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Decarboxylative Hydroxylation of Benzoic Acids

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Abstract

Herein, we report the first decarboxylative hydroxylation to synthesize phenols from benzoic acids at 35°C via photoinduced ligand-to-metal charge transfer (LMCT)-enabled radical decarboxylative carbometalation. The aromatic decarboxylative hydroxylation is synthetically promising due to its mild conditions, broad substrate scope, and late-stage applications.
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Title: Decarboxylative Hydroxylation of Benzoic Acids
Authors: Wanqi Su, Peng xu, and Tobias Ritter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202108971
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Decarboxylative Hydroxylation of Benzoic Acids
Wanqi Su,[a] [b] Peng Xu,[a] and Tobias Ritter*[a]
[a] W. Su, Dr. P. Xu and Prof. Dr. T. Ritter
Max-Planck-Institut fr Kohlenforschung
Kaiser-Wilhelm Platz 1, 45470 Mlheim an der Ruhr, Germany
E-mail: ritter@mpi-muelheim.mpg.de
[b] W. Su
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we report the first decarboxylative hydroxylation to
synthesize phenols from benzoic acids at 35°C via photoinduced
ligand-to-metal charge transfer (LMCT)-enabled radical
decarboxylative carbometalation. The aromatic decarboxylative
hydroxylation is synthetically promising due to its mild conditions,
broad substrate scope, and late-stage applications.
Phenols are valuable building blocks in natural products,
pharmaceuticals, and functional materials and can be
synthesized from a variety of different aryl precursors, yet, not
directly from benzoic acids. Conventional polar or radical
decarboxylation have failed to provide a solution to phenol
synthesis. The high activation barrier for polar decarboxylation
often requires reaction temperatures of 140 °C or more and ortho-
substituents on the substrates.[1] The slow rate of conventional
radical aromatic decarboxylation about three orders of
magnitude slower than the rate of aliphatic counterparts[2,3]
results in undesirable side reactions that outcompete productive
decarboxylation. Consequently, there is currently no general
method available to access phenols directly from benzoic acids.[4]
Here, we report the first general protocol for decarboxylative
hydroxylation of benzoic acids. The phenol synthesis is enabled
by a radical decarboxylation through ligand to metal charge
transfer (LMCT) in copper carboxylates, which produces aryl
radicals for subsequent capture by copper followed by CO
reductive elimination from arylcopper(III). The decarboxylative
hydroxylation follows our recently introduced concept of radical
decarboxylative carbometalation via copper carboxylates.[5]
Independent of the mechanism, the method overcomes the
challenges associated with conventional decarboxylation of
benzoic acids,[6] enables a hitherto unknown transformation, and
can be applied for the late-stage functionalization.[7]
More than 99% of phenol production is based on the cumene
process, the radical oxidative cleavage of isopropylbenzene with
dioxygen to yield phenol and acetone.[8] More complex phenols
can be prepared by transition-metal catalyzed cross-coupling and
CH activation reactions. Common starting materials for such
state-of-the-art methods include aryl diazonium salts,[9] aryl
(pseudo)halides,[10] aryl sulfonium salts,[11] aryl boronic acids,[12]
aryl silanes,[13] and arenes themselves.[14] While benzoic acids are
abundant, stable, and available in large structural diversity from
commercial sources, direct access to phenols by cleavage of the
CC bond via decarboxylation and formation of the CO bond has
Figure 1. (A). No synthetic method available from benzoic acids to phenols. (B).
A general decarboxylative cross-coupling strategy enabled by radical
decarboxylative carbometalation. (C). Example of late-stage decarboxylative
hydroxylation of ataluren on 1 mmol scale.
been elusive (Figure 1A), because conventional decarboxylation
strategies lack the opportunity to combine both steps due to their
intrinsic reactivity profile. Decarboxylative CC and Cheteroatom
bond formation of benzoic acids have mostly been achieved by
transition-metal-mediated or -catalyzed thermal decarboxylative
carbometalation, to generate arylmetal intermediates for
reductive elimination with versatile coupling partners.[1] However,
the activation barriers (2430 kcal/mol)[15] require forcing reaction
conditions, as well as activating ortho-substitutents that can
decreased the barriers by 35 kcal/mol due to their destabilization
effect.[15] For example, decarboxylative etherification of simple
benzoic acids with activating ortho-substituents was achieved
with a Ag/Cu bimetallic catalyst combination at 145 °C with ortho
silicates as oxygen donors.[16] We are not aware of any other
general decarboxylative CO bond forming reaction of benzoic
acids. Radical decarboxylation can proceed much faster at
activation barriers of about 89 kcal/mol[2, 17] to afford synthetically
useful aryl radicals. Aliphatic acids activated through this pathway
have been used successfully for radical addition reactions,[18]
carbometalation,[19] and radical crossover[20]. However, even with
the low barrier for radical aromatic decarboxylation, other
reactions such as hydrogen atom abstraction (HAT) and back
electron transfer (BET) can be even faster[2] and result in
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Figure 2. (A). Decarboxylative CO bond formation of 4-fluorobenzoic acid. Reaction conditions: 4-fluorobenzoic acid (0.05 mmol, 1.0 equiv.), LiOH (4 equiv.),
[Cu(MeCN)4]BF4 (2.5 equiv.), Cu(OTf)2 (2.5 equiv.), MeCN (c = 25 mM), 16 h purple LEDs irradiation, 35 °C. (B). Reaction design. (C). Left: use of copper(I)
thiophene-2-carboxylate (CuTC) as nucleophile. Right: electron delocolization strengthens the CCOO· bond in the TC radical.
undesired reactivity. Radical decarboxylation of benzoic acids has
been successfully used to react with reactive radical acceptors
such as (hetero)arenes,[21] acrylates, or diboron species,[22] but
not to make CO bonds, even with prior activation to activated
esters.[23]
Because conventional decarboxylation strategies so far have
not been successful to address decarboxylative hydroxylation of
benzoic acids, we attempted to approach the problem with a new
concept using copper ligand-to-metal charge transfer (LMCT).
Our group reported a conceptually different decarboxylative
cross-coupling strategy of benzoic acids, which combined a low-
barrier radical decarboxylation process enabled by photoinduced
copper ligand-to-metal charge transfer (LMCT) with subsequent
carbometalation to afford putative arylcopper (III) complexes
(Figure 1B).[5, 24] The light-mediated LMCT from carboxylate to
copper enables radical formation, and the copper mitigates
undesired side reactions, and presumably captures the aryl
radical to form arylcopper(III) for fast reductive elimination. Based
on our findings in fluorination via copper LMCT,[5] we report here
the first practical synthesis of phenols from benzoic acids, through
irradiation of in situ formed copper carboxylates and subsequent
hydrolysis of the resulting aryl esters, as exemplified by
decarboxylative hydroxylation of ataluren, a drug for the treatment
of Duchenne muscular dystrophy, in 62% isolated yield on a 1
mmol scale (Figure 1C).
During the development of our decarboxylative fluorination of
benzoic acids,[5] we discovered a remarkably efficient
decarboxylative CO bond formation reaction when fluoride was
omitted. The aryl carboxylate functioned both as substrate and as
nucleophile to yield homo-coupled benzoic ester in near-
quantitative yield (Figure 2A). Yet, the theoretical yield of such
transformation is limited to 50% based on the limiting reagent, the
benzoic acid. To prevent the sacrificial use of half of the substrate,
we sought to identify an exogenous oxygen-based nucleophile
that is suitable for our strategy. Hydroxide, phenoxide, and
alkoxides shut down productive decarboxylation, possibly due to
outcompeting carboxylate for coordination to copper, which
precludes productive carboxylate to copper LMCT.[25] Aliphatic
carboxylates gave low oxydecarboxylation yields, presumably
because they undergo decarboxylation much faster than
benzoates. Aryl carboxylates performed superior in the CO bond
forming event to all other oxygen-based nucleophiles analyzed.
Assuming that both substrate and nucleophile aryl carboxylates
coordinate to copper, both would also undergo LMCT to generate
carboxyl radicals. A desirable scenario to overcome this
conundrum would be that the nucleophile carboxyl radical would
undergo decarboxylation at a rate slower than the substrate
carboxyl radical. Instead, the nucleophile carboxyl radical should
undergo fast back electron transfer (BET) or hydrogen atom
abstraction (HAT) to reform the acid that can act as nucleophile
(Figure 2B).
Decarboxylation of the electron-rich 4-methoxybenzoyloxyl
radical proceeds slower by about an order of magnitude than for
the electron-neutral benzoyloxyl radical, presumably due to
strengthening of the ArCOO· bond caused by the conjugation of
an appropriately positioned π donor on the arene.[2] Consistent
with this hypothesis, we identified thiophene-2-carboxylate (TC)
as the most promising coupling partner (Figure 2C). π Donation
by the sulfur atom should strengthen the CCOO· bond, which
would provide a sufficient rate difference in decarboxylation of the
two acids to achieve synthetically useful yields based on the
substrate. Purple LEDs irradiation of a mixture of 2a, CuTC, and
Cu(OTf)2 in MeCN resulted in clean conversion to ester 2b in 51%
yield, and an additional 20% of ester 2c, in which the substrate
functioned as both radical donor and nucleophile, corresponding
to a total of 91% mass conversion of 2a that is accounted for.
Hydrolysis was performed without isolation of the esters and
afforded 70% overall yield of phenol 2, together with 20% starting
material. No oxydecarboxylation product of TC was detected and
less than 10% of TC protodecarboxylation was observed,
consistent with our design. While other sources of TC also
provided product, copper(I) thiophene-2-carboxylate (CuTC)
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Table 1.Decarboxylative hydroxylation of benzoic acids.[a]
[a]Standard reaction conditions: 1. lithium carboxylate (0.20 mmol, 1.0 equiv.), CuTC (1.5 equiv.), Cu(OTf)2 (2.5 equiv.), MeCN (c = 25 mM), 16 h purple LEDs
irradiation, 35 °C; 2. 1 M LiOH (aq.), THF/MeOH (1:1, v/v, 55 mM), 40 °C. [b]Yields based on 19F NMR integration with internal standard 2-fluorotoluene (0.20 mmol,
1.0 equiv.). [c]Yields based on 1H NMR integration with an internal standard dibromomethane (0.20 mmol, 1.0 equiv.). [d]Reaction conditions: carboxylic acid (0.20
mmol, 1.0 equiv.), LiOH (4 equiv.), [Cu(MeCN)4]BF4 (2.5 equiv.), Cu(OTf)2 (2.5 equiv.), CD3CN (c = 50 mM), 16 h purple LEDs irradiation, 35 °C. [e]2. Aminolyisis:
nBuNH2 (2.0 mmol, 10 equiv.), benzene (0.10 M), 25 °C.
provided the best result as protodecarboxylation was suppressed
and conversion to ester 2b was increased. We speculate that the
advantage of CuTC can be explained by capture of the aryl radical
by CuTC species with subsequent oxidatiton by Cu(II) to generate
arylcopper(III)TC for CO reductive elimination. The process
deprotonation, decarboxylative oxygenation, and hydrolysis can
be carried out in the same pot but initial deprotonation of the
benzoic acids to form their lithium salts before addition of copper
generally afforded higher yields, consistent with the formation of
copper carboxylates for efficient LMCT. A low concentration (25
mM) was necessary to promote light transmission, due to the
heterogeneity of the reaction mixture.
Both electron-poor and electron-rich substrates, such as 4-
cyanobenzoate (3) and 3,5-dimethylbenzoate (13) can
outcompete TC to afford the corresponding phenols. Electron
neutral benzoates, which are often problematic for thermal
decarboxylation due to the lack of electronic bias,[16] or electron
deficient benzoates, which are often problematic for oxidative
radical decarboxylation due to their high oxidation potential,[21b,22]
performed well. Heteroaryl carboxylates, such as isonicotinic
carboxylates (6, 14) and quinoxaline-2-carboxylate (15), are also
compatible. Functional groups including aryl halides (2, 25, 27,
31), oxidation-sensitive aldehydes (10), enolizable ketones (18,
28), heterocycles (1, 6, 7, 14, 24), sulfonamides (16, 17, 19, 24),
amides (22), ether (12, 31) and nitriles (3, 8, 29) are well tolerated.
α-Heteroatom (9, 12, 16, 17, 22), benzylic (7, 11, 13, 16, 23, 28,
31) and tertiary (9, 23) C−H bonds that are sensitive to HAT
processes also did not pose a problem. Alkyl esters (9) are
tolerated due to the more facile cleavage of aryl esters.[26] The
synthetic utility was further demonstrated by decarboxylative
hydroxylation of several complex small molecules (1, 9, 17, 24,
31) at a late stage. In summary, substrates such as electron-
deficient to electron-rich benzoic acids with versatile functional
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0.00
0.10
0.20
0.30
0.40
0.50
370 470 570 670 770 870
Absorbance (A.U.)
Wavelength (nm)
Figure 3. (A). Proposed reaction mechanism. (B). UV-vis absorption spectra of reaction components (C). Radical cyclisation experiment. (D). Radical trapping
experiment. (E). UV-vis spectral changes observed upon photolysis of a mixture of 2a (1 mM), Cu(OTf)2 (2.5 mM) and CuTC (1.5 mM) in MeCN under purple
LEDs irradiation (046 min).
groups, (hetero)aryl carboxylic acids and several complex small
molecules were included. However, substrates such as benzoic
acids bearing large ortho-substituents and some heteroaryl
carboxylates, gave low yields. Strong coordinating or oxidizable
functional groups, such as phenols and amines are not tolerated.
The remaining mass balance consists mostly of the starting
material, e.g. the benzoic acid that either did not decarboxylate or
served as oxygen nucleophile.
We propose that irradiation of the copper(II) carboxylate results
in carboxylate to Cu(II) charge transfer (LMCT) (Figure 3A).[5]
Subsequent homolysis of the OCu(II) bond produces an
aroyloxyl radical which decarboxylates to afford aryl radical for
immediate capture by copper. While LMCT from Cu(II)TC
proceeds accordingly, TC is regenerated from TC radical by BET
or HAT. Both LMCT steps of the copper(II) carboxylates are
supported by the observation that a mixture of lithium 4-
fluorobenzoate (2a) and Cu(OTf)2, and a mixture of CuTC and
Cu(OTf)2 both show a significant absorbance at 370470 nm in
their UV-vis absorption spectra, which is ascribed to the LMCT
band of copper(II) carboxylates (Figure 3B).[27] The LMCT band
overlaps with the purple LED emission spectrum, consistent with
excitation of the copper(II) carboxylates under the reaction
conditions.[5] Generation of the aroyloxyl radical of the substrate
via LMCT is supported by formation of lactone 33 via 6-endo-trig
intramolecular radical cyclisation[21b](Figure 3C) and formation of
4-methoxybenzoate (36) via radical trapping with
benzene[5](Figure 4D). Decarboxylation of the aroyloxyl radical to
aryl radical is supported by isolation of 4-methoxy-1,1'-biphenyl
(35) from the same radical trapping experiment (Figure 3D).[5] The
generated aryl radical is trapped by a Cu(II)TC complex, or by
Cu(I)TC with subsequent oxidation by Cu(II) to afford an
arylcopper(III)TC in both cases for CO bond reductive
elimination. Copper assisted aryl radical capture[28] with
subsequent CO reductive elimination from arylcopper(III)
complex[29] to yield aryl TC ester[15] is a known process. Reduction
of Cu(II) to Cu(I) as the reaction progresses is supported by the
continuous decrease of the Cu(II)-based d-d transition band (550
nm900 nm)[27] in the UV-vis spectrum of the reaction mixture
upon irradiation (Figure 3E).[5,24]
Radical decarboxylative carbometalation enabled by LMCT in
copper benzoates provides the first decarboxylative hydroxylation
of benzoic acids at 35 °C, a temperature about 100 °C below
conventional decarboxylation of aryl carboxylic acids. Expansion
of LMCT-based decarboxylative carbometalation to enable CO
bond formation beyond the initially discovered CF bond
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formation establishes the utility and power of the new concept for
previously inaccessible decarboxylative functionalizations.
Acknowledgements
We thank Dr. Ruocheng Sang, Xiang Sun and Dr. Fabio Juliá
Hernandez for helpful discussions. We thank analytical
departments of the MPI für Kohlenforschung for characterization
of the compounds. We thank the MPI für Kohlenforschung for
funding.
Keywords: decarboxylation phenol synthesis ligand to metal
charge transfer
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Herein, the first decarboxylative hydroxylation reaction to synthesize phenols from benzoic acids is reported. The method overcomes
the challenges associated with conventional decarboxylation of benzoic acids and can be applied even for the late-stage
functionalization.
Institute and/or researcher Twitter usernames: @ritter_lab
10.1002/anie.202108971
Accepted Manuscript
Angewandte Chemie International Edition
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Article
We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.
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