Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• this context, quinoline and its derivatives are privileged structures in several natural products and biologically active compounds, rendering this scaffold an important synthetic target. An attractive strategy to afford tetrahydroquinolines and quinolines is the Povarov reaction, a type of aza-Diels

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• obtain cyclic ether-fused tetrahydroquinolines 24 has been reported starting from secondary anilines, cyclic ethers and paraformaldehyde (Scheme 18) [35]. In addition to Cu(OTf)2 as a catalyst, the most effective reaction conditions required a substoichiometric amount of p-nitrobenzoic acid as an

• dihydropyrimidines 18. Regioselective synthesis of 1,4-dihydropyridines 20. Synthesis of tetrahydropyridines 21. Synthesis of furoquinoxalines 22. Synthesis of 2,4-substituted quinolines 23. Synthesis of cyclic ether-fused tetrahydroquinolines 24. Practical route for 1,2-dihydroisoquinolines 25. Synthesis of 2,3

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• reacted with alkenyl-2-naphthols 93 in the presence of CPA (R)-C24 to form asymmetric products 94 and eventually axially chiral tetrahydroquinolines 95 through oxidation (Scheme 30). This approach led to the products 95 in high yields and enantiomeric purities. The tosyl group in the product was

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• reaction of 21 and 3-substituted dienes 65 led to the production of 1,2,3,4-tetrahydroquinolines diastereomers 66 and 66’ in good to excellent enantioselectivities (68–99% ee) using also chiral phosphoric acid XIV (Scheme 24). In June 2022, Wang, Mei and co-workers reported a chiral phosphoric acid

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• cyanoarenes is a straightforward and powerful method for the synthesis of primary amines [5], and the reduction of nitroarenes is useful for the synthesis of aniline derivatives [6][7][8][9][10][11]. Nitrogen-containing aliphatic heterocycles, such as piperidines and tetrahydroquinolines, are key motifs in

• smoothly to afford benzylamines, anilines, tetrahydroquinolines, and piperidines using a PEM reactor under ambient conditions. Results and Discussion Reduction of cyanoarenes to benzylamines Benzonitrile (1a) was chosen as the model substrate, and the electroreductive hydrogenation of 1a was performed with

• more π-extended aniline was easily obtained in a high yield. Reduction of quinolines to tetrahydroquinolines The electrochemical reduction of quinolines was performed using a PEM reactor. First, several different cathode catalyst were examined for the reduction of quinoline (6a) (Table 5). Because 4.0

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

• %) (Scheme 73). Later, Hultzsch and co-workers reported a PN3 pincer-supported manganese complex for the synthesis of tetrahydroquinolines via BH methodology [97]. The reaction conditions were optimized with 2-aminobenzyl alcohol and 1-phenylethanol using Mn27. Among the several bases tested in DME at 120 °C

• tetrahydroquinolines (Scheme 74). The active amido complex Mn27-a dehydrogenated the amino alcohol and secondary alcohol into the corresponding carbonyl compounds, and the subsequent base-assisted condensation allowed the formation of the quinoline product, which was further hydrogenated into the target compound

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

• 3–5 h (TLC control). Meanwhile, the disappearance of the diazo reagent was considerably slower in the case of more basic heterocycles (pyrazoles, indolines, tetrahydroquinolines), taking anywhere from 16 to 24 hours, and in some cases (imidazole, 7-azaindazole, ethyl isonipecotate, hexamethylenimine

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

• Xiu-Yu Chen,
• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• -fused tetrahydroquinolines (reaction 1 in Scheme 1) [41][42]. Menéndez and co-workers reported a Yb(OTf)3-mediated Povarov reaction of imines and N-alkyl-1,4-dihydropyridines for the synthesis of hexahydrobenzo[h][1,6]naphthyridines (reaction 2 in Scheme 1) [43]. Khan and co-workers employed a one-pot

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

• pyridine 195 and C4 pyridine 197 can undergo endo-cyclization reactions in the presence of Ni(cod)2, a chiral NHC ligand, and MAD as Lewis acid to afford optically active 5,6,7,8-tetrahydroquinolines 194 and 5,6,7,8-tetrahydroisoquinolines 196 and 198. The endo-selective annulation approach was compatible

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• -alkenylindoles 81 to give enantioenriched, highly substituted, 1,2,3,4-tetrahydroquinolines, which can be oxidized to axially chiral 4-(indol-3-yl)quinolones 82, in a central-to-axial chirality conversion approach with up to 99% yield and high enantioselectivity (up to 99% ee, Scheme 27). In presence of 5 mol

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• tetrahydroquinolines and tetrahydrochromanoquinolines catalyzed by a squaramide catalyst. The corresponding adducts were obtained in excellent yields with excellent diastereoselectivities and enantioselectivities (up to >99:1 dr, 99% ee) [37]. Following a similar strategy, Zhou et al. obtained a series of optically

• -Michael addition of 2-tosylaminoenones with unsaturated pyrazolones using squaramide as catalyst. The reaction proceeded smoothly under mild conditions to afford the corresponding spiro[pyrazolone-tetrahydroquinolines] in high yields (up to 99%) with excellent diastereoselectivities (up to >25:1 dr) and

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• . In this work, N,N-dialkylanilines or N-aryltetrahydroisoquinolines 48 reacted with N-substituted maleimide 49 via annulation to provide a range of tetrahydroquinolines or tetrahydroisoquinolines 50, respectively, with good yield. The mechanistic investigation revealed that an α-amino radical

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

•  30C). A straightforward method for an α-amino C−H bond functionalization was described by Kang et al. in 2020 to promote the synthesis of tetrahydroquinolines from tertiary anilines (Scheme 31B and C) [163]. Tetrahydroquinolines are a class of compounds already known to present varied biological

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• 139 (Scheme 19b). As previously mentioned, photoredox catalysis has been widely used for the generation of imines. The Jiang group applied this to the synthesis of substituted tetrahydroquinolines (THQs) 144 from α-amino acids 145 to give racemic products in good yields and found that the addition of

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• . In 2011, König and co-workers [150] demonstrated that eosin Y (OD13) was an efficient dye for an aza-Henry reaction [151], affording the tetrahydroquinolines 34.2 (Scheme 34). Simultaneously, the Tan group described the use of rose bengal (OD15) in the same transformation [152]. Regarding the strain

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• tetrahydroquinolines by reductive quenching. Selenylation and thiolation of anilines. NiTPP as photoredox catalyst in oxidative and reductive quenching, in comparison with other photocatalysts. C–O bond cleavage of 1-phenylethanol using a cobalt porphyrin (CoTMPP) under visible light. Hydration of terminal alkynes by

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• tetrahydroquinolines and octahydroisoquinolo[2,1-a]pyrrolo[3,4-c]quinolines (Scheme 13) [29]. Importantly, the formation of the key α-amino radical resulted from an oxidation reaction catalyzed by the copper catalyst in the oxidation state +II. Using the [Cu(I)(dap)2]Cl complex as the catalyst and 2 equivalents of TFA

• under air, N,N-dialkylated aniline derivatives were reacted with various N-substituted maleimides and benzylidenemalonitrile to provide polysubstituted tetrahydroquinolines in moderate to good yields. When N-aryltetrahydroisoquinoline was used instead of N,N-dialkylated anilines, octahydroisoquinolo[2,1

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• -substituted tetrahydroquinolines (Scheme 3). To the best of our knowledge, an analogous reaction has not been described for aminoazoles. We were interested to study reactions similar to the ones shown in Scheme 3, involving aromatic aldehydes and pyruvic acid but using aminoazoles instead of anilines

• reactions involving pyruvic acids (pyruvates) and different α-aminoazoles. Synthesis of 4-arylamino-substituted tetrahydroquinolines. Ultrasound-assisted multicomponent reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile, aldehydes, and pyruvic acid/ethyl pyruvate. Synthesis of 3-cyano

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

Regioselective Pd-catalyzed direct C1- and C2-arylations of lilolidine for the access to 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives

• Hai-Yun Huang,
• Haoran Li,
• Thierry Roisnel,
• Jean-François Soulé and
• Henri Doucet

Beilstein J. Org. Chem. 2019, 15, 2069–2075, doi:10.3762/bjoc.15.204

• of β-arylated 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives [6] (Scheme 1a). Three α-arylated 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives have been prepared by Pal et al. via the cyclization of 8-arylethynyl-1,2,3,4-tetrahydroquinolines [9] (Scheme 1b). The best results were obtained using

A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

• Katherine E. Jolley,
• Michael R. Chapman and
• A. John Blacker

Beilstein J. Org. Chem. 2018, 14, 2220–2228, doi:10.3762/bjoc.14.196

• specific study using this technique to racemise and resolve enantiopure tetrahydroquinolines [46][47], and another accessing an intermediate to the drug telaprevir [45]. Our study complements these findings, by supplying a continuous-flow oxidation–reduction sequence which telescopes both N-chloramine and

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• ][1,4]diazepinium salts 10 and the related neutral, free bases 13 were synthesized from 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 and nitriles 9 in the presence of aluminium chloride by the [3+ + 2]-cycloaddition reaction of the in situ generated azocarbenium intermediates 14

• -1,2,3,4-tetrahydroquinolines 8/12 as the key starting material. Results and Discussion The required N-acylated 2,3-dihydro-4(1H)-quinolones 6 were generally prepared following a literature method with the acid-catalysed Fries rearrangement of N-arylazetidin-2-ones of the general form 4 [43][44]. As

• the quinolones 6 and phenylhydrazine with a catalytic amount of AcOH in refluxing n-propyl alcohol. Subsequently, the hydrazones 7 were converted into the 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 via the oxidation with hypervalent iodine(III) reagent PhI(OAc)2 (Scheme 2) [45]. The

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• isoquinoline 82 from diverse 1,2,3,4-tetrahydroquinolines 81 in moderate to good yield (Scheme 29). Ferrous chloride (FeCl2) acted as a single electron transfer agent in the presence of DMSO to facilitate the reaction. Metal-catalyzed oxidant induced dehydrogenation Our next discussion involved the oxidative

• ]. Recently Xiao et al. [94] has reported an acceptor-free oxidative dehydrogenation with a versatile iridium catalyst (Scheme 35). A variety of tetrahydroquinolines 93 were converted to the aromatic quinoline 94 using the iridium catalyst in 2,2,2-trifluoroethanol (TFE) at higher temperature. As an extension

• et al. utilized a modular catalytic system comprised of C-quinones for the oxidative dehydrogenation of tetrahydroquinolines 104 to an (2,1-c)quinoline 105. This was further transformed to 106, an antiprotozoal agent, and 107, a topoisomerase inhibitor, presently in the phase II clinical trial

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• Limited, Bowburn North Industrial Estate, Bowburn, Durham, DH6 5PF, UK 10.3762/bjoc.12.174 Abstract The synthesis of novel tetrahydroquinolines (THQ) and dihydroquinolines (DHQ) are reported using three practical, scalable synthetic approaches to access highly lipophilic analogues bearing a 6-iodo

• temperatures. Coupling these strongly electron-donating scaffolds to electron-accepting moieties caused the resulting structures to exhibit strong fluorescence. Keywords: cyclisation; dihydroquinoline; elimination; reduction; tetrahydroquinoline; Introduction Tetrahydroquinolines (THQ) and dihydroquinolines

• more planar ring structure. Conclusion In conclusion, we have explored a wide range of methods for the synthesis of highly lipophilic tetrahydroquinolines and dihydroquinolines. Their iodo-substituents are reactive substrates for direct cross coupling using the plethora of cross-coupling methodologies

Palladium-catalyzed picolinamide-directed iodination of remote ortho-C−H bonds of arenes: Synthesis of tetrahydroquinolines

• William A. Nack,
• Xinmou Wang,
• Bo Wang,
• Gang He and
• Gong Chen

Beilstein J. Org. Chem. 2016, 12, 1243–1249, doi:10.3762/bjoc.12.119

• iodination, and Cu-catalyzed C−N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns. Keywords: iodination; palladium; remote C–H activation; tetrahydroquinoline; Introduction Tetrahydroquinoline (THQ) is an important N-heterocyclic scaffold found in

• to our previously reported PA-directed SEAr approach. This Pd-catalyzed PA-directed ε-C−H iodination can be used in concert with the PA-directed γ-C−H arylation, PA-directed SEAr iodination, undirected SEAr iodination, and Cu-catalyzed C−N cyclization to quickly access tetrahydroquinolines bearing