Computational studies Michael addition

Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phos-phoranimines. The non-ionic phosphazene bases BEMP (112), BTPP (113) and (114, R = Ph) appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with l,2-bis(4-bromomethylphenyl)ethane is increased by the addition of the phosphazene base BEMP. Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]l,3-dioxolan-5-ol by allyl bromide. " Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of P-BEMP leads to excellent yields of 1,3,4,-oxadiazoles. Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate ester). ... 

Ramirez, M. A., Padron, J. M., Palazon, J. M., Martin, V. S. Stereocontrol led Synthesis of Cyclic Ethers by Intramolecular Hetero-Michael Addition. 6. A Computational Study of the Annelation to 2,3-Disubstituted Tetrahydropyrans. J. Org. Chem. 1997, 62, 4584 590. 

On the other hand, a computational study [159] of the Michael addition of propionaldehyde lithium enolate adding to E-crotonaldehyde indicates an anticlinal conformation around the forming bond (i.e. A eclipsing R2 in the ul topicity and A eclipsing H in the Ik topicity of Figure 5.9). 

Experimental findings and a computational study supported a non-covalent general acid/base activation of the reagents in the epoxidation mediated by diaiyl prolinols, where the oxa-Michael addition of the nucleophilic peroxide is the rate- and stereoselectivity determining-step, followed by a fast ring-closure step to the epoxide. The most stable transition... 

An experimental and computational study describing a cascade transformation that breaks all three C-C bonds in a polarized alkyne moiety has been reported (Scheme 5)." Facile intermolecular Michael addition is followed by the relatively slow intramolecular steps. The slowest step corresponds to the 5-exo trig closure at the carbonyl-substituted alkene. This process is facilitated by the coupling of the intramolecular Michael addition with a concerted proton transfer along a resonance-assisted hydrogen bond path, which avoids the formation of an unfavourable zwitterionic intermediate. 

The Evans mechanism for the Lewis acid-catalysed Michael addition to chiral oxa-zoUdinones and related systems has been challenged rather than chelation, open-chain mono- and bis-coordinated complexes with antiparaUel carbonyls (120) have been proposed, based on the NMR and DFT computational studies. This new mechanism is consistent with the experimental results reported for the conjugate addition of amines to a,j8-unsaturated acylimidazolidinones (119) with aluminium, boron, or zinc Lewis acids. ... 

The enantioselective Michael addition of malononitrile CH2(CN)2 to trans-chalcones R CH=CHCOR catalysed by diarylprolinols (151), has been studied in detail. Both experimental and computational results are consistent with a bifunctional non-covalent activation of the reactants (152). The latter mechanism correctly predicts formation of the (R)-configured products (<75% eef- but is in conflict with the generally accepted iminium mechanism. Furthermore, (151) is likely to form the corresponding oxazolidine derivative as an intermediate, which has not been taken into account. 

The stereoselective Rauhut-Currier reaction catalysed by a cysteine derivative has been explored computationally with DFT (M06-2X). Both methanethiol and a chiral cysteine derivative have been studied as nucleophiles. The complete reaction pathway involves rate-determining elimination of the thiol catalyst from the Michael addition product and the stereochemistry has been found experimentally to be extremely sensitive to the reaction conditions, such as the number of water equivalents and the effect of potassium counterion. 

The modifled SIBFA (sum of interactions between fragments ab initio computed) molecular mechanics method has been employed for the study of the conformation at 1 atm and 15kbar of chiral crotonate (131) (Scheme 19) and of the complexes formed with the diphenylmethylamine and the three solvent molecules present in the experiment. The results obtained suggest that the diastereoselectivity of this Michael addition (18% de at 1 atm and 98% de at ISkbar), induced by high pressure and by the presence of methanol, originates from an important stabilization of the pro-R reactive complex in which the crotonate has a stacked-fransoid conformation. This study has demonstrated that it is possible to account theoretically for the influence of pressure on molecular conformation and/or complex sttucture, using a molecular mechanics method that is able to take into account the variation of volumes of the different entities present in the system studied. ... 

Ruiz-Pemia JJ, Marti S, Moliner V, Tunon 1 (2012) A novel strategy to study electrostatic effects in chemical reactions differences between the role of solvent and the active site of chalcone isomerase in a Michael addition. J Chem Theory Comput 8(5) 1532-1535... 

Computational methods have been u.sed to study a wide range of other ring-closure reactions leading to heterocycles. These have often focused on the competition between various mechanisms. In one example (Figure 3), a mechanism involving Michael addition is predicted to be lower in energy than the alternative cycloaddition mechanism, ... 

The reactivity of conjugated double bonds is well known [126] and we were able to perform Michael-type additions on the double bond of the dehydroproline residue. Computer graphics studies of pristinamycin 11 confirmed the accessibility of this functionality (see Sect. 5.1.4). 

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