Conjugate acceptors reactivity

Early in 2007, the Scheidt group disclosed a highly diastereo- and enan-tioselective intramolecular Michael reaction via an NHC-enolate intermediate. The addition of the NHC catalyst to an ct,p-unsaturated aldehyde followed by subsequent p-protonation generated a reactive enolate intermediate that underwent addition to a pendant conjugate acceptor. A following intramolecular acylation event released the NHC catalyst to afford the bicy-clic acylated enol that readily gave final products upon treatment with MeOH (up to 80% yield, 99% ee) (Scheme 7.68). 

In addition to protonation, a postdoc in the lab, Jan Streuff, explored the use of our catalytically generated enolate in the context of conjugate additions [31]. While the scope of Michael acceptors reactive enough to be intercepted by our chiral enolate complex was limited, we were able to demonstrate a highly diastereo- and enantioselective S3mthesis of vicinal quaternary and tertiary stereocenters with a number of allyl p-ketoesters. In particular, the most enantio- and diastereoselective reactions of this type were observed with 4-piperidinone-derived pronucleophiles (Scheme 10). 

The oxa-Michael reaction is particularly suitable for the rapid generation of molecular complexity when it is embedded in domino reactions. The enolates generated by addition of alcoholates to conjugate acceptors are potent nucleophiles that can further react with suitable electrophiles. Wang and Menche used this reactivity to combine an oxa-Michael reaction with a Tsuji-Trost coupling (Scheme 5-211). " ... 

Keywords Chemical orbital theory, Cw-stability, Cyclic conjugation. Disposition isomers. Diradicals, Donor-acceptor, Electron delocalization, Geminal bond participation, Inorganic heterocycles. Ring strain. Orbital phase. Orbital phase continuity. Polarization, Preferential branching. Reactivity, Selectivity, Stability, Tautomerism, Z-selectivity... 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

Interaction of acceptors of reactive free radicals and compounds that suppress the transfer reaction of an inhibitor radical with the substrate as it occurs in a system comprising antioxidants and polymer chain with conjugated system of double C = C bonds. 

Aniline and nitrobenzene electrophilic substitution reactivity We briefly consider the effect of pi-donor or pi-acceptor substituents on aromatic conjugation patterns for two representative examples aniline (23) and nitrobenzene (24). The leading NBO interactions between ring and substituent in these species are depicted in Fig. 3.47. 

As a result of these substituent-induced polarizations, the complementary conjugative interactions at each ring site become somewhat imbalanced (so that, e.g., the donor-acceptor interaction from C3—C4 to C5—C(, is 23.1 kcal mol-1, but that in the opposite direction is only 16.4 kcal mol-1). From the polarization pattern in (3.133) one can recognize that excess pi density is accumulated at the ortho (C2, C6) and para (C4) positions, and thus that the reactivity of these sites should increase with respect to electrophilic attack. This is in accord with the well-known o, /(-directing effect of amino substitution in electrophilic aromatic substitution reactions. Although the localized NBO analysis has been carried out for the specific Kckule structure of aniline shown in Fig. 3.40, it is easy to verify that exactly the same physical conclusions are drawn if one starts from the alternative Kekule structure. 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

Recently, Kochi et al. described a novel photochemical synthesis for a-nitration of ketones via enol silyl ethers. Despite the already well-known classical methods, this one uses the photochemical excitation of the intermolecular electron-donor-acceptor complexes between enol silyl ethers and tetranitrometh-ane. In addition to high yields of nitration products, the authors also provided new insights into the mechanism on this nitration reaction via time-resolved spectroscopy, thus providing, for instance, an explanation of the disparate behavior of a- and (3-tetralone enol silyl ethers [75], In contrast to the more reactive cross-conjugated a-isomer, the radical cation of (3-tetralone enol silyl ether is stabilized owing to extensive Tr-delocalization (Scheme 50). 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

The mercurio ketone 4 upon reduction with NaBH4 yields a radical which is trapped in situ by reactive acceptors such as vinyl ketones [37]. Treatment of a 1 3 mixture of mercurio ketone 4 and electron deficient terminal alkenes (or fumarate) in CH2C12 with a concentrated solution of NaBH4 in water gives conjugate adducts, Eq. (36). 

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