Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• [32]. Then, we increased the reaction scale to 0.2 mmol and obtained similar results (Table 1, entry 13). At this point, we decided to explore the use of a bifunctional organocatalyst in order to improve the yield. When squaramide SQ-1 was used as a catalyst, we observed a similar yield and

• to determine the role of the squaramide. The relative configuration of the stereogenic centres in compound 5aca was determined by X-ray crystallographic analysis (Scheme 3) [33]; the relative configurations of the other compounds 5 were assigned on the assumption of a uniform mechanistic pathway

• . Considering the high diastereoselectivity observed both in the presence and absence of the squaramide catalyst, we propose a plausible mechanism (Scheme 3) that involves hydrogen bonding activation of the methyl trifluoropyruvate by the NH₂ group of the aminopyrazole. This interaction directs the attack of

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• covered in this review are hydrogen-bond donors such as thioureas and squaramides, Brønsted bases such as tertiary amines, and Brønsted acids such as chiral phosphoric acids. As depicted in Figure 4, a bifunctional squaramide is able to activate both an α,β-unsaturated imine through hydrogen bonding with

• the squaramide moiety and a nucleophile through deprotonation as Brønsted base. On the other hand, a chiral phosphoric acid provides a confined chiral environment where the reactants are approached, activating both the azadiene by interaction with the acidic hydrogen and a dienophile bearing a

• ) and good to excellent enantioselectivities (60–97% ee) when using organocatalyst III. Later, in 2018, Zhou and co-workers developed a bifunctional squaramide-catalyzed enantioselective formal [4 + 2] cycloaddition of benzofuran-derived azadienes 11 with malononitrile (12) [26]. This work provides an

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen”, an interesting approach to recycling the very useful cinchona squaramide organocatalysts was described. This approach involved functionalization of the organocatalyst with a lipophilic linker (octadecyl side chains), resulting in a

• novel lipophilic cinchona squaramide organocatalyst. This organocatalyst was evaluated in a benchmark Michael addition of acetylacetone to trans-β-nitrostyrene, yielding the Michael adduct with high yield and enantioselectivity. The hydrophobic chain of the catalyst allowed the organocatalyst to be

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

• method involves squaramide 51-catalysed chloride abstraction from readily accessible N-carbamoyl α-chloroglycinates 48 or 54 (Scheme 11) [35], with a simultaneous nucleophilic attack of allylsilane 49 (Scheme 11A) or allylstannane 55 (Scheme 11B). The reactions are highly sensitive to moisture and oxygen

• . In the optimisation of the catalyst 78 structure, several important observations were made (Scheme 19). Replacing thiourea (91) as the H-bond donor unit with squaramide (93) or urea (92) did not affect the enantioselectivity of the allylation of the benzaldehyde-derived acetal. On the other hand

• ] exploited the application of hydrogen-bond donor catalysis in asymmetric dearomative α-allylations of in situ-generated Ν-acylquinolinium salts 108 generated with 2,2,2-trichloroethyl chloroformate (TrocCl) (Scheme 22). Screening through a range of catalysts including the known squaramide and thiourea

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• nitroalkenes or guanidine-mediated addition of bisthiomalonates to maleimides, cyclic enones, and acyclic 1,4-dicarbonylbutenes, albeit at low temperatures and with relatively long reaction times, further limited to a narrow scope of thioesters (Scheme 1) [31]. Recently, we described a cinchona-squaramide

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• and changes in the reaction kinetics. The non-covalent immobilisation of chiral organocatalysts can also be carried out within deep eutectic solvents (DESs). Very recently, a cinchonidine-squaramide organocatalyst was immobilised in three types of natural DESs, namely betaine/sorbitol/water, betaine

• influence of various linkers of cinchona squaramide organocatalysts immobilised on a poly(glycidyl methacrylate) (PGMA) solid support [127]. The support consisted of well-defined monodispersed PGMA microspheres, which were prepared through thorough parameter optimisation. Three amine-functionalised cinchona

• selectivity, features a 1,2,3-triazole-4-yl unit as the substituent at the tertiary amine-containing quinuclidine motif, whereas C30 and C31 have an ethyl group attached to the ring in this position. Additionally, catalyst C31 has a longer-chain linker, but its squaramide NH groups are more acidic due to

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

• disclosed organocatalyzed [5 + 1] double Michael additions between pyrazolones and dienones (Scheme 1b) [23]. Very recently, the Chimni group reported a cinchona-derived squaramide-catalyzed 1,4-Michael addition reaction of pyrazolin-5-ones with 2-enoylpyridines (Scheme 1c) [24]. Recently, we developed an

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen

• Gyula Dargó,
• Dóra Erdélyi,
• Balázs Molnár,
• Péter Kisszékelyi,
• Zsófia Garádi and
• József Kupai

Beilstein J. Org. Chem. 2023, 19, 1811–1824, doi:10.3762/bjoc.19.133

• , application, and recycling of a new lipophilic cinchona squaramide organocatalyst. The synthesized lipophilic organocatalyst was applied in Michael additions. The catalyst was utilized to promote the Michael addition of cyclohexyl Meldrum’s acid to 4-chloro-trans-β-nitrostyrene (quantitative yield, up to 96

• , acetonitrile, with 91–100% efficiency, and the catalyst was reused in five reaction cycles without the loss of activity and selectivity. Keywords: baclofen; catalyst recovery; lipophilic cinchona squaramide; organocatalysis; stereoselective catalysis; Introduction In today’s chemical industry, catalytic

• cinchona squaramide organocatalyst. Its catalytic activity and recyclability were examined in a new stereoselective synthesis of baclofen, which is used to treat muscle spasms [30]. Finally, the catalyst was easily recycled by centrifugation over five reaction cycles without significant loss of activity

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

• thiiranium ion by the tosylamide and deprotonation led to the final product 99 or 100 (Scheme 41). Through the coupling reaction of N-(aryl/alkylthio)succinimides 1 with 5H-oxazol-4-ones 101 in the presence of an organocatalyst named cinchona alkaloid-derived squaramide F, a series of α-sulfenylated products

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• investigated to install the all-substituted aza-quaternary stereocenter at the C4 position of the pyrazolinone scaffold. Stereoinduction on this chiral center was regulated by the chiral squaramide catalyst S1 affording the products with excellent enantioselectivities. A stereodefined transition state

• developed an aza-Friedel–Crafts reaction involving β-naphthols 119 as π-nucleophiles and benzothiazolimines 118 as electrophiles. Chiral squaramide S1-assisted this process affording enantioenriched 1-((benzothiazol-2-ylamino)methyl)naphthalen-2-ols 120 with high chemical yields. The activation of the

• . Atroposelective aza-Friedel–Crafts reaction. Coupling of 5-aminopyrazole and 3H-indol-3-ones. Pyrophosphoric acid-catalyzed aza-Friedel–Crafts reaction on phenols. Squaramide-assisted aza-Friedel–Crafts reaction. Thiourea-catalyzed aza-Friedel–Crafts reaction. Squaramide-catalyzed reaction between β-naphthols and

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• (Table 1, entry 11). With this promising result in hand, we next examined the use of squaramides, which were shown to be highly effective hydrogen-bonding catalysts in a broad range of transformations [61][62][63][64]. When achiral squaramide derivatives 11 [65] and 12 [66] were tested in stoichiometric

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• optimization showed that chiral squaramide 47 developed by Jacobsen’s group significantly accelerated the Mukaiyama reaction compared to TMSOTf or TiCl4 thanks to chiral hydrogen bond-donor effect [35]. After Sakurai cyclization promoted by EtAlCl2, the desired product 48 was obtained with the required

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• nitromethane to β-silyl α,β-unsaturated carbonyl compounds catalyzed by bifunctional squaramide catalysts are effective under solvent-free conditions [26]. Zhai and Du demonstrated that asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins are efficiently

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

• squaramide catalyst 3c, however, with low enantioselectivity (Table 1, entry 6). Disappointingly, the reaction catalyzed by ʟ-proline-derived catalysts gave very low enantioselectivity (Table 1, entries 7 and 8). Having identified Takemoto’s catalyst as the most efficient one for this transformation, our

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• presence of a multifunctional squaramide catalyst. Michael adducts were obtained in high enantioselectivities and in moderate diastereoselectivities. Keywords: cyclopentane-1,2-dione; enantioselective catalysis; Michael addition; organocatalysis; squaramide; Introduction Diketones are generally very

• bifunctional hydrogen-bonding catalyst would activate both CPD via a tertiary amino group of a quinuclidine moiety acting as a base via anion-binding, and an oxindole through the squaramide or thiourea moieties of the catalyst as hydrogen bond donors (Figure 1) [29][30][31][32]. Therefore, squaramide and

• thiourea catalysts were screened in a model reaction between CPD 1 and Boc-protected benzylidene oxindole 2a at room temperature in the presence of 10 mol % of catalyst (Figure 2). First, the quinidine-derived squaramide A was used and the desired product was obtained as a mixture of chromatographically

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• . Results and Discussion To verify the feasibility of the reaction, the domino Michael addition/cyclization reaction of 2-isothiocyanato-1-indanone (1a) and barbiturate-based olefin 2a was used as a model reaction, which was carried out in dichloromethane (DCM) with 5 mol % quinine-derived squaramide C1 at

• results, it was found that the yield of product did not increase significantly with the cinchona alkaloid-derived squaramide catalysts (Table 1, entries 2 and 3). Consequently, we decided to explore the effects of different types of catalysts on the reaction. Through experiments, it can be found that

Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

• Akhil K. Dubey and
• Raghunath Chowdhury

Beilstein J. Org. Chem. 2021, 17, 2642–2649, doi:10.3762/bjoc.17.177

• -unsaturated carbonyl compounds catalyzed by bifunctional squaramide catalysts has been developed. This methodology offers both enantiomers of β-silyl nitroalkanes in good to excellent yields (up to 92%) and enantioselectivities (up to 97.5% ee) under solvent-free conditions at room temperature. Control

• 6). The catalytic performance of the squaramide catalysts was also explored for the model reaction. Catalyst VII afforded the conjugate addition product 3a in 78% yield with excellent enantiopurity of 97% ee (Table 1, entry 7). A solvent survey (see Supporting Information File 1 for details

• even with better yields while the enantiomeric excess was unperturbed. Conclusion In summary, we have outlined bifunctional squaramide-catalyzed 1,4-conjugate addition reaction of nitromethane to β-silyl α,β-unsaturated carbonyl compounds to access a series of chiral β-silyl nitroalkanes in high yields

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• syntheses, including total syntheses of natural compounds [15]. The pyrrolidine moiety has been successfully combined with thiourea [16][17][18] and the squaramide unit [19][20]. Thioureas and squaramides often feature the electron-withdrawing group attached to one of the nitrogen atoms to increase the

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

• compounds; however, in order to comply with the requirements of a mini review, additions of amines and amides only will be included. 1. Non-covalent bonding organocatalytic aza-Michael reactions Organocatalysts catalyzing aza-MRs through mainly hydrogen bonding include cinchona alkaloids, squaramide

• . It was concluded that the catalytic activity of the MDO was the result of the cooperative action of both constituents. Several examples of such MDOs are included in the paper. The reported yield varies from 56–90% with excellent ee ≈ 99% in all cases. 1.2. Reactions catalyzed by chiral squaramide

• reactions [34][35]. In 2015, Zhao et al. synthesized spiro[pyrrolidine-3,3'-oxindoles] 29 in single step by asymmetric cascade aza-Michael/Michael addition reaction between 4-tosylaminobut-2-enoates 27 and 3-ylideneoxindoles 26 catalyzed by a chiral bifunctional tertiary amine, squaramide (cat. 28) which

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• , the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst’s quinoline moiety aided in avoiding selectivity-reducing complications related to the production

• region of the catalyst led to racemic products (Table 1, entries 6 and 7). Employing a different hydrogen bond-donating motif such as the squaramide (catalyst 8, Table 1, entry 8) resulted in a substantial drop of the enantiocontrol as well as in the reduction of the reaction rate [29][31] – probably due

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• complex or active nucleophiles. In 2014, Jacobsen et al. developed a highly enantioselective selenocyclization reaction of olefins 26, using the chiral squaramide 28 as a dual hydrogen bond donor (Scheme 6) [16]. Although early-stage enantio-enrichment during the introduction of selenium is hard to

• performances as nucleophile precursors using a triazolium-amide chiral catalyst 34 [21] (Scheme 8a), as well as by Jacobsen in the desymmetrization of oxetanes 35 using TMSBr and squaramide 37 as catalyst [56] (Scheme 8b). For the latter, a more detailed mechanistic study was recently provided [57]. The

• design of more efficient H-donor catalyst structures, offering additional noncovalent interactions in order to provide extra coordination points with the anion, substrate and/or reagent. The most important approaches in this direction used to date are presented in the following. (Thio)urea and squaramide

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

• , provides coumarin derivatives 3 with good to excellent yields and moderate to good enantiomeric excesses (Scheme 5). The authors highlighted that the employed organocatalyst 18 is an alternative to those of squaramide and thiourea commonly used with coumarins. In 2013, Lee et al. reported the

• , with moderate to excellent enantioselectivity followed by two decarboxylations (Scheme 21). Huang’s group has used azadienes to perform an enantioselective 1,4-addition to afford benzofuran-fused six-membered heterocycles with a squaramide catalyst [56]. Based on their previous work, the authors

• results were obtained using a squaramide cinchona alkaloid catalyst 73 in only 1 mol % loading. In addition, the reaction was also very efficient in a gram-scale experiment, which demonstrates the applicability of the method (Scheme 22). More recently, Yuan et al. developed a methodology for the synthesis

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones

• Chandrakanta Parida and
• Subhas Chandra Pan

Beilstein J. Org. Chem. 2021, 17, 1447–1452, doi:10.3762/bjoc.17.100

• presence of the quinine-derived bifunctional squaramide catalyst I in dichloromethane at room temperature (Table 1). Delightfully, after stirring for 12 hours, a product was isolated in 70% yield that was characterized as compound 3a and was supposed to be formed through conjugate addition followed by

• benzoyl-transfer reaction. However, only 20% enantiomeric excess was achieved. Then, the tert-leucine-derived squaramide catalyst II was employed and here both yield and ee slightly improved. Next, we turned our attention to bifunctional thiourea catalysts [26][27] that proved to be fruitful. Thus, the

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