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

• -cored halides can be broadened by converting C–Hal functions into different functional groups. For example, aldehyde and amine functionalities can be readily derived from C(sp3)–Hal functions through hydrolysis–oxidation [13] or substitution [14], respectively. This is of significant interest in the

• ion in aqueous acidic media (Equation 1) [43]. Its practical implementation is surprisingly simple as standard aqueous HBr and H2O2 solutions are effective. The generated bromine can be involved in different chemical mechanisms, such as an Ar-SE (Equation 2) [44] or a radical substitution on activated

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• the basis of readily available 2-chloro-3-nitropyridines via the intramolecular nucleophilic substitution of the nitro group as a key step. The previously unknown base-promoted Boulton–Katritzky rearrangement of isoxazolo[4,5-b]pyridine-3-carbaldehyde arylhydrazones into 3-hydroxy-2-(2-aryl[1,2,3

• ]triazol-4-yl)pyridines was observed. Keywords: aromatic nitro compounds; Boulton–Katritzky rearrangement; isoxazolo[4,5-b]pyridines; nucleophilic substitution; 1,2,3-triazoles; Introduction Nitrogen heterocycles represent a very important class of organic compounds that has found application in various

• shown in Scheme 1C. Since the key step of the synthesis is the intramolecular nucleophilic substitution of the aromatic nitro group, we assumed that the presence of an electron-withdrawing substituent at the pyridine ring would facilitate this transformation. Results and Discussion According to the

Novel route to enhance the thermo-optical performance of bicyclic diene photoswitches for solar thermal batteries

• Akanksha Ashok Sangolkar,
• Rama Krishna Kadiyam and
• Ravinder Pawar

Beilstein J. Org. Chem. 2024, 20, 1053–1068, doi:10.3762/bjoc.20.93

• energy reaching the Earth’s surface requires efforts to be devoted to red-shift the absorption wavelengths of the bicyclic diene in the visible range. As previous reports have demonstrated, this can be practically achieved by substitution with electron-releasing or accepting groups [8][9][33]. The energy

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

• could be efficiently transformed to tautomerically active, H-bonding capable 1,4-dihydropyrazino[2,3-b]quinoxaline-2,3-diones (Figure 1b, DPQDs) via nucleophilic aromatic substitution (SNAr) at the ipso-CN positions. Here, the lactim–lactam tautomerization of DPQDs to arrive at the more stable 2,3-dione

• Information File 1). The double substitution did not proceed presumably due to the strong electron-donating effect of -NH2, diminishing the electrophilicity of the π-system. However, the mono-aminated product 16f has the potential to serve as a useful building block for condensation with carbonyl

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• viral replication in cell-based antiviral assays [24]. That study highlighted the beneficial role of the tyrosine residue and the indispensable role of the C-2 substitution. In this work, we report the synthesis and biological evaluation of further analogues of HeE1-2Tyr (1) against the SARS-CoV-2 RdRp

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• coelicolor [55] (Figure 8a). Further structure-based engineering of BezA successfully repurposed it to catalyze the unprecedented C6-methylation of FPP by a single residue substitution in its substrate-binding pocket [55]. Moreover, efforts have also been made to engineer the TSs to modulate their product

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

• of the desired amide 5a after 16 h at rt, which could be isolated in 80% yield after column chromatography. A survey of carboxylic acids 1 revealed that the one-pot approach is efficient for a variety of substitution profiles (Scheme 2). Aromatic acids bearing methyl substituents at the para-, ortho

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

• synthesized by other methods and the single Suzuki reaction on uracil is well studied [42][69][70][71]. Physical properties The photophysical properties of selected derivatives were investigated by steady-state absorption and photoluminescence spectroscopy. The influence of the substitution pattern on the

• compounds show a very similar absorption band, indicating that the first transition state (S0 → S1) does not seem to be affected by the substitution pattern. Furthermore, all compounds show broadened absorption bands and no major differences in the first absorption band were observed. The greatest

• could be observed with an absorption band at 273 nm and a shoulder at 306 nm. The second highest peak was observed for 5f, followed by 5m. Only one broadened peak was observed in both cases. The influence of the substitution pattern could be revealed by comparing the two regioisomers 5d and 5k. As a

(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

• ]. The direct replacement of substituted benzenes in drug candidates with saturated benzene bioisosteres is a popular approach to this task [11][12][13][14]. Substitution of a mono-substituted benzene (a phenyl group) is relatively straightforward [11][13][15]. More particular attention must be paid to

• benzenes that have more than one substituent; for example, the ortho-, meta-, or para- relative substitution of a disubstituted benzene should ideally be replicated in the saturated bioisostere to ensure ligand–protein binding is conserved through the bioisosteric swap. Bioisosteres of para-substituted

• , 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

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

• diaryliodonium salt 2a. Naphthol 1a forms intermediate B with A after participation with the Cu(II) catalyst. Intermediate B generates C by radical substitution. A final intramolecular transesterification yields the benzocoumarin product 3aa. Conclusion In summary, we have employed ortho-ester-substituted

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

• trimmed to 148 positions in conserved blocks using Gblocks (ver. 0.91b) [49]. A maximum likelihood tree was inferred using IQ-TREE (ver. 2.2.2.6) with the LG+G4 substitution model [37]. Nitrite concentrations observed in cultures of E. coli transformed with NnlA homologs or variants grown in the presence

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

• the displacement of the chloro substituent with the allyl group, affording 21 in good yield. Electrophilic aromatic substitution reactions at the chloroalkyl ether site were possible when promoted by aluminium chloride, with anisole and diphenyl ether giving addition products 22 and 23 containing

• diastereomers isolated in the current work are attributed to the differences in sterics on the faces of the oxocarbenium ion 27, caused by the substitution on the bicyclic ring system. Conclusion The formation of anomeric chlorides due to bond migrations in the dioxabicyclo[3.2.1]octanol ring system has been

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

• aromatic substitution; Introduction Porphyrins are available macroheterocyclic compounds which play an important role in diverse areas of scientific research owing to their unique photophysical, electrochemical, and optical properties [1]. They have been widely studied in biomedical applications, as

• 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

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

• , resulting in daptomycin (12) formation with a ratio of cyclization to hydrolysis of 3:1 (Scheme 4a). The significance of single amino acids for daptomycin bioactivity was evaluated, for instance, the substitution of ʟ-3-MeGlu12 by ʟ-Glu12 in Dap yielded a 7-fold increase of the MIC against B. subtilis

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

• and substitution with azide ions to produce the desired homopropargylic azide. However, this approach gives only access to products bearing the alkyne at the least substituted position. To the best of our knowledge, no general strategy has been employed to access the other regioisomer possessing a

• , reaction 2). Two classes of reagents are commonly used: ethynylbenziodoxolones (EBXs) [32][33] and alkynylsulfones [34]. A potential limitation of this method lies in the substitution of the transferred alkyne. The efficiency of the radical addition to those reagents is known to be highly dependent on the

• remaining (Table 1, entry 15). Styrene was initially selected as model substrate since the addition of azide radicals generated by ABX was well reported [24][29]. We wanted to explore different classes of alkenes as the double bond substitution would greatly impact both the azide radical addition and the

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• groups at position 5. Therefore, the ee values obtained by the complex of ligand IV in the Henry reaction could be used to estimate the impact of this substitution on the resulting enantioselectivity of the studied ligands. The results summarised in Table 4 show that the complex of ligand IV is

• significantly less enantioselective (37–55% ee) than the complex of ligand IIIb. Thus, the alkyl substitution at position 5 of the imidazolidin-4-one or pyrrolidine ring of ligands I–IV can be considered as a fundamental part of the ligand’s structure, which enables them to possess high enantioselectivity. All

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

• diazidoquinazoline 13 and pyrrolidine in 93% yield. A cross peak for the H–C5 position of quinazoline and CH2 groups of pyrrolidine at the second position was observed in the NOESY spectrum and unequivocally proved the structure 16. Selective C2 substitution was achieved between sulfonylquinazoline 12 and

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

• alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε

• 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

• next turned to evaluate the scope of 1,3-dienes. Although the regioselectivity control of allylic substitution can be attributed to many factors, it is agreed that steric hindrance generally is the primary factor affecting the regioselectivity of nucleophilic attack [54][55][56][57]. Monoalkyl

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

• contrast to the most widely used ‘umbrella-like’ NHCs (Figure 1) [2][3]. An extended π-system influences the donor and acceptor properties of the carbene whilst substitution on the polycycle can position groups adjacent to the active centre. The imidazo[1,5-a]pyridin-3-ylidene motif (ImPy), independently

• good yield. The new nitrenoid reagent 7 is readily prepared from 2,6-diisopropylphenylamine in three steps. Alkylation with methyl bromoacetate is followed by formylation of 11 and then substitution [21] of 12 with N-aminopyridinium iodide to yield the bench-stable and crystalline N-acylpyridinium

Introduction of a human- and keyboard-friendly N-glycan nomenclature

• Friedrich Altmann,
• Johannes Helm,
• Martin Pabst and
• Johannes Stadlmann

Beilstein J. Org. Chem. 2024, 20, 607–620, doi:10.3762/bjoc.20.53

• identify a branch. We do something similar. However, the two residues, or chains, that are linked to the root of the branch are both put in round brackets. The substitution points are defined by superscripts. So, LeX fucosylation of an A4 antenna transforms this term to (A4F3). A LeA structure would be

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• 175.94, δC 194.36). Its NMR data closely resemble those of brocaeloid D [23], with the notable addition of a methoxy group (δH 3.20/δC 53.92). HMBC correlations confirmed the presence of a reversed prenyl group and differentiated compound 1 from brocaeloid D by the substitution of a succinimide

Possible bi-stable structures of pyrenebutanoic acid-linked protein molecules adsorbed on graphene: theoretical study

• Yasuhiro Oishi,
• Motoharu Kitatani and
• Koichi Kusakabe

Beilstein J. Org. Chem. 2024, 20, 570–577, doi:10.3762/bjoc.20.49

• PASE on graphene [3][4]. The protein and pyrene are connected via an alkyl chain. The atomic configuration of this alkyl chain is believed not to be largely affected by the substitution of the succinimidyl group with an amino group. On the other hand, proteins alone do not readily form adsorbed

• expected to appear in the case of succinimide substitutions by proteins? To answer this question, we consider imide substitutions extensively. In principle, if the effect of substitution only provides a weak perturbation, the potential energy surface is only slightly changed and the barrier is maintained

• . A substitution effect that does not effectively change the potential energy surface is isotopic substitution. In fact, the adiabatic potential surface defined for a hypothetical motion at the absolute zero is not changed by a change in nuclear mass. Even in density functional theory calculations

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

• the addition of base (DIPEA). The target α,β-disubstituted spirobutenolides 3a–d were isolated in high yields irrespective of the change in the type of substitution in the initial DAS. However, in the case of 3d, the cyclization stage proceeded slower (8 days instead of 3) and under an elevated amount

• reaction products using diazo reagent 1b as an example, but we failed to observe the formation of spirocyclic cyclization products as a result of intramolecular substitution of the bromine atom (Scheme 7). For example, during the attempted cyclization of compound 18, obtained from 2-(bromomethyl)benzoic

• from each of the bromo-substituted alcohols used by us have two main pathways of transformation under the action of base: 1) exo-tet cyclization with substitution of the bromine atom and formation of the spirocycle, and 2) migration of the exocyclic double C=C bond into the imide cycle (the process is

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• be achieved by changing the substitution pattern of the terpyridine from 6,6” to 4,4” (Figure 12). Due to the repulsion between the nitrogen lone pairs, the 4,4”-substituted terpy adopts a “U” conformation in the non-complexed state and can be switched by metal coordinating to a “W” open conformation

• ] has also been used as a switching unit for molecular tweezers. Like the terpyridine unit, substitution in 4 and 4’ or 6 and 6’ gives access to open or closed-by-default systems. An early example of allosterically regulated systems was reported by Fukazawa and co-workers. Their system 26 is composed of