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

• synthetic methodologies is the C–H bond activation process that enables a straightforward access to several important and innovative compounds [14][15][16][17][18]. In the last few years, metals such as ruthenium [19][20][21], rhodium [22][23][24], palladium [25][26][27], and iridium [28][29][30] have been

• widely applied as catalysts for this matter, including in the synthesis of bioactive substances. Although catalysts based on these metals, are known to be efficient in C–H bond activation reactions affording the products in good yields and mild conditions, they are also known to be usually expensive

• isosteviol derivate furnished a useful and versatile oxathiazinane (46). The betulinic acid-derived sulfamate ester preferentially underwent amination at the γ primary C–H bond of the equatorial C23 methyl group with high site- and diastereoselectivity to furnish the oxathiazinane derivative in 76% yield

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

• is also oxidized to Mn(III)/L–N3. Azide radical addition to Mn(II)/L to form Mn(III)/L–N3 was considered as a possible route. Concurrently, the photocatalyst is irradiated by blue LED light to induce hydrogen atom transfer (HAT) at the C–H bond of substrate 12, generating alkyl radicals and enabling

• , citalopram (17b), an antidepressant, was also reacted under amination conditions involving HBF4, affording product 19b in good yield and excellent diastereoselectivity (dr > 20:1). Other multiple benzylic C–H bond-containing molecules, including a dopamine receptor agonist analogue 17c as well as derivatives

• , metallonitrene intermediate 18A is formed from the reaction of catalyst 18 with iminoiodinane, which is subsequently transformed to Mn–imido complex 18B via conversion of substrate 17 into a temporary benzylic radical species, wherein C–H bond cleavage is proposed to be the rate-determining step (inter- and

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• . Later, carboxylate-ligand-assisted C–H bond activation takes place through a concerted metalation–deprotonation transformation to produce the next intermediate. Finally, the corresponding product 142 is formed by a reductive elimination process, along with the regeneration of the active catalytic

• '. The isocyanide is inserted into intermediate 158' to achieve intermediate 159'. A 1,2,3-triazole C–H bond activation occurs using palladium, which subsequently undergoes a reductive elimination process to afford final product 154. Likewise, the Pd(0) species is reformed for the next cycle [64]. The

• −Miyaura cross-coupling produced a series of 5-aryl-4-ethynyl triazoles 136 in the presence of Pd(PPh3)4 as catalyst and K3PO4 as base in 1,4-dioxane as solvent at 100 °C (Scheme 39) [62]. A paper by Sekar et al. described the synthesis of polycyclic triazoles 142 through a domino alkyne insertion and C–H

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• prove instrumental for the further diversification of the thus obtained 3-methyleneisoindolin-1-ones 3da–ka. For substrates bearing two potential reactive sites, the annulation selectively took place at the less congested ortho-C−H bond (see 3la and 3ma). Moreover, the challenging isonicotinic acid

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

• [18][19][20][21]. In the presence of a Brønsted acid source, the alkylmetal bond can be transformed into a C–H bond to afford a hydrofunctionalized olefin product (Scheme 1) [22]. The relevance of the formation of new C(sp3)–C(sp3) bonds has led to great efforts to enable the use of carbon

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

• 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

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• products [1][2][3][4][5][6][7][8]. Prins and related cyclization reactions [9][10], hetero-Diels–Alder cyclization [11], cyclization onto epoxides [12], Petasis–Ferrier rearrangement [13], intramolecular oxa-Michael reactions [14], cyclization through oxidative C–H bond functionalization [15], ring-closing

• enantioselectivity varied with the polarity of the solvent. The optimization study disclosed that the enantioselectivity increases with the decrease of the polarity of the solvent (Scheme 68). Yu and co-workers reported a novel segment-coupling Prins cyclization involving sequential benzylic/allylic C–H bond

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

• complexes are the simplest and most rapid way. In this review, the focus lies on cyclization reactions, C–C-, C–S-, C–B-, C–N-, C–P-, C–O-, and C–H bond formation, primarily summarizing the chemical reaction step involving the EDA complex (Table 1) as well as the underlying mechanisms that have appeared

• reactions, C–C-, C–S-, C–B-, C–N-, C–P-, C–O-, and C–H bond formations. The absence of transitional-metal catalysts and photosensitizers is the most profound feature of EDA-complex- mediated reactions in most cases. On the other hand, the reaction conditions are mild, and light is utilized as the only

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• , while the remaining C–H bond in Flp acquires an enhanced positive charge due to the electron-withdrawing effect of fluorine. Based on these considerations, a fluoroproline–aromatic-system interaction has been previously utilized in the engineering of a few peptide therapeutics [44][45]. 2.3

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• trichloride; dichloroalkenes; Friedel–Crafts alkylation; rearrangement; trifluoroalkanes; Introduction 1,1-Dichloro-1-alkenes are valuable synthetic intermediates and have been employed in Pd-mediated cross couplings of one or both chlorine atoms [1][2][3][4][5][6][7], carbonylation reactions [8], and C–H

• bond alkynylations of heteroarenes [9]. The 1,1-dichloro-1-alkenyl moiety is found in a number of pyrethroid insecticides including permethrin and marine natural products such as caracolamide A [10] (Figure 1). 1,1-Dichloro-1-alkenes 2 are commonly prepared from the corresponding aldehydes 1 in one

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• to be developed [14]. The formation of new C–C bonds through direct C–H bond functionalization in organic chemistry is attractive [15]. Such methodologies are omnipresent and facilitate sustainable organic transformations for the synthesis of complex natural products and pharmaceuticals. In the past

• years, C−H bond functionalization catalyzed by transition metals received a strong emphasis, and other different catalytic systems have also been encouraged [16][17][18][19][20]. Huang and co-workers first realized the addition of alkylazaarenes directly to unsaturated bonds via C(sp3)–H

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• such as potassium tert-butoxide or sodium hydride resulted in no formation of the desired product 3a because 2a was decomposed under the harsh reaction conditions (Table 1, entries 2 and 3). Thus we opted to employ another substrate 2b bearing a phenylthio group which polarizes the α-C–H bond to lead

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• (DFT) calculations. As we are aware that if the carbene formed is a singlet then a C–H bond inserted product is predominating whereas if the dimer is the major product along with the minor C–H bond inserted product then the triplet carbene is generated. During their study, they obtained the C–H

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

• catalysis and photochemistry. Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods

• ][51][52][53][54][55][56][57]. Accordingly, the reactivity and selectivity correlate with the homolytic C–H bond dissociation enthalpy and polarity matching principles [58][59][60][61][62][63][64]. One of the advantages of polarity matching is that it enables C(sp3)–H bond activations that are not

• –H bond is matched to the HAT catalyst. For example, an electrophilic radical abstracts H atoms selectively from the most electron-rich or “hydridic” C–H bond [65]. 1.1.3 Importance of visible light and visible-light photosensitization in synthesis: Unlike many other traditional energy resources

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

• last decade particular attention has been focused on two modern fields, C–H bond activation, and visible-light-induced photocatalysis. Couplings through C–H bond activation involve the use of non-prefunctionalized substrates that are directly converted into more complex molecules, without the need of a

• catalyst, able to insert selectively into one specific C–H bond. Accordingly, not only waste generation was significantly reduced, but also new retrosynthetic connections were envisioned, allowing the conception of more straightforward synthetic protocols [15][16][17][18][19][20]. Besides, the formation of

• these two activation modes. The advantages of the dual catalytic systems over traditional monocatalyzed approaches is also discussed, thus illustrating their sustainable character. Review Visible-light-mediated photocatalysis as a sustainable reoxidation strategy In the context of traditional C–H bond

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• -obtained α-oxyalkyl radical intermediates were then trapped by biphenyl (or vinyl) isocyanides to afford functionalized phenanthridines, such as 9.3a (or quinolines) (Scheme 9, path a) [70]. A photogenerated nitrogen-based radical was likewise used to cleave the C–H bond α-to-nitrogen in amides to form the

• ) radicals to isonitriles. Synthesis of 6-(trifluoromethyl)-7,8-dihydrobenzo[k]phenanthridine. Phenanthridine syntheses by using photogenerated radicals formed through a C–H bond homolytic cleavage in THF (path a) and N,N-dimethylacetamide (path b). Trifluoroacetimidoyl chlorides as starting substrates for

In silico rationalisation of selectivity and reactivity in Pd-catalysed C–H activation reactions

• Liwei Cao,
• Mikhail Kabeshov,
• Steven V. Ley and
• Alexei A. Lapkin

Beilstein J. Org. Chem. 2020, 16, 1465–1475, doi:10.3762/bjoc.16.122

• -addition, respectively [15]. Even though the mechanisms are inherently different, three most important aspects should be primarily taken into account when classifying and rationalising C–H activation reactions: the proximity of C–H bond to the transition metal; the energy of C–H bond cleavage within the

• : https://github.com/sustainable-processes/Pd-catalysed_C-H_activation_reaction_prediction. Results and Discussion Computational approach to rationalise reactivity in Pd-catalysed C–H bond activation reactions Chemical reactivity is simultaneously influenced by many factors including catalysts, reactants

• feature of the proton abstraction (PA) mechanism [25] is that the formation of the metal–carbon bond (M–C) occurs simultaneously with the cleavage of the carbon–hydrogen (C–H) bond, while the hydrogen is being transferred to a basic centre, Scheme 1. Assuming the reaction proceeds through the formation of

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• similar chemoselectivity has been previously observed, being explained as a consequence of the acidity of the C–H bond being cleaved [6][44]. Additional intramolecular cross-coupling reactions were carried out by utilizing dimethyl malonates 8k and 8l, which were prepared through the N-benzylation of 16c

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• recently reported [8][9][11], for example the trifluoromethylation of hydroxyaryls [12][13][14], and the direct introduction of the -OCF3 moiety into an organometallic species [15], a diazo compound [16][17], or an unfunctionalized C–H bond (Scheme 1B). The latter method is particularly interesting

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

• reactions of oxime radicals. These reactions are classified into cyclizations involving C–H bond cleavage and cyclizations involving a double C=C bond cleavage. Keywords: iminoxyl radicals; isoxazolines; oxidative cyclization; oxime radicals; oximes; Introduction Free radicals in which an unpaired

• abstraction with cleavage of the C–H bond [12][13][14][15][16][17][18] and in the processes of functionalization of С=С double bonds [19][20]. Amidoxyl radicals (Figure 1, III) are applied in the functionalization of the double bonds [21][22][23][24][25][26] and in mild oxidations [27]. In contrast to the

• oximes reacted with esters and ketones to give oxidative coupling products in moderate to good yields (products 55a–e and 56a–e, respectively). In the case of asymmetric ketones, the C–H bond at the more substituted carbon was cleaved (products 56d,e). Recently, the copper-catalyzed addition of oximes to

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• Photocatalytic hydrogen atom transfer (HAT) represents a valuable strategy for accessing C(sp3) radicals. This method allows the direct cleavage of a C–H bond and the consequent generation of alkyl radicals without relying on the presence of redox-active functional groups. This results in a superior atom economy

• /desulfonylation of the arylsulfonyl chlorides 14.1 (Scheme 14) [85][86]. The ensuing aryl radical is trapped by an aryl isonitrile 14.2, affording the bisarylation product 14.3. The direct organophotocatalytic activation of the C–H bond of an arene represents an atom-economical and attractive strategy for the

• direct activation of the ß-C–H bond [109]. However, organic dyes have not yet been broadly applied for such transformations. Charged aryl radical species Arene radical cations are valuable intermediates that enable the direct C–H functionalization of the aromatic species. They can be accessed through the

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• further (for instance C–Cl, C–NO2) or a functional group of interest from the medicinal or agrochemical point of view (for instance C–CF3, C–F) [39][40][41]. However, their reactivity is still totally unexplored in terms of both [2 + 2] photocycloaddition and metallations through C–H bond activations. In

• literature [52][53][54][55][56][57][58][59]. The styryl fragment bonded to an oxazolone ring has not been characterized previously by X-ray methods, but it shows internal bond distances and angles similar to those found in related 2-styrylimidazolone species [60]. C–H Bond activation processes on (Z)-4

• ], did not produce the expected cyclobutanes or gave only very low conversions (<5%) after long reaction times (96 h). As this reactivity was poor, it was decided to attempt the reaction using Pd complexes as templates [28][29][30]. The first step in this process was to study the C–H bond activation in

Bipyrrole boomerangs via Pd-mediated tandem cyclization–oxygenation. Controlling reaction selectivity and electronic properties

• Liliia Moshniaha,
• Marika Żyła-Karwowska,
• Joanna Cybińska,
• Piotr J. Chmielewski,
• Ludovic Favereau and
• Marcin Stępień

Beilstein J. Org. Chem. 2020, 16, 895–903, doi:10.3762/bjoc.16.81

• Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, F-35000 Rennes, France 10.3762/bjoc.16.81 Abstract Boomerang-shaped bipyrroles containing donor–acceptor units were obtained through a tandem palladium-mediated reaction consisting of a cyclization step, involving double C–H bond

• measurements show that helicene-like boomerangs may be usable as circularly polarized luminescent materials. Keywords: donor–acceptor systems; double C–H bond activation; helicenes; pyrroles; Introduction Nanographenes and other polycyclic aromatics as well as their heterocyclic analogues are typically

• disadvantage may be obviated by transition-metal-mediated double C–H bond activation [22][23], which is functionally equivalent to conventional oxidative coupling reactions, and has become a powerful synthetic tool with a rapidly growing scope of use [24][25][26]. However, in the field of π-conjugated

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

• David Schönbauer,
• Carlo Sambiagio,
• Timothy Noël and
• Michael Schnürch

Beilstein J. Org. Chem. 2020, 16, 809–817, doi:10.3762/bjoc.16.74

• address a single C–H bond selectively without compromising the others. To circumvent this problem, directing groups can be installed, which guide a metal catalyst to a specific C–H bond [4][5]. In case the directing group is not needed in the final product, this strategy accounts for additional reaction

Synthesis of C₇₀-fragment buckybowls bearing alkoxy substituents

• Yumi Yakiyama,
• Shota Hishikawa and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2020, 16, 681–690, doi:10.3762/bjoc.16.66

• equilibrium between the Pd(IV) intermediates through C–H bond activation. Keywords: buckybowl; C70; rearrangement through C–H bond activation; Introduction The study of buckybowls, the bowl-shaped π-conjugated aromatic hydrocarbons corresponding to the fragments of fullerenes, pioneered by the works on

• succeeded in synthesizing three different alkoxy-substituted C70-fragment buckybowls 5a–c. In particular, 5c was not an intended molecule, but was formed unexpectedly through the rearrangement through the Pd-catalyzed C–H bond activation reaction. The X-ray crystal structure analysis of 5a–c clearly