A, i-Unsaturated ketone

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Allyllic ether 53 is oxidized regioselectively to the /3-alkoxy ketone 54, which is converted into the a,/i-unsaturated ketone 55 and used for annulation[99]. The ester of homoallylic alcohol 56 is oxidized mainlv to the 7-acetoxy ketone 57[99]. 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

It has long been known that a, / -unsaturated sulfones resemble a, /i-unsaturated ketones and aldehydes in undergoing addition reactions with nucleophilic reagents43. These reactions are initiated by nucleophilic attack at the carbon to the sulfone group ... 

O-Methanesulphonyloximes of a,/i-unsaturated ketones yield allylic amines on reduction with lithium aluminium hydride (equation 78)207. 

Baker s yeast can also be used in the saturation of a,/i-unsaturated ketones. The reactions described share the following features (i) remote double bonds are not hydrogenated, (ii) the reaction rate is affected by substitution on or near the double bond and (iii) after a prolonged reaction time reduction of the oxo group can also take place (equations 39 and 40)109. 

Stereoselective reduction of a,(i-unsaturated ketones using lithium aluminium hydride has only been reported in conjunction with the ephedrine bases either in a two-phase system (80-90% yield, ee >70%) or immobilized on a polymer [18, 19]. 

Whilst reactions of a, -unsaturated carbonyl compounds with 2 have been the subject of a number of studies, the corresponding reactions of their enolic tautomers have received little attention. Reaction of the /S-hydroxy-a, /i-unsaturated ketones... 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,/i-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bondforming reactions. 

Scheme 6.159 Representative products obtained from the 166-catalyzed asymmetric aza-MBH reaction between N-sulfonated imines a,(i-unsaturated ketones and acrolein.

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

In this reaction, the peroxydisulfate (n-Bu4N)2S208 (2c) is probably converted to the tetra n-butylammonium peroxysulfate anion 30 by attacking OOH 1,4-addition of the latter to a,/i-unsaturated ketones produces the epoxide product and tetra n-butylammonium sulfate 31. In this reaction 31 was isolated in 80% yield. 

This method has been applied to a,(i-unsaturated ketones, esters, and nitriles to give the corresponding 1,4-diketones, y-keto esters, and y-keto nitriles, respectively (see also 6-54). 

Sequential aldol condensation and hydrogenation. Since the aldol condensation of ketones is an equilibrium reaction, there are some advantages in hydrogenation of the a,/i-unsaturated ketone as formed to shift the equilibrium. Thus it is possible to convert acetone into methyl isobutyl ketone in one step using two different heterogeneous catalysts (equation I). 

An interesting variation on this general approach involves addition of thioglycolic esters to 1,3-diketones or a,(i-unsaturated ketones. The ketonic products of these additions, on treatment under basic conditions, gave the corresponding 3-substituted thiophenes in good yields (60AG573). The reactions are shown in Scheme 11. 

Cyclopropanations of a,/i-unsaturated ketones with sulfur-substituted methylenes have been achieved in several ways using this methodology. Sequential treatment of conjugated enones with (PhS)3CLi,. s-BuLi and electrophiles produces phenylthiocyclopropanes (equation 128)275. Generation of lithium bicyclofl. 1,0]butane-2-olates as intermediates has... 

Dioxiranes are three-membered cyclic ring peroxides that are expected to be very unstable owing to ring strain. They are effective oxygenating agents for epoxidations of olefins, allenes, polycyclic aromatic hydrocarbons, enols. and a, /i-unsaturated ketones for insertions of oxygen into X—H... 

The addition of oxygen nucleophiles (peroxides) to a,(i-unsaturated ketones is also catalyzed by the lanthanoid catalysts, leading to the formation of the corresponding epoxides with up to 96% ee (Scheme 8D.19) [41]. This reaction shall be reviewed in another chapter. 

A tandem 1,4-addition-Meerwein-Ponndorf-Verley (MPV) reduction allows the reduction of a, /i-unsaturated ketones with excellent ee and in good yield using a camphor-based thiol as reductant.274 The 1,4-addition is reversible and the high ee stems from the subsequent 1,7-hydride shift the overall process is thus one of dynamic kinetic resolution. A crossover experiment demonstrated that the shift is intramolecular. Subsequent reductive desulfurization yielded fiilly saturated compounds in an impressive overall asymmetric reductive technique with apparently wide general applicability. 

The chlorination of a,/i-unsaturated ketones by CI2 in MeOH gives mixtures of Markovnikov and anti-Markovnikov methoxychlorides and dichlorides. Significant increase in the proportion of Markovnikov regioisomers was observed in the presence of acid scavengers, such as pyridine. This effect was ascribed to the elimination of the acid-catalysed mechanism, allowing the chlorination to occur via chloronium ion174. 

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). 

A retrosynthetic analysis of a,/J-unsaturated ketones leading to various methods of synthesis is outlined in Section 5.18.2, p. 798. These methods are equally applicable to aromatic aldehydes. Aromatic aldehydes condense with aliphatic or mixed alkyl aryl ketones in the presence of aqueous alkali to form a,[i-unsaturated ketones (the Claisen-Schmidt reaction). 

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

Ishii has shown that diversely substituted pyrroles 152 can be prepared by a one-pot operation involving formation of intermediate a,/ -un saturated imines 153 via a SmCl3-catalyzed self-aldol-type condensation. The targeted heterocydes are formed upon addition of a nitroalkane and subsequent cyclization according to the mechanism depicted in Scheme 8.64 [140]. Interestingly, a,/i-unsaturated ketones also participate in this process. 

Although simple ketones and esters can not be allylated by Pd catalysts, they are allylated with allyl carbonates via their enol ethers of Si and Sn. In the allylation of the silyl enol ether 202 with allyl carbonate 200, transmetallation of 202 with the n-allylpalladium methoxide 201, generated from allyl methyl carbonate (200), takes place to generate the Pd enolates 203 and 204. Depending on the reaction conditions, allyl ketone 205 is formed by the reductive elimination of 203 [100]. When the ratio of Pd Ph3P is small, the a,/i-unsaturated ketone 206 is obtained by -elimination [101]. For example, the silyl enol ether 208 of aldehyde 207 is allylated with allyl carbonate (200) to give a-allylaldehyde 210 via 209. The a-allyl carboxylate 213 is obtained by allylation of ester 211 with allyl carbonate (200), after conversion of ester 211 to the ketene silyl acetal 212 [102], As the silyl group is trapped in these... 

In order to obtain the trans-fused octalin, the cis-fused octaline 423 was oxidized with chromium trioxide in acetic acid to yield the ketone 424. The latter was treated with bromine in acetic acid to produce the a-bromoketone 425 in a yield of 98%. Dehydrobromination of 425 with. /V-phenylbenz-amidine afforded the a/i-unsaturated ketone 426 in 90-95% yield. The... 

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