Sodium borohydride saturated ketones

Reduction of the ketone carbonyl of cis-1, 2,3,4,4a,9b-hexahydro-8-hydroxydi-benzofuran-3-one with trifluoroacetic acid and triethylsilane at 0° produces a mixture of the a- and /3-isomers of the C3 alcohol with an u / ratio of 1 4 (Eq. 211).394 This result can be compared with the isomer ratio of 100 1 that results when sodium borohydride is used as the reducing agent.394 The same cis pair of alcohol isomers is formed in 77% combined yield, but in a reversed ratio of a /3 = 4 1, when the less saturated tetrahydrodibenzofuran analog is used as the substrate (Eq. 212).394... 

A difference in the reactivities and selectivities between tetra-n-butylammonium borohydride and sodium borohydride in the reduction of conjugated ketones is well illustrated with A1-9 2-octalone (Scheme 11.3) [17], Reduction with the sodium salt in tetrahydrofuran is relatively slow and produces the allylic alcohol (1) and the saturated alcohol (2) in a 1.2 1 ratio whereas, in contrast, tetra-n-butylammonium borohydride produces the non-conjugated alcohol (3) (50%) and the saturated alcohol (2) (47%), with minor amounts of the ketone (4), and the allylic alcohol (1) [16]. It has been proposed that (3) results from an initial unprecedented formation of a dienolate anion and its subsequent reduction. 

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). 

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]. 

A 125 ml flask fitted with a magnetic stirring bar, a reflux condenser, a thermometer and a separatory funnel is charged with 7.2 g (9 ml, 0.1 mol) of 2-butanone (methyl ethyl ketone). From the separatory funnel a solution of 1.5 g (0.04 mol, 60% excess) of sodium borohydride in 15 ml of water is added dropwise with stirring at such a rate as to raise the temperature of the readion mixture to 40° and maintain it at 40-50°. Cooling with a water bath may be applied if the temperature rises above 50°. After the addition has been completed (approximately 30 minutes) the mixture is stirred until the temperature drops to 30°. It is then transferred to a separatory funnel and saturated with sodium chloride. The aqueous layer is drained and the organic layer is dried with anhydrous potassium carbonate. Distillation affords 5.5-6.0g (73-81%) of 2-butanol, b.p. 90-95°. 

The CD fragment 1s synthesized starting with resolved bicyclic acid 129. Sequential catalytic hydrogenation and reduction with sodium borohydride leads to the reduced hydroxy acid 1. The carboxylic acid function is then converted to the methyl ketone by treatment with methyl-lithium and the alcohol is converted to the mesylate. Elimination of the latter group with base leads to the conjugated olefin 133. Catalytic reduction followed by equilibration of the ketone in base leads to the saturated methyl ketone 134. Treatment of that intermediate with peracid leads to scission of the ketone by Bayer Villiger reaction to afford acetate 135. The t-butyl protecting... 

Kinetic studies [63,64] have provided rate data for the reduction of various saturated steroid ketones which show the order of reactivity with sodium borohydride to be 5a-3-CO > 6-CO > 7-CO > 12-CO > 17-CO > 20-CO > ii-CO. 

Zinc-modified cyanoborohydride, prepared from anhydrous zinc chloride and sodium cyanoborohy-dride in the ratio 1 2 in ether, selectively reduced aldehydes and ketones but not acids, anhydrides, esters and tertiary amides. In methanol the reactivity paralleled the unmodified reagent. Zinc and cadmium borohydrides form solid complexes with DMF, which may prove to be convenient sources of the reducing agents.Aromatic and a,p-unsaturated ketones were reduced much more slowly than saturated ketones, so chemoselective reduction should be possible. 

Stereoselective reduction of an enone lactone was a key step in the construction of the 20-hydroxyec-dysone side chain. Totally different mixtures of products were obtained when the reduction was carried out with sodium borohydride or by catalytic hydrogenation (Scheme 30). In all cases, the 1,4-reduction mode is preferred. With borohydride, however, this process is followed by a subsequent reduction of the saturated ketone and base-catalyzed rearrangement of the 5-lactone into a y-lactone. 

Oximes.—Oximes of some saturated ketones are reduced by aqueous alkaline sodium borohydride under reflux to give the corresponding alcohols. Selective reduction of a 3,17-dioxime is possible, at C(3). a -Oximino-ketones afford diols. Diborane, in contrast, reduces oximes to give alkyl hydroxylamines a recent variant using sodium borohydride on silica gel in benzene gave the... 

A mixture of the amido ketone (1.70 g, 3.86 mmol) and sodium borohydride (293 mg, 7.72 mmol) in anhydrous methanol (60 mL) was stirred at -10 °C for 25 min. Saturated NaHCOa (40 mL) and CH2CL (80 mL) were added, and the mixture was stirred at 0 °C for 5 min. The organic layer was removed, and the aqueous layer was extracted with CH2CI2 (3 x 40 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 1.68 g (95%) of the secondary alcohol as a white solid. 

The approach using cyclodextrin as a binding site has also been developed. Cyclodextrins are widely utilized in biomimetic chemistry as simple models for an enzyme because they have the ability to form inclusion complexes with a variety of molecules and because they have catalytic activity toward some reactions. Kojima et al. (1980, 1981) reported the acceleration in the reduction of ninhydrin and some dyes by a 1,4-dihydronicotinamide attached to 3 Cyclodextrin. Saturation kinetics similar to enzymatic reactions were observed here, which indicates that the reduction proceeds through a complex. Since the cavity of the cyclodextrin molecule has a chiral environment due to the asymmetry of D-glucose units, these chiralities are expected to be effective for the induction of asymmetry into the substrate. Asymmetric reduction with NAD(P)H models of this type, however, has not been reported. Asymmetric reduction by a 1,4-dihydronicotinamide derivative took place in an aqueous solution of cyclodextrin (Baba et al. 1978), although the optical yield from the reduction was quite low. Trifluoromethyl aryl ketones were reduced by PNAH in 1.1 to 5.8 % e.e. in the presence of 3-cyclodextrin. Sodium borohydride works as well (Table 18). In addition to cyclodextrin, Baba et al. also found that the asymmetric reductions can be accomplished in the presence of bovine serum albumin (BSA) which is a carrier protein in plasma. 

Both sodium borohydride and lithium aluminum hydride contain the 6- hydrogen atom commonly known as a hydride. When 7 or 8 reacts with an aldehyde or ketone, the hydride is attracted to the 6+ carbonyl carbon, suggesting an acyl addition reaction. In the experiment where 2-butanone (9) is treated with NaBH4 in aqueous methanol, the product is alkoxide 11— the acyl addition product expected if hydride attacks the acyl carbon. In 11, the boron is attached to oxygen, and one hydrogen atom from the borohydride is attached to the acyl carbon. This means that a new o-covalent C-H bond is formed. When 11 is treated with an aqueous solution of saturated ammonium chloride in a second step, 2-butanol (12) is isolated in 87% yield. ... 

The selective reduction of enones may be achieved by use of the correct catalyst. Thus reduction of enones by sodium hydride-sodium alkoxide mixtures with zinc(ii) chloride as catalyst gives 1,2- whereas nickel(ii) acetate gives 1,4-reduction. Similarly, use of cobalt(ii) or nickel(ii) chlorides yields only saturated ketones from the borohydride reduction of /3-alkyl- or /3-aryl-thio-enones. ... 

The easily prepared, stable solid reagent diphenylamine-borane (Ph2NH BH8) has been shown to be more reactive than aliphatic amine-boranes and almost as reactive as borane-THF for the reduction of ketones acids are also reduced to alcohols. Polyethylene glycols (PEG) catalyse the reduction of ketones by sodium borohydride under phase-transfer (PT) conditions, for example in solid-liquid PT with PEG as solvent. The solid zinc borohydride-dimethylformamide complex reduces aldehydes and ketones to alcohols, but only one hydrogen atom from each tetrahydridoborate unit is utilized. The different rates of reduction of various classes of ketone (saturated aliphatic faster than aromatic, and a -unsaturated very slow) suggest a possible selectivity between ketones. The corresponding cadmium complex, prepared in situ, reacts similarly. Lithium methylborohydride, LiMeBHj, prepared as shown in equation (1), where... 

The reduction of a,p-unsaturated aldehydes and ketones by NaBH4 leads, in general, to substantial amounts of fully saturated alcohols. In alcoholic solvents, saturated -alkoxy alcohols can be formed via conjugate addition of the solvent. This latter process becomes the main reaction path when reduction is performed in 2-propanol in the presence of sodium isopropoxide. In base, a homoallylic alcohol can become the major product of borohydride reduction of an enone. Analysis of the influence of substrate structure on NaBH4 reduction has shown that increasing steric hindrance on the enone increases 1,2-attack. ... 

---