Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

On-DNA hydroalkylation of N-vinyl heterocycles via photoinduced EDA-complex activation.

The emergence of DNA-encoded library (DEL) technology has provided a considerable advantage to the pharmaceutical industry in the pursuit of discovering novel therapeutic candidates for their drug development initiatives. This combinatorial technique not only offers a more economical, spatially efficient, and time-saving alternative to the existing ligand discovery methods, but also enables the exploration of additional chemical space by utilizing novel DNA-compatible synthetic transformations to leverage multifunctional building blocks from readily available substructures. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated N-vinyl heterocycles enabled by single-electron transfer (SET) and subsequent hydrogen atom transfer through electron-donor/electron-acceptor (EDA) complex activation is detailed. The simplicity and robustness of this method permits inclusion of a broad array of alkyl radical precursors and DNA-tethered nitrogenous heterocyles to generate medicinally relevant substituted heterocycles with pendant functional groups. Moreover, a successful telescoped route provides the opportunity to access a broad range of intricate structural scaffolds by employing basic carboxylic acid feedstocks.

Copper-Catalyzed Regiodivergent Internal Allylic Alkylations.

We report a copper-catalyzed, regioselective, and stereospecific alkylation of unbiased internal allylic carbonates with functionalized alkyl and aryl Grignard reagents. The reactions exhibit high stereospecificity and regioselectivity for either SN 2 or SN 2' products under two sets of copper-catalyzed conditions, which enables the preparation of a broad range of products with E-alkene selectivity. Density functional theory calculations reveal the origins of the regioselectivity based on the different behaviors of homo- and heterocuprates.

Transition metal-free photochemical C-F activation for the preparation of difluorinated-oxindole derivatives.

The development of strategies for single and selective C-F bond activation represents an important avenue to overcome limitations in the synthesis of valuable fluorine-containing compounds. The synthetic and medicinal research communities would benefit from new routes that access such relevant molecules in a simple manner. Herein we disclose a straightforward and mechanistically distinct pathway to generate gem-difluoromethyl radicals and their installation onto N-arylmethacrylamides for the preparation of valuable difluorinated oxindole derivatives. To achieve operational simplicity, the use of a readily available benzenethiol as a photocatalyst under open-to-air conditions was developed, demonstrating the facile multigram preparation of the targeted fluorinated molecules. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide a new basis to support the proposed reaction pathway, indicating that arene thiolate is an efficient organophotocatalyst for this transformation.

Practical, scalable, and transition metal-free visible light-induced heteroarylation route to substituted oxindoles.

The synthetic application of (hetero)aryl radicals in organic synthesis has been known since the last century. However, their applicability has significantly suffered from ineffective generation protocols. Herein, we present a visible-light-induced transition metal-free (hetero)aryl radical generation from readily available (hetero)aryl halides for the synthesis of 3,3'-disubstituted oxindoles. This transformation is amenable to a wide range of (hetero)aryl halides as well as several easily accessible acrylamides, and it is also scalable to multigram synthesis. Finally, the versatility of the oxindole products is demonstrated through their conversion to a variety of useful intermediates applicable to target-directed synthesis.

1,2-Radical Shifts in Photoinduced Synthetic Organic Transformations: A Guide to the Reactivity of Useful Radical Synthons.

The exploration of 1,2-radical shift (RS) mechanisms in photoinduced organic reactions has provided efficient routes for the generation of important radical synthons in many chemical transformations. In this Review, the basic concepts involved in the traditional 1,2-spin-center shift (SCS) mechanisms in recently reported studies are discussed. In addition, other useful 1,2-RSs are addressed, such as those proceeding through 1,2-group migrations in carbohydrate chemistry, via 1,2-boron shifts, and by the generation of α-amino radicals. The discussion begins with a general overview of the basic aspects of 1,2-RS mechanisms, followed by a demonstration of their applicability in photoinduced transformations. The sections that follow are organized according to the mechanisms operating in combination with the 1,2-radical migration event. This contribution is not a comprehensive review but rather aims to provide an understanding of the topic, focused on the more recent advances in the field, and establishes a definition for the nomenclature that has been used to describe such mechanisms.

Metal-Free Photochemical Imino-Alkylation of Alkenes with Bifunctional Oxime Esters.

The concurrent installation of C-C and C-N bonds across alkene frameworks represents a powerful tool to prepare motifs that are ubiquitous in pharmaceuticals and bioactive compounds. To construct such prevalent bonds, most alkene difunctionalization methods demand the use of precious metals or activated alkenes. We report a metal-free, photochemically mediated imino-alkylation of electronically diverse alkenes to install both alkyl and iminyl groups in a highly efficient manner. The exceptionally mild reaction conditions, broad substrate scope, excellent functional group tolerance, and facile one-pot reaction protocol highlight the utility of this method to prepare privileged motifs from readily available alkene and acid feedstocks. One key and striking feature of this transformation is that an electrophilic trifluoromethyl radical is equally efficient with both electron-deficient and electron-rich alkenes. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide detailed mechanistic insight into this reaction.

A three-component difunctionalization of N-alkenyl amides via organophotoredox radical-polar crossover.

Herein, we report a three-component organophotoredox coupling of N-alkenyl amides with α-bromocarbonyls and various nucleophiles. This transition metal-free difunctionalization protocol installs sequential C-C and C-Y (Y = S/O/N) bonds in alkenes. This reaction works with terminal and internal alkenes containing both cyclic and acyclic amides via radical-polar crossover.

A practical and sustainable two-component Minisci alkylation via photo-induced EDA-complex activation.

An operationally simple, open-air, and efficient light-mediated Minisci C-H alkylation method is described, based on the formation of an electron donor-acceptor (EDA) complex between nitrogen-containing heterocycles and redox-active esters. In contrast to previously reported protocols, this method does not require a photocatalyst, an external single electron transfer agent, or an oxidant additive. Achieved under mildly acidic and open-air conditions, the reaction incorporates primary-, secondary-, and tertiary radicals, including bicyclo[1.1.1]pentyl (BCP) radicals, along with various heterocycles to generate Minisci alkylation products in moderate to good yields. Additionally, the method is exploited to generate a stereo-enriched, hetereoaryl-substituted carbohydrate.

From Styrenes to Fluorinated Benzyl Bromides: A Photoinduced Difunctionalization via Atom Transfer Radical Addition.

An operationally simple and practical method is disclosed to achieve the difunctionalization of styrenes, generating fluorinated benzyl bromides via a photoinduced atom transfer radical addition process. The developed method is mild, atom-economical, cost-effective, employs very low photocatalyst loading (1000 ppm), and is highly compatible with a broad range of functional groups on styrene. The versatility of the fluorinated benzyl bromides is demonstrated through their derivatization to a variety of valuable compounds.

Cycloadditions of Donor-Acceptor Cyclopropanes and -butanes using S=N-Containing Reagents: Access to Cyclic Sulfinamides, Sulfonamides, and Sulfinamidines.

We present (3+2)- and (4+2)-cycloadditions of donor-acceptor (D-A) cyclopropanes and cyclobutanes with N-sulfinylamines and a sulfur diimide, along with a one-pot, two-step strategy for the formal insertion of HNSO2 into D-A cyclopropanes. These are rare examples of cycloadditions with D-A cyclopropanes and cyclobutanes whereby the 2π component consists of two different heteroatoms, thus leading to five- and six-membered rings containing adjacent heteroatoms.

N-Heterocyclic carbene based catalytic platform for Hauser-Kraus annulations.

The venerable Hauser-Kraus annulation is an effective and convergent method for generating oxygenated polycyclic aromatic compounds. Despite its application in complex molecule synthesis, the harsh and strongly basic conditions can limit its utility in more functionalized molecular settings. We have developed the first catalytic Hauser-Kraus annulation based on N-heterocyclic carbene catalysis that proceeds under milder conditions. We demonstrate the scope of the transformation in the presence of several functional groups. We also propose a concerted mechanism for the annulation that proceeds through a non-canonical Breslow intermediate.

Controllable, Sequential, and Stereoselective C-H Allylic Alkylation of Alkenes.

The direct conversion of C-H bonds into new C-C bonds represents a powerful approach to generate complex molecules from simple starting materials. However, a general and controllable method for the sequential conversion of a methyl group into a fully substituted carbon center remains a challenge. We report a new method for the selective and sequential replacement of three C-H bonds at the allylic position of propylene and other simple terminal alkenes with different carbon groups derived from Grignard reagents. A copper catalyst and electron-rich biaryl phosphine ligand facilitate the formation of allylic alkylation products in high branch selectivity. We also present conditions for the generation of enantioenriched allylic alkylation products in the presence of catalytic copper and a chiral phosphine ligand. With this approach, diverse and complex products with substituted carbon centers can be generated from simple and abundant feedstock chemicals.