Michael-like addition oxidation

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

An example of a structural substituent that is often metabolized (bioactivated) to an electrophile is the allyl alcohol substituent (C=C—C—OH). Allyl alcohol moieties are found in many commercial chemical substances, either as the free alcohol or as an ester or ether. As illustrated in Scheme 4.1, allyl alcohols (and also as their esters or ethers) that contain at least one hydrogen atom on the alcoholic carbon can be oxidized in the liver by alcohol dehydrogenase (ALDH) to the corresponding a, 3-unsaturated carbonyl metabolite, which is toxic in many cases [29-31]. The hepatotoxicity of allyl alcohol (1), for example, is due to its oxidation by ALDH to acrolein (2), an a,(3-unsaturated aldehyde, which undergoes Michael addition with cellular nucleophiles in the liver [29] (Scheme 4.1). Cyclic allyl alcohols (Scheme 4.1) are expected to undergo similar enzymatic oxidation to yield a,(3-unsaturatcd carbonyl metabolites and are also likely to be toxic. 

Vinyl and ethynyl groups attached to an imidazole ring can be catalytically reduced to the saturated (or less unsaturated) species and cleaved by oxidation. The corresponding 4-carbaldehyde is formed in 71% yield when l-methyl-2,5-diphenyl-4-styrylimidazole is oxidized with osmium tetroxide. However, they may not react like aliphatic alkenes and alkynes not all addition reactions occur normally, Michael additions are known, and the compounds can act as dienophiles in DielsAlder reactions (e.g., Scheme 132). 

Michael addition of the potassium enolate of cy-anacetamide (14) provided the precursor 55 of the pyridone 56. This intermediate was obtained by oxidation of 55 with t-BuOOH in the presence of 20 mol % SeOj on Si02. The addition of 10 % H2SO4 to the reaction mixture directly delivered the lactone 56. Lactones like 56 are not easy to reduce, but treatment with NaBH4/CeCl3 provided the diol 57 in 95 % yield. 57 could be easily converted to camptothecin by heating it to 115 °C in 60 % H2SO4 in EtOH. 

Crafts reactions, and oxidizing reagents like chlorine do not destroy this protection. The regeneration of the carbonyl functions has to be carried out with concentrated aqueous alkali and proceeds as a tandem hetero Michael addition/retro aldol reaction (Scheme 87). Although these drastic conditions set a limit to the general application of this protecting group, it has successfully been used in porphyrine total syn-theses. ... 

Prekinamycin (35), like kinamycins A-F, was isolated from Streptomyces murayamaensis. Carbazole 33, a regioisomer of 7-deoxyprekinamycin (34), was synthesized in only four steps utilizing Pd(OAc), promoted oxidative cyclization as the pivotal step [27]. Similar to Furukawa s approach, the anilino-l,4-naphthoquinone 32 was obtained via Michael addition of the corresponding 2-methoxy-4-methyl-aniline to 1,4-naphthoquinone. Oxidative cyclization proceeded in 84% yield. 

Nature is generally reluctant to carry out classical, central S- 2 reactions, with the exception of methylations - glycosyl- and prenyl-transfer reactions are very S Nl-like. A much preferred route for displacements of sugar substituents is oxidation by a tightly bound nicotinamide cofactor of a p-hydroxyl, elimination of the leaving group, introduction of the substituent in a Michael addition and reduction, as dealt with in Section 6.8. 

Phospha-Michael reactions are useful to establish a P-C bond. The addition of >P(0)H species (e.g., dialkyl phosphites and secondary phosphine oxides) at the end of electron-poor double bonds may be facilitated by bases, like NaOR, NaOH, or DBU [56]. The addition of P-heterocyclic nucleophiles was also studied. Dibenzo[c.e][l,2]oxa-phosphorine oxide (36) added easily on the double bond of methyl vinyl ketone xmder MW conditions in the absence of any solvent (Scheme 12) [57]. 

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