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These steric and electronic features of the new diene significantly impart its reactivity towards
electron poor dienophiles. For example, the second cycloaddition of the new diene could not be
effected using electron deficient dienophiles, except with diethylfumarate (demonstrated by Dr.
Bingli Yan). Therefore ethyl vinyl ether was examined as a small, electron rich dienophile to
better match the character of the diene. Heating 156a in a mixture of toluene/ethylvinylether at
90 °C afforded 70% yield of pyran 157a. This was somewhat unexpected since only a few
inverse electron demand hetero-Diels-Alder reactions of α,β-unsaturated amides have been
reported, and generally result in formation of an aromatic compound (e.g., indole, thiazole,
pyrazole). 105 Since lanthanide Lewis acids including Eu(fod)3 have been used to catalyze hetero-
Diels-Alder reactions, we tested this reagent to accelerate the cycloaddition of 156a and ethyl
vinyl ether. With 10 mol% of Eu(fod)3, the reaction proceeded at rt, giving 157a in 95% yield as
a single diastereomer (Scheme 3.29). 106 Exposure of 157a to aqueous HCl afforded aldehyde
158a, resulting from hydrolysis of the acetal moiety and isomerization of the double bond into
conjugation with the amide.
Scheme 3.29 Hetero Diels-Alder reaction of 156a with ethyl vinyl ether.
MeO 2C
O
O
O
N
H
N Bn
O
N
Ph
156a
O
OEt
(excess)
10 mol% Eu(fod) 3
1,2-dichloroethane
rt, 95%
MeO 2C
O
O
O
N
H
N
Bn
O
N
Ph
OEt
O
1M HCl
CDCl 3, rt
MeO 2C
O
O
O
N
H
N Bn
O
N
Ph
157a 158a
Next, hydrolysis of the oxazolidinone moiety in 156a to the parent diamide was explored
as means to introduce structural diversity in the products and increase the number of hydrogen-
bond donors. It was anticipated that this transformation would increase the water solubility of
these compounds, and improve their pharmacological profile. 8 When 156a was heated to 70 °C
58
O
O
H