Late-Stage Functionalization of Arylacetic Acids by Photoredox-Catalyzed Decarboxylative Carbon–Heteroatom Bond Formation

Article abstract of DOI:10.1002/chem.201802143

The rapid transformation of pharmaceuticals and agrochemicals enables access to unexplored chemical space and thus has accelerated the discovery of novel bioactive molecules. Because arylacetic acids are regarded as key structures in bioactive compounds, new transformations of these structures could contribute to drug/agrochemical discovery and chemical biology. This work reports carbon–nitrogen and carbon–oxygen bond formation through the photoredox-catalyzed decarboxylation of arylacetic acids. The reaction shows good functional group compatibility without pre-activation of the nitrogen- or oxygen-based coupling partners. Under similar reaction conditions, carbon–chlorine bond formation was also feasible. This efficient derivatization of arylacetic acids makes it possible to synthesize pharmaceutical analogues and bioconjugates of pharmaceuticals and natural products.

Full text of DOI:10.1002/chem.201802143

A Journal of
Accepted Article
Title: Late-Stage Functionalization of Arylacetic Acids by Photoredox-
Catalyzed Decarboxylative Carbon-Heteroatom Bond Formation
Authors: Yota Sakakibara, Eri Ito, Tomohiro Fukushima, Kei Murakami,
and Kenichiro Itami
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201802143
Link to VoR: http://dx.doi.org/10.1002/chem.201802143
Supported by

10.1002/chem.201802143
Chemistry - A European Journal
COMMUNICATION
Late-Stage Functionalization of Arylacetic Acids by Photoredox-
Catalyzed Decarboxylative Carbon–Heteroatom Bond Formation
Yota Sakakibara,[a] Eri Ito,[a] Tomohiro Fukushima,[a,b] Kei Murakami,*[a] and Kenichiro Itami*[a,b]
Abstract: The rapid transformation of pharmaceuticals and
agrochemicals enables access to unexplored chemical space and
thus has accelerated the discovery of novel bioactive molecules.
Since arylacetic acids have been regarded as privileged structures in
bioactive compounds, new transformations of these structures would
contribute to drug/agrochemical discovery and chemical biology.
Herein, we report carbon–nitrogen and carbon–oxygen bond
formation through the photoredox-catalyzed decarboxylation of
arylacetic acids. The reaction shows good functional group
compatibility without pre-activation of the nitrogen- or oxygen-based
coupling partners. Under similar reaction conditions, carbon–chlorine
bond formation was also feasible. This efficient derivatization of
arylacetic acids allows us to synthesize pharmaceutical analogues
and bioconjugates of pharmaceuticals and natural products.
decarboxylation.[7] Recent developments on photoredox-
catalyzed reactions allow for the generation of radicals from
carboxylic acids through single electron oxidation of
carboxylates.[8,9] Generally, the thus-generated carbon radicals
are nucleophilic and easily react with a variety of electrophilic
heteroatoms or other radical acceptors.[10,11] Since nitrogen or
oxygen atoms are inherently electronegative, additional steps to
activate nitrogen or oxygen into radical acceptors are
required.[12] In order to pursue streamlined chemical syntheses,
a
direct decarboxylative coupling of carboxylic acids with
unactivated nitrogen or oxygen is highly sought after. In 2014,
Lei reported a photoredox-catalyzed decarboxylative amination
of α-keto acid.[13] Kiyokawa and Minakata reported Ritter-type
decarboxylative amination with acetonitrile in the presence of
PhI(OAc)2 and I2 as the oxidants under fluorescent lamp
irradiation.[14] Quite recently, Fu, Hu and MacMillan reported
The late-stage functionalization of pharmaceutical and
agrochemical molecules has been regarded as a promising way
to accelerate the discovery of new bioactive compounds.[1] Such
rapid and straightforward transformations allows for the
generation of a new family of potential bioactive molecules from
pharmaceutical molecules to access unexplored regions of
chemical space. Analogues of pharmaceuticals differ in structure
from the original molecule, but they generally meet criteria for
bioactive molecules, such as Lipinski’s rule.[2] Therefore, these
analogues would have potential to control different life
phenomenon to express novel bioactivity. A recent study has
revealed that analogues of pharmaceutical compounds can be
used for other biological applications. For example, we have
novel
copper/photoredox
co-catalyzed
decarboxylative
aminations of carboxylic acids.[15]
During our study on photoredox-catalyzed carbon–nitrogen
(C–N) bond formation,[16] we discovered that our photocatalytic
systems could be applicable to the decarboxylative
functionalization of arylacetic acids (Figure 1B).[17] Herein, we
report C–N and C–O bond formation through photoredox-
catalyzed decarboxylation of arylacetic acids. The reaction
shows good functional group compatibility without pre-activation
of the nitrogen- or oxygen-based coupling partner. Furthermore,
our oxidative conditions were applicable for decarboxylative
chlorination using tetrabutylammonium chloride as a safe and
easy-to-handle Cl– source.[9g,10c]
shown that analogues of Celecoxib,
a non-steroidal anti-
inflammatory drug, were found to enhance stomatal
development in plants (Figure 1A) even though higher plants do
not possess orthologs of the originally target gene in human.[3]
Since arylacetic acids have been regarded as privileged
structures in pharmaceuticals and agrochemicals (Figure 1B),
we envisioned that transforming the carboxyl group into other
functionalities would allow for the synthesis of various analogues
that would contribute drug/agrochemical discovery and chemical
biology.[4]
A. Discovery of new bioactive molecule from established pharmaceutical
F3C
F3C
N
N
N
N
O
O
MeO
S
S
NH2
Me
O
O
Celecoxib
non-steroidal anti-inflammatory drug
ZA144
stomatal development enhancing molecule
B. Pharmaceauticals containing arylacetic acid scaffolds
MeO
Cl
NH
OH
X
Carboxylic acid moieties have long been utilized as a handle
Ar
O
Cl
OH
N
Me
to
construct
chemical
bonds
through
the
and
Curtius
Barton
Cl
O
New bioactivity?
O
Indomethacin
rearrangement,[5]
Hunsdiecker
reaction,[6]
Diclofenac
C. This work
Ru photoredox catalyst
Oxidant
OH
Het
+
H–Het
Ar
Ar
[a]
[b]
Y. Sakakibara, E. Ito, Dr. T. Fukushima, Prof. Dr. K. Murakami, Prof.
Dr. K. Itami
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate
School of Science, Nagoya University, Chikusa, Nagoya 464-8602,
Japan.
E-mail: murakami@chem.nagoya-u.ac.jp, itami@chem.nagoya-
u.ac.jp
Dr. T. Fukushima, Prof. Dr. K. Itami
O
Blue light irradiation
[Applicable reagent]
SO2R1
O
CF3
O
H
H
N
H
P
Bu4N+Cl–
O
CF3
H
OEt
OEt
SO2R2
O
O
• Good functional group compatibility
• No pre-activation of heteroatoms
• Imide, carboxylate, phosphonate, alkoxide, or chloride are installable
Figure 1. (A) An example of the discovery of new bioactive molecule from
established pharmaceuticals. (B) Pharmaceuticals containing arylacetic acid
scaffolds. (C) This work.
JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University,
Chikusa, Nagoya 464-8602, Japan
Supporting information for this article is given via a link at the end of
the document.
We launched our study from the reaction of biphenylylacetic
acid (1a: felbinac, an anti-inflammatory drug) with HN(SO2Ph)2
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10.1002/chem.201802143
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COMMUNICATION
(2a) (Figure 2). The use of [Ru(bpy)3]Cl2·6H2O (catalyst) and
potential. Not only benzeneacetic acids but also other arylacetic
acids (naphthalene, indole, and thiophene) gave products 3l–n.
Notably, no aromatic C–H imidation products were observed.
Although a methyl group at the benzylic position did not retard
hypervalent
iodine-based
oxidant
1-butoxy-1λ3-
benzo[d][1,2]iodaoxol-3(1H)-one (IBB) under blue light
irradiation proved to be particularly effective, affording the
corresponding decarboxylative imidation product 3a in 87% yield. the reaction (3o), the introduction of a bulkier phenyl group
Notably, both the catalyst and light are critically important for the
reaction to proceed. Although hypervalent iodine PhI(OAc)2, an
analog of IBB, gave 3a in good yield, other organic and
inorganic oxidants were not effective in this transformation.
Moreover, no C–H imidation products were observed.[16]
completely suppressed the reaction (3p).
OnBu
I
O
Ar
O
O
O
IBB
I
OH
O
[Ru(bpy)3]Cl2·6H2O
IBB
HN(SO2Ph)2 (2a)
Ar
O
nBuO–
O
SO2Ph
OH
1
N
A
B
SO2Ph
3a 87%
OnBu
CH2Cl2
40 °C, 24 h
blue LED light
O
Ph
RuII*
Ph
I
1a (Felbinac)
O
blue light
+
O
Ar
O
RuII
RuIIl
Validation of the necessity of catalyst and light
O
I
O
no blue LED light and [Ru(bpy)3]Cl2·6H2O (0%)
no blue LED light (0%)
C
O
no [Ru(bpy)3]Cl2·6H2O (0%)
– CO2
RO2S
SO2R
RO2S
SO2R
IBB
O
H+
+
N
N
H
O
O
O
E
AcO
I OAc
I+
–
2a
O–K+
PF6 NC
Cl
Cl
S
+K–O
O
S
SO2R
N
O
O
Ar
D
Ar
NC
SO2R
C–N bond formation
(K2S2O8)
trace
O
F
61%a
0%
0%
Figure 3. Possible mechanism of Ru-catalyzed decarboxylative imidation
under blue LED light.
Figure 2. Validation of the necessity of catalyst and light, and the effect of
oxidants.
SO2Ph
optimized
conditionsa
OH
N
A possible mechanism for the decarboxylative imidation is
shown in Figure 3, which is based on our previous study on C–H
imidation.[16] Firstly, carboxylic acid 1 reacts with IBB to give
activated intermediate A in situ (see the Supporting Information
(SI) for details). At the same time, the ruthenium catalyst is
activated by irradiation of blue light to give RuII*. Then A reacts
with RuII* to provide RuIII, radical B, and o-iodobenzoate.
Decarboxylation of B then occurs to give D. In parallel, RuIII
oxidizes imide 2a to provide imidyl radical E.[18] The resulting
proton might react with butoxide (n-BuO–) or 2-iodobenzoate (C).
Finally, a radical-radical coupling between D and E would
produce F. The precise mechanism is not clear at this stage and
other possible pathways from intermediate D might exist; for
example, single electron transfer between D and E to furnish an
ionic intermediate[19] that finally affords F. Judging from the
results that other electron-deficient oxygen nucleophiles
participate in the decarboxylative coupling (vide infra), this
reaction pathway is also possible. The existence of radical
+
2a
SO2Ph
O
4
5
25%
via
ring-opening
reaction
G
H
Scheme 1. Generation of benzyl radical under the conditions.
We then studied the scope of the imide substrate (Figure 4B).
Diarylsulfonimides bearing a methyl or bromo-group smoothly
afforded the corresponding products 6a–c in high yields (87%,
78%, and 87%). A diarylsulfonimide with electronically opposing
substituents (trifluoromethyl and methoxy) on either aryl ring
gave the product 6d in 64% yield. Not only aryl but also an alkyl-
substituted sulfonimide worked nicely to give 6e in 72% yield.
The reaction of a cyclic sulfonimide gave 6f in 45% yield.
Saccharin, a cyclic imide, furnished the corresponding product
6g in 51% yield, with concomitant formation of 6g' in 22% yield.
intermediate
D
was proved through the reaction of
cyclopropane-substituted arylacetic acid 4 as shown in Scheme
1. The reaction of 4 with 2a gave ring-opening product 5 in 25%
yield. This result clearly indicates intermediate G is generated
from 4 under the reaction conditions, which then opens the 3-
membered ring to afford H and eventually the imidated product 5.
Notably, nucleophiles other than imides are also applicable
in this decarboxylative reaction. For example, trifluoroacetic acid
and dibutylphosphonic acid coupled with 1a to give the
corresponding C–O coupling products 6h and 6i in 53% and
63%, respectively (Figure 4C). The reaction of 1a with 2,2,2-
trifluoroethanol afforded 6j in 50% yield. Interestingly, the
addition of sulfonimide 2a accelerated the reaction as only 29%
of 6j was obtained without a catalytic amount of 2a. Notably,
tetrabutylammonium chloride can be used as a chloride source.
The reaction provided the corresponding benzylic chloride 6k in
With the optimal reaction conditions in hand, we performed
the decarboxylative imidation with a range of substrates (Figure
4A). Arylacetic acids having methyl, methoxy, or halogen (Cl, Br,
or I) substituents were converted smoothly to 3b–j in good to
high yields. The yield of 3k was low as the electron-withdrawing
group decreases the reactivity by increasing the oxidation
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10.1002/chem.201802143
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84% yield. Although thiols were not directly installable with this
reaction, a one-pot sequence of decarboxylative chlorination and
SN2 reaction of 1a with 4-tBuC6H4SH afforded 6l in 60% yield
(Figure 4D).
transformations could be applicable in the area of
pharmaceutical/agrochemical chemistry and chemical biology to
accelerate the development of new biological compounds and
tools as well as for affinity-probe-based identification of target
proteins.[20]
Our reaction can be applied to transformations of
pharmaceuticals
having
functionalized
arylacetic
acid
In summary, we have developed
a
decarboxylative
substructures (Figure 5). For example, the reaction of Diclofenac, functionalization of arylacetic acids via oxidative carbon–
which possesses a free N–H moiety, afforded the corresponding
product 7a in 59% yield. The reaction proceeded smoothly in a
gram-scale to give 7a in 1.02 g. Other pharmaceuticals such as
Indomethacin, Flurbiprofen, Ibuprofen, Zaltoprofen, and
Isoxepac were smoothly transformed into the corresponding
benzylamine derivatives (7b–f) in good to high yields. The
decarboxylative chlorination of Isoxepac also proceeded
smoothly to afford 7g in 82% yield. The resulting benzyl chloride
7g can be used as an intermediate to conjugate with other
bioactive molecules. SN2 reactions with bioactive molecules
such as Duloxetine, L-cysteine, vitamin E, and Celecoxib gave
the corresponding conjugates 8a–d in good yields (65%, 48%,
43%, and 62% yields, respectively). These overall
heteroatom bond formation through photoredox catalysis. This
method allows us to directly convert carboxylic acids into
nitrogen, oxygen, or chlorine functionalities. Given the
importance of arylacetic acids and the abundance of
nucleophiles that are available today, this fundamental reaction
will find significant utility in various fields to accelerate the
discovery of new functional molecules and tools.
Figure 4. Scope of the substrate. Optimized reaction conditions: 1 (2.0 equiv), 2 (0.20 mmol), [Ru(bpy)3]Cl2·6H2O (2.5 mol%), IBB (2.5 equiv), CH2Cl2 (4.0 mL)
a
b
c
d
40 °C, 24 h. Variation from optimized reaction conditions: 1 (5.0 equiv), IBB (3.0 equiv). 36 h. CF3CO2H (0.20 mmol), IBB (2.0 equiv). (nBuO)2PO(OH)
(0.20 mmol), IBB (2.0 equiv). 1a (0.20 mmol), CF3CH2OH (4.0 mL: solvent), IBB (2.0 equiv), HN(SO2Ph)2 (25 mol%). 1H NMR yield. Without addition of
e
f
HN(SO2Ph)2. Bu4N+Cl– (0.20 mmol), IBB (2.0 equiv), HN(SO2Ph)2 (25 mol%). Bu4N+Cl– (0.20 mmol), IBB (2.0 equiv), HN(SO2Ph)2 (25 mol%), then 4-tert-
g
h
butylbenzenethiol (1.0 equiv), NaH (10 equiv), DMF (4.0 mL), 2 h.
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COMMUNICATION
1.
2.
3.
D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D.
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[Ru(bpy)3]Cl2•6H2O
IBB
OH
Het
Ar
+
H–Het
2
C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv. Drug Del.
Rev. 1997, 23, 3–25.
Ar
O
CH2Cl2
40 °C, 24 h
7
Pharmaceuticals
Cl
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blue LED light
MeO
Me
4.
5.
6.
7.
SO2Ph
SO2Ph
N
N
E. F. V. Scriven, K. Turnbull Chem. Rev. 1988, 88, 298–368.
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Tetrahedron 2009, 65, 3563–3572.
NH
Cl
SO2Ph
SO2Ph
SO2Ph
Ph
N
N
Me
F
SO2Ph
Cl
O
7a 59% (1.02 g, 47%)a
from Diclofenac
7b 44%
from Indomethacin
7c 73%
from Flurbiprofen
8.
9.
a) J. Xuan, Z.-G. Zhang, W.-J. Xiao, Angew. Chem., Int. Ed. 2015, 54,
15632–15641; b) H. Huang, K. Jia, Y. Chen, ACS Catal. 2016, 6, 4983–
4988. c) Y. Jin, H. Fu, Asian J. Org. Chem. 2017, 6, 368 – 385.
Important reviews and examples on non-photoredox-catalyzed
decarboxylation: a) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev. 2017,
117, 8864–8907; b) J. D. Weaver, A. Recio, A. J. Grenning, J. A. Tunge,
Chem. Rev. 2011, 111, 1846–1913; c) N. Rodriguez, L. J. Goossen,
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4258–4263; h) G. J. P. Perry, J. M. Quibell, A. Panigrahi, I. Larrosa, J.
Am. Chem. Soc. 2017, 139, 11527–11536.
O
Me
O
Me
SO2Ph
SO2Ph
X
N
N
SO2Ph
SO2Ph
S
O
Me
Me
7d 54%
from Ibuprofen
7e 61%
from Zaltoprofen
7f (X = N(SO2Ph)2) 75%
7g (X = Cl) 82%b
from Isoxepac
Further derivatization: 7g + Nucleophile (Nu)c
O
O
O
O
S
N
S
O
CH3
10.
a) S. Ventre, F. R. Petronijevic, D. W. C. MacMillan, J. Am. Chem. Soc.
2015, 137, 5654–5657; b) L. Candish, E. A. Stamdlay, A. Gómez-
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2016, 22, 4753–4756; d) F. L. Vaillant, M. D. Wodrich, J. Waser, Chem.
Sci. 2016, 8, 1790–1800.
NH2
O
O
8a 65%
(Nu = Duloxetine•HCl)
8b 48%
(Nu = L-Cysteine ethyl ester•HCl)
F3C
N
11.
12.
Representative examples of metallaphotoredox-catalyzed coupling with
organohalides: a) L. Fan, J. Jia, H. Hou, Q. Lefebvre, M. Rueping,
Chem. Eur. J. 2016, 22, 16437–16440; b) J. Luo, J. Zhang, ACS Catal.
2016, 6, 873–877; c) C. P. Johnston, R. T. Smith, S. Allmendinger, D.
W. C. MacMillan, Nature 2016, 536, 322–325.
N
O
CH3
O
O
O
O2S
O
O
N
O
a) S. B. Lang, K. C. Cartwright, R. S. Welter, T. M. Locascio, J. A.
Tunge, Eur. J. Org. Chem. 2016, 3331–3334; b) S. Inuki, K. Sato, Y.
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Int. Ed. 2014, 53, 502–506.
O
8c 43%
(Nu = Vitamin E)
8d 62%d
(Nu = Celecoxib)
13.
14.
15.
Figure 5. Transformation of pharmaceuticals. Optimized reaction conditions: 1
(2.0 equiv), 2 (0.20 mmol), [Ru(bpy)3]Cl2·6H2O (2.5 mol%), IBB (2.5 equiv),
a
K. Kiyokawa, T. Watanabe, L. Fra, T. Kojima, S. Minakata, J. Org.
Chem. 2017, 82, 11711–11720.
CH2Cl2 (4.0 mL) 40 °C, 24 h.
Diclofenac (2.0 equiv), 2a (4.0 mmol),
[Ru(bpy)3]Cl2·6H2O (2.5 mol%), IBB (2.5 equiv), CH2Cl2 (80 mL) 40 °C, 72 h. b
Isoxepac (2.0 equiv), Bu4N+Cl– (0.20 mmol), IBB (2.0 equiv), HN(SO2Ph)2 (25
mol%), [Ru(bpy)3]Cl2·6H2O (2.5 mol%), CH2Cl2 (4.0 mL) 40 °C, 24 h. c Nu (1.0
equiv), NaH (2.0 equiv), DMF (0.50 mL), 80 °C, 2 h. d Nu (0.50 equiv).
a) W. Zhao, R. P. Wurz, J. C. Peters, G. C. Fu, J. Am. Chem. Soc.
2017, 139, 12153–12156; b) R. Mao, A. Frey, J. Balon, X. Hu, Nat.
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Acknowledgments
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This work was supported by the ERATO program from JST
(JPMJER1302 to K.I.), JSPS KAKENHI Grant Number
JP17H04868 (K.M.), and the Uehara Memorial Foundation
(K.M.). ITbM is supported by the World Premier International
Research Center Initiative (WPI), Japan. We thank Dr.
Shunsuke Oishi for fruitful discussions and Dr. Gregory J. P.
Perry for proofreading.
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Keywords: decarboxylation • photoredox catalyst • imidation •
ruthenium catalyst • arylacetic acid
20.
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6998.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
OnBu
Yota Sakakibara, Eri Ito, Tomohiro
I
Fukushima, Kei Murakami,* Kenichiro
Itami*
O
Ru(bpy)3
OH
Het
O
Ar
+
H–Het
Ar
Page No. – Page No.
O
blue LED light
(Het = N, O, Cl)
Late-Stage Functionalization of
Arylacetic Acids by Photoredox-
Catalyzed Decarboxylative Carbon–
Heteroatom Bond Formation
Wide-scope decarboxylative C–heteroatom bond formation
Oxidative reaction with photoredox catalyst
Decarboxylative Functionalization: Carbon–nitrogen, carbon–oxygen, and
carbon–chlorine bond formation through photoredox-catalyzed decarboxylation of
arylacetic acids is reported. The reaction shows good functional group compatibility
without pre-activation of nitrogen- or oxygen-based coupling partner. This efficient
derivatization of arylacetic acids allows synthesizing pharmaceutical analogues and
bioconjugates of pharmaceuticals and natural products.
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