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

• ], amidines [11], isothioureas [12][13], whereas thioureas [14][15], ureas [16], phosphoric acids [17][18], and squaramides [19][20] fall into the second category. The Friedel–Crafts reaction, discovered by Charles Friedel and James Crafts in 1877 allows the aromatic C–H bond functionalization through the

• was shown by synthesizing 110, a key intermediate of (R)-bifonazole (Scheme 25b) [55]. Thioureas and squaramides In 2018, Yang, Deng and co-workers developed an aza-Friedel–Crafts aminoalkylation of 4- and 5-hydroxyindoles 111. As electron-demanding component, N-Boc pyrazolinone ketimines 100 were

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

• -unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov

• (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

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

• malonates [25]. Herein, we report the results of an asymmetric organocatalytic Michael addition of CPD to alkylidene oxindoles. Results and Discussion Chiral multifunctional thioureas [26][27] and squaramides [28] are extensively used as catalysts in asymmetric Michael additions. We believed that a

• inseparable diastereoisomers in 53% yield but in low enantiomeric excess for both diastereomers (Table 1, entry 1). With the quinine-derived thiourea B, the reaction was slow and the yield was very low, 12% (Table 1, entry 2). For that reason, we focused on the screening of squaramides. Squaramides were found

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

• asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields

• derivatives Squaramides are related to cinchona alkaloids but are much more effective organocatalysts than the latter due to the ability of dual hydrogen bonding besides a tertiary nitrogen atom of quinuclidine nucleus which may serve both as an H-bond acceptor and a base in asymmetric Michael addition

• -1,2,3-triazoles 35 in good yields (up to ≈72%) and excellent enantioselectivity (up to 99% ee) (Table 7) [41]. In an interesting study, Wu et al. screened a number of cinchona derivatives and squaramides for their relative catalytic efficacies for the enantioselective aza-Michael additions between

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

• to the ability of squaramides to bind anionic species more strongly than ureas. The moderate enantiocontrol observed thus far prompted us to posit that the nitrogen atom on the quinoline moiety of the catalyst could participate to the deprotonation of 5a, therefore, leading to less selective

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

• Dominika Krištofíková,
• Juraj Filo,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2019, 15, 2948–2957, doi:10.3762/bjoc.15.290

• organocatalysts, including chiral squaramides, thioureas, alkaloids and their derivatives, taddols, binol, chiral phosphoric acid, (S)-proline and its derivatives, amide of tryptophan (Figure 1). These catalysts feature varying steric properties from sterically encumbered, such as C1, C5, C8, or C10, to less

• Chiral hydrogen-bond-donating organocatalysts such as thioureas, squaramides, or alcohols failed to catalyze the Ireland–Claisen rearrangement of silyl ketene acetals. Comparison experiments showed that increasing catalyst loading gradually slowed-down the reaction. DFT calculations using long-range

• corrected hybrid density ωB97X-D functional showed that thioureas and squaramides stabilize the starting ground state more than the corresponding transitions states. This fact leads to a higher activation barrier and slower reactions in the presence of hydrogen-bond donating organocatalysts. On the other

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• ]) to the corresponding silanediols. While hydrolyses of dichlorosilanes have been studied extensively [23][24][25], hydrolyses of alkoxy dichlorosilanes are much less explored. Hydrogen bond donor (HBD) catalysis is an emerging field in organic synthesis [26][27][28], employing, e.g., squaramides [29

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides

• Juan V. Alegre-Requena,
• Marleen Häring,
• Isaac G. Sonsona,
• Alex Abramov,
• Eugenia Marqués-López,
• Raquel P. Herrera and
• David Díaz Díaz

Beilstein J. Org. Chem. 2018, 14, 2065–2073, doi:10.3762/bjoc.14.180

• derivative; organogel; self-assembly; squaramide; supramolecular gel; Introduction Since their discovery, squaramides have gained importance across different fields from chemistry to biomedicine due to their synthetic versatility and wide applicability [1]. These compounds, formed by two amine units

• asymmetric catalysis and molecular recognition [5][6]. Besides, squaramides present a dual ability to recognize anions and cations through hydrogen bonding interactions, acting as ion sensors and transmembrane anion transporters [7]. This property has been crucial for the development of new drugs [8][9

• properties of the gels obtained with these compounds. In general, compound 2 formed gels in more solvents, at lower concentration and faster than compound 1. In this work, and based on our previous experience with organogels based on squaramides [21], we decided to prepare and study an analogue of N-stearoyl

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• to investigate the application of chiral calixarene-based squaramides in asymmetric catalysis. Recently, a novel chiral organocatalyst based on the calix[4]arene scaffold carrying squaramide and tertiary amine as catalytic functionalities has been readily developed in two steps from p-tert-butylcalix

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• ligands and organocatalysts. For example, remarkable enantioselectivities of up to 94 to >99% ee have been reported in recent examples of Mannich reactions promoted by organocatalysts, as varied as cinchona-alkaloids, squaramides, phosphoric acids, simple primary amines and L-diphenylprolinol

• organocatalyzed by cinchona-alkaloids, and unprecedented Friedel–Crafts reactions of isatin imines with naphthols and hydroxyquinolines promoted by cinchona-alkaloid-derived thioureas and cinchona-alkaloid-derived squaramides. Slightly lower enantioselectivity levels of up to 94% ee were described in aza-Henry

• reactions performed with bifunctional guanidines. In addition, excellent results (97% ee) were reported in unprecedented domino reactions promoted by squaramides recently. Miscellaneous transformations, including additions of methanol, hydroperoxides and arylboronic acids, were also developed with high

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• and pregabalin [9][10]. Later, hydrogen-bonding activation proved to be more general for obtaining Michael adducts via the addition of 1,3-dicarbonyl compounds to nitroalkenes. Chiral thioureas and squaramides, particularly those with the bifunctional mode of action, served as excellent catalysts in

• numerous Michael additions, as well as other reactions [11][12][13][14]. In this way, chiral thioureas, and squaramides were used to synthesize various GABA derivatives [15][16][17][18][19]. Interestingly, hydrogen-bonding activation of this kind of Michael additions worked well also in aqueous media [20

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel–Crafts alkylation, Michael addition, Diels–Alder and aza-Henry reactions. However, the 1,2-aminoindanol core

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• all cases. Keywords: asymmetric diastereodivergent; enantioselective; Michael addition; nitroalkenes; nitroesters; organocatalysis; squaramides; Introduction The absolute stereochemistry of a molecule has a paramount influence on the properties that this compound will have when interacting with

New hydrogen-bonding organocatalysts: Chiral cyclophosphazanes and phosphorus amides as catalysts for asymmetric Michael additions

• Helge Klare,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2014, 10, 224–236, doi:10.3762/bjoc.10.18

• ) catalysts represent an ever growing class [6][7][8]. The majority of non-specific hydrogen-bonding catalysts are based on the (thio)urea motif (I, Figure 1) [9][10]. More recently squaramides (II, Figure 1) have emerged as complementing motif in HB catalysis [11]. Other H-bonding motifs are less established

• characteristics and the increased steric bulk of “3-D”-PV compared to “2-D” urea or squaramides make phosphorus triamides excellent candidates for asymmetric (HB) organocatalysts. However, the tetrahedral structure of PV-amides also enables a higher degree of conformational freedom combined with a less rigid

• kcal/mol). The proposed ability of squaramides to form stronger hydrogen bonds than ureas is in agreement with the experimentally found higher acidity of squaramides [28]. The strength of hydrogen bonding is also thought to be dependent on the directionality of the hydrogen bonds, with an optimum of