Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• generated via 1,6-hydride shift in both I and II. Finally, an intramolecular Mannich-type cyclization then furnishes products 27. The cascade protocol enjoys several advantageous synthetic features, including high step- and atom-economy, transition-metal-free and room temperature conditions. In all cases

• cyclization leading to the formation of polycyclic azepino[5,4,3-cd]indoles. Synthesis of azepino[3,4,5-cd]indoles via iridium-catalyzed asymmetric [4 + 3] cycloaddition of racemic 4-indolyl allylic alcohols with azomethine ylides. Aldimine condensation/1,6-hydride transfer/Mannich-type cyclization cascade of

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• within the area. Organocatalytic reactions are highly suitable components of cascade transformations as exemplified by the seminal work of Enders [13]. Besides traditional enamine and iminium activation of carbonyl compounds other activation modes were uncovered which significantly broadened the

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• molecular complexity. There are many examples of the organocatalytic synthesis of fused cycles starting from the cyclohexane-1,3-dione. For example, Rueping et al. demonstrated that the cyclohexane-1,3-dione undergoes a cascade reaction with α,β-unsaturated aldehydes [4] and they later employed the method

• substituted cyclopentane diones were uninvestigated until 2014 when we showed that CPD undergoes a Michael addition with nitrostyrenes [22]. Subsequently, different cascade reactions for CPD have been developed: with highly reactive (E)-2-oxobut-3-enoates [23], α,β-unsaturated aldehydes [24] and alkylidene

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• pyridine to afford dimesylated nucleosides 16a,b in 93 and 94% yields, respectively. The reaction of nucleosides 16a,b with NaOH in dioxane/water (1:1) underwent a cascade reaction pathway to form 9a,b in 82 and 84% yields, respectively (Scheme 4). The overall yields for the synthesis of nucleosides 9a,b

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

• -naphthoquinones 35 and β-lapachone (11) for hCE1 (Scheme 9). It is important to note that 35 can be obtained from other reagents, such as 2-naphthol, in a cascade of reactions involving oxidation to 1,2-naphthoquinones followed by Michael addition to the olefin and reoxidation [85]. In addition, Yang and co

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• cascade reagent with the indane framework, namely, 2-isothiocyanato-1-indanone (Scheme 1a) [15], but research on its participation in the construction of chiral compounds has been relatively low [16][17]. On the other hand, as a kind of vital spiroheterocyclic derivatives, spirobarbiturates show a wide

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• . Finally, the residue was purified by distillation to give pure product 3b in 64% yield (1.05 g). Cascade synthesis of 5 via two-phase ring closing of 3b and following substitution with benzenethiol 4 in the presence of K2CO3 (Scheme 4). To a 100 mL flask were added 2b (4.0 mmol), CH3CN (4 mL), H2O (16 mL

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• the design of novel domino reactions. Keywords: cascade; catalysis; coupling; earth-abundant; iron; Introduction Over the past couple decades, the use of transition-metal-catalyzed cross-coupling reactions have become a staple within the organic chemist’s arsenal of carbon–carbon and carbon

• production of byproducts. Iron catalysis offers an attractive, and sustainable, approach to the aforementioned economic and ecological concerns. In the same vein, cascade reactions are important tools to meet such challenges currently facing synthetic chemists and have received considerable attention as of

• late. Introduced by Tietze, cascade reactions are sequences of transformations where subsequent transformations occur only in virtue of functionality formed in previous steps [47]. This process repeats until a product stable under the reaction conditions is formed and the reaction terminates. Compared

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

• Alla I. Vaskevych,
• Nataliia O. Savinchuk,
• Ruslan I. Vaskevych,
• Eduard B. Rusanov,
• Oleksandr O. Grygorenko and
• Mykhailo V. Vovk

Beilstein J. Org. Chem. 2021, 17, 2787–2794, doi:10.3762/bjoc.17.189

• [13], as well as Ir-catalyzed intramolecular dehydrative cross-coupling of 2-(pyrrolidine-1-yl)benzamide [14]. Another approach to compounds of type 1 that relies on a cascade formation of the pyrimidine and pyrrole rings have found much wider application (see Scheme 1B). One of its variations

• derivatives with 4-chloroketones or 4-oxocarboxylic acids in ionic liquids [20][21][22][23] or refluxing acetic acid [24][25]. An alternative approach involves cascade cyclization of anthranilamides with 4-chlorobutanoyl chloride [26][27]. Also, reductive cyclocondensation of 2-nitrobenzamides and

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• the yields, whereas the electronic properties of the substituents on the indole ring did. In 2019, Lin and co-workers reported the asymmetric three-component cascade reaction of 2,3-diketo esters 28, aromatic amines 29, and 1,3-cyclohexanediones 30 to prepare axially chiral arylindoles 31 in a highly

• catalyst developed by our group is critical for increasing the enantioselectivity in this cascade reaction [38]. This catalyst can facilitate the aldol reaction to generate a stereocenter (I-7), which can then be converted to axial chirality (I-8 to I-10) and finally aromatized to give 31 (Scheme 11) [60

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• -friendliness. Ren and colleagues [59] recently reported the preparation of an enantiopure 1,3-oxathiolane 65 utilizing a multienzymatic cascade protocol (Scheme 21). The combined use of surfactant-treated Subtilisin Carlsberg (STS) and Candida antarctica lipase B (CAL-B) resulted in the 1,3-oxathiolane ring in

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• -MRs, each highlighting a certain aspect of the reaction. While Sánchez-Roselló et al. [18] classified these reactions on the basis of the nature of the substrates, Nayak et al. [19] and Bhanja et al. [20] focused on the stereoselective synthesis of nitrogen heterocycles via Michael cascade reactions

• al. reported cinchona-based primary amine catalyzed cascade aza-Michael-aldol reaction of α,β-unsaturated ketones 6 with 2-(1H-pyrrol-2-yl)-2-oxoacetates 5 where triphenylacetic acid was used as an additive. This cascade reaction afforded highly functionalized chiral pyrrolizines 8 in good yields (70

• –91%) with excellent levels of stereocontrol (≈92% ee, >20:1 dr in all cases). The ketone group in the cascade product was reduced asymmetrically to a chiral secondary hydroxy group (Table 1) [26]. In this case, the role of Ph3CCO2H as additive is to furnish the conjugate base Ph3CO2− anion which

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• 50 and 51, an α-ketol rearrangement of 52, and a hemiketal-forming cyclization of 53, all of which occurred as a cascade (Figure 12) [16]. Over a series of optimizations, it was found that performing this cascade in a solution of water at 35 °C over the course of 2.5 days produced a 75% yield of 49

• and a 22% yield of the Diels–Alder adduct, showing that the first step of the cascade had near-quantitative yield, diastereoselectively and regioselectively. The authors speculated that it is possible, considering their own reaction efficiency in conditions reminiscent of natural ones, that the

• -ketol rearrangement to 59. Note that this reaction took advantage of the thermodynamically preferred conversion of an α-ketoester to a β-ketoester seen in other examples in this review. Although not technically a tandem reaction due to the need to add a reagent to continue the cascade, the sequence of

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

• ][28][29]. In industry, pyrrole mainly comes from the extraction of coal tar, the condensation reaction of furan and ammonia under high temperature, or the cascade cyclization reaction of acetylene, formaldehyde, and ammonia. In the laboratory, there are many efficient methods for the synthesis of

• dibromopyrroles 38, respectively. Subsequently, Punniyamurthy and co-workers also described the copper-catalyzed cascade cyclization of 2-nitro-1,3-enynes 34 to tetrasubstituted pyrroles 39 (Scheme 14) [58]. Through screening the conditions, the Cu(OTf)2-promoted (5 mol %) annulation addition reaction of 2-nitro

• trifluoromethylated coumarins [59], we recently developed a Rh-catalyzed approach to trifluoromethyl-substituted pyrroles using the Togni reagent II as trifluoromethyl source. It involves a three-component cascade reaction of 1,3-enynes, anilines, and Togni reagent II to afford fully substituted pyrrole derivatives

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• (GFPP, C25) for sesterterpene biosynthesis. Type I terpene synthases (TPSs) activate these acyclic molecules by the abstraction of diphosphate to produce a reactive allyl cation that can initiate a cascade reaction through typical carbocation chemistry, including cyclisation reactions by intramolecular

• attack of an olefinic double bond to the cationic centre Wagner–Meerwein rearrangements, and proton or hydride migrations [2]. These multistep cascade reactions ultimately result in terpene hydrocarbons that are often (poly)cyclic and contain several stereogenic centres [3][4]. In some cases, water is

• synthases seem to be quite random, only the active site is lined with mostly non-polar residues. They contour the active site and force the substrate into a certain conformation which, after substrate ionisation, determines the reaction pathway that is taken by the cationic cascade. Here we present site

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• Pd(II) [8][9][10], Ru(II) [11][12][13], Rh(III) [14][15][16], Mn(II) [17][18][19], Au(II/I) [20][21][22], Ag(I) [23][24][25] etc. in both cascade and sequential reactions have been published. Electrophilic Hg(II) salts are important reagents in organic synthesis and there is published literature

• , hippuristanol and some analogs were successfully synthesized utilizing a Hg(OTf)2-catalyzed cascade spiroketalization step of the 3-alkyne-1,7-diol motif. The Hg(OTf)2-catalyzed cascade spiroketalization step was proved to be more convenient than Suárez cyclization. A Hg(TFA)2-mediated cyclization was

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

• for the mode of action of this cascade arylation protocol (Figure 10) [73]. In the photocatalytic cycle, the SET event between the photoexcited iridium catalyst 10-II and the substrate oxalate 33 generates a tertiary carbon-centered radical 10-IV by decarboxylation and the reduced iridium(II

Transition-metal-free intramolecular Friedel–Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives

• Tülay Yıldız,
• İrem Baştaş and
• Hatice Başpınar Küçük

Beilstein J. Org. Chem. 2021, 17, 2203–2208, doi:10.3762/bjoc.17.142

• of their important biological and fluorescent uses. To summarize the main syntheses of these studies: in particular, transition metal-catalyzed cascade benzylation–cyclization [17], cyclization of polycyclic aryl triflate esters [18], reaction of β-naphthol and aldehydes [19][20] or inter- or

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• 10% yield when chloranil was used as the oxidant (Scheme 25) [115]. The high electrophilicity of 178 at the C7 position resulted in this product formation. The reaction proceeds through the radical intermediate 181. Sulfides Reddy synthesized the di(indol-5-yl)sulfide (183) via a cascade strategy

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties (Scheme 2). Bojanowski and co-workers developed a methodology to synthetize 3,4-dihydrocoumarins 10 through a decarboxylative and dearomatizative cascade reaction [33]. This reaction was carried out using coumarin-3-carboxylic acids 8

• cascade synthesis of hydrocoumarin 78 mediated by squaramide catalyst with 9-amino-9-deoxy-epi-quinine moiety 73 was reported by Albrecht et al. [59]. In this transformation, the authors developed a Michael addition of azlactones to 2-hydroxychalcones 76 followed by the opening of the azlactone 77 ring to

• cascade reaction. Total synthesis of (+)-smyrindiol (17). Michael addition of 4-hydroxycoumarin (1) to enones 2 through a bifunctional modified binaphthyl organocatalyst 18. Michael addition of ketones 20 to 3-aroylcoumarins 19 using a cinchona alkaloid-derived primary amine catalyst 22. Enantioselective

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

• investigated by means of DFT calculations using the reaction between enaminone 6a and phenyl azide. TS1 and TS2 have been proposed as two transition states, which then converted to IN1 and IN2 as two possible isomers. The stable final products were achieved via a cascade reaction including the elimination of

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