Angewandte
Chemie
substrates with 3a. For example, an F-substituted aryl boronic
acid displayed no reactivity under similar conditions (Table 2,
entry 9) and again, an aryl boronic acid with an NO2
substituent did not react with 3a to give the desired product
3n, thus indicating that the electronic effect has a strong
impact on the outcome of the reaction (Table 2, entry 10).
A comparison of the reactivity of a specific arylborane
with ketones 1 and 3 showed that the substituent of the ketone
may also have a significant effect on the reaction. Thus,
a series of substituted aryl ketones 3 f–3o were tested for the
À
catalytic C C bond grafting reaction with different arylbor-
onic acids (Table 2, entries 11–21). Ketone 3 f, which bears an
electron-donating methoxy group on the phenyl ring, was
found to undergo a coupling reaction with 3,5-dimethylphe-
nylboronic acid to form the desired product 3e in 54% yield
(Table 2, entry 11). It is worth noting that the yield of product
3c increased to 95% when naphthalen-2-yl(quinolin-8-yl)me-
thanone (3j) was reacted with 3-methylphenylboronic acid
under standard reaction conditions (Table 2, entry 12). To
gain further insight into the reaction, the reactions of some
ketones with electron-withdrawing groups on the aromatic
ring were also investigated. For instance, 4-chlorophenyl(qui-
nolin-8-yl)methanone (3k) reacted with arylboronic acids
that bear electron-donating groups to give the desired
products in 66–72% yield (Table 2, entries 13--15). As in
other Rh-catalyzed reactions,[7a,12] a Cl substituent on the
phenyl rings also worked in this catalytic system, which might
allow further modification of the product. The reaction of 4-
fluorophenyl(quinolin-8-yl)methanone (3l) with boronic
acids that bear electron-donating groups proceeded smoothly
to give the corresponding products in 61–70% yield (Table 2,
entries 16–18). However, when 4-nitrophenylboronic acid,
a substrate that bears a strong electron-withdrawing group,
was used to react with the ketone 3l, no product was obtained
(Table 2, entry 19). In contrast, the reaction of 4-nitrophe-
Figure 1. Proposed mechanism for the reaction of ketones with aryl-
boronic acids catalyzed by [Rh(PPh3)3Cl].
a prolonged reaction time (48 h). On the other hand, the
reaction proceeded very fast under an atmosphere of pure O2
(1 atm); ketone 1a was consumed completely in less than 12 h
and the reaction gave 3a in 72% yield along with some
unidentified by-products. This evidence clearly points to the
important role of O2 in the catalytic cycle, and thus proves
that the in situ oxidation of RhI to RhIII by O2 in the presence
of CuI is the turnover-limiting step. Furthermore, the crude
product mixture of 3b and phenylboronic acid obtained under
1
air was analyzed by H NMR spectroscopy (Scheme 2). The
integration results indicated that the crude product mixture
contained 3a and 4-methyl-1,1’-biphenyl (3ba) in a molar
ratio of 1:0.9 (for the molar ratio of biphenyl and the
substituted quinolinone derivative from other reaction sys-
tems, see Table S3 in the Supporting Information). This result
proves that the reductive elimination of B to C, which is the
key step, occurs (Figure 1). Although the key intermediates
were not isolated, the above evidence confirm the proposed
mechanism.
nyl(quinolin-8-yl)methanone (3o),
a ketone that bears
a strong electron-withdrawing group, with phenylboronic
acid or 4-methoxyphenylboronic acid gave the desired
products 3a and 3 f in 93% and 91% yield, respectively
(Table 2, entries 20 and 21).
Based on these findings and previous reports, the follow-
ing reaction mechanism is proposed (Figure 1). First, a RhI
À
complex activates an acetyl C C bond of the chelating ketone
It should be noted that 8-benzoylquinolines have been
frequently used as a core structure for the design of modern
pharmaceuticals and related compounds,[15] such as tubulin
polymerization inhibitors,[15a,b] cannabinoid (CB1) receptor
ligands,[15c] drugs for the treatment of bone metabolic
disorders,[15d] and antiulcer agents.[15e] The current method
1a to afford a five-membered cycloacyl RhIII intermediate
A.[1,5,13] Transmetalation of A with arylboronic acid then gives
intermediate B, in which the Rh center bears a methyl and an
aryl group. Subsequent elimination of the methyl and phenyl
groups on B lead to RhI intermediate C after a phosphine
ligand insertion. The RhI complex C is then oxidized to RhIII
complex D by CuI in the presence of O2.[14] Another
transmetalation of RhIII complex D with arylboronic acid
gives aryl RhIII complex E. Finally, reductive elimination of E
gave product 3a and the RhI complex after the coordination
of two phosphine ligands.
In this proposed mechanism, O2 is the terminal oxidant.
To prove this hypothesis, a catalytic reaction was conducted in
an N2 atmosphere using phenylboronic acid and 1a as the
reagents. In contrast to the 93% yield obtained in air, this
reaction did not give 3a in isolatable quantities, even after
Scheme 2. Molar ratio of the product mixture.
Angew. Chem. Int. Ed. 2012, 51, 12334 –12338
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim