Nazarov cyclization reactions

The Nazarov cyclization of vinyl aryl ketones involves a disruption of the aromaticity, and therefore, the activation barrier is significantly higher than that of the divinyl ketones. Not surprisingly, the Lewis acid-catalyzed protocols [30] resulted only in decomposition to the enone derived from 46,47, and CO. Pleasingly, however, photolysis [31] readily delivered the desired annulation product 48 in 60 % yield. The photo-Nazarov cyclization reaction of aryl vinyl ketones was first reported by Smith and Agosta. Subsequent mechanistic studies by Leitich and Schaffner revealed the reaction mechanism to be a thermal electrocyclization induced by photolytic enone isomerization. The mildness of these reaction conditions and the selective activation of the enone functional group were key to the success of this reaction. 

As described above, our synthetic strategy involves the convergent construction of the central cyclopentanone ring with a carbonylative cross-coupling reaction and a photo-Nazarov cyclization reaction (Chart 2.2). The electrophilic coupling component 51 was synthesized by an intramolecular Diels-Alder reaction [34] and the nucleophilic coupling component 52 by a vinyiogous Mukaiyama aldol reaction [35]. 

Braude, E. A., Coles, J. A. Syntheses of polycyclic systems. III. Some hydroindanones and hydrofluorenones. The mechanism of the Nazarov cyclization reaction. J. Chem. Soc., Abstracts 1952, 1430-1433. 

Nazarov cyclization reaction. Synthesis of cyclopentenones by the acid-catalyzed electrocyclic ring closure of divinyl or allylvinyl ketones available by hydration of divinylacetylenes. 

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. 

SCHEME 2.19 Silicon-directed Nazarov cyclization reaction in presence of Lewis acid. 

Nazarov Cyclization Reaction Neber Rearrangement Nef Reaction Nef Synthesis Negishi Cross Coupling Nencki Reaction... 

Acid-catalyzed cyclization of divinyl ketone 56-57 occurs by conrotatory cyclization of 3-hydroxy pentadienyl cation [31]. This type of cyclization reaction is known as Nazarov cyclization reaction [31]. 

When the coupling of vinyl triflates is carried out in the presence of carbon monoxide and lithium chloride, carbon monoxide insertion occurs, 3fielding unsymmetrical divinyl ketones (eqs 4 and 5). This is a particularly useful procedure for the formation of intermediates for the Nazarov cyclization reaction. ... 

Quite recently. Rueping et al reported Nazarov cyclization reaction catalyzed by a phosphoramide (Scheme 2.107) [185]. Although phosphoric acid (41k) is effective for the Nazarov reaction, use of an N-triflyl phosphoramide (50b) improved the enantioselectivity. This is the first example of the enantioselective organocatalytic electrocyclization reaction. 

SCHEME 549 Rh-catalyzed cascade intermolecular [5 + 2] cycloaddition/Nazarov cyclization reaction. 

Recently, Rueping et al. [36] disclosed the first enantioselective Nazarov cyclization reaction organocatalyzed by a chiral Brpnsted acid. The proposed reaction pathway involves a conrotatory 4n electrocyclization of the divinyl ketone 83 leading to the formation of an enol intermediate which is then snbjected to enantioselective protonation by the chiral Brpnsted acid 82b. This electrocyclization-protonation reaction was conducted with various divinyl ketones 83 under optimized conditions, i.e. in the presence of the chiral A -triflyl phosphoramide 82b (5 mol%) in chloroform at -10°C, affording the corresponding cyclopentenones 84 with 67-78% ee (for examples, see 83a-c 84a-c, Scheme 3.44). 

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 ... 

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. 

Si-directed Nazarov cyclization (13, 133-134). Denmark2 has extended the Si-directed cyclization of (i-silyl divinyl ketones to preparation of linear tricycles (triquinanes). These cyclizations proceed very readily even at low temperatures, and the position of the double bond is controlled by the silyl group. The reactions... 

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. 

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). 

An alternative approach for generating the pentadienyl carbocation that is needed for the Nazarov cyclization has been demonstrated by de Lera and co-workers [20, 21] (Eq. 13.18). Vinylallene acetal 56 is converted to a ca 1 1 mixture of cyclopentenes 57 and 58 upon exposure to toluenesulfonic acid in acetone at room temperature. The reaction presumably involves initial generation of carbocation 59 that undergoes conrotation to give 60. Intramolecular trapping of the carbocation by the pendant hydroxyl group leads to the observed product. Depending on whether the conrotation in 59 takes place clockwise or counterclockwise, E- (57) or Z-(58) products are formed. 

The Ir(lll) complex also funchoned as a catalyst in a tandem Nazarov cyclization-Michael addition. The reaction of monocyclic a-alkylidene-P-keto-y.b-unsaturated ester with nitroalkene gave bicyclic cyclopentenones which possessed an alkyl side chain, with high yield and diastereoselectivity (Scheme 11.36) [47]. 

Nazarov cyclization, 45, 1 Nef reaction, 38, 3 Nenitzescu reaction, 20, 3 Nitriles ... 

Rueping employed N-triflyl phosphoramide 13d in the Nazarov cydization to afford cis-cyclopentenones with moderate diasterselechvihes in excellent yields and ee s. This represents the first example of an organocatalytic electrocyclizahon reaction [62]. Notably, related asymmetric metal-catalyzed Nazarov cyclizations often provide the trans-product [63]. Later, Rueping applied N-triflyl phosphoramide 13e... 

The synthetically most useful reaction of this type is the Nazarov cyclization, in which a cross-conjugated dienone like 4.89 forms a cyclopentenone 4.92 when treated with acid, in this case a Lewis acid. 

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