Substituted cyclohexenone

With cyclohexenones substituted at C-6 or with cyclopentenone or analogs substituted at C-5, high facial selectivities are usually observed and the selectivity does not seem to be very sensitive to the nature of the alkene used [75-81]. However, an increase in the steric differentiation of the two diastereofaces of the starting enone, as illustrated by the influence of the R substituents of 53, led to a spectacular increase of the facial selectivity. When the stereogenic center occupies another position on the starting cyclenone, a low facial selectivity is usually observed (Scheme 15) [82-90]. 

Aromatization. Cyclohexenones substituted with an unsaturated side chain are converted into phenols when heated in ethanol at 100° (sealed tube) with a catalytic amount of this transition metal salt. The double bond can be remote because RhCls catalyzes isomerization of double bonds to give more stable systems (3, 242-243). 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Ethoxy-2-cyclohexenone is a useful intermediate in the synthesis of certain cyclohexenones. The reduction of 3-ethoxy-2-cyclohexenone with lithium aluminum hydride followed by hydrolysis and dehydration of the reduction product yields 2-cyclo-hexenone. Similarly, the reaction of 3-ethoxy-2-cyclohexenone with Grignard reagents followed by hydrolysis and dehydration of the addition product affords a variety of 3-substituted 2-cyclo-hexenones. ... 

When an aryl substituent is placed at C-5 of a 4-substituted cyclohexenone, a new product type containing a cyclobutanone ring is formed. 

Substituted /J--cvclohexenoaes such as 3,5,5-trimethyl-2-cyclohexenone (104) gave with pyrrolidine the corresponding enamine (105) (50a). 

The acid chlorides of to-(2-thienyl) substituted butyric (122) and valeric acids (123), as well as the corresponding 5-alkyl-2-thienyl-substituted compounds, undergo internal Friedel-Crafts reaction (SnCl4,CS2) at the 3-position in 70-80% yield, to give the corresponding cyclohexenones (124) and cycloheptenones (125). ... 

Knochel et al. described Pd-catalyzed Negishi cross-coupling reactions between zinc organometallics and aryl iodides in [BMMlM][Bp4]. Scheme 5.2-20 illustrates the reaction for the formation of a 3-substituted cyclohexenone from 3-iodo-2-cyclo-hexen-l-one [82]. 

Although 2-substituted 2-cyclopentenones are in a base-catalyzed equilibrium with their 5-substituted 2-cyclopentenone isomers (Problem 22.38). the analogous isomerization is not observed for 2-subslitutcd 2-cyclohexenones. Explain. 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aklol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

A comparison of the configuration of the substrates and reaction products shows that the oxiranyl anions arc configurationally stable under the reaction conditions. Only one example is known in which isomerization was observed. When the ci.v-tm-butyl-substituted epoxysilane27 was metalated and quenched with 2-cyclohexenone, addition product 27 was obtained under inversion of the anionic center. Presumably the strain created in forcing the ter/-butyl and the trimethylsilyl group cis on the oxirane ring facilitates the isomerization process13. 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

Table 3.1 Facialselectivity" in the aluminium chloride catalyzed Diels-Alder reactions of 4-, 5-and 6-substituted 2-cyclohexenones 5 with dienes 1-3...

Another class of new ligands was prepared in quantitative yields by Feringa et al., in 1997, by reaction between a-mercapto acids, aniline and 2-pyridine-carboxaldehyde." These pyridyl-substituted thiazolin-4-one ligands were further involved in the copper-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone,... 

Scheme 2.20 Cu-catalysed 1,4-addition of ZnEt2 to 2-cyclohexenone with pyridyl-substituted thiazolin-4-one ligands.

The enol ethers of P-dicarbonyl compounds are reduced to a, 3-unsaturated ketones by LiAlH4, followed by hydrolysis.115 Reduction stops at the allylic alcohol, but subsequent acid hydrolysis of the enol ether and dehydration leads to the isolated product. This reaction is a useful method for synthesis of substituted cyclohexenones. 

The only other functional group is the conjugated unsaturated ester. This functionality is remote from the stereocenters and the ketone functionality, and does not play a key role in most of the reported syntheses. Most of the syntheses use cyclic starting materials. Those in Schemes 13.4 and 13.5 lead back to a para-substituted aromatic ether. The syntheses in Schemes 13.7 and 13.8 begin with an accessible terpene intermediate. The syntheses in Schemes 13.10 and 13.11 start with cyclohexenone. Scheme 13.3 presents a retrosynthetic analysis leading to the key intermediates used for the syntheses in... 

Dauben et al. have investigated the scope of the photochemical type A rearrangement/60 They conclude that the rearrangement occurs only if the fourth carbon atom of the 2-cyclohexenone ring is fully alkyl-substituted. If this requirement is not met, photodimers are the major products. This substituent requirement is necessary but not sufficient to ensure rearrangement since the presence of other groups can inhibit the reaction. 

Scheme 2.33. Formation of highly substituted chiral cyclohexenone derivatives using a domino conjugate addition/Dieckmann condensation.

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

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