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

• reaction between aldehydes with indoles, while focusing on the more environmentally friendly methods developed over the years. Keywords: aldehyde; BIMs; Friedel–Crafts reaction; green chemistry; indole; Review Medicinal properties In recent years, diindolylmethane (DIM, 1) and its derivatives known as

• associated with low catalyst loading, extremely high efficiency and broad substrate scope and the possibility of use of both organic solvents or water, with the drawback however, of the employment of conventional heating [92]. In 2019, Toy et al. proposed an alternative approach for the Friedel–Crafts

• with one another. With the new avenues offered by the advent of nanocatalysis, it did not take long for its application in the Friedel–Crafts arylation of indoles with aldehydes, since the development of more resource-efficient catalytic pathways for the synthesis of BIMs had received great interest

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

• benzyl moiety on the substrate resulted in tandem Friedel–Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel

• –Crafts reactions, rather than an oxocarbenium. Keywords: 1-aryltetralines; Friedel–Crafts reaction; Hock rearrangement; oxidative cleavage; tandem reactions; Introduction The Hock cleavage [1] consists in the acid-catalyzed rearrangement of organic hydroperoxides, leading to the oxidative cleavage of a

• ), successively involving a Schenck-ene photooxygenation of an alkene A, an acid-catalyzed Hock cleavage of hydroperoxide B generating an aldehyde derivative C, and an acid-catalyzed Friedel–Crafts reaction in the presence of an aromatic nucleophile leading to D [17]. In principle, a second Friedel–Crafts

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles

• Chuan Yang,
• Wei Shi,
• Jian Tian,
• Lin Guo,
• Yating Zhao and
• Wujiong Xia

Beilstein J. Org. Chem. 2024, 20, 118–124, doi:10.3762/bjoc.20.12

• ], Friedel–Crafts acylation [12], radical cascade reactions [2][13], and photoinduced radical cyclizations [14][15][16][17]. However, these methods often suffer from drawbacks such as harsh reaction conditions and the requirement of transition-metal catalysts. Although photocatalyzed cyclization reactions

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

• catalyst. The authors demonstrated that the introduction of the two indoles occurs in two distinct steps, a radical process and a Friedel–Crafts alkylation reaction. Coumarin and flavonoid derivatives are very valuable precursors in drug synthesis. In 2015, Ge et al. developed the regioselective and atom

Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet–Spengler reaction

• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2023, 19, 991–997, doi:10.3762/bjoc.19.74

• the use of 3-substituted furans. For example, the intramolecular Friedel–Crafts alkylation reaction (Scheme 1a) of alcohols [9][10][11], alkenes [12] or acetylenes [13] affords the desired tetrahydrofuro[3,2-c]pyridines. A related method is based on a Au(I)-catalyzed domino sequence dearomatization

• /ipso-cyclization/Michael-type Friedel–Crafts alkylation (Scheme 1b) [14][15][16]. Unfortunately, approaches including the intramolecular alkylation of 3-substituted furans are underinvestigated as these substrates are usually hard to reach and the resulting benzyl carbocation is often prone to undergo

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

• Anup Biswas Department of Chemistry, Hooghly Women’s College, Vivekananda Road, Pipulpati, Hooghly - 712103, WB, India 10.3762/bjoc.19.72 Abstract The aza-Friedel–Crafts reaction allows an efficient coupling of electron-rich aromatic systems with imines for the facile incorporation of aminoalkyl

• groups into the aromatic ring. This reaction has a great scope of forming aza-stereocenters which can be tuned by different asymmetric catalysts. This review assembles recent advances in asymmetric aza-Friedel–Crafts reactions mediated by organocatalysts. The mechanistic interpretation with the origin of

• stereoselectivity is also explained. Keywords: asymmetric; aza-Friedel–Crafts reaction; H-bonding; organocatalysis; stereoselectivity; Introduction The ease of a chemical transformation depends on the thermodynamic instability of a chemical bond owing to its fast cleavage under mild reaction conditions. A C–H

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

• . In addition, the lone pair electrons of the nitrogen atom interact with Lewis acids instead of the π-electrons of the ring system thus resulting to its reduced reactivity for electrophilic aromatic substitution reactions, such as a Friedel–Crafts reaction [21][22][23]. Hence, it is challenging to

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• their unique stability, defined reactivity, and versatility in organic synthesis [2]. Leveraging their electron-deficient nature, N-arylsulfonylimines are widely used in organic transformations including nucleophilic addition, cycloaddition, imino-aldol reaction, ene reactions, aza-Friedel–Crafts

Friedel–Crafts acylation of benzene derivatives in tunable aryl alkyl ionic liquids (TAAILs)

• Swantje Lerch,
• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2023, 19, 212–216, doi:10.3762/bjoc.19.20

• Swantje Lerch Stefan Fritsch Thomas Strassner Professur für Physikalische Organische Chemie, Technische Universität Dresden, 01062 Dresden, Germany 10.3762/bjoc.19.20 Abstract An iron(III) chloride hexahydrate-catalyzed Friedel–Crafts acylation of benzene derivatives in tunable aryl alkyl ionic

• liquids (TAAILs) has been developed. Through optimization of the metal salt, reaction conditions and ionic liquids, we were able to design a robust catalyst system that tolerates different electron-rich substrates under ambient atmosphere and allows for a multigram scale. Keywords: Friedel–Crafts

• acylation; homogeneous catalysis; ionic liquids; iron catalysis; TAAILs; Introduction The Friedel–Crafts acylation is one of the oldest metal-catalyzed reactions in organic chemistry [1] and allows for the synthesis of a broad range of diverse compounds [2][3][4][5]. Starting from electron-rich aromatic

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• reactions, as pseudo-heteroarylzinc reagents. Another example developed by Knochel uses the zincated 1,4-dithiin 22 as a nucleophile to add across the N–O bond in anthranil [44], which spontaneously cyclizes to a heterocycle-fused quinoline via a Friedel–Crafts-type pathway onto the released aldehyde moiety

• dependence [95]. On the other hand, simple benzyl cations can undergo more controlled (3 + 2) annulations, as is illustrated by the long-known Friedel–Crafts-type acid-catalyzed cascade reaction of styrene leading to the cyclic styrene dimer 86 (Scheme 13c) [96][97]. This (3 + 2) cycloaddition reactivity of

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• Friedel–Crafts alkylation followed by an anodic oxidative cyclization yielded a defined set of cyclic iodonium salts in a highly substrate-dependent yield. Keywords: electrochemistry; flow chemistry; hypervalent compounds; iodine; oxidation; Introduction Hypervalent iodine compounds (HVI) are well

• , we improved the formation of iodoarenes through a Brønsted acid-mediated Friedel–Crafts reaction followed by an oxidative cyclization to form the desired CDIS 1 (Scheme 1A). This one-pot approach is based on ortho-iodinated benzyl alcohols as starting materials. It allows access to a variety of

• the Friedel–Crafts reaction via GC analysis. Both steps in series resulted in successful product formation with an albeit slightly diminished yield of 49% (Table 3, entry 3). We increased the yield to 54% by introducing an electrolyte (Table 3, entry 2). A further current increase had no beneficial

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• to synthesize more than 4 g of the natural product (+)-yahazunol (61). (+)-Yahazunol (61) can be readily transformed to several members of meroterpenoids of the class, either by Friedel−Crafts reactions or common oxidative manipulations. Total synthesis of dysideanone B (75) and dysiherbol A (79) (Lu

• aromatic common intermediate 9 (Scheme 10). Despite the simplicity, the most obvious disconnections, such as an anionic enone conjugated addition and a direct cationic Friedel–Crafts reaction failed. Highlighting the power of radical disconnection, the group thought of utilizing a β-keto carbon-centered

• radical to circumvent the unsuccessful Friedel–Crafts reaction. Prior reports implicated β-keto radical formation in the ring opening of siloxycyclopropanes with photoinduced electron transfer (PET) to 1,4-dicyanonaphthalene [65]. Inspired by reports on dual photoredox and Ni-catalytic cross-coupling

Ionic multiresonant thermally activated delayed fluorescence emitters for light emitting electrochemical cells

• Merve Karaman,
• Abhishek Kumar Gupta,
• Subeesh Madayanad Suresh,
• Tomas Matulaitis,
• Lorenzo Mardegan,
• Daniel Tordera,
• Henk J. Bolink,
• Sen Wu,
• Stuart Warriner,
• Ifor D. Samuel and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2022, 18, 1311–1321, doi:10.3762/bjoc.18.136

• 23% overall yield. First, hydrolysis of 1, in situ conversion to the acyl chloride and subsequent Lewis acid-promoted Friedel–Crafts acylation reaction produced compound 2 (Scheme 1), where the AlCl3 was also responsible for the demethylation. Compound 2 was then subjected to monoalkylation with 1,4

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• cycloisomerization of the α-ketoester 22, which can be described as a Friedel–Crafts-type reaction or an aldol reaction of an S,O-ketene acetal (Scheme 4). The required ketoester 22 was synthesized from sulfonylchromenone 20, accessible from dihydroxyacetophenone 19 and thiol 18 derived from known alcohol 17 [11][12

• precursor for an intramolecular Friedel–Crafts cyclization (Scheme 9) [24]. Therefore, phenylacetaldehyde 52 was converted to the alcohol 53, which was esterified with the α-ketoacid 54 to give ketoester 55. Grignard addition to the keto carbonyl and subsequent TBS deprotection delivered the tertiary

• alcohol 56, which was dehydroxylated to the diastereomeric cations VIII and IX. Friedel–Crafts reaction gave diastereomeric lactones 57 and 58. The major diastereomer 58 could be converted to the complex polyphenol (−)-hopeanol (59) in seven further steps. (+)-Camptothecin In the formal synthesis of the

Electrochemical Friedel–Crafts-type amidomethylation of arenes by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborate

• Hisanori Senboku,
• Mizuki Hayama and
• Hidetoshi Matsuno

Beilstein J. Org. Chem. 2022, 18, 1040–1046, doi:10.3762/bjoc.18.105

• , Hokkaido 060-8628, Japan 10.3762/bjoc.18.105 Abstract Electrochemical Friedel–Crafts-type amidomethylation was successfully carried out by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborates, such as iPr2NHEtBF4. Constant current electrolysis of

• amidomethylated products in good to high yields. Keywords: electrochemical oxidation; Friedel–Crafts type amidomethylation; N-acyliminium ion; quasi-divided cell; trialkylammonium salt; Introduction Oxidation of amides generates useful intermediates, N-acyliminium ions, which have been widely used in organic

• synthesis [1][2][3][4]. For example, Friedel–Crafts-type amidomethylation [5][6][7][8][9][10][11][12][13][14][15] proceeds efficiently by the reaction of N-acyliminium ions with electron-rich arenes to give the corresponding amidomethylated products in good yields. Since amides are important intermediates

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• using polyphosphoric acid [16] and sulfuric acid failed [42], therefore we tried Friedel–Crafts acylation. For that, 27 was hydrolysed to the corresponding diacid 28 with lithium hydroxide [15]. In a manner similar to [24], firstly, a ‘cold’ Friedel–Crafts acylation in dichloromethane was attempted, in

• the ring closure proceeded on one side of the molecule. It was assumed that this species precipitated, preventing further reaction. We thus turned to a ‘hot’ Friedel–Crafts acylation, in which the reaction mixture was refluxed after the addition of oxalyl chloride, followed by removal of the volatiles

• . Since the ring-closure with a ‘hot’ Friedel–Crafts acylation [43] led to an insoluble material, we wanted to synthesise a soluble derivative by attaching 4-(2-ethylhexyl)-2-methylthiophene groups. This was done by reacting intermediate 27 with compound 32, which was prepared as shown in Scheme 3. In a

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• -phenylphosphinamide (92a) and chloromethyl N,N’-dimethyl-N,N’-diphenylphosphondiamide (92b) via an intramolecular Friedel–Crafts alkylation. Although they tried several different amide derivatives, only phosphinamide 92a and phosphonic diamide 92b gave the corresponding 1-methyl-1,3-dihydrobenzo[d][1,2]azaphosphole 2

• from P-(chloromethyl)amide precursors 92a and 92b through intramolecular Friedel–Crafts alkylation. Synthesis of 2-allylamino-1,5-dihydro-1,2-azaphosphole 2-oxides from N,N’-diallyl-vinylphosphonodiamides. Diastereoselective synthesis of 2-allylamino-1,5-dihydro-1,2-azaphosphole 2-oxides from N,N

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• . On the other hand, the tetrahydrospiro[carbazole-3,5'-pyrimidine] 4 can be converted to aromatized spiro[carbazole-3,5'-pyrimidine] 3 through the oxidation of DDQ. In the absence of the effective dienophile, the normal Friedel–Crafts alkylation of 2-methylindole with aromatic aldehyde gives the well

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• SAC-13, alkylation of m-cresol with isopropanol proceeds via a Friedel–Crafts-type mechanism in much lower selectivity. In contrast, the authors proposed that employing γ-Al2O3 as Lewis acid catalyst, reaction of 39 and isopropanol leads to isopropyl ether 40. This intermediate undergoes a Fries-type

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• catalysts that allow ON/OFF reaction control in photoredox catalysis [120], phosphate diester transesterification [121], Friedel–Crafts reaction, ring opening of epoxides, oligomerization [116], and acyl-transfer reactions [122][123]. While there are further examples by Mirkin [124][125][126], Schmittel

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• [Pd(C3H5)Cl]2 and ligand L1 (Scheme 2) [11]. The reaction, that could also be considered as Friedel–Crafts type, intramolecular allylic alkylation, delivered nine-membered ring bearing 3,4-fused indoles 2 in moderate to good yields. In the asymmetric version of the reaction catalyzed by [Ir(cod)Cl]2

• in their studies on the intramolecular Friedel−Crafts (FC) acylation of 4-substituted indoles [20]. Specifically, N-Ns/Ts-indolyl Meldrum's acid derivatives 28a–f delivered 4,5-fused indoles 29a–f under BF3·OEt2 or Yb(OTf)3 catalysis (Scheme 10A). It should be noted that the authors could not extend

• preference for cyclization onto the C5 position is more dominating than the higher nucleophilicity of the C3 position, making the CAr–C bond formation completely regioselective at the C5 position. Subsequently in 2017, Li and co-workers also applied the intramolecular Friedel–Crafts acylation strategy to get

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• transformations. Organometallics are the most commonly used catalysts to promote C–C bond formation. In addition, other so-called classical reactions are also widely used, such as Friedel–Crafts alkylation and acylation, Wittig and Horner–Emmons reactions, carbonyl addition/substitution, α-alkylation, aldol

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• activated derivatives (intramolecular Friedel–Crafts acylation) [29][30][31] found wide application here. In a different approach, a total synthesis of dengibsin (1a) was accomplished by Wang and Snieckus in 15 steps by means of a directed remote metalation [32], using a benzamide residue as the directing

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• the intramolecular Friedel–Crafts double cyclization reaction and N,N-dibenzylaminoacetaldehyde dialkyl acetals [12][14][15][16] in the Pomeranz–Fritsch-type double cyclization reaction. There is also one example of employing p-quinol acetates as substrates for the synthesis of these compounds [17

• ]. Recently, a methodology for the synthesis of dihydromethanodibenzoazocines based on a combination of Friedel–Crafts and Pictet–Spengler reactions was proposed by Moshkin et al. [18]. We have developed a convenient method for the preparation of C-1-substituted tetrahydroisoquinoline derivatives by using the