Pd(OH)2/C, a Practical and Efficient Catalyst for the Carboxylation of Benzylic Bromides with Carbon Monoxide

Article abstract of DOI:10.1021/acs.oprd.9b00402

A simple, efficient, cheap, and broadly applicable system for the carboxylation of benzylic bromides with carbon monoxide and water is reported. Upon simple reaction with only 2.5 wt % of Pearlman's catalyst and 10 mol % of tetrabutylammonium bromide in tetrahydrofuran at 110 °C for 4 h, a range of benzylic bromides can be smoothly converted to the corresponding arylacetic acids in good to excellent yields after simple extraction and acid-base wash. The reaction was found to be broadly applicable, scalable, and could be successfully extended to the use of ex situ-generated carbon monoxide and applied to the synthesis of the nonsteroidal anti-inflammatory drug diclofenac.

Full text of DOI:10.1021/acs.oprd.9b00402

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Full Paper
Pd(OH)2/C, a Practical and Efficient Catalyst for the
Carboxylation of Benzylic Bromides with Carbon Monoxide
Anne-Marie Wakuluk Machado, Damien Félicien Dewez, Hajar Baguia,
Miguel Imbratta, Pierre-Georges ECHEVERRIA, and Gwilherm Evano
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00402 • Publication Date (Web): 19 Dec 2019
Downloaded from pubs.acs.org on December 19, 2019
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Pd(OH)2/C, a Practical and Efficient Catalyst for the
Carboxylation of Benzylic Bromides with Carbon
Monoxide.
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Anne-Marie Wakuluk-Machado,† Damien F. Dewez,† Hajar Baguia,† Miguel Imbratta,‡ Pierre-
Georges Echeverria,*,‡ and Gwilherm Evano*,†
† Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universitꢀ
libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium.
‡ Minakem Recherche, 145 Chemin des Lilas, 59310 Beuvry-la-Forêt, France.
Dedicated to the memory of Dr. Alexis Coste, a talented, energetic and energizing chemist gone
too soon.
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ABSTRACT. A simple, efficient, cheap and broadly applicable system for the carboxylation of
benzylic bromides with carbon monoxide and water is reported. Upon simple reaction with only
2.5 wt% of Pearlman’s catalyst and 10 mol% of TBAB in THF at 110 °C for 4 hours, a range of
benzylic bromides can be smoothly converted to the corresponding arylacetic acids in good to
excellent yields after simple extraction and acid-base wash. The reaction was found to be broadly
applicable, scalable and could be successfully extended to the use of ex situ-generated carbon
monoxide and applied to the synthesis of the non-steroidal anti-inflammatory drug diclofenac.
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KEYWORDS: palladium catalysis, heterogeneous catalysts, carboxylation, benzylic bromides,
benzylic acids, arylacetic acids, carbon monoxide.
1. INTRODUCTION
Arylacetic (or benzylic) acids are key molecules in organic synthesis. In addition to their use in
a number of chemical transformations, they are also important molecules in the food industry –
phenylacetic acid itself being an important food additive with caramel, floral and honey taste –,
or in the cosmetic industry where phenylacetic acid is commonly used for its honey-like odor
even at low concentrations. This moiety is also found in a plethora of well-known drugs such as
ibuprofen 1, naproxen 2 and diclofenac 3, major non-steroidal anti-inflammatory drugs, or
olopatadine 4, a medication used to decrease the symptoms of allergic conjunctivitis and rhinitis
(Figure 1). Arylacetic acid derivatives are in addition commonly found in a number of drugs that
include penicillin G 5, an antibiotic, clopidogrel 6, an antiplatelet medication, or methyl phenidate
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7, a drug used to treat attention deficit hyperactivity disorder and narcolepsy. Arylacetic acids
and their derivatives are also commonly utilized in the agrochemical sector, representative
examples including 1-naphthaleneacetic acid 8, a synthetic plant hormone found in many
commercial plant rooting horticultural products, or fenvalerate 9, a pyrethroid insecticide.
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Figure 1. Representative arylacetic acid derivatives from the food, cosmetic, medicinal and
agrochemical indutries.
While benzylic acids can be produced by a number of methods from a range of precursors,
which includes the oxidation of homobenzylic alcohols, the hydrocarboxylation of styrenes1,2 or
the more recently developed -arylation of aliphatic carboxylic acids3 and direct
(photo)carboxylation of benzylic C-H bonds,4 all these reactions suffer from limitations in terms
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of precursors availability, scope, efficiency and/or selectivity and the precursors of choice,
notably from an industrial perspective, remain the corresponding benzylic bromides.5
Traditionally, they have indeed been converted in two steps to the corresponding benzylic acids
by cyanation followed by hydrolysis. Despite the obvious limitations of this sequence in terms of
toxicity and efficiency, it is still however a method of choice commonly utilized for the large scale
preparation of a range of arylacetic acids, notably in industrial settings. The main alternative
processes for the conversion of benzylic bromides to the corresponding benzylic acids include
their transformation to benzylic Grignard reagents and their further reaction with carbon dioxide,
a reaction that suffers from significant competitive dimerization of the starting benzylic bromide
due to a facile Wurtz coupling and that is not especially practical –5,6 even if benzylic bromides
can now be directly carboxylated with carbon dioxide by various catalytic7 or electrochemical
processes5 –, their Nef-type oxidation with sodium nitrite and acetic acid8 or their palladium-
catalyzed carboxylation with chloroform under basic conditions9 or with formic acid.10 A more
appealing alternative in terms of cost, efficiency, generality and atom economy lies in their
catalytic carboxylation with carbon monoxide, a reaction that can be catalyzed by a range of acids
and metals:5 while acid catalysts suffer from harsh conditions and limited substrate scope,
various metals have been shown over the years to efficiently mediate the conversion of benzylic
halides and carbon monoxide to the corresponding acids. They include cobalt,11 iron,12
rhodium,13 nickel,14 ruthenium,15 and palladium,16 the latter being usually more efficient, and
therefore, preferred. If a range of palladium-based catalysts have been shown to promote the
carboxylation of benzylic halides to benzylic acids with carbon monoxide, a number of them
however still suffer from competitive reduction or dimerization of the starting halides5 and no
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general heterogeneous palladium catalyst has been reported to date,16 despite a strong potential
in terms of catalyst separation and recovery as well as product contamination. In an attempt to
address these limitations and based on our combined interests in metal catalysis17 and process
chemistry,18 we became interested in developing an efficient, cheap and general heterogeneous
catalytic system for the carboxylation of benzylic bromides with carbon monoxide and we report
herein the results of our investigations.
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2. RESULTS AND DISCUSSION
Optimization of the heterogeneous palladium-based catalytic system. We initiated our
studies by evaluating the efficiency of a range of heterogeneous palladium catalysts for the
carboxylation of a model benzylic bromide, p-tert-butyl-benzyl bromide 10a, which was selected
as the substrate for the optimization for its high boiling point and since its carboxylation yields to
non-volatile p-tert-butyl-phenylacetic acid 11a. This model substrate was therefore reacted with
carbon monoxide (10 bar) in the presence of 10 wt% of the heterogeneous catalyst (5 wt% Pd),
except in the case of Pd(OH)2/C (20 wt% Pd) for which 2.5 wt% were used, 10 mol% of
tetrabutylammonium bromide (TBAB) – an additive commonly used in ligand-free palladium-
based catalytic systems to improve catalyst activity and stability19 and which had been in addition
shown to be efficient when used as a solvent for the carboxylation of benzyl halides –16n and 4
equiv. of water in 50 volumes of THF at 110 °C for 4 hours. Yields, conversions and proportions
of p-tert-butyl-toluene 12a and p-tert-butyl-benzyl alcohol 13a, the only formed byproducts
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resulting from competing reduction and hydrolysis of 10a, respectively, were calculated by H
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NMR analysis of the crude reaction mixtures after filtration of the catalyst: results from these
studies are shown in Figure 2 and reveal that while most studied catalysts (Pd/C, Pd(OH)2/C, Pd
black, Pd/BaSO4, Pd/CaCO3 and Pd/Al2O3) promoted the reaction, Pd/C was found to be quite
efficient but higher yields and conversions were obtained with Pd(OH)2/C and Pd/BaSO4. Due to
the lower cost of the former, it was therefore selected as the optimal catalyst for the rest of the
optimization. In all cases, minor amounts of reduced 12a and hydrolyzed 13a products were
detected in the crude reaction mixtures.
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Having determined the superiority of Pearlman’s catalyst, we next moved to screening the
influence of the solvent utilized for the carboxylation, the solvents for this second step of the
optimization being selected on the basis of their miscibility with water and of their use on a larger
scale. As evidenced by results summarized in Figure 2, the solvent was found to have a dramatic
impact on the outcome of the reaction: while almost no reaction occurred in toluene, poor
conversions were observed in dioxane and acetonitrile. A higher conversion was achieved in DMF
but with a significant increase of competing hydrolysis – a reaction that was found, quite logically,
to be the main reaction when the carboxylation was performed in water – due to the too high
polarity of this solvent. The best result was actually obtained with the solvent we had chosen at
the beginning of our studies, THF, which was therefore selected as the solvent of choice for the
carboxylation.
A broad range of additives commonly utilized in palladium-catalyzed reactions was next
evaluated. While the presence of an additive was found to be crucial for the carboxylation to
occur, no product being basically formed in the absence of additive, tetrabutylammonium salts
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had a positive impact on the outcome of the reaction, except in the case of tetrabutylammonium
iodide which gave a poor conversion and an important amount of competing hydrolysis, a side
reaction that could be facilitated by an in situ Finkelstein reaction. Among all
tetrabutylammonium salts evaluated, TBAB gave the best result. Tetrabutylphosphonium
hydroxide was also found to have a positive impact on the reaction but, as with TBAOH, also
favored the hydrolysis and tetramethylammonium salts, which were evaluated because of their
higher stability since they cannot undergo degradation through a Hofmann elimination, were
found to be inefficient, mostly due to their poor solubility in THF. Triphenylphosphine was also
shown to be a suitable additive but a low conversion and a higher amount of reduced product
12a were noted in this case; increasing the amount of this additive in order to reach a higher
conversion proved to be successful but a too high proportion of competing hydrolysis to
compound 13a was still observed. As a note, increasing the loading of TBAB, which was selected
as the best additive, did not result in a higher yield.
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Having selected the best palladium catalyst, additive and solvent, we next evaluated the
influence of the concentration by performing the reaction in more diluted and concentrated
media. As highlighted in Figure 2, the concentration did not have a major influence on the
reaction, too high concentrations however resulting in higher amounts of hydrolysis while too
low concentrations favored the reduction, the best compromise relying on the use of 40 volumes
of THF. We finally focused on the impact of the last reaction parameters: the pressure of carbon
monoxide, the temperature and the reaction time. Decreasing the pressure to 9, 7 or 5 bar
resulted in decreased yields and lower conversions while performing the reaction at 60 °C instead
of 110 °C (not shown) brought the conversion down to 11%. Finally, a longer reaction time (not
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Figure 2. Optimization of the palladium-catalyzed carboxylation. a with 2.5 wt% Pd(OH)2/C. b with
20 mol%.
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shown) was found to be detrimental since performing the reaction overnight in place of for 4
hours gave a lower yield (76% vs 89%) and a higher amount of reduced product 12a (18% vs 5%),
presumably due to a decarboxylation of the desired product 11a with prolonged reaction times.
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At this stage, we briefly focused our efforts on understanding the origin of the formation of
the reduced product 12a, which could be useful to potentially minimize its proportion. One
possibility that might account for the formation of this byproduct would involve the
decarboxylation of acid 11a; this hypothesis could however be easily discarded since upon
reacting p-tert-butyl-phenylacetic acid 11a under the standard reaction conditions for 4 hours, it
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could be fully recovered and H NMR analysis of the crude mixture revealed the absence of p-
tert-butyl-toluene 12a (Scheme 1, eq. 1). THF and TBAB being hardly reducing agents in
palladium-catalyzed reactions and the reduction being in addition also observed with other
solvents and additives, we therefore wondered if the reduction did not result from the water-gas
shift reaction between carbon monoxide and water that would produce molecular hydrogen
within the reaction mixture. The carboxylation of p-tert-butyl-benzyl bromide 10a was thus
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performed with deuterated water, H NMR analysis of the crude reaction mixture revealed the
formation of deuterated reduced product 12aD with a good level of deuteration (Scheme 1, eq.
2), therefore suggesting that the reduction was due to the reagents needed for the carboxylation,
i.e. carbon monoxide and water, minimizing the formation of the reduced product being
therefore highly challenging if not impossible.
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Scheme 1. Origin of the competing reduction of benzylic bromides.
Screening all parameters of the carboxylation therefore resulted in an optimal system for the
carboxylation based on the use of 2.5 wt% of Pd(OH)2/C (20 wt% Pd), 10 mol% of TBAB, 4 equiv.
of water under 10 bar of carbon monoxide in 40 volumes of THF at 110 °C for 4 hours. These
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conditions resulted in a H NMR yield of 89% for the desired benzylic acid 11a with a full
conversion and around 5% of reduced 12a and hydrolyzed 13a products. The desired acid could
be easily isolated in a pure form by filtration of the crude reaction mixture over a plug of Celite®,
concentration, extraction with a 1M aqueous solution of sodium hydroxide which was washed
with pentane to remove all byproducts, acidification with a 10% aqueous solution of hydrochloric
acid and extraction with diethyl ether. Using this simple and standard procedure, an isolated yield
of 77% could be obtained.
Having in hand the optimized conditions and work-up procedure, we then assessed the scope
and limitations of our system for the palladium-catalyzed carboxylation of a series of benzylic
bromides. Results from these studies will now be overviewed.
Scope and limitations of the Pd(OH)2/C-catalyzed carboxylation of benzylic bromides. To test
the efficiency of our procedure, a set of benzylic bromides 10 with representative electronic and
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steric properties was therefore subjected to our optimized conditions: results from this study are
summarized in Figure 3. As evidenced by these results, our procedure was found to be rather
general and the desired arylacetic acids 11 could be obtained in good to excellent yields in most
cases and without the need for further purification after the acid-base wash. Para-, meta-, and
even ortho- substituted benzylic bromides were shown to be readily carboxylated, the former
giving however a superior yield. Electron-rich and electron-poor substrates worked equally well,
providing the corresponding arylacetic acids 11a-f and 11g-n in good yields. A range of
substituents were tolerated, including a benzyl ether (11f), a nitrile (11g) and a tert-butyl ester
(11i) while a more labile ethyl ester (11h) was cleaved under the reaction conditions and a nitro
group (11j) gave a poorer yield, presumably due to its competing reduction. Interestingly, an
aromatic chloride (11m) and even a bromide (11n) were stable under the reaction conditions and
no competing carboxylation was noted, which offers interesting possibilities for further
derivatization. Interestingly, the procedure was also amenable to the production of
2-naphthalen-2-ylacetic acid 11o in good yield (81%).
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In an effort to further highlight the efficiency and attractiveness of our procedure, we next
briefly studied its extension to the preparation of heteroarylacetic acids, useful building blocks in
medicinal chemistry and agrochemistry (Figure 4). To our delight, benzofuran (15a),
benzothiophene (15b) and indole (15c) derivatives could be obtained in fair to good yields from
the corresponding bromides. As for pyridin-3-ylacetic acid 15d, it was also formed by
carboxylation of the corresponding bromide, but in lower yield due to the poor stability of the
starting material combined with a less efficient reaction and a much more tedious purification.
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Figure 3. Scope and limitations of the Pd(OH)2/C-catalyzed carboxylation of benzylic bromides. a
from ethyl 4-(bromomethyl)benzoate.
Figure 4. Pd(OH)2/C-catalyzed carboxylation of heterobenzylic bromides.
Pd(OH)2/C-catalyzed carboxylation of benzylic bromides on a multigram scale. In a further
effort to demonstrate the synthetic potential of our procedure, a scale up of the carboxylation
of p-bromo-benzyl bromide 10n to p-bromo-phenylacetic acid 11n was next explored (Figure 5).
A 1 L autoclave was therefore charged with 20 grams of p-bromo-benzyl bromide followed by
TBAB, water and Pd(OH)2/C in 800 mL of THF (industrial grade: KF  0.1%). The resulting
suspension was purged with carbon monoxide (3 bar) and then heated to 110 °C before
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pressurizing with 10 bar of carbon monoxide. The reaction mixture was stirred at 110 °C under
10 bar of carbon monoxide for 6 hours: in-process control (LCAP) revealed the formation of 71%
of the targeted product 11n, 10% of starting material and 11% of the reduced product. Shorter
reaction times led to lower conversions and a longer one or the use of additional catalyst did not
improve conversion and selectivity. After cooling to 20-25 °C, the mixture was filtered through
filter cloth to provide a clear solution which was fully concentrated under atmospheric pressure
before adding a 30% aqueous solution of sodium hydroxide, water and dichloromethane. The
aqueous layer was next treated with charcoal before adding 34% hydrochloric acid until pH 1-2
and stirring the resulting white slurry at 20-25 °C for 1 hour. The mixture was then held at 0-5 °C
for 1 hour, and the solid was collected by filtration. The cake was washed twice with cold water
and the solid was oven-dried overnight (40 °C) to afford 10.8 grams of the desired p-bromo-
phenylacetic acid 11n (60% yield, 99.3% LCAP).
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Figure 5. Pd(OH)2/C-catalyzed synthesis of p-bromo-phenylacetic acid on a multigram scale.
Heterogeneous nature of the catalyst and catalyst recycling. On an industrial setting, and
especially for large scale applications, the nature of the catalyst (i.e. heterogeneous vs
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homogeneous) and its recycling are of crucial importance. Indeed, a totally heterogeneous
catalyst with limited leaching ensures low levels of residual palladium into the final product
together with facilitating its recycling. We therefore first decided to address the nature of the
catalyst and to perform leaching studies: ICP analysis of the crude filtrate prior to any extraction
or treatment gratifyingly revealed a really low level of palladium (0.9 ppm) in solution, therefore
highlighting the heterogeneous nature of our system.
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Our catalytic system being heterogeneous, we could therefore next address its potential
recyclability, an important point even if our procedure involves a low catalyst loading. A large
scale carboxylation of 10n was therefore set up and the catalyst that could be recovered after
the filtration step was reused for another carboxylation: as demonstrated by the percentage of
starting material 10n, carboxylated and reduced products 11n and 12n, whose yields were
evaluated by HPLC analysis of the crude reaction mixture, shown in Figure 6, this recycled catalyst
was shown to be much less efficient since lower conversion and yield were obtained under
otherwise identical conditions. In an attempt to solve this problem, a spiking strategy that is
commonly utilized for large scale metal-catalyzed reactions, involving the addition of a minimum
of the fresh catalyst to the recycled one was envisioned. This turned out to be rather fruitful since
a comparable catalytic activity could be restored, at the expense of the conversion however.
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Figure 6. Catalyst recycling.
Pd(OH)2/C-catalyzed carboxylation of benzylic bromides with ex situ-generated carbon
monoxide in a two-chamber reactor. Having demonstrated the efficiency, the applicability and
the scale up of our process for the carboxylation of benzylic bromides with carbon monoxide
relying on the use of a heterogeneous and recyclable catalyst, we next moved to a brief study of
its extension to the use of precursors of carbon monoxide. Certain academic and industrial
laboratories being either not equipped to handle carbon monoxide or reluctant to use it, the use
of stable precursors of this reagent indeed provides an interesting alternative, notably for small
scale reactions. Skrydstrup’s two-chamber reactor COware,20 in which carbon monoxide is ex
situ-generated in one chamber before reacting in the second one, having proved its efficiency for
such processes, we therefore tested its use for our carboxylation. Among all stable precursors of
carbon monoxide reported to date, a combination of formic acid and sulfuric acid21 – the later
dehydrating the former (Morgan reaction)22 at elevated temperatures – was selected, these two
reagents being cheap and readily available.
To test this alternative carboxylation procedure, the CO-generation chamber of a 20 mL two-
chamber COware reactor (Figure 7, chamber A) was charged with 10 equiv. of sulphuric acid while
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the carboxylation chamber (Figure 7, chamber B) was charged with p-tert-butyl-benzyl bromide
10a, 20 wt% of palladium hydroxide on carbon (20 wt% Pd), 10 mol% of tetrabutylammonium
bromide and water (4 equiv.) in THF. The COware reactor was tightly closed, heated at 80 °C and
formic acid (10 equiv.) was then added dropwise in the CO-generation chamber. After 24 hours
at 80 °C – this temperature being selected to stay within the pressure limit of the two-chamber
reactor, – a simple filtration followed by an acid-base extraction provided the desired arylacetic
acid 11a in 54% yield, a yield that was not further optimized but demonstrated that the use of
gaseous carbon monoxide is not strictly needed for our carboxylation. As a note, the amount of
Pearlman’s catalyst as well as the reaction time had to be increased in this case to ensure a full
conversion of the starting material.
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Figure 7. Pd(OH)2/C-catalyzed carboxylation of p-tert-butyl-benzyl bromide with ex situ-
generated carbon monoxide in a two-chamber reactor.
Application to the synthesis of diclofenac. In a final attempt to highlight the synthetic
potential of our carboxylation, notably in medicinal and process chemistry, we envisioned its use
for the synthesis of an API. Diclofenac 3, commercialized under various trade names such as
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VoltarenTM, CataflamTM, or PennsaidTM, was selected as the target due to its importance as a non-
steroidal anti-inflammatory drug which has been among the best-selling anti-inflammatory drugs
for more than a decade and due to the number of processes reported and patented for its
synthesis.23 It was first patented in 1965 by Ciba-Geigy and came into medical use in 1988.24
Among all the syntheses reported and/or patented, the ones relying on an Ullmann coupling
are especially appealing in terms of number of steps and availability/cost of the starting
materials. This was actually already featured in one of Ciba-Geigy’s original routes which involved
a key Ullmann coupling between 2,6-dichloroaniline and o-chloro-benzoic acid.23a Starting from
an o-halo-phenylacetic acid in place of the corresponding benzoic acid resulting in more
straightforward syntheses, several processes have been developed based on this strategy, using
o-iodo-phenylacetic,25 o-bromo-phenylacetic,26 or o-chloro-phenylacetic10,27 acids, the latter
being more appealing in terms of cost, although its amination being challenging. While its
classical preparation from o-chloro-benzyl bromide or chloride rely on a nucleophilic substitution
with a cyanide followed by hydrolysis (Scheme 2, bottom), it could be more conveniently
prepared by a direct carboxylation with carbon monoxide (Scheme 2, top).10 We therefore
envisioned testing the efficiency of our catalytic system for this step: with this goal in mind,
o-chloro-benzyl bromide 10p was thus reacted under our optimized conditions, providing
o-chloro-phenylacetic acid 11p in 70% after filtration and a simple acid-base wash. A further
coupling with 2,6-dichloroaniline under previously reported conditions10 then afforded
diclofenac 3 in two steps from commercially available starting materials.
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Scheme 2. Pd(OH)2/C-catalyzed carboxylation of benzylic bromides applied to the synthesis of
diclofenac.
3. CONCLUSION
In conclusion, we have developed a simple, efficient and broadly applicable system for the
carboxylation of benzylic bromides. Upon simple reaction with carbon monoxide and water in
the presence of only 2.5 wt% of Pearlman’s catalyst and 10 mol% of TBAB in THF at 110 °C for 4
hours, a range of benzylic bromides can be smoothly converted to the corresponding arylacetic
acids in good to excellent yields. The reaction was found to be rather general, scalable and both
its extension to ex situ-generated carbon monoxide and its application to the synthesis of the
non-steroidal anti-inflammatory drug diclofenac highlight its synthetic potential. Attractive
features of this procedure include the low cost of the palladium catalyst, its easy removal by
simple filtration, the operational simplicity of the process and its generality and broad substrate
scope. It should facilitate the synthesis of arylacetic acids and could contribute to the
development of shorter and more efficient industrial processes.
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EXPERIMENTAL SECTION
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General Information. All reactions were carried out in oven-dried glassware unless
otherwise stated.
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All solvents were reagent grade. Tetrahydrofuran was freshly distilled from
sodium/benzophenone under argon prior to use (for small scale reactions – for the large scale
reaction, industrial grade THF (KF  0.1%) was used without purification). N,N-
Dimethylformamide (99.8% purity, Extra Dry over Molecular Sieves, Acroseal®) was purchased
from ACROS Organics and degassed by three cycles of “freeze-pump-thaw” using argon as inert
gas when required.
Palladium hydroxide on carbon (20 wt% Pd, moisture ca 60%) was purchased from ACROS
Organics and used as supplied. Tetrabutylammonium bromide (98% purity) was purchased from
Combi-Blocks and used as supplied. Copper(I) iodide (99,999% purity) used for copper-mediated
coupling reactions was purchased from ACROS Organics and used as supplied. Carbon monoxide
(N47, 99.997%+ purity) was purchased from Air Liquide and used as supplied. Deuterium oxide
(99.9% D) was purchased from Eurisotop and used as supplied. Sulfuric acid (96%, VLSI
Selectipur®) and formic acid (99%+ purity) were respectively purchased from BASF and ACROS
Organics and used as supplied. All other reagents were used as supplied.
Carboxylation reactions were performed using a HEL ltd. CAT 7 autoclave
(https://www.helgroup.com) equipped with B19 PTFE-capped 10 mL glass vials and linked to a
CO cylinder. The 20 mL two-chamber COware reactor was purchased from Sigma-Aldrich.
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Reactions were magnetically stirred and monitored by thin layer chromatography using
Merck-Kiesegel 60F254 plates. Flash chromatography was performed with silica gel 60 (particle
size 35-70 µm) supplied by Merck. Yields refer to chromatographically and spectroscopically pure
compounds unless otherwise stated.
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Proton NMR spectra were recorded using an internal deuterium lock at ambient
temperature on Bruker 300 MHz, Varian 400 MHz and JEOL 400 MHz spectrometers. Internal
reference of H 7.26 was used for CDCl3, and H 2.05 was used for acetone-d6. Carbon-13 NMR
spectra were recorded at 100 MHz using CDCl3 (C 77.16) or acetone-d6 (C 29.84) as internal
reference. 19F NMR spectra were recorded at 376 MHz.
Carboxylation with Deuterated Water. Synthesis and Isolation of p-tert-Butyl-toluene 12aD
and p-tert-Butyl-benzyl Alcohol 13a. Six glass vials containing a PTFE-coated magnetic stirrer were
each charged with p-tert-butyl-benzyl bromide 10a (115 mg, 0.52 mmol), palladium hydroxide on
carbon 20 wt% (3 mg, 2.5 wt%) and tetrabutylammonium bromide (19 mg, 0.06 mmol).
Tetrahydrofuran (2.3 mL, 20 vol.) and deuterium oxide (38 µL, 2.08 mmol) were then added, the
vials were sealed with a PTFE cap and placed in the autoclave. The system was first purged with
5 bar of CO, then pressurized with 10 bar of CO and stirred at 110 °C for 12 hours. The autoclave
was cooled down to room temperature and then gently depressurized. The content of the six
vials was combined and filtered over a short pad of Celite®, which was thoroughly washed with
ethyl acetate (ca 20 mL). The volatiles were removed under reduced pressure. The crude residue
was dissolved in a 1M aqueous solution of sodium hydroxide (10 mL) and washed with pentane
(3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash column chromatography on silica gel
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(pentane to pentane/diethyl ether: 75/25) to afford the reduced product 12aD (64%D, 24 mg,
0.16 mmol, 5%) as a colorless liquid and the hydrolyzed compound 13a (15 mg, 0.09 mmol, 3%)
as a colorless liquid. These compounds have been previously reported.28
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Carboxylation of Benzylic Bromides. General Procedure. Three glass vials containing a
PTFE-coated magnetic stirrer were each charged with the desired benzylic bromide 10 (57 mg,
1.0 equiv.), palladium hydroxide on carbon 20 wt% (1.5 mg, 2.5 wt%) and tetrabutylammonium
bromide (0.1 equiv.). Tetrahydrofuran (2.3 mL, 40 vol.) and distilled water (4 equiv.) were then
added, the vials were sealed with a PTFE cap and placed in the autoclave. The system was first
purged with 5 bar of CO, then pressurized with 10 bar of CO and stirred at 110 °C for 4 hours. The
autoclave was cooled down to room temperature and then gently depressurized. The content of
the three vials was combined and filtered over a short pad of Celite®, which was thoroughly
washed with ethyl acetate (ca 10 mL). The volatiles were removed under reduced pressure. The
crude residue was dissolved in a 1M aqueous solution of sodium hydroxide (5 mL) and washed
with pentane (3 x 5 mL). The aqueous layer was then acidified to pH 1-2 with a 10% aqueous
solution of hydrochloric acid and extracted with diethyl ether (3 x 10 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced
pressure to afford the desired carboxylic acid 11 as a solid. The product thus obtained did not
require further purification.
p-tert-Butyl-phenylacetic Acid 11a. Yield: 77% (113 mg, 0.59 mmol). White solid. This
compound has been previously reported.7a
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p-Tolylacetic Acid 11b. Yield: 80% (90 mg, 0.60 mmol). White solid. This compound has been
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previously reported.29
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m-Tolylacetic Acid 11c. Yield: 69% (81 mg, 0.54 mmol). White solid. This compound has
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been previously reported.29
o-Tolylacetic Acid 11d. Yield: 65% (91 mg, 0.61 mmol). Off-white solid. This compound has
been previously reported.30
p-Methoxy-phenylacetic Acid 11e. Yield: 76% (108 mg, 0.65 mmol). White solid. This
compound has been previously reported.7a
p-Benzyloxy-phenylacetic Acid 11f. Yield: 45% (92 mg, 0.38 mmol). White solid. This
compound has been previously reported.31
p-Cyano-phenylacetic Acid 11g. Yield: 76% (106 mg, 0.66 mmol). White solid. This
compound has been previously reported.32
p-Carboxy-phenylacetic Acid 11h. Prepared according to the general procedure starting
from ethyl p-(bromomethyl)benzoate 10h. Yield: 43% (51 mg, 0.28 mmol). White solid. This
compound has been previously reported.33
p-tert-Butoxycarbonyl-phenylacetic Acid 11i. Yield: 58% (86 mg, 0.36 mmol). White solid.
This compound has been previously reported.34
p-Nitro-phenylacetic Acid 11j. Yield: 38% (55 mg, 0.30 mmol). Yellow solid. This compound
has been previously reported.35
p-Trifluoromethyl-phenylacetic Acid 11k. Yield: 77% (147 mg, 0.62 mmol). Off-white solid.
This compound has been previously reported.7a
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p-Fluoro-phenylacetic Acid 11l. Yield: 68% (96 mg, 0.62 mmol). White solid. This compound
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has been previously reported.7a
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p-Chloro-phenylacetic Acid 11m. Yield: 79% (113 mg, 0.66 mmol). White solid. This
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compound has been previously reported.29
p-Bromo-phenylacetic Acid 11n. Yield: 82% (121 mg, 0.56 mmol). White solid. This
compound has been previously reported.29
Naphthalen-2-ylacetic Acid 11o. Yield: 81% (117 mg, 0.63 mmol). White solid. This
compound has been previously reported.7a
o-Chloro-phenylacetic Acid 11p. Yield: 70% (101 mg, 0.59 mmol). White solid. This
compound has been previously reported.7a
Benzofuran-3-ylacetic Acid 15a. Yield: 63% (90 mg, 0.51 mmol). White solid. This compound
has been previously reported.36
Benzo[b]thiophen-3-ylacetic Acid 15b. Yield: 54% (78 mg, 0.41 mmol). White solid. This
compound has been previously reported.37
N-Tosyl-indol-3-ylacetic Acid 15c. Yield: 58% (93 mg, 0.28 mmol). Brownish solid. This
compound has been previously reported.38
Pyridin-3-ylacetic Acid 15d. This compound was prepared starting from
3-(bromomethyl)pyridine hydrobromide. The hydrobromide (253 mg, 1.0 mmol) was dissolved
in a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and the resulting free
base was extracted with diethyl ether (2 x 5 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure to afford 3-(bromomethyl)pyridine
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14d which was used quickly following the general carboxylation procedure. Instead of an acid-
base wash, trituration of the crude residue in chloroform (5 mL) and filtration delivered the
desired acid 15d. Yield: 37% (46 mg, 0.34 mmol). White solid. This compound has been previously
reported.39
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Multigram Scale Procedure. Carboxylation of p-Bromo-benzyl Bromide 10n. A 1L autoclave
was charged with p-bromo-benzyl bromide 10n (20 g, 80.0 mmol), tetrabutylammonium bromide
(2.58 g, 8.0 mmol), distilled water (5.8 mL, 320 mmol), palladium hydroxide on carbon 20 wt%
(0.5 g, 2.5 wt%) and tetrahydrofuran (industrial grade: KF  0.1%, 800 mL). The resulting
suspension was purged with 3 bar of CO and heated to 110 °C before being pressurized with 10
bar of CO. The reaction mixture was stirred at 110 °C under 10 bar of CO for 6 hours (In-process
control (LCAP): 71% targeted product 11n, 10% starting material 10n, 11% reduced product 12n).
The resulting mixture was cooled down to room temperature and filtered through filter cloth to
provide a clear solution which was concentrated under atmospheric pressure. A 30% aqueous
solution of sodium hydroxyde (80 mL), water (100 mL) and dichloromethane (100 mL) were then
added to the residue and the organic and aqueous phases were separated. The aqueous layer
was treated with charcoal and a 34% aqueous solution of hydrochloric acid was added to reach
pH 1-2. The resulting white slurry was then stirred at 20-25 °C for 1 hour and held at 0-5 °C for an
additional hour before being collected as a solid by filtration. The cake was washed with cold
water (2 x 10 mL) and the resulting solid was oven-dried overnight (40 °C) to yield p-bromo-
phenylacetic acid 11n as a white solid (10.8 g, 50.2 mmol, 60%, 99.3% LCAP). This compound has
been previously reported.29
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COware Two-Chamber Reactor Procedure. Carboxylation of p-tert-Butyl-benzyl Bromide
10a. p-tert-Butyl-benzyl bromide 10a (57 mg, 0.26 mmol), palladium hydroxide on carbon 20 wt%
(12 mg, 20 wt%), tetrabutylammonium bromide (10 mg, 0.03 mmol), distilled water (19 L, 1.04
mmol) and tetrahydrofuran (2.3 mL, 40 vol.) were charged in the carboxylation chamber of a 20
mL two-chamber COware reactor. Sulfuric acid (140 L, 2.6 mmol) was added in the CO-
generation chamber. The COware reactor was tightly closed, heated at 80 °C and formic acid (100
L, 2.6 mmol) was then added dropwise in the CO-generation chamber. The mixture was stirred
at 80 °C for 24 hours. The two-chamber reactor was cooled down to room temperature and then
gently depressurized. The content of the carboxylation chamber was filtered over a short pad of
Celite®, which was thoroughly washed with ethyl acetate (ca 5 mL). The volatiles were removed
under reduced pressure. The crude residue was dissolved in a 1M aqueous solution of sodium
hydroxide (5 mL) and washed with pentane (3 x 5 mL). The aqueous layer was then acidified to
pH 1-2 with a 10% aqueous solution of hydrochloric acid and extracted with diethyl ether (3 x 10
mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure to yield p-tert-butyl-phenylacetic acid 11a as a white solid
(27 mg, 0.14 mmol, 54%). This compound has been previously reported.7a
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Diclofenac Synthesis. Ullmann Coupling on p-Chloro-phenylacetic Acid 11m. A 50 mL
pressure tube fitted with a rubber septum was charged with p-chloro-phenylacetic acid 11m (512
mg, 3.0 mmol), 2,6-dichloroaniline (2.43 g, 15.0 mmol), copper(I) iodide (457 mg, 2.4 mmol),
potassium iodide (498 mg, 3.0 mmol) and potassium carbonate (829 mg, 6.0 mmol). The pressure
tube was evacuated under high vacuum, backfilled with argon and then degassed N,N-
dimethylformamide (6 mL) was added. The pressure tube was then sealed with a Teflon-coated
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screw cap and stirred 12 hours at 165 °C. The resulting dark mixture was cooled down to room
temperature and transferred into a 250 mL round bottom flask. Ethyl acetate (120 mL), water (60
mL), concentrated hydrochloric acid (4.0 mL) as well as charcoal (12 g) and Celite® (12 g) were
added and the resulting slurry was vigorously stirred for 1 hour. The mixture was filtered, the
biphasic filtrate was separated, and the organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc: 80/20 to 60/40) to give the desired acid 3
(293 mg, 0.99 mmol, 34%) as a white solid. This compound has been previously reported.10,25c
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ASSOCIATED CONTENT
Supporting Information. Copies of NMR spectra (PDF) and Primary NMR data files (ZIP). This
material is available free of charge on the ACS Publication Website.
AUTHOR INFORMATION
Corresponding Authors
* Pierre-Georges.Echeverria@minakem.com, Gwilherm.Evano@ulb.be
ORCID
Gwilherm Evano: 000-0002-2939-4766
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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Our work was supported by the Université libre de Bruxelles (ULB), the FNRS (PDR T.0160.18) and
Minakem. D.F.D. and H.B acknowledge the Fonds pour la formation à la Recherche dans
l’Industrie et dans l’Agriculture (F.R.I.A.) for graduate fellowships.
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For selected recent examples, see: (a) Meng, Q.-Y.; Wang, S.; Huff, G. S.; König, B. Ligand-
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Grushin, V.; Alper, H. Novel Palladium-Catalyzed Carbonylation of Organic Halides by
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For a recent representative example, see: Wang, L.; Neumann, H.; Beller, M. A General,
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