An improved system for the palladium-catalyzed borylation of aryl halides with pinacol borane

Article abstract of DOI:10.1021/jo800727s

(Chemical Equation Presented) borylation of aryl halides with an inexpensive and atom-economical boron source, pinacol borane, has been developed. This system allows for the conversion of aryl and heteroaryl iodides, bromides, and several chlorides, containing a variety of functional groups, to the corresponding pinacol boronate esters. In addition to the increase in substrate scope, this is the first general method where relatively low quantities of catalyst and short reaction times can be employed.

Full text of DOI:10.1021/jo800727s

In order to address these issues, we sought to develop a system
where pinacol borane, a cheaper and more atom-economical boron
source, could be employed in the borylation of aryl halides and
concurrently to produce a method applicable to sterically hindered
substrates. Although several systems have been developed for the
borylation of aryl halides with pinacol borane, these methods have
several limitations.6 In general, aryl iodides and bromides are
necessary, while the cheaper and more readily available aryl
chlorides are unsuitable substrates7 We are aware of only one report
in which aryl chlorides are efficiently transformed to the corre-
sponding boronate esters when using pinacol borane as the boron
source.8 However, this method had a limited substrate scope as
only para-substituted electron-rich aryl chlorides were efficiently
converted to the desired products. In addition, all Pd-catalyzed
borylation methods employing pinacol borane rely upon high
quantities of palladium catalyst (>3.0 mol%) in order to efficiently
process the aryl halides. Herein, we report a highly active catalyst
system based upon PdCl2(CH3CN)2 and SPhos (1) as the supporting
ligand for the borylation of aryl and heteroaryl iodides and bromides
with pinacol borane. This method not only allows for the use of
lower amounts of Pd catalyst with shorter reaction times but also
proved general for the borylation of a range of aryl, heteroaryl,
and vinyl chlorides.
We began our work by examining the optimization of the
reaction shown in Table 1. We found that a variety of di-
alkylbiarylphosphine ligands could be employed to afford highly
active catalysts. In general, dicyclohexylphosphino biphenyl
ligands resulted in higher conversion and yield for this process
as compared to the corresponding diphenyl- or di-tert-bu-
tylphosphino compounds. For example, a catalyst based upon
8 allowed for an 86% conversion and yield for the borylation
of 4-bromoanisole, while 7 or 9 resulted in only 53% and 14%
conversion of the aryl halide, respectively. In addition, highly
active systems were observed when 3 (Table 1, entry 3) or 6
(Table 1, entry 6) was employed. The catalyst system derived
from PdCl2(CH3CN)2 and 1, however, produced a near-
quantitative yield of the aryl boronate ester (Table 1, entry 1).9
Initially, we examined the borylation of aryl iodides. Despite
the fact that aryl iodides are more reactive than the correspond-
ing aryl bromides or chlorides, there are no methods, to our
knowledge, for their borylation with low catalyst loadings (i.e.,
An Improved System for the
Palladium-Catalyzed Borylation of Aryl Halides
with Pinacol Borane
Kelvin L. Billingsley and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed April 1, 2008
A highly efficient method for the palladium-catalyzed
borylation of aryl halides with an inexpensive and atom-
economical boron source, pinacol borane, has been devel-
oped. This system allows for the conversion of aryl and
heteroaryl iodides, bromides, and several chlorides, contain-
ing a variety of functional groups, to the corresponding
pinacol boronate esters. In addition to the increase in sub-
strate scope, this is the first general method where relatively
low quantities of catalyst and short reaction times can be
employed.
The utility of aryl boronic acids and esters throughout organic
synthesis is seen by their use as key intermediates in the
preparation of a wide range of synthetic targets.1 Despite their
versatility, standard methods for the preparation of these
compounds can be harsh and, hence, incompatible with a variety
of functional groups.2 However, various techniques have
recently emerged that provide access to aryl boronate esters
under milder reaction conditions.3 In particular, palladium-based
systems for the conversion of aryl halides to the corresponding
carbon-boron bonds have proved to be a powerful synthetic
tool. Recently, we reported a highly active catalyst for trans-
forming aryl chlorides into aryl pinacol-derived boronate esters.4
However, this system required the use of an expensive boron
source, bis(pinacolato)diboron.5 In addition, the reactions of
sterically hindered aryl chlorides were less efficient as they
required higher quantities of Pd as well as an increase in the
number of equivalents of the expensive boron reagent.
(5) (a) For other systems employing bis(pinacolato)diboron in Pd-catalyzed
borylations, see: Fu¨rstner, A.; Seidel, G. Org. Lett. 2002, 4, 541–543. (b)
Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813–9815. (c)
Ishiyama, T.; Itoh, Y.; Kitano, Y.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–
3450. (d) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841–
3844.
(6) (a) For other systems employing pinacol borane in Pd-catalyzed bory-
lations of aryl iodides and bromides, see: Baudoin, O.; Gue´nard, D.; Gue´ritte,
F. J. Org. Chem. 2000, 65, 9268–9271. (b) Murata, M.; Oyama, T.; Watanabe,
S.; Masuda, Y. J. Org. Chem. 2000, 65, 164–168. For a system employing pinacol
borane in Pd-catalyzed borylations of aryl bromides, see: (c) Broutin, P.-E.; Cerna,
I.; Campaniello, M.; Leroux, F.; Colobert, F. Org. Lett. 2004, 6, 4419–4422.
(7) For a review on Pd-catalyzed coupling reactions of aryl chlorides, see:
Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
(8) Murata, M.; Sambommatsu, T.; Watanabe, S.; Masuda, Y. Synlett 2006,
12, 1867–1870.
(1) For a review on the applications of aryl boronic acids and esters, see:
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–9695.
(2) Hall, D. G. Structure, Properties, and Preparation of Boronic Acid
Derivatives In Boronic Acids: Preparation and Applications in Organic Synthesis
and Medicine; Hall, D. G.), Ed.;VCH: Weinham, 2005; pp 1-99.
(3) For a review on transition-metal-catalyzed carbon-boron bond formation,
see: Ishiyama, T.; Miyaura, N. Chem. Rec. 2004, 3, 271–280.
(4) Billingsley, K.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 5359–5363.
(9) Reactions were conducted at a bath temperature of 110 °C. However,
the borylation of aryl iodides and bromides can be conducted at 80 °C, but longer
reaction times are necessary. In addition, NBu3 can be substituted for NEt3 for
the borylation of aryl iodides and bromides, but the reactions of aryl chlorides
proved to be less efficient with NBu3.
10.1021/jo800727s CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5589–5591 5589

TABLE 1. Reaction of 4-Bromoanisole with Pinacol Borane
TABLE 2. Pd-Catalyzed Borylation of Aryl Halides with Pinacol
Boranea
entry
ligand
GC yield (%)
conversion (%)
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
99
<10
94
81
<10
84
46
86
<10
<10
100
28
100
87
15
100
53
86
14
16
10
<3.0 mol%) or reaction times under 1 h. The PdCl2(CH3CN)2/1
combination proved to be highly active in the borylation of
4-iodoanisole producing the desired aryl boronate ester in 94%
yield in only 30 min (Table 2, entry 1). The process remained
efficient at lower levels of catalyst as the boronate ester was
produced in 91% yield after 5 h when 0.10 mol % Pd was
utilized (Table 2, entry 2).
The same catalyst system was highly efficient in the bory-
lation of a range of aryl and heteroaryl bromides. For example,
electron-rich aryl bromides, such as 4-bromoanisole (Table 2,
entry 3) and 4-bromo-N,N-dimethylaniline (Table 2, entry 5),
were successfully transformed into the desired pinacol boronate
esters in 97% and 85% yield, respectively. Although electron-
deficient aryl halides are known to be more challenging
substrates for Pd-catalyzed carbon-boron bond-forming pro-
cesses, 4-bromobenzophenone was smoothly converted to the
desired product in 5 h of reaction time with 1 mol % of Pd
(Table 2, Entry 8). Importantly, this method was also applicable
to a variety of ortho-substituted aryl bromides as the borylation
of the sterically hindered aryl halide, 2-bromomesitylene,
resulted in 90% yield of the corresponding aryl boronate ester
(Table 2, entry 12). In addition, a substrate possessing an ortho-
functional group, 2-bromoanisole, efficiently furnished the
desired product in a high yield (Table 2, entry 10). The PdCl2-
(CH3CN)2/1 catalyst system was also suitable in the borylation
of a vinyl bromide to produce the alkenyl pinacol boronate in
68% yield (Table 2, entry 13).10 In addition, heteroaryl bromides
were efficiently transformed to the desired products (Table 2,
entries 14 and 15). This catalyst system offers a general method
for the conversion of aryl and vinyl bromides to pinacol boronate
ester while maintaining low Pd loadings and minimal reaction
times.
a Reaction conditions: 1 equiv of aryl or heteroaryl halide, 1.5 equiv
of pinacol borane, 3 equiv of NEt3, 1,4-dioxane (0.60 mL/mmol halide),
cat. PdCl2(CH3CN)2, 1/Pd ) 4:1. b Isolated yield based upon an average
of two runs. c NEt3 (1.00 mL/mmol halide) used as solvent instead of
1,4-dioxane.
aryl chloride with pinacol borane.8 However, as previously
stated, this method was only applicable to para-substituted
electron-rich aryl chlorides (i.e., 4-chloroanisole and 4-chloro-
N-methylaniline). We were pleased to discover that the
PdCl2(CH3CN)2/1 catalyst system was efficient in the reaction
of similar substrates as 4-chloroanisole was successfully con-
verted to the pinacol boronate ester in greater than 95% yield
Despite the economic advantages of employing aryl chlorides
in Pd-catalyzed borylation chemistry, there remains only one
report, to our knowledge, of the successful combination of an
(10) For a method for the borylation of alkenyl iodides and triflates, see:
Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. Synthesis 2000, 6, 778–780.
5590 J. Org. Chem. Vol. 73, No. 14, 2008

(Table 2, Entry 4).11 Furthermore, this method was also general
for a wide range of aryl chlorides, as an electron-neutral aryl
halide, 4-n-butylchlorobenzene, resulted in a 62% yield of the
desired product (Table 2, entry 7). Although ortho-substituted
aryl chlorides have proven to be challenging substrates for a
variety of systems, the PdCl2(CH3CN)2/1 catalyst also remained
applicable in these couplings as modest to good yields resulted
in both cases (Table 2, entries 11 and 17). In addition, this
method represents the only process employing pinacol borane
as the boron source by which a heteroaryl chloride (Table 2,
entry 18) or vinyl chloride (Table 2, entry 19) has been
successfully converted to the corresponding pinacol boronate
ester. Despite the success of the catalyst system for a variety of
aryl chlorides, electron-poor substrates still remain problematic.
In general, reactions of these substrates resulted in incomplete
conversion of the aryl chloride as well as an increase in reduced
arene byproduct.
In summary, we have demonstrated the utility of the
PdCl2(CH3CN)2/1 catalyst system in the borylation of a variety
of aryl and heteroaryl halides. The reactions of aryl iodides and
bromides can be conducted with relatively low Pd loadings and
short reaction times while still maintaining a wide substrate
scope. In addition, the method represents the first general system
for the borylation of aryl and heteroaryl chlorides whereby a
range of substrates can be converted to the desired pinacol
boronate esters using pinacol borane.
the septum, followed by the addition of the aryl halide (0.50 mmol),
NEt3 (0.209 mL, 152 mg, 1.50 mmol), and pinacol borane (0.109
mL, 96 mg, 0.75 mmol) in a like manner (aryl halides that were
solids were added with the other solid reagents). The septum was
then replaced with a Teflon screw valve, and the Schlenk tube was
sealed. The reaction mixture was heated to 110 °C until the aryl
halide had been completely consumed as determined by gas
chromatography and was then allowed to cool to room temperature.
The reaction solution was filtered through a thin pad of Celite
(eluting with ethyl acetate), and the eluent was concentrated under
reduced pressure. The crude material so obtained was purified via
flash chromatography on silica gel.
General Procedure for the Pd-Catalyzed Borylation of
Aryl Chlorides with Pinacol Borane. An oven-dried resealable
Schlenk tube possessing a Teflon screw valve was charged with
PdCl2(CH3CN)2 (3.0-4.0%) and SPhos (12.0-16.0%). The Schlenk
tube was capped with a rubber septum and then evacuated and
backfilled with argon (this sequence was carried out a total of two
times). NEt3 (0.500 mL) was added via syringe, through the septum,
followed by the addition of the aryl chloride (0.50 mmol) and
pinacol borane (0.109 mL, 96.1 mg, 0.75 mmol) in a like manner
(aryl halides that were solids were added with the other solid
reagents). The septum was then replaced with a Teflon screw valve,
and the Schlenk tube was sealed. The reaction mixture was heated
to 110 °C until the aryl halide had been completely consumed as
determined by gas chromatography and was then allowed to cool
to room temperature. The reaction solution was filtered through a
thin pad of Celite (eluting with ethyl acetate), and the eluent was
concentrated under reduced pressure. The crude material so obtained
was purified via flash chromatography on silica gel.
Experimental Section
Acknowledgment. We thank the National Institutes of Health
(GM 46059) for funding this work. We are grateful to Merck,
Amgen, and Boehringer Ingelheim for additional support. The
Varian NMR instruments used in this work were purchased with
funds from the National Science Foundation (CHE 9808061 and
DBI 9729592).
General Procedure for the Pd-Catalyzed Borylation of Aryl
Iodides and Bromides with Pinacol Borane. An oven-dried
resealable Schlenk tube possessing a Teflon screw valve was
charged with PdCl2(CH3CN)2 (1.0-2.0%) and 1 (4.0-8.0%). The
Schlenk tube was capped with a rubber septum and then evacuated
and backfilled with argon (this sequence was carried out a total of
two times). 1,4-Dioxane (0.30 mL) was added via syringe, through
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Although a solvent mixture of 1,4-dioxane and triethylamine was
effective for the borylation of aryl iodides and bromides, the reactions of aryl
chlorides did not proceed to completion after 24 h under these conditions.
However, if the reaction was conducted in just triethylamine as the solvent, then
complete conversion of the aryl chloride was observed in all cases.
JO800727S
J. Org. Chem. Vol. 73, No. 14, 2008 5591