Efficient synthesis of functionalized pyrimidones via microwave-accelerated rearrangement reaction

Article abstract of DOI:10.1016/j.tetlet.2005.12.057

An efficient synthesis of functionalized pyrimidones via microwave-accelerated rearrangement reaction of amidoxime DMAD adducts is described. In most cases, the pyrimidone formation was furnished in reasonable yield after 2 min of microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2005.12.057

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1315–1317
Efficient synthesis of functionalized pyrimidones via
microwave-accelerated rearrangement reaction
Yong-Li Zhong,* Hua Zhou, Donald R. Gauthier, Jr. and David Askin
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 2 December 2005; accepted 12 December 2005
Available online 28 December 2005
Abstract—An efficient synthesis of functionalized pyrimidones via microwave-accelerated rearrangement reaction of amidoxime
DMAD adducts is described. In most cases, the pyrimidone formation was furnished in reasonable yield after 2 min of microwave
irradiation.
Ó 2005 Elsevier Ltd. All rights reserved.
Substituted pyrimidones of type C represent an impor-
tant class of compounds due to their well-known biologi-
cal activity.1 Pyrimidones of this type were recently
found to inhibit a series of hepatitis C virus (HCV)
NSSB polymerase2 and have also shown anxiolytic
activity.3 Most synthetic strategies toward these densely
functionalized heterocycles are based on two synthetic
methods. The first is a three-step sequence that involves
two condensations and a deprotected step from com-
mercially available materials.4 The second method uses
a Michael reaction between substituted amidoximes of
type A with dimethyl acetylenedicarboxylate (DMAD)
followed by thermal rearrangement of intermediate B
(Scheme 1).5 The Michael reaction/thermal rearrange-
ment sequence typically affords pyrimidones in only
30–40% overall yield in the few examples that have been
reported.2,3,5
reactions.6 Reactions that typically require high temper-
atures and extended reaction times have been tremen-
dously accelerated using microwave irradiation.7
Herein, we report on a two-step, one-pot conversion
of aldoximes to pyrimidones via a microwave-assisted
thermal rearrangement of intermediate B.
For reaction optimization studies, we focused on ami-
doxime DMAD adducts 1a, which were isolated as a
mixture of cis/trans (ratio ca. 6–10:1) crystalline solid
Table 1. Solvent effect for the microwave-assisted rearrangement
O
NH2
OH
Microwave
O
CO2Me
HN
N
180-185 oC
solvent
N
CO2Me
The use of microwave irradiation to assist organic reac-
tions has shown considerable advantages over thermal
F
MeO2C
1a
1
F
Entries
Solventsa
Neat
1,2-Dichlorobenzene
DME
1,2-Dichloroethane
1,4-Dioxane
DMF
IPA
Toluene
Acetonitrile
o-Xylene
Assay yield (%)
1
2
3
4
5
6
7
8
52
62
54
50
66
38
35
47
48
68
NH2
O
NH2
N
OH
Microwave
o-xylene
DMAD/MeOH
-10 oC to rt
R
N
O
CO2Me
HN
R
R
N
CO2Me
OH
A
B
CO2Me
C
Scheme 1.
9
10
Keywords: Pyrimidone; Hydroxyamidine; Rearrangement; Hetero-
cyclic compounds; Microwave irradiation.
a DME = ethylene glycol dimethyl ether, DMF = N,N-dimethyl-
*
Corresponding author. Tel.: +1 732 594 8372; fax: +1 732 594
formamide; IPA = 2-propanol.
5170; e-mail: yongli_zhong@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.057

1316
Y.-L. Zhong et al. / Tetrahedron Letters 47 (2006) 1315–1317
in quantitative yield by treatment of 4-fluoro-N0-
hydroxybenzenecarboximidamide with DMAD in
methanol. Intermediate 1a was irradiated8 for 2 min
(internal temperatures reached 185 °C) in a variety of
solvents and all reactions gave >95% conversion (Table
1). We were also delighted to find that several solvents
provided assay yields in >60%.9
The desired pyrimidone 1 is isolated by direct precipita-
tion from the crude mixture via filtration to afford 60%
isolated yield in >95% purity (entry 1).
The scope of the reaction sequence was investigated and
all substrates shown in Table 2 were converted to pyrimi-
dones in reasonable yield over two steps. In practice, the
Table 2. Synthesis of pyrimidones
Entry
Starting material
Product
Conditions
Yield (%)b
O
N
NH2
N
OH
HN
1
2
3
rt to 185 °C over 85 s
60
61
48
OH
CO2Me
R
R = F
R
1 R = F
R = CF3
R = CF3O
2 R = CF3
3 R = CF3O
O
NH2
OH
CO2Me
HN
4a
rt to 185 °C over 160 s
50
F3C
N
OH
F3C
N
4
O
NH2
N
OH
HN
5
6
7
rt to 185 °C over 85 s
rt to 182 °C over 85 s
rt to 185 °C over 85 s
50
50
59
N
5
CO2Me
N
OH
N
O
N
NH2
N
OH
HN
CO2Me
OH
6
O
O
O
OH
CO2Me
OH
N
HN
O
O
N
NH2
7
O
N
NH2
N
OH
HN
R
8
9
rt to 185 °C over 85 s
48
50
OH
R = Me
CO2Me
R
8 R = Me
9 R = CO2Et
R = CO2Et
O
N
OH
CO2Me
HN
H
N
NH2
N
10a
rt to 185 °C over 120 s
39
H
N
OH
O
Ph
10
O
Ph
O
OH
HN
NH2
H
H
N
N
OH
N
CO2Me
N
11a
rt to 170 °C over 300 s
67
O
O
MeO
OMe
MeO
OMe
OMe
OMe
11
a The hydroxyamidines were prepared by reaction of their corresponding nitrile with 50% aqueous hydroamine in methanol.
b Isolated yield.

Y.-L. Zhong et al. / Tetrahedron Letters 47 (2006) 1315–1317
1317
5. Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423–
1424.
amidoxime was dissolved in methanol, DMAD
(1.05 equiv) was added dropwise at ꢀ10 °C, and then
slowly allowed to warm to ambient temperature over
6 h (>98% conversion). The reaction mixture was con-
centrated and then dissolved in o-xylene. The solution
was microwave irradiated8 for 1–2 min and the resulting
slurry was aged at room temperature for 1 h. The crys-
talline solid was isolated by filtration, washed with tolu-
ene, MTBE, and finally 1:1 methanol/0.5 N HCl. The
solid was then dried under vacuum to afford the desired
pyrimidone. A variety of substituted aldoximes includ-
ing aromatic (entries 1–6),10 and functionalized aliphatic
(entries 7–9), and N-protected a-amino amidoximes (en-
tries 10 and 11) were efficiently cyclized to the corre-
sponding pyrimidones in an average isolated yield of
52%.11
6. For reviews, see: (a) Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199–9223; (b) Lidstro¨m, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
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In conclusion, we have developed a practical and effi-
cient procedure for the rapid construction of highly
functionalized pyrimidones via microwave irradiation.
Acknowledgement
We thank Dr. Philip J. Pye for helpful discussions.
8. Smith Synthesizer microwave set at 80% of a total output
of 1000 W or with the temperature control set to 185 °C.
9. The control experiment using thermal heat: A solution of
1a (1.00 g) in o-xylene (5 mL) was heated in reflux using an
oil bath for 3.5 h to give >95% conversion. The assay yield
and isolated yield of desired product 1 were 61% and 53%,
respectively.
References and notes
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11. All new compounds gave satisfactory analytical and
spectral data in accordance to their structures. Selected
1
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8.05 (dd, J = 8.7, 5.5 Hz, 2H), 7.33 (t, J = 8.7 Hz, 2H), 3.84
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8.61 (br d, J = 4.5 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.88
(td, J = 8.0, 1.5 Hz, 1H), 7.44 (dd, J = 8.0, 4.5 Hz, 1H),
4.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 169.8, 156.9,
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