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Synthesis of tetrahydroquinolines

Recent Literature

Gold-catalyzed intramolecular hydroarylation and transfer hydrogenation of N-aryl propargylamines provides tetrahydroquinolines and 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines in good yields. The method offers simple reaction conditions, good substrate compatibility, high efficiency, and excellent regioselectivity.
N. Yi, Y. Liu, Y. Xiong, H. Gong, J.-P. Tan, Z. Fang, B. Yi, J. Org. Chem., 2023, 88, 11945-11953.

The combination of Brønsted acid catalysis with visible-light induction enables a highly enantioselective synthesis of 2-substituted tetrahydroquinolines from 2-aminoenones through a relay visible-light-induced cyclization/chiral phosphoric acid-catalyzed transfer hydrogenation reaction.
W. Xiong, S. Li, B. Fu, J. Wang, Q.-A. Wang, W. Yang, Org. Lett., 2019, 21, 4173-4176.

A chiral phosphoric acid as the sole catalyst enables an enantioselective synthesis of tetrahydroquinolines from 2-aminochalcones via chiral phosphoric acid-catalyzed dehydrative cyclization, followed by chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester. Various 2-aminochalcones could be applicable to this protocol, and the desired tetrahydroquinolines were obtained in excellent yields and with excellent enantioselectivities.
D. Y. Park, S. Y. Lee, J. Jeon, C.-H. Cheon, J. Org. Chem., 2018, 83, 12486-12495.

A highly efficient gold-catalyzed tandem hydroamination/asymmetric transfer hydrogenation provides tetrahydroquinolines in excellent yields and enantioselectivities in the presence of a chiral phosphate. In this reaction, the gold catalyst acts as a π-Lewis acid in the hydroamination step and as an effective chiral Lewis acid in the asymmetric hydrogen-transfer.
Y.-L. Du, Y. Hu, Y.-F. Zhu, X.-F. Tu, Z.-Y. Han, L.-Z. Gong, J. Org. Chem., 2015, 80, 4754-4759.

Consecutive hydroamination/asymmetric transfer hydrogenation under relay catalysis of an achiral gold complex/chiral Brønsted acid binary system allows a direct transformation of 2-(2-propynyl)aniline derivatives into tetrahydroquinolines with high enantiomeric purity.
Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc., 2009, 131, 9182-9183.

A transfer hydrogenation protocol for the reduction of quinolines, quinoxalines, pyridines, pyrazines, indoles, benzofurans, and furan derivatives with borane-ammonia (H₃N-BH₃) as the hydrogen source and a commercially available RuCl₃·xH₂O precatalyst provides the corresponding alicyclic heterocycles in very good isolated yields.
T. Bhatt, K. Natte, Org. Lett., 2024, 26, 866-871.

A boronic acid catalyzed one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation with a carbonyl compound provides N-alkyl tetrahydroquinolines in the presence of Hantzsch ester under mild reaction conditions. The organoboron catalysts behave as both Lewis acids and hydrogen-bond donors.
P. Adhikari, D. Bhattacharyya, S. Nandi, P. K. Kancharla, A. Das, Org. Lett., 2021, 23, 2437-2442.

With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamate precursors.
B. H. Yang, S. L. Buchwald, Org. Lett., 1999, 1, 35-37.

An environmentally friendly iridium-catalyzed direct cyclization of N-methylanilines with 1,3-propanediol provides tetrahydroquinolines with water as the sole by-product. Under similar reaction conditions, direct cyclization of anilines with 1,3-propanediol produced tetrahydrobenzoquinolizines.
M. Minakawa, K. Watanabe, S. Toyoda, Y. Uozumi, Synlett, 2018, 29, 2385-2389.

A ligand- and base-free silver-catalyzed reduction of quinolines provides a facile, environmentally friendly, and practical access to various 1,2,3,4-tetrahydroquinoline derivatives at room temperature. Mechanistic studies revealed that the effective reducing species was Ag-H.
Y. Wang, B. Dong, Z. Wang, X. Cong, X. Bi, Org. Lett., 2019, 21, 3631-3634.

A lanthanide/B(C₆F₅)₃-promoted hydroboration reduction of indoles and quinolines with pinacolborane (HBpin) provides a range of nitrogen-containing compounds in good yields. Large-scale synthesis and further transformations to bioactive compounds indicate that the method has potential practical applications.
J. Zhang, Z. Chen, M. Chen, Q. Zhou, R. Zhou, W. Wang, Y. Shao, F. Zhang, J. Org. Chem., 2024, 89, 887-897.

The use of unsupported nanoporous gold (AuNPore) as a catalyst and organosilane with water as a hydrogen source enables a highly efficient and regioselective hydrogenation of quinoline derivatives to 1,2,3,4-tetrahydroquinolines. The AuNPore catalyst can be readily recovered and reused without any loss of catalytic activity.
M. Yan, T. Jin, Q. Chen, H. E. Ho, T. Fujita, L.-Y. Chen, M. Bao, M.-W. Chen, N. Asao, Y. Yamamoto, Org. Lett., 2013, 15, 1484-1487.

B(C₆F₅) enables a metal-free hydrogenative reduction of substituted N-heteroaromatics using hydrosilanes as reducing agents. The optimized conditions were successfully applied to quinolines, quinoxalines, and quinoline N-oxides. The initial step in the catalytic cycle involves 1,4-addition of the hydrosilane to the quinoline to give a 1,4-dihydroquinoline followed by (transfer) hydrogenation to deliver the tetrahydroquinoline.
N. Gandhamsetty, S. Park, S. Chang, Synlett, 2017, 28, 2396-2400.

An efficient and convenient palladium-catalyzed reductive system by employing sodium hydride as the hydrogen donor and acetic anhydride as an activator enables the transfer hydrogenation and acetylation of a wide range of N-heteroarenes including quinoline, phthalazine, quinoxaline, phenazine, phenanthridine, and indole.
F. Luo, X. Chen, J. Yu, Y. Yin, X. Hu, Y. Hu, X. Liu, X. Chen, S. Zhang, Y. Hu, Synthesis, 2023, 55, 1451-1459.

Boronic acid catalyzed one-pot reductions of quinolines with Hantzsch ester followed by N-arylations via external base-free Chan-Evans-Lam coupling provide N-aryl tetrahydroquinolines under mild reaction conditions. The use of an inexpensive N-arylation protocol, aerobic reaction conditions, and functional group diversity are important practical features.
D. Bhattacharyya, S. K. Senapati, A. Das, Synlett, 2023, 34, 651-656.

Upon activation with trifluoromethanesulfonyl anhydride, secondary N-arylamides undergo smooth intermolecular dehydrative [4 + 2] aza-annulation with alkenes under mild conditions to give 3,4-dihydroquinolines, amenable to further functionalization. The use of NaBH₄ or DDQ in a subsequent step enables the synthesis of tetrahydroquinolines or quinolines, respectively.
Y.-H. Huang, S.-R. Wang, D.-P. Wu, P.-Q. Huang, Org. Lett., 2019, 21, 1681-1685.

A Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones provides unprotected, cyclic β-amino acids featuring either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines allows for retaining both nitrogen and oxygen functionalities in the product. The traceless, redox neutral process proceeds with very low catalyst loading.
J.-S. Yu, M. Espinosa, H. Noda, M. Shibasaki, J. Am. Chem. Soc., 2019, 141, 10530-10537.

A metal-free photocatalytic selective hydroxylation of benzylic methylenes to secondary alcohols utilizes low-cost eosin Y as photocatalyst, O₂ as green oxidant, and inexpensive triethylamine as inhibitor for overoxidation. The mild reaction conditions enable the production of secondary benzylic alcohols in good yields.
Z. Tan, T. Chen, J. Zhu, W. Luo, D. Yu, W. Guo, J. Org. Chem., 2024, 89, 2656-2664.

A three-component Povarov reaction of aldehydes, anilines, and benzyl N-vinylcarbamate in the presence of 0.1 equiv of a chiral phosphoric acid afforded cis-2,4-disubstituted tetrahydroquinolines in good yields and excellent enantiomeric excesses. This three-component reaction enables a very short synthesis of torcetrapib.
H. Liu, G. Dagousset, G. Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc., 2008, 131, 4598-4599.

A chiral BINOL-derived phosphoric acid diester catalyzed an inverse electron-demand aza Diels-Alder reaction of aldimine with enol ethers to give tetrahydroquinoline derivatives with excellent enantioselectivity.
T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc., 2006, 128, 13070-13071.