Table 1 Palladium coupling of 8-bromoquinoline with acrolein and acrolein diethyl acetal. Influence of the reaction conditions
Acrolein
Acrolein diethyl acetal
Conversion (%)a
Reaction conditions
Conversion (%)a
Selectivity (%)a
Selectivity (%)a
Pd(OAc)2, K2CO3, KCl, nBu4NOAc, DMF, 90 ◦C, 24 h
[Palladacycle] (1%), NaOAc, NMP, 140 ◦C, 24 h
100
93
2/67 (50)b
4/8
>99
2/90
5/3
3/56 (51)b
4/7
67
5/61 (43)b
4/<1
a Determined by GC analysis. b Isolated yield.
Then, the heteroarylation of acrolein diethyl acetal with 8-
bromoquinoline 1a was performed using the commercially avail-
able palladacyclic cat◦alyst (1 mol% Herrmann’s palladacycle,
NMP, NaOAc, 140 C) (Scheme 1).5 Under these reaction
conditions, lower conversion was achieved (67%) compared to
the Cacchi’s conditions (quantitative). This can be attributed to
the rate acceleration effect of added halide ions as previously
reported.11 As expected from our previous work,6 the ester 5,
resulting from a b-hydrogen elimination via the H gem to the
diacetal, was the main product (61% selectivity, 43% isolated
yield) together with traces of quinoline 4 (<1%) produced from
direct dehalogenation of the substrate (Table 1). Under identical
conditions, the reaction of 8-bromoquinoline with acrolein was
studied. After 24 h reaction, high conversion (93%) was achieved
(Table 1); however, the coupling compound 2 was not detected.
After isolation and characterisation, it was established that 5H-
pyrido[3,2,1-ij]quinolin-3-one 3 was synthesized preferentially
(isolated yield 51%), the main by-product being quinoline 4
produced from dehalogenation (7%).
Mesylate and even more triflate derivatives are known to be
efficient substrates for the palladium coupling reaction.12 We
synthesized the triflate derivative 1b and the mesylate derivative 1c
from the commercially available 8-hydroxyquinoline in good yields
according to reported literature procedures.13 Under the same
conditions, the cyclization of the mesylate substrate 1c provided
selectively the tricyclic compound 3 with moderate yield (30%
conversion, Table 2). On the other hand, the triflate substrate 1b
yielded the tricyclic compound 3 (40% isolated yield, Table 2)
after 24 h reaction time. It can be concluded that the leaving group
has no influence on the selectivity of the reaction excepted that
dehalogenation was avoided starting from activated alcohols.
In the literature, few reports were dealing with the synthesis
of such tricyclic compounds that required usually many reaction
steps. To our knowledge, no related mechanism to the formation
of the tricyclic compound 3 via a palladium-catalyzed coupling
reaction was reported in the literature.
Due to the presence of the nitrogen in the quinoline, a small
change in the reaction conditions exhibited a strong modification
in the selectivity of the reaction. Considering the different results,
the following mechanism is proposed that account to the one pot
formation of the tricyclic compound (Scheme 2).
Starting from the acrolein diethyl acetal, the formation of
the propionic ester results from a b-hydrogen elimination that
occurs selectively at the H gem to diacetal group (Scheme 2).
A strong interaction between the nitrogen of the heteroaromatic
ring and the palladium center was proposed: this additional bond
blocks the rotation along the Pd–CH–CH–Ar bond necessary to
perform the syn b-hydrogen elimination of the benzylic hydrogen
reported for the classical Heck coupling. As a consequence,
after hydrolysis the resulting enol acetal yields the arylpropionic
ester 5.
Following the same initial idea, the existence of internal
strong interactions should influence similarly the reactivity of the
acrolein. After the initial steps of the expected Heck arylation of
acrolein by the 8-bromoquinoline, we proposed that a relatively
stable 6-membered palladacycle is formed by coordination of the
quinoline ring through the nitrogen atom to the Pd(II)-center. As
previously, this internal interaction prevents the internal rotation
along the Pd–CH–CH–Ar bond. As a consequence, only hydrogen
gem to the aldehyde may be abstracted, yielding intermediately the
highly reactive ketene 6 together with a palladium hydride species
still coordinated to the ketene moiety. Palladium intermediates are
well known to undergo cascade transformations when adequate
function is present at proximity.9 In the considering reaction,
we proposed that following the initial coupling and b-hydride
=
elimination steps, a syn addition of [H–Pd] to the C N of
the quinoline ring occurs through the transition state TS. As
the next step, the base attacks the acid benzylic proton of 7
to give the species 8 that undergoes reductive elimination to
afford the tricyclic quinolinone 3, regenerating the palladium
catalyst.
In conclusion, starting from 8-substituted quinoline, three
different compounds may be formed by small change in the
reaction conditions. The specific reactivity of the Hermann’s pal-
ladacycle allowed the one pot synthesis of a tricyclic quinolinone.
To our knowledge, the single step procedure described in the
communication is the shortest route to synthesize tricyclic fused
quinolinones. Further works are under progress to extend the
procedure to the synthesis of various benzoquinolizinones and
to establish clearly the mechanism of formation of 3.
Table 2 Palladium coupling of 8-substituted quinolines with acrolein.
Influence of the leaving group
Substrate
Conversion (%)a
Isolated yield 3 (%)
1a
1b
1c
80
100
30
51
40
N.d.b
SN thanks the “Ministe`re de l’Education Nationale, de
l’Enseignement Supe´rieur et de la Recherche” for a grant.
a Determined by GC analysis. b Not determined.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3760–3762 | 3761
©