Radical C(sp3)-H functionalization and cross-coupling reactions

Abstract

C─H functionalization reactions are playing an increasing role in the preparation and modification of complex organic molecules, including pharmaceuticals, agrochemicals, and polymer precursors. Radical C─H functionalization reactions, initiated by hydrogen-atom transfer (HAT) and proceeding via open-shell radical intermediates, have been expanding rapidly in recent years. These methods introduce strategic opportunities to functionalize C(sp³)─H bonds. Examples include synthetically useful advances in radical-chain reactivity and biomimetic radical-rebound reactions. A growing number of reactions, however, proceed via "radical relay" whereby HAT generates a diffusible radical that is functionalized by a separate reagent or catalyst. The latter methods provide the basis for versatile C─H cross-coupling methods with diverse partners. In the present review, highlights of recent radical-chain and radical-rebound methods provide context for a survey of emerging radical-relay methods, which greatly expand the scope and utility of intermolecular C(sp³)─H functionalization and cross coupling.

Fig. 1 ∣. Mechanisms and components of radical-chain, radical-rebound, and radical-relay reactions.

Aa ∣ General mechanism of radical-chain reaction. Ab ∣ Representative initiators/reagents for radical-chain reactions. Ba ∣ General catalytic cycle of radical-rebound reactions. Bb ∣ Representative iron and manganese catalysts for radical-rebound reactions. Ca ∣ General mechanism of radical-relay reactions involving radical trapping reagents. Cb ∣ General mechanism of catalytic radical-relay reactions. Cc ∣ Representative oxidants and HAT reagents for radical-relay reactions. Cd ∣ Representative radical trapping reagents. Ce ∣ Representative catalytic radical-relay coupling partners. [O] = O₂/2e⁻, H₂O₂, or other O-atom transfer reagent. NFSI, N-fluorobenzenesulfonimide; Selectfluor I (R = CH₂Cl), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); Selectfluor II (R = CH₃), 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); TMP, 5,10,15,20-tetramesitylporphyrin; TPFPP, 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin; PDP, N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine; HAT, hydrogen atom transfer; ET, electron transfer; TBPB, tert-butyl peroxybenzoate; DTBP, di-tert-butyl peroxide; NHPI, N-hydroxyphthalimide; B₂cat₂, bis(catecholato)diboron.

Fig. 2 ∣. Late-stage C(sp³)─H functionalization reactions via radical chain and radical rebound.

Aa ∣ General mechanism for radical-chain reaction with a N─X reagent. Ab ∣ Fluorination reactions of C(sp³)─H bonds. Ac ∣ Site-selective aliphatic C─H halogenation and xanthylation reactions with N─X reagents. Ad ∣ Benzylic C(sp³)─H hydroxylation reaction. B ∣ Iron-catalyzed C─H oxidation reaction. Ca ∣ Manganese-non-heme catalyzed chiral desymmetrization of cyclohexane. Cb ∣ Manganese-catalyzed benzylic amination reaction. Cc∣ Manganese-porphyrin or -salen catalyzed C─H functionalization reactions. HFIP, hexafluoroisopropanol; PDP, N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine; ^TIPSmcp, N,N′-dimethyl N,N′-bis(2-(5-triisopropylsilylpyridyl)methyl)-1,2-trans-diaminocyclohexane; Pc, phthalocyanine; TMP, 5,10,15,20-tetramesitylporphyrin; TMS, trimethylsilyl.

Fig. 3 ∣. Radical relay involving radical addition to trapping reagents.

Aa ∣ Oxygenation with Co/NHPI cocatalysts. Ab ∣ Oxygenation with decatungstate photocatalysts. Ba/b ∣ PINOylation methods. Ca ∣ Azidation/cyanation via radical trapping with sulfonyl–X reagents (X = N₃, CN). Cb ∣ Thiol coupling via radical trapping with sulfonylthiolates. Da ∣ Amination of heterobenzylic C(sp³)─H bonds with DEAD. Db ∣ Amination initiated by LMCT with Ce^IV reagents. Ea ∣ Giese-type alkylation with decatungstate photocatalysts. Eb ∣ Polarity reversal HAT/Giese-type alkylation. Fa ∣ Minisci reaction with decatungstate photocatalyst. Fb ∣ Photochemical Minisci-type pyridylation. G ∣ Photochemical borylation. NHPI, N-hydroxyphthalimide; DEAD, diethyl azodicarboxylate; LMCT, ligand-to-metal charge transfer; TFA, trifluoroacetic acid; (TRIPS)₂, bis(2,4,6-triisopropylphenyl) disulfide; PFBI–OH, hydroxyl perfluorobenziodoxole; HFIP, hexafluoroisopropanol; B₂cat₂, bis(catecholato)diboron; ClB(cat), B-chlorocatecholborane; DT, decatungstate.

Fig. 4 ∣. Timeline of representative Kharasch-Sosnovsky (K-S)-type reactions.

a ∣ Original Kharasch-Sosnovsky reaction. b ∣ Kharasch-Sosnovsky reaction mechanism. c ∣ First asymmetric allylic oxidation. d ∣ Synthesis of triterpenes. e ∣ Examples of asymmetric allylic oxidation. f ∣ Cross-coupling reaction of benzylic C─H bonds and 1,3-dicarbonyl compounds. g ∣ An alternative HAT reagent. h ∣ C─N bond formation reaction. i ∣ Mechanistic insights for C─N bond formation. j ∣ Allylic oxidation with limiting C─H substrate. k ∣ Cross coupling of benzylic C─H bonds and arylboronic esters. l ∣ Cross coupling of C(sp³)─H and C(sp²)─H bonds. TBS, tert-butyldimethylsilyl; BPhen, bathophenanthroline; N~N, β-diketiminate ligand: 2,4-bis-(2,6-dichlorophenylimino)pentyl; Ad, 1-adamantyl; Phen, phenanthroline; phd, 1,10-phenanthroline-5,6-dione.

Fig. 5 ∣. Summary of Cu/NFSI-catalyzed radical-relay functionalization, functionalization/diversification, and cross-coupling reactions of benzylic C(sp³)─H bonds.

a ∣ Sulfonimidation. b ∣ Enantioselective cyanation. c ∣ Trifluoromethylation. d ∣ Azidation reaction. e ∣ Amination methods with amides and ammonia surrogates. f ∣ Thiocyanation. g ∣ Isocyanation/amine coupling sequence. h ∣ Fluorination/diversification. i ∣ Chlorination/diversification. j ∣ Cross coupling of benzylic C─H bonds and alcohols. k ∣ Cross coupling of benzylic C─H bonds and azoles with N-site selectivity. l ∣ Enantioselective cross coupling of benzylic C─H bonds and arylboronic acids. m ∣ Enantioselective alkynylation. NFSI, N-fluorobenzenesulfonimide; Selectfluor II, 1-fluoro-4-methyl-1,4-diazoniabicylco[2.2.2]octanebis(tetrafluoroborate); 1-Np, 1-naphthalene; TMS, trimethylsilyl; F-TEDA-PF₆, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate); TBACl, tetrabutylammonium chloride; TMSOTf, trimethylsilyl triflate; TFA, trifluoroacetyl-protected amine.

Fig. 6 ∣. Catalytic cycle and radical functionalization mechanisms for Cu/NFSI-catalyzed radical-relay reactions.

a ∣ Inner sphere radical coupling via reductive elimination. b ∣ Radical-polar crossover pathway. c ∣ Radical addition to Cu-bound ligand. NFSI, N-fluorobenzenesulfonimide.

Fig. 7 ∣. Radical-relay C─H functionalization and cross-coupling reactions with catalysts other than copper.

DTBP, di-tert-butyl peroxide; dppb, 1,4-bis(diphenylphosphino)butane; L_n, ligands; DCP, dicumyl peroxide; phd, 1,10-phenanthroline-5,6-dione.

Fig. 8 ∣. Photoredox C(sp³)─H functionalization/cross coupling via radical relay.

a ∣ Four pathways for photoredox-promoted C─H functionalization/cross coupling. b ∣ The photoredox toolbox includes HAT reagents, photocatalysts, and metal-/iodine-based catalysts utilized for representative methodologies. HAT, hydrogen atom transfer; SET, single electron transfer; BI─OH, hydroxyl benziodoxole, PFBI─OH, hydroxyl perfluorobenziodoxole; PIDA, phenyliodonium diacetate; TBADT, tetra-n-butylammonium decatungstate; TBPB, tert-butyl peroxybenzoate; 4CzIPN, 2,4,5,6-tetra(carbazole-9-yl)isophthalonitrile; [Acr⁺Mes], 9-mesityl-1,3,6,8-tetramethoxy-10-phenylacridin-10-ium tetrafluoroborate; bpy, 2,2'-bipyridine; PhI(pBBA)₂, bis(4-bromobenzoyloxy)iodobenzene; p-F-ppy, 5-fluoro-2-(2-pyridinyl-κN)phenyl-κC; dFppy, 2-(2,4-difluorophenyl)pyridine; dtbbpy, 4,4'-di-tert-butyl-2,2’-bipyridyl; 5,5'-dmbpy, 5,5'-dimethyl-2,2'-bipyridyl.

Fig. 9 ∣. Different methods for radical-relay C(sp³)─H functionalization and cross coupling using carbon-centered radicals access via photoredox methods.

a ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving single electron transfer. b ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving copper catalysts. c ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving nickel catalysts. d ∣ Photoredox-promoted C─H functionalization/cross-coupling reactions involving iodine-based catalysts . SET, single electron transfer; PhI(pBBA)₂, bis(4-bromobenzoyloxy)iodobenzene; BI–OH, hydroxyl benziodoxole, PFBI–OH, hydroxyl perfluorobenziodoxole; TFA, trifluoroacetic acid, TBADT, tetra-n-butylammonium decatungstate; NaDT, sodium decatungstate; Ketone-1, 4-methoxy-4'-trifluoromethylbenzophenone; Ketone-2, 4,4'-dichlorobenzophenone, BRSM, based on recovered starting material.

Fig. 10 ∣. Nickel-catalyzed arylation of C(sp³)─H bonds of inexpensive (co)solvents enabled by in situ generation of HAT reagents.

Aa ∣ Energy transfer pathway for arylation of C(sp³)─H bonds. Ab ∣ Single electron transfer pathway for arylation of C(sp³)─H bonds. Ba ∣ Examples of arylated products involving energy transfer. Bb ∣ Examples of arylated product involving single electron transfer. Bc ∣ Enantioselective arylation of benzylic C(sp³)─H bonds with a chiral bis-imidazoline ligand. EnT, energy transfer; SET, single electron transfer; R.E., reductive elimination; dF(CF₃)ppy, 3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl; dtbbpy, 4,4'-di-tert-butyl-2,2'-dipyridyl; BiIM, biimidazoline; DMBP, 4,4'-dimethoxybenzophenone.

Fig. 11 ∣. Radical-relay reactions involving electrochemistry.

Aa ∣ General mechanism for NHPI-mediated electrochemical oxygenation reaction of C(sp³)─H bonds. Ab ∣ Oxygenation of allylic C─H bonds. Ac ∣ Oxygenation of heterobenzylic C(sp³)─H bonds. Ad ∣ Quinuclidine-mediated oxygenation of C(sp³)─H bonds. Ae ∣ N-alkyl ammonium ylides as a new class of HAT-mediators. Af ∣ NHPI-mediated iodination followed by pyridination of alkylarenes. Ba ∣ Oxygenation reactions involving metal-oxo complexes. Bb ∣ Oxygenation of secondary benzylic C(sp³)─H bonds using Fe-TAML complex. Bc ∣ Hydroxylation of C(sp³)─H bonds in amine derivatives using a ruthenium-based catalyst. C ∣ Azidation of C(sp³)─H bonds using Mn^III catalyst. D ∣ Photoelectrochemical azidation reaction of C(sp³)─H bonds. NHPI, N-hydroxyphthalimide; Cl₄NHPI, tetrachloro-N-hydroxyphthalimide; RVC, reticulated vitreous carbon; TBAP, tetrabutylammonium perchlorate; TAML, tetraamido macrocylic ligand; dtbpy, 4,4'-di-tert-butyl-2,2'-dipyridyl; DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; 1,10-Phen, 1,10-phenanthroline; TFA, trifluoroacetic acid.