Cyclohexanones nucleophilic attack

Phenyl vinyl sulfones reacted with cyclohexanone enamines 332 to afford adducts which, upon hydrolysis, gave 2-(2-phenylsulfonyl)alkylcyclohexanone 333a . However, in the reaction with phenyl styryl sulfone, two products 333b and 334 were obtained by the nucleophilic attack at the and a-carbon atoms . Steric effects, electrostatic interactions between the nitrogen atom of the enamine and the oxygen atoms of the sulfone group, and medium effects contribute to the regioselectivity of the reaction. ... 

When a nucleophilic reagent, Nu X+ (or Nu—X), is reacted with a ketone, com-plexation of oxygen by X+ may precede attack at carbon. Geometric changes associated with such complexation have been calculated for a series of 4-substituted cyclohexanones. The results allow the facial selectivity of the subsequent nucleophilic attack to be predicted, and without the need to calculate the transition-state geometry. 

In accord with experimental data, LUMO maps for both cyclohexanone and 1,3-dioxan-5-one clearly anticipate preferential nucleophilic attack onto the axial carbonyl face,... 

The simplest case of substrate-controlled diastereoselection is the incorporation of the controlling stereocenter and the prostereogenic center into a cyclohexane or cyclopentane ring. In the classical example of nucleophilic attack on a conformationally anchored cyclohexanone, axial and equatorial attack are possible, leading to diastereomers 1 and 2, respectively. 

Wipf has shown that 4,4-disubstituted cyclohexanones undergo nucleophilic attack where the facial selectivity is determined by dipolar control. Thus, compounds of the type 23 underwent nucleophilic attack anti to the electronegative substituent at C(4), whereas the fluorinated analogue, 24, underwent attack syn to the oxygen, in accordance with the inversion of the dipole moment. They found that the logarithm of the experimentally observed facial selectivity for nucleophilic attack was correlated linearly (R = 0.998) with the calculated dipole moments. The facial selectivities were also shown to depend upon the nature of the nucleophile, hydride ions and alkynyl carbanions being essentially unselective. 

The preferred direction of nucleophilic attack on cyclohexanones has also been explained in terms of the torsional strain between the forming carbon-nucleophile bond and the adjacent bonds on C(2) and C(6)66,68,81 (Scheme 17). If the ring is flat, attack from the axial side is staggered whereas equatorial attack is eclipsed. However, if the ring is puckered, attack from the axial side is eclipsed and the equatorial side is staggered. Shi and Boyd have confirmed with calculations at the 6-21G or 6-32G level that the flatter the ring the more axial attack80. 

The Sn reactions of cyclohexanone acetals substituted at C(2) with sulfur, iodine, or chlorine are thought to occur when the nucleophile attacks the oxocarbenium ion intermediate with the substituent on C(2) in an axial conformation.104 The most stereospecific reactions (i.e. >92% trans), were when the substituent at C(2) was sulfur. This mechanism (Scheme 26) is supported by HF/6-31G calculations that show the oxocarbenium ion (66) with the sulfur at C(2) in the axial position to be the most stable, and by the high yield of the trans-isomer (67) in the products. 

Unsaturated nitro compound and nitriles do not usually suffer nucleophilic attack by enols or enolates and both are good at conjugate addition. The addition of the morpholine enamine 57 of cyclohexanone to 58 demonstrates that the nitro group is more effective than the ester at promoting conjugate addition.7... 

In the explanation favored today, the reason for this stereoelectronic effect is as follows The electronically preferred direction of attack of a hydride donor on the 0=0 double bond of cyclohexanone is the direction in which two of the C—H bonds at the neighboring a positions are exactly opposite the trajectory of the approaching nucleophile. Only the axial C—H bonds in the a positions can be in such an antiperiplanar position while the equatorial C—H bonds cannot. Moreover, these axial C—H bonds are antiperiplanar with regard to the trajectory of the H nucleophile only if the nucleophile attacks via a transition state B, that is, axially (what was to be shown). The antiperiplanarity of the two axial C—H bonds in the a positions is reminiscent of the antiperiplanarity of the electron-withdrawing group in the a position relative to the nucleophile in the Felkin-Anh transition state (formula C in Fig. 8.8 cf. Fig. 8.11, middle row). 

We will look more closely at the reactions of cyclohexene along with other alkenes in later chapters. For now, we return to the chemistry of cyclohexanones. Before you had read this chapter you might simply have drawn the mechanism for nucleophilic attack on cyclohexanone as shown. 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

Carbon-centered nucleophiles can also be used to advantage in the reaction with epoxides. For example, the lithium enolate of cyclohexanone 96 engages in nucleophilic attack of cyclohexene oxide 90 in the presence of boron trifluoride etherate to give the ketol 97 in 76% yield with predominant syn stereochemistry about the newly formed carbon-carbon bond <03JOC3049>. In addition, a novel trimethylaluminum / trialkylsilyl triflate system has been reported for the one-pot alkylation and silylation of epoxides, as exemplified by the conversion of alkenyl epoxide 98 to the homologous silyl ether 99. The methyl group is delivered via backside attack on the less substituted terminus of the epoxide <03OL3265>. 

Figure 6-7. Axial and equatorial nucleophilic attack at cyclohexanone.

The Felkin-Anh model has also been used to explain the preference for axial attack by nucleophiles on cyclohexanones and the effect of proximate substituents on facial selection. The anti periplanar geometry that Anh regarded as important in nucleophilic attack of carbonyl compounds is compromised by torsional strain in the reactions of cyclohexanones from the equatorial face. Felkin slated Whereas both torsional strain and steric strain can be simultaneously minimised in a reactant-like transition state when the substrate is acyclic... this is not possible in the cyclohexanone case.. ..These reactions all proceed via reactant-like transition states. In the absence of polar effects, their steric outcome is determined by the relative magnitude of torsional strain and steric strain [in the axial and equatorial transition states] [16]. 

---