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

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

• 1,2,3-triazoles through multicomponent reactions and the relevant mechanistic aspects have been surveyed by Chen, Ren, et al. [27]. The 1,3-dipolar cycloaddition reaction between azides and alkynes is the most efficient pathway for the preparation of disubstituted 1,2,3-triazole derivatives. The copper

• -catalyzed azide–alkyne cycloaddition (CuAAC) for the synthesis of 1,4-disubstituted 1,2,3-triazole derivatives was initially discovered by the groups of Meldal and Sharpless. Then, Ru-catalyzed azide–alkyne cycloaddition (RuAAC), affording selectively 1,5-disubstituted 1,2,3-triazoles, was introduced [38

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• -ethynylpyrene (40) under copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction conditions to yield the double-headed nucleoside 41 (Scheme 10) [23]. The double-headed nucleoside 41 was phosphitylated and then incorporated into oligonucleotides and was found to form highly stable DNA duplexes and three

• nucleosides were further reacted with propargylated nucleobases through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction followed by treatment with methanolic ammonia to give the C-3′-substituted double-headed ribofuranonucleosides 46a–c and 50a–e (Scheme 11) [36]. The double-headed nucleosides

• ]. Hrdlicka and co-workers [24] also synthesized 5-C-triazolyl-functionalized double-headed nucleosides 154a,b starting from 5-C-ethynyl-functionalized LNA uridine 152. The LNA uridine 152 was reacted with 1-azidopyrene (153a) and 1-azidomethylpyrene (153b) separately under copper-catalyzed alkyne azide

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• apparition of side-products and a drop of the yields (Scheme 40). Recently, a one-pot reaction was reported by Yavari and Nematpour that includes the formation of an hexasubstituted biguanide from TMG, and a copper-catalyzed N-arylation [81]. Using TMG and DIC/DCC as reagents, and 10 mol % of CuI

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• -bromobenzoate via palladium-catalyzed isocyanide insertion [32][33] (a method that is limited to tertiary-substituted isocyanides) or 2) the palladium or copper-catalyzed coupling of bromolactams with amines (a method that requires the usually lengthy synthesis of the bromoprecursors) [19][34]. Therefore, the

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• tetraacetate (Scheme 39) [60][61]. To develop novel bone-targeting prodrugs, a copper-catalyzed carbene insertion of tetraethyl diazomethyldiphosphonate (216) with N-Boc-protected amino acids 214 and 215 provided a simple method to synthesize phosphonodepsipeptides 217 and 218 containing a C-1

• -catalyzed carbene insertion. Synthesis of phosphonodepsipeptides with a C-1-hydroxyalkylphosphonate motif via a copper-catalyzed carbene insertion reaction. Funding The project was supported by the National Natural Science Foundation of China (Nos. 21772010 and 21572017).

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• chlorine at the purine C2 position by azide, and 3) copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) with different alkynes. Pathway B included: 1) the two-step synthesis of 2,6-bistriazolylpurine derivatives 6 from 2,6-dichloropurine derivative 1 [22] and 2) the SNAr–Arbuzov reaction with

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• structures modified with sulfate groups, and their capability to interact with biological components has been demonstrated recently [31][32]. In this work, we therefore coupled dPGS to C2-symmetrical discotic peptide amphiphiles using copper-catalyzed azide alkyne cycloaddition chemistry. The evaluation of

• , post-functionalization using a subsequent copper-catalyzed azide–alkyne cycloaddition reaction became accessible [35][36]. At the same time the other two unmodified side arms of the dendritic amphiphile make sure that the fidelity of the β-sheet motifs and directed supramolecular polymerization remains

• copper-catalyzed azide–alkyne cycloaddition (Scheme 2). The reaction took place in degassed DMSO at 50 °C with CuSO4 pentahydrate, sodium ascorbate and tris(benzyltriazolylmethyl)amine (TBTA) as chelating species. HPLC-monitoring of the reaction showed a full conversion after three days and the crude

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• benzoate to give (−)-141 in good yield. Next, the benzoate-protected ynoate (−)-141 was converted into aldehyde (Z)-(+)-143a by employing a copper-catalyzed methylation of the alkyne moiety to the corresponding enoate (Z)-(+)-142 followed by an ester reduction–oxidation sequence using DIBAL-H and TPAP

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• RNA in a highly selective and efficient way. The more traditional strategies rely on reaction of isothiocyanates or NHS esters with aliphatic amines [13][14], or on addition of thiols to the α,β-unsaturated carbonyl face of maleimides [15]. Over the past years, the copper catalyzed alkyne–azide

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• presence of transition metal salts is an essential transformation that permits the preparation N-(het)aryl-substituted amines and their derivatives including various nitrogen-containing heterocycles [1][2][3][4][5], an important class of compounds throughout chemical research. The copper-catalyzed

• , whereas originally it required very high temperatures, and some limitations including mostly low yields and intolerance of sensitive functional groups have been partially overcome [14]. A search for new efficient reagents for copper-catalyzed N-arylation has led to the recognition of arylboronic acids as

• , and 3-furyl residues, respectively, to be introduced at the N1 position of the pyrimidone ring, affording compounds 3u–w. Stimulated by the reported examples of the copper-catalyzed N-alkenylation of heterocycles [40][43][44][45][46][47][48], we extended the reaction scope to β-styrylboronic acid (4

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• obtained using the less reactive triphenylphosphine dicobaltpentacarbonyl complex 63 as the catalyst (Scheme 35). In a later study [72], Riera and Fustero generalized the use of trifluoromethylalkynes as substrates for the PKR. The copper-catalyzed trifluoromethylation of terminal alkynes described by Qing

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• oximes reacted with esters and ketones to give oxidative coupling products in moderate to good yields (products 55a–e and 56a–e, respectively). In the case of asymmetric ketones, the C–H bond at the more substituted carbon was cleaved (products 56d,e). Recently, the copper-catalyzed addition of oximes to

• the C=C double bond of maleimides was reported [96]. The iminoxyl radicals were detected by EPR spectroscopy, but the non-radical mechanism (copper-catalyzed Michael addition) can not be excluded completely. Application of the oxime radicals in organic synthesis: intramolecular reactions There are two

Synthesis and properties of quinazoline-based versatile exciplex-forming compounds

• Rasa Keruckiene,
• Simona Vekteryte,
• Ervinas Urbonas,
• Matas Guzauskas,
• Eigirdas Skuodis,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 1142–1153, doi:10.3762/bjoc.16.101

• , bearing a quinazoline unit as the acceptor core and carbazole, dimethyldihydroacridine, or phenothiazine donor moieties, were designed and synthesized in two steps including a facile copper-catalyzed cyclization and a nucleophilic aromatic substitution reaction. The photophysical properties of the

Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C–H selenation of 2-arylimidazo[1,2-a]pyridine with selenium

• Mio Matsumura,
• Tsutomu Takahashi,
• Hikari Yamauchi,
• Shunsuke Sakuma,
• Yukako Hayashi,
• Tadashi Hyodo,
• Tohru Obata,
• Kentaro Yamaguchi,
• Yasuyuki Fujiwara and
• Shuji Yasuike

Beilstein J. Org. Chem. 2020, 16, 1075–1083, doi:10.3762/bjoc.16.94

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• such copper-based reagents will be depicted and copper-catalyzed reactions are therefore beyond the scope of this review. Review Copper-based difluoromethylating reagents In this section the key advances made to access copper-based difluoromethylating reagents are summarized. The CF2H moiety [28][29

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• reactions, and ranged from 6% to 50% for copper-catalyzed cross-coupling reactions [13]. Much information could be obtained from this screening. Electron-deficient aryl bromides led to better yields than neutral and electron-rich partners, as observed in previous reports on photochemically- or

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• ], and perform C–H functionalization through aerobic dearomatization of phenols [35]. These broad synthetic outcomes further led to a unified approach for the preparation of 1,2-oxy-aminoarenes by phenol–amine couplings (Scheme 10) [36]. We reported the formation of a C–N bond through copper-catalyzed

• in such systems in order to develop predictive tools for reactivity control [41]. Such knowledge is most likely to result in new advances in the fast-expanding field of redox catalysis. Copper complexes with amidophenolate type benzoxazole ligands for alcohol oxidations. Copper-catalyzed aerobic

• oxidation of alcohols and representative substrate scope. Introduction of H-bonding network in the ligand coordination sphere. Well-defined isatin copper complexes. Catalyst control in the biomimetic phenol ortho-oxidation. Structural diversity accessible by direct functionalization. Copper-catalyzed

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• incorporating silicon or boron into new or existing drugs, in addition to their use as building blocks in cross-coupling reactions en route to various targets of both natural and unnatural origins. In this review, recent protocols relying on copper-catalyzed sp3 carbon–silicon and carbon–boron bond-forming

• interesting class of substrates for medicinal and polymer chemistry. Nevertheless, they can be transformed into a variety of building blocks for subsequent use in complex molecule synthesis. The first example of a copper-catalyzed C(sp3)–Si bond formation was reported by Oshima and co-workers in 1984 [25]. In

• bond formation Organoboron compounds are widely used in C–C and C–X (X = N, O) bond constructions. Straightforward methods for their synthesis involve the copper-catalyzed addition of organoboron compounds to alkynes, alkenes, and unsaturated carbonyl compounds, as well as the nucleophilic borylation

Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment

• Jan Geldsetzer and
• Markus Kalesse

Beilstein J. Org. Chem. 2020, 16, 670–673, doi:10.3762/bjoc.16.64

• formation of the (Z)-enamide should occur in a copper-catalyzed Buchwald-type reaction (Scheme 3). Based on a previous work of Buchwald and his group [13], we decided to use copper(I) iodide and N,N′-dimethylethylenediamine (DMEDA) as the catalytic system in THF, which was reported to be the solvent of

Copper-catalyzed O-alkenylation of phosphonates

• Nuria Vázquez-Galiñanes,
• Mariña Andón-Rodríguez,
• Patricia Gómez-Roibás and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2020, 16, 611–615, doi:10.3762/bjoc.16.56

• Feringa recently reported a catalytic method for the synthesis of mixed alkyl aryl phosphonates based on a copper-catalyzed arylation of phosphonates with diaryliodonium salts [32]. Encouraged by this work, in the context of an electrophilic alkenylation of phosphonates, we reasoned that the action of a

• groups, and final reductive elimination would form the new C(sp2)–O bond, providing an acyclic enol phosphonate with concomitant regeneration of the Cu(I) catalyst (Scheme 1b). Herein we report the successful realization of such a copper-catalyzed oxygen-alkenylation strategy and show that a range of

• , Table 1). We first run the reaction under the conditions reported for the copper-catalyzed O-arylation of phosphonates (CuCl as catalyst, 2,6-di-tert-butylpyridine (dtbpy) as additive in dichloromethane at 40 °C) [32]. Under those conditions, enol phosphonate 3a was the only product of the reaction

Regioselectively α- and β-alkynylated BODIPY dyes via gold(I)-catalyzed direct C–H functionalization and their photophysical properties

• Takahide Shimada,
• Shigeki Mori,
• Masatoshi Ishida and
• Hiroyuki Furuta

Beilstein J. Org. Chem. 2020, 16, 587–595, doi:10.3762/bjoc.16.53

• -tethered BODIPY derivatives serve as a substrate in the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, which is known as “click” reaction, allowing for a biological tissue labelling [35][36]. In addition, ethynyl-substituted BODIPYs yield unique π-conjugated BODIPY-based macrocycles by

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

• definition and fails as a real “click” reaction. Although this cyclization reaction requires elevated temperatures and often yields both the 1,4- and 1,5-regioisomers, the Cu or Ru alkyne–azide cycloaddition falls exactly into the above definition [11]. In this respect, the copper-catalyzed cycloaddition

• suitable ligands [14]. Ligands serve to increase and modulate the reactivity of copper salts. In the first attempt, tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA) considerably speds up the copper-catalyzed cyclization [15]. Many structurally diverse ligands, such as nitrogen-, phosphorus-, carbon

• -, oxygen-, and sulfur-containing ligands were investigated soon after the disclosure of the auxiliary effect of ligands on copper-catalyzed alkyne–azide cycloaddition reactions [16][17]. Heterogeneous catalysts are safer than their homogeneous counterparts. They also offer some advantages, such as the ease

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

• , Sapporo, Hokkaido 001-0021, Japan 10.3762/bjoc.16.50 Abstract A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The

• ligand on the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters with hydrosilanes, placing a focus on (Z)-isomer substrates, which generally gave slightly lower enantiomeric excess with the chiral bisphosphines compared to the (E)-isomer substrates. Results and Discussion

• ongoing in our laboratory. Experimental A typical procedure for the copper-catalyzed enantioselective conjugate reduction (Table 1, entry 4; Table 2, entry 1): In a glove box, CuCl (1.5 mg, 0.015 mmol), L4⋅HBF4 (9.8 mg, 0.015 mmol), and LiOt-Bu (2.4 mg, 0.03 mmol) were placed in a vial containing a

Copper-catalyzed remote C–H arylation of polycyclic aromatic hydrocarbons (PAHs)

• Anping Luo,
• Min Zhang,
• Zhangyi Fu,
• Jingbo Lan,
• Di Wu and
• Jingsong You

Beilstein J. Org. Chem. 2020, 16, 530–536, doi:10.3762/bjoc.16.49

• substituted polycyclic aromatic hydrocarbons (PAHs) is a desired but challenging task. A copper-catalyzed C7–H arylation of 1-naphthamides has been developed by using aryliodonium salts as arylating reagents. This protocol does not need to use precious metal catalysts and tolerates wide variety of functional

• of our ongoing research on direct C–H bond functionalization [20][27][28][29], we herein represent a copper-catalyzed remote C–H arylation of PAHs with aryliodonium salts as arylating reagents (Scheme 1). This protocol is compatible with different PAH substrates including 1-naphthamides, phenanthrene