Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• to acyl fluorides are inspiring greater interest in these compounds. Various synthetic approaches have been investigated with two main strategies being pursued: fluorine-transfer to acyl radicals and nucleophilic fluorination of acyl electrophiles [15]. The latter approach is the most intensively

• unreliable isolation of acyl fluoride intermediates, we next considered whether BT-SCF3-mediated deoxyfluorination of carboxylic acids could be coupled with a subsequent acylation in an overall one-pot process. Selecting amines as nucleophilic coupling partners, a short optimisation study was carried out to

• only 10 mol % of DIPEA (92% 19F NMR yield, Scheme 5b). This reaction could result from base-assisted nucleophilic attack of adventitious water present in the reaction mixture. In addition to addition/elimination of fluoride ions to thioesters 3, a second potential mechanistic pathway exists for the

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26][27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• be activated, and the 5-position deactivated for the nucleophilic attack that occurs during the oxidative addition of the metal catalyst. This may explain the formation of only the 6-substituted product during the Sonogashira reaction. As mentioned above, new reaction conditions had to be chosen to

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• , producing the vicinal N-heterocycle-substituted olefin 9 as a mixture of stereoisomers in 65% yield. Finally, 4aa proved to be a viable nucleophilic VBX for the carboiodanation of 3-methoxybenzyne [35], furnishing the new ortho-alkenylated arylbenziodoxole 10 with exclusive C–C bond formation at the distal

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• , deiodination at the bridgehead position, and nucleophilic substitution at the alkyl chloride. From 1,2-BCP (±)-4, a variety of 1,2-BCPs were prepared through basic chemical transformations (Scheme 1B) [26]. Selective deprotection gave access to free alcohol-containing 1,2-BCPs (±)-5 and (±)-8. Oxidation and

• ]propellane (129). Gassman reported the initial synthesis of [3.1.1]propellane (129) in 1980 [61], and this was recently optimised by Uchiyama (Scheme 13A) [47]. Cyclisation to the bridged structure 126 was achieved by enolate formation and intramolecular nucleophilic substitution of iodide diester 125. A

• substrate. Employing Lewis acid catalysis Deng and co-workers reported an alternative pathway to indole-derived BCHs. Polysubstituted BCHs were accessed by nucleophilic addition of the indole to the activated bicyclobutane followed by a Mannich cyclisation [81]. The synthesis of wide variety of tri- and

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• angle of 176°, explaining the preference for the different skeletal rearrangements in the two possible configurations at C4 in these rigid ring systems [19][21]. The involvement of the ring-oxygen in nucleophilic displacement reactions in 1,6-anhydroglucose derivatives has also been invoked to explain

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• , enol ethers, and enamides, proved unproductive in generating the anti-Markovnikov product [90]. The authors attribute this outcome to the high stabilization of the corresponding cations from these substrates, rendering them unresponsive to nucleophilic attack by the chloride anion. Notably, neither the

Synthesis of new representatives of A₃B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

• Victoria M. Alpatova,
• Evgeny G. Rys,
• Elena G. Kononova and
• Valentina A. Ol'shevskaya

Beilstein J. Org. Chem. 2024, 20, 767–776, doi:10.3762/bjoc.20.70

• single pentafluorophenyl ring was prepared through the regioselective nucleophilic aromatic substitution reaction of the p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with 9-mercapto-m-carborane. The reaction of this porphyrin with sodium azide led to the selective substitution of

• biomolecules via the nucleophilic aromatic (SNAr) substitution reactions [15][16]. A variety of nucleophiles such as amines [17][18], alcohols [18][19][20], thiols [17][19][21][22][23], and carboranes [17][24][25][26][27] have been studied in selective SNAr substitution reactions of the p-fluorine atoms in

• conjugates with functionalized linker groups suitable for bioconjugation or which may be efficient for PDT and BNCT improvement. Results and Discussion Synthesis Nucleophilic substitution reactions of the four p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1) are well studied [15][16

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• increase the ratio of intramolecular nucleophilic attack, resulting in macrocyclic products via preorganization of substrate and enzyme in an active conformation [17][18]. Chemoenzymatic strategies, which merge practical enzymatic transformations with modern organic synthetic methods to increase the

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• , further oxidation would generate the corresponding carbocation, which upon reaction with a nucleophilic alkyne would form the product (Scheme 1B, reaction 3). Based on precedence in the literature, this method should allow to transfer efficiently both aryl- and alkyl-substituted alkynes [41][42][43][44

• since the formation of a stabilized carbocation might be required for the reaction to occur. Xu [41] and Molander [42] previously reported the quenching of similar cationic species by alkynyl-BF3K salts. Boronate 5a was therefore selected as nucleophilic alkyne. Gratifyingly, using Cu(dap)2Cl in DCE

• -component reaction, had surprisingly little influence on the transformation. At lower concentration only a slight decrease of yield was observed, whereas higher concentration led to a similar yield (Table 5, entries 10 and 11). The source of nucleophilic alkyne was evaluated, changing the counter ion from

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