Reduction of Unsaturated Ketones

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. 

Reductions of unsaturated ketones and a-acetoxy ketones usually are effected with an excess of reducing agent. For optimum yields of saturated ketones, the intermediate enolate salt obviously must not become protonated while... 

Reduction of a., -unsaturated carbonyl compounds. Hydrosilanes, particularly (QH,)2SiH2, in the presence of Pd(0), and a Lewis acid, particularly ZnCl2, can effect selective conjugate reduction of unsaturated ketones, aldehydes, and carboxylic acid derivatives. Chloroform is the solvent of choice. In addition, 1 equiv. of water is required. Experiments with D,0 and (C6H,),SiD2 indicate that... 

Semmelhack et al. chose CuBr, together with either Red-Al or LiAl(OMe)3H in a 1 2 ratio, to afford presumed hydrido cuprates, albeit of unknown composition [llj. In THF, both the former Na complex and the latter Li complex are heterogeneous (and of differing reactivities), yet each is capable of 1,4-reductions of unsaturated ketones and methyl esters (Eq. 5.4). Commins has used a modified version, prepared from lithium tri-t-butoxy-aluminium hydride and CuBr (in a 3 4.4 ratio), to reduce a 3-substituted-N-acylated pyridine regioselectively at the a-site [12]. 

Reduction of unsaturated ketones to unsaturated alcohols is best carried out Nit v complex hydrides. a,/3-Unsaturated ketones may suifer reduction even at the conjugated double bond [764, 879]. Usually only the carbonyl group is reduced, especially if the inverse technique is applied. Such reductions are accomplished in high yields with lithium aluminum hydride [879, 880, 881, 882], with lithium trimethoxyaluminum hydride [764], with alane [879], with diisobutylalane [883], with lithium butylborohydride [884], with sodium boro-hydride [75/], with sodium cyanoborohydride [780, 885] with 9-borabicyclo [3.3.1]nonane (9-BBN) [764] and with isopropyl alcohol and aluminum isopro-... 

Reduction of unsaturated ketones to saturated alcohols is achieved by catalytic hydrogenation using a nickel catalyst [49], a copper chromite catalyst [50, 887] or by treatment with a nickel-aluminum alloy in sodium hydroxide [555]. If the double bond is conjugated, complete reduction can also be obtained with some hydrides. 2-Cyclopentenone was reduced to cyclopentanol in 83.5% yield with lithium aluminum hydride in tetrahydrofuran [764], with lithium tris tert-butoxy)aluminium hydride (88.8% yield) [764], and with sodium borohydride in ethanol at 78° (yield 100%) [764], Most frequently, however, only the carbonyl is reduced, especially with application of the inverse technique (p. 21). 

The main methods of reducing ketones to alcohols are (a) use of complex metal hydrides (b) use of alkali metals in alcohols or liquid ammonia or amines 221 (c) catalytic hydrogenation 14,217 (d) Meerwein-Ponndorf reduction.169,249 The reduction of organic compounds by complex metal hydrides, first reported in 1947,174 is a widely used technique. This chapter reviews first the main metal hydride reagents, their reactivities towards various functional groups and the conditions under which they are used to reduce ketones. The reduction of ketones by hydrides is then discussed under the headings of mechanism and stereochemistry, reduction of unsaturated ketones, and stereochemistry and selectivity of reduction of steroidal ketones. Finally reductions with the mixed hydride reagent of lithium aluminum hydride and aluminum chloride, with diborane and with iridium complexes, are briefly described. 

TABLE 5.7 Hydrogen Transfer Reduction of Unsaturated Ketones over MgOai>... 

Aldehydes may be prepared by selective hydrogenation of substituted acroleins in much the same manner as the selective reduction of unsaturated ketones (method 196) however, there are few examples adequately described. - ... 

Alcohols 3-8, obtained by the reduction of the corresponding ketones with equimolar amounts of BMS and are obtained with high ees (ee values given are obtained using 0.1 equiv of (R)-1). Enantioselectivity is excellent (often similar or only slightly lower than those reported in the CBS reduction) for aromatic and hindered methyl ketones, (e.g. 3-5) and is also good for linear and a-monobranched enones (e.g. 7 and 8), but lower for linear methyl ketones like 2-octanone (6). In should be noted that in the reduction of unsaturated ketones, the time of addition is critical (the optimum being around 15-20 min) in order to avoid concomitant olefin hydroboration. In sharp contrast to the CBS process, the use of catecholborane (instead of BMS) or alternative solvents proved to be detrimental. 

The combination of silicon hydrides and a Pd° catalyst is essentially useless for reduction of electron-deficient alkenes. However, addition of catalytic amounts of zinc chloride creates a new three-component mixture that enables rapid conjugate reduction of a,p-unsaturated ketones and aldehydes. In fact, soluble palladium complexes of various oxidation states were equally efficient catalysts, an obvious practical advantage of this approach. The generality of the method with respect to the substrate, its experimental simplicity, and its easy applicability to large-scale work make it a method of choice for conjugate reduction of unsaturated ketones and aldehydes. 

The synthesis of the nonsteroidal anti-inflammatory drug nabumetone (9) was developed by Hoechst-Celanese [71]. It was prepared via a Heck coupling of 2-bromo-6-methoxy-naphthalene (1) with methyl vinyl ketone in the presence of palladium catalyst [71]. Further reduction of unsaturated ketone provided 9. Nabumetone was also obtained in a one-step coupling reaction of 2-bromo-6-methoxy-naphthalene with 3-buten-2-ol followed by isomerization of enol [72]. 

Figure 7.1. Postulated transition structures for the asymmetric reduction of unsaturated ketones by BINAL-H [12]. Structures (a) and (b) differ in the orientation of Rjat and Run, the saturated and unsaturated ketone ligands, respectively, (a) UI topicity P reagent attacking Re face of ketone, (b) Lk topicity P reagent attacking Si face of ketone, (c) Alternate chair that is destabilized by the gauche pentane conformation accented by the bold lines (c/. Figure 5.5). Transition structures containing this conformation were considered by Noyori to be unimportant [12].

Even in the presence of other silicon reagents like PhjSiHj, Michael acceptors are totally unaffected. The addition of catalytic amounts of zinc chloride to the Pd(0)/silane system, however, creates a three-component mixture that allows rapid conjugate reduction of a,p-unsaturated aldehydes and ketones. The conjugate reduction was shown to be both regio- and stereoselective. The use of dideuterodiphenylsilane in the reduction of unsaturated ketones yielded satmated ketones containing one deuterium atom at the P-position. On the other hand, when traces of D2O were added to the nondeuterated mixture, incorporation of deuterium occurred in the a-position (Scheme 16). ... 

Lanthanide chlorides and sodium borohydride reductions of unsaturated ketones... 

In the reduction of unsaturated ketones of type (192), problems arise of stereoisomerism in the ce- and jS-positions. The o -position to the keto group becomes the equilibrium position under the conditions of working up the reaction products, and the stereochemistry of the ketonization of enolates of lype of (194) has been discussed above (p. 53) consequently, here we discuss only stereochemical questions connected with the f3 -position. In the overwhelming majority of cases,the more stable isomer is formed [90] (Schemes 25, 52, 53, 87), and an example of this is the reduction of the ketone (195) to (196) (Scheme 52). The formation of the more stable isomers shows the predominating influence in this case of the conformational factor and not the accessibility of the p -position for the proton donor. The opinion has been expressed [91] that the stereochemistry of such reactions is determined by the stereoelectronic factor, i.e., predominant axial attack this is apparently not in harmony with subsequent results [67, 92]. 

The number of stages can be reduced by using the direct alkylation of the intermediate enols formed in the reduction of -unsaturated ketones of type (42) with lithium in liquid ammonia. By this method, for example, the ketone (401) has been converted into the tricyclic intermediate (402) with the anti-trans-configuration [49]. 

Shortly after. List applied a TRIP-derived catalyst 31 already known from the reduction of unsaturated ketones (see section 2.1 in this chapter). By employing this bulkier anion they were able to increase the enantioselectivity up 93%. Not only aromatic imines but also aliphatic imines could be reduced with good results. Besides, it was possible to keep the good yields (81%) despite the lowering of catalyst loading to 1 mol%" (Scheme 32.19). 

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