Facile and innovative catalytic protocol for intramolecular Friedel–Crafts cyclization of Morita–Baylis–Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF₃·OEt₂ catalysis

• Karthikeyan Soundararajan,
• Helen Ratna Monica Jeyarajan,
• Raju Subimol Kamarajapurathu and
• Karthik Krishna Kumar Ayyanoth

Beilstein J. Org. Chem. 2021, 17, 2186–2193, doi:10.3762/bjoc.17.140

• intramolecular Friedel–Crafts cyclization protocol the Morita–Baylis–Hillman adduct 5a, was surveyed as the model substrate. The optimization experiments are listed in Table 1. The cyclization of MBH adduct 5a was examined in presence of metal(III)–salen complex (5 mol %) as catalysts and BF3·OEt2 (2.5 mol %) as

• )Cl] catalyst was sufficient to access indene from MBH adducts (Table 1, entry 8). In order to analyse the role of the BF3·OEt2 in promoting the synthesis of indenes, two optimization reactions at a co-catalyst loading of 1.5 mol and 3 mol % were attempted (Table 1, entries 10 and 11). Though these

• ]+ calcd for C20H17N3O, 315.1372; found, 315.1397. Literature-reported approaches to synthesise indene from MBH adducts [10][11][12][13][14]. Proposed model for the intramolecular Friedel–Crafts cyclization. Reactions of azomethine imine 7a with 2-substituted 1H-indenes 6a and 6b. Optimization of reaction

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• the alkylating reagent on both efficiency and selectivity, we decided to perform a quick optimization study. As a model reaction, we evaluated the influence of various parameters on the reaction between diethyl malonate (1b) and iodobutane (2d) or bromobutane (2d') in the presence of a stoichiometric

• (Scheme 4). These standard reactions were easy and delivered the expected products 9 in good to excellent yields. We then performed a quick optimization study of the reaction between 2-methylmalonic acid (9a) and benzyl alcohol (8d) (Table 4). Starting from classical Steglich's conditions (1.0 equiv of

• these reagents, which constitute an attractive class of pronucleophiles. Main routes to SMAHOs. Preparation of α-halo-MAHOs. Preparation of SMAHOs from Meldrum's acid. Saponification of substituted malonates. Scope of the mono-esterification of substituted malonic acids. adr = 1:1. Optimization of the

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• and several natural products with pyroglutamate substructures. Effect of the aryl substituent on reaction efficiency and selectivity. Proposed transition state model. Optimization of the cyclopropenimine-catalyzed addition of alanine imine 1 to methyl acrylate. Substrate scope of amino ester imine

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

• -workers reported a one-pot synthesis of substituted anthracenes 37 from o-tolualdehyde 34 and aryl iodides 35 via a palladium-catalyzed C–H arylation with a silver oxidant (Scheme 8) [42]. During optimization studies, the authors noted that steric and electronic effects strongly affected the cyclization

• the direct synthesis of 9,10-dicyanoanthracenes from 9,10-anthraquinones [49]. Despite the challenges presented by the different substrates, a long study of reaction optimization allowed the authors to synthesize 9,10-dicyanoanthracene (70a), 2,6-dibromo- (70b), and 2,6-diiodo-9,10-dicyanoanthracene

• synthesized substituted anthraquinones bearing Me, Et, or hydroxy groups, such as compounds 176a–e, in moderate to good yields (45–94%) through a [4 + 2] cycloaddition reaction of 1,4-substituted naphthoquinones 174 and α,β-unsaturated aldehydes 175 catalyzed by ʟ-proline. During optimization studies, the

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

• acceptor to create a dendron-like structure. To overcome the high steric hindrance of both coupling partners, careful optimization of the LG and the reaction temperature was imperative [118][278][280][282]. A [31 + 30 + 30 + 30 + 30] fragment coupling allowed assembling a 151mer polymannoside 97, the

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

• with various heterocyclic C–H acids, resulting in the synthesis of coumarin/quinolinone fused dihydropyranones and dihydropyridinones 47. The reaction optimization and the scope and limitations study were carried out using an achiral NHC, but the enantioselective version was also performed using 4

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

• ]. Notably, optimization of the therapeutic window of ASOs is closely related to improved delivery, and a variety of chemical strategies have been investigated in this context, such as ASO–lipid conjugates for improved endosomal escape [21], ASO–triantennary N-acetylgalactosamine (GalNAc) conjugates for

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• . attempted to fluorinate some polycyclic aromatics with Selectfluor, but intractable mixtures were obtained. Thus, they examined the utility of 25-1 in the fluorination of polycyclic aromatics. Although a detailed optimization was conducted, the fluorination of over 20 polycyclic aromatics was poor giving

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• ]. Based on an initial optimization study, manganese(I) pentacarbonyl bromide was deemed as the optimal catalyst, enabling a robust racemization-free allylation process. In addition to tryptophan-containing peptides, diazepam and nucleoside analogues were found to be viable allylation substrates, affording

Cerium-photocatalyzed aerobic oxidation of benzylic alcohols to aldehydes and ketones

• Girish Suresh Yedase,
• Sumit Kumar,
• Jessica Stahl,
• Burkhard König and
• Veera Reddy Yatham

Beilstein J. Org. Chem. 2021, 17, 1727–1732, doi:10.3762/bjoc.17.121

• herein report a mild aerobic photocatalytic oxidation of benzylic alcohols to aldehydes and ketones using 10 mol % CeCl3·7H2O (Scheme 1). Results and Discussion A variety of reaction parameters was tested during the optimization of the reaction with 4-iodobenzyl alcohol (1a) as the model substrate and

• 4.3 mmol of 1a and reaction time was 72 h; b42 h reaction time; c48 h reaction time. Selective oxidation of 3-bromobenzyl alcohol in the presence of 3-phenylpropanol. Compound 1af was recovered unchanged from the reaction mixture. Optimization of the reaction conditions.a Supporting Information

Correction: Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2021, 17, 1725–1726, doi:10.3762/bjoc.17.120

• mixture using 2-fluoro-4-nitrotoluene as an internal standard. Corrected graphical abstract of the original publication. Supporting Information Supporting Information File 130: General information, synthetic procedures, additional optimization results, NMR spectra for known compounds (1H, 19F) and full

A systems-based framework to computationally describe putative transcription factors and signaling pathways regulating glycan biosynthesis

• Theodore Groth,
• Rudiyanto Gunawan and
• Sriram Neelamegham

Beilstein J. Org. Chem. 2021, 17, 1712–1724, doi:10.3762/bjoc.17.119

• weights connecting TFs is computed as the number of shared glycogenes they regulate. The TF unipartite graph was then subjected to a greedy modularity optimization-based approach implemented in the igraph R package [48]. TF–glycogene interactions in each community were subjected to overrepresentation

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• show the scope and the limitations of the different catalysts. An optimization of the reaction conditions in terms of obtaining full conversion in the shortest time possible with the lowest reasonable achievable catalyst loading was not undertaken. The results are shown in Figure 1. The benchmark

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

• /bjoc.17.116 Abstract Peptide nucleic acid (PNA) is arguably one of the most successful DNA mimics, despite a most dramatic departure from the native structure of DNA. The present review summarizes 30 years of research on PNA’s chemistry, optimization of structure and function, applications as probes

2,4-Bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines: synthesis and photophysical properties

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli,
• Noureddine Chaaben,
• Kamel Alimi,
• Stefan Jopp and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 1629–1640, doi:10.3762/bjoc.17.115

• catalysis. With this precursor in hand, we intended to expand the π-conjugation by introducing two arylethynyl groups by Sonogashira reactions [66][67][68][69]. For the optimization, we studied the reaction of 2 with phenylacetylene (3a) and we obtained the desired product 4a in up to 72% as best yield

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

• Discussion We initiated our investigation by utilizing benzhydrazide 1a and ethynylbenzene (2a) as the standard substrates (Table 1). After preliminary solvent optimization, we discovered that the desired ortho-selective C−H activation occurred efficiently by the treatment of hydrazide 1a with terminal

• alkyne 2a and a stoichiometric amount of Cu(OAc)2 in DMSO (Table 1, entries 1–3). Reaction optimization revealed that the most appropriate temperature was 90 °C (Table 1, entries 3–6). An evaluation of bases showed that Na2CO3 was optimal (Table 1, entries 7–11). The best result was obtained when Cu(OAc

• . Proposed reaction pathway. Optimization of the copper-mediated C−H/N−H functionalization with terminal alkyne 2a.a Supporting Information Supporting Information File 232: Characterization data for 3 and copies of 1H, 13C, and 19F NMR spectra. Funding Generous support by National Natural Science

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• polymerization. Extensive optimization led us to a set of conditions that routinely provided 4-nitro[2.2]paracyclophane (4) in good yields regardless of the scale of reaction (nitration has been performed on scales ranging from 0.5 g to 30 g). The 1H NMR of the crude reaction mixture invariably shows two other

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

• Ivan P. Mosiagin,
• Olesya A. Tomashenko,
• Dar’ya V. Spiridonova,
• Mikhail S. Novikov,
• Sergey P. Tunik and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2021, 17, 1490–1498, doi:10.3762/bjoc.17.105

• [3,4-c]isoquinolin-4-ium bromide 8. Free-radical cyclization of dihalogeno-substituted salts 9 and 12. N-alkylation of the base 6a. Isomerization of compounds 17a and 18a. N-Alkylation of compounds 18a and 19. Optimization of the reaction conditions for the cyclization of 1a with TTMSS/AIBN in MeCN

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• studies for their affinities towards cannabinoid CB1 and CB2 receptors. Results and Discussion Optimization of the reaction The reaction conditions were optimized using 2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)-1-phenylethan-1-ol (1a, 5 mmol) and 1H-indole (2a, 5 mmol) as model substrates (Table 1). At

• was also able to fully block CB1 receptor activation (IC50 value of 5.22 ± 0.68 µM). Our results indicate that the new DIM derivatives act as potent CB1 receptor antagonists with inverse agonistic activity, i.e., they stabilize the inactive receptor conformation. Further optimization is warranted

• and 3ad. Plausible reaction mechanism for the synthesis of fluoromethylated unsymmetrical DIMs, shown for compound 3a as an example. Optimization of the reaction conditions for the preparation of 5-methoxy-3-(2,2,2-trifluoro-1-(1H-indol-3-yl)-1-phenylethyl)-1H-indole (3a)a. Substrate scope of the

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

• salts has been discovered. Results and Discussion Optimization of reaction conditions and chemical synthesis The base-catalyzed imination of aromatic aldehydes is a valuable method in organic synthesis to synthesize a variety of heterocyclic building blocks [29]. Among all the reported iminoesters

• derivative 3ga and 1-indolyl-3,5,8-substituted γ-carbolines 3aa–ac and 3ba–ea. Optimization of the reaction conditions for the transformation of 1-methylindole-2-carbaldeyde (1a) to γ-carboline 3aa. Optical data for γ-carboline 3ac. IC50 values of γ-carbolines 3ac, 3bc, 3ca, 3ga and doxorubicin against

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

• suitable for the reaction though a moderate enantiomeric excess was detected. Finally, the best catalyst turned out to be the pyrrolidine-containing bifunctional thiourea catalyst VII and the desired product was isolated in 80% yield with 80% ee. Then, solvent optimization was carried out to obtain better

• 2 (0.1 mmol), 10 mol % VII in 0.6 mL 1,2-dichloroethane were reacted at 25 °C for 12 hours. Yields correspond to isolated yields after silica gel column chromatography and ees were determined by chiral HPLC. Catalyst screening and optimization of the reaction conditions. Scope of α-nitroketones 2 in

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

• mechanistic study. Plausible mechanism of the CN-K-catalyzed cyanomethylarylation of alkenes. Optimization of the reaction conditions and control experimentsa. Supporting Information Supporting Information File 160: Full experimental details, compound characterisation, and copies of NMR spectra. Funding The

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

• in the efforts to explain the properties and reactivity of this class of compounds. In 1977, S. Ernst et al. proved by X-ray diffraction that biguanide has no hydrogen atom in position 3, an observation that has been later confirmed by quantum chemical geometry optimization studies (Figure 1, 1b) [1

• understood about the role of microwaves on this specific conversion, i.e., thermal or non-thermal effects. Therefore, further investigations in this direction would be of great interest. Another optimization was also attempted by the replacement of HCl with other similar reagents. For example, to exacerbate

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• ; reaction optimization data; reactivity of other glycosyl donors; proposed structures of side-products; detailed description of 19F NMR studies; stability tests for various glycosyl donors. Supporting Information File 145: Copies of NMR spectra. Supporting Information File 146: DFT calculations. Funding

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

• -stereochemistry in the major product. Asymmetric Prins cyclization Mullen and Gagné reported a first catalytic asymmetric Prins cyclization reaction between 2-allylphenol 292 and glyoxylate ester 293 using (R)-[(tolBINAP)Pt(NC6F5)2][SbF6]2 (294) as chiral catalyst [110]. An optimization study revealed that the

• enantioselectivity varied with the polarity of the solvent. The optimization study disclosed that the enantioselectivity increases with the decrease of the polarity of the solvent (Scheme 68). Yu and co-workers reported a novel segment-coupling Prins cyclization involving sequential benzylic/allylic C–H bond