Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• conditions, we proceeded to investigate the generality of this Cu-catalyzed system. Initially, a series of anilines bearing diverse substituents was examined, and the results are summarized in Scheme 2. When copper(II) trifluoroacetate was employed as the catalyst, para-halogen-substituted anilines 1b–e

• cyclopentanone oxime (2f), cyclohexanone oxime (2g), or azetidinone oxime (2h) were employed as alternative substrates to cyclobutanone oxime, the corresponding spirotetrahydroquinoline products were not observed. To showcase the practical utility of our Cu-catalyzed spirotetrahydroquinoline formation process

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

• stoichiometric quantities of a copper reagent [3]. This pioneering work, known as the “classical Ullmann reaction”, was extended by Ullmann and Goldberg to enable the C–N and C–O bond formation [4][5][6]. Subsequently, key developments in Cu-catalyzed cross-coupling reactions were achieved, including the

• ], however, no comprehensive review focusing on Cu-catalyzed electrochemistry has been reported to date. Copper catalysts are potential candidates for pharmaceutical applications owing to their abundance, low cost, and lower toxicity compared with noble transition metals such as palladium [39]. In terms of

• catalysis to organic synthesis, focusing on recent developments in Cu-catalyzed electrochemical reaction categorized into four types: 1) C–H functionalization, 2) olefin addition, 3) decarboxylative functionalization, and 4) coupling reactions (Figure 3). This review aims to provide insight into the

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , 98160, México 10.3762/bjoc.20.256 Abstract A series of 1,5-disubstituted tetrazole-indole hybrids were synthesized via a high-order multicomponent reaction consisting of an Ugi-azide/Pd/Cu-catalyzed hetero-annulation cascade sequence. This operationally simple one-pot protocol allowed high bond-forming

• synthesis of a novel bis-heterocyclic hybrid, 1,5-disubstituted-tetrazole-indoles. The compounds were achieved through a high-order multicomponent reaction consisting of two sequential processes: an Ugi-azide reaction and a further Pd/Cu-catalyzed heteroannulation (Scheme 1d). Results and Discussion Our

• -heterocyclic system [23], involves a two-step sequence starting with an Ugi-azide multicomponent reaction, followed by a Pd/Cu-catalyzed heteroannulation process, as depicted in Scheme 2. Conditions for the Ugi-azide reaction were optimized based on our recent findings, i.e., the reaction was performed in

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

• in Kwon’s review [34]. Cu-catalyzed oxygen atom transfer with TBHP were discussed in the review [35]. The review by Xiao considered visible light-driven C–C bond cleavage enabled with organic peroxides [36]. This comprehensive review summarizes all ever published studies on radical peroxidation with

• intermediate D and on to product 95. Difunctionalization of unsaturated С–С bonds with ROO fragment With C-containing second component Alkyl fragment: The first example of the alkylation–peroxidation of C=C double bonds using TBHP and C–H as partner has been reported in 1995 on the example of Cu-catalyzed

• aid of the ortho-directing group to give the palladium intermediate B, which undergoes reductive elimination to establish the C−C bond. A Cu-catalyzed difunctionalization of styrenes 211 with TBHP and N-hydroxyphthalimide (NHPI) (212) as sources of O-functional groups was reported (Scheme 66) [135

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• –heteroatom bonds vicinal to alkenyl or alkynyl groups, which are highly valuable for downstream synthesis. At present, unstabilized nucleophiles [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] are commonly used in Cu-catalyzed allylic substitutions because of the inner-sphere

• mechanism and relatively harsh reaction conditions such as anhydrous, anaerobic, and low temperatures are usually required (Scheme 1a). Therefore, using stabilized nucleophiles in Cu-catalyzed allylic substitutions is a tremendous challenge. On the other hand, since the pioneering work of van Maarseveen [52

• ] and Nishibayashi [53] groups in 2008, Cu-catalyzed asymmetric propargylic substitutions have made significant progress [54][55][56][57][58][59][60]. The protocol allows the use of stabilized nucleophiles via the outer-sphere mechanism, and the copper allenylidene intermediate formed by copper and

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• bearing an affinity or reporter tag. To carry out this bioorthogonal reaction well-known chemistries were developed including traceless Staudinger ligation, Cu-catalyzed azide–alkyne cycloaddition (CuAAC), strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron-demand Diels–Alder reaction

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• are not always readily accessible. Typically, the preparation methods involve SNAr reactions with N-centered nucleophiles [5], nitroarene reduction [6] and transition metal (e.g., Pd, Cu)-catalyzed C–N cross coupling of aryl halides, aryl sulfonates or arylboronic acid reagents with ammonia or NH

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• hexaketocyclohexane octahydrate as the CO source again. This cyclic hexaketone is a non-toxic stable solid and therefore, it is simple and safe to use unlike of carbon monoxide. It was used as reagent to obtain indol-α-ketoesters by the Cu-catalyzed direct double-carbonylation of indoles and alcohols [76]. The

• -3-yl aryl ketones reported by Zhao and co-workers [73] (path a) and Zhang and co-workers [74] (path b). Pd-catalyzed carbonylative synthesis of BIMs from aryl iodides and N-substituted and NH-free indoles with of TFBen as CO source. Cu-catalyzed direct double-carbonylation and monocarbonylation of

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• Suzuki–Miyaura and Sonogashira couplings on 4aa or 4ba afforded the desired products 5 and 6 in 47% and 74% yields, respectively. In the former case, the C–Br bond on the pyrazole moiety remained intact, highlighting the superior leaving group ability of the BX group. Cu-catalyzed Ullmann coupling

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

• substrate and participating in the key bond-forming/breaking steps via substrate–TM interactions [73][74]. This paradigm has been employed in the activation of NHPI esters under photoinduced copper (Cu) and palladium (Pd) catalysis. In 2017, Peters and Fu reported a Cu-catalyzed decarboxylative C(sp3)–N

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• example, Wan and co-workers developed a cascade reaction of α-diazo esters, nitriles, and carboxylic acids via the generation of nitrile ylides and Mumm rearrangement affording unsymmetric diacyl α-amino acid esters as products (Scheme 1a) [39]. In 2017, Zhang, Hu, and co-workers developed a Cu-catalyzed

• , 76–86% yields) provided better chemical yields in this reaction compared with those containing electron-donating groups (4b–e, 31–84% yields). For the case with a strong electron-donating group (methoxy, 3g) only traces of 4g were produced. Besides benzoic acid, the current Cu-catalyzed reaction was

• ][40][41][58][59], a possible mechanism for this Cu-catalyzed reaction of β-trifluoromethyl β-amino esters was proposed in Scheme 4. Initially, β-trifluoromethyl β-amino ester 1a reacts with tert-butyl nitrite to form trifluoromethylated β-carbonyl diazo intermediate A. Then, the diazo intermediate A

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• under the catalysis of AcOH at 110 °C for 6 h afforded the monocycloaddition product 19a in 93% LC yield [71]. The isolated compound 19a was used for an N-propargylation to produce compound 20a in 94% LC yield. The following Cu-catalyzed click reaction afforded triazolobenzodiazepine 21a in 88% LC yield

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• site-selective NHC–Cu-catalyzed hydroboration of enantiomerically enriched allenes and conversion to the corresponding β-vinyl ketones demonstrates the importance of the strategy. An example is shown below (Scheme 44). 2.2.4 Reaction with organozinc reagents: Organozinc reagents, such as diethylzinc

• heterocyclic compounds with CO2 resulting in higher yields than those obtained with the imidazolylidene carbene ligand, IPr (Scheme 70). 2.7 C(sp2)–H Alkenylation and allylation In 2016, Chang and co-worker [93] achieved an NHCs–Cu-catalyzed efficient C(sp2)–H allylation of polyfluoroarenes 183 and

• conversion occurred using either Pd–NHC or Cu–NHC alone. 2.9 C(sp2)–H amidation Chang and co-workers [96] reported an NHC–Cu-catalyzed direct amidation of C–H bonds by using N-chlorocarbamates or N-chloro-N-sodiocarbamates as amino source. In this mechanism, a copper–aryl intermediate reacts with the

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

• . 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

• Cu-catalyzed oxidative coupling reactions [43]. However, due to complex mechanisms, Cu-catalyzed C–H functionalization reactions developed only slowly in the last decade. Since recently the Cu-catalyzed oxidative coupling has emerged as a powerful synthetic strategy due to the development of CDC

• triggers the whole coupling reaction. The potential application of NHIP as a catalyst for oxidative coupling reactions with oxygen as a terminal oxidant was explored. In 2011, Garcia-Mancheño et al. developed a Cu-catalyzed CDC of cyclic benzyl ethers 10 with aliphatic or α,β-unsaturated aldehydes 13 or 14

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• construction of stereogenic centers using polar organometallics [1]. In this way, 1,4-additions of typical organometallics such as dialkylzinc, Grignard reagents, and trialkylaluminum have been developed [2][3][4][5][6][7][8][9]. Recently, also Cu-catalyzed conjugate additions of organozirconium [10][11] or

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

• . Except lately, in 2020, Chen and group [82] reported a Pd/Cu-catalyzed regio- and stereoselective synthesis of C2-alkenylated pyridines starting from internal alkynes 84 and pyridinium salts in a stereodivergent manner (Scheme 17a). The interesting part of this work was the switching of the alkene

• organoboron coupling partners, Wu and co-workers [91] reported a protocol for the Cu-catalyzed C–H arylation of pyridine N-oxides 9 with arylboronic esters 114 and prepared C2-arylated pyridines 115 in moderate to good yields (Scheme 22). By using an inexpensive Cu catalyst, the method allows for the simple

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

• azetidines 19 were also synthesized using this methodology (Scheme 5b). Nitronate anions were also found suitable for Mannich-type trapping reactions [28][29]. Anderson and co-workers accomplished several Cu-catalyzed conjugate additions of R2Zn to nitroolefins 20, followed by subsequent reaction with p

• asymmetric conjugate addition. The magnesium enolates 56 then participated in a copper(II)-mediated intramolecular oxidative coupling to afford benzofused spirocyclic cycloalkanones 57 (Scheme 14) [45]. Our team became interested in domino reactions of metal enolates generated by Cu-catalyzed asymmetric

• participated in the Cu-catalyzed homoconjugate addition of Grignard reagents and subsequent enolate trapping to give densely functionalized cyclobutanes 77 with high diastereoselectivity (Scheme 20). The enolates were alkylated, allylated, benzylated, benzoylated, and thienylated. Minnaard and co-workers

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• final ring-opened adduct 37. Copper-catalyzed reactions In 2009, Pineschi and co-workers explored the Cu-catalyzed rearrangement/allylic alkylation of 2,3-diazabicyclo[2.2.1]heptenes 47 with Grignard reagents 48 (Scheme 8) [41]. The reaction is thought to proceed via the Lewis acid-catalyzed [3,4

• success of the reaction, hypothesizing it inhibited the classical [3,3]-sigmatropic Lewis acid-catalyzed rearrangement often observed. Both alkyl and aryl Grignard reagents were amenable to the reaction; however, heteroaryl Grignard reagents resulted in poor conversion. The Cu-catalyzed borylative

• intercepted by an electrophile to generate the difunctionalized system. This methodology has been applied several times to strained bicyclic alkenes with a variety of electrophiles. In 2015, Hirano and Miura developed a Cu-catalyzed aminoboration of bicyclic alkenes 1 with bis(pinacolato)diboron (B2pin2) (53

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• (TBTA) was also added as an additive to increase the yield of triazoloporphyrins 103a,b. When TBTA, a tertiary amine with a 1,2,3-triazole ring, is added to a Cu-catalyzed click reaction, it forms a complex to stabilize the Cu(I) oxidation state and speeds up the reaction. Further, these 1,2,3-triazole

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• radical cyclization of an alkynyl ketone as the key step. The synthesis started by a Cu-catalyzed conjugate addition of the vinyl Grignard reagent, followed by TMS α-propargylation under basic conditions, affording the TMS-alkynyl ketone 76 as the major diastereomer (Scheme 11). Originally a Au-catalyzed

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• on the SiMe(OSiMe3)2 unit, which were readily converted through Pd- or Cu-catalyzed electrophilic substitution reactions into an array of furfurals decorated at C3 with carbon- or heteroatom-containing substituents (Scheme 1). Conversely, all of our subsequent efforts to achieve cross-coupling

• activation by alkoxides did not prove useful, C3–Si bond functionalization is achieved from benzyldimethylsilyl units upon siloxane formation in the presence of TBAF. Protocols for fluoride-promoted Pd/Cu-catalyzed arylation, as well as Cu-catalyzed allylation and methylation, have been developed. Overall

• reduced pressure. and purified by silica gel column chromatography. Procedure for the Pd/Cu-catalyzed arylation of C3-benzyldimethylsilyl-substituted 2-furyl carbinol 4c (preparation of compounds 18 and 19) A flame-dried Schlenk tube was charged with CuI (20 mol %) and Pd2(dba)3 (2.5 mol %) and heated

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes

• Mio Matsumura,
• Kaho Tsukada,
• Kiwa Sugimoto,
• Yuki Murata and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 863–871, doi:10.3762/bjoc.18.87

• their applications in the biological and pharmaceutical fields. The Cu-catalyzed tandem reaction for the synthesis of novel alkynyl imidazopyridinyl selenides is presented. A one-pot synthesis route afforded alkynyl imidazopyridinyl selenides in moderate to good yields. This was achieved by a two-step

• attention [15][19][20][21][22][23][24][25][26]. This method involves a transition-metal-catalyzed one-pot, three-component reaction in which two functional groups are simultaneously introduced on the Se atom via double selenation. As examples, the following Cu-catalyzed one-pot reactions have been reported

• with an imidazo[1,2-a]pyridine ring, this study focused on the Cu-catalyzed one-pot C(sp2)–Se and C(sp)–Se bond formation for the synthesis of novel alkynyl imidazopyridinyl selenides using Se powder, 2-arylimidazo[1,2-a]pyridines, and terminal alkynes. Results and Discussion Synthesis of alkynyl

Continuous flow synthesis of azobenzenes via Baeyer–Mills reaction

• Jan H. Griwatz,
• Anne Kunz and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2022, 18, 781–787, doi:10.3762/bjoc.18.78

• reliable synthesis of symmetric ABs in high yields via a Cu-catalyzed oxidative coupling of aniline derivatives [17]. This synthesis can be also used for the formation of non-symmetric AB, however, only for a selected set of anilines. One of the most applied methods to access non-symmetric azobenzenes is

• , which can lead to higher yields and purity [22]. Flow chemistry to prepare azobenzenes has been previously applied to the Cu-catalyzed synthesis of symmetric substituted AB derivatives [23][24]. However, non-symmetric substituted ABs are not accessible by this method in an efficient way. Herein, we

Direct C–H amination reactions of arenes with N-hydroxyphthalimides catalyzed by cuprous bromide

• Dongming Zhang,
• Bin Lv,
• Pan Gao,
• Xiaodong Jia and
• Yu Yuan

Beilstein J. Org. Chem. 2022, 18, 647–652, doi:10.3762/bjoc.18.65

• Dongming Zhang Bin Lv Pan Gao Xiaodong Jia Yu Yuan College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. of China 10.3762/bjoc.18.65 Abstract An efficient Cu-catalyzed strategy for the direct C–H amination of arenes in high yields using N-hydroxyphthalimide as

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• oxindoles [7][8][9][10][11] and also of aminoboronic acids [12], we recently exploited a molecular hybridization strategy to synthesize chiral oxindole-based β-aminoboronic acids and spiro derivatives [13]. Apart from our work and a quite recent report describing a useful Cu-catalyzed enantioselective