Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• . Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower

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

• [46]. A similar type of reaction methodology was employed for the formation of a bicyclic nucleoside analog. 4'-C-vinylribofuranoside derivative 21 on treatment with Hg(TFA)2 followed by reduction with NaBH4 leads to the formation of bicyclic nucleoside derivative 22 (Scheme 10) [49]. Pyrrolidine and

• depending on the reaction conditions (Scheme 13) [53][58]. Cyclization of 4-cycloocten-1-ol (35) with Hg(OAc)2 resulted in formation of two types of fused bicyclic products, 9-oxabicyclo[3.3.1]nonane (36) and 9-oxabicyclo[4.2.1]nonane (37) (Scheme 14) [59][60]. It was observed that the regioselective

• -amino alcohol 38 leading to the formation of (1R,2R,6R)-9-benzyl-9-azabicyclo[4.2.1]nonan-2-ol (39). The bicyclic derivative 39 through the number of consequent reactions formed a highly potent (+)/(−)-pyrido[3,4-b]homotropane (40), a bridged nicotinoid (Scheme 15) [61]. Similarly, precursor 41 at room

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

• efficient HAT photocatalyst to perform the desired C–H abstraction (Scheme 10) [62]. The catalytic reaction required near-ultraviolet light irradiation (Kessil 34 W 390 nm LEDs) and the exclusion of both oxygen and water to the success of the reaction. A variety of cyclic, acyclic, and bicyclic aliphatic

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• Abstract This work presents an examination of the selective functionalization of norbornadiene through nitrile oxide 1,3-dipolar cycloaddition/ring-opening metathesis (ROM)/cross-metathesis (CM) protocols. Functionalization of commercially available norbornadiene provided novel bicyclic scaffolds with

• of natural products (especially macrocycles) [12], alkaloids [13], amino acids and functionalized biomolecules such as peptides [14][15][16][17][18][19][20] or various drugs [21]. Due to the ring strain, bicyclic systems and derivatives, such as norbornadiene derivatives can easily be converted

• view of chemodifferentiation. The reactions were performed with various olefin metathesis catalysts to find the most optimal conditions (Figure 1). The starting divinyl-substituted bicyclic isoxazolines were synthesized according to literature methods, as shown in Figure 2, utilizing nitrile oxide

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

• , respectively, has proved to be the most effective for the promotion of the conjugate addition of 4-hydroxycoumarins 1 to 2-hydroxycinnamaldehydes 109, leading to chiral bridged bicyclic acetal products 110 with high ee (Scheme 35). The mechanistic study performed showed that possibly the phenolic hydroxy group

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• electrophiles, while maintaining a high degree of N-1 regioselectivity. Keywords: indazole; N-alkylation; regioselective; sodium hydride; tetrahydrofuran; Introduction Indazole (benzo[c]pyrazole) is an aromatic bicyclic heterocycle and can be viewed as a (bio)isostere of indole [1]. While only a few naturally

• -alkylation, varying reaction conditions, such as the choice of base [17][21], acid [22], solvent, and/or N-alkylating reagent may also facilitate regioselective indazole N-alkylation [23][24][25]. Bookser et al. have investigated the N-alkylation of related bicyclic azolo-fused-ring heterocycles, including

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

• ). These bicyclic structures may present unique biological activities including neuroprotective properties (15), as it was recently reported by Joubert and co-workers [58], as well as acting as agonists of nicotinic receptors (16) [59], representing an alternative option for the treatment of cigarette

• free amine derivative was produced in 43% overall yield. The 2,8-dioxabicyclo[3.3.1]nonane skeleton is contained in biflavonoids and was shown to exhibit many medicinal activities like antiviral, anti-inflammatory and antitumor properties. The bicyclic compound 49 was aminated at the benzylic position

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

• out for the synthesis of stereochemically pure PS-ONs and one of these methods employs the proline-derived bicyclic oxazaphospholidine monomer [122] which was later used in the scalable synthetic process of therapeutic stereopure PS-ASOs [123]. When the modified ONs were hybridized with their

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• enabled formation of relatively stable triplexes at physiological pH of 7.4. Later, the same research group reported that 1,8-naphthyridin-2,7-(1,8H)-dione (K, Figure 6), a bicyclic mimic of protonated cytosine, afforded stronger binding to G–C base pairs compared to J, most likely due to the increased

• surface area of the bicyclic nucleobases that enabled better π-stacking [97]. Despite the superior binding properties, the original report on K has not been followed up with more detailed studies and J remains the current gold standard for triple-helical recognition of G–C base pairs in PNA. However, more

• , most likely because of enhanced stacking of the bicyclic π-system [104][105]. However, beyond the original studies, 7-Cl-bT has not been further explored for either duplex or triplex stabilization. Similar to L, substitution of thymine with 2-thiouracil (s2U) or 5-halouracils (e.g., BrU, Figure 6

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

• diastereoselectivity in the synthesis of bicyclic compounds (dr > 20:1, Scheme 19, 37d, 37e, and 37g). Substrates containing Lewis base moieties (Scheme 19, 36k) were tolerated in the reported reaction conditions, thereby representing a synthetic gain over other olefin isomerization methodologies. An important feature

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones

• Chandrakanta Parida and
• Subhas Chandra Pan

Beilstein J. Org. Chem. 2021, 17, 1447–1452, doi:10.3762/bjoc.17.100

• contemporarily [19][20][21]. In recent years 4-arylidenepyrrolidine-2,3-diones have been explored mainly for the preparation of bicyclic dihydropyran derivatives through the catalytic inverse-electron-demand hetero-Diels–Alder reaction [22][23][24]. We postulated that 4-arylidenepyrrolidine-2,3-diones could also

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

• methodologies and the biological applications of double-headed nucleosides. Keywords: acyclic double-headed nucleosides; bicyclic double-headed nucleosides; furanosyl double-headed nucleosides; modified nucleosides; pyranosyl double-headed nucleosides; Introduction Nucleosides are the constructional subunits

• ][31][65]. Bicyclic double-headed nucleosides In this section we have included the double-headed nucleoside monomers, which have a locked nucleic acid type conformation and the additional nucleobase is attached at one of the carbon or nitrogen atoms constituting the bridge (Figure 1). All examples

• discussed herewith are constituted by furanosyl carbohydrate moiety. Nielsen and co-workers [67] synthesized the bicyclic double-headed nucleoside (1R,4R/S,5R,6R,8S)-8-hydroxy-1-hydroxymethyl-4,6-di(uracil-1-yl)-3,7-dioxabicyclo[3.2.1]octane (122), where the additional nucleobase is attached at the bridge

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

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• (Table 1, entries 9–14). The corresponding isomeric imidazo[4,5-e]thiazolo[2,3-c]triazines 5 were formed in trace amounts and were detected only in the 1H NMR spectra of the evaporated reaction mixtures. The reactions of bicyclic structures 3a–g with dimethyl acetylenedicarboxylate proceeded with similar

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

• -fused bicyclic transition state model was proposed to rationalize the stereochemical outcome, in which the sodium metal is chelated by the oxygen and the nitrogen atoms of sulfinyl imine (Scheme 17), occurring the nucleophilic attack to the Si face of the imines with RS configuration. Su and Xu reported

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• formation of the expected N-benzylaminodiol either at room temperature or under reflux conditions, probably due to the strong steric hindrance of the bicyclic system and the hydroxymethyl group. The 1H NMR spectroscopic measurements in CDCl3 clearly showed that the crude product was a five-component

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

• °C to afford corresponding fluorinated bicyclic compound 284 [108]. A catalytic amount of TMSCl generates TMS-protected alcohol 279 and HCl. The activated aldehyde 280 reacts with 279 to form the intermediate 281. Then, the TMS group in 281 is attacked by F− in the presence of HCl to give the

• . Formation of the oxocarbenium ion 289, followed by an intramolecular nucleophilic attack by the alkynyl bond on the cyclopropane unit gave cyclic oxocarbenium intermediate 290. Further, the attack of a halide anion (from TiX4) leads to the Prins cyclization to give bishalogenated bicyclic THP with all-cis

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• synthesis of LNA involves the tosylation of a 4'-C-hydroxymethyl derivative, followed by a base-induced ring closure to afford the 2'-O,4'-C-linked bicyclic nucleoside derivative (Scheme 6) [127][128]. Incorporation of LNA into a variety of oligonucleotides with varying lengths and sequences has shown

• [148], and in the use of antisense oligonucleotides for splice modulation through the induction of Dmd exon-23 skipping in mice in vitro [149]. Recently, a lot of attention has been paid to modifying the LNA scaffold to incorporate various heteroatoms, modify the bicyclic framework, and to change the

• and 2',4'-diF-rC nucleosides (Figure 9C) [206]. Through NMR, these nucleosides were found to be essentially locked in the northern (C3'-endo) sugar pucker, albeit without the need for the bicyclic structures typical for locked nucleic acids [206]. The 2',4'-diF-rU nucleoside was introduced into an RNA

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• the high nucleophilicity of the amino group in the substrate 23 to control the regioselectivity of the reaction (Scheme 9). 3 Indoles Indoles have a bicyclic structure consisting of a six-membered benzene ring fused with a five-membered nitrogen-containing pyrrole ring. Figure 3 depicts some of the

• opening resulting in imine intermediate E. A consecutive intramolecular cyclization and tautomerization yields azepino[5,4,3-cd]indoles 143b. 9 Quinolines Quinolines are bicyclic aromatic heterocycles consisting of a fused pyridine and benzene ring. Quinoline and its derivatives are important both from

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• -lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1–23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• the convex face of the bicyclic system. Amide 9p with an enantiomerically enriched cyclohex-2-enyl substituent cyclized with exclusive diastereoselectivity and only two diastereomers 12pA differing in the orientation of the hydroxy group were obtained in high yield. The radical coupling with TEMPO

• also occurred exclusively at the convex face of the bicyclic system. The configurations of the fused lactams were assigned by chemical derivatization and NOE experiments (vide infra). Functionalization reactions of lactams 12 Base-mediated isomerization reactions Lactams 12 are mixtures of two, four

• bicyclic annulated racemic compound 12o reduced the number of diastereomers as expected to two, 13oA and 13oB, in a 4:1 ratio. The relative configurations of the major and the minor diastereomers were determined by NOE experiments (see Supporting Information File 1). Further functionalization of lactams 12

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• of 1,1-dichloro-1-alkenones. The reaction scope was found to be broad, with various chain lengths and aryl substituents tolerated. For substrates containing an electron-rich aromatic ring, further reactions take place, resulting in bicyclic and/or rearrangement products. Keywords: aluminium

• ) equivalents of AlCl3, a further two products were obtained, whose structures were elucidated as the 8,9-dihydrobenzo[7]annulen-9-ones 9 and 10 (Scheme 4). Presumably, these bicyclic compounds arise via an intramolecular Friedel–Crafts alkylation of 6b, promoted by the ortho/para-directing nature of the

• rise to [6,7]bicyclic ketones 9, and 10 and the linear acid chloride 13, respectively. We have also found that when the ketone is not present, the trifluoroalkyl substrate is converted into bicyclic vinyl chloride 17 when treated with AlCl3. We hope that this short communication will inspire other

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• operations overall from methyl N-Boc-prolinate. The key step proceeds in each case via N,O-diacylation, then selective oxidative hydrolysis of the intermediate bicyclic pyrrole and establishes a precedent for the synthesis of related C(7a)-hydroxylated pyrrolizidines. Keywords: acyloxypyrroles; bacterial

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• fluorinated bicyclic compounds has attracted much attention [40][41][42][43][44][45][46][47]. In this regard, the development of new protocols to relevant monofluorinated bicyclic molecules involving novel versatile fluorine-containing building blocks is of key importance. Fluoroalkenes are recognized to be

• to a new synthetic approach to novel monofluorinated bicyclic compounds, namely norbornenes and bicyclo[2.2.2]oct-2-enes and their subsequent functionalization. The present study is our follow-up work on the Diels–Alder reaction involving β-fluoro-β-nitrostyrenes [57]. A recent review reported that

• straightforward way to numerous fluorine-containing bicyclic compounds not previously available. The syn-dihydroxylation of compound 2f with the N-methylmorpholine-N-oxide (NMO)–OsO4 system resulted in a mixture of the corresponding diols 5 in a 36:64 ratio in 65% yield. Again, exo-dihydroxylation is to be

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• stability of different redox states both in non-coordinated form and as being a ligand. It is important that these bicyclic dioxolene species exhibit the typical properties of sterically hindered o-quinones, such as redox transformations between o-qiunone, semiquinone and catecholate forms as well as

• was discussed previously [29]. The reaction of 4 with malononitrile-derived gem-dithiolate (5b, Scheme 1, route 2) also proceeded under mild conditions in DMF and bicyclic o-quinone 6b was obtained in a good yield. The brown crystals suitable for X-ray analysis were grown from an acetone/diethyl ether

• of this species is the subject of further investigations. The bicyclic fragment in 7 is essentially flat (Figure S5 in Supporting Information File 1). The steric interactions between the tert-butyl groups and atoms of the fused heterocycle are weaker for the four-membered thiete ring than in the case