Construction of CF₂ moieties in FDA-approved drugs (2016–2025): industrial routes, mechanisms, and scale-up considerations

• Wenyan Yao,
• Huanhuan Zhang,
• Xiaolong Yang and
• Feng Liu

Beilstein J. Org. Chem. 2026, 22, 1122–1150, doi:10.3762/bjoc.22.91

• –CF2 Direct CF2 functionalization of aromatic rings typically employs metal-catalyzed methods, such as the reaction of ethyl bromodifluoroacetate with 2-haloarenes in the presence of copper powder, or metal-catalyzed coupling using difluoromethyl 2-pyridylsulfone (Hu's Reagent). Among the four drugs

Amino acid-based surfactants: sustainable synthesis and antimicrobial mechanisms

• Rafaela Gomes Bezerra,
• Lourdes Pérez and
• Francisco Fábio Oliveira de Sousa

Beilstein J. Org. Chem. 2026, 22, 1067–1085, doi:10.3762/bjoc.22.85

• from moderate to high values depending on amino acid functionality, alkyl chain length, and purification strategy [10][37]. For structurally more complex surfactants, especially those derived from multifunctional amino acids such as lysine, arginine, and histidine, selective functionalization often

Synthesis of functionalized, 13-alkyl-substituted coralyne derivatives and investigation of their interactions with duplex and abasic site-containing DNA

• Laurin Beckmann,
• Jason Lennard Kunze,
• Hannah Karola Strunk,
• Maurice Michel and
• Heiko Ihmels

Beilstein J. Org. Chem. 2026, 22, 1057–1066, doi:10.3762/bjoc.22.84

• abasic site-containing DNA (AP-DNA), different synthetic routes towards the functionalization of coralyne were tested. In particular, the alkylation of the benzylic position in papaverine and subsequent cyclization by treatment with acetic anhydride in sulfuric acid led to the synthesis of a coralyne

• DNA damage upon irradiation [30][31][32][33][34]. And this feature that can be utilized in photodynamic therapy (PDT) [35]. To further explore the high propensity of coralyne to bind to DNA and to induce DNA photodamage, we aimed at the further functionalization of this scaffold with additional DNA

• , several approaches towards the functionalization of the coralyne core were tested starting from the alkylation of the benzylic position in papaverine and subsequent coralyne formation by a Pictet–Gams-type cyclization. One route eventually enabled the synthesis of conjugate 2g with an attached alkoxyamine

The role of spacer length and flexibility in peptide self-assembly

• Julian Link,
• Albin Lahu,
• Manfred Wagner,
• Tanja Weil and
• David Y. W. Ng

Beilstein J. Org. Chem. 2026, 22, 986–996, doi:10.3762/bjoc.22.77

• of the pro-assembling tripeptide Ile-Cys-Ala (ICA), which forms fibrous networks upon functionalization with aromatic groups at the N-terminus [35]. To enable both, π–π interactions and fluorescence-based characterization, we chose a naphthalene imide fluorophore as the hydrophobic segment (Nap). The

Novel macrocycles: from synthesis to supramolecular function

• Veronica Iuliano,
• Carmen Talotta,
• Margherita De Rosa,
• Paolo Della Sala,
• Konrad Tiefenbacher,
• Pablo Ballester and
• Carmine Gaeta

Beilstein J. Org. Chem. 2026, 22, 982–985, doi:10.3762/bjoc.22.76

• ], resorcinarenes [7], and cucurbiturils [8] emerged as some of the most extensively investigated classes of macrocyclic hosts. Their widespread popularity was driven by their straightforward functionalization and unique structural properties. In contrast to first-generation receptors, such as crown ethers [2

• major driving force in the field is the effort to combine synthetic versatility of macrocycles with practical supramolecular performance. This expanding structural diversity has, in turn, enabled increasingly sophisticated supramolecular functions. Precise functionalization strategies allow researchers

• functionalization, and selective host–guest recognition properties. By organizing recent examples by internal and external stimuli, the authors outline how macrocyclic systems can regulate cargo release via supramolecular recognition and nanovalve mechanisms. The Review also discusses current challenges and future

Electrochemical reduction of unsaturated carbon–carbon bonds via 3d transition-metal catalysis

• Geon Kang,
• Minki Jeon,
• Pooja Kumari Jat,
• Cheoljae Kim and
• Isaac Choi

Beilstein J. Org. Chem. 2026, 22, 955–981, doi:10.3762/bjoc.22.75

• , and the successful late-stage electrohydrogenative functionalization of structurally complex molecules and drug derivatives further underscored the practical applicability of this strategy in medicinal chemistry contexts. To probe the involvement of catalytically relevant Fe–H species, radical probe

• method proved readily amenable to late-stage functionalization of complex molecules (Scheme 16B). The broad functional-group tolerance observed in this system was attributed to the ability of the nickel catalyst to effectively inhibit direct cathodic reduction of olefins. Furthermore, the electrochemical

Recent advances in copper-catalyzed direct hydroamination of alkenes with (hetero)aromatic amines

• Hyejeong Lee and
• Yunmi Lee

Beilstein J. Org. Chem. 2026, 22, 925–947, doi:10.3762/bjoc.22.73

• conditions. Overall, this study highlights the key role of Lewis acid activation in controlling the reactivity and chemoselectivity of conjugate addition. As reported by Su et al., copper catalysis can be further extended to a tandem dehydrogenation–conjugate addition sequence for the β-functionalization of

A practical CO₂-mediated synthesis of 5,6-carboxylated silicon-rhodamines for targeted probe development

• Dongjie Hou,
• Shaowei Wu,
• Ning Xu,
• Pengjun Bao,
• Wenhao Jia,
• Qinglong Qiao and
• Zhaochao Xu

Beilstein J. Org. Chem. 2026, 22, 915–924, doi:10.3762/bjoc.22.72

• carboxylated SiR derivatives while delivering good to excellent yields. Sequential one-pot functionalization of brominated silicon-rhodamine In the carboxylation of 1b, a prominent side peak was observed in addition to the desired product peak (Figure 3b). NMR (Supporting Information File 1, Figure S17) and

• functionalization with HaloTag ligands through a one-pot sequence (Figure 2b). After treatment of compounds 1a–c with n-BuLi and CO2, the reaction mixtures were extracted with ethyl acetate and concentrated, and the resulting crude carboxylated intermediates were directly subjected to amide coupling with the

• SiR probes. Long-term live-cell super-resolution imaging using one-pot-functionalized silicon-rhodamine probes Encouraged by the successful one-pot functionalization of silicon-rhodamine scaffolds, we next evaluated the performance of the resulting HaloTag-targeted SiR probes in long-term super

Palladium-catalyzed benzocyclization reactions of quinoline-2-carboxamides via sequential C–H/N–H functionalization

• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2026, 22, 905–914, doi:10.3762/bjoc.22.71

• University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan 10.3762/bjoc.22.71 Abstract A novel benzocyclization protocol has been developed for the synthesis of quinoline-fused lactams by palladium-catalyzed sequential C–H/N–H functionalization of quinoline-2-carboxamides and 1,2-dihaloarenes. The reaction

• -metal catalysts. This can reveal their selectivity in terms of reaction position(s) in chemodivergent synthesis (Scheme 2c). The present report explores benzocyclization reactions involving sequential C–H/N–H functionalization by a palladium catalyst. Results and Discussion First, the C–H/N–H annulation

• ). The optimized conditions were used to investigate the substrate scope of this C–H/N–H functionalized reaction. First, the substituents at the amido group of quinoline-2-carboxamides 1 were examined (Table 2). The C–H/N–H functionalization reactions afforded good to excellent yields, regardless of the

Unsymmetrical sulfoxides with sterically hindered catechol fragment: synthesis, structure, electrochemical properties, and antiradical activity

• Daria A. Burmistrova,
• Vasiliy A. Fokin,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Maxim V. Arsenyev,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2026, 22, 828–837, doi:10.3762/bjoc.22.65

• , imparting resistance to various solvents [9][10]. Furthermore, catechol-containing compounds can serve as antioxidant biomimetic additives in lubricants [11]. One effective approach for the fine-tuning of polyphenol properties is functionalization via the introduction of heteroatoms (S, Se, Te) [12][13][14

Total synthesis of the capsular polysaccharide repeating unit towards the development of a glycoconjugate vaccine against Klebsiella pneumoniae ST512

• Shuo Zhang,
• Ondřej Daněk and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2026, 22, 821–827, doi:10.3762/bjoc.22.64

• assembly and subsequent functionalization of long oligosaccharide chains are hampered by their intrinsically low reactivity [29]. Overcoming these challenges relying on a linear strategy employing four key building blocks 1–4, we describe the first chemical synthesis of the hexasaccharide repeating unit

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• reactions. Due to their unique chemical properties and high versatility, fullerenes are finding increasing application in organic synthesis. In this work, the authors focused on the functionalization of C60 with a helicene component via Cu(II)/L13-catalyzed enantioselective 1,3-dipolar cycloaddition of

Synthesis of depressin, cryptomeridiol and 4-epi-cryptomeridiol enabled by a terpenoid chiral pool-producing platform

• Yao Kong,
• Tao Wang,
• Chen Wang,
• Pengcheng Zhang,
• Yuanning Liu,
• Kaibiao Wang,
• Fen Liu,
• Hongli Jia and
• Zhengren Xu

Beilstein J. Org. Chem. 2026, 22, 683–690, doi:10.3762/bjoc.22.53

• the selective late-stage functionalization. In addition, since the precursors for terpene cyclases are general no matter they are provided by the IU pathway or MVA/MEP pathways, a diversity of terpene skeletons would be easily accessible by simply integrating known or newly discovered terpene cyclases

Photoorganocatalytic trifluoromethylation of (het)arenes in green conditions

• Egor N. Boronin,
• Svetlana E. Kaurkina,
• Milena M. Svetlakova,
• Anton S. Bolshakov,
• Maxim V. Arsenyev,
• Vasilii F. Otvagin,
• Alexey Yu. Fedorov,
• Timothy Noël and
• Alexander V. Nyuchev

Beilstein J. Org. Chem. 2026, 22, 662–671, doi:10.3762/bjoc.22.50

• transformations were performed in acetonitrile, which reduces their ecological compatibility, particularly for large-scale applications. Tlili and co-workers have described the use of an organic photocatalyst for the CF3-functionalization of styrenes with the Langlois reagent (sodium trifluoromethanesulfinate

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• ]arenes containing four amino groups at the wide rim and one, two or four propargyl or 2-azidoethyl groups at the narrow rim of the macrocycle, which can be used for expanding functionalization of the calixarene core in the well-known amine acylation (or similar reactions) and CuAAC ‘click’ reactions. Two

• all cases, p-aminocalix[4]arenes were obtained as the readily cleavable tert-butoxycarbonyl (Boc) derivatives, which was crucial for certain transformation and purification steps. To confirm the functionalization capabilities of the five obtained multifunctional calixarenes, they were reacted with

• virtually any functional units attached to them via triazole groups. Keywords: calixarene amines; dimeric capsules; functionalization; tetraureacalixarenes; triazoles; Introduction Considered generally as multifunctional molecular cores, calixarenes in their native forms as cyclic oligophenols actually

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• potential. Therefore, further functionalization of 2,4-diaryl[1,3]oxazolo[4,5-d]pyrimidines at position 7 of the structure-forming core was carried out in this work. Results and Discussion Chemistry The synthesis of 1,3-oxazolo[4,5-d]pyrimidine derivatives 1–9 was accomplished according to the previously

Dialkylaminoalkylation of β-ketosulfones via ring-opening of 3-sulfonylpyrrolidines

• Evgeny M. Buev,
• Alexander V. Pavlushin,
• Vladimir S. Moshkin and
• Vyacheslav Y. Sosnovskikh

Beilstein J. Org. Chem. 2026, 22, 383–389, doi:10.3762/bjoc.22.26

• , that allows a broad functionalization of the 3-(sulfonyl)butan-1-amine with various substituents and their utilization as building blocks. We believe this approach has promising features for further development and pharmaceutical applications. Valuable amino sulfonic acids and aminosulfones. Selected

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• catalysis, electrophilic activation, strong base-counter-cation systems, and N-based activating groups that enable chemoselective bond cleavage. Together, these developments provide powerful tools for amide functionalization and offer new opportunities for efficient, practical, and selective syntheses

• scope of the esterification was indeed broad under mild conditions, enabling late-stage functionalization. For example, esterification of a fenofibric acid-derived primary amide with menthone derivatives furnished the corresponding ester 50 in 98% yield. In 2024, Aisa et al. reported a facile and

• , continue to provide powerful platforms for amide functionalization. Electrophilic activation, particularly via in-situ generation of keteniminium or related highly reactive intermediates, has enabled transamidation, esterification, and halogenation under metal-free conditions. Strong bases, especially when

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• highlighted. Collectively, these concepts create a roadmap for the development of new strategies that harness π-bond localization to expand the synthetic utility of aromatic compounds. Keywords: arene activation; arene functionalization; dearomatization; metal–arene π-complexes; strained molecules

• into a general, efficient synthetic strategy that enables an entirely new retrosynthetic logic, and (2) to enable previously inaccessible mechanistic pathways for selective arene functionalization. With this review, we aim to assess the current landscape of synthetically applied systems that achieve

• introduced by Cheong and Altman in 2020 (Figure 10A) [83]. In this study, the authors explored an intramolecular, decarboxylative C–H functionalization of benzylic electrophiles, uncovering a decisive role of the base in governing site selectivity. Computational and mechanistic analyses revealed that only

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• , the peri-functionalization approach paved a new pathway for the generation of chiral helical molecules. In this article, we highlight the key advancements in these parallel approaches for the generation of helical chiral architectures. Keywords: catalysis; C–H functionalization; helical chirality

• functionalizations are one of these approaches. In the following section, we discuss the parallel approaches, i.e., peri-C–H functionalization, over the prevalent approach for the generation of helical chirality, which generally considers π extension. The peri-C–H functionalization approach provides direct access to

• -functionalization, where a bulkier handle provides the required enantiomerization barrier to screw helical chirality (Figure 1C and D). A straight forward preparation of various carbohelicenes via an organocatalytic enantioselective hydroamination reaction of polyaromatic phenols with diazodicarboxamide derivatives

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• oxidative functionalization that does not disrupt the heterocycle or oxidize sulfur has not been previously reported. Dihydrothiophenes exhibit a broad spectrum of biological activity [47][48][49]. In this regard, the development of new routes for their modifications with the use of inexpensive and easily

Circumventing Mukaiyama oxidation: selective S–O bond formation via sulfenamide–alcohol coupling

• Guoling Huang,
• Huarui Zhu,
• Shuting Zhou,
• Wanlin Zheng,
• Fangpeng Liang,
• Zhibo Zhao,
• Yifei Chen and
• Xunbo Lu

Beilstein J. Org. Chem. 2026, 22, 158–166, doi:10.3762/bjoc.22.9

• conditions, exhibits a broad substrate scope and high chemoselectivity, and clearly distinguishes itself from classical Mukaiyama-type oxidations. The reaction is readily scalable to gram quantities and is applicable to late-stage functionalization of complex alcohols, including bioactive molecules such as

• versatile intermediates for enantioselective S–C bond formation under mild and metal-free conditions. Keywords: asymmetric synthesis; late-stage functionalization; selective oxidation; sulfenamides; sulfinimidate esters; Introduction Sulfur is a privileged heteroatom in organic chemistry, celebrated for

• is applicable to gram-scale synthesis as well as late-stage functionalization of complex molecules such as RU58841. Preliminary studies with ʟ-menthol-derived sulfinimidate esters revealed partial kinetic resolution, and the individually isolated diastereomers underwent stereospecific Grignard

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• functionalization of α-fluorocarbonyl compounds via halogen atom transfer (XAT) (Scheme 9A) [27]. Conventional defluorination reactions had largely been limited to trifluoromethyl groups, which possess relatively positive reduction potentials [28][29][30][31][32][33][34]. On the other hand, reductive

• transformations of monofluoroalkyl groups have been considered difficult due to their negative reduction potentials. In contrast, the authors focused on the comparatively small bond dissociation energy (BDE) of C(sp³)–F bonds. Based on the hypothesis that this property could enable C–F bond functionalization via

• a halogen‑atom transfer (XAT) mechanism, they initiated the development of monofluoroalkyl group functionalization. Upon visible-light irradiation in the presence of an Ir photocatalyst and dibutylzirconocene, α-fluorocarbonyl compounds 45 underwent XAT with low-valent zirconium species to generate

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• , electroorganic synthesis has become a powerful and reliable strategy for the functionalization of organic compounds under green and mild reaction conditions [36][37][38][39]. The control of selectivity through the variation of parameters such as current, voltage, electrolyte, electrodes, and the type of

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• tryptophan were explored. Different approaches were adopted for the functionalization of C4–C7 prenylindoles at C-3 using Negishi cross-coupling methods. The asperdinones are among the rare tryptophan-derived indole alkaloids which appear to have undergone epimerization due to genetic alteration of specific

• alternative approach to C-7 functionalization of Nα-Boc-tryptophan methyl ester, we chose a CH activation protocol [33]. Treatment of N1-Piv-Nα-Boc-tryptophan methyl ester (10) with but-3-en-2-one (MVK) in the presence of [RhCp*Cl2]2 catalyst according to Ma et al. [34] led to the 7-(3-keto-1-butyl)-alkylated

• ), members of a new class of prenylated 3-indolyl-2,5-benzodiazepine-1,4-diones and diketopiperazine alkaloids, respectively, through Negishi cross-coupling and related C–H functionalization strategies. Importantly, no epimerization was observed during the Negishi coupling or throughout the subsequent steps