Divinyl ketones, cyclization

Acylations by a,3-unsaturated acyl halides provide routes to a,3,a, 3 -unsaturated ketones. Care must be taken in choice of reaction conditions, since Lewis acids are excellent catalysts for Nazarov cy-clizations to cyclopentenones (Scheme 2). Indeed, this can be exploited as a synthesis of the five-mem-bered ketones without isolation of the intermediate divinylic ketones. Cyclizations are also observed after acylations of cyclohexenes with vinylacetyl chloride derivatives (equation The acylation-cycloalkylation sequence provides a complement for the Robinson annelation, since the carbonyl function is located adjacent to the bridgehead position. This potential has been realized in natural product syntheses. ... 

The size of the silicon substituent also plays a role in the extent of stereoinduction. Although the rate of cyclization slows somewhat with increasing size of substituent, the cyclizations usually proceed at ambient temperature in 2-4 hours. In contrast to divinyl ketone 16 a, the methvldiphenylsilyl derivative 19a affords an 86 14 (20/21) mixture in 83% yield. The triiso-propylsilyl derivative 19 b affords a 90 10 mixture in 70% yield. The corresponding five-mem-bered-ring divinyl ketone cyclizes to give a 3 1 mixture, even with the triisopropylsilyl substituent. 

The reaction of alkenyl iodides or triflates, alkenylstannanes, and CO affords divinyl ketones[397,398]. Thus the capnellene skeleton 538 has been synthesized by the carbonylation of the cyclopentenyl triflate 536 with the alkenyltin 537[392], The macrocyclic divinyl ketone 540 has been prepared in a moderate yield by the carbonylative cyclization of 539[399]. 

While most synthetic examples of this cyclization have involved protonation of divinyl ketones to give 3-hydroxy-1,4-pentadienyl cations, theoretical studies suggest that the cyclization would occur even more readily with alternative substituents at C-3. °... 

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 ... 

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 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. 

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... 

Addition of P—H bonds to unsaturated systems also continues to be used as a route to heterocyclic systems. Thus base-catalysed cyclization of the phosphine (32) [prepared by the addition of methyl methacrylate (2 moles) to phenylphosphine], followed by subsequent hydrolysis and decarboxylation, affords the phosphorinanone (33). The phosphorinanone system is also directly accessible by the addition of phenylphosphine to divinyl ketones.28 The radical-initiated addition of phenylphosphine to dialkynyl systems (34) gives the heterocyclohexadienes (35).29 80 The stereochemistry of the addition of phenylphosphine to cyclo-octa-2,7-dienone to give... 

A similar coupling with a,p-unsaturated acid chlorides provides p-silyl divinyl ketones (Nazarov reagents). These ketones cyclize in the presence of a Lewis acid, particularly BF3 etherate, to cyclopentenones, generally with retention of the silyl group. 

Cyclopentenones. Trimethylvinylsilane has been used to prepare annelated cyclopentenones by cyclization of intermediate divinyl ketones (9, 498-499). The major limitation is that the double bond in the product is located at the most stable position (ring fusion). A modification using the Grignard reagent derived from 1 results in 4,5-annelated-2-cyclopentenones, as outlined in equation (I) for a typical case. The overall yields are in the range 39-65%. The c/s-isomers are formed predominately or exclusively. The same sequence can be applied to acyclic a,/i-unsaturated aldehydes to furnish 4- and 5-substituted 2-cyclopentenones, a cyclization that is not possible in the absence of the /f-trimcthylsilyl group.2... 

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

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

This coupling when carried out in the presence of carbon monoxide (15-50 psi) results in cross-coupled ketones in generally good yield." This reaction is a particularly attractive route to divinyl ketones, which are substrates for Nazarov cyclization. The geometry of the vinyl triflate is retained. 

SIUCON-DIRECTED NAZAROV CYCLIZATIONS OF DIVINYL KETONES... 

Cyclization of Divinyl Ketones from p(-Substituted Enones... 

Cyclization Divinyl Ketones from of-Hydroxy Enones... 

CYCLIZATION OF DIVINYL KETONE EQUIVALENTS FROM SOLVOLYSIS... 

CYCLIZATION OF DIVINYL KETONES FROM IN SITU CONSTRUCTION... 

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. 

It is the structural variety of the precursors which lends versatility to the Nazarov cyclization and which also serves as the organizational framework for this chapter. To facilitate presentation die reaction is divided into five categories (i) (Lewis) acid-promoted and photochemical cyclization of divinyl and allyl vinyl ketones (ii) silicon- and tin-directed Nazarov cyclizations of divinyl ketones (iii) in situ generation/cyclization of divinyl ketones (iv) solvolysis to produce divinyl ketone equivalents (v) coupling reactions to form and cyclize divinyl ketones. The logic of this sequence follows from the order of decreasing structural similarity of the precursors to divinyl ketones. The last three subgroups encompass considerable structural diversity which will be discussed in each section. 

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. 

Following the suggestion of Braude and Coles, Nazarov established the role of the tautomeric divinyl ketones as the true precursors of cyclization. By conducting the cyclization of the allyl vinyl ketone (1) in D3PO4 it was established that one deuterium is introduced into Ae cyclic product (2 Scheme 9). Direct cyclization of the divinyl ketone (3) with D3PO4 gave identical resdts. ... 

Thus, in the following section the two different precursors are considered as equivalent and the oigan-ization follows structural patterns. In many other variants of the Nazarov cyclization, divinyl ketones are implicit intermediates formed from other precursors. In this section only diose cases where a divinyl or allyl vinyl ketone was directly cyclized will be discussed. 

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. 

A usefid feature of the Nazarov cyclization is the construction of fused bicyclic systems by annulation of a flve-membered ring. This requires one of the vinyl groups to be embedded in a ring. These precursors can be formed easily by vinyl alkyne addition to cyclic ketones followed by dehydration and hydrolysis. This procedure woiks well for symmetrical ketones but it gives regioisomers from unsymmetrical ketones such as 1- or 2-octalone."- A superior method, reported by Paquette, 76 involves the acylation of cycloalkenylsilanes to provide divinyl ketones (equation 6). The advantages of this protocol are discussed in Section 6.3.7.4.3. 

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