taylor, S. A.; Bender, M. L.; Gorodetsky, B.; Lee, P. T. K.; Dickie, D. A.;
McCoolum, B. M.; Pye, C. C.; Walsby, C. J.; Clysburne, J. A. C. J. Org.
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1257–1268.
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3482–3485.
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2008, 10, 4879–4882. (b) Knochel, P. Synfacts 2009, 2, 191–192.
(46) Rosen, B. M.; Wilson, D. A.; Wilson, C. J.; Peterca, M.; Won, B. C.;
Huang, C.; Lipski, L. R.; Zeng, X.; Ungar, G.; Heiney, P. A.; Percec, V.
J. Am. Chem. Soc. 2009, 131, 17500–17521.
(40) For an example employing aryl cyanides, see: Yu, D.-G.; Yu, M.;
Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009, 11,
3374–3377.
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V. Angew. Chem., Int. Ed. 2010, 49, 7002–7005.
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Rosen, B. M.; Percec, V. Org. Lett. 2009, 11, 4974–4977. (b) Knochel, P.;
Gavryushin, A. Synfacts 2010, 1, 84–85.
(49) Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.; Resmerita, A.-M.;
Corcoran, P.; Hoang, L. M.; Rosen, B. M.; Percec, V. J. Am. Chem. Soc.
2010, 132, 1800–1801.
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Resmerita, A.-M.; Liu, C.; Rosen, B. M.; Percec, V. J. Org. Chem. 2010, 75,
5438–5452.
(41) For examples employing aryl ethers, esters, and carbamates, see: (a)
Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428–2432. (b) Tobisu,
M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866–4869.
(c) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.; Zhao, K.-Q.;
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Angew. Chem., Int. Ed. 2010, 49, 4566–4570.
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reducing agent37b,38a-e,51,52 in Ni-catalyzed homocoupling
and cross-coupling. NiCl2-phosphine complexes including
NiCl2(dppp) were capable to undergo oxidative addition to
aryl mesylates. The catalytic cycle of Ni-catalyzed borylation
of aryl halides or sulfonates has not been well elaborated.
Nevertheless, the reductions of NiCl2(dppp)/L precatalyst
and of the oxidative addition adduct are expected to be
fundamental steps in this reaction. It was hypothesized that
the less efficient Ni-catalyzed neopentylglycolborylation of
aryl mesylates49 could be due to slower reduction of the
precatalyst or oxidative addition adduct than for the corre-
sponding aryl halides. The addition of Zn as reducing agent
is believed to increase the rate of these processes.
Phenol-derived electrophiles such as mesylates and tosy-
lates are often less expensive than aryl halides. Although a
great diversity of phenols is commercially available, aryl
halides are still extremely important intermediates in organic
synthesis. Therefore, the development of rapid and efficient
methods to convert aryl halides to boronic acids and boronic
acid derivatives is an important technical challenge. To
determine the effect of the external reducing agent, an array
of zerovalent metals such as Al, Ca, Fe, Mg, Mn, and Zn
were tested in the NiCl2(dppp)/dppf-catalyzed neopentylgly-
colborylation of 4-iodo-, 4-bromo-, and 4-chloroanisole
(Table 1). The results from Table 1 were obtained in the
presence of a diversity of zerovalent metals and were not
optimized. However, they strongly support the universality
of the activation concept by zerovalent metals, and in addi-
tion they demonstrate that this process is not restricted to Zn.
For the case of 4-iodoanisole (compare entries 1 and 2 with
entries 3-8 in Table 1), the reaction time to 100% conversion
was reduced from 1 to 0.5 h in the presence of zerovalent metals.
The most significant acceleration by zerovalent metals was
observed in the case of 4-bromoanisole (compare entry 9 with
entries 10-17 in Table 1) and 4-chloroanisole (compare entry
18 with entries 19-26 in Table 1).
TABLE 1. Neopentylglycolborylation of Halogenated Anisole Catalyzed
by NiCl2(dppp)/dppf Activated with Different Metals
entry
X
metala
time (h)
convnb/yieldc (%)
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
none
none
Zn
Mn
Fe
Al
Mg
Ca
none
Zn
Mn
Mn
Fe
1.0
0.5
0.5
0.5
1.0
0.5
0.7
0.5
1.0
0.7
1.0
2.0
24
1.0
1.0
1.5
14
1.0
1.0
2.0
2.0
22
100/100 (85)
66/66 (40)
100/100 (95)
100/100 (92)
100/100 (95)
100/100 (78)
100/97 (82)
92/86 (76)d
26/26/(22)
100/98 (68)
74/70
100/97 (76)
88/86 (73)
100/75 (58)
84/84
100/93 (67)
73/73 (46)
7/7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Al
Mg
Mg
Ca
none
Zn
Mn
Fe
Fe
Al
100/98 (70)
100/98 (85)
11/11
100/100 (73)
100/76 (49)
57/55
1.0
1.0
1.7
24
Mg
Mg
Ca
100/95 (84)
54/54 (30)d
aMetals are all 325 mesh. bConversion determined by GC. cYield
determined by GC. Isolated yield in parentheses. dIsolated yield for
potassium trifluoroborate.
Comparison of Different Particle Sizes of Zn. In certain
cases, it appears that other zerovalent metals such as Mg and
Mn exhibit reducing activity comparable to that of Zn for
4-chloroanisole (compare entries 19, 20, and 25 in Table 1)
but require a longer reaction time. However, considering the
already demonstrated power of Zn to accelerate the neopen-
tylglycolborylation of aryl mesylates and tosylates, it would
be advantageous to develop a single universal catalytic
system. Zn metal is available in many forms including
powder, chips, sheets, and wire. Typically, when Zn has been
employed as a reductant in Ni-catalyzed chemistry, it is
supplied in the form of a nonactivated powder. In all
experiments reported in this publication, nonactivated Zn
or other zerovalent metals were used. Zn powder provides
the largest surface area per unit mass and can be more
uniformly dispersed through the reaction medium. However,
monolithic Zn provides easier recovery and recycling.
The NiCl2(dppp)/dppf-catalyzed neopentylglycolboryla-
tions of aryl iodides, bromides, and chlorides were per-
formed using either 325 mesh Zn powder or Zn chips
(Table 2). Both Zn powder and Zn chips accelerate the Ni-
catalyzed neopentylglycolborylation.
As expected as a result of larger surface area, yields were
generally better for Zn powder in equal or shorter reaction time.
Nevertheless, in some cases comparable yields could be achieved
in equivalent reaction time (Table 1, entries 3 and 6).
Ni-Catalyzed Neopentylglycolborylation of Aryl Iodides.
The Zn-activated neopentylglycolborylation catalyzed by
NiCl2-based systems was compared using several mixed-ligand
and single-ligand catalysts for a diversity of aryl iodide sub-
strates. The neopentylglycolborylation of 4-iodoanisole using
the mixed-ligand catalyst NiCl2(dppp)/dppf was extremely effi-
cient and rapid in the presence of 2 equiv of Zn, leading to 95%
yield after only 30 min (entry 1 in Table 2). An extensive array of
ortho-andpara-substituted aryl iodides, bromides, and chlorides
has been tested in the Ni-catalyzed neopentylglycolborylation.
In this report, the borylation of ortho-substituted aryl halides will
be used as the benchmark for reaction efficiency, as para- and
meta-substituted aryl halides are generally more reactive. Simi-
larly, electron-rich ortho-substituted aryl iodides 2-iodotoluene
and 2-iodoanisole were previously borylated using NiCl2(dppp)/
dppf in the absence of Zn, providing 78% yield (24 h) and 80%
yield (1 h), respectively.50 Here, it is found that the presence of 2
equiv of Zn accelerates the reaction, increasing the yield to 85%
for 2-iodotoluene (1 h, Table 3 Entry 1) and 96% for 2-iodoa-
nisole (1 h, Table 3 Entry 2). It should be noted that these yields
correspond to a two-step process of neopentylglycolborylation
followed by conversion of the boronate ester to the more readily
(51) Zembayashi, M.; Tamao, K.; Yoshida, J.; Kumada, M. Tetrahedron
Lett. 1977, 18, 4089–4092.
(52) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627–2637.
7824 J. Org. Chem. Vol. 75, No. 22, 2010

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TABLE 2. Neopentylglycolborylation of Aryl Halides Catalyzed by
NiCl2(dppp)/dppf Activated with Zn Powder and Zn Chips
TABLE 3. Neopentylglycolborylation of Aryl Iodides Catalyzed by
NiCl2-Based Mixed-Ligand Systems Activated with Zn Powder
aConversion determined by GC. bIsolated yield. cIsolated yield for potas-
sium trifluoroborate. dMonoborylated product. eDiborylated product.
isolated potassium trifluoroborate. Therefore, the yields of the
first step of this process may in fact be higher than reported as
potassium trifluoroborates. The Ni-catalyzed and Zn-activated
neopentylglycolborylation of 2-iodoanisole was explored using
other mixed-ligand catalysts such as NiCl2(dppp)/PPh3, and
NiCl2(PPh3)/dppp, and single-ligand catalysts such as NiCl2-
(dppp)/dppp, NiCl2(PPh3)/PPh3, NiCl2(dppp), and NiCl2-
(PPh3)2, but in all cases in significantly diminished yield. The
electron-deficient aryl iodides methyl 2-iodobenzoate and
2-fluoro-1-iodobenenze were also investigated. Methyl 2-iodo-
benzoate was also neopentylglycolborylated in the absence of
Zn using the mixed-ligand catalysts NiCl2(dppp)/dppf (97%
yield, 5 h) and NiCl2(dppp)/PPh3 (81% yield, 5 h).50
c
aConversion determined by GC. bIsolated yield. Isolated yield for
potassium trifluoroborate.
Ni-Catalyzed Neopentylglycolborylation of Aryl Bromides.
In an earlier report, NiCl2(dppp)/dppp-catalyzed neopentyl-
glycolborylation of 4-bromoanisole provided 90% in 18 h.45a
Using the mixed-ligand NiCl2(dppp)/dppf catalyst in the pre-
sence of Zn activator, 91% yield could be obtained in only 1 h
(Table 4, entry 11). Using NiCl2(dppp)/dppf and Zn activator, a
similar yield could be obtained for 2-bromoanisole (95% of the
trifluoroborate salt, after 1 h (Table 4, entry 3)). However, the
use of single-ligand catalytic systems (Table 4, entries 4, 6-8) or
other mixed-ligand systems (Table 4, entries 5 and 9) in the
presence of Zn or the mixed-ligand NiCl2(dppp)/dppf catalyst in
the absence of Zn50 provided significantly lower yields. Similarly
high yields could be obtained in 1 h for 2-bromotoluene and
However, in the presence of Zn0 the reaction reaches high
yields in a very short reaction time using either NiCl2(dppp)/
dppf (81% yield, 0.5 h) or NiCl2(dppp)/PPh3 (90% yield, 1 h)
(Table 3, entries 9 and 11). For 2-fluoro-1-iodobenzene, 89%
yield was achieved in 1 h using NiCl2(dppp)/dppf alone, whereas
80% yield was obtained in only 30 min in the presence of Zn
(Table 3, entry 17).
The Ni-catalyzed neopentylglycolborylation of aryl iodides,
including less reactive ortho-substituted aryl iodides, was gener-
ally efficient even without the use of Zn as an additive. However,
more sluggish reactions were observed for aryl bromides and aryl
chlorides in the absence of Zn.
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TABLE 4. Neopentylglycolborylation of Aryl Bromides Catalyzed by
NiCl2-Based Mixed-Ligand Systems Activated with Zn Powder
very long reaction times (44 h) in the absence of Zn.50 Here, in
the presence of Zn, good yields could be achieved in only 1-6 h
(Table 4, entries 10, 13). 1,2-Dibromobenzene could be effi-
ciently diborylated (Table 4, entry 10), whereas in previous
efforts without Zn additive only a low yield of a mixture of
mono- and diborylated adducts was obtained.50 Nevertheless,
attempts to prepare diborylated 2,5-dibromothiophene were
not as successful, as protodeborylation seemed to be more
rapid for this system, resulting in a mixture of 2,5-diborylated
thiophene and 2-borylated-thiophene (Table 4, entry 15).
Ni-Catalyzed Neopentylglycolborylation of Aryl Chlorides.
The mixed-ligand NiCl2(dppp)/dppf catalytic system was
discovered while pursuing the neopentylglycolborylation of
relatively unreactive aryl chloride electrophiles.48a Despite,
the higher activity of the mixed-ligand NiCl2(dppp)/dppf
catalytic system, electron-rich aryl chlorides did not provide
particularly high yields. For example, in the absence of Zn
4-chloroanisole achieved only 56% yield after 20 h48 and 7%
in 1 h (Table 1 entry18). Here, it is shown that using Zn as an
additive provides 91% yield in only 1 h (Table 5, entry 9).
Even 1-chloro-3,5-dimethoxy benzene could be neopentyl-
glycolborylated in 53% yield 1-chloro-3,5-dimethoxyben-
zene after only 3 h (Table 5, entry 11).
Electron-rich ortho-substituted aryl chlorides are among the
most challenging substrates for Ni-catalyzed neopentylglycol-
borylation.50 Nevertheless, NiCl2(dppp)/dppf in the presence of
Zn provides good yields of 2-chlorotoluene (71%) and 2-chlor-
oanisole (90%) in only 1 h (Table 5, entries 1, 2). The results
from Table 5 demonstrate that both the mixed-ligand NiCl2-
(dppp)/dppf catalyst and the Zn activator were needed for a high
catalytic performance. The single-ligand catalyst (Table 5, en-
tries 3, 5-7) and other mixed-ligand catalysts (Table 5, entries 4,
8) were less effective. In the presence of Zn, electron-deficient
para-substituted aryl chlorides (Table 6, entries 8-10) could be
borylated in comparable yield, but in a fraction of the time
required in the absence of Zn.48a The contrast between Ni-
catalyzed borylation with and without Zn is clearer for ortho-
substituted electron-deficient aryl chlorides. For example, using
NiCl2(dppp)/dppf alone, only 26% yield was obtained after
24 h.48a The use of this catalyst in conjunction with Zn provided
95% yield after conversion to the trifluoroborate salt in only 1 h
(Table 6, entry 1). As has been shown repeatedly, this effect
requires both the very efficient NiCl2(dppp)/dppf mixed-ligand
catalyst as well as the Zn activator. Significantly lower yields
were obtained for single-ligand (Table 6, entries 2, 4-6) or other
mixed-ligand (Table 6, entries 3, 7) catalysts even in the presence
of Zn. Impressively, a 76% yield of o-diborylated benzene was
obtained in 3 h from o-dichlorobenzene (Table 6, entry 11), and
91% borylation yield was obtained from 1-chloro-2-trifluoro-
methylbenzene in 4 h (Table 6, entry 12), despite worse yields
under extended reaction times (24-65 h) using NiCl2(dppp)/
dppf without Zn as an additive.
c
aConversion determined by GC. bIsolated yield. Isolated yield for
potassium trifluoroborate. dYield for diborylated product. eYield for
monoborylated product and deborylated product. 4 equiv of neopen-
tylglycolborane was used.
f
2-bromothiophene (Table 4, entries 1, 2, 14). The true advantage
of the Zn-activated system is, however, exemplified by
the neopentylglycolborylation of methyl 2-bromobenzoate
(Table 4, entry 2), o-dibromobenzene (Table 4, entry 10),
1-bromo-2-trifluoromethylbenzene (Table 4, entry 12), and
1-bromo-2,6-difluorobenzene (Table 4, entry 13). In previous
work the NiCl2(dppp)/dppf-catalyzed neopentylglycolboryla-
tion of methyl 2-bromobenzoate was plagued by very high
levels of protodeborylation, resulting in a diminished yield
(11% in 20 h).50 Through the use of Zn additive, the borylation
process was significantly accelerated, allowing for complete
conversion in 1 h and obviating the need to run the reaction for
longer times, where protodeborylation begins to dominate.
Furthermore, the doubly ortho-substituted 1-bromo-2,6-di-
fluorobenzene and the ortho-substituted 1-bromo-2-trifluoro-
methylbenzene were isolated in poor-to fair yield after only
Conclusions
In two recent reports from our laboratory the power of the
mixed-ligand systems for the Ni-catalyzed borylation of less
reactive aryl chlorides48a and ortho-substituted aryl halides50
was established. Using the particularly efficient mixed-
ligand catalyst NiCl2(dppp)/dppf, similar borylations of phenol-
derived aryl mesylates and tosylates were shown to be
feasible, and in fact the catalyst significantly accelerated the
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JOCArticle
TABLE 5. Neopentylglycolborylation of Electron-Rich Aryl Chlorides
Catalyzed by NiCl2-Based Mixed-Ligand Systems Activated with Zinc Powder
TABLE 6. Neopentylglycolborylation of Electron-Deficient Aryl
Chlorides Catalyzed by NiCl2-Based Mixed-Ligand Systems Activated
with Zinc Powder
c
aConversion determined by GC. bIsolated yield. Isolated yield for
potassium trifluoroborate.
reaction in the presence of Zn additive.49 Unlike aryl sulfo-
nates, aryl halides suffer from both protodeborylation and
hydrodehalogenation side reactions, and therefore the abil-
ity to accelerate productive borylation and limit overall
reaction time is of particular value. By combining the highly
active mixed-ligand NiCl2(dppp)/dppf catalyst with Zn acti-
vation, the neopentylglycolborylation of aryl iodides, bro-
mides, and chlorides, including ortho-substituted, proceeds
extremely quickly, typically achieving complete conversion
and high yield in 1 h or less. Although the use of super-
stoichiometric Zn powder may be disadvantageous for some
applications, easier product isolation due to increased yield
and decreased byproduct contamination, as well as a signi-
ficantly reduced reaction time, is quite compelling. Further-
more, similar efficacy with easily recoverable and recyclable
Zn chips and the extension to other zerovalent metal addi-
tives has been demonstrated.
c
aConversion determined by GC. bIsolated yield. Isolated yield for
potassium trifluoroborate. d4 equiv of neopentylglycolborane was used.
Experimental Section
Preparation of Neopentylglycolborane. To a cooled solution
(0 °C) of neopentylglycol (6.0 mmol, 2.0 equiv) dissolved in toluene
(3 mL) was slowly added (CH3)2S BH3 (6.0 mmol, 2.0 equiv) via a
3
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 until the
gas evolution ceased (60-90 min). Neopentylglycolborane was
used directly without further purification.
General Procedure for Neopentylglycolborylation. To an oven-
dried 25 mL Schlenk tube were added Zn powder or chips (6 ꢀ 10-3
mol), Ni-based catalyst (1.5 ꢀ 10-4 mol), and ligand (3 ꢀ 10-4 mol)
(see Tables 1-6) along with the appropriate aryl halide (if it is solid)
(3 ꢀ 10-3 mol). The ortho-substituted aryl halide, catalyst, and
ligand were degassed by pumping and backfilling with nitrogen
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Leowanawat et al.
JOCArticle
three times. Toluene was added to the reaction mixture (3 mL)
along with the appropiate aryl halide (if it is liquid) and Et3N
(1.26 mL 9 ꢀ 10-3 mol). Neopentylglycol borane was added
dropwise to the reaction mixture. The reaction was placed into a
preheated oil bath at 100 °C with stirring under an inert atmo-
sphere. Samples were taken in time through the septum under
nitrogen, and the conversion was followed by GC. After complete
consumption of the starting material, the reaction was then
quenched with a saturated NH4Cl solution (50 mL) and extracted
with ethyl acetate (3 ꢀ 25 mL). No difference between the crude GC
and the last recorded GC prior quenching except for the disap-
pearance of the in situ prepared neopentylglycolborane peak was
observed. The organic fractions were combined and dried over
MgSO4. Following filtration the solvent was removed under reduced
pressure and the crude reaction mixture was immediately purified on
a silica gel column with the appropriate eluent.
7.41-7.15 (m, 1H), 6.82 (t, J = 7.5 Hz, 2H), 3.81 (s, 4H), 1.07 (d,
J = 0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 166.0 (dd, J =
247.5, 13.5 Hz), 131.9, 111.1, 72.8, 32.0, 21.8; HRMS (CIþ) calcd
for C11H14BF2O2 (Mþ þ H) 227.1055, found 227.1055.
Methyl 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (2l).
White solid, mp 111-113 °C (lit.49 114 °C); 1H NMR (500 MHz,
CDCl3) δ8.01 (d, J= 8.3 Hz, 2H), 7.86 (d, J = 8.1 Hz, 2H), 3.92 (s,
3H), 3.79 (s, 4H), 1.03 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
167.4, 133.9, 131.9, 128.6, 72.5, 52.2, 32.0, 22.0.
4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (2m).
White solid; mp 122 °C (lit.49 124-125 °C); 1H NMR (500 MHz,
CDCl3) δ7.87 (d, J= 8.0 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 3.78 (s,
4H), 1.02 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 134.4, 131.1,
119.2, 114.0, 72.5, 32.0, 21.9.
2-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)acetonitrile
(2n):48a White solid, mp 77-78 °C; 1H NMR (500 MHz, CDCl3)
δ 7.80 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.7 Hz, 2H), 3.77 (s, 4H),
3.75 (s, 2H), 1.02 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 134.8,
132.3, 127.2, 117.9, 72.5, 32.0, 23.9, 22.0.
General Procedure for Aryl Trifluoroborate Synthesis. The
trifluoroborates were prepared from the corresponding crude
boronic esters according to the following procedure. In a
Nalgene bottle were added a stirr 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 in 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 recrystallized from acetone to yield the
corresponding trifluoroborate.
2-(4-Methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2a).
1
White solid, mp 54-56 °C (lit.49 59 °C); H NMR (500 MHz,
CDCl3) δ 7.74 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 3.82
(s, 3H), 3.75 (s, 4H), 1.01 (s, 6H); 13C NMR (126 MHz, CDCl3)
δ 161.7, 135.4, 113.0, 72.1, 55.0, 31.8, 21.8.
2-(2-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2b)49
1
Yellowish solid; H NMR (500 MHz, CDCl3) δ 7.66 (dd, J =
22.9, 7.3 Hz, 2H), 7.56-7.37 (m, J = 12.6, 7.3 Hz, 2H), 3.79 (s, 4H),
1.07 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 133.8, 130.6, 129.2,
121.0, 120.3, 72.6, 33.3, 21.8.
5,5-Dimethyl-2-(o-tolyl)-1,3,2-dioxaborinane (2c)50 Colorless
liquid; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.4 Hz, 1H),
7.27 (td, J = 7.5, 1.3 Hz, 1H), 7.14 (t, J = 7.7 Hz, 2H), 3.76 (s, 4H),
2.51 (s, 3H), 1.02 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 144.1,
135.0, 130.2, 130.1, 124.8, 72.4, 31.8, 22.5, 22.0.
Potassium Trifluoro(4-methoxyphenyl)borate (3a). White solid,
mp >250 °C; 1H NMR (500 MHz, DMSO-d6) δ7.21 (d, J=8.0 Hz,
2H), 6.65 (d, J=8.2 Hz, 2H), 3.67 (s, 3H); 13C NMR (126 MHz,
DMSO-d6) δ 157.5, 132.6, 112.2, 54.9.
Potassium Trifluoro(2-fluorophenyl)borate (3b). White solid,
mp >250 °C (lit.53 304-305 °C); 1H NMR (500 MHz, DMSO-d6)
δ 7.34 (s, 1H), 7.16-6.99 (m, 1H), 6.91 (t, J = 6.9 Hz, 1H), 6.78 (t,
J = 8.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 165.7 (d, J =
239.1 Hz), 134.2, 125.8, 122.5, 113.7 (d, J = 26.1).
5,5-Dimethyl-2-(thiophen-2-yl)-1,3,2-dioxaborinane (2d). White
solid, mp 90-91 °C (lit. 91-92 °C);50 1H NMR (500 MHz, CDCl3)
δ 7.61-7.54 (m, 2H), 7.19-7.15 (m, 1H), 3.76 (s, 4H), 1.03 (s, 6H);
13C NMR (126 MHz, CDCl3) δ 135.8, 131.5, 128.2, 72.6, 32.2, 22.1.
2,5-Bis(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)thiophene (2e).
White solid, mp 155-156 °C (lit.50 156-157 °C); 1H NMR
(500 MHz, CDCl3) δ 7.59 (s, 2H), 3.75 (s, 8H), 1.02 (s, 12H); 13
NMR (126 MHz, CDCl3) δ 136.2, 72.3, 31.9, 21.8.
C
Potassium Trifluoro(o-tolyl)borate (3c). White solid, mp 229 °C
(lit.54 232 °C);1H NMR (500 MHz, DMSO-d6) δ7.31 (d, J=5.7 Hz,
1H), 6.87 (dd, J = 15.4, 5.9 Hz, 3H), 2.28 (s, 3H); 13C NMR
(126 MHz, DMSO-d6) δ 140.5, 131.6, 128.2, 125.1, 123.3, 21.7.
Potassium Trifluoro(2-methoxyphenyl)borate (3g). White solid,
2-(3,5-Dimethoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2f).
White solid, mp 112 °C (lit.49 115 °C); 1H NMR (500 MHz,
CDCl3) δ6.97 (d, J = 2.4 Hz, 2H), 6.55 (t, J= 2.4 Hz, 1H), 3.82 (s,
6H), 3.77 (s, 4H), 1.04 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
160.3, 110.7, 103.8, 72.2, 55.2, 31.8, 21.8.
1
mp >250 °C (lit.50 >250 °C); H NMR (500 MHz, DMSO-d6)
2-(2-Methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2g).
1
White solid, mp 40 °C (lit.50 39-40 °C); H NMR (500 MHz,
δ 7.29 (dd, J=6.9, 1.4 Hz, 1H), 7.02 (td, J=7.9, 1.9 Hz, 1H), 6.73-
6.65 (m, 2H), 3.62 (s, 3H); 13C NMR (126 MHz, DMSO-d6)
δ 162.5, 133.2, 126.6, 119.1, 109.6, 54.7.
Potassium Trifluoro(2-(methoxycarbonyl)phenyl)borate (3h).
White solid, mp >260 °C (lit.50 >250 °C); 1H NMR (500 MHz,
DMSO-d6) δ 7.45 (d, J = 7.3 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H),
7.16 (d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.3 Hz, 1H), 3.65 (s, 3H);
13C NMR (126 MHz, DMSO-d6) δ 172.2, 136.5, 132.7, 128.3,
125.8, 124.9, 51.3.
CDCl3) δ7.65 (dd, J= 7.2, 1.3 Hz, 1H), 7.39-7.33 (m, 1H), 6.94 (t,
J = 7.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 4H),
1.04 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 163.8, 135.9, 131.8,
120.4, 110.6, 72.6, 55.9, 31.9, 22.0.
Methyl 2-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (2h)50
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz,
1H), 7.55-7.46 (m, 2H), 7.38 (dd, J= 8.0, 2.5 Hz, 1H), 3.92 (s, 3H),
3.80 (s, 4H), 1.12 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 169.0,
132.7, 131.9, 131.3, 128.6, 128.3, 72.5, 52.3, 31.7, 22.0.
1,2-Bis(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzene (2i)50
Acknowledgment. Financial support by the NSF (DMR-
0548559) and by the P. Roy Vagelos Chair at Penn is grate-
fully acknowledged.
1
White solid; H NMR (500 MHz, CDCl3) δ 7.60 (dd, J=5.4,
3.3 Hz, 2H), 7.33 (dd, J=5.5, 3.3 Hz, 2H), 3.76 (s, 8H), 1.07 (s, 12H);
13C NMR (126 MHz, CDCl3) δ 132.3, 128.7, 72.7, 32.0, 22.1.
5,5-Dimethyl-2-(2-(trifluoromethyl)phenyl)-1,3,2-dioxaborinane
(2j)50 Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J=7.2
Hz, 1H), 7.66-7.60 (m, 1H), 7.52-7.41 (m, 2H), 3.78 (s, 4H), 1.05
(s, 6H); 13C NMR (126 MHz, CDCl3) δ 136.7, 133.8, 130.8, 129.3,
125.44, 125.40, 72.4, 31.8, 21.9.
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.
(53) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020–3027.
(54) Navarre, L.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2004, 1, 69–73.
2-(2,6-Difluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2k).
Yellowish solid, mp 42-44 °C; 1H NMR (500 MHz, CDCl3) δ
7828 J. Org. Chem. Vol. 75, No. 22, 2010