Palladium-catalyzed C-H activation of anilides at room temperature: Ortho-arylation and acetoxylation

Article abstract of DOI:10.1039/c3ra41981a

Room-temperature ortho-arylation and acetoxylation of anilides have been achieved using cationic palladium (Pd[TFA]⁺) as catalyst and (NH ₄)₂S₂O₈ as oxidant. Preliminary investigation of the mechanism

Full text of DOI:10.1039/c3ra41981a

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Palladium-catalyzed C–H activation of anilides at
room temperature: ortho-arylation and acetoxylation3
Cite this: RSC Advances, 2013, 3, 9649
Fan Yang, Feijie Song,* Wei Li, Jingbo Lan and Jingsong You*
Received 20th January 2013,
Accepted 26th April 2013
DOI: 10.1039/c3ra41981a
www.rsc.org/advances
Room-temperature ortho-arylation and acetoxylation of anilides
have been achieved using cationic palladium (Pd[TFA]+) as
catalyst and (NH4)2S2O8 as oxidant. Preliminary investigation of
the mechanism suggests that palladium may have different
oxidation states in the catalytic cycles of these two transforma-
tions.
temperature, including the addition to C–C multiple bonds,7b,c
the carboxylation,8 the decarboxylative acylation,9 and the above-
mentioned oxidative cross-coupling of two simple arenes.4
Encouraged by the pioneering work, we reasoned that the
utilization of cationic palladium as catalyst could realize the
dehydrogenative coupling reaction of simple arenes with arenes
bearing electron-rich directing groups at room temperature. The
high electrophilicity of cationic palladium species might be
beneficial to the metalation of both coupling partners.
Amides are electron-rich functional groups that are widely used
to direct the highly regioselective ortho-functionalization of
aromatic rings.10 Given the importance of arylated anilides in
the synthesis of valuable aniline derivatives,11 we herein report a
Pd(TFA)+-catalyzed dehydrogenative cross-coupling of anilides
with arenes at room temperature using low-cost, easy-to-handle,
and environmentally friendly (NH4)2S2O8 as oxidant (Scheme 1). In
addition, this catalytic system is successfully extended to the room-
temperature acetoxylation of anilides. Of particular note is that no
exclusion of air or moisture is required in these transformations.
The Pd(TFA)+-catalyzed oxidative C–H/C–H cross-coupling of
pivalanilides with arenes have been successively reported by
Buchwald10g and Dong,10h who employed O2 as the oxidant at 80–
100 uC and Na2S2O8 as the oxidant at 70 uC, respectively. However,
the removal of the pivaloyl group is often difficult after the
coupling reaction. In contrast, the acetyl group of the arylated
acetanilides could be readily removed under basic conditions.11c
Thus, our study mainly focused on acetanilides and the coupling
reaction of N-(o-tolyl)acetamide 1a with o-xylene 2c was first used
to optimize the conditions. It was found that the best result of
95% yield was obtained by using 10 mol% of Pd(OAc)2 as catalyst,
Chelation-assisted palladium-catalyzed direct C–H arylation has
emerged as a promising strategy for the regioselective construction
of biaryl linkages in the past decade.1,2 However, those
transformations frequently encounter elevated temperature (often
more than 100 uC), which may limit their application to the
synthesis of more delicate molecules. In recent years, a number of
coupling reactions between arenes bearing directing groups and
organic halides or surrogates, or organometallic reagents (C–H/C–
X type) have been achieved at room temperature.3 However, the
more challenging yet efficient oxidative C–H/C–H cross-coupling
reactions, which do not need the preactivation of both coupling
partners, have rarely been realized at ambient temperature
probably due to the low reactivity of C–H bonds. In 2006, a
pioneering work of Lu and co-workers disclosed the first
palladium-catalyzed oxidative cross-coupling of two simple arenes
at room temperature, albeit with low catalytic efficiency and
limited substrate scope.4 Very recently, a room-temperature
dehydrogenative
cross-coupling
reaction
between
N-methoxybenzamides and arenes was involved in the first step
for the synthesis of phenanthridinones.5
Cationic palladium species have been found to be highly
reactive catalysts towards aryl C–H bond activation due to their
high electrophilicity.6 Among these catalysts, Pd(TFA)+ generated
in situ from Pd(OAc)2 and trifluoroacetic acid (TFA) is the most
effective and widely used one.7 A variety of Pd(TFA)+-catalyzed C–H
functionalizations of arenes have been achieved at ambient
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College
of Chemistry, and State Key Laboratory of Biotherapy, West China Medical School,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
E-mail: jsyou@scu.edu.cn; fsong@scu.edu.cn; Fax: +86 28-85412203
Scheme 1 Electrophilic Pd2+ catalyzed dehydrogenative cross-coupling of anilides
Electronic supplementary information (ESI) available: detailed experimental
3
with arenes.
procedures and analytical data. See DOI: 10.1039/c3ra41981a
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Table 1 Scope of the ortho-arylation of anilides at room temperaturea
20.0 equiv of TFA as acid, and 2.0 equiv of (NH4)2S2O8 as oxidant
(ESI , Table S1, entry 3). Control experiments showed that the
3
reaction was totally ineffective in the absence of either Pd(OAc)2 or
TFA (ESI , Table S1, entries 15 and 16). Replacing TFA with HOAc,
3
PivOH or HBF4 gave the desired product 3c in less than 16% yield
(ESI , Table S1, entries 9–11), showing the superiority of Pd(TFA)+
3
to other cationic palladium species. Reducing the amounts of
Pd(OAc)2 to 5 mol%, TFA to 10.0 equiv or o-xylene to 10.0 equiv
could all give the coupling product 3c, albeit with slightly lower
efficiency (ESI , Table S1, entries 12–14).
3
With the optimized conditions in hand, the scope of this room-
temperature dehydrogenative coupling reaction with respect to
anilides and arenes was then examined (Table 1). Arenes with
neural or electron-rich substituents smoothly coupled with N-
(o-tolyl)acetamide 1a to give the arylated products in good yields of
up to 95% (Table 1, 3a–3e). However, the reaction of arenes
bearing electron-withdrawing groups such as 1,2-dichlorobenzene
and 1-bromo-2-methylbenzene afforded the desired products in
low yields of 35% and 31%, respectively (Table 1, 3f and 3g). The
use of 1,2-dimethoxybenzene and 1-bromo-2-methylbenzene as
coupling partners resulted in the formation of two regioisomers as
an inseparable mixture (Table 1, 3e and 3g). Surprisingly, when
monosubstituted arenes such as toluene and anisloe were used as
the substrates, only their para-arylated products were obtained
(Table 1, 3b and 3n). It was noteworthy that not only chlorine and
bromine atoms, but also iodine substituents on acetanilides were
compatible with the current catalytic conditions, demonstrating
the high chemoselectivity of this reaction towards C–H activation
(Table 1, 3i–3k). The acetanilide bearing a second potential
directing group such as ester also showed high regioselectivity and
the desired product arylated at the ortho position of amide was
obtained in 62% yield (Table 1, 3l). In addition, other anilides such
as pivalanilides, N-acetyl-1,2,3,4-tetrahydroquinolines and N-acetyl-
2,3-dihydroindoles all smoothly coupled with arenes and their
reaction efficiencies were comparable to acetanilides (Table 1, 3m–
3p). Unfortunately, arenes with other electron-rich chelating
groups such as aryl ureas, O-phenylcarbamates and phenol esters
failed to give the desired arylated products in synthetically useful
yields.
b
c
b
c
d
d
Next, the feasibility of this catalytic system to other C–H
functionalization reactions was investigated. Phenols are widely
found in natural products, medicines, and argochemicals.12
Although many methods have been developed for the synthesis
of phenol derivatives by the transition-metal-catalyzed C–H
oxygenation of arenes,10j,13 rare examples have been realized at
room temperature.10j,13k Previously reported acetoxylation of
acetanilides catalyzed by Pd(OAc)2 at 100 uC offered a good
platform to test the catalytic capability of the Pd(TFA)+/(NH4)2S2O8
system described herein.13f Thus, the reaction of
N-phenylacetamide 1b with HOAc rather than arenes was
attempted under otherwise identical conditions to the arylation
reaction. Pleasantly, the acetoxylated product 4a was obtained in
41% yield. Further optimization increased the yield of 4a to 67%
by reducing the amount of TFA to 5.0 equiv (Table 2, 4a).
Subsequently, it was found that a variety of acetanilides with
methyl, ester, and halogen substituents could all give the
a
Reaction conditions: anilide (0.5 mmol, 1.0 equiv), arene (10.0
mmol, 20.0 equiv), Pd(OAc)2 (0.05 mmol, 10 mol%), TFA (10.0 mmol,
20.0 equiv), (NH4)2S2O8 (1.0 mmol, 2.0 equiv), r.t., 24 h. Isolated
b
yield. Yield for the mixture of two regioisomers. Ratio of the two
isomers determined by 1H NMR is given in the parentheses. 36 h.
c
d
(NH4)2S2O8 (1.5 mmol, 3.0 equiv), 48 h.
acetoxylated products in synthetically useful yields (Table 2, 4b–
4f). When acetanilide was substituted with a strong electron-
withdrawing nitro group, the product was obtained in a low yield
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Table 2 Palladium-catalyzed ortho-acetoxylation of acetanilides at room tem-
peraturea
ð2Þ
To our surprise, the reaction of the complex 5b with HOAc
failed to yield the acetoxylated product. It was suspected that the
presence of anilide substrates in the reaction system might help
dimeric Pd complexes to dissociate and thus facilitate the
acetoxylation reaction.15 Treatment of N-phenylacetamide 1b with
5 mol% of 5b and 2.0 equiv of (NH4)2S2O8 did afford the desired
product 4a in 62% yield (eqn (3)). However, no reaction happened
in the absence of (NH4)2S2O8. Given the high redox potential of
(NH4)2S2O8 (2.01 V),16 it was possible that Pd(II) was oxidized to the
hexacoordinated Pd(IV) intermediate in the acetoxylation reac-
tion.13c,f
ð3Þ
b
In conclusion, the electrophilic Pd(TFA)+-catalyzed direct ortho-
arylation and acetoxylation of acetanilides have been realized at
room temperature using (NH4)2S2O8 as oxidant. Both transforma-
tions are operationally simple and no exclusion of air/moisture is
required. On the basis of preliminary studies, it is possible that
these two reactions proceed via different mechanisms with the
arylation involving a Pd(0)/Pd(II) catalytic cycle and the acetoxyla-
tion involving a Pd(II)/Pd(IV) catalytic cycle.
a
Reaction conditions: acetanilide (0.5 mmol, 1.0 equiv), HOAc (10.0
mmol, 20.0 equiv), Pd(OAc)2 (0.05 mmol, 10 mol%), TFA (2.5 mmol,
5.0 equiv), (NH4)2S2O8 (1.0 mmol, 2.0 equiv), r.t.. Isolated yield.
b
HOPiv instead of HOAc was used. HOPiv = pivalic acid.
We thank the financial support from the National Basic
Research Program of China (973 Program, 2011CB808600), and
the National NSF of China (21202105, 21025205, 21272160, and
21021001).
of 35% (Table 2, 4g). Notably, the pival group could also be
introduced to the ortho position of acetanilides simply by replacing
HOAc with HOPiv (Table 2, 4i).
To gain some insight into the mechanism, the competition
reaction between benzene and deuterated benzene was conducted
for 8 h. As shown in eqn (1), no kinetic isotope effect was observed
for benzene (kH/kD = 1.1), illustrating that the C–H bond cleavage
of simple arenes might proceed via an electrophilic palladation
mechanism and it was not involved in the rate-limiting step of the
ortho-arylation reaction of acetanilides.
Notes and references
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ð1Þ
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trifluoroacetate anion were synthesized from Pd(OAc)2, TFA, and
N-(o-tolyl)acetamide 1a or N-phenylacetamide 1b at room tem-
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3
for details).10h,14 The exposure of complex 5a to o-xylene and TFA
at room temperature resulted in the formation of 3c in 92% yield
(eqn (2)), implying that complex 5a might be the truly active
catalytic species. No (NH4)2S2O8 was needed for this transforma-
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in the process.
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9652 | RSC Adv., 2013, 3, 9649–9652
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