Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• developments and illustrates the influences of copper salt, ligand, and substitution pattern of the substrate on the regioselectivity and stereoselectivity. Keywords: copper-catalysis; copper vinyl allenylidene intermediate; 1,3-enyne; 1,4-enyne; yne-allylic substitution; Introduction Copper is earth

• nucleophiles (Scheme 1b). However, to achieve a highly selective yne-allylic substitution, a range of challenges must be addressed. First, how to achieve the regioselectivity under the coexistence of alkenyl and alkynyl units; second, how to realize the enantioselectivity control that is remote from the

• substitutions, the realm of yne-allylic substitution remains relatively unexplored. This scarcity of reports stems primarily from the inherent challenges posed by the presence of two unsaturated bonds in the substrates, which often complicates the control of regioselectivity. Additionally, the competition among

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• initial study, it can be concluded that the mechanism for our system proceeds according to mechanism two. The following simulations were performed on this conclusion. Regioselectivity PO exhibits two distinct electrophilic sites, which can be subject to nucleophilic attack (Figure 2B). Thus, the

• regioselectivity of the CO2 insertion into PO must be addressed as part of the full mechanistic investigation. The compound 3-boryl-2-propen-1-amine is now considered as the catalyst (Figure 2B). As observed in Figure 2A, the bond length and electron density at the bond critical point (BCP) difference are minimal

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• reported over the years (Figure 2) [2]. Conventionally, benzophenones are synthesized by Friedel–Crafts acylation of benzoyl halides and aromatic compounds. However, the regioselectivity of Friedel–Crafts benzoylation at the desired position is difficult to control [9]. On the other hand, 2

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidation strategy to obtain α-chlorosulfoxides from sulfides using hydrochloric acid as a bifunctional reagent [22]. This strategy accommodates a broad range of substrates and offers high diastereoselectivity and regioselectivity. Several LSF modifications of amino acids and pharmaceutical derivatives

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• ][116][117], regioselectivity, and site-selectivity [16][17][118][119][120]. However, this approach is also computationally demanding and requires a good initial guess of the TS structure. Moreover, it may face difficulties in simulating some classes of reactions and large-size molecules [121], and the

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

• present in the substrates to access the corresponding radical cation. The reaction shows high regioselectivity and good to moderate diastereoselectivity with satisfactory yield. The limitation, which will be further addressed by a more powerful catalyst, is related to the unreactivity of unsubstituted

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

• the position of the double bond in the molecule. Notably, a longer reaction time was required for less reactive or more hindered substrates. The reaction was stereoselective as only the anti products were obtained. A good regioselectivity was generally observed, as at least 80% of the main regioisomer

• were usually obtained when the substituents at the double bond differed significantly. When the substituent hindrance was less pronounced, the ratio was less significant (2f, 2j). Interestingly, a reverse regioselectivity was observed depending on the starting alkenes. For the terminal alkenes, the

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

• between catalyst, substrate and the DABCOnium moiety. Subsequently, a random forest model was used to predict exo/endo- and regioselectivity of the reaction. Using random forest as an interpretable machine learning model allowed to extract the important features of the model, which indicated that 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

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

• efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls

• -acetoacetylcoumarin 41, 3-bromoacylpyran 42, and semicarbazide 40 (Scheme 12) [65]. Alternatively, the corresponding chromenes can replace the 3-bromoacylpyrans. A notable advantage of this process is its catalyst-free nature and the achievement of good regioselectivity. Due to the high heterocycle density, this

• regioselectivity, with 3,4-fused pyrazoles being accessible when cyclic β-oxodithioesters are employed as substrates. However, aromatic amines cannot be successfully employed in the sequence. Alkenoyl derivatives as key intermediates The Michael addition and cyclocondensation of hydrazines and α,β-unsaturated

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

• LUMO (Figure 1) [11]. Reactions with nucleophiles (Nu) proceed with perfect regioselectivity at the distal β-position relative to the meso-position [12][13][14][15]. On the other hand, reactions with electrophiles (El) also occur preferentially at the β-positions, but the regioselectivity depends on

• governed the regioselectivity. Reactivities of norcorroles with various reagents. Top and side views of the X-ray structures of a) 2a and b) 1 [2]. Mesityl groups and hydrogen atoms were omitted for clarity. Thermal ellipsoids are drawn at 50% probability. UV–vis–NIR absorption spectra of 1 and 2a in

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

• compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways. Keywords: DFT; indazole; indazole substitution; mechanism; N1-substituted indazole; N2-substituted indazole; regioselectivity; Introduction Indazoles constitute an important class of

• pharmacophore in medicinal chemistry and the challenges in obtaining either N1- or N2-alkylated indazoles as the dominant regioisomer [30][34][35][36][37][38][39], we were interested in exploring the regioselectivity with methyl 5-bromo-1H-indazole-3-carboxylate (6, Figure 1) as a multifunctional model compound

• potassium carbonate, isopropyl bromide and cesium carbonate, and bromocyclohexane with potassium carbonate, and only afforded yields not higher than 52% in various solvents [41][42][43]. Recently, Alam and Keeting [37] explored the regioselectivity in the alkylation of variously substituted indazoles

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• combination with an ML model to predict a variety of properties. These properties encompass the site of metabolism [31][33], the strengths of hydrogen bond donors and acceptors [34][35][36], and the regioselectivity of electrophilic aromatic substitution reactions [14]. Building on the methodology from

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• simple lithium salts for hypervalent iodine catalyst activation. The activated hypervalent iodine catalyst allows the intermolecular coupling of soft nucleophiles such as amides onto electronically activated olefins with high regioselectivity. Keywords: amide coupling; hypervalent iodine catalysis

• α-phenylstyrene produced the respective oxazoline products with high regioselectivity and reasonable yields using iodoanisole as the catalyst precursor (Figure 3, products 24 and 25). The proposed catalytic cycle (Figure 4) begins with iodotoluene A which is oxidized by Selectfluor salt into the

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• using tertiary alkyl oxalates and aryl bromides (Scheme 10). This is achieved through the synergistic combination of photoredox and nickel catalysis. This approach facilitates the formation of diverse trisubstituted olefins with outstanding regioselectivity and syn-stereoselectivity. The proposed

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• high regioselectivity. Herein, we report the electroreductive hydroarylation of electron-deficient alkenes and styrene derivatives using (hetero)aryl halides under mild reaction conditions. Notably, the present hydroarylation proceeded with high efficiency under transition-metal-catalyst-free

• versatile building blocks in organic syntheses. To achieve this transformation with high efficiency and predictable regioselectivity, numerous efforts have been made to develop transition-metal-catalyzed reactions based on a C–H activation strategy [1][2][3][4] or the reductive coupling of aryl halides with

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• carbonyl compounds, such as dimethyl acetone-1,3-dicarboxylate and 1,3-diphenylacetone, and with 1,3-bis(silyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, allow for a convenient synthesis of a great variety of products. The regioselectivity and course of the reaction depends

• of the substituent located at carbon C3 of the chromone moiety and also on the type of nucleophile employed. Keywords: cyclizations; 1,3-dicarbonyl compounds; domino reactions; heterocycles; regioselectivity; silyl enol ethers; Introduction Domino reactions (also called cascade or tandem reactions

• undergo cyclization reactions under mild conditions. In case of 1,3-diphenylacetone (4a) some activation of the methylene group is observed as well, because of benzylic stabilization. Dianions of 1,3-dicarbonyl compounds follow a different regioselectivity as compared to simple monoanions [6][7][8][9][10

Two-fold addition reaction of silylene to C₆₀: structural and electronic properties of a bis-adduct

• Masahiro Kako,
• Masato Kai,
• Masanori Yasui,
• Michio Yamada,
• Yutaka Maeda and
• Takeshi Akasaka

Beilstein J. Org. Chem. 2024, 20, 1179–1188, doi:10.3762/bjoc.20.100

• results. To obtain some insight into regioselectivity, we performed density functional theory (DFT) calculations using the B3LYP/6-31G(d) method [45][46][47][48]. We first compared the relative stabilities of mono-adducts (Dip2SiC60) with 6,6-silirane (2a), 6,6-sila-fulleroid (2b), 5,6-silirane (2c), and

• difference except for the carbons adjacent to the addition site. Therefore, neither the double bond lengths nor the POAV values of 2a are regarded as affecting the regioselectivity. The frontier orbitals of 2a were then examined to elucidate the reactivity in the second silylene addition. The ground states

• charge densities are nearly zero on the cage carbon atoms except those adjacent to the addition site. The charge densities of 2a are regarded as affecting the regioselectivity. Thus, it is suggested that the regioselectivity in the silylene addition could not be estimated by the charge densities of 2a

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• considering the most atom-economical options, namely chlorine and bromine, the latter typically exhibits some advantages over the former. These include: (i) better regioselectivity in radical processes, attributed to the lower bond enthalpy of H–Br (88 kcal/mol) compared to H–Cl (103 kcal/mol) [17], (ii

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• reaction took place in the presence of Pd(OAc)2 (2 mol %), 1,10-phenantroline (4 mol %) under 1 bar of CO at 110 °C in DMF. After the right time, six products were isolated, while, in three cases, when the benzene ring was meta-substituted, a regioisomeric mixture was obtained. The regioselectivity was

• starting from indoles and o-dibromoarenes as substrates [59]. In this tandem reaction, various symmetrical bromoarenes were utilized to eliminate the problem with regioselectivity. Two tests by using 2-bromo-5-methoxyphenyl triflate and 2-bromo-4-methoxyphenyl triflate were performed to evaluate the

• regioselectivity of the process. The regioselectivity was good with a regioisomeric ratio of 95:5. All reactions took place in the presence of Pd(OAc)2 as catalyst, cataCXium as ligand, and K2CO3 as base. Besides, the authors proposed glyoxylic acid monohydrate as an environmentally friendly CO surrogate (Scheme

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• -coupling; fluorescence; heterocycles; regioselectivity; Introduction Organic life is a complex interplay of many different building blocks. One of these building blocks is uracil. Discovered for the first time in 1901 by Alberto Ascoli, it is now known to be one of the four nucleobases of RNA [1]. It

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• , respectively. Tetrazole and 5-methyltetrazole both proved to be excellent substrates. Regardless of the presence or absence of the 5-substituent, they underwent preferential alkenylation at the N1 position over the N2 position with the identical regioselectivity of 7:3 (see 4ja and 4ka). Among other five

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• , HCl gas was bubbled through neat alkene 1 for several hours, as depicted in Scheme 3A [35]. This example highlights an intriguing regioselectivity that might have been challenging to predict through a simple analysis of the stability of the corresponding cations. Alternatively, the HCl gas was bubbled

• alkenes (Scheme 17). Remarkably, various functional groups were well tolerated, and the product 114 was obtained with unexpectedly high regioselectivity. In 2022, Paquin and colleagues devised a practical hydrochlorination reaction, utilizing a mixture of methanesulfonic acid and hand-ground CaCl2 in

• the higher-substituted carbon atom to furnish intermediate species C. The irreversibility of the hydride addition and the regioselectivity thereof were supported by a deuterium labelling study with PhSiD3. The next steps involve homolytic cleavage of the cobalt–carbon bond to yield a carbon-centered

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• . Developing more efficient and diverse macrocyclization strategies is urgently needed to overcome issues such as insufficient regioselectivity, intermolecular oligomerization, the overuse of protective groups, and other drawbacks [8]. In the biosynthetic logic, these natural products are produced by the large

• the current issues, such as insufficient regioselectivity, intermolecular oligomerization, and the overuse of protective groups. The biosynthetic studies demonstrated that thioesterase (TE) domains exhibit a high level of chemoselectivity and regioselectivity in late-stage macrocyclizations. This

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• hours without compromising selectivity. Although tetrabutylammonium azide (TBAA) is better soluble in DMSO than NaN3, practical challenges associated with its use led to the preference for NaN3. Confirmation of regioselectivity for the sulfonyl group dance products The regioselectivity and the structure

• , thioether substituents were installed in the presence of K2CO3. For alkylthiols, DMF was used, but arylthiols required milder conditions with MeOH and cooling to acquire regioselectivity to the C4 position which resulted in yields up to 91%. Oxidation with purified mCPBA (commercial mCPBA with 68% purity

• further optimized since the products were only needed for analytical purposes. Two different pyrrolidine-substituted derivatives were additionally synthesized to prove the regioselectivity of the sulfonyl group dance products (Scheme 8). Compound 16 was obtained in the C4-selective SNAr reaction between