Merging Photoredox with Palladium Catalysis: Decarboxylative ortho-Acylation of Acetanilides with α-Oxocarboxylic Acids under Mild Reaction Conditions

Article abstract of DOI:10.1021/acs.orglett.5b03192

A room temperature decarboxylative ortho-acylation of acetanilides with α-oxocarboxylic acids has been developed via a novel Eosin Y with Pd dual catalytic system. This dual catalytic reaction shows a broad substrate scope and good functional group tolera

Full text of DOI:10.1021/acs.orglett.5b03192

Letter
pubs.acs.org/OrgLett
Merging Photoredox with Palladium Catalysis: Decarboxylative
ortho-Acylation of Acetanilides with α‑Oxocarboxylic Acids under
Mild Reaction Conditions
Chao Zhou,† Pinhua Li,*,† Xianjin Zhu,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A room temperature decarboxylative ortho-
acylation of acetanilides with α-oxocarboxylic acids has been
developed via a novel Eosin Y with Pd dual catalytic system.
This dual catalytic reaction shows a broad substrate scope and
good functional group tolerance, and an array of ortho-
acylacetanilides can be afforded in high yields under mild conditions.
ortho-Acylacetanilides are important structural motifs and
synthetic intermediates in the preparation of natural products
and pharmaceutically bioactive compounds, such as acridones,
cinnolines, fluorenones, indoles, quinolones, and benzodiaze-
pines.1 Owing to their unique properties, the development of a
practical synthetic strategy for their preparation is highly
desirable. In the past decade, general methods for the synthesis
of ortho-acylacetanilides via direct C−H activation and
functionalization of aniline derivatives by using relatively
nonhazardous acylating agents have been developed. Evidently,
transition-metal-catalyzed direct C−H functionalization plays
one of the most important roles in organic synthesis, which
enables the construction of carbon−carbon and carbon−
heteroatom bonds efficiently without the use of stoichiometric
organometallic reagents.2 In 2010, Ge disclosed an ortho-
acylation of acetanilides through a Pd-catalyzed decarboxylative
coupling of α-oxocarboxylic acids, and subsequently, a numbers
of direct acylation of aromatic C(sp2)−H bonds through Pd(II)-
catalyzed decarboxylative cross-coupling with α-oxocarboxylic
acids were reported.3 In 2011, our group and others
independently developed the oxidative cross-coupling of
aldehydes with acetanilides.4 After then, Yuan and Zhou showed
that benzyl alcohols could act as the acylating agents.5
Meanwhile, Sun, Kwong, and Zhang indicated that toluene
could also act as the acyl precursors.6
Recently, visible light photoredox catalysis has emerged as a
powerful tool in organic synthesis, which makes use of the
photoredox catalyst that, upon excitation by visible light, engages
in single electron transfer (SET) with the general functional
groups, activating the substrates toward a diverse array of useful
organic transformations.7 More intriguingly, dual catalysis
realized by combining visible light photoredox catalysis and
transition-metal catalysis has recently attracted prominent
attention. Exploration of the dual catalytic strategy has allowed
the development of powerful organic transformations, which are
not easily accessible and can overcome the drawbacks of a single
catalytic system. Most recently, the successful merger of
photoredox and transition metal catalysis has been demonstrated
by Sanford,8 MacMillan,9 Glorius,10 Rueping,11 Molander,12 and
others13 for the specific installation of unique functional groups,
and which will be identified as a kind of useful synthetic method.
Based on our exploration in photoredox catalysis and inspired
by the reported results,14 we hypothesize that the decarboxylative
ortho-acylation of acetanilides with α-oxocarboxylic acids can be
realized by merging palladium catalysis with visible light
photoredox catalysis. This assumed process has been carried
out by using an Eosin Y and palladium dual catalytic system. It is
important to note that an organic dye (such as Eosin Y) is
cheaper and easier to modify compared with transition-metal
photoredox catalysts, such as Ru- and Ir-complexes.9−13 Herein,
we report the first combination of organic dye (Eosin Y) as
photoredox catalyst and palladium catalyst for the ortho-acylation
of acetanilides with α-oxocarboxylic acids under visible light
irradiation at room temperature.
An initial study was performed by using [Ru(bpy)3]Cl2 as a
photoredox catalyst in Pd-catalyzed ortho-acylation of acetanilide
(2a) with phenylglyoxylic acid (1a) in air under the irradiation of
3 W blue LED for 15 h. It was pleasing to find that the reaction
does indeed proceed and afforded the desired acylation product
3a in 36% yield (Table 1, entry 1). An improved yield (52%) of
3a was obtained when an oxygen balloon was used instead of air
atmosphere. In the absence of palladium or visible-light
irradiation, none of the desired product was formed, and only
a trace amount of the product was detected without [Ru(bpy)3]-
Cl2 (Table 1, entries 2−4). Subsequently, a number of
photocatalysts, including Ru- and Ir-complexes and organic
dyes, palladium sources, solvents, and molar ratio of substrates
were examined to improve the reaction efficiency. It must be
highlighted that the color of light emitting diode (LED) was used
to match the absorption wavelength of photoredox catalyst. For
Received: November 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03192
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of Anilides
b
entry
photocatalyst
solvent
DCE
light source
yield (%)
c
1
Ru(bpy)3Cl2
Ru(bpy)3Cl2
blue LED
blue LED
blue LED
dark
36, 52
d
2
DCE
n.r.
3
DCE
trace
n.r.
42
4
Ru(bpy)3Cl2
Ir(ppy)3
rose bengal
acridine
methylene blue
fluorescein
eosin Y
DCE
5
DCE
blue LED
green LED
blue LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
green LED
6
DCE
59
7
DCE
62
8
DCE
49
9
DCE
trace
e
f
10
11
12
13
14
15
16
17
18
19
20
21
22
DCE
71, 72, 42
g
eosin Y
DCE
61
h
eosin Y
DCE
49
i
eosin Y
DCE
68
j
eosin Y
DCE
66
eosin Y
toluene
acetonitrile
DMF
44
57
42
61
eosin Y
eosin Y
eosin Y
1,4-dioxane
chloroform
chlorobenzene
chlorobenzene
chlorobenzene
eosin Y
63
k
l
eosin Y
80, 61, 82
m
n
eosin Y
61, 82
o
p
eosin Y
66, 81
a
Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), Pd(OAc)2
(5.0 mol %), photocatalyst (3.0 mol %), solvent (2.0 mL), rt, O2, 3 W
b
c
d
LED for 15 h. Isolated yield. Air atmosphere. Without Pd(OAc)2;
e
f
n.r. = no reaction. Eosin Y (5.0 mol %). Eosin Y (1.0 mol %).
Pd(TFA)2 (5.0 mol %). PdCl2 (5.0 mol %). Pd(CH3CN)2Cl2 (5.0
mol %). Pd(PPh3)2Cl2 (5.0 mol %). Pd(OAc)2 (3.0 mol %).
Pd(OAc)2 (10 mol %). 2a (0.50 mmol, 1.0 equiv). 2a (1.0 mmol,
g
h
i
j
k
l
m
n
o
p
2.0 equiv). 10 h. 20 h.
example, blue light was used for [Ru(bpy)3]Cl2, while green light
was used for Rose Bengal. Among the photocatalysts examined,
Eosin Y showed the highest reactivity (Table 1, entries 5−10).
For palladium sources, Pd(OAc)2 was the best of choice (Table
1, entries 10−14). Solvent screening revealed that chlorinated
solvents were better than others, and chlorobenzene was the
most effective medium for the reaction, affording product 3a in
80% yield (Table 1, entries 15−20). The loading of palladium
and photoredox catalyst, the ratio of 1a to 2a, as well as the
reaction time were optimized, which are outlined in Table 1
(entries 21 and 22).
a
Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol), Pd(OAc)2 (5.0
mol %), Eosin Y (3.0 mol %), chlorobenzene (2.0 mL), rt, O2, 3 W
green LED for 15 h. Isolated yield.
b
Next, the generality of this ortho-acylation was investigated
under the optimal reaction conditions. As summarized in Scheme
1, a broad range of substituted acetanilides were examined to be
applicable to this transformation. In general, m- and p-substituted
acetanilides with electron-donating and electron-withdrawing
groups on the benzene rings could be applied to the reaction with
2a and afforded the desired products (3a−j) in good yields. This
reaction also proceeded well as acetanilides, possessing strong
electron-withdrawing groups, such as trifluoromethyl and acetyl
group at the p-positions (3h and 3i). Furthermore, the reactions
of m,p- and m,m-disubstitued acetanilides with 2a generated
good yields of the corresponding products (3k and 3l). It should
be noted that o-methyl, o-fluoro, and o-chloro substituted
acetanilides reacted with 2a to afford the corresponding products
(3m−o) in 76−82% yields under the present conditions, but no
reaction was found in Pd(TFA)2/(NH4)2S2O8 system.3
However, much more hindered o-substituted acetanilides [o-
ethyl, o-(iso-propyl), and (o-tert-butyl) acetanilides], failed in the
reaction under the current catalysts system. N-(Naphthalen-1-
yl)acetamide reacted with 2a, affording the desired product 3p in
68% yield. Except acetanilides, N-phenylbutyramide and N-
phenylpivalamide also underwent the ortho-acylation with 2a to
generate the desired products 3q and 3r in 82% and 77% yields,
respectively.
As shown in Scheme 2, a variety of substituted phenylglyoxylic
acids, including methyl, methoxy, halogen, and trifluoromethyl
groups on the phenyl rings were compatible in the reaction with
1a under the optimal reaction conditions, providing the desired
products (4a−g) in high yields. It is worth noting that ortho-
B
DOI: 10.1021/acs.orglett.5b03192
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Scope of α-Oxocarboxylic Acids
Scheme 3. Plausible Mechanistic Cycle
the desired product and Pd(II) catalyst occurs to complete the
catalytic cycle.
In summary, a dual catalytic system for the ortho-acylation of
acetanilides has been developed, and its applicability to a broad
range of substrates was highlighted. In comparison with single
transition-metal procedure, stoichiometric or overstoichiometric
amounts of oxidants can be used instead by a photoredox catalyst
and molecular oxygen system. It is important to note that Eosin Y
used as photoredox catalyst makes this system both attractive and
a more environmentally sound alternative. Moreover, a plausible
reaction mechanism is proposed based on the control experi-
ments and ESR studies. Further attempts to apply this new type
of combined catalysis to other substrates and metal catalysts are
currently underway.
a
Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol), Pd(OAc)2 (5.0
mol %), Eosin Y (3.0 mol %), chlorobenzene (2.0 mL), rt, O2, 3 W
green LED for 15 h. Isolated yield.
b
ASSOCIATED CONTENT
* Supporting Information
■
S
hindered phenylglyoxylic acids were also feasible coupling
partners, leading to products 4h−j in 78−81% yields. 1-Naphthyl
and 2-naphthyl α-oxocarboxylic acids also gave good yields of the
corresponding products 4k and 4l. Furthermore, aliphatic α-
oxocarboxylic acids, such as 2-oxopropanoic acid and 4-methyl-
2-oxopentanoic acid, were also compatible in this reaction, giving
fair yields of 4m and 4n.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03192.
Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
To understand this transformation, a plausible reaction
pathway was proposed with phenylglyoxylic acid (1a) and
acetanilide (2a), as shown in Scheme 3. At first, Eosin Y was
excited to its excited state (Eosin Y)* under visible light
irradiation. An oxidation of phenylglyoxylic acid with formed
(Eosin Y)* generated benzoyl radical (I), which was trapped by
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to its adduct II
in 63% isolated yield along with the formation of (Eosin Y)•−.
Subsequently, electron transfer from (Eosin Y)•− by molecular
oxygen regenerated Eosin Y for next run and produced
superoxide radical anion III (O2•−), which was confirmed by
electron spin resonance (ESR). However, the Pd-catalytic cycle
could be initiated by a C−H activation of acetanilide to form a
palladacycle intermediate IV, which reacted with the formed
benzoyl radical (I) in situ to afford a Pd(III) intermediate V,
followed by a one-electron oxidation via superoxide radical anion
to generate a Pd(IV) intermediate VI along with the formation of
O22− and H2O2. Subsequently, a reductive elimination of VI to
* E-mail: pphuali@126.com
* E-mail: leiwang88@hotmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21572078, 21372095) and the
Natural Science Foundation of Anhui (No. 1308085MB25) for
financial support of this work.
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