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Review
. 2021 Sep 20;60(39):21116-21149.
doi: 10.1002/anie.202016666. Epub 2021 Jul 21.

Recent Advances in Photoredox-Mediated Radical Conjugate Addition Reactions: An Expanding Toolkit for the Giese Reaction

Anastasia L Gant Kanegusuku  1 , Jennifer L Roizen  1
Affiliations
Review

Recent Advances in Photoredox-Mediated Radical Conjugate Addition Reactions: An Expanding Toolkit for the Giese Reaction

Anastasia L Gant Kanegusuku et al. Angew Chem Int Ed Engl. .

Abstract

Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin-mediated Giese reactions were nearly forty years ago. With the global recognition of organometallic photocatalysts for the mild and tunable generation of carbon-centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox-mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon-centered radical intermediates that can engage in radical conjugate addition processes.

Keywords: Giese reaction; photocatalysis; photoredox catalysis; radical Michael addition; radical conjugate addition.

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Figures

Figure 1.
Figure 1.
Structures and electrochemical potentials of Ir/Ru/Rh complexes (in acetonitrile).a See ref . b See ref . c See ref . d See ref . e See ref . f See ref .
Figure 2.
Figure 2.
Structures and electrochemical potentials or half potentials of organocatalysts and alternative transition metal photocatalysts (in acetonitrile). a See ref . b See ref and . In CH3CN:H2O (1:1) c See ref . d See ref . e See ref . f See refs and .
Scheme 1.
Scheme 1.
Until recently, most Giese reactions relied on tin hydride, or tin hydride and AIBN. Conditions were tuned to minimize potentially competitive off-pathway reactions.
Scheme 2.
Scheme 2.
Key precedent: Fukuzumi and co-workers induce changes in the mechanism of photocatalyst quenching with an acid catalyst
Scheme 3.
Scheme 3.
Photocatalytic reductive dehalogenation reaction enables diastereoselective synthesis of C-glycosides without the use of tributyl tin reagents
Scheme 4.
Scheme 4.
Photocatalytic dehalogenative carbon-radical formation streamlines access to heteroarylated unnatural amino acids, and expands radical precurosor scope to include alkyl iodides and alkyl bromides. NHPI = N-hydroxypthalimide
Scheme 5.
Scheme 5.
Photocatalytic conditions rely on dual roles of (TMS)3SiH to streamline access to Vorinostat precursor.
Scheme 6.
Scheme 6.
The putative reaction mechanism for a Mn-driven deiodinative Giese reaction parallels that for tin hydride-mediated processes. Consequently, these two non-photocatalysed processes feature similar substrate scopes.
Scheme 7.
Scheme 7.
Tertiary benzylic radical forms and reacts more effectively under conditions that are photoredox-mediated than tin hydride-mediated.
Scheme 8.
Scheme 8.
Indirect dehalogenation enables photoredox-mediated radical generation from otherwise inert benzyl halides
Scheme 9.
Scheme 9.
Lewis acid co-catalyst allows for the photochemically-mediated reduction of enones to generate allylic radical anions
Scheme 10.
Scheme 10.
Dual-acting chiral rhodium complexes serve as chiral template and photocatalyst for the asymmetric conjugate addition of enolate radicals
Scheme 11.
Scheme 11.
Key Precedent: Electron-rich alkenes can generate aryl radical cations in the presence of chemical oxidant additives
Scheme 12.
Scheme 12.
Acridinium photocatalyst 10 enables the direct generation of allylic and benzylic radical cations for alkylation
Scheme 13.
Scheme 13.
Oxidation of aminotrifluoroborates offers a strategy for the installation of primary amines and sets the stage for the non-metal photoredox-mediated oxidation of a wider scope of organotrifluoroborates
Scheme 14.
Scheme 14.
Organotrifluoroborates expand the scope of enantioselective Giese reactions
Scheme 15.
Scheme 15.
Traditionally, amines have served as aminyl radical precursors in conjugate addition/cyclization cascade sequences.
Scheme 16.
Scheme 16.
Conjugate addition of α-silylaminyl radicals provide access to high value N-heterocycles
Scheme 17.
Scheme 17.
α-silylamines engage in enantioselective photocatalyzed Giese reactions with the aid of Lewis acid co-catalysts
Scheme 18.
Scheme 18.
Hydrogen-bonding strategies can induce enantioselective Giese reactions, even those involving of α-silylamine radicals
Scheme 19.
Scheme 19.
Photoxidation of α-organosilanes can generate carbon-centered radicals that participate in enantioselective Giese reactions in the presence of a chiral organocatalyst
Scheme 20.
Scheme 20.
α-aminyl radicals react with dehydroalanine derivatives to generate unnatural amino acid derivatives
Scheme 21.
Scheme 21.
Giese reactions engaging tert-butylcarbamoylated compounds as radical precursors provide simplified syntheses of alkylated amines
Scheme 22.
Scheme 22.
Photomediated α-C(sp3)─H alkylation of electron deficient primary amine derivatives
Scheme 23.
Scheme 23.
Key precedent: N-(acyloxy)-phthalimides (A), oxalates (B), and carboxylic acids (C) are used as radical precursors for conjugate addition reactions for dating back over 25 years
Scheme 24.
Scheme 24.
Radical addition resulting from the decarboxylation of N-(acyloxy)-phthalamides offers complimentary stereoselectivity to traditional organocuprate-mediated conjugate addition reaction for the formation of quaternary carbon centers
Scheme 25.
Scheme 25.
N-(acyloxy)-phthalamide radical precursors streamline the synthesis of trans-clerodane diterprenoids
Scheme 26.
Scheme 26.
N-phthalimidoyl oxalates are readily prepared, user-friendly radical precursors for the generation of quaternary carbon-centers
Scheme 27.
Scheme 27.
Metal-free decarboxylation of biomass-derived N-(acyloxy)phthalimides offers an environmentally sustainable method for derivitizing amino acid among other sustainably produced carboxylic acids.
Scheme 28.
Scheme 28.
Application of Rh-based chiral Lewis acid enables enantioselective Giese reaction using N-(acyloxy)-phthalamide radical precursors
Scheme 29.
Scheme 29.
Diastereoselective Giese reactions produce enantioenriched β-thiolated/selenolated amino acids
Scheme 30.
Scheme 30.
Iridium photocatalyst enables oxidative decarboxylation to generate alky, α-oxy, and α-aminoalkyl radicals for conjugate addition
Scheme 31.
Scheme 31.
Oxidative decarboxylation generates benzylic carbon-centered radicals for conjugate addition
Scheme 32.
Scheme 32.
Oxalate radical precursors engage in selective 1,6-conjugate addition reactions
Scheme 33.
Scheme 33.
Zinc sulfinates generate carbon-centered radicals under reductive quenching conditions
Scheme 34.
Scheme 34.
Hydroxyacid-derived oximes engage in oxidative decarboxylation to generate iminyl radicals to initiate serial cyclization /Giese reactions
Scheme 35.
Scheme 35.
Hydroxyacid-derived oximes engage in oxidative decarboxylation to generate iminyl radicals to initiate serial cyclization /Giese reactions
Scheme 36.
Scheme 36.
Key precedent: Oximes are iminyl-radical precursors capable of inducing β-scission / radical conjugate addition cascade sequences
Scheme 37.
Scheme 37.
Cyclic oximes engage in photoredox-mediated β-scission / radical conjugate addition cascade reactions
Scheme 38.
Scheme 38.
Key precedent: Hofmann-Löffler-Freytag reaction enables oxidative functionalization at remote C(5) position via 1,5-HAT
Scheme 39.
Scheme 39.
PCET enables amides to serve as direct precursors to amidyl radicals in the course of alkene carboaminiation reactions.
Scheme 40.
Scheme 40.
Amides, sulfonamides, and carbamates undergo PCET and SET processes, and the resultant amidyl radicals direct Giese reactions
Scheme 41.
Scheme 41.
Photocatalysis enables non-prefunctionalized amidyl radical formation via PCET or SET processes
Scheme 42.
Scheme 42.
Site-selective, remote allylation of prefunctionalized aliphatic amides allows for C─C bond formation at secondary centers
Scheme 43.
Scheme 43.
Photoredox-mediated site-selective, remote alkylation of aliphatic amides occurs enantioselectively in the presence of a chiral Lewis acid
Scheme 44.
Scheme 44.
Iminyl radicals guide alkylation reactions at C(5)─H bonds and can be used to access γ-C(sp3)─H functionalized ketones.
Scheme 45.
Scheme 45.
Sulfamyl radicals guide Giese reactions
Scheme 46.
Scheme 46.
Secondary centers undergo productive Giese reactions
Scheme 47.
Scheme 47.
Multiple possible reaction mechanisms are consistent with data for sulfamate ester directed Giese reactions
Scheme 48.
Scheme 48.
Alkoxyl radicals generated by UV irradiation engage in 1,5-HAT processes for remote alkylation reactions with modest success
Scheme 49.
Scheme 49.
N-alkoxyphthalamides serve as user friendly alkoxyl radical precurosors to efficiently engage aliphatic alcohols in site-selective Giese reactions
Scheme 50.
Scheme 50.
N-alkoxyphthalamides engage in enantioselective Giese reactions under photoredox-mediated conditions
Scheme 51.
Scheme 51.
Light-mediated strategies for the catalytic homolysis of free alcohols to generate alkoxy radicals
Scheme 52.
Scheme 52.
Proposed reaction mechanism by which alkoxy radicals generated under light-mediated cerium-catalyzed conditions are utilized as HAT agents to engage cyclohexane in Giese reactions
Scheme 53.
Scheme 53.
Coordination between Ir catalyst and phosphate base engages inert C(sp3)─H bonds in PCET to enable innately selective Giese reactions
Scheme 54.
Scheme 54.
Photoredox-mediated TBADT-catalyzed direct C─H homolysis of light-chain, gaseous hydrocarbons generate alkyl radicals for Giese reactions
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