Chen et al.
SCHEME 2. Preparation of 4-Chloro-2(1H)-pyridinones
SCHEME 1. Preparation of 3-Bromo-2(1H)-pyridinones
Results and Discussion
activities9 and their application as intermediates in the construc-
tion of complex natural products.10 In the syntheses of 2(1H)-
pyridone derivatives, the most general approach for accessing
substituted 2-pyridinones is from acyclic substrates which often
incorporate a Michael addition as the key step.11 However, these
methods are not general for the preparation of halogenated or
N-substituted 2(1H)-pyridinones which are essential for further
elaboration of the 2(1H)-pyridinone core.12 To the best of our
knowledge, only one route has been reported in the literature
describing the synthesis of halogenated N-substituted 2(1H)-
pyridinones starting from acyclic substrates.13 In 2002, Dechoux
and co-workers reported a synthetic route to this class of
compounds which centered on a Michael-type addition between
an amine and a methyl propiolate followed by bromocyclization
of the ensuing δ-dienaminoester.13a This method required long
reaction times (ca. 48 h). Later, an extension of this methodology
was achieved by Vounatsos and co-workers through the
utilization of microwave heating (Scheme 1), and the reaction
time was reduced to 30 min but with lower product yields (29-
53%).13b Most recently, we have reported the preparation of
4-chloro-2(1H)-pyridinones via the Vilsmeier-Haack reaction
of 1-acetyl,1-carbamoyl cyclopropanes (Scheme 2).13c At the
same time, as our interest continued in the development of
synthetic applications of functionalized ketene dithioacetals,3-6,14
we also found that 4-chloro/bromo N-substituted 2(1H)-pyri-
dinones could be prepared via a domino reaction of R-acetyl-
R-carbamoyl ketene dithioacetals with Vilsmeier reagents.
In the initial experiments, based on our previous research on
the reactions of R-acetyl ketene dithioacetals with Vilsmeier
reagents,3c,14 the reaction of R-acetyl-R-carbamoyl cyclic ketene
dithioacetal 1a16 with Vilsmeier reagent (DMF-POCl3) was
selected as the model reaction. It was found that R-chlorovinyl
ketene dithioacetal 2a1 was obtained in 90% yield by reacting
1a1 with 2.0 equiv of POCl3 in DMF at room temperature for
4-5 h (Scheme 3). To our delight, when the reaction of 1a1
(1.0 equiv) with POCl3 (2.0 equiv) was performed in DMF at
100 °C for 50 min, the 4-chloro N-substituted 2(1H)-pyridinone
3a1 could be isolated in 87% yield (Scheme 3 and Table 1,
entry 1). On the other hand, it was observed that when 1a1
(1.0 equiv) was treated with excess POCl3 (5.0 equiv) in DMF
at 100 °C for a longer reaction time (up to 2 h) under otherwise
identical conditions as above, 3a1 was produced in 85% yield
and further formylation was not observed. This apparently is
due to the stronger electron deficiency of the core of 3a1 and
is different from our recent observations on the Vilsmeier-
Haack reaction of 1-acetyl-1-carbamoyl cyclopropanes (Scheme
2).13c The structure of 3a1 was determined based on its
spectroscopic and analytical data and confirmed by X-ray crystal
analysis.15
The above result indicates a novel and efficient route to
4-halogenated N-substituted 2(1H)-pyridinones,13 with the nature
of further elaboration of the 2(1H)-pyridinone core and an active
dithiocarbonyl functionality, from readily available acyclic
starting materials. Therefore, the scope of this reaction was
extended to some other substrates 1a (R ) -(CH2)3) or 1b (R
) Et) with variable R and R1 groups under the above optimal
conditions, and the results are described in Table 1. It is obvious
that the electronic effects of substituents at the nitrogen (R1)
have little influence on this reaction. All of the selected
substrates, bearing an aryl group (with either an electron-
donating or electron-withdrawing group on the benzene ring)
and an aliphatic group at the nitrogen, could efficiently react
with DMF-POCl3 to give the corresponding 4-chloro N-
substituted 2(1H)-pyridinones 3 in high yields (75-87%,
Table 1, entries 1-8). More importantly, the reaction also pro-
ceeded smoothly even in the case of using the substrates with
a sterically hindered ortho-substituted aromatic amine unit, for
example 1a4-1a7, and the desired products 3a4-3a7 were
obtained dominantly in high yields (Table 1, entries 4-7). In
addition, the desired 4-bromo-2(1H)-pyridinone 3a9 was also
obtained under the identical conditions as above in good
yield by reacting 1a1 with the DMF-PBr3 system (Table 1,
entry 9).
(9) (a) Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. ReV. 2000, 20,
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D. J. Chem. Soc., Perkin Trans. 1 1991, 2537-2540. (e) Thorsett, E. D.;
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(15) Crystal data for 3a1: C15H12Cl3NOS2, red crystal, M ) 392.75,
monoclinic, P21/c, a ) 8.7752(9) Å, b ) 22.221(2) Å, c ) 8.8261(9) Å,
R ) 90.00°, â ) 97.234(2)°, γ ) 90.00°, V ) 1707.3(3) Å3, Z ) 4, T )
293(2), F000 ) 880, R1 ) 0.0383, wR2 ) 0.0827; for the details please see
Supporting Information.
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9260 J. Org. Chem., Vol. 72, No. 24, 2007