Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• via radical pathway (Scheme 56) [125]. In the first step, TBHP oxidizes Cu(I) to form tert-butoxy radical A and Cu(II). HAT from TBHP to tert-butoxy radical A gives the tert-butylperoxy radical B, which in turn abstracts a hydrogen atom from the α-position of DIPEA to form the α-amino radical C

• . Chlorine atom transfer from CHCl3 to the α-amino radical C results in the formation of the dichloromethyl radical D, which adds to styrene 180 to form the C-centered radical E. The authors further assume three possible pathways of the process. Pathway 1 involves single-electron transfer by Cu(II) to give

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• that dimerize to form iodine (I2). Subsequent anodic oxidation of in-situ formed Et3N produced an α-amino radical. The iodine then reacts with the alkene to form an iodonium intermediate, which undergoes intramolecular cyclization with losing an electron, and a second water attack to yield the desired

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• benzylic fluorination method that employed unprotected amino acids as radical precursors, Figure 12 [50]. Oxidation of glycine by Ag(II) promotes decarboxylation and results in the α-amino radical, which performs a HAT on the benzylic substrate to furnish the benzylic radical. This subsequently undergoes

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• activator NHC 73. The mechanism was similar to the previous one. Therein, firstly, the alcohol is condensed with the benzoxazolium salt and generated the adduct 74 in situ. Then, the excited photocatalyst is reductively quenched by adduct 74, followed by proton elimination, generating α-amino radical

• -state *[Ir(III)] complex can effectively oxidize the nitrogen atom of activated NHC–alcohol adduct 66 via SET. The resulting nitrogen radical cation intermediate 67 weakens the adjacent C–H bond, making it more acidic and susceptible to deprotonation by a suitable base, ultimately yielding an α-amino

• radical intermediate 68. This carbon-centered radical, positioned near three heteroatoms, undergoes rapid β-cleavage to produce a carbamate 69 and a deoxygenated alkyl radical 70. The formation of carbamate byproduct 69, having a strong C=O double bond, acts as thermodynamic driving factor for the C–O

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• the chiral phosphate co-catalyst (Scheme 5B). This event leads to the generation of a potent IrII reductant that begins the photocatalytic cycle by reducing 16 into radical anion 17 while regenerating the ground state of the IrIII photocatalyst. After fragmentation, α-amino radical 18 was proposed to

• ester 98 and Cs2CO3 in DMF resulted in the generation of the excited charge transfer complex 99. Subsequent SET mediated by the thiol catalyst followed by fragmentation afforded α-amino radical 100, which was then oxidized by the resulting thiol-radical species, regenerating the thiol catalyst while

• formation of α-amino radical 107 through photoinduced SET followed by fragmentation. Subsequent oxidation of 107 by radical cation q-Ac•+ afforded iminium ion 108 before nucleophilic addition of the in situ-generated tetrachlorophthalimyl anion (–TCPhth) led to the formation of aminal product 105. Of note

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• proton transfer from the oxidized indole radical cation [75], generated by SET from the activated photocatalyst. The α-amino radical generated by reductive decarboxylation of a DMAT derivative with a redox-active ester (−1.26 V to −1.37 V vs a saturated calomel electrode) would enable turnover of the

• the importance of steric effects [99]. Indeed, while the addition of the nucleophilic α-amino radical to the α-styrenyl position affords the 6-membered ring (kinetic product via intramolecular 6-exo-trig ring closure) [100] the resulting radical is unstabilized, the 7-membered ring (obtained via

• visible-light irradiation of the photoredox catalyst [Ir(dF(CF3)ppy)2(dtbpy)]PF6 to access the excited state *[Ir(dF(CF3)ppy)2(dtbpy)]PF6, which can trigger SET oxidation of 8. Rapid decarboxylation leads to α-amino radical V (and the reduced photocatalyst), which is intercepted by the pendant double bond

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• into the C–O bond of the oxabicyclic alkene 30a to afford the σ-allyl intermediate 38 which can isomerize to the more stable π-allyl intermediate 39. Addition of the α-amino radical to the Ni(II) center generates the Ni(III) complex 41. Reductive elimination, followed by protodemetalation, leads to the

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• in the formation of spirolactam 157 in 73% yield (Scheme 13). The reaction is estimated to take place initially with the one electron reduction to α-amino radical 164. This step is thought to be facilitated after TFA protonates the formed imine. Afterwards, radical addition of 164 to 156, generates

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• cation I and a CuI species. This process regenerated CuII in the presence of molecular oxygen. The deprotonation of the nitrogen radical cation produces an α–amino radical II, which was further oxidized to the iminium ion III to which the copper alkynylide added forming the desired product (Scheme 17

• functionalization reactions Benzylic or α-amino C–H groups and even the stable C(sp3)–H group were functionalized through the corresponding benzylic radical, α-amino radical, or alkyl radical. In 2016, Greaney and co-workers [92] investigated the direct C–H azidation with benzylic C–H compounds 47 and the Zhdankin

• . In this work, N,N-dialkylanilines or N-aryltetrahydroisoquinolines 48 reacted with N-substituted maleimide 49 via annulation to provide a range of tetrahydroquinolines or tetrahydroisoquinolines 50, respectively, with good yield. The mechanistic investigation revealed that an α-amino radical

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• )‒H arylation as shown in Figure 3 [55]. Thus, the in situ-generated nickel(0) 3-IV undergoes an oxidative addition with the aryl iodide 2 to form the nickel(II)–aryl complex 3-V. The photoredox-generated nucleophilic α-amino radical 3-VIII readily combines with the nickel(II) species 3-V to generate

• reaction (Figure 16) [120]. A photogenerated α-amino radical 16-IV intercepts with the nickel catalytic cycle to generate a key nickel(III) intermediate 16-VII, which readily undergoes reductive elimination to afford the desired cross-coupled product 74a. In 2017, Kamagai and Shibasaki showed that a robust

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• generate α-amino radical 137• and DPZ•−, which can reduce 136 to give α-carbonyl radical 136•. The CPA is then proposed to form a ternary hydrogen-bonded complex 138 to mediate enantioselective radical coupling that furnishes the desired products 139 in good yields and excellent enantioselectivities (48

• a CPA provided good enantioselectivity (Scheme 20) [69]. The putative mechanism proceeds via a reductive quenching cycle to give α-amino radical 145• after decarboxylation, which is then oxidised further to the imine 146 in the presence of oxygen. Imine 146 is in equilibrium with the enamine

• , which are photocatalytically generated in situ from redox-active esters 242 (Scheme 38) [99]. The mechanism advanced by Wang et al. proposes that 241 acts as a sacrificial reductant to generate the reduced photocatalyst, which can then reduce 242 in a second SET step to give α-amino radical 242• after

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

Distinctive reactivity of N-benzylidene-[1,1'-biphenyl]-2-amines under photoredox conditions

• Shrikant D. Tambe,
• Kwan Hong Min,
• Naeem Iqbal and
• Eun Jin Cho

Beilstein J. Org. Chem. 2020, 16, 1335–1342, doi:10.3762/bjoc.16.114

• extensively explored under visible-light photocatalysis [10][11][12][13][14][15][16]. N-Benzylidenes can undergo facile single-electron reduction to generate α-amino radical intermediates, which can participate in diverse processes, depending upon the nature of the substrates and the reaction conditions

• partner and an electron donor in the photoredox cycle (Scheme 1c). It is likely that the presence of the additional phenyl group in the substrate stabilizes the α-amino radical intermediate and modulates its reactivity [46][47]. In addition to the cross-coupled 1,2-diamines, we envisioned the generation

• ] to the imine 1a, where the radical cation A donates a proton to 1a to form the α-amino radical intermediates B and C, which undergo cross-coupling to give the desired unsymmetrical vicinal diamine 2a. On the other hand, in CH3OH, 1a preferentially abstracts a proton from CH3OH rather than from A

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• addition of a trifluoromethyl radical to silyl enol ethers derived from ketones using the same reaction conditions (Scheme 12) [28]. 1.3 Oxidation reactions In 2015, Bissember and co-workers used the Sauvage catalyst to generate an α-amino radical, which was used to perform the synthesis of annulated

• tetrahydroquinolines and octahydroisoquinolo[2,1-a]pyrrolo[3,4-c]quinolines (Scheme 13) [29]. Importantly, the formation of the key α-amino radical resulted from an oxidation reaction catalyzed by the copper catalyst in the oxidation state +II. Using the [Cu(I)(dap)2]Cl complex as the catalyst and 2 equivalents of TFA

• -a]pyrrolo[3,4-c]quinoline derivatives were obtained for the first time. This transformation starts with the oxidation of the excited photocatalyst with O2. The aniline is then oxidized into an N-centered radical cation, which further gives the α-amino radical. The latter reacts with the maleimide to

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• with heteroaryl chlorides 92 and 94 to obtain products 93 and 95 in 84% and 35% yield, respectively [66]. These results represent a breakthrough in the direct α-C–H functionalization of piperazines. The generation and trapping of the α-amino radical derived from 87 with radical acceptors under mild

• photoredox catalysis conditions could avoid the aforementioned side reactions associated with direct α-lithiation trapping and transition-metal-catalyzed C–H functionalization of piperazines. However, the involvement of an α-amino radical in the reaction process adds another layer of difficulty in achieving

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• are emerging as a powerful tool in amine synthesis. This article reviews synthetic applications of amine radical cations produced by visible light photocatalysis. Keywords: α-amino radical; amine radical cation; catalysis; distonic ion; free radical; iminium ion; photoredox; visible light

• light-mediated reductions such as reductive dehalogenation [47][48][49][50][51], reductive radical cyclization [52][53][54], reduction of activated ketones [49], and reduction of aromatic azides [55]. The third mode involves deprotonation of amine radical cation 2 to form α-amino radical 3, which is

• [61][62]. α-Amino radical 3 is strongly reducing [45][63], thus making the second one-electron oxidation facile. The last mode involves cleavage of a C–C bond α to the nitrogen atom, yielding a neutral free radical 6 and iminium ion 5. Iminium ion 4, an excellent electrophile, is amenable to