Carbonylative suzuki couplings of aryl bromides with boronic acid derivatives under base-free conditions

Article abstract of DOI:10.1021/ol5003362

The carbonylative Suzuki-Miyaura reaction between aryl bromides and arylboronic acid equivalents is herein reported, using base-free conditions and a limited excess of carbon monoxide generated ex situ from stable CO-precursors. Under these conditions, unsymmetrical biaryl ketones were obtained in modest to excellent yields. This method was adapted to the synthesis of the triglyceride and cholesterol regulator drug, fenofibrate, and its ¹³C-labeled derivative in good yields from the appropriate CO-precursor.

Full text of DOI:10.1021/ol5003362

Letter
pubs.acs.org/OrgLett
Carbonylative Suzuki Couplings of Aryl Bromides with Boronic Acid
Derivatives under Base-Free Conditions
Klaus M. Bjerglund,‡,† Troels Skrydstrup,*,† and Gary A. Molander*,‡
†Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary Nanoscience Center
(iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
‡Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
ABSTRACT: The carbonylative Suzuki−Miyaura reaction
between aryl bromides and arylboronic acid equivalents is
herein reported, using base-free conditions and a limited excess
of carbon monoxide generated ex situ from stable CO-
precursors. Under these conditions, unsymmetrical biaryl
ketones were obtained in modest to excellent yields. This
method was adapted to the synthesis of the triglyceride and
cholesterol regulator drug, fenofibrate, and its 13C-labeled
derivative in good yields from the appropriate CO-precursor.
he palladium-catalyzed carbonylative Suzuki−Miyaura
Treaction represents a viable three-component coupling
protocol for rapid access to unsymmetrical benzophenones.1,2
Such structures are key components in a variety of important
pharmaceuticals including Tricor,3 Sector,4 and Evistor,5 in
addition to being a masked but essential fragment in the
benzodiazepine family. Furthermore, benzophenones have
other useful applications such as sun blockers and photo-
initiators in UV-curing inks.
Although there is now considerable literature precedence for
this carbonylative transformation, the majority of the work has
been carried out with iodides. Only a handful of reports focus
on the use of the more challenging aryl bromides as viable
substrates,6 and in all cases these transformations were carried
out with boronic acids as the nucleophilic coupling partner and
in the presence of an organic or inorganic base. With the
considerable advances in the development and application of
stable, crystalline borate salts and boronic acid derivatives,7 we
considered whether these would be useful coupling partners for
this carbonylation reaction with aryl bromides. In this report,
we demonstrate the successful identification of a catalytic
system that promotes the coupling of (hetero)aryl bromides
with (hetero)aryl trihydroxyborates or DABO boronates (2,8-
dioxa-5-aza-1-borabicyclo[3.3.0]octanes). The process was
performed in a two-chamber reactor with ex situ generated
carbon monoxide, thereby avoiding the handling of this toxic
but useful diatomic gas. Furthermore, all the carbonylation
reactions were carried out in the absence of base.
into another in which the actual carbonylation reaction takes
place. The experimental outline illustrated in Scheme 1 relies
on the use of the acid chloride, COgen (9-methyl-9H-fluorene-
9-carbonyl chloride), as a solid CO precursor. This setup was
also applied to the development of an air-tolerant carbonylative
Suzuki coupling, although the method was only adaptable for
aryl iodides.9
In our examination of the usefulness of aryl bromides for this
carbonylative coupling, preliminary experiments were carried
out between potassium phenyltrifluoroborate10 and p-bromo-
acetophenone. Although a range of experimental conditions
were tested, including numerous Pd(0) and Pd(II) sources,
phosphine ligands, and solvents, poor conversions, precipitation
of palladium black, and competitive diaryl formation were
observed for all cases. More successful were alternative aryl
borate salts such as sodium phenyltrihydroxyborate.11 With
these borate derivatives, neither base nor water was required for
cross-coupling. Initial studies had already demonstrated the
usefulness of Pd(acac)2 as the palladium source, and a small
ligand screening was therefore undertaken as depicted in Table
1. Tricyclohexylphosphine, which was previously shown to be
the ligand of choice in the reductive carbonylation of aryl
iodides and bromides using the two-chamber system,12 also
provided some carbonylative coupling to benzophenone A
(entries 1−3). The conversion was nevertheless low, and a
considerable amount of the corresponding biphenyl was
produced as a side product. Increasing the catalyst loading
from 2 to 5 mol % or the ligand/Pd ratio only had a modest
effect.
In previous work, we described a simple, alternative setup for
performing Pd-catalyzed carbonylation reactions without the
need of a CO cylinder.8 The method relies on the use of carbon
monoxide releasing molecules (CORMs), which upon
activation provide a desired quantity of CO from one chamber
Received: January 31, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Ex Situ Generation of CO in a Two-Chamber
System and Application in Pd-Catalyzed Tranformations
Table 2. Carbonylative Suzuki−Miyaura Reaction of Aryl
a
Bromides with Aryl Trihydroxyborates
Table 1. Optimization of the Carbonylative Suzuki−Miyaura
a
Reaction with 4-Bromoacetophenone
b
distribution
entry Pd(acac)2 (mol %)
ligand (mol %)
bromide/A/B
1
2
3
4
5
6
7
2
5
5
5
5
5
5
Cy3P·HBF4 (2)
Cy3P·HBF4 (5)
Cy3P·HBF4 (10)
i-Pr3P·HBF4 (10)
n-Butyl3P·HBF4 (10)
t-Bu2MeP·HBF4 (10)
45:26:29
38:36:25
32:45:24
19:46:35
85:0:15
24:46:30
16:82:2
CataCXium A·HI
(10)
a
Chamber A: COgen (1.25 mmol), Pd(dba)2 (5 mol %), (t-Bu)3P·
HBF4 (5 mol %), DIPEA (1.5 equiv) in toluene (3 mL). Chamber B:
p-bromoacetophenone (0.5 mmol), potassium phenyl trihydroxybo-
rate (0.55 mmol), Pd(acac)2 (X mol %), ligand (Y mol %), toluene (3
b
1
mL). Determined by H NMR.
Of the other trialkylphosphines tested (entries 4−7), only
CataCXium A·HI demonstrated its worth, providing a good
conversion for the coupling reaction as well as high selectivity
for the benzophenone (entry 7), leading to A in an 82%
isolated yield.13
a
Chamber A: COgen (1.25 mmol), Pd(dba)2 (5 mol %), (t-Bu)3P·
HBF4 (5 mol %), DIPEA (1.5 equiv) in toluene (3 mL). Chamber B:
p-bromoacetophenone (0.5 mmol), potassium phenyltrifluoroborate
(0.55 mmol), Pd(acac)2 (0.025 mmol), CataCXium A·HI (0.05
mmol), toluene (3 mL). Prior to addition of solvent the reaction
chamber was evacuated three times and placed under an argon
With the reaction conditions for the carbonylative Suzuki
reaction with bromides and trihydroxyaryl borates at hand, the
generality of the reaction was tested next, the results of which
are illustrated in Table 2. The four aryl bromides containing
electron-withdrawing groups all furnished acceptable to good
yields (entries 1−4). The obtained yields were particularly
satisfying considering that CO insertion is generally slow with
the electrophilic aromatic ring systems.14 Meta- and para-
substituents were tolerated on the trihydroxyaryl borate, leading
to good yields of the benzophenones (entries 4 and 5). A
similar attempt with an o-methyl substituent proved trouble-
some and resulted in a low conversion of 27% (result not
shown). Using m- or p-methoxyphenyl bromide gave good to
excellent yields of the benzophenone (entries 6 and 7). A Boc-
protected indole bromide was also a good substrate for this
carbonylative coupling, yielding an 81% yield of the desired
product (entry 8). Lastly, an acceptable yield was obtained with
b
atmosphere. Isolated by flash column chromatography.
an electron-donating substituent present on the trihydroxyaryl
borate (entry 9).
Unfortunately, the procedure for preparing the trihydroxy-
arylboronic acid derivatives required dissolving the boronic
acids in hot toluene and precipitation with sat. NaOH (aq),11
a
protocol that was not compatible with a range of boronic acids.
In particular, heteroarylboronic acids, which were insoluble in
hot toluene, led to decomposition. Other boronic acid
derivatives were therefore desired, and a search in the literature
suggested that DABO boronates could represent viable
substrates for this carbonylative coupling. Following the
Rychnovsky protocol for the preparation of DABO boronates,
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Letter
Table 3. Carbonylative Suzuki−Miyaura Reaction of Aryl
Scheme 2. Synthesis of Fenofibrate from an Aryl DABO
Boronate
a
Bromides with Aryl DABO Boronates
for 10 min prior to heating increased the yield to 95% (Table 3,
entry 1).
Coupling of phenyl DABO boronate with 2-bromoanthra-
cene-9,10-dione furnished a 44% yield of the desired ketone
(entry 2), even though the corresponding bromide is relatively
electron poor. Because these reaction conditions are base-free,
coupling of an aryl bromide carrying the Fmoc-protecting
group was possible (entry 3). A Boc-protected 3-bromoindole
yielded a similar result, with the ketone being obtained in a 77%
isolated yield (entry 4). Three other DABO boronates could
equally be coupled successfully to p-bromoacetophenone,
including a m-chlorophenyl, a trans-2-styryl, and a thienyl
derivative (Table 3, entries 5−7). The 3-thienyl DABO
boronate reacted well with 3-bromopyridine, yielding a 73%
yield of the diheteroaromatic ketone (entry 8). Finally, the mild
conditions used for synthesizing the DABO boronates allowed
access to another heteroaromatic boronic derivative with a
pyridine core (entry 9), although its coupling with the
bromoacetophenone requires further optimization (entry 9).
To highlight the applicability of the developed carbonylative
system, we prepared a pharmaceutically relevant benzophe-
none, fenofibrate (Tricor by Abbott), a triglyceride and
cholesterol regulator. As depicted in Scheme 2, coupling of
the p-chlorophenyl DABO boronate to the appropriately
functionalized aryl bromide led to fenofibrate in an 83%
yield. Gratifyingly, the 13C-labeled version could be prepared in
a similar yield simply by using the readily available 13C-labeled
COgen.
a
Chamber A: COgen (1.25 mmol), Pd(dba)2 (5 mol %), (t-Bu)3P·
HBF4 (10 mol %), Cy2NMe (1.5 equiv) in DMF (3 mL). Chamber B:
p-bromoacetophenone (0.5 mmol), potassium phenyltrifluoroborate
(0.55 mmol), Pd(acac)2 (0.025 mmol), CataCXium A·HI (0.05
mmol), toluene (3 mL), H2O (0.3 mL). CO release for 10 min before
b
heating to 80 °C. Isolated by flash column chromatography.
In summary, two methods have been developed for the
synthesis of unsymmetrical aryl ketones by a carbonylative
Suzuki−Miyaura cross-coupling with a two-chamber system.
Particularly noteworthy, the reaction conditions are suitable for
a range of aryl bromides, and the use of either the trihydroxy or
the DABO boronates allows these couplings to proceed under
base-free conditions. The method has also been demonstrated
to be adaptable to the synthesis and site specific isotope
labeling of fenofibrate.
these coupling partners were readily accessed.15 Applying the
optimized coupling conditions from Table 2 in the reaction of
the phenyl DABO boronate with p-bromoacetophenone
resulted in only trace amounts of product. Nevertheless, the
addition of a small quantity of water to the reaction (see
Supporting Information) led to a significant improvement,
resulting in the formation of the benzophenone in an 81%
yield.16 On the other hand, release of CO at 20 °C and stirring
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Organic Letters
Letter
(12) Korsager, S.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J.
Org. Chem. 2013, 78, 6120.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(13) There is the possibility that iodide may have a beneficial role on
the carbonylative coupling; however, the addition of TBAI or KI to the
reaction conditions in Table 1, entry 1 supressed product formation.
Furthermore, use of CataCXium A rather than the corresponding HI
salt as in entry 7 did not significantly change the product distribution.
(14) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J.
Org. Chem. 1998, 63, 4726.
(15) Reilly, M. K.; Rychnovsky, S. D. Synlett 2011, 16, 2392.
(16) Other boronic acid derivatives were evaluated such as phenyl
MIDA boronate, phenyl iminodiacetic acid boronate, and the cyclic
sodium phenyl triolborate from 1,1,1-tris(hydroxymethyl)ethane. The
latter was the only other derivative to display any reactivity in the
presence of water, although only a 30% conversion to product was
observed.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ts@chem.au.dk.
*E-mail: gmolandr@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are deeply appreciative of generous financial support from
the Danish National Research Foundation, (Grant No.
DNRF59), the Villum Foundation, the Danish Council for
Independent Research: Technology and Production Sciences,
the Lundbeck Foundation, the Carlsberg Foundation, and
Aarhus University for generous financial support of this work.
Furthermore, we thank the NIH (NIGMS R01 GM081376) for
support of this research.
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