Beneficial Effect of Mukaiyama Reagent on Macrobislactamization Reactions

Abstract

An expeditious two-step procedure was developed to accede to new tetraamide macrocycles. The key step of this diversity-oriented procedure is a highly efficient Mukaiyama salt promoted macrobislactamization. Preliminary mechanistic investigations are also reported.

Key words

tetraamide macrocycles - Mukaiyama reagent - macrobislactamization

References and Notes

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6

Two-step Synthesis of Tetraaromatic Tetraamide Macrocycles; General Procedure: Step 1: One-Step Synthesis of Diamine 6 and 7
ortho-Phenylene diamine (1.85 mmol, 2.0 equiv), EDCI (1.94 mmol, 2.1 equiv) and HOAt (0.37 mmol, 0.4 equiv) were successively added to a solution of diacid derivative (isophthalic or dipicolinic acid; 0.92 mmol, 1.0 equiv) in DMF (50 mL) under an inert atmosphere. After the addition, the reaction mixture was allowed to stir at r.t. for 16 h. The mixture was concentrated under reduced pressure to a crude oil that was purified by flash column chromatography (silica gel, CH₂Cl₂-5% MeOH) to afford the expected diamine (6 or 7) as a pale yellow powder, with chemical yields given in the text. Compound 6: R _f 0.6 (CH₂Cl₂-10% MeOH); mp 198 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.77 (s, 2 H), 8.59 (s, 1 H), 8.15 (br d, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.7 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 2 H), 6.99 (td, J = 8.2 Hz, J′ = 1.3 Hz, 2 H), 6.80 (dd, J = 8.1 Hz, J′ = 1.2 Hz, 2 H), 6.62 (td, J = 8.2 Hz, J′ = 1.3 Hz, 2 H), 4.94 (br s, 4 H). ¹³C NMR (75.3 MHz, DMSO-d ₆): δ = 165.0, 143.6, 135.2, 131.0, 128.8, 127.7, 127.2, 127.1, 123.5, 116.7, 116.6. Compound 7: R _f 0.17 (CH₂Cl₂-5% MeOH); mp 240 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.70 (s, 2 H), 8.18-8.35 (m, 3 H), 7.16 (dd, J = 7.8 Hz, J′ = 1.2 Hz, 2 H), 7.03 (td, J = 8.1 Hz, J′ = 1.5 Hz, 2 H), 6.81 (dd, J = 8.1 Hz, J′ = 1.2 Hz, 2 H), 6.63 (td, J = 7.5 Hz, J′ = 1.2 Hz, 2 H), 5.00 (br s, 4 H). ¹³C NMR (75.3 MHz, DMSO-d ₆): δ = 162.5, 149.3, 144.5, 140.0, 128.0, 127.7, 125.2, 122.7, 116.7, 116.4.
Step 2: Macrobislactamization Reaction for the Synthesis of 1, 2 and 3 Mukaiyama salt (2-chloromethylpyridinium iodide; 0.75 mmol, 2.5 equiv), tri-n-butylamine (1.5 mmol, 5.0 equiv) and the diamine derivative (6 or 7, 0.3 mmol, 1.0 equiv) were successively added to a solution of diacid derivative (isophthalic or dipicolinic acid, 0.30 mmol, 1.0 equiv) in CH₂Cl₂ (100 mL) under an inert atmosphere. The reaction mixture was stirred at reflux temperature for 16 h. After cooling to r.t., Et₂O (200 mL) was added providing a white precipitate that was collected by filtration. The corresponding tetraaromatic tetraamide macrocycles (1, 2 or 3) were obtained as a white powder, with chemical yields given in Table [1] . Compound 1: mp 310 °C. IR (KBr): 3240 (NH), 1648 (CO), 1603 (NH), 1303 (CN), 755 (CH) cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.18 (br s, 4 H), 9.16 (d, J = 5.4 Hz, 2 H), 8.50-8.63 (m, 3 H), 8.38 (d, J = 8.1 Hz, 2 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.52-7.70 (m, 4 H), 7.22-7.40 (m, 4 H). EI-MS: m/z (%) = 477 (67) [M + H⁺]. Compound 2: mp 304 °C. IR (KBr): 3474 (NH), 3245 (CH), 1685 (CO), 1591 (NH), 1307 (CN), 749 (CH) cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.94 (s, 2 H), 10.17 (s, 2 H), 8.24 (br t, 3 H), 8.00-8.12 (m, 1 H), 7.68 (br d, 2 H), 7.52 (m, 4 H), 7.21 (m, 4 H), 6.75 (m, 1 H). EI-MS: m/z (%) = 479 (100) [M + H⁺], 496 (8) [M + NH₄ ⁺]. Compound 3: mp 196 °C. IR (KBr): 3423 (NH), 3247 (CH), 1677 (CO), 1600 (NH), 1308 (CN), 754 (CH) cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.00 (s, 4 H), 8.40 (d, J = 8.0 Hz, 4 H), 8.30 (t, J = 7.7 Hz, 2 H), 7.82-7.86 (m, 4 H), 7.37-7.41 (m, 4 H). EI-MS: m/z (%) = 479 (30) [M + H⁺], 496 (28) [M + NH₄ ⁺].