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References
is obvious that the aromatic aldehydes containing elec-
tron-donating group afforded the corresponding prod-
ucts in higher yields and purities than those substrates
containing electron-withdrawing group. Particularly, in
the cases of 4-Cl, 3-Br, 4-CN and 3,5-dichloro substi-
tuted benzaldehydes (entries 7, 10, 11 and 13), the
purities of the products were relatively low. In princi-
ple, the electron-deficient imines should be favored for
the aza hetero-Diels–Alder reaction with Danishefsky’s
diene. However, in our previous work we observed the
same tendency of substituent effect on the yields of the
reaction.12 It was speculated that the cycloadducts con-
taining electron-withdrawing groups might be unstable
and decomposed during the reaction process. Accord-
ingly, reducing the reaction time for cycloaddition step
to 0.5 h afforded the corresponding products in
improved yields or purities when the reactions of 4-Cl,
3-Br, 3,5-dichlorobenzaldehydes were taken as the sub-
strates (entries 16–18). Therefore, reducing the reaction
time is a key point for getting satisfactory results for
the reaction of electron-withdrawing group substituted
benzaldehydes. This should be considered when a par-
allel liquid-phase synthesis was performed using this
strategy. Moreover, the reaction of 4-cycanobenzalde-
hyde under same experimental conditions gave the cor-
responding PEG-bound product 7k in >90%
conversion, but the purity of final product 8k after
hydrolysis was only ꢀ50%. HPLC and HRMS analyses
showed that the cyano group in the product 8k was
partially hydrolyzed into amide during the basic cleav-
age of polymer-supported product, and as a result, led
to the low purity of product. The cycloaddition reac-
tions of olefinic and aliphatic aldehydes (such as trans-
cinnamaldehyde and 3-phenylpropionaldehyde) were
also examined under various experimental conditions,
but the conversion of PEG-bound amine for the forma-
tion of the corresponding PEG-bound products 7 was
rather low (<50%).
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In conclusion, we have developed a novel liquid-phase
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Acknowledgements
16. A typical procedure for the synthesis of 1-(4-car-
boxyphenyl)-2-(4-methoxyphenyl)-2,3-dihydro-4-pyridone
(Table 1, entry 4) is as follows: the PEG supported amine
4 (0.23 g, 6.25×10−2 mmol, containing all 0.13 mmol
NH2), 4-methoxybenzaldehyde (0.15 mL, 1.25 mmol),
Zn(ClO4)2·6H2O (4.65 mg, 1.25×10−2 mmol) and the
Danishefsky’s diene (0.40 mL, 75% purity, 1.50 mmol)
were added to 0.5 mL of methanol and the reaction
Financial support from the National Natural Science
Foundation of China, the Chinese Academy of Sci-
ences, the Major Basic Research Development Program
of China (Grant No. G2000077506) and the Science
and Technology Commission of Shanghai Municipality
are gratefully acknowledged.