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26.9.1.1.8.3 Variation 3: Intramolecular Aldol Condensation

DOI: 10.1055/sos-SD-026-00987

Marsden, S. P.Science of Synthesis, (2005261077.

The intramolecular aldol condensation is a powerful method for the construction of cyclic enones. Again, the reaction can be promoted under acidic or basic conditions. In unsymmetrical systems, the potential for the formation of regioisomers exists and ring size plays a role in determining this. In the cyclizations of oxoaldehydes, nucleophilic attack on the aldehyde is generally the observed process.[‌148‌] For example, oxoaldehyde 161 could potentially form two cyclohexene products 162 or 163 depending on whether the reaction is through the ketone or the aldehyde enolate, respectively; only enone 162, the product of the former pathway is observed (Scheme 34).[‌148‌] The situation is more complicated with diketones. Diketones such as 164 and 166 can potentially form two products, with the enones being tri- or tetrasubstituted. For cyclopentenone formation, the tetrasubstituted products such as 165 are generally observed.[‌149‌] Compounds of type 168 could be formed directly, or might arise from equilibration of an initially formed aldol adduct 167. Treatment of independently prepared 167 under the conditions used to form 168 from 166 returned 167 quantitatively, ruling out the isomerization mechanism.[‌150‌] Enone 167 could be converted into 168 under alternative conditions. Control in the cyclohexenone series is less well defined. In ketones such as 169, which are differentially substituted at the positions external to the linking chain, the presence of branching substituents can divert the reaction away from the formation of tetrasubstituted alkenes 171 and toward the trisubstituted alkene 170.[‌152‌] If the two ketones have identical substituents external to the linking chain but are sterically differentiated, control of the reaction conditions can be made to select the desired isomer. Thus, under acidic conditions the diketone 172 undergoes addition by nucleophilic attack on the less hindered ketone to yield 173.[‌153‌] Under enamine-forming conditions, the less sterically encumbered enamine is favored, leading to attack on the more hindered ketone and formation of 174. The use of silyl enol ethers in intramolecular aldol condensations is also possible; as for the intermolecular reactions, this process frequently stops at the aldol stage but in favorable cases in situ elimination to yield the enone directly is seen, as in the formation of 175.[‌154‌]

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