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

• Cu-catalyzed electrochemical C–H activation strategy through C–H alkynylation of arylamides followed by electrooxidative cascade annulation (Figure 4) [48]. This reaction enables sustainable C–H functionalization by utilizing electricity as the terminal oxidant instead of stoichiometric amounts of

• desired annulation products. Moreover, the same products were generated using alkynyl carboxylic acids instead of terminal alkynes via decarboxylative C–H alkynylation and annulation. Cyclic voltammetry (CV) studies exhibited an oxidative current at 0.95 V vs SCE in the presence of the Cu(II) salt, base

• enantioselective C–H alkynylation of ferrocene carboxamides with terminal alkynes by using Cu/BINOL and an electrocatalytic system (Figure 5) [49]. 8-Aminoquinoline-assisted C–H functionalization provided planar chiral ferrocenes with high yield and enantioselectivity. This reaction can be applied to a wide range

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

• ]. Three-component coupling of amines, aldehydes or ketones, and terminal alkynes catalyzed by Cu(OTf)2 is a fruitful tool for the production of α-substituted propargylamines 10 (Scheme 7) [20]. The reaction involves the alkynylation of the corresponding imines formed in situ and provides higher yields

• the coupling with copper triflate as catalyst, without ligand, co-catalyst or other additives. The reaction involved the formation of the imine XVII followed by alkynylation to propargylamine XVIII, cyclization, and oxidation to quinoline 23 (Scheme 17) [34]. Three component oxidative annulation to

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• transformations of biomolecules, such as thiol–yne reaction and decarboxylative alkynylation. The thiol–yne reaction of cyclohexanethiol (90) with phenylacetylene (89) in the presence of 1 mol % of H2TPP (18) under red LED irradiation provided the desired product 91 in up to 85% yield while the decarboxylative

• alkynylation reaction of N-hydroxyphthalimide esters (NHPI) 92 with alkynyl p-tolylsulfones 93 in the presence of H2TPP (18) resulted in 44–93% yields depending on the substituents (Figure 17b and c). Furthermore, the authors approved the biological application of porphyrin photoredox catalysts by using them

• in red light-induced C–X-bond formation on biologically relevant molecules 95–97, based on a thiol–yne reaction and decarboxylative alkynylation protocol (Figure 17d). Last year, Moyano and colleagues reported on amino-functionalized porphyrins as bifunctional organophotocatalysts, effectively

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

• include arylation, iodination, alkynylation, thiophenolation, amination, and esterification, were carried out. Among these reactions, esterification was achieved in moderate yield under metal-free conditions by reacting the synthesized naproxen methyl ester (2-methoxyphenyl)iodonium

• bis(4-methoxyphenyl)iodonium diacetate (70) or ArI(OH)OTs highly regioselective gemfibrozil methyl ester derived iodonium salts 71 were obtained in moderate to good yield. These salts were then used for various modifications like alkynylation, arylation, esterification, etherification, fluorination

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

• -carbon alkynoyl building blocks [121][122] could be generated catalytically [123], thereby facilitating reactions under mild reaction conditions and opening novel one-pot pathways for consecutive multicomponent syntheses of pyrazoles. Sonogashira alkynylation of terminal alkynes and (hetero)aroyl

• palladium-catalyzed oxidative carbonylative Sonogashira alkynylation and cyclocondensation with arylhydrazines [144]. In 2009, Müller and co-workers introduced an alternative approach for synthesizing alkynones through a one-pot process [145]. Azulen-3-ylalkynones 126, obtained by glyoxylation of azulene

• isolated. However, attempts to carry out the cyclization with phenylhydrazine, Boc-hydrazine, or hydrazine hydrate failed. Alternatively, alkynylation can be achieved through copper catalysis. Glyoxylation of N-methylindole with oxalyl chloride and subsequent Stephens–Castro coupling with phenylacetylene

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

• (110a and 110b, respectively). These protected compounds were subjected to alkynylation using 4-THPO-1-butyne on the carbonyl group at C-17, yielding steroids 111. Subsequent catalytic hydrogenation of the triple bonds, followed by deprotection of the alcohols from their THP ether groups and oxidation

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• discovery and development of the synthesis of homopropargylic azides by the azido-alkynylation of alkenes. Initially, a strategy involving SOMOphilic alkynes was adopted, but only resulted in a 29% yield of the desired product. By switching to a radical-polar crossover approach and after optimization, a

• terminal azide, despite its implication in the synthesis of complex molecules [3][6]. Therefore, the development of a straightforward reaction to synthesize homopropargylic azides would be of general interest. The azido-alkynylation of alkenes would allow to generate the desired motif in a single step

• the development of the azidobenziodazolone scaffold [17]. This class of derivative showed an improved safety profile while retaining the redox properties of the original reagent. A single example of azido-alkynylation has been reported by Ramasastry and co-workers during a mechanistic study for an

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

• ), alkynylation [88] (Scheme 24C) and C(sp3)–C(sp3) cross-coupling [89] (Scheme 24D). Finally, similar chemistry has been extended to the decarboxylative borylation of RAEs under Ni [90] and Cu [91] catalysis (Scheme 24E). Importantly, the Wang group has independently studied the decarboxylative Negishi coupling

• of RAEs with organozinc reagents under Co-catalysis, effecting diverse arylation, alkenylation, and alkynylation reactions [92]. The second type of reaction is referred to as cross-electrophile coupling and involves the Ni-catalyzed reaction of NHPI esters with aryl- and vinyl halides under reducing

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• acetaldehyde dimethyl acetal as a masked form of acetaldehyde, which is hydrolyzed in situ, allowing for a higher product yield and fewer byproducts [15]. The group of Müller describes an elegant consecutive four-component reaction involving an alkynylation–cyclization–iodination–alkylation sequence toward

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• generated by a consecutive four-component reaction starting from ortho-haloanilines, terminal alkynes, N-iodosuccinimide, and alkyl halides in yields of 11–69%. Initiated by a copper-free alkynylation, followed by a base-catalyzed cyclizive indole formation, electrophilic iodination, and finally

• state, in good yield. Keywords: alkynylation; catalysis; cyclization; indoles; iodination; multicomponent reactions; Introduction Indoles and their derived substitution patterns are omnipresent heterocyclic structural motifs in nature [1], many natural products [2][3], drugs [4][5][6][7][8], and dyes

• transition-metal catalysis [31], we disclosed an activating group-free alkynylation–cyclization sequence to (aza)indoles [32][33] that could be readily concatenated with a concluding N-alkylation of the 7-azaindole intermediate in the sense of consecutive three-component coupling–cyclization–alkylation

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• oligomers 5 can be synthesized by a Glaser oxidative dimerization of monomers 6 (Scheme 1). The obvious route for the synthesis of the latter is the sequential alkynylation of 2,7-diiodonaphthalene 8. In accordance with this strategy, diiodide 8 was cross-coupled with copper(I) arylacetylides (Castro

• –Stephens reaction, method A) and arylacetylenes (Sonogashira reaction, method B). In all cases, even when using a small excess of 8, in addition to the desired monoalkynyl derivative 7, a double alkynylation product 9 was formed (Table 1). The Sonogashira coupling was somewhat more efficient, yielding

• compounds 7a–e in 42–62% yields, but also gave higher amounts of products 9a–e (10–30%). Thus, the Pd- and phosphine-free Castro–Stephens coupling was a good enough alternative to synthesize alkynes 7. The structure of the double alkynylation product 9e was confirmed by X-ray diffraction data (see

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• ferrocene ligands. All types of metal enolates generated via these processes were able to react with Michael acceptors and afforded the corresponding products in good yields. The alkynylation of enolates generated by conjugate addition was described by Teodoro and Silva (Scheme 32) [68]. Even though the

• conjugate addition of trialkylaluminum or Grignard reagents was realized only in an achiral manner, this work merits discussion here. Aluminum and magnesium enolates were alkynylated with ethynylbenziodoxolone (EBX). This diastereoselective electrophilic alkynylation afforded the corresponding α

• conjugate alkynylation and consecutive aldol addition (Scheme 49) [91]. The chiral ruthenium complex C2 (Phebox-type)-catalyzed procedure delivered β-hydroxyketone derivatives 192 having α-propargyl groups in good yields, however, only with low diastereoselectivities (up to 3:1). While the syn-diastereomers

Earth-abundant 3d transition metals on the rise in catalysis

• Nikolaos Kaplaneris and
• Lutz Ackermann

Beilstein J. Org. Chem. 2022, 18, 86–88, doi:10.3762/bjoc.18.8

• allow for indirected C–H transformations and herein, homolytic C–H cleavages are described for transformative manganese-catalyzed brominations of tertiary C–H bonds [14]. Finally, electrooxidation enabled the site-selective alkynylation of tetrahydroisoquinolines within a TEMPO/copper regime [15]. As

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• involving the addition of arylamines to β-NQS 18 followed by N-alkynylation and then Cu(I)-catalyzed heterocyclization with tosyl azide in toluene at room temperature, leading to triazoles 50c–k in moderate to excellent yields (Scheme 14). The research group that most explored the formation of heterocycles

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• electrochemical microreactors can be a viable tool for developing efficient transition-metal electrocatalysis. C(sp3)–H alkynylation of tetrahydroisoquinolines. L* = chiral ligand. TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. BPO = benzoyl peroxide. Substrate

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

• photophysical properties (Scheme 16). In 2019, Vlla’s group [76] explored the copper-catalyzed alkynylation of dihydroquinoxalin-2-ones 34 with terminal alkynes under irradiation. 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one 35 was subjected to an oxidation process with a CuII salt to generate a nitrogen radical

• ). In 2020, Zhang’s group [77] described the photoinduced copper-catalyzed decarboxylative alkynylation of redox-active esters with terminal alkynes. N-Hydroxy-tetrachlorophthalimide (TCNHPI, 36) derived from carboxylic acids was identified as the ideal radical precursor. Under irradiation, the CuI

• the alkyl radical and underwent reductive elimination to deliver the desired product. Liu’s group [78] further applied this protocol to the asymmetric decarboxylative alkynylation of N-hydroxy 2,3-naphthalimide-derived ester 37 with terminal alkynes. Remarkably, the N-hydroxy 2,3-naphthalimide-derived

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• , alkynylation, boronization, phosphorization, etc); ii) discovery of new transformations of 1,3-enynes to other N-heterocycles; and iii) more extensive investigations into the mechanism. Ag/I2-mediated electrophilic annulation of 2-en-4-ynyl azides 1. The proposed mechanism of Ag-catalyzed aza-annulation. The

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

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

• selectivity, which is observed at the more electron-rich and the less sterically hindered position. Manganese-catalyzed late-stage C–H alkynylation Alkynes are invaluable intermediates in organic synthesis and are conventionally prepared via palladium-catalyzed cross-coupling reactions [62]. Moreover, they

• alkynylations of bioactive structural motifs are rare [63]. In 2017, the Ackermann group disclosed a late-stage Mn(I)-catalyzed C–H alkynylation of various complex peptide scaffolds [64]. As shown in Scheme 9, manganese(I) catalysis remarkably resulted in racemization-free alkynylation, representing a step

• alkynylation. Mn-catalyzed late-stage fluorination of sclareolide (1) and complex steroid 3. Late-stage radiofluorination of biologically active complex molecules. Late-stage C–H azidation of bioactive molecules. a1.5 mol % of Mn(TMP)Cl (5) was used. bMethyl acetate was used as a solvent. cThe ratio of α/β

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

• 134 were used as starting material in the Sonogashira and Suzuki reactions. The Sonogashira−Hagihara cross-coupling led to alkynylation at position 5 of the triazole ring in the presence of CuI and Pd(PPh3)4 as catalytic system as well as K3PO4 as base in THF as solvent at 65 °C. However, the Suzuki

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

• Institute for Sustainable Chemistry (WISCh), Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany 10.3762/bjoc.17.113 Abstract The efficient copper-mediated oxidative C–H alkynylation of benzhydrazides was accomplished with terminal alkynes. Thus, a heteroaromatic removable N-2

• context, You [25], Huang [26], Liu [27], Li [28], and co-workers elegantly disclosed copper-mediated/catalyzed cascade C−H alkynylation and annulation with terminal alkynes to afford 3-methyleneisoindolinone derivatives, through the assistance of 8-aminoquinoline [29] or 2-aminophenyl-1H-pyrazole [30

• ] auxiliaries (Figure 1a). Besides, the cobalt(II)- [31] or nickel(II)-catalyzed [32][33], pyridine oxide (PyO)-directed tandem alkynylation/annulation was realized by Niu and Song et al., which also provided the 3-methyleneisoindolin-1-one scaffolds (Figure 1b). Notably, a sustainable cupraelectro-catalyzed

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

• trifluoromethyl alkynylation product 84 with alkynyl sulfone 83, alkene 81, and Togni reagent 82 as substrates catalyzed by 2,4,6-trimethylpyridine (TMP). The EDA complex formed by electron donor TMP and electron acceptor Togni reagent 82 facilitated electron transfer, yielding trifluoromethyl radical to initiate

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• alkynylation of cyclopropanes 161 with terminal alkynes that led to the formation of the isomeric fluorinated enynes 164 and 165. Shortly before, a Pd-catalyzed ring-opening sulfonylation of gem-difluorocyclopropanes with the formation of 2-fluoroallylic sulfones 166 has been reported (Scheme 71) [122]. The

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• developed by the authors conferred an excellent methodology to obtain the 9-azabicyclo[3.3.1]nonane ring present in (±)-euphococcinine (2). Kibayashi synthesis – 2002 Kibayashi et al. performed the enantioselective synthesis of (−)-adaline (1). Their approach had as key steps SN2-type alkynylation

• . After the treatment of (−)-46 with the lithium acetylide ethylenediamine complex in THF, a nucleophilic alkynylation occurred, with a reversal of configuration in the reaction center. Then, removal of the 1-(2-hydroxyphenyl)ethyl group via cleavage of the C–N bond, leading to (6S)-ethynylpiperidine

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• epoxidation [37] of 5-methyl-2-methylene-4-penten-1-ol gave the epoxyalcohol 92 in 94% ee, which was oxidized to the aldehyde 93. While the addition of the lithium salt of methyl propynoate proceeded in a nondiastereoselective fashion, the use of a zirconium/silver-mediated alkynylation gave the alcohol 94