Theoretical study on the mechanisms of Proline‐catalyzed Mannich reaction between acetaldehyde and N‐Boc imines

Abstract

The mechanisms of the single and double Mannich reactions between acetaldehyde and N‐Boc imines are clarified by density functional theory calculations. For single addition of Mannich reaction, the energy difference between the transition states of different configurations correspond to an enantiomeric excess value of 90.58% (without solvent) and 98.46% (in acetonitrile) in favor of the (S)‐configuration product. For bis‐addition of Mannich reaction, the calculated enantiomeric excess value is 95.02% (without solvent) and 98.57% (in acetonitrile) in favor of the (S, S)‐configuration product. These calculated results are in good agreement with the experimental results. The calculations clearly demonstrate that the hydrogen‐bonding determine the stereochemistry of the reactions. Copyright © 2012 John Wiley & Sons, Ltd.

A revisit to proline-catalyzed amination under basic conditions: Insight into the key intermediates and stereocontrolling transition state models for the reversal of enantioselectivity

“…Consistent with the conventional results for proline catalysis [13][14][15][16][17][18][19][20][21][22][23][24][25], the lower-energy TS involving s-trans enamine (TS Ia) is energetically more preferred than that involving s-cis enamine (TS Ic). The calculated free energy difference between them is 4.3 kcal/mol, which is comparable to the previously reported results using the PCM model by Sunoj et al [20].…”

“…In accordance with the experimental proposals [2,[4][5][6][7][8][9][10][11][12] and the theoretical studies of the enamine-mediated reactions [13][14][15][16][17][18][19][20][21][22][23][24][25], the representation to differentiate the nucleophilic intermediates and various stereochemical channels in the CAN bond forming step have been illustrated in Scheme 2. The different combinations of the s-cis or s-trans-conformations, the (E)-or (Z)-configurations of the enamine intermediates, and the anti-or syn-attacking modes of the electrophile to the enamine intermediates constitute the various stereochemical possibilities of the TSs in the CAN bond forming step.…”

“…Although various organocatalysts have been developed to reach high level of efficiencies and to widen the scope of substrates, proline, owing to its good performance in a broad range of asymmetric transformations such as aldol [4], Mannich [5], and amination reactions [6] etc., has been identified as a universal catalyst and is still the hot topic in the field of organocatalysis [1][2][3][4][5][6][7][8][9][10][11][12]. For the enamine-mediated process in proline catalysis, the widely accepted Houk-List transition state model (TSA in Scheme 1), which underlines that the proton of the enamine carboxylic acid (intermediate I in Scheme 2) plays an essential role in directing the electrophile approaching the above face of s-trans-enamine in the stereocontrolling addition step, has been successfully employed to rationalize the stereoselectivity of various reactions [2,[13][14][15][16][17][18][19][20][21][22][23][24][25]. Recently, several experimental evidences have shown that the reactivity and selectivity of the proline-catalyzed transformations are sensitive to the basic additives [7][8][9]11,12].…”

Acetaldehyde in asymmetric organocatalytic transformations

“…After which the formation C-C bond formation take place with almost no activation barrier. This was further confirmed by Gan and co-workers 31 in the detailed mechanistic studies of reaction through density functional with three equivalents of N-Boc-imines (37, 3 equiv.) in the presence of (S)-proline in acetonitrile at 0 o C. The reaction was found to give double Mannich product (38) with remarkably high enantioselectivities with both (S) and (R)-proline; however, the products with aliphatic aldehyde were obtained in low yields 5 (Scheme 8, Eq III).…”

Formation of a vanillic Mannich base – theoretical study

“…Mechanism of the Mannich reaction performed in the presence of different catalysts, such as proline (List et al, 2002;Parasuk & Parasuk, 2008;Chang et al, 2012), complexes of some metals and amines (Córdova, 2004), amino acids (Fu et al, 2008) and derivatives of urea and thiourea (Yalalov et al, 2008;Azuma et al, 2014), has been a subject of theoretical investigations. However, there are very limited data on the Mannich-type reactions catalyzed by ILs from biologically relevant ethanolamines (Abbott et al, 2002).…”