A, 3-Unsaturatcd ketones

An empirical increment system permits prediction of charge distribution in a,/ -unsaturated carbonyl compounds, assuming additivity of electronic effects and neglecting the conformational dependence of carbon-13 chemical shifts [290]. Moreover, carbonyl and alkenyl carbon shifts of a, /3-unsaturatcd ketones may be used to differentiate between planar and twisted conjugated systems, as shown in Table 4.29 [291] and outlined for phenones in Section 3.1.3.8. 

The following example shows lithium divinylcuprate serving as a Michael donor, adding to the double bond of an a,/3-unsaturatcd ketone. In this conjugate addition, the vinyl group adds to the (3 carbon atom to give an enolate ion. Protonation at the a carbon gives the product. 

Treatment of an a-,/3-unsaturatcd ketone with basic aqueous hydrogen peroxide yields an epoxy ketone. The reaction is specific to unsaturated keloncs isolated alkene double bonds do not react. Propose a mechanism. 

Benary reaction. Action of Grignard reagents on enamino ketones or aldehydes yields (i-substitut-ed a,(3-unsaturatcd ketones or aldehydes. 

SCHEME 45. Ir(I)-catalyzed asymmetric hydrogenation of a,/3-unsaturatcd ketones. 

The introduction of various metal-catalyzed reactions, however, remarkably expanded the scope of the epoxidation of Q,.3-unsaturatcd ketones. Enders et al. have reported that a combination of diethylzinc and A-methyl-pseudoephedrine epoxidizes various o,. j-unsaturatcd ketones, under an oxygen atmosphere, with good to high enantioselectivity (Scheme 23).126 In this reaction, diethylzinc first reacts with the chiral alcohol, and the resulting ethylzinc alkoxide is converted by oxygen to an ethylperoxo-zinc species that epoxidizes the a,/3-unsaturated ketones enantioselectively. Although a stoichiometric chiral auxiliary is needed for this reaction, it can be recovered in almost quantitative yield. 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

Reactions of a,(3-unsaturatcd acylzirconocene chlorides with stable carbon nucleophiles (sodium salts of dimethyl malonate and malononitrile) at 0°C in THF afford the Michael addition products in good yields (Scheme 5.38). Direct treatment of the reaction mixture with allyl bromide in the presence of a catalytic amount of Cul -2LiCl (10 mol%) in THF at 0 °C gives the allylic ketone in a one-pot reaction. This sequential transformation implies the electronic nature of a,P-unsaturated acylzirconocene chloride to be of type E as shown in Scheme 5.37. 

A slightly more complicated case is provided by the photoreaction of the o,.3-unsaturatcd ketone... 

The titaniated (25)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazines derived from cyclo(L-Val, Gly) or cyclo(L-Val, Ala) (1, R1 = H, CH3) react with a,/I-unsaturatcd aldehydes exclusively by 1.2-addition (cf. nearly exclusive 1,4-addition of ,//-unsaturated ketones with cuprate complexes of 2,5-dialkoxy-3,6-dihydropyrazines, see Section D. 1.5.2.3.1.4.) in a highly diastereoselective mode to give virtually only the (l S,2R)-diastereoniers 2 ". In reactions with the corresponding lithiated pyrazines both regioselectivity and diastereofacial differentiation at C-2 are also remarkably high (dc 95 %), but the diastereomeric excess at C-l is substantially smaller (30 50%) ... 

E)-3-Arylidenethiochroman-4-oncs possess thioether and oi,[)-unsaturatcd ketone functionalities both of which are susceptible to oxidation by DMD. In fact, chemoselective oxidation at sulfur is observed with a separable mixture of the sulfoxide and sulfone being produced in >5 1 ratio. A similar situation holds for the related thioflavanones. Epoxidation of the alkenic double bond in the thiochromanone 1,1-dioxides alone can be achieved using methyl(trifluoromethyl)-dioxirane (Scheme 65) <1994T13113>. However, reaction of NaOCl with 3-arylidenethioflavanones gives the epoxide and subsequent oxidation with DMD then gives a mixture of the sulfoxide and sulfone <2003MRC193>. 

An important biological process is the basis for a general coupling method of aldehydes into symmetrical acyloins, such as BllTYROIN. The key catalyst is 5-(2-hydroxyethyl)-4-methyl-l,3-thiazole, an analog of thiamin. Condensation of ketones and aldehydes with excess acetonitrile can be accomplished in a simple way to produce a.p-unsaturatcd nitriles. Cyclohexanone leads to CY-CLOHEXYLIDENEACETONITRILE while benzaldehyde gives CINNA-MONITRILE. 

The net effect of the Stork reaction is the Michael additirm of a ketone to an n,/3-unsaturatcd carbonyl compound. For example, cyclohexanone reacts with the cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-onc yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 2.3.8). 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an a,/3-unsaturated carbonyl acceptor in a Vlichael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence of (1) enamine formation from a ketone, (2) Michael addition to an o ,j8-unsaturatcd carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Method A Dithiocarbamic acid and ,/3 unsaturated ketones (a,/J-unsaturatcd acids). B Dithiocarbamic acid and j -halo carboxylic acids. C Dithiocarbamic acid and -propiolactone. 

The a j3 ratio is suspiciously dependent upon the solvent, coordination may be playing a part here too, and there is a further complication in both series. For nucleophilic attack on a carbonyl to take place, coordination to the oxygen atom by a Lewis or protic acid is often necessary, as we have already seen with n, T-unsaturatcd ketones. This means that there is a pre-equilibrium step between the bare carbonyl compound, used in the calculations, and the reactive species. There will be a higher concentration of the intermediate with the metal or other catalyst coordinated to the more basic of the two carbonyl groups, which will be the (3 carbonyl in 4.171. However, when the coordination is to the less basic carbonyl group, it will create a more reactive species. The balance of all these effects is hard to predict, and the overall story is too complicated for simple analysis. This is not an uncommon situation, and care must be taken in any analysis of subtle steric and electronic effects like those operating here and in much of the discussion about enones above. 

With strains of Saccharomyces the (25,35)-isomer is produced predominantly, accompanied by some of the (2/J,3,S )-isomer. Similar to ft-keto esters, the formation of the undcsired isomer can be decreased by the addition of an a,/i-unsaturatcd carbonyl compound, e.g.. methyl vinyl ketone, or an allylic alcohol. These additives probably act as inhibitors for the enzyme which produces the (2/ ,35)-isomer202 203. More recently, the microbial reduction of a variety of simple 2,2-disubstituted cyclic 1,3-diketones of various ring size has been investigated204 205 206. In most cases one of the substituents in the 2-position is methyl. The configuration of the hydroxy group in the reduced product is always S, and the enantiomeric excess is often high (Table 7). 

Addition of l,3-bis(methylthio)allyllithium to aldehydes, ketones, and epoxides followed by mercuric ion-promoted hydrolysis furnishes hydroxyalkyl derivatives of acrolein5 that are otherwise available in lower yield by multistep procedures. For example, addition of 1,3-bis-(methylthio)allyllithium to acetone proceeds in 97% yield to give a tertiary alcohol that is hydrolyzed with mercuric chloride and calcium carbonate to saturated aldehyde.8 Similarly, addition of l,3-bis(methylthio)allyl-lithium to an epoxide, acetylation of the hydroxyl group, and hydrolysis with mercuric chloride and calcium carbonate provides a 5-acetoxy-a,/ -unsaturatcd aldehyde,6 as indicated in Table I. Cyclic cis-epoxides give aldehydes in which the acetoxy group is trans to the 3-oxopropenyl group. 

Reactions. In a reaction reminiscent of methylene transfer with dimethyloxo-sulfonium methylide, EDSA reacts with ,/)-unsaturatcd aldehydes and ketones in aprotic solvents to give cyclopropanes in 65-90% yield.1 EDSA reacts with ,/3-unsaturated esters to give esters of acyclic polybasic acids.2... 

No chromium chelates of CKj/S-unsaturatcd /3-keto amines (j8-amino ketones) have been previously reported, although a wide variety of these ligands are known. The following... 

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