Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• cyclization of perfluorinated phenylpyrilium salts using arylhydrazine [12]; the process is based on the fluorine nucleophilic substitution thus limiting its applicability to a wider range of substrates. Pyridyl-substituted diarylamines may be considered as the possible precursors for N-arylpyridoindazolium

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• cyclophanyl-imidazole-based library of ligands. The synthesis of ligands based on the [2.2]paracyclophane (PCP) moiety, thanks to its structural features and inherent planar chirality upon selective substitution, has been recently reviewed by the same author [46]. Starting from 4-formylcyclophane 37, a GBB

• instead, the authors synthesized a series of 2-amino-protected compound 41 through an aromatic nucleophilic substitution on 2-chloropyrimidin-4-amines. Derivatives 41 were then reacted under the optimized conditions, leading to the formation of a series of GBB adducts 42, finally deprotected with TFA to

• diversification points. The scope of the reaction was limited: alkyl aldehydes and aryl/benzyl isocyanides could not be used, and 4 distinct compounds were obtained in yields of 23–40%. Nevertheless, these results represent an improvement compared to previous studies where substitution on C4 of the 2

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• ): UPGMA, and minimum diagnostic length (lambda): 24. Additionally, in MEGA X, phylogenetic trees were made using Neighbor-joining [43]. Evolutionary distances were calculated employing the Poisson correction method, measured in amino acid substitution units per site. Ambiguous positions were removed for

• each sequence pair using the pairwise deletion option. Bootstrap phylogeny testing was conducted with 1000 replicates, utilizing the Poisson model for amino acid substitution and uniform rates between sites while handling gaps and missing data through pairwise deletion. The genomes associated with LanM

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• product 3a for further transformations. Comparable yield and enantioselectivity were observed relative to those of the smaller-scale reaction (0.1 mmol scale, Scheme 4). The bromomethyl group in 3a readily undergoes nucleophilic substitution reactions, leading to the formation of optically active δ

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• reported before [26][27][28], we developed a new synthetic route which is shown in Scheme 5. In the first step trifluoromethylketone 17 was prepared by a nucleophilic acyl substitution of methyl 2-iodobenzoate 16 with Ruppert’s reagent. Ketone 17 was then reacted with an excess of Ruppert’s reagent and

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• case of bisamides 5d, 6a, 6c, 7b, 8a, and 8c (Table 2), additional transformation products were also isolated from the reaction mixture. According to 1H and 13C NMR, MS, and X-ray diffraction studies these were the corresponding ketobisamides 12, which are products of a nucleophilic substitution of the

• of acid also led to the formation of amides 10b–d as main products and the corresponding ketobisamides 12d–e as minor products (Table 2, entries 10, 11, 18, 23, and 24). This can be explained by the formation of HCl in the reaction mixture due to the substitution of chlorine in the vinyl chloride

Synthesis and characterization of 1,2,3,4-naphthalene and anthracene diimides

• Adam D. Bass,
• Daniela Castellanos,
• Xavier A. Calicdan and
• Dennis D. Cao

Beilstein J. Org. Chem. 2024, 20, 1767–1772, doi:10.3762/bjoc.20.155

• undergo reversible chemical reduction processes, as determined by cyclic voltammetry in CH2Cl2 solvent (Figure 4). There are two factors at play. The imide substitution is impactful as the N-phenyl derivatives are roughly by 100 mV easier to reduce than the N-hexyl analogs. The anthracene scaffold also

• difference can be attributed to a significantly higher HOMO level in 8-Hex arising from having fewer electronegative atoms in the aromatic backbone. For the same reasons, compound 9 is a superior electron acceptor by 0.36 V. These trends confirm the value of backbone atom substitution for fine-tuning

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• limited reactivity, modulated by their substitution [19]. Results and Discussion Synthesis of 3H-benzo[e][1,4]diazepin-5-ones As part of our continued interest in developing new and efficient strategies for synthesizing complex fused nitrogen heterocycles, we decided to evaluate the use of amine groups

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• mesylate 1, whose basic treatment promoted the substitution of the mesylate group at C-21 by the 17α-hydroxy group and the oxetane ring formation in a 16% yield (Scheme 1) [10]. Winkler et al. developed the synthesis of alkylated derivatives of 17-spirooxetanosteroids from non-alkylated frameworks (Scheme

• compared to the stereoisomers 75, with enhanced activity observed upon substitution of the aromatic ring. Interestingly, hydrolysis of the acetate group on C-3 did not significantly affect the antiproliferative effect, indicating that the activity is primarily influenced by the stereochemistry and

• reactions. To increase the molecular diversity at the morpholine ring, tertiary amines were formed by nucleophilic substitution. A final removal of the cyclic ketal group in aq sulfuric acid provided spiromorpholinone derivatives 134a–e, 136a–e, and 138 (Scheme 37). Spiromorpholinones were evaluated as

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• isolated in a high yield of 84% with reisolation of the 5-(2-iodophenyl)-1H-tetrazole (6) in 90% yield. Other para-halogenated benzaldehydes 4b–f were isolated in good yields of up to 88%. ortho-Substitution led to a lower yield of the iodinated product 4g (43%) compared to the para-iodinated analogues 4d

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• infra). Thirdly, we wanted to assess substitution α to the nitrogen (R), as this was thought to impact the stability of the intermediary 1,4-biradical 2 [29][30]. To obtain comparable results, all reactions were performed in a LuzChem photoreactor under identical conditions. Deuterated acetonitrile was

• extending the reaction time to reach full conversion, significant amounts of Norrish type II cleavage were obtained and product 3b was isolated in only 16% yield. This substrate was therefore abandoned. Interestingly, ethyl (1c) and benzyl (1d) substitution was detrimental to the cyclization, indicated by

• ) protecting group (entries 5–7 in Table 1). When changing to phenyl substitution at the nitrogen, azetidinol 3h was formed in 12% yield with a substantial amount of unselective side reactions (Table 1, entry 8). By introducing an ethyl group (1i), only 27% conversion were achieved, with 2% product formation

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• report the synthesis of a new series of triazinephosphonate derivatives and their use as dopants in the preparation of new modified Nafion membranes. The triazinephosphonate derivatives were prepared by substitution of chlorine atoms in cyanuric chloride. Diverse conditions were used to obtain the

• , in the same experimental conditions. Results and Discussion Preparation of triazine derivatives The synthesis of 1,3,5-triazinephosphonate (TP) derivatives, to be used as dopants on new membranes, were carried out from the commercially available cyanuric chloride (1), through the substitution of

• nucleophilic substitution using hydrobromic acid, as a 33% solution in acetic acid, to afford the corresponding bromide derivative 9 [54] (Scheme 2). Subsequently 1-(benzyloxy)-4-(bromomethyl)benzene (9) underwent Michaelis–Arbuzov reaction with triethyl phosphite to afford diethyl [4-(benzyloxy)phenyl

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• combination with an ML model to predict a variety of properties. These properties encompass the site of metabolism [31][33], the strengths of hydrogen bond donors and acceptors [34][35][36], and the regioselectivity of electrophilic aromatic substitution reactions [14]. Building on the methodology from

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• , substituted 3-fluoropyrrolidines, particularly in the form of 2-carboxy derivatives (fluoroprolines), have been extensively explored. These compounds represent valuable nonnatural amino acids, and depending on the regio- and stereochemistry of fluorine substitution, fluoroproline substututions can enhance the

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• )–H functionalisation reactions in drug-discovery campaigns [17]. Although much is unknown about the precise details, several benzylic fluorides have been reported to be unstable, which is an effect that is apparently dependent on the substitution of the ring. While primary benzylic fluorides are

• from 61–75% across a series of nine benzylic substrates with various substitution patterns on the aromatic ring. In 2018, Yu and co-workers reported a palladium-catalysed enantioselective fluorination of benzylic C(sp3)–H bonds with the use of a transient chiral directing group 6 [43]. This approach

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• an ammonium hypoiodite species which first facilitates the α-iodination of the pronucleophile, followed by a phase-transfer-catalyzed nucleophilic substitution by the azide. Furthermore, we also show that an analogous α-nitration by using NaNO2 under otherwise identical conditions is possible as well

• can be accessed by different approaches [6][7][8]. Maybe the most classical way to access organic azides is based on the utilization of pre-functionalized starting materials where a suited leaving group undergoes substitution using nucleophilic azide sources such as NaN3 or TMSN3 [6][7][15]. In

• first, which then facilitates the α-iodination of 1a (hereby either the formed benzoate or the hypoiodite itself may serve as a base). Intermediate 3 then undergoes a phase-transfer-catalyzed nucleophilic substitution with NaN3 thus delivering the final product 2a. With optimized conditions and a

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• conversion of simple aliphatic carboxylic acids into alkylnitriles. Notably, this new decarboxylative cyanation protocol exhibited extraordinary insensitivity to substitution pattern of alkyl acids, affording the corresponding alkylnitriles including primary and tertiary alkylnitriles with good reaction

• functional group compatibility and is applicable to alkyl acids with all substitution pattern. Due to the wide utility of alkylnitriles, we expect this method to be widely adopted within the synthetic and medicinal chemistry communities. The present work also demonstrated electrophotochemical transition

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• is introduced on the azobenzene to increase the water solubility. The influence of ortho, meta, and para-substitution patterns of the azobenzene on the lectin binding has also been studied. Synthesis The β-O-galactosyl p,p'-bis-substituted azobenzene derivative 1 was prepared from galactose and

• the half-live varied from 26 h to 29 days at room temperature depending on the type of glycosidic linkage and the substitution pattern on the azobenzene moiety. The bistability of the azobenzene derivatives is suitable for the investigation of azobenzene isomers on the binding affinity with LecA. All

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• , based on the syn-elimination mechanism, the ʟ-α-methyl,ʟ-β-hydroxy substrate produced by A2-type KR can also result in a trans (E) double bond [18][22], and some DH domains are reported to have epimerase activity on the α-substitution [23]. Thus, the stereochemical outcomes of KRs in γ- and δ-modules

• denotes as product without α-substitution) and A1-type KRs, and B0- and B1-type KRs cannot be distinguished in the phylogenetic trees of both subdomains. This implies that KRs likely exhibit promiscuity for α-substitution, and the structural differences in the α-position should not affect the original

• possessed Q at this residue. This substitution can be reasonable, as it serves as a hydrogen bond donor to activate the β-keto moiety of a substrate [31][32]. Additionally, the presence of K (4), which activates the catalytic tyrosine, was more conserved in C2-type KRs. In general, C2-KRs show similarity to

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• reduction. This electrophilic aromatic substitution usually needs harsh reaction conditions, tedious synthetic procedures and sometimes encounters the trouble of separating positional isomers caused by orientation or steric effects of the pre-existed amino group on the aryl moiety. Nevertheless, anilines

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• followed by the addition of diisopropylamine, either in a one-pot synthesis or in two consecutive steps (Table 1). Subsequently, different aliphatic and aromatic substituents were attached to the pyrazole nitrogen by nucleophilic substitution with suitable organohalides 16 and cesium carbonate [3]. Due to

• benzylic residues differed depending on the benzylic residue's functional groups and the pyrazole substitution pattern. For starting materials 15a and 15d, an excess of product 17 was usually observed. With the ester-functionalized triazene 15c and m-substituted benzylic reagents, regioisomer 18 was the

• phenylacetylene gave the products 21ed and 21jd with yields of 57% and 28%, whereas substituted derivatives (e.g., 19g or 19n) resulted in yields of over 90% (21gd or 21nd) using the same alkyne. The different substitution patterns on the 4- or 5-position of the pyrazole (R1) do not clearly influence the

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• ethylene glycol units of different chain lengths ranging from 2–5 (25, 26, and 27), by varying the aromatic substitution in the ortho, meta and para-positions and finally obtained the desymmetrized products 28, 29, and 30 in good to excellent yields (Scheme 15). This has been effectively depicted in the

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• (i.e., 62e–h, 30–82%) of the corresponding hydrocarbons. m-Substitution also provided a good product yield (i.e., 62i and 62j, 67 and 68%). Additionally, electron-rich benzylic alcohols yielded the product in a lower yield (i.e., 62k and 62l, 53 and 59%) compared to 62a. This was due to the generation

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• substitution patterns on the redox catalytic activity. Keywords: cross-dehydrogenative coupling; O2 activation; phenotellurazine; redox catalysis; Te catalysis; Introduction Tellurium catalysis has become increasingly important in recent years. This is due to its unique chalcogen bonding ability, thus

• of secondary versus tertiary N-centers, the effect of heterocyclic versus non-heterocyclic structures, and the effect of various substitution patterns. Results and Discussion With this aim in mind, we thus started investigating Te(II) redox catalyst candidates that do not necessarily carry a N-atom

• this reaction: PTeZ1 (3aa, 73% after 3 h). In other words, the cyclic phenotellurazine character of the catalyst does not seem to be essential in the context of this particular reaction, as opposed to the ortho/para substitution pattern of Te- and N-atoms. Nevertheless, all results considered, we

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations

• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2024, 20, 1278–1285, doi:10.3762/bjoc.20.110

• comparatively high thermal stability [43][44][45]. The viscosities of TAAILs with different aryl substitutions and a butyl chain are shown in Figure 1. At 25 °C the highest measured viscosity was 1675 cP for the TAAIL with the 4-Br substitution and the lowest viscosity (521 cP) for the TAAIL with the

• increasing viscosity of the TAAILs, which can be explained by the increase in molar mass and stronger van-der-Waals interactions. The only exceptions are the methoxy and 2,4-difluoro substituted TAAILs, demonstrating that the effects of the aryl substitution can have a stronger influence on the viscosity

• difference between Ered and Eox. The anodic limit Eox is mainly influenced by the anion of the ionic liquid, resulting in similar values for Eox for the NTf2-based TAAILs. The cathodic limit Ered depends on the cation and at what voltage the imidazolium cation is reduced. The substitution on the aryl ring