The Reduction of a,-Unsaturated Ketones

The reduction of allylic systems is frequently used to generate isolated double bonds. Suitable systems are obtained from oe,jS-unsaturated ketones via allylic alcohols (ref. 185, p. 256 ref. 283, 284) for example, the preparation of A -cholestene (135). 

An older method,which also retains the double bond in its original location, utilizes the fact that thioketal formation from A -3-ketones does not induce bond migration. Subsequent desulfurization with Raney nickel gives the A -olefin (see section XI-D). 

A direct reduction of the A -3-keto system can be effected with lithium aluminum hydride-aluminum chloride. The last two methods are unsatisfactory with A -3-ketones (ref. 185, p. 253 ref. 255, but cf. ref. 229). 

Both the Wolff-Kishner and Clemmensen reductions of a, -unsaturated ketones give olefins. There has been considerable confusion concerning the exact product composition in the case of A -3-ketones. Wolff-Kishner reduction gives A -, 5a-A - and 5 -A -olefins, and, depending on the substrate reaction conditions and work-up, any one or more of these may be isolated. (See ref. 287 for a recent review of the Wolff-Kishner reduction.) 

In any event, isolation is tedious and yields of single olefin are not very good, although the use of potassium /-butoxide is reported to favor 

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As mentioned above, MPVO catalysts are very selective towards carbonyl compounds. Alkenes, alkynes or other heteroatom-containing double bonds are not affected by these catalysts, while they can be reduced by transition-metal catalysts. Examples of the reduction of a,/ -unsaturated ketones and other multifunctional group compounds are compiled in Table 20.3. 

The reduction of a,/ -unsaturated ketones, e.g., 7, by lithium in ammonia is another possibility for generation of enolates19. This method has been mainly used in the preparation of enolates for stereo- and regioselective alkylations in the steroid and terpenoid fields (see... 

The reduction of a,/ -unsaturated ketones to olefins may also be effected via the tosylhydrazones (see section XI-A). 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

General procedure for the asymmetric reduction of a, -unsaturated ketones [32]... 

Reduction of a, -unsaturated ketones to unsaturated hydrocarbon is rather rare, and is almost always accompanied by a shift of the double bond. Such reductions are accomplished in good to high yields by treatment of the p-toluenesulfonylhydrazones of the unsaturated ketones with sodium borohydride [785], borane [786] or catecholborane [559], or by Wolff-Kizhner reduction or its modifications [590]. However, complete reduction to saturated hydrocarbons may also occur during Wolff-Kizhner reduction [597] as well as during Clemmensen reduction [750]. 

Lithium-ammonia reduction of a,/ -unsaturated ketones (entry 6, Scheme 1.4) provides a very useful method for generating specific enolates.26 The desired starting materials are often readily available, and the position of the double bond in the enone determines the structure of the resulting enolate. This and other reductive methods for generating enolates from enones will be discussed more frilly in Chapter 5. Another very important method for specific enolate generation, the addition of organometallic reagents to enones, will be discussed in Chapter 8. 

Reduction of aryl diazonium ions by Ti(IEL) in the presence of a,/ -unsaturated ketones and aldehydes leads to /> arylation and formation of the saturated ketone or aldehyde. The early steps in this reaction parallel the copper-catalyzed reaction. However, rather than being oxidized, the radical formed by the addition step is reduced by Ti(IEL).109 Scheme 11.7 illustrates some typical examples of arylation of alkenes by diazonium ions. 

In any event, isolation is tedious and yields of single olefin are not very good,255,273 288 although the use of potassium /-butoxide is reported to favor formation of the A4-olefin in good yield.289 It has been shown290 that Wolff-Kishner reduction of a,/ -unsaturated ketones involving double bond shift involves a nonsymmetrical intermediate. 

An example of an acid-base reaction following a two-electron process is the reduction of ,j2-unsaturated ketones. In these reductions the radical formed in the first one-electron uptake is further reduced and reacts according to the scheme (25) ... 

The combination of MAD with some complex aluminum hydride reagents enables the conjugate reduction of a -unsaturated ketones [142]. Although selectivity is profoundly affected by the structure of substrates, the 1,4 addition of hydride to quinone monoketals and quinol ethers is successfully mediated by MAD to give reduction products in good yield (Sch. 104) [143]. 

In order to study the factors determining the regioselectivity of sodium borohydride reduction of a, -unsaturated ketones, reactions with 3-methylcyclohexenone, carvone and cholestenone were carried out in 2-propanol, diglyme, triglyme or pyridine. Mixtures of 1,2- and 1,4-reduction products were obtained in the alcoholic and ether solvents, whereas pure 1,4-reduction was observed in pyridine. Addition of triethylamine to NaBH4 in diglyme led to formation of triethylamine borine, EtsN BHs. Similarly, with pyridine, pyridine borine could be isolated, leading to exclusive 1,4-reductions. 

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. 

Reduction of a,fi-unsaturated ketones. House et al.1 have compared the reduction of aj3-unsaturated ketones under standard Birch conditions (Li + t-BuOH in NH3-THF) and with sodium or lithium and t-BuOH in hexamethyl-phosphoric triamide (1, 430-431 2, 208-210)-THF. In general, more of the less stable epimer is obtained with Na-HMPT. Factors which favor formation of the less stable epimer include the use of low temperatures (— 33 to—78°), the presence of a proton donor (/-BuOH), use of a cosolvent such as THF, and the presence of excess metal throughout the reduction. Thus the enone (1) is reduced in either... 

Reduction of a. -unsaturated ketones. This reducing agent is the reagent of choice for reduction of enones of type (1) to the a,-unsaturated alcohols... 

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... 

Reduction.—Contrary to accepted belief, epimerization can precede reduction in the reaction of a-chiral ketones with sodium borohydride in anhydrous media, such as alcohols or ethers this undesirable event can be nullified by the addition of as little as 2% of water. An overdue report has been published on the occurrence of 1,4-addition in the reduction of ajff-unsaturated ketones with sodium borohydride no methods of avoidance are suggested... 

Thiophenes can be prepared from the sultones of a -unsaturated ketones. From the 3-sultone of pulegone (89), the thiophene (91) has been obtained through reduction with LiAlH4 to (90), followed by... 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

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 ... 

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