Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• : aromatic nucleophilic substitution; azide–tetrazole equilibrium; 4-azido-2-sulfonylquinazolines; quinazolines; sulfonyl group dance; Introduction The quinazoline core is a privileged structure with a wide range of applications. Quinazoline derivatives exhibit a broad spectrum of biological activities

• efficiencies [5][6][7]. Consequently, ongoing efforts focus on advancing methodologies for synthesizing established quinazoline-based drugs and acquiring novel modified quinazoline derivatives for pharmaceutical or materials science purposes. Aromatic nucleophilic substitution [8] or metal-catalyzed reactions

• [9][10] are commonly employed for quinazoline modification (Scheme 1). Existing literature underscores the reactivity of the C4 position in aromatic nucleophilic substitutions of quinazolines I while achieving regioselective replacement at the C2 position poses challenges [11]. Modification of the C2

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• alkene followed by a nucleophilic addition, is unknown (Scheme 1b, bottom). The radical-polar crossover strategy has been steadily emerging in synthetic organic chemistry during the last few years [43][44][45][46]. This strategy allows complex chemicals to be assembled with high step economy that would

• crossover process [47][48][49][50]. However, activated alkyl halides are not suitable for these carboamination reactions due to the direct nucleophilic substitution of activated alkyl halides with nucleophilic reagents under the necessary alkaline conditions [51]. Recently, a Pd-catalyzed alkyl Heck

• process (Scheme 1c). In this process, the hybrid α-ester alkylpalladium radical species from diazo ester adds to the double bond of 1,3-dienes or allenes, followed by the allylpalladium radical-polar crossover path. As with the classical Tsuji–Trost reaction, a subsequent nucleophilic attack of an amine

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• report from the literature [24] a plausible reaction mechanism is shown in Scheme 6. It involves the nucleophilic attack of the aminopyridine 1 to the HPW-activated carbonyl compound 2, followed by iminium ion formation (iii) and [4 + 1] cycloaddition with the isocyanide. A 1,3-hydrogen shift yields the

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• ; imidazolium; NHC; Introduction Imidazolium-derived nucleophilic heterocyclic carbenes (NHCs) have had a sustained impact across the fields of organometallic and main group chemistry, transition-metal catalysis, materials synthesis and organocatalysis [1]. Laterally annellated polycyclic NHCs offer a useful

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• under basic conditions resulting in achiral product 25. No proton signals related to the expected cyclization product were detected in the proton NMR spectrum. The formation of phthalide from compound 18 under the action of base is difficult to explain. In this case, for some reason, the nucleophilic

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• competing Brønsted acid catalysis in gold-catalyzed alkene functionalization remains a consideration [2], and while it is assumed that alkene activations follow the same prototypical mechanisms as allene and alkyne activations, that is (1) π-activation with nucleophilic attack followed by (2

• ]. Protic additives are widely accepted to “facilitate proton transfer,” but they can also influence the aggregation of charged intermediates. Most mechanistic discussions incorporate protodeauration of alkylgold intermediates and consider a continuum from rate or enantio-determining nucleophilic attack

• /protodeauration paradigm for gold catalysis, we propose the data is also consistent with a mechanism involving gold-mediated tautomerization to release a proton, and concerted nucleophilic attack/proton transfer to the alkene (Scheme 2). Substrate effects: Substrate trends in 5-exo-trig alkene hydroamination may

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• II, which could be transferred to III by cyclization and epoxidation. Oxidation and methylation of intermediate III would produce IV. Compounds 1–4 could be obtained by nucleophilic attack at C-8 with the hydroxy or thiol group from IV via intermediate V, followed by oxidation and cyclization

• (pathway b), while nucleophilic attack at C-14 of intermediate IV by a chloride could generate compound 5 (pathway a). In addition, compound 5 might also be derived from intermediate IV by cleavage of the ester bond at C-2 to form the intermediate VI [15], followed by chlorination (pathway c). Compounds 1

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• difluoromethylene units. To meet the demands of synthetic chemists within the life science discovery and manufacturing arenas, many fluorination methods have been developed over the years to introduce difluoromethylene groups into organic systems. Approaches using nucleophilic fluorination include halogen exchange

• two equivalents of quinuclidine. We propose that the fluoride ion, generated in situ, deprotonates enolic forms of 1,3-dicarbonyls and accelerates the rate-limiting enolization of 2-fluoro-1,3-dicarbonyl intermediates. The resulting enolates are nucleophilic and could react with fluorine or in situ

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• step involves the activation of the carbonyl group by the catalyst. This renders it susceptible to a nucleophilic attack from the indole, leading to the formation of the intermediate product. Subsequently, a second nucleophilic attack occurs by another molecule of indole, yielding the final BIM product

• ion activates the carbonyl group of the aldehyde, enabling a nucleophilic attack by a molecule of indole, producing the azafulvenium salt IV. The azafulvenium salt is formed, only when utilizing aromatic aldehydes, as opposed to aliphatic aldehydes, which cannot produce a stable conjugated system

• . Finally, another nucleophilic attack by a second molecule of indole to IV is occurring, forming the desired BIM 12, while simultaneously releasing the catalyst, rendering it available for another catalytic cycle [80]. Halogen bonding processes Recently, halogen bonding (XB) interactions have emerged as an

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• radical-polar crossover affords cation 27 that delivers functionalized product 31 upon nucleophilic addition. The Doyle and Knowles groups reported the use of NHPI esters as radical precursors in the context of a radical redox annulation method [48] (Scheme 8A). This transformation occurs through an

• oxidation of 35 to 36, the photocatalyst is regenerated and product 37 is formed through intramolecular nucleophilic cyclization facilitated by the phosphate base. Importantly, the activation of NHPI esters through PCET may also play a role in transformations mediated by the cyanoarene-based donor–acceptor

• aromatic ring, forming intermediate 41, which was then oxidized to cation 42, thereby completing the photocatalytic cycle. The reaction proceeded by regioselective nucleophilic addition of H2O, accompanied by the loss of MeOH to deliver spirocycle 43. Notably, the dearomative spirocyclization of biaryl

Facile approach to N,O,S-heteropentacycles via condensation of sterically crowded 3H-phenoxazin-3-one with ortho-substituted anilines

• Eugeny Ivakhnenko,
• Vasily Malay,
• Pavel Knyazev,
• Nikita Merezhko,
• Nadezhda Makarova,
• Oleg Demidov,
• Gennady Borodkin,
• Andrey Starikov and
• Vladimir Minkin

Beilstein J. Org. Chem. 2024, 20, 336–345, doi:10.3762/bjoc.20.34

• University, 1 Pushkin St., 355017, Stavropol, Russian Federation 10.3762/bjoc.20.34 Abstract A convenient method for the synthesis of a series of 2-(arylamino)-3H-phenoxazin-3-ones based on the nucleophilic substitution reaction between sterically crowded 3H-phenoxazin-3-one and arylamines performed by

• ][12]. At the first stage, this reaction follows one of three possible reaction pathways, including Schiff base formation (attack at the C(3) center), Michael addition at C(1), or nucleophilic substitution (SNH) at the C(2) center [13][14][15]. Most readily used is the pathway involving carbonyl–amine

• highly basic amines (Scheme 1) [6]. The choice for one of the other two possible reaction pathways (nucleophilic additions to either the C(1) or C(2) center) critically depends on the electrophilicity. Figure 1 shows the distribution of electronic density in 6,8-di-tert-butyl-3H-phenoxazin-3-one (1

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• ), it was non-scalable and displayed low modularity. Indeed, the imide groups along with their substituents were introduced at a rather early stage of the synthesis, with the ultimate synthetic step being the formation of the thiepine ring via a two-fold nucleophilic aromatic substitution by sodium

• corresponding boronic acid 9 and a Suzuki–Miyaura cross-coupling between 8 and 9 gave rise to dimer 10, followed by the oxidation of both acenaphthene units into 1,8-naphthalic anhydrides. Installation of the thiepine ring was achieved by a double nucleophilic aromatic substitution induced by sodium sulfide

• synthesis and a final closure of the 7-membered ring by C–C bond formation. This is in sharp contrast with the widely adopted strategy relying on the late-stage insertion of the sulfur atom with concomitant ring closure, using either electrophilic or nucleophilic sulfur reagents. By way of example, thiepine

Nucleophilic functionalization of thianthrenium salts under basic conditions

• Xinting Fan,
• Duo Zhang,
• Xiangchuan Xiu,
• Bin Xu,
• Yu Yuan,
• Feng Chen and
• Pan Gao

Beilstein J. Org. Chem. 2024, 20, 257–263, doi:10.3762/bjoc.20.26

• yields. Even when sulfonium salt 1g bearing a C(sp3)–Br bond is susceptible to nucleophilic attack, the desired product 3ga can still be obtained in good yield. Furthermore, substrate 1h featuring two sulfonium salt motifs could undergo dual thioetherification at both reaction sites, resulting in the

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• nucleophilic substitution of benzylic bromides with sodium azide and a subsequent copper(I)-catalyzed double click reaction in one pot [17]. In summary, these contributions by renowned experts demonstrate the broad diversity of impressive catalytic domino, tandem, and one-pot processes towards many valuable

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• , despite the presence of two pyridine nitrogen atoms, is extremely inert towards nucleophilic and oxidative amination reactions. Although molecule 5 does not explicitly contain deactivating electron-donating substituents such as alkoxy and dialkylamino (except for alkyl groups), the observed inertness may

• (base 5). At the same time, in contrast to quinoquinoline 3, which sometimes adopts a twisted shape [11][13], molecule 5 each time remains almost flat. Nitration, nucleophilic methoxylation, and basicity measurements The nitration reaction of compound 5 should proceed in the same way as in other

• quinolines, at the benzene ring, and the resulting nitro compounds could potentially be subjected to further transformations, including nucleophilic substitution of nitro groups. Indeed, under the action of a small excess of the nitrating mixture, dipyridoacenaphthene 5 undergoes double nitration at

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• reacts with the copper catalyst generating the Cu-carbene intermediate B, which undergoes nucleophilic attack by acetonitrile to form the intermediate C. Subsequently, nucleophilic addition of benzoic acid to intermediate C affords the acetimidic anhydride D with the release of CuI catalyst for the next

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• careful review of the product structure it was revealed that the purported dibenzodiazepine products were, in fact, diarylimines, which resulted from a nucleophilic addition of the aniline reagents to the aldimine substrates, followed by elimination of an tosylamine product. This was one of the principle

• takes places to deliver palladium species III. Then the insertion of CO that is released by Mo(CO)6, should afford intermediate IV that undergoes a base-promoted intramolecular cyclization via nucleophilic attack of the amine [31]. Finally, the dibenzodiazepinone 4a would be obtained through reductive

Comparison of glycosyl donors: a supramer approach

• Anna V. Orlova,
• Nelly N. Malysheva,
• Maria V. Panova,
• Nikita M. Podvalnyy,
• Michael G. Medvedev and
• Leonid O. Kononov

Beilstein J. Org. Chem. 2024, 20, 181–192, doi:10.3762/bjoc.20.18

• versus α:β = 13:1 for 2). One could speculate that a more nucleophilic carbonyl oxygen of the chloroacetyl group at O-9 in sialyl donor 2 might participate in a stabilization of the intermediate glycosyl cation from the α-side (as we discussed earlier [52][53]) diminishing the α/β ratio. Conversely, at

Synthesis of the 3’-O-sulfated TF antigen with a TEG-N₃ linker for glycodendrimersomes preparation to study lectin binding

• Mark Reihill,
• Hanyue Ma,
• Dennis Bengtsson and
• Stefan Oscarson

Beilstein J. Org. Chem. 2024, 20, 173–180, doi:10.3762/bjoc.20.17

• -butylsilyl-4,6-acetal-protected donor, as developed by the Kiso group [13][14], was chosen. After some initial testing the known N-Troc-protected donor 3 [15][16] (Scheme 1) was selected [17]. Since donor 3 possessed a Troc group, which contains 3 chlorine atoms, nucleophilic introduction of an azido group

Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• ], in the presence of a nucleophilic species. Recently, we applied this idea to the rearrangement of 1-indanyl hydroperoxides into 2-substituted chromane derivatives, involving the nucleophilic allylation of the rearranged oxocarbenium intermediate (Scheme 1b) [12][13]. Furthermore, it is interesting to

• reactions. Highly nucleophilic arenes like 1,3,5-trimethoxybenzene react easily under mild conditions and result in a stabilized benzylic cation in acidic conditions, allowing a second intramolecular Friedel–Crafts reaction involving the aryl substituent of the substrate. These reactions are favored by π

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• process. The [2 + 2] CA–RE sequence proceeds successively, as depicted in Scheme 1, where electron-donating groups are denoted as EDGs. During the [2 + 2] CA process, the nucleophilic attack by the terminal alkyne carbon of an electron-rich alkyne on an electron-deficient alkene, such as TCNE and 7,7,8,8

• TCNQ with electron-rich alkynes, the alkyne terminal carbon executes a nucleophilic attack on the exocyclic carbon of the dicyanovinyl (DCV) group of TCNQ, affording dicyanoquinodimetanes (DCNQs) [12][13]. Intense ICT bands of TCBD and DCNQ are observed at around 450–470 nm and 680–710 nm, respectively

• equivalents of TCNEO relative to the alkyne substrate for the generation of the TCBD products [100]. For the reaction, the formal [3 + 2] cycloaddition reaction is postulated to initiate through the initial nucleophilic attack of the alkyne carbon on the electrophilic TCNEO carbon, yielding a zwitterionic

Multi-redox indenofluorene chromophores incorporating dithiafulvene donor and ene/enediyne acceptor units

• Christina Schøttler,
• Kasper Lund-Rasmussen,
• Line Broløs,
• Philip Vinterberg,
• Ema Bazikova,
• Viktor B. R. Pedersen and
• Mogens Brøndsted Nielsen

Beilstein J. Org. Chem. 2024, 20, 59–73, doi:10.3762/bjoc.20.8

• -annelated IF-DTF 12 by removal of the tosyl (Ts) group under alkaline conditions, followed by nucleophilic substitution to incorporate the hexyl chain on the pyrrole. Furthermore, treatment of the IF-DTF ketone 4 with Lawesson’s reagent (using a recently established protocol [20]) yielded the large dimer 13

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• the mentioned reactions, the first step of the catalytic cycle is the nucleophilic attack of the phosphine on the electrophile, in many cases an electron-deficient olefin. The zwitterion formed from this conjugate addition can subsequently act as a nucleophile or as a base [3][4][5]. The efficiency of

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes

• Nedra Touj,
• François Mazars,
• Guillermo Zaragoza and
• Lionel Delaude

Beilstein J. Org. Chem. 2023, 19, 1947–1956, doi:10.3762/bjoc.19.145

• CACTUS, Campus Vida, 15782 Santiago de Compostela, Spain 10.3762/bjoc.19.145 Abstract The synthesis of zwitterionic dithiocarboxylate adducts was achieved by deprotonating various aldiminium or 1,2,3-triazolium salts with a strong base, followed by the nucleophilic addition of the in situ-generated

• carbenes available to the chemist [7]. Among them, the cyclic (alkyl)(amino)carbenes (CAACs, E) introduced by Bertrand et al. in 2005 [8] have attracted a great deal of attention, thanks to their remarkable nucleophilic (σ-donating) and electrophilic (π-accepting) properties, which allow them to activate a

• observed for C2 when replacing its acidic proton with a CS2 group among all the nucleophilic carbene precursors that we have investigated so far [40][75]. Yet, we do not have an explanation for it. On IR spectroscopy, the most intense absorption in the ATR spectra of compounds 4a–c and 6a–f was always due

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• and proceeds through a by base-promoted annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates. The reaction mechanism of this formal [4 + 3] annulation includes the in situ generated allylic ylide, nucleophilic substitution, Michael additon, and elimination processes

• ylide B. Thirdly, the intermediate C is formed by the nucleophilic substitution of a halide ion in substrate 1 by the allylic ylide B. Then, Michael addition of the amino group to the C=C bond results in the cyclic intermediate D. Finally, the spiro[indoline-3,5'-[1,2]diazepine] 3 is produced by the