INTRODUCTION:

Schiff base are the compounds containing azomethine group (-HC=N-) and were first reported by Hugo Schiff in 1864.¹ They are condensation products of ketones (or) aldehydes with primary amines which is generally takes place in the presence of acid or base catalyst with heat. (Scheme 1) The common Schiff bases are crystalline solids, which are weakly basic in nature generally form insoluble salts with strong acids.

Scheme 1: General scheme for synthesis of a Schiff base.

Schiff’s bases are important class of organic compounds having a broad range of applications in different fields like: analytical, biological and chemistry.^2,3 Some compounds are act as corrosion inhibitors⁴ and used as catalysts in polymer⁵ and dyes⁶ industries. Schiff bases have more importance in pharmaceutical fields due to its broad spectrum of biological actions like

antimbacterial,⁷ antifungal,⁸ antiviral,⁹ anti-inflammatory,¹⁰ analgesic,¹¹antiepileptics,¹² anti-TB,¹³ anticarcinogenic,¹⁴ antioxidant,¹⁵anthelmintic,¹⁶antimalarial.¹⁷

The tetrahydroisoqunioline ring system is a privileged fundamental scaffold of various alkaloids isolated from natural sources and abundantly found in various plants, soils, and marine microorganisms.¹⁸ Many tetrahydroisoquinoline compounds are considered as antitumor,¹⁹ anticonvulsant, antithrombotic,²⁰ analgesic,²¹ antiinflammatory,²² antifungal, and antibacterial agents.²³ Moreover, tetrahydroisoquinolines are useful compounds as antagonist to NMDA and D1 receptors,²⁴Parkinson’s disease,²⁵ enzyme inhibitory actions for glucosidases,²⁶ and monoamine oxidases.²⁷ The main objective of this present research work is to synthesize and characterize Schieff bases containing tetrahydroisoquinolines moieties.

EXPERIMENTAL SECTION:

Materials and method:

The required chemicals in this work were purchased from Sigma-Aldrich, Alfa Aesar, Acros and other commercial suppliers and used as received without further purification. TLC analysis was performed on Merck 60 F₂₅₄ silica gel TLC plates. ¹H and ¹³CNMR spectra were recorded on Bruker 300 and 600 MHz spectrometer and are reported as chemical shifts (d) in parts per million (ppm). Internal standards or residual solvent signals were used as reference. HRMS (m/z) was recorded in Q-Tof Micro mass spectrometer (LC-MS, ESI mode). Melting points were determined in a capillary melting point apparatus and are uncorrected.

Synthesis of Schiff base from Tetrahydroisoquinoline based Aldehydes:

Equimolar amount of different aminobenzaldehydes (1a, 0.5 mmol) and various aromatic amines (2a, 0.5 mmol) were dissolved in ethanol and few drops of glacial acidic acid were added then the reaction mixture was refluxed for 8 hours in oil bath. The crude product was dried under vacuum and washed 2-3 times with water to remove acetic acid then the pure crystalline product (4) recovered by recrystallization with absolute ethanol.

Substrate Scope:

Various substituted aminobenzaldehydes 1 and aromatic amines 2 were subjected under standard condition for synthesis of an array of Schiff bases 4 (scheme 2). A range of aromatic amines were chosen and the desired products (4a-4m) were obtained in moderate to excellent yields.

Reaction condition: 1a (0.5 mmol), 2a (0.5 mmol), solvent (6 ml), Isolated yield.

Scheme 2: Tetrahydroisoquinoline containing Schiff bases and Substrate Scope

RESULT AND DISCUSSION:

Characterization Data of Products:

(E)-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)aniline, [4h]

Yield 78.6%; Colorless crystalline solid; mp 170-171οC; 1H NMR (600 MHz, CDCl₃) δ 2.47 (dd, J = 16.3, 2.5 Hz, 1H), 3.02-3.14 (comp, 1H), 3.46 (ddd, J = 14.4, 12.6, 4.0 Hz, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 4.27 (ddd, J = 14.3, 5.4, 1.3 Hz, 1H), 4.31-4.49 (comp, 2H), 6.03 (s, 1H), 6.56 (s, 1H), 6.71 (td, J = 7.3, 1.1 Hz, 1H), 6.91-6.95 (comp, 2H), 7.0 (dd, J = 8.4, 1.1 Hz, 1H), 7.11-7.15 (comp, 2H), 7.18-7.21 (comp, 2H), 7.26-7.31 (comp, 2H). 13C NMR (150 MHz, CDCl₃) δ 24.56, 45.48, 46.57, 55.87, 56.10, 73.81, 108.39, 111.41, 113.78, 118.06, 118.79 (2C), 120.90, 122.14, 126.31, 127.58, 128.73, 129.13, 129.19 (2C), 143.84, 148.04, 148.40, 150.77; HRMS (ESI, m/z) calcd for C₂₄H₂₄N₂O₂ [M⁺Na]⁺ 395.4596, observed 395.1871.

Figure 1: ¹H NMR and ¹³C NMR of compound 4h

(E)-N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)-2,6 dimethylaniline, [4c]

Yield 65.0%; Yellow crystalline solid; mp 106-108^οC; 1H NMR (600 MHz, CDCl₃) δ 2.19 (s, 6H), 3.00 (t, J = 5.8, 2.7 Hz, 2H), 3.40 (t, J = 5.8Hz, 2H), 4.26 (s, 2H), 6.96 (dd, J = 8.0, 6.9 Hz, 1H), 7.05-7.09 (comp, 3H), 7.17-7.21 (comp, 3H), 7.25-7.28 (comp, 2H), 7.53 (ddd, J = 6.6, 5.8, 1.7 Hz, 1H), 8.26 (dd, J = 7.9, 1.7 Hz, 1H), 8.63 (s, 1H) .13C NMR (150 MHz, CDCl₃) δ 18.3 (2C), 29.2, 51.98, 55.92, 119.50, 123.4, 123.5, 125.9, 126.2, 126.4, 126.9, 127.9 (2C), 128.1, 128.9, 130.0, 134.6, 132.0, 134.1, 134.4, 151.76, 153.65, 161.25; HRMS (ESI, m/z) calcd for C₂₄H₂₄N₂ [M+Na]⁺ 363.4608, observed 363.1939.

(E)-3-chloro-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)-4-fluoroaniline, [4m]

Yield 84.7%; Colorless crystalline solid; mp 179-180^οC; 1H NMR (600 MHz, CDCl₃) δ 2.48 (dd, J = 16.4, 3.8 Hz, 1H), 3.01-3.09 (comp, 1H), 3.43 (ddd, J = 14.2, 12.6, 4.0 Hz, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 4.23-4.28 (comp, 2H), 4.44 (d, J = 16.7 Hz, 1H), 5.85 (s, 1H), 6.56 (s, 1H), 6.73 (td, J = 7.3, 1.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.98-7.05 (comp, 3H), 7.10 (s, 1H), 7.15 (td, J = 7.8, 7.2, 1.6 Hz, 1H), 7.19-7.23 (comp, 1H); HRMS (ESI, m/z) calcd for C₂₄H₂₂ClFN₂O₂ [M+Na]⁺ 447.8951, observed 447.1324.

(E)-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)-4-methyl aniline, [4i]

Yield 86.4%; Colorless crystalline solid; mp 170-171^οC; 1H NMR (600 MHz, CDCl₃) δ 2.29 (s, 3H), 2.46 (dd, J = 16.4, 3.8 Hz, 1H), 3.03-3.11 (comp, 1H), 3.40-3.48 (ddd, J = 14.3, 12.6, 4.0 Hz, 1H), 3.85 (s, 3H), 3.88 (s, 3H), 4.23-4.32 (comp, 2H), 4.44 (d, J = 16.6 Hz, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.70 (td, J = 7.3, 1.1 Hz, 1H), 6.99 (d, J = 7.3, 1H), 7.06-7.11 (comp, 1H), 7.18-7.21 (comp, 4H), 7.12-7.15 (comp, 1H), 7.20 (s, 1H). HRMS (ESI, m/z) calcd for C₂₅H₂₆N₂O₂[M+Na]⁺ 409.4861, observed 409.1993.

(E)-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)-3-nitroaniline [4k]

Yield 78.5%; Yellow crystalline solid; mp 156-157^οC; 1H NMR (600 MHz, CDCl₃) δ 2.46 (dd, J = 16.6, 3.6 Hz, 1H), 3.06-3.13 (comp, 1H), 3.41-3.46 (ddd, J = 14.2, 12.6, 4.2 Hz, 1H), 3.88 (s, 3H), 4.12 (s, 3H), 4.24-4.30 (comp, 2H), 4.42 (d, J = 16.6 Hz, 1H), 6.10 (s, 1H), 6.55 (s, 1H), 6.72 (td, J = 7.4, 1.1 Hz, 1H), 6.99 (d, J = 7.4, 1H), 7.08-7.14 (comp, 1H), 7.20-7.24 (comp, 4H), 7.12-7.17 (comp, 1H), 7.29 (s, 1H). HRMS (ESI, m/z) calcd for C₂₄H₂₃N₃O₄ [M+Na]⁺ 440.4571, observed 440.1678.

(E)-3,4-dichloro-N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)aniline, [4f]

Yield 72.6%; Yellowish brown crystalline solid; mp 154-155^οC; 1H NMR (600 MHz, CDCl₃) δ 2.37 (dd, J = 16.2, 3.7 Hz, 1H), 3.01-3.11 (comp, 1H), 3.46 (ddd, J = 14.4, 12.4, 4.1 Hz, 1H), 4.23-4.29 (comp, 2H), 4.45 (d, J = 16.8 Hz, 1H), 5.87 (s, 1H), 6.64 (s, 1H), 6.77 (td, J = 7.1, 1.1 Hz, 1H), 6.84-6.89 (comp, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.98-7.08 (comp, 3H), 7.14 (s, 1H), 7.22 (td, J = 7.7, 7.1, 1.6 Hz, 1H), 7.28-7.32 (comp, 1H), 7.40-7.46 (comp, 1H); HRMS (ESI, m/z) calcd for C₂₂H₁₈Cl₂N₂[M+Na]⁺404.2977, observed 403.9982.

(E)-N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)benzylidene)-2,3-dimethylaniline, [4d]

Yield 68.7%; Yellow crystalline solid; mp 108-110^οC; 1H NMR (600 MHz, CDCl₃) δ 2.33 (s, 6H), 3.10 (t, J = 5.7, 2.8 Hz, 2H), 3.39 (t, J = 5.6 Hz, 2H), 4.28 (s, 2H), 6.99 (dd, J = 8.1, 6.8 Hz, 1H), 7.04-7.09 (comp, 3H), 7.20-7.23 (comp, 3H), 7.28-7.33 (comp, 2H), 7.58 (ddd, J = 6.6, 5.7, 1.6 Hz, 1H), 8.28 (dd, J = 7.7, 1.7 Hz, 1H), 8.64 (s, 1H); HRMS (ESI, m/z) calcd for C₂₄H₂₄N₂ [M+Na]⁺ 363.4608, observed 363.0142.

CONCLUSION:

We have synthesized some novel tetrahydroisoquinoline containing Schiff bases using acetic acid as a catalyst in good to excellent yield by simple condensation reaction. Considering the easy availability of these starting materials, this method provides a novel and convenient way of constructing various tetrahydroisoquinoline based heterocyclic compounds. The resulting backbone resembled a range of natural products and bioactive molecules useful for the treatment of various pathophysiological conditions.

CONFLICT:

The authors declare that there is no conflict of interest.

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Received on 03.06.2022 Modified on 24.07.2022

Research J. Pharm. and Tech 2022; 15(9):4115-4118.

DOI: 10.52711/0974-360X.2022.00691