Chemoselective Catalytic α-Oxidation of Carboxylic Acids: Iron/Alkali Metal Cooperative Redox Active Catalysis

Article abstract of DOI:10.1021/jacs.0c00727

We developed a chemoselective catalytic activation of carboxylic acid for a 1e- radical process. α-Oxidation of a variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more acidic carbonyls. Extensive mechanistic studies revealed that the cooperative actions of iron species and alkali metal ions derived from 4 ? molecular sieves substantially facilitated the enolization. For the first time, catalytic enolization of unprotected carboxylic acid was achieved without external addition of stoichiometric amounts of Br?nsted base. The formed redox-active heterobimetallic enediolate efficiently coupled with free radical TEMPO, providing synthetically useful α-hydroxy and keto acid derivatives.

Full text of DOI:10.1021/jacs.0c00727

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Article
Chemoselective Catalytic #–Oxidation of Carboxylic Acids:
Iron/Alkali Metal Cooperative Redox Active Catalysis
Tsukushi Tanaka, Ryo Yazaki, and Takashi Ohshima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00727 • Publication Date (Web): 13 Feb 2020
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Chemoselective Catalytic –Oxidation of Carboxylic Acids:
Iron/Alkali Metal Cooperative Redox Active Catalysis
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Tsukushi Tanaka, Ryo Yazaki* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582 Japan
ABSTRACT: We developed a chemoselective catalytic activation of carboxylic acid for a 1e– radical process. –Oxidation of a
variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently
under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more
acidic carbonyls. Extensive mechanistic studies revealed that the cooperative actions of iron species and alkali metal ions derived
from 4Å molecular sieves substantially facilitated the enolization. For the first time, catalytic enolization of unprotected carboxylic
acid was achieved without external addition of stoichiometric amounts of Brønsted base. The formed redox-active heterobimetallic
enediolate efficiently coupled with free radical TEMPO, providing synthetically useful –hydroxy and keto acid derivatives.
with oxygen provides –hydroxy acid (Scheme 2-ii).21
Although non-functionalized carboxylic acids are converted
Introduction
Ubiquitous carboxylic acids are ideal carbonyl donors for the
synthesis of functionalized carboxylic acid derivatives.1
Enolate generation of carboxylic acids, enediolates, is quite
difficult, however, due to the intrinsic low acidity of –
protons. Moreover, the innate Brønsted acidic carboxylic acid
functionality disrupts the deprotonation of –protons.
Therefore, more than two equivalents of a strong base such as
LDA is required for efficient enolization (Scheme 1-i).2,3 For
carboxylic acid enolization under mild conditions, Evans et al.
achieved a direct aldol reaction of carboxylic acid using more
than two equivalents of boron triflate and base (Scheme 1-
ii).4,5 Catalytic activation of carboxylic acid was recently
reported by Kanai and Shimizu et al. (Scheme 1-iii).6
Although the method required only a catalytic amount of
borane, more than a stoichiometric amount of base was
employed. Furthermore, these mild enolization methods were
only applied to redox-neutral coupling using 2e– electrophiles
and catalytic –functionalization of carboxylic acids through a
1e– radical process, which could complement the
chemoselectivity, and functional group tolerance restricted in
the classical 2e– ion reaction, has never been achieved.7-9
into –hydroxy acids in high yields using this method,
aldehyde and benzoic acid derivatives concomitantly form
through dehydrative decarboxylation, resulting in moderate to
low chemical yield of –hydroxy acids, especially when using
–aryl carboxylic acids as the starting material. Furthermore,
carboxylates, such as alkali metal salts, readily undergo
decarboxylation to afford alkyl radical species under redox-
active conditions, as exemplified by transition-metal or
photoredox catalysis (Scheme 2-iii).22-24 Therefore, catalytic
activation of carboxylic acid under mild conditions and
subsequent –oxidation through a radical process remains a
particularly formidable task.
Scheme 1. Carboxylic Acid Activation Mode
Herein, we developed
carboxylic acid through
a
direct –functionalization of
a
redox-active heterobimetallic
enediolate generation strategy for a 1e– radical process
(Scheme 1-iv).
–Oxidation of carboxylic acids is a powerful process for
synthesizing the –hydroxy and keto acids present in
biologically active natural and non-natural compounds.10-18 In
the biochemical reaction, –oxidation of carboxylic acid (fatty
acid) with oxygen produces an –hydroperoxy acid
intermediate, which is preferentially converted into aldehyde
through dehydrative decarboxylation (Scheme 2-i).19,20 For
chemical synthesis, pre-activation of carboxylic acid by more
than two equivalents of strong base followed by treatment
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(i) Classical activation using strong base
used instead of Fe(OAc)2 (entries 4 and 5). Neither copper(I)
nor copper(II) catalysts were effective (entries 6 and 7).
Li
O
LDA
(>2.0 equiv)
O
1
2
3
4
5
6
7
8
O
X
R’
H
R’
Li
HO
HO
Without using any ligand, product 3aa was observed in 47%
yield (entry 8). Evaluation of 1,10-phenanthroline derivatives
revealed that electron-rich L5 exhibited the highest catalytic
performance, providing product 3aa in 96% yield (entries 9–
13). Bipyridine (L7 and L8) and DMAP (L9) ligand produced
better yields than the reaction without a ligand, but were not as
effective as L5 (entries 14–16). The reaction could be
performed under 5 mol% catalyst over a prolonged reaction
time, affording product 3aa in 95% yield (entry 17). No
desired product was observed without Fe(OAc)2 (entry 18).
Both the ligand and molecular sieves efficiently facilitated the
reaction (entries 19 and 20). Although the reaction proceeded
without 4Å molecular sieves at 100 °C to afford product 3aa in
75% yield, the aryl aldehyde was concomitantly generated
through decarboxylation, indicating that 4Å molecular sieves
were crucial for suppressing undesired decarboxylation under
mild reaction conditions (entry 21). In addition, no –
oxidation was observed under boron-catalyzed conditions,
highlighting the importance of the redox-active iron catalyst
(Supplementary information).
O
2e– reaction
R
R
R
Li-endiolate
(ii) Soft enolization strategy using stoichiometric amount of boran and base
O
nBu2BOTf
iPr2NEt
[B]
O
O
OH
R’
O
H
R’
H
[B]
HO
HO
O
2e– reaction
R
R
R
B-endiolate
(iii) Boran-catalyzed reaction using stoichiometric amount of base
9
BH3·SMe
(catalyst)
DBU
NPG
R’
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[B]
O
O
NHPG
R’
O
H
H
[B]
HO
HO
O
2e– reaction
R
R
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B-endiolate
(iv) This work: redox active heterobimetallic enediolate generation strategy
[M]
[Fe],[M]
(catalyst)
O
O
O
OR’
H
OR’
[Fe]
HO
HO
O
1e– reaction
M = Na, K
R
R
R
redox active
heterobimetallic
enediolate
Scheme 2. Decarboxylation of Carboxylic Acid
Table 1. Optimization Study
Results and Discussion
We focused on TEMPO, a commercially available free radical
compound, as an oxidation reagent. Lithium amide-mediated
–oxidation of carboxylic acid using TEMPO was previously
reported.25-28 Undesired dimerization of carboxylic acid was
inevitably observed, however, resulting in low chemical
yield.25 Because it is quite difficult to deprotonate a less acidic
–proton (RCH2COOH) over the highly acidic proton of
carboxylic acid (RCH2COOH), we began our investigation
with the addition of more than stoichiometric amounts of
carbonate salt as a Brønsted base and molecular sieves as a
desiccant (Details described in Supporting Information). To
our surprise, the use of a Fe(OAc)2/phenanthroline complex as
a redox-active catalyst led to considerable production of the
desired product 3aa without the Brønsted base.29,30 Molecular
sieves facilitated the reaction rate, providing product 3aa in
moderate yield (Table 1, entries 1-3). A survey of molecular
sieves revealed that 4Å molecular sieves were optimal. Poor
catalytic performance was observed when FeCl2 or FeCl3 was
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Yields were determined by 1H NMR analysis using 2-
however, cinnamaldehyde derivative 3a was observed as a
a
1
2
methoxynaphthalene as an internal standard. Isolated yield was
major product through –oxidation followed by
b
shown. The reaction was performed at 100 °C using 1,4-dioxane
decarboxylation/dehydrogenation sequence.31
instead of THF.
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We next investigated the chemoselective nature of the
present iron catalysis (Scheme 4). When the reaction was
performed in the presence of –aryl ketone 4a, product 3aa
was observed in 43% yield with the concomitant formation of
product 5aa (Scheme 4-i). In contrast, 3aa was exclusively
formed in the presence of alkyl ketone 4b (Scheme 4-ii). It
is noteworthy that chemoselective –oxidation of carboxylic
acid was achieved even in the presence of highly reactive
diethyl malonate (4c) (Scheme 4-iii). Furthermore, neither
ester 4d nor amide 4e had any detrimental effects, and the
product 3aa was exclusively formed with the quantitative
recovery of 4d and 4e, indicating that the present catalysis
could chemoselectively activate protecting group-free
carboxylic acid (Scheme 4-iv, v).
With the optimized conditions in hand, we next explored
the substrate scope of the catalytic direct α–oxidation of
carboxylic acid (Table 2). The present catalysis could be run
on a gram scale with 1 mol% catalyst and the corresponding
–oxidized carboxylic acid 3aa was isolated in 97% yield.
Esterification upon treatment with TMSCHN2 and MeOH after
the catalysis delivered the methyl ester product in 85% yield.
A variety of substituents on the aromatic ring, e.g., methyl,
halogen, phenyl, methoxy, acetoxy, trifluoromethyl, and
sulfonyl functionalities, had no detrimental effects (Me-3ba–
Me-3pa). Under the present iron-catalyzed conditions the
desired Me-3ia was obtained in 81% yield, although under
LDA activation conditions, lithium-halogen exchange of aryl
iodide 1i predominantly proceeded. Highly congested ortho-
substituted substrates provided the products in high yield when
the amounts of the catalyst and TEMPO (Me-3ca, Me-3fa,
Me-3za) were increased. When 2-(4-acetoxyphenyl)acetic
acid 1m-Ac was used as a substrate, deacylated product Me-
3ma was isolated after esterification using MeOH.
Chemoselective –oxidation was achieved over a thioether
functionality (Me-3qa). A Boc-protected substrate bearing
relatively acidic aniline N–H survived under the optimized
conditions (Me-3ra). The cyano-substituted substrate afforded
the product in moderate yield, presumably with competitive
coordination ability (Me-3sa). Both electron-rich substrates,
which preferentially undergo decarboxylation under classical
–oxidation reactions, and deficient di-substituted substrates
could be used, and the products were isolated in high yield
(Me-3ta–Me-3va). Readily oxidized protecting group-free
benzylic hydroxy groups survived, suggesting that an oxonium
cation intermediate, which is generally assumed to be
generated in classical TEMPO oxidation, was not generated
(Me-3wa). Notably, substrates bearing extremely reactive
benzyl bromide were applicable to the present catalysis,
although the yield was moderate (Me-3xa). Naphthyl
functionalities afforded the products in high yields (Me-3ya).
3-Thienyl substrate provided the product in high yield,
although 2-thienyl substrate exhibited low reactivity,
presumably due to undesired coordination to the catalyst (Me-
3a, Me-3a). Late-stage –oxidation of unmodified
pharmaceuticals, such as isoxepac, diclofenac, and
indomethacin, efficiently confirmed the usefulness of the
present catalysis (Me-3a–Me-3a, 3a). We further
investigated the substrate scope using functionalized TEMPO
derivatives. No detrimental effects were observed using
TEMPO derivatives bearing a hydroxy group and terminal
alkyne, which could be further elaborated (Me-3yb, Me-3yc).
4-Acetoamide TEMPO was also applicable and the product
was isolated in 62% yield (Me-3yd). When –unsaturated
carboxylic acid was used, –unsaturated –oxidized product
Me-3a was selectively obtained in 58% yield. This product
could serve as a versatile starting material due to the potential
for further elaboration of the ,–unsaturated functionality.
On the other hand, –unsaturated carboxylic acid was not
applicable under optimized reaction conditions (not shown).
Although aliphatic carboxylic acid 1 was found to be inert
under optimized conditions, activation of 1 was achieved
under heated conditions (160 °C) (Scheme 3). In this case,
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The usefulness of the present catalysis was demonstrated
by further elaboration of the product (Scheme 5).25,32 Direct
esterification was achieved under conventional condensation
conditions. Treatment of Zn dust provided the –hydroxy
ester 7 in 97% yield. Oxidation upon treatment of m-CPBA
provided –keto ester 8 in 98% yield. Peptide coupling
followed by reductive N–O bond cleavage produced the –
hydroxy amide 10 in high yield, and treatment of m-CPBA
afforded –keto amide 11 in high yield.
Scheme 3. Aliphatic Carboxylic Acid under Heated
Conditions
Scheme 4. Chemoselective Activation of Carboxylic Acids
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Table 2. Substrate Scope
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b
aIsolated as carboxylic acid. 1 mol% of Fe(OAc)2 and L5 were used for 72 h. 1.19 g of the product 3aa was isolated as carboxylic acid.
c4.0 equiv of TEMPO 2a, and 10 mol% of Fe(OAc)2 and L5 were used. d2-(4-acetoxyphenyl)acetic acid (1m-Ac) was used as a substrate.
e4.0 equiv of TEMPO 2a, and 20 mol% of Fe(OAc)2 and L5 were used. fYield was determined by 1H NMR analysis using dibenzyl as an
internal standard. g2.1 equiv of corresponding TEMPO derivatives (2b–2d), and 10 mol% of Fe(OAc)2 and L5 were used. hYield based on
recovered esterified starting material (Me-1y) was shown.
We next performed mechanistic studies to obtain insight
into the detailed reaction mechanism (Scheme 6). When 1.0
Scheme 5. Transformation of the Products
equivalent of TEMPO was used, product 3aa was observed in
73% yield, while 1.4 equivalent of TEMPO produced product
3aa in 90% yield (Scheme 6-i). We detected
tetramethylpiperidine after performing the reaction on a large
scale. These results clearly indicated that TEMPO served as an
oxidant to generate iron(III) species; one TEMPO molecule
could receive three electrons and three protons, generating
water and tetramethylpiperidine (Scheme 6-ii).31 In this case,
product 3aa can theoretically be generated in up to 75% yield
with 1.0 equivalent of TEMPO. We also performed the
reaction under oxygen atmosphere to reduce the amount of
TEMPO required, but decarboxylation predominantly
proceeded.
The initial-rate kinetic studies of the reaction of 1a and 2a
were performed (Scheme 7). Negative order kinetic
dependency with respect to the carboxylic acid 1a was
observed, presumably due to the acidic proton of carboxylic
acid inhibiting the enolization step. The zeroth dependency on
TEMPO indicated that TEMPO would not be involved in the
turnover-limiting transition state. The reaction rate displayed
0.7th dependency on the catalyst, suggesting that an inactive
oligomeric species would exist in equilibrium with an active
monomeric species.33
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Scheme 6. Control Experiments in terms of TEMPO was enough for high yield (85% yield), although the reaction
1
was retarded (Scheme 10).
2
3
Scheme 8. Kinetic Isotope Effect (KIE) Studies under
Optimized Conditions.
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Scheme 7. Initial-rate Kinetic Study
A series of kinetic isotope effect (KIE) studies were performed
to gain mechanistic insight into the turnover-limiting step
(Scheme 8).34-36 When two parallel reactions were performed
under optimized conditions using 1a and 1a(d2), a relatively
large KIE (kH/kD = 2.01) was observed, indicating that
enolization of carboxylic acid makes a major contribution to
limiting the turnover (Scheme 8-i). In contrast, a smaller KIE
(kH/kD = 1.36) was observed in the absence of ligand L5,
indicating that L5 does not facilitate enolization; instead, L5
would facilitate the formation of an active monomeric species
from an inactive di- or multinuclear iron species (Scheme 8-ii)
(vide infra). We also confirmed that an iron(III) complex, –
oxo iron(III) acetate perchlorate, exhibited efficient catalytic
performance, indicating that an active monomeric species
would be generated from an iron(III) complex in the presence
of L5 (Scheme 8-iii)
Scheme 9. Effect of Alkali Metal Salts
We next performed mechanistic studies to elucidate the
role of 4Å molecular sieves. The initial reaction rate increased
when a large amount of 4Å molecular sieves was added,
suggesting that 4Å molecular sieves facilitate the turnover-
limiting enolization step (Supporting information). We
checked the effect of alkali metals, which are a component of
4Å molecular sieves (Scheme 9). Omission of 4Å molecular
sieves afforded product 3aa in low yield (entry 2). While the
addition of sodium trifluoromethanesulfonate as a cationic
sodium ion source did not increase the catalytic activity (entry
3), the addition of a catalytic amount of sodium acetate or
potassium acetate, which would be generated in situ from
carboxylic acid and 4Å molecular sieves, efficiently increased
the catalytic activity (entries 4 and 5). Calcium acetate as a
control alkaline earth metal salt did not facilitate the reaction
(entry 6).37 We confirmed the formation of sodium, potassium,
and calcium carboxylate by ICP-MS analysis (Supporting
information). Catalytic amount of sodium acetate (20 mol%)
Scheme 10. Catalytic Fe/Na Bimetallic Conditions
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Scheme 11. Effect of Sodium Ion for Enolization Using
1
2
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4
5
6
7
8
9
Iron(III) Complex
We further investigated the role of 4Å molecular sieves in
the enolization step using deuterated 1a(d2) (Scheme 11). In
these control experiments, readily available –oxo iron(III)
acetate perchlorate was used as an iron(III) species. Proton
1a(d2)
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exchange
of
deuterated
(ArCD2COOH→ArCHDCOOD) was observed in the presence
of 4Å molecular sieves (51% conversion). In sharp contrast,
proton exchange was scarcely observed when each component
was used alone. Furthermore, combined use of an iron(III)
catalyst with sodium acetate efficiently promoted the proton
exchange. These results clearly indicated that the enolization
of carboxylic acid was achieved by a bimetallic system
comprising iron(III) carboxylate and sodium or potassium
carboxylate.38
Scheme 12. Radical Clock Experiments
No homo-coupling product was observed in each
conditions. Furthermore substrate 1 having a terminal olefin
at the 5-exo position provided –oxidized product Me-3a
without the formation of cyclized product Me-3a’ (Scheme
12). The substrate 1 also provided the –oxidized product
Me-3a over Me-3a’, suggesting that the –radical species
following heterobimetallic enediolate formation would be
highly reactive and coupled with TEMPO rapidly.
Several experiments were performed to confirm whether
4Å molecular sieves serve as a sodium or potassium ion
1
source (Scheme 13). In the H NMR measurement of 1a and
the sodium salt of 1a (1a-Na), the chemical shifts of the –
protons were 3.537 ppm and 3.414 ppm, respectively (Scheme
13-i). A mixture of 1a and 1a-Na (1:1 ratio) exhibited a singlet
peak at 3.478 ppm (Scheme 13-ii). A premixed sample of 1a
with 4Å molecular sieves exhibited a 3.514 ppm chemical
shift, indicating that 4Å molecular sieves served as a sodium
(and potassium) ion source and provided carboxylate salt
(Scheme 13-iii). The formation of sodium and potassium
carboxylate was further confirmed by ICP-MS analysis
(Supporting information).39
On the basis of a series of mechanistic studies, we present
a plausible catalytic cycle in Figure 1. Iron(II)/L5 complex I
would first be oxidized by TEMPO, generating iron(III)
species II.40 Then, the carboxylate exchange would proceed to
afford the iron carboxylate III with the concomitant formation
of TEMPOH, which would act as an oxidant.31 The formed
iron carboxylate III would be in equilibrium with di- or
multinuclear iron species IV. The CSI-MS spectrum of an
CH3CN solution of Fe(OAc)2 , L5, and TEMPO (1:1:1 ratio)
exhibited series of signals at m/z 284.7821, assignable to
[Fe2L2(OH)3]3+(H2O)(TMP) (L
= L5, TMP = 2,2,6,6-
tetramethylpiperidine), and m/z 427.1717, assignable to
[Fe2L2(OH)3]2+(H2O)(TMP), indicating that iron(II) salt would
be oxidized by TEMPO to afford catalytically active iron(III)
species and dinuclear iron complex would be more stable
under CSI-MS conditions (see Supporting information in
detail).41 Ligand L5 would efficiently form mononuclear iron
carboxylate III. Deprotonative activation would be achieved
by alkali metal carboxylate to generate redox active iron/alkali
metal heterobimetallic enediolates V, whose formation was
supported by a series of experiments using deuterated 1a(d2)
(Scheme 11). Further cross coupling with TEMPO would
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proceed via highly reactive radical species VI, delivering the
examine the utility of the present heterobimetallic catalysis for
efficient enolization of carboxylic acid without
product with the regeneration of iron(II) species I.42
a
1
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5
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9
stoichiometric amount of Brønsted base are in progress in our
group.
1
Scheme 13. H-NMR Analysis of Carboxylic Acid and Its
Sodium Salt
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
yazaki@phar.kyushu-u.ac.jp
ohshima@phar.kyushu-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
O
This work was financially supported by JSPS KAKENHI
Grant Number JP15H05846 in Middle Molecular Strategy,
JP18H04263 in Precisely Designed Catalysts with
Customized Scaffolding, Grant-in-Aid for Scientific
Research (B) (#17H03972), Grant-in-Aid for Challenging
Research (Exploratory) (#19K22501) and Platform Project
for Supporting Drug Discovery and Life Science Research
(Basis for Supporting Innovative Drug Discovery and Life
Science Research (BINDS)) from AMED under Grant
OTMP
MO
Ln(RCOO)2FeII
R’
TEMPO
I
TEMPO
OM
Ln(RCOO)2FeII
[Fen]
resting state
Ln(RCOO)2FeIIIOTMP
O
R’
VI
IV
II
O
H
HO
R’
facilitation effect of ligand
Number JP19am0101091. T.T. thanks JSPS for
a
TEMPOH
2 H+, 2 e-
predoctoral fellowship. R.Y. thanks Qdai-jump Research
Program. We are grateful to Dr. Midori Watanabe at
Kyushu University for ICP-MS measurement, Prof.
Tatsuya Uchida and Dr. Takeshi Tanaka at Kyushu
University for CSI-MS analysis. Prof. Yusuke Sunada at
The University of Tokyo is gratefully acknowledged for
fruitful discussion.
OM
O
H
H2O
Ln(RCOO)2FeIII
O
Ln(RCOO)2FeIII
turnover-limiting
O
R’
R’
H
N
V
III
redox active
heterobimetallic
enediolate
RCOOH RCOOM
M = Na, K
Figure 1. Proposed Catalytic Cycle
In conclusion, we developed a chemoselective catalytic –
oxidation of carboxylic acid. The enolization of carboxylic
acid proceeded without external addition of stoichiometric
amounts of a Brønsted base. A variety of carboxylic acids,
including functionalized pharmaceuticals, could be oxidized
under optimized conditions. Functional groups sensitive to
oxidation conditions, such as primary benzylic alcohol and
thioether, could be applicable to the present catalysis because
a strong oxidant, an oxonium cation intermediate, was not
generated. Chemoselective enolization of carboxylic acid was
also achieved, even in the presence of more acidic carbonyls.
Extensive mechanistic studies revealed that the alkali metal
ions derived from 4Å molecular sieves efficiently facilitated
the turnover-limiting enolization step. To the best of our
knowledge, this is the first example of the generation of redox-
active heterobimetallic enediolates from unprotected
carboxylic acid under catalytic conditions. Studies to further
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