Alkyl-1,3-cyclopentanone, condensation

Although chemically related to the above cycloalkylamines, pentethylcyclanone (71) is stated to have antitussive activity. The compound is prepared rather simply by alkylation of the anion (70a) of the self-condensation product of cyclopentanone (70) with N-(2-chloroethyl)-morpholine. ... 

Alkylation at carbon positions activated by electron-withdrawing groups is illustrated by the spiroannelation of cyclopentanone and cyclohexanone by sonication of the parent compound with potassium t-butoxide and 1,4-dibromobutane (Eq. 3.22). The so-nochemical improvement is especially large with cyclopentanone which is normally particularly prone to self-condensation [119]. 

The title compound can be prepared by condensing an alkyl a-bromocaprylate with a trialkyl propane-1,1,3-tricarboxylate to give a substituted cyclopentanone. Hydrolysis, decarboxylation, and esterification of the resulting monocarboxylic... 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

After the cyclopentanone ring is formed from a Dieckmann condensation of the starting material, alkylation of the a-carbon followed by hydrolysis of the j8-keto ester and decarboxylation forms the desired product. 

The interaction between the sodium salt of phenylacetic acid and isopropyl magnesium bromide results into a doubly charged species known as the Ivanov reagent. This product on treatment with cyclopentanone affords aldol condensation to yield the corresponding hydroxy acid. The resulting product on being subjected to alkylation with N-(2-chloro-ethyl)-dimethylamine gives the desired official compound. 

This disconnection suggests that 147 is prepared by enolate alkylation of cyclopentanone (Section 22.9). If a Dieckmann condensation is planned, the precursor to cyclopentanone is 148, which in turn is derived from diester 149. Another ester may be chosen at this point (methyl, etc.). Diester 149 is derived from the dicarboxylic acid, which is prepared by oxidative cleavage (ozonolysis) of cyclohexene. Bromocyclohexane 146 is now the clear precursor to cyclohexene by an E2 reaction (Chapter 12, Section 12.1). 

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