Ketone enolates cyclization

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

In contrast to a,(3-unsaturated phosphonium salts, ot,(3-unsaturated phosphonates (161)1331 alkylate ali-cyclic ketone enolates efficiently, while the homologous diethyl butadiene phosphonate (162)133bintramolecular cyclization. Heathcock reports that... 

A substantial number of important syntheses that depend on the attack of ketone enolates on ortho-functionalized aryl or heteroaryl halides, and that lead to cyclized products are discussed in Section 2.2.4.2. 

Some /J-heteroatom substituted a,/J-unsaturated acyl silanes react with methyl ketone enolates in a stepwise stereoselective cyclopentannelation process, formally a [3 + 2] annelation, which may proceed through aldol reaction followed by Brook rearrangement and cyclization (Scheme 111)223. 

A synthetic method for the prepararation of cyclobutanones via an intramolecular cyclization of a ketone enolate has been reported.83 Enol triflates having a silyloxy group at the ft-position under the influence of TBAF give a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction (Scheme 49). 

The mechanism of this three-component coupling reaction is probably analogous to the aforementioned insertion of acyl chlorides (above). One can imagine assembling an intermediate acylpalladium species either by oxidative addition to an acyl chloride or, in this case, by oxidative addition to the aromatic iodide followed by migratory insertion into carbon monoxide. Once formed, the acylpalladium intermediate can insert into the SCB to furnish a 7-(chlorosilyl)propyl ketone, which cyclizes in the presence of the amine to afford cyclic enol ethers. 

Vinyl-l//-isochromenes can be prepared in moderate yield by a palladium-catalyzed coupling of ( )-(3-(2-bromo-phenyl)allyloxy)tenM)i i r l)si Iyl derivatives 157 with ketones. The reaction proceeds via initial ketone arylation to furnish the intermediate 158 followed by intramolecular cyclization of the ketone enolate onto the tethered allylic system (Scheme 50) <2000CG1675>. 

Intramolecular nucleophilic substitution of a chlorine atom in an a-chloro amide, by a ketone enolate, causes cyclization and this has been used in the synthesis of some alkaloid ring systems (equation 87)576. The product of this reaction is a key intermediate for the synthesis of Strychnos, Aspidosperma, Schizozygane and Eburnamine alkaloids. 

The photostimulated reaction of benzylamines with an o-iodo (bromo) substituent (281) and ketone enolate ions gave the product 282 that cyclized spontaneously to give 283 (equation 174)327. 

Another S l reaction that leads to a substitution product that cyclized in a subsequent step is the reaction of (o-iodoaryl)acetic acid derivatives with ketone enolate ions. Thus, substrate 298 reacts under irradiation with ketone enolate ions to give 299 [R = Me (75-80%), R = z-Pr (75-80%), R = t-Bu (85-90%)] (equation 183)332. The substitution products 299 are the key intermediates for the synthesis of 3-benzazepines and 3-benzoxepines332. 

Cyclization of 2,3-dichloroquinoxaline with ketone enolates gives rise to similar products 20 the reaction, however, proceeds under milder conditions and gives higher yields in comparison to monohalogeno-l,4-diazines (Scheme 15) (72YZ736). 

So far the mechanism is almost the same as that of the Robinson annelation but the cyclization is now the attack of a ketone enolate on an ester group (it doesn t matter which one as they are equivalent) and so it is an intramolecular Claisen ester condensation (Chapter 28). The intermediate must be redrawn to allow cyclization. 

Enolization occurs on the side of the ketone away from the bromine atom and the enolate cyclizes as before but the cycloprop an one intermediate is symmetrical so that the product is the same whichever C-C bond breaks after nucleophilic attack by the methoxide ion. 

An attractive feature of this procedure is the directness with which the annulation of 3-hydroxycyclopentanone systems onto preexisting ketone skeletons can be accomplished to give usefully functionalized products. However, this method does have important limitations in its scope. The most common difficulty is that the "cyclopropanone" condensation with a wide range of ketone enolates often occurs in only low to modest yields. A two-fold excess of the cyclopropanone hemiketal is therefore used to provide at least some improvement in the yields of this step. In contrast, the subsequent "homoenolate cyclization generally occurs in quite acceptable yields. A simpler representative example that illustrates the contrasting yields in the two steps is the following 913... 

An intramolecnlar palladium-mediated allylic alkylation via a ketone enolate of piperidinone 54 was reported by Williams and coworkers for the synthesis of R)-l-hydroxyquinine 57 (eqnations 17 and 18) °. The key step involves a palladium-mediated Sjv2 -type cyclization reaction of enol ether 55 in the presence of BnsSnF, giving rise to a quinuclidine ketone, which was immediately rednced to 56 to avoid equilibration and /3-elimination. Interestingly, none of the undesired C3-vinyl stereoisomer was observed. 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

This cyclization reaction is not restricted to sulfone-stabilized carbanions. Indeed, phosphorus ylides, ester- and ketone-enolates participate also in the 5-endo-dig carbometallation reaction [17a]. The synthesis of fused bicyclo as well as spirobicyclo derivatives can be accomplished via the intramolecular carbometallation reactions of various stabilized carbanions with alkoxyacetylenes [17a]. Moreover, some asymmetric... 

The mechanism is a conjugate addition of the central enolate of the keto-ester to the enal fcw- il5 by an aldol cyclization of the ketone enolate on to the aldehyde and dehydration. 

Cyclization. Silyl enol ethers of to-alkynyl ketones undergo cyclization with (THF)W(C0>5. Similarly, 4-alkynols give dihydropyrans. ... 

Same measures of stereocontrol had previously been observed in approaches to pyrethroid acids involving intramolecular enolate alkylation. As outlined in Figure 3, workers at Sumitomo have investigated the cyclization of a methyl ketone enolate (5). They obtained a 9 1 ratio of cis trans products upon ring closure initiated by sodium hydroxide. The methyl ketone was subsequently converted to the corresponding carboxylic acid via the haloform reaction. 

Figure 3. Stereoselection in the cyclization of the methyl ketone enolate...

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