Toluene derivatives as simple coupling precursors for cascade palladium-catalyzed oxidative C-H bond acylation of acetanilides

Article abstract of DOI:10.1039/c2cc37352a

A palladium-catalyzed cascade cross-coupling of acetanilide and toluene for the synthesis of ortho-acylacetanilide is described. Toluene derivatives can act as effective acyl precursors (upon sp³-C-H bond oxidation by a Pd/TBHP system) in the oxidative coupling between two C-H bonds. This dehydrogenative Pd-catalyzed ortho-acylation proceeds under mild reaction conditions.

Full text of DOI:10.1039/c2cc37352a

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Toluene derivatives as simple coupling precursors for
cascade palladium-catalyzed oxidative C–H bond
acylation of acetanilides†
Cite this: Chem. Commun., 2013,
49, 689
Received 8th October 2012,
Accepted 3rd December 2012
Yinuo Wu,a Pui Ying Choy,a Fei Maob and Fuk Yee Kwong*a
DOI: 10.1039/c2cc37352a
www.rsc.org/chemcomm
A palladium-catalyzed cascade cross-coupling of acetanilide and and Li reported Pd-catalyzed ortho-C–H-bond functionalization of
toluene for the synthesis of ortho-acylacetanilide is described. 2-arylpyridines using aromatic and aliphatic aldehydes, respec-
Toluene derivatives can act as effective acyl precursors (upon tively.10,11 In 2010, Ge and co-workers disclosed the ortho-acylation
sp3-C–H bond oxidation by a Pd/TBHP system) in the oxidative of acetanilides that could be done by employing a-oxocarboxylic
coupling between two C–H bonds. This dehydrogenative Pd-catalyzed acid via a Pd-catalyzed decarboxylative pathway (Scheme 1B).12 In
ortho-acylation proceeds under mild reaction conditions.
2011, our group13 and others14 independently reported oxidative
coupling of aldehydes with acetanilides. Very recently, Yuan showed
that benzylalcohols could act as the acylating agents.15 With our
continuous interest to develop more convenient C–H bond cross-
coupling reactions,16 herein we report a facile synthesis of
2-aminobenzophenone derivatives by Pd-catalyzed ortho-C–H bond
oxidative coupling/acylation of anilides employing toluene deriva-
tives as the simple coupling partners (Scheme 1B).
We began to investigate the feasibility of ortho-C–H bond
acylation by using toluene derivatives as the potential acyl source
(ESI,† Table S1). In our initial trial, para-chlorotoluene was used as
the model coupling partner in the cross-coupling of acetanilide. We
found that this protocol was viable and the desired product 3al
could be afforded in 15% yield (entry 1). A screening of metal
catalysts revealed that Pd(OAc)2 and Pd(TFA)2 were applicable
catalysts, while Ni(acac)2 and Rh(PPh3)3Cl were found to be inferior
(entries 1–6). The effectiveness of the oxidant was also examined
(entries 7–10). TBHP was the most suitable oxidant in this reaction.
Other oxidants screened were essentially not effective. Increasing the
ortho-Acylacetanilides are important structural motifs and resource-
ful intermediates for preparing natural products and pharma-
ceutically useful heterocycles,1 such as fluorenones, cinnoline,
acridones, indazoles, indoles, quinolines and benzodiazepines.2
The traditional method for the synthesis of 2-aminobenzophe-
nones is the Friedel–Craft acylation of anthranilic acids with arenes
in the presence of AlCl3 (Scheme 1A).3 Yet, this reaction suffers
from poor regioselectivity when substituted arenes are employed.
An alternative synthetic pathway for directly accessing this scaffold
is the reaction between anilines and benzonitriles promoted by a
stoichiometric amount of BCl3/AlCl3.4 With the growing demand
for sustainable synthesis of fine chemicals and pharmaceutical
intermediates,5 the direct catalytic C–H functionalization of aniline
derivatives by using a relatively non-hazardous acylating agent and
under mild reaction conditions becomes more desirable.
Direct C–H bond functionalizations/cross-couplings promoted
by transition metal complexes have been successful as a valuable
tool for the modular and facile synthesis of structurally similar, yet
diversified organic molecules.6 With the assistance of a directing
group, the ortho-C(sp2 or sp3)–H bond cleavage (ortho-metallation) can
be facilitated in the presence of transition metals (e.g. Pd, Ir, Rh, Ru,
Cu, Fe, etc.), leading to a versatile C–H bond functionalization upon
trapping with appropriate electrophiles or nucleophiles under basic
or oxidative conditions, respectively.7 In view of minimizing the
waste/side product formation in aromatic ketone synthesis,8 the
oxidative coupling between two C–H bonds from two coupling
partners is highly attractive.9 In 2009, research groups of Cheng
a State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom,
Kowloon, Hong Kong. E-mail: fuk-yee.kwong@polyu.edu.hk; Fax: +852-2364-9932
b School of Pharmaceutical Sciences, Sun Yat-sen University, China
Scheme 1 Traditional approaches and recent catalytic C–H bond
functionalization protocols for the preparation of 2-acylacetanilides.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cc37352a
c
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Table 1 Scope of Pd-catalyzed oxidative ortho-acylation of acetanilide with
different toluene derivativesa
Table 2 Scope of acetanilides in Pd-catalyzed oxidative ortho-acylationa
a
Reaction conditions: acetanilide 1b–n (1.0 mmol), Pd(OAc)2
(10 mol%), TBHP (12 mmol), 4-chlorotoluene 2l (2 mL) were stirred
at 80 1C for 24 h under air. Isolated yields were reported.
a
Reaction conditions: acetanilide 1a (1.0 mmol), Pd(OAc)2 (10 mol%),
TBHP (12 mmol), toluene derivatives 2b–o (2 mL) were stirred at 80 1C
for 24 h under air. Isolated yields were reported.
to ortho-substituted products. Carboxylic ester groups were toler-
able under this catalytic system (3ml and 3nl). We also attempted
stoichiometry of TBHP significantly increased the yield of the to examine tertiary acetanilides (e.g. N-acetyl-1,2,3,4-tetrahydro-
desired product (entries 11–14). Surprisingly, lowering the reaction quinoline and N-methylacetanilide) in this reaction, yet very low
temperature gave a better yield (entries 14–17). These results were substrate conversion and only a trace amount of desired products
possibly due to the minimization of reagent decomposition. The were observed from GC-MS analyses.21
reaction temperature of 80 1C was found to be optimal (entry 15).
In addition to the acetamido group, other directing amido
Further lowering the reaction temperature decreased the substrate moieties were tested in this ortho-acylation reaction (Scheme 2).
conversion. 1,2-Dichloroethane, dioxane and acetonitrile were not iso-Propyl and tert-butyl groups (e.g. 6 and 7) were applicable in
effective solvents for this reaction (entry 18–20).
this reaction while the phenyl moiety gave slightly lower yield of
With our optimized reaction conditions in hand, we next tested the desired product 5.
the scope of the toluene derivative as the simple acyl source
We suggest that the reaction mechanism begins with aliphatic
(Table 1). Naphthalene with the methyl group at either a or b- C–H bond oxidation to aldehyde by the oxidant in the presence of
position gave good product yields (3ab and 3ac). It is worth noting the palladium complex at elevated temperature (Scheme 3).22 Con-
that ortho-hindered substrates were feasible coupling partners in trol experiments revealed that in the presence of only toluene
this catalytic system (3ae and 3af).17 Electron-donating 4-methoxy- and TBHP (i.e. without Pd catalyst), no significant benzaldehyde
toluene gave slightly lower yield of the product 3ag, presumably due
to the difficult C–H bond cleavage of the C(O)–H bond.18 ortho- and
para-Fluoro/chloro substituted toluenes were compatible substrates
(3ai–3al). In particular, the bromo group remained intact during the
course of the reaction (3ai). This entry potentially offers further
structural fine-tuning using other traditional cross-coupling reac-
tions.19 Heterocyclic benzoxazole gave lower product yield (3ao).
Scheme 2 Scope of other amido directing groups.
Various substituted acetanilides (1b–m) were also examined and
the results are compiled in Table 2. No significant electronic effect
of para-substituted acetanilides was found (3cl, 3dl, 3hl and 3jl).
Yet, meta-substituted acetanilides gave good corresponding pro-
duct yields when the electron donating group (e.g. –Me, ÀOMe; 3gl,
3il, respectively) is at the para-position. These results were possibly
due to the facilitation of the electrophilic palladation. In contrast,
meta-chloroacetanilides showed lower yield (3bl). Particularly note-
worthy is that the ortho-substituted acetanilides were also found to
be compatible in this catalyst system (3el and 3fl). These results
were different from previously reported a-oxocarboxylic acid
protocol,20 in which our route may offer a complementary access
Scheme 3 A plausible reaction mechanism.
c
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formation was observed as judged by GC-MS analysis.23 The t-BuOꢀ
radical reacts with TBHP to generate t-BuOOꢀ.24 This species then
abstracts an H atom to give reactive acyl radicals.25,26 Meanwhile, the
acetanilide undergoes directed electrophilic palladation and gener-
ates a palladacyclic intermediate (Scheme 3).27 We hypothesize that
the acyl radicals would react with the palladacycle to afford the
ketone product via either a Pd(IV)28 or a dimeric Pd(III)29 pathway. The
Pd(II) species is regenerated by the reductive elimination process.
Moreover, we also attempted to add a radical scavenger (e.g. ascorbic
acid30) to the reaction, the rate of reactions was greatly suppressed
and only a trace amount of the product was detected. Thus radical
intermediates may involve in this reaction. In order to eliminate the
possibility of the carboxylic acid that could also serve as the acyl
source, we carried out independent experiments which apply
carboxylic acid instead of toluene as a coupling partner. However,
no desired product was obtained from these control experiments.
In conclusion, we have reported a cascade cross-coupling of
acetanilide and toluene for the synthesis of ortho-acylacetanilide.
Toluene derivatives can be employed as effective acyl precursors in
the oxidative coupling between two C–H bonds. This sequential Pd-
catalyzed ortho-acylation proceeds under mild reaction conditions.
Fluoro, bromo, chloro, methoxy, amide, ester and benzoxazolyl
groups are compatible in this catalytic system. We believe that this
new synthetic method using simple toluene derivatives as the
coupling partners would stimulate chemists to advance other rele-
vant catalytic acylation processes.
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We thank the Research Grants Council of Hong Kong
(PolyU5010/11P) for financial support. We are grateful to Prof.
Albert S. C. Chan (PolyU) for sharing GC instruments.
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c
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