Asymmetric Intermolecular Iodinative Difunctionalization of Allylic Sulfonamides Enabled by Organosulfide Catalysis: Modular Entry to Iodinated Chiral Molecules

Abstract

Electrophilic halogenation of alkenes is a powerful transformation offering a convenient route for the construction of valuable functionalized molecules. However, as a highly important reaction in this field, catalytic asymmetric intermolecular iodinative difunctionalization remains a formidable challenge. Herein, we report that an efficient Lewis basic chiral sulfide-catalyzed approach enables this reaction. By this approach, challenging substrates such as γ,γdisubstituted allylic sulfonamides and 1,1-disubstituted alkenes with an allylic sulfonamide unit undergo electrophilic iodinative difunctionalization to give a variety of iodine-functionalized chiral molecules in good yields with excellent enantio-and diastereoselectivities. A series of free phenols as nucleophiles are successfully incorporated into the substrates. Aside from phenols, primary and secondary alcohols, fluoride, and azide also serve as efficient nucleophiles. The obtained iodinated products are a good platform molecule, which can be easily transformed into various chiral compounds such as α-aryl ketones, chiral secondary amines, and aziridines via rearrangement or substitution. Mechanistic studies revealed that the chiral sulfide catalyst displays a superior effect on control of the reactivity of electrophilic iodine and the enantioselective construction of the chiral iodiranium ion intermediate and catalyst aggregates might be formed as a resting state in the reactions.

Molecular Understanding and Practical In Silico Catalyst Design in Computational Organocatalysis and Phase Transfer Catalysis—Challenges and Opportunities

“…Zhao and co-workers reported the observation of a negative NLE in their difunctionalization of allylic sulfonamides via iodination [ 123 ]. Together with observing a fractional reaction order with respect to the catalyst, the authors proposed the involvement of catalyst aggregation in the resting state ( Figure 11 A).…”

“… Examples of recent work with proposed NLE. ( A ) Difunctionalization of allylic sulfonamides via iodination as reported by Zhao and co-workers [ 123 ]. ( B ) Proline derivative-catalyzed [12+2] cycloaddition as reported by Jørgensen and co-workers [ 125 ].…”

Chiral sulfide and selenide catalysts for asymmetric halocyclizations and related reactions

“…The usefulness of indane-based chiral sulfide catalyst 4b was further demonstrated in the intermolecular iodofunctionalizations of substituted allylamine derivatives (Scheme 9). 17 Phenol, fluoride and azide were employed as nucleophiles with iodinating reagents to obtain difunctionalized products in good to high enantioselectivities. The formation of a well-organized transition-state structure, that includes a methanesulfonate anion generated from a methanesulfonic acid additive, is proposed on the basis of experimental results.…”

“…The importance of the amide moiety as a hydrogen-bonding donor group on the chiral sulfide catalyst is also clarified in this report. 17…”

Organosulfide-Catalyzed Enantioselective Intermolecular Iodinative Difunctionalization of Allylic Sulfonamides

“…中山大 学化学学院赵晓丹课题组 [8] 也一直致力于该领域, 利用 他们课题组自主发展的茚骨架的手性硫/硒催化剂, 实 现了一系列高创新性且极具挑战的烯烃的高对映选择 性亲电硫官能团化和氯官能团化. 近日, 该课题组利用 基于茚骨架的手性硫催化剂实现了烯丙基磺酰胺的不 对称分子间碘代双官能团化反应 [9] , 这是第一例有机催 化的高对映选择性烯烃分子间碘代双官能团化反应, 为 碘代手性分子的模块化合成提供了一条便捷的途径 (Scheme 1b).…”