Buchwald–Hartwig versus Microwave-Assisted Amination of Chloroquinolines: En Route to the Pyoverdin Chromophore

Abstract

The reaction of 2-chloro-6,7-dimethoxy-3-nitroquinoline with a series of amines and aminoalkanoates under basic microwave-mediated conditions and under Buchwald–Hartwig amination conditions is reported. The microwave irradiation favored the reaction with amines, resulting in yields of up to 80%, whereas amino acid functionalization gave yields comparable to those of Buchwald–Hartwig amination. tert-Butyl (2R)-4-[(6,7-dimethoxy-3-nitroquinolin-2-yl)amino]-2-hydroxybutanoate was successfully cyclized to the pyoverdin chromophore, a subunit of siderophores.

Key words

amination - aminonitroquinolines - Buchwald–Hartwig amination - microwave heating - pyoverdins - siderophores

• References and Notes


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• 13 General Procedure A Et₃N (0.84 mmol) was added to a solution of 7 (0.19 mmol) and the appropriate amine hydrochloride 12·HCl (0.84 mmol) in absolute EtOH (3 mL) in a microwave vial, and the mixture was stirred for 1.5 h at 80 °C with microwave heating. The mixture was then poured onto H₂O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na₂SO₄), and the solvents were removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes–EtOAc). N-Benzyl-6,7-dimethoxy-3-nitroquinolin-2-amine (8d) Amorphous red solid; yield: 44 mg (87%); R_f  = 0.85 (hexanes–EtOAc 1:1). FTIR (ATR): 3800 (w), 3731 (w), 3627 (w), 3408 (w), 2928 (m), 2260 (w), 2211 (w), 2191 (w), 2172 (w), 2155 (w), 2139 (w), 2079 (w), 2044 (w), 2026 (w), 1986 (w), 1968 (w), 1611 (vs), 1569 (w), 1533 (m), 1494 (s), 1464 (m), 1417 (s), 1371 (m), 1352 (m), 1231 (vs), 1162 (m), 1009 (w), 846 (w), 734 (w), 700 (w), 616 (w), 493 (w), 469 (w), 448 (w), 424 (w) cm^–1. ¹H NMR (700 MHz, CDCl₃): δ = 3.98 (s, 3 H), 4.05 (s, 3 H), 4.92 (d, J = 5.7 Hz, 2 H), 6.95 (s, 1 H), 7.26 (s, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.44 (d, J = 7.5, 2 H), 8.28 (s, 1 H), 8.55 (s, 1 H). ¹³C NMR (176 MHz, CDCl₃): δ = 45.32, 56.21, 56.47, 102.80, 106.49, 127.81, 128.11, 128.69, 129.00, 133.32, 135.29, 139.27, 148.26, 152.21, 154.66, 156.99. MS (ESI): m/z = 362.11 [M + Na]⁺, 340.13 [M]⁺, 294.14 [M-NO₂]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₈N₃O₄: 340.1297; found: 340.1293.
• 14 Surry D, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 6338
• 15 Dorel R, Grugel CP, Haydl AM. Angew. Chem. Int. Ed. 2019; 58: 17118
• 16 General Procedure B The appropriate amine (1.02 mmol), 7 (0.85 mmol), Pd(OAc)₂ (34 µmol), XPhos (14; 68 µmol), and Cs₂CO₃ (4.09 mmol) were dissolved in degassed anhyd toluene (2 mL) under inert gas atmosphere, and the mixture was stirred for 20 h at the reflux. The suspension was cooled to r.t., filtered, and rinsed with toluene (50 mL) and EtOAc (10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography [silica gel, hexanes–EtOAc (2:1)]. tert-Butyl (2R)-4-[(6,7-Dimethoxy-3-nitroquinolin-2-yl)amino]-2-(tetrahydro-2H-pyran-2-yloxy)butanoate [(R)-8h] Red solid; yield: 104 mg (25%); mp 76 °C; R_f  = 0.64 (hexanes–EtOAc); [α]_D ²⁰ +46.0 (c = 0.50, CH₂Cl₂). FTIR (ATR): 3407 (w), 2929 (m), 2854 (w), 2253 (w), 1740 (m), 1611 (s), 1569 (w), 1535 (m), 1495 (s), 1465 (m), 1418 (s), 1369 (m), 1356 (m), 1299 (m), 1231 (vs), 1160 (s), 1124 (m), 1075 (m), 1032 (s), 1006 (m), 913 (w), 869 (w), 846 (w), 813 (w), 767 (w), 732 (w), 697 (w), 647 (w), 615 (w), 577 (w), 471 (w), 419 (w) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.47 (d, J = 4.8 Hz, 9 H, t-Bu), 1.52–1.96 (m, 6 H), 2.02–2.42 (m, 2 H), 3.39–3.63 (m, 0.5 H), 3.66–3.87 (m, 0.5 H), 3.96 (s, 3 H), 4.03–4.07 (m, 4 H), 4.40 (dd, J = 9.0 Hz, 4.0 Hz, 1 H), 4.63–4.77 (m, 2 H), 4.96 (m, 1 H), 6.91 (s, 1 H), 7.02 (s, 1 H), 8.21 (s, 1 H), 8.78 (s, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 19.91, 25.37, 28.01, 28.11, 30.60, 32.08, 37.57, 56.09, 56.37, 63.42, 72.90, 81.63, 98.47, 99.87, 105.56, 106.25, 115.96, 134.78, 134.84, 147.48, 149.26, 149.51, 156.71, 171.81. MS (ESI): m/z = 514.22 [M + K]⁺, 514.22 [M + Na]⁺, 492.23 [M]⁺, 408.18, 352.11. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₃N₃NaO₈: 514.2160; found: 514.2162.
• 17 tert-Butyl (1S)-8,9-Dimethoxy-5-nitro-2,3-dihydro-1H-pyrimido[1,2-a]quinoline-1-carboxylate [(S)-15b] Red solid; yield: 18.0 mg (65%); mp 157 °C. R_f  = 0.4 (EtOAc–hexanes 2:1); [α]_D ²⁰ –18.0 (c = 0.50, CH₂Cl₂). FTIR (ATR): 2929 (m), 2853 (w), 2257 (w), 1994 (w), 1732 (m), 1650 (m), 1621 (m), 1596 (m), 1563 (m), 1526 (s), 1455 (m), 1428 (m), 1393 (m), 1367 (m), 1334 (m), 1269 (s), 1251 (vs), 1220 (m), 1204 (m), 1189 (m), 1150 (vs), 1099 (m), 1060 (m), 1013 (s), 988 (m), 912 (m), 879 (m), 846 (m), 817 (m), 727 (vs), 665 (m), 645 (m), 615 (w), 579 (w), 518 (w), 477 (w), 451 (w) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.44 (s, 9 H), 2.03–2.20 (m, 1 H), 2.35 (m, 1 H), 3.47 (m, 1 H), 3.76–3.64 (m, 1 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 4.74 (dd, J = 6.2, 2.3 Hz, 1 H), 6.35 (s, 1 H), 6.82 (s, 1 H), 7.60 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃) δ = 22.91, 28.07, 40.61, 56.20, 56.46, 56.93, 83.41, 95.22, 109.69, 111.67, 129.40, 137.36, 141.40, 142.29, 144.96, 153.69, 169.94. MS (ESI): m/z = 412.15 [M + Na]⁺, 390.16 [M]⁺, 334.10 [M – t-Bu]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₄N₃O₆: 390.1660; found: 390.1642. UV/vis: ε_232 nm = 7.55, ε_299 nm = 2.59, ε_358 nm = 2.54, ε_433 nm = 1.08 (in 10⁶ mL/mol cm).
• 18 Orlandi M, Tosi F, Bonsignore M, Benaglia M. Org. Lett. 2015; 17: 3941
• 19 N ²-Hexyl-6,7-dimethoxyquinoline-2,3-diamine (16a) Colorless to light-yellow oil; yield: 13 mg (95%). FTIR (ATR): 3408 (w), 3246 (w), 2953 (m), 2926 (s), 2854 (m), 2160 (w), 2106 (w), 2082 (w), 2049 (w), 2027 (w), 1974 (w), 1724 (w), 1616 (m), 1509 (s), 1463 (s), 1446 (s), 1420 (vs), 1372 (m), 1254 (vs), 1216 (s), 1153 (m), 1014 (m), 882 (w), 848 (w), 804 (w), 752 (w), 731 (w), 614 (w), 453 (w), 433 (w) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.89 (t, J = 8.3 Hz, 7.6 Hz, 3 H), 1.17–1.54 (m, 6 H), 1.70 (p, J = 7.2 Hz, 2 H), 3.22 (bs, 2 H), 3.55 (t, J = 7.2 Hz, 2 H), 3.93 (s, 3 H), 3.97 (s, 3 H), 6.81 (s, 1 H), 7.05 (s, 1 H), 7.17 (s, 1 H), 8.08 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.07, 22.64, 26.94, 29.70, 31.69, 41.85, 55.91, 55.94, 104.90, 109.95, 118.08, 127.62, 129.71, 139.93, 146.49, 147.67, 149.65. MS (ESI): m/z = 338.16, 304.20 [M]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₆N₃O₂: 304.2020; found: 304.2019.