One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• Chemistry and Center for Green Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA 10.3762/bjoc.20.81 Abstract A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide

• and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE). Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

• [10][11] (Figure 1). The tetrazole ring can also be found in functional materials for photography, imaging, and military applications [12][13][14][15][16][17]. The hydroisoquinoline core, such as 1,2,3,4-tetrahydroisoquinoline and pyrazino[2,1-a]isoquinolinone, is also a privileged heterocycle which

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

• proximity of the metallic centers which allows MMLCT transitions. These properties have been used to generate reactive oxygen species (ROS) and efficient photocatalytic oxidative cyanation of N-phenyl-1,2,3,4-tetrahydroisoquinoline. The photocatalytic activity of the catalyst could be allosterically imbibed

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• cytotoxic agents. Keywords: 1,4-dihydroisoquinol-3-one; heterocyclic diazo compounds; hydroarylation; Regitz diazo transfer; triflic acid; Introduction Besides being derivatives of (or a precursor to) the 1,2,3,4-tetrahydroisoquinoline core which itself bears a special significance from the standpoint of

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• -hydrazinylquinoline. Thus, the reaction of compound 2c with methylamine, 1,2,3,4-tetrahydroisoquinoline, 1-methyl-1,2,3,4-tetrahydroisoquinoline, (2-fluorophenyl)methylamine, and 5-methylisoxazolyl-3-amine proceeded smoothly under mild conditions (methanol, 0 °C to rt), similarly to the previously obtained dienes 4b

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

• such as piperidine, tetrahydroisoquinoline derivatives, and pyrrolidine were also tolerated well in this reaction. The use of the non-toxic and inexpensive acetone cyanohydrin makes this method more advantageous compared to the known methods. 2 Cyanation of arenes and heteroarenes 2.1 Cyanation of

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• approaches to the monomeric 1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids are typically inspired by their biosynthesis and comprise Bischler–Napieralski-type cyclizations of arylacetamides (followed by reduction of the resulting 3,4-dihydroisoquinolines) or Pictet–Spengler-type cyclizations of

• -tetrahydroisoquinoline alkaloids (Figure 2 and Table 1). Since, as mentioned above, we recently demonstrated that substituted 1-benzyl-1,2,3,4-tetrahydroisoquinolines exhibit both cytotoxic and calcium channel-modulating activities, we subjected these alkaloids to our established screening systems in order to gain new

• ” retained antiproliferative activity, while losing activity on TPC2 [15]. This prompted us to analyze both TPC2 modulating and antiproliferative activities of the alkaloids from this project. TPC2 modulation To assess the activity of racemic 1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids on TPC2 in

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• ]. In this context, few methods have been developed for the dehydrogenative cross-coupling of tetrahydroisoquinolines with terminal alkynes because of the prevalence of the tetrahydroisoquinoline moiety in natural products and bioactive molecules [3][4][5][6][7][8][9][10]. These methods proceed through

• the oxidation of the tetrahydroisoquinoline to an iminium intermediate with various chemical oxidants such as peroxides and DDQ followed by reaction with the copper acetylide species to deliver the 2-substituted tetrahydroisoquinoline product (Scheme 1A). These methods usually require elevated

• electrosynthesis was conducted in a microreactor equipped with two Pt electrodes as the anode and cathode and operated with a constant current (Table 1). Under the optimized conditions, a solution of tetrahydroisoquinoline 1a (1 equiv), alkyne 2 (1.5 equiv), Cu(OTf)2 (10 mol %), TEMPO (20 mol %), n-Bu4NPF6 (0.2

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

• different approach for the use of cinchona-based organocatalysts. Instead of using the cinchona derivative alone, they employed a mixture of cinchona derivative and amino acid such as ᴅ-proline, termed as the modularly designed organocatalyst (MDO) for the synthesis of bridged tetrahydroisoquinoline

• (quinidinethiourea + ᴅ-proline), instead of the expected domino Mannich/Michael product, the bridged tetrahydroisoquinoline product 25a was obtained in high yield (90%) and excellent dr (94:6) and ee value (99%) (Table 5). The controlled reactions using 23 and 24 as the catalyst gave the product in very poor yield

• -nitrophthalimide to α,β-unsaturated ketones. Diastereoselective synthesis of bridged 1,2,3,4-tetrahydroisoquinoline derivatives using modularly designed organocatalyst. Synthesis of spiro[pyrrolidine-3,3'-oxindoles] via asymmetric cascade aza-Michael reaction catalyzed by squaramide. Asymmetric aza-Michael

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

• tetrahydroisoquinoline derivatives, 7,12-dihydro-6,12-methanodibenzo[c,f]-azocine-5-carboxylic acids by three component Petasis reaction with the use of aminoacetaldehyde acetals bearing substituted benzyl groups as the amine components followed by Pomeranz–Fritsch double cyclization reaction. By applying this method

• ; cyclization; multicomponent reactions; synthetic methods; tetrahydroisoquinoline; Introduction The tetrahydroisoquinoline moiety is the key structure in large number of natural and synthetic biologically important molecules. Among them, isoquinoline alkaloids constitute a large family of natural products

• exhibiting a huge range of structural diversity and biological activity [1][2][3]. Within this family several structural motifs can be identified, for instance, the isopavines, constrained alkaloids possessing the 1,2,3,4-tetrahydroisoquinoline skeleton incorporated into the double cyclized azabicyclo[3.2.2

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• , delivering the corresponding regioisomers 8l and 8l’ in 62% with 1:1.6 ratio. Moreover, the naphthalene and tetrahydroisoquinoline-derived acrylamides were also compatible, giving the polycyclic products 8m and 8n in 77% and 70%, respectively. Additionally, protecting groups such as isopropyl, benzyl, or

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

• 152, in a subsequent cyclization to obtain the intermediate 156 then, a substitution at the sulfur atom occurred to form 154a and 157 [131] (Scheme 41). In 2017, Reddy and co-workers described the stereoselective synthesis of (S)-1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (163), (S)-1

• -benzyl-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (164), (−)-O,O-dimethylcoclaurine (165) and (+)-O-methylarmapavine (166) alkaloids via chiral tert-butylsulfinamide through a haloamide cyclization. The strategy was based on the addition of organomagnesium bromide or chloride to chiral N

• -sulfinyl imine 160. A subsequent base promoted cyclization of chloroamides (158 and 162) and the products 165 and 163 were obtained in 91% and 93% yields respectively. The N-methylation of alkaloids 163 and 165 using 37% formaldehyde and sodium borohydride formed the tetrahydroisoquinoline 164 and 166 in

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• also evaluated the construction of fluorinated tetrahydroisoquinoline structures starting from nitrones, but this required four consecutive reactions with different conditions and chromatographic separation at each step [25] (Scheme 1). Herein we report a single-step protocol for the construction of

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• octahydroindole [10], tetrahydroquinoline [11], tetrahydroisoquinoline [11][12], β-carboline [13], morpholine [14], and isoindoline [15] moieties have been developed. Obtained in an enantiomerically pure form, phosphonoproline and its analogues [16][17][18][19] were among the first compounds in this series

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

• Aleksandar Pashev,
• Nikola Burdzhiev and
• Elena Stanoeva

Beilstein J. Org. Chem. 2020, 16, 1456–1464, doi:10.3762/bjoc.16.121

• products 25 and 26, respectively, containing an exocyclic double bond to the tetrahydroisoquinoline moiety (Scheme 5). The reaction with succinic anhydride (5) furnished the tetrahydroisoquinoline 27 with an open-chain acid substituent to the exocyclic double bond. Unlike 1-methyldihydroisoquinoline (19

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• aromatic (products 88a–d) and aliphatic (products 88e,f) substituents are applicable. Oximes with an isoindoline or tetrahydroisoquinoline fragment also undergo this transformation to give substituted oxadiazolines (products 88g,h). The authors note that T(p-F)PPT plays the role of a photocatalyst that

Anthelmintic drug discovery: target identification, screening methods and the role of open science

• Frederick A. Partridge,
• Ruth Forman,
• Carole J. R. Bataille,
• Graham M. Wynne,
• Marina Nick,
• Angela J. Russell,
• Kathryn J. Else and
• David B. Sattelle

Beilstein J. Org. Chem. 2020, 16, 1203–1224, doi:10.3762/bjoc.16.105

• 873 million) [40]. It looks unlikely that this target will be met, thus the development of new potent anthelmintic drugs that act via novel mechanisms of action are urgently needed. Current anthelmintics – schistosomiasis Praziquantel (PZQ, 5), an N-acylated tetrahydroisoquinoline-piperazinone

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

• with singlet oxygen to produce an imine, which was used as a substrate in the Ugi-type reaction. Thus, the oxidations of both 1,2,3,4-tetrahydroisoquinoline and dibenzylamine using TPP were carried out with high yield and selectivity, and the Ugi products were obtained after removal of the solvent and

• direct addition of isocyanide and carboxylic acid. The Ugi products were obtained in 41–89% and 72–96% yields from 1,2,3,4-tetrahydroisoquinoline (Scheme 60) and dibenzylamine (Scheme 61), respectively [102]. Furthermore, Che and co-workers obtained a wide range of Mannich-type products by coupling N

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

• reaction in photocatalysis, the oxidation of N-aryl tetrahydroisoquinoline (Scheme 31) [45]. Upon oxidation, the in situ-formed iminium ion was reacted with nitroalkanes, enamines, and indoles. In all cases, the 1-substituted tetrahydroisoquinolines were isolated in good to excellent yields. The reaction

• mechanism suggested by the authors was in agreement with the literature [46]: The excited copper catalyst oxidizes the tetrahydroisoquinoline and forms an N-centered radical cation. The copper catalyst is regenerated upon oxidation with O2. The resulting superoxide radical anion allowed the formation of the

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• -cyclodextrin as the cocatalyst provide 196 in a good yield and excellent stereoselectivity (Scheme 61). In 2011, Hurvois and his group reported a stereoselective electrochemical total synthesis of the tetrahydroisoquinoline alkaloid (−)-crispine A (200) and its natural enantiomer [108]. The initial steps

Hoveyda–Grubbs catalysts with an N→Ru coordinate bond in a six-membered ring. Synthesis of stable, industrially scalable, highly efficient ruthenium metathesis catalysts and 2-vinylbenzylamine ligands as their precursors

• Kirill B. Polyanskii,
• Kseniia A. Alekseeva,
• Pavel V. Raspertov,
• Pavel A. Kumandin,
• Eugeniya V. Nikitina,
• Atash V. Gurbanov and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2019, 15, 769–779, doi:10.3762/bjoc.15.73

• synthesis of 2-vinylbenzylamines is reported. This involves obtaining 2-vinylbenzylamine ligands from tetrahydroisoquinoline by alkylation and reduction followed by the Hofmann cleavage. The resultant 2-vinylbenzylamines allowed us to obtain new Hoveyda–Grubbs catalysts, which were thoroughly characterised

• methods have been reported for the synthesis of 2-(N,N-dialkylaminomethyl)styrenes [39][40][41][42][43][44][45][46] relying on different approaches: i) from o-vinylbenzyl chloride [43], ii) by the Hofmann cleavage of quaternary tetrahydroisoquinoline salts under the action of silver oxide [39][42] and iii

• styrenes 5 with a cyclic tertiary amino group from 1,2,3,4-tetrahydroisoquinoline (Scheme 2). In this case, the initial isoquinoline was reduced in the presence of formic acid and then converted into the desired products 5 by a one-pot solvent-free reaction under the action of the corresponding dihalide in

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• architectural extreme are: the ecteinascidins, antitumor tetrahydroisoquinoline alkaloids from the colonial Ascidian Ecteinascidia turbinata as exemplified by ecteinascidin 729 (4) [6]; ulbactins F (5a) and G (5b), two polycyclic thiazoline congeners isolated from a culture extract of a sponge derived

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• tetrahydroisoquinoline derivatives using DDQ and Ruppert–Prakash reagent (Scheme 31). A variety of amines proceeded smoothly to give the corresponding products in 15–90% yields under mild conditions. Based on previous literature, the author proposed a possible mechanism in Scheme 31. Firstly, oxidation of N-substituted

• tetrahydroisoquinoline with DDQ generates dihydroquinoline salt A. Next, CuCF3, generated by the reaction of CuI and CF3TMS/KF, undergoes a nucleophilic addition with A affording the desired products and the copper salt. The generated copper salt would be reused to form CuCF3 in the nucleophilic step again. So, only a

• group of Liu. Trifluoromethylation of terminal alkenes reported by the group of Wang. Trifluoromethylation of tetrahydroisoquinoline derivatives reported by Li and the proposed mechanism. Trifluoromethylation of phenol derivatives reported by the group of Hamashima. Trifluoromethylation of hydrazones

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• tetrahydroisoquinoline derivatives were synthesized using a pyridine-based chiral ligand (PyBox, Scheme 12) in the presence of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). The coupling products were isolated in fair yields with ee’s (enantiomeric excesses) up to 79%. The milling copper balls were also identified as

• , aliphatic amines and sulfonamides worked smoothly under these conditions to obtain the desired product in 3 h. They have also extended the methodology for the synthesis of tetrahydroisoquinoline by using o-formyl phenethyl bromide with amine and KCN (Scheme 30) [120]. Since the discovery in 1890, the

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• ; steroidomimetic; synthesis; tetrahydroisoquinoline; Introduction 1,2,3,4-Tetrahydroisoquinoline (THIQ) motifs are present in many natural alkaloids [1]. THIQ derivatives have also been investigated as potential therapeutics in a wide range of diseases and recent studies have explored their potential as

• deliver the 1,2,3,4-tetrahydroisoquinoline product. Relative to the original Pomeranz–Fritsch conditions, the Bobbitt modification features a reduced acid concentration that advantageously reduces the formation of side products [8][9][10]. The key cyclization in the PFB synthesis reaction is an

• to access libraries of regioisomeric N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives that might facilitate the design of new structural templates for steroid-binding receptors. We thus evaluated the robustness and flexibility of this approach to the THIQ system and considered, in particular, the