Background: The domino Knoevenagel/intramolecular hetero Diels–Alder (IMHDA) reaction
is the most powerful tool in organic synthesis, especially in the area of heterocycles and natural products.
The most widely used heterodienes are usually those where the olefinic bond is flanked between symmetrical
1,3-dicarbonyl compounds. However, the study on the mode of cycloaddition of a heterodiene
wherein the olefinic segment is flanked between a keto C=O and a lactone C=O group is of interest.
Methods: We carried out a domino Knoevenagel/hetero-Diels–Alder reaction of 2-(4-methyl-3-pentenyl)
benzaldehyde 1 with cyclic 1,3-dicarbonyl compounds 2 using 10 mol% L-proline or D,L-proline in
acetonitrile to afford the novel chromenone derivatives. This is the first example of the highly
diastereoselective preparation of tetracyclic naphtho chromenone and isochromeno chromenone
derivatives in a one-pot process.
Results: To test the scope of the IMHDA reaction, aldehyde 1 was also reacted with dimedone (2b)
and N’N-dimethylbarbituric acid (2c). These two reactions smoothly afforded the respective products
3b-c as cis isomers exclusively. Similar results were observed with the unsymmetrical 1,3-dione, such
as 4,4-dimethyl-1,3-cyclohexanedione 2d produced the corresponding product 3d. However, the reaction
of an unsymmetrical 1,3-dione, 4-hydroxycoumarin (2e), with 2-(4-methyl-3-pentenyl)
benzaldehyde 1 in the presence of a catalytic amount of L-proline in refluxing acetonitrile proceeded in
6 h, wherein both the keto C=O and the lactone C=O groups were involved in the cycloaddition to give
a 2.6:1 mixture of the corresponding angular tetrahydrobenzo isochromeno chromenone 4a and the linear
isomer tetrahydrobenzo isochromeno chromenone 4b.
Conclusion: We have elaborated a simple and efficient route to novel polycyclic derivatives by intramolecular
domino Knoevenagel/hetero Diels–Alder reaction of symmetrical as well as unsymmetrical
cyclic 1,3-diones with aromatic aldehyde 1. Importantly, the reaction is diastereoselective to produce
exclusively cis-products. Further exploration towards the synthetic utility of 2-(4-methyl-3-pentenyl)
benzaldehyde is underway in our laboratory.