Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol.

The ability of alkylamines to spontaneously liberate hydride ions is typically restrained, except under specific intramolecular reaction settings. Herein, we demonstrate that this reactivity can be unlocked through simple treatment with formaldehyde in hexafluoroisopropanol (HFIP) solvent, thereby enabling various intermolecular hydride transfer reactions of alkylamines under mild conditions. Besides transformations of small molecules, these reactions enable unique late-stage modification of complex peptides. Mechanistic investigations uncover that the key to these intermolecular hydride transfer processes lies in the accommodating conformation of solvent-mediated macrocyclic transition states, where the aggregates of HFIP molecules act as dexterous proton shuttles. Importantly, negative hyperconjugation between the lone electron pair of nitrogen and the antibonding orbital of amine's α C-H bond plays a critical role in the C-H activation, promoting its hydride liberation.

Eu(OTf)3 -Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo-[1.1.0]butanes with Nitrones: Access to Polysubstituted 2-Oxa-3-azabicyclo[3.1.1]heptanes.

Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na.

Direct assembly of complex fluorinated motifs from simple fluorine sources is an attractive frontier of synthetic chemistry. Reported herein is an unconventional protocol for achieving tetrafluoroisopropylation by using commercially available CF2HSO2Na as a convenient source of the tetrafluoroisopropyl [(CF2H)2CH] group, which finds widespread applications in life science and material science. Visible-light-induced hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes have been thus developed. Various structurally diverse α-tetrafluoroisopropyl carbonyls and cyclopentanones are selectively constructed under mild conditions. A photocatalytic triple difluoromethylation cascade, driven by consecutive reductive radical/polar crossover processes, leads to the direct assembly of a tetrafluoroisopropyl moiety from CF2HSO2Na. This C1-to-C3 fluoroalkylation protocol provides a practical strategy for the rapid construction of polyfluorinated compounds that are otherwise difficult to access, thus significantly enhancing the boundary of fluoroalkylation chemistry.

Recent advances of 5-endo-trig radical cyclization: promoting strategies and applications.

5-endo-trig radical cyclization has long been recognized as one of the most straightforward ways for the construction of densely functionalized five-membered rings. Nevertheless, according to Baldwin's rules, the 5-endo-trig radical cyclization is kinetically disfavored due to stereoelectronic effects and thus usually proceeds via a slow rate, which renders its application a challenging task. In recent years, with the emergence of efficient radical generation methods and effective cyclization strategies, 5-endo-trig radical cyclization has been successfully accelerated to a synthetically useful rate and has been utilized in the access of diverse five-membered carbo- and heterocyclic compounds. This review comprehensively summarizes the methodologies involving the 5-endo-trig radical cyclization process, with particular emphasis on the elucidation of the promoting strategies, which include the polar effect, geometrical constraints, spin delocalization effect, and persistent radical effect. Each of these strategies is discussed in detail, with illustrative examples from recent literature studies to highlight their practical applications and effectiveness. It is anticipated that the in-depth understanding of the 5-endo-trig radical cyclization provided by this review would inspire further innovation of this privileged reaction mode and expand its applications. Moreover, the potent ring-closure-promoting strategies revealed herein would also contribute to achieving other challenges of cyclizations with particular significance for organic synthesis.

Controllable Synthesis of Cyclopenta[b]indolines via Photocatalytic Fluoroalkylative Radical Cyclization Cascade of Ynamides.

A de novo method for direct construction of cyclopenta[b]indolines via a photocatalytic fluoroalkylative radical cyclization cascade of ynamides has been established, which proceeds via a sequence of radical addition, 1,5-HAT, 5-endo-trig cyclization, intramolecular arylation, and oxidative deprotonation. This protocol allows for the controllable assembly of a tricyclic architecture with three contiguous stereocenters, showcasing its high efficiency, compatibility, and regio- and diastereoselectivity for accessing pharmacologically significant fluoroalkylated cyclopenta[b]indolines. It represents one of the very few examples of tetrafunctionalization of alkynes.