Cycloheptanones, formation

While this methodology could be extended to more-substituted cyclooctene oxides (Scheme 56, Equation 12), examination of cycloheptene oxide (Scheme 56, Equation 13) revealed the need for considerably longer reaction times, leading to reduced yields due to competing carbenoid-insertion pathways (cycloheptanone formation and reductive alkylation) <2002AGE2376, 2003OBC4293>. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Enamines formed in this way may be distilled or used in situ. The ease of formation of the enamine depends on the structure of the secondary amine as well as the structure of the ketone. Thus pyrrolidine reacts faster than morpholine or piperidine, as expected from a rate-controlling transition state with imonium character. Six-membered ring ketones without a substituents form pyrrolidine enamines even at room temperature in methanol (20), and morpholine enamines are generated in cold acetic acid (21), but a-alkylcyclohexanones, cycloheptanone, and linear ketones react less readily. In such examples acid catalysis with p-toluenesulfonic acid or... 

Ethynylarion of cyclohexanone and cycloheptanone with lithium acetylide afforded yields between 50 and 60%. Appreciable amounts of the ketones were recovered indicating an appreciable degree of enolate formation. Under similar conditions the more easily enolizable cyclopentanone gave the ethynyl carbinol in a poor (-20%) yield [2],... 

See Reference 112 for the cycloalkanone data. cThe enthalpy of formation of cycloheptanone was obtained from Reference 112. The enthalpy of formation of methylenecyclohep-tane was obtained by combining the directly measured enthalpy of hydrogenation (Reference 22) to form methylcycloheptane and the suggested gas-phase enthalpy of formation of this latter hydrocarbon from Reference 8. 

On the other hand, the parent, unsubstituted cyclohexanone enters into an apparently much more complex reaction pathway leading to the formation of a tricyclic, cyclohep-tanone-containing product.93 Also, cycloheptanones as starting materials give annu-... 

Carbenoid 4-32 can be generated as shown in Example 4.22. The insertion of 4-32 into the Cl — C2 bond leads to the formation of cycloheptanone in 70% yield. Other homologues give even higher yields of ring-expanded products. 

Aryl-substituted ketones react directly with elemental sulfur in hexa-methylphosphorus triamide with formation of l,2-dithiole-3-thiones.46,47 Aryl-substituted acetaldehydes can condense likewise with carbon disulfide to give the analogous 4-aryl-substituted l,2-dithiole-3-thiones.48 The same reaction was observed with aryl-substituted acetic acid esters, in which a methylthio group is incorporated into the reaction product (26).49 Thioketones and enthioles react analogously. 50,51 The parent l,2-dithiole-3-thione (27) has been prepared from the tetra-methyl acetal of malondialdehyde and phosphorus pentasulfide.52 In the presence of ammonia the reaction of cyclohexanone or cycloheptanone with carbon disulfide and sulfur gives as by-products the condensed 1,2-dithiole-3-thiones 28a and 28b, respectively.53... 

Both simple carbonyl compounds and a,j8-unsaturated ketones react with this reagent with exclusive formation of epoxides (oxiranes), not cyclopropanes. Yields are as follows benzaldehyde, 75% cycloheptanone, 97% benzalacetophenone, 87% carvone, 89% eucarvone, 93% pulegone, 90% A -cholestene-3-one, 90%. 

Table 6. Formation of 3-Substituted Cycloheptanones by Ring Expansion of 2-Substituted Cyclohexanones and Analogs...

Two ring enlargements of this type are described in Organic Syntheses, namely the formation of cycloheptanone from cyclohexanone (33-36% yield) by de Boer and Bakker (1963) and of 2-phenylcycloheptanone from cyclohexanone and phenyldiazo-methane (41-46% yield) by Gutsche and Johnson (1963). 

Codeposition of magnesium atoms and cycloheptanone has been studied. Of the magnesium vapourized, 13 % led to the formation of l,T-dihydroxybicycloheptyl and 13% led to volatile hydrocarbon products, consisting of cycloheptene (91 %), nor-carane (5 %), and cycloheptane (4 %). Aldol condensation products were also found. The mechanisms proposed involved the pinacol intermediate (239). ... 

Under slightly different conditions, using 1,3-propanedithiol, acyloins and acyloin acetates lead to the formation of 1,3-dithianes where hydrogen has replaced the hydroxyl or acetoxyl groups . Hydrolysis to the ketone provides a method of converting acyloins to ketones and desulphurization allows conversion of acyloins to hydrocarbons (equation 10). Reduction of l,l-dimethyl-5-hydroxysila-4-cycloheptanone gave l,l-dimethylsila-4-cycloheptanone by this method (equation 11) . A similar reaction is believed to be involved in the action of D-proline reductase . ... 

A proposed mechanism for the formation of cycloheptanone 228 is illustrated in (Scheme 102). The reaction is believed to proceed through precoordination of the metal to the double bond of the allene that is proximal to the cyclobutane. Insertion and C—C bond cleavage leads to metallacycle P-II. CO insertion gives either intermediate P-III or P-IV, and reductive elimination provides the [6-1-1] cycloadduct 228. 

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