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

• electrophilic nature of alkylidene 28, the reaction also produced 29, an addition product of 28 with ethanol, as well as an addition product of 28 with water. Screening of Lewis acids revealed that the addition of magnesium chloride effectively suppressed the formation of the water adduct, and although the by

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

• indicated that protonation of low-valent cobalt species leads to the formation of a Co(III)–H intermediate [95], which then reacts with the alkyne to regenerate the monoligated Co(II) catalyst (Scheme 3D). DFT calculations further support that proton delivery from HFIP to the cobalt–alkyne adduct proceeds

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

• -carbon electrophilicity via copper-centered activation and radical generation, followed by the C–N bond formation and proton transfer, yielding the aza-Michael adduct. Overall, these studies demonstrate that copper-based nanomaterials provide versatile heterogeneous platforms for aza-Michael reactions

The trans-influence in gold chemistry from a catalytic perspective

• Manfred Bochmann

Beilstein J. Org. Chem. 2026, 22, 838–856, doi:10.3762/bjoc.22.66

• occupied molecular orbitals (HOMO, HOMO−1, HOMO−2, HOMO−3). According to natural bond orbital analysis, the Au–CO coordination involves a single bond, with major contributions from the gold 6s, 6py, and 6dx²−y² molecular orbitals [12][30]. The Au–CO adduct is therefore best regarded as a σ-complex. These

• pyrazine can be protonated, alkylated or interact with metal ions and Lewis acids such as B(C6F5)3, the excitation energies are modulated by these interactions, leading to a wide range of emission colours (Figure 1) [39]. The B(C6F5)3 adduct, for example, shows orange emission at 77 K which changes to

• H–H bond cleavage had been reported earlier by Rocchigiani et al. for the highly electrophilic ether adduct [(C^N–CH)Au(C6F5)OEt2]+ which shows “frustrated Lewis pair” (FLP)-like reactivity (Scheme 7) [32]. The electrophilic character of CO ligated to gold explains why gold is more active than

Rongalite addition to dienones: diastereoselectivity in cyclic sulfone synthesis; stereochemical rationalization and prospects as a general conjugate nucleophile

• Melina Goga,
• Hao Zong,
• James Franco,
• Jazmine Prana,
• Rudolph Michel,
• Antonia Muro,
• Elana Rubin,
• Janet Brenya,
• Henk Eshuis and
• Magnus W. P. Bebbington

Beilstein J. Org. Chem. 2026, 22, 742–752, doi:10.3762/bjoc.22.56

• substrates 7 and 9 (Scheme 3) suggested that a maximum in permitted steric congestion might be demonstrated by reaction of dibenzalacetone substrate 11 [28] with Rongalite. Pleasingly, this reaction was successful, leading to adduct 12a. Notably, in this case, no trace of the minor isomer was observed in the

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

• diastereoselectivity, while the AgOAc/(R)-Fesulphos L13 catalytic system gives an inversion of diastereoselectivity and the formation of predominantly endo-adduct 39 with up to 95% ee (Scheme 19). The authors used various substituted styrenes in the reactions, as well as vinyl heteroarenes containing 2-thiazolyl, 2

• form pyrrolidine 64. Further treatment of 64 with cinnamaldehyde and N-phenylmaleimide leads to the second (3 + 2) cycloaddition adduct 65. Addition of ICl to 65 results in cyclization involving the styrene groups, which is accompanied by the formation of decahydropyrrolo[2,1,5-cd]indolizine 66. The

• adduct in good yield (47–96%) and high enantioselectivity, regardless of the electronic nature and position of the substituents (82–98% ee). The authors suggest that bidentate coordination of the chiral copper complex with silylimine 77 is crucial for substrate activation, which is presumably accompanied

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• aldehyde, followed by conjugate addition and cyclo-condensation with a 1,3 dinucleophile. Members of this reaction family are variations on the Biginelli and Hantzch reactions, where the dinucleophile is urea and the ammonia adduct of a second equivalent of the dicarbonyl, respectively [31]. A similar

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

• 1), addition of water affords adduct M, which subsequently converts to the ester via deprotonation. In dry solvents (path 2), nucleophilic attack by the departing OSO₂F− anion on L produces intermediate N, containing an S–O bond that is ultimately cleaved under basic conditions to yield the ester

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• Scheme 33B [194]. The proposed precursor 136, with a hydroxy group at C-7 was thought to undergo elimination to form a 6,7-olefin 136a which can be oxidatively cleaved to, in turn, reveal dialdehyde 136b. Aldol addition towards the C-6 aldehyde and elimination of the aldol adduct to form a 5,6-olefin

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• preferential formation of the endo-adduct (upper pathway). The predominance of exo-isomers in some cases probably reflects insufficient stabilization due to secondary orbital interactions in the transition state [43]. It should be noted separately that secondary cyclic amino acids such as azetidine-2

• ), including O···H–N hydrogen bonds between barbiturate rings and O···H–Ph contacts involving maleimide carbonyl oxygens and phenyl ring hydrogens. The crystal structure of adduct 4c includes a molecule of dichloromethane. Due to the disorder of the dichloromethane molecule, the exact distances of the

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

• nucleophile toward diphenylketene to generate a cyclohexadienyl intermediate that captures a second ketene molecule (Figure 11B). Subsequent ring closure furnishes a product complex that, upon oxidation with molecular oxygen, liberates the [2 + 2 + 2] bis-adduct, dihydroisochroman-3-one, in 73% yield. This

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• desired 1,4-addition adduct was not detected (Scheme 4A). Michael adducts formed with α,β-unsaturated methyl ketones (e.g., compound 5). However, the subsequent haloform reaction failed to produce the target acid, yielding only trace amounts of a complex, difficult-to-separate mixture (Scheme 4B). Also

• -unsaturated malonate 6 with 2a–c, various bases (sodium methoxide, triethylamine, potassium hydroxide) and solvents (ethanol, DMF, pyridine) were tested, mostly at room temperature, with an additional attempt at refluxing in ethanol/DMF. The desired malonate Michael adduct 7 (isolated and fully characterized

• , see Supporting Information File 1) was obtained exclusively when potassium hydroxide was used as base in the reaction between 2b and arylidenemalonate 6 in DMF at room temperature. The malonate Michael adduct 7 was then subjected to various decarboxylation conditions. The Krapcho protocol (NaCl or

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• adduct in 83% ee (Table 1, entry 9). Replacing the five-membered pyrrolidine ring in the catalyst structure with the more flexible six-membered piperidine ring (catalyst H, Table 1, entry 13) reduced its selectivity slightly (78% ee). However, the catalyst derived from phenylglycine (catalyst F) or

• ]. Although basic conditions caused partial racemization during the protection or deprotection step, the Boc-protected amine was obtained in low enantiomeric purity. Chiral HPLC analysis and comparison with an authentic sample revealed the S-configuration of the Mannich adduct [29]. Absolute configurations 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

• ]. For example, using 1 equivalent of reagent 29, the cross-coupling of 3-iodo-6-prenyl-N-acetylindole (27) led to the adduct 32 in 52% yield accompanied by the reduced product 37 in 30% and the dehydro product 38 in 10% yield. Control experiments revealed that the iodozinc reagent from 29 was unaffected

Tandem hydrothiocyanation/cyclization of CF₃-iminopropargyl alcohols with NaSCN in the presence of AcOH

• Ruslan S. Shulgin,
• Ol’ga G. Volostnykh,
• Anton V. Stepanov,
• Igor’ A. Ushakov,
• Alexander V. Vashchenko and
• Olesya A. Shemyakina

Beilstein J. Org. Chem. 2025, 21, 2694–2702, doi:10.3762/bjoc.21.207

• ), 5.56 s (CH2) ppm, 19F NMR: δ 60.3 ppm), that disappeared by the end of the reaction (Figure 1c and d). Probably, the salts 2f,g are unstable and decompose under the reaction conditions. The formation of products 2 and 3 can be explained by different directions of cyclization of the primary adduct of

• imino group in the E-isomer of adduct A leads to 4-thiocyano-2,5-dihydrofuran 3. Taking into account the NMR monitoring data, it can be assumed that the yield and ratio of products are influenced by the stereoselectivity of the reaction and the stability of salts 2 under reaction conditions. We also

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• TBSO-substituent on the dienophile and the diene. As a result of such endo-addition, the benzyloxy group in the diene and the acylpyridine of the dienophile are oriented cis to each other in adduct 99. Next up was the formation of the C20–OH by addition of MeMgBr to the ketone 99, which initially gave

• [53]. This delivered the desired exo-adduct with good ee on a decagram-scale and installed three stereocenters with the correct configuration. The aldehyde moiety was converted to the terminal alkyne 110 via Seyferth–Gilbert homologation using the Ohira–Bestmann reagent. Reduction of the ethyl ester

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• reaction with these substrates is not commonly reported in the literature [37][39]. The reaction of EDA in EtOH as solvent was investigated; however, a complex mixture of products was observed, with no evidence of formation of the Knoevenagel adduct. This outcome appears to result from both mono- and

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• rearrangement. Finally, a White–Chen C–H oxidation [33][34][35] was employed to install the lactone ring, thereby completing the synthesis. The synthesis began with commercially available compound 19 and known compound 20 (Scheme 2). These were joined via an intermolecular aldol reaction to give adduct 21

• into the pentacyclic diene intermediate 93 via a two-step sequence. Subsequent [4 + 2] cycloaddition of 93 with singlet oxygen yielded an unstable endoperoxide adduct 94, which rearranged to diketone 95. A five-step sequence, featuring an intramolecular aldol reaction to assemble the pentacyclic core

• adduct and ultimately enabled the completion of the synthesis. This strategic pivot offers a key lesson for handling fragile cycloaddition adducts. Suzuki’s synthetic effort towards illisimonin A A synthetic study aimed at constructing the tricyclo[5.2.1.01,5]decane core of illisimonin A was reported by

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• adduct was subjected to AgOTf-catalyzed lactonization to successfully construct the D ring of target molecular framework. Next, a 1,4-addition reaction introduced a vinyl group to compound 68, affording compound 70. A Pauson–Khand cyclization of 70 under [RhCl(CO)2]2/CO conditions smoothly furnished the

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• smoothly to deliver the aldehyde which was immediately subjected to the condensation reaction with benzylhydroxylamine. The corresponding nitrone 10 then underwent an intramolecular cycloaddition. Adduct 11 was isolated as the major product in 42% yield for 2 steps. Comprehensive NMR analysis revealed the

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• explained to some extent by their structural diversity. Figure 1 shows the general formula of iridoids. The authors [16] have established regiocontrol of the effect of the 1,6-anhydro bridge on the Dieckmann condensation of dicarboxylic acid diester 16, obtained in four steps from 13, the Diels–Alder adduct

• compound was synthesized from the Diels–Alder adduct 14 between LG and 1,3-butadiene by two methods – vicinal hydroxylation of the double bond followed by periodate cleavage of the vic-diols and ozonolysis of the double bond. Alternatively, Wagner oxidation of the double bond in adduct 14 by treatment with

• in a stable aldehyde 23. This aldehyde is a product of intramolecular aldol–croton condensation and can be used in the synthesis of bartsioside (24) or its analogues [21][22] (Scheme 4). The authors [19] performed similar oxidative transformations with Diels–Alder adduct 25 obtained from LG and

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• mechanism involving single-electron oxidation of an enamine intermediate, addition of the resulting radical to the olefin, single-electron oxidation of the adduct to form a carbocationic intermediate, and intramolecular nucleophilic attack on the carbocation to form the pyrrolidine ring. The reaction

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• addition happened to generate the spiroindoleninium intermediate. This transient species was subsequently trapped by water physisorbed in the silica gel, forming hemiaminal adduct 132. A 1,5-hydride shift was then mediated by Al2O3, ultimately affording the spiro[indoline-3,3'-pyrrolidin]-2-one derivatives

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• introduce reactants in a sequential manner. Thus, we changed the reaction conditions by first reacting 0.2 mmol each of 1a and 2a in 2 mL MeOH at 40 °C for 40 min to form the Schiff base Int-I followed by the addition of 0.2 mmol each of 3a and TMSN3 (4) to obtain the desired 1,5-DS-T 5a as Ugi–azide adduct

• conditions: 1) 0.2 mmol each of 2-azidobenzaldehyde (1a) and 2-yn-1-amines 2 in MeOH (2 mL), 40 °C for 40 min; then addition of 0.2 mmol each of 2-isocyanoacetate (9) and TMSN3 (4), 40 °C for 12 h; 2) changing solvent to MeCN (2 mL), 130 °C for 2 h. Control reactions to trap the Ugi–azide adduct. Gram-scale

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• -(phenylethynyl)-N-tosylbenzamide (25a) to afford the amidyl radical B, which then proceeded intramolecular 5-exo-dig radical annulation to form the five-membered intermediate C. The oxidation of C followed by capturing an AcO− generated the intermediate E, which was converted into triacetate adduct F through