Acyl radicals from α-keto acids using a carbonyl photocatalyst: Photoredox-catalyzed synthesis of ketones

Article abstract of DOI:10.1021/acs.orglett.0c02351

Acyl radicals have been generated from α-keto acids using inexpensive and commercially available 2-chloro-thioxanthen-9-one as the photoredox catalyst under visible light illumination. These reactive species added to olefins or coupled with aryl halides via a bipyridylstabilized Ni(II) catalyst, enabling easy access to a diverse range of ketones. This reliable, atom-economical, and eco-friendly protocol is compatible with a wide range of functional groups.

Full text of DOI:10.1021/acs.orglett.0c02351

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Letter
Acyl Radicals from α‑Keto Acids Using a Carbonyl Photocatalyst:
Photoredox-Catalyzed Synthesis of Ketones
Da-Liang Zhu, Qi Wu, David James Young, Hao Wang, Zhi-Gang Ren, and Hong-Xi Li*
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ABSTRACT: Acyl radicals have been generated from α-keto acids using
inexpensive and commercially available 2-chloro-thioxanthen-9-one as
the photoredox catalyst under visible light illumination. These reactive
species added to olefins or coupled with aryl halides via a bipyridyl-
stabilized Ni(II) catalyst, enabling easy access to a diverse range of
ketones. This reliable, atom-economical, and eco-friendly protocol is
compatible with a wide range of functional groups.
Scheme 1. Photoredox-Catalyzed Generation of Acyl
Radicals from α-Keto Acids
etones are key components of synthetic building blocks,
natural products, pharmaceuticals, and organic functional
K
materials,1,2 and a large number of protocols have been
developed for their preparation.3,4 Among these, radical
acylation reaction via visible light photocatalysis is a
sustainable methodology employing mild reaction condi-
tions.5−8 α-Oxocarboxylic acids as acylation reagents have
attracted much attention recently due to their low cost,
stability, easy preparation, and high reactivity.9,10 Conversion
of α-keto acids into acyl radicals can be achieved via single-
electron transfer (SET) from the corresponding carboxylate by
photocatalytic oxidation and subsequent decarboxylation.11
[Ru(phen)3]2+,12 [Ir{dF(CF3)ppy}2(dtbbpy)]+,13 Eosin Y,14
and Acr+-Mes15 are commonly used as photoredox catalysts to
promote the formation of acyl radicals from α-keto acids
(Scheme 1a). The high cost, toxicity, and limited abundance of
platinum group metal-based photocatalysts, however, limit
their synthetic application.16 It is similarly challenging to adjust
the electrochemical potential of (toxic) organic dyes by varying
their substituents.17
Aromatic carbonyls are attractive redox-active partners due
to their lower cost, ready availability, and easy structure
manipulation.18 These compounds have been employed as
hydrogen atom transfer,19−22 energy transfer,23 or SET24
agents to induce a variety of organic transformations. Although
photoexcited carbonyls possess relatively high redox potentials
[E*red = 1.28 V vs the saturated calomel electrode (SCE) for
thioxanthen-9-one],23d they have not been used as photoredox
catalysts to induce decarboxylation of α-keto acids (Eox ≈ 1.0 V
vs SCE)12 to generate acyl radicals. Our ongoing interest in
visible light photocatalysis23d,25 and decarboxylative acylation1b
led us to build on these prior studies and investigate cheap and
commercially available 2-chloro-thioxanthen-9-one (Cl-TXO)
as a visible light photoredox catalyst for mediating (i) Ni-
catalyzed decarboxylative arylation of α-oxo acids with
arylhalides and (ii) hydroacylation of olefins with α-oxo
acids to generate a family of useful ketones (Scheme 1b).
The mechanism of these dual catalytic systems is somewhat
complex, and we propose that they proceed as depicted in
Scheme 2. The anion of α-keto acid RCOCO2H is easily
−
oxidized [Ered = 1.039 V for PhCOCO2 vs SCE in DMF
(Figure S1)] by the excited Cl-TXO [E(Cl-TXO*/Cl-TXO•−)
Received: July 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02351
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 2. Pathway of Decarboxylative Arylation
Table 1. Parameters for Decarboxylative Arylation of
a
Phenylglyoxylic Acid with 4-Bromobenzonitrile
variations from conditions given
above
conversion of 1a
yield
(%)
entry
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
none
>99
>99
0
20
5
27
0
2
78
56
15
0
7
0
90
46
0
<1
<1
<1
0
<1
69
51
9
TXO instead of Cl-TXO
BPHO instead of Cl-TXO
Eosin Y instead of Cl-TXO
Rose Bengal instead of Cl-TXO
fac-Ir(ppy)3 instead of Cl-TXO
no photoredox catalyst
no photoredox catalyst
using 10 mol % Cl-TXO
no H2O
no dtbbpy
no nickel
no Li2CO3
no light
b
c
0
0
0
91
= 1.468 V vs SCE in DMF based on electrochemical and
spectroscopic data (Figures S1 and S2)] to produce carboxyl
sunlight instead of CFL
>99
radical RCOCO2 and ketyl radical anion [Cl-TXO]•−.
•
a
•
1a (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2 equiv), NiCl2·gylme (0.02
Unstable RCOCO2 extrudes CO2 to generate acyl radical
PhCO•. The reduced [Cl-TXO]•− transfers one electron to
LnNiIX generating LnNi0 with concomitant regeneration of
photoredox catalyst Cl-TXO [E(NiII/Ni0) = −1.20026 and
Ered(Cl-TXO) = −1.506 V vs SCE]. The oxidative addition of
arylhalide (ArX) to LnNi0(solvent) (A) gives LnNiII(Ar)X (B),
which in turn intercepts an acyl radical to generate the Ni(III)
species LnNiIII(Ar)(COR)X (C). Subsequent reductive elim-
ination provides ketone and Ni(I) complex LnNiI(X) (D),
completing the cycle.
mmol, 10 mol %), dtbbpy (0.024 mmol, 12 mol %), Li2CO3 (0.4
mmol, 2.0 equiv), H2O (3.0 mmol, 15 equiv), photocatalyst (20 mol
%), 6 mL of DMF, N2, irradiation under 45 W CFL for 24 h with
cooling by a fan, high-performance liquid chromatography conversion
b
c
and yield. Using 2 mol % fac-Ir(ppy)3. Under 365 nm.
mol %) and TEMPO (2 equiv) under 45 W CFL gave acyl-
TEMPO adduct 2,2,6,6-tetramethylpiperidin-1-yl benzoate
(details in the Supporting Information). These observations
suggest that a SET process from 2a to Cl-TXO* is favorable
and confirmed the formation of an acyl radical intermediate.
No ketone product was observed in the absence of Cl-TXO
(entry 7). The irradiation of 1a and 2a in DMF without Cl-
TXO under 365 nm for 24 h afforded 3aa in <1% yield (entry
8). These conditions preclude triplet−triplet energy transfer
between Cl-TXO* and the Ni catalyst.27 Decreasing the Cl-
TXO loading resulted in a 69% yield of 3aa (entry 9). The
absence of H2O was also detrimental, with the yield of 3aa
decreasing to 51% (entry 10). Water presumably assists in
solubilizing Li2CO3 in DMF. Screening solvents identified
DMF as the most suitable choice (Table S1). Without dtbbpy
to stabilize the metal catalyst, the light-driven reaction was
greatly suppressed, giving 3aa in only 9% yield (entry 11). The
absence of nickel or base resulted in no coupling (entries 12
and 13). Likewise, no reaction occurred in the dark (entry 14).
The yield of 3aa reached 91% after sunlight irradiation for 8 h
[entry 15; the maximum power density was ∼4.81 mW cm−2
(Figure S3c)]. This cross-coupling reaction (see the
Supporting Information) also worked well on the gram-scale
reaction of 1a (1.09 g, 6 mmol) and 2a (1.8 g, 12 mmol) to
give 3aa in 66% HPLC yield (0.820 g) under 2 × 45 W CFL
irradiation for 72 h and in 77% HPLC yield (0.956 g) under
sunlight for 8 h (Figure S3d).
To evaluate this hypothesis, we initiated our investigation
with the model reaction of 4-bromobenzonitrile (1a) with
phenylglyoxylic acid (2a) in the presence of 20 mol % Cl-
TXO, 10 mol % NiCl2·glyme, 12 mol % dtbbpy (dtbbpy =
4,4′-di-tert-butyl-2,2′-bipyridine), and 2.0 equiv of Li2CO3
under the irradiation of a 45 W compact fluorescent lamp
(CFL) in a H2O/DMF mixture for 24 h (Figure S3a,b). To
our delight, the formation of 4-benzoylbenzonitrile (3aa) was
achieved in 90% yield (Table 1, entry 1). The excited-state
redox potential of the photocatalyst clearly had a significant
influence on the decarboxylative arylation (entries 1−6). The
utilization of thioxanthen-9-one [TXO, E(TXO*/TXO•−) =
1.34 V vs SCE in DMF23e] instead of Cl-TXO drastically
decreased the efficacy of the cross-coupling, affording 3aa in a
more modest 46% yield (entry 2). Benzophenone [BPHO,
E(BPHO*/BPHO•−) = 1.149 V vs SCE in MeCN], Eosin Y
(E* = 1.18 V vs SCE), Rose Bengal (E* = 0.99 V vs SCE), and
fac-Ir(ppy)3 (E* = 0.31 V vs SCE)23e with lower excited-state
oxidation potentials did not perform well in this coupling
(entries 3−6, respectively). Stern−Volmer quenching studies
(Figure S4) revealed that 1a did not quench the emission of
excited-state Cl-TXO in DMF. By contrast, a solution of 2a
and Li2CO3 did gradually decrease the photoluminescence
intensity (λex = 374 nm) of Cl-TXO together with a
concomitant increase in 2-oxo-2-phenylacetate concentration
(Figure S5). Carbon dioxide was the byproduct identified by
gas chromatography (GC) analysis (see Figure S6). The
addition of 2.0 equiv of 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO) to the standard reaction mixtures gave an only 14%
yield of the desired product. Reaction of 2a with Cl-TXO (20
The scope of this decarboxylative arylation of α-keto acids
was explored using the optimized reaction conditions
described above. As shown in Scheme 3, aryl bromides
substituted with electron-withdrawing groups in the para and/
or meta positions (3aa−3ga) were isolated in good yields (61−
88%). The reaction of 2-bromobenzonitrile (1h), methyl 2-
B
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a
excellent yields (Scheme 3). Phenylglyoxylic acids substituted
with electron-rich and electron-neutral groups at para or meta
positions reacted efficiently with 1a to form cross-coupling
products (3aa−3ae and 3ag−3ai) in synthetically useful yields
of 80−93%. A substrate containing an electron-deficient group
on the phenyl ring also afforded desired product 3af in 52%
yield. Arylglyoxylic acids 2j−2m with methyl or methoxy
groups at the ortho position provided the desired ketones in
72−77% yields. Heteroaromatic α-oxocarboxylic acids could
be employed in the reaction (2n), albeit proceeding in a
modest 51% yield. This protocol was found to be equally
effective for the decarboxylative arylation of aliphatic keto acids
(2o and 2p) with 1a, producing 3ao and 3ap, respectively, in
44−46% yields. The oxalate monoamide 2-[methyl(phenyl)-
amino]-2-oxoacetic acid was a viable substrate and afforded
desired amide product 3aq in 62% yield.
Scheme 3. Substrate Scope for Decarboxylative Arylation
The acyl radical is initially generated by photoredox catalysis
during the decarboxylative arylation. The resulting reactive acyl
radical could also potentially be trapped by electrophilic
olefins, so we evaluated the utilization of α-oxo acids as
Michael acceptors (Scheme 4). Reaction of 2a with 4a and
a
Scheme 4. Substrate Scope for Hydroacylation of Olefins
a
1 (0.2 mmol, 1 equiv), 2 (0.4 mmol, 2 equiv), NiCl2·gylme (0.02
mmol, 10 mol %), dtbbpy (0.024 mmol, 12 mol %), Li2CO3 (0.4
mmol, 2.0 equiv), H2O (3.0 mmol, 15 equiv), Cl-TXO (20 mol %), 6
mL of DMF, N2, irradiation under a 45 W CFL for 24 h, isolated
yields.
bromobenzoate (1i), and (2-bromophenyl)(phenyl)-
methanone (1j) with 2a resulted in the formation of the
desired products 3ha (58%), 3ia (49%), and 3ja (41%),
respectively. Aryl bromides containing groups at the 3,5- or
3,4-positions of the phenyl rings gave 3ka−3na in 78−89%
yields. 2-Bromonaphthalene (1o) also reacted smoothly to
afford 3oa in 71% yield. This coupling was similarly successful
with heteroaryl halides, including those containing 3-
bromoquinoline (2p), 2-bromo-6-(trifluoromethyl)pyridine
(2q), and 1-(6-bromopyridin-2-yl)ethan-1-one (2r) in 60−
80% yield. Noteworthy is the acylation of aryl chlorides, such
as 2-chloro-6-(trifluoromethyl)pyridine that also produced 3qa
in 51% yield. Aryl bromides bearing electron-donating
substituents were unsuitable substrates for this transformation,
failing to give decarboxylative arylation products. However,
electron-rich aryl iodides did serve as efficient coupling
partners, generating the desired products 3sa−3za in good
yields (Scheme S1). Additionally, we observed a higher
efficiency for electron-deficient aryl iodides than for the
corresponding aryl bromides.
a
2 (0.4 mmol, 2 equiv), 4 (0.2 mmol, 1 equiv), Cs2CO3 (0.4 mmol,
2.0 equiv), H2O (0.3 mL), Cl-TXO (20 mol %), 6 mL of DMF, N2,
irradiation under a 45 W CFL for 24 h, isolated yields.
Li2CO3 in the presence of Cl-TXO in a DMF/H2O mixture
produced desired product 5aa in 27% yield (Table S2, entry
1). When Li2CO3 was replaced with Cs2CO3, the same
reaction gave 5aa in 71% yield (entry 2). 2-Arylglyoxylic acids
containing different functional groups on the aromatic ring also
showed good reactivity to give products 5aa−5ak in 42−71%
yields. The synthetic utility of this coupling was demonstrated
using a variety of electron-deficient olefin acceptors, producing
desired products 5ba−5fa in 64−73% yields. Substrate 2a
reacted smoothly with α,β-unsaturated ketone 4g−4i, affording
the corresponding 5ga−5ia, respectively, in 54−73% yields.
We propose that photoexcited Cl-TXO* oxidative decar-
boxylates α-ketocarboxylate to generate acyl radical I and ketyl
radical anion [Cl-TXO]•− (Scheme S2). Addition of the acyl
radical to the alkene generates alkyl radical II. The SET from
This decarboxylative cross-coupling was also performed on a
wide range of α-oxo acids with 1a. All reactions progressed
cleanly to furnish the desired coupling products in moderate to
C
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[Cl-TXO]•− to intermediate II, followed by protonation,
delivers the desired product and regenerates the Cl-TXO
photocatalyst.
Zhi-Gang Ren − College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
China; orcid.org/0000-0002-0740-8397
To further demonstrate the utility and generality of this
cross-coupling reaction, we employed it in the synthesis of
cytotoxic naphthylphenstatin that inhibits tubulin polymer-
ization and induces tumor cell apoptosis28 (Scheme 5a).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02351
Notes
The authors declare no competing financial interest.
Scheme 5. Synthetic Applications
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21771131 and 21971182) and the “Priority Academic
Program Development” of Jiangsu Higher Education Institu-
tions. D.-L.Z. thanks the Postgraduate Research & Practice
Innovation Program of Jiangsu Province (KYCX20_2652).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02351.
1
Experimental procedures and H, 13C and 19F NMR
spectra and characterization data for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Hong-Xi Li − College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, China;
orcid.org/0000-0001-8299-3533; Email: lihx@
suda.edu.cn
Authors
Da-Liang Zhu − College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
China
Qi Wu − College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, China
David James Young − College of Engineering, Information
Technology and Environment, Charles Darwin University,
Darwin, Northern Territory 0909, Australia
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