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

• involvement of a fluorescent intermediate in the cascade synthetic process. Keywords: cascade reactions; copper-catalyzed three-component coupling; gold-mediated 6-endo hydroamination; tandem cyclizations; tetrahydroisoquinoline alkaloids; Introduction The bis-tetrahydroisoquinoline (THIQ) alkaloid family

• modular synthetic strategy involving the cascading assembly of the left THIQ segment. A concise modular synthetic process was developed to construct the substructure 14 of saframycin A (1), featuring copper(I)-catalyzed three-component coupling, and subsequent tandem 2,3-diaminobenzofuran formation

• -fluorobenzene (see Scheme 2 and Supporting Information File 1 for details). Copper(I)-catalyzed three-component coupling reaction of alkyne 8, THIQ 9, and benzaldehyde, proceeded with exquisite control of regioselectivity to afford 10 in an excellent yield of 92% [43][44][45][46]. This efficient cascade

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

• alkyltrifluoroborate into its corresponding alkyl radical. o-Halo-substituted aryl selenides and sulfides 13 can be achieved by a three-component coupling reaction performed with an aryne precursor, potassium halides and electrophilic chalcogen species as reactants, in the presence of Cu(OTf)2 (Scheme 10) [23]. Under

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

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• stoichiometric amount of LiCl was essential for the efficiency of the subsequent three-component coupling with aldehydes and amines. A variety of primary, secondary, and tertiary organozinc reagents as well as secondary amines and aromatic aldehydes could be used for the straightforward preparation of α-branched

• ]. In this context, while significant contributions have highlighted the reliable use of diverse organometallic species in the three-component coupling, most examples of sp3-hybridized compounds have remained restricted to allyl [5] or benzyl [5][6] organometallic reagents. Conversely, examples of

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• organocatalytic enantioselective Hosomi–Sakurai reaction of imines using allyltrimethylsilane was reported by List and co-worker [32]. In this approach, the direct synthesis of Fmoc-protected homoallylic amines 47 was achieved by a three-component coupling of allyltrimethylsilane (46) with the in situ-formed N

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• regarded as stable phosphonium enolate zwitterions. The first zwitterions of this type were published in 1955 [31], but the first crystal structure of a phosphonium enolate zwitterion was reported only in 2007 by Zhu et al., who synthesized the compound via a three-component coupling between an

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

• 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

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• enantioselectivity of the three-component coupling of glyoxylic acid (employed as its solid, easy-to-handle monohydrate) with 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonylamide, and an arylboronic acid was significantly affected by the nature of the boronic acid. Whereas the reaction with phenylboronic acid

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

• derivatization is possible through the oxidation of the silyl motif to alcohol or the dehydration of the aldol adduct. Other tandem conjugate addition/enolate-trapping reactions In 2016, Nishiyama and co-workers have studied a three-component coupling reaction of alkynes, enones, and aldehydes via direct

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

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• studies revealed PEG-200 and K3PO4 as suitable solvent and base, respectively. Aryl halides with electron-donating and electron-withdrawing groups afforded the corresponding products in good yields with 0.15 mmol of catalyst in PEG at 60 °C. A three-component coupling of alkyne with a heterogeneous

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

•  9). In addition to perfluoroalkyl iodides, this protocol was further extended to alkyl halides, trifluoromethylthiolate, amines, cycloketone oxime esters, and carboxylic acid N-hydroxyphthalimide esters (NHPI). In 2018, Peters and Fu [57] explored the copper-catalyzed three-component coupling of

• , 18 (Scheme 10 and Scheme 11). Based on previous mechanistic studies [41], the authors found that the photoexcited ligand–CuI−amido species transferred electrons to alkyl halides to produce alkyl radicals, which reacted with alkenes and amines to generate the three-component coupling products. In the

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• , ketones and silanes were also found to be compatible to give the desired three-component coupling products. Similarly, the scope of aryl bromides 3 and alkenes 92 were found to be broad. A possible catalytic cycle was proposed to account for the mechanism of the reaction (Figure 22) [140]. Photoexcited

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

Copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters with chiral phenol–carbene ligands

• Shohei Mimura,
• Sho Mizushima,
• Yohei Shimizu and
• Masaya Sawamura

Beilstein J. Org. Chem. 2020, 16, 537–543, doi:10.3762/bjoc.16.50

• plays crucial roles in both the catalytic activity and stereoselectivity [19][20][21]. Notably, these catalyst systems were also applicable for three-component coupling reactions using hydrosilanes as hydride reagents [17]. Based on this knowledge, we decided to investigate the effects of the phenol–NHC

Synthesis of triphenylene-fused phosphole oxides via C–H functionalizations

• Md. Shafiqur Rahman and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2020, 16, 524–529, doi:10.3762/bjoc.16.48

• through two distinct C–H functionalization reactions as key steps. The phosphole ring was constructed by a three-component coupling of 3-(methoxymethoxy)phenylzinc chloride, an alkyne, and dichlorophenylphosphine, involving the regioselective C–H activation of the C2 position of the arylzinc intermediate

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

• Thomas J. Cogswell,
• Craig S. Donald and
• Rodolfo Marquez

Beilstein J. Org. Chem. 2020, 16, 135–139, doi:10.3762/bjoc.16.15

• , three component coupling. Optimized conditions for the synthesis of diene 5. Ring-closing metathesis reaction of diene 5 to yield dihydropyridone 7 [20][21][22][23]. Total synthesis of aza-goniothalamin 1. Supporting Information Supporting Information File 218: Experimental, characterization data and

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• protocol also provided a concise route for the synthesis of the antiulcer drug zolimidine in 95% yield. A three-component coupling reaction (3-CCR) for the synthesis of N-fused pyridines was reported by Balijapalli and Iyer [40]. The reaction was catalyzed by CuO/CuAl2O4 and ᴅ-glucose. The reaction had

• have commercial value since it is a good synthetic procedure for the synthesis of the drugs saripidem and necopidem in 62% and 59% yields, respectively. Cu supported on Zinc aluminate (ZnAl2O4) was unprecedentedly used for the three-component coupling reaction of aromatic aldehydes, 2-AP and

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• pyrrolo[1,2-a]indoles by sodium ethoxide-promoted cyclization. The three-component coupling also becomes viable through a Co(III)-catalyzed hydroarylation strategy as Ellman and co-workers demonstrated (Scheme 39) [99]. The reaction of arene 21 with vinyl ketones and aldehydes in the presence of [CoCp

• )-catalyzed hydroarylation of imines with arenes. Co(III)-catalyzed addition of arenes to ketenimines. Co(III)-catalyzed three-component coupling. Co(III)-catalyzed hydroarylation of aldehydes. Co(III)-catalyzed addition of arenes to isocyanates. Acknowledgements We thank the Ministry of Science and

Three-component coupling of aryl iodides, allenes, and aldehydes catalyzed by a Co/Cr-hybrid catalyst

• Kimihiro Komeyama,
• Shunsuke Sakiyama,
• Kento Iwashita,
• Itaru Osaka and
• Ken Takaki

Beilstein J. Org. Chem. 2018, 14, 1413–1420, doi:10.3762/bjoc.14.118

• Kimihiro Komeyama Shunsuke Sakiyama Kento Iwashita Itaru Osaka Ken Takaki Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, 1-4-1 Higashi-Hiroshima City 739-8527, Japan 10.3762/bjoc.14.118 Abstract The cobalt/chromium-catalyzed three-component coupling of aryl

• , whereas the chromium salt generates highly nucleophilic allylchromium intermediates from allylcobalt species, without the loss of stereochemical information, to allow the addition to aldehydes. Keywords: chromium; cobalt; diastereoselective; homoallyl alcohols; hybrid catalyst; three-component coupling

• three-component coupling method is herein reported for the direct synthesis of highly diastereoselective multi-substituted homoallyl alcohols employing a cobalt/chromium hybrid catalyst (Scheme 5). Results and Discussion Initially, suitable reaction conditions were investigated for the three-component

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• shows the five possible [2 + 2 + 1] (designated as “A” strategies) and five possible [3 + 1 + 1] (designated as “B” strategies) target bond dissection maps for constructing this ring via three-component coupling strategies. Schemes 4 to 6 show literature examples of how this ring was made according to

• order to complete the ligation to the five-membered pyrazole ring. A literature search revealed that there were no documented examples of the A2, A3, B1, B2, B3, and B5 strategies, which indicates that the chemical space for three-component coupling reactions to pyrazole has not yet been fully explored

• pharmaceuticals (three to twelve-membered). Target bond dissection maps based on 3-partitions have been applied to syntheses of cyclohexanone, pyrazole, and the Biginelli adduct to identify potentially new three-component coupling reactions for their synthesis. These conjectured reactions were examined for their

Bridgehead vicinal diallylation of norbornene derivatives and extension to propellane derivatives via ring-closing metathesis

• Sambasivarao Kotha and
• Rama Gunta

Beilstein J. Org. Chem. 2016, 12, 1877–1883, doi:10.3762/bjoc.12.177

• stereocontrolled manner in a single step is not a trivial exercise. Generally, it was accomplished by radical three-component coupling reactions or Michael-type additions of organocopper reagents starting with conjugated carbonyl compounds [33][34]. But, the resulting alkyl groups are in trans orientation. Our

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

• Bo Yang,
• Chuanye Tao,
• Taofeng Shao,
• Jianxian Gong and
• Chao Che

Beilstein J. Org. Chem. 2016, 12, 1487–1492, doi:10.3762/bjoc.12.145

• -component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke–Blackburn–Bienaymé

A convergent, umpoled synthesis of 2-(1-amidoalkyl)pyridines

• Tarn C. Johnson and
• Stephen P. Marsden

Beilstein J. Org. Chem. 2016, 12, 1–4, doi:10.3762/bjoc.12.1

• expensive bespoke ligands, based upon the electrophilic activation of pyridine N-oxides and subsequent reaction with acidic carbon nucleophiles [16][17][18][19][20]. Specifically, we have demonstrated that α-pyridyl,α-alkylamino acid derivatives can be prepared in a one-pot three component coupling between

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• lower. Recently, a new entry to isoquinolinium ions has been established. In their studies of the three-component coupling of aldehydes, amines, and alkynes (A3 reaction), the Ma group serendipitiously discovered that isomerization of exocyclic iminium ion 30 results in the formation of endocyclic

• -component coupling of pyridine, benzoyl chloride and phenylacetylene [27], the Arndtsen group tackled the challenge of developing a catalyst for the alkynylation of cyclic N-acyliminium ions with unactivated alkynes [28]. Using the reaction of N-acylquinoline and phenylacetylene as their model, they

• –77%), but poor enantioselectivities (1–11% ee). However, the use of activated acetylenes provides a functional group handle for elaboration, which the authors demonstrate in the preparation of indolizidine 223AB. Building on their initial discovery of a non-asymmetric, copper-catalyzed, three