Intramolecular aldol reactions

Intramolecular aldol reactions which give five- or six-membered rings are preferred to those giving strained three- or four-membered rings on the one hand, or eight- to thirteen-membered rings (medium rings) on the other. Acid-catalysed cyclization of the symmetrical diketone nona-2,8-dione can give two enols. ‘Click’ the diagram below to view the possible enol structures:

One of the possible enols can cyclize through an eight-membered cyclic transition state, and the other through a six-membered ring. In each case the product would first be formed as an aldol, this would then dehydrate to the cyclic enone with the same ring size as the transition state. In practice, only the less strained six-membered ring is formed and the enone can be isolated in an 85% yield. ‘Click’ the two different reaction paths below to view 3D models of the reactions:

Six-membered ring formation: (Formed)

Eight-membered ring formation: (Not formed)

P. Hammar, C. Ghobril, C. Antheaume, A. Wagner, R. Baati and F. Himo, J. Org. Chem., 2010, 75, 4728–4736.

W. Gati and H. Yamamoto, Acc. Chem. Res., 2016, 49, 1757–1768.




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