Alkaline-Earth-Catalyzed sp³ C–H Functionalization of Methyl Azaarenes and Its Use in a One-Pot Four-Component Synthesis of Azaarenyl Benzylpyrazolones

Abstract

The sp³ C–H functionalization of methyl azaarenes by using calcium triflate as the catalyst is described, together with its use in the first synthesis of azaarenyl benzylpyrazolones by a one-pot four-component reaction.

Key words

nitrogen heterocycles - azaarenes - sp³ C–H functionalization - multicomponent reactions - pyrazolones

• References


For syntheses of methyl azaarenyl derivatives, see:
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• 15 2-Aryl-4-(1-Aryl-2-hetarylethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-ones 5a–u; General Procedure Ca(OTf)₂ (10 mol%) was added to a stirred solution of MeCOCO₂Et (1.13 mmol), arylhydrazine 3 (0.942 mmol), aryl aldehyde 2 (0.934 mmol), and 2-methylazarene 1 (0.942 mmol) in H₂O (3 mL), and the mixture was heated to 100 °C. When the reaction was complete (TLC; ~5 h), the mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give a crude solid that was purified by column chromatography. 5-Methyl-2-phenyl-4-(1-phenyl-2-quinolin-2-ylethyl)-1,2-dihydro-3H-pyrazol-3-one (5a) Pink solid; yield: 227.9 mg (80%); mp 67–68 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.97 (t, J = 9 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 2 H), 7.69–7.62 (m, 2 H), 7.63 (t, J = 7 Hz, 1 H), 7.44 (t, J = 7 Hz, 2 H), 7.17–7.02 (m, 7 H), 4.32 (d, J = 9 Hz, 1 H), 3.77 (dd, J = 2, 13.5 Hz, 1 H), 3.76 (t, J = 13.5 Hz, 1 H), 1.72 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.3, 148.5, 144.8, 144.3, 139.6, 138.3, 132.7, 130.6, 129.1 (2C), 128.6 (2C), 128.4, 127.8, 127.7 (2C), 126.8, 126.4, 126.2, 125.1, 122.9, 121.8 (2C), 100.8, 42.7, 42.1, 13.4. 4-[2-(7-Chloroquinolin-2-yl)-1-(4-nitrophenyl)ethyl]-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (5m) Brown solid; yield: 222.7 mg (78%); mp 105–106 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.01–7.95 (m, 4 H), 7.8 (d, J = 7.5 Hz, 2 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.45–7.38 (m, 3 H), 7.26 (d, J = 7.5 Hz, 2 H), 7.21–7.18 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 4.48 (d, J = 9.5 Hz, 1 H), 3.77 (t, J = 13.5 Hz, 1 H), 3.66 (dd, J = 2.5, 14.0 Hz, 1 H), 1.74 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.3, 151.5, 150.7, 147.9, 146.5, 145.3, 139.2, 138.5, 137.2, 129.0, 128.8, 128.6, 128.4, 125.6, 125.5, 125.2, 123.7, 122.9, 122.0, 99.4, 42.0, 41.4, 13.3.