Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• situ-generated acetone imines in a (3 + 3) manner to afford meta-substituted anilines (Scheme 1C) [53][54]. Various EWGs (ester, carbamoyl, ketone, trifluoromethyl) have been successfully employed which motivated us to evaluate other possible EWGs. Results and Discussion Based on the fact, that many

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• -unsaturated ketone with hydrazine and acetic acid forms a 1-acylpyrazoline, while the chromene moiety and hydrazine form the pyrazole nucleus by ring opening/ring closing cyclocondensation. Upon oxidation with DDQ, the pyrazolylpyrazoline products can be readily converted into the corresponding bispyrazoles

• similar to a Michaelis–Arbuzov reaction, yielding an α,β-unsaturated ketone 97. The domino sequence concludes by cyclocondensation of intermediate 97 with phenylhydrazine, ultimately affording fully substituted pyrazoles 96 after the elimination of dimethyl phosphonate (Scheme 34) [117]. β-Thioalkyl-α,β

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• regardless of the electronic properties of the substituents on the N-phenyl ring. When dissymmetric diaryl ketone-derived substrates were employed, the C–N bond formation occurred selectively on the most electron rich aromatic ring. According to the proposed mechanism, this dehydrogenative cyclization of

• one, which is consistent with the finding of ketone side-product. In 2018, the group of Zhang established an intramolecular C(sp2)–H functionalization of aldehyde-derived N-(2-pyridinyl)hydrazones 15 to produce 1,2,4-triazolo[4,3-a]pyridines 16 (Scheme 4) [39]. Interestingly, the hydrazone was in situ

• synthesis of pyrazolo[4,3-c]quinoline derivatives 22 from 7-chloro-4-hydrazinoquinolines 20 and aromatic aldehydes 21 (Scheme 5) [40]. In 1992, Chiba and Okimoto reported the electrooxidative cyclization of aldehyde and ketone-derived N-acylhydrazones 23a and 23b to build 1,3,4-oxadiazoles 24a and Δ3-l,3,4

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• , instead of a methyl ketone substituent, were investigated (Table 3). First, the reaction was performed with phenyl ketone 1m, but product 3m was obtained in low yield (Table 3, entry 1: 7%). This yield was lower than that obtained in the batch reaction (30%), and because 28% of 1m were recovered, the flow

• derivatives 2. aFlow rate was 6 mL/h and premixing zone was 0.2 mL. Screening of reaction conditions in the flow reaction systema. Scope of substratesa. Sequential transformation of phenyl ketone 1m and aldehydes 1n–ra. Supporting Information Supporting Information File 29: The exploratory investigation

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

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• structure B, which is further destabilized by the neighbouring ketone. A similar resonance hybrid will be formed for molecules substituted in the 4-position, like 6b, explaining the selectivity towards p-quinones. Abstraction of a proton rearomatizes the molecule before another cation is formed in the

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

• -2H-furan-3-one framework at position C-17 [22]. The one-pot procedure involved the condensation of diethyl oxalate with the α-hydroxy ketone moiety of derivatives 28, immediately followed by a cyclization between the 17α-hydroxy group and the carbonyl group of the α-ketoester in 29. Spiro compounds

• . reported the synthesis of spiropyrrolidines at the ketone group of 17α-methyltestosterone (50a), cholest-4-en-3-one (50b), 5α-cholestan-3-one (50c), and 3-MOMO-estrone [34]. To construct the spiro heterocycle, an addition of p-toluenesulfonyl hydrazide to the carbonyl group of compounds 50a–c was carried

• superior results compared to phenyl-substituted compounds. Frank et al. synthesized a series of 16-spiroisoxazolines through a regio- and a highly stereoselective 1,3-dipolar cycloaddition between the double bond of the α,β-unsaturated steroidal ketone 73 and various arylnitrile oxides [45]. The reaction

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• in unexpected conversions, including the formation of an allylic carbocation at C1, followed by transannular hydride transfer from C8 to afford ketone 20 in 62% yield. With the 5/8/5 tricyclic scaffold 20 in hand, site- and diastereocontrolled C9 hydroxylation of 20 produced a substrate 21 for the

• evolution using site-saturation mutagenesis targeting the putative active sites L110 and Y112, led to the variant MoBsc9 Y112M, which substantially improved the enzymatic conversion into 22, achieving an isolated yield of up to 67%. Diastereoselective reduction of the C8 ketone was then achieved using the

• protocol of Nakada and co-workers [27], enabling the chemo-enzymatic total synthesis of cotylenol (1). Similarly, diastereoselective reduction of the C8 ketone in 20 yielded the biosynthetic intermediate 8 for brassicicenes. Although substrate 8 has a different oxidation state at C8 and lacks the C9

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

• success. Being conscious about the challenges associated with intermolecular ring openings at four-membered heterocycles, we considered an in situ tethering approach, which has proved an attractive alternative in our recent study on oxetane-ring openings [31]. Therefore, electron-deficient ketone 7 was

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

• substituted C–H site next to the ketone (black arrow). Our ML model predicts a pKa value of 24.7 for the experimental site of reaction. Also, our ML model predicts that the reaction site should be at the highlighted circle. For this site, the ML model predicts a pKa value of 16.4. It is generally accepted

• that the most substituted C–H site next to a ketone will form the more stable carbanion (thermodynamic anion), whereas the least substituted carbanion will be the least stable carbanion (kinetic anion). This can generally be controlled by the type of base used. For the reaction in Scheme 1a, n-BuLi is

• Claisen reaction where the experimental site of reaction occurs at the least substituted ketone. Our ML model predicts the pKa value here to be 20.5; however, the lowest ML-predicted pKa value is 4.2. Again, the ML model correctly predicts the most stable carbanion (lowest pKa value), but other factors

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

• pioneering report in 2013 that used photocatalyst 9-fluorenone under visible-light irradiation to generate a photoexcited aryl ketone, capable of HAT to promote benzylic fluorination with Selectfluor (Figure 23) [69]. The reaction tolerated an exceptional range of functional groups and enabled the

• cation would then be trapped by the previously liberated fluoride. This reactivity was demonstrated on one primary, one tertiary and eight secondary substrates. When diphenylmethane substrates were subjected to the reaction conditions benzylic ketone products were observed. As highlighted by the examples

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

• -withdrawing, or electron-donating group at the para-position of the benzene ring were compatible and led to the corresponding products 3ba–fa in good to excellent yields (72–97%) and enantioselectivities (90–95% ee). The α,β-unsaturated ketone 1f with a strong electron-withdrawing group (cyano) in the para

• -position of the benzene ring, was found to be more reactive as the reaction was completed within 4 h and the desired Michael adduct 3fa was isolated in 89% yield and 92% ee. Notably, the α,β-unsaturated ketone with a substituent in the meta-position of the benzene ring was also tolerated and the desired

• product 3ga was isolated in good yield (82%) and excellent enantioselectivity (95% ee). To our delight, the α,β-unsaturated ketone with a substituent in the ortho-position of the benzene ring, led to the product 3ha in good yield (76.5%) and highest enantioselectivity (98.5% ee). Moreover, 1-naphthyl

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• can be used as starting materials in the studied condensation. We tested this hypothesis using the interaction of ketone 1b and phenylhydrazine hydrochloride (2a). It was shown that reflux of the starting compounds in ethanol for 1 h leads to the target hydrazone 3b in 64% yield (Scheme 3). It should

• order to test the Boulton–Katritzky reaction for unsubstituted hydrazones we investigated the condensation of ketone 1d with hydrazine. The process was carried out with 3-fold excess of hydrazine hydrate in EtOH at reflux for 4 h. Unexpectedly, in this case instead of desired hydrazone 3n we have

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

• -halo ketone products in usually very high yields (Scheme 1a) [18][19]. However, the haloalkenes used in this previous study as α-substituted ketone precursors were limited to either styryl analogs or stilbene type haloalkenes, with the only exception of 1-bromocycloheptene as fully aliphatic

• for the synthesis of dialkyl bromoketones would result in a mixture of regioisomers given the presence of enolizable protons on each side of the ketone (Scheme 1b). Recently Toy et al. have disclosed the selective synthesis of unsymmetrical α-haloketones by reductive halogenation of an α,β-unsaturated

• (Scheme 3). No α-tosyloxy ketone products were observed in the crude reaction mixtures, either with catalytic or stoichiometric use of TsOH·H2O, even when the reactions were incomplete. These observations ruled out the possibility of double SN2 attack by tosylate followed by bromide. TsOH·H2O accelerates

Synthesis of indano[60]fullerene thioketone and its application in organic solar cells

• Yong-Chang Zhai,
• Shimon Oiwa,
• Shinobu Aoyagi,
• Shohei Ohno,
• Tsubasa Mikie,
• Jun-Zhuo Wang,
• Hirofumi Amada,
• Koki Yamanaka,
• Kazuhira Miwa,
• Naoyuki Imai,
• Takeshi Igarashi,
• Itaru Osaka and
• Yutaka Matsuo

Beilstein J. Org. Chem. 2024, 20, 1270–1277, doi:10.3762/bjoc.20.109

• Fusion, Resonac Corporation, 5-1 Okawa-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-0858, Japan Institute of Materials Innovation, Institutes for Future Society, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan 10.3762/bjoc.20.109 Abstract Evaporable indano[60]fullerene ketone (FIDO) was

• improving their thermal stability, and more specifically, of designing evaporable fullerene derivatives [16][17][18]. Recently, we reported on perovskite solar cells fabricated with indano[60]fullerene ketone (FIDO), which was synthesized through fullerene cation chemistry. These cells demonstrated long

• . Additionally, the ketone structure acts as a Lewis base, resulting in a passivation effect on Pb2+ [19]. In this study, we designed and synthesized indano[60]fullerene thioketones (FIDSs) with various para-substituents. The vacuum-deposition performance and thermal stability of FIDS were assessed by both

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• cyclization can be explained by the higher electrophilicity of the aldehyde as compared to the ketone. The yields were in general quite good (51–65%). Relatively low yields (51–52%) were obtained for chromones containing methyl substituents, presumably due to the lower electrophilicity of the chromone based

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• efficient Ugi4CR approach. Easy access to isatin from the 3-protected oxindole scaffold was demonstrated using mild reaction conditions. Flexibility of the carboxylic acid component and also the carbonyl one (ketone/aldehyde) was exhibited in the library of Ugi adducts obtained in moderate to good yields

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• [15], and the Nazarov reaction [16][17][18][19][20]. The Nazarov cyclization is one of the most versatile and simple methods for preparing indanones from aryl vinyl ketone derivatives [16][17][18][19][20]. The Nazarov reaction is classically formulated as a 4π conrotatory electrocyclization of a

• pentadienyl cation [1][2][3][4][5][6][7][8][9][10][11][12]. Until the past decade, the conditions used for the Nazarov reaction generally involved the use of a stoichiometric amount of a strong Lewis acid (e.g., BF3, TiCl4, SnCl4, AlCl3) in relation to the divinyl ketone derivative [21][22][23]. However

• , Dhoro and Tius demonstrated that weak acids could also be used as efficient catalysts for the Nazarov reaction [24]. In this context, some research groups developed methodologies that allowed the use of a catalytic amount of Lewis acid. By using more reactive divinyl ketone derivatives, the

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• formed active catalyst dehydrogenates the alcohol to generate the alkoxy complex Mn-L3-II. The liberated aldehyde undergoes aldol condensation with the ketone to afford the α,β-unsaturated ketone, followed by the selective hydrogenation with Mn-L3-III to give the desired alkylated product (Scheme 27). In

• ketone led to the linear α-alkylated product, followed by the alkylation of the methylene ketone with the second benzyl alcohol then afforded the dialkylated product. Remarkably, the drug donepezil, a steroid derivative and a fatty acid derivative were synthesized using this procedure (Scheme 29B). In

• . Furthermore, β-alkylation of 1-phenyl-1-ethanol with benzylic alcohols was also studied with 2 mol % of the Mn4 pre-catalyst, 5 mol % of Cs2CO3 in t-AmOH at 135 °C for 20 h (Scheme 32). NMR studies endorsed the formation of intermediates such as aldehyde, ketone, and α,β-unsaturated ketone. The proposed

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

• 1883 and involves its synthesis from phenylhydrazine and an aldehyde or ketone using an appropriate acid catalyst [8]. In the following years, new processes were developed for the synthesis of indole such as the Castro, Bischler, and Larock synthesis etc. [2][9][10]. Carbonylation reactions represent a

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

• -containing electron-withdrawing groups such as methyl ester and ketone did not show much of an effect in the outcome of the reaction, providing compounds 4bd and 4be in high yields and good er. On the other hand, product 4bq was obtained in a higher yield but with a lower er. The p-halogen-containing

(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

• (±)-30. In a related strategy, Procter and co-workers prepared 1,2-BCHs (±)-33a–e from BCBs 32 via a SmI2-catalysed radical relay alkene insertion (Scheme 3C) [35]. This approach relied on single-electron reduction of the ketone moiety and ring-expansion from the ketyl radical anion. Electron-deficient

• 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

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• 10 and 11 can be oxidized to the same 9-oxospiroviolane (12) in the same 92% isolated yield, hence confirming the structural assignment of 10 and 11. By reacting with 2,4-dinitrophenylhydrazine [34], ketone 12 was further converted to hydrazone derivative 13, which gave a brownish-yellow crystal

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 exo-face. This process was used to prepare the known compounds 10a–c, and the novel materials 10d–f [9]. Thus, the reaction of o-dibromoxylene with cyrene gave the alcohol 10d in 71% yield over two-steps through the spirocyclic ketone 9d. Alkylation of 2 with methyl iodide gave an inseparable

• mixture of ketone 9e and the O-alkylated enol ether by-product, which was then reduced using NaBH4 to give alcohol 10e with 98:2 selectivity. Similarly, the reaction of 4-methoxybenzyl bromide and 2 gave ketone 9f in 35% yield without chromatography, and when reduced resulted in only a single alcohol

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• that the only difference between compounds 3 and 2 is the position of the hydroxy group [28]. Analyses of the NMR data of compound 4 concluded that it is an analogue of 2. In comparison with 2, compound 4 has a ketone carbonyl signal at δC 219.1 and we finally confirmed its structure by comparing it

• a precursor for derivatives 2–4. The biosynthetic pathway is likely to involve enzymatic modifications at the C-2 and C-3 positions, leading to the formation of diols 2 and 3, with additional oxidation steps producing ketone 4 (Figure 3b). This supports the presence of three P450s in the cav cluster