Cation Nazarov cyclization

Upon treatment of a divinyl ketone 1 with a protic acid or a Lewis acid, an electrocyclic ring closure can take place to yield a cyclopentenone 3. This reaction is called the Nazarov cyclization Protonation at the carbonyl oxygen of the divinyl ketone 1 leads to formation of a hydroxypentadienyl cation 2, which can undergo a thermally allowed, conrotatory electrocyclic ring closure reaction to give a cyclopentenyl cation 4. Through subsequent loss of a proton a mixture of isomeric cyclopentenones 5 and 6 is obtained ... 

A third and critical advance in the development of the Nazarov cyclization was the demtmstration that it belongs to the general class of cationic electrocyclic reactions (Scheme 4). This broadened its definition to include reactions which involve pentadienylic cations or equivalents and thus expanded the range of precursors for cyclopentenones. Further, the stereochemical features of electrocyclization enhanced the utility of the reaction and, in addition, stimulated the development of a photochemical variant. 

The Nazarov cyclization is an example of a 47r-electrocyclic closure of a pentadienylic cation. The evidence in support of this idea is primarily stereochemical. The basic tenets of the theory of electrocyclic reactions make very clear predictions about the relative configuration of the substituents on the newly formed bond of the five-membered ring. Because the formation of a cyclopentenone often destroys one of the newly created centers, special substrates must be constructed to aUow this relationship to be preserved. Prior to the enunciation of the theory of conservation of orbital symmetry, Deno and Sorensen had observed the facile thermal cyclization of pentadienylic cations and subsequent rearrangements of the resulting cyclopentenyl cations. Unfortunately, these secondary rearrangements thwarted early attempts to verify the stereochemical predictions of orbital symmetry control. Subsequent studies with Ae pentamethyl derivative were successful. - The most convincing evidence for a pericyclic mechanism came from Woodward, Lehr and Kurland, who documented the complementary rotatory pathways for the thermal (conrotatory) and photochemical (disrotatoiy) cyclizations, precisely as predicted by the conservation of orbital symmetry (Scheme 5). 

Beyond the disrotatory or conrotatory stereochemical imperative which must accompany all Nazarov cyclizations there exists a secondary stereochemical feature. This feature arises because of the duality of allowed electrocyclization pathways. When the divinyl ketone is chiral the two pathways lead to dia-stereomers. The nature of the relationship between the newly created centers and preexisting centers depends upon the location of the cyclopentenone double bond. The placement of this double bond is established after the electrocyclization by proton loss from the cyclopentenyl cation (equation 5). Loss of H, H or in this instance generates three tautomeric products. The lack of control in this event is a drawback of the classical cyclization. Normally, the double bond occupies the most substituted position corresponding to a Saytzeff process. The issue of stereoselection with chiral divinyl ketones is iUustrated in Scheme 7. The sense of rotation is defined by clockwise (R) or counterclockwise (5) viewing down the C—O bond. Thus, depending on the placement of the double bond, the newly created center may be proximal or distal to the preexisting center. If = H the double bond must reside in a less substituted environment to establish stereoselectivity. 

A interesting variation on this theme employing the isomeric enynol acetates (Scheme 24) has been developed by Rautenstrauch. The cyclizations are induced by a Pd" catalyst in warm acetonitrile. The proposed mechanism is intriguing. Reaction is initiated by an anchimerically assisted palladation to (35) followed by opening the dioxolenium ion to a pentadienylic cation (36). The closure of (36) is analogous to the silicon-directed Nazarov cyclization in the ejection of the Pd" electrofuge from (37). Both secondary and tertiary acetates can be employed as well as both acyclic and monocyclic systems. 

Janka, M., He, W., Frontier, A. J., Eisenberg, R. Efficient Catalysis of Nazarov Cyclization Using a Cationic Iridium Complex Possessing Adjacent Labile Coordination Sites. J. Am. Chem. Soc. 2004, 126, 6864-6865. 

Allylsilanes are good acceptors of 1,3-dipolar compounds such as nitrones [503] and oxyallyl cations [504]. West et al. have used allylsilanes to trap oxyallyl cations generated during the Nazarov cyclization of l,4-dien-3-ones (Scheme 10.188). The tandem bicyclization provides bicyclo[2.2.1]heptanes with high diastereoselectivity. 

Another synthetically useful carbon bond-forming reaction involves reaction of diiron nonacarbonyl with halo-carbonyl compounds. Noyori found that a,a -dibromoketones (498) react with diiron nonacarbonyl [Fe2(CO)9] to give an iron stabilized alkoxy zwitterion (499). The intermediate Jt-allyl iron species reacts with alkenes in a stepwise manner (initially producing 500) to give cyclic ketones such as 501, 23 and the product is equivalent to the product of a [3-t2]-cycloaddition with an alkene (sec. 11.11). This cyclization method is now known as Noyori annulation. This reaction is related to the Nazarov cyclization previously discussed in Section 12.3.C. Enamines can react with 498, but the initially formed enamino ketone product eliminates the amino group to form cyclopentanone derivatives. Intermediates such as 499 may actually exist as cations hound to a metal rather than as the alkoxide-iron structures shown.323b-d noted that Zn/B(OEt)3 is... 

Electrocyclic reactions are not limited to neutral polyenes. The cyclization of a pentadienyl cation to a cyclopentenyl cation offers a useful entry to five-membered carbocycUc compounds. One such reaction is the Nazarov cyclization of divinyl ketones. Protonation or Lewis acid complexation of the oxygen atom of the carbonyl group of a divinyl ketone generates a pentadienyl cation. This cation undergoes electrocyclization to give an allyl cation within a cyclopentane ring. The allyl cation can lose a proton or be trapped, for example by a nucleophile. Proton loss occurs to give the thermodynamically more stable alkene and subsequent keto-enol tautomerism leads to the typical Nazarov product, a cyclopentenone (3.220). 

In cases that provide a mixture of alkene regioisomers or in which the less-substituted alkene is desired, control of the position of the new alkene is possible using a trialkylsilyl group to direct its introduction. Desilylation is generally preferred over deprotonation, and the known (3-cation stabilizing effect of a silyl group helps to reduce side reactions resulting from the intermediate aUyl cation. The silicon-directed Nazarov cyclization has been made use of twice in a synthesis of the sesquiterpene A -capnellene 349 (3.221). ... 

The Nazarov cyclization is a four-electron cyclization and occurs thermally by a conrotatory process. The stereochemical outcome across the new carbon-carbon bond is often obscured by the loss of a proton at one of these centres during the cyclopentenone formation. If, however, the proton loss occurs exo to the five-membered ring or if the aUyl cation is quenched by a nucleophile, then the stereochemistry can be observed. For example, trapping the allyl cation by reduction with... 

It should be pointed out that this reaction has been carried out photochemically (i.e., the photo-Nazarov cyclization Fi2) or under near-critical water conditions. More importantly, it has been improved to occur in a controllable fashion, through a directed Nazarov cyclization or an interrupted Nazarov reaction. It is worth noting that two practically directed Nazarov cyclizations have been developed, one by Denmark by using the jS-cation stabilizing effect and electrofuge of silicon (Scheme 2),2 > 2tt,6,i3 and the other from Ichikawa by application of a /3-cation destabilizing effect and the... 

Q -electron-donating effect of fluorine to control the regiochemistry (Scheme 3). Analogous to silicon, tin is also used to direct the Nazarov cyclization. " The interrupted Nazarov reaction has been developed by West et al. to extend the reaction of the cationic endocyclic intermediate with carbon nucleophiles. Furthermore, this reaction has been extended to imino-Nazarov cyclization of vinyl allenyl imine. ... 

The Nazarov cyclization reaction may be defined as an acid (protic or Lewis) induced cationic Trr-electrons electrocyclic ring closure reaction of a,a -divinyl ketones to form cyclopentenones. 

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