C.-S. Li, E. Lacasse / Tetrahedron Letters 43 (2002) 3565–3568
3567
Diphenylacetylene
O
N O
Ph
Mo(CO)6
79%
PhNCO, cat. Et3N
15%
NO2
O
O
O
Me
Ph
Me
6
80%aq. HCO2H,
HOAc, 60oC, 12h
Me
O
Ph
NH2
O
O
O
Me
Ph
52%
Ph
Ph
7
O
8
Scheme 3.
and then transformed to the desired trisubstituted
pyran-4-one as described before (Scheme 4). Another
possibility would be to take advantage of the acidity of
the proton at the 4-position of the isoxazole ring and
hence, alkyl substituents could potentially be intro-
duced relatively easily.8
for 30 min, filtered through Celite and extracted with
EtOAc (2×). The combined EtOAc extracts were
washed with saturated aqueous NaCl, dried (anhydrous
MgSO4) and concentrated. The crude residue was chro-
matographed over silica gel and eluted with ꢀ30%
EtOAc in hexanes to provide the isoxazole
intermediate.
In summary, we have developed a convenient synthesis
of 2-substituted, 2,5-disubstituted and 2,6-disubstituted
pyran-4-ones from isoxazole intermediates.9 The isoxa-
zole intermediates were easily synthesized from readily
available starting materials such as nitro compounds
and acetylenes. A common intermediate such as the
5-stannyl substituted isoxazole might provide the
opportunity to easily synthesize a wide range of pyran-
4-one analogs. In addition, it could be further function-
alized to provide highly substituted pyran-4-ones.
Reductive cleavage of the isoxazole intermediate. To a
0.05 M solution of isoxazole intermediate (1.0 equiv.) in
acetonitrile:water (9:1) was added Mo(CO)6 (0.5
equiv.). The mixture was heated under reflux and
stirred for 3 h. Solvents were evaporated in vacuo. The
residue was chromatographed over silica gel and eluted
with 50% EtOAc in hexanes to give the enamino ketone
intermediate.
Cyclization of the enamino ketone intermediate. The
enamino ketone intermediate (1 mmol) was dissolved in
HOAc (1 mL) and diluted with 80% aqueous HCO2H
(4 mL). The mixture was heated to 60°C and stirred
overnight. After cooling to room temperature, the mix-
ture was added to water and extracted with EtOAc.
The EtOAc extract was washed successively with 1 M
aqueous NaOH (3×10 mL, until the washing was not
acidic) and brine; dried (anhydrous MgSO4) and con-
centrated. The residue was chromatographed over silica
gel and eluted with EtOAc to give the pyran-4-one
product.
General experimental procedures
1
All compounds have been characterized by H NMR,
MS and either HRMS or combustion analysis.
Synthesis of the isoxazole intermediate. To a solution of
acetylene (3.0 equiv.) and nitro compound (1.0 equiv.)
in benzene (so as to give a 0.2 M solution of the
acetylene) was added Et3N (two drops) and phenyl
isocyanate (4.0 equiv.). The mixture was refluxed
overnight and cooled to room temperature. Water was
added and the mixture was stirred at room temperature
80%aq. HCO2H,
HOAc, 60oC, 3h
O
N O
O
N O
O
Me
Me
Ph
Ph
85%
9
3a
NaOH, PhCH2Br,
DMF, r.t., 4h
O
N O
Mo(CO)6
79%
Me
Ph
Ph
37%
+ 19% dialkylated
product
10
80%aq. HCO2H,
HOAc, 60oC, 12h
Me
Ph
O
O
Ph
O
NH2 O
Me
Ph
61%
12
11
Ph
Scheme 4.