91-21-4

Usage

Uses

Used in Pharmaceutical Industry:
1,2,3,4-Tetrahydroisoquinoline is used as a reagent in the preparation of 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, which are antiproliferative tubulin inhibitors. These inhibitors have potential applications in cancer treatment by preventing the proliferation of cancer cells.
1,2,3,4-Tetrahydroisoquinoline can also be used for the synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), which has strong applications in peptides and peptidomimetics design and discovery. This makes it a valuable compound for the development of new drugs and therapeutic agents.
Additionally, 1,2,3,4-tetrahydroisoquinoline has been made into some derivatives with potential for prevention of parkinsonism, cancer treatment, and acting as Anticonvulsant Agents. These applications highlight its versatility and importance in the pharmaceutical industry.

Synthesis

To a solution of the isoquinolinone (1.156 g, 9.90 mmol) and tert-butyl alcohol (0.88 mL, 11.9 mmol) in THF (30 mL) at ?78 °C was added liquid ammonia (about 280 mL). Lithium was added in small pieces until the blue coloration persisted, after which the solution was stirred at ?78 °C for 30 min. The blue coloration was dissipated with piperlyne, 4-methoxybenzyl chloride (4.83 g, 31.00 mmol) in THF (5 mL) was introduced by syringe, and the mixture was stirred for an additional 150 min at ?78 °C. Solid ammonium chloride was added and then the ammonia was allowed to evaporate. The pale yellow residue was partitioned between CH2Cl2 (30 mL) and water (40 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic layers were washed with 10% sodium thiosulfate solution (20 mL), dried over magnesium sulfate, and concentrated. Flash chromatography (EtOAc:hexane, 2:1) on silica gave 2.21 g (75%) of the tetrahydroisoquinolinone.??Reference: Schultz, A. G.; Guzi, T. J.; Larsson, E.; Rahm, R.; Thakker, K. Bidlack, J. M. J. Org. Chem. 1998, 63, 7795–7804.

Reference

https://www.alfa.com/en/catalog/L08143/ https://www.ncbi.nlm.nih.gov/pubmed/21235510 https://en.wikipedia.org/wiki/Tetrahydroisoquinoline Okuda, K, Y. Kotake, and S. Ohta. "Parkinsonism-preventing activity of 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline derivatives in C57BL mouse in vivo. Biological & Pharmaceutical Bulletin 29.7(2006):1401-1403. Luca, Laura De, et al. "3D Pharmacophore Models for 1, 2, 3, 4‐Tetrahydroisoquinoline Derivatives Acting as Anticonvulsant Agents." Archiv Der Pharmazie 339.7(2006):388-400. Hatano, H, et al. "Tumor-specific cytotoxic activity of 1, 2, 3, 4-tetrahydroisoquinoline derivatives against human oral squamous cell carcinoma cell lines."Anticancer Research 29.8(2009):3079-3086.

Synthesis Reference(s)

The Journal of Organic Chemistry, 40, p. 1191, 1975 DOI: 10.1021/jo00897a001Tetrahedron Letters, 26, p. 4633, 1985 DOI: 10.1016/S0040-4039(00)98771-9

InChI:InChI=1/C9H11N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-4,10H,5-7H2/p+1

Upstream product

• 119-65-3 isoquinoline 
• 24331-94-0 1,4-dihydro-3(2H)-isoquinolinone 
• 24423-87-8 3,4-dihydro-isoquinoline 2-oxide 
• 542-88-1 bis(2-chloromethyl)ether 
• 60-29-7 diethyl ether 
• 156-28-5 2-phenylethylamine hydrochloride 
• 5435-44-9 (E)-3-Ureido-but-2-enoic acid ethyl ester 
• 855386-32-2 2-chloromethyl-phenethylamine 
• 1196-38-9 3,4-dihydroisoquinolin-1(2H)-one 
• 4456-77-3 4H-isoquinolin-1,3-dione 
• 109-87-5 Dimethoxymethane 
• 64-04-0 phenethylamine 
• 2744-08-3 decahydroisoquinoline 
• 201230-82-2 carbon monoxide 

Downstream Products

• 88014-15-7 2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanol 
• 2744-08-3 (4aS^*,8aS^*)-1,2,3,4,4a,5,6,7,8,8a-perhydroisoquinoline 
• 145474-49-3 2-cinnamyl-1,2,3,4-tetrahydroisoquinoline 
• 852923-09-2 3-bromo-4-(3,4-dihydro-1H-[2]isoquinolyl)-4-phenyl-butan-2-one 
• 855354-32-4 3-(3,4-dihydro-1H-[2]isoquinolylmethyl)-biphenyl-4-ol 
• 1612-65-3 2-methyl-1,2,3,4-tetrahydroisoquinoline 
• 107059-85-8 2-p-tolylazo-1,2,3,4-tetrahydro-isoquinoline 
• 6282-21-9 1,12-bis-(3,4-dihydro-1H-[2]isoquinolyl)-dodecane-2,11-dione 
• 101717-81-1 2-(2-benzyloxy-ethyl)-1,2,3,4-tetrahydro-isoquinoline 
• 102949-77-9 2-(2-benzhydryloxy-ethyl)-1,2,3,4-tetrahydro-isoquinoline 
• 855654-06-7 4-(3,4-dihydro-1H-[2]isoquinolyl)-4-phenyl-3-piperidino-butan-2-one 
• 64047-66-1 2-methyl-2-[3-(1-methyl-pyrrolidinium-1-yl)-propyl]-1,2,3,4-tetrahydro-isoquinolinium; dibromide 

Relevant academic research and scientific papers

Engineering of Thermostable β-Hydroxyacid Dehydrogenase for the Asymmetric Reduction of Imines

The β-hydroxyacid dehydrogenase from Thermocrinus albus (Ta-βHAD), which catalyzes the NADP+-dependent oxidation of β-hydroxyacids, was engineered to accept imines as substrates. The catalytic activity of the proton-donor variant K189D was further increased by the introduction of two nonpolar flanking residues (N192 L, N193 L). Engineering the putative alternative proton donor (D258S) and the gate-keeping residue (F250 A) led to a switched substrate specificity as compared to the single and triple variants. The two most active Ta-βHAD variants were applied to biocatalytic asymmetric reductions of imines at elevated temperatures and enabled enhanced product formation at a reaction temperature of 50 °C.

CARBALDEHYDE OXIMES AS BUTYRYLCHOLINESTERASE REACTIVATORS

The present invention relates to compounds for their use in the reactivation of butyrylcholinesterase. Such compounds are useful in the treatment or prevention of the intoxication with at least one organophosphorus nerve agent. The invention also relates

carba Nicotinamide Adenine Dinucleotide Phosphate: Robust Cofactor for Redox Biocatalysis

Here we report a new robust nicotinamide dinucleotide phosphate cofactor analog (carba-NADP+) and its acceptance by many enzymes in the class of oxidoreductases. Replacing one ribose oxygen with a methylene group of the natural NADP+ was found to enhance stability dramatically. Decomposition experiments at moderate and high temperatures with the cofactors showed a drastic increase in half-life time at elevated temperatures since it significantly disfavors hydrolysis of the pyridinium-N?glycoside bond. Overall, more than 27 different oxidoreductases were successfully tested, and a thorough analytical characterization and comparison is given. The cofactor carba-NADP+ opens up the field of redox-biocatalysis under harsh conditions.

Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists

The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC50 = 7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.

Chemoselective and Tandem Reduction of Arenes Using a Metal–Organic Framework-Supported Single-Site Cobalt Catalyst

The development of heterogeneous, chemoselective, and tandem catalytic systems using abundant metals is vital for the sustainable synthesis of fine and commodity chemicals. We report a robust and recyclable single-site cobalt-hydride catalyst based on a porous aluminum metal–organic framework (DUT-5 MOF) for chemoselective hydrogenation of arenes. The DUT-5 node-supported cobalt(II) hydride (DUT-5-CoH) is a versatile solid catalyst for chemoselective hydrogenation of a range of nonpolar and polar arenes, including heteroarenes such as pyridines, quinolines, isoquinolines, indoles, and furans to afford cycloalkanes and saturated heterocycles in excellent yields. DUT-5-CoH exhibited excellent functional group tolerance and could be reusable at least five times without decreased activity. The same MOF-Co catalyst was also efficient for tandem hydrogenation–hydrodeoxygenation of aryl carbonyl compounds, including biomass-derived platform molecules such as furfural and hydroxymethylfurfural to cycloalkanes. In the case of hydrogenation of cumene, our spectroscopic, kinetic, and density functional theory (DFT) studies suggest the insertion of a trisubstituted alkene intermediate into the Co–H bond occurring in the turnover limiting step. Our work highlights the potential of MOF-supported single-site base–metal catalysts for sustainable and environment-friendly industrial production of chemicals and biofuels.

Homogeneous pressure hydrogenation of quinolines effected by a bench-stable tungsten-based pre-catalyst

We report on an operationally simple catalytic method for the tungsten-catalyzed hydrogenation of quinolines through the use of the easily handled and self-contained precursor [WCl(η5-Cp)(CO)3]. This half sandwich complex is indefinitely storable on the bench in simple screw-capped bottles or stoppered flasks and can, if required, be prepared on a multi-gram scale while the actual catalytic transformations were performed in the presence of a Lewis acid in order to achieve both decent substrate conversions and product yields. The described method represents a facile and atom-efficient access to a variety of 1,2,3,4-tetrahydroquinolines that circumvents the use of cost-intensive and oxygen-sensitive phosphine ligands as well as auxiliary hydride reagents.

Water-involving transfer hydrogenation and dehydrogenation of N-heterocycles over a bifunctional MoNi4 electrode

A room-temperature electrochemical strategy for hydrogenation (deuteration) and reverse dehydrogenation of N-heterocycles over a bifunctional MoNi4 electrode is developed, which includes the hydrogenation of quinoxaline using H2O as the hydrogen source with 80% Faradaic efficiency and the reverse dehydrogenation of hydrogen-rich 1,2,3,4-tetrahydroquinoxaline with up to 99% yield and selectivity. The in situ generated active hydrogen atom (H*) is plausibly involved in the hydrogenation of quinoxaline, where a consecutive hydrogen radical coupled electron transfer pathway is proposed. Notably, the MoNi4 alloy exhibits efficient quinoxaline hydrogenation at an overpotential of only 50 mV, owing to its superior water dissociation ability to provide H* in alkaline media. In situ Raman tests indicate that the NiII/NiIII redox couple can promote the dehydrogenation process, representing a promising anodic alternative to low-value oxygen evolution. Impressively, electrocatalytic deuteration is easily achieved with up to 99% deuteration ratios using D2O. This method is capable of producing a series of functionalized hydrogenated and deuterated quinoxalines.

Metallic Barium: A Versatile and Efficient Hydrogenation Catalyst

Ba metal was activated by evaporation and cocondensation with heptane. This black powder is a highly active hydrogenation catalyst for the reduction of a variety of unactivated (non-conjugated) mono-, di- and tri-substituted alkenes, tetraphenylethylene, benzene, a number of polycyclic aromatic hydrocarbons, aldimines, ketimines and various pyridines. The performance of metallic Ba in hydrogenation catalysis tops that of the hitherto most active molecular group 2 metal catalysts. Depending on the substrate, two different catalytic cycles are proposed. A: a classical metal hydride cycle and B: the Ba metal cycle. The latter is proposed for substrates that are easily reduced by Ba0, that is, conjugated alkenes, alkynes, annulated rings, imines and pyridines. In addition, a mechanism in which Ba0 and BaH2 are both essential is discussed. DFT calculations on benzene hydrogenation with a simple model system (Ba/BaH2) confirm that the presence of metallic Ba has an accelerating effect.

Covalent Organic Frameworks toward Diverse Photocatalytic Aerobic Oxidations

Photoactive two-dimensional covalent organic frameworks (2D-COFs) have become promising heterogenous photocatalysts in visible-light-driven organic transformations. Herein, a visible-light-driven selective aerobic oxidation of various small organic molecules by using 2D-COFs as the photocatalyst was developed. In this protocol, due to the remarkable photocatalytic capability of hydrazone-based 2D-COF-1 on molecular oxygen activation, a wide range of amides, quinolones, heterocyclic compounds, and sulfoxides were obtained with high efficiency and excellent functional group tolerance under very mild reaction conditions. Furthermore, benefiting from the inherent advantage of heterogenous photocatalysis, prominent sustainability and easy photocatalyst recyclability, a drug molecule (modafinil) and an oxidized mustard gas simulant (2-chloroethyl ethyl sulfoxide) were selectively and easily obtained in scale-up reactions. Mechanistic investigations were conducted using radical quenching experiments and in situ ESR spectroscopy, all corroborating the proposed role of 2D-COF-1 in photocatalytic cycle.

Nanosized CdS as a Reusable Photocatalyst: The Study of Different Reaction Pathways between Tertiary Amines and Aryl Sulfonyl Chlorides through Visible-Light-Induced N-Dealkylation and C-H Activation Processes

It has been found that the final products of the reaction of sulfonyl chlorides and tertiary amines in the presence of cadmium sulfide nanoparticles under visible light irradiation are highly dependent on the applied reaction conditions. Interestingly, with the change of a reaction condition, different pathways were conducted (visible-light-induced N-dealkylation or sp3 and sp2 C-H activation) that lead to different products such as secondary amines and various sulfonyl compounds. Remarkably, all of these reactions were performed under visible light irradiation and an air atmosphere without any additive or oxidant in benign solvents or under solvent-free conditions. During this study, the CdS nanoparticles as affordable, heterogeneous, and recyclable photocatalysts were designed, successfully synthesized, and fully characterized and applied for these protocols. During these studies, intermediates resulting from the oxidation of tertiary amines are trapped during the photoinduced electron transfer (PET) process. The reaction was carried out efficiently with a variety of substrates to give the corresponding products at relatively short times in good to excellent yields in parallel with the use of the visible light irradiation as a renewable energy source. Most of these processes are novel or are superior in terms of cost-effectiveness, safety, and simplicity to published reports.