N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• /phthalimides as new alternative sulfenylating reagents can meet this demand. In this context, we observed that most of the reactions have used unactivated C–H bonds, such as C(sp2)–H and C(sp3)–H bonds. In some reactions, chiral organocatalysts catalyzed asymmetric sulfenylation processes. In most cases, there

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• drug and natural compounds containing functionalized ether α-C(sp3)–H bonds CDC reactions can be applied. This review mainly focuses on the CDC reactions of ether oxygen α-C(sp3)–H bonds via non-noble metal-catalysis (Scheme 1d). Review Non-noble metal-catalyzed CDC reactions involving ether α-C(sp3)–H

• bonds The possible mechanism of the CDC reaction involving ether α-C(sp3)–H bonds mainly follows the two pathways outlined in Scheme 2. Route a: First, the C(sp3)–H bond at the α-position of the oxygen atom undergoes a single-electron transfer under the combined action of the transition metal and an

• . Route b: the α-C(sp3)–H bonds are activated by a combination of transition metals and radical initiators to give the alkyl radicals, which are coupled with other radical receptors to afford the target product. Cu-catalyzed reactions Copper (common oxidation states are +I, +II and +III) has a

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

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• dialkylpyridines with alkenes. It is to be noted that the ligands’ backbones were found to be crucial for the regioselectivity of the addition to benzylic C(sp3)–H bonds, as N-arylamine-bridged bis(phenolato) Zr complexes provided branched products whereas N-alkylamine-bridged bis(phenolato) Zr complexes provided

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• catalyst. The same year, Besset and co-workers extended this methodology to a larger class of acrylamides [106]. I.3) Transition-metal-catalyzed trifluoromethylthiolation of aliphatic C(sp3)–H bonds Despite the important progresses presented in the previous section, some limitations of the

• formation of C(sp2)–ORF bonds starting from benzaldehyde (ORF = 2,2-difluoroethoxy 50g, 2,2-difluoropropoxy 50h, and 1,1,1,3,3,3-hexafluoroisopropoxy 50i). II.2) Fluoroalkoxylation of aliphatic C(sp3)–H bonds by transition-metal-catalysis The functionalization of C(sp3) centers by transition-metal-catalyzed

• fluorinated residues [131][136][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207][208] is of high importance. Besides, in comparison with the functionalization of C(sp2) centers on aromatic and vinylic derivatives, transition-metal-catalyzed functionalization of C(sp3)–H bonds remains

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

• processes [132][133][134]. Fluorinated substituents in the ketone molecule are used to achieve higher electrophilicity and reactivity. Both radical and ionic mechanisms were reported for CH-functionalization reactions [134][135]. An example of an oxidative hydroxylation involving aliphatic C(sp3)–H bonds is

•  32). It should be noted that other α-carbonyl CH bonds are not affected under these reaction conditions, which makes the method suitable for the late-stage functionalization of complex molecules. The method for selective remote CH-hydroxylation involving unactivated C(sp3)–H bonds employing

• oxidative coupling of primary amines and benzylic amines. General scheme of dioxirane and oxaziridine oxidative organocatalysis. Dioxirane organocatalyzed CH-hydroxylation involving aliphatic C(sp3)–H bonds. Enantioselective hydroxylation of CH-acids catalyzed by chiral oxaziridines. Iodoarene

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

• radicals [98]. Concurrently, Guo and co-workers reported a similar approach towards the synthesis of dihydrofurans 101 through the sequential radical addition/cyclization of inactivated C(sp3)−H bonds 100 with olefinic dicarbonyl species 99 (Scheme 19) [99]. Both accounts found the reaction was shut down

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

• ]. In this review, we highlight the developments in C–H activation enabled by nickel photocatalysis. Review Arylation The arylation of C(sp3)‒H bonds constitutes a potential tool for the rapid diversification of simple organic molecules into valuable scaffolds [48][49][50][51][52]. In 2014, Doyle

• dimethylaniline (1a) and should intercept with the nickel catalytic cycle to result in the desired products 4. In another work by the same laboratory, a strategy for the arylation of α-amino C(sp3)–H bonds in various acyclic and cyclic amine compounds 6 was realized using photoredox-mediated hydrogen atom

• iridium(III) photocatalyst 2-I. Subsequently, Ahneman and Doyle reported a related process for the synthesis of a variety of benzylic amines 7 by the arylation of α-amino C(sp3)‒H bonds with aryl iodides 2 involving photoredox nickel catalysis (Scheme 4) [55]. In this protocol, bis(oxazoline) (BiOx) was

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

• heterogeneous vanadium-based catalysts have been employed to obtain alcohols and carbonyl compounds through oxidation, including VOSO4, Na(VO3), VO(acac)2, VOX3, among others. Obtaining ketones and aldehydes from hydrocarbon compounds through vanadium-mediated activation of C(sp3)–H bonds in a benzylic position

• has a further effect improvement, however, it is even more challenging. In front of this, White and co-workers (2020) adopted a strategy consisting of an initial hydroxylation of the C(sp3)–H bonds adjacent to N- or O-heteroatoms followed by a methylation step (Scheme 19B and C) [137]. The

• in the azidation of inert C(sp3)–H bonds using organic electrosynthesis in a straightforward procedure, enabling the azidation of a series of primary, secondary and tertiary alkyl moieties (Scheme 22B and C) [144]. In general, the new methodology proved to be resource-economic and straightforward

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

• molecular complexity of drugs in drug discovery programs, aiming at molecules with better selectivity for biological targets [6][15][16]. One ideal way to achieve more complex molecular architectures is by hydroalkylation of olefins, a reaction that forms new C(sp3)–C(sp3) and C(sp3)–H bonds at the expense

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

• Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan 10.3762/bjoc.17.74 Abstract A Mn(II)/bipyridine-catalyzed bromination reaction of unactivated aliphatic C(sp3)−H bonds has been developed using N-bromosuccinimide (NBS) as the brominating reagent. The reaction proceeded in moderate-to-good yield, even on a

• reported the manganese-porphyrin-catalyzed chlorination and bromination of C(sp3)−H bonds, respectively (Scheme 1d). Groves et al. also reported the manganese-salen-catalyzed fluorination of benzylic C(sp3)−H bonds [49]. Although these methods are efficient, they have a limited substrate scope

• reaction of substrate 1n bearing two methine C(sp3)–H bonds occurred selectively at the terminal position giving product 2n in 27% yield. The C(sp3)–H bromination reaction took place selectively at the methine C(sp3)–H bond when using substrate 1o, which has both methine and benzylic C(sp3)–H bonds, which

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• review, we highlight photosensitized C–H fluorination as a recent strategy for the direct and remote activation of C–H (especially C(sp3)–H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of

• (especially C(sp3)–H) bonds into other functional groups would not only enormously expand the synthetic maneuverability but would also intensify the use of hydrocarbon feedstocks in organic synthesis. In this context, the advantage of direct C–H fluorination over traditional fluorination methods is that it

• of aryl triflates [29] and arylpalladium complexes [2][47], few permit a one-step transformation of unactivated C(sp3)–H bonds to C(sp3)–F bonds [1][3][36][38][48]. Such a transformation would be highly valuable for the late-stage functionalization (LSF) of complex molecules, such as those in Scheme

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

• C(sp3)–H bond activation reactions, was effective at room temperature. The coupling displayed high selectivity for β-methyl C(sp3)–H bonds. Of note is that a substitution at the C5-position of the 8-aminoquinoline ring was beneficial for the C–H activation step as the functionalization of 5-chloro-8

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• ring, and the yield of the target product weakly depends on the electronic effects of substituents in this ring (products 70a–d). Good yields were obtained even with substrates having inert non-benzyl C(sp3)–H bonds (products 70f–h). It is important to note that products with two substituents in the α

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• diastereoisomeric purity (dr > 99:1) (Scheme 38). 2.9. Direct fluorination of β-methylene C(sp3)−H The direct fluorination of β-methylene C(sp3)−H bonds of Phe derivatives 157a–v having installed the bidentate auxiliary, 2-(pyridine-2-yl)isopropylamine (PIP-amine) 158, was attempted using Selectfluor in the

• other hand, when the quinoline-based ligand 162 was used, it was shown to promote the palladium-catalyzed direct electrophilic fluorination of β-methylene C(sp3)–H bonds. Thus, fluorinations of ʟ-phenylalanine 4-trifluoromethylphenylamides 161a–l carrying a range of functional groups such as fluoro

• 152. Synthesis of β-fluorophenylalanine derivatives from α- or β-hydroxy esters 152a and 155. Synthesis of a series of β-fluoro-Phe derivatives via Pd-catalyzed direct fluorination of β-methylene C(sp3)–H bonds in Phe substrates functionalized with the PIP auxiliary group. Synthesis of series of β

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• more stable trans product, 246. The direct activation of C(sp3)–H bonds attached to N-Cl tosylamines 253 was achieved via a radical pathway affording the products of silylation 254–258 in good chemical yields (Scheme 43) [81]. Most benzylic or benzylic-like positions are sufficiently activated to give

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• (Scheme 10). Notably, this reaction used an air and moisture-stable chiral palladium complex as the catalyst, which worked well at low catalyst loading (as low as 0.5 mol %). In 2015, Shi et al. [47] introduced a Pd(II)/Pd(IV)-catalyzed fluorination of β-methylene C(sp3)–H bonds of α-amino acid

• derivatives (Scheme 11a). This process was carried out under the strongly binding bidentate 2-(pyridine-2-yl)isopropylamine (PIP) auxiliary. A range of substrates containing both aliphatic and benzylic C(sp3)–H bonds was finally converted to the corresponding fluorinated products with excellent

• , Xu’s group [49] presented the palladium-catalyzed direct fluorination of unactivated C(sp3)–H bonds at the β-position of carboxylic acids with NFSI (Scheme 12). To achieve this transformation, an 8-aminoquinoline-derived auxiliary was developed as an effective directing group for the activation of the

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• , perhaps because the α,β-unsaturated double bond affected the iodination. Mohan et al. successfully developed an efficient copper-catalyzed aerobic oxidative amination of C(sp3)–H bonds to synthesize imidazo[1,5-a]pyridine derivatives [122]. The reaction was also applicable to amino acid derivatives, as

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• the amides 47 (Figure 26). The development of sustainable methods for the activation of less-reactive undirected C(sp3)–H bonds is challenging however, highly desired in organic synthesis. Mal and co-workers also demonstrated that acidic C(sp3)–hydrogen bonds within a molecule could be used to control

• exothermic reactions between amines and iodine(III) [114]. By this process undirected C(sp3)–H bonds were shown to be functionalized for dehydrogenative imination reactions. Overall, at 1,5-distances (remote) a dehydrogenative and intramolecular C(sp3)–H imination by 4H elimination was readily done via

Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• using cobalt complexes as well as the cobalt-catalyzed reductive carboxylation of α,β-unsaturated nitriles and carboxyamides in the presence of Et2Zn proceed. A Co complex has been demonstrated to act as an efficient catalyst in the carboxylation of allylic C(sp3)–H bonds. Employing zinc as the

Cobalt-catalyzed nucleophilic addition of the allylic C(sp³)–H bond of simple alkenes to ketones

• Tsuyoshi Mita,
• Masashi Uchiyama,
• Kenichi Michigami and
• Yoshihiro Sato

Beilstein J. Org. Chem. 2018, 14, 2012–2017, doi:10.3762/bjoc.14.176

• remained underdeveloped even though C–O bond formation of allylic C(sp3)–H bonds was firmly established by using SeO2 [14] or CrO3/3,5-dimethylpyrazole [15] (ene-type allylic oxidation). Although the most prominent work on catalytic allylic functionalization studied thus far is considered to be a palladium

• that thermal cleavage of allylic C(sp3)–H bonds is possible without using highly basic organolithium or organomagnesium reagents (Grignard reagents) that react with ketones rather than deprotonating the allylic C(sp3)–H bonds. Based on the observed perfect branch selectivity, we propose the catalytic

• , affording branched homoallylic alcohols in high yields with perfect branch selectivities. The intermediate of the reaction would be a nucleophilic allylcobalt(I) species generated via cleavage of the low reactive allylic C(sp3)–H bond of simple terminal alkenes. Keywords: alkenes; C–H activation; C(sp3)–H

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• and PhI(OCOt-Bu)2. These λ3-iodanes have been widely used in atom-transfer reactions, particularly for the generation of metal-bound nitrenes that are highly active species for the aziridination of alkenes and the direct amination of benzylic, allylic or tertiary C(sp3)–H bonds [80][81][82][83][84][85

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• the substrates for both the chiral C(sp3)–H amination and for the following cross-coupling reaction (Scheme 18) [48]. In the first step, the C(sp3)–H bonds of PIDA derivatives were efficiently converted via an auto-amination with the external sulfonimidamide 31 to form the corresponding aminated

Selective carboxylation of reactive benzylic C–H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system

• Toshifumi Dohi,
• Shohei Ueda,
• Kosuke Iwasaki,
• Yusuke Tsunoda,
• Koji Morimoto and
• Yasuyuki Kita

Beilstein J. Org. Chem. 2018, 14, 1087–1094, doi:10.3762/bjoc.14.94

• oxidations was recognized for displaying the new reactivities of hypervalent iodine reagents toward C(sp3)–H bonds [38][39]. By exploiting the radical behavior of trivalent iodine reagents discovered previously [40][41], the activation of trivalent iodine reagents, e.g., phenyliodine(III) diacetate (PIDA

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• CF3 source in allylic trifluoromethylation (Scheme 30). It was found that allyl substrates bearing an aromatic moiety showed relatively low efficiency. At the same year, the group of Li [51] achieved a copper-catalyzed trifluoromethylation via oxidation of C(sp3)–H bonds adjacent to nitrogen atom in