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

• hexaketocyclohexane octahydrate as the CO source again. This cyclic hexaketone is a non-toxic stable solid and therefore, it is simple and safe to use unlike of carbon monoxide. It was used as reagent to obtain indol-α-ketoesters by the Cu-catalyzed direct double-carbonylation of indoles and alcohols [76]. The

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• . Monofluorination of 2-ketoesters using fluorine gas has been scaled up to the manufacturing level [33], whereas preparative methods for the synthesis of 2,2-difluoro-3-ketoesters using fluorine gas have not been realized. Ethyl benzoylacetate (4a) was used as a model system for the development of conditions for

• yields. As was observed in attempted fluorination reaction of 1c towards difluorodiketone 3c, methoxy ketoester derivative 4b gave substantial amounts of product arising from competing fluorination of the aromatic ring. Structures of difluorinated ketoesters 5a–h were confirmed by NMR spectroscopy. The

• fluorinations of ethyl benzoylacetate derivatives 4a–g. Conclusion From our experiments, we conclude that quinuclidine is the most effective mediating agent for the difluorination of 1,3-dicarbonyl species using fluorine. Difluorinations of 1,3-diketones 1 and 1,3-ketoesters 4 were achieved by the addition of

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• complex as a catalyst and a Brønsted base were applied in the procedure. It is interesting to note that in such a method, sulfenylation of NH-oxindoles resulted in the thiolated products with excellent enantioselectivities (up to 99% ee). In 2013, sulfenylation and chlorination of β-ketoesters 93, and 95

• . Sulfenylation and chlorination of β-ketoesters. Intramolecular sulfenoamination of olefins. Plausible mechanism for intramolecular sulfenoamination of olefins. α-Sulfenylation of 5H-oxazol-4-ones. Metal-free C–H sulfenylation of electron-rich arenes. TFA-promoted C–H sulfenylation indoles. Proposed mechanism

New one-pot synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones based on 5-aminopyrazoles and azlactones

• Vladislav Yu. Shuvalov,
• Ekaterina Yu. Vlasova,
• Tatyana Yu. Zheleznova and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2023, 19, 1155–1160, doi:10.3762/bjoc.19.83

• few (Scheme 1). To obtain 4-arylpyrazolo[3,4-b]pyridin-6-ones, the only known one-step method is most often used, including the acid-catalyzed condensation of aminopyrazoles with ketoesters [1][16][18] (method A). Its significant disadvantage is the low yields of the target products (11–60%). Yields

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

• Kasturi U. Nabar,
• Bhalchandra M. Bhanage and
• Sudam G. Dawande

Beilstein J. Org. Chem. 2023, 19, 1008–1014, doi:10.3762/bjoc.19.76

• generation of carbene as a reactive intermediate [36][37]. Also, spirocyclic iodonium ylides have been used for radiolabeling techniques [38]. In 2013, Shibata’s research group reported a novel trifluoromethanesulfonyl iodonium ylide for trifluoromethylthiolation of enamines, indoles, and ketoesters

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• easily available, which have been established as versatile synthetic building blocks for the synthesis of cyclic scaffolds [25]. In 2016, Zhu et al. reported the first example of a Rh-catalyzed C–H functionalization of enaminones with alkynes and α-diazo-β-ketoesters to access naphthalenes [26]. Very

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

• reacted smoothly with thiourea 2a under the optimized conditions, giving the corresponding products in 30–80% yields (3a–d). In addition, allyl and benzyl acetoacetate were also suitable substrates to give the desired 2-aminothiazoles 3e and 3f in 78% and 52% yields, respectively. β-ketoesters containing

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• Marc Paul Beller Ulrich Koert Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 4, 35032 Marburg, Germany 10.3762/bjoc.18.129 Abstract This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• were used as key intermediates. For reasons of clarity and better comparability all syntheses are strongly summarized highlighting the key step only. The presentation of the examples is structured in three parts: α-Ketoesters as key intermediates: (+)-euphorikanin A, (−)-preussochromone A

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• 1,3-diketones, β-ketoesters, or β-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1–2

• , β-ketoesters or β-ketoamides are a commonly used 2-step route to 3,4,5-trisubstituted isoxazoles [24][25]. Xiao Zhou et al. recently reported a direct access to 3,4,5-trisubstituted isoxazoles via an enolate-mediated 1,3-dipolar cycloaddition of β-functionalized ketones with nitrile oxides using

• , we herein report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides (Figure 1). No additional metal catalyst was used. Results and

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• of 5-unsubstituted dihydropyrimidinones from β,γ-unsaturated ketoesters in low melting ʟ-(+)-tartaric acid–N,N-dimethylurea mixtures is reported. This solvent-free method is very general and provides easy access to 5-unsubstituted dihydropyrimidinone-4-carboxylate derivatives in good yields

• ketoacids [39]. In the present study, in continuation of our interest in the synthesis of functionalized DHPMs [27], we utilized β,γ-unsaturated ketoesters and subjected them to the melt conditions to achieve the synthesis of 5-unsubstituted DHPMs. We envisaged that the simple Michael addition reaction of

• urea derivatives with β,γ-unsaturated ketoesters and subsequent intramolecular condensation could lead to 5-unsubstituted DHPM derivatives. β,γ-Unsaturated ketoester 7, derived from benzaldehyde and pyruvic acid [40], on exposure to ʟ-(+)-tartaric acid–N,N-dimethylurea (DMU) melt underwent smooth

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• reported a squaramide-catalyzed asymmetric nitroso aldol reaction of cyclic β-ketoesters and malonamate [61]. Inspired by this, we decided to investigate the use of malonamate in the asymmetric nitroso aldol reaction using thiourea catalysis. Herein, we report a novel nitroso aldol reaction of malonamates

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• blocks was developed. Regioisomeric methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC

• analysis, 1H, 13C, and 15N NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data. Keywords: β-enamino ketoesters; heterocyclic amino acids; 15N-labeled 1,2-oxazole; NMR (1H; 13C; 15N); 1,2-oxazole (isoxazole); X-ray structure analysis; Introduction 1,2-Oxazoles (isoxazoles) constitute an

• Meldrum’s acid in the presence of EDC·HCl and DMAP, followed by methanolysis of the corresponding adducts [27][28][31][36][37][38]. Reaction of the resulting β-keto esters 2a–h with N,N-dimethylformamide dimethylacetal afforded cycloaminyl β-enamino ketoesters 3a–h. After isolation of compounds 3a–h from

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

• halogenated 2-hydroxypyridines (pyridin-2(1H)-ones) 38 and α,β-unsaturated 1,4-diketones or 1,4-ketoesters 39 in different solvents. The best results (yield 96%, ee >91%) were obtained on using squaramide catalyst in chloroform. However, for others, the yields ranged from 50–98% with good to excellent

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• compared to the one-pot procedure. The obtained products possess a (R)-configuration, determined by X-ray crystallography (Scheme 26). Sebesta and colleagues described an enantioselective Michael/hemiketalization addition of hydroxycoumarins 1 to enones 2 and ketoesters 86 using squaramide 85 [62]. The

• conjugate addition of 4-hydroxycoumarin (1) to β,γ-unsaturated α-ketoesters 106 was reported the Kim’s group [69]. In this case, a bifunctional binaphthyl-modified thiourea organocatalyst 108 was used, and among the solvents probed (such as CH2Cl2, CH3CN and toluene), the best results were achieved when the

• [dihydrofurocoumarin/pyrazolone] 83. Michael/hemiketalization addition enantioselective of hydroxycoumarins (1) to: (a) enones 2 and (b) α-ketoesters 86. Synthesis of 2,3-dihydrofurocoumarins 89 through Michael addition of 4-hydroxycoumarins 1 to β-nitrostyrenes 88. Synthesis of pyrano[3,2-c]chromene derivatives 93

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• -dichlorocamphorsultam) 17-2 [75] (Scheme 37). The maximum enantioselectivity of enolates of β-ketoesters with (−)-9-1 or (+)-9-2, first prepared by Lang in 1988 (see section 1-9), was 70% ee. The asymmetric fluorination with (+)- or (−)-17-2 afforded up to 75% ee as indicated in Scheme 38. The dichloro reagent 17-2

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• esters 29, such as 1,3-diketones, β-ketoesters, cyclic 1,3-diketone (dimedone), and β-ketoamide, respectively, to afford desired 1,4,5-trisubstituted 1,2,3-triazoles containing glycosyl with high yield. It should be pointed out that no byproducts were recognized under optimized reaction conditions. In

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• developed by Widenhoefer [25][29] relied heavily on the acidity of the carbonyl substrate, and this hampered the use of less enolizable substrates, like alkenyl β-ketoesters. The same group addressed this limitation by proposing the use of trimethylsilyl chloride (TMSCl) as an additive in the intramolecular

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• literature. To avoid the formation of two isomers, the reaction is generally carried out with β-ketoesters, α,γ-dicarbonyl esters, β-ketoaldehydes, or in later modifications acetylenic ketones [47][48]. The reaction was used for the 1939 commercial synthesis of pyridoxine (vitamin B6) [2], the first

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

• Giovanna Bosica,
• Kaylie Demanuele,
• José M. Padrón and
• Adrián Puerta

Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235

• equivalents of the β-ketoester ethyl acetoacetate (2) with benzaldehyde (1a) and ammonia (Scheme 1) [11]. This procedure was later optimized over the years using different substrates by varying the β-ketoesters and aldehydes in order to prepare a larger array of 1,4-dihydropyridines (1,4-DHPs) [12]. In

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

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• bearing fluorine and nitrogen atoms involves the asymmetric addition of α-fluoro-β-ketoesters or α-fluoro-α-nitro esters to appropriate electrophiles [84][85][86][87][88][89]. Results and Discussion Initially, we prepared a series of Ugi adducts 8 by varying acid, 2-oxo-aldehyde, amine, and isocyanide

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• the formation of 5- and 7-oxothiazolopyrimidine-6-carbonitriles (Scheme 1) [12][13]. The synthesis of thiazolopyrimidines through the reaction of 2-aminothiazoles with 1,3-ketoesters in the presence of acids, bases or condensing agents (Scheme 2) has been studied fairly well [6][8][14][15][16]. The

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• . 1,3-Diketones and 1,3-ketoesters 45 undergo cross-dehydrogenative C–O coupling with oximes under the action of oxidizing agents [46], such as KMnO4, Mn(OAc)3 or the KMnO4/Mn(OAc)3 system (Scheme 15). A radical mechanism is suggested for the formation of the C–O coupling products 46 in which the

• oxidizing agent serves to generate oxime radicals from oximes and perform one-electron oxidation of 1,3-dicarbonyl compounds 45. The formation of oxime radicals under the reaction conditions was confirmed by EPR spectroscopy [46]. 1,3-Diketones and 1,3-ketoesters with easily oxidizable groups, such as allyl

• the oxime group. The lowest yield was obtained with an aromatic oxime (product 46e, yield 27%). Later, the Cu(BF4)2 (cat.)/t-BuOOH oxidative system [87] was proposed as an alternative to stoichiometric metal-containing oxidants, such as KMnO4, Mn(OAc)3, and KMnO4/Mn(OAc)3 (Scheme 16). 1,3-Ketoesters

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

• Dominika Krištofíková,
• Juraj Filo,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2019, 15, 2948–2957, doi:10.3762/bjoc.15.290

• rearrangements of O-allyl β-ketoesters [35][36][37]. Hiersemann and Strassner studied the Claisen rearrangement with H-bond-donating organocatalysts by computational methods and concluded that thioureas are not efficient in transition-state stabilization [38]. Regarding the usefulness of the Ireland–Claisen

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• substrates were successfully fluorinated with high enantioselectivities. In 2013, the Kesavan group [73] reported the use of tartrate-derived bidentate bisoxazoline-Cu(II) complexes for the enantioselective fluorination of aliphatic cyclic and acyclic β-ketoesters with up to 98% yields (Scheme 30). In this

• method, (S,S)-Nap-(R,R)-Box as the most suitable diastereomeric ligand forms a 5-membered chelate with copper. In the same year, an efficient and highly enantioselective fluorination of β-ketoesters catalyzed by diphenylamine-linked bis(thiazoline)-Cu(OTf)2 complexes was reported by Du and co-worker

• (Scheme 31a) [74]. Che and co-workers [75] achieved a similar α-fluorination of β-ketoesters and N-Boc-oxindoles (Scheme 31b). Compared with Du’s method, Che employed both AgClO4 and chiral iron(III)-salan complexes as the catalyst. In 2016, the group of Nishikata [76] described a copper-catalyzed site