A Facile Route to Substituted Bidentate and Tridentate Ligands Capable of Forming Six-membered Chelate Rings with Transition-Metal Ions

Abstract

A facile one-pot synthesis of mono(hpp)- or di(hpp)-substituted N-heterocyclic ligands from halogenated N-heterocycles and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (H-hpp) is presented. N,N-Bidentate and N,N,N-tridentate ligands incorporating electron-donating and electron-withdrawing substituents can also be readily synthesized using this method.

Key words

palladium - catalysis - C–N bond-forming reactions - N-heterocyclic ligands - one-pot synthesis

• References and Notes

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• 22 General Procedure In a typical procedure, for mono-hpp substitution reactions, a 100 mL oven-dried round-bottomed flask was charged with (±)-BINAP (3 mol% with respect to N-haloheterocycle) and dissolved in dry toluene (5 mL) under an inert N₂ atmosphere at ca. 60 °C to give a clear colorless solution. To this solution was added Pd(OAc)₂ (2 mol% with respect to the halogenated N-heterocycle), and the reaction mixture was stirred at ambient temperature under N₂ atmosphere to give a clear dark red solution. To this solution was added the halogenated N-heterocycle (1 mmol), and the reaction was heated to 60 °C under N₂ atmosphere for 15–20 min, with a concomitant color change from dark-red to yellow. To the resulting clear yellow solution was added H-hpp (1.1 equiv with respect to starting halogenated N-heterocycle), followed by the addition of KOt-Bu (2.5 equiv with respect to halogenated N-heterocycle), and the resulting brownish-red solution was heated at elevated temperature and for the time indicated in Table 1. After this time, the reaction mixture was cooled to r.t., and the solvent was evaporated to dryness. To the resulting brownish-green solid was added an aliquot of a mixture of toluene and Et₂O (10:60, v/v), and the mixture was filtered. The pale-yellow filtrate was evaporated to dryness. The desired product was isolated as colorless or yellow solid by tri­turation with acetone (1–2 mL). Subsequent drying under vacuum afforded the compound in the yield as indicated in Table 1.
• 23 Except for compounds 4 and 7–13, all of the C–N coupled products are known compounds.^11–14 The yields reported in Table 1 for existing compounds were found to be similar to those of the literature reports, and their characterization data were found to be in good agreement to those mentioned in the literature reports.
• 24 1-(6-Bromopyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (4) White solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 3.86 (t, J = 6.0 Hz, 2 H), 3.39 (t, J = 4.8 Hz, 2 H), 3.22 (m, 4 H), 2.0 (quin, J = 6.0 Hz, 2 H), 1.87 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 158.05, 148.91, 140.69, 137.76, 119.21, 115.78, 48.46, 48.30, 43.58, 43.07, 23.03, 22.32 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₂H₁₅N₄Br: 295.0558; found: 295.0631.
• 25 1-(6-Methylpyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (7) White solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 5.6 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 6.53 (d, J = 7.2 Hz, 1 H), 3.75 (t, J = 6.0 Hz, 2 H), 3.27 (t, J = 5.6 Hz, 2 H), 3.10 (m, 4 H), 2.29 (s, 3 H), 1.89 (quin, J = 6.0 Hz, 2 H), 1.76 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 155.45, 155.35, 149.51, 135.75, 115.68, 115.16, 48.16, 47.95, 43.24, 43.07, 23.85, 22.98, 22.07 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₃H₁₈N₄: 231.1610; found: 231.1671.
• 26 1-(6-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (8) Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.44 (t, J = 8.0 Hz, 1 H), 7.27 (m, 1 H), 6.24 (dd, J = 12.0 Hz, 1 H), 3.92 (t, J = 6.0 Hz, 2 H), 3.85 (s, 3 H), 3.45 (t, J = 5.6 Hz, 2 H), 3.26 (m, 4 H), 2.04 (quin, J = 6.0 Hz, 2 H), 1.92 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 162.27, 154.04, 149.67, 138.61, 109.14, 100.96, 52.86, 48.26, 48.17, 43.23, 43.05, 23.15, 22.18 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₃H₁₈N₄O: 247.1559; found: 247.1632.
• 27 1-(5-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (9) White solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 2.8 Hz, 1 H), 7.46 (d, J = 9.2 Hz, 1 H), 7.12 (dd, J = 12.0 Hz, 1 H), 3.76 (s, 3 H), 3.72 (t, J = 6.0 Hz, 2 H), 3.32 (t, J = 5.6 Hz, 2 H), 3.19 (m, 2 H), 2.03 (quin, J = 6.0 Hz, 2 H), 1.85 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 151.54, 150.39, 150.20, 132.90, 122.82, 120.71, 55.81, 48.55, 48.33, 44.68, 43.37, 23.22, 22.44 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₃H₁₈N₄O: 247.1559; found: 247.1631.
• 28 1-(3-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (10) White solid. ¹H NMR (400 MHz, CD₃CN): δ = 7.93 (d, J = 3.0 Hz, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.17 (dd, J = 12.0 Hz, 1 H), 3.79 (s, 3 H), 3.50 (t, J = 6.0 Hz, 2 H), 3.24 (m, 6 H), 2.06 (quin, J = 6.0 Hz, 2 H), 1.83 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 152.89, 150.62, 150.15, 139.84, 119.95, 118.48, 56.0, 48.28, 48.19, 46.76, 45.9, 24.52, 22.91 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₃H₁₈N₄O: 247.1559; found: 247.1635.
• 29 1-(5-Nitropyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (11) Yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 9.02 (d, J = 4.0 Hz, 1 H), 8.13 (dd, J = 12.0 Hz, 1 H), 7.86 (d, J = 10.0 Hz, 1 H), 4.01 (t, J = 6.0 Hz, 2 H), 3.44 (t, J = 6.0 Hz, 2 H), 3.25 (m, 4 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.90 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.0, 148.34, 144.28, 137.10, 130.70, 114.68, 48.19, 48.14, 43.46, 42.95, 23.29, 21.93 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₂H₁₅N₅O₂: 262.1304; found: 260.1348.
• 30 1-[6-(2,3,4,6,7,8-Hexahydro-1H-pyrimido[1,2-a]pyrimidin-1-yl)pyridin-3-yl]ethanone (12) White solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (dd, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.8 Hz, 1 H), 7.75 (dd, J = 8.8 Hz, 1 H), 3.97 (t, J = 5.6 Hz, 2 H), 3.42 (t, J = 6.0 Hz, 2 H), 3.24 (m, 4 H), 2.47 (s, 3 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.89 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.74, 158.58, 148.87, 135.23, 115.54, 48.28, 48.19, 43.37, 42.89, 26.09, 23.34, 22.08 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₄H₁₈N₄O: 259.1559; found: 259.1614.
• 31 6-{2,3,4,6,7,8-Hexahydro-1H-pyrimido[1,2-a]pyrimidin-1-yl}nicotinic Acid (13) White solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.82 (dd, J = 2.0 Hz, 1 H), 8.14 (dd, J = 8.0 Hz, 1 H), 7.01 (dd, J = 6.4 Hz, 1 H), 3.77 (t, J = 6.0 Hz, 2 H), 3.39 (t, J = 6.0 Hz, 2 H), 3.31 (m, 4 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.89 (quin, J = 6.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.43, 154.8, 150.2, 149.20, 139.13, 124.05, 116.23, 48.08, 47.76, 45.41, 40.12, 21.80, 20.47 ppm. ESI-HRMS (CHCl₃): m/z [M + H]⁺ calcd for C₁₃H₁₆N₄O₂: 261.1352; found: 261.1420.