Solvent-free microwave synthesis of novel 6-hydroxypyrimidin-4(1H)-one derivatives using arylmalonates

Article abstract of DOI:10.1016/j.tetlet.2007.08.134

The disclosure herein describes the rapid synthesis of novel 6-hydroxypyrimidin-4(1H)-one derivatives via a solvent-free microwave cyclocondensation reaction using di-(2,4,6-trichlorophenyl)malonates and a variety of heterocyclic amines.

Full text of DOI:10.1016/j.tetlet.2007.08.134

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8250–8252
Solvent-free microwave synthesis of novel
6-hydroxypyrimidin-4(1H)-one derivatives using arylmalonates
Stephanie M. Chichetti, Sean P. Ahearn, Bruce Adams and Alexey Rivkin*
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur,
Boston, MA 02115, United States
Received 10 August 2007; accepted 29 August 2007
Available online 7 September 2007
Abstract—The disclosure herein describes the rapid synthesis of novel 6-hydroxypyrimidin-4(1H)-one derivatives via a solvent-free
microwave cyclocondensation reaction using di-(2,4,6-trichlorophenyl)malonates and a variety of heterocyclic amines.
Published by Elsevier Ltd.
Derivatives of 4-hydroxypyridin-2(1H)-one have been
shown to be promising pharmaceutical agents for the
treatment of cancer,1 central nervous system disorders,2
sex hormone-related conditions,3 the stimulation of
bone formation,4 and the suppression of allergy associ-
ated inflammations.5 As a result of these therapeutic
properties, interest has grown in the development of
methodology for the rapid synthesis of 4-hydroxy-
pyridin-2(1H)-one derivatives.3a,6
chlorophenyl)malonates and a variety of heterocyclic
amines.
μW, 250 oC
15 min
OH
NC
Cl
NC
NH2
Cl
Cl
Cl
N
O
H
ð1Þ
ð2Þ
2 (83%)
1
O
O
O
O
We recently reported the synthesis and SAR studies of
Cl
Cl
Cl
Cl
N
3-aryl-4-hydroxyquinolin-2(1H)-one analogues as
a
3a
novel class of fatty acid synthase inhibitors (e.g., 2,
IC50 = 136 nM).1 In order to expedite these SAR studies
we developed a rapid synthesis of 3-phenyl-4-hydroxy-
μW, 250 oC
15 min
OH
N
quinolin-2(1H)-ones via
a solvent-free microwave
cyclocondensation reaction using di-(2,4,6-trichloro-
NH2
N
O
phenyl)-2-phenylmalonate (e.g., 1 ! 2, Eq. 1).7
Cl
Cl
4
5 (74%)
O
O
During the course of these studies we discovered that
2-aminopyridine (4) reacted efficiently with di-(2,4,6-
trichlorophenyl)-2-phenylmalonate (3a), under our
microwave conditions, to provide 4-hydroxy-3-phenyl-
2H-pyrido[1,2-a]pyrimidin-2-one (5) in 74% yield
(Eq. 2).8 This microwave reaction proved to be very
practical and we therefore sought to explore the reaction
scope further. To date, the scope of this type of cyclo-
condensation reaction has not been reported. Herein,
we report the scope and the yields of the microwave
cyclocondensation reaction to prepare derivatives of
6-hydroxypyrimidin-4(1H)-one by using di-(2,4,6-tri-
O
O
Cl
Cl
Cl
Cl
3a
The results from Table 1 show that di-(2,4,6-trichloro-
phenyl)-2-phenylmalonate reacted efficiently with a vari-
ety of commercially available heterocyclic amines and 2-
methylpropionamidine to provide the desired products
(4–17) in good yields. In a typical solvent-free micro-
wave reaction, a mixture of the heterocyclic amines
and di-(2,4,6-trichlorophenyl)-2-phenylmalonate in a
1:2 ratio, respectively, was heated at 250 °C for
15 min. The internal pressure of the reaction vessel never
surpassed 1 bar. Upon completion, the reaction was
*
Corresponding author. Tel.: +1 617 992 2295; fax: +1 617 992
2403; e-mail: alexey_rivkin@merck.com
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.08.134

S. M. Chichetti et al. / Tetrahedron Letters 48 (2007) 8250–8252
8251
allowed to reach room temperature and diluted with
diethyl ether and the precipitate, which was the product,
collected by filtration. The purity of products 5–16, as
determined by LCMS and NMR, was 95–99% and no
additional purification was required. The only exception
was product 17, which required purification via
chromatography.
phenyl)malonates (Table 2, 3a–f).9 The results show that
a variety of di-(2,4,6-trichlorophenyl)malonates reacted
efficiently with 1,3-benzoxazol-2-amine to provide the
desired corresponding products 13a–f in high yields.
These products were purified via precipitation with
diethyl ether and filtration.
Table 2. Microwave reaction with various malonatesa
Table 1. Microwave reaction of heterocyclic aminesa
OH
μW, 250 oC
15 min
μW, 250 o
15 min
C
R
OH
N
N
N
N
O
NH2
O
N
O
NH2
Cl
N
O
Cl
Cl
13a-f
R
18
Cl
O
O
4
5 (82%)
O
O
O
O
Cl
Cl
Cl
Cl
O
O
Cl
Cl
Cl
Cl
3a-f
3a
Malonate
R
Product (yield)
O
OH
N
OH
Cl
3a
13a (90%)
EtO
N
N
O
N
O
6 (87%)
7 (74%)
3b
3c
3d
3e
3f
13b (84%)
13c (88%)
13d (87%)
13e (75%)
13f (67%)
Cl
OH
N
OH
N
N
S
N
O
O
N
O
8 (89%)
9 (79%)
Me
OH
OH
N
N
N
N
O
O
10 (74%)
11 (89%)
OH
N
OH
N
O
a Isolated yields of compounds, which were characterized by 1H NMR,
13C NMR, and LCMS.
O
S
O
S
EtO
N
O
N
O
12 (78%)
13a (90%)
In summary, we have shown that the short reaction
time, in combination with the high yields and minimal
purification of the products, makes this microwave
reaction with di-(2,4,6-trichlorophenyl)malonates ideal
for the rapid preparation of 6-hydroxypyrimidin-
4(1H)-one derivatives. The key to the success of these
microwave reactions is the use of di-(2,4,6-trichlor-
ophenyl)malonates. The advantage of using di-(2,4,
6-trichlorophenyl)malonates is that they form the inter-
mediate anilide and undergo electrophilic aromatic
cyclization more efficiently than less reactive malonates,
such as diethyl-2-phenylmalonate. Furthermore, the
by-product from the microwave reaction is 2,4,6-tri-
chlorophenol, which reduces, relative to ethanol, the
internal pressure in a closed microwave reaction vessel
and allows the reaction to proceed efficiently. Further
application of di-(2,4,6-trichlorophenyl)malonates in
cyclocondensation reactions is currently under
investigation.
OH
N
OH
N
N
O
N
O
14 (82%)
15 (81%)
OH
N
OH
N
N
O
N
O
N
OH
16 (74%)
17 (79%)
a Isolated yields of compounds, which were characterized by 1H NMR,
13C NMR, and LCMS.
To further demonstrate the simplicity and potential gen-
erality of this microwave reaction, we conducted the
microwave reaction with a variety of di-(2,4,6-trichloro-

8252
S. M. Chichetti et al. / Tetrahedron Letters 48 (2007) 8250–8252
Smith, R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2615–2620;
Acknowledgments
(b) DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Fisher, M.
H.; Lo, J. L.; Yang, Y. T.; Cheng, K.; Smith, R. G. Bioorg.
Med. Chem. Lett. 1999, 9, 2621–2624.
The authors would like to acknowledge Christopher
J. Dinsmore, Mark T. Goulet, and Ben Munoz for their
helpful suggestions in the preparation of the manuscript.
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