The Journal of Organic Chemistry
NOTE
undergoes formylation of the amino group and halogenation of the
acyl group to give intermediate A, which can be transformed into
3-halo-2-(formamidomethylene)-N-aryl-3-enamide 6 upon treat-
ment with water. An intramolecular cyclization of A occurs to form
intermediate B, which looses dimethylamine to afford pyrimidin-
4(3H)-one 3. In the same fashion, enaminone 2h or 2i undergoes
formylation and halogenation reactions mediated by Vilsmeier
reagent to give intermediate C. Intramolecular cyclization of C,
followed by aromatization of intermediate D with the elimination of
dimethylamine, furnishes pyridine of type 5. When R1 is a methyl
group, pyridine 5 undergoes further halogenation to give rise to
pyridine 4.
In summary, a facile one-pot synthesis of pyrimidin-4(3H)-
one of type 3 was developed via a Vilsmeier reaction of
aminopropenamides 2, which involved sequential formylation,
halogenation, and intramolecular nucleophilic cyclization reac-
tions. The protocol was extended to the synthesis of halogenated
pyridine of types 4 and 5. The simple execution, readily available
substrates, mild conditions, and wide range of synthetic potential
of the products make this protocol very attractive.
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’ EXPERIMENTAL SECTION
Typical Procedure for the Synthesis of Substituted Pyr-
imidin-4(3H)-ones 3 (with 3a1 as an example). To a mixture of
anhydrous DMF (4.0 mmol) and CH2ClCH2Cl (20 mL) was added
POCl3 (6.0 mmol) at 0 °C under stirring. The mixture was stirred for 15
min, to which point 2a (0.44 g, 2.0 mmol) was added in one portion.
Then, the mixture was heated to 70 °C and stirred for 2.0 h. After 2a was
consumed as monitored by TLC, the resulting mixture was poured into
saturated aqueous NaCl (50 mL) and extracted with dichloromethane (3 Â
20 mL). The combined organic phases were washed with water (3Â
20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (silica gel, petroleum ether:
diethyl ether = 8:1) to give a 74% yield of 3a1: white solid; mp112À114 °C;
1HNMR(300MHz, CDCl3) δ2.44 (s, 3H), 5.85 (s, 1H), 6.88 (s, 1H), 7.24
(d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 8.17 (s, 1H), 8.52 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 21.6, 121.3, 123.3, 126.9, 130.7, 131.4, 134.4,
140.3, 150.5, 152.7, 158.8; IR (KBr, neat) 3140, 3064, 2923, 1679, 1579,
1512, 1371, 1232, 892, 820 cmÀ1. Anal. Calcd for C13H11ClN2O: C, 63.29;
H, 4.49; N, 11.36. Found: C, 62.91; H, 4.29; N, 11.08.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, spectral
b
and analytical data, and copies of 1H NMR and 13C NMR spectra
for compounds 2À6. This material is available free of charge via
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: dwdong@ciac.jl.cn.
’ ACKNOWLEDGMENT
Financial support of this research by the National Natural
Science Foundation of China (20572013 and 20872136) is
greatly acknowledged.
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