Efficient palladium-catalyzed synthesis of 2-aryl propionic acids

Article abstract of DOI:10.3390/molecules25153421

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.

Full text of DOI:10.3390/molecules25153421

molecules
Communication
Efficient Palladium-Catalyzed Synthesis of 2-Aryl
Propionic Acids
Helfried Neumann 1 , Alexey G. Sergeev 2 , Anke Spannenberg 1 and Matthias Beller 1,
*
1
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany;
Helfried.Neumann@catalysis.de (H.N.); Anke.Spannenberg@catalysis.de (A.S.)
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK; A.Sergeev@liverpool.ac.uk
Correspondence: Matthias.Beller@catalysis.de
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: José Pérez Sestelo
Received: 2 July 2020; Accepted: 24 July 2020; Published: 28 July 2020
Abstract: A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic
acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were
obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9)
which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with
ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade
transformation leads with high regioselectivity to the desired products in good yields and avoids the
need for additional purification steps.
Keywords: Heck reaction; styrene; methoxycarbonylation; profene; palladium
1. Introduction
2-Aryl propionic acids, such as ibuprofen, ketoprofen, naproxen, and flurbiprofen, belong
to an important class of non-steroidal anti-inflammatory drugs (NSAIDs) which are extensively
used in the treatment of inflammatory diseases and for the relief of pain [
numerous known synthetic methods for their preparation [ ], the regioselective carbonylation
of styrenes provides straightforward and easy access [ ]. Although notable progress has
been reported in the enantioselective hydroxycarbonylation of styrenes [ ], still, the racemic
1]. Among the
2,3
4
5–7
hydroxy/alkoxy-carbonylation continues to be attractive for the scientific community, too.
Here, palladium complexes in the presence of acid represent state-of-the-art catalyst systems for
the synthesis of 2-aryl propionic acid. Recent catalyst developments in this area include the preparation
of heterogeneous Pd-TPPTS complexes supported onto acidic resins [
8] as well as homogenous systems
such as-PdCl(allyl)(tri-oxo-adamantyl cage phosphines) [ ], water-soluble Pd-TPPTS complexes [10],
9
palladium(II) complexes containing naphthyl(diphenyl)-phosphine ligands [11] or bulky bidentate
phosphines [12], and PdCl2(PPh3)2/HCl/CO/THF in combination with heteropolyacids [13].
Some years ago, our group reported a two-step protocol for the synthesis of ketoprofen and
suprofen. These two drugs were synthesized following a tandem carbonylative Suzuki coupling and
subsequent hydroxycarbonylation [14]. Inspired by this previous work and our interest in carbonylation
reactions [15], here we describe a more flexible two-step, one-pot procedure for the synthesis of diverse
2-aryl propionic acids. Specifically, we utilized the palladium-catalyzed Heck reaction with aryl
bromides and ethylene to give the corresponding styrene derivatives [16,17] which are directly
hydroxycarbonylated to the desired 2-aryl propionic acids without changing the palladium catalyst.
2. Results and Discussion
In preliminary experiments, we optimized the Heck reaction of 4-bromoanisole 1a and ethylene
to yield 4-methoxystyrene 2a
. Optimal results (90% yield) were obtained using a mixture of
Molecules 2020, 25, 3421; doi:10.3390/molecules25153421
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Molecules 2020, 25, 3421
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Pd(OAc)2/BuPAd2 [18] (0.5 mol%/2.0 mol%) in the presence of 1.5 eq NEt3 and 20 bar ethylene.
To directly perform the carbonylation step, the reaction solution was acidified with 0.5 mmol HCl and
the autoclave was pressurized with 40 bar CO yielding in total 72% of 2-(4-anisyl) propionic acid 3a
along with 6% of the linear isomer 4a (Table 1, entry 1). Because of the good water solubility and its
boiling point, dioxane was identified as the best solvent. To improve the selectivity for the desired
branched carboxylic acid and to facilitate the final purification, the influence of phosphine ligands was
evaluated (Table 1). Interestingly, in the presence of some of the ligands (e.g., P(o-tolyl)3 and Johnphos),
only the Heck reaction occurred and no carbonylation process was observed (Table 1, entries 2 and
3). On the other hand, ligands 1,1’-bis(diphenylphosphino)ferrocene (DPPF), P(t-Bu)3, t-Bu-XPhos,
and 2-diadamantyl- phosphino-(2,6-diisopropylphenyl)-1H-imidazole allowed for both catalytic steps
but gave somewhat lower product yields of 55%, 70%, 65%, and 33%, respectively (Table 1, entries 4–7).
Table 1. Palladium-catalyzed two-step synthesis for 2-aryl propionic acid 3a.
Entry
Ligand
2a (%)(c)
3a (%)(d)
4a (%)(d)
1
2
3
4
5
n-BuPAd2
P(o-tolyl)3
JohnPhos (e)
DPPF (e)
90
59
66
89
90
72
0
0
55
70
6
0
0
2
5
(t-Bu)3P
6
91
65
9
N
PAd2
i-Pr
N
7
8
93
91
33
75
4
4
i-Pr
n-BuP(t-Bu)2
9
91
92
84
85
3
4
10
(a) First step: Pd(OAc)2 (0.5 mol%), ligand (2.0 mol%), dioxane (2 mL), NEt3 (1.5 mmol), 4-bromoanisole
(1 mmol), ethene (20 bar), 0.2 eq hexadecane 120 ◦C, 20 h; (b) second step: 83
µL HCl (6M), CO (40 bar),
100 ◦C, 20 h; (c) a sample of the first half reaction was submitted to the GC to determine the yield of
styrenes; (d) a sample was esterified with MeOH and trimethylsilyl diazomethane to determine the overall
yield by GC; (e) JohnPhos ((2-biphenyl)di-tert-butyl-phosphine), DPPF (1,1’-bis(diphenylphosphino)ferrocene),
t-Bu-XPhos (2-di-tert-butylphosphino-20,40,60-triisopropylbiphenyl), NMDPP (neomenthyldiphenylphosphine),
MDPP (menthyldi-phenylphosphine).

Molecules 2020, 25, 3421
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Inspired by some original investigations of Chiusoli and co-workers [19] and a patent
application [20], which described the palladium-catalyzed methoxycarbonylation of styrenes using a
neomenthyldiphenylphosphine ligand (NMDPP), we also tested the commercially available NMDPP
ligand in our one-pot, two-step reaction (Table 1, entry 9). To our delight, 4-methoxystyrene was
obtained with a 91% yield, and the following carbonylation gave an overall yield of 84% of 2-(4-anisyl)
propionic acid with only 3% of the undesired linear aryl propionic acid. Similar results were obtained
in the presence of a menthyldiphenylphosphine ligand (MDPP) [21] (Table 1, entry 10).
Based on these results, we synthesized related terpene-based ligands isopinocampheyl-
diphenylphosphine (ISPCDPP) (7) and neoisopinocampheyldiphenylphosphine (NISPCDPP) (9)
according to the route shown in Scheme 1.
Scheme 1. Synthesis of the ligands isopinocampheyldiphenylphosphine (ISPCDPP) (7) and
neoisopinocampheyldiphenylphosphine (NISPCDPP) (
converted to the corresponding borane adduct.
9). (a) For purification, the ligands were
The synthesis of the novel ligand isopinocampheyldiphenylphosphine ISPCDPP (
from commercially available (+)isopinocampheol ( ) which was converted to isopinocampheyl
chloride ( ) with inversion at the reacting stereocenter [22] Next, conversion of ( ) into the Grignard
and subsequent quenching with diphenylchlorophosphine gave rise to ISPCDPP ( ). With regard
to the synthesis of NISPCDPP ( ), (+)isopinocampheol ( ) was treated with mesyl chloride in
pyridine to give isopinocampheol methansulfonate ( ) [23]. Subsequent nucleophilic substitution
with potassium diphenylphosphide occurred with inversion of configuration to yield the novel ligand
neoisopinocampheyldiphenylphosphine NISPCDPP ( ). The ligand structure was confirmed by X-ray
analysis (Figure 1). See details in Supplementary Materials.
7) started
5
6
6
7
9
5
8
9
Figure 1. Molecular structure of NISPCDPP (
9) in the crystal. Hydrogen atoms are omitted for clarity.
Displacement ellipsoids correspond to 30% probability [24].

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Catalytic experiments revealed the best yield of 3a (89%) in the presence of NISPCDPP (
9
) (Table 2,
entries 1). Hence, this ligand was used in all following experiments. In general, the palladium-catalyzed
one-pot, two-step procedure can be used to prepare a variety of 2-aryl propionic acids in good to very
good overall yields in the presence of the NISPCDPP/Pd(OAc)2 system. Both the Heck reaction and
the carbonylation step proceeded with high chemo- and regioselectivity. Since the optimal reaction
conditions were developed using electron-rich anisole as substrate, other electron-rich substrates
showed good results, too. Exemplarily, methyl- and t-butyl-substituted aryl bromides gave 74% and
85% yield of the corresponding methyl 2-arylpropionate (Table 2, entries 2 and 3). Nevertheless,
this cascade process also tolerates electron-withdrawing substituents, such as chloride, fluoride,
trifluoromethyl, and cyano giving, 75%, 77%, 84%, 72%, and 68% yield, respectively (Table 2, entries
4–8). Notably, the reaction of 1-bromo-3-fluoro-4-phenyl-benzene 1i gave the desired 2-aryl propionic
acid which is a known drug under the brand name Flurbiprofen® in 77% yield (Table 2, entry 9).
Finally, one of the most important NSAIDs Naproxen® was prepared in a similar fashion in 60% overall
yield (Table 2, entry 10).
Table 2. Palladium-catalyzed two-step, one-pot reaction to profenes.
Yield (%)(d)
Methyl 2-aryl Propionate
Yield (%)(d)
Methyl 3-aryl Propionate
Entry
Aryl Bromide
Styrene (c)
1(f)
2a (90%)
3a (89, 55%)
3b (74, 70%)
3c (85, 60%%)
4a (1%)
4b (1%)
4c (1%)
2
3
2b (75%)
2c (87%)
4
2d (80%)
3d (75, 21%)(e)
4d (3%)
5
6
7
8
2e (79%)
2f (85%)
2g (87%)
2h (79%)
3e (77, 36%)(e)
3f (84, 54%)
3g (72, 55%)
3h (68, 54%)
4e (1%)
4f (1%)
4g (3%)
4h (4%)

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Table 2. Cont.
Yield (%)(d)
Yield (%)(d)
Methyl 3-aryl Propionate
Entry
Aryl Bromide
Styrene (c)
Methyl 2-aryl Propionate
9
2i (79%)
3i (77, 74%)
4i (2%)
4j (2%)
10
2j (70%)
3j (60, 36%)(e)
(a) First step: Pd(OAc)2 (0.75 mol%), NISPCDPP (
9
) (3.0 mol%), dioxane (2 mL), NEt3 (1.5 mmol), aryl bromide
(1 mmol), ethene (20 bar), 0.2 eq hexadecane, 120 ◦C, 20 h; (b) second step: 83
µ
L HCl (6M), CO (40 bar), 100 ◦C, 20 h;
(c) a sample of the first half reaction was submitted to the GC to determine the yield of styrenes; (d) a sample was
esterified with MeOH and trimethylsilyl diazomethane to determine the overall yield by GC analysis, (GC/isolated
yield%); (e) the difference in GC yield and isolated yield is caused by a non-complete esterification with H2SO4/MeOH
or in taking several samples for GC analysis; (f) usage of ligand ISPCDPP (7) gives 2a, 3a, and 4a in 90%, 86%,
and 1% yield, respectively.
3. Conclusions
In conclusion, we developed a general and convenient two-step, one-pot protocol for the
synthesis of 2-aryl propionic acids. Following our protocol, the anti-inflammatory drugs naproxen
and flurbiprofen are easily accessible. Key steps of this process are the Heck reaction of ethylene
with different substituted aryl bromides and a subsequent hydroxycarbonylation. Notably, both steps
proceed in the presence of the same catalyst giving the desired products in 60–85% overall yield.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/15/3421/s1,
Experimental and crystallographic details for (9).
Author Contributions: H.N. carried out the screening experiments and the scope. A.G.S. synthesized for the
first time the ligands ISPCDPP (7) and NISPCDPP (9) shown in the Scheme 1. A.S. performed the X-ray crystal
structure analysis shown in Figure 1. H.N. and M.B. developed the project and wrote the manuscript. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was funded by State of Mecklenburg-Western Pommerania and the Federal State of
Germany (BMBF).
Acknowledgments: We gratefully thank the analytical department for measuring samples and Sandra Leiminger
and Andreas Koch for technical support.
Conflicts of Interest: The authors declare no conflicts of interest.
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).