Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• hydride catalysis, and enantiotopic group-selective allylations of 1,1-diborylalkanes as core strategies. At the same time, the authors provide detailed mechanistic insights into the stereocontrol and provide a perspective on currently unresolved challenges in the field. Concerning Full Research Papers

• allenes with diisobutylaluminum hydride, which is followed by the allylation with p-toluenesulfonyl cyanide in a regio- and stereoselective manner. They propose a new way to access accessing acyclic β,γ-unsaturated nitriles with α-all-carbon quaternary centers. In the process, they managed to achieve a

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• homoallylic alcohols 18/19 via metal hydride atom transfer/radical polar crossover (MHAT/RPC) method (Scheme 6) [41]. This mild and high-yielding protocol displays good functional group tolerance and has a broad substrate scope, even providing access to medicinally relevant spirooxetanes. The proposed MHAT

• /RPC mechanism starts with a single-electron oxidation of the cobalt catalyst followed by a reaction with the siloxane to generate a cobalt–hydride complex. Subsequent hydride transfer to the alkene produces radical pair 23 which collapses to alkylcobalt intermediate 24. Another single-electron

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• either a 1,5-hydride shift to give D or a direct cyclization with the aryl ring via intermediate E, which upon deprotonation lead to the final products 16 and 17. In a 2016 study by Van der Eycken’s group (Scheme 9), an innovative copper-catalyzed alkylarylation of activated alkenes using isocyanides as

• alkyl chloride and generating an alkyl–PdI–Cl radical hybrid species III. The alkyl radical then adds to the acrylamide double bond, forming a quaternary carbon radical intermediate IV. This intermediate undergoes intramolecular radical cyclization onto the aromatic ring, followed by either β-hydride

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• , heterogeneous catalytic hydrogenation of the enamine with palladium on carbon was chosen. While the hydride reduction of the acyliminium intermediate gave a nearly 1:1 diastereomer ratio, a 9:1 ratio was obtained for the catalytic hydrogenation (Scheme 4). While the hydride reduction of the N-acyliminium

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• intermediate 168 formed through hydride transfer from 167 (Scheme 54A) [95]. Similarly, Huang and co-workers (2020) employed the same NHC catalyst but used ambient air as the external oxidant for acyl azolium intermediate formation (Scheme 54B) [96]. On the other hand, Ohshima and co-workers (2020) directly

• been successfully done for this method. Similarly, Hou and co-workers (2022) also used CO2 to carry out an auto-tandem Cu-catalyzed carboxylation of styrenes via β-hydride elimination (208) (Scheme 60B) [104]. Impressively, several natural product-like compounds (e.g., 207) were successfully prepared

• -branched (L/B) selectivity of >20:1. The reaction involves the formation of palladium hydride (Pd–H) 270 as the key species followed by alkyne and CO insertion reactions via 271 and 272 (Scheme 68A) [116]. On the one hand, Jia and co-workers (2021) utilized environmentally benign water as the hydrogen

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• at C10 was then introduced via a Michael addition (MeMgBr, CuI) to afford 22 in a yield of 65% (4:1 dr at C10). Initial attempts on the carbonyl 1,2-transposition protocol reported by Dong and co-workers were ineffective [45], leading to premature hydride termination and the formation of alkene 23

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• Seeun Lim Teresa Kim Yunmi Lee Department of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea 10.3762/bjoc.21.63 Abstract This study introduces a highly selective hydrocyanation method based on copper-catalyzed hydroalumination of allenes with diisobutylaluminum hydride, followed

• cyanating reagents, such as p-toluenesulfonyl cyanide (TsCN) and N-cyano-N-phenyl-p-toluenesulfonamide [29]. The hydroboration of allenes with 9-BBN (9-borabicyclo[3.3.1]nonane) as the hydride source, followed by regioselective cyanation with allylic boranes, provided nitrile-substituted quaternary carbon

• -catalyzed regioselective hydroalumination of allenes using diisobutylaluminum hydride (DIBAL-H), we envisioned that the nucleophilic attack of allylaluminum reagents on electrophilic cyanating reagents could provide a regioselective pathway for the synthesis of alkyl nitriles bearing quaternary carbon

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• (II) complex of bisTfMePhe have differed significantly. Here, sodium hydride (NaH) was identified as optimal base leading to a yield of 85% when using DMF as solvent at 0 °C to room temperature (Table 2, entry 4). Testing different base equivalents, solvents, solvent mixtures and temperatures didn’t

• ) complex 1 was synthesized according the procedure described by Romoff et al. [16]. Sodium hydride was used as a 60% dispersion in mineral oil. Triethylamine was dried over CaH2 and distilled freshly before use. Perfluorobutanesulfonyl fluoride was dried over CaCl2 and freshly distilled before use. Other

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• transmetalation of organolithium and organoboron compounds, copper hydride catalysis, and enantiotopic-group-selective transformations of 1,1-diborylalkanes. Detailed mechanistic insights into stereochemical control and current challenges in this field are also discussed. Keywords: allylic substitution; chiral

• transfer (TS2). The structural features of the tert-butyl group allow more efficient pyramidalization compared to the rigid adamantyl framework, suggesting that the flexibility of the transferring group plays a crucial role in facilitating transmetalation. Copper hydride chemistry for enantioselective

• allylic substitution reactions Among the various approaches in copper-catalyzed asymmetric allylic substitution, copper hydride (CuH) catalysis has received significant attention due to its unique ability to generate configurationally well-defined chiral organocopper species 28 under mild conditions

Total synthesis of (±)-simonsol C using dearomatization as key reaction under acidic conditions

• Xiao-Yang Bi,
• Xiao-Shuai Yang,
• Shan-Shan Chen,
• Jia-Jun Sui,
• Zhao-Nan Cai,
• Yong-Ming Chuan and
• Hong-Bo Qin

Beilstein J. Org. Chem. 2025, 21, 601–606, doi:10.3762/bjoc.21.47

• DIPEA, affording compound 17 with an 89% yield [11]. For the following alkylation step with tert-butyl bromoacetate, three bases were tested: potassium carbonate, cesium carbonate, and sodium hydride. Considering the targeted alkylation of a phenolic hydroxy group and the pKa requirements of this

• consumption of the starting material. Subsequently, when the base was changed to the stronger base sodium hydride [12], the reaction proceeded much better. Within 2 hours, the starting material was completely converted, yielding compound 18 with 95% isolated yield. Proton abstraction of the hydrogen in the α

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

• motifs such as a benzofuran, indazole, and quinoline were also shown to undergo the desired Markovnikov amidation with high efficiency (23j–l). Several mechanistic experiments were performed to rationalize the reaction pathways. As shown in Figure 7, copper hydride, generated from a copper precatalyst

• the targeted amidated product upon protonation, while simultaneously regenerating the active copper hydride species. 2.2 Hydroamidation of alkynes In 2022, Sato and co-workers introduced a copper-catalyzed hydroamidation of alkynes 25 using dioxazolones 24 as amide sources (Scheme 9) [99]. A

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

• remains a significant challenge owing to the high energy barrier required for oxidative addition and facile β-hydride elimination [12]. The development of radical approaches facilitated by transition-metal catalysis has provided a promising solution to overcome the limitations of conventional coupling

• . First, TEMPO is converted to TEMPO+ through anodic oxidation, and iminium intermediate 15 is created through hydride transfer from THIQ (13) to TEMPO+. TEMPO–H, generated during the hydrogen transfer step, then returns to TEMPO+ through anodic oxidation. Chiral acetylide species 17 is produced from the

• (Figure 15) [70]. In this catalytic system, catalytic amounts of Cu(sBOX) (L3) and Co(salen) complexes promote the formation of chiral nitriles 89 in the presence of PhSiH3 (88) as the hydride source and TMSCN (21) as the cyanide source via the effective sequential addition of a hydrogen atom and a CN

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• intermediate XXXV. Finally, the final product 35 is yielded via a 1,3-hydride shift. The reaction between diazo derivatives, nitriles, and azodicarboxylates catalyzed by Cu(OTf)2 is an efficient synthetic method to obtain 2,3-dihydro-1,2,4-triazole derivatives 36 (Scheme 27) [45]. The reaction proceeds via a

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• reduction can be accomplished via catalytic hydrogenation, involving stepwise reactions and workup, use of additional reagents, and reaction time between 3 and 24 hours [11][12]. Most commonly, metal hydrides are employed, typically lithium aluminum hydride [13][14][15][16][17][18], requiring an inert

• aluminum hydride, sodium borohydride is a non-pyrophoric and easy-to-handle reducing agent. Since the first attempts in 1967, NaBH4 has been employed to reduce β-nitrostyrene scaffolds to the corresponding nitroalkanes [19][20][21]. Several catalysts have been combined with NaBH4 to facilitate full

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• derivatives. Upon abstraction of a hydride from tris(trimethylsilyl)silane (TTMS) by an excited benzophenone derivative, the formed silane radical can undergo a XAT with an alkyl bromide to generate an alkyl radical. Consequently, the alkyl radical undergoes a Giese-type reaction with the Dha derivative

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• and highly reactive BrCCl3 radical anion. Anyway, the N-Ph-THIQ can undergo numerous pathways towards the iminium ion 1a (see reference [28] for details). The oxidation of compound 2d may occur according to the same mechanism. However, alternative mechanisms, such as the direct hydride transfer from

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

• Yukiko Karuo,
• Keita Hirata,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• fluorine-containing building blocks have been developed [21][22][23][24][25]. Jubault and Poisson et al. reported SN2’ reactions of hydride or alcohols to electrophilic fluorine-containing alkenes gave the corresponding fluoroalkenes (Scheme 1B) [21]. In recent years, many fluorine-containing coupling

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• H2 over CO2 becomes crucial for effective CO2 reduction [7]. Additionally, the strength of the interaction between the catalyst and the resulting system after hydride transfer presents a limitation. The formation of a robust LA–oxygen interaction may impede proton transfer to the basic oxygen atom

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

• the DDQH• radical to generate a carbocation and DDQH−. In path B, the reaction involves direct hydride transfer to DDQ, forming DDQH− and a carbocation. In both pathways, the amine nucleophile captures the carbocation, resulting in the final amination product after losing a proton. Subsequently, DDQH

• form a cyclic alkyl radical. The alkyl radical is further oxidized by [Co(III)] to produce the target amination product and a [Co(II)–H] species via direct hydrogen transfer or β-hydride elimination. Deprotonation of [Co(II)–H] by MeO− regenerates the [Co(I)] complex, which is subsequently oxidized

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• carried out for the verification of the intermediate leading to the product 11. Although we initially assumed that the epoxy ring opening occurred by hydride generated through the β-elimination of the n-C10H21MgBr-based cuprate species, the TLC analysis of the reaction mixture did not show any evidence of

• well compares with the one by Alexakis et al. [57]. In their instance, the reaction of t-Bu2CuCNLi2 and cyclohexene oxide afforded a mixture of products in 10 and 50% yields as a result of the epoxy ring opening by t-Bu group and hydride, respectively. Their additional experiment to quench the

• corresponding intermediate by D2O proved that no deuteration occurred. This result clearly indicated that hydride was released from the t-Bu group of the Cu(III) species formed after the nucleophilic attack of the epoxy ring. In our case, since the strongly electron-withdrawing CF3 group would render the rate

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

• abstraction reaction from tin hydride or hydrosilane by radical initiators such as AIBN has effectively been used. When tin and silyl radicals generated in this way are reacted with isocyanides, they are more susceptible to steric hindrance than group 16 or 15 heteroatom radicals due to the greater number of

• radicals abstract hydrogen from the tin hydride or hydrosilane, and the reduction reaction proceeds with the concomitant formation of stannyl or silyl cyanide 15 as byproducts (Scheme 9a) [38][43]. In the presence of acrylonitrile, the formed alkyl radical can add to acrylonitrile, affording the addition

• with alkenyl, alkynyl, aryl, and isocyano groups as unsaturated groups. Intramolecular cyclization of ortho-alkynylaryl- or ortho-alkenylaryl isocyanides Fukuyama et al. reported that the reaction of an aryl isocyanide with an alkenyl group at the ortho-position with tin hydride in the presence of AIBN

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• 93 (Scheme 33) [116]. The presence of two equivalents of sodium hydride deprotonates the acidic α-NH of arylhydrazine, thereby determining the regioselective attack in addition–elimination sequence furnishing a hydrazine enaminone intermediate, and ultimately leading to pyrazole 93 after cyclization

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• -difluoroethylene was based on 1,2-dichloro-1,2-difluoroethane (HCFC-132) [48][49][50][51][52], prepared from 1,1,2,2-tetrachloro-1,2-difluoroethane (CFC-112) by reduction using lithium aluminum hydride [48][49][50][51] or photoreduction (Scheme 2) [51]. The resulting HCFC-132 reacted with zinc [47][49][52] or

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• Scheme 1 compound 6 was treated with isopropyl iodide (7) in DMF in the presence of sodium hydride to provide products 8 and 9 in 38% and 46% yields, respectively. The structures of both compounds were unambiguously assigned using X-ray crystallography and 1H and nuclear Overhauser effect (NOE) NMR

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• sodium hydride, yielding moderate yields (ranging from 23% to 68%). The cyclization initially formed the non-isolated intermediate i, which was oxidized by molecular oxygen from air, introducing the hydroxy group at the α-position of the cyano group. The protocol utilised mild conditions and short

• reported a novel and straightforward method for synthesizing spiro 2,5-dihydrofuran derivatives starting from 17-ethynyl-17-hydroxysteroids such as lynestrenol (38) (Scheme 12) [25]. The 17-hydroxy group of steroids underwent allylation using allyl bromide and sodium hydride. After formation of the alkenyl

• promoted by the action of sodium hydride, alkylation of the morpholine nitrogen atom on 129 provided a diverse range of compounds (Scheme 36). In 2013, the same reaction sequence was reported by Poirier’s group, resulting in a spiromorpholinone at C-3 position derived from epi-ADT that exhibited activity