Nucleophiles reaction with enones

Most main group organometallic compounds undergo nucleophilic reactions with carbonyl groups, whereas 1,4-conjugate addition to enones... 

The stereocontrolled synthesis of alkenes and the use of vinyl- and alkyl-aluminum and -aluminate reagents as nucleophiles has been described above. In addition, the aluminum reagents are also useful in diene synthesis, in reactions with enones and epoxides, and in cyclizations. 

Various other tricyclic cyclopropane systems with the nortricyclene skeleton, e.g. 27-29, can be obtained via alkoxypalladation of norbornadiene and subsequent reaction with enones, cuprates, or other carbon nucleophiles. ... 

Zhao and coworkers reported the use of 2-pyrazolin-5-ones as suitable nitrogen nucleophiles for the Michael reaction with enones [108]. In this report the use of 32 mol% of 9-epi-9-amino-9-deoxyquinine and 40mol% of benzoic add was necessary to obtain high yields and enantioselectivities. 

Penta-coordinated stannates undergo the Michael reaction with enones and nitroalkenes or cyanoalkenes due to the high nucleophilicity (Schemes 3-201, 3-202, and 3-203). This strategy is applicable to ketene stannyl acetals, which are less reactive than ketene silyl acetals due possibly to the easy equilibrium between 0-Sn and C-Sn tautomers, the C-Sn tautomers being predominating at temperatures above 0 Normally, Qf-stannyl esters are much less reactive with electrophiles. However,... 

Irradiation of cyclohexenone 32 with the tertiary a-silylamine EtjNCHjSiMej in methanol solution in the presence of the electron acceptor 9,10-dicyanoanthracene (DCA) yields predominantly the desi-lylated adduct 32b. The product ratios depend on amine concentration. " The mechanism proposed for adduct formation is outlined in Scheme 24. Oxidation of the tertiary amine by singlet DCA yields the amine cation radical, which undergoes desilylation upon nucleophilic reaction with the solvent. Addition of the a-aminoalkyl radical to the neutral enone affords the radical adduct, which is reduced by DCA and protonated by solvent. " Intramolecular trapping of the radical adduct can compete with reduction by DCA"-, as seen in the reaction of 32 with an a-silylanihne, which yields the tandem addition product 32c (Scheme 24). ... 

Apparently the Lewis acid induced and the fluoride-induced reactions of allylsilanes with enones follow different pathways. The perpendicular approach of the nucleophilic allylsilane... 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic... 

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,/J-unsaturated esters (entry 5, Scheme 1.12). 

Since allylsilane can be considered as a very soft nucleophile because of the involvement of o-7i conjugation between the -electrons of the double bond and the o-electrons in the carbon-silicon bond, the addition of allylsilanes to ,/3-unsaturated enone moiety occurs exclusively via 1,4-addition19,20. A typical Sakurai-Hosomi reaction is illustrated in the reaction of allylsilane 66 with enone 67 in the presence of TiCU to give 68 which is used for the synthesis of a cyclic enediyne (equation 45)108. A similar reaction has been used for the synthesis of ewf-herbasolide 70 from enone 69 (equation 46)109. Prenylsilane undergoes 1,4-addition with squaric acid chloride 71 followed by dechlorosilylation to give 72 as the predominant product (equation 47). Interestingly, other simple allylsilanes react in a 1,2-addition fashion to yield 73110. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

The Mannich reaction gave a base that was methylated without isolation to give the salt 58. Elimination with NaHCC>3 gave the enone, nucleophilic epoxidation with HO2- gave the epoxide... 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

The first issue confronted by Myers was preparation of homochiral epoxide 7, the key intermediate needed for his intended nucleophilic addition reaction to enone 6. Its synthesis began with the addition of lithium trimethylsilylacetylide to (R)-glyceraldehyde acetonide (Scheme 8.6).8 This afforded a mixture of propargylic alcohols that underwent oxidation to alkynone 10 with pyridinium dichromate (PDC). A Wittig reaction next ensued to complete installation of the enediyne unit within 11. A 3 1 level of selectivity was observed in favour of the desired olefin isomer. After selective desilylation of the more labile trimethylsilyl group from the product mixture, deacetalation with IN HC1 in tetrahydrofuran (THF) enabled both alkene components to be separated, and compound 12 isolated pure. 

Selenium-stabilized carbanions can be also generated by 1,4-addition of nucleophilic reagents to a-selanyl a,[3-unsaturated carbonyl compounds. The conjugate addition of trialkylsilyllithium compounds to 133, followed by reaction with allyl iodide, afforded the addition products 134 with good m-stereoselectivity (R = Me dr 86 14 R = Ph dr 94 6) (Scheme 34).214 The addition of lithium dialkylcuprates to 2-phenylselanylcycloalk-2-enones has also been used for the synthesis of natural products.215,216... 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

---