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

• 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

• intramolecular hydroamination in the presence of base. Conclusion In conclusion, we have reported on the chelation-assisted oxidative copper-promoted cascade C−H alkynylation and intramolecular annulation. The removable N-2-pyridylhydrazide was utilized to facilitate copper(II)-promoted C−H activations. Thus

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cascade aza-Michael addition/olefin hydroalkylation reaction between N-tosylallylamines and α,β-unsaturated ketones using a catalytic system of a gold(I) complex and a silver salt [45]. The spiro compound 25, which was obtained in moderate yield and with poor diastereoselectivity after a 20 h reaction

• on a control experiment with substrate 34 that had a tethered internal olefin and furnished the expected cyclization product 35. This reaction indicated a radical cascade initiated by a hydrogen atom transfer from a cobalt hydride to the terminal olefin of 34, followed by a 5-exo-trig cyclization

• an MHAT process. In 2008, Norton and co-workers [76] developed a pioneering radical cascade approach based on the generation of carbon free radicals from an MHAT process. The rates (kH) of hydrogen atom transfer (HAT) from the chromium metal hydride CpCr(CO)3H to olefins with diverse substitution

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• methylene protons of butyronitrile functioning as a proton shuttle during the cyclization cascade. Screening weaker bases with stronger conjugate acids to facilitate the requisite proton transfers identified LiHMDS as optimal; the LiHMDS-promoted condensation of Asmic with benzonitrile afforded imidazole 7f

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• affording intermediary benzyl carbenium ions, which are then trapped by a variety of electron-rich aromatics via Friedel–Crafts alkylation. This cascade Prins/Friedel–Crafts cyclization protocol paves an expedient path to medicinally useful 4-aryltetralin-2-ol and 5-aryltetrahydro-5H-benzo[7]annulen-7-ol

• derivatives. Keywords: 4-aryltetralin-2-ol; 5-aryl-benzo[7]annulen-7-ol; cascade reaction; Prins/Friedel–Crafts; Introduction 2,4-Disubstituted tetralins (Figure 1, 1), especially 2-functionalized tetralins are privileged building blocks for medicinal chemistry applications which are known to exhibit a wide

• to 2,4-disubstituted tetralin compounds and thus facilitate their biological investigations. The cascade Prins/Friedel–Crafts reaction to form multiple chemical bonds in one operation has emerged as an atom-economic and straightforward strategy for the construction of oxygen-containing heterocycles

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• –c are shown to undergo a novel cascade imination-heterocylization in the presence of the organic base DIPEA to provide 1-indolyl-3,5,8-substituted γ-carbolines 3aa–ea in good yields. The γ-carbolines are fluorescent and exhibit anticancer activities against cervical, lung, breast, skin, and kidney

• cancer cells. Keywords: γ-carboline; cascade reaction; cell uptake; cytotoxicity; fluorescence; Introduction Carbolines are privileged aza-heterocycles found in the core of several natural and synthetic compounds and are known for their biological applications. Among the four different isomers, 9H

• alkaloid ingenine B [20]. The iodine-catalyzed [3 + 3] cycloaddition of indolyl alcohol to enaminones [21] and the thiourea-catalyzed iso-Pictet–Spengler reaction of isotryptamine with aldehydes [22], are some noteworthy contributions to the field. A cascade or domino reaction is an interesting approach

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson–Kaas, Van Leusen and Ullmann-type reactions as key tools

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2021, 17, 1374–1384, doi:10.3762/bjoc.17.96

• role as donors in the intramolecular partial charge-transfer cascade to transfer the extra electronic density. Apart from pure affection besides many more reasons for the constant fascination and utility of this beautifully simple yet much effective heteroaromatic system, this unique nitrogen

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• attempting telescoped reaction sequences, potential requirements for intermediate purification and issues arising due to heterogeneity. Hence, a batch or semi-batch (cascade CSTR’s) approach often offers a more convenient and sometimes superior synthetic approach. Efforts directed towards addressing these

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• recyclability, broad substrate scope, and high functional group tolerance (Scheme 1). Results and Discussion Our initial investigation focused on the CN-K photocatalyzed cascade alkyl radical addition/cyclization reaction of the N-arylallylamine 1a with tert-butyl N-hydroxyphthalimide (NHPI) ester (2a), a

• experiments was performed (Scheme 7). The cyanomethylarylation reaction of 7a gave the desired compound 8a as the major product in 70% yield, along with 23% yield of the byproduct 15. The latter compound was generated through a cascade alkyl radical addition/cyclization of the NHPI ester 2d to N-aryl

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• determined following a single-crystal X-ray analysis (Scheme 11). The stereoselective synthesis of diastereomeric 2-chloro-2-aroylaziridines 36 and 32 was successfully accomplished through a three-component cascade coupling reaction of silyldichloromethanes 33, arylnitriles 34 and chiral N-tert

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• by introducing a nucleophile into the enol ether, which traps the reactive oxocarbenium ion intermediate 60, leading to the formation of THP [39]. The first example of an MAP cascade reaction was reported by Rychnovsky and co-workers using allylsilane 62 as an internal nucleophile, as shown in Scheme

• -Lewis-acid-promoted asymmetric Prins cyclization strategy. List and co-workers’ iIDP Brønsted acid-promoted asymmetric Prins cyclization strategy. Zhou and co-workers’ strategy for chiral phosphoric acid (CPA)-catalyzed cascade Prins cyclization. List and co-workers’ approach for asymmetric Prins

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

• -radical cascade reactions could efficiently construct various carbocycles and heterocycles with multifarious structures and complexity [59][60][61]. Centered on this context, we give a clear overview on a variety of novel cyclization reactions initiated by EDA complexes from the recent years. In 2016

Metal-free visible-light-enabled vicinal trifluoromethyl dithiolation of unactivated alkenes

• Xiaojuan Li,
• Qiang Zhang,
• Weigang Zhang,
• Jinzhu Ma,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2021, 17, 551–557, doi:10.3762/bjoc.17.49

• in natural products, drug molecules, biologically active molecules, and functional materials. However, the highly selective incorporation of two different sulfur-bearing moieties across double bonds remains challenging [42]. Herein, we describe a visible-light-enabled cascade radical

• -induced cascade radical difunctionalization of unactivated alkenes to provide partially trifluoromethylated dithioethers. The approach features practical conditions, good functional group tolerance, and a broad substrate scope allowing the incorporation of two distinctive sulfur-containing motifs into

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• from Aspergillus niger (AnFaeA, Figure 1C). Coloration is the result of successive reactions: (i) release of the free 5-bromo-4-chloro-indoxyl-3-ol by an enzyme cascade, wherein TxAbf-catalyzed cleavage of the glycosidic bond was made possible by the prior release by AnFaeA of the ferulate moiety [21

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

• prepared the (−)-adaline (1) and the non-natural isomer (−)-euphococcinine (2) through a four-step intramolecular Mannich cyclization cascade reaction [57]. In this methodology, the alkaloids were prepared by treating the convenient N-sulfinylamino ketone ketal precursor on heating with NH4OAc:HOAc. Oxo

• %, respectively. The conversion of precursors N-sulfinylamino ketone ketals directly to the desired homotropanes represents a four-step intramolecular Mannich cyclization cascade reaction, being the most efficient method to date for the (−)-adaline (1) and (−)-euphococcinine (2) syntheses. Specific rotation was

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• substrates. Keywords: DFT calculations; gold catalysis; Nazarov reaction; N-heterocycles; Introduction In the development of new and effective catalysts, step economy is surely one of the major goals. A reduction of the number of steps in the synthesis of complex compounds can be attained by cascade

• reactions, which allow for structural modifications on the organic compounds by forming several chemical bonds in one pot. To this end, gold catalysis [1][2][3][4][5][6][7] has been widely exploited to construct various cyclic and heterocyclic frameworks through cascade reactions triggered by the activation

• of a triple bond, which has ultimately led to the total synthesis of several natural compounds [2][8]. The gold-catalyzed rearrangement of suitably substituted propargylic esters in particular provides a platform for cascade processes that involve a cationic or an allene intermediate generated in the

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• % yield (Scheme 6B). This adduct 92a underwent decarboxylation to afford 92b in 72% yield [42]. Exposure of freshly prepared 92b to triazabicyclodecene [45] led to a ring-expansion/aromatization/aldol cascade producing 93, which was reduced with Et3SiH/TFA smoothly to give indane 94 in 68% yield over two

• -cation equivalent in [3 + 2] cycloaddition in the synthesis of (±)-cuparene (13) [69]. The recent advances of [3 + 2] annulation in natural product synthesis. (A) The preparation of meloscine (158) features a cascade radical annulation of divinylcyclopropane [70]. (B) Thiyl-radical-mediated [3 + 2

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• Within the last few years, we have developed and implemented a number of novel synthetic methodologies in our laboratories, involving acid-mediated cascade transformations of nitroalkenes and nitroalkanes, which target materials science and medicinal chemistry applications. It was demonstrated that upon

Using multiple self-sorting for switching functions in discrete multicomponent systems

• Amit Ghosh and
• Michael Schmittel

Beilstein J. Org. Chem. 2020, 16, 2831–2853, doi:10.3762/bjoc.16.233

• triggered the back cascade translocation. Excitingly, when the self-sorted system in SelfSORT-I was treated with 2-cyano-2-phenylpropanoic acid (50) [62][63] as a chemical fuel, the protonation of 49 entailed the same cascade translocation resulting in SelfSORT-II but now with the effect that it slowly

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• initiate a cationic cyclisation cascade, leading to structurally highly complex and usually polycyclic terpenes in just one enzymatic transformation. The initially formed products are non-functionalised terpene hydrocarbons or, if the terminal cationic intermediate of the cyclisation cascade is trapped by

• rearrangement to a2•+ and a hydride shift to b2•+ (Scheme 3A). This hydride migration is in reverse order compared to a similar step along the cationic cyclisation cascade during the biosynthesis of 2 (Scheme S1 in Supporting Information File 1). The subsequent inductive ring opening to c2•+ and α-cleavage of

Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases

• Julia N. Artsemyeva,
• Ekaterina A. Remeeva,
• Tatiana N. Buravskaya,
• Irina D. Konstantinova,
• Roman S. Esipov,
• Anatoly I. Miroshnikov,
• Natalia M. Litvinko and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2020, 16, 2607–2622, doi:10.3762/bjoc.16.212

• of magnesium ions on metabolic transformations of nucleosides [45], in particular on the phosphorylation of the primary hydroxy group of pentoses, catalyzed by ribokinases [46], as well as on the cascade synthesis of nucleosides starting from pentoses [47][48][49][50] has been described. Based on the

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• radical precursors in this system, allowing for both alkyl [44] and acyl [45] RCA reactions. In the case of acyl DHPs, they propose that direct excitation of the DHP leads to radical generation rather than the iminium intermediate (Scheme 9c). The same system was used for the radical cascade reaction

• separately developed a Minisci-type reaction using phthalimide esters 123; however, their system did not extend past isoquinoline substrates 124 (Scheme 17b) [62]. Zheng and Studer expanded the scope of this type of reactivity to a three-component cascade reaction with alkyl bromides 125 and enamides 126

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• to the possibility of creating enantiomerically pure compounds with several stereocenters through the directed regulation of diastereoselectivity in subsequent transformations, which can be realized as stepwise or cascade processes. Due to this reason, the Michael reaction was successfully used over

• addition of β-keto phosphonates to nitroolefins and subsequent reductive cyclization of enantioenriched, diastereomerically pure Michael adducts was developed. The present study also demonstrates that the diastereoselective cascade Henry/acetalyzation reaction with keto nitro phosphonates and aldehydes

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• even anthracene. At higher temperature, the cycloadducts undergo an intramolecular SE(Ar) reaction leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and some substituted styrenes, cascade reactions take place, which likely include

• cyclobutene and several cationic intermediates and mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene as the substrate. Keywords: alkynes; aromatic substitution; cyclization; cycloaddition; iminium salts; Introduction In recent

• consider the reactivity of the electrophilic (“electron-poor”) acetylenic bond toward 1,3-dienes, and show how the expected [4 + 2] or [2 + 2] cycloaddition products can enter subsequent cascade reactions toward carbocycles which incorporate a C(CF3)NMe2 structural unit. Results and Discussion The Diels

Metal-free synthesis of phosphinoylchroman-4-ones via a radical phosphinoylation–cyclization cascade mediated by K₂S₂O₈

• Qiang Liu,
• Weibang Lu,
• Guanqun Xie and
• Xiaoxia Wang

Beilstein J. Org. Chem. 2020, 16, 1974–1982, doi:10.3762/bjoc.16.164

• oxa-Michael additions of 2’-hydroxychalcones [9][10], or through condensation cyclization reactions of o-hydroxyacetophenones with ketones/aldehydes [11][12], in addition to other alternative transformations [13][14]. Moreover, radical cascade cyclizations of o-allyloxybenzaldehydes by employing

•  1a). Besides, in 2016 Li’s group [28] reported a silver-catalyzed straightforward approach for the synthesis of phosphonate-functionalized chroman-4-ones via a phosphoryl radical-initiated cascade cyclization of 2-(allyloxy)arylaldehydes using K2S2O8 as an oxidant, however, diphenylphosphine oxide

• (DPPO) was not suitable for the transformation (Scheme 1b). So the development of metal-free and greener methods to approach chroman-4-ones bearing a phosphine oxide moiety is still highly desirable. Herein, we present a transition-metal-free radical cascade cyclization to access the desired chroman-4

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• double activation catalysis (Figure 2, (2)) [49][50]. Similarly, if both catalysts activate the same coupling partner but in a sequential fashion (the activated substrate leads to an intermediate further activated by the second catalyst), this falls in the category of cascade catalysis (Figure 2, (3