Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• notably. Later, the same group developed an alternative method by using glyoxylic acid immobilized on silica, and the reaction conditions were optimized using microwave irradiation and avoiding the use of solvent or additional catalysts [93]. In this way, derivatives of 42a were obtained in good yields

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• -workers in 2003 (Scheme 13) [28]. Working in acetonitrile at room temperature, very high yields were obtained with recycling of the catalyst with negligible loss of activity. The reaction is successful also by operating it in ethanol as a solvent under microwave irradiation [29]. More recently, the

• reaction is facilitated under microwave irradiation and can be extended to the preparation of an imidazo-fused (benzo)thiazole skeleton 34 starting from (benzo)thiazol-2-ones instead of pyridin-2-ones. Moreover, the Cu(OTf)2 in [bmim]BF4 can be recovered and reused for multiple processes. The key step of

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• spaces dedicated to either high temperature reactions, cryogenic/microwave reactions, or reaction workup. On each bench, a translational combination of robotic arms performs the specific experiments using the modular platforms, while consumables and samples are transferred between benches through a

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

•  1, entries 9–12). We attempted to decrease the reaction time by increasing the temperature, but these changes resulted in decreased yields of 3a (Table 1, entries 13 and 14). Surprisingly, when using microwave (MW) heating at 70 ⁰C for 10 min in ACN, product 3a was formed in 74% yield (Table 1

• , entry 15). An additional solvent screen under microwave conditions offered no improvement (Table 1, entries 16–18). Finally, multivariate screening ultimately showed that 3a could be obtained in 79% 1H NMR yield (75% isolated yield, Table 1, entry 19) when using 1a (1.0 equiv), 2a (2.0 equiv) in ACN (1

• M) with Cs2CO3 (1.0 equiv) under microwave irradiation at 70 °C for 10 min. Though the yield only improved by 5% compared with using 1.3 equiv of 2a, these were nonetheless adopted as the optimal reaction conditions. Once the optimal reaction conditions were established, we then investigated the

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• quinazolinone scaffold. They have obtained new benzochromenopyrimidinones, abbreviated as BCPOs, whose synthesis has been accomplished in two steps. First, a microwave-assisted reaction of ethyl cyanoacetate, selected aromatic aldehydes, and 2-naphthol was performed. The second step was the condensation of the

• obtained intermediates with the appropriate commercial lactams, under microwave irradiation (Scheme 8). As a result, compound 8a has been identified as a promising derivative potentially useful in further AD drug discovery for its antioxidant activity (4.7 TE in ORAC-FL assay), moderate hAChE inhibition

• eliminated through microwave-assisted treatment under acidic conditions, resulting in the intramolecular cyclization of the amine onto the ketone derived from glyoxaldehyde (Scheme 14). Vézina-Dawod and co-workers [60] introduced a strategy, which consists of two reactions, for synthesizing highly

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• -dinitrophenylboronic acid has a marginally lower pKa than pentafluorophenyl boronic acid [46]; however, it undergoes protodeboronation, several orders of magnitude slower [47]. The synthesis of porphyrin 31 with a benzothiophene moiety, proved challenging (Table 1, entries 14–19). Use of a microwave-assisted procedure

• (Table 3, entries 7 and 8). The same success could not be replicated for OET-o-BrPPs with no reactivity being observed by TLC or by mass spectrometry. Likewise, a microwave-assisted coupling [48], resulted in no product formation (Table 3, entry 9). Thiophene-3-ylboronic acid (21) was also chosen for

Interaction of a pyrene derivative with cationic [60]fullerene in phospholipid membranes and its effects on photodynamic actions

• Hayato Takagi,
• Çetin Çelik,
• Ryosuke Fukuda,
• Qi Guo,
• Tomohiro Higashino,
• Hiroshi Imahori,
• Yoko Yamakoshi and
• Tatsuya Murakami

Beilstein J. Org. Chem. 2024, 20, 2732–2738, doi:10.3762/bjoc.20.231

• (LUMITRONIX LED-Technik GmbH, Hechingen, Germany) containing 120 LED lamps assembled in an aluminium cylindrical container with a diameter of 8.5 cm. ESR measurements conditions: microwave frequency 9.78 GHz, microwave power 10 mW, receiver gain 5.02 × 104, modulation amplitude 1.00 G, modulation frequency

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt

• Dominik L. Reinhard,
• Anna Schmidt,
• Marc Sons,
• Julian Wolf,
• Elric Engelage and
• Stefan M. Huber

Beilstein J. Org. Chem. 2024, 20, 2401–2407, doi:10.3762/bjoc.20.204

• ), 0.1 M, 135 h at rt, 43%, (b) 1.5 equiv mCPBA, 3.0 equiv TfOH (at 0 °C), (DCM), 0.1 M, 20 h at rt, 85%, (c) 1.0 equiv NaBArF24, (acetone), 0.5 M, 2 h at 50 °C under microwave irradiation, 72%. Gold(I)-catalyzed cyclization of propargylic amide 11 as benchmark reaction for Au–Cl activation. Determined

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• new methodology used bench-stable allyl-1,3,2-dioxaborinane (27) in the reaction with preformed crude N-aryl-, N-benzyl- and N-allylimines in the presence of 2–8 mol % of the relatively simple 3,3’-Ph2-BINOL catalyst 3 at 50 °C in a microwave reactor at 10 W irradiation for 1 hour to afford amines 26

• crystal XRD of the corresponding hydrochloride salt. Microwave-induced one-pot asymmetric allylation of in situ-formed arylimines, catalysed by (R)-3,3’-diphenyl-BINOL. Aldehyde and amine scope [26]. aThe reaction was conventionally heated at 50 °C for 24 hours instead of microwave irradiation. b1.0 equiv

• amine was used. c8 mol % BINOL catalyst was used. d4 mol % BINOL catalyst was used. Microwave-induced one-pot asymmetric allylation of in situ-formed arylimines, catalysed by (R)-3,3’-diphenyl-BINOL. Crotylation studies [26]. aNot determined, but estimated to be high; racemate did not produce 4 clear

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• deuteration of formamide product while increasing formamide equivalents increases the yield at the cost of deuterated %. Excess reaction time increases side product formation and thermal degradation of the aldehyde starting material. To combat this, microwave irradiation was employed which dramatically

• increased the overall yield of the reaction (Table 1, entry 5). In summary, minimal formamide (1–2 equiv), excess [D2]-formic acid, and heating to 170 °C in a microwave reactor for 5 minutes is expected to give excellent yields in good deuteration %. A tentative mechanism to [D3]-formamides is shown in

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ). However, increasing acidity and using trifluoroacetic acid (Table 1, entry 17) did not improve the overall yield. We also tried microwave activation conditions since this is a known technique for reactions of this type [32], but unfortunately, we did not find any improvement in the yield (Table 1, entry

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• Discussion We started our optimization with the reaction between acetonitrile and phenyl trifluoromethyl sulfoxide (1a, Table 1). We firstly chose the same stoichiometry as described in our previous study and tried to reduce the reaction time by the help of microwave heating (Table 1, entry 1). Under these

• conditions, a significant amount of degradation products was observed and the yield was rather low. The same result was obtained when the reagent was first added at 0 °C and then heated for one hour under microwave irradiation (Table 1, entry 2). To avoid degradation, the temperature was reduced while the

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

• microwave-assisted pseudo-five-component synthesis of tris(pyrazolyl)methanes 35, where first β-ketoesters and hydrazines form pyrazolones 36. One equivalent reacts in a Knoevenagel condensation with 4-formylpyrazole 34 to give pyrazolidine pyrazole 37, while the second equivalent undergoes a Michael

• = Cl, Br). The resulting 4-halopyrazoles 111 can either be isolated or undergo further Suzuki coupling with arylboronic acids. Both couplings use the Pd catalyst in a sequential fashion. To increase the yields, both cyclization and Suzuki coupling are carried out with microwave support. Some of the

• methyl esters 144. Subsequently, these esters are converted to various 3-hydroxypyrazoles 143 with hydrazine salts by microwave-assisted cyclization (Scheme 49) [152]. The method tolerates a large number of functional groups. In addition, X-ray structural analysis proved that the products are aromatic 3

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

• tested in a previous study [3]. The reaction requires rather severe heating under microwave irradiation (200 °C, chlorobenzene, sealed vial), ensuring complete conversion of the diazo compound in a rather short time. Initial experiments using p-anisidine as a nucleophile showed that the target β-lactam

• were carried out using microwave activation. We then introduced various aromatic and aliphatic amines as well as alcohols and mercaptans into the reaction. In order to demonstrate the structural diversity of the compounds obtained, a wide range of diazotetramic acids 1 of different structures was used

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

• earth (RE) triflates before the report by Longo et al. [5], who found La and Gd performing better than Eu and Yb, and similarly to Sc in a model reaction between 2-aminopyridine (1), benzaldehyde (2) and tert-butyl isocyanide to give 3 under microwave (MW) heating. However, when methyl isocyanoacetate

• (OTf)3 (5 mol %) as acidic catalyst, and a non-microwave instant heating reactor, performing the reaction at 60 °C and obtaining 25 in 78% yield. Moving forward to investigate the scope of the reaction with different 2-aminoamidines and isocyanides, they obtained 18 different products with isolated

• multistep procedure, however, by employing 3,6-diamino-1,2,4-triazin-5-one 44 as amidine derivative, 46 could be simply obtained through a GBB-3CR. The amino group in position 3 was opportunely protected to drive the GBB reaction to the selective formation of 45. Microwave heating appeared to be beneficial

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

• out, resulting in the corresponding N-tosylhydrazones 51a–c. Afterwards, the compounds were subjected to microwave irradiation in the presence of (3-azidopropyl)boronic acid and potassium or cesium carbonate, yielding 3-spiropyrrolidines 52a–c in high overall yields as 1:1 mixture of diastereomers

• 140a,b (α/β 35:65), which were successfully separated. The following aminolysis of the isolated compounds was achieved by microwave heating using 3 equivalents of butylamine in ethanol at 180 °C. Finally, formation of morpholinones 142 and 143 was accomplished by N-acylation of the corresponding amino

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 into palladium(II)/(IV)-catalysed C–H fluorination of 8-methylquinolines using N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as an electrophilic “F+” source under microwave conditions (Figure 5) [39]. Benzylic fluorination was achieved in good yields on three examples, each bearing

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• KSF clays as recyclable and heterogeneous catalysts to catalyze the Cannizzaro reaction by 1,4-diazabicyclo[2.2.2]octane under microwave irradiation and solvent-free conditions giving the products in excellent yields within seconds. The solid clay applied in the first cycle can be recovered and reused

• in subsequent reactions. Reddy and coworkers carried out the Cannizzaro reaction of aromatic aldehydes to the corresponding alcohols in high yields by crossed-Cannizzaro reactions employing solid-supported KF-Al2O3 as catalyst [26] under microwave irradiation using solvent-free conditions. The use of

• of α-hydroxycarboxylic acids [47]. They are also used in the development of different nanoparticle preparations and other reactions for synthesis of bioactive compounds [48][49][50]. Green synthesis methodologies, such as microwave-assisted [51][52][53] and ultrasound-assisted reactions [54] are

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

• into the scaffold. Benzyl azide (6), obtained using a previously reported procedure [27], was used in the CuAAC reaction. The α-acetamide carboxamide 1,2,3-triazole oxindole hybrid 7 was easily obtained in 61% yield using Cu(OAc)2 as catalyst, ascorbic acid, DMF as solvent, and microwave reaction

• obtained using an Ugi four-component reaction (Ugi4CR). (B) The synthetic strategy reported in this work. Library of α-acetamide carboxamide oxindole hybrids 5 accessed via the Ugi4CR. Microwave-assisted CuAAC reaction to access α-acetamide carboxamide 1,2,3-triazole oxindole hybrid 7. Library of α

Spin and charge interactions between nanographene host and ferrocene

• Akira Suzuki,
• Yuya Miyake,
• Ryoga Shibata and
• Kazuyuki Takai

Beilstein J. Org. Chem. 2024, 20, 1011–1019, doi:10.3762/bjoc.20.89

• exchange interaction between the nanographene and FeCp2 spins. The narrowing of the ESR linewidth of FeCp2-ACFs-55 upon higher excitation microwave power suggests the inhomogeneity of the environment for FeCp2+ molecules in the nanographene host. The observed induction of spin magnetism by the interfacial

• at the excitation microwave powers of 1, 9, and 100 mW. The ESR linewidth of the spectrum for FeCp2-ACFs-150 was extremely broad to analyze the spectra, such as estimation of the linewidths and intensities, where the spectra are merged with the baseline contribution on the wider field range, being

• ]. These g-values are almost constant within the error bar in the excitation microwave power-dependence measurement. Figure 7b shows the excitation microwave power dependence of the ESR linewidth ΔHpp for ACFs and FeCp2-ACFs-55. If we only consider the magnetic dipole interaction, ΔHpp is proportional to

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• was also unsuccessful to increase the product yield. The increased use of microwave conditions in organic synthesis [20] and our previous promising studies on microwave-assisted MCRs [21], motivated us to use microwave conditions for further optimization. Accordingly, we investigated several sets of

• reaction conditions with or without solvents at low or high temperature under microwave irradiation and the results are summarized in Table 1. Notably, the reaction with water as a solvent provided a promising yield of 52%, whereas other solvents and conditions resulted only in trace product formation

• , temperature or assisting techniques such as sonication or microwave. Collectively, this building block strategy opens a new avenue to screen acid bioisostere or amide bioisostere compound libraries to revisit or investigate novel drug targets. The diverse scaffold generation from this method also provides

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• LED lamp (527 nm) for 1 min or 10 min. PS: 40 μM, 4-oxo-TEMP: 80 mM, in 60 mM phosphate buffer (pH 7.0). Measurement conditions: temperature 296 K, microwave frequency 10.03 GHz, microwave power 10 mW, receiver gain 5.0 × 104, modulation amplitude 1.00 G, modulation frequency 100 KHz, sweep time 83.89

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• extracting crocins include ultrasound-assisted extraction (UAE), supercritical fluid extraction, enzyme-linked extraction, and microwave-assisted extraction. Among these methods, the UAE exhibits a higher extraction yield [23][24]. Recently, Fiorito et al. developed a technique that utilizes cost-effective

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• is known for its chemical and thermal stability. Herein, we report a straightforward approach to the GBB-3CR using HPW as catalyst in ethanol under microwave (μw) heating. This convenient environmentally benign methodology is broad in scope, provides the heterobicyclic products in high yields (up to

• existing ones. Keywords: GBB-3CR; imidazo[1,2-a]pyridine; microwave; phosphotungstic acid; Introduction Imidazo[1,2-a]pyridine is a privileged structure that plays an important role in organic synthesis and in the pharmaceutical industry. This scaffold is present in drugs with several biological

• catalyst in ethanol under microwave (μw) heating. This convenient environmentally benign methodology is broad in scope, provides the heterobicyclic products in high yields (up to 99%), with a low catalyst loading (2 mol %) in only 30 minutes. Results and Discussion A search in the literature revealed a

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

• development of greener synthetic technologies, like photocatalysis, organocatalysis, the use of nanocatalysts, microwave irradiation, ball milling, continuous flow, and many more. Thus, in this review, we summarize the medicinal properties of BIMs and the developed BIM synthetic protocols, utilizing the

• various oxidation and hydrogenation reactions [105]. NanoAg-Pt doped silicate constitutes an efficient and recyclable catalyst that can be reused without a notable loss in catalytic activity (Scheme 17). Wanting to avoid the use of conventional heating, Karthikeyan and his co-workers turned to microwave

• rendered inactive. Thus, Karthikeyan’s approach implemented faster reaction rates, while avoiding conventional heating with the application of microwave-assisted irradiation in solvent-free conditions with the drawback of limiting the generality of his methodology [105]. In 2014, Chabukswar and his