A General, Activator-Free Palladium-Catalyzed Synthesis of Arylacetic and Benzoic Acids from Formic Acid

Article abstract of DOI:10.1002/anie.201802384

A new catalyst for the carboxylative synthesis of arylacetic and benzoic acids using formic acid (HCOOH) as the CO surrogate was developed. In an improvement over previous work, CO is generated in situ without the need for any additional activators. Key to success was the use of a specific system consisting of palladium acetate and 1,2-bis((tert-butyl(2-pyridinyl)phosphinyl)methyl)benzene. The generality of this method is demonstrated by the synthesis of more than 30 carboxylic acids, including non-steroidal anti-inflammatory drugs (NSAIDs), under mild conditions in good yields.

Full text of DOI:10.1002/anie.201802384

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Accepted Article
Title: A General Pd-catalyzed Synthesis of Arylacetic and Benzoic
Acids using Formic Acid without Activator
Authors: Lin Wang, Helfried Neumann, and Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802384
Angew. Chem. 10.1002/ange.201802384
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10.1002/anie.201802384
Angewandte Chemie International Edition
COMMUNICATION
A General Pd-catalyzed Synthesis of Arylacetic and Benzoic
Acids using Formic Acid without Activator
Lin Wang, Helfried Neumann, Matthias Beller*
Abstract: A new catalyst for the carbonlyative synthesis of arylacetic
and aryl acids using formic acid (HCOOH) as CO-surrogate was
developed. Advantageously compared to previous work, CO is
generated in-situ without the need of any additional “activators”. Key
to success for this method, is the use of a specific system consisting
anhydrides[16] and DCC[17] have to be added (Figure 2, c), which
in turn leads to waste and complicates work-up.
of
palladium
acetate
and
1,2-bis((tert-butyl(2-
pyridinyl)phosphanyl)methyl)benzene (L1). The generality of this
protocol is demonstrated in the synthesis of more than 30 carboxylic
acids including non-steroidal anti-inflammatory drugs (NSAIDs)
under mild conditions in good yields.
Arylacetic acids constitute an interesting class of organic
carboxylic acids, which are used for various applications.[1]
Among them, their use as non-steroidal anti-inflammatory drugs
(NSAIDs), known to cure osteoarthritis and rheumatoid arthritis
(RA), relieve pain and decrease fever, is noteworthy.[2] Important
representatives such as Indomethacin, Sulindac, Ketorolac,
Diclofenac, etc. are shown in Figure 1.[3]
Figure 2. Synthesis of aryl-acetic- and aryl- acid via the transition-metal-
catalyzed carbonylation of arylethyl- and aryl halides.
Figure 1. Typical aryl-acetic-acid NSAIDs
Herein, we report the first “activator-free” carbonylation
reactions of benzylic and aryl halides with plain formic acid
(Figure 2).
Common protocols to synthesize these compounds start
from benzylic halides or related substrates either by cyanation[4]
(Figure 2, a) or carbonylation with CO[5] (Figure 2, b). Clearly,
both methodologies require the utilization of toxic and harmful
chemicals. In this respect, application of safe and benign CN- or
CO-surrogates is of continuing interest. While little work has
been performed on greener CN-releasing agents so far,[6]
various CO surrogates have been reported in recent years.[7] In
Recently, we reported palladium complexes with 1,2-bis((tert-
butyl(2-pyridinyl)phosphanyl)methyl)-benzene (L1) and related
ligands for the alkoxycarbonylation of olefins and alcohols.[18]
Notably, these catalysts show superior activity for both terminal
and internal olefins. Key to success for this improvement is the
so-called “built-in-base”, which facilitates the attack of the
nucleophile on the intermediate palladium acyl species. Based
on that work, we had the idea that such ligands will also be able
to improve the rate of carbonylation reactions using CO-
surrogates.
Hence, at the start of this project several ligands including L1
were compared in the carbonylation of 1-(chloromethyl)-3-
methylbenzene (1a). Gratifyingly, the desired product 3-methyl-
benzeneacetic acid 2a was obtained in 81% yield in the
presence of L1. Meanwhile, the reaction resulted in a small
amount of by-product 2a’ which was formed via nucleophilic
attack of formic acid. Next, several ligands (L2 – L9) were tested
in the benchmark reaction as well. Except for 1,2-bis((tert-
butyl(2-furyl)-phosphanyl)methyl)-benzene (L2), which led to a
slightly lower yield (76%) of product, all other ligands were
inferior to L1 both reactivity and selectivity wise. Notably, ligands
with different backbone (L4 and L5) caused dramatic decrease
of selectivity, while monodentate phosphines such as L8 and L9
could not catalyze the reaction at all.
fact, alcohols[8], aldehydes[9], formates[10], dimethyl formamide
[12]
(DMF) or N-formylsaccharin[11]
,
chloroform
, and even
biomass[13] showed reactivity in transition-metal catalyzed
carbonylation reactions. However, the use of formic acid
(HCOOH) as an inexpensive, safe and low-toxic[14] CO surrogate
is still a challenge.
It is well established that numerous transition metal catalysts
decompose formic acid to CO2 and H2.[15] Apparently, selective
and efficient generation of CO via decomposition of formic acid
is a more difficult task. Hence, to promote CO formation,
(half)stoichiometric amounts of “activators” such as acid
[a]
Leibniz-Institut für Katalyse an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802384
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methodology can be applied for special substrates such as 1q
and 1r: 4-Methylphenethyl bromide (1q) which contains an un-
activated C(sp3)-Br bond was converted into 3-(4-
methylphenyl)propanoic acid (2q). Here, the corresponding ester
and olefin were obtained as by-products. Using 1,2-
bis(chloromethyl)benzene (1r) the lactone 2r was generated by
subsequent carbonylation and nucleophilic substitution cascade.
2a, 81%
2a, 76%
100%
2a, 40%
2a'
2a
Scheme 1. Pd-catalyzed carbonylation of benzyl and related halides with
80%
2a, 35%
formic acid.
60%
40%
2a, 0%
2a',18%
2a, 0% 2a, 0%
2a', 20% 2a', 15%
20%
0%
L1
L2
L3
L4
L5
L6
L7
L8
L9
Figure 3. Ligand effect for Pd-catalyzed carbonylation of 1a with formic acid.
Reaction conditions: 1a (1 mmol), formic acid (0.5 mL, 13 mmol), Pd(OAc)2
(0.005 mmol), ligand (0.02 mmol), TMEDA (1 mmol), in DMF (1.5 mL) at 115
oC for 24 h. Isolated yields. TMEDA = Tetramethylethylenediamine, DMF =
dimethylformamide.
After optimizing the reaction conditions (see Table S1 in
Supporting Information), we explored the substrate scope and
limitations of this novel protocol (Scheme 1). It is worth
mentioning that reaction rates were investigated in detail (see
Figure S2 in Supporting Information). For example, the
carbonylation of 1a is completed in 1 h, which demonstrates the
high activity for this substrate.
Comparing the reactivity of benzyl chloride (1b) and benzyl
bromide (1b’), the latter gave a higher yield (84% vs 72%) in
agreement with the stability of the C(sp3)-X bond. Similarly,
various phenylethyl chlorides with electron-donating groups such
as methyl, methoxy, ethyl, iso-propyl and tert-butyl as well as
fluoride-substituted derivatives were carbonylated in good yields
ranging from 72% to 83% (Scheme 1. 2c – 2i). On the other
hand carbonylation of 1j and 1k with chloride substituents gave
lower yields of the desired products. Notably, the influence of the
position of the substituent on the aromatic ring turned out to be
small.
Next, the utility of our protocol is showcased in the
straightforward synthesis of small-molecular drugs and
hormones. For instance, 1-naphthaleneacetic acid (NAA), which
is a synthetic plant hormone for rooting, was obtained in 71%
yield via the carbonylation of 1-naphthalymethyl chloride
(Scheme 1, 2l); Felbinac, the active metabolite of Fenbufen,
could be prepared in 73% yield without further optimization
(Scheme 1, 2n). Related analogues were obtained in similar
Reaction conditions: arylethyl halide (1 mmol), formic acid (0.5 mL, 13 mmol),
Pd(OAc)2 (0.005 mmol), L1 (0.02 mmol), TMEDA (1 mmol), in DMF (1.5 mL)
at 115 oC for 12 h. Isolated yields. i-Pr = isopropyl, t-Bu = tertbutyl. a. Reaction
time = 24 h. b. Reaction conditions: 1r (1 mmol), formic acid (0.5 mL, 13 mmol),
Pd(OAc)2 (0.01 mmol), L1 (0.04 mmol), TMEDA (1 mmol), in DMF (1.5 mL) at
115 oC for 24 h.
Scheme 2. Synthesis of Diclofenac sodium from the reaction of 2k with 2,6-
dichlorobenzenamine.
As shown in Scheme 2, this carbonylation protocol can be
used in part for a convenient synthesis of important NSAIDs. For
example, Diclofenac sodium was obtained from the reaction of
2k with 2,6-dichloro-benzenamine, albeit in moderate yield.[19]
In addition to benzylic halides, aryl bromides and chlorides
could be converted into the corresponding benzoic acids via
carbonlyation with formic acids. In general for the carbonylation
of aryl bromides, only 0.25 equivalents TMEDA were required
(Figure S2 in Supporting Information). In terms of applicability it
is interesting that diverse functional groups such as nitrile- and
yields (Scheme 1, 2m, 2o and 2p).
Furthermore, the
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10.1002/anie.201802384
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COMMUNICATION
hydroxyl-groups were compatible in the reactions. Among the
products synthesized, 2-naphthoic acid (NPA, 4i, 90% yield) has
been used as NMDA-receptor inhibitor.
As shown in the benchmark investigations (Figure 3), both
the backbone and the heterocyclic P-substituent of the ligands
were crucial for catalytic activity.
Sterically hindered substrates are more difficult to carbonylate
as demonstrated by the lower yield of 4h (47%) compared to 4i
(90%). A reasonable explanation is that the bulky groups of L1
hindered the coordination of substrate to the metal center.
Next, the mechanism of our novel methodology was
investigated: To confirm in situ generation of carbon monoxide,
so-called open-system experiments were performed at ambient
pressure (Scheme S1, Figure S4). Indeed, under otherwise
standard reaction conditions gas formation (CO) was observed;
however, for all substrates significantly lower product yields
were obtained, probably due to the lower gas pressure. To
understand the interaction of the optimal catalyst with formic
acid in more detail, we investigated the carbonylation reactions
of 3-methyl benzyl chloride (1a), benzyl chloride (1b), benzyl
bromide (1b´) and 4-methoxybromobenzene (3a) with HCOOD
and DCOOH instead of HCOOH (Figure 4). In general, the
yields of corresponding arylacetic or benzoic acids decreased in
the order HCOOH > HCOOD >> DCOOH. More specifically, in
the presence of HCOOD 1a could still be converted to D-2a in
good yield (63%). In contrast, with DCOOH the product yield
dropped to 30% under identical reaction conditions. For the less-
reactive benzyl chloride (1b), the difference between HCOOD
and DCOOH was even more pronounced. Similar reactivity was
seen in the carbonylation reactions of 1b’ and 3a.
Scheme 3. Pd-catalyzed carbonylation of aryl bromides with formic acid.
Reaction conditions: aryl bromide (1 mmol), formic acid (0.5 mL, 13 mmol),
Pd(OAc)2 (0.005 mmol), L1 (0.02 mmol), TMEDA (0.25 mmol), in DMF (1.5
mL) at 115 oC for 24 h. Isolated yield.
Despite significant developments in the past decades,[20]
carbonylation of non-activated aryl chlorides is still difficult
compared to aryl iodides and bromides. Owing to the stronger
C(sp2)-Cl bond, generally higher temperature, CO pressure
and/or base are necessary for this transformation.
93%
HCOOH HCOOD DCOOH
100%
80%
60%
40%
20%
0%
84%
81%
73%
72%
63%
50%
40%
35%
30%
18%
9%
Scheme 4. Pd-catalyzed carbonylation of selected aryl chlorides with formic
acid. Reaction conditions: aryl chloride (1 mmol), formic acid (0.5 mL, 13
mmol), Pd(OAc)2 (0.03 mmol), L1 (0.12 mmol), TMEDA (0.25 mmol), in DMF
(1.5 mL) at 130 oC for 24 h. Isolated yield.
2a
X=Cl, 2b
X=Br, 2b
4a
Figure 4. Pd-catalyzed carbonylation of benzyl and aryl halides with
deuterated formic acid (HCOOD and DCOOH). General reaction conditions for
carbonylation of 1a, 1b and 1b’: substrate (1 mmol), HCOOD or DCOOH (0.5
mL), Pd(OAc)2 (0.005 mmol), L1 (0.02 mmol), TMEDA (1 mmol) in DMF (1.5
mL) at 115 oC for 24 h. Isolated yields. General reaction conditions for
carbonylation of 3a: 3a (1 mmol), HCOOD or DCOOH (0.5 mL), Pd(OAc)2
(0.005 mmol), L1 (0.02 mmol), TMEDA (0.25 mmol) in DMF (1.5 mL) at 115 oC
for 24 h. Isolated yields.
Nevertheless, the new carbonylation protocol is applicable
for various aryl chlorides (Scheme 4, Table S2). Using 3f as
model substrate, to our delight the desired product 4f was
obtained in 70% yield under the optimized conditions (3 mol%
Pd(OAc)2, 12 mol% L1, 0.25 equivalent TMEDA, in DMF at 130
oC for 24 h). Other substrates with -CN, -C(O)CH3, -F
substituents ) gave the corresponding products in 23-60% yield.
These observations demonstrate the importance of the
activation of the C-H/D bond in formic acid for the generation of
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10.1002/anie.201802384
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COMMUNICATION
CO and thus the overall carbonylation process. We observe
generation of carbon monoxide from D-CO2H is more difficult
compared to H-CO2D and HCO2H. Indeed, the results of the
Pd(OAc)2/L1 catalyzed decomposition of HCOOH, HCOOD and
DCOOH (Figure 5) are in accordance with carbonylation results.
Hence, CO formation from HCOOH showed the highest rate and
selectivity. Thus, using 13 mmol formic acid after 24 h the gas
pressure reached 10.9 bar with a ratio of CO:CO2 = 3.5:1. For
HCOOD, the decomposition rate was slower than HCOOH,
while the selectivity to generate CO was much inferior (CO:CO2
= 1:1.5). Finally, CO generation from DCOOH under the same
conditions showed the lowest rate and selectivity (CO:CO2
1:3). This selectivity change is rather surprising.
=
12
CO:CO2 = 3.5:1
10
CO:CO2 = 1:1.5
8
Scheme 5. Possible catalytic cycle for Pd-catalyzed carbonylation of benzyl
6
CO:CO2 = 1:3
and aryl halides with formic acid.
4
2
Acknowledgements
HCOOH
10
HCOOD
15
DCOOH
20
0
We are grateful for the financial support from Sino-German
(CSC-DAAD) Postdoc Scholarship Program (57251553). We
also thank the analytical department in Leibniz-Institute for
Catalysis at University of Rostock (LIKAT) for their excellent
technical and analytical support.
0
5
25
Time/h
Figure 5. Pd(OAc)2/L1-catalyzed decomposition of HCOOH, HCOOD and
DCOOH.
[10b], [17]
Keywords: biphosphine
• formic acid • activator free •
Based on the accepted mechanism
for C-X
carbonylations and the shown labeling experiments, a catalytic
cycle is proposed. Notably, in our process the Pd/L1 catalyst
has a dual function: It allows for the decomposition of formic acid
and activates the C(sp3)-X bond of the substrate. As shown in
Scheme 5, generation of CO from formic acid is promoted by
O-H hydrogen bonding to the nitrogen of the pyridine ligand
(intermediate A). This facilitates the activation of the C-H bond
of formic acid, and the in-situ-generated CO subsequently
inserts into the C-Pd bond of B forming intermediate C. In the
presence of an excess of formic acid, intermediate D will be
likely formed followed by reductive elimination. Finally, the acid
anhydride E forms aryl acetic acid by hydrolysis or release of
carbonylation of 1-chloromethyl benzene • Synthesis of medicine
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In summary, we developed an effective protocol to
synthesize the arylacetic as well as aryl acids via Pd-catalyzed
carbonlyation of arylethyl and aryl halides. Formic acid was
added as the CO-surrogate, which generated CO in-situ under
an “activator-free” condition. This methodology shows good
application scope, which even could be used for carbonlyation of
aryl chlorides. Furthermore, several supporting experiments
were explored. According to these data, a possible mechanism
was proposed.
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Entry for the Table of Contents
Layout 1:
COMMUNICATION
Lin
Wang,
Helfried
Neumann, Matthias Beller*
From HCOOH to arylacetic
and benzoic Acids. The first
“activator-free” carbonylation
reactions of benzylic and aryl
halides with plain formic acid
is reported. The activation of
the C-H bond in formic acid
is important for the overall
carbonylation process.
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