Cyclopentanones nucleophilic addition reactions

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

A wide range of donor ketones, including acetone, butanone, 2-pentanone, cyclopentanone, cyclohexanone, hydroxyacetone, and fluoroacetone with an equally wide range of acceptor aromatic and aliphatic aldehydes were shown to serve as substrates for the antibody-catalyzed aldol addition reactions (Chart 2, Table 8B2.6). It is interesting to note that the aldol addition reactions of functionalized ketones such as hydroxyacetone occurs regioselectively at the site of functionaliztion to give a-substitutcd-fi-hydroxy ketones. The nature of the electrophilic and nucleophilic substrates utilized in this process as well as the reaction conditions complement those that are used in transition-metal and enzymatic catalysis. 

In alkenyl- and alkynylcarbene complexes the addition of nucleophiles to the carbene carbon competes with the addition to the 3-carbon of the conjugated C-C multiple bond. [17] The regioselectivity of the addition of amines to alkynylcarbene complexes is temperature dependent 1,2-addition is favoured by lower temperatures. [17c] Enolates turned out to be efficient C-nucleophiles for Michael addition reactions to unsaturated metal carbenes. The product distribution may depend on steric factors as shown in Scheme 7 for the addition of different enolates to alkenylcarbene complex 10. The less bulky acetone enolate 11 adds to the carbene carbon protonation of the primary addition product results in demetalation and in the formation of a mixture of isomeric enones 12. In contrast, the more bulky cyclopentanone enolate 13 adds to the less shielded vinylic position. 

The diastereoselectivity observed for the conjugate addition to the nonchelated enone sulfoxide (98a) was improved by the use of diorganomagnesium reagents with DME as solvent. Under the same reaction conditions, nucleophilic additions to the corresponding cyclohexenone (101) proceeded with moderate stereoselectivity, giving cyclohexanones (102) as products with somewhat lower enantiomeric excesses than for cyclopentanones (99b) (Scheme 5.35 and Table 5.4) [99]. It should also be noted that in several cases the addition of a highly complexing additive such as 18-crown-6 served to raise the amount of asymmetric induction by about 20% (Table 5.4). 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

The Michael addition of organometallic nucleophiles to enones in the presence of copper(I) salts produces enolates which on treatment with phenylselenenyl bromide give a-seleno ketones. For example, the reaction of the zirconium enolate of 15 with a mixture of phenylselenenyl bromide and diphenyl diselenide affords a mixture of diastereomeric (2R)- and (2V)-phenylse-leno)cyclopentanones 16 in 50% and 31 % isolated yield, respectively12. The analogous reaction with phenylselenenyl chloride gives only the tram-isomer in 27% yield formation of the cw-product is not observed12. 

Enamines can undergo reactions in which the iS-carbon acts as a carbanion. When pyrrolidine enamines of cyclopentanone and cyclohexanone were reacted with diethyl 2-vinylcyclopro-pane-l,l-dicarboxylate (1), a 1,7-addition was observed due to the attack of the C-nucleophile on the terminal carbon atom. ... 

The addition of cyclopropenone 1,3-propanediyl ketal to electron deficient olefins produces cyclopentanone ketals 4,4,5-trisubstituted 3,3-[l,3-propanediylbis(oxy)]cyclopentenes 1 in 42-86 % yield with high regioselectivitv. Presumably diradicals or zwitterions are not involved as reactive intermediates, and the reaction starts with nucleophilic attack of the strained cyclopropene olefin onto the electron-deficient olefin2. 

Is this analysis of reactivity with NaCN correct In an experiment that reacts cyclopentanone (9) with potassium cyanide, a low yield of 10 is obtained, consistent with cyanide as a weak nucleophile. Compounds that have both a CN unit and an OH unit are called cyanohydrins. The direct acyl addition of cyanide to 9 gives a poor yield of 10, suggesting that the reaction may be reversible or that cyanide is a relatively poor electron donor, or both. On the other hand. 

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