Synthesis of Calix[4]pyrrole-Based Acrylate and Acrylamide Monomers:
Precursors for Preparation of Anion-Selective Polymer Membranes

Abstract

Octamethylcalix[4]pyrrole derivatives with hydroxy alkyl and amino alkyl side chains were prepared and converted into the corresponding acrylate and acrylamide derivatives, respectively.

Key words

calix[4]pyrrole - macrocycle - acrylate - acrylamide - receptor - polymer

References and Notes

• 1a Sessler JL. Gale PA. Cho W.-S. In Anion Receptor Chemistry. Monographs in Supramolecular Chemistry   RSC Publishing; Cambridge: 2006. 
• 1b Suksai C. Tuntulani T. Top. Curr. Chem.  2005,  255:  163 
• 1c Martínez-Máñez R. Sancenón F. Chem. Rev.  2003,  103:  4419 
• 2 Bayer A. Ber. Dtsch. Chem. Ges.  1886,  19:  2184 
• 3a Gale PA. Sessler JL. Král V. Lynch V. J. Am. Chem. Soc.  1996,  118:  5140 
• 3b Gale PA. Sessler JL. Král V. Chem. Commun.  1998,  1 
• 3c Gale PA. Anzenbacher P. Sessler JL. Coord. Chem. Rev.  2001,  222:  57 
• 3d Anzenbacher P. Jursikova K. Lynch VM. Gale PA. Sessler JL. J. Am. Chem. Soc.  1999,  121:  11020 
• 4a Nishiyabu R. Anzenbacher P. J. Am. Chem. Soc.  2005,  127:  8270 
• 4b Nishiyabu R. Anzenbacher P. Org. Lett.  2006,  8:  359 
• 4c Nishiyabu R. Palacios MA. Dehaen W. Anzenbacher P. J. Am. Chem. Soc.  2006,  128:  11496 
• 4d Palacios MA. Nishiyabu R. Marquez M. Anzenbacher P. J. Am. Chem. Soc.  2007,  129:  7538 
• 5 Anzenbacher P. Nishiyabu R. Palacios MA. Coord. Chem. Rev.  2006,  250:  2929 
• 9 Soumen D. Kuntal P. Sabayasachi S. Tetrahedron Lett.  2006,  47:  5851 
• 10 Bucher C. Zimmerman RS. Lynch V. Král V. Sessler JL. J. Am. Chem. Soc.  2001,  123:  2099 
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• 11b Lee C.-H. Lee J.-S. Na H.-K. Yoon D.-W. Miyaji H. Cho W.-S. Sessler JL. J. Org. Chem.  2005,  70:  2067 

6

Synthesis of 2 and 3Method A
To the corresponding substrate (1 mmol) and anhyd Et₃N (2.5 equiv for each hydroxy group) in anhyd CH₂Cl₂ (80 mL) at -10 °C to 0 °C under Ar, acryloyl chloride (1.1 equiv for each hydroxy group) was added dropwise over 0.5 h. The reaction mixture was stirred for another 0.5 h, warmed to r.t. and left to stir overnight. The reaction mixture was then washed with sat. NaHCO₃, H₂O (2 × 30 mL), dried over MgSO₄, and evaporated to dryness. Recrystallization from MeOH-CH₂Cl₂ or flash chromatography (SiO₂, 0-5% MeOH in CHCl₃) afforded the product as a white solid. Method B
To the corresponding substrate (0.5 mmol) and anhyd (i-Pr)₂NEt (2.5 equiv for each hydroxy group) in anhyd DMF (25 mL) at -10 °C to 0 °C under Ar, the solution of N-hydroxysuccinimidyl acrylate (1.1 equiv for each hydroxy group) in anhyd DMF (1 mL) was added dropwise over 0.5 h. The reaction mixture was stirred for another 0.5 h, warmed to r.t. and left to stir overnight. The reaction mixture was then evaporated to dryness and diluted with CH₂Cl₂. After that the procedure is similar to method A.
Compound 2: yield 15% (A), 31% (B); mp >200 °C (dec.). ¹H NMR (250 MHz, CDCl₃ and DMSO-d ₆): δ = 2.19-2.21 (m, 8 H, CH₂), 2.44-2.50 (m, 12 H, CH₃), 3.92 (t, ³ J = 5.7 Hz, 8 H, CH₂), 5.69 (dd, J = 8.8, 1.3 Hz, 4 H, cis CH₂=CH), 5.80 (d, J = 2.3 Hz, 8 H), 5.95 (dd, J = 14.5, 8.8 Hz, 4 H, CH₂=CH), 6.23 (dd, J = 14.5, 1.5 Hz, 4 H, trans CH₂=CH), 8.23 (br s, 4 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 26.3, 37.7, 38.7, 61.7, 104.3, 128.6, 130.4, 136.6, 166.0. MS (MALDI-TOF): 765.54 [MH⁺]. Anal. Calcd for C₄₄H₅₂N₄O₈ (764.91): C, 69.09; H, 6.85; N, 7.32. Found: C, 68.94; H, 6.88; N, 6.99. Compound 3: yield 29% (A), 60% (B); mp >200 °C (dec.). ¹H NMR (250 MHz, CDCl₃): δ = 1.47-1.58 (m, 18 H, CH₃), 2.23-2.28 (m, 4 H, CH₂), 4.03-4.08 (m, 4 H, OCH₂), 5.80 (dd, J = 8.5, 1.3 Hz, 2 H, cis CH₂=CH), 5.90-5.95 (m, 8 H, HetH), 6.11 (dd, J = 14.0, 8.3 Hz, 2 H, CH₂=CH), 6.35 (dd, J = 15.0, 1.5 Hz, 2 H, trans CH₂=CH), 7.04 (br s, 4 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 27.5, 29.0, 30.1, 35.2, 37.6, 43.9, 61.6, 103.0, 104.0, 128.5, 130.4, 137.2, 138.7, 166.1. MS (MALDI-TOF): 596.26 [M⁺]. Anal. Calcd for C₃₆H₄₄N₄O₄ (596.76): C, 72.46; H, 7.43; N, 9.39. Found: C, 72.55; H, 7.68; N, 9.11.

7

Synthesis of 5 Similarly to the reported procedure,⁹ to a solution of pyrrole (1.7 mL, 24 mmol) and 4-hydroxybutan-2-one (2.1 mL, 24 mmol) in 50% aq EtOH (15-20 mL), concd HCl (1-1.5 mL) was added dropwise over 1 h at r.t. under Ar. After 0.5 h a precipitate formed. The dark solution was stirred for additional 1-2 h, then filtered, and the precipitate was washed with H₂O and small amount of MeOH, dried, and recrystallized from MeOH-CH₂Cl₂ (1:1) to afford a white solid.
Synthesis of 6 To a solution of dipyrromethane¹⁰ (1 mmol) and ketone (1 mmol) in MeOH (5 mL), MsOH (0.1 mL) was added dropwise over 0.5 h at r.t. under Ar. The dark solution was stirred until the precipitation occurred or for 2-3 h. The solution was then evaporated under reduced pressure, treated with H₂O, and the precipitate that formed was filtered off, washed with H₂O and small amount of MeOH, dried, and recrystallized from MeOH-CH₂Cl₂ (1:1) to afford a white solid.
Compound 5: yield 50%; mp >200 °C (dec.). ¹H NMR (250 MHz, CDCl₃ and DMSO-d ₆): δ = 1.39 (br s, 12 H, CH₃), 2.03-2.10 (m, 8 H, CH₂), 3.34 (t, ³ J = 5.7 Hz, 8 H, OCH₂), 5.68-5.77 (m, 8 H, HetH), 7.58 (br s, 4 H, NH). ¹³C NMR (75 MHz, CDCl₃ and DMSO-d ₆): δ = 26.5, 37.5, 43.0, 58.9, 103.2, 137.44. MS (MALDI-TOF): m/z = 549.59 [MH⁺]. Anal. Calcd for C₃₂H₄₄N₄O₄ (548.34): C, 70.04; H, 8.08; N, 10.21. Found: C, 69.94; H, 8.37; N, 9.99. Compound 6: yield 60%; mp >200 °C (dec.). ¹H NMR (250 MHz, CDCl₃): δ = 1.50 (br s, 6 H, CH₃), 1.53 (br s, 12 H, CH₃), 2.13-2.18 (m, 4 H, CH₂), 3.58 (t, ³ J = 5.0 Hz, 4 H, OCH₂), 5.88-5.95 (m, 8 H, HetH), 7.04 (br s, 4 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 26.6, 29.1, 29.3, 35.2, 37.5, 42.9, 59.5, 102.8, 103.8, 138.5, 139.2. MS (MALDI-TOF): m/z = 489.59 [MH⁺]. Anal. Calcd for C₃₀H₄₀N₄O₂ (488.66): C, 73.74; H, 8.25; N, 11.47. Found: C, 74.04; H, 8.37; N, 11.79

8

Synthesis of 8 To a solution of pyrrole (1 mmol) and ketone 7 ¹¹ (1 mmol) in MeOH (5 mL), MsOH (0.1 mL) was added dropwise over 0.5 h at r.t. under Ar. The dark solution was stirred until the precipitation occurred or for 2-3 h. The solution was then evaporated under reduced pressure, treated with H₂O, and the precipitate that formed was filtered off, washed with H₂O and small amount of MeOH, dried and recrystallized from MeOH-CH₂Cl₂ (1:1) to afford a white solid of 8.
Compound 8: yield 59%; mp 171-173 °C (dec.). ¹H NMR (250 MHz, CDCl₃): δ = 1.18-1.34 (m, 20 H, CH₂ and CH₃), 1.97-2.05 (m, 8 H, CH₂), 3.47-3.69 (m, 8 H, NCH₂), 5.83-5.97 (m, 8 H, HetH), 7.02 (br s, 2 H, NH), 7.09 (br s, 2 H, NH), 7.62-7.80 (m, 16 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 23.4, 23.6, 23.9, 26.1, 26.2, 26.4, 37.3, 38.3, 38.4, 39.0, 104.0, 123.0, 123.1, 132.1, 133.6, 133.7, 133.8, 136.9, 137.1, 168.3. MS (MALDI-TOF): m/z = 1121.71 [M]⁺. Anal. Calcd for C₆₈H₆₄N₈O₈ (1121.28): C, 72.84; H, 5.75; N, 9.99. Found: C, 72.72; H, 5.69; N, 10.12. Tetramine 9 To a solution of compound 8 (1 mmol) in anhyd EtOH (50 mL) and anhyd toluene (50 mL), N₂H₄·H₂O (10 mL, 200 mmol) was added. The clear solution was heated at reflux overnight, then allowed to cool. The precipitate that formed was filtered off. The mother liquor was evaporated to dryness to afford oily residue, which was treated with H₂O, and the precipitate that formed was filtered off, washed with H₂O, and this crude product (100% conversion according to TLC: 60% EtOAc in hexanes) was used for the next step.
Synthesis of 4Method A
To the tetramine 9 (1 mmol) and anhyd Et₃N (10 mmol) in anhyd CH₂Cl₂ (80 mL) at -10 to 0 °C under Ar, acryloyl chloride (4.4 mmol) was added dropwise over 0.5 h. The reaction mixture was stirred for another 0.5 h, warmed to r.t. and left to stir overnight. The reaction mixture was then washed with sat. NaHCO₃, H₂O (2 × 30 mL), dried over MgSO₄ and evaporated to dryness. Flash chromatography (SiO₂, 0-5% MeOH in CHCl₃) afforded the product as a white solid. Method B To the tetramine 9 (0.5 mmol) and anhyd (i-Pr)₂NEt (2.1 mmol) in anhyd DMF (25 mL) at -10 to 0 °C under Ar, the solution of N-hydroxysuccinimidyl acrylate (2.1 mmol) in anhyd DMF (1 mL) was added dropwise over 0.5 h. The reaction mixture was stirred for another 0.5 h, warmed to r.t. and left to stir overnight. The reaction mixture was evaporated to dryness and diluted with CH₂Cl₂. After that the procedure is similar to method A. Compound 4: yield 10% (A), 25% (B); mp 127-129 °C (dec.). ¹H NMR (250 MHz, CDCl₃): δ = 1.14-1.19 (m, 8 H, CH₂), 2.09-2.14 (m, 8 H, CH₂), 2.78-2.84 (m, 12 H, CH₃), 3.04-3.14 (m, 8 H, NCH₂), 5.71-5.77 (m, 8 H, HetH), 6.09 (dd, J = 8.8, 1.0 Hz, 4 H, cis CH₂=CH), 6.24 (dd, J = 14.3, 8.8 Hz, 4 H, CH), 6.61 (dd, J = 14.3, 1.0 Hz, 4 H, trans CH₂=CH), 8.60 (br s, 4 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 24.9, 26.4, 37.9, 38.6, 39.8, 104.0, 126.1, 126.2, 130.8, 131.0, 136.9, 137.1, 137.3, 137.5, 165.6. MS (MALDI-TOF): m/z = 839.83 [MNa⁺]. Anal. Calcd for C₄₈H₆₄N₈O₄ (817.07): C, 70.56; H, 7.90; N, 13.71. Found: C, 70.71; H, 7.69; N, 14.12.