CC BY 4.0 · SynOpen 2019; 03(04): 157-163
DOI: 10.1055/s-0039-1690333
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Copyright with the author(s) (2019) The author(s)

Efficient Straightforward Synthesis of Amidopiperazinophanes as Versatile Novel Supramolecular Scaffolds

a  Department of Organic Chemistry, University of Madras, Guindy Campus Chennai – 600 025, India   Email: thiruorgchem81@gmail.com   Email: perumalrajakumar@gmail.com
b  Department of Chemical Engineering, Biotechnology and Materials, FCFM, Universidad de Chile, Av. Beauchef 851, Santiago, Chile
,
Sivasamy Selvarani
a  Department of Organic Chemistry, University of Madras, Guindy Campus Chennai – 600 025, India   Email: thiruorgchem81@gmail.com   Email: perumalrajakumar@gmail.com
,
Gracia Francisco
b  Department of Chemical Engineering, Biotechnology and Materials, FCFM, Universidad de Chile, Av. Beauchef 851, Santiago, Chile
,
Perumal Rajakumar
a  Department of Organic Chemistry, University of Madras, Guindy Campus Chennai – 600 025, India   Email: thiruorgchem81@gmail.com   Email: perumalrajakumar@gmail.com
› Author Affiliations
We thank UGC, New Delhi, India for financial support. A.T. thanks CSIR-UGC, New Delhi for a Senior Research Fellowship and S.S. thanks DST for the award of a PURSE Fellowship. A.T. and F.G. also acknowledge Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT-CONICYT (No, 3180511) Chile, for financial support.
Further Information

Publication History

Received: 01 September 2019

Accepted after revision: 02 November 2019

Publication Date:
02 December 2019 (online)


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.

Supporting Information

 
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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 2025 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.