Conjugated addition/amination reaction

SCHEME 2.27 Organocatalyzed conjugated addition/amination reaction of a,P-unsatnrated aldehydes. 

In a second series the same authors realized cascade reactions of conjugate addition/amination reactions. The corresponding highly substituted aldehydes 88... 

Fig. 13 DIB-mediated methoxylative phenol dearomatization/Diels-Alder cyclodimeiization cascade reaction of 5-fluoro-2-methoxyphenol, followed by substitution of the vinylic fluorine atom by conjugate addition/elimination reactions with amines...

Ammonia and amines undergo conjugate addition to a 3 unsaturated carbonyl compounds (Section 18 12) On the basis of this information predict the pnncipal organic product of each of the following reactions... 

Nucleophilic Addition Reactions. Many nucleophiles, including amines, mercaptans, and alcohols, undergo 1,4-conjugate addition to the double bond of methacrylates (12—14). 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

The reaction of 5-methoxy-2(5//)-furanone 168 with amines was also studied (89T6799). The conjugated addition of ethanolamine to the furanone 168 gave the racemic amino lactone 275 (R = CH2CH20H). Similarly, piperazine reacted with two equivalents of 168 to provide the diadduct 276 as a single diastereomer (no traces of the other isomer were detected). With tryptamine, the reaction was nearly quantitative with the the formation the tran -adduct 277 (R = tryptophanyl) (Scheme 72) (89T6799). 

With the success in Lewis acid-catalyzed thiol conjugate addition reactions mentioned above, we further tried to apply the J ,J -DBFOX/Ph-nickel(II) aqua complex catalyst to the catalyzed asymmetric conjugate addition reactions of hydroxyl-amines [88, 89]. However, after some preliminary examinations, we found that... 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

Both primary and secondary amines add to a /S-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

The effect of the solvent on the product distribution is observed in the conjugate addition of amines to 1-bromo-l-(phenylsulfonyl)alkenes (54) (equation 54)46. When the reaction is conducted in benzene at room temperature for 4 days, the adduct 55 is formed in good yield. On the other hand, the reaction in DMSO at 80-90 °C for 2.5 h affords 2-(phenylsulfonyl)aziridines (56) and no adduct (55) is isolated. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

Ethyleneimine reacts with (p-tolylsulfonyl)acetylene to give only the (Z)-product 115 via trans addition (equation 91), while primary and secondary aliphatic amines afford ( )-products76. With nonterminal acetylenes such as l-(ethylsulfonyl)-l-propyne, the reactions of ethyleneimine, n-propylamine and f-butylamine give mixtures of ( )- and (Z)-adducts. The double conjugate addition of sodium sulfide, selenide and telluride to bis(l-propynyl)sulfone (116) produces heterocycles (117) as illustrated in equation 9277. 

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