Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes.

The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

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.

Nickel-Catalyzed Regioselective Alkenylarylation of γ,δ-Alkenyl Ketones via Carbonyl Coordination.

We disclose a nickel-catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ-alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr2 ⋅DME as a catalyst and LiOtBu as base. The reaction proceeded with a wide range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and electron-rich and electron-deficient arylboronate esters. The reaction also worked with both cyclic and acyclic alkenyl triflates. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.

Ni-Catalyzed Arylbenzylation of Alkenylarenes: Kinetic Studies Reveal Autocatalysis by ZnX2 *.

We report a Ni-catalyzed regioselective arylbenzylation of alkenylarenes with benzyl halides and arylzinc reagents. The reaction furnishes differently substituted 1,1,3-triarylpropyl structures that are reminiscent of the cores of oligoresveratrol natural products. The reaction is also compatible for the coupling of internal alkenes, secondary benzyl halides and variously substituted arylzinc reagents. Kinetic studies reveal that the reaction proceeds with a rate-limiting single-electron-transfer process and is autocatalyzed by in-situ-generated ZnX2 . The reaction rate is amplified by a factor of three through autocatalysis upon addition of ZnX2 .

Ni-Catalyzed Regioselective 1,2-Dialkylation of Alkenes Enabled by the Formation of Two C(sp3)-C(sp3) Bonds.

We disclose a Ni-catalyzed vicinal difunctionalization of alkenes with benzyl halides and alkylzinc reagents, which produces products with two new alkyl-alkyl bonds. This alkene dialkylation is effective in combining secondary benzyl halides and secondary alkylzinc reagents with internal alkenes, which furnishes products with three contiguous all-carbon secondary stereocenters. The products can be readily elaborated to access complex tetralene, benzosuberene, and bicyclodecene cores. The reaction also features as the most efficient alkene difunctionalization process to date with catalyst loadings down to 500 ppm and the catalytic turnover number (TON) and turnover frequency (TOF) registering up to 2 × 103 and 165 h-1 at rt, respectively.

An Expedient Route to 9-arylmethylanthracene Derivatives via Tandem Ni-catalyzed Alkene Dicarbofunctionalization and Acid-promoted Cyclization-aromatization.

We report a nickel-catalyzed one pot synthesis of 9-arylmethylanthracene motifs, which find applications in medicinal and material chemistry. In this synthesis, we apply three component alkene dicarbofunctionalization of 2-vinylaldimines with aryl iodides and arylzinc reagent to generate a 1,1,2-diarylethyl scaffold, which then undergoes an acidpromoted cyclization followed by aromatization to furnish 9-arylmethylanthracene cores. With the new method, a number of differently-substituted 9-arylmethylanthracene derivatives can be synthesized in good yields.

Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives.

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Synergistic Bimetallic Ni/Ag and Ni/Cu Catalysis for Regioselective γ,δ-Diarylation of Alkenyl Ketimines: Addressing ß-H Elimination by in Situ Generation of Cationic Ni(II) Catalysts.

We disclose unprecedented synergistic bimetallic Ni/Ag and Ni/Cu catalysts for regioselective γ,δ-diarylation of unactivated alkenes in simple ketimines with aryl halides and arylzinc reagents. The bimetallic synergy, which generates cationic Ni(II) species during reaction, promotes migratory insertion and transmetalation steps and suppresses ß-H elimination and cross-coupling, the major side reactions that cause serious problems during alkene difunctionalization. This diarylation reaction proceeds at remote locations to imines to afford, after simple H+ workup, diversely substituted γ,δ-diaryl ketones that are otherwise difficult to access readily with existing methods.

Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies.

We report a Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents to generate 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents. Mechanistic investigations by radical probes, competition studies and quantitative kinetics reveal that the current reaction proceeds via a Ni(0)/Ni(I)/Ni(II) catalytic cycle by a rate-limiting direct halogen atom abstraction via single electron transfer to alkyl halides by a Ni(0)-catalyst.

Ni-Catalyzed Regioselective ß,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones.

We disclose a [(PhO)3P]/NiBr2-catalyzed regioselective ß,δ-diarylation of unactivated olefins in ketimines with aryl halides and arylzinc reagents. This diarylation proceeds at remote locations to the carbonyl group to afford, after simple H+ workup, diversely substituted ß,δ-diarylketones that are otherwise difficult to access readily with existing methods. Deuterium-labeling and crossover experiments indicate that diarylation proceeds by ligand-enabled contraction of transient nickellacycles.

Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins.

Transition metal (TM)-catalyzed difunctionalization of unactivated olefins with two carbon-based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp3 )-[M] (alkyl-TM) species or substrates lacking in ß-hydrogen (ß-Hs), development of this class of reaction still remains seriously limited due to complications of ß-H elimination arising from the in situ-generated C(sp3 )-[M] intermediates. Over the years, different approaches have been harnessed to suppress ß-H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp3 )-[M] intermediates bearing ß-Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of ß-H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments.

Ni-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Olefins by Intercepting Heck Intermediates as Imine-Stabilized Transient Metallacycles.

We disclose a strategy for Ni-catalyzed dicarbofunctionalization of olefins in styrenes by intercepting Heck C(sp3)-NiX intermediates with arylzinc reagents. This approach utilizes a readily removable imine as a coordinating group that plays a dual role of intercepting oxidative addition species derived from aryl halides and triflates to promote Heck carbometalation and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress ß-hydride elimination and facilitate transmetalation/reductive elimination steps. This method affords diversely substituted 1,1,2-triarylethyl products that occur as structural motifs in various natural products.

Ni-Catalyzed Regioselective Reductive 1,3-Dialkenylation of Alkenes.

Dicarbofunctionalization is an important efficient synthetic technique for adding two chemical moieties across an alkene. Here, a novel method of reductive dicarbofunctionalization has been developed using a single alkenyl triflate as the electrophile, combined with an unactivated alkene. The reaction does not require an external auxiliary and proceeds with complete regioselectivity.

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.

Pd-Catalyzed 1,3-Alkenylarylation of Skipped Diene via Metal Migration.

We disclose a palladium-catalyzed difunctionalization of skipped diene with alkenyl triflates and arylboronic acids to produce 1,3-alkenylarylated products. The reaction proceeded efficiently with Pd(acac)2 as a catalyst and CsF as a base for a wide range of electron-deficient and electron-rich arylboronic acids as well as oxygen-heterocyclic, sterically hindered, and complex natural product-derived alkenyl triflates bearing various functional groups. The reaction produced 3-aryl-5-alkenylcyclohexene derivatives with 1,3-syn-disubstituted stereochemistry.

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.

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.

Ni-Catalyzed Regio- and Stereoselective Alkylarylation of Unactivated Alkenes in γ,δ-Alkenylketimines.

We disclose a Ni-catalyzed vicinal alkylarylation of unactivated alkenes in γ,δ-alkenylketimines with aryl halides and alkylzinc reagents. The reaction produces γ-C(sp3)-branched δ-arylketones with the construction of two new C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. Electron-deficient alkenes play crucial dual roles as ligands to stabilize reaction intermediates and to increase catalytic rates for the formation of C(sp3)-C(sp3) bonds. This alkene alkylarylation reaction is also effective for secondary alkylzinc reagents and internal alkenes, and proceeds with a complete regio- and stereocontrol, affording products with up to three contiguous all-carbon all-cis secondary stereocenters.

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.