Michael coupling

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

Many of the known chemical syntheses such as Wittig [29, 165], Knoevenagel [29], aldol [292], Ugi [29,293], Michael addition [29], Hantzsch [29,156,157], Diels-Alder [294], Azo coupling [136,182], Suzuki coupling [29,155] or enamine [29, 295] reactions (Table 1.8), to name but a few, have been carried out successfully in mi-... 

In 1976, Stetter extended the synthetic utility of the Breslow intermediate (1) as an acyl anion equivalent by showing that aldehydes could be coupled with Michael acceptors to generate 1,4-dicarbonyl compounds [55]. 

There is some similarity between the cracking of petroleum and the cracking of biomass. However, biomass is more complex chemically both in terms of structrual types and functional groups. In petrochemistry, hydrocarbons are fractionated and they are then functionalized by oxidation, halogenation, nitration and other chemical processes so as to add value. The commodity chemicals are then built up into more complex molecules using such popular synthetic methods as Friedel Craft reactions, Michael and aldol condensations, and Heck and Suzuki couplings. The speciality products of these reactions are then further elaborated into formulations for use in everyday applications ranging from personal care... 

Dithioacetal monoxides undergo Michael addition to acrylonitrile. The addition products are easily converted into y-ketonitriles 382 (equation 221). Benzenesulphinyl allylic carbanions 383 derived from the corresponding allylic sulphoxides react selectively at the y-position with a variety of cycloalkenones to give the l,4-adducts " (equation 222). Recently, Nokami and coworkers have synthesized some prostaglandin analogues via a three-component coupling process involving 1,4-addition of phenylsul-phinyl allylic carbanion (equation 223) . ... 

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Et2Zn also participates in the reductive coupling as a formal hydride source. Results for the Ni-catalyzed, Et2Zn-promoted homoallylation of carbonyl compounds with isoprene are summarized in Table 7 [30]. Et2Zn is so reactive that for the reaction with reactive aromatic aldehydes it causes direct ethylation of aldehydes, and the yields of homoallylation are diminished (runs 1 and 2). Unsaturated aldehydes seem to be subject to the Michael addition of Et2Zn. Accordingly, for the reaction with cinnamaldehyde, none of the expected homoallylation product is produced instead, the 1,4-addition product of Et2Zn, 3-phenylpentanal is produced exclusively (run 3). 

Coupling of the aminomethylindole 2-558 with acrolein in a Michael manner followed by a HWE reaction with phosphonates 2-560 afforded 2-561 which cyclized under basic conditions to give the desired product 2-566 via the intermediates 2-562-2-565 in 55 % yield (Scheme 2.127). The reaction sequence was also conducted in a stepwise manner, resulting in a greatly reduced yield this clearly demonstrates again the advantage of domino strategies over conventional methods. 

Adie EJ, Kalinka S, Smith L, Francis MJ, Marenghi A, Cooper ME, Briggs M, Michael P, Milligan G, Game S (2002) A pH-sensitive fluor, CypHer 5, used to monitor agonist-induced G protein-coupled receptor internalization in live cells. BioTechniques 33 1152-1157... 

Nitroalkenes are shown to be effective Michael acceptor B units in three sequential reactions (A + B + C coupling) in one reaction vessel. The sequence is initiated by enolate nucleophiles (A) and is terminated by aldehydes or acrylate electrophiles (C). The utility of this protocol is for rapid assembly of complex structures from simple and readily available components. A short total synthesis of a pyrrolizidine alkaloid is presented in Scheme 10.16.114... 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. 

Even though the short oligosaccharide segment made of seven units may not be considered as a true polymer chain, the chemistry devised by them should be easily applicable to longer saccharidic chains. Liu and Zhang used the Michael reaction for coupling a dextran (Dex) with an amino-functionalized terminal and acrylolyl end-capped PCL [146]. Sun et al. also synthesized Dex-b-PCL by disulfide bond formation [147]. 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

Classical C,C-coupling reactions of AN anions (Henry, Michael, and Mannich) involve complex systems of equilibria and, consequently, generally not performed in protic solvents. The introduction of the silyl protecting group allows one to perform these reactions in an aprotic medium to prepare or retain products unstable in the presence of active protons. In addition, the use of nucleophiles which are specifically active toward silicon (e.g., the fluoride anion) enables one to design a process in which the effective concentration of a-nitro carbanions is maintained low. 

By contrast, L-phenylalanine methyl ester does not react with BENA generated from 1-nitropropane (R =H) due apparently to low nucleophilicity of the amino group. However, the N, C -coupling reaction of the ester of this amino acid with another internal BENA (R = CC>2Me) proceeds rather readily but is characterized by extremely low diastereoselectivity. Probably, the last N,C-coupling does not occur via an intermediate a-nitroso alkene but by a classical Michael addition to BENA MeCH=C(C02Me)N(05i )2 as to Michael substrate. 

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