A novel strategy for the synthesis of uracil derivatives using bis(pentafluorophenyl)imidodicarbonate

Article abstract of DOI:10.1016/j.tetlet.2008.07.183

The disclosure herein describes a novel strategy for the synthesis of uracil derivatives via a solvent-free microwave cyclocondensation reaction using bis(pentafluorophenyl)imidodicarbonate.

Full text of DOI:10.1016/j.tetlet.2008.07.183

Tetrahedron Letters 49 (2008) 6081–6083
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A novel strategy for the synthesis of uracil derivatives
using bis(pentafluorophenyl)imidodicarbonate
*
Stephanie M. Chichetti, Sean P. Ahearn, Alexey Rivkin
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The disclosure herein describes a novel strategy for the synthesis of uracil derivatives via a solvent-free
microwave cyclocondensation reaction using bis(pentafluorophenyl)imidodicarbonate.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 July 2008
Accepted 30 July 2008
Available online 8 August 2008
Uracil derivatives have been shown to be promising pharma-
ceutical agents for the treatment of viral diseases.1 In addition, ura-
cil derivatives have often served as precursors to 2,4-dichloro-
pyrimidines, which have been used as intermediates in the synthe-
sis of a variety of pharmaceutical agents (e.g., 2 ? 3 ? 4).2 The
combination of pharmacological application and synthetic utility
has generated interest in the development of methodology for
the synthesis of uracil derivatives such as 2 (Scheme 1).3
(Eq. 1). This discovery was in large part due to our recent work
in the development of the rapid synthesis of 3-aryl-4-hydroxy-
quinolin-2(1H)-one analogs via a solvent-free microwave cyclo-
condensation reaction using di-(2,4,6-trichlorophenyl)-2-phenyl-
malonate.5
O
μW, 250 oC
20 min
NH
Currently, there are several reported methods for the synthesis
of substituted uracil derivatives.3 However, these synthetic meth-
ods are limited because they often require highly toxic reagents
or the use of harsh conditions.4
In an ongoing medicinal chemistry program, we required the
synthesis of 2,4-dichloropyrimidines such as 3. During the course
of these studies, we discovered that 3-methoxyaniline (5) reacted
efficiently with bis(pentafluorophenyl)imidodicarbonate (6), under
solvent-free microwave conditions, to provide 2 in 72% yield
O
NH2
O
N
H
O
ð1Þ
F
F
F
F
H
F
F
O
N
O
F
F
5
2 (72%)
O
O
F
F
6
The synthesis of 2 via our microwave method proved to be prac-
tical, and we therefore sought to explore the reaction scope further.
To date, the synthesis of uracil derivatives using this type of cyclo-
condensation reaction has not been reported. Herein, we report the
scope of the microwave cyclocondensation to prepare uracil deriv-
atives using bis(pentafluorophenyl)imidodicarbonate.
O
O
KOCN
NH
OH
Acetic Acid
H2O, 90 oC
The results from Table 1 show that bis(pentafluorophenyl)imid-
odicarbonate reacted efficiently with a variety of commercially
available substrates to provide 7–20 in good yields. Reaction of
meta-substituted anilines provided exclusively the regioisomers
7–10. A variety of heterocyclic amines reacted efficiently to pro-
vide 12–14. The broad scope of the reaction is highlighted by the
reaction of (2E)-3-amino-3-(4-bromophenyl)acrylonitrile and 3-
methoxyphenol to provide the corresponding 15 and 16 in high
yield. N-Alkylated anilines 17 and 18 were shown to be well
tolerated in the reaction and provided exclusively the single regio-
isomer. It is worth noting that the reactive functional groups, such
as the methyl ester in 12 and nitrile in 15, were tolerated in the
reaction scope.
O
N
H
O
O
NH2
1
2
Cl
N
O
POCl3
NH
O
N
Cl
O
N
N
N
N
3
4
Scheme 1.
* Corresponding author. Tel.: +1 617 992 2295; fax: +1 617 992 2403.
E-mail address: alexey_rivkin@merck.com (A. Rivkin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.183

6082
S. M. Chichetti et al. / Tetrahedron Letters 49 (2008) 6081–6083
Table 1
Table 2
Microwave reaction of aminesa
Chlorination reaction of uracil derivativesa
O
μW, 250 oC
20 min
O
Cl
N
NH
POCl3
NH
N
O
NH2
O
N
H
O
MeCN
135 oC, 5 h
F
F
F
F
O
N
H
O
O
Cl
H
F
O
F
N
O
F
F
F
5
2 (72%)
19 (68%)
2
O
O
F
6
Cl
Cl
N
N
O
O
Ph
O
N
Cl
O
N
Cl
O
NH
NH
O
Ph
20 (76%)
21 (80%)
O
N
H
O
O
N
O
H
Cl
Cl
7 (53%)
8 (44%)
N
N
N
N
O
O
O
Cl
S
Cl
Cl
NH
NH
22 (78%)
23 (42%)
O
N
H
O
S
N
H
O
Cl
N
Cl
N
9 (74%)
10 (46%)
O
O
N
N
N
N
N
Cl
N
O
NH
NH
Ph
O
O
N
O
N
O
O
24 (27%)
25 (16%)
H
H
O
Isolated yields of compounds, which were characterized by 1H NMR, 13C NMR,
a
11 (55%)
12 (47%)
and LCMS.
O
O
NH
NH
N
N
N
Bis(pentafluorophenyl)imidodicarbonate is easily prepared in one
step by the reaction of commercially available pentafluorophenol
and N-(chlorocarbonyl)isocyanate.6
N
N
N
H
O
N
H
O
Ph
13 (51%)
14 (53%)
The conversion of uracil derivatives to their corresponding 2,4-
dichloropyrimidines is typically accomplished using POCl3.3a This
reaction is highly sensitive, and may fail if the starting material
is not of high purity. The results in Table 2 show that the products
from the microwave cyclocondensations can be successfully con-
verted to the corresponding 2,4-dichloropyrimidines 19–25 with-
out further purification requiring column chromatography.
In summary, we have developed a novel method for the synthe-
sis of uracil derivatives using bis(pentafluorophenyl)imidodicar-
bonate. This is the first example of this type of cyclocondensation
for the synthesis of uracil derivatives. The combination of high
yields, short reaction times, and minimal purification required
makes this microwave method highly efficient. Further application
of bis(pentafluorophenyl)imidodicarbonate in cyclocondensation
reactions is currently under investigation.
O
O
NH
NH
O
N
H
O
O
O
Br
15 (84%)
16 (51%)
O
O
NH
NH
O
O
N
O
N
O
Ph
17 (62%)
18 (78%)
Acknowledgments
a
Isolated yields of compounds, which were characterized by 1H NMR, 13C NMR,
and LCMS.
The authors would like to thank Bruce Adams and Bridget A.
Becker for help in obtaining the spectral data, and Christopher L.
Hamblett for helpful suggestions in the preparation of the
manuscript.
In a typical solvent-free microwave cyclocondensation, a mix-
ture of the substrate and bis(pentafluorophenyl)imidodicarbonate
in a 1:2 ratio, respectively, was heated at 250 °C for 20 min. Upon
completion, the reaction was allowed to reach room temperature
and diluted with diethyl ether and the product, which precipitated
out, was collected by filtration and washed with acetone to remove
trace impurities. The purity of products 7–18, as determined by
LCMS and NMR, was 95–99% requiring no additional purification.
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