Dual-Role Catalysis by Thiobenzoic Acid in Cα-H Arylation under Photoirradiation

Article abstract of DOI:10.1021/acscatal.0c04722

Thiobenzoic acid (TBA) can serve as a single-electron reducing agent under photoirradiation from a blue light-emitting diode, in the presence of appropriate electron acceptors, and the resulting sulfur-centered radical species undergoes hydrogen atom abstraction. This dual-role catalysis by TBA enables regioselectivie Cα-H arylation of benzylamines, benzyl alcohols, and ethers, as well as dihydroimidazoles, with cyano(hetero)arenes in good yield, without the need for a transition-metal photocatalyst and/or synthetically elaborated organic dyes.

Full text of DOI:10.1021/acscatal.0c04722

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Letter
Dual-Role Catalysis by Thiobenzoic Acid in Cα−H Arylation under
Photoirradiation
Fumihisa Kobayashi, Masashi Fujita, Takafumi Ide, Yuta Ito, Kenji Yamashita, Hiromichi Egami,
and Yoshitaka Hamashima*
Cite This: ACS Catal. 2021, 11, 82−87
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ABSTRACT: Thiobenzoic acid (TBA) can serve as a single-electron reducing agent
under photoirradiation from a blue light-emitting diode, in the presence of
appropriate electron acceptors, and the resulting sulfur-centered radical species
undergoes hydrogen atom abstraction. This dual-role catalysis by TBA enables
regioselectivie Cα−H arylation of benzylamines, benzyl alcohols, and ethers, as well as
dihydroimidazoles, with cyano(hetero)arenes in good yield, without the need for a
transition-metal photocatalyst and/or synthetically elaborated organic dyes.
KEYWORDS: Cα−H arylation, thiobenzoic acid, photocatalysis, organocatalysis, late-stage functionalization
irect C−H functionalization is an important class of
Dchemical transformations, because it can streamline the
synthetic routes to target molecular architectures in a highly
atom- and step-economical manner.1 Although transition-
metal catalysis has played a pivotal role in this regard,2
photoinduced radical reactions have also made a significant
contribution.3 Traditionally, photosensitizers, including benzo-
phenones4 and polyoxometalates,5 have long been employed
for C−H activation via single-electron transfer (SET) or
hydrogen-atom transfer (HAT) processes, but intensive
investigation is still continuing to develop more-efficient
photoexcited HAT catalysts (Scheme 1A, direct HAT
process).6 Since the pioneering work by MacMillan,7
tremendous efforts have been devoted to developing visible-
light photoredox catalysis8 for C−H functionalization chem-
istry. In particular, synergistic catalysis between photoredox
catalysts (PCs) and HAT catalysts is a powerful method9 for
the selective manipulation of C(sp3)−H bonds to enable
various transformations that are inaccessible via classical ionic
pathways. In these reactions, PCs are essential to generate a
heteroatom radical species via SET, and this species undergoes
a subsequent HAT event (Scheme 1A, indirect HAT process
1). However, such processes require the construction of well-
harmonized catalytic cycles to avoid complications. Thus, a
simple reaction setup, in which the oxidized PCs can also serve
as a HAT catalyst, is highly desirable for developing new
reactions.
Cα−H arylation of benzylamines with a synergistic catalyst
system consisting of Ir(ppy)3 and thiobenzoic acid (TBA, 1)
(Scheme 1B).11 In this reaction, Ir(ppy)3 serves as a SET
catalyst and TBA works as a hydrogen atom abstractor. Since
the conjugate base of TBA (TB−), which has a less-positive
anodic potential (Eopx = +0.8 V vs Ag/AgCl in DMA),11 is
readily converted to a sulfur-centered radical, the reduction of
in-situ-generated Ir(IV) species by amine substrate is
effectively blocked, and the inherent selectivity of SET catalysis
alone is outcompeted to achieve excellent N-benzyl selectivity.
During our further investigations with TBA, we were
inspired by recent reports in which the reducing ability of a
parent compound is enhanced via photoexcitation.12 Consid-
ering that sulfur-containing compounds are good substrates in
photochemical reactions,13 we considered that it might be
possible to perform the above benzylic Cα−H arylation
without the need for Ir-based PCs, if either TBA or TB− could
be excited photoelectronically. Provided that the excited state
of TBA or TB− serves as a one-electron reducing agent,14
a
sulfur radical species would be formed concomitantly and
might function as a HAT catalyst (Scheme 1C). Although the
Received: October 30, 2020
Revised: December 9, 2020
As part of our research program on C−H functionaliza-
tion,10 we recently reported regioselective and chemoselective
https://dx.doi.org/10.1021/acscatal.0c04722
© XXXX American Chemical Society
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Letter
Scheme 1. Representation of HAT Processes and
Regioselective Cα−H Arylations Mediated by TBA
Table 1. Optimization of the Reaction Conditions of Cα−H
a
Arylation with TBA
entry
deviation from the optimized conditions
yield of 4a (%)
c
1
2
3
4
5
6
7
8
9
LED lamp (365 nm)
LED lamp (425 nm)
none (standard conditions)
without TBA
without LED irradiation
thioacetic acid instead of TBA
thiophenol instead of TBA
methyl thioglycolate instead of TBA
without K3PO4
69 (15)
85 (15)
c
c
83 (7)
b
NR
b
NR
c
44 (17)
trace
c
22 (trace)
c
47 (25)
10
11
12
KOAc instead of K3PO4
K2HPO4 instead of K3PO4
CH2Cl2 instead of DMA
69
77
23
a
The reaction was performed with N,N-dimethylbenzylamine (2a)
(0.6 mmol), terephthalonitrile (0.2 mmol), TBA (20 mol %), and
K3PO4 (20 mol %) in DMA (1 mL) at room temperature under LED
b
irradiation (455 nm, 3 W), unless otherwise noted. No reaction.
c
The yield of 4a′ is given in parentheses.
experiments are indicative of the essential role of photo-
sensitized 1. Thus, the reaction did not proceed at all in the
absence of TBA (Table 1, entry 4). In addition, no reaction
occurred without photoirradiation (Table 1, entry 5).
Interestingly, thioacetic acid could promote the reaction, albeit
in a lower yield (Table 1, entry 6).20 Given the miserable
results with thiophenol (Table 1, entry 7) and methyl
thioglycolate (Table 1, entry 8), it appears that the presence
of a thiocarboxylate unit as a part of the chromophore is
essential to absorb blue light. Although the chemical yield was
only moderate, the reaction proceeded even in the absence of
K3PO4, probably because 2a could facilitate deprotonation of 1
(Table 1, entry 8). The use of other bases slightly decreased
the reaction efficiency, but 4a was obtained in good yields
(Table 1, entries 9 and 10). These results suggest that the
deprotonated form of 1 is more favorable for this trans-
formation. As was seen in our previous study,11 N,N-dimethyl
acetamide (DMA) was the solvent of choice (Table 1, entries
11 and 12).
Having established the optimized reaction conditions, we
investigated the generality of the C−H arylation of benzyl-
amine derivatives (Table 2A). A methyl group at the ortho
position had little influence on the reaction efficiency (4b and
4k), and the results were comparable to those seen in the case
of a para-methyl-substituted benzylamine (4c and 4l).
Regardless of the electronic nature, a methoxy group (4d
and 4m) and halogens (4e and 4n) were well-tolerated, and
substrates having heterocycles were successfully converted to
the desired coupling products (4f−4h, 4o, and 4r) in good
yield. Note that nonprotected secondary and primary amines
were available for this reaction (4i−4o), even though direct
C−H functionalization of nonprotected amines is still
rare.9j,p,11 Although synergistic catalysis with Ir(ppy)3
smoothly promoted the reaction with cyanopyridines, the
reaction catalyzed by TBA alone was found to be less efficient
than that with terephthalonitrile. Thus, the reaction of 2a with
reactivities of TBA and its O-ester were previously examined
under photoirradiation conditions,15,16 the putative dual-role
action of TBA has not been explored. Furthermore, to our
knowledge, this type of photocatalysis mode (Scheme 1A,
Indirect HAT process 2) has not been described in the
literature. Herein, we disclose this novel photocatalytic activity
of TBA and we describe its applications for regioselective Cα−
H arylation of benzylamines, benzyl alcohols and ethers, as well
as dihydroimidazoles (Scheme 1C).
To test our hypothesis, we focused on Cα−H arylation of
benzyl amines, considering the bond dissociation energy
(BDE) of 1 (PhC(O)S−H, 87.4 kcal/mol).11,17 Since TBA
potassium salt (TB−K+) showed its best absorption in the
range of 350−400 nm,18 we reinvestigated C−H arylation of
N,N-dimethylbenzylamine (2a) with terephthalonitirile (3) in
the presence of 20 mol % of 1 and K3PO4 in DMA under
irradiation at 365 nm with an LED light (Table 1, entry 1).
Although the reaction proceeded reluctantly, compared to that
under the previous reaction conditions (Scheme 1B), we were
delighted to find that the desired reaction occurred in 6 h to
give 4a in 69% yield, accompanied by the formation of a meso
diamine 4a′ in 15% yield. Further UV−vis spectroscopy
measurements revealed that a bathochromic shift occurred
when TB−K+ and the amine substrate 2a were mixed, and the
resulting mixture absorbed light in the range of 400−450 nm.19
Thus, when irradiated at either 425 or 455 nm, the reaction
gave the arylated product 4a in yields of 85% or 83%,
respectively (Table 1, entries 2 and 3). We chose the
wavelength of 455 nm for further studies, because of the
better product ratio (Table 1, entry 3). The following control
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a
Table 2. TBA-Catalyzed Cα−H Arylation under Photoirradiation
a
b
The reaction was performed with substrate (0.6 mmol) and acceptor (0.2 mmol) in DMA (1 mL) under LED irradiation (455 nm, 3 W). Run
c
for 12 h. The reaction was performed with substrate (0.4 mmol) and acceptor (0.2 mmol) in DMF (1 mL) under LED irradiation (425 nm, 3 W).
d
Compound 6a was converted to 7 quantitatively by oxidation with MnO2 in CH2Cl2.
cyanopyridine gave the coupling product 4p in 48% yield.
However, the use of a stoichiometric amount of TBA
potassium salt (TB−K+) furnished 4p in 90% yield. When
more reactive coupling partners are used, a catalytic amount of
TBA can promote the Cα−H heteroarylation without
difficulty. For example, the model substrate 2a and a tertiary
amine bearing a furyl group underwent the reaction with 3-
chloro-4-cyanopyridine under the standard catalytic conditions
to give the corresponding products 4q and 4r in yields of 67%
and 61%, respectively.
Notably, the amount of both TBA catalyst and the substrate
amine could be reduced. For example, the reaction of 2a with 3
in a 1:1 ratio could be performed on a 1 mmol scale in the
presence of 5 mol % of 1, affording the product 4a in 76% yield
(Scheme 2). Under the same reaction conditions, the reaction
proceeded in 52% yield, even with 1 mol % of the catalyst.
Since thiyl radicals are known to promote benzylic C−H
functionalization of alkyl benzyl ethers,9a,b we envisaged that
the present catalytic system would be applicable to benzyl
alcohols (Table 2B).19 As we had hoped, benzyl alcohol was
converted to the desired diphenylmethanol 5a in 74% yield.21
Although alcohol substrates were generally less reactive than
amine substrates, various benzyl alcohols could be used (5b−
Scheme 2. Cα−H Arylation with a Reduced Catalyst
Amount
5e). The hydroxyl group was not essential for the reaction to
proceed. Thus, benzyl methyl ether and dibenzyl ether
underwent the reaction without difficulty to give the
(hetero)arylated products (5f−5h) at synthetically useful
levels. Unlike the reaction with benzylamines, no reaction
occurred in the absence of the base.18 As discussed earlier, this
result further supports our idea that the anionic form of TBA is
more amenable to the SET process under photoirradiation.
Further investigation led to the discovery of a unique Cα−H
arylation of 2-substituted dihydroimidazoles (Table 2C).19
The reaction was conducted in DMF using a 425 nm blue LED
lamp, since this gave a better yield.18 The exact reaction site
has not yet been determined, because of the isomerization of
the amidine moiety,22 but the coupling products were obtained
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Letter
in good to high yield.23 As for substituents at the C2 position,
various groups were well-tolerated. Notably, not only
heteroaryl, but also alkyl-substituted compounds were
applicable, and the desired arylated products 6e−6h were
formed in reasonable yield. In some cases, further oxidation of
the product gave substituted imidazoles as byproducts, which
were useful in establishing the product structure. Simple
treatment of 6a with MnO2 gave the corresponding imidazole
7 quantitatively. This reaction sequence would provide an
alternative access to 2,4-disubstituted imidazoles.24
radical species B, together with a persistent radical anion C.
Then, the intermediate B abstracts the hydrogen atom of the
substrate regioselectively to generate a benzylic radical
intermediate D. Finally, the persistent radical effect would
enable cross-coupling between radicals C and D,25 affording
the arylated product with the liberation of the cyanide anion.
In summary, we have demonstrated a direct organocatalytic
Cα−H arylation of benzylamines, benzyl alcohols, and ethers,
as well as dihydroimidazoles, with cyanoarenes under blue light
irradiation from an LED. The present reaction does not require
an external photocatalyst. Instead, it exploits the unique
reactivity of the photoexcited TBA to act simultaneously as a
photoexcited one-electron reducing agent and a HAT catalyst.
To our knowledge, this is the first example of the photo-
excitation-triggered dual action of TBA. Since the reaction
could be performed under mild reaction conditionsand,
thus, various functional groups were well-toleratedthe
selective late-stage functionalization of clinically used medi-
cines was possible. In addition, all the materials required for
the present reaction are inexpensive, which is advantageous for
practical use. Although there is still room for improvement, in
terms of the catalytic activity and the substrate scope, the dual-
role catalysis demonstrated here would facilitate the further
design of multifunctional photocatalysts, which opens up the
possibility of creating new C−H functionalizations driven by
photonic energy. Further investigation is underway in our
laboratory.
To confirm the utility of our reaction, late-stage Cα−H
arylation of some medicinal drugs was examined (Scheme 3).
Scheme 3. Late-Stage Cα−H Arylation of Medicinal Drugs
Under the standard reaction conditions and even with reduced
substrate/acceptor ratios,18 amine-containing drugs were
coupled with cyano(hetero)arenes in a regioselective manner,
affording 8a−8c in isolated yields of up to 90%. In addition,
amidine-containing naphazoline was converted to the arylated
product 8d in 67% yield. These examples suggest that TBA-
catalyzed Cα-H functionalization is potentially applicable for
single-step derivatization of multifunctionalized molecules,
which should be especially useful for structure−activity
relationship studies.
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04722.
Experimental procedure and characterization data
(PDF)
Although the reaction mechanism remains to be elucidated
in detail, a putative reaction mechanism for the amine substrate
is outlined in Figure 1. No significant change of color or UV−
vis spectrum of the reaction mixture was observed when TBA
potassium salt and 3 were mixed. This suggests that the EDA
complex is not involved in the catalytic cycle. First, the
conjugate base of TBA is generated and excited by photo-
irradiation. Then, SET from photoexcited A to an electron-
deficient aromatic acceptor occurs to give a sulfur-centered
AUTHOR INFORMATION
■
Corresponding Author
Yoshitaka Hamashima − School of Pharmaceutical Sciences,
University of Shizuoka, Suruga-ku, Shizuoka 422-8526,
Japan; orcid.org/0000-0002-6509-8956;
Email: hamashima@u-shizuoka-ken.ac.jp
Authors
Fumihisa Kobayashi − School of Pharmaceutical Sciences,
University of Shizuoka, Suruga-ku, Shizuoka 422-8526,
Japan
Masashi Fujita − School of Pharmaceutical Sciences, University
of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
Takafumi Ide − School of Pharmaceutical Sciences, University
of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
Yuta Ito − School of Pharmaceutical Sciences, University of
Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
Kenji Yamashita − School of Pharmaceutical Sciences,
University of Shizuoka, Suruga-ku, Shizuoka 422-8526,
Japan
Hiromichi Egami − School of Pharmaceutical Sciences,
University of Shizuoka, Suruga-ku, Shizuoka 422-8526,
Japan; orcid.org/0000-0002-7784-4987
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04722
Figure 1. Proposed catalytic cycle.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the University of
Shizuoka and the Platform Project for Supporting Drug
Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research;
BINDS) from the Japan Agency for Medical Research and
Development (AMED), under Grant No. JP19am0101099.
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(18) See the Supporting Information.
(19) We assume that the bathochromic shift observed upon addition
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Information.
(20) The UV−vis absorption band of potassium thioacetate
exceeded more than 400 nm when mixing the amine substrate, the
spectrum of which is given in the Supporting Information. Therefore,
we surmise that the reaction with thioacetic acid would also proceed
in a similar fashion, as described in Figure 1.
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reaction to give the racemic and meso diols in yields of 10% and 12%,
respectively.
(22) Under the present reaction setting, N-methylated amidine
substrate gave an inseparable regioisomeric mixture of products.
1
(23) H NMR signals of the methylene and methine moieties of 6
were broad, suggesting that 6 exists as an equilibrium mixture of
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