The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• evidence on structure–activity relationships in this chemotype. Results and Discussion Encouraged by scattered reports on N-acyl-Pictet–Spengler reactions using N-alkoxycarbonyl activation [10][15][18][19][20][21] (noteworthy, N-Boc is not reliably resistant to the strongly acidic cyclization conditions

• activation by TPC2-A1-P is better targetable than by TPC2-A1-N. This result is in accordance with our previous observations that TPC2-blocking activity is only observed for monomeric benzyltetrahydroisoquinolines if they are decorated with aromatic residues, which imitate the two benzenoid rings of the

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

• oxathiolane nucleoside analogues, it was noticed that unnatural (−)-enantiomers have higher anti-HIV activity and lower toxicity in comparison to natural (+)-enantiomers. The activation of such analogues was established to occur preferentially by the enzymes (kinases) or by the target enzymes (polymerases

• activation of oxathiolane acetates 35a–d. The reaction was complete after a reduced reaction time and suitable for large-scale production with good yield at ambient temperature (Scheme 39). The usefulness of this method was that even without isolation of enantiomerically pure oxathiolane substrate, the

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• gives only a low cyclization yield (Table 1, entry 12). It is unclear, if water is directly involved with this mechanism, but studies indicate that water may lower the activation barrier for the radical cyclization owing to its solvent effect, as has been previously reported for the radical synthesis of

AlBr₃-Promoted stereoselective anti-hydroarylation of the acetylene bond in 3-arylpropynenitriles by electron-rich arenes: synthesis of 3,3-diarylpropenenitriles

• Yelizaveta Gorbunova,
• Dmitry S. Ryabukhin and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2663–2667, doi:10.3762/bjoc.17.180

• ]. Recently, we have shown that reactions of 3-arylpropenenitriles (cinnamonitriles, ArCH=CHCN) with arenes (Ar′H) under the superelectrophilic activation by the Brønsted superacid CF3SO3H (TfOH, triflic acid) or the strong Lewis acid AlBr3 result in the formation of 3,3-diarylpropanenitriles (Ar(Ar′)CHCH2CN

• our work on electrophilic transformations of alkynes [18][19][20], we investigated reactions of 3-arylpropynenitriles under electrophilic activation conditions (see [21] for the chemistry of superelectrophilic species). The goal of this work was to study the reactions of 3-arylpropynenitriles with

• ; ArCH=CHCN) (see our work [17]) and 3-arylpropynenitriles 1 (this work) under electrophilic activation reveals unambiguously that the electrophilic intermediates generated from acetylene nitriles 1 possess higher reactivity. Thus, the hydroarylation of 3-arylpropynenitriles 1 promoted by AlBr3 proceeds

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of

• aldehydes and hydrogen-bond activation of nitroalkenes. Keywords: asymmetric organocatalysis; hydrogen bond; Michael addition; pyrrolidine; thiourea; urea; Introduction Asymmetric organocatalysis became one of the strategic ways for the efficient synthesis of chiral compounds [1]. Bifunctional catalysis

• itself, in which the carboxylic function acts as an ancillary hydrogen-bond donor for the direction of one of the reagents [9]. Amines serve as basic units and nucleophilic components capable of carbonyl compounds activation via enamine or iminium ion formation [10][11]. In particular, pyrrolidine became

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

• appears that in this case, both activation mechanisms, namely through hydrogen bonding and iminium ion formation are operating. Using the same chiral cinchona-based primary-tertiary diamine as catalyst (cat. 11), Zhai et al. developed a highly efficient intramolecular enantioselective aza-Michael addition

• 108 to aliphatic α,β-unsaturated aldehydes 109 and synthesized biologically active acyclonucleoside 110 via an iminium-ion activation mechanism. The initially formed product was reduced in situ to afford the final product in 82–89% yield and 89–96% ee (Table 25) [66]. In a similar method, Joie et al

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• allylic functionalization of 2-alkylazaarenes. Due to the high pKa value of alkyl azaarenes, the functionalization of benzylic C(sp3)–H was challengeable and pre-activation of the benzylic proton with suitable Lewis acids was often required prior to deprotonation of the alkyl chain by a stoichiometric

In-depth characterization of self-healing polymers based on π–π interactions

• Josefine Meurer,
• Julian Hniopek,
• Johannes Ahner,
• Michael Schmitt,
• Jürgen Popp,
• Stefan Zechel,
• Kalina Peneva and
• Martin D. Hager

Beilstein J. Org. Chem. 2021, 17, 2496–2504, doi:10.3762/bjoc.17.166

• mechanical behavior was studied using rheology. The activation of the supramolecular interactions results in a breaking of these noncovalent bonds, which was investigated using IR spectroscopy, leading to a sufficient increase in mobility and, finally, a healing of the mechanical damage. This scratch-healing

• transitions (see Figure 1). Both polymers feature a glass transition temperature (Tg) at −58 °C (P1) and −51 °C (P2), respectively. Furthermore, the polymers have an endothermic transition at 129 °C (P1) and 126 °C (P2). This transition is associated with the activation of the perylene domains, which was also

• transition is associated with the endothermic signal measured in the DSC and based on the activation of the π–π interactions. Such a behavior could also be observed for other supramolecular polymers; however, the temperature window, in which the drop of the storage and loss moduli occurred, is rather small

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• the directing group could be removed easily under basic conditions. Keywords: amination; C–H activation; copper; ferrocene; mono-selectivity; Introduction Ferrocene-based compounds have broad applications from asymmetric catalysis to medicinal discovery [1][2][3][4][5][6][7][8]. Therefore, the

• preparation of ferrocene–drug conjugates effectively. Mechanistic studies indicated that the C–H activation step was the rate-determining step. 3d-Transition-metal-catalyzed C–H functionalization to access functionalized ferrocenes. Scope of ferrocenes with morpholine. Scope of various amines with 1a

Exfoliated black phosphorous-mediated CuAAC chemistry for organic and macromolecular synthesis under white LED and near-IR irradiation

• Azra Kocaarslan,
• Zafer Eroglu,
• Önder Metin and
• Yusuf Yagci

Beilstein J. Org. Chem. 2021, 17, 2477–2487, doi:10.3762/bjoc.17.164

• conventional 2D materials have a wide bandgap that requires UV light irradiation for their activation. Since 94% of the rays from the sun are not sufficient to activate these conventional semiconductor materials, many strategies have been proposed to design photocatalysts that can harvest in a wide spectrum of

Synthesis and investigation on optical and electrochemical properties of 2,4-diaryl-9-chloro-5,6,7,8-tetrahydroacridines

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 2450–2461, doi:10.3762/bjoc.17.162

• yield (Table 1, entries 8 and 9). However, increasing the amount of K3PO4 to 4 equivalents gave a nearly quantitative yield (Table 1, entry 12). We believe that a supplementary activation of the boronic acid, by adding a high amount of base, improved the nucleophilicity and facilitated the

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

• activation. DHFPP = 2,3-dihydro-FPP. The products of SmTS1. A) Structures of sestermobaraenes A–F (1–6) and sestermobaraol (7). B) The total ion chromatogram of the products obtained with SmTS1 from GFPP. Peak labels a, b and c indicate unknown products, asterisks indicate degradation products from GFPP that

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

• Andrey I. Puzanov,
• Dmitry S. Ryabukhin,
• Anna S. Zalivatskaya,
• Dmitriy N. Zakusilo,
• Darya S. Mikson,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2417–2424, doi:10.3762/bjoc.17.158

• bond of these oxadiazoles quantitatively resulted in E/Z-vinyl triflates. The reactions of the cationic intermediates have been studied by DFT calculations and the reaction mechanisms are discussed. Keywords: acetylene-oxadiazoles; Friedel–Crafts reaction; hydroarylation; superelectrophilic activation

• the transformations of these heterocyclic compounds in electrophilic media. The main goals of this work were the synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and the study of their reactions with/without arenes under the conditions of superelectrophilic activation by the Brønsted superacid CF3SO3H

• at very low temperature –70 to –60 °C, that resulted in low to moderate yields of the target acetylene derivatives. Then, electrophilic reactions of 5-acetylenyloxadiazoles 3a–d in different acids were studied. In our recent study on the electrophilic activation of 5-styryl-1,2,4-oxadiazoles 1 [24

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

• proved that the reaction mechanism proceeds via activation of the alkynyl group with Hg(OTf)2 salt and addition of 2-chloropyridine N-oxide. The resulting activated alkynyl complex was demercurated, followed by the SN2′ reaction thus formed undergoes demercuration to yield 3-coumaranone (Scheme 51) [111

Phenolic constituents from twigs of Aleurites fordii and their biological activities

• Kyoung Jin Park,
• Won Se Suh,
• Da Hye Yoon,
• Chung Sub Kim,
• Sun Yeou Kim and
• Kang Ro Lee

Beilstein J. Org. Chem. 2021, 17, 2329–2339, doi:10.3762/bjoc.17.151

• A. fordii have shown Epstein–Barr virus activation effects and an enhancement of HTLV-I-induced colony formation of lymphocytes [8]. As an ongoing search for bioactive secondary metabolites from Korean medicinal sources, we investigated the methanolic extract of the twigs of A. fordii which resulted

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• development of the research area of asymmetric anion-binding organocatalysis. Key early elucidation studies with chloride as counter-anion confirmed this type of alternative activation, which was then exploited in several processes and contributed to the advance and consolidation of anion-binding catalysis as

• catalyst-bound alkoxide species (3·OEt) that is then able to attack the benzaldehyde for product 2 formation. However, it took some time until the scientific community started considering and taken cognizance of the potential of this type of activation mode in catalysis. In this regard, Jacobsen and co

• , right). However, based on the freshly coined concept of anion-binding activation [30][31] and as the exact interaction mode of the catalyst remained elusive, Jacobsen’s group focused their attention towards mechanistic studies of thiourea-catalyzed reactions. In 2007, they reported a Pictet–Spengler

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

• developments in the field of photoredox nickel-catalyzed C‒H functionalization reactions with a range of applications until summer 2021. Keywords: C–H activation; functionalization; nickel; photocatalysts; photoredox; visible light; Introduction During the last decades, transition-metal-catalyzed

• ]. In this review, we highlight the developments in C–H activation enabled by nickel photocatalysis. Review Arylation The arylation of C(sp3)‒H bonds constitutes a potential tool for the rapid diversification of simple organic molecules into valuable scaffolds [48][49][50][51][52]. In 2014, Doyle

• challenging operation in organic synthesis. While significant advances had been accomplished with (hetero)aromatic C(sp2)–H alkylations [79][80][81], examples for C(sp3)–C(sp3) couplings through C–H activation are scarce [82][83][84]. In this context, a synergistic combination of photoredox catalysis and

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

• hours. As a result, an alkene compound was used for activation with TFA in the synthesis of xanthene through intramolecular Friedel–Crafts alkylation for the first time. Keywords: alkene activation; intramolecular Friedel–Crafts alkylation; trifluoroacetic acid; xanthene; Introduction The interest in

• , entry 14). After determining the most suitable conditions for the intramolecular Friedel–Crafts reaction with alkene activation, the synthesis of the new xanthene derivatives was performed according to this method. The synthesized xanthene derivatives with their isolated yields are shown in Figure 1

• as AlCl3, H2SO4, or H3PO4, which have generally corrosive properties, were used, in this study, an intramolecular ring closure reaction was carried out under easy operating conditions with an organic Brønsted acid catalyst with high yields. So, the xanthene synthesis with alkene activation was

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

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

• obtaining diaryl sulfides [117]. Selenides Along with the oxygen insertion, Black et al. also performed the oxidative selenium insertion into the C-7 position of highly electrophilic 2-methylindole derivative 184. The dual role of selenium dioxide consists of activation of the C-7 position giving the

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• by treatment with PCC/Celite in dichloromethane (DCM). Finally, treatment with a catalytic amount of CF3SO3H provided the corresponding anthracenes 30a–c in good yields (57–75%) [40]. Metal-catalyzed C–H bond activation In 2016, Hong’s group developed a synthetic strategy to generate substituted

• anthracene derivatives 33. The strategy involved a palladium(II)-catalyzed tandem transformation with diphenyl carboxylic acids 31 and acrylates 32 (Scheme 7) [41]. This new methodology involved a carboxyl-directed C–H alkenylation, a carboxyl-directed secondary C–H activation, an intramolecular C–C-bond

• activation In 2009, Liang et al. reported an efficient and highly regioselective route to construct substituted tetracyclic benz[a]anthracene derivatives 115 (Scheme 26) [60]. For this purpose, the authors developed an efficient palladium-catalyzed tandem C–H activation/bis-cyclization reaction of

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• (6mer, 8mer, 10mer and 12mer) following a convergent preactivation-based iterative strategy [135]. These compounds were subsequently conjugated to keyhole limpet hemocyanin, revealing that the length of the glucans affected the immunogenic properties. A pre-activation-based iterative one-pot

• . Peracetylated thioglycoside donors 52 were reacted with 4-methylbenzoylated (MBz) acceptors 53, following NIS/AgOTf activation (Scheme 7C). Upon global deprotection, a collection of well-defined oligoxylans with 4–10 monosaccharide units was obtained [205]. A convergent approach was also employed to prepare a β

• trichloroacetimidate donor 75 was controlled by SN2 displacement of the α-trichloroacetimidate LG upon activation with BF3·OEt2 in CH2Cl2/n-hexane (3:2) (Scheme 11B). The orthogonal N-trichloroacetyl (N-TCA) and N-benzyloxycarbonyl (N-Cbz) PGs permitted the synthesis of chitobioses with different PA. N-TCA groups

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

• , the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst. Keywords: asymmetric synthesis; green chemistry; 2H-chromen-2-one; organocatalysis; Introduction Coumarins are important naturally occurring

• ammonium salts derived from cinchona alkaloids [28]. Therefore, the asymmetric synthesis of coumarin derivatives is herein presented according to the activation mode, i.e., via covalent or non-covalent bonding. Furthermore, the use of bifunctional catalysts and multicatalysis are discussed as well

• addition of 4-hydroxycoumarin (1) by the Re face of the enones 2 through a bifunctional modified binaphthyl organocatalyst 18 with primary amine [37]. The reaction occurs through the activation of the enone substrate by formation of an iminium ion intermediate and, in the presence of an acid additive

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

• active molecules can be obtained through C–H activation processes. However, the use of expensive and not readily accessible catalysts complicates the process of pharmacological application of these compounds. A plausible way to overcome this issue is developing and using cheaper, more accessible, and

• equally effective catalysts. First-row transition (3d) metals have shown to be important catalysts in this matter. This review summarizes the use of 3d metal catalysts in C–H activation processes to obtain potentially (or proved) biologically active compounds. Keywords: bioactive compounds; C–H

• activation; 3d metals; drugs; medicinal chemistry; Introduction The discovery of new biologically active substances represents not only an advance in the chemistry field but also offers innovative chances for pharmacological and biomedical sciences. Every year, several molecules are discovered and studied

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• unmodified PS-ASO [43]. It is important to notice that C-5 modifications, besides resulting in improved nuclease stability and providing improved target hybridization, allow for activation of RNase H. This was demonstrated by Matsuda and co-workers when they incorporated modification 2 or 3 into a 17-mer ON

• the cationic moiety emerges. Additionally, sugar modifications tend to bring higher nuclease resistance compared with nucleobase modifications. However, a drawback is the lack of RNase H activation for most of the sugar-modified derivatives. This is contrary to the nucleobase-modified variants that