Enamides, Michael reactions

Similarly, the 2-cyano-6-oxazolopiperidine 75 (Scheme 16) can be used to provide a variety of substituted piperidines <99TL3731, 99H(51)2065>. Conversion to the enamide 76 provides a means to introduce C-3 alkyl groups by Michael reaction <99TL3699>. Electrochemical bis-bromination and dehydrohalogenation affords the vinyl bromide 77, which can imdergo substitution at the 4-position by the addition of nucleophiles as simple as water <99T8931>. 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

A similar reaction of vincinal aromatic or heterocyclic diamines 104 with 2-benzoylamino-3-chloropropenoic acid 102 resulted in sprro-2-oxazolines fused to a pyrazinone nucleus 108. It is believed that the enamide 102 first isomerizes to the A-acyl imine 103 followed by Michael addition of the diamine 104. The resulting Michael adduct 105 cyclizes to 106 or 107 either of which leads to the same oxazoline 108. Single-crystal X-ray confirmed the structure of 108. Unsymmetrical diamines gave two isomeric products with the predominant product... 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

A two-electron oxidation of N-acetyltyrosine ethyl ester with mushroom tyrosinase, or with periodate, afforded the N-acetyIdopa ester 142, together with the (Z)-enamide 145 and the 6-acetoxydopa amide 146 (Fig. 40) (284). It is assumed that 145 originates from dopaquinone 143 via 144 by tautomerization. Michael addition of acetate to quinone 143 is believed to be the origin of 146. The formation of quinone methide 144 from dopa ester 142 by tyrosinase is reminiscent of the formation of iminochromes and quinone methides catalyzed by this enzyme in their formation from a-methyl dopa ester (285), and such reactions may well occur in mammalian systems. 

Kitazume et al. examined the first example of Michael additions via the MBH-type reaction that used 3-fluoromethylprop-2-enamide as a chiral auxiliary electrophile towards activated olefins in the DABCO ionic liquid system. The reaction of (45)-3-[( )-4,4,4-trifluorobut-2-enoyl]-4-isopropyl-2-oxazolidinone (297) with activated vinyl moiety proceeded smoothly at 80 °C to give the corresponding adducts 298 in moderate yields, albeit with low diastereoselectivity (Scheme 1.109). 

Li and coworkers reported the conjugate addition of alkyl groups to enamides mediated by zinc in aq. NH4CI to generate a -amino acid derivatives (Eq. 4.73). No reaction was observed in the absence of water. Both secondary and tertiary alkyl groups such as linear (2-butyl, 2-propyl, 2-pentyl), cyclic (cyclohexyl, cyclopentyl, cycloheptyl), and bulky ones (tert-butyl) were all transferred to the substrate successfully. Even simple primary iodides and methyl iodide provided the desired products in good yields. Miyabe et al. as well as Jang and Cho reported the addition of alkyl radicals from alkyl iodide to a,p unsaturated ketones, esters, and nitriles mediated by indium in aqueous media. Indium-mediated Michael addition of allyl bromide to l,l-dicyano-2-arylethenes also proceeded well in aqueous medium. ... 

Azide additions to a,P-unsatnrated systems are another method for the preparation of 1,2,3-triazoles. Cydoaddition of aryl azides to a,P-unsaturated aldehydes 88 in the presence of catalytic diethylamine and DBU afforded 1,4-disubstituted-l,2,3-triazoles 89 via an inverse electron-demand process (13CC10187). Michael addition of sodium azide with ethyhdene bisphospho-nates 90 in cydoaddition reactions via sonication afforded bisphosphono-1,2,3-triazoles 91 (13T4047).A one-pot protocol for the synthesis of 1,2,3-triazoles was prepared from unactivated alkenes with azidosulfenylation of the carbon-carbon double bond followed by the copper-catalyzed azide—alkyne cycloaddition (13JOC5031). 1,5-Disubstituted-l,2,3-triazoles 93 were synthesized from enamides 92 with tosyl azide (13AG(E)13265). Reaction of ethyl 3-(alkylamino)-4,4,4,-trifluoro-but-2-enoates 94 with mesyl azide in the presence of DBU afforded l,2,3-triazole-4-carboxylates 95 (13EJ02891). 

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