Synlett 2018; 29(15): 2066-2070
DOI: 10.1055/s-0037-1609494
letter
© Georg Thieme Verlag Stuttgart · New York

A De Novo Synthetic Route to 1,2,3,4-Tetrahydroisoquinoline Derivatives

Renáta A. Ábrahámi
a   Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary   Email: kiss.lorand@pharm.u-szeged.hu   Email: fulop@pharm.u-szeged.hu
,
Santos Fustero
c   Departamento de Química Orgánica, Facultad de Farmàcia, Universidad de Valencia, Av. Vicente Andrés Estellés, s/n 46100 Valencia, Spain
,
Ferenc Fülöp*
a   Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary   Email: kiss.lorand@pharm.u-szeged.hu   Email: fulop@pharm.u-szeged.hu
b   MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, H-6720 Szeged, Eötvös u. 6, Hungary
,
Loránd Kiss*
a   Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary   Email: kiss.lorand@pharm.u-szeged.hu   Email: fulop@pharm.u-szeged.hu
› Author Affiliations
We are grateful to the Hungarian Research Foundation (NKFIH Nos. K 115731 and K 119282) for financial support. The financial support of the GINOP-2.3.2-15-2016-00038 project is also acknowledged. This research was supported by the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008.

Further Information

Publication History

Received: 09 February 2018

Accepted after revision: 07 March 2018

Publication Date:
22 March 2018 (online)


Abstract

A novel synthetic approach was developed for the construction of the 1,2,3,4-tetrahydroisoquinoline framework possessing varied functions. The synthetic strategy was based on oxidative ring opening of some indene derivatives through their C=C bond, followed by double reductive amination of the dicarbonyl intermediates with various primary alkyl- or fluoroalkylamines.

Supporting Information

 
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  • 8 1,2,3,4-Tetrahydroquinolines 3–9, 12, and 13: General ProcedureNaIO4 (1.5 equiv) was added to a stirred solution of the dihydroxy compound 2 or 11 (4 mmol) in THF–H2O (25 mL + 2 mL), and the mixture was stirred for 1 h at 20 °C under argon. H2O (40 mL) was added to dissolve the precipitate, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The extracts were then combined and dried (Na2SO4). The crude diformyl product was immediately used in the reductive cyclization without purification. The appropriate fluorinated amine (1 equiv) and NaHCO3 (2 equiv) were added to the solution of the diformyl intermediate in EtOH (20 mL), and the mixture was stirred at 20 °C for 10 min. NaCNBH3 (1 equiv) and AcOH (2 drops) were added, and the mixture was stirred for a further 4 h at 20 °C. The mixture was then diluted with H2O (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexane–EtOAc).2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinoline(3)Brown oil; yield: 247.3 mg (31%); Rf  = 0.17 (hexane–EtOAc, 20:1). 1H NMR (400 MHz, DMSO-d 6): δ = 2.77–2.84 (m, 4 H, H-3, H-4) 2.83–2.95 (td, 1 J = 15.6, 2 J = 4.3 Hz, 2 H, CH2CHF2), 3.71 (s, 2 H, H-1), 6.02 –6.39 (tt, 1J = 55.8, 2 J = 4.3 Hz, 1 H, CHF2), 6.98–7.18 (m, 4 H, Ar-H). 13C NMR (100 MHz, DMSO-d 6): δ = 29.2, 51.8, 56.6, 59.5 and 59.8 and 60.02 (t, 2 J C,F= 28 Hz, CCHF2), 114.5 and 116.9 and 119.3 (t, 1 J C,F= 237.5 Hz, CHF2), 126.4, 126.9, 127.1, 129.3, 134.6, 135.3. 19F NMR (376 MHz, DMSO): δ = –115.2. MS: (ESI) m/z = 198.2 [M + 1]; Anal. Calcd for C 11H13F2N: C, 66.99; H, 6.64; F, 19.27; N, 7.10. Found: C, 66.96; H, 6.63; F, 19.26; N, 7.10. For details of the other synthesized compounds, see the Supporting Information.
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