1-[2-(4-Methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl-7-coumarinyloxy)ethyl]-1H-1,2,3-triazol-4-yl}pentyl)-1H-1,2,3-triazole

Abstract

Nature often produces compounds with a high degree of symmetry to reduce structural information and complexity. Synthesis of identical twin drugs, through the linkage of two identical pharmacophoric entities, is a classical strategy to produce more potent and/or selective drugs. Herein, two units of the privileged core of the coumarin hymecromone were linked together using “click chemistry”. Synthesis of 1-[2-(4-Methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl-7-coumarinyloxy)ethyl]-1H-1,2,3-triazol-4-yl}pentyl)-1H-1,2,3-triazole was achieved by coupling of two identical units of an azido coumarin with a symmetrical alkine using copper(I)-catalyzed alkyne-azide cycloaddition reaction, in good yields and with complete regioselectivity.

1. Introduction

Aiming to reduce structural information and complexity, nature often produces compounds with a high degree of symmetry, as observed for the macromolecules HIV protease, hemoglobin and insulin. The linkage of two identical pharmacophoric entities, generating an “identical twin drug” or homodimer derivative, is a classical strategy used in medicinal chemistry to produce more potent and/or selective drugs compared to the single entities. These new compounds will have specific pharmacokinetic and pharmacodynamic properties, which normally differ from what it would be expected by simple doubling the dose of the drug [1].

Coumarins are a large class of compounds that display a wide variety of interesting biological properties [2,3,4,5,6,7], being their 2H-chromen-2-one nuclei the structural feature responsible for this “privileged” pharmacological profile. This planar ring system is composed by one aromatic ring, capable of establishing hydrophobic, π-π, CH-π and cation-π interactions, and one lactone ring, which contains two oxygen atoms that may interact via hydrogen bonding with a series of amino acid residues, such as serine, threonine, cysteine, asparagine, glutamine, and tyrosine [8].

In order to explore the possibility of potency and selectivity enhancements provided by the synthesis of twin drugs, two units of the privileged 2H-chromen-2-one nuclei of hymecromone (7-hydroxy-4-methylcoumarin) were linked together using “click chemistry”, a set of highly efficient conjugation reactions commonly used to join two or more entities [9].

2. Experimental Section

2.1. General Information

All chemicals were purchased as reagent grade and used without further purification. Solvents were distilled and/or dried according to standard methods [11]. Column chromatography was performed on silica gel 60 (0.040–0.063 mm) using CH₂Cl₂ and CH₂Cl₂/EtOAc (5:1 v/v or 2:1 v/v). Microwave-assisted reactions were performed on a CEM Discover^® Microwave System. Melting points were determined on a Fisatom 431 apparatus, which were uncorrected. MS spectra were recorded on Q-Tof micro Waters high resolution mass spectrometer, operating in electrospray ionization mode. Nuclear magnetic resonance spectra were recorded on Bruker Advance DPX 400 (400 MHz) spectrometer. Chemical shifts (δ) are given in parts per million downfield from tetramethylsilane. 7-(2-Azidoethoxy)-4-methyl-2H-chromen-2-one (1) was synthesized according to reported methods [10] and coupled with commercial 1,8-nonadiyne (2) by using the copper(I)-catalyzed alkyne-azide cycloaddition reaction, in good yields and with complete regioselectivity (Scheme 1).

2.2. Synthesis of 1-[2-(4-Methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl-7-coumarinyloxy)ethyl]-1H-1,2,3-triazol-4-yl}pentyl)-1H-1,2,3-triazole (3)

1,8-nonadiyne (2) (0.15 mL, 1.1 equiv) was added to a solution of 1 in DMF (0.5–1 M, 0.1 mL) in a microwave flask (0.2 mL) equipped with a stirring bar. Sodium ascorbate (0.1 equiv) and CuSO₄ (0.03 equiv) were added, the tube was sealed, and the mixture was stirred for 25 seconds at room temperature, followed by heating under microwave irradiation at 70 °C (18 W) in 2 cycles of 20 min. Consumption of the reactant was followed by TLC (CH₂Cl₂/EtOAc 2:1 v/v). The reaction mixture was partitioned between H₂O and EtOAc, the aqueous phase was extracted with EtOAc three times. The organic phase was dried over MgSO₄, filtered, concentrated, and the residue purified by column chromatography with a CH₂Cl₂/EtOAc gradient [10]. Yield 67%; mp 168 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 2H), 7.64 (d, 2H, J 8.8 Hz), 6.96 (d, 2H, J 2.6 Hz), 6.91 (dd, 2H, J 8.8, 2.6 Hz), 6.19 (d, 2H, J 1.2 Hz), 4.73 (t, 4H, J 5.0 Hz), 4.50 (t, 4H, J 5.0 Hz), 2.57 (t, 4H, J 7.6 Hz), 2.36 (d, 6H, J 1.2 Hz), 1.57 (quint, 4H, J 7.6 Hz), 1.31 (quint, 2H, J 7.6 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 160.9, 160.1, 154.6, 153.4, 146.9, 126.5, 122.4, 113.5, 112.5, 111.4, 101.4, 66.9, 48.7, 28.7, 28.1, 24.9, 18.1; HRMS (ESI) m/z, calcd. for C₃₃H₃₅N₆O₆ [M + H]⁺: 611.2573, found: 611.3377.