Kinetically stabilized 1,3-diarylisobenzofurans and the possibility of preparing large, persistent isoacenofurans with unusually small HOMO–LUMO gaps

• Qian Liu and
• Glen P. Miller

Beilstein J. Org. Chem. 2024, 20, 1099–1110, doi:10.3762/bjoc.20.97

• spectroscopy. After 51 hours of reaction in boiling CH2Cl2, Diels–Alder adduct 27 was observed in 22% yield. Compound 27 was identified by 1H NMR and 13C NMR spectroscopies as well as high-resolution ESI mass spectrometry. Although the lack of reactivity observed for 3 and 23 limited our kinetic analysis, we

• -plane. The out-of-plane rotations provide for enhanced steric congestion both above and below the most reactive 1,3-carbons of the furan ring, dramatically reducing their reactivity with dienophiles including DMAD, acrylonitrile and singlet oxygen. Due to these non-planar conformations, the HOMO and

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• accelerated by enzymes. These enzymes share a similar mechanism of cytosine deamination and a similar tertiary structure. Despite this similarity, individual enzymes are selective for the corresponding cytosine-containing substrates with little or no cross-reactivity. Cytosine deaminase, which is present in

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• desired reactivity. Substitution of a hydrogen atom with a halogen atom within an organic skeleton significantly increases the electrophilicity of the linked carbon centre, enhancing concerted (SN2) as well as carbenium ion-mediated (SN1) substitutions, common – for instance – on benzylic positions

• bonds of aryl halides also exhibit high reactivity, particularly towards transition-metal-mediated cross-coupling processes or Ar-SN reactions. Benzyl and aryl halides, collectively referred to as 'aryl-cored halides', have found extensive applications across various fields, including synthesis [1

• results on various substrates, the direct use of molecular bromine poses sustainability challenges. Its innate reactivity requires stringent safety protocols during transportation, storage, and handling [24]. A related concern involves the stability of the diluting media, often requiring the use of toxic

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• high reactivity of intermediate 7a (Scheme 4). After optimizing the successful synthesis of alkoxylated and diketone derivatives of 7a, we were intrigued to investigate whether other dicyanopyrazinoquinoxaline derivatives could undergo a similar transformation. To assess the efficacy of the reaction

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• attractive class of reagents due to their stability, accessibility, and diverse chemical reactivity [1]. Diaryliodonium(III) salts, in particular, have been widely recognized as efficient arylating reagents for a range of carbon, nitrogen, oxygen, sulfur, and other nucleophiles, and can be employed in the

• modifying their physical properties, and stability and controlling the reactivity of arylation processes, as demonstrated in various studies [9][10]. For instance, the Gaunt group reported that the use of a fluoride counterion in diaryliodonium(III) salt can trigger phenol O-arylation by activating the

• ] nucleophiles due to their excellent reactivity and aryl group selectivity over aryl(anisyl)iodonium(III) salts [32] and aryl(mesityl)iodonium(III) salts [33]. Based on our previously reported conditions for the synthesis of diaryliodonium(III) salts [21], we designed a more practical synthetic protocol for the

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• products, methylenomycin furan (MMF) hormones, and MMF derivatives. Moreover, the molecular probe has been tested in crude supernatants of various Streptomyces strains and enables identification of MMFs. Keywords: Diels–Alder reaction; furans; methylenomycin furan hormones; natural products; reactivity

• oxygen atom in the ring destabilizing the diene HOMO. Thus, when it comes to substituents on a furan ring, it is better to place electron-withdrawing groups in the three and/or five positions of the furan to aid in the natural flow of the electrons [19]. Due to this reactivity, we expected that a Diels

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• bearing a secondary amino group and an internal triple bond [16]. In the same research group, it has been demonstrated that with a terminal alkynyl group, the reactivity is completely different leading to the formation of dihydroindol-2-one derivatives [17]. The process was versatile and efficient towards

• subsequent years, this kind of synthesis was investigated by other groups. Watanabe's group improved the process by studying the reactivity of Pd(PPh3)2/SnCl2 as a new catalyst system [22]. This made it possible to conduct the reaction under milder conditions, making the process less expensive and more

• conditions. In addition, Pd(phen)2(BF4)2 and Pd(tfa)2 in conjunction with tertramethyl-1,10-phenanthroline (tm-phen) reactivity were investigated. The process was generalized: by using Pd(OAc)2 (1–1.5 mol %) and 1,10-phen (2–3 mol %) to catalyze the reaction of some substrates and Pd(tfa)2 (0.1–1 mol %) and

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• before. Before exploring the reactivity of the olefin towards other aryldiazonium salts, we performed a brief optimization of the process by testing several other N,N-ligands. Therefore, five other N,N-ligands were evaluated as follows: PyraBox (L2), QuinOx (L3), PyOx L4 and L5, and PyriBOx (L6) (Figure

• in the er. Pd(acac)2 and Pd(MeCN)2(OTs)2 were also tested without significant improvements. Despite the fact that palladium acetate slightly better performed as shown in Table 1, we decided to continue with palladium trifluoroacetate due to its higher reactivity in forming palladium complexes with N

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

• , we were interested in the reactivity of other BT-SRF reagents developed in our group and tested three longer-chain derivatives under deoxyfluorination conditions. Employing BT-SC4F9 and BT-SC8F17, 19F NMR yields of 2a of 84% and 81% were achieved (Table 1, entries 6 and 7), however, BT-SCF(CF3)2

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

• product 3 show similar reactivity under the employed reaction conditions. Therefore, the reaction had to be optimized to overcome this competition and to achieve a higher yield and selectivity for the desired product (Supporting Information File 1, Table S1). Finally, the transformation was realized by

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

• ). Observing no byproducts originating from phenylacetylene, we speculate that the lack of reactivity stems from the relatively low electron density of the terminal alkyne, which likely leads to direct coordination of pyrazole to the iodine(III) reagent. To probe the relative reactivity of different azoles

• attributed to its much greater Lewis basicity compared to other azoles, likely killing the reactivity of the iodine(III) electrophile by direct coordination. The present reaction could be performed on a preparative scale. Thus, 1 mmol-scale synthesis of the vinylazoles 4aa and 4ba could be successfully

(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

• was also employed for the synthesis of 1,2,4-BCHs [35]. Heterocycle-substituted BCHs were accessed by [2π + 2σ] photocycloaddition by Glorius and co-workers [79] and Houk, Glorius and co-workers [80]. This reactivity was enabled by triplet energy transfer catalysis activating the heterocyclic

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• salts is an efficient tool for the construction of two or more chemical bonds in a one-pot process. Ortho-functionalized diaryliodonium salts have showcased distinct reactivity in the exploration of benzocyclization or arylocyclization. With this strategy of ortho-ester-substituted diaryliodonium salts

• , expanding the benzocoumarin family (Scheme 1b) [14]. Recently, ortho-functionalized diaryliodonium salts, due to their coordinating and electrophilic effects, have exhibited unique reactivity and chemoselectivity [15]. As such, a wide range of functional groups including the trimethylsilyl group, boronic

• explored the reactivity of ortho-functionalized diaryliodonium salts containing electron-withdrawing groups (EWGs) such as fluorine and nitro groups [29][30]. These ortho-substituted diaryliodonium salts undergo selective benzocyclizations and arylocyclizations with aromatic acids, leading to 3,4

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• in diverse bacteria and environments. These results suggest the natural product NNG may also be found in diverse environments. The reactivity of the nitramine functionality begs for further studies confirming the natural abundance and physiological functions of NNG and other nitramine natural

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• indicated that CavA specifically oxidizes albicanol (5) and drim-8-ene-11-ol (6) to synthesize 7–9, while other substrates showed no reactivity with CavA (Figure 4c). Following this, we increased the substrate concentration to enrich and isolate these products, elucidating their structures through NMR

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

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

• alkene reactivity is essential. Two reactivity scales for alkenes are available in the literature, one considering the reactivity of the alkene itself (Mayr scale) [25] and the other the stability of the corresponding cation after protonation (hydride affinities) [26]. In the polar hydrochlorination

• to the electrophilicity parameter E, the nucleophilicity parameter N, and a nucleophile-dependent slope parameters [27]. The nucleophilicity parameter N, as proposed by Mayr, provides a dependable estimation of the reactivity of a given nucleophile, such as an alkene in our case (Figure 1

• ). Conveniently, these parameters are freely available on Mayr's database of reactivity parameters [28]. On the other hand, one can assess the stability of the in situ-generated cation. The greater its stability, the easier the protonation of the alkene will be, making it more reactive towards hydrochlorination

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

• DMSO at room temperature for 10 min using anhydrous NaOAc as a base to afford the corresponding boronated porphyrin conjugates 18–20 in 80–87% yields. Exploring the reactivity of the p-fluorine atom similar nucleophilic substitution reactions of porphyrin 6 were carried out with 1,8-diamino-3,6

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

• , coenzyme A (CoA), phosphopantetheine, and thiophenol. The thiophenol thioesters exhibited the highest cyclization rates, suggesting that chemical reactivity precedes cofactor recognition [54]. Moreover, CDA3 TE had a broad substrate spectrum, even indicating activity to cyclize daptomycin and its analogs

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

• reactivity of the C-centered radical with Ph-EBX (2). Aliphatic alkenes, enamides, enol ethers and acrylates were tested in the reaction but did not lead to formation of the desired products (Scheme S1, Supporting Information File 1). In almost all cases >70% of the EBX reagent was left after 16 hours of

• solubility in DME, which might cause the low yield observed. Ynonetrifluoroborate 5d could not be introduced as nucleophile, probably due to its reduced reactivity caused by the electron-withdrawing acyl group. Unfortunately, although Molander previously reported the use of vinyl-trifluoroborate 11 to trap

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

• [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

• reactivity in the SNAr reactions in comparison to polar solvents such as DMSO and DMF. This is explained by solvent hydrogen bond acidity and basicity descriptors α and β, for example, α(DMSO) = 0, β(DMSO) = 0.88, α(MeOH) = 0.43, β(MeOH) = 0.47. The rate constant of the SNAr process escalates with an

• substrates, but the step sulfoxide → sulfone was entirely slower and required stirring overnight (except for 8d (R = iC3H7)). With 2-chloro-6,7-dimethoxy-4-sulfonylquinazolines 8 in hand, we started to explore the reactivity in SNAr reactions (Scheme 5). Sulfonyl group dance reactions did not work in

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

• a highly emerging area of research and exhibit complementary reactivity to those well-developed carbene-mediated MCRs [30][31][32][33][34][35][36][37][38][39][40][41][42]. In the radical-mediated difunctionalization of alkenes, the carbon-centered radical species from a diazo compound can add to

Enhanced reactivity of Li⁺@C₆₀ toward thermal [2 + 2] cycloaddition by encapsulated Li⁺ Lewis acid

• Hiroshi Ueno,
• Yu Yamazaki,
• Hiroshi Okada,
• Fuminori Misaizu,
• Ken Kokubo and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2024, 20, 653–660, doi:10.3762/bjoc.20.58

• +@C60 has been the focus of intensive studies in chemistry, physics, and related interdisciplinary fields over the past 13 years [9]. A noteworthy discovery during these investigations is the significant enhancement of reactivity arising from the encapsulated Li+. Both experimental and theoretical

• approaches have diligently explored the details of reaction kinetics, quantitatively elucidating the impact of encapsulated Li+ on the reactivity of the outer fullerene cage as a specialized “encapsulated” Lewis acid catalyst [10][11]. While previous studies have revealed valuable insights, such as

• range of unsaturated substrates having a relatively lower HOMO level. With the previously uncovered reactivity of Li+@C60 in hand, we synthesized Li+@C60 derivatives in this study through the thermal [2 + 2] cycloaddition of styrene derivatives, which do not react with empty C60 through the same

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

• reactivity of the imine formation [24]. The most common catalysts are those derived from triflate salts such as Sc(OTf)3 [25], Yb(OTf)3 [26], In(OTf)3 [27] and Gd(OTf)3 [28], and inorganic Brønsted or Lewis acids like HClO4 [29], ZrCl4 [30], InCl3 [31], BiCl3 [32], RuCl3 [33], NH4Cl [34], HCl [35], LaCl3

• obtained. Meta,para-substituted aromatic aldehydes showed a high reactivity with yields greater than 84% for products 4s–w. Notably, the use of tri-substituted aromatic aldehydes gave imidazo[1,2-a]pyridines 4x–z in moderate to excellent yields (35–99%), though the hydroxy substituent at the ortho position

• and methyl isocyanoacetate furnished the desired products (4ff–ii and 4jj–ll, respectively) in moderate yields (55–68%), possibly due to the lower reactivity of these isocyanides compared to tert-butyl and cyclohexyl isocyanides [54]. In the latter cases, transesterification of the ester group with

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

• provide scope to influence the reactivity profile of their resulting metal complexes through steric shielding, direct stabilising interactions with the metal, or by proximal effects to reactive species. Given the sensitivity of metal catalysis to even subtle steric and electronic changes in the ligand

• seen with imidazolidines (cf. for IPr TEP[Ir] = 2050.2 cm−1) [34]. A benchmarking exercise was then performed looking at the reactivity of 13 compared against reaction of symmetrical IPrAuCl across a range of known gold-mediated transformations of alkynes featuring intermolecular attack [35

• ) complex is catalytically competent across several transformations with excellent conversions at 1 mol % loading and with broadly comparable reactivity to IPrAuCl. Having validated the AImOx motif as a viable ligand platform for development, further elaboration and applications will be reported in due

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

• obtained when unsubstituted propiolic acid was used as OH-substrate (2g). The reasons for this result may be due to the increased reactivity of the terminal triple bond of the propiolic moiety, which favors the participation of the OH-insertion intermediate in side processes. However, we were unable to

• by the higher reactivity of benzyl bromide and the lower conformational mobility of the side chain with the ortho-phenylene link. As a result, new spirocyclic compounds 5 were obtained in high (5a,b) or moderate (5c) yields. With some other bromo-substituted OH substrates, we obtained O–H insertion