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

• alkyl radical 12 is captured by intermediate 122, resulting in the formation of complex 123. At this point, the metal center has undergone a two-electron oxidation, making it well-suited for reductive elimination yielding the cross-coupling product 124. Under these catalytic conditions, various TM

• ester 10, regenerating pyridine 137 while forming alkyl radical 12, CO2 and phthalimide–B(pin) adduct 139. Subsequently, radical–radical coupling between 12 and one equivalent of 138 affords dihydropyridine 140, which upon re-aromatization, facilitated by ZnCl2 acting as a Lewis acid, yields product 141

• ] (Scheme 33A). The mechanism of this redox neutral reaction involves reductive fragmentation of the radical precursor 3 mediated by the cathode under constant-current electrolysis (Scheme 33B). The resulting alkyl radical 9 attacks the protonated quinoline 168, forming radical cation intermediate 169

Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process

• Kazuhiro Okamoto,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2024, 20, 264–271, doi:10.3762/bjoc.20.27

• this case, intramolecular radical trapping by the uracil nucleobase was preferred, leading to the formation of the cyclized alkyl radical D. Continuous radical recombination furnished dimer 4. Conclusion We observed additive-controlled inter- and intramolecular chemoselectivity in the hydroamination of

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• smoothly delivered an electron donor–acceptor (EDA) complex II via coulombic interactions. Upon 456 nm blue LED light irradiation, the EDA complex II underwent a single electron transfer (SET) process, followed by subsequent decarboxylation to produce the alkyl radical intermediate A, accompanied by

• transformations, as depicted in Scheme 14. The dual-catalytic cycle comprised a photocatalytic cycle and a copper catalytic cycle, interconnected through an intermolecular single-electron transfer. Within the context of the photocatalytic cycle, the generation of the C(sp3)-centered alkyl radical A was

• depicted in Scheme 16. Initially, a photoactive EDA complex II was transiently formed through the combined action of NaI, PPh3, and the γ,σ-unsaturated phthalimide 33a. Upon irradiation with blue LEDs, the alkyl radical A was generated through a single-electron transfer from the iodide anion to the γ,σ

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical–polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• primary, secondary, and tertiary alkyl halides. The mechanistic investigation revealed the generation of a silyl–copper intermediate which activates the alkyl halides by a single electron transfer to form alkyl radical intermediates [54]. It was suggested that substituting B2pin2 for PhMe2Si-Bpin would

Visible-light-induced nickel-catalyzed α-hydroxytrifluoroethylation of alkyl carboxylic acids: Access to trifluoromethyl alkyl acyloins

• Feng Chen,
• Xiu-Hua Xu,
• Zeng-Hao Chen,
• Yue Chen and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2023, 19, 1372–1378, doi:10.3762/bjoc.19.98

• pivalic anhydride as activator to afford Ni(II) intermediate F. Subsequently, trapping of the alkyl radical C generates high-valent Ni(III) intermediate G, which undergoes facile reductive elimination to furnish the final coupling product 3 and Ni(I) intermediate H. The single-electron transfer (SET

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• amenable to all radical generation approaches/substrate classes nor can they form all desired bonds from alkyl radical intermediates, limiting the toolkit of radical reactions. Recently, radical ligand transfer (RLT) [9][10][11] has emerged as a radical functionalization paradigm with the potential to

• alkyl C–H bond to a high valent iron oxo species, resulting in formation of iron hydroxo and alkyl radical intermediates [15]. Subsequent RLT of the hydroxo ligand to the alkyl radical produces a hydroxylated product, allowing for metabolism and excretion of previously diverse bioactive compounds

• charge transfer (LMCT) which, following cage escape, could add to the alkene to generate an alkyl radical. This alkyl radical could then be chlorinated via RLT from a second Cu(II) chloride species, furnishing the dichlorinated product. While copper was unable to be used catalytically in this early

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

• mechanism follows a ‘monophotonic’ oxidative quenching (OQ) route in which [FeIII(btz)3]3+ is oxidatively quenched to [FeIV(btz)3]4+ by the alkyl halide substrate after excitation with green light. After addition of the alkyl radical to the alkene or alkyne substrate, the catalyst is regenerated by

• strongly reducing 3MLCT excited state (*E1/2 = −1.6 V to −1.8 V vs Fc), which then induces SET to the alkyl halide generating an alkyl radical via cleavage of the C(sp3)–X bond. The authors propose that this radical then engages in a radical chain propagation pathway leading to product 30 and a new alkyl

• reducing enough to engage the model substrate perfluorooctyl iodide and instead *[FeII(btz)3]2+ was verified as the key catalytic species by transient absorption spectroscopy; even though the strongly reducing α-amino alkyl radical intermediate might also engage in the reduction of alkyl halides or act as

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• of an alkyl halide to a carbonyl group, implementation of the Barbier-type ring closure relied thus on the preliminary introduction of both aldehyde and alkyl halide functional groups on a suitable substrate. The mechanism was first thought to involve the coupling of an alkyl radical and a ketyl

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• reported a Ru(bpy)3Cl2-catalyzed synthesis of N-Boc proline oxindole derivatives under visible-light assistance [47]. Therein, N-hydroxyphthalimide (NPhth) esters were utilized as alkyl radical precursors, which can be readily prepared from highly available carboxylic acids. In 2015, Cheng and co-workers

• -membered ring structure 3ra could be successfully isolated with a good yield (66%). A number of alkyl radical precursors were then synthesized and evaluated in the reaction (Scheme 3). We found that redox-active esters derived from primary, secondary, and tertiary aliphatic carboxylic acids were all

• ][10][11][12][13]. Selected photocatalytic decarboxylative radical cascade reactions of N-arylamides. Arylamide substrate scope with isolated yields of products. Alkyl radical precursor scope with isolated yields of products. Selected mechanistic experiments. Optimization tablea. Supporting

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• -coupling involving aldehyde C–H bond cleavage. DABCO-derived cationic catalysts in inactivated C–H bond cleavage for alkyl radical addition to electron-deficient alkenes under photoredox catalysis conditions. Electrochemical diamination and dioxygenation of vinylarenes catalyzed by triarylamines

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• of the alkyl radical generating the cross-coupled product cannot be ruled out [57][60]. In 2020, Gutierrez and co-workers developed a Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes 14 with alkyl bromides 13 and aryl Grignard reagents 2 (Scheme 4) [61]. Using

• sterically hindered tertiary alkyl bromides, the authors were able to favor intermolecular radical addition of the generated alkyl radical 17 to the vinylcyclopropane, outcompeting radical rebound to an aryl Fe species. The incipient radical can then undergo ring-opening of the cyclopropane 18. Work by

• radical 28 (Scheme 5). Regioselective Giese addition to the π-system 21 would generate the transient 2° alkyl radical 29. Due to the high energetic barrier associated with direct cross-coupling between sterically hindered 3° alkyl radicals and aryliron complexes, it is assumed the persistent aryliron

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

• generate a trifluoromethyl radical and LnCuIISO2Cl (intermediate A in Scheme 8). The formed trifluoromethyl radical adds to the alkene moiety to deliver a new alkyl radical, which is trapped by the LnCuII-SO2Cl species. Free SO2Cl– decomposes rapidly to SO2 and Cl–. However, in this transformation, SO2Cl

• – is stabilized by the copper complex. The alkyl radical reacts with LnCuII-SO2Cl to deliver the target product 5. A mechanistic study demonstrated that [Cu(dap)2]Cl can coordinate with the reactive intermediate SO2Cl and suppresses the extrusion of SO2. Thus, [Cu(dap)2]Cl achieves a unique

• to its triplet state CuICN*, in which the fluoroalkyl iodides were reduced to Rf• and I−. Subsequently, the radical Rf• attacks the alkene forming a new alkyl radical species. This radical species is then trapped by CuII(CN)n to generate a CuIII intermediate, which undergoes reductive elimination to

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

• oxidation of 4-V by the photoexcited iridium(III) photocatalyst 4-II results in the nickel(III) species 4-VI. Photolysis of 4-VI generates a chloride radical, which rapidly abstracts the α-oxy C(sp3)−H of the ether to provide the alkyl radical species. The alkyl radical rebound to 4-VIII produces the nickel

• ) species 6-VI generated from the nickel(II) pre-catalyst by a SET process, captures the alkyl radical 6-IV to furnish the nickel(I)–alkyl species 6-VII. Subsequently, the nickel(I)–alkyl species 6-VII undergoes oxidative addition into aryl bromide 3b followed by a reductive elimination to provide the

• ) photocatalyst 10-III. The active iridium(III) photocatalyst 10-I is regenerated by a SET process between 10-III and the nickel(I) species 10-X. The addition of the tertiary radical 10-IV to the terminal alkyne 34 followed by an intramolecular 1,5-HAT results in a nucleophilic secondary alkyl radical species 10

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• to manganese-catalyzed C–H fluorination [22], the resting Mn(III) catalyst is oxidized to O=Mn(V)–N3 complex 10B. Subsequently, an alkyl radical is generated upon H-abstraction by forming Mn(VI) intermediate 10C. The resulting alkyl radical is then trapped by Mn(IV)–N3 intermediate 10D, affording

• to Mn(IV) takes place on the anodic surface, resulting in the formation of a trans-diazide Mn(IV) intermediate (Figure 5). The high-valent manganese(IV) complex is susceptible to HAT from the substrate 14, generating an alkyl radical [45][46]. Subsequently, further azide radical transfer from the

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• on the solvent radical cage efficiency and, consequently, on the concentration and “life-time” of the alkyl free radicals generated after the solvent cage collapse. In the latter case, the alkyl radical needed more time to cyclize before engaging in another solvent cage. After a β–H abstraction, it

• Markovnikov-type addition to generate a carbon-centered radical (B) that attacks the electron-deficient olefin (Scheme 22A). The newly formed alkyl radical (C) is then reduced by a Fe(II) species to an enolate (D) in an electron transfer (ET) step; a proton abstraction then delivers the hydroalkylated product

• . A very clever experiment was designed by Baran and Holland [80] to corroborate the hypothesis of enolate D formation by the Fe(II) reduction of alkyl radical C. They performed an intermolecular hydroalkylation in the presence of benzaldehyde, and then trapped the putative enolate intermediate in an

Recent advances in the application of isoindigo derivatives in materials chemistry

• Andrei V. Bogdanov and
• Vladimir F. Mironov

Beilstein J. Org. Chem. 2021, 17, 1533–1564, doi:10.3762/bjoc.17.111

• for fine-tuning the properties of polymers due to the introduction of substituents of different structures in each of the thiophene rings. Using the example of OSCs consisting of a mixture of a polymer 25 and PC71BM (1:1.5, w/w), the effect of the length of the alkyl radical on the efficiency of such

• containing a short n-butyl substituent at the isoindigo nitrogen atoms and the longest and most branched alkyl radical in the p-phenylene fragment (Scheme 18). Sun et al. showed that such a combination of substituents provides the best miscibility of the polymer with the acceptor fullerene component, which

• electron donor/acceptor nature, the heterocyclic substituents, and the branching of the alkyl radical at the endocyclic nitrogen atom. Research on methods to obtain polymer isoindigo thin films and the use of additives will, in our opinion, significantly improve the efficiency of materials. In addition

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• of alcohol byproducts confirmed the homolytic nature of the bond cleavage at C-4 and served to assess the half-life of the alkyl radical generated. To this purpose, the reaction of dicyanoglutarimides bearing a radical clock substituent (cyclopropylmethyl or 5-hexenyl) was investigated. The reaction

• turn, this next abstracts hydrogen at C-3, regenerating the carrier and continuing the cycle. The C–H bond at position 3 of Guareschi imides is unusually weak. Hydrogen abstraction by an alkyl radical and formation of a hydrocarbon C–H bond is strongly exothermic (calculated enthalpy change: ≈20 kcal

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• recyclability, broad substrate scope, and high functional group tolerance (Scheme 1). Results and Discussion Our initial investigation focused on the CN-K photocatalyzed cascade alkyl radical addition/cyclization reaction of the N-arylallylamine 1a with tert-butyl N-hydroxyphthalimide (NHPI) ester (2a), a

• classical alkyl radical precursor [57][58][59], to construct indoline product 4. Surprisingly, the solvent acetonitrile incorporated indoline 3a was observed as the major product (21%, Table 1, entry 1). Stimulated by this result, we questioned whether it would be possible to develop a general and efficient

• experiments was performed (Scheme 7). The cyanomethylarylation reaction of 7a gave the desired compound 8a as the major product in 70% yield, along with 23% yield of the byproduct 15. The latter compound was generated through a cascade alkyl radical addition/cyclization of the NHPI ester 2d to N-aryl

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• homolytic cleavage of the weak Br–N3 bond in bromine azide [54][55]; (3) the bromine radical can also be generated from NBS with the formation of a succinimide radical; (4) alkyl radical intermediate A is then formed via hydrogen abstraction by the succinimidyl radical and/or azidyl radical [56][57]; (5

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• 104. Subsequently, alkyl radical 104 is captured by indole 98, giving benzyl radical 105. The alkylated indole derivative 100 and morpholine salts are provided via proton-coupled electron transfer (PCET) with EDA complex 102 formed by morpholine and 99 (Scheme 36). As a rare example of EDA

• yield of this reaction can reach 7.6 g ⋅ h−1 on a gram scale, indicating that the flow step is promising in photochemistry. In 2019, Aggarwal and colleagues [38] employed Katritzky salt 119 as electron acceptor and HE 79 as electron donor to form an EDA complex, providing the corresponding alkyl radical

Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2020, 16, 3069–3077, doi:10.3762/bjoc.16.256

• [48]. The first step would involve the formation of a trialkylborane species via the hydroboration of the alkene, as previously observed by 11B NMR spectroscopy [48][49]. In the presence of oxygen, the trialkylborane would, similarly to Et3B, generate an alkyl radical. The latter would react with

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• catalytic amount of tributylstannane [40] led to a radical cyclization, in which the resultant alkyl radical formed was trapped by AIBN to give a proposed nitrogen-centered radical 70. An 1,4-hydrogen abstraction of the nitrogen-centered radical on 70 produced carbon-centered radical 71, which underwent