Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenation of Imines: A Density Functional Theory Study of Reaction Mechanism and the Origins of Enantioselectivity

Abstract

The phosphoric acid catalyzed reaction of 1,4-dihydropyridines with N-arylimines has been investigated by using density functional theory. We first considered the reaction of acetophenone PMP-imine (PMP=p-methoxyphenyl) with the dimethyl Hantzsch ester catalyzed by diphenyl phosphate. Our study showed that, in agreement with what has previously been postulated for other reactions, diphenyl phosphate acts as a Lewis base/Brønsted acid bifunctional catalyst in this transformation, simultaneously activating both reaction partners. The calculations also showed that the hydride transfer transition states for the E and Z isomers of the iminium ion have comparable energies. This observation turned out to be crucial to the understanding of the enantioselectivity of the process. Our results indicate that when using a chiral 3,3'-disubstituted biaryl phosphoric acid, hydride transfer to the Re face of the (Z)-iminium is energetically more favorable and is responsible for the enantioselectivity, whereas the corresponding transition states for nucleophilic attack on the two faces of the (E)-iminium are virtually degenerate. Moreover, model calculations predict the reversal in enantioselectivity observed in the hydrogenation of 2-arylquinolines, which during the catalytic cycle are converted into (E)-iminium ions that lack the flexibility of those derived from acyclic N-arylimines. In this respect, the conformational rigidity of the dihydroquinolinium cation imposes an unfavorable binding geometry on the transition state for hydride transfer on the Re face and is therefore responsible for the high enantioselectivity.

Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α‐Branched Aldehydes

“…We recently reported a density functional theory study on the mode of action of diarylphosphoric acid organocatalysts in the transfer hydrogenation of ketimines using Hantzsch esters as hydrogen donors. [7] Our results showed that diarylphosphoric acids act as bifunctional Lewis base/Brønsted acid (LBBA) catalysts.[8] Moreover, we showed that both E and Z iminium (presumably in equilibrium under the reaction conditions) species are competent substrates for the hydride transfer. Following imine protonation, the resulting phosphate engages in two hydrogen bonds, one with the iminium and one with the N À H group of the dihydropyridine.…”

“…For instance, in our previous study we calculated that protonation of a PMP ketimine has a barrier smaller than 2 kcal mol À1 . [7] Therefore, the barrier for enamine protonation should not be much higher. The enantioselectivity is thus determined in the hydride transfer step.…”

“…[10] We considered the transfer hydrogenation of imine 3, whose reaction with Hantzsch ester 2c in the presence of catalyst 1a leads to the corresponding amine 5 in 87% yield and 96% enantiomeric excess. [11] In line with our computational approach to investigate ketimine and quinoline reduction, [7] we employed compound 4 as a model for the bulky BINOL derived phosphoric acid 1a, with a biphenyl instead of the binaphthyl backbone and bulky mesityl substituents instead of triisopropylphenyl groups in the 3 and 3' positions. The dihydropyridine used in this study is dimethyl Hantzsch ester 2b (Scheme 2).…”

“…[7] The computational approach used here has been extensively shown to be appropriate for studying enantioselectivity in a variety of organocatalytic processes. [10] We considered the transfer hydrogenation of imine 3, whose reaction with Hantzsch ester 2c in the presence of catalyst 1a leads to the corresponding amine 5 in 87% yield and 96% enantiomeric excess.…”

Triazolopyridines. Part 30. Hydrogen transfer reactions; pyridylcarbene formation

“…Organocatalytic transfer hydrogenation using dihydropyridines as hydride donors and Brönsted acid catalysis has also been intensively investigated. 21,22 Sasson et al reported in 2000 that Pd/C, Zn combination in water in presence of organic hydrogen acceptors (benzaldehyde, nitrobenzene or 4-nitroanisole) acts as a direct hydrogen transfer from water to an organic substrate, giving the reduction product. 23 However, this methodology had not been explored in any depth using other hydrogen donors and substrates.…”