Palladium-catalyzed, direct boronic acid synthesis from aryl chlorides: A simplified route to diverse boronate ester derivatives

Article abstract of DOI:10.1021/ja1089759

Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. A simple and efficient palladium-catalyzed, direct synthesis of arylboronic acids from the corresponding aryl chlorides using an underutilized reagent, tetrahydroxydiboron B₂(OH)₄, is reported. To ensure preservation of the carbon-boron bond, the boronic acids were efficiently converted to the trifluoroborate derivatives in good to excellent yields without the use of a workup or isolation. Further, the intermediate boronic acids can be easily converted to a wide range of useful boronates. Finally, a two-step, one-pot method was developed to couple two aryl chlorides efficiently in a Suzuki-Miyaura-type reaction.

Full text of DOI:10.1021/ja1089759

Published on Web 11/24/2010
Palladium-Catalyzed, Direct Boronic Acid Synthesis from Aryl Chlorides: A
Simplified Route to Diverse Boronate Ester Derivatives
Gary A. Molander,*,† Sarah L. J. Trice,† and Spencer D. Dreher*,‡
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, and
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway,
New Jersey 07065, United States
Received October 5, 2010; E-mail: gmolandr@sas.upenn.edu
In this communication, the development of the first direct
Abstract: Although much current research focuses on developing
synthesis of boronic acids via palladium-catalyzed cross-coupling
new boron reagents and identifying robust catalytic systems for
of aryl chlorides with tetrahydroxydiboron B2(OH)4 (1) is
the cross-coupling of these reagents, the fundamental prepara-
outlined.20-23 This protocol allows the direct synthesis and isolation
tions of the nucleophilic partners (i.e., boronic acids and deriva-
of arylboronic acids and also permits the preparation of trifluo-
tives) has been studied to a lesser extent. Most current methods
roborates and diverse boronate analogs without the use of highly
to access boronic acids are indirect and require harsh conditions
reactive organometallic species or through manipulation of the
arylboronates. Additionally, the method permits the coupling of
two aryl chlorides in a two-step, one-pot reaction, representing an
efficient manner in which to perform Suzuki-Miyaura-type cou-
pling reactions. Further, all reagents are bench stable, obviating
the use of a glovebox, and the method does not require the use of
or expensive reagents. A simple and efficient palladium-catalyzed,
direct synthesis of arylboronic acids from the corresponding aryl
chlorides using an underutilized reagent, tetrahydroxydiboron
B2(OH)4, is reported. To ensure preservation of the carbon-boron
bond, the boronic acids were efficiently converted to the trifluo-
roborate derivatives in good to excellent yields without the use
of a workup or isolation. Further, the intermediate boronic acids
can be easily converted to a wide range of useful boronates.
anhydrous solvents.
Microscale high-throughput experimentation (HTE) techniques24
revealed that the use of Pd(OAc)2 with X-Phos (3:1 ligand/
Finally, a two-step, one-pot method was developed to couple two
palladium), KOAc (3 equiv), and EtOH at 80 °C for 18 h was
optimal to convert 4-chloroanisole to the corresponding borylated
product. Attempts to translate this lead into a robust scale-up
procedure revealed that reaction success was highly dependent upon
how the active catalyst was formed. During the HTE studies, the
catalyst and ligand were dosed to the sample plates in appropriate
solvents based on component solubility, and then the dosing solvents
were removed under high vacuum prior to addition of the remaining
reagents.
aryl chlorides efficiently in a Suzuki-Miyaura-type reaction.
The Suzuki-Miyaura cross-coupling reaction has become of
immense utility and thus importance,1,2 and yet there does not
exist a simple, robust, catalytic, and functional group tolerant
method that provides direct access to the boronic acid, with
straightforward conversion to related derivatives. Thus, arylbo-
ronic acids are normally accessed by hydrolysis of boronate
esters, and consequently many other boronic acid derivatives
(e.g., organotrifluoroborates) are derived ultimately from these
same boronate esters. The boronate esters can be accessed in a
number of ways, including iridium-catalyzed C-H activation
with bis(pinacolato)diboron3 and transmetalation from reactive
organometallics.4 The harsh reaction conditions used in the latter
approach severely limit functional group incorporation into the
boronic acid derivatives.5 Another common method makes use
of bis(pinacolato)diboron or related reagents to access arylbo-
ronates catalytically according to Miyaura’s widely used
protocol.6-12 When boronic acids are the targets required in any
of these protocols, the boronate esters must be converted by way
of oxidation,13 hydrolysis,14 reduction,15 or transesterification.16
These methods are inherently inefficient in terms of both atom
economy and step economy, employ harsh reaction conditions
(NaIO4, aq HCl, LAH, diethanolamine, BBr3), or require the use
of excess polymer-supported boronic acid.16,17 Further, the
transformation of pinacol boronate esters to the analogous
trifluoroborates often suffers from difficulties in purification,
rendering these protocols exceedingly tedious.18,19
For initial synthetic studies and scale-up in the laboratory,
the protocol was different: all of the components were mixed,
and thus tetrahydroxydiboron 1 (eq 1) was exposed to the
nonligated Pd(II) precatalyst. The use of 11B NMR to monitor
stability demonstrated that 1 decomposed completely after 1 h
of stirring at rt in EtOH in the presence of various Pd(II) species
{e.g., Pd[(allyl)Cl]2 and Pd(OAc)2}. However, if the Pd(II)
source and the ligand were mixed together for 1 h at 65 °C in
EtOH prior to the addition of 1, decomposition of 1 was greatly
reduced. It thus appeared that, in the HTE experiments, the
solvent removal process allowed the Pd(OAc)2 to become
efficiently complexed to the ligand, thereby minimizing the
decomposition of 1. To eliminate the need to activate the catalyst
before adding the B2(OH)4 and substrate, we found that the use
of a recently reported preformed catalyst 2 performs as advertised
in undergoing rapid transformation to the active Pd(0) species
(eq 2), allowing the cross-coupling to occur in a more efficient
and simplified manner without extensive decomposition of the
tetrahydroxy diboron.25 As mentioned, the use of alcohol
solvents, most notably ethanol, was optimal for solubility and
reactivity. Under these conditions the tetrahydroxy diboron is
in equilibrium with various ethyl esters, providing some similar-
ity to bispinacol boronate (eq 1). In the HTE experiments the
† University of Pennsylvania.
‡ Merck Research Laboratories.
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C O M M U N I C A T I O N S
ligand to palladium ratio (3:1) and concentration (0.1 M) were
also found to be essential to achieve high yields.
reaction vials). The reactions were sealed and then purged with
nitrogen. Degassed ethanol was added via syringe (followed by
the aryl chloride if it was a liquid), and the reaction was heated to
80 °C for the required time (4-18 h). The reaction was cooled to
rt and then filtered through a pad of Celite, rinsing with EtOAc.
After the reaction was concentrated, it was taken up in MeOH and
cooled to 0 °C, and then aqueous KHF2 was added dropwise. The
bath was removed, and the reaction was allowed to stir at rt until
conversion to the trifluoroborate was complete (∼20 min) as
monitored by 11B NMR. The reaction was concentrated, dried, and
purified by continuous Soxhlet extraction with acetone. Once the
extraction was complete, the acetone was removed and the
trifluoroborate was obtained by precipitation with ether. A similar,
user-friendly procedure was used for the synthesis of the boronate
esters (see Supporting Information for details).
In this manner the trifluoroborate salts were obtained in good to
excellent yields after their conversion from the corresponding
boronic acid (Table 2). The method tolerates a wide range of
substituents, including nitro, cyano, ester, and aldehyde groups. In
general, aryl rings substituted with electron-rich functional groups
(entries 10 and 11) fared better than those with electron-withdrawing
groups (entries 2, 3, 4, and 6). Systems with ortho substituted groups
led to good yields (entry 8), and most impressively highly hindered
2,6-disubstituted aryl chlorides also cross-couple very effectively
(entry 13). The latter compares very favorably to the only other
related Miyaura-type coupling of such systems, which employed
aryl bromides or iodides with 5-10 mol % catalyst loading and
B2pin2 or pinacolborane.17b Importantly, the reaction works equally
well on gram scale (entry 1). Aryl bromides were not effective
under this set of conditions, owing to homocoupling, and research
continues to find a suitable set of conditions for these substrates.
Utilizing this convenient protocol (Table 1), diverse boronate
derivatives, including pinacol boronates (entry 1), MIDA boronates
(entry 3), and pinanediol boronates (entry 4), were synthesized.
The boronic acid can also be isolated in excellent yield after aqueous
workup by simply washing the crude solid with hexane (Table 1,
entry 5).
Table 1. Palladium-Catalyzed Direct Synthesis of a Boronic Acid
and Derivatives
Table 2. Boronic Acid Synthesis and Direct Conversion to
Trifluoroborates
Of greatest interest was the direct conversion of the intermediates
to the more robust aryltrifluoroborates (Table 2). Avoiding the
workup, treatment with KHF2 using an operationally simple and
efficient protocol affords the ‘protected’ form of the boronic acid
in higher yields. Thus all reagents were first weighed on the bench
(including the aryl chloride if it was a solid) into a vessel capable
of being sealed with a Teflon cap (commonly used for microwave
a General conditions: 1 mol % of 2, 2 mol % of X-Phos, 1 mol % of
NaOt-Bu, 3 equiv of KOAc, 1.5 equiv of 1, EtOH (0.1 M), 80 °C, 18 h. b
mmol scale reaction. c 3.0 equiv of 1. d 3 mol % of 2, 50 °C, 24 h.
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Heteroaryls generally require higher catalyst loading and longer
reaction times (entry 14), and the reactions must be performed at
reduced temperatures to eliminate homocoupling of the formed
boronic acid with the starting chloride, which occurs rapidly at
temperatures over 80 °C even at low catalyst loads. Initial
optimization of the heteroaryl borylation reaction was carried out
with 3-chlorothiophene and was not found to be general across
different heteroaromatic systems. Further development of a general
method utilizing heteroaryl chlorides is currently ongoing in our
laboratory.
The method can also be extended to a ‘one-pot’ Suzuki-Miyaura
reaction (Table 3).8 In this simple procedure, two aryl chlorides
can be coupled to one another without the isolation of the
intermediate boronic acid, which is the common practice. The first
aryl chloride is used to synthesize the boronic acid in a manner
similar to the methods described above. Upon the addition of a
second aryl chloride and 3 equiv of aqueous K2CO3 (which appears
to decompose the excess tetrahydroxydiboron), the reaction was
stirred overnight at 80 °C. Following an aqueous workup, the
unsymmetrically coupled compounds were obtained in good to
excellent yield after column chromatography.
in good to excellent yield over two steps with low catalyst loads.
Efforts to extend the method to a more diverse set of aryl bromides
and heteroaryls are currently ongoing.
Acknowledgment. We thank the NIGMS (R01 GM035249) and
NSF GOALI program (CHE-0848460) for their financial support
of this research. S.L.J.T. thanks past and present members of the
Merck Research Laboratories West Point Medicinal Chemistry
Department for their support and Merck & Co., Inc. for funding
this PhD research. Additionally, Dr. Corneliu Stanciu (University
of Pennsylvania) is acknowledged for his many insightful conversa-
tions, and Dr. Rakesh Kohli (University of Pennsylvania) for his
help in obtaining HRMS data.
Supporting Information Available: Experimental details and
spectral data for all compounds synthesized. This material is available
free of charge via the Internet at http://pubs.acs.org.
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In summary, we have reported the first palladium-catalyzed,
direct synthesis of boronic acids with a wide range of aryl chlorides
utilizing a preformed catalyst (2) and tetrahydroxydiboron (1). All
of the reagents utilized are air stable so that the method does not
require the use of a glovebox or anhydrous solvents. The method
tolerates a wide range of functional groups and allows easy and
direct access to a diverse set of boronic acids, boronate esters, and
trifluoroborates. In this process, the use of expensive pinacol is
avoided, which also alleviates the need to hydrolyze and remove
this unnecessary additive. Additionally, an efficient one-pot cross-
coupling of two aryl or heteroaryl chlorides can be accomplished
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