Synthesis of New Arylmethylene Derivatives of Resorcinarene via the Catalyzed Mannich Reaction

Abstract

The C-arylation of Mannich base is used to obtain a series of new arylmethylene resorcinarene derivatives. Initially, aminomethyl derivative as the intermediate is formed in the Mannich reaction of resorcinarene with iminodiacetic acid. Next, activated aromatic rings act as a nucleophile in the reaction with this Mannich base and the arylmethylene derivatives of resorcinarene are prepared. The mixture of isomeric products is obtained for monosubstituted phenyl rings. Reaction with a suitably substituted phenyl ring gives one main product in good yields.

Key words

resorcinarene - Mannich reaction - C-arylation - regioisomers - O-alkylation

• References and Notes

• 1 Tramontini M. Synthesis 1973; 703
• 2 Airola K, Böhmer V, Paulus EF, Rissanen K, Schmidt C, Thondorf I, Vogt W. Tetrahedron 1997; 53: 10709
• 3 Leigh DA, Linnane P, Pritchard RG, Jackson G. J. Chem. Soc., Chem. Commun. 1994; 389
• 4 Iwanek W, Mattay J. Liebigs Ann. 1995; 1463
• 5 Gawdzik B, Wzorek A, Mattay J, Iwanek W. Org. Prep. Proced. Int. 2009; 41: 217
• 6 Wzorek A, Mattay J, Iwanek W. Tetrahedron: Asymmetry 2012; 23: 271
• 7 Bukharov SV, Nugumanova GN, Mukmeneva NA, Syakaev VV, Burilov AR, Pudovik MA, Konovalov AI. Russ. J. Gen. Chem. 2002; 72: 1320
• 8 Matsushita Y, Matsui T. Tetrahedron Lett. 1993; 34: 7433
• 9 Nummelin S, Falabu D, Shivanyuk A, Rissanen K. Org. Lett. 2004; 6: 2869
• 10 Urbaniak M, Iwanek W. Tetrahedron 2006; 62: 1508
• 11 Urbaniak M, Iwanek W. Synth. Commun. 2008; 38: 4345
• 12 Urbaniak M, Mattay J, Iwanek W. Synth. Commun. 2011; 41: 670
• 13 Urbaniak M, Gawdzik B, Wzorek A, Kaca W, Lechowicz Ł. J. Incl. Phenom. Macrocycl. Chem. 2015; 81: 357
• 14 Typical Procedure for the Preparation of Resorcinarene Derivatives 2–8: A mixture of resorcinarene (0.5 g, 0.7 mmol, 1 equiv) and the appropriate aromatic compound (10–60 equiv) in MeCN (10 mL) was stirred and heated until completely dissolved. Then an aqueous solution of formaldehyde (37%, 0.53 mL, 7 mmol) and iminodiacetic acid (0.05 g, 10%) were added, and the reaction mixture was refluxed for 18 h at 85 °C. The reaction mixture was evaporated to dryness, CHCl₃ (100 mL) was added and the mixture was washed with H₂O (3 × 100 mL). The CHCl₃ solution was evaporated and the residues were separated by chromatography. Tetra(methylene 2-phenol) Resorcinarene (2a): The synthesis of derivatives 2a required a 60-fold molar excess of the phenol (4 g), HPLC purification to yield a white solid (0.16 g, 20% yield); mp 200–203 °C. ¹H NMR [600 MHz, (CD₃)₂SO]: δ = 9.94 (s, 4 H, ArOH), 8.69 (s, 8 H, ArOH), 7.40 (s, 4 H, ArH), 6.96 (t, J = 7.4 Hz, 4 H, ArH), 6.77–6.81 (m, 8 H, ArH), 6.65 (t, J = 7.2 Hz, 4 H, ArH), 4.40 (t, J = 7.5 Hz, 4 H, ArCHRAr), 3.76 (s, 8 H, ArCH ₂Ar), 2.16 [t, J = 6.6 Hz, 8 H, CHCH ₂CH(Me)₂], 1.35–1.43 [m, 4 H, CH₂CH(Me)₂], 0.93 [d, J = 6.2 Hz, 24 H, CH(Me)₂]. ¹³C NMR [150 MHz, (CD₃)₂SO]: δ = 23.27, 24.46, 26.52, 32.52, 42.71, 114.61, 114.86, 119.82, 122.98, 125.46, 126.92, 127.38, 129.66, 149.79, 154.57. HRMS (ESI): m/z [M⁺ + Na⁺] calcd for C₇₂H₈₀O₁₂Na: 1159.55472; found: 1159.55554. Tri(methylene 4-aniline) Mono(methylene 2-aniline) Resorcinarene (3b): The synthesis of derivatives 3b required a 24-fold molar excess of the N,N-dimethylaniline (2.2 mL), the crude product was purified by column chromatography to yield a white solid (0.35 g, 40% yield); R_f 0.44 (EtOAc–hexane, 1:1); mp 182–185 °C. ¹H NMR [600 MHz, (CD₃)₂SO]: δ = 11.09 (s, 2 H, ArOH), 8.69 (s, 2 H, ArOH), 8.51 (s, 4 H, ArOH), 7.54 (d, J = 7.3 Hz, 1 H, ArH), 7.31–7.35 (m, 3 H, ArH), 7.27 (s, 2 H, ArH), 7.21 (t J = 7.3 Hz, 1 H, ArH), 7.11 (t, J = 7.3 Hz, 1 H, ArH), 6.96 (d J = 8.4 Hz, 4 H, ArH), 6.89 (d J = 8.1 Hz, 2 H, ArH), 6.59 (d J = 7.7 Hz, 6 H, ArH), 4.39 (t, J = 7.0 Hz, 2 H, ArCHRAr), 4.36 (t, J = 7.0 Hz, 2 H, ArCHRAr), 3.86 (s, 2 H, ArCH ₂Ar), 3.84 (s, 2 H, ArCH ₂Ar), 3.72 (s, 4 H, ArCH ₂Ar), 2.81 (s, 12 H, N(Me)₂], 2.78 (s, 6 H, N(Me)₂], 2.73 [s, 6 H, N(Me)₂], 2.17–2.26 [m, 4 H, CHCH ₂CH(Me)₂], 1.96–2.08 [m, 4 H, CHCH ₂CH(Me)₂], 1.31–1.42 [m, 4 H, CH₂CH(Me)₂], 0.92 (d J = 6.2 Hz, 24 H, CH(Me)₂]. ¹³C NMR [150 MHz, (CD₃)₂SO]: δ = 23.09, 23.18, 23.45, 23.48, 26.45, 26.51, 28.66, 28.84, 32.44, 32.50, 41.05, 42.78, 45.94, 113.16, 113.18, 115.73, 115.82, 115.88, 121.94, 124.82, 124.87, 125.63, 125.66, 129.04, 129.25, 129.80, 149.07, 149.11, 149.35, 149.40, 149.52, 149.82, 150.13. HRMS (ESI): m/z [M⁺ + Na] calcd for C₈₀H₁₀₀O₈N₄Na: 1267.74385; found: 1267.74523. Tetramethylene 2-Ethoxy(4-methoxyphenyl) Resorcinarene (8): The synthesis of derivatives 8 required a 12-fold molar excess of the 2-(4-methoxyphenyl)ethanol (1.1 mL), the crude product was purified by column chromatography to yield a white solid (0.69 g, 72% yield); R_f 0.6 (EtOAc–hexane, 1:3); mp 170–172 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.54 (s, 8 H, ArOH), 7.11 (d, J = 8.2 Hz, 8 H, ArH), 7.10 (s, 4 H, ArH), 6.86 (d, J = 8.8 Hz, 8 H, ArH), 4.81 (s, 8 H, ArCH ₂O), 4.36 (t, J = 8.2 Hz, 4 H, ArCHRAr), 3.79 (s, 12 H, OMe), 3.72 (t, J = 6.9 Hz, 8 H, OCH ₂CH₂Ar), 2.86 (t, J = 6.9 Hz, 8 H, OCH₂CH ₂Ar), 2.04 [t, J = 7.5 Hz, 8 H, CH ₂CH(Me)₂], 1.41–1.51 [m, 4 H, CH₂CH(Me)₂], 0.98 [d, J = 6.9 Hz, 24 H, CH₂CH(Me)₂] ¹³C NMR: δ = 22.82, 26.03, 30.52, 35.08, 42.71, 55.21, 68.24, 72.25, 109.11, 114.03, 122.73, 124.03, 129.74, 130.05, 149.67, 158.28. HRMS (ESI): m/z [M⁺ + Na] calcd for C₈₄H₁₀₄O₁₆Na: 1391.72217; found: 1391.72274.
• 15 Mansikkamäki H, Nissinena M, Rissanen K. CrystEngComm. 2005; 7: 519
• 16 Iwanek W, Stefańska K, Szumna A, Wierzbicki M. Tetrahedron 2015; 71: 2222