Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• further oxidized, and thus producing the respective benzylic cation. Intramolecular cyclization in the cationic position under participation of the methyl ester function provided the core for (+)-grandilodine C (191) and (+)-lapidilectine B (192), while allylation of the benzylic position allowed

• quenchers (e.g., PhSSPh) to the reaction mixture. When monosubstitution of the aryl group is present, the formed radical cation, the product of the photooxidation of the cinnamyl ether, readily cyclizes to cyclobutene radical cation 217. The latter cleaves the benzylic C–C bond to produce the 1,4-radical

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• HFIP. The regioselective amination of benzylic positions in alkylarenes [82] and ethers [83] directed by steric effects was achieved by the development of sterically hindered “bowl-shaped” imide-N-oxyl radical precursors (Scheme 7). The presented example with a sterically hindered N-hydroxyimide

• -hydroxybenzimidazole core has several modification sites that allow one to control the properties of the catalyst over a wide range. The authors demonstrated the high efficiency of N-hydroxybenzimidazole catalysts in the benzylic CH-amination with diethyl azodicarboxylate and the CH-fluorination of aldehydes with

• photoredox-catalyst or electrochemically on an anode. An example of the photochemical aerobic benzylic CH-oxidation employing a heterogeneous photoredox catalyst, nanosized TiO2, was demonstrated by our group [85] (Scheme 9). Mixing of NHPI and TiO2 leads to the emergence of visible light absorbance

Using UHPLC–MS profiling for the discovery of new sponge-derived metabolites and anthelmintic screening of the NatureBank bromotyrosine library

• Sasha Hayes,
• Aya C. Taki,
• Kah Yean Lum,
• Joseph J. Byrne,
• Merrick G. Ekins,
• Robin B. Gasser and
• Rohan A. Davis

Beilstein J. Org. Chem. 2022, 18, 1544–1552, doi:10.3762/bjoc.18.164

• hydroxy group were positioned at C-3 and C-4 of the aromatic ring, respectively, based on NMR chemical shift data comparison with related marine natural products [19]. The E configuration for the oxime in 1 was assigned by the diagnostic carbon chemical shifts of the benzylic methylene (C-7, δC 27.8) [21

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• of benzaldehyde led to the formation of adduct 14 (in 75% yield), which arose from the addition of a benzyl carbanion 17 to benzaldehyde. The generation of such a nucleophile strongly suggests the formation of pentavalent silicon intermediate 15 [27], which then produced a (stabilized) benzylic

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

• Maxime Pypec,
• Laurent Jouffret,
• Claude Taillefumier and
• Olivier Roy

Beilstein J. Org. Chem. 2022, 18, 845–854, doi:10.3762/bjoc.18.85

• through steric and electronic interactions involving peptoid amides and nearby side chains [17][18]. For example, N-substituted monomers bearing benzylic-type Nα-chiral groups including the phenylethyl [19][20][21], naphthylethyl [17][22][23][24], and triazolium groups [25][26][27], alkyl ammonium [28

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• cyclopropanes, Li and co-workers treated compound 36 with triflic acid (TfOH) in refluxing HFIP (Scheme 13) [24]. The reaction afforded compound 37 in 82% through the regioselective intramolecular ring-opening of the cyclopropane ring at the benzylic carbon atom. Very recently, our group has reported the

Green synthesis of C5–C6-unsubstituted 1,4-DHP scaffolds using an efficient Ni–chitosan nanocatalyst under ultrasonic conditions

• Soumyadip Basu,
• Sauvik Chatterjee,
• Suman Ray,
• Suvendu Maity,
• Prasanta Ghosh,
• Asim Bhaumik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 133–142, doi:10.3762/bjoc.18.14

• The substrate scope and the generality of the reaction under the optimized conditions were explored through the synthesis of various products using differently substituted primary amines 1, cinnamaldehydes 3, and dialkyl but-2-ynedioates 2. Aromatic, aliphatic, benzylic, and various other types of

Efficient synthesis of ethyl 2-(oxazolin-2-yl)alkanoates via ethoxycarbonylketene-induced electrophilic ring expansion of aziridines

• Yelong Lei and
• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 70–76, doi:10.3762/bjoc.18.6

• heating, diazo esters 1 undergo a Wolff rearrangement to generate ethoxycarbonylketenes A by loss of nitrogen. The nucleophilic attack of 2-arylaziridine 2 on the ketene moiety produces zwitterionic intermediates B, in which the aziridinium is opened to form the benzylic carbocation stabilized through the

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• of other metals such as Au, Pt, Pd, Rh, Ag, and Fe and found that they were less efficient compared to Ru. The benzylic alcohols showed higher reactivity than aliphatic alcohols towards this methodology. Moreover, this protocol worked well for differently substituted heterocyclic alcohols and

A photochemical C=C cleavage process: toward access to backbone N-formyl peptides

• Haopei Wang and
• Zachary T. Ball

Beilstein J. Org. Chem. 2021, 17, 2932–2938, doi:10.3762/bjoc.17.202

• -nitroaryl compounds. Various 2-nitrobenzyl derivatives are used to photocage heteroatom functional groups, including alcohols, amines, carboxylic acids, and phosphates [11]. Typical photochemical pathways result in cleavage of a benzylic C–X bond following initial benzylic H-atom abstraction [11][13]. In

• contrast, photorelease systems based on C–C or C=C bond photocleavage are quite rare [14][15]. We recently reported a vinylogous analogue of this photo-deprotection process, which allowed photocleavage of alkenyl sp2 C–X bonds, rather than benzylic sp3 C–X cleavage [16][17]. We now report that further

• residue (Figure 1C, step, i + iv → ii) [18][19][20]. Subsequent investigations validated the use of photoreactive boronic acids as an approach to reversible backbone N–H modification via photocleavage of an alkenyl C–N bond [16][17]. Traditional 2-nitroaryl groups allow cleavage of benzylic C–X bonds (e.g

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• . Notably, the reaction did not proceed in the dark or in the absence of the photosensitizer at 30 °C; further, the reaction generated the desired product in lower yield at 120 °C. The scope was broad and tolerated a wide array of 1,3-keto esters and 1,3-diketones, as well as both benzylic and aliphatic C

• generating a benzylic radical which can be oxidized by Ag(I) to afford the corresponding benzylic cation. Nucleophilic trapping with an amine will produce the final product. In the same year, Song and co-workers reported a dehydrogenative 1,2-difunctionalization of conjugated alkenes 107 with silanes 92 and

• radical across the alkene to afford the benzylic radical. Oxidation of the corresponding radical affords the benzylic carbocation which is attacked by the indole nucleophile. The authors applied the reaction methodology to pyrrole as a substrate; however, only one example was given in a 50% yield. Further

Biological properties and conformational studies of amphiphilic Pd(II) and Ni(II) complexes bearing functionalized aroylaminocarbo-N-thioylpyrrolinate units

• Samet Poyraz,
• Samet Belveren,
• Sabriye Aydınoğlu,
• Mahmut Ulger,
• Abel de Cózar,
• Maria de Gracia Retamosa,
• Jose M. Sansano and
• H. Ali Döndaş

Beilstein J. Org. Chem. 2021, 17, 2812–2821, doi:10.3762/bjoc.17.192

• results of its corresponding nickel(II) [18] and palladium(II) [19][20] complexes with the analogous tests obtained in the case of having a benzylic substituent at the same position. Also, DFT calculations are run in order to study the conformational analysis of the synthetized complexes. Results and

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

• [3,4-d][1,2,3]triazine compounds 5 (Scheme 4). The successful cyclizations gave the desired pyrazolo[3,4-d][1,2,3]triazines 5 in moderate to good yields. Not all cyclization products were air-stable. While compounds 5a–d with a benzylic side chain in R1'' were stable, a full characterization was

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

• developed convenient access to phenolic benzyltetrahydroisoquinolines opens the possibility for flexible late stage etherification with various aromatic, benzylic and related residues for a comprehensive investigation of the chemical space around this pharmacophoric backbone. Experimental Materials and

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

• give imines, iminium salts, aldehydes and other, in some cases dimeric products [49]. Here, oxidation of the benzylic amino moiety should lead either to iminium ions (or N-acyl iminium ions) 4a as strong electrophiles or to stabilized radicals 4b which could undergo cyclization to give the fluorenone

• backbone. Expected 9-aminofluorene intermediates 5 were envisaged to undergo subsequent oxidation by the same oxidant to hopefully provide the fluorenones 3 in a domino reaction. Results and Discussion After comprehensive literature search for successful oxidations of benzylic C–N bonds we tested a variety

• of oxidizing agents, oxidizing systems, and radical initiators on a set of model molecules 2 (see Table 1) in a preliminary screening for suitable oxidants for the intramolecular ring-closure reaction. The set of model molecules 2 bears different benzylic N-containing functional groups, including

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• functionalization reactions Benzylic or α-amino C–H groups and even the stable C(sp3)–H group were functionalized through the corresponding benzylic radical, α-amino radical, or alkyl radical. In 2016, Greaney and co-workers [92] investigated the direct C–H azidation with benzylic C–H compounds 47 and the Zhdankin

• reagent. After investigating a range of reaction parameters, copper salts and visible light were found to be necessary for the transformation. The reaction is highly selective for the benzylic position. In the same year, Bissember’s group [93] reported a copper-photocatalyzed α-amino C–H functionalization

• between N-heteroarenes 69 and redox-active esters 68. In 2018, Gong and co-workers [43] used benzyltrifluoroborates 71 as a benzylic radical source for the visible-light-induced alkylation of imines 70. In the catalytic system, chiral ligands initiated benzylic radical formation and governed the

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

• our studies on a direct benzylic allylic reaction of 2-alkylpyridines with MBH carbonates as allylic precursors under base- and catalyst-free conditions. As depicted in Scheme 2, we envisioned that the MBH carbonate 2 can undergo the SN2’ reaction with the nucleophilic 2-picoline 1a, giving the

• pyridinium cation intermediate A. The in situ generated tert-butoxide anion has enough basicity to deprotonate of the activated benzylic proton of intermediate A and generates the anion B1, which can be tautomerized into more stable enamine intermediate B2. Finally, the intermediates B1 or B2 occur an

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

• -Alk) and 9-(azidomethyl)anthracene (Az-2) as click components was investigated. The detailed 1H NMR spectrum of the resulting anthracene functional polymer (PCL-Anth) exhibited the characteristic signals of triazole and benzylic protons at 5.5 ppm and 8.70 ppm, respectively (Figure 4a). The obtained

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines

• Matthew J. Fleming and
• David M. Hodgson

Beilstein J. Org. Chem. 2021, 17, 2385–2389, doi:10.3762/bjoc.17.155

• with cross-coupling using the same carbenoid and epoxide 5 (Scheme 5), where the presence of LTMP also proved necessary. A cinnamylamine 23 could be obtained in a tin-free process (Scheme 10), which utilises the increased acidity of a benzylic ether 22. In this case, the presence of LTMP was necessary

• stereoselectivity. However, neither isopropyl or neopentyl benzylic ethers 26 and 27 [23][24] led to a significant change in the E/Z ratio for cinnamylamine 23 (Scheme 11). Conclusion In summary, we report a new, convergent access to allylic alcohols and amines. The process proceeds by selective cross-coupling of α

• epoxide 5. Synthesis of vinylsilane 14. Allylic alcohol 8 from epoxide 5 and sulfone 15. Allylic amines from aziridine 17. Cyclopropylidene synthesis from aziridine 20. Cinnamylamine 23 synthesis from aziridine 17. Cinnamylamine 23 synthesis from isopropyl or neopentyl benzylic ethers 26 and 27

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

• the racemic naphthohydroquinone hongconin (197) starting from the ortho-allyl alcohol derivative 195. The starting material was cyclized using a Hg(II) salts to get an inseparable mixture of products 196a and 196b in the ratio of 1:5 [121]. The synthetic route proceeded by benzylic alcohol ortho

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• has a remarkable structural feature: the phosphate moiety is located at the benzylic position as well as at the position α to an amide group, which makes it a good leaving group for the design and development of new reactions. Accordingly, diethyl (2-oxoindolin-3-yl) phosphates 2 have been used

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

• photoredox nickel-catalyzed arylation of α-oxy C–H bonds of tetrahydrofuran (THF) and oxetane were also shown. Further, the catalytic system also proved compatible for the C‒H arylation of the benzylic system. As shown in Figure 2 [54], the mechanism for the transformation is proposed to involve the

• iridium(III) photocatalyst 2-I. Subsequently, Ahneman and Doyle reported a related process for the synthesis of a variety of benzylic amines 7 by the arylation of α-amino C(sp3)‒H bonds with aryl iodides 2 involving photoredox nickel catalysis (Scheme 4) [55]. In this protocol, bis(oxazoline) (BiOx) was

• . Notably, the photocatalytic conditions proved suitable for the benzylic C(sp3)−H and unactivated alkane cyclohexane C‒H arylations. The catalytic cycle is proposed to involve the oxidative addition of nickel(0) 4-IV into an aryl chloride 8a to form nickel(II) intermediate 4-V (Figure 4) [56]. The SET

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

• -cyclotrimerization reaction catalyzed by a cobalt/zinc reagent [40]. With regard to substituted anthracenes, this method consisted of a [2 + 2 + 2] cycloaddition reaction of 1,6-diynes 27 with 4-aryl-2-butyn-1-ols 28 (Scheme 6). The authors converted the resulting benzylic alcohols 29 to the corresponding aldehydes

• prepared substituted anthracenes 77, bearing phenyl, methyl, chloro, or methoxy groups, such as 77a–c in excellent yields (94–96%) by treating the corresponding 2-benzylic aromatic aldehydes/ketones 76 with a catalytic amount of In(OTf)3 (Scheme 18) [51]. In addition, the authors explored this methodology

• agent. One-pot procedure to synthesize substituted 9,10-dicyanoanthracenes. Reduction of bromoanthraquinones with NaBH4 in alkaline medium. In(III)-catalyzed reductive-dehydration intramolecular cycloaromatization of 2-benzylic aromatic aldehydes/ketones. Acid-catalyzed cyclization of new O-protected

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

• heterogeneous vanadium-based catalysts have been employed to obtain alcohols and carbonyl compounds through oxidation, including VOSO4, Na(VO3), VO(acac)2, VOX3, among others. Obtaining ketones and aldehydes from hydrocarbon compounds through vanadium-mediated activation of C(sp3)–H bonds in a benzylic position

• to oxidize ethylbenzene without significant loss of activity and metal leaching. The authors have suggested a mechanism for the reaction involving radical species bearing a benzylic carbon–vanadium bond. Fluorine presents unique features and may lead to essential changes in the structural and

• reaction showed to be chemoselective, maintaining good yields with compounds bearing varied functional groups, whereas low yields were observed for benzylic fluorination. Preliminary mechanistic studies suggested the C–H abstraction to be the rate-determining step and the high oxygen sensitivity of the

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

• was observed at the less sterically hindered benzylic position. The proposed reaction mechanism for radiofluorination is depicted in Figure 2. Although the trans-difluoro-substituted Mn(IV) complex is the reactive F-transfer intermediate in 19F chemistry, the formation of a trans-18F-difluoro

• adjacent carbamate group. The naturally available substrate 9b was shown to undergo the azidation process at the less sterically hindered position. An analogue of rasagiline (Azilect®), a Parkinson’s disease drug, successfully underwent benzylic azidation, providing product 11c. Other complex molecules

• bearing aromatic groups were also successfully azidated, predominantly at the benzylic position (see 11e and 11f). Notably, diazidation of 9e was observed as the major side reaction (18%). Interestingly, OBz-substituted artemisinin 9g was converted to OBz-substituted N3–artemisinin 11g via azidation at