The Reduction of a-Substituted Ketones

Borohydrides reduce a-substituted ketones to the corresponding a-substituted alcohols, and such products can be further reduced to olefins (see section VIII). Other reagents serve, through participation of the carbonyl group, to remove the substituent while leaving the ketone intact. The zinc or chromous ion reduction of a-halo ketones is an example of this second type, which is not normally useful for double bond introduction. However, when the derivative being reduced is an a,jS-epoxy ketone, the primary product is a -hydroxy ketone which readily dehydrates to the a,jS-unsaturated ketone. Since 

Hydriodic acid at low concentration in acetic acid will also effect the reduction of a,j5-epoxy ketones to a,jS-unsaturated ketones  

A third type of reduction of a-substituted ketones is typified by the expulsion of the substituent and the reduction of the keto function to form an olefin. Wolff-Kishner reductions of a-hydroxy, a-acetoxy, a-halo, °° and a-epoxy (see below) ketones are the most frequently encountered steroid examples of this general class.  

The reduction of 2-a-halo-5a-cholestan-3-ones (142) is illustrative the yield rises with decreasing atomic number of the halogen, °° 

It is important to exclude air in all hydrazone-type reductions involving olefins (otherwise, over-reduction occurs due to diimide formation) in the above example, as an added precaution cyclohexene was used as a solvent. 

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FePc-derivatives (95) prepared from TCB and FeCl3 in ethylene glycol as mentioned before were used as electron transfer carriers for the reduction of a-substituted ketones and others with l-benzyl-l,4-dihydronicotinamide or benzenethiol (Eq. 50) -. ... 

The scheme was verified usii chronopotentiometric and potentio-static methods (Alberts and Shain, 1963). A similar scheme was considered for the reduction of o- and p-nitrophenols and nitroanilines but the theoretical treatment is more involved owing to the irreversibility of the first four-electron reduction step. Similarly also a chemical reaction is interposed between the first and second electrode process in the reductions of a-substituted ketones of the type RCO.CHg—X (for X=NR2, NR, SR, SRf, OR, PRJ and halogen) and in the reductions of a,)9-unsaturated ketones. In both these systems enolate is a primary electro-inactive reduction product that must be first transformed into the electro-active keto-form. The rate of this transformation, which is acid-base catalysed, limits the wave-height of the more negative wave of the saturated ketone. Similarly it was explained why the more negative wave observed on curves of benzil is smaller than expected for the given concentration of benzoin. 

Two waves arise with the indicated half-wave potentials. The wave height for the process P2 + Zb -> P3 occurring at the more negative potential will obviously depend on the rate at which electroactive P2 is generated from Pi, which is itself assumed to be electroinactive. Examples where this type of behavior arises are the reductions of a-substituted ketones, aromatic bicarbonyl compounds such as p-diacetylbenzene, terephthaldialdehyde and a,/8-unsaturated ketones. Restricting ourselves to one type of example discussed by Zuman, " the following is the scheme for reduction of an a-substituted... 

Scheme 4.5 Reduction of a-substituted ketones in the presence of iron catalyst.

Adsorption of the ketone on montmorillonite clay enhances the axial attack of NaBH reduction to >99% for 4-t-butylcyclohexanone 3.26 and 78% for 3,3,5-trimethylcyclohexanone 3.29 [SRI], Other hindered substituted borohydrides also give higher levels of equatorial attack [CYl]. From the numerous studies to date, it appears that torsional and steric factors are very often predominant, as illustrated by the reduction of eight-membered cyclic taxane derivatives [SH7]. An interesting solvent effect in the reduction of a sugar derivative has been recently shown. The reduction of a substituted rigid six-membered ketone with DIBAH in CH2CI2 or... 

The first reaction was involved in a synthesis of morphine, the starting ketone being made by reduction of a substituted naphthalene O. Amer. Chem. Soc., 1950, 72, 3704). No doubt an epoxide could have been used as the electrophile. 

Another example of dynamic kinetic resolution is the reduction of a sulfur-substituted ketone. Thus, yeast reduction of (R/S)-2-(4-methoxyphenyl)-l, 5-benzothiazepin-3,4(2H, 5H)-dione gave only (2S, 3S)-alcohol as a product out of four possible isomers as shown in Figure 8.39c [29kj. Only (S)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded... 

The most plausible mechanism for the interconversion of la and Ih is shown in Scheme 2. Similar mechanism has been put forward for epimerization of a-substituted ketones under basic conditions and for the equilibration via an enolate prior to nucleophilic substitution was observed by Numazawa et al. (ref. 13). The same mechanism seems to operate in the reduction of some steroid a-haloketones (ref. 14) or tra/ty-3-chloroflavanone (ref. 15) with sodium borohydride where an inversion of configuration takes place at the a carbon parallel to the reduction of the... 

The reduction of a-sulfur substituted ketone 27 and its analogues usually gives the anti-mercaptol alcohol like roc-14 which can be elaborated into cis-dihydrobenzoxathiin 30. 

Prochiral aryl and dialkyl ketones are enantioselectively reduced to the corresponding alcohols using whole-cell bioconversions, or an Ir1 amino sulfide catalyst prepared in situ.695 Comparative studies show that the biocatalytic approach is the more suitable for enantioselective reduction of chloro-substituted ketones, whereas reduction of a,/ -unsaturated compounds is better achieved using the Ir1 catalyst. An important step in the total synthesis of brevetoxin B involves hydrogenation of an ester using [Ir(cod)(py) P(cy)3 ]PF6.696... 

Dehalogenation of a-substituted ketones and esters via radical anions has also been examined for its synthetic utility. As reported by Molander, Sml2 is an especially effective reagent for this transformation (equation l)44. Yields are typically high (70-100%) for X = Cl, OAc, OSiMe3, OCOCH2PI1, OTs, etc.). A mechanism for the reduction of esters (Scheme 10) has been suggested. 

In view of the high reactivity of these reduction systems [Zn—HC1 gas-Ac20 (or Et20)], zinc reductions of a-substituted, a,/3-unsaturated, and aryl ketones have also been studied, as summarized in Table V in which considerably different results have been obtained depending... 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

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