Cyclohexanones nucleophilic addition

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

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. 

A way forward might be to form the imine 7.3 [and hence its enamine tautomer 7.4] by reacting the phenylamine 7.2 with cyclohexanone (Scheme 7.18). Then to generate the benzyne anion 7.5 by treating the tautomers with sodamide and sodium fcr/-buloxide in THF. Cydization to the required indole 7.1 occurs through nucleophilic addition to the benzyne, followed by protonation during work-up. 

Nucleophilic addition to asymmetric carbonyl compounds is stereospecific. For example, most nucleophiles preferentially add to cyclohexanone rings from the more-crowded axial face rather than from the less-crowded equatorial face. 

Cyclohexanones in which the chair inversion is constrained by substitution undergo diastereoselective nucleophilic addition, the nature of which (i.e., preferentially axial or preferentially equatorial) depends on the nature of the substituents. The explanation of this effect has been extensively explored [95, 189, 193-197]. The simplest explanation, shown in Figure 8.5, involves a distortion of the carbonyl group from planarity in such a way as to improve 71-type donation from the ring C— bond or the axial bond (often a C—H bond) in the a position, whichever is the better donor. A secondary effect is the improved interaction between the distorted n orbital and the HOMO of the... 

In a side-reaction 10-15% carboxylic acids are produced by oxidative cleavage of the ketone enolates. The cleavage is favoured by higher temperatures e.g. cyclo-hexanol leads to 80% cyclohexanone and 16% adipic acid at 25 °C, whilst at 80 °C 5% ketone and 42% diacid are found. These acidic by-products are easily separated, since they remain in the alkaline solution during workup. The oxidation of 6 gave the acetal 7 as main product (28%) together with 4% of the ketone 8 and 56% of unchanged 6. The acetal 7 is probably formed by nucleophilic addition of the alcohol 6 at the activated triple bond of ketone 8. 

Shi and Boyd80 have studied the barriers to nucleophilic addition of lithium hydride to substituted cyclohexanones. They found that the unsubstituted cyclohexanone had a... 

It has however been suggested by Cieplak (9) that the stereochemistry of nucleophilic addition to cyclohexanone is determined by a combination of steric and stereoelectronic effects. According to this interesting model, steric hindrance favors the equatorial approach while electron donation favors the axial approach. The stereoelectronic effect favors the axial approach because the axial C —H bonds next to the carbonyl group (C — Ha and Cn-Ha) are better electron donors than the Cn-C-j and Cc-Cfi a bonds (cf 7A 7 and 7A-8). J... 

Cieplak, A. S. Stereochemistry of nucleophilic addition to cyclohexanone. The importance of two-electron stabilizing interactions. J. Am. Chem. Soc. 1981, 103, 4540-4552. 

Studies of Felkin s model have shown that the transition state for nucleophilic addition to a carbonyl compound is strongly stabilized when the C2-X and Nu- Cj bonds are antiperiplanar.41 Let us apply this rule to a configurationally rigid cyclohexanone. 

Besides by these epoxidations, oxaspiropentanes have been prepared through the nucleophilic addition of 1-lithio- 1-bromocyclopropanes to ketones at low temperature. Thus for example, the dibromocyclopropane 96 prepared by addition of dibromo-carbene to cyclohexene 52) underwent metalation with butyllithium to give the lithio-bromocyclopropane 97 which was converted into the oxaspiropentane 98 upon simple addition to cyclohexanone, Eq. (28) 53,54). 

Nitro-l-(phenylsulfonyl)-l//-indole 829 undergoes nucleophilic addition reactions with enolates of diethyl malonate and cyclohexanone, lithium dimethylcuprate (Scheme 159), and indole anion (Equation 209) to afford the corresponding 3-substituted 2-nitroindoles in low to high yields <1997TL5603, 1999TL7615>. 

Cieplak ° countered the Anh explanation with an alternative orbital model. He noted that reductions of cyclohexanones and other additions at carbonyls occasionally resulted in the major product coming from the Eelkin-Anh minor TS. Arguing that since the incipient bond was electron deflcient—a partial bond lacks the full two-electron occupation—it is donation of density from the Oc2-l into the Oc-nuc oi ital that will stabilize the TS (Scheme 6.3). Support for the Cieplak model was provided by experimental results for nucleophilic addition to... 

Wu, Y.-D. Tucker, J. A. Houk, K. N. Stereoselectivities of nucleophilic additions to cyclohexanones substituted by polar groups. Experimental investigation of reductions of trans-decalones and theoretical studies of cyclohexanone reductions. The influence of remote electrostatic effects, J. Am. Chem. Soc. 1991,113, 5018-5027. 

Figure 21.7 lists nucleophiles that add to a carbonyl group, as well as the products obtained from nucleophilic addition using cyclohexanone as a representative ketone. These reactions are discussed in the remaining sections of Chapter 21. In cases in which the initial addition adduct is unstable, it is enclosed within brackets, followed by the final product. 

The mode of addition to substituted cyclohexanones (equation 21) depends greatly on the nature and position of the substituents, as well as on the structure of the organometallic reagent. Table 22 lists results of nucleophilic additions to a variety of cyclohexanones. Some broad generalizations can be made. ... 

This seemingly simple result may have far reaching consequences. For example, it may help to explain the effect of added lithium salts in nucleophilic additions to cyclohexanones as discussed earlier in this chapter. Thus, model (63) shown in Figure 472.135-137 explain the enhancement of rate and may also be relevant to the origins of stereoselectivity in this reaction. Of course, the exact location of the lithium atom and the aggregation state of the adding nucleophile are subject to speculation, since for lithium these parameters seem to be highly variable. 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water (Section 19.6). Hemiacetals are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction can occur. Protonation of the -OH group followed by an El-like loss of water leads to an oxonium ion, R2C=OR, which undergoes a second nucleophilic addition of alcohol to yield the acetal. For example, reaction of cyclohexanone with methanol yields the dimethyl acetal. The mechanism is shown in Figure 19.12 (p. 778). 

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