The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• , Scheme 18) gave product 108 with higher 1,2-cis selectivity. In protocol A, the tosylamide forms an intramolecular hydrogen bonding with the benzylic oxygen forming a quasi-bicyclic intermediate acting as a 1,2-trans directing protecting group. Thus, following subsequent formation of the oxocarbenium ion

Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• pharmaceuticals and agrochemicals nowadays, largely due to the unique ability of fluorinated groups to influence the physicochemical and biochemical properties of molecules [1][2][3]. Among the various fluorinated functionalities, the difluoromethyl (CF2H) group and its aryl-substituted derivative, the benzylic

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• Information File 1, Figure S2 [57], and the benzylic position on the THIQ ring [58]. Indeed, termination of the reaction just after 90 minutes instead of 20 h resulted in the isolation of the fluorescent intermediate 18 in 55% yield (Scheme S1, Supporting Information File 1). Even with the use of both

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• area of medicinal chemistry [93][94][95][96][97]. In 2018, Buchwald and co-workers unveiled the enantioselective synthesis of benzylic amines through the asymmetric Markovnikov hydroamidation of alkenes utilizing diphenylsilane in copper catalysis under mild reaction conditions [98]. Dioxazolones, as

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• ][22][23][24]. Moreover, copper-catalyzed asymmetric radical cross-coupling has advanced significantly over the past decade [25][26][27], with notable examples including Liu and Stahl’s enantioselective cyanation of benzylic C–H bonds using a Cu/chiral bisoxazoline catalyst [28], along with the Peters

• 2022, Xu and co-workers established a site- and enantioselective cyanation of benzylic C(sp³)–H bonds using an electro-photochemical strategy (Figure 7) [55]. The reaction conditions show a broad substrate tolerance, and the late-stage functionalization of complex molecules derived from natural

• pair (AQDS•−, 20•+) then generate a benzylic radical 23 and a semiquinone radical ([AQDS–H]•) through proton transfer. The benzylic radical intermediate 23 subsequently reacts with the chiral copper catalyst L3Cu(II)(CN)2 (25) to form a Cu(III) complex 26, which undergoes reductive elimination to

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• slight decrease observed for 5ac, with chiral (R)-1-((1-phenylethyl)amino)-1,2-benziodoxol-3-(1H)-one (2c), can be attributed to potential steric hindrance induced by the methyl group attached to the benzylic carbon, which may hinder the nucleophile’s access to the electrophilic center of the HIR. The

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• chromene (12) were tolerated. Benzylic azides were accommodated including those bearing nitro (2), iodo (3), and boronic ester groups (5, 21). Strained rings were effective including cubane (18) and bicyclopentane (20). While 18 and 20 were isolated in lower yield, no evidence of ring opening was observed

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

• recombination of radicals F and D leads to the product 67. Photochemical peroxidation of isochromans and other benzylic C(sp3)–H substrates 68 with TBHP was developed using Ir(ppy)3 as the photocatalyst and Bronsted acid as an additive (Scheme 25) [68]. Visible light irradiation of [IrIII(ppy)3] to give the

• the presence of Cu/TBHP. The cyclohexyl radical C attacks at the α-carbon of α,β-unsaturated ketone D generating a benzylic radical E. Finally, a radical cross-coupling between B and benzylic radical E furnish the formation of cycloalkyl–peroxy product 106. The acid-catalyzed radical additions of

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• in arylfluoroacetamides 8 as final products. Further, Zaheer and group developed an α-arylation of synthetically valuable α-fluoro-α-nitroacetamides (9, R = NO2, Scheme 3) under gentle conditions to form a quaternary benzylic fluorocarbon center. The protocol was found to be effective for the α

• to achieve the fluorinated products having a tetrasubstituted benzylic carbon center in good to excellent yields. The strategy was also used for the synthesis of α-arylated α-fluoro(arylsulfonyl)acetonitriles in good yield. In a recent study, Dohi et al. achieved the arylation along with

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• ]-proton shift reaction in this study is expected to proceed via the reaction mechanism reported by Soloshonok [25][26][27][28][29][30][31][32], as shown in Scheme 6. First, DBU interacts with the benzylic hydrogen of the imine (R)-16, and this hydrogen is about to be abstracted as a proton. This hydrogen

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• synthetic route. Results and Discussion Initially, 3-arylbenzofuran-2(3H)-ones 3aa–ma were prepared following a SbCl3-catalyzed Friedel–Crafts alkylation of phenols 1a–m with benzylic alcohols 2a–d, earlier reported by us (Scheme 1) [21][22][23]. All the synthesized 3-arylbenzofuran-2(3H)-ones were

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

• . For example, Liu and colleagues demonstrated the electrochemical oxidation of benzylic C–H bonds to ketones using tert-butyl hydroperoxide as the radical initiator [14]. This method was applied to functionalize bioactive molecules, with celestolide, ibuprofen methyl ester, and papaverine being

• oxidized at the benzylic position in good yields. A gram-scale test was conducted to confirm the potential for large-scale applications. According to the authors, the electrochemical oxidation of t-BuOOH at the anode leads to a tert-butyl peroxyl radical that activates the C–H bond at the benzylic position

• scaffolds. During the reaction, the arylcyclopropane is oxidized at the anode to form a radical cation, causing the weakening of the Cα–Cβ bond. The radical cation then undergoes a three-electron SN2 reaction to generate a benzylic radical, which loses an electron at the anode to form a benzylic carbocation

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• , entry 1). Assignment of the relative configurations as cis or trans was achieved by 1H NMR analysis, considering the chemical shifts of the proton in the α-position of the β-lactam nitrogen atom and the geminal protons in the benzylic position (see Supporting Information File 1). The difference in the

• . Across all tested substrates, nucleophilic attack predominantly occurred at the homobenzylic position, leading to the regioselective formation of clavam derivative with 2-benzylic substitution due to aryl stabilization of the radical intermediate (see mechanistic discussion below). We briefly

Efficient one-step synthesis of diarylacetic acids by electrochemical direct carboxylation of diarylmethanol compounds in DMSO

• Hisanori Senboku and
• Mizuki Hayama

Beilstein J. Org. Chem. 2024, 20, 2392–2400, doi:10.3762/bjoc.20.203

• Pt cathode and a Mg anode in the presence of carbon dioxide induced reductive C(sp3)−O bond cleavage at the benzylic position in diarylmethanol compounds and subsequent fixation of carbon dioxide to produce diarylacetic acids in good yield. This protocol provides a novel and simple approach to

• dioxide; Introduction Electrochemical reduction of benzyl alcohol derivatives can induce reductive cleavage of a C(sp3)–O bond [1] at the benzylic position to generate the corresponding benzylic anion species. This protocol has been frequently applied to electrochemical carboxylation [2][3][4][5][6][7][8

• presence of carbon dioxide to give the corresponding phenylacetic acids [12]. We found that alkyl benzyl carbonates and benzal diacetates (benzylidene diacetates) were also applicable to electrochemical carboxylation with C(sp3)–O bond cleavage at the benzylic position, yielding phenylacetic acids [13] and

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• analyses of microsomal stability confirm prolongation of t1/2 of the new deuterated analogs. We also report the first preparation of [D2]-isonitriles from [D3]-formamides via a modified Leuckart–Wallach reaction and their use in an MCR to afford products with [D2]-benzylic positions and likely

• reagents in MCRs and determination of discrepancies in deuterium retention with MCRs has yet to be explored, although one would expect scrambling to be limited. Thus, we began by gathering highly deuterated aldehydes (>95% D) prepared via NHC catalysis [13] and developed a route to deuterated [D2]-benzylic

• production or external purchase and have progressed along the value chain to the clinic and full approval [5]. Literature inspection reveals that an established common method to prepare deuterated benzylic isonitriles is reduction of a nitrile in the presence of a deuterium source (Scheme 1) [16][17][18

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Novel truxene-based dipyrromethanes (DPMs): synthesis, spectroscopic characterization and photophysical properties

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2024, 20, 2163–2170, doi:10.3762/bjoc.20.186

• synthesis of only truxene was established by Dehmlow’s research group in 1997 [10]. Remarkably, one of the advantages of truxene over the other polyaromatic hydrocarbons (PAHs) is the presence of three benzylic positions, that generally permit to assemble a myriad of functionalized truxene-based

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• mechanism. In the case of tertiary alkanethiols and arylmethanethiols, the corresponding imidoyl radicals 2 decompose to give tertiary alkyl and benzylic radicals, respectively, to form isothiocyanates 5. On the other hand, we have investigated the radical addition of diphenyl disulfide to isocyanides under

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• for our needs [52][53]. Benzylic bromination followed by nucleophilic substitution offers a general approach for the introduction of the nitrogen atom [54][55][56]. Consequently, the continuous flow Wohl–Ziegler bromination of 2b was attempted [57]. Even though we could observe excellent LCMS

• -conversion for the mono-brominated compound, we encountered several problems related to the stability of the product (see Supporting Information File 1). To circumvent these issues, we came across the possibility of inserting an oximino group into the benzylic position which can then be converted into an

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• postulated for the synthesis of benzofuran derivatives from styrene derivatives by iodane reagents [29][30]. Subsequently, intermediate D is attacked by H2O at the benzylic carbon atom to afford intermediate E. Intramolecular proton shift occurs, generating the intermediate F, which undergoes phenyl

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• cation is formed with two resonance structures (not counting further movement into the other aromatic rings destroying the aromaticity of one more ring). Resonance structure A has the cation in a benzylic position and will be the preferred site for nucleophilic attack of methanol compared to resonance

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• iodanes (NHIs) as suitable reagents for the mild oxidation of activated alcohols. Two different protocols, both involving activation by chloride additives, were used to synthesize benzylic ketones and aldehydes without overoxidation in up to 97% yield. Based on MS experiments an activated hydroxy(chloro

• mild oxidation of primary and secondary benzylic alcohols to aldehydes and ketones as an alternative to λ5-iodanes. Results and Discussion Initially, we investigated a variety of pyrazole-, triazole-, and oxazole-substituted hydroxy-NHIs previously developed by our group [25]. However, none of them

• to undesired oxidations of the triple bond. The behavior of secondary benzylic alcohols was tested next, giving 4-methylacetophenone (4t) in an excellent yield of 97% and 1-indanone (4u) in 46%. It is worth noting that for some derivatives oxidized by method A, an acylation of the alcohol was

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

• , over recent years much attention has been focused on C(sp3)–H fluorination, and several methods that are selective for benzylic C–H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles

• . This review aims to give context to these transformations and strategies, highlighting the different tactics to achieve fluorination of benzylic C–H bonds. Keywords: benzylic; C–H functionalization; fluorination; photoredox catalysis; Introduction The development of new fluorination methodologies is

• which several have been disclosed in the chemical literature [11][12]. Benzylic C(sp3)–H bonds are comparatively weaker compared to unactivated C(sp3)–H bonds, with bond dissociation enthalpies (BDEs) falling in the range of 76–90 kcal mol−1 (Figure 1B), due to the increased stability of benzylic

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• α-S(e)CN-functionalization of different pronucleophiles [39] as well as the benzylic azidation of alkylphenol derivatives with NaN3 using TBAI as a catalyst [41]. Considering the fact that TBAI clearly represents one of the most easily available quaternary ammonium iodides and keeping in mind our

• successfully demonstrated matching combination of this catalyst with NaN3 and DBPO for our benzylic azidations [41], we were thus wondering if the use of these simple bulk chemicals also allows for the oxidative α-azidation of different carbonyl-based pronucleophiles. As outlined in this contribution, this

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• have provided innovative strategies, substrates in all of these reaction systems are generally limited to benzylic, α-amino-, and α-oxy aliphatic acids, presumably due to the necessity of stabilized radical intermediates for the following radical cyanation step. We and others have recently demonstrated

• investigated (Figure 2). Arylacetic acids with relatively stable benzylic radicals as the corresponding intermediates have been proved to be suitable substrates to the reaction, providing the desired decarboxylative cyanation products with generally good yields (2–18). To show the synthetic potential of this