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

• regioselectivity of transesterifications of hydroxylated alkyl and/or aryl moieties are sparser [26][34][35][36]. The extent to which Lipozyme® TL IM catalyzes feruloyl transfer reactions involving substituted benzylic alcohols was thus investigated to establish its usefulness for the preparation of both various

• polyhydroxylated molecules of interest (e.g., antioxidants) [4][26] and of novel chromogenic feruloylated substrates with various physicochemical features for screening applications. Accordingly, we observed that transesterifications only occurred when using primary benzylic alcohols; no phenol acylation was

• ], 4NTC–linker–Fe (12) is almost certainly a better analogue of ferulate linkages found in plant-based structures. Conclusion The use of immobilized Lipozyme® TL IM provides the means to perform the regioselective transesterification of the vinyl ferulate 2 to the primary hydroxy group of benzylic

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

• regioisomers were assigned by chemical shifts of the singlet of the methoxy group. The products having the MeO and NO2 groups in the adjacent position have the signal of the methoxy protons shifted to a lower field. The assignment of the exo/endo-isomers was carried out by the position of the benzylic proton

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• substitution reactions of this type are synthetically appealing as they avoid pre-generation of an active electrophile such as an alkyl halide. A selection of benzylic alcohols 2 was reacted under the standard conditions with BT-SC2F5 (1.25 equiv) and NEt(iPr)2 (2 equiv) in MeCN at −40 °C, providing the

• generated as a significant side product. Finally, the suitability of this methodology for the preparation of (heptafluoropropyl) thioethers was investigated by reacting a selection of benzylic alcohols 2 with BT-SC3F7. As for the pentafluoroethylthiolation reactions, efficient conversion was observed with

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• 19, Kamala Nehru Nagar, Ghaziabad, UP-201002, India 10.3762/bjoc.16.259 Abstract A convenient practical approach for the synthesis of 2-(pyridin-2-yl)ethanols by direct benzylic addition of azaarenes and aldehydes under catalyst- and solvent-free conditions is reported. This reaction is metal-free

• azaarene derivatives under neat conditions through a highly atom-economical pathway. To evaluate the preparative potential of this process, gram-scale reactions were performed up to a 10 g scale. Keywords: aldehydes; azaarenes; benzylic addition; green chemistry; solvent-free conditions; Introduction

• malononitrile under catalyst-free conditions have been reported [29]. Wang et al. reported the functionalization of benzylic C–H bonds of 2-methylazaarenes by nucleophilic addition to aromatic aldehydes catalyzed by acetic acid using harmful chlorinated solvent, and this reaction suffers from longer reaction

Metal-free nucleophilic trifluoromethylselenolation via an iodide-mediated umpolung reactivity of trifluoromethylselenotoluenesulfonate

• Kevin Grollier,
• Alexis Taponard,
• Arnaud De Zordo-Banliat,
• Emmanuel Magnier and
• Thierry Billard

Beilstein J. Org. Chem. 2020, 16, 3032–3037, doi:10.3762/bjoc.16.252

• , entry 9). With the optimal conditions in hand, the reaction was exemplified with various other electrophiles (Scheme 2). The reaction gave generally good results with reactive electrophiles such as benzylic, allylic or propargylic ones (3a–k). Noteworthy, in the reaction with 2-(bromomethyl)pyridine (2g

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

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• ’ “Suman”, which means “Sunflower”), a beautifully simple yet much effective bowl-shaped C3-symmetric polycyclic aromatic hydrocarbon having three benzylic positions clipped between three phenyl rings in the triphenylene framework has attracted a tremendous attention of researchers worldwide. Therefore

• mixture of compounds. In sharp contrast, their attempt under flash vacuum pyrolysis (FVP) at high temperature was also fruitless may be due to the presence of three benzylic sp3 carbons which are unable to endure such harsh reaction conditions. Therefore, next they converted compound 6 into 1,5,9

• Z-oct-4-ene in toluene was found to be a more effective alkene source for the ring-opening reaction in comparison to the gaseous ethylene, as it increases solubility and also improve the lifetime of the catalyst. 2.1 Derivatization at benzylic position As can be inferred from the architecture of

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• visible-light-inactive molecules using PSCats 3.1 Benzylic C–H fluorination A seminal paper in the field of transition-metal-free direct C–H fluorination comes from Chen and co-workers, who applied aryl ketones as PSCats [135]. They discovered that the choice of the PS impacted the selective formation of

• mono- vs difluorinated products at the benzylic position; 9-fluorenone affords benzylic monofluorination and xanthone affords benzylic difluorination (Scheme 5). Importantly, this metal-free direct C–H fluorination proceeded without the need for any specialized photochemical equipment; under visible

• -light irradiation by a household (19 W) compact fluorescent light (CFL) bulb (emitting variable wavelengths in the range of ≈365–625 nm) [195] and under mild conditions. Control reactions revealed that both the PS and light were essential for the reaction to occur. According to their report, benzylic C

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• equiv) in dichloromethane. The reaction was slow and required heating (50–65 °C) for 26 h to reach a 75% conversion and afforded a mixture of E/Z-1a in 60% yield. However, a low E/Z selectivity (40:60) was observed (Table 1, entry 1). When using neat benzylic alcohol, completion was achieved after 20 h

One-pot synthesis of oxazolidinones and five-membered cyclic carbonates from epoxides and chlorosulfonyl isocyanate: theoretical evidence for an asynchronous concerted pathway

• Esra Demir,
• Ozlem Sari,
• Yasin Çetinkaya,
• Ufuk Atmaca,
• Safiye Sağ Erdem and
• Murat Çelik

Beilstein J. Org. Chem. 2020, 16, 1805–1819, doi:10.3762/bjoc.16.148

• . Noteworthy, the C2–N4 bond length does not change much along the IRC for the formation of 10; however, it is shortened more rapidly to give 11. The presence of partial double bond between C2–C(Ph) (benzylic position) allows electron delocalization around the reacting center, which results in stabilization of

• the transition state and so lowering the activation energy barrier (Figure 3a). On the other hand, stabilization of the benzylic cation is not possible along the IRC path for TS1′ (Figure 3b), since the bond distance C2–C(Ph) is found as around 1.50 Å showing a single bond character. This can be the

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

Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• of the ortho-bromine substituent was again accomplished by metalation using TMPMgCl·LiCl and subsequent reaction with 1,2-dibromotetrachloroethane to afford 11 in 76% yield. A second bromination at the benzylic position provided the dibrominated derivative 12 in 66% yield. The substitution reaction

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

• Dandan Li,
• Naoya Oku,
• Yukiko Shinozaki,
• Yoichi Kurokawa and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1489–1494, doi:10.3762/bjoc.16.124

• correlations from the exchangeable proton to C4a and C3 supported this linkage as well as hydroxylation at the benzylic position. Finally, the chemical shift of C8a at 137.4 ppm was in favor of N-substitution, and comparison with the literature values from 4-methoxy-1,3-dimethyl-2(1H)-quinolone (6, δ 138.4

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• in the presence of Ba(OH)2 to give the corresponding thietane-3-ols 145. In this reaction H2S first was deprotonated to the hydrogensulfide anion (−SH) by Ba(OH)2. The obtained anion nucleophilically attacked the less steric or benzylic ring carbon atom of the oxirane ring, giving mercaptoalkanolates

Distinctive reactivity of N-benzylidene-[1,1'-biphenyl]-2-amines under photoredox conditions

• Shrikant D. Tambe,
• Kwan Hong Min,
• Naeem Iqbal and
• Eun Jin Cho

Beilstein J. Org. Chem. 2020, 16, 1335–1342, doi:10.3762/bjoc.16.114

• derivatives (Scheme 2). First, the C–C cross-coupling process with Cy2NMe was explored, with variations of the benzylidene moiety. The reactions with both electron-donating (2b–2e) and electron-withdrawing substituents (2i–2m) proceeded well. Several functional groups, such as benzylic ones (2b and 2c

Ferrocenyl-substituted tetrahydrothiophenes via formal [3 + 2]-cycloaddition reactions of ferrocenyl thioketones with donor–acceptor cyclopropanes

• Grzegorz Mlostoń,
• Mateusz Kowalczyk,
• André U. Augustin,
• Peter G. Jones and
• Daniel B. Werz

Beilstein J. Org. Chem. 2020, 16, 1288–1295, doi:10.3762/bjoc.16.109

• thioketones 8 in the presence of a Lewis acid was based on the assumption that the coordination of the catalyst by two ester groups activated the cyclopropane ring and allowed a nucleophilic attack of the C=S group on the benzylic position of the cyclopropane derivative (Scheme 4). The subsequent ring-closure

• scandium triflate, Sc(OTf)3 as a catalyst, yielding highly functionalized tetrahydrothiophene derivatives of type 9. These formal [3 + 2]-cycloaddition reactions occurred via a nucleophilic attack of the sulfur atom on the activated cyclopropane ring at the most reactive benzylic position. The formation of

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• benzylic C–H bond is present in the γ-position with respect to the oxime group (example 63e, yield 14%). Almost in all examples, an aryl substituent (R1 = Ph or substituted phenyl) was located at the oxime group; the product 63f with R1 = Et was obtained in a moderate yield of 40%. In the presence of only

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• wide redox window (E = 3.22 eV, +1.65 V/−1.77 V), can be exploited as photocatalysts for various transformations, including the reductive dehalogenation of benzylic halides (Scheme 7) [52]. In this protocol, the excited state photocatalyst OD18 can generate C(sp3) radicals through the reductive

• generation, the use of hydroxylamine derivatives has turned out to be very efficient [128][139]. The generation of amidyl radicals using organophotoredox catalysis was first reported by Pandey and Laha in 2015 (Scheme 30) [146]. They developed an intermolecular cross-dehydrogenative benzylic C(sp3) amination

• powerful HAT reagent, allowing the formation of the benzylic radical from 30.1. The absence of any activating group on the nitrogen renders this process atom-economical. In 2016, the Leonori group paved the way for the generation of amidyl radicals by SET reductions of hydroxylamines (Scheme 31) [134]. The

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• formation [64]. 2.2. Stereoselective benzylic fluorination of N-(2-phenylacetyl)oxazolidin-2-one using NFSI Treatment of oxazolidinone 122 with N-fluorobenzenesulfonimide (NFSI) in the presence of NaHMDS afforded the fluorinated oxazolidinone derivative 123. The reductive removal of the chiral auxiliary

• ] (Scheme 33). 2.7. Photocatalyzed benzylic fluorination of N-phthalimido phenylalanine The photocatalyzed benzylic fluorination of phthalimide-protected phenylalanine methyl ester 145, using the photosensitizer 1,2,4,5-tetracyanobenzene (TCB), and Selectfluor in acetonitrile was carried out using a pen

• LED light source (365 nm) and Selectfluor in MeCN [72]. Alternatively, a visible light (14 Watt CFL) mediated benzylic fluorination of a series of N- and C-terminally protected phenylalanines 147 using Selectfluor and dibenzosuberenone in acetonitrile, afforded the β-fluorophenylalanine derivatives

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• ). Meldrum’s acid and its derivatives are versatile reagents in organic synthesis that can be transformed into a wide range of compounds. In 2006, the group of Fillion described the highly enantioselective synthesis of all-carbon benzylic quaternary stereocentres via a conjugate addition of dialkylzinc

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• 6D, in which the H-atom is transferred from the secondary benzylic sp3 carbon to the redox-active ligand, acting as a cooperative H-atom acceptor. Following a proton-coupled electron transfer (PCET) to generate 6E, the oxidized product (benzaldehyde) is released and final elimination of H2O2

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

• David Schönbauer,
• Carlo Sambiagio,
• Timothy Noël and
• Michael Schnürch

Beilstein J. Org. Chem. 2020, 16, 809–817, doi:10.3762/bjoc.16.74

• group [2][6][7]. For example, in tetrahydroisoquinolines (THIQs) the benzylic C1-position is significantly more reactive compared to the others and its selective functionalization has been reported [8]. The THIQ moiety is of special interest due to its presence in several different natural products [9

• decomposition of the reaction components (Figure 1). Then, the substrate scope of the transformation was investigated, reacting different benzylic pyridinium salts with N-phenyl-THIQ (1, Scheme 2). Initially, steric effects were investigated using ortho, meta, and para-methylated benzylpyridinium salts. The

• towards desired bioactive compounds. At last, we turned our interest towards non-benzylic Katritzky salts, showcasing that also the reaction with unactivated secondary alkyl and allyl radicals takes place (Scheme 5). For the less reactive secondary alkyls the more expensive catalyst [Ir(dtbbpy)(ppy)2]PF6

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• reagent (7), to successfully convert benzyl phosphate 6 to benzylic silanes 8. Curiously, the reaction proceeded even in the absence of a ligand, albeit with lower yield (25%; Scheme 3). However, only one example was reported and a more general method for the preparation of alkylsilanes was developed by

• more stable trans product, 246. The direct activation of C(sp3)–H bonds attached to N-Cl tosylamines 253 was achieved via a radical pathway affording the products of silylation 254–258 in good chemical yields (Scheme 43) [81]. Most benzylic or benzylic-like positions are sufficiently activated to give

• -position on the ring could be accessed. A dual catalytic cycle was proposed, where the Cu–Si species formed in situ undergoes transmetallation to the Pd(II) species resulting from the attack of Pd(0) on the aziridine ring, ultimately affording the silylated product with silicon at the benzylic site (Scheme

Synthesis of C₇₀-fragment buckybowls bearing alkoxy substituents

• Yumi Yakiyama,
• Shota Hishikawa and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2020, 16, 681–690, doi:10.3762/bjoc.16.66

• dioxole derivative 5b together with an unexpected regioisomer 5c. Results and Discussion Synthesis of dialkoxides 5a–c Dialkoxides 5a–c were prepared according to the previous report on the synthesis of 1 (Scheme 1) [18][20]. The benzylic carbanion generated by the addition of 130 mol % n-BuLi to 2 in THF

• ring’s plane (Figure 3c, red coloured part) in 5b were 0.80–0.84 Å from the peripheral benzylic carbons and 0.80–0.89 Å from the peripheral aromatic carbons, respectively, while 0.74–0.79 Å and 0.79–0.99 Å in 1, respectively (Table 2) [18]. As observed in the crystal of 5a, 5b formed convex-to-concave

• interactions are omitted for clarity. a) Definition of POAV angle (φ). b) Side and c) top view of the molecular skeleton of 1. The double-headed arrow show the perpendicular line from the peripheral carbons to the bottom hexagonal ring coloured in c). In b) and c), pink colored atoms are benzylic, and blue

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• attempts to oxidize the methyl group at the benzylic position in starting materials 2 and 3 to provide the corresponding aldehyde compounds 13 and 14 failed, despite using rigorous reaction conditions of SeO2 or alternative strong oxidizing agents (e.g., MnO2 and oxone). Thus, we considered the critical

• role of the electronic effects of the nitrogen atoms on this cyclic substrate, and then we revised our synthetic strategy by a) tethering an alkene functional group on the aromatic ring and b) then conducting the oxidation of the benzylic group to afford the aldehyde product. Towards this end, we

• Information File 1, Figure S7) and δ 6.57 and 7.63 ppm with a J value of 15 Hz for compound 18 (Supporting Information File 1, Figure S9) as inferred by 1H NMR analysis. The resulting Suzuki-coupled products 16 and 18, were subjected to benzylic oxidation expecting the olefin functionality would facilitate