Dual photoredox/palladium-catalyzed C-H acylation of 2-arylpyridines with oxime esters

Article abstract of DOI:10.1055/s-0040-1707252

An unprecedented dual photoredox/palladium-catalyzed iminyl-radical-mediated C-C bond cleavage and directed ortho C-H acylation of 2-arylpyridines by using oxime esters is described. Oxime esters can serve as efficient acyl sources through formation of the corresponding acyl radicals by photoredox-catalyzed iminyl-radical-mediated C-C bond cleavage. This redox-neutral protocol features excellent regioselectivity, a broad substrate scope, and good functional-group tolerance with respect to both components, giving a broad range of aryl ketones with generally good yields.

Full text of DOI:10.1055/s-0040-1707252

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
cluster
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en
B.-Q. He et al.
Cluster
Synlett
Dual Photoredox/Palladium-Catalyzed C–H Acylation of 2-Arylpyri-
dines with Oxime Esters
Bin-Qing He
R2
R2
O
O
N
N
PC
Pd
Yuan Gao
O
N
+
R3
O
R5
Peng-Zi Wang
Hong Wu
H
R3
R4
R1
R1
sequential iminyl-radical-mediated
C–C bond cleavage/C–H acylation
32 examples
45–95% yield
Hong-Bin Zhou
Xiao-Peng Liu*
Jia-Rong Chen*
• excellent regioselectivity • mild conditions • redox-neutral
0
0
0
0-0
0
0
1-
6
0
5
4-2
5
4
7
Key Laboratory of Pesticides and Chemical Biology Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei 430079, P. R. of China
liuxp@mail.ccnu.edu.cn
chenjiarong@mail.ccnu.edu.cn
Published as part of the Cluster Radicals – by Young Chinese Organic Chemists
Received: 24.06.2020
Accepted after revision: 26.07.2020
Published online: 21.08.2019
and -keto acids,9 toluene derivatives,10 and benzylic
ethers.11 Despite their advantages, most of these arene C–H
acylation reactions still require stoichiometric oxidants and
elevated temperatures (>80 °C). As a result, the quest for
new acyl sources and the design of general room-tempera-
ture and redox-neutral methods for C–H acylation contin-
ues to be an important challenge for this area.
DOI: 10.1055/s-0040-1707252; Art ID: st-2020-l0369-c
Abstract An unprecedented dual photoredox/palladium-catalyzed
iminyl-radical-mediated C–C bond cleavage and directed ortho C–H ac-
ylation of 2-arylpyridines by using oxime esters is described. Oxime es-
ters can serve as efficient acyl sources through formation of the corre-
sponding acyl radicals by photoredox-catalyzed iminyl-radical-
mediated C–C bond cleavage. This redox-neutral protocol features ex-
cellent regioselectivity, a broad substrate scope, and good functional-
group tolerance with respect to both components, giving a broad
range of aryl ketones with generally good yields.
(a) State-of-the-art Pd(II)-catalyzed ortho C–H acylation of 2-arylpyridines
via
N
N
N
[Pd]/oxidant
O
PdII Ln
+ [acyl source]
H
elevated temp.
∗
Key words photocatalysis, palladium catalysis, C–H activation, acyla-
tion, iminyl radical, oxime esters
acyl sources
O
O
∗
∗
∗
OH
NH2
Cl
∗
O
O
∗
OH
ref. 10
∗
∗
Over recent decades, palladium-catalyzed direct C–H
activation/functionalization has been established as one of
the most attractive and powerful platforms for the con-
struction of various carbon–carbon and carbon–heteroat-
om bonds.1 Because of the prevalence of benzophenone
motifs in numerous pharmaceuticals, fragrances, and agro-
chemicals,2 the palladium-catalyzed oxidative C–H acyla-
tion reactions of directing arenes have been particularly
well explored.3 There have been many advances in relation
to the substrate scope, functional-group compatibility, and
range of catalyst systems for these transformations. In this
context, a wide variety of readily available acyl sources
have been identified as being capable of coupling with pal-
ladacycle intermediates formed by C–H activation of 2-
arylpyridines (Scheme 1a). Representative acyl sources in-
clude aldehydes,4 alcohols,5 arylmethyl amines and chlo-
rides,6 alkenes and alkynes,7 diketones,8 carboxylic acids
∗
∗
OH
ref. 9
H
∗
∗
ref. 7
O
O
O
ref. 4
refs. 5,6
ref. 8
ref. 11
(b) Photoredox/Pd-catalyzed C–H acylation of 2-arylpyridines with oxime esters
(this work)
R2
R1
R2
O
O
N
PC
Pd
N
O
N
+
R3
O
R5
H
room temperature
R3
R4
sequential iminyl radical-mediated
C–C bond cleavage/C–H acylation
R1
34 examples
• excellent regioselectivity • mild reaction conditions • redox-neutral process
Scheme 1 State-of-the-art Pd(II)-catalyzed ortho C–H acylation of 2-
arylpyridines, and a new reaction design
The field of nitrogen radical chemistry has recently wit-
nessed a renaissance, triggered mainly by the introduction
of visible-light photoredox catalysis for the formation of
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B.-Q. He et al.
Cluster
Synlett
various open-shell nitrogen radical species under mild con-
ditions.12 In this area, our laboratory has also been interest-
ed in developing new methods that permit selective nitro-
gen-mediated reactions through the use of photoredox ca-
talysis.13 As part of this program, we recently disclosed that
cyclic iminyl radicals generated from easily prepared oxime
esters under visible-light-driven photoredox catalysis can
undergo -C–C bond cleavage to form cyanoalkyl radi-
cals.14,15 With radical species of this type, we developed a
wide range of carbon–carbon and carbon–heteroatom
bond-forming transformations toward the synthesis of di-
verse cyano-group-containing molecules. These radical
processes are highly selective and proceed through a redox-
neutral mechanism, such that no stoichiometric additives
are required. Given that palladium-catalyzed radical chem-
istry has been well established,16 we questioned whether
the chemistry of iminyl radicals might be applied to palla-
dium-catalyzed C–H functionalization of arenes. Moreover,
the Wu group recently reported that acyclic -keto oxime
esters can undergo photocatalytic single-electron transfer
(SET) reduction and -fragmentation via the corresponding
iminyl radicals, thereby permitting a range of radical trans-
formations of alkenes.17 Inspired by these studies and in
consideration of the significant advantages of metallapho-
toredox-catalyzed reactions,18 we attempt to explore the
possibility that -keto oxime esters might serve as an effec-
tive class of acyl-radical precursors to participate in the ac-
ylation of 2-arylpyridines under dual photoredox/palladi-
um catalysis (Scheme 1b). This strategy features mild reac-
tion conditions and requires no external oxidant. Notably,
the feasibility of our reaction design was recently corrobo-
rated by the investigations of the group of Wang and Li,19
who showed that a combination of the photoredox catalyst
Eosin Y or 9-mesityl-10-methylacridinium perchlorate
with Pd(TFA)2 permitted the efficient room-temperature
decarboxylative ortho-acylation of acetanilides, azoben-
zenes, or azoxybenzenes in the presence of O2 or air as an
oxidant. Sanford and co-workers also reported that combin-
ing photoredox catalysis and palladium-catalyzed C–H acti-
vation permitted room-temperature aromatic C–H aryla-
tion with aryldiazonium salts as aryl-radical sources.20 In
addition, many other dual catalytic strategies for C–H func-
tionalization have been reported.21 Here, we describe how
we translated our idea into experimental reality.
as additives typically play an important role in palladium-
catalyzed C–H functionalization.23 We therefore screened a
range of commonly used silver salts (entries 3–6), and we
found that AgOTf (2.0 equiv) provided an obvious enhance-
ment in the yield, giving a 42% yield of 3aa (entry 5). More-
over, an increase in the amount of AgOTf to 2.5 equivalents
significantly improved the reaction efficiency, with 3aa be-
ing isolated in 75% yield (entry 7). At the current stage, we
are unsure of the role of AgOTf in the process; however,
mechanistic studies are currently ongoing to elucidate this
in more detail.24 Compared with Pd(TFA)2, other palladium
salts [Pd(OAc)2 and PdCl2] gave lower yields (entries 8 and
9). Finally, the results of a series of control experiments
showed that the photocatalyst, palladium salt, and visible
light are all essential to the ortho C–H acylation reaction
(entries 10–12). We further examined other N-heterocycles
as directing groups, as illustrated by the case of 2-
phenylimidazole (1a-1); however, its reaction did not pro-
ceed under the standard conditions (entry 13).
Table 1 Condition Optimizationa
[Pd] (10 mol%)
fac-Ir(ppy)3 (1 mol%)
HN
N
O
N
N
O
N
or
+
H
OAc
H
7 W blue LEDs, additive
DMF, Ar, rt, 10 h
1a
1a-1
2a
3aa
Entry
Reactant
[Pd]
Additive (equiv)
Yieldb (%)
1
2c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a-1
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
PdCl2
–
21
–
30
3c
Ag2CO3 (2.0 )
AgOAc (2.0)
AgOTf (2.0)
AgTFA (2.0)
AgOTf (2.5)
AgOTf (2.5)
AgOTf (2.5)
AgOTf (2.5)
AgOTf (2.5)
AgOTf (2.5)
AgOTf (2.5)
28
4c
26
5c
42
6c
32
7c
82 (75)d
64
8c
9c
55
10c
11c,f
12c,g
13c
–
NRe
NR
NR
NR
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
a Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), fac-Ir(ppy)3 (1
mol%), Pd catalyst (10 mol%), additive, DMF (2.0 mL), rt, 7 W blue LEDs, 10
Initially, we selected 2-phenylpyridine (1a), and butane-
2,3-dione O-acetyloxime (2a) as the model substrates to ex-
plore the feasibility of the target ortho C–H acylation (Table
1).22 To our delight, when the reaction was performed in
the presence of the photocatalyst fac-Ir(ppy)3 (1 mol%) and
Pd(TFA)2 (10 mol%) in DMF at room temperature under irra-
diation by 7 W blue LEDs for ten hours, the desired reaction
occurred to give the expected product 3aa in 21% yield, al-
beit with moderate conversion (Table 1, entry 1). Extending
the reaction time to 24 hours slightly increased the yield to
30% (entry 2). It has been well documented that metal salts
h.
b NMR yield.
c 24 h.
d Isolated yield.
e NR = no reaction.
f Without a photocatalyst.
g Without visible-light irradiation.
With the optimized conditions in hand, we first investi-
gated the substrate scope of the acyl radical precursor by
using a range of oxime esters 2 (Scheme 2). In addition to
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
B.-Q. He et al.
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2a, oxime esters 2b–d bearing linear or branched alkyl
chains reacted well with 1a to give the corresponding prod-
ucts 3ab–ad in yields of 47–71%. As shown in the cases of
2e and 2f, variation of the iminyl group (R4) was tolerated,
and the expected products 3ae and 3ab were obtained in
good yields with release of propionitrile during the course
of acyl-radical formation. Notably, a variety of aryl acyl rad-
icals generated from oxime esters 2g–m with electronically
diverse substituents (H, Br, Cl, F, or Me) at the para- or meta-
position of the phenyl ring all participated in the reaction
smoothly after a prolonged reaction time or in the presence
of 3 mol% of photocatalyst. The desired products 3ag–am
were obtained in yields of 54–89%. Again, the reaction of 2n
also worked well to afford 3ag in 64% yield. In agreement
with our previous study,14 structural modification of the
acyl moiety on the oxime had somewhat of an effect on the
reaction. For example, oxime esters 2o–r also provide to be
suitable for the reaction, albeit with a lower reaction effi-
ciency, leading to product 3aa in 45–63% yield, probably as
result of their inherent redox potential.
electron-withdrawing or electron-donating groups at vari-
ous positions of the aromatic ring para or meta to the pyr-
idinyl group, reacted readily with 2a to give 3ba–ia in yields
of 47–95%. As shown in the case of 3ea, the presence of the
strongly electron-withdrawing group CF3 resulted in an ob-
vious decrease in the yield. Furthermore, the reactions of
substrates 1j–m with electronically diverse functional
groups (Br, Me, CO2Et) on the pyridine ring also proceeded
smoothly to give 3ja–ma in good yields. We were pleased to
find that other directing groups such as quinoline also facil-
itated the ortho C–H acylation: as such, products 3na and
3oa were isolated in yields of 65% and 64%, respectively.
Note that halogen atoms Cl and Br on the arene or pyridine
ring were fully compatible with the current catalytic sys-
tem, suggesting that Pd(0) species are not intermediates in
this process.
R2
R1
R2
R1
Pd(TFA)2 (10 mol%)
fac-Ir(ppy)3 (3 mol%)
O
N
N
O
N
+
OAc
H
AgOTf (2.5 equiv)
7 W blue LEDs
DMF, Ar, rt, 48 h
1
2a
3
Pd(TFA)2 (10 mol%)
fac-Ir(ppy)3 (1 mol%)
O
O
N
N
R
O
3ba, R = F, 50%
3ca, R = Cl, 56%
3da, R = Br, 55%
3ea, R = CF3, 47%
3fa, R = Me, 70%
3ga, R = tBu, 95%
N
+
R3
O
R5
H
N
AgOTf (2.5 equiv)
7 W blue LEDs
DMF, Ar, rt, 24 h
N
O
R3
O
R4
N
O
1a
2
3
R
O
O
O
O
R
3ha, R = Br, 51%
3ia, R = Me, 49%
N
N
N
N
OAc
OAc
OAc
OAc
3ja, R = Br, 68%
3ka, R = Me, 57%
R
2a
2b
2c
2d
(3ad, 71%)
N
(3aa, 75%)
(3ab, 67%)
(3ac, 47%)
O
N
O
N
O
O
O
O
N
N
OAc
OAc
N
CH3
OAc
3la, R = CO2Et, 75%
3ma, R = Me, 55%
R
2e
2f
(3ab, 68%)
3na, 65%
3oa, 64%
(3ae, 69%)
2g, R = H (3ag, 72%)
2h, R = Br (3ah, 81%)
2i, R = Cl (3ai, 89%)
2j, R = F (3aj, 5j4%)a
2k, R = Me (3ak, 73%)a
Scheme 3 Scope of 2-arylpyridines. Isolated yields based on 1 are re-
O
O
ported.
R
N
N
OAc
OAc
2l, R = Me (3al, 86%)b
2m, R = Br (3am, 78%)a
2n
To gain some insight into the mechanism, we then car-
ried out control experiments with the cyclic oxime ester 2s
(Scheme 4). We found that 2s reacted smoothly with 1,1-
diphenylethylene (4) and -methylstyrene (6) under the
conditions that we previously developed for the generation
of iminyl radicals from oxime esters.14 The corresponding
,-unsaturated ketones 5 and 7 with acetonitrile group in
the ortho-position of the phenyl ring were obtained in good
yields. These results, together with our previous studies14
and the work of the Wu group,17 suggest that a cyclic iminyl
radical 2s-A might be involved in the process; this radical is
formed by SET reduction of 2s followed by C–O cleavage.
Subsequently, radical 2s-A might trigger -C–C bond cleav-
age to form the relatively more-stable acyl radical 2s-B. In
addition, upon addition of the radical scavenger TEMPO in a
stoichiometric amount under the standard conditions, the
model reaction between 1a and 2a was completely inhibit-
(3ag, 64%)
O
O
O
O
O
O
O
O
N
N
N
N
O
Ar
O
Ph
O
Et
O
tBu
2o, Ar = p-CF3C6H4
(3aa, 50%)
2p
(3aa, 51%)
2q
(3aa, 45%)
2r
(3aa, 63%)
Scheme 2 Scope of the oxime esters. Isolated yields based on 1a are
reported. a 48 h. b 48 h, 3 mol% of fac-Ir(ppy)3.
Next, we proceeded to examine the scope of the 2-
arylpyridine under the standard conditions; however, the
reactions proceeded slowly. In contrast, the reaction effi-
ciency was significantly increased when 3 mol% of the pho-
tocatalyst was used with an extended reaction time of 48
hours (Scheme 3). It appears that a diverse set of electroni-
cally and sterically diverse functional groups on the phenyl
ring are well tolerated. For instance, substrates 1b–i with
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
B.-Q. He et al.
Cluster
Synlett
ed, and the corresponding radical-trapping adduct 2a-B-
TEMPO was detected. This observation indicated that acyl
radical 2a-B might be involved in this process.
N
N
O
PdII CO2CF3
– TFA
H
2a-B
O
Ph
O
O
1a
PdII(CO2CF3)2
Ph
1a-A
fac-Ir(ppy)3 (2 mol%)
OAc
N
+
(1)
Ph
CO2CF3
DMF, 7 W blue LEDs
Ar, rt, 16 h
N
Ph
4 (10 equiv)
2a-B
CN
PdIII
Pd catalysis
O
2s
5, 70%
CH3CN
SET reduction
C–O cleavage
1a-B
CO2CF3
O
CO2CF3
N
β-C–C bond
cleavage
O
O
4
N
SET
PdIV
fac-IrIV(ppy)3
O
N
2a-A
CN
2s-A
2s-B
1a-C
N
fac-IrIII(ppy)3
O
O
Me
Ph
SET
–OAc
O
Photocatalysis
Me
Ph
6 (10 equiv)
fac-Ir(ppy)3 (2 mol%)
OAc
N
–
+
(2)
(3)
DMF, 7 W blue LEDs
Ar, rt, 16 h
O
CN
3aa
N
2s
7, 71% (E/Z = 1:1)
OAc
visible light
*fac-IrIII(ppy)3
2a
Pd(TFA)2 (10 mol%)
fac-Ir(ppy)3 (1 mol%)
O
N
3aa
(not detected)
N
O
Scheme 5 Proposed mechanism
N
+
OAc
H
AgOTf (2.5 equiv)
7 W blue LEDs
DMF, Ar, rt, 24 h
O
O
2a-B-TEMPO
(detected by HRMS)
TEMPO (2.0 equiv)
1a
2a
2a-B
Funding Information
Scheme 4 Mechanistic study
We are grateful to the NNSFC (21971081 and 91856119), the Science
and Technology Department of Hubei Province (2017AHB047), and
the Program of Introducing Talents of Discipline to Universities of
On the basis of these experimental results and reports
in the literature,15,19,20 a plausible mechanism for the reac-
tion of 1a and 2a is proposed, as shown in Scheme 5. First,
irradiation of the photocatalyst fac-Ir(ppy)3 produces an ex-
cited state *fac-Ir(ppy)3 that undergoes a SET with oxime
ester 2a to form the iminyl radical 2a-A upon C–O bond
cleavage. Iminyl radical 2a-A then undergoes further -C-C
bond cleavage to form the more stable acyl radical 2a-B.
Meanwhile, 1a undergoes pyridine-directed electrophilic
palladation to generate the five-membered cyclopalladated
complex 1a-A.25 We hypothesize that, at this stage, 1a-A re-
acts with acyl radical 2a-B to furnish a Pd(III) intermediate
1a-B; this is followed by another SET oxidation by the oxi-
dizing-state fac-IrIV(ppy)3 to form the Pd(IV) complex 1a-C,
closing the photocatalytic cycle. Finally, C–C bond-forming
reductive elimination of 1a-C occurs to yield the desired
product 3aa with regeneration of the Pd(II) catalyst, com-
pleting the palladium-catalysis cycle.
In summary, we have developed the first example of a
dual photoredox and palladium-catalyzed iminyl-radical-
mediated C–C bond cleavage and directed ortho C–H acyla-
tion of 2-arylpyridines by using oxime esters without any
external oxidant.26 This room-temperature redox-neutral
protocol features excellent regioselectivity, a broad sub-
strate scope, and good functional-group tolerance with re-
spect to both components, providing practical access to a
range of aryl ketones. We expect that this strategy will find
application in the design of many new synthetically useful
reactions.
China (111 Program, B17019) for support of this research.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707252.
S
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References and Notes
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(26) 1-(2-Pyridin-2-ylphenyl)ethanone (3aa); Typical Procedure
A 10 mL, flame-dried, round-bottomed Schlenk flask equipped
with a magnetic stirrer bar was charged with 1a (0.2 mmol,
31.04 mg), 2a (0.4 mmol, 57.26 mg), AgOTf (0.5 mmol, 128.47
mg), fac-Ir(ppy)3 (0.002 mmol, 1.31 mg), and Pd(TFA)2 (0.02
mmol, 6.65 mg). The flask was evacuated and backfilled with Ar
three times, and the mixture was irradiated with 7 W blue LED
strips until the reaction was complete (24–48 h; TLC). The
mixture was then poured into a separatory funnel containing
20 mL of sat. aq NaCl and washed with CH2Cl2 (20 mL). The
organic layers were separated, dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The crude product was puri-
fied by flash chromatography (silica gel) to give a colorless oil;
yield: 29.6 mg (75%).
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1H NMR (400 MHz, CDCl3):  = 8.64 (d, J = 4.4 Hz, 1 H), 7.78 (t, J =
7.7 Hz, 1 H), 7.60 (dd, J = 12.9, 7.7 Hz, 2 H), 7.53 (t, J = 6.9 Hz, 2
H), 7.47 (d, J = 8.1 Hz, 1 H), 7.27 (t, J = 5.9 Hz, 1 H), 2.23 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 204.1, 157.6, 149.2, 141.5, 138.8,
136.7, 130.3, 129.1, 128.6, 127.6, 122.5, 122.3, 30.5. HRMS (EI):
m/z [M + H]+ calcd for C13H12NO: 198.0913; found: 198.0918.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E