Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts. Keywords: Eschenmoser coupling reaction; Hantzsch thiazole

• polar aprotic solvent. Acetonitrile is the best solvent for the reaction if the intermediary salt (e.g., 6a) may be isolated, since it is only sparingly soluble in it. Since the pKa values of known primary aliphatic/aromatic α-thioiminium salts (N–H acidity) in water [10][32][33] are less than 7 and 6

• leaving aniline moiety, prefers cyclization to give 13 (Scheme 6). Another key factor for successful ECR concerns the acidity of C–H in particular α-thioiminium salts 6a,b, 10a,b, 12a, 15 (pKaC) or the ease of proton transfer between the carbon and nitrogen in imidothioate followed by formation of the

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• )) and includes a chiral auxiliary, an amino acid, and a bifunctional linker capable to arrange the components in the Schiff base complex. Such templates provide a significant C–H acidity at the α-amino acid carbon and a possibility for recycling of the chiral auxiliaries (for reviews see [5][14][15][16

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• exploratory work, thiophosphorus acids were chosen due to their appropriate acidity and intrinsic chirality. Thiophosphorus acids undergo a tautomeric equilibrium between the thiolic and the thionic forms [22] (Scheme 1). If the substituents R1 and R2 are different, the phosphorus atom is always chiral

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• investigate their suitability as substrates in the Regitz diazo transfer. We reasoned that if the C–H acidity of the methylene group in 11 would turn out to be insufficient for the Regitz protocol to be directly applied, these substrates could have been additionally activated by trifluoroacetylation

Post-synthesis from Lewis acid–base interaction: an alternative way to generate light and harvest triplet excitons

• Hengjia Liu and
• Guohua Xie

Beilstein J. Org. Chem. 2022, 18, 825–836, doi:10.3762/bjoc.18.83

• . In 2002, Monkman reported the addition of camphor sulfonic acid (CSA) to the fluorescent polymer poly{2,5-pyridylene-co-1,4-[2,5-bis(2-ethylhexyloxy)]phenylene} (compound 1 in Figure 2) containing pyridine groups led to the protonation effect [26]. CSA has strong acidity and low volatility, which is

• acids B(C6F5)3 and B(C6H5)3 as electron acceptors, respectively [29]. B(C6F5)3 displays high chemical stability and Lewis acidity [30]. Moreover, its good solubility endows the possibility to form Lewis acid–base adducts in films by solution processing. The strong electron attraction of the fluorine

• substituents on the benzene rings of B(C6F5)3 is responsible for its stronger Lewis acidity compared to B(C6H5)3, and reacted efficiently with the basic fluorescent materials. In 2011, Hayashi investigated the modification of pyridyl-conjugated polymer films with the Lewis acid BF3 [31]. Through repeated acid

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• results due to its high Brønsted acidity [26]. Using inductive heating resulted in a highly improved catalytic system that showed long-term stability. This example is of relevance for the fragrance and flavour industries, as isopulegol (2) can be transformed into menthol in one step by catalytic

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• -derived bisisothiocyanate fragments 5e,f afforded the desired hetero-combination macrocycles M7–M12 without additional difficulties. It should be noted that the incorporation of CF3 groups on the aryl moieties was to increase the acidity of thiourea so as to provide better hydrogen-bonding complexation

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• all these reactions is the combination of its weak Brønsted acidity [42] that, by protonation of the substrate, leads to the formation of cationic species [43] and the stabilization of the latter through cation–π interactions [44] within the electron-rich aromatic cavity of the capsule, thus providing

• excess of tetrabutylammonium bromide (3) as a competitive guest for the capsule, to demonstrate the importance of the presence of an accessible cavity, and iii) acetic acid (4) in order to mimic only the Brønsted acidity of the capsule without providing the stabilization properties related to the

• with water content lower than 50 mM, while in the presence of increasing amounts of water a second capsule B is also present comprising overall 15 water molecules, 6−7 of which spontaneously incorporated into a single edge of the cubic suprastructure leading to increased Brønsted acidity. Therefore, we

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

• . Also, a higher C–H acidity of the proton at the stereogenic centre and possible racemisation can’t be excluded. A heteroaromatic oxindole derivative afforded the product 3j in lower yield and high ee values. 4- and 5-bromo oxindole derivatives (2l and 2k, respectively) were also used as starting

Mechanistic studies of the solvolysis of alkanesulfonyl and arenesulfonyl halides

• Malcolm J. D’Souza and
• Dennis N. Kevill

Beilstein J. Org. Chem. 2022, 18, 120–132, doi:10.3762/bjoc.18.13

• show a component with decreased electron density at the oxygen, which is relayed to give increased acidity for the hydrogen of the OH group and increased electrophilicity (solvent ionizing power) for a solvent in which it is a major component. Maskill and co-workers [26][27] investigated the solvolyses

• [32]. Probably the best known LFER is the Hammett equation which presents a way of correlating the behavior of reactants with a substituent present in an aromatic ring with the effect of that substituent on the acidity of benzoic acids in water at 25 °C. As one would expect as once moves away from the

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• naphthoquinones A prevail in all pH regions except for extreme acidity, where there is a shift to the form of 2-hydroxy-1,4-naphthoquinone-4-arylimines [73][74]. However, in weakly acidic or alkaline solutions, A is the most stable tautomer (Scheme 3C) [75]. Fragoso and co-workers [76] studied the tautomeric

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• metal. Ruthenium complexes have astonishing characteristics such as high electron transfer ability, low redox potentials, high Lewis acidity, and greater stabilities of the reactive metallic species like oxometals, metallacycles, and metal carbene complexes [27]. The wide availability of highly reactive

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• (Brønsted acidity/basicity, hydrogen-bonding units, and counter-anions toward metals) [48][49]. In 2019, Shi, Lin, and co-workers achieved an enantioselective synthesis of axially chiral quinoline-derived biaryl atropisomers via Pd-catalyzed C–H olefination of 8-phenylquinoline (11) using a novel chiral

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

• acidity of the hydrogen-bond donating unit. This notion has often been realized with substituted aryls such as 3,5-bis(trifluoromethyl)phenyl. Ellman introduced a different approach and developed N-sulfinylureas. An additional potentially useful feature is the stereogenic center on sulfur. tert

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• value (index to express acidity of weak acids) of the polymer [35]. Polymers responsive to pH can be classified by the functional groups present within their polymerised structure [35][41][42]. Including (i) polyacids with weakly acidic groups (i.e., -COOH or -SO3H), (ii) polybases with weakly basic

• . Furthermore, a response to pH can be utilised to release the therapeutic agent at a site of specific acidity, thus ensuring targeted delivery. Poly(acrylic acid)-based cryogels have been investigated as a pH oscillator in oscillatory bromate-sulphite-ferrocyanide reactions as potential soft materials for

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines

• Matthew J. Fleming and
• David M. Hodgson

Beilstein J. Org. Chem. 2021, 17, 2385–2389, doi:10.3762/bjoc.17.155

• with cross-coupling using the same carbenoid and epoxide 5 (Scheme 5), where the presence of LTMP also proved necessary. A cinnamylamine 23 could be obtained in a tin-free process (Scheme 10), which utilises the increased acidity of a benzylic ether 22. In this case, the presence of LTMP was necessary

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• was achieved by increasing the reaction time and acidity of the reaction medium, while elevated temperature showed no effect (Scheme 3) [40]. The mercuricyclization was also employed in the field of carbohydrate chemistry for the synthesis of α-ᴅ-C-glycopyranosyl derivatives. The reaction 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

• other hand, such electron-withdrawing groups, α to the reactive centre, dramatically changes the acidity of the substrate (and thus the reactivity of the enolate conjugate base) and as consequence its reactivity which can drastically impact the enantioselectivity in SN2 alkylation processes. In this

• reactive centre dramatically increases the acidity at this position and, in preliminary studies, we found that under biphasic basic conditions 2-oxindole 5 was undergoing alkylation also in the absence of a phase-transfer catalyst (not ideal when designing a catalytic enantioselective process). Despite

• reactions can be occasionally performed even in absence of base under water-enriched/organic biphasic conditions [41][42][43][44][45][46][47]. Taking inspiration from these studies, it was envisaged that by employing base-free neutral reaction conditions – given the likely acidity of substrate 5 – that it

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• triphenylphosphine (TPP) in catalyzing oxa-Michael additions. A matrix consisting of three differently strong Michael acceptors and four alcohols of varying acidity was used to assess the activity of the three catalysts. All test reactions were performed with 1 mol % catalyst loading, under solvent-free conditions

• more electron-rich catalysts is less pronounced. The experimental activity trend was rationalized by calculating the Michael acceptor affinities of all phosphine–Michael acceptor combinations. Besides this parameter, the acidity of the alcohol has a strong impact on the reaction speed. The oxidation

• triarylphosphines TPP, MMTPP and TMTPP as catalysts for the oxa-Michael reaction three varyingly strong Michael acceptors, namely acrylonitrile (1), acrylamide (2) and divinyl sulfone (3) were reacted with four different alcohols of similar molecular mass but different acidity (Figure 1). The stoichiometry of

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• developed by Widenhoefer [25][29] relied heavily on the acidity of the carbonyl substrate, and this hampered the use of less enolizable substrates, like alkenyl β-ketoesters. The same group addressed this limitation by proposing the use of trimethylsilyl chloride (TMSCl) as an additive in the intramolecular

• hydroalkylation cascades. In 2016, the Cui group reported the hydroalkylation of olefins 59 using p-quinone methides 60 as electrophilic partners (Scheme 24A) [91]. Alkenyl alcohols could be employed without needing to protect the hydroxy functional group, and the acidity of the phenolic hydrogen present in the

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• (4.8) were all too weak. While these results seem to make sense, when we compare the pKa values, they do not explain why a mixture of nitric and sulfuric acids causes rearrangement. It is possible that we are comparing the wrong values. pKa measures acidity in water. Under our reaction conditions it

• might better to compare the Hammett acidity function, H0, as this is more suitable for concentrated acids. On this scale triflic acid H0 = −14.1, perchloric acid H0 = −13, and sulfuric acid H0 = −12.0 are more similar and might explain why nitration conditions cause rearrangement [67]. Alternatively

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

• 3) [229]. Based on infrared studies, the higher catalytic activities of the metallated ILs was attributed to their higher Lewis acidity compared to both the metal-free catalysts and the metal salts. A mechanism was therefore proposed in which a synergistic effect of the metallated ILs takes place

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• either the leaving ability of the oxindole nitrogen (R1: Cl, NO2) or the acidity of the >C=NH2+ group (R2: Cl, CF3) increasing the proportion of the nucleophile >C=NH, then the formation of the thiazole (route a) is further accelerated (Scheme 2). Although the addition of a base generates the required C3

• fulfilled – i.e., the substantial acidity of a hydrogen at C3 and a more stable α-thioiminium group necessary for the internal nucleophilic addition giving the thiirane intermediate (route b). It is well known that the acidity of carbon acids in acetonitrile is much lower than in polar aprotic solvents

• methanol) such an increase of acidity should be also distinct but it is known that polar protic solvents much better solvate anions and thus decrease their nucleophilicity. Therefore, dimethylformamide has been chosen as the best solvent. Indeed, when dimethylformamide (DMF) was used as the solvent for the