Methyl vinyl ketone reductive coupling

Scheme 22.8 Use of methyl vinyl ketone (MVK) in intermolecular hydrogen-mediated reductive aldol coupling.a)...

Organometallics are formed at the cathode if transient radicals produced in reductions react with the active electrode. This occurs as a side reaction in cathodic coupling (Sect. 12.2, Eq. (185)) of carbonyl compounds, e.g., of acetone 3 9 or of activated olefins, e.g., of methyl vinyl ketone 41or acrylonitrile. Furthermore, in cathodic cleavage (Sect. 13.2, Eq. (227) ) of alkyl bromides or iodides organometallics are formed, e.g., ME(CH2CH2CN)2(ME = Pb, Tl, Sn, Hg) 481 bis(p-substituted benzyl)mercury 485 or dicyclopropylmercury 489 ... 

The synthesis of the nonsteroidal anti-inflammatory drug nabumetone (9) was developed by Hoechst-Celanese [71]. It was prepared via a Heck coupling of 2-bromo-6-methoxy-naphthalene (1) with methyl vinyl ketone in the presence of palladium catalyst [71]. Further reduction of unsaturated ketone provided 9. Nabumetone was also obtained in a one-step coupling reaction of 2-bromo-6-methoxy-naphthalene with 3-buten-2-ol followed by isomerization of enol [72]. 

The nickel-catalyzed reductive coupling reaction of methyl vinyl ketone with enyne 43 bearing a P-dicarbonyl moiety proceeds with liberation of the P-dicarbonyl enolate (Scheme 5.56) [39]. Reductive coupling of 43 with enone would afford nickelaoxacyclooctadiene 44. Transmetalation is accompanied by carbonickelation to yield 45. Intermediate 45 engages in P-carbon elimination through a six-membered cyclic transition state to liberate nickel enolate 46, which should be transformed to the corresponding zinc enolate to complete the catalytic cycle, and zinc enolate 47, which is eventually protonated upon hydrolysis. 

For reductive cross-coupling between a,P-unsaturated ketones and aldehydes, Kim et al. made use of In-InCl3 in aqueous media to prepare p,y-unsaturated ketones from methyl vinyl ketone and aryl aldehydes [282] (Figure 8.128). A radical mechanism was proposed, with InCb activating the carbonyl group for cyclopropanation and addition. Uemura also studied the same reaction, with InCl3 (10 mol%) as catalyst, Al as reductant, and requiring the presence of TMSCl [283]. 

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

Palladium phosphines served as improved catalysts for additions across the C-C bond of biphenylene. Olefins could be incorporated by a Heck-type vinylation, presumably involving insertion into the aryl-Pd bond of a biphenylyl metallacycle followed by P-elimination and reductive elimination of product (9). Suzuki-type additions could be made using arylboronic acids (10). It was also found that weakly acidic C-H bonds could serve as addition partners, such as methyl ketones or benzylic nitriles (11, 12) [21]. In these reactions, Pd(0) was proposed to insert first into the biphenylene C-C bond generating L2Pd(2,2 -biphenylyl), which was then protonated by p-cresol to leave a Pd-aryl bond that went on to couple with the conjugate base of the substrate to give the product. 

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