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

• compounds (Scheme 16) [68]. The novel iodine(III) intermediate was generated through nucleophilic substitution of a heteroatom nucleophile, which initiated the reaction. A subsequent aryl migration from the iodine to the heteroatom resulted in the formation of the arylated nucleophile. In addition to

• diaryliodonium salts 40 (Scheme 18) [69], which however, does not produce the diarylated compounds. The intramolecular aryl migration from the iodine to the nitrogen leads to a quaternary ammonium ion intermediate A. Consequently, a nucleophilic ring opening of cyclic amine in 42 occurred via cleavage of the

• 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

C–H Trifluoromethylthiolation of aldehyde hydrazones

• Victor Levet,
• Balu Ramesh,
• Congyang Wang and
• Tatiana Besset

Beilstein J. Org. Chem. 2024, 20, 2883–2890, doi:10.3762/bjoc.20.242

• of 5-thioxo-1,2,4-triazolium inner salts by the nucleophilic thiocyanation of N,N-dialkylhydrazonoyl bromides, in situ generated from aldehyde-derived hydrazones in the presence of an oxidant (NBS, (NH4)2S2O8), Scheme 1). In 2024, the synthesis of 2‑imino-1,3,4-thiadiazoles was achieved by

• % yield) using readily available reagents, namely NBS and the nucleophilic reagent AgSCF3. This approach provides a straightforward access to an unprecedented class of trifluoromethylthiolated derivatives. This method offers new avenues for synthesizing a plethora of valuable SCF3-containing molecules

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• addition to the application of isocyanides in a variety of MCRs, one of the unique reactions involves the formation of zwitterions from isocyanides upon reaction with acetylene and active olefin compounds such as alkyl acetylenedicarboxylates and gem-diactivated olefins. Due to having nucleophilic and

• electron-donating substituents (Scheme 3). The cause of this phenomenon is probably related to the electron-widthdawing effect of these substitution groups in olefin, which affects the nucleophilic attack of the isocyanides. When a carboxylate substituent was present instead of the carbonitrile in the gem

• synthesizing pyrrole-fused dibenzoxazepine is illustrated in Scheme 5. The reaction is initiated by the nucleophilic attack of the isocyanide 2 on the gem-diactivated olefin 1 to give the zwitterion intermediate 7. The reaction proceeds with the nucleophilic attack of the zwitterion intermediate 8 on the

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• reagents is rather limited. Indeed, most examples involve dimethyl- or diethylzinc compounds as more elaborated dialkylzinc reagents represent a considerable synthetic challenge. Indeed, dialkylzinc reagents are accessible essentially through nucleophilic displacement of ZnCl2 by Grignard reagents or

• remains tenuous. Indeed, until recently, mixed alkylzinc species were only employed by Carretero and co-workers in related nucleophilic additions to activated imines under Cu catalysis [22]. In 2022, our group demonstrated that alkyl iodides offer a reliable source of heteroleptic organozinc compounds

• nucleophilic organozincate complexes (e.g., LiBuZnBrCl), which is a well-established process in THF [29][30]. Due to the hygroscopic character of LiCl and the necessity to determine the amount of organozinc by iodolysis [20] in order to adjust the stoichiometry of the reagents for the multicomponent coupling

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

• -acylamine; oxazole; propargylamine; Introduction Propargylamine is an important motif in the synthesis of heterocyclic compounds [1][2][3][4] and drug discovery [5][6] due to its multifunctionality, which includes a basic and nucleophilic amino group, an electrophilic and dipolarophilic triple bond, and an

• ] 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

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• polyfunctional precursors 1, 2, and 3, two pathways are theoretically possible (Scheme 2 and Scheme 3). The first one involves the N-nucleophilic Michael addition to the activated multiple bond of the imide, leading to the formation of linear intermediates 6 or 8 (pathways A1 and B1) at the expense of the endo

• imidazole nucleophilic center not involved in the first step. This process leads to the formation of alternative final products: imidazo[1,2-a]imidazoles 10 and 12, imidazo[1,5-a]pyrimidines 4, 5, 11 and 14, and imidazo[1,2-a]diazines 13 and 15. The analysis of the spectral data (1H and 13C NMR, 2D NMR

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• by these findings, we now explored difluoromethylation reactions with compounds bearing less nucleophilic functional groups. Ketones caught our particular attention as they contain a weak nucleophilic carbonyl oxygen adjacent to an electrophilic carbonyl carbon. Previous studies have focused on

• with the generation of difluorocarbene from TMSCF2Br and KFHF. This is followed by a nucleophilic attack of the oxygen atom of ketone 1 on the difluorocarbene. Subsequently, a protonation–deprotonation sequence occurs, which can either be intermolecular, involving a molecule of HF, or intramolecular

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• were found to be suitable for the reaction, delivering 1,3-enynes with medium to high yields and excellent regioselectivities (Scheme 3, 3a–e, 3n–p). Interestingly, when the 3-position of indole was blocked by a methyl group, the 2-position of indole underwent nucleophilic attack with an E/Z ratio of 2

• chelation interaction between the enolate derived from acyclic 1,3-dicarbonyl compounds and copper (Scheme 5, 8a–j). Detailed control experiments indicate that the terminal alkyne moiety is critical and the reaction proceeds through an SN1 mechanism. An outer-sphere nucleophilic attack through copper

• acetylide-bonded allylic cation as the key intermediate is proposed (Scheme 6a). It is worth noting that the nucleophilic attack favors a less sterically hindered site. Therefore, disubstituted alkene moiety prefers γ-attack while trisubstituted alkene moiety is inclined to α-attack (Scheme 6b). Lin and He

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

• nucleophilic substitution reaction between cyanuric chloride and 4-aminophenylphosphonate or 4-hydroxyphenylphosphonate derivatives. These synthesized dopants were used to prepare the modified Nafion membranes using a casting methodology. Almodovar and Tomé reported the synthesis and characterization of nine

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

• Yukiko Karuo,
• Keita Hirata,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• blocks. When using them as nucleophilic reagents [15][16][17][18][19][20], the reaction between anion species, such as fluorine-containing Horner–Wadsworth–Emmons reagents, and carbonyl compounds led to E-selective olefination (Scheme 1A) [15]. On the other hand, some reactions with electrophilic

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• initial study, it can be concluded that the mechanism for our system proceeds according to mechanism two. The following simulations were performed on this conclusion. Regioselectivity PO exhibits two distinct electrophilic sites, which can be subject to nucleophilic attack (Figure 2B). Thus, the

Efficient modification of peroxydisulfate oxidation reactions of nitrogen-containing heterocycles 6-methyluracil and pyridine

• Alfiya R. Gimadieva,
• Yuliya Z. Khazimullina,
• Aigiza A. Gilimkhanova and
• Akhat G. Mustafin

Beilstein J. Org. Chem. 2024, 20, 2599–2607, doi:10.3762/bjoc.20.219

• reactions was made. It has been suggested that a nucleophilic substitution of the peroxide oxygen atom occurs in peroxydisulfate [32]. Regarding phenols (Elbs reaction), there is also a nucleophilic substitution of the phenolate ion. For aromatic amines (Boyland–Sims reaction), a neutral nitrogen atom of

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

• unit and a nucleophilic fragment in the side chain various transformations are possible. For example, a pyranone ring can be opened and recyclized into the novel heterocyclic system. Indeed, previously we have shown that various allomaltols 1 containing a hydrazide moiety are converted into substituted

• 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

• the nucleophilic activity of the amide nitrogen atom is insufficient for this transformation. In this regard, we hypothesized that application of basic reagent can facilitate this process by generating an anion from the amide moiety. For this purpose, we tested the investigated process using various

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 review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• cation is formed by oxidation of the substrate at the anode. This radical cation is subsequently deprotonated to produce an allyl radical. The allyl radical is further oxidized to form the allyl cation, which is then attacked by the nucleophilic sulfonamide, leading to the formation of the desired C–N

• then attacked by the nucleophilic amidosulfinate, which also functions as an electrolyte. The amidosulfinate is generated through the formation of a Lewis acid–base adduct. A subsequent oxidation step, accompanied by deprotonation, yields the sulfonamide product. SO2 captures the excess electrons via

• . Mechanistically, this transformation can be understood as follows: first, a Br/Cl/CF3 radical is formed via anodic oxidation, which subsequently attacks the olefin. The newly formed benzyl radical is oxidized to a carbocation, which undergoes nucleophilic attack by DMF. Hydrolysis of the imine delivers the final

HFIP as a versatile solvent in resorcin[n]arene synthesis

• Hormoz Khosravi,
• Valeria Stevens and
• Raúl Hernández Sánchez

Beilstein J. Org. Chem. 2024, 20, 2469–2475, doi:10.3762/bjoc.20.211

• -substitued resorcinols are notoriously difficult to engage in the cyclization reaction towards resorcin[n]arenes since the nucleophilic character of the attacking aromatic carbon is diminished. Specifically, there is no literature information on 2-chlororesorcinol or 2-iodoresorcinol being used in this

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

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose (5) readily accessible form levoglucosan (1, Scheme 1) [24]. Activation of the C4 hydroxy group as triflate and direct treatment with a nucleophilic halogen furnished intermediates 8–11. The latter compounds proved to be difficult to purify

Phenylseleno trifluoromethoxylation of alkenes

• Clément Delobel,
• Armen Panossian,
• Gilles Hanquet,
• Frédéric R. Leroux,
• Fabien Toulgoat and
• Thierry Billard

Beilstein J. Org. Chem. 2024, 20, 2434–2441, doi:10.3762/bjoc.20.207

• obtain 1,2-disubstituted compounds [72][73][74]. Therefore, the reaction of alkenes with electrophilic sources of phenylselenyl in presence of DDPyOCF3 as a nucleophilic source of the CF3O group was studied (Table 1). First, we started from the optimal conditions previously established for the

• trifluoromethoxylation by nucleophilic substitution, using an excess of DNTFB as a reservoir of CF3O− [68]. Thus, by adding cyclohexene (1a) to the preformed mixture of DNTFB (2 equiv) and DMAP (1 equiv), followed by the addition of PhSeCl, only a low yield of the expected α-trifluoromethoxylated,β-phenylselenylated

• from the competitive opening of the transient episelenonium by the more nucleophilic chloride anion competing with the less nucleophilic CF3O− anion. To avoid this side reaction, the phenylselenyl chloride was replaced by phenylselenyl bromide, assuming that the bromide anion released is less

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

• intramolecular interaction between fluorine and metals would also facilitate the smooth progress of these reactions. Such high potential of 1a allowed us to apply it to nucleophilic epoxidation because the resultant epoxyester 2a is recognized as an intriguing building block (Scheme 1). Another expectation to 2a

• 2 were recognized as versatile building blocks for the construction of 2-amino-3-hydroxypropanoates with 2,3-anti stereochemistry, if appropriate amines work nicely in a nucleophilic manner [44]. After the brief optimization of the conditions for the reaction of 2b and p-anisidine, good yields with

• 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

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• corresponding thiol [35][36][37][38], in the nucleophilic substitution reaction in the aromatic ring of catechol [39][40] or under electrochemical conditions [41][42][43]. An anodic activation of catechols in the presence of a thiol leads to S-functionalized catechols with triazole, triazine, pyrimidine

• moiety. A feature of heterocyclic thiols used as starting reagents is the possibility of thiol–thione tautomerism which leads to the appearance of two nucleophilic centers: a sulfur or nitrogen atom. Therefore, in the case of their interaction with 3,5-di-tert-butyl-6-methoxymethylcatechol, the

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• highly enantioselective nucleophilic addition of primary (10), secondary, and even tertiary allylboronates, as well as allenylboronates to a broad set of imines, bearing the N-phosphinoyl group. The new approach allowed the activation of both the substrate and the reagent using aminophenol organocatalyst

• -Fmoc-aryl- and -alkylimines, catalysed by a chiral disulfonimide 45 (Scheme 10). Since allyltrimethylsilane (46) belongs to the type 2 allylation reagents [33], the nucleophilic addition proceeds via an open transition state (Figure 1). Two possible mechanistic pathways were proposed, where the Fmoc

• method involves squaramide 51-catalysed chloride abstraction from readily accessible N-carbamoyl α-chloroglycinates 48 or 54 (Scheme 11) [35], with a simultaneous nucleophilic attack of allylsilane 49 (Scheme 11A) or allylstannane 55 (Scheme 11B). The reactions are highly sensitive to moisture and oxygen

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• catalysis with hydrogen bonding units has been essential for achieving high reactivity and enantioselectivities [21][22]. Additionally, the reactivity of the nucleophilic addition is influenced by substitutions near the electron-poor double bond. This approach requires 30 mol % of catalyst and a reaction

• nucleophilic catalyst. Test reactions between cyclohexenone and thiomalonate 1 conducted in toluene at room temperature indicated the formation of the product with high conversions and efficiencies (Scheme 2). Application of epi-aminoquinine (AQ-1) in combination with 2-fluorobenzoic acid (system A) led to the

• , such a sterically demanding nucleophile preferentially reaches the face of the reactive site from above the plane leading to the observed (S)-product. The most pronounced effect exhibited by the thioester group concerning nucleophilic reactivity and stereochemical outcome of the reaction was observed

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• general enough to cover the space of interest. One pioneering study in the field of mechanistic transferability for enantioselectivity prediction was published by Reid and Sigman [120] in 2019. The authors manually combined 367 different published reactions of BINOL-phosphoric acid catalysed nucleophilic

• descriptors, Asahara and Miyao [108] considered different CPA-catalysed nucleophilic additions to imines, comprising aza-Mannich reactions and Friedel–Crafts reactions among others. Different reactions were also combined by Liles et al. [124]. For a transfer hydrogenation reaction, the authors used a workflow

• [107] (Figure 11B). Werth and Sigman [127] investigated multiple nucleophilic additions to nitroalkenes, catalysed by bifunctional hydrogen bond donors, observing good correlations to new bi-functional donors, new nucleophiles, new electrophiles and even similar cascade-type reactions. In the authors