Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• to yield the alkylated derivatives 3 (Figure 1b). Indoles play a crucial role in many natural and industrial processes. Therefore, the direct chemical manipulation of the indole system is a matter of paramount importance [24][25][26][27]. Moreover, the sulfonyl group is an extremely versatile

• observed that the addition of DABCO to the solution of 2a induced a bathochromic shift of the absorption spectrum towards the visible region, thus indicating the formation of an EDA complex between these chemical species. Importantly, we also confirmed that indole 1a and 2a do not form a photoactive EDA

• halogen-bonded EDA complex (Ia) between the sulfone 2a and DABCO (Figure 4). When irradiated, this photoactive aggregate led to the formation of reactive alkyl radicals (IIa), which may react with indole 1a eventually yielding the product 3a through a classical HAS pathway [31][32][33]. Then, we

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• (24a–f, 82–87% yields). The substitution of the indole at the C3-position did not impact the reaction and the product 24g was obtained in 91% yield. Substituted pyridines and pyrimidine (24h and 24i) were also used as directing groups (7 examples, up to 86% yield). This methodology was extended to the

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• -coordinated heterocycle 21. Hydride transfer from the BH3-amide 22 to HBpin regenerated the borohydride catalyst 19, and gave a neutral aminoborane 23, which then underwent B‒N/B‒H transborylation with HBpin to give the N‒Bpin dihydropyridine 24 and BH3 (Scheme 6). The mechanism of stoichiometric indole

• reduction with Me2S·BH3 was investigated by Fontaine, and applied to a catalytic variant using HBpin as the turnover reagent (Scheme 7) [70]. Computational analysis showed two plausible, cooperative catalytic cycles: 1) hydroboration of indole 25 with BH3 to give a H2B-N-indoline 26, which then underwent B

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

• equivalent of a simple allyl cation in (3 + 2) cycloadditions. More recently, our group was able to extend the scope of dihydrodithiin-mediated cycloadditions to indole substrates [30]. Indoles are formal styrene analogs, with very different electronic properties and reactivity profiles, and initially gave

• . This protonation effectively prevents any possible side reactions of the dearomatized products with electrophiles. A remarkably wide substrate scope was observed for this dearomative indole cyclopentannulation reaction, as demonstrated by the smooth ring expansion of the natural alkaloid drug yohimbine

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

• reduction steps allowed the total synthesis of GB13 (8), himgaline (126), and GB22 (125) in only one third of the number of steps of prior syntheses (Scheme 10). Concise syntheses of eburnane alkaloids (Qin 2018) [68][69]: Eburnane indole alkaloids comprise a highly diverse class of natural products mainly

• discoveries, namely a photoredox-catalytic nitrogen-centered radical cascade [72], which has resulted in the impressive collective total synthesis of 33 alkaloids of three different classes of indole natural products (please see the inset of Scheme 11 for concise representation). Specifically, this included

• reduction of the amide using Wilkinson’s catalyst provided diastereoisomeric indole 131. Careful manipulation of the nitrile and alcohol side chains allowed selective cyclizations to the nitrogen atom of the indole core to conclude the total syntheses of 132–134. Samarium diiodide-mediated reductive

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• from the indoline to B(C6F5)3. The resultant iminium ion is deprotonated by a second indoline molecule with the formation of an ammonium ion and the final indole. The ammonium ion reacts with a HB(C6F5)3 anion with the release of a H2 molecule and the regeneration of B(C6F5)3 for the next catalytic

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• influence of the substituent position in the CPAs (Figure 3). In the BINOL-derived CPA, the R-substituent and the phosphorus atom are separated by three bonds. In the indole-based CPAs 1 and 2, the distance is reduced to two bonds, whereas in CPA 3 it is three bonds, and in 4 it is just one bond. Both 3 and

• enantioselective catalyst. On the other hand, their successful completions attest to the inexpensive and scalable requirements we had set. Indole scaffolds The synthesis of racemic tryptophol CPA 1 is shown in Scheme 2. Commercially available tryptophol (5, 225 $/mol) was N-arylated into 6 via copper-catalyzed

• prepare chiral thiophosphorus acids have been described [41][42][43]. Once equipped with our new methods [38], the synthesis of indole-derived 2 was undertaken (Scheme 3). Known 3-allylindole (10) [44] was obtained from indole uneventfully. Intermediate 11 was furnished in moderate yield via our palladium

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

• Koert et al. in the racemic synthesis of the bisindole alkaloid (rac)-cladoniamide G (103, Scheme 17) [33]. The synthesis started with benzaldehyde 97 and indole 99 which were converted to the indole building blocks 98 and 100, respectively. These were connected to bisindole 101, which reacted with

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• step using milder conditions (Scheme 3). The newly developed synthesis started from 7 that was Boc-protected at the indole to yield 11. Removal of the benzyl group by catalytic hydrogenation to 12 was followed by coupling with benzyloxycarbonyl (Cbz) and methoxymethyl (MOM)-protected threonine to give

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

• nitrogen atom of 4b to yield N,3-diamidomethylated indole 6 in 4–34% (1H NMR yield), although similar electrolysis with 2 F/mol of electricity gave only 5b in 66% yield with 68% conversion. It is thought that supplying an excess amount of electricity under the conditions of a lower concentration of the

• proton source (supporting electrolyte), iPr2NHEtBF4, caused competitive electrochemical reduction of a proton and the N-benzyl group of 5b at the cathode. We also carried out electrochemical amidomethylation of indole (4c) and found that a mixture of 3-amidomethylated indole 5c and N,3-diamidomethylated

• indole 6 was produced. However, N-amidomethylated indole was not observed in the 1H NMR spectra of the crude products. These results indicate that amidomethylation firstly occurs at the C3 position of 4c and then the second amidomethylation takes place on the indole nitrogen atom of 5c. Despite our

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• family and is associated with a broad spectrum of biological properties. 3-Formyl-9H-pyrido[3,4-b]indole is a such potent precursor belonging to this family which can be tailored for installing diversity at various positions of β-carboline to generate unique molecular hybrids of biological importance

• and substituents was also studied during investigation of fluorescence properties of these derivatives. Keywords: β-carboline; DABCO; fluorescence; MBH reaction; Michael addition; structure–fluorescence activity relationship; Introduction Among the polycyclic alkaloids based on indole, the tricyclic

• -9H-β-carbolines for generating diversity at the β-carboline skeleton as outlined in Figure 3 [51][52][53][54][55][56]. Therefore, we herein report the synthesis of C-3-substituted pyrido[3,4-b]indole MBH adducts from substituted 3-formyl-9H-β-carbolines by the application of the MBH reaction followed

Post-synthesis from Lewis acid–base interaction: an alternative way to generate light and harvest triplet excitons

• Hengjia Liu and
• Guohua Xie

Beilstein J. Org. Chem. 2022, 18, 825–836, doi:10.3762/bjoc.18.83

• with the Lewis acids discussed in this review and thus lead to a significant shift of their optoelectronic properties. It has been confirmed that organic molecules containing pyrimidine, pyrazine, and indole groups display similar interactions upon the addition of Lewis acids [40][41][42]. Lewis acid

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

• dienophiles in refluxing toluene afforded diverse spirotetrahydrocarbazoles. This reaction is an important development of the Levy reaction by using 2-methylindole to replace ethyl indole-2-acetate and successfully provides facile access to important polysubstituted spiro[carbazole-3,3'-indolines], spiro

• [carbazole-2,3'-indolines], spiro[carbazole-3,5'-pyrimidines] and spiro[carbazole-3,1'-cycloalkanes] in satisfactory yields and with high diastereoselectivity. Keywords: Diels–Alder reaction; indole; indolo-2,3-quinodimethane; Levy reaction; tetrahydrocarbazole; spirooxindole; Introduction

• ][48][49][50]. On the other hand, the Diels–Alder reaction of the in situ generated indole-2,3-quinodimethanes with various dienophiles is also a powerful method for rapid construction of functionalized tetrahydrocarbazoles [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. In

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability. Keywords: drug substance; indole synthesis; key intermediate; protecting group; telescoping

• to the hydrazine derivative 4, followed by a Fischer indole synthesis with ethyl 4-oxopiperidine-1-carboxylate (5) provided tetracyclic compound 6. Its reduction with sodium cyanoborohydride in trifluoroacetic acid (TFA) to cis-indoline derivative (±)-7, followed by N-methylation [(±)-8] and

• chiral chromatography. Later, alternate syntheses of lumateperone were described, also by the researchers of the originator company [8][9][10] (Scheme 2). The reaction of (2-bromophenyl)hydrazine (12) with 4-piperidone monohydrate hydrochloride (13) gave pyrido[4,3-b]indole congener 14, which was reduced

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

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• reaction, synthesis of glycosylurea, dihydropyrimidinones, pyrimidopyrimidinediones, and functionalized indole derivatives in this novel and green reaction medium [34][35][36][37][38]. We have also developed an efficient method for the synthesis of trisubstituted hydantoin derivatives from β,γ-unsaturated

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

• Jonali Das Sajal Kumar Das Department of Chemical Sciences, Tezpur University, Napaam, Tezpur-784028, Assam, India 10.3762/bjoc.18.33 Abstract Indole-3,4- and 4,5-fused carbo- and heterocycles are ubiquitous in bioactive natural products and pharmaceuticals, and hence, a variety of synthetic

• as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by

• an SEAr reaction as the ring-closure step can generate indole 3,4-fused cabo- and heterocycles or/and their indole 4,5-fused counterparts (Scheme 1B). This is primarily due to the fact that such substrates have two proximal nucleophilic sites: the indole C5 as the ortho position and intrinsically

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• closely related analogues, one containing a bromo substituent and the other one incorporating an 8-membered instead of a 7-membered ring. The key transformation in this four-step synthesis, with an overall yield of 29%, is the Fischer indole reaction of 2-nitrophenylacetyl acetoacetate with 1-benzyl-1

• -phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1H-indol-2-yl)acetate in 55% yield. Keywords: anticancer; Fischer indole synthesis; Heck reaction; heterocyclic compounds; indolobenzazepines; latonduines; paullones; Introduction Indolobenzazepines are fused heterocyclic

• unit is shifted and the indole ring is flipped (D). Isomer D has been shown to be a potent tubulin-polymerase inhibitor, while B was only mildly cytotoxic towards cancer cells at a concentration of 1 µM [5][6]. Backbone C, despite being very similar to the other three scaffolds, remained a synthetic

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• combining thiazole, selenazole, pyrazole, indazole, and indole moieties with both carboxyl functional groups and cycloaminyl units [27][28][29][30][31]. In recent decades, various methods of constructing 1,2-oxazole ring systems have been developed [1][2][3][4][5][6][7][32]. The two primary pathways to 1,2

Chemoselective N-acylation of indoles using thioesters as acyl source

• Tianri Du,
• Xiangmu Wei,
• Honghong Xu,
• Xin Zhang,
• Ruiru Fang,
• Zheng Yuan,
• Zhi Liang and
• Yahui Li

Beilstein J. Org. Chem. 2022, 18, 89–94, doi:10.3762/bjoc.18.9

• , heterocycles, such as carbazole, can also be used as nucleophiles in this reaction. Keywords: indole; N-acylation; nucleophilic substitution; thioesters; Introduction Molecules containing N-acylindoles have attracted wide attention in the synthetic polymers and pharmaceutical industry because of their unique

• structural, chemical, and biological properties [1]. For example, indomethacin is a nonselective inhibitor of COX1 and COX2, which is used for treating fever, pain and swelling [2]. Indole analog L-768242 exhibits nanomolar potencies (Ki) with superior selectivity for the hCB2 receptor over the human central

• cannabinoid (hCB1) receptor [3] (Figure 1). Indole has multiple reactive sites, and chemoselective N- or C-functionalization of indoles is a challenging and important task [4][5]. Acylation of indoles frequently takes place at the C3 position because of the relatively strong electron cloud density. As N

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• arenes and heteroarenes using heterogeneous catalysts In 2012, a novel strategy for the 3-cyanation of indole in the presence of Ru(III)-exchanged NaY zeolite (RuY) was reported [36]. In this reaction K4[Fe(CN)6] was utilized as the cyano source in DMF at 110 °C. The Cu(OAc)2 and O2 (1 atm) was found

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• 1% in proteins, but is highly conserved in binding sites on protein surfaces mediating PPI [43], it is an attractive target for the development of selective diversifications. C–H activation of the indole C2 position by Pd-catalysis allows both selective arylation [44][45][46][47][48] and formation

• phthaloyl-protected N-terminal alanine was also used for macrocyclisation in peptide stapling [51][52]. Besides addressing the indole C2, the regioselective enzymatic halogenation at C5, C6, or C7 using FAD-dependent tryptophan halogenases opens a broad area of Pd-catalysed late-stage diversifications [53

• diastereomers, i.e. cis/trans isomers or conformers with a high interconversion barrier. For complestatin-based macrocyclic peptides, the existence of biaryl atropisomers caused by the indole of tryptophan has been reported [82]. Recently, the occurrence of isomers was also observed in our group for SMC

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• molecular formula was determined to be C18H22N2O3 based on its NMR and HR–ESI–TOFMS data (m/z 313.1556 [M – H]–, Δ – 0.2 mmu), corresponding to nine degrees of unsaturation. The UV spectrum, exhibiting the absorption maxima at 229 and 282 nm, was typical of an indole functionality. The IR absorption bands

• , and two amino protons. The remaining OH group should be a part of a carboxylic acid functionality considering the lack of oxygenated carbons besides carbonyls, and two degrees of unsaturation, not accounted for by double bonds, were consistent with the indole ring. As expected, assembling the above

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• ]. In the same year, the Du group investigated the FeCl2·4H2O decarboxylative radical alkylative cyclization of cinnamamides 131/134 as an expedient approach towards dihydroquinolinone 133 and pyrrolo[1,2-a]indole 135 analogues in good yield and excellent diastereoselectivity (Scheme 27) [120]. In terms

• the indole starting material 134, with tertiary peresters failing to react. The mechanism begins with an outer-sphere SET from Fe(II) to perester 132 leading to the O–O bond cleavage, generating the reactive alkyl radical 136, Fe(III), CO2, and t-BuO−. Addition of 136 across the alkene 131a generates

• -carbonyl alkyl bromides 147 and indole derivatives 146 (Scheme 30) [124]. Although the reaction operated in the absence of the iron catalyst, its use is crucial for high yielding reactions. Preliminary mechanistic studies suggest the reaction proceeds through a radical addition of the carbon-centered alkyl