The Nazarov Cyclization allows the synthesis of cyclopentenones from divinyl ketones.
Mechanism of the Nazarov Cyclization
The reaction is catalyzed by strong Lewis or Brønstedt acids, and one or more equivalents of the Lewis acid are normally necessary:
The regioselectivity of the cyclization is quite low if the side chains have a similar degree of substitution.
Nazarov reactions with more highly substituted substrates generate the product having the double bond with the highest degree of substitution:
Electron-donating and -withdrawing substituents can polarize the conjugated system in the Nazarov Reaction, which facilitates the cyclization and gives better regioselectivity:
W. He, X. Sun, A. J. Frontier, J. Am. Chem. Soc., 2003, 125, 14278. DOI
Another approach uses silicon's ability to stabilize β-carbocations (β-effect). In addition, the TMS group behaves like a proton and is removed after nucleophilic activation:
S. E. Denmark, T. K. Jones, J. Am. Chem. Soc., 1982, 104, 2642.
A limiting factor is also the stereoselectivity. As the substituents α to the keto group are prone to racemization using strong Lewis or Brønstedt acids due to equilibria involving proton transfer, the diastereoselectivity is often low:
A more detailed look at the mode of the cyclization reveals that 4 π electrons are involved in a conrotatory mechanism, but any diastereoselectivity involving the new formed σ bond is lost after elimination of the proton:
The Nazarov Cyclization is a rare example of a Lewis acid-catalyzed 4-π conrotatory electrocyclic reaction. Asymmetric induction could be achieved if a chiral Lewis acid were able to control the direction of the conrotatory closure. However, only a few such reactions have been reported. Common drawbacks are low enantioselectivity and the use of nearly stoichiometric amounts of the chiral Lewis acids, which must still be overcome.
V. K. Aggarwal, A. J. Belfield, Org. Lett., 2003, 5, 5075. DOI
The catalyst shown below to the right induces an asymmetric proton transfer, which generates the stereogenic center α to the keto group:
The Nazarov reaction can be performed under mild, metal-free reaction conditions using molecular iodine as the catalyst. Various divinyl ketones including aromatic systems undergo the I2-catalyzed reaction with good yields. Addition of iodine to the double bond or a putative iodine-catalyzed cis-trans isomerization seem not to be important side reactions here.
J. J. Koenig, T. Arndt, N. Gildemeister, J.-M. Neudörfl, M. Breugst, J. Org. Chem., 2019, 84, 7587-7605.
Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-Nazarov Cyclization: Access to Functionalized 2-Aminopyrroles
C. Shu, Y.-H. Wang, C.-H. Shen, P.-P. Ruan, X. Lu, L-W. Ye, Org. Lett., 2016, 18, 3254-3257.