(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• substrate. Employing Lewis acid catalysis Deng and co-workers reported an alternative pathway to indole-derived BCHs. Polysubstituted BCHs were accessed by nucleophilic addition of the indole to the activated bicyclobutane followed by a Mannich cyclisation [81]. The synthesis of wide variety of tri- and

• by Lewis acid-catalysed cyclisation of bicyclobutanes with aldehydes [84] and polysubstituted 2-oxa-BCHs bearing more complex substitution patterns were synthesised by triplet energy transfer catalysis from benzoylformate esters and bicyclobutanes [85]. Reports of polysubstituted scaffolds larger

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

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

• more efficient reactions with alkene 88 (Table 6). In 2022, Oestreich reported the in situ formation of HCl by Lewis acid-induced Grob fragmentation of acid chloride 92 (Scheme 15B) [68]. The inconvenience of this method is that 92 has to be prepared in two steps, including a Birch reduction (Scheme

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• increase the yield of different transformations. Using fluoride scavenger such as TMSCl, TFAA or TMS2(O) led to similar or lower yields (Table 7, entries 3–5). We were pleased to see that in the presence of BF3·Et2O, 4a was obtained in 75% yield (Table 7, entry 6). Addition of a less acidic boron Lewis

• acid B(OTFE)3 had a detrimental effect (Table 7, entry 7). Increasing the stoichiometry of BF3 to 2 equivalents lowered the yield significantly (Table 7, entry 8). In contrast, the loading could be reduced to 30 mol % without impacting the formation of 4a (Table 7, entries 9 and 10). Finally, a fine

Enhanced reactivity of Li⁺@C₆₀ toward thermal [2 + 2] cycloaddition by encapsulated Li⁺ Lewis acid

• Hiroshi Ueno,
• Yu Yamazaki,
• Hiroshi Okada,
• Fuminori Misaizu,
• Ken Kokubo and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2024, 20, 653–660, doi:10.3762/bjoc.20.58

• approaches have diligently explored the details of reaction kinetics, quantitatively elucidating the impact of encapsulated Li+ on the reactivity of the outer fullerene cage as a specialized “encapsulated” Lewis acid catalyst [10][11]. While previous studies have revealed valuable insights, such as

• electronic effects of the encapsulated Li+ Lewis acid, commonly exhibits significantly higher reactivity compared to empty C60. The much-enhanced reactivity often leads to the formation of multiadducts more notably than in the case of empty fullerenes, and hence, achieving the selective monofunctionalization

• target monofunctionalized products. The results underscore the significantly enhanced reactivity of Li+@C60 in the thermal [2 + 2] cycloaddition reaction due to the electronic effect of the encapsulated Li+ Lewis acid. Moreover, the formation of undesirable bis- and multiadducts was notably suppressed

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• (pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops. Keywords: 2,3

• entirely unexplored prior to our investigations. Likewise, we identified an optimized BH3⋅NH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid and subsequent treatment with formic acid as the most suitable conditions to prepare the desired 2,3-dihydro[1,3]thiazolo[4,5-b

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• protodeauration pathways [15]. Widenhoefer, however, then showed that even HOTf acid catalyzed hydroaminations proceed with anti-selectivity [31]. In contrast, additions of water and indoles to alkenes are proposed to proceed via a Lewis acid-assisted Bronsted acid mode and computations suggest that gold is not

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• highest fungicidal activity [11]. Brønsted or Lewis acid catalysis – conventional synthetic methods The indole moiety is part of many natural products, agrochemicals, and pharmaceuticals. In medicinal chemistry, indole and its derivatives are considered important compounds, since they exhibit valuable

• catalyst due to present moisture or formation of adducts with the substrate, long reaction times, lower yields, and production of large amounts of toxic waste during work-up. The general mechanisms of protic acid and Lewis acid-catalyzed syntheses of BIMs is shown in Scheme 2. In either case, the first

• . The difference between the two mechanistic pathways is the nature of activation of the carbonyl group. Protic acids induce the protonation of the carbonyl group of the aldehyde or ketone, enhancing its electrophilic character. Whereas, Lewis acid catalysts bind to the heteroatom of the carbonyl group

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• resulting concentration of radicals. In such instances, opting for a stronger catalytic reductant or utilizing a stoichiometric electron donor can greatly improve the efficiency of radical generation. On the other hand, additional factors such as the ability of Brønsted and Lewis acid additives to promote

• oxyalkylation product 28. Li and co-workers described the activation of NHPI esters towards SET using a Lewis acid catalyst, allowing for the functionalization of styrene radical acceptors with nucleophiles that do not necessarily engage in hydrogen-bonding interactions, such as electron-rich (hetero)arenes [47

• ] (Scheme 7A). Cyclic voltammetry measurements of a model NHPI ester showed a shift in its reduction potential from –1.79 V to –1.51 V (vs SCE in MeCN) in the presence of In(OTf)3. As such, it was hypothesized that the Lewis acid lowers the LUMO of the NHPI ester via interaction with the oxygen lone pair in

Synthesis of the 3’-O-sulfated TF antigen with a TEG-N₃ linker for glycodendrimersomes preparation to study lectin binding

• Mark Reihill,
• Hanyue Ma,
• Dennis Bengtsson and
• Stefan Oscarson

Beilstein J. Org. Chem. 2024, 20, 173–180, doi:10.3762/bjoc.20.17

• synthesis starting from unprotected N-acetylgalactosamine and a Lewis acid-promoted reaction starting from per-acetylated galactosamine were initially tested. As reported [11], the Fischer synthesis gives low yields and α-selectivity. The Lewis acid-promoted reaction, which had worked well to produce β

Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a

1-Butyl-3-methylimidazolium tetrafluoroborate as suitable solvent for BF₃: the case of alkyne hydration. Chemistry vs electrochemistry

• Marta David,
• Elisa Galli,
• Richard C. D. Brown,
• Marta Feroci,
• Fabrizio Vetica and
• Martina Bortolami

Beilstein J. Org. Chem. 2023, 19, 1966–1981, doi:10.3762/bjoc.19.147

• starting or stopping the electrolysis, 3) the absence of fuming, most probably due to the ability of the IL to stabilize the Lewis acid, 4) reduced sensitivity to moisture, due to the protective action of the IL, and 5) the possibility of recycling the same sample of IL for subsequent reaction cycles. In

• investigation using lower amounts of BF3·Et2O revealed that a 92% yield of 2a could be realized using 3 equiv of the Lewis acid by extending the reaction time to 65 h (Table 1, entry 10). A further reduction in the amount of BF3·Et2O to 2 equiv resulted in a lower yield of 66% after the same reaction time (65 h

• anions could coordinate the Lewis acid BF3 through the negatively charged oxygen [107], decreasing availability of BF3 for catalysis. Otherwise, ILs possessing bis(trifluoromeylsulfonyl)imide and hexafluorophosphate anions afforded hydrated product 2a with slightly better yields (87%) compared to those

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• oxidation/cyclization with NXS or Cu(OAc)2. Notably, some of the resultant CF3-substituted 1,6-dihydropyridazines exhibited aggregation-induced emission [102][103] (Scheme 16). The hydrocyanation of acylhydrazones is an important method for the preparation of α-hyrazino acids. Hu et al. reported a Lewis

• acid-catalyzed hydrocyanation of trifluoromethylated acylhydrazones, in which the product was the precursor for the preparation of chiral fluorinated amino acids [104] (Scheme 17a). Meanwhile, Hu et al. provided a novel and efficient process for the synthesis of polysubstituted 3-trifluoromethyl-1,2,4

C–H bond functionalization: recent discoveries and future directions

• Indranil Chatterjee

Beilstein J. Org. Chem. 2023, 19, 1568–1569, doi:10.3762/bjoc.19.114

• its combination with organometallic chemistry for site-selective C−H bond functionalization [3][4]. Recent years have witnessed many viable strategies for the synthesis of complex targets utilizing photoredox catalysis, electroorganic catalysis, Lewis acid catalysis, and transition-metal-free

Lewis acid-promoted direct synthesis of isoxazole derivatives

• Dengxu Qiu,
• Chenhui Jiang,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2023, 19, 1562–1567, doi:10.3762/bjoc.19.113

• nitrite as a nitrogen-oxygen source, and solely using aluminum trichloride as the additive. This approach circumvents the need for costly or highly toxic transition metals and presents a novel pathway for the synthesis of isoxazole derivatives. Keywords: aluminum trichloride; Lewis acid; isoxazole

• the Lewis acid to realize the sp3 C–H-bond activation of nitrogen heterocycles to synthesize isoxazole derivatives. Results and Discussion At the outset of this study, we chose the reaction of 2-methylquinoline (2a) with phenylacetylene (1a) in the presence of AlCl3 (3 equiv) and sodium nitrite (10

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• -catalyzed sulfenylation by N-(sulfenyl)succinimides/phthalimides In 2012, Chen and co-workers found that in the reaction of N-(organothio)succinimides 1 and sodium sulfinates 2 using a Lewis acid in ionic liquids (ILs) and water as a green solvent system leads to the formation of thiosulfonates 3 (Scheme 2

• ) [44]. Among different Lewis acid catalysts, such as Cu(OTf)2, Mg(OTf)2, Zn(OTf)2, Sc(OTf)3, Eu(OTf)3, and Yb(OTf)3, it was found that Sc(OTf)3 gave higher product yield. In addition, the combination of Sc(OTf)3/ILs displayed good recyclability in this transformation. In 2014, Anbarasan and Saravanan

• nucleophilic attack of TMSN3 to deliver product 11 (Scheme 7). Tian and Chang et al. could synthesize 3‑sulfenylated coumarin compounds 13 by using N-sulfanylsuccinimides 1 under a Lewis acid catalysis system (Scheme 8) [48]. Additionally, oxidation of 3-sulfenylated coumarins utilizing (diacetoxyiodo)benzene

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• of ethers to obtain symmetric and asymmetric 1,1-bis-indolylmethane derivatives (Scheme 23) [84]. The reaction proceeds through the tandem oxidative coupling of the C–O bond and cleavage of the C–H bond. Fe plays a dual role in catalysing the C–C bond coupling and C–O bond cleavage as Lewis acid

• pathway. Initially, a tert-butoxyl radical is generated by thermal decomposition. Then, the tert-butoxyl radical extracts an α-hydrogen atom from tetrahydrofuran to form tetrahydrofuran radical A. Sc(OTf)3 as a Lewis acid activates pyridine forming the pyridine complex B. Then, radical A adds to the more

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

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

• system. Like the classical Friedel–Crafts reaction, the aza-Friedel–Crafts reaction also requires the presence of a Lewis acid catalyst for rate acceleration. The reaction can be very easily modulated by different Lewis acidic metallic compounds which effectively form a coordinate bond by accepting the

• benzofuran-2(3H)-one derivative 144 having an aza-quaternary stereocenter. The achiral Lewis acid tris(pentafluorophenyl)borane was required as additive in the reaction system to enhance the chemical yield and enantioselectivity. After two additional steps, i.e., demethylation of the phenolic ether and ester

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• work-up of intermediate H (Scheme 2b). Review Conventional method for the Clauson–Kaas synthesis of N-substituted pyrroles This section describes Clauson–Kaas pyrrole syntheses using traditional methods, such as Brønsted acid or Lewis acid-catalyzed reactions in various organic solvents at higher

• excellent yields. To obtain the best reaction conditions, various Lewis acid catalysts (e.g., FeCl3 CuCl2, InCl3, Cu(OTf)2, Mg(OTf)2, Zn(OTf)2, Yb(OTf)3, Y(OTf)3, Bi(OTf)3, La(OTf)3 and Sc(OTf)3), different solvents (e.g., CH2Cl2, CHCl3, CH3CN, CH3NO2, n-hexane, and dioxane), temperatures (90–110 °C), and

• various substituted anilines, primary arylamides, and sufonylamides 20 and 2,5-DMTHF (2) in the presence of 10 mol % MgI2 etherate in MeCN at 80 °C (Scheme 9a). MgI2 etherate is a main-group Lewis acid catalyst that selectively activates electron-rich aromatic amines. This is a mild, efficient, and highly

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• example, when esters 1a are subjected to Lewis acid-induced denitration, highly electron-deficient enones (reaction b) [4] are obtained. The latter compounds are highly reactive and undergo reaction with, e.g., mercaptoacetaldehyde affording thiophenes (reaction c) [5] or with activated (hetero)aromatic

• compounds to give diarylated (oxoalkyl)malonates [6]. In the reaction using tin(II) chloride as the Lewis acid, the ring opening and nucleophilic attack of the nitro group occur, to produce functionalized isoxazolines (reaction d) [7]. In contrast, denitration under basic conditions generates highly

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• of −7.13 eV and an even more negative NBO charge of −0.368 at the C-2 position. We can confer from these data that Zn enolates obtained from acylimidazoles are somewhat less reactive than silyl enol ethers obtained in the Lewis acid-promoted conjugate addition of Grignard reagents [23]. This finding

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• ). A direct selective C4-alkylation of pyridine has been reported by the groups of Hiyama [62] (Scheme 12a) and Zhang [63] (Scheme 12c) in 2010 and 2020, respectively. The Hiyama group developed a C-4-selective alkylation of pyridines using a Ni/Lewis acid cooperative catalytic system in combination

• with a bulky N-heterocyclic carbene ligand and (2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD) as the Lewis acid which allowed the direct C-4 alkylation of pyridines 1 (Scheme 12a). With the optimized reaction conditions in hand the group also screened the alkene and pyridine substrate scope which resulted C4

• nickel Lewis acid catalyst with amino pendant linked NHC complex (Scheme 21). In addition, the authors were able to isolate the bimetallic intermediate structure η2,η1-pyridine–Ni(0)–Al(III) complex 112, as a support for their mechanism for the para-C–H functionalization. They further investigated the

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• ) chloride (Scheme 26). Alkyne–carbonyl metathesis is proposed to proceed via [2 + 2] cycloaddition and –reversion steps, catalysed by a Brønsted or Lewis acid, with the catalyst proposed to form a σ-complex with the carbonyl group and/or a π-complex with the alkyne [68]. 3.7 Hydroarylation The construction

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• Following the seminal work of Feringa in 1997 [21], the tandem asymmetric organozinc conjugate addition followed by subsequent aldol reaction was scarcely applied in the last decade. Welker and Woodward studied the reaction of zinc enolates 2 with chiral acetals 3 (Scheme 2) [22]. The Lewis acid (TiCl4 or

• the transient iminium species 68 to afford the corresponding aminomethylation products 69 (Scheme 18) [50]. As seen from Table 2, the diastereoselectivities were somewhat compromised compared to what one can expect from the reactions of cyclic enolates. This erosion was likely caused by Lewis acid

• developed a Lewis acid-promoted conjugate addition to unreactive Michael acceptors such as amides or vinyl heterocycles [60]. Trimethylsilyl triflate or boron trifluoride-activated unsaturated amides underwent highly efficient and enantioselective addition of Grignard reagents. When this methodology was