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

• providing evidence for the involvement of radical species and a few suggesting non-radical pathways in the presence of a Lewis acid or oligovanadate complexes in solution [77][82][83][84][85][86][87][88][89][90]. Because most of the reactions are not likely to occur through either a direct metal-mediated C

• /hemiacetal avoiding undesirable elimination to the enamine, or attack at other electrophilic sites in complex substrates. The presence of a fluorine source like diethylaminosulfur trifluoride (DAST) or the Lewis acid boron trifluoride diethyl etherate (BF3·OEt2) result in the formation of reactive iminium or

•  19D). In carbocyclic substrates the displacement of a C–F bond or ionization with a Lewis acid is difficult, but mesylates are stable and suitable for AlMe3 activation. As already mentioned, indoles are an important class of molecules with potential antidiabetic properties since they can act as GPR40

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• pyridine derivative with a Lewis acid, forming complex 5-6, and then the fluorination with F2/N2 was carried out. In total, sixty-two stable N-fluoropyridinium salts possessing different non-nucleophilic counteranions and electron-withdrawing or -donating groups were efficiently synthesized [33]. Figure 2

• ’-Difluorobipyridinium salts In 1998, the Umemoto group reported a new series of N,N’-difluorobipyridinium salts 24-2, N,N’-difluoro-2,2’-, -2,4’-, -3,3’-, and -4,4’-bipyridinium salts. These were synthesized by the direct fluorination of bipyridines 24-1 with 10–20% F2/N2 in the presence of a Lewis acid, a Brønsted

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• external Lewis acid and trimethylaluminum as a methyl source (Scheme 7) [61]. The late-stage methylation of simple heterocyclic motifs was initially investigated using (S,S)-Mn(CF3–PDP) (21), providing methylated lactams 22a–e. Notably, methylation site selectivity was observed for the carbon atoms

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

• suggested that iridium serves as a π-Lewis acid (although one could propose a C–H activation pathway) that activates the olefin by coordination due to the correlation observed between the nature of the Ir counterion and the reaction yields. Radical-based approaches Olefin hydroalkylation via metal hydride

• ) [121]. Notably, the organic photocatalyst eosin Y was employed, and the cyclizations proceeded with excellent diastereoselectivity, usually higher than 19:1. When 1,3-ketocarbonyl substrates 100 were employed, the use of a weak Lewis acid (LiBr) was required to accomplish the cyclizations, and no

• reaction was observed in its absence. The authors highlighted the role of the solvent hexafluoro-2-propanol (HFIP) in the stabilization of the radical cation induced by PET and its assistance in the hydrogen shift process. Miscellaneous Lewis acid catalysis in olefin hydroalkylation reactions The ability

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• develop a novel Prins/Friedel–Crafts cyclization strategy for the synthesis of 4-aryl-2-hydroxytetralins starting from 2-(2-vinylphenyl)acetaldehydes (Scheme 2). In this protocol, we envisioned that the aldehyde 5 would give rise to an oxocarbenium ion species 6 upon treatment with a Lewis acid. The

• vinyl aldehydes 13, next the cascade Prins/Friedel–Crafts reaction was examined. We started our investigations by applying aldehyde 13a as the model substrate (Scheme 5). A Lewis acid screening was carried out to identify the best catalyst for the tandem intramolecular Prins/Friedel–Crafts reaction

• to the formation of the expected 4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (14aa), 51:49 mixture of cis/trans-diastereomers) as a colorless oil in 50% yield (Table 1, entry 1). The use of Et2AlCl as the Lewis acid gave tetralin 14aa in a slightly improved 55% yield (Table 1, entry 2

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• , 47, and 56%, respectively. Nevertheless, it was not possible to further increase the yield of the product using this solvent. For subsequent attempts, we investigated the reaction using different Lewis acid catalysts, including AlCl3 (Table 1, entry 9, 10% yield), FeCl3 (entry 10, 17%), I2 (entry 11

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson–Kaas, Van Leusen and Ullmann-type reactions as key tools

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2021, 17, 1374–1384, doi:10.3762/bjoc.17.96

• bisoxazole truxene derivative 21 by virtue of Van Leusen reaction as a key step (Scheme 6). To this context, we first treated the hexabutylated derivative 2 with 1,1-dichlorodimethyl ether acting as a formyl source in the presence of Lewis acid such as titanium tetrachloride (TiCl4) in Rieche manner to yield

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• ) [105]. Li and Xu reported a method for the enantioselective synthesis of β,γ-unsaturated α-amino acids 100, by a Lewis acid-promoted diastereoselective Petasis reaction of vinylboronic acids 98, (R)-N-tert-butanesulfinamide and glyoxylic acid (99). They found that the best results were obtained working

• with InBr3 as Lewis acid, in dichloromethane at room temperature [106]. Under these reaction conditions, sulfinyl imine is formed first along with the boronate by interaction of the corresponding vinylboronic acid with the carboxylic group of the imino acid intermediate. The transfer of the vinyl unit

• to the electrophilic iminic carbon took place in a quite rigid system, with chelation of the Lewis acid with the nitrogen of the imine and carboxylate oxygen, forming a five-membered ring. The migration of the vinyl group occurred to the Re face of the imine, which is less shielded than the Si face

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• benzoxazoles might be explained by the subsequent hydrolysis of this relatively fragile ring under the strongly acidic aqueous conditions. Recently, a protocol using a Lewis acid (AlCl3) as an activating agent of the cyanoguanidine in dry THF allowed improving the yields up to 70% (Scheme 11B) [32]. Related

• 90% yield. A Lewis acid-promoted cyclization (boron trifluoride etherate at 60 °C) avoided the use of high temperatures, while providing the products in comfortable yields. Dicyanamide has also been shown to react with hydroxylamine hydrochloride to form [1,2,4]oxadiazole-3,5-diamine (Scheme 29A) [49

• substituted cyanoguanidine as the intermediate. Practically, very little improvement was made over synthetic procedures reported 50 years ago. To the best of our knowledge modern activations such as Lewis acid-promoted additions, catalysis or microwave irradiation have never been tried for this reaction

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• products 4b–f was available in low yields (16–26%) by the Chan–Evans–Lam coupling of berberrubine (1b, Scheme 1). The formation of the 10-O-arylated products may be explained by an initial Lewis acid-catalyzed demethylation of berberrubine (1b) [38] to derivative 6 (Scheme 2) that reacts subsequently in

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• , Riga, LV-1006, Latvia Department of Chemistry, University of Latvia, Jelgavas str. 1, Riga, LV-1004, Latvia 10.3762/bjoc.17.78 Abstract Liquid SO2 is a polar solvent that dissolves both covalent and ionic compounds. Sulfur dioxide possesses also Lewis acid properties, including the ability to

• equilibrium. Keywords: fluorosulfite; glycosyl fluoride; Lewis acid; liquid sulfur dioxide; metal-free glycosylation; Introduction The glycosylation reaction is still one of the most important and basic synthetic strategies in carbohydrate chemistry that provides access to the various types of

• conventional solvents are: (1) it is aprotic solvent with Lewis acid properties; (2) it dissolves both covalent and ionic compounds [39]; (3) it has good price–quality ratio: ≤5 EUR/kg for the high-purity product (99.98%, H2O content ≤50 ppm); (4) it can be easily recycled by changing temperature and/or

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• Lewis acid, which furnished the expected tetrahydropyran 23 as a single diastereomer via an oxocarbenium intermediate 21 (Scheme 5) [29][30]. The reaction was dependent from the nature of the aromatic ring, which plays a crucial role in the product formation. Homoallylic alcohols with an electron-rich

• ][33]. The racemization occurs during allyl transfer as a result of 2-oxonia-Cope rearrangement through a 3,3-sigmatropic shift, which plays a crucial role during the reaction, as shown in Scheme 7. The Prins cyclization between alcohol (R)-35 and aldehyde 36 was investigated under different Lewis acid

• a 2-oxonia-Cope-mediated side-chain exchange reaction and is entirely consistent with Willis and co-workers’ result [29], which leads to the partial racemization observed in the desired product formation. Another Lewis acid, SnBr4, was found to be more efficient than BF3·OEt2/HOAc in terms of

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• between benzimidazole-linked aminopyridine and Lewis acid activated aldehyde which further on nucleophilic addition with substituted isocyanide leads to intermediate B. A 5-exo-dig intramolecular cyclization with isocyanide aids in the formation of the imidazo[1,2-a]pyridine intermediate C. The final

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• γ-lactam scaffold [40][41][42][43][44]. The pyrrolidinone fragment is often synthesized by transition metal- [45][46][47][48][49][50] or Lewis acid-catalyzed cyclization reactions [51][52][53][54]. The Diels–Alder reaction can also be used for the preparation of functionalized γ-lactams in a single

Synthesis, structural characterization, and optical properties of benzo[f]naphtho[2,3-b]phosphoindoles

• Mio Matsumura,
• Takahiro Teramoto,
• Masato Kawakubo,
• Masatoshi Kawahata,
• Yuki Murata,
• Kentaro Yamaguchi,
• Masanobu Uchiyama and
• Shuji Yasuike

Beilstein J. Org. Chem. 2021, 17, 671–677, doi:10.3762/bjoc.17.56

• phosphorus center can be easily chemically modified and converted to phosphole derivatives with different electronic properties by reactions such as oxidation, alkylation, and coordination to a Lewis acid [1][2][3][4][5][6][7][8]. Theoretically, pentacyclic benzonaphthophosphindole contains six structural

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

• supported metal species (Ru, Ir), due to the ability to activate molecular hydrogen, functioning as redox centres. The mechanisms of the metal-catalysed solvolytic reactions of plastics are all very similar and typical of conventional organic processes: a metal ion acts as Lewis acid centre for the

• weight ratio of 35 was required. The catalyst could be reused, showing significant activity decrease starting from the fourth cycle due to biochar formation. A mechanism was hypothesised in which Zn2+ ions act as a Lewis acid activator for the carbonyl ester bond. In a previous work, complete

• which Zn ions act as Lewis acid activators for the C=O ester bonds toward nucleophilic attack by EG. In addition to soluble catalysts, metal-containing insoluble materials, namely solid acid catalysts, were developed for the glycolytic depolymerisation of PET by EG. Representative data are summarised in

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• also confirmed by DFT calculations at the B3LYP/6-31G* level, with a C2–C3 bond considerably shorter than the C1–C2 bond, with dC2–C3 = 1.359 Å and dC1–C2 = 1.427 Å. More recently, Vasilyev et al. reported that Lewis acid activation of α-(trifluoromethyl)allyl alcohol 101 allowed the transient

• a longer reaction time, allenes 127 undergo a subsequent intramolecular hydroarylation reaction leading to indenes 128. The authors suggested the formation of FeCl3–HFIP complexes being involved in a Lewis acid-assisted Brønsted acid catalysis. The CF3-substituted propargyl alcohol 129 was found to

• ↔142’ (Scheme 35). Oxygen-stabilized α-(trifluoromethyl)carbenium ions (oxocarbenium ions) have been exploited for chemical synthesis [92][93][94]. Ketone 143a and ketoxime 143b undergo Friedel–Crafts reactions in the presence of Brønsted or Lewis acid to furnish the corresponding CF3-containing

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• imines 115, which led to alkylideneazetidines 116 (Scheme 52) [102]. The MgI2 acted as a Lewis acid and reducing agent, effecting the distal C–C bond cleavage in 113a to form an allenyl ketone, or an equivalent fluoro,iodo-enone species, either of which could then have added to the imine 115 and led to

• O–H and N–H bonds of water, alcohols, carboxylic acids, and amines to form the observed products 121. 1,1-Difluoro-2-siloxy-2-vinylcyclopropane (122) was subjected to a fluoride-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones such as 123. These compounds underwent a Lewis acid-catalyzed

• , Br, Scheme 63) [114]. In this transformation, BX3 played a dual role as both a Lewis acid catalyst and a source of the halide ion nucleophile. This reaction resulted in the generation of the trifluoromethyl ketones 145 and halodifluoromethyl ketones 146 and 147 in high yields. As in the previous

Total synthesis of decarboxyaltenusin

• Lucas Warmuth,
• Aaron Weiß,
• Marco Reinhardt,
• Anna Meschkov,
• Ute Schepers and
• Joachim Podlech

Beilstein J. Org. Chem. 2021, 17, 224–228, doi:10.3762/bjoc.17.22

• Lewis acid, while the utilization of 1.5 equivalents led to a significant overreaction with the predominant formation of 5-bromobenzene-1,3-diol (59%) together with a smaller amount of the required product 8 (30%). The subsequent protection with the TBS group yielded the known aryl bromide 9a [24] with

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• , even at an elevated temperature. Path A with a barrier of 22.6 kcal·mol−1 is certainly more feasible. We assume that the Cp2Zr(OH)Cl species just leaves the initial complex, as this seems to be the simplest possibility in absence of any Lewis acid which could catalyze this decomposition. Scheme 9 shows

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• piperidine derivatives 1 because of the accelerating effect of the nitrogen atom that stabilizes the oxyallyl cation intermediate 4 formed upon the ring closure. This was in analogy to that found for the classical Brønsted or Lewis acid-catalyzed Nazarov reaction involving N-heterocycles [27][28][29][30][31

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• product 145 in 76% yield. The hexacyclic compound 145 was converted to kopsanone (19) in three steps. Miscellaneous In 2012, Wang and co-workers reported a Lewis acid-catalyzed intramolecular [3 + 2] cross-cycloaddition (IMCC) of cyclopropane 1,1-diesters with non-activated alkene to generate bridged [n

• mechanism. (C) The completion of total synthesis of kopsanone (19). (A) Synthesis of phyllocladanol (21) features a Lewis acid-catalyzed formal intramolecular [3 + 2] cross-cycloaddition of cyclopropane 1,1-diesters with alkenes [68]. (B) (5,6-Dihydro-1,4-dithiin-2-yl)methanol 151 used as a versatile allyl

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• -bromoacetaldehyde acetal by using aluminum(III) chloride as a Lewis acid catalyst through [1 + 2 + 2] annulation. This new versatile methodology provides a wide scope for the synthesis of different functional N-(hetero)aryl-4,5-unsubstituted pyrrole scaffolds, which can be further derived to access multisubstituted

• under the conditions; the obtained results are listed in Table 1. The mixture was heated in 1,4-dioxane at 80 °C. No reaction occurred in the absence of the catalyst (Table 1, entry 1); however, in the presence of the strong Lewis acid Bi(OTf)3, the expected product 4a was obtained in 36% yield after 6

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• that the Lewis acid-catalyzed reaction of diaziridines with donor–acceptor cyclopropanes and aziridines affords the perhydropyridazine or triazine derivatives, respectively, in good yields [31][32][33]. The use of microwave irradiation in organic synthesis complies with the principles of green