Me₃Al-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines

• Krishna M. S. Adusumalli,
• Lakshmi N. S. Konidena,
• Hima B. Gandham,
• Krishnaiah Kumari,
• Krishna R. Valluru,
• Satya K. R. Nidasanametla,
• Venkateswara R. Battula and
• Hari K. Namballa

Beilstein J. Org. Chem. 2021, 17, 2765–2772, doi:10.3762/bjoc.17.186

• (Table 1, entry 4). Moreover, TMS-OTf was also found to be not much effective as MeAl3 leading to generation of the desired product in comparably lesser yields than Me3Al (Table 1, entry 5). After identifying the suitable Lewis acid for this transformation, we next moved to optimize other reaction

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• ) catalyst to obtain nucleoside derivative 79a, followed by deprotection using methanolic ammonia (Scheme 27). Cousins et al. [49] carried out the coupling of enantiomerically enriched oxathiolane propionate 44 with silylated cytosine in the presence of the Lewis acid trimethylsilyl iodide (TMSI), which gave

• . [40] described coupling of crude 1,3-oxathiolane precursor 20 with silylated acetylcytosine utilizing TMSOTf as a Lewis acid, which gave a mixture of α- and β-anomers (1:2 ratio) of 81 (Scheme 30). The mixture of anomers was further separated by silica gel column chromatography. (+)-BCH-189 (1a) and

• -glycosylation of the enantiomerically pure 5-acetoxyoxathiolane 35a with presilylated cytosine as the key convergent step. This N-glycosylation reaction required the Lewis acid TMSI in a significant quantity to produce the desired cytidine 1 (Scheme 37). As shown in a plausible mechanism in Scheme 37, it is

AlBr₃-Promoted stereoselective anti-hydroarylation of the acetylene bond in 3-arylpropynenitriles by electron-rich arenes: synthesis of 3,3-diarylpropenenitriles

• Yelizaveta Gorbunova,
• Dmitry S. Ryabukhin and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2663–2667, doi:10.3762/bjoc.17.180

• ]. Recently, we have shown that reactions of 3-arylpropenenitriles (cinnamonitriles, ArCH=CHCN) with arenes (Ar′H) under the superelectrophilic activation by the Brønsted superacid CF3SO3H (TfOH, triflic acid) or the strong Lewis acid AlBr3 result in the formation of 3,3-diarylpropanenitriles (Ar(Ar′)CHCH2CN

• 2m correspondingly were obtained; other regioisomers were not isolated in amounts that were high enough for their identification. This transformation was also tested with another strong Lewis acid, aluminum chloride (AlCl3), for the reaction of nitrile 1a with benzene. However, in this case, mainly

Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates

• Tomáš Chvojka,
• Athanasios Markos,
• Svatava Voltrová,
• Radek Pohl and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 2657–2662, doi:10.3762/bjoc.17.179

• isomerization of N-allyl amides [20], but still possess drawbacks, especially for stereoselective synthesis of tri- and tetrasubstituted enamides. Recently, we have reported a triflic acid-mediated reaction of N-fluoroalkyl-1,2,3-triazoles leading to (Z)-β-enamido triflates [21] and Lewis acid-mediated reaction

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• noticeably, while the yield was preserved. Ketone 3 and enone 4 were used for the optimization of reaction conditions. Firstly, the ketone 3 was reacted with hydrazoic acid in the presence of boron trifluoride etherate as a Lewis acid (Table 1, entry 1). The desired tetrazole 13 was obtained after

• trifluoromethanesulfonate (TMSOTf) is superior to BF3⋅OEt2 as a catalyst in both dichloromethane (DCM) and acetonitrile (ACN), while ACN appears to be the better choice as solvent. A particularly good yield was obtained with TMSOTf in ACN. Also, it is evident that an increase in the amount of TMSN3 and Lewis acid did not

• provide any significant change in yield. Myers and co-workers described BF2OTf⋅OEt2 as a powerful Lewis acid formed in situ from BF3⋅OEt2 and TMSOTf, which was especially efficient in ACN [45]. This prompted us to investigate the application of BF2OTf⋅OEt2 in our synthesis (Table 1, entries 9–11). As we

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• silyl ethers. Ooi et al. utilized an axially chiral organoaluminum Lewis acid catalyst (18) to convert a series of α,α-dialkyl-α-siloxyaldehydes 16 to α-siloxyketones 17 in high yields and >74% ee (Figure 5) [7]. This reaction is noteworthy for its tolerance of silyl protecting groups, which are

• base or Lewis acid, the possibility exists to couple the rearrangement to other compatible reactions without any intervention. Such tandem reactions are attractive synthetic “tricks” that can allow for complex modifications with efficiency and often high selectivity. This short section introduces this

• catalyzed by Al(III) or Sc(III) liganded by 11. Ligand 11: for 9, m = 1 and Ar = 2,6-iPr2C6H3; for 12, m = 1 and Ar = 2,6-Me2C6H3; and for 14, m = 0 and Ar = 2,4,6-iPr3C6H2. Asymmetric rearrangement of α,α-dialkyl-α-siloxyaldehydes 16 to α-siloxyketones 17 catalyzed by chiral organoaluminum Lewis acid 18

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• functionalized pyridines and pyrroles. Review Synthesis of pyridines via tandem annulation of 1,3-enynes In 2015, Reddy and co-workers reported the synthesis of substituted pyridines via Lewis acid-mediated aza-annulation of 2-en-4-ynyl azides 1 (Scheme 1) [49]. They discovered that Ag-mediated intramolecular

• standard conditions. The proposed catalytic cycle included aza-Michael addition of arylamines, Lewis acid copper(II)-catalyzed intramolecular 5-endo-dig cyclization, protonation, and oxidation to provide the final products, tetrasubstituted pyrroles 39. The introduction of a trifluoromethyl group into

• electrophiles or Lewis acid catalysts to form pyridines and pyrroles. Series of iodinated, aminated, selenylated, sulfenylated, esterified, and hydroxylated pyridine derivatives have been prepared based on 1,3-enynes. In addition, we also reviewed the tandem cyclization of 1,3-enynes to realize various

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• prospective possibility to obtain ent-21 from precursor 20 by utilizing an antipode ligand in a Noyori reduction. As the continuation, intermediate 40 was coupled with (E)-p-methoxycinnamic acid (17) under Steglich conditions and treated with a Lewis acid to remove the MOM protection giving ester 41

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• (Table 1, entry 15). Prolonging the reaction time to 8 h did not improve the yield (Table 1, entry 15), whereas shortening the reaction time to 5 h reduced the yield (Table 1, entry 16), and thus revealing 6 h to be best reaction time. Finally, the effect of Lewis acid catalysts, such as ZnCl2, FeCl3

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• existence of two competing Brønsted acid and Lewis acid mechanistic pathways leading to the same product with high enantioselectivity was then uncovered. Jacobsen et al. reasoned that the key for this highly selective transformation lies in attractive cation–π and cation–dipole secondary interactions

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• catalysts (Scheme 11) [63]. Here, the use of a zinc-based Lewis acid (LA) was found to activate α-hydroxy C‒H bonds by forming alkoxide (O‒LA) and suppressing the C‒O bond formation by inhibiting the formation of a nickel alkoxide species. The authors also claimed that the use of the zinc-based LA also

Transition-metal-free intramolecular Friedel–Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives

• Tülay Yıldız,
• İrem Baştaş and
• Hatice Başpınar Küçük

Beilstein J. Org. Chem. 2021, 17, 2203–2208, doi:10.3762/bjoc.17.142

• intramolecular coupling of arynes by aldehydes or phenols [21][22][23][24], and Lewis acid-catalyzed cyclization of salicylaldehydes and cyclohexenones or tetralones [25]. Some other new and prominent synthesis methods of xanthenes are the tandem arylation/Friedel–Crafts reaction of o-hydroxy bisbenzylic

• method using π-activated alcohols has frequently been used for xanthene synthesis. Some of these methods are the stereoselective synthesis of 9-vinyl-substituted unsymmetrical xanthenes and thioxanthenes by intramolecular FCA reaction [39], Lewis acid-catalyzed intramolecular FCA [40], and the synthesis

Facile and innovative catalytic protocol for intramolecular Friedel–Crafts cyclization of Morita–Baylis–Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF₃·OEt₂ catalysis

• Karthikeyan Soundararajan,
• Helen Ratna Monica Jeyarajan,
• Raju Subimol Kamarajapurathu and
• Karthik Krishna Kumar Ayyanoth

Beilstein J. Org. Chem. 2021, 17, 2186–2193, doi:10.3762/bjoc.17.140

• -carboxylates [9], indenes [10][11][12][13] and indanones [14]. However, most of the reported Friedel–Crafts reactions utilize either strong Lewis acid catalysts or severe reaction conditions resulting in low yield, unwanted byproducts and tedious workup methodologies [15][16]. Therefore, developing an

• convinced us to explore them as suitable chiral Lewis acid catalysts for the Friedel–Crafts cyclization of MBH adducts. Mononuclear(salen) complexes of aluminium, chromium, manganese and cobalt were chosen and screened for the current investigation. Results and Discussion To evaluate the scope of the

• co-catalyst. Though all metal–salen complexes catalysed the reaction (Table 1, entries 1–4), but the [Cr(III)salenCl]/BF3·OEt2 combination promoted the cyclization effectively (45%, Table 1, entry 4). Regardless of Lewis acid character, BF3·OEt2 provides a number of undesired byproducts in absence of

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• synthesized the similar compound 40, using a catalytic Lewis acid Zn(NTf2)2 and stoichiometric Lewis base γ-picoline combination in n-butyronitrile as solvent (Scheme 7c) [61]. This electron-donating solvent and toluene in the former reaction acted as stabilizers to the electron-deficient silicon species in

• the similar mechanisms. First, the Brønsted or Lewis acid coordinates with silane 51 leading to a solvent-stabilized electron-deficient silane complex 57, where N-protected indole attacks in a Friedel–Crafts fashion to give the 3-silylindoles 60 along with molecular hydrogen (Scheme 7b and Scheme 7d

• ). A repetition of the processes leads to the bis(indol-3-yl)silanes 40. Han described a Lewis acid-promoted C3-silylation of N-protected substituted indoles by a disproportionation mechanism of the latter. He used both B(C6F5)3 and Al(C6F5)3 in the reactions (Scheme 8a and Scheme 8c) which followed a

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• efficiently cyclized [42]. Friedel–Crafts alkylation of arenes with aromatic aldehydes The Lewis acid-catalyzed Friedel–Crafts alkylation of electron-rich arenes with aromatic aldehydes has proven an efficient and often direct method to prepare anthracene derivatives. Kodomari and co-workers disclosed a

• intramolecular cyclization until 2012 [52]. Mohanakrishnan’s group has contributed with numerous methodologies for the synthesis of anthracene derivatives, mainly methodologies involving Lewis acid-mediated intramolecular cyclizations. For example, in 2012 they reported an annulation protocol to synthesize

• ortho-acetal diarylmethanols. Lewis acid-mediated regioselective cyclization of asymmetric diarylmethine dipivalates and diarylmethine diols. BF3·OEt2/CF3SO3H-mediated cyclodehydration reactions of 2-(arylmethyl)benzaldehydes and 2-(arylmethyl)benzoic acids. Synthesis of 2,3,6,7

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

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