Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• in Scheme 2. Unfortunately, the substrates 8a,b displayed low reactivity due to their significantly higher oxidation potential compared to the excited photoredox catalysts (>2.5 V vs SCE) [49]. However, other derivatives exhibited a satisfactory product yield ranging from moderate to good. Substrate

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• become increasingly popular in recent years probably due to their useful reactivity, ease of handling, and low toxicity [13]. In particular, hypervalent iodine compounds have been shown to be effective reagents and catalysts for a range of cyclization reactions [14]. In 2015, we reported the iodoarene

Phenylseleno trifluoromethoxylation of alkenes

• Clément Delobel,
• Armen Panossian,
• Gilles Hanquet,
• Frédéric R. Leroux,
• Fabien Toulgoat and
• Thierry Billard

Beilstein J. Org. Chem. 2024, 20, 2434–2441, doi:10.3762/bjoc.20.207

• )benzene (DNTFB) [66][67]. This DDPyOCF3 solution has shown a good reactivity to obtain various fluorinated compounds and especially trifluoromethoxylated molecules [68][69][70][71]. As another chapter of this research program, we propose here an easy and complementary access to CF3O-substituted alkyl

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• -to-handle reagent, NaOCl·5H2O. Because very little has been disclosed about the reactivity of such 2,3-epoxyesters, their epoxy ring opening by a variety of nucleophiles was carried out and we succeeded in clarifying these chemo- as well as regioselective processes proceeding via the SN2 mechanism to

• organometallic species [16][17][18][19]. At least in part, its high reactivity was considered to be due to the significantly lower-lying LUMO energy level by the attachment of electron-withdrawing trifluoromethyl (CF3) and ethoxycarbonyl groups [20]. As we previously pointed out [10][21], the effective

• like to describe in detail the results of the preparation of epoxyesters 2 with various Rf groups as well as their reactivity with diverse nucleophiles [39]. Results and Discussion Preparation of (E)-2,3-epoxypropanoates 2 with Rf groups at the 3 position Because the urea·H2O2 complex proved its

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

• boroxine with dramatically increased reactivity towards C=N electrophiles. Because of the small steric size of the (BO2) group, the reaction is highly selective towards (E)-α-trifluoromethyl homoallylic amine 44, which otherwise is difficult to obtain in a regiospecific manner. It has to be noted though

• acid activation mode appears to be the most plausible. Interestingly, chiral phosphoric acids failed to catalyse this reaction, but the use of chiral sulphonimide 45 afforded 82–97% ee and 65–84% yield on a set of aromatic and aliphatic aldehydes. The low reactivity of the allyltrimethylsilane (46

• analogues, a novel tetrakis-triazole-based H-bond donor catalyst 111 was identified as most promising. Among different nucleophilic allylating reagents, 2-methallyltributyltin (107) emerged as optimal in terms of reactivity and enantioselectivity. It was speculated that the enantioinduction is realised via

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• –protein conjugates are reacted via CuAAC with an azide tag. While the CuAAC has been employed in various studies and has had large impact on many biological discoveries, an unspecific reactivity was often reported [54][64]. Recently, we described this background-forming reaction, which is based on an

• alkyne probe from the CuAAC reaction mixture or by increasing the concentration of the reducing agent such as tris(2-carboxyethyl)phosphine (TCEP). The reversed chemical proteomics approach in which the azide probe and alkyne tag are used suffers from similar unspecific reactivity of the terminal alkyne

• of the probe is necessary to identify any unspecific bands stemming from side reactivity of the azide–protein conjugate. In case a photo-crosslinker is used, another control experiment needs to be included, in which the cells/lysate are treated with the probe but not UV-irradiated. The non-covalent

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

• catalysis with hydrogen bonding units has been essential for achieving high reactivity and enantioselectivities [21][22]. Additionally, the reactivity of the nucleophilic addition is influenced by substitutions near the electron-poor double bond. This approach requires 30 mol % of catalyst and a reaction

• enhancing the reactivity of a relatively inert acceptor does not necessarily lead to increased reaction rates, involves the use of more reactive nucleophiles. In this context, varying the stabilization energy of carboxylic acid derivatives by switching from oxoesters to thioesters is the significant

• reactivity by chiral quaternary ammonium salt in the asymmetric variant of the phase-transfer catalysis. Nevertheless, no product was formed despite several conditions being examined. Finally, an attempt to activate the electrophile was performed. We chose iminium salt catalysis particularly employing chiral

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• catalysts or photochemical procedures have been developed to enable this transformation [7][8][9]. The reactivity of hypervalent iodine reagents can be enhanced via Lewis acid catalysis [10]. For example, PIDA becomes a stronger oxidant upon coordination of BF3·OEt2, enabling chemistry that was not

• described in some group-transfer schemes [23][24][25], and in particular, fluorinated alcohol solvents, such as 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), have been reported to enhance hypervalent iodine reactivity by providing a H-bonding solvent cluster that enhances the electrophilicity of the iodine

• recently developed a metal-free aziridination of unactivated olefins via the intermediacy of an N-pyridinium iminoiodinane (Scheme 1b) [34]. We rationalized the enhanced reactivity towards olefin aziridination as a result of charge-enhanced iodine-centered electrophilicity arising from the cationic N

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• , equipping experimentalists with the knowledge necessary to follow the developments in the field. The rest of the review is divided into three parts: (1) ML for reactivity and selectivity prediction, (2) ML for the design of privileged organocatalysts and (3) ML for catalyst and reaction design. Ultimately

• , the authors developed a separate model to gain a sufficiently interpretable model, finding that some parameters remain important throughout the different subsets. This example demonstrates both the strength of careful data analysis and the intricacies of dealing with chemical reactivity data. The

• . With HTE platforms established and due to their importance to ML campaigns, the past few years have seen a trend in creating larger experimental chemical reactivity datasets, in particular for transition metal catalysis [47][48]. 2.2 Increasing data availability in ML for organocatalysis While, to the

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• scope of reactivity and determination of deuterium retention using a combination of deuterated aldehydes, [D1]-, and/or [D2]-isocyanides. We began with the venerable Ugi 4-component reaction (Ugi-4CR), first reported by Ivar Ugi in 1959 [28]. The Ugi-4CR utilizes an amine, carbonyl, carboxylic acid, and

• the Passerini reaction [40][41][42][43] discovered 60 years prior to the Ugi reaction. It uses the reactivity of isocyanides, aldehydes, and carboxylic acids to yield α-acyloxy amides (Scheme 6). Six deuterated analogs are reported in good yield with no observation of deuterium scrambling. For the

Synthesis and reactivity of the di(9-anthryl)methyl radical

• Tomohiko Nishiuchi,
• Kazuma Takahashi,
• Yuta Makihara and
• Takashi Kubo

Beilstein J. Org. Chem. 2024, 20, 2254–2260, doi:10.3762/bjoc.20.193

• , electrical properties, and reactivity. The generation of the DAntM radical was confirmed by its ESR spectrum, which showed two broad signals. The unpaired electron is primarily localized on the central sp2 carbon and slightly delocalized over the two anthryl moieties. Although the DAntM radical undergoes

• . Keywords: anthracene; cation; dimerization; radical; reactivity; Introduction Organic radicals have garnered significant attention in various research fields, including catalysis [1][2][3][4], chromophores [5][6][7][8], and as agents in dynamic nuclear polarization [9][10][11][12]. Recently, highly stable

• the field of radical chemistry. However, reducing the reactivity of radical species can mean losing one of their most attractive properties. Therefore, it is very important to explore aromatic hydrocarbon radicals that are sufficiently stable for handling, yet reactive under specific conditions

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• apparently smaller than those previously reported for the reaction between DBA-OHex and benzyl azide (Table S1 in Supporting Information File 1). However, the Ea values were previously measured in DMSO-d6 and C6D6, and it is known that there is a solvent polarity effect on the reactivity of SpAACs. In order

• to quantitatively compare the reactivity of DBAs with different substituents, the reaction between DBA-OHex and benzyl azide was also monitored in CDCl3. The Ea in CDCl3 was 71.1 kJ mol−1 (Table S1 in Supporting Information File 1). This result clearly suggests that DBA 5 with electron-withdrawing

• ) is more energetically demanding than the counter monoadduct (out) due to steric factors. The second azide addition follows this step. The alkyne, which is diagonally positioned relative to the triazole group, shows the highest reactivity due to its significant distortion. This finding correlates with

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• the possible substitution patterns, meta-substituted anilines hold a special place. These compounds are difficult to access due to the inherent ortho-/para-directional reactivity of the amino group, at the same time they are widely used in medicinal chemistry, resulting in several marketed drugs

• /chemoinformatics calculations were also performed to correlate the observed reactivity with the charges on the carbonyl group of 1,3-diketones. Unfortunately, no reliable correlation was found between the charges and the reactivity of the 1,3-diketones with the present set of heterocyclic substituents or with the

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO2-containing analogue of anticancer drug-candidate enastron (SO2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions – synthesis

• synthesis of new S-heterocyclic systems we tried to combine the broad synthetic potential of Biginelli condensation and high reactivity β-ketosulfone 1 (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide) in various condensation reactions [14][15][16][17][18][19][20]. It was also worth mentioning that the thiopyran

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• nitrogen-containing compounds [3][4][5][6][7]. Furthermore, by adjusting the substituents on the nitrogen, reactivity can be controlled and solubility in various solvents can be tuned (Figure 2). However, the use of isocyanide as a C1 resource is somewhat limited compared to that of carbon monoxide [8

• on molecular transformations by the reactions of heteroatom radicals with isocyanides using methods 1 and 2. Thus, in this perspective, we mainly focused on the use of method 1 and method 2 for the generation of heteroatom radicals and the reactivity of them with isocyanides. Among these three

• can add to isocyanides to form the imidoyl radicals. In this reaction, telluro radicals (ArTe•) also forms in situ, but the relative reactivity of them toward isocyanides might be very low. In addition, dimerization of ArTe• to (ArTe)2 is very fast, and therefore, the ArTe-substituted imidoyl radical

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

• approach this ideal, representing a reactivity-based concept where reactive functionalities are generated and consumed in each step [24]. MCR can be conducted in a domino, sequential, or consecutive fashion, offering a versatile approach to synthetic design by creating countless new sequences by

• ) [69] approach without reducing the reactivity of the Michael system. In this one-pot procedure, the borylation of aryl halides with pinacolborane gives aryl pinacolyl boronates 53, which are then coupled with bromoenal 51 to generate the intermediary enal 54. Subsequent cyclization with tosylhydrazine

• employed, likely due to the more electron-rich internal nitrogen atom reacting with the Michael system. When phenylhydrazine is used, an inverse reactivity is observed [73][74][75]. Remarkably, when hydroxyethylhydrazine is utilized, a mixture of regioisomers is formed, likely attributed to steric

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• , curcumin showcases its Michael donor–acceptor ability in different ways, such as simple Michael addition, [4 + 2] annulation, Michael addition followed by cyclization or one-pot multicomponent reactions (MCR), etc. (Scheme 1) [25]. In 2011, our group reported the reactivity of curcumin as a Michael donor

• ]. Other groups have also investigated the Michael donor–acceptor reactivity of curcumins [25]. For instance, a quinine-thiourea catalyzed Michael addition of curcumins to nitroalkenes reported by Ye et al. stopped at the single Michael addition stage [35]. In the subsequent year, Yan et al. demonstrated a

• reported in due course. Biologically active derivatives of cyclohexanones. X-ray structure of 4a (CCDC 2351387). Origin of stereoselectivity in the double Michael addition. The Michael donor–acceptor reactivity of curcumin: previous vs present work. A plausible reaction mechanism. Scale-up reaction

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• hydrazones can act as radical acceptors for the synthesis of functionalized amines or hydrazones through reductive functionalization [21][25][26] or oxidative C(sp2)–H functionalization [27][28], respectively. Consequently, given their rich reactivity profile, exploring new synthetic transformations of

• appealing opportunities to take advantage of the versatility of this reagent. Such an approach can either ameliorate the previous methods in a more sustainable and efficient fashion or provide a mean for the discovery of new reactivity. Herein, this review aims to give an overview of the state of the art in

• reactivity profile of hydrazones, the electrooxidative transformations of such a molecular building block provides a fascinating route to valuable compounds under mild and safe reaction conditions. Alone, the electrooxidation of NH-aryl, -tosyl, and -acylhydrazones triggered the cyclization of a radical

Radical reactivity of antiaromatic Ni(II) norcorroles with azo radical initiators

• Siham Asyiqin Shafie,
• Ryo Nozawa,
• Hideaki Takano and
• Hiroshi Shinokubo

Beilstein J. Org. Chem. 2024, 20, 1967–1972, doi:10.3762/bjoc.20.172

• ) norcorrole. The radical reactivity of Ni(II) norcorroles was investigated by density functional theory (DFT) calculations. Keywords: 16π; antiaromatic; norcorrole; porphyrinoid; radical; Introduction Considerable attention has been directed toward antiaromatic norcorroles [1][2][3] due to the fascinating

• the electrophile [16][17][18]. In addition, C–C double bonds of the norcorrole skeleton outside the π-delocalization pathway exhibit a reactivity similar to an alkene to afford hydrogenated norcorroles by hydrogenation [19] or reduction with hydrazine [20] and [3 + 2]-cycloadducts with 1,3-dipoles [21

• presented. We also discuss the selectivity of the radical addition to Ni(II) norcorroles using DFT calculations. Results and Discussion Reactivity with azo radical initiators We selected 2,2'-azobis(isobutyronitrile) (AIBN) as a radical source. Ni(II) dimesitylnorcorrole 1 was treated with AIBN in refluxing

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• higher reactivity than (Z)-1,2-difluoroethylene in this reaction. The reaction of either (E)- or (Z)-1,2-difluoroethylene with perfluoroaldehydes resulted in the formation of three isomeric oxetanes in a 1.0:1.7:1.3 ratio in a high yield of 78–94% (Scheme 22) [49]. All data reported for the [2 + 2

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• precursors of alkylating reagents presents an opportunity to find new ways to diversify indazole reactivity by simple modifications of reaction conditions. Mechanistic understanding would allow for further diversification in related systems. The indazole ring presents annular tautomerism regarding the

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• pentafluorobenzyl bromide, followed by a nucleophilic aromatic substitution (SNAr) with thiols and phenols. This approach is based on the well-established reactivity of perfluoroaromatic compounds in nucleophilic aromatic substitutions [32][33][34][35]. By varying the reaction conditions and the number of

• generating new DPP derivatives through nucleophilic aromatic substitution reactions with thiols and phenols. The main objective of this study was to employ the N,N’-bis(pentafluorobenzyl)-DPP 2 as an electrophile and investigate its reactivity with thiols and phenols (Scheme 1). All SNAr reactions were

• functionalized DPP derivatives. As anticipated, it displayed reactivity with thiols and phenols through nucleophilic aromatic substitution at the pentafluorobenzyl groups, yielding both symmetrical (disubstitution) and non-symmetrical (monosubstitution) derivatives in satisfactory yields (Scheme 1). Thiols are

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol. Keywords: amino acids; DEL

• results, thiazole 2b, benzothiazole 2i and benzimidazole 2t react very well with sodium nitrite in an acidic environment (Scheme 6, red section). Among the various subclasses of compounds, pyrazole 2l exhibited a high reactivity using t-BuONO and EtONa in ethanol (Scheme 6, red section). On the other hand

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• versatile methods for the preparation of structurally diverse β-lactam derivatives is of great importance and relevance. Continuing the investigation of the reactivity and synthetic potential of diazotetramic acids (1), we have recently shown that these diazo reagents can act as precursors of β-lactam

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

• and a hydrophilic corona and can serve as heterogeneous systems for solubilizing hydrophobic chemicals in water. By concentrating reactants in nanometer-sized vessels, their reactivity is altered, and reaction rates are often accelerated. As a result, mild reaction conditions can be achieved

• template, selecting the ligand building blocks with highest affinity and bringing them in proximity within the binding site. Building blocks are opportunely chosen to have complementary reactivity and therefore to react irreversibly within the binding site and assemble into the final ligand. Before the

• Almost 90 different amidines had already been tested until 2018 [1], however, room for novel building blocks or old ones with novel reactivity is still available as demonstrated for example by Dömling et al. [48]. They focused on the use of 2,4-diaminopyrimidines 41 to synthetize