Microwave Irradiation as an Efficient Tool for the Generation of N-Heterocyclic o-Quinodimethanes: Synthesis of Polyheterocyclic Compounds by Diels-Alder Reactions

Abstract

Microwave irradiation provides a general methodology for the generation of o-quinodimethanes derived from 1,2,4-tri­azine, pyrazole and 1,2,3-triazole. The cycloaddition reactions of such compounds with electron-deficient dienophiles allow the ­corresponding heteropolycyclic adducts to be obtained within 15 minutes in 51-87% yield.

Diels-Alder reactions - microwaves - heterocycles - o-quinodimethanes

References and Notes

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15

Experimental Procedure.
A mixture of bromoderivative (1 equiv), NaI (5 equiv if 1 is employed or 3 equiv in the case of 2 and 3), DMF (0.1 mL) and the corresponding dienophile (2 equiv) was placed in an open vessel and irradiated at 10 W in a focused microwave reactor (Discover^®, CEM) for 15 min. The crude product was purified by flash column chromatography (silica gel, Merck type 60, 230-400 mesh) using hexane-EtOAc as the eluent to obtain the adduct.
Data for 8: mp 204-205 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.35 (s, 3 H, CH₃), 8.60 (s, 1 H, H-5), 9.05 (s, 1 H, H-9), 10.14 (s, 1 H, H-3) ppm. ¹³C NMR (125 MHz, CDCl₃):
δ = 25.0 (CH₃), 126.0 (C-5), 126.3 (C-9), 132.2, 135.7 (C-9a and -4a), 143.9, 149.6 (C-8a and -5a), 165.6 (C=O). MS (EI): m/z = 214 [M⁺].
Data for 10: mp 165.5-166.5 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.86 (dd, 1 H, J = 7.3, 15.4 Hz, H-4), 2.90 (s, 3 H, CH₃), 2.93 (dd, 1 H, J = 7.3, 16.1 Hz, H-10), 3.23 (dd, 1 H, J = 1.6, 15.4 Hz, H-4), 3.34 (dd, 1 H, J = 1.6, 7.3 Hz, H-5), 3.36 (dd, 1 H, J = 1.8, 7.3 Hz, H-9), 3.55 (dd, 1 H, J = 1.8, 16.1 Hz, H-10), 7.37 (t, 1 H, J = 6.3 Hz, p-H Ph), 7.44 (t, 2 H, J = 6.3 Hz, m-H Ph), 7.46 (t, 2 H, J = 6.3 Hz, o-H Ph), 7.47 (s, 1 H, H-3) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 21.1 (C-4), 21.7 (C-10), 25.3 (CH₃), 39.6, 39.9 (C-5 and -9), 123.5 (m-C), 127.5 (p-C), 129.3 (o-C), 137.7 (C-3), 179.0, 179.4 (C=O), 115.2, 135.9, 139.1 ppm. MS (EI): m/z 281 [M⁺].
Data for 16: yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (m, 6 H, 2 × CH₃), 4.21 (m, 4 H, 2 × CH₂), 4.51 (br s, 2 H, H-4a and -7a), 5.30 (br s, 2 H, H-4b and -7b), 7.54 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.4 (CH₃), 42.0, 44.3 (C-4 and -7), 63.2 (COOCH₂), 122.3 (p-C), 129.3 (m-C), 129.9 (o-C), 140.7 (ipso-C), 155.3, 155.6 (COO), 136.3 ppm. MS (EI): m/z = 345 [M⁺].

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18

Experimental Procedure.
A mixture of hydroxyderivative 17 or 18 (1 equiv), ionic liquid 19 (2.8 equiv), PTSA (2 equiv) and xylene (1 mL) was placed in an closed vessel and irradiated at 15 W in a focused microwave reactor (Discover®, CEM) for 3.5 min (final temperature 150 °C). The organic layer was separated from this two-phase system. The ionic liquid was washed with xylene (2 × 1 mL). The combined organic layers were dried with MgSO₄ and the solvent removed at reduced pressure. The resulting bromoderivatives, 2 or 3, can be directly employed or purified by flash column chromatography (silica gel, Merck type 60, 230-400 mesh) using hexane-EtOAc 2:1 as the eluent.