Nazarov cyclizations mechanism

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. 

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 majority of yc/n-dichIorocycIopropane substrates examined in this study provided the desired a-chlorocyclopentenones as a result of sequential electrocyclic ring opening and Nazarov cyclization. In general, those substrates lacking additional substitution on the cyclopropane moiety provided products 75 selectively as a result of regioselective elimination to deliver the more electron-rich olefin. The mechanism for this transformation is believed to involve disrotatory halocyclopropane ring opening... 

The Nazarov cyclization (Chapter 36) normally gives a cyclo-pentenone with the alkene in the more substituted position. That can be altered by the following sequence. Give a mechanism for the reaction and explain why the silicon makes all the difference. 

Ironically, until 1953, Nazarov incorrectly described the mechanism of the general transformation which now bears his name. In 1952, Braude and Coles were the first to suggest the intermediacy of car-bocations and demonstrated that the formation of 2-cyclopentenones actually proceeds via the a,a -divi-nyl ketones (equation 1). This fact together with further mechanistic clarification, has led to the specific definition of the Nazarov cyclization as the acid-catalyzed closure of divinyl ketones to 2-cyclopentenones. This process was already documented in 1903 by Vorliinder who isolated a ketol of unknown structure by treatment of dibenzylideneacetone with concentrated sulfuric acid and acetic acid followed by mild alkaline hydrolysis (equation 2). The correct structure of Vorliinder s ketol, finally proposed in 1955, ° arises from Nazarov cyclization followed by oxidation and isomerization. Other examples of acid-catalyzed cyclizations of divinyl ketones exist in the early literature. ... 

The first modem thinking about the mechanism of the Nazarov cyclization is due to Braude and Coles,who suggested the intermediacy of a P-keto carbocation from either divinyl or allyl vinyl ketones. The ring is formed by intramolecular attack on the enone with concomitant generation of an a-keto carbocation. Loss of a -proton from this intermediate affords the product. Nazarov - himself provided support for this proposal by demonstrating the incorporation of deuterium from D3PO4 in different positions ftom divinyl or allyl vinyl ketones. 

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). 

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. 

SCHEME 10.82 The proposed mechanism of the sugar-directed Nazarov cyclization. 

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. 

Denmark and co-workers reported a good example of torquoselection in the silicon-directed Nazarov cyclization (see Section 3.4.5.1). They demonstrated that cyclohexenyl-derived divinyl ketones 26 cyclize to give the relative stereoisomer 27 as the major product (see Section 3.4.5.1 for the mechanism of the silicon-directed reaction). The use of bulky alkyl groups (such as /-butyl) and/or bulky silicon substituents gave the best selectivity, at the expense of the chemical yield. It is interesting that the corresponding cyclopentenyl-derived systems gave only poor torque-selectivity. 

In terms of asymmetry transfer, several effective means of controlling the absolute asymmetry of the product have emerged. Denmark and coworkers have published extensively on the use of silicon substituents to aid selectivity in Nazarov cyclizations (see Section 3.4.5.1). In one example of asymmetry transfer, they used a stereogenic trimethylsilyl-bearing carbon atom to control the sense of conrotation. Treatment of ketone 63 with ferric chloride gave product 64 in excellent yield and with complete transfer of asymmetry (see Section 3.4.5.1 for the mechanism of the silicon-directed... 

Rautenstrauch reported another mechanistically intriguing example. Treatment of enynol acetate 111 with a palladium(II) catalyst in warm acetonitrile resulted in the formation of cyclopentenone 115. The proposed mechanism involves generation of divinyl cationic species 113, followed by electrocyclization, and elimination of the palladium(ll) electrofuge in a manner comparable to the silicon-directed Nazarov cyclization (see Section 3.4.5.1). 

Figure 8 Postulated mechanism of the Brpnsted-acid-catalyzed as3munetiic Nazarov cyclization.

Electrocyclization reactions are powerful synthetic tools to prepare compounds of great molecular diversity. These reactions allow for the formation of many substituted cyclic and polycychc compounds important in medicine, materials science, cosmetics, and so on. The well-established mechanisms and predictable outcomes of electrocyclization reactions permit the elaboration of logical blueprints for the synthesis of important molecules. Among these, the Nazarov cyclization is a salient member of the family. Reported first in 1941 by Ivan Nikolaevich Nazarov [1], this reaction has been studied extensively and many variations and applications have been developed over the years. In this chapter, we will present selected examples highlighting the versatility and synthetic power of this transformation [2]. In its simplest form, the Nazarov employs a divinyl ketone as the starting material, a cross-conjugated compound which can be regarded as a 3 -oxa-[3]dendralene. 

A cyclization mechanism of the same kind known as the Nazarov reaction is presented in Figure 9.47. The positive charge is stabilized by only one +M effect in the final state against two +M effects in the initial state bnt the decrease of entropy contributes to the decrease in internal energy of the system. 

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... 

A synthesis of cyclopentenones somewhat related to those shown earlier was found from conjugated 1,3-enynes (equation 19) Cyclopentenones are obtained by the hydrolysis of the enol acetates. This transformation involves a 1,3-migration of the acetate to form pentadienyl cation and the formation of the gold carbene after a Nazarov-type cyclization. DFT calculations support this mechanism and provide interesting insight into the mechanism of the final stages of the process. 

Kursanov, D. N., Fames, Z. N., Zaretskaya, I. I., Nazarov, I. N. Reaction mechanism of the cyclization by means of deuterium. I. Cyclization of isopropenyl allyl ketone. Bull. Acad.Scl. USSR, Chem. Scl. (English Translation) 1953, 103-107. 

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