Reactions Nazarov

A variant of the Nazarov reaction is the cyclization of allyl vinyl ketones 8. These will first react by double bond isomerization to give divinyl ketones, and then cyclize to yield a cyclopentenone 9 bearing an additional methyl substituent ... 

For the preparation of divinyl ketones, as required for the Nazarov reaction, various synthetic routes have been developed. A large variety of substituted divinyl ketones, including vinylsilane derivatives, can thus be prepared. The Nazarov cyclization, and especially the vinylsilane variant, has found application for the synthesis of complex cyclopentanoids. 

Shi, F.-Q., Li, X., Xia, Y, Zhang, L. and Yu, Z.-X. (2007) DFT Study of the Mechanisms of In Water Au(I)-Catalyzed Tandem [3,3]-Rearrangement/Nazarov Reaction/[l,2]-Hydrogen Shift of Enynyl Acetates A Proton-Transport Catalysis Strategy in the Water-Catalyzed [l,2]-Hydrogen Shift. Journal of the American Chemical Society, 129, 15503-15512. 

As discussed previously, West and coworkers developed a two-step domino process, which is initiated by a Nazarov reaction. This can be extended by an electrophilic substitution. Thus, reaction of 1-179 with TiCl4 led to 1-182 via the intermediate cations 1-180 and 1-181. The final product 1-183 is obtained after aqueous workup in 99% yield (Scheme 1.43) [23]. It is important to mention here that all six stereocenters were built up in a single process with complete diastereoselectivity hence, the procedure was highly efficient. 

A very new example for the combination of an Au -catalyzed [3,3]-rearrangement and a Nazarov reaction has been disclosed by Zhang and coworker. Thus, cyclopen-tenones could be easily achieved by converting en-ynyl acetates in the presence of AuCl(PPh3)/AgSbF6 [320]. 

Finally, the Nazarov reaction was used to build a quaternary center in a study aimed at the synthesis of a potential precursor of cephalotaxine <2000S2113>. 

The addition of allenyl ether-derived anions to Weinreb [4] or to morpholino amides [5] follows a slightly different pathway (Eq. 13.2). For example, the addition of lithioallene 6 to Weinreb amide 7 at -78 °C, followed by quenching the reaction with aqueous NaH2P04 and allowing the mixture to warm to room temperature leads to cyclopentenone 9 in 80% yield [6]. The presumed intermediate of this reaction, allenyl vinyl ketone 8, was not isolated, as it underwent cyclization to 9 spontaneously [7]. These are exceptionally mild conditions for a Nazarov reaction and are probably a reflection of the strain that is present in the allene function, and also the low barrier for approach of the sp and sp2 carbon atoms. What is also noteworthy is the marked kinetic preference for the formation of the Z-isomer of the exocyclic double bond in 9. Had the Nazarov cyclization of 8 been conducted with catalysis by strong acid, it is unlikely that the kinetic product would have been observed. 

Although the preparation of the substituted allene ether substrates for the Nazarov reaction is not the topic of this chapter, it is necessary to mention a few aspects of their synthesis. Lithioallene 1 (Eq. 13.13) can be trapped with chlorotri-methylsilane to give 35 [6]. Exposure of 35 to sec- or tert-butyllithium leads to allenyl-lithium 36, which can be trapped with alkyl halides or other electrophiles to give 37. Desilylation of 37 leads to 38. This is somewhat laborious, but it leads to allene 38 uncontaminated by propargyl ether 39. Exposure of 39 to n-butyllithium, followed by quenching with acid, typically produces mixtures of 38 and 39 that are difficult to separate. Fortunately, one need not prepare allenes 38 in order to access the C6-sub-... 

A very unusual Nazarov cyclization of propargyl vinyl ketones has been reported by Hashmi et al. (Eq. 13.16) [18]. Propargyl alcohol 50 was oxidized to ketone 51 with the Dess-Martin periodinane. Attempts to purify 51 by column chromatography on silica gel led to cyclopentenone 53 in 59% isolated yield. This suggests that the solid support catalyzed the isomerization of 51 to allenyl vinyl ketone 52, which was not isolated, but which underwent spontaneous cyclization to 53. This result is consistent with earlier observations of the great ease with which allenyl vinyl ketones undergo the Nazarov reaction (cf. 8, Eq. 13.2). 

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

Contrary to the cw-selective Br0nsted acid-catalyzed Nazarov reaction, known metal-catalyzed asymmetric versions often generate the tran -products. Since the cw-cyclopentenones could be readily isomerized to the corresponding trani-products without loss of optical purity (Scheme 62), the advantage of the organocatalytic method is that it provides access to both diastereomers of 150 with high enantioselectivity. 

The Nazarov reaction [196] is a conrotatory electrocyclization involving four electrons over a five-carbon span. Usually, a more highly substituted cyclopentenone is obtained. However, contrathermodynamic products may be generated by placing a silyl group at the p-position of a bare vinyl moiety in the cross-conjugated dienone [197]. The acceptor facilitates and controls the regiochemistry of the cyclization process. 

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 ... 

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... 

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

Metalloenolates derived from a, /9 -unsaturated a-diketones undergo a cyclization reaction with lithium tetramethylpiperidide (LiTMP) to give a -hydroxycyclopente-nones, the first example of a base-induced Nazarov reaction (Scheme 51).85 If these reactions represent conrotations, they are the first such reactions to be described for enolates. 

Thus the natural product damascenone 10, responsible in part for the smell of roses, cyclises in acid to the cation 11 that can lose a proton from one side only to give3 12. The disconnection for the Nazarov reaction is of the single bond in the five-membered ring opposite the carbonyl group 12a. 

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