Study of Mechanism to Asymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinidine

Abstract

Benzothiazol-β-amino esters, acted as β-amino acids derivatives, perform excellent bioactivity in antibacterial and antivirus. To gain highly and purely optical single enantioisomer of benzothiazol-β-amino esters with simple organocatalyst, recently, the development for a classic Mannich reaction of diethyl malonate (Nu) with benzothiazol imine (EI) in the presence of cinchona alkaloid derivatives as organocatalyst has been made. The study for mechanism of applying unmodified cinchona alkaloid-chiral quinidine as potent organocatalyst to asymmetric Mannich reaction of benzothiazol-β-amino esters plays a vital role in asymmetric synthesis. In this work, the mechanism for Mannich reaction of benzothiazol-β-amino esters catalyzed by simple chiral quinidine organocatalyst was investigated through a combination of experiment with theoretical approaches (DFT). All geometry structures of reactants (Nu and EI), intermediates and product were optimized completely with the moderate approach M06-2X/6-311G (d,p) basis set in the gas phase. Afterward, the effect of solvent for DCM was took into consideration, and CPCM was used as polarization continuum model. Frequency calculations were performed at the same level of 6-311G (d,p) basis set as the geometry optimizations to confirm stable transition state (TS), which was verified further by means of IR vibrating frequency calculations (zero and only one imaginary frequency respectively). As comparison of (R)TS pathway with (S)TS pathway in potential energy profile, it enables to elaborate that (S)TS pathway executes to afford unique enatioisomer (S). The calculating results indicate that (1) Active sites of quinidine have been confirmed, that are 9-hydroxyl and tertiary amine; (2) The product exhibits S enantiomer as major configuration; (3) Moreover, the results of DFT calculation indicated that the stereo selectivity of the reaction could be improved by lower reaction temperature. The lower temperature is, the more distereoselectivity is upgraded. The calculation demonstrated that all of results are able to be in agreement with experimental data that β-amino acid esters derivatives carrying S as major configuration could arrive to range of 81%～95% ee.

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

“…48 with experimental and theoretical approaches (M06-2X/6-311G(d,p) in gas phase and dichloromethane (CPCM)) (Scheme 17). 49 In line with experimental results, the S enantiomer is obtained as major product in the range of 81% to 95% ee and lower reaction temperature improves stereoselectivity. and computational techniques (B3LYP/def2-TZVP//BP86/ SVP).…”

“…Organocatalysts are used in condensed media; thus, most of the studies have used the continuum-based models; in some cases explicit solvation was shown to yield better quantitative a g r e e m e n t w i t h e x p e r i m e n t a l o b s e r v ations. 15,33,34,38,39,42,46,49,69,71…”

“…The latter mainly deal with the mechanistic studies of syntheses in the presence of CA, which play a crucial role in the acceleration of the reaction and the enantiodifferentiation of the products. B3LYP , with modest basis sets has been used in most of the studies; nevertheless, the energetics have been corrected with higher basis sets and Truhlar’s M05-2X, M06-2X, and M06-L functionals, parametrized to include dispersion for organic reactions, as well as functionals with dispersion corrections. ,,,,,,,,, Since CAs tend to form complexes with substrates via H-bonds and long-range interactions, the usage of split valence triple-ζ basis set including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Organocatalysts are used in condensed media; thus, most of the studies have used the continuum-based models; in some cases explicit solvation was shown to yield better quantitative agreement with experimental observations. ,,,,,,,,, …”

“…Xie et al examined the mechanism for the Mannich reaction of diethyl malonate and benzothiazol esters catalyzed by quinidine with experimental and theoretical approaches (M06-2X/6-311G­(d,p) in gas phase and dichloromethane (CPCM)) (Scheme ). In line with experimental results, the S enantiomer is obtained as major product in the range of 81% to 95% ee and lower reaction temperature improves stereoselectivity.…”

Organocatalytic Asymmetric Synthesis of Benzothiazolopyrimidines via [4 + 2] Cyclization of 2-Benzothiazolimines and Aldehydes

“…The asymmetric Mannich reactions catalyzed by chiral primary and secondary amines and bifunctional organocatalysts for new C–C bond formation have been widely used in the effective synthesis of natural products and pharmacologically active chiral compounds. , Aldehydes and α,β-unsaturated aldehydes activated by secondary amines are frequently applied for the construction of multifunctional heterocycles through [2 + 2], [3 + 2], and [4 + 2] cyclization, in which the asymmetric Mannich reaction is working as the key step. , Recently, our group developed the secondary chiral amine-catalyzed three-component asymmetric Povarov reaction between anilines and aldehydes via chiral enamine intermediates which serve as electron-rich olefins . As part of our research interests in developing new catalytic strategies to construct useful bioactive frameworks, we herein report the direct asymmetric synthesis of benzothiazolopyrimidines via chiral secondary amine-catalyzed [4 + 2] cyclization of 2-benzothiazolimines and aldehydes (Scheme b).…”