Conjugate Addition–Enantioselective Protonation of N-Aryl Glycines to α-Branched 2-Vinylazaarenes via Cooperative Photoredox and Asymmetric Catalysis

Abstract

An enantioselective protonation strategy has been successfully applied to the synthesis of chiral α-tertiary azaarenes. With a dual catalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer that is mediated by visible light, a variety of α-branched 2-vinylpyridines and 2-vinylquinolines with N-aryl glycines underwent a redox-neutral, radical conjugate addition-protonation process and provided valuable chiral 3-(2-pyridine/quinoline)-3-substituted amines in high yields with good to excellent enantioselectivities (up to >99% ee). An application of this methodology to a two-step synthesis of the enantiomerically pure medicinal compound pheniramine (Avil) is also presented.

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis

“…[10] Subsequently,two crossover experiments were conducted to gain insight into the mechanism of this nickel-catalyzed reaction. [10] Subsequently,two crossover experiments were conducted to gain insight into the mechanism of this nickel-catalyzed reaction.…”

“…[8] Herein, we report the first nickel-catalyzed, regioselective arylboration of unactivated terminal alkenes,d elivering 1,ndifunctionalized (n > 2) products ( Figure 1b). [10] Stimulated by the pioneering studies on 1,2-arylboration of styrenes [3a-e] and our previous work in the nickel-catalyzed migratory cross-couplings, [11,12] we hypothesized that if areaction could be initiated by insertion of olefins into aN i ÀB bond, and an ickel migration occurred before the CÀCb ond formation, a1 , n-arylboration (n > 2) reaction of unactivated alkenes would be achieved ( Figure 1c). [10] Stimulated by the pioneering studies on 1,2-arylboration of styrenes [3a-e] and our previous work in the nickel-catalyzed migratory cross-couplings, [11,12] we hypothesized that if areaction could be initiated by insertion of olefins into aN i ÀB bond, and an ickel migration occurred before the CÀCb ond formation, a1 , n-arylboration (n > 2) reaction of unactivated alkenes would be achieved ( Figure 1c).…”

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis

“…[9] Accordingly, an array of diarylsubstituted alkylboronic esters are prepared, and they are valuable synthons and an important pharmacophores in many drugs and other biologically relevant molecules (see Table S1 in the Supporting Information). [10] Stimulated by the pioneering studies on 1,2-arylboration of styrenes [3a-e] and our previous work in the nickel-catalyzed migratory cross-couplings, [11,12] we hypothesized that if areaction could be initiated by insertion of olefins into aN i ÀB bond, and an ickel migration occurred before the CÀCb ond formation, a1 , n-arylboration (n > 2) reaction of unactivated alkenes would be achieved ( Figure 1c). Remarkably,t he incorporation of ab oron group will provide substantial opportunities for further transformations.…”

Sulfur‐Center‐Involved Photocatalyzed Reactions

“…developed the enantioselective photocatalyzed radical conjugation addition and protonation reactions of α‐aryl glycines 89 to α‐branched 2‐vinylpyridines 90 and 2‐vinylquinolines 91 , which achieved the synthesis of important pharmaceutical and biological backbones. The enantiomerically enriched antihistamine drug ( R )‐pheniramine was efficiently obtained with 91 % ee . Control experiments were conducted to disclose the possible pathway of the protonation step.…”

“…The enantiomerically enriched antihistamined rug (R)-pheniramine was efficiently obtained with 91 % ee. [27] Control experiments were conducted to disclose the possible pathway of the protonation step. Several reactions with N-Boc-protected glycine 94 (NHPI;B oc = tert-butyloxycarbonyl, E 1/2 red % + 1.10 vs. SCE in MeCN), which has ar elativelyh igher oxidative potential and could not be oxidized by DPZ (*DPZ, E t (S*/SC À ) =+0.91 Vv s. SCE in DCM, Ir III */Ir II =+1.21 vs. SCE in MeCN).…”