Solvent effect unsaturated ketones

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

The Claisen rearrangement is an electrocyclic reaction which converts an allyl vinyl ether into a y,8-unsaturated aldehyde or ketone, via a (3.3) sigmatropic shift. The rate of this reaction can be largely increased in polar solvents. Several works have addressed the study of the reaction mechanism and the electronic structure of the transition state (TS) by examining substituent and solvent effects on the rate of this reaction. 

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... 

The formation of peracids as the effective oxidizing species has often been proposed for oxidations with sodium percarbonate in the presence of organic acids or acid anhydrides30-32. It was observed that at room temperature and in dichloromethane as solvent, the addition of acetic anhydride induced the epoxidation by sodium perborate of mono-, di- and trisubstituted alkenes, including a,/i-unsaturated ketones in a slightly exothermic reaction33 (equation 6). 

Kotsuki et al.909 have developed a method to effect the Michael addition of [3-ketoesters with ethyl acrylate in the presence of triflic acid under solvent-free conditions [Eq. (5.335)]. Nonactivated cyclohexanones as Michael donors and a,/3-unsaturated ketones as acceptors are also reactive. The use of menthyl acrylates did not result in any significant asymmetric induction. 

In non-hydroxylic solvents, the effects of the cation co-ordination become important, particularly if the cation is Li+ or Zn + 2. Lithium borohydride reductions of cyclohexanone, in THF, for example, are strongly inhibited by addition of the stoichiometric amount of the lithium specific [2.1.1]cryptand (Handel and Pierre, 1975). In the reduction of a,P-unsaturated ketones, lithium borohydride shows a strong selectivity for 1,2-addition (D Incan et al., 1982a,b) but in the presence of the cryptand, conjugate addition is favoured indeed, the selectivity is then indistinguishable from tetrabutyl-ammonium borohydride (D lncan and Loupy, 1981 Loupy and Seyden-Penne, 1979, 1980). 

None of these mechanistic proposals is sufficiently general to use to rationalize all of the stereochemical data observed on the hydrogenation of a,[3-unsaturated ketones. By a judicious combination of segments of each of these proposals along with the Horiuti-Polanyi mechanism (2), it is possible, however, to develop a uniform mechanistic rationale that can be useful in determining the effect of solvent on product stereochemistry. In addition, the influence of hydrogen availability, the type and quantity of catalyst, and the nature of other substituents on the reacting molecule on the product isomer distribution can also be more readily understood. 

The stereoselectivity in the hydrogenation of bicyclic and polycyclic a,P-unsaturated ketones with the double bond at the ring juncture has been the subject of extensive investigations.252 Formation of cA-2-decalone in the hydrogenation of A1,9-2-octalone (115) with palladium catalysts increases with increasing polarity of aprotic solvents and also in the presence of acid, especially in nonhydroxylic solvents.253,254 Hydro-bromic acid has been found to be more effective than hydrochloric acid for cA-2-de-calone, especially in tetrahydrofuran (eq. 3.72).255 Formation of alcoholic products was also completely depressed in the presence of hydrobromic acid, although the rate of hydrogenation became considerably lower than in the presence of hydrochloric acid.256... 

Solvent effects. The final step of a total synthesis of 3-vetivone (2) involves the intramolecular y-alkylation of the -unsaturated ketone 1. Under a variety of base-solvent combinations 1 is converted into 4, the product of kinetically favored o-alkylation (70% using KO-t-Bu, t-BuOH). However, alkylation takes the desired course with NaOH in DMSO-HjO mixtures, the ratio 4/2 being dependent on the amount of water present. Best results are obtained with 25% aqueous DMSO (4/2 = 7 93). Actually, the /3-vetivone as obtained contains 7% of the lt)-epimer (3). 

The importance of solvent effects is illustrated by the observation that cyclohexenone 11 yielded the acetoxyketone 14 as the major product and the unsaturated ketones 13 and 15 in glacial acetic acid. ... 

The ease and the stereochemical course of hydrogenation of a,p-unsaturated ketones are particularly influenced by the nature of the solvent and the acidity or basicity of the reaction mixture. Some efforts have been made to rationalize the effect of the various parameters on the relative proportions of 1,2- to 1,4-addition, as well as on the stereochemistry of reduction. For example, the product distribution in -octalone hydrogenation in neutral media is related to the polarity of the solvent if the solvents are divided into aprotic and protic groups. The relative amount of cis- -decalone decreases steadily with decreasing dielectric constant in aprotic solvents, and increases with dielectric constant in protic solvents, as exemplified in Scheme 21 (dielectric constants of the solvents are indicated in parentheses). Similar results were observed in the hydrogenation of cholestenone and of testosterone. In polar aprotic solvents 1,4-addition predominates, whereas in a nonpolar aprotic solvent hydrogenation occurs mainly in the 1,2-addition mode. 

Halo-ajS-unsaturated ketones and esters are highly susceptible to 8 2 displacement at the carbon attached to halogen, so strong bases are undesirable for such substrates [60, 91, 92]. However, relatively weak bases, such as sodium acetate and even triethylamine, are effective when the reaction is conducted in alcohol solvents [60]. Sodium acetate suspended in methanol, and aqueous or solid carbonate in ethanol give best results for haloenones (Scheme 2-33) [60] and haloesters [91], respectively. 

The palladium(II) catalyst, because of its Lewis acidity, may play a role in the addition of aUylic tin to the ketone however, acylation of crotyltin was not reported to form a tertiary alcohol using palla-dium(II). It appears that solvent effects dominate in these cases. As part of the same study, substitute vi-nylstannanes were shown to undergo acylation with retention of configuration however, the resulting a, -unsaturated ketones were not configurationally stable to the reaction conditions. Isomerically pure (Z)- 1-propenylstannane was acylated to afford a 50 50 mixture of alkenes (equation 87). The (Z)-a, un-saturated ketone was shown to isomerize to a mixture of (Z)- and ( )-isomers under the reaction conditions. Mixtures of (Z)- and ( )-2-substituted vinylstannanes were acylated to afford mainly the ( )-a, -unsaturated ketone (equation 88). ... 

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