Synthetic approach to 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides based on common β-keto amide precursors

• Yordanka Mollova-Sapundzhieva,
• Plamen Angelov,
• Danail Georgiev and
• Pavel Yanev

Beilstein J. Org. Chem. 2023, 19, 1804–1810, doi:10.3762/bjoc.19.132

• ., 4000 Plovdiv, Bulgaria 10.3762/bjoc.19.132 Abstract β-Keto amides were used as convenient precursors to both 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides. The utility of this approach is demonstrated with the synthesis of fourteen novel and four known quinolone derivatives, including

• natural products of microbial origin such as HHQ and its C5-congener. Two compounds with high activity against S. aureus have been identified among the newly obtained quinolones, with MICs ≤ 3.12 and ≤ 6.25 µg/mL, respectively. Keywords: antibacterial; β-keto amides; enaminones; 4-quinolones; quorum

• sensing; Introduction Among the vast number of biologically active quinoline derivatives [1][2], the subclass of 4-quinolones (also referred to as 4-oxo-1,4-dihydroquinolines, quinolin-4(1H)-ones, or 4-hydroxyquinolines) is of great importance with its rich variety of bioactive compounds. Perhaps the

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• through an intramolecular aza-Wittig reaction, yielding cyclopropane-fused 2-quinolones [2]. A nitro group not only activates substrates and stabilizes the α-anion as an electron-withdrawing group but also acts as a nucleophile, electrophile, and leaving group, exhibiting diverse reactivities [3]. For

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• protocol is appropriate for both ketosulfonyl reagents and α-sulfonyl-substituted alkyl acetates providing the target quinoline derivatives in good to excellent yields. Keywords: aza-Wittig reaction; azides; cyclocondensation; quinolones; sulfonamides; Introduction The quinoline scaffold has a wide

Cyclometalated iridium complexes-catalyzed acceptorless dehydrogenative coupling reaction: construction of quinoline derivatives and evaluation of their antimicrobial activities

• Hongling Shui,
• Yuhong Zhong,
• Renshi Luo,
• Zhanyi Zhang,
• Jiuzhong Huang,
• Ping Yang and
• Nianhua Luo

Beilstein J. Org. Chem. 2022, 18, 1507–1517, doi:10.3762/bjoc.18.159

• loading offers the potential to access the aryl/heteroaryl quinolones in suitable amounts. In addition, the antibacterial and antifungal activities of the synthesized quinolines were evaluated in vitro, and the experimental results showed that the antibacterial activities of compounds 3ab, 3ad, and 3ah

• ciprofloxacin (Figure 1c). In recent years, the synthesis of quinolines has received great attention and remarkable achievements have been made to produce quinolones by various methods: Skraup reaction [12], Doebner–Miller reaction [13], Combes synthesis method [14], Conrad–Limpach reaction [15], Pfitzinger

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• developed to date. The most potent TcTS inhibitors described are non-carbohydrate-based molecules (anthraquinones [14], chalcones and quinolones [15]) with low micromolar activity, whereas sialic acid-based analogues typically show high millimolar inhibitory activity [16], with few exceptions such as a

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• -alkenylindoles 81 to give enantioenriched, highly substituted, 1,2,3,4-tetrahydroquinolines, which can be oxidized to axially chiral 4-(indol-3-yl)quinolones 82, in a central-to-axial chirality conversion approach with up to 99% yield and high enantioselectivity (up to 99% ee, Scheme 27). In presence of 5 mol

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• -quinolones 92 in very good yields (67–95%) with high ee (82–97%) (Table 20) [59]. Following a similar approach, Yang et al. reported asymmetric aza-Michael additions of anilines 94 to β-nitrostyrenes 93 using a chiral binol-derived phosphoric acid diester catalyst (cat. 95). They succeeded in preparing β

• -2,3-dihydro-4-quinolones 99 were obtained in good yields of up to 95% and good ee (58–72%) (Table 22) [61]. 2. Covalent-bonding organocatalysis of aza-Michael reactions This category of organocatalysts includes N-heterocyclic carbenes and pyrrolidine derivatives. 2.1 Catalysis by N-heterocyclic

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• quinolones 56, indolo[3,2-c]quinolines 57, β-amino acids 58, and 1,4-dihydropyridine derivatives 59 were obtained through this route in moderate yields (Scheme 26). Besides nucleophiles, aromatic amines also reacted with redox-active radical precursors, such as NHPI [95] and N-alkoxyphthalimides 55 [96]. The

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• high levels of selectivity, reactivity, and functional group tolerance, providing a large number of complex nitrogen heterocycles like azaindolines, pyrrolo-quinolines and -quinolones in excellent yields. Amongst the synthesized scaffolds, especially azaindolines are known to be present in M4

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• acids to 3-methyl-2-cyclohexanone catalysed by L9/Pd(TFA)2 [49]. Addition reaction of phenylboronic acid to various enones, lactones, and chromones catalysed by L9/Pd(TFA)2 [48][51]. Addition reactions of arylboronic acids to substituted chromones and N-Cbz-4-quinolones catalysed by L9/Pd(TFA)2 [51

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• enantioselectivity (85:15 er). Photocatalyst 174 was next applied to the formal [2 + 2] photocycloaddition of quinolones 181, which is analogous to the reaction developed by Krische et al. in Scheme 25. Similarly, the mechanism that is proposed proceeds through complex 182 that can be photosensitised into its

• the [2 + 2] photocycloaddition of 2-pyridones 186 and acetylenedicarboxylates 187 catalysed by ent-183 to give cyclobutenes 188 (Scheme 28b) [82]. Another intermolecular reaction was later developed, this time using catalyst 185 for the [2 + 2] photocycloaddition of quinolones 189 and electron

• -deficient alkenes 190 to synthesise cyclobutanes 191 (Scheme 28c) [83]. Recently, Bach et al. also employed this methodology for the intramolecular [2 + 2] cycloaddition of quinolones 192 containing either a pendant alkene or allene to obtain cyclobutanes 193 (Scheme 28d) [84]. Recently, ent-185 was applied

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

• Dandan Li,
• Naoya Oku,
• Yukiko Shinozaki,
• Yoichi Kurokawa and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1489–1494, doi:10.3762/bjoc.16.124

• . Though not alkylated, the close structural similarity to 3 suggests that 1 is also a member of the 2-alkyl-4-quinolone class signaling molecules/antibiotics known from Pseudomonas aeruginosa and some Burkholderia species [26][27]. Quinolones of this class are classified into two lineages, those with or

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• , it was shown that upon the treatment with an amine, this enolate produced the final chiral amide product with a good yield (82%) and ee (96%). While the methodology for the ACAs of Grignard reagents to chromones and coumarins has been established successfully, quinolones remained challenging

• substrates for such transformations until very recently. It was not until 2019 that this problem was solved, when the Harutyunyan group employed a catalytic system based on L4/Cu, which efficiently catalysed the ACA of Grignard reagents to N-protected quinolones 17 at room temperature (Scheme 6) [18

• ). When the method was applied to the ACA of Grignard reagents to N-substituted 2-quinolones, their lower reactivity led to a lower conversion. Performing the reaction in the presence of TMSBr resolved this and allowed the reaction to proceed for various Grignard reagents and substrates with an excellent

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• of the fused ring structure. On the contrary, when the substituent R is electron withdrawing the pyridine nitrogen furthest away from the phosphine is more nucleophilic and hence is attacked resulting in isomeric ligand 72. Thus triazolopyridines and quinolones can undergo ring-chain isomerism, which

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• variants of known antibiotics are being developed and were approved in the last few years, also comprising drugs active against Pseudomonas aeruginosa, one of the currently most problematic bacterial pathogens [1]. Especially among the quinolones, cephalosporins and carbapenems new compounds have been

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• ]. Some of these routes suffer from harsh reactions conditions and there is clearly room for novel methods complementary to those already present. Heindel and Fine reported back in 1970 that 4-(1H)-quinolones can be synthesized in a straightforward fashion by simply heating 4-chloroquinolines in ethanol

• ethyl group and yields quinolone (6) after tautomerization. Standard hydrolysis (LiOH, H2O/THF) of ester 6 gave the 4-quinolone-3-carboxylic acid (7) in 87% yield (not shown). Quinolones, and fluoroquinolones (FQs) in particular, are among the most commonly prescribed antibiotics in the world [34

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• Group, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium 10.3762/bjoc.15.18 Abstract Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover

• are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized

• from 3-iodinated quinolones by methylation and iodine–metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially

An overview on recent advances in the synthesis of sulfonated organic materials, sulfonated silica materials, and sulfonated carbon materials and their catalytic applications in chemical processes

• Hashem Sharghi,
• Pezhman Shiri and
• Mahdi Aberi

Beilstein J. Org. Chem. 2018, 14, 2745–2770, doi:10.3762/bjoc.14.253

• disulfonic-functionalized ILs. The catalytic applications of 1-(1-sulfoalkyl)-3-methylimidazolium chloride acidic ILs for the hydrolysis of cellobiose and the synthesis of quinolones. The synthetic route of immobilized 1,4-diazabicyclo[2.2.2]octanesulfonic acid chloride on SiO2 and its catalytic applications

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• antibiotics, bacterial signalling and iron metabolism [1]. Structural optimisation of quinolones possessing intriguing properties can lead to the discovery of important drug classes, as demonstrated by the fluoroquinolone antibiotics, which were inspired by the observation of an antibacterial quinolone side

• primary amines 12, which following metal-catalysed cyclisation would give 1,2-disubstituted quinolones 14. Upon the successful synthesis of analogues of the form 14, biological evaluation of these and the natural products 1, 4 and 5–7 (synthesised during our previous study [11]) would then be possible. In

• natural product analogues. Modular coupling of alkynes 10 and amines 12 with commercially available acid chloride 9 was proposed to give 1,2-disubstituted quinolones 14. Sonagashira coupling of alkynes 10a and 10b with commercially available acid chloride 9 to give ynones 11a and 11b. Conjugate addition

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• production at a concentration of 10 µM. Various analogues were synthesized resulting in compound 42 (M64), where similar as in the quinolones described by Lu et al., introduction of the electron-withdrawing nitro function led to very potent inverse agonist (Figure 18) [72]. M64 (42) proved a very potent

Gold-catalyzed post-Ugi alkyne hydroarylation for the synthesis of 2-quinolones

• Xiaochen Du,
• Jianjun Huang,
• Anton A. Nechaev,
• Ruwei Yao,
• Jing Gong,
• Erik V. Van der Eycken,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2018, 14, 2572–2579, doi:10.3762/bjoc.14.234

• . Subjecting these adducts to a gold-catalyzed intramolecular alkyne hydroarylation process allowed to efficiently construct the 2-quinolone core bearing a branched substituent on the nitrogen atom. Keywords: gold catalysis; hydroarylation; 2-quinolones; Ugi reaction; Introduction Quinoline and its oxidized

• -inflammatory [12][13] and anticancer [9][13][14][15][16][17][18][19]. In addition, 2-quinolones were identified as promising entities for the treatment of neuropathic pain [20][21][22] and erectile dysfunction [23]. Therefore, the elaboration of practical methodologies for the synthesis [24] and

• derivatives with most recent strategies focusing on the implementation of transition metal-catalyzed C–H activation methods [35][36]. One of the common approaches towards 2-quinolones 2 involves the intramolecular Friedel–Crafts hydroarylation [37][38] of N-arylamides of 3-substituted propynoic acids 1

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• have the same outcome, typically resulting in oiling out of the product, and requiring organic solvent extraction. The yields ranged from modest (47%) to excellent (97%) on scales from 1 gram up to 25 gram batches with spectral data matching known quinolones [26]. A plausible mechanism for the

Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• coumarin derivatives were obtained in moderate-to-good yields. Notably, ketone (24e), ester (24d) moieties were tolerated in the reaction. In addition, 2-quinolones (24f and 24g) were obtained using alkynes bearing a Boc protected carbamate in place of the MOM protected ether. Scheme 23 shows a plausible

• -light-driven hydrocarboxylation of alkynes. Visible-light-driven synthesis of γ-hydroxybutenolides from ortho-ester-substituted aryl alkynes. One-pot synthesis of coumarines and 2-quinolones via hydrocarboxylation/alkyne isomerization/cyclization. Proposed reaction mechanism for the Co-catalyzed

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• -1,2,3,4-tetrahydroquinolines 8/12 as the key starting material. Results and Discussion The required N-acylated 2,3-dihydro-4(1H)-quinolones 6 were generally prepared following a literature method with the acid-catalysed Fries rearrangement of N-arylazetidin-2-ones of the general form 4 [43][44]. As

• the quinolones 6 and phenylhydrazine with a catalytic amount of AcOH in refluxing n-propyl alcohol. Subsequently, the hydrazones 7 were converted into the 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 via the oxidation with hypervalent iodine(III) reagent PhI(OAc)2 (Scheme 2) [45]. The

• displacement ellipsoids are drawn at the 30% probability level. Preparation of N-acylated 2,3-dihydro-4(1H)-quinolones 6. Synthesis of α-acetoxyazo compounds 8a–g. Reaction conditions: for synthesis of 8a: 7a (10.42 mmol), PhI(OAc)2 (12.50 mmol), AcOH (10 mL); for synthesis of 8b–g: 7b–g (0.71 mmol), PhI(OAc)2

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

• Dandan Li,
• Naoya Oku,
• Atsumi Hasada,
• Masafumi Shimizu and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2018, 14, 1446–1451, doi:10.3762/bjoc.14.122

• -1 Yanagido, Gifu 501-1193, Japan 10.3762/bjoc.14.122 Abstract Exploration of rhizobacteria of the genus Burkholderia as an under-tapped resource of bioactive molecules resulted in the isolation of two new antimicrobial 2-alkyl-4-quinolones. (E)-2-(Hept-2-en-1-yl)quinolin-4(1H)-one (1) and (E)-2

• [21][22][23][24][25], Gram-positive [26][27] and Gram-negative bacteria [28][29][30], and a marine sponge [31]. Among a variety of substituted 4-quinolones, 2-alkyl-4-quinolones are the most common core in antibiotics [32], which were originally discovered as anti-anthrax metabolites produced by

• revealed 5-lipoxygenase inhibitory activity [33], plant-growth promoting activity [32][34], and IGF-dependent cell-specific cytotoxicity [14]. A recent metabolomic analysis using LC–MS verified the presence of more than 50 2-alkyl-4-quinolones [35], most of which remain chemically and biologically