Nazarov Cyclization Reaction - Mechanism

Mechanism

The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by Shoppe to be an intramolecular electrocyclization and is outlined below. Activation of the ketone by the acid catalyst generates a pentadienyl cation which undergoes a thermally allowed 4π conrotatory electrocyclization as dictated by the Woodward-Hoffman rules. This generates an oxyallyl cation which undergoes an elimination reaction to lose a β-hydrogen. Subsequent tautomerization of the enolate produces the cyclopentenone product.

As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization in particular is the generation of the pentadienyl cation followed by electrocyclic ring closure to an oxyallyl cation. In order to achieve this transformation, the molecule must be in the s-trans/s-trans conformation, placing the vinyl groups in an appropriate orientation. The propensity of the system to enter this conformation dramatically influences reaction rate, with α-substituted substrates having an increased population of the requisite conformer due to allylic strain. Coordination of an electron donating α-substituent by the catalyst can likewise increase the reaction rate by enforcing this conformation.

Similarly, β-substitution directed inward restricts the s-trans conformation so severely that E-Z isomerization has been shown to occur in advance of cyclization on a wide range of substrates, yielding the trans cyclopentenone regardless of initial configuration. In this way, the Nazarov cyclization is a rare example of a stereoselective pericyclic reaction, whereas most electrocyclizations are stereospecific. The example below uses triethylsilyl hydride to trap the oxyallyl cation so that no elimination occurs. (See Interrupted cyclizations below)

Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the University of Hawaii show dramatic rate acceleration due to the removal of β-hydrogens, obviating a large amount of steric strain in the s-cis conformer.