The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• conditions. The study was started by reacting 2-aminopyridines, indole-3-carbaldehyde 62 and ethyl isocyanoacetate (63) under open air in the presence of Yb(OTf)3 catalyst (Scheme 24, conditions a). The results showed that fused polycyclic indoles 67 were obtained (albeit in lower yields, 25%) instead of the

• underwent cyclization and dehydration to produce linked polyheterocyclic indoles 75. The authors managed to prepare five adducts in 15–33% yield. Another mechanistic scenario occurred at higher temperature (Scheme 25, conditions b). The secondary amine of diol 73 substituted both secondary alcohols to

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• fascinating but at the same time challenging. Pyrazoles [4][5][6][7], benzofurans [34], and indoles [35][36] are popular scaffolds as they are prevalent in many bioactive molecules. Compounds bearing both pyrazole and indole moieties or pyrazole and benzofuran moieties (Figure 1) are highly attractive since

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• of efforts to developing efficient thio/selenocyanation approaches [33][34][35][36][37][38][39][40][41]. Specifically, a plethora of synthetic strategies have been reported for the thiocyanation of heteroaromatic compounds including arenes, indoles, carbazoles, pyrroles, and imidazopyridines [42][43

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• simple oxygen atmosphere (Scheme 1a) [30][31][32]. Most recently, we also showed that phenotellurazines could catalyze the oxidative dimerization of indoles, likewise under a simple oxygen atmosphere. 2-Methoxyphenotellurazine PTeZ2 proved to be the optimal catalyst in the latter case (Scheme 1b) [33

• cross-dehydrogenative coupling of indoles [33], in the same benchmark reaction. To our satisfaction, PTeZ2 proved to be the most active catalyst so far in this study (3aa, 99% after 3 h). In order to further optimize the catalyst structure, we then reduced the catalytic loading by one order of magnitude

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• 2-salicyloyl-8H-thieno[2,3-b]indoles 39a–i in mostly moderate to good yields (Scheme 21) [41]. The formation of these products can be explained, similarly to the formation of products 35, by 1,4-addition of the carbon atom of 38 to the chromone to give intermediate AB, cyclization by nucleophilic

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• yields up to 85%. The proposed mechanism suggested the formation of the dehydrogenation product and the desired product due to the metal–ligand cooperation (Scheme 39). de Ruiter and co-workers studied PCNHCP-based manganese complexes for the α-methylation of ketones and indoles with methanol as a C1

• -Alkylation of heterocyclic compounds with alcohols Functionalized heterocyclic compounds are omnipresent structural skeletons in bioactive compounds [82]. Remarkably, the alkylation of indoles and quinolines received significant interest since they are common compounds in pharmaceutical and agrochemical

• industries [83][84][85]. Various manganese catalysts have been reported (Figure 4) for the C-alkylation of heterocyclic compounds with several alcohols, including indoles and quinolines. In 2017, Kirchner’s group established a new method for the aminomethylation of aromatic compounds with secondary amines

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• powerful method for the introduction of a C1 building block into organic substrates using carbon monoxide, its surrogates, or compounds able to act as carbon monoxide sources [11]. In recent years, many groups have used the carbonylation approach for the synthesis and functionalization of indoles, which is

• what we are discussing in this mini-review. Review Carbonylative synthesis of indoles Synthesis of indoles by Pd(0)-catalyzed carbonylation reaction of halide compounds Processes using organic halides as their starting materials involving the oxidative addition of Pd(0) to C–X bonds to give Ar–PdII–X

• selective cyclization to the indole derivative in the presence of Pd(OAc)2 and AlCl3. A variety of indole derivatives were synthetized in good isolated yields (Scheme 3). Synthesis of indoles by Pd(II)-catalyzed carbonylation reaction Oxidative carbonylation reactions, as well as all other types of

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• efficient chemoenzymatic synthesis of DMTs or drimanyl indoles [44]. (a) Representative bioactive drimane-type sesquiterpenoids (DMTs). (b) Reported biosynthetic pathways of DMTs from fungi. Chemical structures and HPLC analysis. (a) Chemical structures of isolated sesquiterpenes 2–4 from S. clavuligerus

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

• quinolines and indoles [24], pyridines [25], and imines [26], the reactions of 5 and 15c with ammonia borane (3 equiv) in the presence of a catalytic amount of B(C6F5)3 in toluene as an aprotic solvent at a temperature of 80 °C afforded aminoboranes 17b (R1 = F) and 17c (R1 = CH3) as main products along with

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• constant is higher for the second complexation than the first. The authors later reported a similar system with triazole linkages between the porphyrin and the indoles that act as binding sites for the metal (square planar complex) [76]. These tweezers present a fluorescence quenching upon copper(I

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

• Periklis X. Kolagkis Eirini M. Galathri Christoforos G. Kokotos Laboratory of Organic Chemistry, Department of Organic Chemistry, National and Kapodistrian University of Athens, Athens, 15771, Greece 10.3762/bjoc.20.36 Abstract The synthesis of indoles and their derivatives, more specifically bis

• 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

• pharmaceutical and biological activities. Among indole derivatives, bis(indolyl)methanes (BIMs) are profoundly interesting, due to their wide range of pharmaceutical properties. The most common approach involves the electrophilic substitution of various aldehydes and ketones by indoles, utilizing either protic

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with

• -catalyzed asymmetric hydrogenation of indoles to synthesize chiral indolines has been widely studied (Scheme 1a) [21][22]. Representative examples include Ir- or Ru-catalyzed asymmetric hydrogenation of 2,3,3-trisubstituted 3H-indole [23][24]. Generally, these methods employ precious metals and/or

• relatively strict reaction conditions (up to 150 bar H2). In 2022, Liu’s group reported an asymmetric hydrogenation of 3H-indoles catalyzed by a chiral Mn complex, which showed good yield and enantioselectivity [25]. In addition to metal catalysis for the enantioselective reduction, asymmetric

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• ][42][43][44][45][46], azulenes and their homologous compounds [32][47][48][49][50][51][52][53][54][55][56][57][58], boron dipyrromethenes (BODIPYs) [41][59][60][61], porphyrins [62][63][64], chlorophylls [65][66], triazenes [67][68], ynamides [69][70][71], arylynamines [72], indoles [73], and γ

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

• of the substrates bearing substituents at the C5 position on the indole skeleton reacted well, furnishing the products in moderate to good yields from 53–79% (3e–i) except the 5-CHO-substituted substrate which afforded product 3j in 28% yield. Indoles with substituents at the C7 position of the

Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions

• Julika Schlosser,
• Olga Fedorova,
• Yuri Fedorov and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 101–117, doi:10.3762/bjoc.20.11

• [7], quinoxalines [8], naphthalimides [9], phenanthridines [10], cyanines [11], or indoles [12], as well as metal-organic complexes [13], and several others [1][2][4]. In this context, benzoquinolizinium derivatives and resembling polycyclic azoniahetarenes are an established class of DNA-binding

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• and efficiency in various XH insertion reactions [27][28][29]. In many cases (e.g., indoles, indazoles, benzotriazoles, tetrazoles, Scheme 3) the reaction progressed expeditiously (as indicated by gas evolution upon adding diazo reagent to the mixture of NH-substrate and catalyst) and was completed in

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

• is noteworthy that the use of diphenyl disulfide as a sulfenylating agent was not effective in this protocol. N-(Aryl/alkylthio)phthalimide as an efficient sulfenylating reagent could also react with indoles to produce 3-thioindoles in the presence of 0.5 mol % of MgBr2, as a Lewis acid [68

• -catalyzed C–H sulfenylation at the C2-position of protected and unprotected indoles 105 to form 2-thioindoles 106 (Scheme 44) [78]. The reaction initiated with TFA-promoted electrophilic addition of 1 to 105 towards C3-sulfenylated indole I, which was protonated by TFA, led to intermediate II. Then

• acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• state, in good yield. Keywords: alkynylation; catalysis; cyclization; indoles; iodination; multicomponent reactions; Introduction Indoles and their derived substitution patterns are omnipresent heterocyclic structural motifs in nature [1], many natural products [2][3], drugs [4][5][6][7][8], and dyes

• -catalyzed processes for accessing indoles have become attractive alternatives over the past decades [19][20][21][22][23][24]. Besides Larock's indole synthesis employing alkyne anellation [25] and Cacchi's cyclization of ortho-alkynylanilines [20][22] catalytic syntheses of indoles from alkynes have become

• increasingly interesting [26][27]. In addition, as one-pot processes with a huge exploratory potential and diversity-oriented character, syntheses of indoles by multicomponent reactions have aroused considerable interest [28][29][30]. As part of our program to develop heterocycle syntheses based upon

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

• form cationic intermediate C and Fe(II) through a single electron transfer (SET) process. Subsequent abstraction of a proton from species C by a basic tert-butoxy anion generated from DTBP affords the product. Li et al. reported Fe-catalyzed CDC reactions of C(sp2)–H bonds of indoles and C(sp3)–H bonds

• 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

• indoles with 1,4-dioxane C(sp3)–H bonds via Ni(II) catalysis (Scheme 35) [100]. The selectivity of the reaction is determined by the catalyst used, which provides an efficient strategy for the selective construction of cyclic ethers containing heteroaromatic structures. Huang et al. reported a highly

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• 44, from which reductive elimination of iodobenzene would generate 40. In 2021, Sen and Gremaud disclosed a blue LED-mediated formal C–H insertion reaction between iodonium ylides (e.g., 31) and pyrroles (e.g., 45), indoles and furans, producing malonate-substituted heterocycles 46 (Scheme 9) [126

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

• Kasturi U. Nabar,
• Bhalchandra M. Bhanage and
• Sudam G. Dawande

Beilstein J. Org. Chem. 2023, 19, 1008–1014, doi:10.3762/bjoc.19.76

• generation of carbene as a reactive intermediate [36][37]. Also, spirocyclic iodonium ylides have been used for radiolabeling techniques [38]. In 2013, Shibata’s research group reported a novel trifluoromethanesulfonyl iodonium ylide for trifluoromethylthiolation of enamines, indoles, and ketoesters

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

• aza-Friedel–Crafts process between indoles 4 and cyclic N-sulfonyl ketimines 5. The authors employed the BINOL-based chiral phosphoric acid P2 bearing two imidazoline moieties at the ortho-positions as the catalyst which activates both reactants through H-bonding where the NH group of the nucleophile

• than with indoles (Scheme 3) [26]. In 2018, Kim and co-workers developed an aza-Friedel–Crafts protocol involving pyrroles 9 as the π-nucleophile in combination with cyclic N-sulfimines 12. The chiral phosphoric acid P4 was used to catalyze the introduction of a pyrrole-substituted aza-quaternary

• for the functionalization of the C3–H bond in indoles 9 in the presence of BINOL-derived chiral phosphoric acid P6 as the catalytic agent. They utilized trifluoromethyl ester-substituted N-unprotected imine 15 as the potential electrophile to install an aza-quaternary stereocenter in the C3 position

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

• solvent at 100 °C (Scheme 6). Finally, compounds 13 were used to prepare various arylpyrrolo- and pyrazolopyrrolizinones for diverse biological activity. In 2007, Török and co-workers [60] reported a convenient one-pot synthesis of N-sulfonyl-substituted pyrroles, indoles, and carbazole via a modified

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• -dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to

• in CH2Cl2 at room temperature using our integrated photoreactor enabled efficient cyclization to give a decarboxylated compound with the correct mass (m/z 426.2) after 16 h. While we were delighted to find that the proposed radical–radical coupling in the synthesis of extracyclic fused indoles was

• functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a