Hindered ketones 1,6 addition

While ketones are known to react, in some cases, in a Wittig-like manner with Schrock s [Mo]2 catalyst, ADMET polymerization does proceed for some ketone dienes [91], with optimum results for hindered ketones. Additionally, some of these monomers were copolymerized with 1,9-decadiene [92]. Unhindered ketones have been successfully polymerized with Grubbs [Rujl and [Ru]2 catalysts (Figure 13.12) [47, 84]. 

Titanium tetrakis(diethylamide) selectively adds to aldehydes in the presence of ketones and to the least hindered ketone in compounds containing more than one ketone. The protection is in situ, which thus avoids the usual protection-deprotec-tion sequence. Selective aldol and Grignard additions are readily performed employing this protection methodology. ... 

As a general procedure, a mixture of the steroidal ketone (50 mg) and lithium aluminum deuteride (20 mg) in dry ether (5 ml, freshly distilled from lithium aluminum hydride) is heated under reflux until the reduction is complete according to thin layer chromatography test. The excess deuteride is then decomposed by the careful addition of a few drops of water and the reaction mixture is worked up by the usual procedure. For hindered ketones or esters the use of other solvents, such as tetrahydrofuran or dioxane, may be preferable to allow higher reaction temperatures. 

Double bonds in conjugation with the carbon-hetero multiple bond also lower addition rates, for similar reasons but, more important, may provide competition from 1,4 addition (p. 977). Steric factors are also quite important and contribute to the decreased reactivity of ketones compared with aldehydes. Highly hindered ketones like hexamethylacetone and dineopentyl ketone either do not undergo many of these reactions or require extreme conditions. 

In a reaction very much like 16-19, oximes can be prepared by the addition of hydroxylatnine to aldehydes or ketones. Derivatives of hydroxylamine, for example, H2NOSO3H and H0N(S03Na)2, have also been used. For hindered ketones, such as hexamethylacetone, high pressures (e.g., 10,000 atm) may be necessary. " ... 

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... 

Grignard additions are sensitive to steric effects and with hindered ketones a competing process leading to reduction of the carbonyl group can occur. A cyclic TS is involved. 

Twofold Michael additions have been utilized by the groups of Spitzner [2] and Hagiwara [3] to construct substituted bicyclo[2.2.2]octane frameworks. In Hagiwara s approach towards valeriananoid A (2-6) [4], treatment of trimethylsily-enol ether 2-2, prepared from the corresponding oxophorone 2-1, and methyl acrylate (2-3) with diethylaluminum chloride at room temperature (r.t.) afforded the bicyclic compound 2-4 (Scheme 2.2). Its subsequent acetalization allowed the selective protection of the less-hindered ketone moiety to provide 2-5, which could be further transformed into valeriananoid A (2-6). 

Magnesium enolates derived from hindered ketones are also possible Michael donors. For example, enolization of f-butyl alkylketones with (i-Pr)2Mg allows the 1,4-addition on the chalcone. A long reaction time (>3 h) limits the competing 1,2-addition and increases the proportion of the threo isomer (equation 77). 

Magnesium enolates derived from hindered ketones are able to initiate polymerization. For example, addition of 2, 4, 6 4-trimethylacetophenone in toluene to a suspension of (DA)2Mg results in the isolation of (DA)Mg(OC(=CH2)-2,4,6-Me3C6H2), which is found to be an excellent initiator for the living syndioselective (a > 0.95) polymerization of methyl methacrylate (equation 86). 

The acid portion of 1 was assembled by enantio-and diastereocontrolled addition of Z-crotyl borane to the aldehyde 8, following the Brown protocol. Hydroboration and oxidation led to 9, which was condensed with the allenyl silane 10 to give 11 with high diastereocontrol. Conversion of the alcohol to the iodide followed by three-carbon homologation by the Myers procedure then led to 1, which was cyclized with > 10 1 regio- and diasterocontrol to give 12. Ozonolysis and methylenation of the less hindered ketone then delivered 3. 

The two-directional tandem metathesis of 1 to 2 proceeded smoothly using 20 mol % of the second generation Grubbs catalyst (now commercially available only from Aldrich and from Materia) under an atmosphere of ethylene. The conversion of 2 to 3 took advantage of the differing reactivity of the two ketones. Addition of hydride to 2 from the less hindered face of the less hindered ketone delivered 4. 

The final step in a synthesis of modhephene (3) involved addition of a methyl group to the hindered ketone l.J The ketone does not react, however, with... 

Dicarbonyl compounds.1 The reaction of enol silyl ethers with methyl vinyl ketone catalyzed by BF3 etherate results in 1,5-dicarbonyl compounds. Almost quantitative yields can be obtained, even from hindered ketones, by addition of an alcohol or even, to a less extent, of water. 

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. 

Figure 13.30 shows that even sterically hindered ketone enolates can he alkylated. The carbon atom in the /3-position relative to the carhonyl carhon of an ,/i-dialkylated a,/3-unsatu-rated ketone can be converted into a quaternary C atom via 1,4-addition of an Gilman cuprate (for conceivable mechanisms, see Figure 10.46). As can he seen, a subsequent alkylation allows for the construction of another quaternary C atom in the a-position even though it is immediately adjacent to the quaternary center generated initially in the /1-position.

A variety of functionalised organic halides have been found to be compatible with the Sml2-mediated Barbier and Grignard reactions. For example, ben-zyloxymethyl chloride can be used in conjunction with Sml2 for the alkoxy-methylation of ketones.120 This addition has been found to work well even for hindered ketones such as 101, an intermediate in White s 1987 approach to 2-desoxystemodinone (Scheme 5.70).121 It is important to note that, in contrast to analogous organometallics, decomposition via a-elimination is not observed. 

The addition of hydrogen to hindered ketones usually occurs preferentially from a less hindered side and the stereochemistry is less influenced by the nature of solvents than in the cases of unhindered ketones, as generalized in ASB rules 1 and 2. According to these rules, the axial alcohols are formed predominantly in the hydrogenation of hindered cyclohexanones under both acidic and neutral (or alkaline) conditions. The ABS rule, however, is oversimplified, as pointed out by Dauben et al.,180 since the addition of hydrogen from a less hindered side does not always give axial alcohols as in the cases of 5a-cholestan-l-one (28)181 and the 12-oxo steroid 29 (hecogenin),182 where... 

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