Cyclization, Nazarov

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  

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

With the use of trimethylsilyl-substituted starting materials after Denmark et al., the disadvantageous formation of a mixture of isomers can be avoided. The vinyl silane derivatives react by loss of the TMS group in the last step  

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. 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

Acid-catalyzed electrocyclic formation of cyclopentenone from divinyl ketone. 

Example 2, cyclization of in situ generated di-vinyl ketone  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 174, Springer-Verlag Berlin Heidelberg 2009 

Nazarov, I. N. Torgov, I. B. Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (1900—1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an as)Tnmetric Nazarov cychzation as of the Bayliss—Hillman reaction. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 187, Springer International Publishing Switzerland 2014 

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The few exceptions to this general rule arise when the a-carbon carries a substituent that can stabilize carbonium-ion development well, such as oxygen or sulphur. For example, 1-trimethylsilyl trimethylsilyl enol ethers give products (72) derived from electrophilic attack at the /J-carbon, and the vinylsilane (1) reacts with a/3-unsaturated acid chlorides in a Nazarov cyclization (13) to give cyclopentenones such as (2) the isomeric vinylsilane (3), in which the directing effects are additive, gives the cyclopentenone (4) ... 

An important cyclization procedure involves acid-catalyzed addition of diene-ketones such as 58, where one conjugated alkene adds to the other conjugated alkene to form cyclopentenones (59). This is called the Nazarov cyclization Cyclization can also give the nonconjugated five-membered ring. ... 

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]. 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

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... 

Nazarov cyclizations of methoxymethoxylallene deliver a-methylenecyclopent-2-enone derivatives 105-107 [49, 50]. 

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. 

Mercuric acetate and thallic acetate have also been used for the oxidative cydiza-tion of vinylallenes (Eq. 13.24) [29]. Exposure of vinylallene 75 to stoichiometric mercuric acetate in acetic acid led to cydopentenone 76 in 75% yield. With thallium acetate as the oxidant, the yield of 76 was 60%. The presumed mechanism of the oxidative cyclization involves a Nazarov cyclization of acetoxymercury intermediate 77. 

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]. 

This approach is related to Mehta s in so far as the carbon atoms and were connected to afford a desired hydroazulene (Eq. 2). Ensuing manipulation of functional groups led to the functionalized racemic hydroazulene 263. The cyclopentenone 261 was synthesized from an acyclic precursor by a Nazarov cyclization [134]. 

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... 

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