Ketones, a-halo reduction

A variety of a-substituted ketones (a-halo, -hydroxy, -methoxy and -amino) have been converted into alkenes by reductive elimination. Obviously, this approach, depends not only on the feasibility of a-functionalization but also on the ability to introduce the a-substituent regioselectively. a-Halo ketones, which are readily prepared from the starting ketone," have been subjected to reductive elimination conditions to afford the desired alkenic products. For example, in the preparation of ( )-eriolanin (Scheme 5)," the protected dihydroxy keto ester is treated sequentially with LDA and Br to afford the a-bromo... 

In addition to the reduction of ketones (e.g., aromatic and aliphatic ketones, a-halo ketones, hydroxyketones, enones, and ketoesters), oximes can be reduced to the corresponding amine with this reagent. In general, ketone oxime ethers, such as 39, can give rise to amines 40 in excellent chemical yield with good to excellent optical purity.5d... 

Asymmetric reductions of a-fiinctionalized ketones, such as a-hydroxy ketones, a-halo ketones, a-sulfonoxy ketones, 1,2-diketones, a-keto acetals or thio ketals, acyl cyanides and a-amino or imino ketones with boron-based chiral reducing agents in a stoichiometric or catalytic manner have been reviewed. The oxazaborolidine-catalyzed borane reduction of protected a-hydroxy ketones, a-keto acetals and a-sulfonoxy ketones has been discussed in more detail. 

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

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... 

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. ... 

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. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Aqueous solutions of vanadous chloride (vanadium dichloride) are prepared by reduction of vanadium pentoxide with amalgamated zinc in hydrochloric acid [213], Reductions are carried out in solution in tetrahydrofuran at room temperature or under reflux. Vanadiiun dichloride reduces a-halo ketones to ketones [214], a-diketones to acyloins [215], quinones to hydroquinones [215], sulfoxides to sulfides [216] and azides to amines [217] (Procedure 40, p. 215). 

Reduction of a-halo ketones. a-Bromo and a-chloro ketones are reduced to the purent ketone hy this reagent in CM iC N at room temperature in 3 12 hours. Yields tre in I he range 75 )5" . 

It is not possible to use zinc for reductive debromination in the presence of a-halo ketones and for transformations involving these intermediates, sodium iodide has been used.103,262 In some instances, e.g. 5,6-dihalo-3-ketones, iodide does not always give a completely halogen-free product, and zinc does not give clean debromination.263,264 The use of chromous chloride has proved advantageous in such cases and is the reagent of choice for vicinal dichlorides, which are inert to iodide ... 

Enantioselective reductions. The neat reagent (1), prepared from ( + )-< -pinene, reduces aryl a-halomethyl ketones slowly but in high chemical yield to (R)-halohydrins in 90-96% ee, but optical induction is mediocre in the case of aliphatic a-halo ketones (35-66% ee). The chiral halohydrins are useful precursors to chiral epoxides. 

Preparation. The general preparation of u-hydroxy acids is by the hydrolysis of an a-halo acid or by Ihe acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 0-Hydroxy acids may be made by catalytic reduction of 0-keut esters followed by hydrolysis. 0-Hydroxy acids can also he prepared by ihe ReformaCsky reaction y-Hydroxy acids are seldom obtained in the free slate because of ihe case wilh which they form... 

In some circumstances, the production of a 2-halo alcohol by reduction of the carbonyl group of an a-halo ketone with metal hydrides is a useful synthetic reaction ... 

Two possible mechanisms can be envisaged for this reduction, both involving the formation and protonation of Sm(III) enolates. Molander proposed that a-halo ketones react with Sml2 to give a ketyl radical 32 that is then quenched by the cosolvent.29 A second reduction then gives carbanion 33 that undergoes (3-elimination to produce the enol tautomer of the product ketone (Scheme 4.20). 

---