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

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• main reaction products. Keywords: aldol condensation; [4 + 2]-cycloaddition; diffusion mixing; formaldehyde; Knoevenagel condensation; three-component reactions; Introduction Formaldehyde is a reactive electrophilic reagent widely used as a C1 building block in multicomponent reactions [1][2][3]. Its

• ), 115.0, 85.6, 39.3, 37.8, 27.4; HRMS–ESI+ (m/z): [M + H]+ calcd for C21H19O2, 303.1380; found, 303.1383. Equipment for carrying out reactions by the diffusion mixing method. Knoevenagel and Diels–Alder reactions in the multicomponent synthesis of substituted cyclohexadienes under formaldehyde

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

• ]quinolinones 42 was achieved via the one-pot reaction of tetronic acid, 5-aminoindazole and arylaldehydes under copper catalysis and ultrasonic irradiation, in acetonitrile as solvent. The mechanism involves a Knoevenagel condensation between the tetronic acid and the arylaldehyde as first step, followed by a

• reaction of isatin, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (i.e. kojic acid) and malononitriles or cyanoacetates (Scheme 32) [51]. Compared to other Lewis acids, Cu(OTf)2 proved to be the best. Mechanistically, the process begins with a Knoevenagel-type condensation between isatin and the cyano

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• /CH2Cl2 at room temperature (17% yield). Subjecting the methoxylated benzaldehyde intermediate 9 to a Doebner–Knoevenagel condensation with malonic acid and pyridine afforded the brominated cinnamic acid analogue 10 in 54% yield [19]. Amidation chemistry using carbonyldiimidazole (CDI) [18] and the

• (4-OCH3); LRESIMS (m/z): 293/295/297 [M + H]+. Doebner–Knoevenagel condensation of 3,5-dibromo-4-methoxybenzaldehyde with malonic acid 3,5-Dibromo-4-methoxybenzaldehyde (9, 80.0 mg, 0.27 mmol), malonic acid (56.0 mg, 0.54 mmol) and dry pyridine (1 mL) were refluxed at 100 °C for 5 h. The reaction

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

• findings reinforced the theory that developing MTDLs could provide a more effective approach for addressing complex neurodegenerative disorders than conventional single-target strategies. Knoevenagel-based multicomponent reactions: Several quinazolinone derivatives have already been developed as MTDLs

• , inspired by natural alkaloids such as deoxyvasicinone and evodiamine with promising inhibition of ChEs and antioxidant and neuroprotective effects against glutamate-induced OS in HT-22 cells [41]. In 2016, Dgachi et al. [42] applied a Knoevenagel-based multicomponent approach to further explore the

• benzodioxepinones 12 in all cases (Scheme 11). The synthesized compounds demonstrated excellent drug-like features. Parkinson disease (PD) Knoevenagel–Michael addition/cyclization (MCR 3 + 2): Sirtuins, a group of enzymes that rely on NAD+ to function as protein deacetylases, have garnered attention across multiple

The charge transport properties of dicyanomethylene-functionalised violanthrone derivatives

• Sondos A. J. Almahmoud,
• Joseph Cameron,
• Dylan Wilkinson,
• Michele Cariello,
• Claire Wilson,
• Alan A. Wiles,
• Peter J. Skabara and
• Graeme Cooke

Beilstein J. Org. Chem. 2024, 20, 2921–2930, doi:10.3762/bjoc.20.244

• transport properties was most clearly observed in compound 3b which has a 60-fold improvement in mobility compared to 2b. This study demonstrates that the choice of the solubilising group has a profound effect on the hole mobility on these organic semiconductors. Keywords: Knoevenagel condensation; organic

• the Knoevenagel condensation with malononitrile was successfully reported [33]. Theoretical studies Density functional theory (DFT) calculations of two derivatives of compounds 2 and 3, having methoxy groups instead of the longer alkyl chains have been reported in the literature [32], providing

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

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

• tolerated in this consecutive four-component reaction, as the 1,3,4-thiadiazine synthesis competes with the thiazole synthesis. Salicylaldehydes 14 and 4-hydroxy-6-methyl-2H-pyran-2-one (16) can also be used to produce 1,3-dicarbonyl compounds 18 by Knoevenagel condensation and subsequent cyclization. This

• approach was also used to synthesize pyrazoles since the intermediary-formed diketone 18 forms the corresponding pyrazoles 17 in a Knorr reaction with 2-hydrazinyl-4-phenylthiazoles 15 in a one-pot process (Scheme 4) [52]. Piperidine was used as a catalyst for the Knoevenagel condensation. Remarkably

• formate (Scheme 8) [58]. Upon reaction with β-ketoesters, hydrazone 30 is formed, which reacts via intramolecular Knoevenagel condensation to give the corresponding pyrazoles 27. The method tolerates β-ketoesters with alkyl substituents and various ketoamides. In addition, an example could be synthesized

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

• a variation of the GBB reaction employing benzothiazole acetonitrile 104 (X = S) in place of the amidine component (Scheme 33). Knoevenagel condensation with an aldehyde in the presence of 2-(hydroxymethyl)pyrrolidinium acetate produced conjugated imines 105 as the reaction intermediates. Once

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• via Knoevenagel adduct formation as a first step, which may become a significant limitation of this reaction. However, we have never observed and isolated Knoevenagel adducts of aromatic aldehydes 4 and N,N-dimethylbarbituric acid (5) during the synthesis of 5-aryldeazaalloxazines 2a–x in either of

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

• with similar yields. In 2006, Akita et al. used an intramolecular Knoevenagel–Claisen type condensation between a β-ketoester and an acetate residue to synthesize spiro-2H-furan-3-ones [24]. For instance, the intermediate orthoester 35 was obtained in 86% yield after a cyclization–carbonylation

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

• -terminus of SorbB catalyzes conversion of thioester 31 using NADPH to liberate aldehyde 32, and subsequent Knoevenagel condensation-type cyclization leads to sorbicillin (33). The FAD-dependent monooxygenase SorbC, utilized in the chemo-enzymatic total synthesis of 2, catalyzes the oxidative

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• -dicarboxylate (3) with 2,3-unsubstituted parent chromone (9a) afforded benzocoumarine 17 in 56% yield (Scheme 3) [32]. The formation of the product can be explained by 1,4-addition of 3 to the chromone to give intermediate A and ring cleavage to give intermediate B. Subsequent Knoevenagel reaction by attack of

• crude form for the next step. Treatment of the latter with triethylamine in methanol resulted in ring-cleavage to give intermediate E. Subsequent base-mediated Knoevenagel reaction with extrusion of water gave intermediate F which underwent lactonization and resulted in the formation of the final

• ) [32]. The formation of the products can be explained by Michael reaction (1,4-addition) of 3 to the chromone and ring cleavage to give intermediate G. Subsequent Knoevenagel reaction by attack of the methylene carbon to the aldehyde resulted in the formation of the final products. The regioselective

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

• synthesis has been reported for several transformations, such as epoxide opening [56], ketal formation and deprotection [57][58], Mannich reaction [59], intramolecular Sakurai cyclization [60], alcohol oxidation [61], aromatic hydrocarbon nitration [62], imine allylation [63], Knoevenagel condensation [64

• in moderate to good yields. With the β-ketoesters prepared, we began the synthesis of the Knoevenagel derivatives. To do so, we employed an adapted protocol from the literature. Using 1.00 equiv of β-ketoester, 1.50 equiv of aldehyde, 0.60 equiv of acetic acid, and 0.25 equiv of piperidine, the

• different compounds containing the indanone moiety. Synthesis of unsaturated β-ketoesters (Knoevenagel derivatives). aIsolated yield after purification using silica gel column chromatography. Synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones mediated by bismuth triflate. aIsolated yield after purification

Multi-redox indenofluorene chromophores incorporating dithiafulvene donor and ene/enediyne acceptor units

• Christina Schøttler,
• Kasper Lund-Rasmussen,
• Line Broløs,
• Philip Vinterberg,
• Ema Bazikova,
• Viktor B. R. Pedersen and
• Mogens Brøndsted Nielsen

Beilstein J. Org. Chem. 2024, 20, 59–73, doi:10.3762/bjoc.20.8

• variety of reactions; that are, phosphite- or Lawesson’s reagent-mediated olefination reactions (to introduce DTF motifs), Ramirez/Corey–Fuchs dibromo-olefinations followed by Sonogashira couplings (to introduce enediynes motifs), and Knoevenagel condensations (to introduce the vinylic diester motif). By

• as a mixture of E and Z isomers (ca. 4:1). Further functionalization of the IF-DTF ketone 11 was obtained by Ramirez/Corey–Fuchs dibromo-olefination and Knoevenagel condensation to yield vinylic dibromide 14 and diester 15, respectively, as illustrated in Scheme 2. We noted that the dibromo

• -olefinations, and Knoevenagel condensations. In particular, the acetylenic scaffolds presented in this work may be useful precursors for even more elaborate, conjugated and carbon-rich structures in future work. Experimental Anhydrous MeOH was obtained by distillation from activated Mg and stored over 3 Å

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• scaffolds is the introduction of a benzylidene moiety on C5 via a Knoevenagel reaction. Here, a facile synthesis of 5-arylidenerhodanines via a Knoevenagel reaction in an ʟ-proline-based deep eutectic solvent (DES) is reported. This method is fast (1 h at 60 °C), easy, catalyst-free and sustainable as no

• compounds are the more active ones. Keywords: antioxidant; deep eutectic solvent; Knoevenagel; ʟ-proline DES; rhodanine; Introduction Rhodanines and related five-membered heterocycles with multiple heteroatoms (i.e., thiazolidinediones, thiazolidinones, hydantoins, thiohydantoins) are very interesting

• Knoevenagel condensation of rhodanine with different aldehydes [3]. The reactions were performed in ChCl/urea (1:2) at 90 °C, without needing a catalyst and the products were obtained in low to good yields (10–78%). On another hand, ʟ-proline is well known as an organocatalyst and its use in aldol and

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

• have developed a new convenient protocol for the synthesis of 3-sulfonyl-substituted quinolines (sulfonamides and sulfones). The approach is based on a Knoevenagel condensation/aza-Wittig reaction cascade involving o-azidobenzaldehydes and ketosulfonamides or ketosulfones as key building blocks. The

• , the method for the synthesis of 3-acyl-substituted quinolines from o-azidobenzaldehydes and 1,3-dicarbonyl compounds was reported [70][71] (Figure 2a). A combination of Knoevenagel condensation and aza-Wittig reaction allowed to build up target products in high yields. In case of [70], the procedure

• quinolines (sulfonamides and sulfones) (Figure 2b). Herein, we report the successful implementation of this approach. Results and Discussion The Knoevenagel condensation/aza-Wittig reaction cascade was used for the preparation of 3-sulfonyl-substituted quinolines. The process proceeds in a domino fashion

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• reaction [33]. Thus, Knoevenagel condensation using the diaryl ether 29 and malonic acid gave the corresponding α,β-unsaturated compound 30, which was submitted to a concomitant hydrogenation of the double bond and the nitro group to give compound 31. Sequential diazotization/halogenation and

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• from a haliclona marine sponge [4], and vertinolide (5) from Verticillium intertextum [5] (Scheme 1). As outlined in Scheme 2, a variety of methods has been reported for the synthesis of conjugated dienones, mostly via addition/elimination reactions such as Knoevenagel condensation or Claisen–Schmidt

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• as ligands in organometallic catalysts [9] and as versatile organocatalysts [10] in a very wide range of organic reactions such as classical benzoin condensation, transesterification, acylation, Knoevenagel reaction, Claisen condensation etc. The electrochemical generation of carbenes from ILs avoids

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• different kinds of aromatic aldehydes and 5-arylidene-1,3-dimethylbarbituric acids. 5-Arylidene-1,3-dimethylbarbituric acids could be easily generated through Knoevenagel condensation of aromatic aldehydes and 1,3-dimethylbarbituric acid under the catalysis of Lewis acid. We envisioned whether the desired

• 3-substituted indole, which undergoes dehydration to form the key intermediate indole-based ortho-quinodimethanes (o-QDMs, A). In the meantime, the cyclic 1,3-diones and aromatic aldehyde undergo Knoevenagel condensation to afford the different kinds of dienophiles. Subsequently, the Diels–Alder

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• molecules through π–π stacking with the hydrophobic aromatic wall of the host. Finally, the boat was investigated as a catalyst for the Knoevenagel condensation reaction (Figure 2) of a series of aromatic aldehydes with 1,3-dimethylbarbituric acid and Meldrum’s acid in aqueous media. One of the primary

• ]. Notably, the dissipative conditions were realized by addition of a fuel acid [113][114] that surprisingly ignited a base-catalyzed Knoevenagel addition reaction (Figure 25). As DABCO is a stronger binding ligand (log β = 7.20) [115] towards zinc porphyrin (ZnPor) than pyridine (log K = 4.45) [90] the

• 115 reclaims the proton back (Figure 25, top). As a result, State-II may be afforded under dissipative conditions. A surprising facet of this State-I/State-II interconversion (Figure 24) [112] was the finding that the protonated DABCO (60-H+) was a rather efficient base catalyst for a Knoevenagel

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• usually achieved by a nucleophilic substitution of an alkyl halide by the deprotonated malonate [12][13][14][15][16][17][18][19], but other strategies could be envisioned: Cu-catalyzed arylation reactions for aryl-substituted MAHOs [20][21][22][23]; Knoevenagel/reduction sequences for benzyl-substituted

• compound 5 is commercially available or easily accessible on a relatively large scale (Scheme 3) [56]. Therefore, we first achieved an alkylation step of 5 using a Knoevenagel reaction with benzaldehyde, followed by an in situ reduction of the resulting alkylidene [57][58]. Even if the reaction worked well

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

• to name type-I Guareschi pyridone synthesis the two-component reaction between a β-aminocarbonyl and a cyanoacetic ester, a reaction first reported in 1893 [34]. It is a classic combination of a Knoevenagel condensation and ester aminolysis typical for many heterocyclic syntheses. The type-II

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• to fragrance chemists. This section investigates the aldol reaction as this is a vital C–C and C=C bond forming tool within this class of reactions. Other sequences such as the Knoevenagel and Darzens condensation, however, will also be considered as part of the evaluation. The condensation of

• of 1,2-aminoalcohol 110 (90% yield, anti/syn 7:3, 78% ee). At the end of the Henry reaction an in-line plug of silica gel removes the catalyst before the second reduction step to prevent issues of chelation and palladium deactivation. Knoevenagel condensations are also of considerable interest to the

• processing volumes and short reaction times make the reactions quite suitable for continuous production via a flow system. Needless to say, the first example of Knoevenagel condensations in flow comes from Venturello et al. back in 1989 [154]. The authors exploited a glass column filled with 10 grams of