A. Rivkin, B. Adams / Tetrahedron Letters 47 (2006) 2395–2398
Table 2. Microwave reactions of anilines with malonatesa
2397
Given the simplicity and potential generality of this
microwave reaction, we investigated the scope for the
synthesis of a variety of derivatives of 4-hydroxy-3-phen-
ylpyridin-2(1H)-one as shown in Table 2. The results
show that a variety of commercially available hetero-
cyclic amines, aminocrotononitrile, and aminocyclo-
hexenone reacted efficiently with activated malonate 7
to provide the desired corresponding products 20–30
in high yields and purity (90–99%). In most cases,
malonate 2 also provided products 20–30, albeit in lower
yields. These products were purified via precipitation
with diethyl ether and filtration.
O
O
EtO
or
OEt
OH
Ph
2
N
N
N
N
NH2
N
H
O
Cl
Cl
O
O
19
20 (2: 58% 7: 95%)b
O
O
Cl
Cl
Cl
Cl
7
μW, 250 oC, 15 min
In summary, we have shown that activated malonate 7 is
superior to malonate 2, with respect to the scope of the
microwave reaction to form 4-hydroxy-3-phenylpyridin-
2(1H)-one derivatives. The yields and purification of the
products are also improved by use of malonate 7. In
addition, using activated malonate 7 allows for the reac-
tion to proceed efficiently in closed vessel microwave
systems, which are commonly used by medicinal chem-
ists. The short reaction time, in combination with the
high yields and minimal purification of the products,
makes this microwave reaction with activated malonate
7 ideal for the rapid preparation of libraries of 4-hydro-
xy-3-phenylquinolin-2(1H)-ones and related products.
Further investigations of the scope of this microwave
reaction with di-(2,4,6-trichlorophenyl)-2-phenylmalo-
nate are currently underway.
OH
OH
N
O
O
N
O
N
O
H
H
O
22 (2: 0% 7: 71%)
21 (2: 20% 7: 83%)
OH
OH
O
N
O
O
N
O
N
N
N
O
N
H
H
23 (2: 64% 7: 89%)
24 (2: 0% 7: 71%)
OH
Ph
OH
N
N
N
N
N
O
N
O
H
H
Ph
Acknowledgement
25 (2: 48% 7: 87%)
26 (2: 56% 7: 91%)
We thank Christopher J. Dinsmore, Mark T. Goulet,
and Ben Munoz for their helpful suggestions in the prep-
aration of this manuscript.
O
OH
O
OH
N
O
N
N
H
O
N
H
O
Supplementary data
27 (2: 63% 7: 92%)
28 (2: 58% 7: 87%)
Supplementary data associated with this article can
OH
N
OH
O
N
O
N
H
N
H
O
H
References and notes
Br
29 (2: 36% 7: 80%)
30 (2: 61% 7: 86%)c
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mined by LCMS and NMR, was 95–99% when malon-
ate 7 was used and no additional purification was re-
quired. In contrast, reactions with malonate 2 gave,
following filtration, products that were impure and
required further purification via reverse phase liquid
chromatography.