Reversibility enone formation

The aldol reaction is often used to make enones by dehydration of the aldol itself, a reaction which often occurs under equilibrating aldol conditions, but has to be induced in a separate step when lithium enolates or silyl enol ethers are used. In general one has to accept whatever enone geometry results from the dehydration, and this is usually controlled by thermodynamics, particularly if enone formation is reversible. Simple enones such as 46 normally form as the E isomer but the Z isomer is difficult to prepare. When the double bond is exo to a ring, e.g. 47, the E isomer is again favoured, but other trisubstituted double bonds have less certain configurations. 

The cycloadduct 113 was then transformed into y,3-unsaturated cyclohexenone 114, which was subjected to intramolecular [4 + 2] cycloaddition. Upon exposure to pyrrolidine in MeOH at 60°C, enone 114 afforded intramolecular Diels-Alder adduct 116 in 78% yield after chromatography. This seemed to be the result of initial reversible iminium formation via dehydrative condensation of pyrrolidine and enone 114. Under the reaction condition, isomerization of the transient iminium species to several distinct dienamine constitutional and stereoisomeric forms would occur. Among all possible isomers in dynamic equilibration, only dienamine 115 is conducive to a favorable intramolecular Diels-Alder transition state, resulting in ketone 116 after enamine hydrolysis. The final steps of the synthesis involved Wittig methylenation followed by... 

FIGURE 17.58 Reversible cyanohydrin formation from an enone. 

Titanium-catalyzed cyclization/hydrosilylation of 6-hepten-2-one was proposed to occur via / -migratory insertion of the G=G bond into the titanium-carbon bond of the 77 -ketone olefin complex c/iatr-lj to form titanacycle cis-ll] (Scheme 16). cr-Bond metathesis of the Ti-O bond of cis- iij with the Si-H bond of the silane followed by G-H reductive elimination would release the silylated cyclopentanol and regenerate the Ti(0) catalyst. Under stoichiometric conditions, each of the steps that converts the enone to the titanacycle is reversible, leading to selective formation of the more stable m-fused metallacycle." For this reason, the diastereoselective cyclization of 6-hepten-2-one under catalytic conditions was proposed to occur via non-selective, reversible formation of 77 -ketotitanium olefin complexes chair-1) and boat-1), followed by preferential cyclization of chair-1) to form cis-11) (Scheme 16). 

In this section, reactions of zinc dienolates with carbonyl compounds, imines and conjugated enones will be considered all of these reactions have been proved to be reversible, and, hence, conditions favouring either kinetic or thermodynamic control will drive the reaction towards the formation of different regioisomers. Generally, equilibrating conditions lead to attack at the position of 190, as a thermodynamically more stable conjugated carbonyl or carboxylic compound is formed on the other hand, kinetic control leads to attack at the electron richer a-position. 

Heating of the 3-trichlorostannyl ketone in DMSO also results in formation of 2-methylencyclohexanone (Eq. (25), Table 4) [31], which is formally the reverse reaction of a hydrostannylation of the enone with HSnCl3. This alternative route... 

Among bicyclic cyclohex-2-enones, the formation of tricyclo[4.4.2.01,6]dodecane-2,7-dione from bicyclo[4.4.0]dec-l(6)-ene-2,7-dione and ethene proceeds in 95% yield,101 and that of 8-mcthyl-tricyclo[6.4.0.01,4]dodecan-5-ones from 6-methylbicyclo[4.4.0]dec-l(2)-en-3-one and ethene in 77% yield,102 respectively. Steroids containing cyclohex-2-enone subunits,103 e.g. 17/ -acetoxy-5a-androst-1 -en-3-one,104 often afford /raw-fused cycloadducts with alkenes. When such reactions are performed on silica gel, complete reversal of stereochemistry to that observed in solution can occur.105... 

Surface adsorption can also influence observed stereochemistry in a profound way. In enone photocycloadditions on silica gel and on alumina, the reaction which normally occurs from the less hindered alpha face is shifted toward the more hindered beta face, Eq. (9) Adsorption thus apparently disfavors conformational inversion in the intermediate biradical, as is required for formation of trans-fused products. The magnitude of the effect is sufficient to be synthetically useful the above reaction represents a complete reversal of stereochemistry from that observed in methanolic solution... 

Another interesting example was reported by Yamaguchi et al. by using a simple L-proline rubidium salt 27 (Scheme 8D. 15) [32], A reversible iminium salt formation, involving the amine moiety of the catalyst and the carbonyl group of an enone, was proposed as the key intermediate. 

When the cyclopropene has a single carbomethoxy or aryl substitunt at the 3-position, the predominant stereoisomer of the enone obtained has the substituent cis-to the ketone 260 261). One possible explanation is the formation of a bicyclobutane by peracid attack from the side away from this substituent, followed by a stereocontrolled rearrangement. If the 3-substituent is hydroxymethyl, the reverse stereochemistry is observed in the enone, in agreement with a peracid attack directed by this group to the same face of the cyclopropene, followed again by rearrangement 262). 

An aldol condensation involves a series of reversible equilibrium steps. In general, formation of product is favored by the dehydration of the B-hydroxy ketone to form a conjugated enone. Here, dehydration to form conjugated product can t occur. In addition, the B C equilibrium favors B because of steric hindrance. 

Halohydrin formation with subsequent reductive dehalogcnation represents an interesting variation on the theme. For example, when the enone rac-1 was treated with A -bromosuccin-imide in aqueous dimethyl sulfoxide, the bromohydrin roc-2 was formed, predominantly as one diastereomer (the relative configuration at C-3 was not established)23. Reduction with tri-butyltin hydride gave the diastereomeric products exo-3 and endo-3 in 27% and 63% yield, respectively. Here, the product distribution can be explained by the preferred attack of the hydride reagent on the exo-face of the intermediate bicyclic carbon radical, i.e., by kinetic control. Thus, the predominant endo-orientation of the 2-(2-hydroxypropyl) substituent at C-3 was achieved, in contrast to what may be expected from a reversible, i.e., thermodynamically controlled, hydration of the enone rac-1. 

Stereochemistry is also affected in a significant way by surface adsorption. When enone photocycloadditions are allowed to occur as adsorbates on silica gel or alumina, larger fractions of reaction product derived from attack on the more hindered P face are observed. Thus, surface adsorption apparently influences conformational inversion, enhancing the formation of /ra s-fused products. This effect is synthetically useful, for sometimes a complete reversal of stereochemistry is observed compared with that seen in methanolic solution. 

With aldehydes, this rapid and reversible reaction leads to the formation of a P-hydroxy aldehyde or aldol (aid for aldehyde and ol for alcohol). When using ketones, P-hydroxy ketones are formed. The aldol products can undergo loss of water on heating under basic or acidic conditions to form conjugated enones (containing both C=0 and C=C bonds) in condensation reactions. Conjugation stabilises the enone product and this makes it relatively easy to form. 

The indication is that, in basic medium, the aldol Edition reaction has a preference for formation of the more-substituted addition product. Under the more forcing conditions that lead to the enone, aldol reversal must occur, and formation of the C-1 condensation product must be favored over formation of the C-3 condensation product. This preference may be the result of more facile dehydration of the C-1 addition product. 

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