Efficient Straightforward Synthesis of Amidopiperazinophanes as Versatile Novel Supramolecular Scaffolds

Abstract

A simple one-pot synthesis of amidopiperazinophanes with a combination of electron-deficient amide groups and electron-rich alkyne and piperazine functionalities has been achieved by using multicomponent reaction (MCR) methodology with the Mannich reaction. Herein, we demonstrate the synthesis of macrocyclic amide structures in good yields. These macrocycles, with electron donor/acceptor sites, are versatile molecules for host–guest and binding.

Key words

supramolecular - piperazine - host-guest - amide - Mannich reaction - multicomponent reaction

• References

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• 24 Synthesis of Precyclophane Amides; General Procedure A: A solution of the diacid chloride (3.0 g, 1.48 mmol) in anhydrous dichloromethane (100 mL) and a solution of the amine (4.82 g, 2.96 mmol) and triethylamine (1.65 g, 1.63 mmol) in anhydrous dichloromethane (100 mL) were simultaneously added dropwise with stirring to dichloromethane (500 mL) over 6 h. After the addition was complete, the reaction mixture was stirred for another 6 h. The solvent was removed under reduced pressure and the residue obtained was then dissolved in dichloromethane (300 mL), washed with water (2 × 100 mL) to remove triethylamine hydrochloride and then dried over anhydrous Na₂SO₄. Filtration and removal of the dichloromethane gave the crude precyclophane, which was purified by column chromatography (SiO₂) using CHCl₃/MeOH (97:3) as eluent.Synthesis of Piperazinophanes/Cyclophane Amides by Mannich Reaction; General Procedure B:²³ A mixture of precyclophane diyne (0.2 g, 3.98 mmol), piperazine (0.04 g, 3.98 mmol), and formaldehyde (0.02 g, 7.96 mmol, from 37–41% aq. formaldehyde) and CuCl (0.04 g, 3.98 mmol) in dioxane (30 mL) was heated to reflux for 2 h under nitrogen. After the reaction was complete, the solvent was removed under reduced pressure, the residue was extracted with CHCl₃ (3 × 100 mL), washed with water (2 × 100 mL), brine (150 mL) and dried over anhydrous Na₂SO₄. The solvent was removed and the crude product was purified by column chromatography on silica gel using CHCl₃/MeOH (24:1) as eluent. S-Propargyloxy-2-aminothiophenol 19: The S-propargyloxy-2-aminothiophenol (19) was prepared and obtained as dark-brown liquid, which was reported earlier from our laboratory.^3b Preparation of Diacid Chlorides: The diacid chlorides 20–25 were prepared from the corresponding diacids, as reported earlier by our group.²² Representative Analytical DataN ¹,N ³-Bis(2-(prop-2ynylthio)phenyl)isophthalamide (14): By following General Procedure A, the precyclophane amide diyne 14 was obtained as a brown solid from diacid chloride 21 (3.0 g, 1.48 mmol) and S-propargyloxy-2-aminothiophenol 19 (4.84 g, 2.97 mmol). Yield: 4.38 g (65%); mp 120 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.21 (t, J = 2.4 Hz, 2 H), 3.50 (d, J = 2.7 Hz, 4 H), 7.16 (t, J = 7.5 Hz, 2 H), 7.48 (t, J = 8.1 Hz, 2 H), 7.69 (t, J = 7.8 Hz, 2 H), 8.20 (d, J = 6.6 Hz, 2 H), 8.60 (s, 2 H), 8.60 (s, 2 H), 8.62 (s, 2 H), 9.60 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 25.3, 72.8, 79.5, 120.6, 122.0, 124.7, 125.9, 129.6, 130.7, 131.0, 135.6, 136.5, 140.3, 164.2. MS (EI-TOF): m/z = 456 [M⁺]. Anal. Calcd for C₂₆H₂₀N₂O₂S₂: C, 68.33; H, 4.45; N, 6.20.5-Hydroxy-N ¹,N ³-bis(2-(prop-2-ynylthio)phenyl)isophthal Amide (17): By following General Procedure A, the precyclophane amide diyne 17 was obtained as a white solid from the diacid chloride 24 (3.0 g, 1.38 mmol) and S-propargyloxy-2-aminothiophenol 19 (4.48 g, 2.8 mmol). Yield: 4.34 g (67%); mp 152 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.58 (s, 2 H), 3.52 (s, 4 H), 7.16 (s, 2 H), 7.43 (s, 2 H), 7.64 (s, 4 H), 7.99 (s, 1 H), 8.39 (s, 2 H), 9.55 (s, 2 H), 9.89 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 24.2, 72.5, 79.1, 116.1, 117.5, 120.9, 122.8, 124.4, 129.9, 135.2, 136.2, 139.4, 158.0, 164.1. MS (EI-TOF): m/z = 472 [M⁺]. Anal. Calcd for C₂₆H₂₀N₂O₃S₂: C, 65.97; H, 4.20; N, 6.02. Cyclophane Amide 1: The cyclophane amide 1 was afforded as a white solid from the precyclophane amide diyne 13 (0.4 g, 0.88 mmol), piperazine (0.08 g, 0.88 mmol), formaldehyde (0.05 g, 1.76 mmol, from 37–41% aq. formaldehyde) and CuCl (0.09 g, 0.88 mmol). Yield: 0.15 g (31%); mp 186 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.56 (s, 8 H), 3.04 (s, 4 H), 3.56 (s., 4 H), 7.14 (t, J = 7.5 Hz, 2 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.64 (t, J = 7.5 Hz, 2 H), 7.68 (s, 4 H), 8.12 (d, J = 8.1 Hz, 2 H), 9.69 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 25.6, 46.8, 51.4, 79.2, 80.2, 119.1, 120.3, 122.8, 124.6, 131.5, 136.3, 137.1, 140.3, 164.3. MS (EI-TOF): m/z = 566 [M⁺]. Anal. Calcd for C₃₂H₃₀N₄O₂S₂: C, 67.89; H, 5.26; N, 9.97.Cyclophane Amide 4: General Procedure B was followed for the synthesis of cyclophane amide 4 as a white solid from the precyclophane amide diyne 16 (0.4 g, 0.88 mmol), piperazine (0.08 g, 0.88 mmol), formaldehyde (0.05 g, 1.76 mmol, from 37–41% aq. formaldehyde) and CuCl (0.09 g, 0.88 mmol). Yield: 0.18 g (36%); mp 120 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.22 (s, 8 H), 3.11 (s, 4 H), 3.66 (s, 4 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.38 (t, J = 7.8 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 8.01 (d, J = 6.3 Hz, 2 H), 8.12 (t, J = 7.8 Hz, 1 H), 8.39 (d, J = 7.8 Hz, 2 H), 10.76 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 22.7, 46.8, 50.5, 78.2, 82.0, 123.4, 123.8, 125.5, 126.4, 129.5, 130.9, 138.6, 139.3, 150.5, 163.1. MS: m/z = 567 [M⁺]. Anal. Calcd for C₃₁H₂₉N₅O₂S₂: C, 65.49; H, 5.26; N, 12.37.