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

• fragility of secondary and tertiary benzyl fluorides, as they observe elimination and hydrolysis in many cases [20][100], thereby raising question marks over their suitability as synthetic targets. Monofluorinated methyl arenes, however, are much more stable to these decomposition pathways. The nucleophilic

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• assembly) activates the pyrazol-5-one 2a through hydrogen bonding and forms the corresponding enol. Simultaneously, the enol form of the pyrazol-5-one attacks the Re-face of the α,β-unsaturated ketone 1b to provide the intermediate 5 (Scheme 5), which after hydrolysis leads to product ent-3ba'. In situ

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• utilizing a hypervalent iodine-catalyzed oxidative hydrolysis reaction. This catalytic process provides both symmetrical and unsymmetrical dialkyl bromoketones with moderate yields across a broad range of bromoalkene substrates. Our studies also reveal the formation of Ritter-type side products by an

• alternative reaction pathway. Keywords: bromoalkenes; bromoketones; hypervalent iodine; oxidative hydrolysis; Ritter-type; Introduction Organic synthesis heavily relies on oxidative transformations to facilitate chemical reactions. One popular method for achieving these transformations is using redox-active

• catalytic amount of TsOH·H2O (0.2 equiv each), in the presence of m-CPBA (1.2 equiv) proved to be the most superior conditions (59% NMR yield, Table 2, entry 3). To rule out the possibility of direct involvement of m-CPBA in the oxidative hydrolysis reaction, 1a was reacted in the absence of any hypervalent

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• these products can be explained, similarly to the formation of 35a–f, by generation of intermediate Y which afforded iodonium salt Z upon addition of iodine. Cyclization by attack of the salicylate hydroxy group to carbon C5 gave intermediate AB. Hydrolysis of the iodide upon aqueous work-up to give an

• is, on the other hand, significantly more difficult and usually requires the use of the Schlenck technique to avoid hydrolysis of the moisture sensitive compounds. The handling of these reagents, which have to be stored at low temperature, requires some experience. In fact, the synthesis of the

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• radical resulting from reaction of o-anisidine with SeO2 is stabilized by resonance (Scheme 7). It combines with the hydroxyl radical and undergoes subsequent oxidation to give 2-methoxycyclohexa-2,5-diene-1,4-dione. This iminoquinone upon hydrolysis gives 2-methoxycyclohexa-2,5-diene-1,4-dione, and the

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• 2 via Baeyer–Villiger oxidation, followed by hydrolysis to yield another crucial aldehyde/acid intermediate 3 [11][15]. Commencing from 3, diverse ring rearrangement reactions can occur, leading to the formation of distinct products. In the AlpJ-catalyzed reaction, compound 3 undergoes ring

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

• ) and FdZ (IId) form tetrahedral intermediates after hydrolysis of the N3–C4 double bond in the active sites of A3Gctd and A3A [59][60]. The intermediates formed had the same R-stereochemistry at the C4 atom of the nucleobase as previously observed for CDA, and thus confirming the general mechanism of

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

• -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

• ) greater electrophilicity of the halo compound due to better leaving group ability of the halide ion, (iii) reduced toxicity, presumably due to faster hydrolysis [18], and (iv) easier oxidation of the halide to molecular halogen (E0 = 1.087 V (SHE) for Br2/Br−; E0 = 1.358 V (SHE) for Cl2/Cl−) [19

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

• –elimination pathway will dominate over hydrolysis. This preference was crucial to prevent the formation of undesired carboxylic acid products [28][30][31]. These results also align with the observations previously reported by Takeda and co-workers [24]. The reaction was carried out using a large excess (10

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

• . Conclusion In this study, novel analogues of the antiviral HeE1-2Tyr (1) were synthesized and evaluated with respect to the in vitro inhibitory activity towards SARS-CoV-2 RdRp. To obtain the benzoxazole analogue, a new synthetic strategy avoiding base-mediated hydrolysis was successfully applied. For the

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

• carried out using 2 mol % of PdI2, 20 mol % of KI and 40 bar of a 4:1 mixture of CO–air, in methanol or ethanol in the presence of an ortho-ester (1:3 mixture) as solvent to prevent hydrolysis of the substrate. After 15 hours at 80 °C the indoles derivatives were isolated in good yields (Scheme 4). Two

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

• temperature gave the NH-unprotected γ-lactam 5a and the drug (R)-rolipram 5b in 79% and 97% yields, respectively, with excellent enantioselectivity. Hydrolysis of γ-lactam 5a in 6 N HCl aqueous solution at 100 °C for 10 hours then led to the formation of (R)-baclofen hydrochloride (6) in 76% yield (Scheme 6

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

• employed as acylation reagents [1][2][3]. The strong C–F bond makes acyl fluorides relatively stable towards hydrolysis and easier to handle than other acyl halides [4][5][6][7][8]. Their reactions with nucleophiles are typically less violent than for the corresponding acyl chlorides with acyl fluorides

(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

• -workers also reported the modification of these 1,2-BCHs to increase the number of derivatives accessible using this approach (Scheme 3B) [38]. Transformation of the naphthyl ketone moiety of BCH (±)-25d by Baeyer–Villiger oxidation followed by hydrolysis gave carboxylic acid (±)-26. Through Curtius

• alkenes including acrylates, vinyl sulfones, and acrylamides could all be incorporated and the number of accessible bifunctional 1,2-BCHs was increased further by chemical transformation (Scheme 3D) [35]. Among the reported transformations were reduction of the ketone (to (±)-34), hydrolysis of the

• homologation and hydrolysis led to aldehyde (±)-46 which could then be oxidised to acid (±)-47 using a Pinnick oxidation. BCH 42b also led to ester (±)-48 via a Horner–Wadsworth–Emmons reaction followed by hydrogenation of the formed alkene. 1,2-BCH 44 could be turned into amine (±)-49 by oxime formation and

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

• carcinogenicity [3][4][5][6][7][8]. Biotic and abiotic degradation of cyclic nitramines often produce linear nitramine byproducts. For example, degradation of RDX and HMX by microbes or alkaline hydrolysis forms the linear nitramine 4-nitro-2,4-diazabutanal (NDAB) [9][10][11][12]. Linear nitramines are also

• orthologous protein sequences and could facilitate NNG hydrolysis in the active site (Figure S4, Supporting Information File 1). The function of these residues are being investigated. There are also several nearby conserved basic residues. The significance of these residues will be further discussed below

• , Supporting Information File 1). Notably, the YjgF protein previously proposed to aid in deamination of imines – a proposed direct product of NNG degradation by NnlA – is absent [20]. This observation suggests this protein is not needed to aid in glyoxylate formation. Therefore, imine hydrolysis to glyoxylate

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

• chiral auxiliary 10a, and following a survey of conditions and isolation protocols, a 90% yield was obtained when 10a was heated in the presence of 2 equivalents of SOCl2 and 5 equivalents of pyridine in DCE. Flash chromatography of the chloroalkyl ether 11a resulted in significant loss due to hydrolysis

• groups were small, and attempts to prevent the formation of 13d by slow addition of alcohol 10d to a solution of SOCl2/pyridine in DCE reduced the yield of 11d to 14%. Heating sulfite 13d with tetrabutylammonium chloride led only to hydrolysis back to 10d without rearrangement, indicating that these

• sulfites were not intermediates in the reaction manifold. Furthermore, the isolation of some starting alcohols in the reactions of 10b and 10d following chromatography was attributed to hydrolysis of the corresponding dialkyl sulfite 13b and 13d on silica, a process that can be acid or base-catalysed [26

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

• polyketides or peptides, and form an ester bond. Then, they catalyze either intramolecular macrocyclization to give macrolactones or macrolactams with attacking of internal nucleophiles (alcohols or amine), or hydrolysis to release linear acids or peptides (Scheme 1b). Although TE domains may display

• TycC TE, the precursor was effectively converted into the macrocyclic tyrocidine A (1), exhibiting a low rate of substrate hydrolysis (Scheme 2a). In addition, TycC TE demonstrated a broad range of substrate tolerance, as it can cyclize a series of decapeptide-NACs that contain non-native residues in

• , 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

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• GGPP, followed by hydrolysis by acid phosphatase. GC–MS analysis revealed that AsCPS synthesizes the same product to ObCPS_11g (see Supporting Information File 1, Figure S4A and B). It should be noted that the stereochemistry of CPP needs further verification due to the lack of chiral resolution of our

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

• first attempts in iPrOH did not provide the starting material conversion. The reaction in THF resulted in the full conversion of the starting material, but the analysis of the crude product revealed the quantitative formation of hydrolysis product 5a. Assuming the instability of intermediate 2a, a one

• -pot reaction was performed by adding sodium 4-methylphenylsulfinate in the first step which was followed by NaN3. As the result, the formation of hydrolysis product 5a and 2,4-diazidoquinazoline (6a) was observed. Next, the reaction 1a → 4a in DMSO yielded diazidoquinazoline 6a as a major product and

• hydrolysis product 5a. In MeCN the conversion to derivative 2a was stopped at 50% and was not facilitated by an extra addition of sulfinate. To our delight, in MeOH we observed the formation of intermediate 2a over 5 hours, and after the subsequent addition of sodium azide product 4a was isolated in 31

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae

• Jia Tang,
• Yixiang Zhang and
• Yudai Matsuda

Beilstein J. Org. Chem. 2024, 20, 638–644, doi:10.3762/bjoc.20.56

• spectrometry (HRMS) analysis revealed the molecular formula of 1 to be C25H36O5, corresponding to the 4-desmethyl form of (6R,10′R)-epoxyfarnesyl-DMOA methyl ester (Figure 2C). Furthermore, the molecular formula of 2 was determined to be C25H38O6, indicating that 2 is formed by the hydrolysis of the epoxide

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

• -diisopropylphenylamine, could not be converted into the desired imidazolium salt (Scheme 1a, path b). Applying a range of conditions, including those successful on other annulated systems, led to unreacted starting material or hydrolysis products after work-up (see Supporting Information File 1) [5][18][19][23][24][25

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

• cruciferous vegetables, as hydrolysis products from the metabolism of glucosinolates [1]. In 2017, Müller and her research team showcased the ability of BIMs to operate as anti-inflammatory drugs by acting as GPR84 agonists [2]. GPR84 is a protein-coupled receptor found in immune cells, which regulates a

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• 4aa [35] was isolated in 62% yield (Scheme 4). On the basis of the transformation of 3aa to 4aa, a tentative reaction mechanism is proposed. As shown in Scheme 5, the spiropyridazine-benzosultam 3aa was firstly oxidized to intermediate A. Next, an aziridine was formed with the hydrolysis of the amide

Synthesis of N-acyl carbazoles, phenoxazines and acridines from cyclic diaryliodonium salts

• Nils Clamor,
• Mattis Damrath,
• Thomas J. Kuczmera,
• Daniel Duvinage and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 12–16, doi:10.3762/bjoc.20.2

• amounts of 2a were observed (Table 1, entry 1). The predominant side products were 2,2'-diiodobiphenyl and 9H-carbazole. The formation of free carbazole indicated the formation and subsequent hydrolysis of 2a. The presence of 2,2'-diiodobiphenyl suggests the reaction of 1a with iodide released by each

1-Butyl-3-methylimidazolium tetrafluoroborate as suitable solvent for BF₃: the case of alkyne hydration. Chemistry vs electrochemistry

• Marta David,
• Elisa Galli,
• Richard C. D. Brown,
• Marta Feroci,
• Fabrizio Vetica and
• Martina Bortolami

Beilstein J. Org. Chem. 2023, 19, 1966–1981, doi:10.3762/bjoc.19.147

• 1 (after drying the IL under vacuum for 16 h), there was a significant increase in product yield from 53% to 87%. Then, we investigated addition of water to BMIm-BF4, as the literature reports that the hydrolysis of the anion of this IL is quite slow in the presence of excess water (less than 5% BF4

• ‒ hydrolysis in a 1:1 in volume IL/water solution kept at 45 °C for 24 h) [105]. It should be noted that the same treatment carried out on 1-methyl-3-octylimidazolium tetrafluoroborate (OMIm-BF4) evidenced a much higher extent of BF4‒ hydrolysis. This is probably due to the weaker interaction between cation

• and anion of the IL as the length of the side alkyl chain increases, which makes the BF4‒/water interaction more effective. Although Saihara and co-workers demonstrated that BF4‒ hydrolysis generates HF, which reacts with the surrounding glass container yielding SiF62‒ (signal at −130 ppm in 19F NMR