Alkylation of a, P-Unsaturated Ketones

Treatment of methyl cyclohexanonecarboxylate (6.83) with methyl vinyl ketone (6.84) in the presence of a base gives rise to the Robinson 

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A noteworthy development is the use of KH for complexing alkylboranes and alkoxyboranes to form various boron hydrides used as reducing agents in the pharmaceutical industry. Potassium tri-j -butylborohydride [54575-50-7] KB(CH(CH2)C2H )2H, and potassium trisiamylborohydride [67966-25-0] KB(CH(CH2)CH(CH2)2)3H, are usefiil for the stereoselective reduction of ketones (66) and for the conjugate reduction and alkylation of a,P-unsaturated ketones (67). 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

The introduction of a sulfonyl group on cyclic compounds allowed y-alkylation of a,p-unsaturated ketones (Scheme 68). ... 

On the basis of this empirical relationship, the absolute configuration of the dextrorotatory alcohols formed in the reduction of a series of aryl alkyl ketones (75) with (—)-quinine-LAH in ether was assigned as R (84). Reduction of a series of a,p-unsaturated ketones (76) with (- )-quinine-LAH gave a product mixture consisting mainly of dextrorotatory unsaturated alcohols (77) (85). The unsaturated alcohols 77 were shown to have the R configuration. 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation 1)13 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and select simple alkene and alkyne dienophiles, although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. The most extensively studied reaction in the series is the [4 -t- 2] cycloaddition reaction of a,P-unsaturated ketones with enol ethers and Desimoni,... 

Bromocamphor has been employed as the chiral starting material in an enantiospecific synthesis (ref. 146) which involved the formation of an indanone (CD moiety) related structurally to that used by Hoffmann-La Roche and led finally to (-)-estrone. Attempts to alkylate the a,p-unsaturated ketone with 2-(3-methoxyphenyl)ethyl iodide failed, not surprisingly, due to an elimination rather than the desired substitution reaction and accordingly the use of an a-methylenic derivative of the ketone and 3-methoxybenzyl chloride were obligatory. By the use of (-)-3-bromocamphor, which is readily available from (-)-borneol by oxidation to (-)-camphor and bromination, natural (+)-estrone could be obtained. 

Borane, monoalkylboranes and dialkylboranes (such as thexylborane and 9-BBN) were shown to be powerful reducing agents for carbonyl derivatives (sec. 4.6.A). When the B—H unit is removed, as in trialkylboranes, addition to the alkene moiety of a,p-unsaturated ketones or aldehydes occurs. An alkyl group of the borane is transferred to the terminal position of the alkene moiety (1,4-addition) and boron is transferred to the oxygen, giving a boron enolate (sec. 9.4.D). Initial hydroboration of acrolein with tricyclopentylborane gave boron enolate 196.1 0... 

The use of optically resolved PTC catalysts for the synthesis of enantiomerically pure compounds is no doubt an attractive field. Asymmetric PTC has become an important tool for both laboratory syntheses and industrial productions of enantiomerically enriched compounds. Recently, Lygo and coworkers [207-216] reported a new class of Cinchona alkaloid-derived quaternary ammonium PTC catalysts, which have been applied successfully in the enantioselective synthesis of a-amino acids, bis-a-amino acids, and bis-a-amino acid esters via alkylation [207-213] and in the asymmetric epoxidation of a/p-unsaturated ketones [214-216]. 

Similarly, specific enolates of unsymmetrical ketones can be obtained by reduction of a,p-unsaturated ketones with lithium in liquid ammonia. Alkylation of the intermediate enolate gives an a-alkyl derivative of the corresponding saturated ketone which may not be the same as that obtained by base-mediated alkylation of the saturated ketone itself. For example, base-mediated alkylation of 2-decalone generally leads to 3-alkyl derivatives whereas, by proceeding from the enone 11, the 1-alkyl derivative is obtained (1.26). The success of this procedure depends on... 

The treatment of a,p-unsaturated ketones with organocopper reagents provides another method to access specific enolates of unsymmetrical ketones. Lithium dialkylcuprates (see Section 1.2.1) are used most commonly and the resulting enolate species can be trapped with different electrophiles to give a,p-dialkylated ketones (1.27). Some problems with this approach include the potential for the intermediate enolate to isomerize and the formation of mixtures of stereoisomers of the dialkylated product. The intermediate enolate can be trapped as the silyl enol ether and then regenerated under conditions suitable for the subsequent alkylation. Reaction of the enolate with phenylselenyl bromide gives the a-phenylseleno-ketone 12, from which the p-alkyl-a,p-unsaturated ketone can be obtained by oxidation and selenoxide elimination (1.28). 

The 1,4-disilylation of a,p-unsaturated ketones usinga disilane with a palladium BINAP catalyst has also been achieved with good enantiomeric excess. For example, with a,p-unsaturated ketone (2.157), the initially formed product (2.158) can be converted into the P-silyl ketone (2.159) by addition of methyllithium followed by hydrolysis. However, quenching the intermediate lithium enolate (formed on addition of MeLi) with an alkylating agent leads to an a-substituted product... 

Recently, Harada and co-workers have developed aZZo-threonine-derived oxazaborolidinone (OXB) 127 as an efficient chiral Lewis acid catalyst for the activation of a,p-unsaturated ketones. They found that 127 could catalyze the AFC alkylation of furans and indoles with simple acyclic d,p-unsaturated ketones in high yields and excellent enantioselectivity (furans up to 99% yield, 91% ee indoles up to 96% yield, 94% ee) (Scheme 6.52). In this catalytic system, employing AZ,ZV-dimethylaniline as an additive was crucial to the reactivity and enantioselectivity of the reaction. 

The reaction of chalcone (2) with indole (3) (1 1 molar ratios in a 1 mmol scale) was performed to optimize the experimental conditions with respect to temperature, time, and ratio of MSSA to the substrate. It was found that 200 mg of MSSA was sufficient to obtain the desired Michael adduct in 98% yield in 90 min at room temperature in CH3CN. A variety of a,p-unsaturated ketones and electron-deficient olefins were tested under the optimized reaction conditions (Scheme 1.3a). All the reactions proceeded easily and the products 4 were isolated with comparable yields (85%-98%) in short reaction times. No side products such as N-alkylation products were detected. 

Murai and coworkers also reported that olefinic C-H bonds of a,p-unsaturated carbonyl compounds could be functionalized in the same way using RuH2(CO)(PPh3)3 as catalyst. Thus, alkylation of a,fl-unsaturated ketones [76, 86] and aldehydes [87] with various alkenes furnished the corresponding products in high yields (Scheme 19.53). In the reaction of 1-cyclohexenecarbaldehyde,... 

Cinchona-based primary amines were first applied as chiral catalysts for the iminium ion activation of a,p-unsaturated ketones in 2007. Thus, alkylation product 6 was obtained with moderate optical yield in the reaction between indole 4 and ketone 5 catalyzed by cinchona based amine 3 in the presence of double amount of trifluoroacetic acid (Scheme 3.12). ... 

This oxygenation reaction proceeds under milder conditions as compared to conventional methods. Despite the lower reactivities, VO(OR)3 and VO(acac>2 can be employed as an oxidant, although a stoichiomettic amount is required in each case. Use of a,p-unsaturated ketones leads the different reaction routes. 2-Cyclohexen-l-ones 54 undergo dehydrogenative aromatization to give the aryl alkyl ethers 55 [105]. More than 2 equiv. of VO(OR)Cl2 are required to complete the reaction, since the oxovanadium(V) compound is a one-electron oxidant. Isophorone is also oxidatively aromatized to the aryl ether 56 with the migration of the methyl group (Scheme 2.45). 

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