Ketones sterically hindered

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

This reduction is not as suitable for sterically hindered ketones, since in these cases the alcohol is the major product. The reduction of 11- and 12- " keto steroids, for example, is usually very slow. Furthermore, the 11-keto steroid (76) yields only about 10% of the 11,1 l-d2 labeled analog (77), the main product being the 1 IjS-dj-l la-hydroxyl derivative (78). ... 

Another side-reaction can be observed with sterically hindered ketones that contain an a-hydrogen—e.g. 18. By transfer of that hydrogen onto the group R of RMgX 2, the ketone 18 is converted into the corresponding magnesium enolate 19, and the hydrocarbon RH 14 is liberated ... 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

The scope of this methodology was extended by these authors to more sterically hindered ketones that provided the corresponding alcohols with enhanced enantioselectivities. As shown in Scheme 9.3, the results demonstrated that the steric and electronic properties of the substrates influenced the reaction course. 

The success of this transformation depends upon the oxidation potential of the ESE group (Eox 1.5 V), which is lower than that of the alkyl silyl ether group (Eax 2.5 V). Recently, Schmittel et al.35 showed (by product studies) that the enol derivatives of sterically hindered ketones (e.g., 2,2-dimesityl-1-phenyletha-none) can indeed be readily oxidized to the corresponding cation radicals, radicals and a-carbonyl cations either chemically with standard one-electron oxidants (such as tris(/>-bromophenyl)aminium hexachloroantimonate or ceric ammonium nitrate) or electrochemically (equation 10). 

Catalytic hydrogenation in neutral medium gives an axial alcohol from sterically hindered ketone and an equatorial alcohol from sterically unhindered ketones. 

The activated Ba(OH)2 was used as a basic catalyst for the Claisen-Schmidt (CS) condensation of a variety of ketones and aromatic aldehydes (288). The reactions were performed in ethanol as solvent at reflux temperature. Excellent yields of the condensation products were obtained (80-100%) within 1 h in a batch reactor. Reaction rates and yields were generally higher than those reported for alkali metal hydroxides as catalysts. Neither the Cannizaro reaction nor self-aldol condensation of the ketone was observed, a result that was attributed to the catalyst s being more nucleophilic than basic. Thus, better selectivity to the condensation product was observed than in homogeneous catalysis under similar conditions. It was found that the reaction takes place on the catalyst surface, and when the reactants were small ketones, the rate-determining step was found to be the surface reaction, whereas with sterically hindered ketones the adsorption process was rate determining. 

The second is that sterically hindered ketones bearing hydrogen atoms on their a-carbons, R2CH(CO)R (cf. 3b), tend to be converted to their enolates (6), where the Grignard reagent, R MgX, is lost as R —H in the process via 4b (Scheme 4). 

No product was formed in this reaction in the absence of the soluble lanthanide salt or even in the presence of CeCL. Heteroaryl Grignard reagents react smoothly in the presence of LaCl3 2LiCl even with highly sterically hindered ketones like 211 (equation 137). 

This ketone was usually obtained in 10-20% yield, except with a sterically hindered ketone such as 3,3-dimethyl-2-butanone. In this last case, the main product was the unsaturated ketone isolated in 75% whereas the expected alcohol was formed in less than 20% yield. 

Better yields of cyclobutanones were obtained with steroidal ketones.85 86 In the reaction of 5a-cholestan-3-one (5) with diazocyclopropane, spiroannulation to give 6 (30%) dominated insertion to give 7 (24%), and with 3/ -acetoxy-5a-pregnane-l 1,20-dione (8) only spiroannulation to give 9 (60%) was observed.85 A comparable high yield (78%) of a spiroannulation product 11 was obtained with trispiro[2.0.2.0.2.1]decan-10-one (10).84 It is apparent that efficient formation of oxaspiropentanes as direct precursors of cyclobutanones only takes place with sterically hindered ketones. 

The method is a modification of one used by Barton and McCombie.8 Reduction of ketones.9 Ketones can be reduced to alcohols by Bu3SnH in the presence of either AIBN or a Lewis acid, but this reaction is limited to unhindered ketones. However, even sterically hindered ketones, such as f-butyl methyl ketone, can be reduced under high pressure (10 kbar) in the absence of a catalyst. This method is particularly useful in the case of cyclopropyl and a,p-epoxy ketones, which are reduced to the corresponding alcohols. Reduction of these ketones with Bu3SnH under radical conditions results in ring-opened products. 

The addition of hydrogen cyanide to a carbonyl group of an aldehyde or most ketones produces a cyanohydrin. Sterically hindered ketones, however, don t undergo this reaction. 

With sterically hindered ketones the following side products are received ... 

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