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

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• )]/[Cu(I)]*/[Cu(II)] species and the reduction of the Zhdankin reagent by the copper catalyst to form an azidyl radical, which then reacted with the olefin. The resulting benzyl radical could then be oxidized, probably by the catalyst in the +II oxidation state, to generate a benzylic carbocation and the

• active [Cu(I)] catalyst. Finally, the solvent or the nucleophile introduced to the reaction medium reacted with the latter. Later, Greaney and co-workers reported the photocatalytic azidation of benzylic C–H bonds (Scheme 10) [27]. Using the Sauvage catalyst [Cu(I)(dap)2]PF6 and the Zhdankin reagent, a

• copper photocatalyst initiated the formation of the azidyl radical, which abstracted the benzylic hydrogen atom from the substrate. Then, the benzylic radical reacted with the Zhdankin reagent, producing the azidated product and propagating the radical chain through the reaction of the iodane radical

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• -trifluoromethylated styrenes no lactone formation took place in these reactions, and only the Kharasch-addition product was observed. The benzylic radical resulting from radical addition to these styrene derivatives seems to be too electron poor for efficient oxidation induced cyclization, thus resulting in a

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

• Panagiotis S. Gritzapis,
• Panayiotis C. Varras,
• Nikolaos-Panagiotis Andreou,
• Katerina R. Katsani,
• Konstantinos Dafnopoulos,
• George Psomas,
• Zisis V. Peitsinis,
• Alexandros E. Koumbis and
• Konstantina C. Fylaktakidou

Beilstein J. Org. Chem. 2020, 16, 337–350, doi:10.3762/bjoc.16.33

• carbamates [61][64][65] where 1H NMR spectroscopy has been used in order to distinguish between the two [61][65]. Thus, the imine benzylic proton of the E-stereoisomers shows a singlet in the area 8–8.7 ppm, whereas the ones belonging to a Z-conformation are upfield and appear between 7.3–7.6 ppm. Indeed

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions

• Clément Ghiazza and
• Anis Tlili

Beilstein J. Org. Chem. 2020, 16, 305–316, doi:10.3762/bjoc.16.30

• high yields. Benzylic bromides and chlorides furnished the desired products in moderate to good yields. However, less activated substrates led to marginal amounts of the trifluoromethylselenylated compounds. Also, when secondary benzylic halides were used in the reaction, low yields were observed

The reaction of arylmethyl isocyanides and arylmethylamines with xanthate esters: a facile and unexpected synthesis of carbamothioates

• Narasimhamurthy Rajeev,
• Toreshettahally R. Swaroop,
• Ahmad I. Alrawashdeh,
• Shofiur Rahman,
• Abdullah Alodhayb,
• Seegehalli M. Anil,
• Kuppalli R. Kiran,
• Chandra,
• Paris E. Georghiou,
• Kanchugarakoppal S. Rangappa and
• Maralinganadoddi P. Sadashiva

Beilstein J. Org. Chem. 2020, 16, 159–167, doi:10.3762/bjoc.16.18

• been reported for other carbene hydrolyses [37][38][39]. As can be seen from Figure 5, the highest activation energy barrier is 42.2 kJ/mol. We had previously considered an alternative mechanism in which a benzylic proton is instead removed by the base [40]. For the previous mechanism, which we have

• now recalculated at the B3LYP/6-311++G(d,p) level of theory in DMF (using a PCM, see Scheme S1 and Figures S15 and S16, Supporting Information File 1), an activation energy barrier of 20.6 kJ/mol was obtained for the formation of the resulting benzylic α-carbanion and H2. This benzylic α-carbanion

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose

• Lukáš Kerner and
• Paul Kosma

Beilstein J. Org. Chem. 2020, 16, 9–14, doi:10.3762/bjoc.16.2

• of 10, the olefinic proton was absent, whereas the 13C NMR spectrum showed downfield shifts for the anomeric carbon atom (146.48 ppm) and the adjacent ring carbon atom (133.95 ppm). Evidence from an HMBC experiment additionally indicated a correlation between the benzylic protons and the latter

Palladium-catalyzed synthesis and nucleotide pyrophosphatase inhibition of benzo[4,5]furo[3,2-b]indoles

• Hoang Huy Do,
• Saif Ullah,
• Alexander Villinger,
• Joanna Lecka,
• Jean Sévigny,
• Peter Ehlers,
• Jamshed Iqbal and
• Peter Langer

Beilstein J. Org. Chem. 2019, 15, 2830–2839, doi:10.3762/bjoc.15.276

• of the reaction of 3 was studied using different amines. The reaction of 3 with various anilines afforded products 5a–g in good to excellent yields (Table 2). No impact of the functional groups of the anilines on the yield was observed. The reactions of 3 with aliphatic or benzylic amines under our

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• asymmetric induction was proposed to be realized via a combination of chiral Lewis acid-bound radical (generated through a single-electron anodic oxidation) and benzylic radical, generated through the anodic oxidation of 95. As per the proposed catalytic cycle, initial coordination of the Lewis acid catalyst

• to 2-acylimidazole derivatives 94 generates the Lewis acid/enolate complex 100 upon deprotonation (Scheme 35). This is followed by the formation of intermediate 101 by electrolysis-induced SET oxidation. In a parallel electrochemical cycle, benzylic radical species 95 was delivered by the anodic

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• of the inner ring with respect to the azo bond (i.e., the ortho-position with respect to the benzylic position) to afford subseries 4. This π-electron delocalization would increase the electron density of the azobenzene unit, and was also expected to have an effect on the trans–cis azobenzene

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• fluoride source and PhI(OPiv)2 as a hypervalent iodine oxidant (Scheme 8). Very recently, they [44] optimized this transformation and achieved the benzylic C–H radiofluorination with no-carrier-added Ag[18F]F. This method was applied to the radiolabeling of diversely substituted 8-methylquinoline

• derivatives (Scheme 11a). This process was carried out under the strongly binding bidentate 2-(pyridine-2-yl)isopropylamine (PIP) auxiliary. A range of substrates containing both aliphatic and benzylic C(sp3)–H bonds was finally converted to the corresponding fluorinated products with excellent

• inert C–H bonds, alkyl bromides and -triflates: In a 2012 study, Lectka’s group [67] disclosed the catalytic fluorination of a series of aliphatic, benzylic, and allylic substrates with moderate yields. In this case, the authors employed a multicomponent catalytic system, involving Selectfluor, the

Multiple threading of a triple-calix[6]arene host

• Veronica Iuliano,
• Roberta Ciao,
• Emanuele Vignola,
• Carmen Talotta,
• Patrizia Iannece,
• Margherita De Rosa,
• Annunziata Soriente,
• Carmine Gaeta and
• Placido Neri

Beilstein J. Org. Chem. 2019, 15, 2092–2104, doi:10.3762/bjoc.15.207

• 6 in CDCl3 at 298 K at 0.95 (27H), 1.05 (54H), and 1.22 ppm (81H = 54H + 27H; accidentally isochronous) attributable to tert-butyl groups, and three singlets at 2.56, 2.80, and 3.12 ppm in a 2:1:2 ratio, attributable to OMe groups were also found. The methylene benzylic resonance of 6 was revealed

• present at 5.13 ppm and 4.96 ppm (1:2) attributable to the benzylic methylene groups of the central benzene core of 6 in 7+6 pseudo[2]rotaxane. A DOSY experiment (Figure 3, top) evidenced that the resonances in the 1H NMR spectrum of the 1:1 mixture of 6 and 7+·TFPB− in CDCl3 at 298 K all show the same

• -tetrachloroethane as internal standard, an apparent association constant of 1.01 ± 0.03 × 104 M−1 was calculated for the 7+6 pseudo[2]rotaxane. When 1 equiv of 7+·TFPB− salt was added to the 1:1 mixture of 6 and 7+·TFPB− in CDCl3 (Figure 4c), then, in addition to the benzylic resonances of the 7+6 pseudo[2]rotaxane

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• was isomerized in the presence of base and dehydrated to give diene 45. Reduction of 45 with 10% Pd/C afforded 8 in good yield (60%) after recrystallization. Benzylic oxidation of 8 (CrO3/HOAc, 45%), followed by C-14 ether cleavage (BBr3) and subsequent sodium borohydride reduction afforded 46 with

• the desired stereochemistry of the C-7 benzylic hydroxy group. Compound 46 was converted to triptonide 2 by Alder periodate reaction (NaIO4, 74%), and a sequencing m-CPBA epoxidation and basic hydrogen peroxide oxidation (H2O2/OH−) procedure (two steps, 28%). Finally, sodium borohydride reduction of 2

• isomerization of olefin 43, the benzylic oxidation of 8, the use of m-CPBA to introduce the C-9,11 epoxide and the non-stereoselective reduction of the C-14 carbonyl group using sodium borohydride, caused an unacceptable overall yield (1.6%). This pioneering work undoubtedly established the basis for the future

Metal-free mechanochemical oxidations in Ertalyte^® jars

• Andrea Porcheddu,
• Francesco Delogu,
• Lidia De Luca,
• Claudia Fattuoni and
• Evelina Colacino

Beilstein J. Org. Chem. 2019, 15, 1786–1794, doi:10.3762/bjoc.15.172

• carboxylic acid derivatives were observed in any sample. Similar results were obtained for alcohols containing an aliphatic carbon ring in their backbone, such as cyclohexylmethanol (5a). Interestingly, the oxidation reaction of benzylic alcohols proceeded smoothly to completeness in about 10 minutes even

• without need for TEMPO. The results changed significantly with benzylic alcohols decorated with an electron-withdrawing group in the aromatic ring such as 4-nitrobenzylalcohol (and 4-cyanobenzylalcohol), which required 5 mol % of TEMPO to be oxidized. Based on these experimental results, we hypothesize

• benzylic alcohols 6a or 7a to afford the corresponding intermediate benzyl hypobromites 6c or 7c (Scheme 5, reaction 3). In the final step, the base deprotonates the acidic benzylic proton leading to the corresponding benzaldehyde 6b or 7b (Scheme 5, reaction 4). The oxidation of furfuryl alcohol gave

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• NaBH4/ZnCl2 mixture (chelation controlled) gave the aziridine alcohol 20 as a major product. Reductive opening of the aziridine ring produced the amino alcohol 21 which was transformed into the substituted oxazolidin-2-one 22. Its catalytic hydrogenation effected deoxygenation at the benzylic position

• cleavage of the aziridine ring occurred regiospecifically at the N–C3 bond (benzylic position) to provide N-Boc-ᴅ-phenylalaninol ((R)-118) after saponification. When mesylation of (2S,1'R/S,1''R)-28 was followed by LiAlH4 reduction the aziridine (2R,1'R)-119 was produced from which the acetate (2R,1'R)-120

• these conditions the acetate function was also hydrolyzed the carboxy group was formed by oxidation of the hydroxymethyl residue. To complete the synthesis N- and O-benzylic protecting groups were removed during the Birch reaction. A polyoxamic structural framework was found in polyoxins, natural

A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

• András György Németh,
• György Miklós Keserű and
• Péter Ábrányi-Balogh

Beilstein J. Org. Chem. 2019, 15, 1523–1533, doi:10.3762/bjoc.15.155

• , we have turned our attention to different benzylic alcohols that could be utilized to further examine the functional group tolerance of the reaction. Notably, chlorine, bromine and iodine substituents were compatible with the transformation, providing 3m, 3n, 3r and 3s in 81–89% yield. The nitrile