Palladium-catalyzed oxidative sp2 C-H bond acylation with alcohols

Article abstract of DOI:10.1021/ol200017a

An efficient method was developed for the direct acylation of arene sp ² C-H bonds with alcohols using palladium chloride as a catalyst and peroxide as the oxidant. The alcohols were oxidized to their corresponding aldehydes in situ and efficiently coupled with 2-arylpyridines to give aryl ketones in chlorobenzene.

Full text of DOI:10.1021/ol200017a

ORGANIC
LETTERS
Palladium-Catalyzed Oxidative sp2 C-H
Bond Acylation with Alcohols
2011
Vol. 13, No. 7
1614–1617
†
‡
†
,†
ꢀ ‡
Fuhong Xiao, Qi Shuai, Feng Zhao, Olivier Basle, Guojun Deng,* and
Chao-Jun Li*,‡
Key Laboratory for Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China, and
Department of Chemistry, McGill University, Montreal, QC, H3A2K6, Canada
gjdeng@xtu.edu.cn; cj.li@mcgill.ca
Received January 4, 2011
ABSTRACT
An efficient method was developed for the direct acylation of arene sp2 C-H bonds with alcohols using palladium chloride as a catalyst and
peroxide as the oxidant. The alcohols were oxidized to their corresponding aldehydes in situ and efficiently coupled with 2-arylpyridines to give
aryl ketones in chlorobenzene.
The direct conversion of C-H bonds into C-C bonds
can potentially lead to a more efficient synthesis with a
reduced number of synthetic operations and thus has
attracted great interest.1 Since the seminal work reported
by Murai,2 great progress has been achieved in the transi-
tion-metal-catalyzedactivationand subsequent reactionof
C-H bonds.3 The combination of transition metals and
directing groups is a useful strategytofacilitate arene C-H
bond cleavage4 and to realize C-C5 and C-X6 bond
† Xiangtan University.
‡ McGill University.
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10.1021/ol200017a
Published on Web 02/28/2011
2011 American Chemical Society

formation. Weand othershavedevelopedvariousmethods
to generate C-C bonds directly from two different simple
C-H bonds in the presence of an oxidizing reagent
through a cross-dehydrogenative coupling (CDC) cat-
alyzed by copper, palladium, or other transition metals
(Scheme 1, eq 1).7 The C-H bond adjacent to a heteroa-
tom or an unsaturated C-C bond showed unique reactiv-
ity toward transition metals withhigh selectivity.8 In recent
years, the oxidative coupling of two different aryl C-H
bonds for the synthesis of an arene-arene linkage has
witnessed remarkable progress.7b In a challenging fashion,
we recently reported the direct cross-coupling of an un-
activated arene C-H bond with a cyclic alkane to produce
a new Csp3-Csp2 bond.9
Aryl ketones are key functionalities in the pharmaceu-
tical, fragrance, dye, and agrochemical industries.10 The
classical routes to synthesize aryl ketones mainly rely on
the Friedel-Crafts acylation of aromatic compounds in
the presence of corrosive AlCl3 and oxidation of the
corresponding secondary alcohols by chromium reage-
nts.11 From a synthetic point of view, the direct introduc-
tion of carbonyl functional groups onto the aromatic
motifs via C-H bond cleavage will both be a more
Scheme 1. Transition-Metal-Catalyzed CDC Reactions and
Direct Acylations from Aldehydes and Alcohols
environmentally friendly alternative in aryl ketone synth-
esis and potentially provide a regioselectivity complemen-
tary to classical Friedel-Crafts acylation. However, the
CDC reaction of aryl C-H bonds with acyl C-H bonds
remains a challenge. Recently, we12 and others13 have
developed a transition-metal-catalyzed oxidative sp2 C-H
bond acylation with aldehydes. Various ketones can be
synthesized efficiently and selectively using aromatic or
aliphatic aldehydes as the carbonyl source. Encouraged by
these discoveries, it further occurred to us that alcohols
could serve as the acylation reagents since alcohols can be
readily oxidized into aldehydes.14 Alcohols are naturally
abundant, stable, commercially available, and easy to
handle and thus can be potentially used as ideal acylation
reagents. Herein, we report a palladium-catalyzed regio-
selective acylation of aromatic C-H bonds using alcohols in
the presence of peroxide as an oxidant, affording the ketones
in good yields.
Our initial investigations were focused on the acylation
of 2-phenylpyridine (1a) with benzyl alcohol (2a), and the
results are summarized in Table 1. When 2-phenylpyridine
reacted with 3 equiv of benzyl alcohol in the absence of any
catalyst using 2 equiv of tert-butyl hydroperoxide (TBHP)
as the oxidant, no desired product was detected by GC-MS
and 1H NMR methods (Table 1, entry 1). A trace amount
of the desired product was observed when 5 mol % of PdO
was employed (entry 2). Subsequently, various palladium-
(II) salts were tested for this direct acylation in the presence
of TBHP under an atmosphere of air (entries 3-9).
Moderate yieldswereobservedwhenPd2(dba)3, Pd(acac)2,
and Pd(COD)Cl2 were used as the catalysts. The yields
could be further improved by using Pd(OAc)2 and Pd-
(CH3CN)2Cl2. The best result was obtained using PdCl2 as
the catalyst, and the desired product was obtained in 86%
yield as a single regioisomer (entry 9). Other oxidants were
also tested for this transformation: both TBP (tert-butyl
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Org. Lett., Vol. 13, No. 7, 2011
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Table 1. Optimization of the Reaction Conditionsa
Table 2. Scope of the Oxidative Acylation of 2-Phenylpyridinea
a Conditions: 1a (0.2 mmol), 2a (0.6 mmol), catalyst (5 mol %),
oxidant (2.0 equiv), 140 °C, 24 h in air unless otherwise noted. b GC yield.
c 3 equiv of TBHP were used.
peroxide) and dicumyl peroxide were effective oxidants for
the direct acylation, and the desired product was obtained
in high yields (entries 10 and 11); other peroxides were less
effective, and no desired product was observed when
oxygen was used as the sole oxidant (entries 12-14). The
effect of solvents on this reaction was also investigated.
The reaction was efficient under neat conditions (entry 15).
Other solvents, however, significantly decreased the yields
(entries 16-18). The yield can be improved to 95% by
increasing the oxidant to 3 equiv (entry 19) (after the
reaction, only a small amount of leftover benzyl alcohol
was observed by GC and a large amount of benzaldehyde
was formed).
The direct acylation of 2-phenylpyridine with various
primary alcohols was conducted under the optimized
reaction conditions, and the results are summarized in
Table 2. The reactions with benzylic alcohols bearing
electron-donating groups (entries 2 and 3) and electron-
withdrawing substituents at the aromatic ring (entries 4
and 5) proceeded to give the desired products in good to
excellent yields. A slightly lower yield was obtained when
4-bromobenzyl alcohol was used, and the desired product
was achieved in 78% yield (entry 6). The reaction yield
decreased dramatically when (4-nitrophenyl)methanol was
a Conditions: 1a (0.2 mmol), 2 (0.6 mmol), PdCl2 (5 mol %), oxidant
(3 equiv), 140 °C, 24 h in air unless otherwise noted. b Isolated yield based
on 1a. c GC yield.
used as the substrate (entry 7), and only a 7% yield was
observed by the GC method. The position of the substi-
tuents on the phenyl ring of benzyl alcohols slightly
affected the reaction yield. Moderate to good yields were
achieved when (2-methylphenyl)methanol, (2-chloro-
phenyl)methanol, and (3-methylphenyl)methanol were
used (entries 8-10). To our delight, this reaction is not
limited to benzyl alcohol and its derivatives. Aliphatic
alcoholssuchas1-hexanol and 1-octanol were alsoreactive
toward 2-phenylpyridine and gave the desired products in
62% and 67% yields, respectively (entries 11 and 12). It
should be noted that the reaction gave the monoacylation
products selectively in all cases, and only trace amounts of
biacylated products were observed.
The reaction results of 2-phenylpyridine derivatives
with benzyl alcohol are presented in Table 3. A series of
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Org. Lett., Vol. 13, No. 7, 2011

Table 3. Reaction of Benzyl Alcohol with 2-Arylpyridinesa
Scheme 2. Tentative Mechanism
A tentative mechanism to rationalize this transforma-
tion is illustrated in Scheme 2. The active palladium
catalyst reacts with 2-phenylpyridine by chelation-direc-
ted C-H activation to generate intermediate A.2 The
reaction of A with TBHP generates intermediate B. The
reaction of B with aldehyde which is produced from the
oxidation of alcohol provides the acyl intermediate C
based on Sanford’s work and our early studies.12a,15
Finally, the reductive elimination of intermediate C
affords coupling product 3 and regenerates Pd(II) for
further reactions.
In summary, we have demonstrated a novel palladium-
catalyzed acylation of arene C-H bonds in the presence of
an oxidant. The cheap and readily available benzylic and
aliphatic alcohols were oxidized in situ to aldehydes and
used as acylation reagents. This new methodology enabled
cross-coupling with both benzylic alcohols and aliphatic
alcohols in good yield with high regioselectivity. Explora-
tion of the substrate scope and reaction mechanism will be
further investigated.
a Conditions: 1 (0.2 mmol), 2a (0.6 mmol), PdCl2 (5 mol %), TBHP
(3 equiv), 140 °C, 24 h in air unless otherwise noted. b Isolated yields
based on 1.
functional groups including methyl, methoxy, chloro, and
trifluoromethyl were tolerated under the optimal reaction
conditions, and the desired productswereobtainedingood
to excellent yields (Table 3, entries 1-5). However, only a
trace amount of the acylation product was observed when
2-o-tolylpyridine was used as the substrate (entry 6),
possibly due to the increased steric effect which prevents
the formation of a coplanar conformation of the two
aromatic rings. When benzo[h]quinoline 1i was subjected
to the procedure, a 89% yield of the acylation product was
isolated (entry 8).
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20902076)
and Xiangtan University “Academic Leader Program”
(09QDZ12). We are also grateful to the Canada Research
Chair (Tier I) Foundation (to C.J.L.).
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Arnold, P. L.; Sanford, M. S.; Pearson, S. M. J. Am. Chem. Soc.
2009, 131, 13912.
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