Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• . Nucleophilic substitution of the nitro group with sulfur nucleophiles, including thioacetate or disulfide anions as well as thioacetamide, yielded bis(thiophen-3-yl)disulfide and sulfide derivatives. The disulfide served as a suitable precursor for the preparation of 3-alkylthio-substituted thiophene-2,5

• TTs from the activated 3-nitrosubstituted thiophenes [29][30]. This strategy provides an effective access to the 3-hydroxy-TTs via the nucleophilic substitution of the nitro group in 3-nitrothiophene precursors using S-nucleophiles, such as alkyl thioglycolates or mercaptoacetone (Scheme 1, route V

• addition to potassium thioacetate, the reactivity of ester 1 was investigated with other related S-nucleophiles, such as potassium ethyl xanthate (KSC(S)OEt), sodium diethyldithiocarbamate (NaSC(S)NEt2) as well as thioacetamide in the presence of K2CO3 and Na2S2 (Table 1, entries 2–5). In each case, the

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• their subsequent reaction with O-nucleophiles in the second chamber. The method is easy to setup, control and gives access to new haloacetimidates under mild conditions, similar to the ones used for the synthesis of the more commonly used trichloroacetimidates. Keywords: gaseous reagents; glycosyl

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

• method for the enantioselective α-C(sp3) alkenylation of ketones containing imidazole auxiliaries (Scheme 10) [24]. The transformation was catalyzed by a chiral-at-rhodium Lewis acid 42. A variety of ketone electrophiles 40 and alkenyl trifluoroborate nucleophiles 41 were converted to the corresponding α

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

• conditions, the authors attenuated the silver catalyst’s activity through ligand addition. This allowed for a umpolung addition of the substrate 87, affording six-membered spirocyclic intermediate 88. When the NFSI was used as ligand without nucleophiles, the tricyclic azepinoindole 89 was obtained via a

• was used as the ligand and amides as nucleophiles, the spirocyclic indole framework 91 was obtained via the capture of imine intermediate 88. When the PPh3 was used as ligand in the absence of nucleophiles, the substrate 87 with an unprotected indole nitrogen facilitated the formation of intermediate

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• nucleophiles [7][8][9][10][11], radicals [12][13][14][15] and electrophiles [16][17][18] to give cyclobutanes and cyclobutenes [19][20], which are building blocks in regio- and stereoselective synthesis [21][22][23][24][25][26][27] (Scheme 1a). Additionally, BCB has been used in bioconjugation due to its high

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• stabilized allyl cation intermediates that undergo regioselective trapping by internal O- and N-nucleophiles furnishing functionalized heterocycles. This method provides access to tetrahydrofuran or pyrrolidine frameworks, each bearing a trifunctionalized (E)-configured vinyl side chain. The use of a shorter

• linker provides entry to 1,2,3,6-tetrahydropyridines. Additionally, in the absence of internal nucleophiles, this methodology yields aryl-substituted 1,3-dienes. This work introduces a palladium-free, single-step alternative to multistep heterocycle construction from propargylsilanes and highlights the

• described by us recently, among other possible transformations [21][22]. Interestingly, the addition of O-nucleophiles to form 1,3-carbofunctionalization products, can only be achieved in an intramolecular fashion. In the presence of an excess (5 equiv) of external an O-nucleophile R–OX (alcohol, carboxylic

Photochemical reduction of acylimidazolium salts

• Michael Jakob,
• Nick Bechler,
• Hassan Abdelwahab,
• Fabian Weber,
• Janos Wasternack,
• Leonardo Kleebauer,
• Jan P. Götze and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2025, 21, 1973–1983, doi:10.3762/bjoc.21.153

• suitably electrophilic substrate at the carboxylic acid oxidation level provides an acylazolium species B, which typically reacts directly with nucleophiles or may first be transformed into the corresponding enolate derivative. Regardless of the individual pathway, NHC-catalyzed reactions of this type

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• catalytic sites. The OH group on the phosphorus atom functions as a Brønsted acid site, while P=O serves as a Lewis base site, which enables the simultaneous activation of both nucleophiles and electrophiles in one reaction (Figure 1). The chiral properties of the catalysts are derived from the chiral

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• selectivity in glycosylations with various types of nucleophiles [67][68]. This remarkable stereoselectivity has been attributed to intermolecular hydrogen bonding, which forms a transient tether between the glycosyl donor and acceptor, thereby guiding the reaction towards a preferred stereochemical outcome

• reduced reaction temperatures (−20 to −60 °C), N-phenyl trifluoroacetimidate (PTFA) donors are sufficiently stable to be used in glycosylation reactions at 0 °C or ambient temperature, while remaining reactive enough to glycosylate conformationally hindered nucleophiles in the presence of catalytic TMSOTf

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• nucleophiles in the DKR of various bridged biaryls bearing different linkages to give diverse nitrogen heterocycle-substituted atropoisomeric biaryls. In 2021, our group achieved the catalytic enantioselective DKR of biaryl lactones 46 with α-acidic isocyanides (Scheme 8a) [48]. By using Ag2CO3 and cinchonine

• lactones with carbon nucleophiles. The success lies in the tandem enantioselective ring-opening of lactones with α-acidic isocyanides, followed by a rapid cyclization driven by aromatization, overcoming the long-standing stereochemical leakage problem caused by the undesired lactol formation [45

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• act as both electrophiles and nucleophiles [7]. This makes enaminones very reactive, providing an excellent scaffold for organic synthesis. Thus, enaminones are valuable building blocks in the preparation of several carbocyclic [8][9][10][11], heterocyclic [12][13][14][15][16][17][18] as well as

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• -, particularly 2-methylideneoxetanes have become valuable intermediates in oxetane chemistry as they readily undergo a variety of chemical transformations, including ring-opening reactions with nucleophiles, epoxidations, cyclopropanations and [3 + 2] cycloadditions with nitrile oxides [51][52]. In addition

• cell membrane permeability were measured and the results suggested that these substrates might be promising bioisosteric replacements for thioesters. Five years later, the research group expanded the scope of this methodology to include alcohols as the nucleophiles (Scheme 35) [85], thus avoiding the

• years later, the group extended the scope of nucleophiles to azoles, sulphoximines (and other HN=S species), phosphites, phosphonites or secondary phosphine oxides, and developed selective reaction conditions for the alternative sulphur–fluoride exchange (SuFEx) pathway by employing hard anionic

Optimized synthesis of aroyl-S,N-ketene acetals by omission of solubilizing alcohol cosolvents

• Julius Krenzer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2025, 21, 1201–1206, doi:10.3762/bjoc.21.97

• addition, since condensations are affected by the bimolecular addition as an elementary step, special attention to the concentration of the nucleophiles has to be paid. According to Mayr’s nucleophilicity scales [8][9][10], a nucleophilicity parameter N for the specific S,N-ketene acetal intermediate 4 can

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• engrafted with human erythrocytes, after oral administration of the compounds [5][9]. Triazolopyrazines halogenated on the pyrazine ring represent synthetically useful targets for elaboration of this active scaffold, and the regioselectivity of amine nucleophiles (amongst others) has been explored by Korsik

• -halogenated triazolopyrazines with amine nucleophiles, and the only likely product from reaction with primary amines at room temperature. Biological studies All compounds (1–15) were assayed for antimalarial activity against the chloroquine sensitive P. falciparum 3D7 strain, and a preliminary assessment of

• C20H2635ClN6NaO2, 439.1620; found, 439.1616. (A) Position numbering on the pyrazine ring of 1,2,4-triazolo[4,3-a]pyrazine. (B) Illustration of ipso- and tele-substitution products for reactions of nucleophiles with 5-halogenated 1,2,4-triazolo[4,3-a]pyrazine, where X = halogen and Nuc = nucleophile. Key COSY

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• asymmetric allylic amination of allylic esters with isatin derivatives 11 as nucleophiles. The reaction proceeds efficiently, yielding the products (S)-13 with good-to-high enantioselectivity. A scale-up reaction was also successfully conducted at a 1 mmol scale. Additionally, when malononitrile was added to

• palladium catalysts with amines as nucleophiles have been reported [14][15][16][17][18][19][20][21][22][23][24][25], there have been only a few reports on the N-substitution of isatin using asymmetric methods. Recently, Wolf’s group reported a transition-metal-catalyzed (Pd-catalyzed) asymmetric allylic

• enantioselectivity as the 0.1 mmol scale reaction (entry 14). Next, we investigated the substrate scope of the palladium-catalyzed asymmetric allylic amination of 1,3-diphenyl-2-propenyl acetate (12) with isatin derivatives 11 as nucleophiles under the optimized conditions using (aR)-(−)-6 as the ligand and Na3PO4

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• enamides as nucleophiles, rendering them more stable than enamines. This stability is reflected in their frequent occurrence in natural products [4]. As a result, research on the synthetic applications of enamides has historically lagged behind that of enamines [5][6]. Beyond their use in hydrogenation

• cephalotaxine, cephalezomine H, (−)-cephalotaxine, (−)-cephalotine B, (−)-fortuneicyclidin A, (−)-fortuneicyclidin B, and (−)-cephalocyclidin A. Unlike enamines, tertiary enamides can participate in cyclization reactions initial as nucleophiles, and upon protonation, alkenylation, or alkylation, the resultant

• resulting iminium ion can be readily captured by a wide variety of nucleophiles, including alkenes and alkynes. These aza-Prins cyclizations have potential applications in the synthesis of natural alkaloids, as exemplified by She’s total synthesis of (−)-dihydrolycopodine and (−)-lycopodine [17]. These

Harnessing tethered nitreniums for diastereoselective amino-sulfonoxylation of alkenes

• Shyam Sathyamoorthi,
• Appasaheb K. Nirpal,
• Dnyaneshwar A. Gorve and
• Steven P. Kelley

Beilstein J. Org. Chem. 2025, 21, 947–954, doi:10.3762/bjoc.21.78

• regioselective, diastereoselective, and metal-free protocol for alkene amino-hydroxylation, which compared favorably to prior art in this area [25][26][27][28][29][30][31][32]. Naturally, we wondered if other O-nucleophiles were competent in the ring-opening of the aziridinium intermediate. Indeed, almost all

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• by nitrogen nucleophiles [59][60]. When the reaction was conducted with 5 mol % of AgOTf in toluene at 80 °C for 20 hours, pyrazolo[1,5-a][1,4]diazepine 16a was obtained in 46% yield, while complete conversion of the starting material 15a was not achieved (Table 1, entry 1). Increasing the

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• nucleophiles [24]. Therefore, it is reasonable that the transimination reaction between 3a’–e’ and 4 preferentially takes place at the carbon atom of the imine (C=N) linkage instead of the carbonyl carbons at the 2- or 3-positions. Lastly, the covalent bond between the tetrahedral carbon atom and the

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• inception (Scheme 1). Early studies were mainly focused on palladium catalysts [5][6][7][8], as demonstrated by the independent pioneering works of Tsuji and Trost in the 1960s and 1970s, respectively. While palladium catalysts demonstrated excellent reactivity with soft stabilized nucleophiles in the

• phosphoramidite ligands significantly advanced this field, with contributions from numerous research groups including Hartwig, Helmchen, Carreira, Alexakis, and You [19]. In general, soft nucleophiles that typically possess conjugate acids with pKa values less than 25 have been utilized in most Pd and Ir

• nucleophiles 5 that have conjugate acids with pKa values greater than 25 such as organolithium, organomagnesium, organozinc, and organozirconium reagents. This crucial distinction effectively expanded the scope of allylic substitution reactions beyond traditional boundaries. The evolution of copper-catalyzed

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• also suitable as nucleophiles for the cyclization into 2-aminoproline and 2-aminopipecolic acid derivatives 6 (Figure 2, reaction 3). The starting disubstituted malonic esters are readily available by C-alkylation of inexpensive and readily available diethyl acetamidomalonate, followed by

• facilitated the cyclization, and the 6-membered heterocycles 6h,i could be obtained in 27% and 18% yield, respectively. In addition to sulfonamides, carbamates such as N-Boc and benzamide are also suitable as nucleophiles for the anodic decarboxylation/cyclization reaction. However, the corresponding 2

• tethered nitrogen nucleophiles such as sulfonamides, carbamates, and benzamide. The decarboxylative cyclization of a stereogenic center-containing sulfonamide proceeds with excellent diastereoselectivity (97:3 dr). The N-protected 2-aminoproline derivatives can be incorporated into dipeptides by an ester

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• oxygen [42]. Through energy transfer (EnT) from the ruthenium-based photocatalyst to triplet oxygen, singlet oxygen is produced in a targeted manner, which oxidizes histidine to an endoperoxide, significantly increasing its reactivity toward nucleophiles (Figure 4A). This strategy employs a

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• nucleophilic species present in the reaction medium, MMS can act as a methylene source. Under hydrolysis conditions, it can be a source of formaldehyde (Scheme 5a), but with other nucleophiles, after nucleophilic addition, the sulfide group can work as a leaving group, allowing for a sequential domino process

• phosphites can also undergo an addition to the C=O bond of the carbonyl component (Abramov reaction) giving α-hydroxy phosphonates 33 as byproducts (Scheme 26a) [72]. Competition between the two nucleophiles for the electrophilic carbonyl compound depends on their relative reactivity [74][77] and this lack

• difficult to separate [86][87][88]. Probably, the high reactivity of the imines generated by formaldehyde leads to their polymerization [84] or even to the incorporation of other nucleophiles present in the reaction mixture, such as the solvent or a second molecule of the amidine component (Scheme 32) [84