Mechanistic Investigation of the 2,5‐Diphenylpyrrolidine‐Catalyzed Enantioselective α‐Chlorination of Aldehydes

Abstract

The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly. Furthermore, the rate-determining step in the overall reaction was determined and the presence of nonlinear effects was probed.

Electrospray Ionization Mass Spectrometric Study on the Direct Organocatalytic α‐Halogenation of Aldehydes

“…[5] Recently, an electrophilic N-chlorination of the enamine intermediate instead of a direct C-chlorination has been proposed based on isotope effects, nonlinear effects, kinetic studies, and DFT calculations.…”

“…[3][4][5] The catalytic cycle currently accepted for the organocatalytic a-chlorination of aldehydes is shown in Scheme 1 for the reaction of butanal (1) and N-chlorosuccinimide (NCS) catalyzed by l-prolinamide (3) to produce 2-chlorobutanal (2). The reaction proceeds via the formation of the iminium ion 4, which releases a proton to form the enamine intermediate 5.…”

“…The slow reaction of intermediate 6 with water to give product 2 and the catalyst 3 is the rate-determining step of the catalytic cycle, which is in accordance with the results obtained by Halland et al in their study on the influence of water and acid on the reaction rate. [5] The addition of water before the reacting solution enters the ESI source allowed for the interception of the protonated …”

“…Reaction with water yields the product 2 and succinimide (NHS). [5] Recently, an electrophilic N-chlorination of the enamine intermediate instead of a direct C-chlorination has been proposed based on isotope effects, nonlinear effects, kinetic studies, and DFT calculations.[5] The interception and characterization of the possible reactive NÀX + intermediate in solution is an important challenge. Marigo and Jørgensen discussed quite recently the organocatalytic direct asymmetric a-heteroatom functionalization of aldehydes and ketones.…”

Organocatalytic Asymmetric α-Chlorination of 1,3-Dicarbonyl Compounds Catalyzed by 2-Aminobenzimidazole Derivatives

“…Next, the chlorinating agent would be activated by hydrogen bond either with the ammonium moiety (II, Figure 2) or with the second benzimidazol moiety (IV, Figure 3) favoring a tight transition state which would render the final product, regenerating the catalyst. On the other hand, an alternative and previously suggested [35,43,44] initial N-chlorination of the catalysts and subsequent chlorine inner transfer to the coordinated dicarbonyl compound seems to be discarded, since no chlorine incorporation to the organocatalysts was detected by ESI-MS after mixing them with the chlorinating reagents. the corresponding product 5a with opposite configurations.…”