The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• building blocks for the construction of more elaborate structures [7][8][9][10][11]. An outstanding class of quinine derived organocatalysts exhibits a bifunctional mode of activation by the incorporation of an acidic unit, such as urea, thiourea, squaramide or sulfonamide moieties, giving rise to the

• synthesis of new amino-substituted-DMAP-based sulfonamides [39] and quinine-based squaramide-type organocatalysts [40]. Motivated by the excellent results obtained with our aforementioned catalysts, we developed a new chiral bifunctional sulfonamide–quinine organocatalyst that unites both classes. The

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

• rearrangement, we tried to optimize its reaction course under mild conditions using various bases, solvents, and hydrogen-bond-donating catalysts. We also present a computational explanation and NMR kinetic study for the inefficient Ireland–Claisen rearrangement under thiourea and squaramide catalysis. Results

• catalyst’s action in the rearrangement, we have studied the effect of catalyst loading in the reaction of ester 1c with squaramide C1. The reaction with Et3N as a base and Me3SiOTf without any chiral organocatalyst afforded acid 3c with 74% yield. Repeating the reaction in the presence of squaramide C1 (5

• of squaramide C1 completely stopped the reaction (Table 3, entry 6). We also studied the effect of the amount of base on the Ireland–Claisen rearrangement of ester 1c in the presence of sulfanediamine C6 (Table 4). The best yield of acid 3c (74%) was recorded with 4.9 equivalents of Et3N without

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

• describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long

• concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition. Keywords: glutamic acid

• 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

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

• both catalysts gave the Michael adduct in excellent yields, high ees were obtained only when 54b was used as organocatalyst (up to 94% ee, Scheme 16). During the last decade, squaramide catalysts have become a powerful alternative to the urea/thiourea and guanidine catalysts as multiple hydrogen bond

• donors in order to design novel bifunctional catalytic scaffolds [54][55]. Hybrid calixarene hosts bearing bis-squaramide moieties at the endo (or lower) and exo (or upper) rims and their recognition properties toward anionic guests have been already reported [56][57]. Therefore, it would be interesting

• 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

• -dicarbonyl compounds 5 performed in the presence of chiral cinchona alkaloid-derived squaramide 6 [36]. A range of chiral 3-amino-2-oxindoles 7 was obtained under mild reaction conditions in high to quantitative yields (78–99%) and uniformly excellent enantioselectivities (90–99% ee) as shown in Scheme 2. In

• diastereoselectivity of 90% de was achieved in the reaction of 1-benzoylacetone (R2 = Me, R3 = Ph) which afforded the corresponding single diastereoisomeric product in 96% yield and 95% ee. In 2018, Tanyeli et al. reinvestigated this type of reactions in the presence of related cinchona alkaloid-derived squaramide

• asymmetric formal [3 + 2] annulation reaction between N-Boc-isatin imines 3 and 1,4-dithiane-2,5-diol (53) as equal equivalent of 2-mercaptoacetaldehyde [78]. The domino reaction catalyzed by chiral tertiary amine-squaramide catalyst 54 began with the addition of 2-mercaptoacetaldehyde to isatin imine 3

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

• medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide

• catalyst. Furthermore, specific organocatalysts can provide respective stereoisomers of the key Michael adduct in up to 99:1 er. Keywords: kinetic resolution; Michael addition; organocatalysis; pregabalin; squaramide; Introduction Asymmetric organocatalysis has considerably broadened possibilities for

• addition of dimethyl malonate. An initial catalyst screening was performed in dichloromethane, based on our previous experiences with this type of Michael additions [18]. We have employed a range of squaramide and thiourea organocatalysts C1–C7 [18][27][28][29][30][31][32][33][34], as well as two newly

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• development of chiral bifunctional urea 1 [35], thiourea 2 and 3 [36][37], sulfonamide 4 [38][39][40] and squaramide 5 [38][39][40] catalysts derived from chloramphenicol base (Figure 1), which showed excellent reactivity and enantioselectivity for this asymmetric transformation. A typical example of the

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• the first squaramide-containing chiral PTCs E, which also turned out to be very promising catalysts for the asymmetric α-fluorination of compounds 1 [44]. The groups of Ma and Cahard have intensively investigated the use of chiral spirocyclic phosphonium salts F as phase-transfer catalysts for

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• substrates, and chiral products were obtained in good yields and selectivities. Remarkably, the performance of tetrakistriazoles was found to be comparable (or in some cases superior) to the well-established thiourea- and squaramide-based catalysts developed for similar transformations. Quaternary

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• - and fused-pyrrolidinoxindole architectures, such as lactam 13 and aminal 15, found in several natural product families. Related approaches with organic catalysts were explored in 2012 by Yuan and co-workers [24][25] and in 2014 with tertiary amine squaramide catalysis by Lou and co-workers [26]. The

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• Hee Seung Jang Yubin Kim Dae Young Kim Department of Chemistry, Soonchunhyang University, Soonchunhyang-Ro 22, Asan, Chungnam 31538, Korea 10.3762/bjoc.12.149 Abstract Chiral binaphthyl-modified squaramide-catalyzed enantioselective addition of diphenyl phosphonate to ketimines derived from

• organocatalyst; ketimines; organocatalysis; squaramide; Introduction α-Aminophosphonate derivatives are important compounds as structural mimics of natural α-amino acids [1][2][3]. Chiral α-aminophosphonates have been shown a wide range of biological activities including antibacterial [4] and anticancer

• of organocatalysts [38][39][40][41][42][43][44][45], we have reported the catalytic asymmetric decarboxylative aldol addition reaction of isatins with benzoylacetic acids catalyzed by chiral binaphthyl-based squaramide [46]. Here we wish to report the enantioselective addition reaction of diphenyl

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• transformation, Chen and co-workers showed that squaramide 103 catalyzes the addition of thiols to N-acryloylbenzamides to access thioether 101c [49]. The authors found that exclusion of water by addition of 4 Å molecular sieves as a desiccant was essential for achieving good enantioselectivity. When the R2

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• enantioselectivities (up to 95% ee, Scheme 26) [42]. The hydroxy group acted as an electron transporter and formed the hydrogen bond with substrates. This hydroxy group played an important role in controlling the enantioselectivity. Squaramide catalysts Bajaj and co-workers reported the first squaramide (cat. 13

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• an heuristic model (Figure 3) to account for the experimentally encountered selectivity where the catalyst is proposed to act in a bifunctional way. In this proposal the imidazolone would be coordinated to the two NH bonds of the squaramide and the ortho-ArH in C1, whilst the nitroalkene would form a

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

• acting through hydrogen bonding, such as thiourea, urea, squaramide, and thioamide frameworks. These have been efficiently employed in a few organocatalytic processes such as Friedel–Crafts alkylations, Michael additions, Diels–Alder reactions and aza-Henry reactions, as discussed below. Friedel–Crafts

• the acyl phosphonate 24a, in dichloromethane at room temperature, with subsequent addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and methanol to give the corresponding ester derivative 25a (Scheme 10a) [39]. The use of the analog squaramide 23 afforded the product with slightly lower selectivity

• catalyst, in its Z form, which is stabilized due to an intramolecular hydrogen bond (Scheme 14). In 2012, Dong and co-workers studied the catalytic activity of several β-amino alcohol-based squaramide organocatalysts involved in the Michael addition of acetylacetone (36a) to β-nitrostyrene (3a) in

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

• of bifunctional tertiary amine/squaramide catalysts [28][29][30][31][32] and, interestingly, we found that catalysts containing the same backbone chirality provided different diastereoisomers, thus allowing the development of a diastereodivergent process. In this report, we wish to present the

• facial stereoselection of those versions in which two stereocentres are generated in the reaction become of special utility to synthetic chemists. In this case, using two different bifunctional tertiary amine/squaramide organocatalysts [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52

• general for a variety of nitroalkene Michael acceptors and nitroacetate donors. For this reason, we initially studied the reaction using squaramide 4 as catalyst that leads to the formation of syn-3 adducts. In this sense, and as it can be seen in Table 1, the reaction performed excellently in almost all

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

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

• –Onitrobenzene (2.19 Å). This is in accordance with the experimentally observed higher acidity [27] of thiourea over urea. Squaramide complex II forms the strongest hydrogen bonds of all computed motifs. The bond lengths NHsquaramide–Onitrobenzene are shortest with 2.11 Å while the bonding energy is highest (8.3

• 180° [29]. This is supported by the computational results with smaller mean N–H–O angles for urea/thiourea (167°/173°) compared to squaramide (178°). The open-chain PV-triamide complex III exhibits a weaker ability to form hydrogen bonds with a bonding energy of 4.2 kcal/mol (Table 1), which is

• , squaramide and phosphor-diamide-based catalysts [43][44][45]. The BINOL-based catalysts 1 and 2 (Scheme 1) without Brønsted base functional group are both ineffective and only traces of the product could be isolated even after prolonged reaction times (Table 2). In contrast, catalyst 4, derived directly from

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• solvent-free conditions by using a planetary ball mill (Scheme 7) [46]. Cinchona-derived chiral squaramide IX, at low catalyst loading of 0.5 mol %, efficiently catalyses the solvent-free Michael reaction of acetylacetone (9) with various substituted nitroalkenes 7 in a short reaction time (5–30 minutes

• ) under ball-milling (400 rpm) to provide an easy access to Michael adducts 10 in good to high yield (63–95%) and excellent enantioselectivity (91–99% ee). The chiral squaramide IX also catalyses the Michael reaction of β-ketoesters 11 with nitrostyrene to provide Michael adducts 12 in 73–95% yield, 1.4:1

• to 5.3:1 dr and 91–99% ee. The solvent-free ball-milling of dimethyl malonate with nitrostyrene in the presence of IX provides the corresponding Michael adduct in 80% yield and 91% ee. However, chiral squaramide catalysed Michael addition of dicarbonyl compounds to nitroalkenes in dichloromethane by

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• unsaturated 1,4-diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C–C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and

• calculated VCD spectra of the reaction product 3a. Keywords: Michael addition; non-covalent catalysis; organocatalysis; squaramide; thiourea; Introduction The asymmetric 1,4-conjugated addition (Michael reaction) of C-nucleophiles to enones is a powerful tool for obtaining a significant variety of

• investigated the organocatalytic approach to the asymmetric desymmetrization of the title compounds with malonates. Three types of organocatalysts providing noncovalent interactions were used for this purpose: Cinchona alkaloids (I–V), thiourea derivatives (VI, VII) and squaramide derivatives (VIII, IX

Enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes catalyzed by binaphthyl-derived organocatalysts

• Saet Byeol Woo and
• Dae Young Kim

Beilstein J. Org. Chem. 2012, 8, 699–704, doi:10.3762/bjoc.8.78

• , bifunctional tertiary-amine thioureas, thiophosphorodiamides, and squaramide-based organocatalysts [34][35][36]. Findings In the framework of our research program for the development of synthetic methods for the enantioselective construction of stereogenic carbon centers [37][38][39][40][41][42], we recently

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32