Scope of the palladium-catalyzed aryl borylation utilizing bis-boronic acid

Article abstract of DOI:10.1021/ja303181m

The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C-B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts.

Full text of DOI:10.1021/ja303181m

Article
pubs.acs.org/JACS
Scope of the Palladium-Catalyzed Aryl Borylation Utilizing Bis-
Boronic Acid
Gary A. Molander,*,† Sarah L. J. Trice,† Steven M. Kennedy,† Spencer D. Dreher,‡
and Matthew T. Tudge‡
†Roy and Diana Vagelos Laboratories and Penn/Merck Laboratory for High Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
‡Department of Process Research and the Catalytic Reactions Discovery Development Laboratory, Merck and Co. Inc., 126 East
Lincoln Avenue, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: The Suzuki-Miyaura reaction has become one
of the more useful tools for synthetic organic chemists. Until
recently, there did not exist a direct way to make the most
important component in the coupling reaction, namely the
boronic acid. Current methods to make boronic acids often
employ harsh or wasteful reagents to prepare boronic acid
derivatives and require additional steps to afford the desired
boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a
wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos
preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C−B bond, all boronic
acids were readily converted to their more stable trifluoroborate counterparts.
BPin).11−17 These reagents are more robust than most trialkyl
borates, and the catalytic processes employing them are more
functional-group tolerant than transmetalation routes (Scheme
1).
INTRODUCTION
The Suzuki-Miyaura cross-coupling (SMC) reaction has
■
become one of the most widely applied methods in current
synthetic organic chemistry.1,2 In fact, it is currently estimated
that 25% of all reactions performed in the pharmaceutical
industry consist of cross-coupling reactions, and among these,
Suzuki coupling reactions play a major role.3−5 Most research
in the area of SMC has been dedicated to improving substrate
scope, lowering catalyst load, and reducing reaction time and
temperatures using a variety of electrophiles, boronic acids, and
surrogates. Little effort, however, has been focused on the
synthesis of the boronic acid partner itself even though other
synthetically useful reactions such as the Chan-Lam coupling6
and the Petasis-Borono Mannich7 reactions also employ
boronic acids.
Scheme 1. Current Methods To Synthesize Boronic Acids
The current state-of-the-art in the synthesis of boronic acids
includes transmetalation via metal/halogen exchange or
directed ortho metalation,8−10 C−H activation,11 or the
palladium catalyzed Miyaura borylation.12−17 Although these
methods supply the requisite boron species in reasonable yields,
all current methods result in the formation of boronate esters,
and require additional steps (acid hydrolysis,18−21 oxida-
tion,22−25 or reduction26) to reveal the boronic acid if it is
the required boron partner. Of greatest importance when
applying these methods is the choice of borylating reagent.
Although the transmetalation reactions utilize a relatively atom
economical boron source (trialkyl borates), these protocols are
extremely limited by functional group tolerability. By contrast,
the C−H activation and Miyaura borylation methods utilize
bis(pinacolato)diboron (B2Pin2) or pinacolborane (H-
However, by modern standards, B2Pin2 is an extremely
wasteful reagent, dramatically reducing the efficiency of
discovery and synthesis in both industrial and academic
Received: April 10, 2012
© XXXX American Chemical Society
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pursuits. Pinacol makes up >90% of the mass of B2Pin2.
Because it is not an integral component of the final desired
boronic acid partner and must be removed, pinacol is simply an
unwanted byproduct of current borylation reactions. Given the
current annual demand for B2Pin2, tons of pinacol are being
used and disposed of needlessly each year. If the boronic acid is
required, in addition to the unnecessary generation of waste,
the resulting pinacol boronates are often challenging to
hydrolyze. Additionally troublesome is the finding that pinacol,
once released, is notoriously difficult to remove from reaction
mixtures.27−30 Laborious extraction or distillation techniques
are often required that further detract from the overall process
efficiency.
homocoupling. However, during substrate scope exploration,
the borylation of some aryl chlorides resulted in a significant
amount of the homocoupled product. Mechanistically, it can be
rationalized that the oxidative addition complex, once formed,
can undergo a transmetalation with either BBA or the rapidly
forming boronic acid (Scheme 2).35,36
Scheme 2. Competing Catalytic Cycles
RESULTS AND DISCUSSION
■
We recently reported an efficient method to synthesize the
boron coupling partner directly with a more atom economical
reagent.31 This method represented the first direct synthesis of
boronic acids from aryl halides, solving many of the problems
associated with the use of B2Pin2 or H-BPin.
Our first report of this novel method focused on less
expensive and more abundant aryl chlorides and demonstrated
that the intermediate boronic acid obtained could be used to
access various boronate esters and trifluoroborates, as well as
cross-coupled products in a one-pot, two-step borylation-
Suzuki sequence. It also demonstrated tolerance of a wide range
of functional groups and proceeded with low catalyst loads (1
mol %) and bench stable reagents, eliminating the use of a
glovebox or anhydrous solvents. The key to the success of this
process was the use of a relatively underutilized reagent, bis-
boronic acid [BBA, referred to as tetrahydroxydiboron,
B2(OH)4, Scheme 1]32,33 and Buchwald’s first generation
XPhos phenethylamine preformed catalyst 1A (Figure 1).34
Figure 1. Buchwald’s first (1) and second (2) generation preformed
catalysts. XPhos (A) ligand (L).
If sufficient BBA is supplied to the catalytic cycle, then the
oxidative addition complex should preferentially react with BBA
over the boronic acid. This is in fact what was experimentally
observed. When 3 equiv of BBA were used, yields improved,
sometimes on the order of 20%. The use of excess borylating
agent is not unique to this method and is common in reactions
wherein B2Pin2 is employed.12
Interestingly, when 4-bromoanisole was subjected to the
identical conditions optimized for 4-chloroanisole (utilizing 1.5
equiv of BBA and 1), there was a significant amount of
homocoupled and halide-reduction product observed. Kinetic
experiments determined that 4-bromoanisole underwent the
borylation at a rate 18% slower than 4-chloroanisole, indicating
that the transmetalation step was the rate limiting step of the
process, and that the arylpalladium halide species represents the
resting state of the catalyst (Figure 2). The more rapid
oxidative addition of aryl bromides versus that of aryl chlorides
permits a more rapid buildup of this intermediate, thereby
providing sufficient time for it to react with the ever-increasing
supply of the boronic acid being formed as opposed to the
diminishing supply of BBA being consumed.
Through the course of high throughput experimentation
(HTE), it was discovered that rapid and efficient Pd(0)
catalyst formation was essential to protect BBA from the facile
decomposition that occurs when it is exposed to Pd(II). The
finding that the commercially available XPhos preformed
catalyst 1A forms this requisite Pd(0) species rapidly in the
presence of equimolar amounts of strong base (NaOt-Bu) at
the reaction temperature (80 °C) greatly simplified the original
optimized method, which involved heating Pd(OAc)2 in the
presence of XPhos and KOAc in EtOH for 20 min at 80 °C
before the addition of the aryl chloride and BBA in EtOH.
Through the use of 1A, all reagents could simply be added to
the reaction flask at the same time, with subsequent addition of
EtOH and heating to conduct the reaction.
The first general method employing 1A was optimized on 4-
chloroanisole. Through HTE, it was preliminarily concluded
that 1.5 equiv of BBA was sufficient for the successful
borylation of aryl chlorides, as 4-chloroanisole yielded the
corresponding trifluoroborate in 90% yield with minimal
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Figure 3. Color change indicating completion of the borylation
reaction: left to right: air stable solids during degassing; colorless
reaction solution; completion of reaction [aryl chlorides turn yellow
(left), aryl bromides turn orange (right)].
Figure 2. Kinetics experiments comparing 4-bromo and 4-
chloroanisole under reaction conditions using catalyst 1A or 2A
(Figure 1).
affording the corresponding trifluoroborates in good to
excellent yield after aqueous workup and treatment with
KHF2. For comparison, reported literature yields of pinacol
boronates previously synthesized utilizing B2Pin2 in the
Miyaura borylation are also included in the Tables through-
out.12,38−41 In most cases, the yields are equivalent or superior
to those of previously published results (Tables 1−4 and 6). As
noted (vida infra) all of the trifluoroborates obtained with this
improved method are accessed in higher yields than those
reported previously in our communication.31 The reaction can
also be run on a 12 mmol scale, allowing a dramatic reduction
in both palladium (from 0.5 mol % to 0.1 mol %) and solvent
(from 0.1 M in EtOH to 0.5 M) with almost no decrease in
yield (Table 1, entry 5d). Although not as operationally simple,
our original reaction procedure (prior to the discovery of the
preformed catalyst 1A) can be performed very efficiently with
less expensive Pd(OAc)2 (Table 1, entry 1a). In this protocol,
before the addition of the predissolved BBA (in EtOH) and
substrate, 0.5 mol % of Pd(OAc)2, 1.5 mol % of XPhos, and
KOAc (3 equiv) are stirred in EtOH for 20 min at 80 °C,
activating the catalyst by reduction from Pd(II) to Pd(0).
Without this preactivation, the Pd(OAc)2 decomposes BBA to
boric acid almost instantaneously as monitored by 11B NMR.
Sterically hindered substrates (mono- or disubstituted at the
ortho positions) result in good to excellent yields (Table 1,
entries 15 and 16). However, substrates with electron-
withdrawing groups in this same position represent the only
major limitation of the current method, leading to poor yields
and mixtures of products in some cases (Table 1, entries 6, 7,
10, and 18). That these low yields are not due to
protodeboronation by KHF2 was determined by quenching
the reactions with pinacol, where equally low yields were
observed. Interestingly, a hydroxyl group in this position also
affords the product in only 17% yield (Table 1, entry 11), while
the methyl ether in the same position leads to a reasonable
yield of 66% (Table 1, entry 9). Although the reactions are run
in ethanol, no transesterification occurs except in the case of the
ortho-methyl benzoate (Table 1, entry 18). This phenomenon
can be avoided by running the reaction in MeOH with no
apparent loss in yield.
Shortly after the publication of the communication
describing the work above, Buchwald et al. disclosed the
synthesis and application of a second generation XPhos
preformed catalyst 2A (Figure 1).37 This improved catalyst
allows rapid formation of the requisite Pd(0) species at room
temperature with a weak base, eliminating the need for
additional strong base (NaOt-Bu). Additionally, the improved
catalyst provides trifluoroborates in higher yields for every aryl
chloride substrate examined in the original communication
(vida infra).
In this work, we disclose the full scope of the direct synthesis
of boronic acids from a wide range of aryl electrophiles
employing 2A as catalyst. This new method represents an
improvement from the previous communication, as the general
method proceeds efficiently with half the catalyst load (0.5 mol
% Pd), with XPhos (3:1 ligand/palladium), KOAc (3 equiv), at
80 °C in EtOH with reaction times ranging from 1 to 9 h.
Although we have previously demonstrated the isolation of the
boronic acid product, often it was difficult to obtain the pure
crystalline form of these materials without some loss in yield.
As this loss in yield did not accurately quantify the reaction
conversion, crude boronic acids were immediately converted to
the corresponding trifluoroborates (eq 1). Conversion to the
crystalline trifluoroborate also ensures preservation of the C−B
bond during prolonged bench storage. Additionally, the Soxhlet
extraction technique used to purify the trifluoroborate salt is
operationally simpler and potentially less wasteful than column
chromatography, which is often required for purification of
pinacol boronates when B2Pin2 is used.12
All reagents used in the improved method are commercially
available and bench stable, eliminating the use of a glovebox.
Further, the use of degassed, nonanhydrous ethanol provides a
green alternative to more common borylation methods utilizing
ethereal solvents, often at high temperatures.12 Of great
surprise and delight was our finding of a readily observable
color change that occurs at the completion of all borylation
reactions: the reactions uniformly change from colorless to
yellow for the aryl chlorides and from colorless to orange for
the aryl bromides, further facilitating analytical end-point
analysis and ease of method execution (Figure 3).
Aryl bromides also perform well under the standard
borylation conditions, performing better than their pinacol
boronate counterparts in some instances (Table 2).14,41−45 In
general, yields are slightly lower with the bromides as compared
to the corresponding chlorides, and reaction times are slightly
longer. It is believed that this increase in reaction time leads to
more of the observed palladium-catalyzed hydride reduction
side products in susceptible substrates. For example, the 4-nitro
substituted chloride (Table 1, entry 14) undergoes full
conversion in 2 h with 7% reduction to the amine, while the
The scope of the borylation with aryl chlorides is outlined in
Table 1. In general, functional groups are well tolerated,
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Table 1. Boronic Acid Synthesis from Aryl Chlorides and
Conversion to Trifluoroborates
Table 2. Boronic Acid Synthesis from Aryl Bromides and
Conversion to Trifluoroborates
A
A
A
General conditions: 0.5 mol % of 2A, 1 mol % of A, 3.0 equiv of
KOAc, 3.0 equiv of B2(OH)4, EtOH (0.1 M), 80 °C for time indicated.
a
Yields of pinacol boronate esters utilizing B2Pin2 in cited literature.
b
A
Palladium-catalyzed hydride reduction of product observed, see
General conditions: 0.5 mol % of 2A, 1 mol % of A, 3.0 equiv of
c
d
Supporting Information for relative amounts. From the acetonide. 5
KOAc, 3.0 equiv of B2(OH)4, EtOH (0.1 M), 80 °C for time indicated.
(1) 0.5 mol % of Pd(OAc)2, 1.5 mol % of XPhos, 3.0 equiv of KOAc,
a
mol % of 2B, 3 equiv of DIEA, 3.0 equiv of B2(OH)4, MeOH (0.2 M),
50 °C for time indicated. 0.1 M MeOH.
e
80 °C in 3 mL EtOH for 20 min. (2) 3.0 equiv of B2(OH)4 dissolved
b
in 12 mL of EtOH, 4-chloroanisole, 80 °C for 1 h. Yield from
c
previous method with 1A as catalyst (ref 31). Yields of pinacol
Table 3. Comparison of the Palladium-Catalyzed Hydride
Reduction
d
boronate esters utilizing B2Pin2 in cited literature. 12 mmol reaction
run with 0.1 mol % of 2A, 0.2 mol % of A, 3 equiv of KOAc, 3 equiv of
e
B2(OH)4, EtOH (0.5 M) at 80 °C for 3 h. Palladium-catalyzed
hydride reduction of product observed, see Supporting Information for
f
relative amounts. MeOH used as solvent .
corresponding bromide (Table 2, entry 5) requires 4 h and
leads to 20% reduction. In addition to the reduction of nitro
groups, hydride reduction was also observed with ketones and
aldehydes. The amount of reduction was decreased through the
use of MeOH as solvent.46
With regard to the groups most affected by the palladium-
catalyzed hydride reduction, aldehydes are by the far the most
sensitive (Table 3), with reduction amounts ranging from 30%
(Table 2, entry 13) to 66% (Table 1, entry 20) of the isolated
product, depending on how long the reaction is heated (4 vs 20
h). This problem can, however, be avoided through the use of
the acetonide (Table 2, entry 7), affording the aldehyde in 87%
yield after simple deprotection of the boronic acid intermediate
before converting to the trifluoroborate (Scheme 3).
A proposed mechanism for the observed palladium-catalyzed
hydride reduction is outlined in Scheme 4. After oxidative
addition of the aldehyde-containing aryl halide to Pd(0), the
oxidative addition complex I is in equilibrium with the
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Scheme 3. Aldehyde-Containing Trifluoroborate Synthesis
Table 5. One-Pot Borylation/Cross-Coupling of Substrates
Forming a Mixture of Internal and Trifluoroborate Salts
a
Scheme 4. Proposed Mechanism of Observed Palladium-
Catalyzed Hydride Reduction of Aldehydes
a
One-pot borylation/Suzuki: 5 mol % 2B, 3 equiv DIEA, 3.0 equiv
B2(OH)4, MeOH (0.2 M), 50 °C for time indicated. 3 equiv 1 M
K3PO4, 1 equiv second halide. 50 °C, 15 h.
a
Table 6. Electrophile Scope
entry
X
time
% isolated yield
b
1
2
3
4
5
Cl
2
93, 97 (ref 12)
b
Br
4
94, 93 (ref 44)
b
I
7
73, 82 (ref 40)
b
OMs
OTf
16
2
0, 83 (ref 61)
b
99, 93 (ref 40)
a
General conditions: 0.5 mol % 2A, 1 mol % A, 3.0 equiv KOAc, 3.0
b
equiv B2(OH)4, EtOH (0.1 M), 80 °C for time indicated. Yields of
pinacol boronate esters utilizing B2Pin2 in cited literature.
IV by EtOH leads to the formation of the reduced aldehyde V,
regenerating the catalytically active species II.
alcoholysis complex II, with EtOH adding selectively at the
Pd−X bond.46,47 Acting as a Lewis acid, II activates the
aldehyde carbonyl and delivers hydride via a six-membered
transition state III, giving rise to complex IV.48 Alcoholysis of
Kinetic studies were also performed with 2A in the presence
of 4-chloro- and 4-bromoanisole, and as expected, reaction
times are faster with 2A as compared to 1A. As seen previously
with 1A, 4-chloroanisole borylates at a rate 23% faster than the
corresponding 4-bromoanisole (Figure 2) and 4-iodoanisole
does not undergo full conversion under the general reaction
conditions with 2A (vida infra). The borylation rate is therefore
ArCl > ArBr > ArI. This rate order has been observed by
Buchwald et al. in their SMC reactions utilizing 2A as catalyst
wherein transmetalation was experimentally determined to be
the rate-determining step,37 and in Stille coupling reactions.49
These relative rates have been ascribed to the electrophilicity of
the intermediate organopalladium halides, which depend
critically on the electronegativity of the halide component.
Further studies demonstrated that the rate of the reaction of
both 4-bromo- and 4-chloroanisole were decelerated with the
addition of increasing amounts of bromide ions (in the form of
n-Bu4NBr) to the reaction mixtures. The effect was more
pronounced with 4-bromoanisole than with 4-chloroanisole.
The borylation was also extended to heteroaryl halides. As
outlined in Table 4, for substrates with the heteroatom in the
same ring as the halide (Table 4, entries 1, 7, and 8), a newly
developed catalyst system was used. This system, with its
structure and synthesis disclosed for the first time in this article
(see Supporting Information), uses cataCXium A as the ligand
(Figure 4). This complex was found to provide higher yields
Table 4. Boronic Acid Synthesis with Heteroaryl Halides
a
5.0 mol % 2B, 3 equiv DIEA, 3.0 equiv of B2(OH)4, MeOH (0.2 M),
b
50 °C for time indicated. Yields of pinacol boronate esters utilizing
B2Pin2 in cited literature. 0.5 mol % 2A, 1 mol % A, 3 equiv KOAc,
c
3.0 equiv of B2(OH)4, EtOH (0.1 M), 80 °C for time indicated.
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CONCLUSIONS
■
In summary, the scope of the palladium-catalyzed direct
borylation using bis-boronic acid has been explored. The
method is effective with a wide range of functional groups with
both chloro- and bromo-substituted aryls, providing easy access
to the corresponding trifluoroborates in good to excellent
yields. The method can also be extended to aryl iodides and
triflates. Although heteroaryls remain a challenge, much
progress has been made with respect to their borylation. All
reagents used in the method are bench stable and commercially
available. The use of exceedingly low catalyst loadings,
employing ethanol as solvent, combined with the relatively
benign side-products of the reaction, offer a greener, more
economical method than those previously used to perform
transition metal-catalyzed borylations. Further, all reactions
undergo a readily observable color change at their completion,
making the reactions easy to monitor. The major advantage of
the method is that it allows practitioners to bypass the synthesis
of atom inefficient boronate esters to access boronic acids
directly, or to advance efficiently to the more stable
aryltrifluoroborates.
Figure 4. New catalyst system for heteroaryl borylation.
and faster reaction times than the XPhos-based 2A (Figure 1).
These substrates required a higher catalyst load (5 mol %),
lower reaction temperatures (50 °C), and DIEA as base.
Additionally, MeOH was found to be a superior solvent to
EtOH. Upon making the trifluoroborate of these substrates
(Table 4, entries 1, 7, and 8), a mixture of the internal salt and
potassium trifluoroborate salt were observed. To avoid this
mixture and provide a quantifiable way to assess the yield, the
compounds were subjected to a one-pot borylation/cross-
coupling reaction (Table 5). No product could be isolated for
heteroaryls with a halide in the 2-position.
For those substrates with the heteroatom in the ring adjacent
to the one bearing the halide, the general method applied to the
regular aryl halides discussed (vida infra) worked remarkably
well (Table 4). Most surprising was the stability of pyrazole,
isoxazole, oxazole, and oxadiazole functional units under the
prescribed conditions. Although many heteroaryl substrates
were attempted, several failed to provide reasonable amounts of
borylated product. This finding does not appear to be unique to
this method. Through a thorough literature search of heteroaryl
boronates synthesized from B2Pin2 or H-BPin, two trends can
be found: either the method reported is purely for one
functionalized heteroaryl,50−60 or only a few examples were
synthesized under reaction conditions considered under a
“general” methods procedure.14,40,42,44,61−64 Also noteworthy is
that the heteroaryls examined in this search are among just a
handful of heteroaryl borylated products that can be found in
the literature, and there is no publication dedicated solely to the
Miyaura borylation of heteroaryls using B2Pin2. Our findings,
coupled with the literature results, provide evidence that a
general method for the borylation of hetereoaryls remains
elusive, and that each substrate or general class of substrates
may need to be treated on a case-by-case basis. However, as
demonstrated in Table 4, discovery of a method to borylate a
particular substrate or class can likely be achieved rapidly
through HTE.
Additionally, the two-step, one-pot borylation/Suzuki cross-
coupling method we previously published offers a practical
solution to many of the challenges associated with heteroaryl
borylation (Table 5). The heteroaryl halides couple remarkably
well as the electrophilic partner in the SMC reaction, including
2-substituted heteroaryl substrates. The full scope of this one
pot process is the focus of current research.
The borylation method was also examined with other aryl
electrophiles.12,40,44,61 Aryl iodides and triflates borylate in good
to excellent yield (Table 6), while mesylates failed to give rise
to any product under the conditions optimized for aryl
chlorides. As expected, 4-iodoanisole did not perform as well
as its chloro- and bromo counterparts. The reaction did not go
to full conversion even after 7 h of reaction time, and palladium
was observed to precipitate from the reaction mixture.
ASSOCIATED CONTENT
* Supporting Information
All experimental details associated with the content of this
manuscript. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
gmolandr@sas.upenn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research described was supported by the NIGMS (R01
GM081376) and the NSF GOALI program. S.L.J.T. is
supported by a Merck Doctoral Fellowship through the MRL
Doctoral Program. S.L.J.T. dedicates this paper to Dr. Joe
Vacca. Nick Perrotto (Merck Process Chemistry) is acknowl-
edged for his help in obtaining kinetics data and Rakesh Kohli
(University of Pennsylvania) for his help in obtaining HRMS
data. We thank BASF for a generous donation of BBA. We also
thank Accerlyrs Library Studio and Virscidian Inc. Analytical
Studio Professional.
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