Cyclopentenones Nazarov cyclization

They are examples of what is known, after its Russian discoverer, as the Nazarov cyclization. In its simplest form, the Nazarov cyclization is the ring closure of a doubly a, 3-unsaturated ketone to give a cyclopentenone. Nazarov cyclizations require acid, and protonation of the ketone sets up the conjugated n system required for an electrocyclic reaction. 

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 ... 

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 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). 

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]. 

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. 

A Pd-catalysed variant of the Nazarov cyclization of 1 -ethynyl-2-propenyl acetate derivatives to form cyclopentenone dierivatives involving 1,2-acetoxy migration is... 

The Nazarov Cyclization allows the synthesis of cyclopentenones from divinyl ketones. 

Trialklysilyl groups control the course of the Nazarov cyclization.78 80 For example, the presence of the trimethylsilyl substituent in 80a results in the exclusive formation of the less stable cyclopentenone isomer 8178 (Scheme 12) arising from desilylation of the P-trimethylsilyl carbenium ion intermediate 82, whereas in the absence of the silyl substituent in 80b the thermodynamically more stable cyclopentenone 83 is obtained. 

The work of Nazarov on vinyl ethynyl carbinols involves condensation of vinylacetylene with ketones in the presence of caustic potash and also their conversions, many of which are catalytic in nature. A review of his work involving polymerization, isomerization, hydrogenation, and other conversions was published by him (252). Hydration of divinylacetylenes in methanol solution in the presence of mercuric sulfate and sulfuric acid gave vinyl alkyl ketones. These can be reacted with hydrogen sulfide, amines, etc., to yield heterocyclic compounds. Substituted vinyl alkyl ketones underwent spontaneous cyclization to cyclopentenones. Nazarov summarized a decade of this research in this field in 1951 (253). His general review of organic syntheses based on acetylene is also of interest in this connection (254). 

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. ... 

Sho]q>ee has clarified an early report by Japp and Maitland on the formation of a cyclopentenone by treatment of either divinyl ketone or tetrahydropyrone with ethanolic hydrochloric acid (Scheme 2). Tliis case illustrates a broader definition of the Nazarov cyclization that includes a wide variety of pre-... 

Most of the variants of the Nazarov cyclization are operational equivalents in that they involve starting materials which are transformed into divinyl ketones under conditions which also induce subsequent closure to 2-cyclopentenones. Thus, the identification of divinyl ketones as key intermediates by Braude and Coles was critical in several ways for the development of the Nazarov cyclization in suggesting the use of precursors other than dienynes. A case in point is the 1953 report by Raphael on the use of a pro-pargyl amine as the divinyl ketone precursor (Scheme 3). A second important, although somewhat later advance was the recognition that Lewis acids can effectively induce tte cyclization of divinyl ketones, an improvement over the classical reagent, 90% phosphoric acid. 

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. 

The Nazarov cyclization is well suited for the construction of simple cyclopentenones adorned with various substitution patterns. A collection of representative structures prq>aied from either allyl vinyl or divinyl ketones is shown in Scheme 10. Many different alkyl groups are compatible with the substitution patterns. Aromatic substituents, especially at the a-position, have a beneficial effect on the reaction rate and yield. In all of those cases where a choice is possible, the double bond resides in the thermodynamically most stable position. 

The abnormal Nazarov cyclization reported by Hiyama leads to transposed cyclopentenones by incorporating carboxylic acids as nucleophiles in the reaction medium. Both acyclic and monocyclic divinyl ketones can be employed, as shown in Scheme 15. Dioxolane acetals have also been used successfully in place of the carbonyl group. 

Due to their ready isomerization simple cyclopentenones present a particular challenge in the Nazarov cyclization. In all of the cases studied in a- and -monosubstituted and a, -disubstituted systems the cy-clopentenone product contained the double bond in the less substituted position, as required by loss of the silicon electrofuge (Scheme 17). The relative conBguration of substituents in disubstituted cases is controlled by kinetic protonation and weakly favors the cis isomers. Substituent effects in rate were particularly noted in these cases where substitution with a- and -alkyl groups greatly accelerated and decelerated the reactions, respectively. 

The facile elimination of -heterosubstituents in ketones allows for the ready construction of a,p-enones. Three different heteroatoms have been employed, chlorine, nitrogen and oxygen. The -chloro enones (products of Friedel-Crafts acylation) suffer Nazarov cyclization under standard conditions. -" Jacquier has prepared a series of -amino enones (31) from Mannich condensations." These substrates undergo cyclization in modest yields under standard conditions (equation 23). Takeda has found that the readily available" tetrahydro-4-pyranones (32) produce 2-cyclopentenone-4-carboxylates upon treatment with TMS-I (equation 24). " It is noteworthy that the putative a-carboalkoxy divinyl ketones have been independently cyclized by Marino using TMS-I. ... 

A significant advance in the use of Friedel-Crafts acylation of alkenes to prepare divinyl ketones was the employment of vinylsilanes to control the site of electrophilic substitution. Two groups have developed this approach to cyclopentenone annulation using slightly different strategies. In the method described by Magnus the reagent vinyltrimethylsilane (80) is used primarily as an ethylene equivalent (equation 44). The construction of bicyclic systems followed readily as Nazarov cyclization proceeded under the reaction conditions. Tin(lV) chloride was found to be the most effective promoter of the overall transformation. As expected the position of the double bond is thermodynamically controlled. 

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