Synthesis of CF<Subscript>3</Subscript>-substituted 1,2,3,4-tetrahydroisoquinolines and 1,2,3,6-tetrahydropyridines

A three-step method for the preparation of CF₃-substituted 1,2,3,4-tetrahydroisoquino-lines and 1,2,3,6-tetrahydropyridines has been suggested. The first step includes alkylation of isoquinoline or 4-methylpyridine at the nitrogen atom with the formation of salts, which are involved into the reaction with Grignard reagent or lithium triethylborohydride to give enamines. The enamines undergo nucleophilic trifluoromethylation upon the action of Me₃SiCF₃ under acidic conditions.     

Some reactions of 1-alkyl-1,2,3,4-tetrahydropyridines with organic azides. Synthesis of 1-alkylpiperidylidene-2-sulfonamides

The 1,3-dipolar cycloaddition reaction of 1-substituted-1,2,3,4-tetrahydropyridines 4a-d with organic azides 5 afforded the respective 1-substituted-piperidylidene-2-sulfonamides 6 . In contrast, the reaction of (E)-1-(1-propenyl)-1,2,3,4-tetrahydropyridine ( 4e ) with 4-chlorobenzenesulfonyl azide yielded 6m as well as 1-(4-chlorophenyl)sulfonimine-1,2,3,4-tetrahydropyridine ( 7 ) arising from addition of the azide to the (E)-1-(1-propenyl) substituent of 4e .     

A comparative study using conventional methods,ionic liquids,microwave irradiation and combinations thereof for the synthesis of 5-trifluoroacetyl-1,2,3,4-tetrahydropyridines

This study reports a comparison between conventional methods, ionic liquids, microwave (MW) irradiation, and combinations thereof for the synthesis of a series of fourteen 1-aryl-2-arylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines. In all of the reactions tested, the products were obtained at very good yields (87–97%), but the reaction times were very different, depending on the method used. Comparing to other methods, the time decreased to 1?min when [BMIM]BF₄ under MW irradiation was used, thus evidencing a synergic effect.     

Synthesis of 1,2,4-trisubstituted-1,2,5,6-tetrahydropyridines

A novel method for the synthesis of 1,2,4-trisubstituted- or 1,2,3,4-tetrasubstituted-1,2,5,6-tetrahydropyridine is presented. The process was carried out by the bromomethoxylation of 4-substituted-1,2,5,6-tetrahydropyridines 1 with N-bromosuccinimide (NBS) in methanol, dehydrobromination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and boron trifluoride etherate (BF₃-OEt₂)-catalyzed cross coupling of the corresponding enamine with trimethylsilyl-based nucleophiles. Homokainoid analogs were also synthesized via the protocol.     

Steric and electronic substitution effects on the thermal oxidation of 5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyridines

Various 4-aryl substituted 5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyridines were oxidized to their corresponding 4-aryl-5-carboethoxy-2-oxo-1,2-dihydropyridines by potassium peroxydisulfate in aqueous acetonitrile under thermal conditions. The products were obtained in good to excellent yields. Based on the proposed mechanism, the removal of the hydrogen from the C₄-atom of the heterocyclic ring by the hydroxyl radical formed in situ is occurred in the rate determining step, which is influenced by the steric and electronic effects of the substituted aryl group attached to this atom and also the stability of the radical intermediate involved in the oxidation reaction. The experimental results were supported by the computational studies.     

Electron-transfer induced oxidation of 2-oxo-1,2,3,4-tetrahydropyridines using TiO<Subscript>2</Subscript> anatase-nanoparticles: steric and electronic substitution effects

The steric and electronic effects of 4-substitution in various 4-aryl substituted 5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyridines were investigated by exposing them to the UV-light in the presence or absence of the TiO₂ anatase-nanoparticles. The results clearly indicate the effective presence of the photo-catalyst and also the electron-donating effect of 4-aryl substitution on drastic decreasing of the irradiation time. The experimental results concerning the electronic nature of 4-substitution were supported by the DFT computational studies and cyclic voltammetric measurements.     

A flexible method for the synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines from chloro-containing propargylamines

A general approach for the stereoselective synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines is described. The addition of 4-chloro-1-butyne to Ellman sulfinimines to produce chloro-containing propargylamines, reduction with Lindlar catalyst, and cyclization using LHMDS provides efficient, stereoselective access to diverse 2-substituted 1,2,5,6-tetrahydropyridines. For substrates incompatible with the LHMDS cyclization reaction conditions removal of the sulfinamide moiety and cyclization with Cs₂CO₃ allows the preparation of the corresponding 2-substituted 1,2,5,6-tetrahydropyridines. This method can be extended to the synthesis of 2-substituted piperidines through reduction of the chloro-containing propargylamine with PtO₂.     

Multicomponent Reactions Based on SO2 Surrogates: Recent Advances

Compounds containing sulfonyl-derived functional groups have received intensive attention owing to their widespread applications in life science, pharmaceuticals and materials science. To access this type of compounds, the multi-component sulfonylation reactions relying on sulfur dioxide (SO₂) insertion strategy have emerged as novel and attractive approaches in the past decade. The utilization of SO₂ surrogates for SO₂ insertion in the multicomponent reactions (MCRs) have improved reaction flexibility and step economy. Moreover, some advances have been achieved in the challenging but practical asymmetric MCRs for the construction of high value-added chiral sulfones. This review aims to summarize the progress made in the MCRs involving SO₂ surrogates from 2019 to 2022, and point out the potentials and challenges in this field.     

The dramatic effect of thiophenol on the reaction pathway of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with thiophenolates: ring expansion versus nucleophilic substitution

Ethyl 4-methyl-2-oxo-7-phenylthio-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylate and/or ethyl 6-methyl-2-oxo-4-(phenylthiomethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained in the reaction of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with PhSNa or PhSK with or without PhSH, depending on the reagent ratio, reaction time, or temperature, as a result of ring expansion and/or nucleophilic substitution. The reaction pathway was affected strongly by the basicity-nucleophilicity of the reaction media. The results obtained were confirmed by reactions of 4-mesyloxymethyl-6-methyl-5-tosyltetrahydropyrimidin-2-one with PhSNa/PhSH and ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with NaCN/HCN or NaCH(COOEt)₂/CH₂(COOEt)₂.     

N-Methylmorpholinium 4-aryl-5-cyano-3-methoxycarbonyl-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates: synthesis and properties

Reactions of aromatic aldehydes with cyanothioacetamide and dimethyl malonate in the presence ofN-methylmorpholine affordedN-methylmorpholinium 4-aryl-5-cyano-3-methoxycarbonyl-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. The latter were used to synthesize substituted 6-(alkylthio)-2-oxo-1,2,3,4-tetrahydropyridines. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 485–487, March, 2000.     

N-aryl-2-hydroxy-1,2,3,4-tetrahydropyridines and N-aryl-2-chloromethylene-1,2,3,4-tetrahydropyridines — successive intermediates in the Hantzsch synthesis of 1,4-dihydropyridines

Esters of 4-chloro-2-arylideneacetoacetic acid I and esters of N-arylaminocrotonic acid II form stable N-aryl-3,4-trans-2-hydroxy-1,2,3,4-tetrahydropyridines III. Their regio- and stereoselective dehydration results in N-aryl-2-chloromethylene-1,2,3,4-tetrahydropyridines with an exocyclic bond, IV. Compounds IV isomerize to the corresponding N-aryl-2-chloromethyl-1,4-dihydropyridines V in acid medium. Michael addition of compounds I and II in chloroform or benzene forms carbocyclic derivatives of cyclohexene VI.Latvian Institute of Organic Synthesis, Riga LV-1006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 915–920, July, 1997.     

Stereocontrolled synthesis of polysubstituted piperidines from vinylogous Mannich adducts and aldehydes

Condensation of readily available 5-(aminoalkyl)furan-2-ones, derived from the Mannich-type reaction between 2-silyloxyfurans and acyliminium ions, with an α-unsubstituted aliphatic aldehyde leads to substituted 1,2,3,4-tetrahydropyridines in a process involving an enamine conjugate addition. Reduction of the tetrahydropyridine double bond then affords 3,4,5-tri- or 3,4,5,6-tetra-substituted piperidines stereoselectively.     

Synthesis of amino substituted 4-oxo-1,2,3,4-tetrahydropyridines from arylhydrazones and methyl acrylate

Arylhydrazones react with methyl acrylate in the presence of aluminium chloride to afford amino substituted 4-oxo-1,2,3,4-tetrahydropyridines.     

Synthesis of polyfunctionalized 1,2,3,4-tetrahydropyridines from ethyl acetoacetate and cyclic aminals

Polyfunctionalized 1,2,3,4-tetrahydropyridines were synthesized in up to 90% yield by condensation of ethyl acetoacetate with cyclic aminals in methanol.     

Intrinsic kinetic study on the oxidation of 6-pentyl-1,2,3,4-tetrahydroanthacene-9,10-diol

A new working solution consisting of 2-pentylanthraquinone (PAQ) and 6-pentyl-1,2,3,4-tetrahydroantraquinone (4HPAQ) was hydrogenated and then oxidized by O₂ to produce H₂O₂. The oxidation reaction was conducted in a well-stirred batch reactor at 30~50^oC and 0.10~0.20 MPa. By measuring the concentrations of generated H₂O₂ by iodometry, the intrinsic kinetics for the gas-liquid oxidation of 6-pentyl-1,2,3,4-tetrahydroanthacene- 9,10-diol (4HPAQH₂, the only hydrogenated product in the hydrogenated working solution) with molecular oxygen were studied. An exponential model was employed to describe the reaction rate and the kinetic parameters were obtained. The results show that the reaction rate is 0.7 and 1.4 order in the concentration of 4HPAQH₂ and oxygen pressure respectively, and the activation energy for oxidation is 41.3 kJ/mol. This revised version was published online in June 2006 with corrections to the Cover Date.     

A Visible Light Photocatalytic Cross‐Dehydrogenative Coupling/Dehydrogenation/6π‐Cyclization/Oxidation Cascade: Synthesis of 12‐Nitroindoloisoquinolines from 2‐Aryltetrahydroisoquinolines

A visible light‐induced photocatalytic dehydrogenation/6π‐cyclization/oxidation cascade converts 1‐(nitromethyl)‐2‐aryl‐1,2,3,4‐tetrahydroisoquinolines into novel 12‐nitro‐substituted tetracyclic indolo[2,1‐a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1‐aminoanthraquinone in combination with K₃PO₄. Further, the 12‐nitroindoloisoquinoline products can be accessed directly from C1‐unfunctionalized 2‐aryl‐1,2,3,4‐tetrahydroisoquinolines by extending the one‐pot protocol with a foregoing photocatalytic cross‐dehydrogenative coupling reaction, resulting in a quadruple cascade transformation.     

Highly regioselective intermolecular arylation of 1,2,3,4-tetrahydropyridines

Using a catalytic amount of PdCl2(dppf) x CH2Cl2 in combination with Ag3PO4 and NaOAc, a range of arylated 1,2,3,4-tetrahydropyridines are synthesized in good yields and with complete selectivity at the beta-position. The reaction is compatible with a variety of electron-donating and electron-withdrawing aryl iodides as well as with heteroaryl iodides. The application of these tetrahydropyridines toward the synthesis of polysubstituted piperidines is also demonstrated.     

Oxidative Reactions of Azines. 6. Lactamization of 4-Aryl- and 4-Phenethenyl-substituted 1,2,3,6-Tetrahydropyridines and Dihydroxylation of 4-Aryl-1,2,5,6-tetrahydropyrid-2-ones Using Potassium Permanganate

Oxidation of 4-phenyl-, 4-(4-pyridyl)-, and 4-phenethenyl-1,2,3,6-tetrahydropyridines with potassium permanganate can stop at the stage of the introduction of an oxo group into the allyl C₍₂₎ position of the piperideine fragment. In contrast to their precursors, 4-aryltetrahydropyridin-2-ones obtained in this way can be converted to 3,4-dihydroxy-2-oxopiperidines under Wagner reaction conditions.     

New furochromone derivatives as promising in-vitro anti-proliferative agents toward HepG-2 and MCF-7 cell lines with molecular docking studies

Based on the considerable features of the multicomponent reactions (MCRs) in the field of organic and medicinal chemistry, the present work was designed to synthesize a new series of imidazole, pyridine, and pyrimidine derivatives using MCRs to obtain new anti-proliferative agent beside exploration of their interaction mechanism by molecular docking technique. MCRs of furochromone carbaldehyde 1 , benzoin, and ammonium acetate afforded the corresponding 2,4,5-trisubstituted imidazole 2 . However, MCRs of 1 with benzoin, amine derivatives, and ammonium acetate yielded the corresponding 1,2,4,5-tetrasubstituted imidazole 3a,b . In addition, pyridine 4a,b-5a,b and pyrimidine derivatives 6a,d were synthesized via condensation of 1 with different carbonyl compounds and ammonium acetate or benzyl urea, respectively. The in-vitro anti-Proliferative activities of the new furochromone derivatives were screened toward MCF-7 and HepG-2 cancer cell lines as well as the normal cell line (human normal melanocyte, HFB4) in comparison to the known anticancer drugs: 5-fluorouracil and doxorubicin using MTT assay. Compounds 5a and 5b revealed effective anti-proliferative activity against MCF-7 cell lines with IC ₅₀ 18 and 22 μg/mL, respectively, compared to 5-fluorouracil (IC ₅₀ of 13 μg/mL). However, compounds 6a-d exhibited potent activity against HepG-2 cancer cell lines of IC ₅₀ ranging from 18 to 20 μg/mL compared to doxorubicin (IC ₅₀ of 14 μg/mL). Moreover, the binding mode of the most active furochromones 5a,b and 6a-d inside the active site of the epidermal growth factor receptor (EGFR) kinase enzyme (PDB ID: 5CAV) were studied using molecular docking technique. Compounds 6b,c showed excellent docking results compared to the known EGFR inhibitors ( 4ZQ ).     

Borane-Catalyzed Tandem Cyclization/Hydrosilylation Towards Enantio- and Diastereoselective Construction of trans-2,3-Disubstituted-1,2,3,4-Tetrahydroquinoxalines

Recent years have witnessed marked progress in the efficient synthesis of various enantioenriched 1,2,3,4-tetrahydroquinoxalines. However, enantio- and diastereoselective access to trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines remains much less explored. Herein we report that a frustrated Lewis pair-based catalyst generated via in situ hydroboration of 2-vinylnaphthalene with HB(C₆F₅)₂ allows for the one-pot tandem cyclization/hydrosilylation of 1,2-diaminobenzenes and 1,2-diketones with commercially available PhSiH₃ to exclusively afford trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines in high yields with excellent diastereoselectivities (>20 : 1 dr). Furthermore, this reaction can be rendered asymmetric by using an enantioenriched borane-based catalyst derived from HB(C₆F₅)₂ and a binaphthyl-based chiral diene to give rise to enantioenriched trans-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines in high yields with almost complete diastereo- and enantiocontrol (>20 : 1 dr, up to >99 % ee). A wide substrate scope, good tolerance of diverse functionality and up to 20-gram scale production are demonstrated. The enantio- and diastereocontrol are achieved by the judicious choice of borane catalyst and hydrosilane. The catalytic pathway and the origin of the excellent stereoselectivity are elucidated by mechanistic experiments and DFT calculations.