Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• hemiaminal opening and amine–ketone condensation, iminium ion 65 was produced for the next pyrrole nucleophilic addition to form a strategically important C–C bond and afford 66, which was protected as Boc carbamate in the same pot to give 67 in 96% yield from 64. In this tandem sequence, the nucleophilicity

• synthesis, they used an electron-rich and nucleophilic pyrrole as the precursor of the electron-deficient pyridine to enable a tandem sequence involving an intramolecular nucleophilic addition of the pyrrole to an iminium ion to form a key C–C bond. The pyrrole group was then converted to the desired

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• (C6F5)3B triggered a Meinwald rearrangement, generating aldehyde 66. Nucleophilic addition, oxidation of the resulting alcohol, and base-promoted epimerization at C6 of 67' delivered 67. Subsequent dihydroxylation of the alkene in 67 and protection of the resulting 1,2-diol as a cyclic carbonate

• delivered 68. A one-pot desilylation/oxidation of 67 produced an aldehyde, which was subject to selective nucleophilic addition in the presence of a ketone, allowing for access to the furan precursor 68 [37]. Oxidation–cyclization–aromatization of 68 with Dess–Martin periodinane (DMP) constructed the

• (50) and D (52), respectively. Alternatively, nucleophilic addition of MeOH to 54a and 56a, followed by ring-opening elimination, arrived at the corresponding γ-keto aldehyde intermediates 72/73. Subsequent intramolecular aldol cyclization of these intermediates furnished gracilisoids C/G (51/55) and

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

• reaction proceeded via 5-endo-dig cyclization. This pathway involved enol ether attack on the gold-activated alkyne, leading to the formation of oxonium intermediate 2. Subsequently, nucleophilic addition of methanol culminated in the formation of indene motif 5 (Scheme 2, path a). When methanol served

• terminal alkyne proceeded via a gold(I)-catalyzed propargyl-Claisen rearrangement, generating a β-allenic intermediate 35. This intermediate underwent a Markovnikov-type nucleophilic addition followed by a 5-exo-trig cyclization to stereoselectively construct the furo[3,2-b]furan bicyclic framework 36

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

• cationic intermediate C, which was converted into D through nucleophilic addition of 31a. Trapping D by the weak nucleophile H2O formed the by-product 34, while trapping of D by CH3CN generated species E, which was trapped by H2O and formed intermediate F. Furthermore, oxidation of F at the anode produced

• phenylselenium cation C and phenylselenium radical B through radical cation species A. Simultaneously, the cathodic reduction of 17a generated anion D and radical B. Then, addition of B with the alkyne portion in 16a gave a radical intermediate E, which proceeded a one-electron oxidation followed by nucleophilic

• addition and then deprotonation to yield the desired 18a via intermediate G. Another possible pathway is that phenylselenium cation C attacked 16a afforded the alkenyl cation G, which underwent cyclization and deprotonation to produce 18a. It should be noted that this conversion proceeded under metal

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• , Wittig reaction with MOMPPh3Cl and LDA gave the putative methyl enol ether, which could be directly converted into 1,3-dithiane 12 with propane-1,3-dithiol. Nucleophilic addition to chiral epoxide 13 and oxidative hydrolysis of 1,3-dithiane to ketone delivered chiral β-hydroxyketone 14. Evans−Tishchenko

• analysis. The major one 48b was used for further study to install the pyrrolidine system. Thus, nucleophilic addition of an N,O-enolate, derived from precursor 49 with LDA, to the ketone functionality in 48b was implemented to generate a pair of inseparable regioisomers 50a and 50b, arose from C4 and C7

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• the DFT calculations (Scheme 5, Figure 2). Firstly, reductive amination of an aldehyde started from a nucleophilic addition of the amine to the carbonyl group of the aldehyde. In the presence of acid, this step could occur via acidic catalysis involving a protonation step of an amine (Step_2) or

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

• condensation between 27 and the aldehyde afforded INT-A, which was activated by the CPA catalyst through hydrogen bonding interaction. The nucleophilic addition of isocyanide to Int-A produced INT-B bearing a stereogenic center. Subsequently, INT-B underwent intramolecular cyclization to generate axially

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• an ortho-substituent into the benzene ring also has no effect on the synthesis efficiency (compound 3f). A slight decrease in yield was observed only for the naphthyl-substituted annulation product 3k. The plausible mechanism of the reaction involves the nucleophilic addition of the Ni-enolate of 1

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

• indicate that the key to the success of this process is the formation of an unexplored ternary Ni-complex with 3-bromochromone and a pyridinium salt, which is crucial for the effective activation of the α,β-unsaturated system towards the nucleophilic addition. Keywords: chromones; dehalogenation

• enaminones. This transformation is simple, straightforward, and proceeds under mild conditions. Results and Discussion The initial challenge in achieving the desired reactivity was the activation of the unsaturated system towards the nucleophilic addition of the amine. The most common strategy to increase

• -bromochromones to Ni(II) and a pyridinium salt, giving rise to a ternary Ni-complex which activates the α,β-unsaturated carbonyl compound towards nucleophilic addition. The presented method is operationally simple and can be conducted using low catalyst loadings of a Ni-catalyst and an inexpensive organic

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• constructed by condensation of dialdehyde 160 with compounds 161–163 yielding diketones 164–166. Next, diketones 164–166 were subjected to nucleophilic addition reaction by lithiated triisopropylsilyl (TIPS) acetylene, followed by SnCl2-mediated reduction of the intermediate diols. Finally, azulene-embedded

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

• incorporated into cyclization reactions. The iminium species generated from enamides via nucleophilic addition or substitution are capable of engaging in further electrophilic additions or isomerization processes. Exploiting the multiple reactivities of enamides facilitates the development of diverse

• nucleophilic addition or substitution, the resulting iminium ions often undergo direct hydrolysis, preventing further use in a cascade nucleophilic addition. As a result, enamines are not ideal partners in tandem reactions for the synthesis of nitrogen-containing products. As analogues to enamines, the

• iminium intermediates can serve as electrophiles. Due to the presence of an amide, the resulting iminiums from the enamides can be stabilized to take part in the second nucleophilic addition, though direct isomerization of the iminiums to the enamides is also possible (Figure 1). Guided by these

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• nucleophilic addition, and subsequent release of one molecule of amide, reactivating the active ruthenium(II) catalyst. In contrast, for diazomalonates, intermediate Int-78 releases ammonia with the help of Ru(II) or acetic acid, ultimately yielding 3H-indole 80. This change in selectivity may be due to the

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• observation of enantioselectivity must be explained by relative energies of stereoisomeric forms of TS 9-10. Reversible formation of product 10 from nucleophilic addition step via TS 9-10 is slightly endothermic (Figure 3). In 10, cyanide is still attached via nitrogen to calcium, forming a formal Ca–N–C–C–N

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• into tetrahydroquinoline (THQ)-based 6-6-4-membered ring systems through a combination of nucleophilic addition and borate-mediated [2 + 2] photocycloaddition, offering a catalyst-free approach to construct conformationally constrained 2D/3D frameworks with high functional group compatibility and

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

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

• decompose into DMS (dimethyl sulfide), which then can act as a nucleophile in several MCRs (Scheme 4) [19][20][21][22]. In this context, DMSO can be used as a source of the methylsulfanyl (-SCH3) group after DMS follows a nucleophilic addition or substitution, allowing one to obtain different types of

• 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

• in the case of formaldehyde, making the reaction more regioselective. In the cases shown above, we discussed different ways to activate DMSO. In almost all of them, MMS appears as the reactive species due to its high electrophilicity, which allows for an efficient nucleophilic addition, and the

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• dioxazolone 7. Subsequently, nitrene insertion of INT-12 into the Cu–C bond, forms INT-13, which then undergoes isomerization and protodemetalation, followed by catalyst regeneration, as suggested by the DFT calculations. Finally, the nucleophilic addition of the amine to the electrophilic intermediate INT-15

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• (Scheme 16) [33]. The reaction, which occurs with formation of C–C, C–N and C–O bonds, involves a nucleophilic addition of the activated alkyne XIV to the in situ-generated iminium ion XV, followed by cyclization to form a quinoxalin-2-one intermediate XVI. A subsequent 5-endo-dig cyclization involving

• corresponding saturated compounds. Subsequent nucleophilic addition of the cyclic vinyl ether to the iminium salt generates an intermediate XXI susceptible of intramolecular electrophilic attack to give a tricyclic structure XXII. The final deprotonation provides the desired product 24. The multicomponent

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

• intermediate Int-9. As the assumed rate-determining step the intramolecular nucleophilic addition takes place, followed by further cyclization and finally, release of the organocatalyst to form the axially chiral product 9. Various aryl-substituted indolines 9 were obtained in good yields and high enantiomeric

• enantioselectivity during the nucleophilic addition, and the subsequent aromatization completes central-to-axial chirality conversion delivering products 68. Dynamic kinetic resolution of naphthylindoles 69 was performed by reaction with bulky electrophiles such as azodicarboxylates 70 or o-hydroxybenzyl alcohols 72

• . The proposed reaction pathway follows hydrogen bonding with alkynylnaphthylamine and later nucleophilic addition of the allene intermediate. The synthesis on the preparative scale provided product 183 with almost no deterioration in yield or enantioselectivity (90%, 91% ee). This product could then be

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• hydrogen bonding with the protonated tertiary amine. Then, a Michael addition of malononitrile to the azadiene takes place to obtain exclusively the (S)-intermediate A. Subsequently an intramolecular nucleophilic addition of the nitrile leads to the intermediate B, which undergoes tautomerization to

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• mainly include: nucleophilic addition or nucleophilic substitution with H2O2 or ROOH [17][18], autoxidation with O2, pericyclic reactions of unsaturated bonds with O3 or O2, and metal-catalyzed peroxidation (Isayama–Mukaiyama hydrosilylperoxidation [19][20], for example) [21][22][23]. As the topic is

• to generate the iodoperoxidate intermediate C. Finally, nucleophilic addition of anion of carboxylic acid to intermediate C generates the desired product 216. Based on the iodination/peroxidation strategy the approach to α-hydroxy-β-peroxyethylarenes 219 and α-alkoxy-β-peroxyethylarenes 218 from

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• ] because of their easily modifiable dipeptide frameworks. Several methods exist for accessing PCPAs, such as the amination of 1-halo-1-alkynes [16][17], tandem reactions of α-imino esters with nucleophiles and electrophiles [18], and the nucleophilic addition of an acetylide to α-carbonylated N-acylimines

• derivative has been employed (Scheme 1) [13][14]. Recently, we have demonstrated that the central carbonyl group of DEMO is highly electrophilic, facilitating the nucleophilic addition of less reactive reagents such as acid amides [23][24][25][26]. When the reaction was conducted in the presence of acetic

• anhydride, the intermediately formed hemiacetal underwent acetylation, leading to N,O-acetals 1. In this method, an acid amide can be used as an amine masked with an acyl group. Subsequent elimination of acetic acid occurred to afford 2 in situ upon treatment with a base, enabling nucleophilic addition with

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids

• Andrey N. Komogortsev,
• Constantine V. Milyutin and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 2585–2591, doi:10.3762/bjoc.20.217

• was isolated in unchanged form. It should be mentioned that the key step of the studied recyclization is an intramolecular nucleophilic addition of a nitrogen atom at the double bond of the pyranone ring. Comparing the chemical properties of the considered amides and hydrazides it can be assumed that

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• , Via Gobetti 85, 40129 Bologna, Italy 10.3762/bjoc.20.210 Abstract The direct nucleophilic addition of amides to unfunctionalized alkenes via photoredox catalysis represents a facile approach towards functionalized alkylamides. Unfortunately, the scarce nucleophilicity of amides and competitive side

• reactions limit the utility of this approach. Herein, we report an intramolecular photoredox cyclization of alkenes with β-lactams in the presence of an acridinium photocatalyst. The approach uses an intramolecular nucleophilic addition of the β-lactam nitrogen atom to the radical cation photogenerated in

• functionalization of amides with alkenes under photoredox conditions. Another viable approach for amide functionalization through photoredox catalysis involves the nucleophilic addition, in the presence of base, of an amide to a radical cation obtained by oxidation of an unfunctionalized alkene moiety (Figure 1A

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• anionic species from, for example, malonate. One reason could be because of the formation of the less stable alkoxide by the progress of the nucleophilic addition. If this is really the case, the presence of the strongly electron-withdrawing fluorine-containing groups in our instance should nicely affect