Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• (Table 1, entry 9). Attempts to generate 2a in situ using 1 equivalent of TsNH2 (4) in combination with 1 or 2 equivalents of PhIO (5) resulted in aziridination yields of 19% and 27%, respectively (Table 1, entries 10 and 11). Finally, exclusion of ambient light had no impact of the aziridination of 1a

• challenging iminoiodinanes). In situ preparation of the iminoiodinane intermediates is possible, and for those reagents that undergo facile decomposition, aziridination is more efficient using these conditions (yields for in situ-generated iminoiodinanes are in parentheses in Scheme 3, with N-o-methyl (6g

• ), 0.40 mmol iminoiodinane 2, 1.0 mL HFIP, N2 atmosphere. Conditions using in situ-generated iminoiodinane: 0.20 mmol cyclopentene (1b), 0.20 mmol sulfonamide, 0.40 mmol iodosylbenzene (PhIO), 1.0 mL HFIP, N2 atmosphere. a) 20 °C for 16 h, b) 40 °C for 16 h. a) The broadening of the hydroxide proton

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• Brønsted acid, such as Tf2NH and TfOH, with Bu4NBF4 might be effective to promote the gem-difluorination of alkynes because of the in situ generation of HF equivalents (Figure 1, reaction 6, chemical method). In addition, the electrogenerated acid (EGA) [43][44][45][46][47][48][49][50][51][52] from a

• also needs only electricity and solid Bu4NBF4, which realizes in situ formation of “HBF4” equivalents. Conclusion In summary, we have carried out the gem-difluorination of carbon–carbon triple bonds using Tf2NH/Bu4NBF4 or EGA from Bu4NBF4/CH2Cl2. The feature superiority of these methods is that they do

Electrochemical allylations in a deep eutectic solvent

• Sophia Taylor and
• Scott T. Handy

Beilstein J. Org. Chem. 2024, 20, 2217–2224, doi:10.3762/bjoc.20.189

• reducing the waste generated in these allylations. While non-sacrificial graphite electrodes had failed to result in any reaction, it seemed possible that the use of a catalytic amount of tin metal or a tin salt with graphite electrodes would result in a superior reaction due to in situ reduction and/or

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

• interrupted Kröhnke reaction (Scheme 1B) [51][52]. The main step of this process is an intermolecular cyclization of the formed 1,5-diketone followed by aromatization. Previously we have shown that 1,3-diketones bearing an electron-withdrawing group (EWG) adjacent to one of the carbonyls readily react with in

• 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

Novel truxene-based dipyrromethanes (DPMs): synthesis, spectroscopic characterization and photophysical properties

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2024, 20, 2163–2170, doi:10.3762/bjoc.20.186

• pointed out, though for the first time truxene was reported in 1894 by Kipping [9], whereby 3‐phenylpropionic acid in situ cyclized under acidic conditions to indan‐1‐one which under the same conditions offered a mixture of both isomers, that is truxene as well as isotruxene. However, the practical

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• to imidoyl units generated in situ by radical addition to isocyanides, innovative molecules with a variety of functions can be obtained. In other words, if functional groups can be prepared simultaneously with the formation of an imidoyl group, it would be an extremely useful method for the synthesis

• lack of geometrical isomerization of the C–N double bond of the dithiolation products [32]. The thioselenation product 6’, an imine derivative, can be converted to a β-lactam derivative by [2 + 2] cycloaddition with ketene generated in situ. For example, thioselenation of RNC (R = (EtO)2P(O)–CH2) gave

• can add to isocyanides to form the imidoyl radicals. In this reaction, telluro radicals (ArTe•) also forms in situ, but the relative reactivity of them toward isocyanides might be very low. In addition, dimerization of ArTe• to (ArTe)2 is very fast, and therefore, the ArTe-substituted imidoyl radical

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

• efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls

• of the carbonyl groups and their derivatives. 1,3-Dicarbonyl compounds as key intermediates The most common and classic synthesis of ring-forming pyrazoles is the cyclocondensation of 1,3-dicarbonyl compounds with hydrazines (Knorr synthesis) [42][43]. Therefore, the in situ generation of 1,3

• -dicarbonyl compounds and their one-pot transformation pave the way for MCR syntheses of pyrazoles. 1,3-Dicarbonyl compounds can, for example, be generated in situ from enolates and carboxylic acid chlorides. They can be converted to the corresponding pyrazoles 1 in a consecutive multicomponent reaction with

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• synthesize functionalized pyrimidobenzothiazoles [37]. An in situ generated conjugated α-cyanoester/malononitrile has been successfully employed as substrate in the double Michael reaction with curcumins by Lalitha et al. [38]. An organocatalytic cascade double Michael reaction between curcumins and 2

Understanding X-ray-induced isomerisation in photoswitchable surfactant assemblies

• Beatrice E. Jones,
• Camille Blayo,
• Jake L. Greenfield,
• Matthew J. Fuchter,
• Nathan Cowieson and
• Rachel C. Evans

Beilstein J. Org. Chem. 2024, 20, 2005–2015, doi:10.3762/bjoc.20.176

• mechanisms of structural changes using in-situ light irradiation with rapid, time-resolved data collection. However, X-ray irradiation has been shown previously to induce Z-to-E isomerisation of Azo-PS, which can lead to inaccuracies in the measured photostationary state. Here, we investigate the effect of

• light and X-ray irradiation on micelles formed from two different PS, containing either an Azo or AAP photoswitch using SAXS with in-situ light irradiation. The effect of X-ray irradiation on the Z isomer is shown to depend on the photoswitch, solvent, concentration and morphology. We use this to create

• brilliance of synchrotron X-ray sources enables the mechanisms of structural changes in PS to be studied, using in-situ light irradiation with time-resolved data collection. For example, Tribet and co-workers used this approach to explore the kinetics of micellisation and dissolution of cationic Azo-PS, both

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

• 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

• point of view, the authors proposed the formation of N-pyridyl radical 18 through the anodic oxidation of in situ-generated anion 17. Subsequent radical cyclization, second anodic cyclization and deprotonation yielded the fused heterocycle 16. Similarly, Youssef and Alajimi disclosed the electrochemical

• undergo deprotonation delivering the oxadiazole 24a. Alternatively, from 23b (R2 ≠ H), nucleophilic addition of methanol to oxycarbenium 26b yielded the oxadiazoline 24b (Scheme 6) [41][42]. In 2020, Lei, Zhang and Gao et al. described the electrooxidative cyclization of in situ-generated α-keto acid

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

• Abstract A flow photochemical reaction system for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence was developed, which utilizes in situ-generated 2-benzopyrylium intermediates as the photoredox catalyst and electrophilic substrates. The key 2-benzopyrylium intermediates were

• catalytic cycles). In catalytic cycle I, the key cationic components, 2-benzopyrylium intermediates A, are generated in situ by the activation of the alkyne moiety of ortho-carbonyl alkynylbenzene derivatives 1 in the presence of the π-Lewis acidic metal catalyst [M]X [AgNTf2 or Cu(NTf2)2] and subsequent

• feature of this sequential transformation is that the in situ-generated 2-benzopyrylium intermediates A are used not only as an electrophile but also as a photoredox catalyst. However, as this reaction is carried out under relatively harsh conditions (i.e., light irradiation, use of an excess amount of

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• -methoxyethylamine. Attempts to obtain directly 2-oxoazetidine carboxylic acid (or its decarboxylation product) or its trifluoroethyl ester by running the synthesis with water or trifluoroethanol were also unsuccessful. Acylation of the π-excessive double bonds of N-alkylindole and dihydropyran by the in situ

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

• -free conditions. Although some new metal or Brønsted acid catalysts have been reported in the last few years, the main innovations can be found in the use of organic catalysts, enzymes, and compartmentations. A few reports on the in situ generation of reactants and on the reaction conducted under flow

• metastable imines, could serve as a starting point for the development of other TGS projects involving imine-based multicomponent reactions. 1.4 In situ generation of reactants and use of enabling technologies Despite their high versatility, isocyanides have some drawbacks, such as their repellent smell (but

• only for most of unhindered small ones), their partial instability and their potential toxicity [27], thus in situ generation represents a sustainable alternative for their conventional use and this issue has been recently reviewed by Baht and Heravi [28]. In situ generation of isocyanides has been

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

• stability and is highly hygroscopic, it is often prepared in situ and Gilmour [3][4][5][6][7][8] has reported a range of fluorination protocols utilising hypervalent iodine(I/III) catalysis (Scheme 1A). Lennox has also demonstrated that 1 can be generated cleanly by electrochemical oxidation [9][10]. In an

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

• synthesis of 2H-furan-3-ones from mestranol [23]. Initially, a 1,3-dipolar regioselective cycloaddition occurred between the alkyne group of mestranol and an alkanonitrile oxide generated in situ from the corresponding oxime, yielding isoxazoles 31. Later, a reductive ring cleavage of the isoxazole ring was

• of these compounds via an intramolecular [3 + 2] cycloaddition reaction between (Z)-steroidal arylidene derivatives 42 and azomethine ylides (Scheme 13) [26]. The latter were generated in situ from sarcosine (MeNHCH2CO2H) and a mono- or dicarbonyl compound such as isatin, acenaphthenequinone, and

• et al. reported the synthesis of cycloadducts 47 from reaction of (E)-16-arylidene derivatives 46 and azomethine ylides generated in situ from substituted isatins and sarcosine [27] (Scheme 14). The resulting spiro compounds proved to be potent antiproliferative agents against human cancer cell lines

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

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• deprotonation to form exomethylene. Subsequent in situ removal of the silyl protecting groups led to the total synthesis of brassicicene K (27). Thus, the biosynthetic proposal featuring the Wagner–Meerwein-type skeletal rearrangement (9→11) through the catalysis of P450 enzyme BscF was successfully emulated by

• brassicicenes 27–29. In situ generation of highly reactive intermediates: trichodimerol and the bisorbicillinoid family The bisorbicillinoid family, isolated from fungi such as Penicillium chrysogenum, has dimeric intricate scaffolds, as exemplified by trichodimerol (2) (Scheme 4) [28][29]. The biosynthetic

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

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• ) as a co-product, which strongly inhibits various MTs [16][17][18][19]. To overcome these limitations, numerous in situ SAM supply and SAM regeneration systems have been developed [4][20][21][22][23][24][25][26], thereby enabling preparative biocatalytic scale methylation reactions [27]. Such

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• –12 against Staphlyococcus aureus indicated that 7 and 12 were bacteriostatic, while 9 and 10 were bactericidal. Compound 9 was also active towards another two commensal Gram-positive bacteria Bacillus sp. and Planococcus sp. isolated from the host sponge. Compound 9 can be detected in situ in the

• -biphenyldiol (4-BP, 26, Figure 9). An in situ algal bloom was simulated to test the algicidal activity of compound 26. These experiments demonstrated that even low concentrations of 26 can cause changes in overall phytoplankton community. Mechanistic investigations suggested that compound 26 could disrupt

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• generated in situ simply by mixing PIFA with a Lewis acid, in this case AlCl3. The importance of this protocol arises from the oxidation of an AlCl3-based chlorine atom, which is an available and cheap reagent. Then it is used as an electrophile source in the chlorination process with an umpolung reactivity

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• reduction of A afforded the desired benzylamine (2a). However, nucleophilic attack of 2a on A, followed in situ by reduction, proceeded competitively to form dibenzylamine (3a). We considered that by protonating 2a to form 2a-H+, its nucleophilic nature could be suppressed, thereby inhibiting the formation

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

• mechanism. Excess NFSI functioned as both a fluorine source and HAT reagent precursor (Figure 13) [20]. Fluorine abstraction from NFSI by copper(I) generates an N-centred radical that is selective for benzylic C(sp3)–H bonds [52][53], affording the benzylic radical via HAT. Subsequent FAT with the in situ

• iodine as a super-stoichiometric oxidant. The catalyst system has precedent for also facilitating oxygenation reactions [82], which was observed as a competing pathway under these conditions. The catalytic cycle proposed by the authors begins at resting state I (Figure 31), which is generated in situ and

• under these conditions, but required first generating the monobenzyl fluoride in situ from the corresponding benzyl chloride before undergoing the photochemical transformation to give the difluorination product. The authors showed that this HAT-radical-polar crossover approach could be applied to other

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

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

• peroxide catalyzed by tetrabutylammonium iodide (TBAI). By utilizing these readily available bulk chemicals a variety of cyclic β-ketocarbonyl derivatives can be efficiently α-azidated under operationally simple conditions. Control experiments support a mechanistic scenario involving in situ formation of

• catalysis concept for such transformations [32][33][34][35][36]. These oxidative approaches, which usually proceed via the in situ formation of catalytically-competent ammonium hypoiodite species, can normally be carried out under operationally simple conditions, thus allowing for the use of easily

• lead to any noteworthy levels of product formation (Table 2, entries 1–4). In sharp contrast, the use of Bu4NOH + I2, which is known to give Bu4NIO in situ [41][42][43][44], results in the formation of 2a in a yield comparable to the above-described catalytic system. Accordingly, and in strong analogy

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

• melting point capillary apparatus. Specific optical rotations were measured in solution using sodium light at 589 nm where no absorption occurred for all compounds. Absorption spectra were recorded on a Cary-5000 spectrophotometer from Agilent Technologies. Photochromic reactions were induced in situ by a