Palladium-Catalyzed N-Arylation of Hydroxypiperidines with meso-Bromophenyl(polyalkyl)porphyrins

Abstract

New amino derivatives of porphyrins containing cyclic amino and hydroxypiperidine groups bound through the meso phen­yl rings are prepared by the Pd-catalyzed amination of meso-bromophenyl(polyalkyl)porphyrins. The reaction allows for the introduction of piperidine, morpholine, 3- and 4-hydroxypiperidine groups with 50-80% product yields, but in the case of trans-3,4-dihydroxypiperidine and trans-3-hydroxy-4-(4-hydroxypiperidin-1-yl)piperidine the reaction leads to extensive hydrodebromination of the porphyrin substrate.

hydroxypiperidines - porphyrins - palladium catalysis - aminations - arylations

References and Notes

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<A NAME="RG33907ST-10">10</A>

5-(4′-Bromophenyl)-2,3,7,8,12,18-hexamethyl-13,17-dibutylporphyrine (3): A solution of 2,3,7,13,17,18-hexamethyl-8,12-dibutylbiladiene-a,c hydrobromide (1.4 g, 2.12 mmol), 4-bromobenzaldehyde (0.8 g, 4.32 mmol) and concd hydrobromic acid (0.5 mL) in n-BuOH (50 mL) was refluxed for 4 h, then iodine (0.3 g, 1.2 mmol) was added and refluxed for an additional 15 min. n-BuOH was removed by steam distillation, the precipitate was collected by filtration, washed with H₂O, dried at 70 °C, dissolved in CHCl₃ and chromatographed on a column with neutral alumina. The first colored band containing porphyrin was collected, concentrated to a minimum volume and the product 3 (0.52 g, 37%) was precipitated by addition of MeOH, collected by filtration, washed with MeOH and dried at 70 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.15 (s, 2 H, 10-H, 20-H), 9.94 (s, 1 H, 15-H), 7.86 (AB quartet, 4 H), 4.02 (t, 4 H, CH₂), 3.62 (s, 6 H, Me), 3.53 (s, 6 H, Me), 2.46 (s, 6 H, Me), 2.30 (m, 4 H, CH₂), 1.82 (m, 4 H, CH₂), 1.14 (t, 6 H, Me), -3.30 (br s, 2 H, NH). MS (MALDI): m/z [M + H] calcd for C₄₀H₄₆BrN₄: 661.28; found: 660.95.

<A NAME="RG33907ST-11">11</A>

In the reactions with hydroxypiperidines part of t-BuONa was consumed in the deprotonation of the hydroxyl group in hydroxypiperidine. Therefore we increased the amount of the base (t-BuONa) from 4 equiv to 8 equiv, which improved the product yield (cf. entries 2 and 3, Table [2] ).

<A NAME="RG33907ST-12">12</A>

Representative Experimental Procedure: meso-Bromophenylporphyrin 3 (33 mg, 0.05 mmol), 4-hydroxypiperidine (1c; 15 mg, 0.15 mmol), t-BuONa (40 mg, 0.42 mmol), Pd(OAc)₂ (1.35 mg, 0.006 mmol), and ligand L₃ (4.8 mg, 0.0122 mmol) were placed in the reactor, which was evacuated and dioxane (5 mL) was vacuum-transferred to the reactor. The reactor was filled with argon and the mixture was stirred at 100 °C for 24 h. Then the solvent was removed under reduced pressure, MeOH (5 mL) was added to the viscous residue, the sediment formed was separated by centrifugation, washed with MeOH, dried and subjected to column chromatography on neutral alumina (5/40) using CHCl₃-PE (4:6) as eluent. The debrominated product 8 (5 mg, 17%) was isolated from the first fraction, the amination product 7c (24 mg, 70%) from the second fraction.

<A NAME="RG33907ST-13">13</A> Spectral data for 7c. ¹H NMR (400 MHz, CDCl₃): δ = 10.13 (s, 2 H, 10-H, 20-H), 9.92 (s, 1 H, 15-H), 7.60 (d, 2 H), 7.01 (d, 2 H), 4.02 (t, 4 H, CH₂), 3.77 (m, 1 H), 3.66 (m, 2 H), 3.61 (s, 6 H, Me), 3.52 (s, 6 H, Me), 2.99 (m, 2 H), 2.41 (s, 6 H, Me), 2.31 (m, 4 H, CH₂), 1.99 (m, 2 H), 1.70-1.84 (m, 6 H), 1.17 (t, 6 H, Me), -3.20 (br s, 2 H, NH). ¹³C NMR (100.57 MHz, CDCl₃): d = 145.54, 144.73, 143.55, 142.72, 139.99, 137.40, 137.00, 135.82 (C_pyrrole), 151.03, 133.41, 133.26, 115.03 (C_Ar), 118.87 (C-5), 96.34 (C-10, C-20), 95.41 (C-15), 67.65 (CHOH), 47.22 (CH₂N), 35.16, 33.84, 26.08, 23.00 (CH₂), 14.85, 14.12, 11.99, 11.58 (Me). MS (MALDI): m/z [M + H] calcd for C₄₅H₅₆N₅O: 682.44; found: 682.51

<A NAME="RG33907ST-14">14</A>

Aldrich/ACD Library of FT NMR Spectra, Version 1.11, 1999.