Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• drug”) class of PROTAC molecules with a PEG linker is frequently used to promote targeted protein degradation. The standard protocol for their synthesis involves nucleophilic aromatic substitution of 4-fluorothalidomide with a PEG-amine. We report herein the identification of a commonly ignored

• synthesis of iVeliparib-AP6 [5] starts with a nucleophilic aromatic substitution (SNAr) reaction wherein 4-fluorothalidomide (1) reacts with amino-PEG7-OH 2 to give alcohol 3 (Scheme 1). Subsequent alcohol oxidation followed by reductive amination of the resulting aldehyde 4 with veliparib [6][7] provides

• addition intermediate is stabilized by an oxygen atom only. As such, the erosion of 3 by taurine was minimal. Conclusion Nucleophilic aromatic substitution of 4-fluorothalidomide (1) has provided a convenient entry to the IMiD class of PROTAC molecules. Although the yield of the desired product is

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• , photoredox-catalytic, and nucleophilic aromatic substitution reactions, as well as in the two-step synthesis of cyclobutanone. The molecules synthesized under the optimal conditions are presented in Figure 6b, employing the stable noisy optimization by branch and fit (SNOBFIT) algorithm. SNOBFIT offers a

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• intramolecular. In the presence of a base, the triflate anion is extracted, forming a cationic trifluoromethanesulfonyl group as an intermediate. Thus, the products are believed to form via a sulfonyl-directed nucleophilic aromatic substitution pathway. Finally, the products are obtained through the dissociation

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

• Ruben Manuel Figueira de Abreu,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2708–2719, doi:10.3762/bjoc.20.228

• likely by nucleophilic aromatic substitution during aqueous workup. Interestingly, electron-donor groups, such as N,N-dimethylamino, proved to be beneficial in terms of yield when they are located at the alkyne-linked aryl group (Scheme 4a). In contrast, the N,N-dimethylanilino group is disadvantageous

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• preparation of biologically active compounds [15]. The synthesis was achieved via a sulfonyl group rearrangement driven by the azide–tetrazole equilibrium in quinazolines. The researchers utilized two synthetic pathways to prepare the target compounds. The first pathway involved a nucleophilic aromatic

• substitution (SNAr) reaction between 2-chloro-6,7-dimethoxy-4-sulfonylquinazoline derivatives and NaN3, while the second involved an SNAr reaction between 2,4-dichloro-6,7-dimethoxyquinazoline and alkyl/arylsulfinates, followed by substitution with NaN3. Using this developed methodology, the adrenoblockers

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• +) cations, used as visible light fluorescent dyes, have been synthesized via a nucleophilic aromatic substitution (SNAr) reaction with primary alkylamines (e.g., 1a+; Figure 1) [15][16]. The highly planar geometry of the TATA+ core unit induces π–π stacking structures in single-crystal and film states, as

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• synthesis of highly fluorescent DPP derivatives through straightforward nucleophilic aromatic substitution reactions with thiols and phenols. These nucleophilic substitutions occur at room temperature and manifest a remarkable selectivity for the 4-position of the pentafluorophenyl groups. Both symmetrical

• pentafluorobenzyl bromide, followed by a nucleophilic aromatic substitution (SNAr) with thiols and phenols. This approach is based on the well-established reactivity of perfluoroaromatic compounds in nucleophilic aromatic substitutions [32][33][34][35]. By varying the reaction conditions and the number of

• generating new DPP derivatives through nucleophilic aromatic substitution reactions with thiols and phenols. The main objective of this study was to employ the N,N’-bis(pentafluorobenzyl)-DPP 2 as an electrophile and investigate its reactivity with thiols and phenols (Scheme 1). All SNAr reactions were

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• could be efficiently transformed to tautomerically active, H-bonding capable 1,4-dihydropyrazino[2,3-b]quinoxaline-2,3-diones (Figure 1b, DPQDs) via nucleophilic aromatic substitution (SNAr) at the ipso-CN positions. Here, the lactim–lactam tautomerization of DPQDs to arrive at the more stable 2,3-dione

Synthesis of new representatives of A₃B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

• Victoria M. Alpatova,
• Evgeny G. Rys,
• Elena G. Kononova and
• Valentina A. Ol'shevskaya

Beilstein J. Org. Chem. 2024, 20, 767–776, doi:10.3762/bjoc.20.70

• single pentafluorophenyl ring was prepared through the regioselective nucleophilic aromatic substitution reaction of the p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with 9-mercapto-m-carborane. The reaction of this porphyrin with sodium azide led to the selective substitution of

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• ), it was non-scalable and displayed low modularity. Indeed, the imide groups along with their substituents were introduced at a rather early stage of the synthesis, with the ultimate synthetic step being the formation of the thiepine ring via a two-fold nucleophilic aromatic substitution by sodium

• corresponding boronic acid 9 and a Suzuki–Miyaura cross-coupling between 8 and 9 gave rise to dimer 10, followed by the oxidation of both acenaphthene units into 1,8-naphthalic anhydrides. Installation of the thiepine ring was achieved by a double nucleophilic aromatic substitution induced by sodium sulfide

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• ]. Organocatalytic aryl C–H activation via a nonradical process represents an enormous challenge in organic synthesis, although the nucleophilic aromatic substitution with cleavage of the electrophilic aryl C–H bond has only recently been developed by transition-metal-catalyzed aryl C–H activation [57]. In the

• presence of a chiral phosphoric acid, the azo group has recently been revealed to be a useful moiety that may efficiently activate an aromatic ring for formal nucleophilic aromatic substitution, resulting in the cleavage of the aryl C–H bond and direct arylation of the nucleophile [58]. In 2018, Tan and co

• -workers showed that azo groups enable the organocatalytic asymmetric arylation of indoles. The nucleophilic aromatic substitution between the azobenzene derivative 24 and indoles 25 was carried out in the presence of 2.5 mol % chiral phosphoric acid (CPA 8, Scheme 9a), leading to the intermediate I-4

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

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• to hydroquinone 12 with N,N-diethylhydroxylamine (N,N-DEHA) and cyclized via intramolecular nucleophilic aromatic substitution to isolate 6-hydroxybenzofuro[2,3-b]pyridine (13) with 82% yield. Conveniently, the synthesis of 13 was achieved in a one-pot reaction from 11 with no significant differences

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• be prepared via two similar procedures previously described in the literature [17][18]. Our synthetic route is based on the protocol offered in T. Pelkey’s publication [18] using DMF as a solvent for the nucleophilic aromatic substitution of the nitro group in 2-nitrobenzaldehyde (1) instead of the

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• ring at the C6 position of purine to act as leaving group. Keywords: 2,6-bistriazolyl purines; nucleophilic aromatic substitution; purine nucleosides; triazoles; Introduction Modified purine derivatives are an important class of compounds which possess a wide spectrum of biological activities [1][2

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• . Keywords: Arbuzov reaction; 2,6-bistriazolylpurines; nucleophilic aromatic substitution; purinylphosphonates; Introduction Acyclic nucleoside phosphonates (ANPs) are an important compound class due to their biological activity profile [1][2][3][4][5][6]. Compounds bearing a phosphonate moiety in their N9

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• ), complex mixtures were obtained with less than 5% conversion to the desired amide product 31. The library process was completed by carrying out the nucleophilic aromatic substitution with a 3-fold excess of amine in DMF at 60 °C overnight to afford 32a–h, after a removal of Boc or Cbz groups [20] where

Metal-free synthesis of biarenes via photoextrusion in di(tri)aryl phosphates

• Hisham Qrareya,
• Lorenzo Meazza,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 3008–3014, doi:10.3762/bjoc.16.250

• nowadays a growing interest in the forging of Ar–Ar bonds under transition-metal-free conditions [24][25]. Apart the most common pathways, e.g., the Friedel–Crafts functionalization [26] or nucleophilic aromatic substitution [27], alternative approaches have emerged that make use of photogenerated

Synthesis of 4-substituted azopyridine-functionalized Ni(II)-porphyrins as molecular spin switches

• Jannis Ludwig,
• Tobias Moje,
• Fynn Röhricht and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2589–2597, doi:10.3762/bjoc.16.210

• Dommaschk et al. [4][27]. Synthesis of azopyridines 11, 14, 16 and 18 by nucleophilic aromatic substitution. Synthesis of 3-(3-bromophenylazo)-4-cyanopyridine (20), which was hydrolyzed to yield 3-(3-bromophenylazo)-4-pyridinecarboxylic acid (21). Modular approach for the C–C connection of the Ni(II

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• second step, the naphthalene nucleus was functionalized via a nucleophilic aromatic substitution with the Boc-protected amino acids ʟ-Dap and ʟ-Lys. The reaction was carried out in dry DMSO at 60–65 °C for 1.5–2 hours. After two preparative HPLC purifications in an acidic environment (with TFA) and

Synthesis and properties of quinazoline-based versatile exciplex-forming compounds

• Rasa Keruckiene,
• Simona Vekteryte,
• Ervinas Urbonas,
• Matas Guzauskas,
• Eigirdas Skuodis,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 1142–1153, doi:10.3762/bjoc.16.101

• , bearing a quinazoline unit as the acceptor core and carbazole, dimethyldihydroacridine, or phenothiazine donor moieties, were designed and synthesized in two steps including a facile copper-catalyzed cyclization and a nucleophilic aromatic substitution reaction. The photophysical properties of the

• nucleophilic aromatic substitution reaction. The dimethyldihydroacridine and phenothiazine-containing quinazoline compounds formed molecular glasses with glass-transition temperatures of 123 °C and 116 °C, respectively. The ionization potentials estimated by cyclic voltammetry of the derivatives were found to

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

• trans-6e as an orange solid with 97% purity. The synthesis of compounds 6f–h was performed following a nucleophilic aromatic substitution route on 28b (Scheme 4) since precursors 8 or 17 with the required substituent Y were not available. We performed nucleophilic aromatic substitutions with the

Synthesis of a dihalogenated pyridinyl silicon rhodamine for mitochondrial imaging by a halogen dance rearrangement

• Jessica Matthias,
• Thines Kanagasundaram,
• Klaus Kopka and
• Carsten S. Kramer

Beilstein J. Org. Chem. 2019, 15, 2333–2343, doi:10.3762/bjoc.15.226

• pyridinyl motif. In fact, only two pyridinyl silicon rhodamines (13 and 14) are known so far, although halogenated pyridines are highly interesting for further functionalization or vector conjugation by nucleophilic aromatic substitution. For the implementation of the dihalogenated pyridine motif into the

Synthesis and properties of sulfur-functionalized triarylmethylium, acridinium and triangulenium dyes

• Marco Santella,
• Eduardo Della Pia,
• Jakob Kryger Sørensen and
• Bo W. Laursen

Beilstein J. Org. Chem. 2019, 15, 2133–2141, doi:10.3762/bjoc.15.210

• influence the overall reactivity of the system towards subsequent nucleophilic aromatic substitution. When the reaction was followed by MALDI–TOFMS spectrometry it was thus possible to observe simultaneously the presence of the target compound and all of the intermediates involved in the reaction. This