Nazarov reaction Regioselectivity

Electron-donating and -withdrawing substituents can polarize the conjugated system in the Nazarov Reaction, which facilitates the cyclization and gives better regioselectivity ... 

Recent applications of the Nazarov reaction, the cyclization of a 3-hydroxyphenyl-penta-l,4-dienyl cation, were reviewed.142 Tandem processes and asymmetric cycliza-tions were a particular focus of attention. Irradiation of (40) in aqueous base results in regioselective and stereoselective formation of (42).143 The allylic cation (41) is proposed as the key intermediate. A computational investigation was performed into the cofacial intermolecular n-n orbital interaction between n-conjugated main chains (C H +2) and allylic cations C3H54".144... 

In chapter 16 we shall see how the use of vinyl silanes has solved some of the regioselectivity problems inherent in the Nazarov reaction.19 Meanwhile we look at some recent developments on... 

The most widely used electron-donating a-substituents are alkoxy groups. Indeed, these substrates are so reactive that they enabled the first truly catalytic examples of Lewis acid-catalyzed Nazarov reactions. Whereas stoichiometric quantities of Lewis acid are often required due to slow protonation of the Lewis acid enolate, a-alkoxy appended systems show efficient catalytic turnover. For example, Trauner and co-workers reported the efficient Nazarov cyclization of 37 in the presence of 10 mol % of aluminium trichloride. " Not only do a-alkoxy groups lower the activation barrier to cyclization, but they also localize the resultant positive charge at one a-carbon, ensuring a highly regioselective elimination. 

In 2008, Jin and Yamamoto [23] reported a useful cascade reaction of ketone-tethered 1,3-enynes (Scheme 4.12). Under rather acidic conditions (AuCl3/3AgSbF ), an initial heteroenyne metathesis is suggested to rationalize the intermediacy of dienone 48, which would undergo a Nazarov reaction to form the cyclopentenone product (i.e., 47). Alternatively, regioselective hydrolysis of the alkyne would probably afford diketone 49, which could yield 48 via intramolecular aldol reaction and dehydration. Some adventitious H O might be sufficient, as it is catalytic during the reaction. 

Denmark and co-workers have published extensively on the use of (3-silyl substituted divinyl ketones (see 82) in the Nazarov cyclization. Such silyl groups control the collapse of the intermediate cyclopentenylic cations 84, and thus aid the regioselectivity of elimination, as well as the minimization of side reactions (secondary cationic rearrangements). Such stabilization derives from the known P-cation stabilizing effect of silicon, which through stabilization of 84, ensures maximum efficiency of the cyclization, with controlled formation of the final double bond. An important consequence of the final elimination step is that the double bond is placed in the thermodynamically less stable position (see 85). The most common Lewis acid used in the silicon-directed Nazarov cyclization is anhydrous iron(III) chloride, at temperatures below ambient. Alternatively, in cases where the... 

---