Microwave-Assisted Synthesis of Highly Fluorescent Pyrrolopyridazine Derivatives

Abstract

A fast, efficient, and general method for the preparation of highly fluorescent derivatives containing the pyrrolopyridazine moiety by microwave irradiation is reported. The first synthesis of pyrrolopyridazine derivatives using non-symmetrically substituted alkynes and alkenes by microwave and classical heating is also reported.

microwaves - cycloadditions - fluorescent - pyridazines - ylides

References and Notes

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13

[3+2] Dipolar Cycloaddition under MW Irradiation; General Procedure. Pyridazinium bromide (5 mmol) and dipolarophile (5.5 mmol) were suspended in anhyd benzene (10 mL) and then Et₃N (5.5 mmol) was added. The solution was irradiated for 5 min (20% magnetron power). The hot mixture was filtered to remove Et₃NHBr and the clear solution was concentrated. The crude product was purified by flash chromatography (silica, CH₂Cl₂-MeOH).

14

5,6,7-Tri(methoxycarbonyl)pyrrolo[1,2- b ]pyridazine ( 2a). White solid; mp 168-169 °C. IR (KBr): 1130, 1230 (s-m), 1460, 1505, 1560, 1600 (s-m), 1709 (s), 1722 (s), 1725 (s), 2950 (w), 3096 (w) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 3.92 (s, 3 H, 5-CH₃), 3.96 (s, 3 H, 7-CH₃), 4.02 (s, 3 H, 6-CH₃), 7.17-7.15 (dd, J = 9.2, 4.4 Hz, 1 H, 3-H), 8.57-8.55 (dd, J = 4.4, 1.8 Hz, 1 H, 4-H), 8.65-8.63 (dd, J = 9.2, 1.8 Hz, 1 H, 2-H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.98, 52.32, 53.07, 102.82, 117.11, 117.63, 128.43, 128.75, 131.85, 145.08, 158.65, 162.70, 165.61. Anal. Calcd for C₁₃H₁₂N₂O₆: N, 9.59. Found: N, 9.48.
5,7-Di(methoxy-carbonyl)pyrrolo[1,2- b ]pyridazine ( 3a). Light-brown solid; mp 147-148 °C. IR (KBr): 1132, 1229 (s-m), 1464, 1502, 1561, 1601 (s-m), 1711 (s), 1718 (s), 2958 (w), 3106 (w) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 3.92 (s, 3 H, 5-CH₃), 3.96 (s, 3 H, 7-CH₃), 7.10-7.07 (dd, J = 9.2, 4.4 Hz, 1 H, 3-H), 8.00 (s, 1 H, 6-H), 8.52-8.51 (dd, J = 4.4, 1.6 Hz, 1 H, 4-H), 8.64-8.62 (dd, J = 9.2, 1.6 Hz, 1 H, 2-H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.49, 51.76, 105.01, 116.57, 119.46, 122.53, 127.98, 133.08, 144.20, 159.58, 163.90. Anal. Calcd for C₁₁H₁₀N₂O₄: N, 11.96. Found: N, 11.89.
6,7-Dihydro-5,7-di(methoxycarbonyl)pyrrolo[1,2- b ]pyridazine ( 5a). Dark-red solid; mp 109-110 °C. IR (KBr): 1132, 1229 (s-m), 1464, 1502, 1561, 1601 (s-m), 1729 (s), 1746 (s), 2958 (w), 3106 (w) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.97-2.92 (dd, J = 16.1, 6.4 Hz, 1 H, 6_b-H), 3.28-3.21 (t, J = 16.1, 12.2 Hz, 1 H, 6_a-H), 3.80 (s, 3 H, 7-CH₃), 3.96 (s, 3 H, 5-CH₃), 4.93-4.88 (q, J = 12.2, 6.4 Hz, 1 H, 7-H), 6.54-6.51 (dd, J = 9.2, 4.8 Hz, 1 H, 3-H), 7.24-7.23 (dd, J = 4.8, 1.6 Hz, 1 H, 4-H), 7.60-7.58 (d, J = 9.2 Hz, 1 H, 2-H). ¹³C NMR (100 MHz, CDCl₃): δ = 30.03, 50.35, 52.87, 65.72, 118.79, 126.08, 126.92, 136.72, 151.27, 163.46, 169.21. Anal. Calcd for C₁₁H₁₂N₂O₄: N, 11.86. Found: N, 11.76.
5-Cyano-6,7-dihydro-7-methoxycarbonylpyrrolo[1,2- b ]pyridazine ( 5c). Mauve solid; mp 107 °C. IR (KBr): 1134, 1231 (s-m), 1461, 1496, 1558, 1598 (s-m), 1744 (s), 2241 (w-m), 2960 (w), 3102 (w) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.95-2.89 (dd, J = 15.8, 6.8 Hz, 1 H, 6_b-H), 3.28-3.21 (t, J = 15.8, 12.2 Hz, 1 H, 6_a-H), 3.82 (s, 3 H, CH₃), 4.92-4.87 (q, J = 12.2, 6.8 Hz, 1 H, 7-H), 6.50-6.47 (dd, J = 9.2, 4.2 Hz, 1 H, 3-H), 6.89-6.87 (dd, J = 4.2, 1.6 Hz, 1 H, 4-H), 7.20 (br s, 1 H, 2-H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.65, 53.07, 65.28, 118.76, 118.93, 124.67, 126.10, 136.79, 152.19, 169.93. Anal. Calcd for C₁₀H₉N₃O₂: N, 20.68. Found: N, 20.60.