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

Article abstract of DOI:10.1002/adsc.200900874

An efficient method was developed for the direct acylation of arene sp ² C-H bonds with aldehydes using palladium acetate as catalyst and peroxide as oxidant. The solvent-free oxidative acylation reaction assisted by a pyridine directing group provides an easy access to aromatic, aliphatic, and optical active ketones.

Full text of DOI:10.1002/adsc.200900874

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DOI: 10.1002/adsc.200900874
2
À
Palladium-Catalyzed Oxidative sp C H Bond Acylation with
Aldehydes
Olivier Baslꢀ,a Johan Bidange,a Qi Shuai,a and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2 K6, Canada
Fax : (+1)-514-398-3797; phone: (+1)-514-398-8457; e-mail: cj.li@mcgill.ca
Received: December 17, 2009; Revised: March 9, 2010; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900874.
À
Abstract: An efficient method was developed for
the direct acylation of arene sp C H bonds with al-
dehydes using palladium acetate as catalyst and per-
oxide as oxidant. The solvent-free oxidative acyla-
tion reaction assisted by a pyridine directing group
provides an easy access to aromatic, aliphatic, and
optical active ketones.
In recent years, the coupling of two aryl C H
2
À
bonds for the synthesis of an arene-arene linkage has
witnessed remarkable progress.[3] In a challenging
fashion, we recently reported the direct cross-coupling
À
of an unactivated arene C H bond with a cyclic
3
2
[4]
À
alkane to produce a new Csp Csp bond. On the
other hand, there are reported methods for the car-
bonylation of arene compounds but they are often
limited by the prefunctionalization of the substrates
or by the necessity to handle toxic carbon monoxide
gas.[5] In order to overcome these limitations, we
À
Keywords: acylation; aliphatic aldehydes; C H
functionalization; oxidative cross-coupling; palladi-
um catalysis
À
postulated the C C bond formation via cross-dehy-
drogenative-coupling between aromatic C H bonds
À
and aldehydes (Table 1).
Metal-catalyzed direct selective functionalization (of
À
an arene) by unactivated C H bond cleavage has at-
tracted considerable attention because it is ecological-
ly and economically advantageous compared to tradi-
tional cross-coupling methods employing organome-
tallic reagents.[1] Nevertheless, in most cases these re-
actions still require a functionalized partner to gener-
Table 1. Optimization of the reaction conditions.
À
À
ate the desired C C bond [Figure 1, Eq. (1)]. The C
H bond adjacent to a heteroatom or a double bond
can be selectively functionalized; we and others have
developed various methods to generate C C bonds
directly from two different C H bonds in the pres-
ence of an oxidizing reagent through a cross-dehydro-
genative coupling (CDC) catalyzed by copper, iron or
other transition metals [Figure 1, Eq. (2)].[2]
À
À
[a]
NMR yield using an internal standard based on starting
À
Figure 1. Metal-catalyzed C H bond functionalization and
CDC reactions.
material 1a.
Not determined.
[b]
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Olivier Baslꢀ et al.
Table 2. Scope of the oxidative acylation reaction.[a]
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Our first attempt employing the previously report-
ed ruthenium-catalyzed oxidative cross-coupling
method[4] failed to generate the desired ketone cou-
pling product of 2-phenylpyridine with benzaldehyde.
Moreover, none of the tested ruthenium and rhodi-
um[6] complexes have shown any catalytic activity
under the described conditions. Many research groups
have focused on exploring the Pd-catalyzed coupling
À
reaction with C H bonds through cyclopalladation as-
sisted by directing groups.[1b,c] As a representative ex-
À
ample, we recently developed an aromatic C H bond
methylation reaction with tert-butyl peroxide cata-
lyzed by a palladium(II) salt.[7] In the present work,
when palladium(II) chloride was employed as a cata-
lyst together with tert-butyl peroxide (Table 1,
entry 4), the expected acylated product was obtained
in 50% yield with a similar conversion. Replacing the
oxidant by tert-butyl hydroperoxide (TBHP) offered
the ketone product in 70% yield as a single regioiso-
mer (Table 1, entry 5). Oxygen, the ideal oxidant, was
also tested under these conditions, but only a trace
amount of the product could be detected by GC-MS
(Table 1, entry 6). An excellent yield was achieved
combining PdACHTUNGTRENNUNG(OAc)2 as a catalyst and TBHP as an
oxidant. During the course of our research, Cheng
and co-workers reported a similar acylation reaction
À
between arene C H bonds and aromatic aldehydes
catalyzed by Pd(OAc)2 using xylenes as a solvent
G
under an atmosphere of oxygen gas.[8] When replacing
aromatic aldehydes by various aliphatic aldehydes,
the desired acylation product was not obtained by
Cheng and co-workers. Under the current solvent-
free conditions, the scope of the palladium-catalyzed
oxidative acylation reaction was also applicable to ali-
phatic aldehydes. Indeed, the method presented
herein provides a solvent-free alternative to the previ-
ously reported method, and overcomes its major limi-
tations.
Next, we examined the scope of the oxidative acy-
lation reaction. Despite the use of benzaldehyde,
which offered the desired ketone in very good yield,
we concentrated our attention on the unprecedented
study of aliphatic aldehydes. Simple aliphatic ade-
hydes, such as decanal, heptanal, hexanal offered the
desired coupling products in satisfactory yields when
employed in a slight excess (Table 2, entries 3, 4, and
5). For lower boiling point aldehydes such as pentanal
and propanal, a larger excess of the aldehyde had to
be used in order to obtain the desired products in
similar isolated yields (Table 2, entries 2 and 8).
Under the optimized conditions, branched and cyclic
aldehydes offered products 3f and 3g in good yields.
An interesting feature of this new oxidative acylation
procedure is the possibility to use acetaldehyde as a
substrate to produce commercially important aceto-
phenone derivatives. In regards of the low boiling
point of this aliphatic aldehyde, the reaction was per-
[a]
[b]
2-Phenylpyridine 1 (0.2 mmol).
Isolated yield based on pyridine substrate.
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Palladium-Catalyzed Oxidative sp C H Bond Acylation with Aldehydes
Table 3. Oxidative acylation of benzo[h]quinone.[a]
formed with a large excess of substrate 2i to produce
the acetophenone derivative product 3i with a re-
markably good yield.
Then we investigated the use of benzo[h]quinoline
(4) as the arene substrate. The planar geometry of 4 is
considered to be responsible for the high efficiency of
À
the metal-catalyzed C H bond functionalization gen-
erally observed.[9] In fact, good yields were obtained
for all aliphatic aldehyde substrates. Acetaldehyde
was also coupled with high efficiency under the de-
scribed conditions. Nevertheless, the acetophenone
derivative product (5e) was isolated along with a non-
separable by-product. This by-product appeared to
result from the aldol condensation of the ketone
product with another equivalent of acetaldehyde. The
identity the a,ß-unsaturated ketone (5g) was con-
firmed by reacting crotonaldehyde with benzo[h]qui-
noline under the optimized conditions (Table 3,
entry 6).
The aldehyde functionality is abundant in nature.
With this new methodology in hand, we considered
the possibility to cross-couple optical pure natural
products with arenes. Interestingly, citronellal[10] react-
ed in high efficiency with benzo[h]quinoline to pro-
duce the enantiomeric pure ketone 5h without race-
mization (Scheme 1).
In order to acquire a better understanding of the
reaction mechanism, the palladium dimer complex A
was synthesized according to the literature proce-
dure.[11] Considering A as a potential active species in
the catalytic cycle, the reaction to produce ketone 5c
was tested in the presence of a catalytic amount of
the palladacycle. The use of A as a catalyst offered
the desired ketone product with the same yield as
when PdACHTUNGTRENNUNG(OAc)2 was employed. After formulating the
hypothesis that the in situ formation of A constitutes
the first step of the postulated catalytic cycle, we de-
cided to investigate the reactivity of this particular
palladium complex in the presence of aldehydes
(Scheme 2). When A was stirred with the aliphatic al-
dehyde 2f in the absence of peroxide and under an
argon atmosphere, no desired product was detected.
Importantly, under the same conditions, benzaldehyde
appeared to be totally unreactive. In fact, all the non-
oxidative conditions tested to demonstrate path A
failed to produce the desired coupling product. These
[a]
[b]
Benzo[h]quinoline 4 (0.2 mmol).
Isolated yield based on pyridine substrate.
Scheme 1. Oxidative acylation with enantiomeric pure citronellal.
Adv. Synth. Catal. 2010, 352, 1145 – 1149
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Olivier Baslꢀ et al.
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Scheme 2. Possible mechanisms for the oxidative acylation.
(m, 4H), 1.53–1.55 (m, 1H), 1.36 (qd, 2H, J1 =3 Hz, J2 =
12.5 Hz), 1.08–1.15 (m, 1H), 0.96–1.02 (m, 2H); 13C NMR
(125 MHz, CDCl3, 293 K): d=209.4, 157.9, 149.4, 141.3,
results tend to demonstrate that a catalytic cycle in-
volving Pd(II)/Pd(0) is unlikely to be operative. Palla-
dium(IV) complexes have been proposed as key inter- 138.9, 136.9, 130.0, 129.4, 128.5, 128.3, 122.9, 122.1, 53.1,
À
22.9, 11.2; IR: nmax =2961, 2930, 2873, 1684, 1586, 1460,
1438, 1426, 748, 729 cmÀ1; HR-MS: m/z=266.1538, calculat-
ed for C18H20ON (M+1): 266.1539.
mediates in the oxidative direct C H bond functional-
ization of arenes and the Stanford group has recently
clearly demonstrated the dramatic role of these high
oxidation state palladium species.[12] Therefore, path B
should be considered as a reasonable alternative. The
oxidation of the Pd(II) complex (A) by peroxide in
the presence of an aldehyde would generate a Pd(IV)
intermediate (8). Intermediate 8 would undergo re-
ductive elimination to produce the desired acylated
product and re-generate Pd(II).
Acknowledgements
We are grateful to the Canada Research Chair (Tier 1) Foun-
dation (to C.-J. L.), NSERC, the Canada Foundation for In-
novation (CFI), and FQRNT for their financial support.
In summary, we have developed a highly efficient
Pd-catalyzed pyridine-directed oxidative sp2 C H
À
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ates and extension of the scope are ongoing and will
be reported in due course.
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2
À
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