An Efficient, One-Pot Regioselective Synthesis of Highly Functionalized Chromen-5-ones and Pyrano[3,2-c]chromen-5-ones via a Tandem Knoevenagel–Michael–Cyclization Sequence

Abstract

A facile, convenient, efficient, and high-yielding regio­selective synthesis of a combinatorial library of hitherto unreported highly functionalized chromen-5-ones and pyrano[3,2-c]chromen-5-ones has been developed by one-pot three-component coupling of substituted aromatic aldehydes, dimedone/4-hydroxycoumarin with NMSM in the presence of catalytic amount of piperidine in ethanol medium. This transformation presumably proceeds via domino Knoevenagel condensation–Michael addition–intermolecular cyclization sequence creating three new bonds (two C–C and one C–O) and one stereocenter in a single operation.

Key words

NMSM - Michael addition - regioselectivity - chromenes and pyranochromenes - one-pot synthesis

• References

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• 20 General Procedure for the Synthesis of Tetrahydrochromen-5-one 5a–j: A solution of the requisite aldehyde (1.0 mmol), cyclic 1,3-dicarbonyl compound (1.0 mmol), NMSM (1.0 mmol), and piperidine (0.2 equiv) in EtOH (2 mL) was stirred for the appropriate time (Table 2). After reaction was complete as indicated by TLC, the product was filtered and washed with EtOH (2 mL) to remove the excess base and other impurities. Finally, the products were recrystallized from EtOH.
• 21 General Procedure for the Synthesis of Pyrano[3,2-c]chromen-5-ones 6a–f: A solution of the requisite aldehyde (1.0 mmol), 4-hydroxycoumarin (1.0 mmol), NMSM (1.0 mmol), and piperidine (0.2 equiv) in EtOH (2 mL) was stirred for the appropriate time (Table 3). After reaction was complete as indicated by TLC, the product was filtered and washed with EtOH (2 mL) to remove the excess base and other impurities. Finally, the products were recrystallized from EtOH.
• 22 Crystallographic data for compound 5a in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplemental publication No. CCDC 897843. Copies of the data can be obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]]. 7,7-Dimethyl-2-(methylamino)-3-nitro-4-(4-nitrophenyl)-7,8-dihydro-4H-chromen-5(6H)-one (5a): white solid; yield: 86%; mp 220–222 °C. IR (KBr): 3203, 2598, 1682, 1637, 1515, 1469, 1357, 1263, 1137, 1056, 825, 694, 632, 544 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.91 (s, 3 H, Me), 1.06 (s, 3 H, Me), 2.13 (d, J = 16 Hz, 1 H, CH), 2.28 (d, J = 16.5 Hz, 1 H, CH), 2.64 (dd, J = 18 Hz, 2 H, CH₂), 3.12 (d, J = 5.5 Hz, 3 H, NMe), 5.0 (s, 1 H, CH), 7.53 (d, J = 9.0 Hz, 2 H, ArH), 8.11 (d, J = 8.5 Hz, 2 H, ArH), 10.28 (q, J = 5.0 Hz, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 27.2, 28.8, 28.9, 32.4, 36.6, 39.6, 50.1, 108.1, 114.6, 123.5, 130.1, 146.7, 150.6, 157.6, 162.0, 195.9. ESI–MS: 374 [M⁺ + 1]. Anal. Calcd for C₁₈H₁₉N₃O₆: C, 57.90; H, 5.13; N, 11.25. Found: C, 57.96; H, 5.07; N, 11.31. 2-(Methylamino)-3-nitro-4-para-tolylpyrano[3,2-c]chromen-5(4H)-one (6a): white solid; yield: 86%; mp 258–260 °C. IR (KBr): 3211, 2923, 2369, 1728, 1674, 1628, 1359, 1264, 1153, 1110, 948, 807, 771, 689, 530, 438 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.22 (s, 3 H, Me), 3.22 (d, J = 5.0 Hz, 3 H, NMe), 5.03 (s, 1 H, CH), 7.06 (d, J = 8.0 Hz, 2 H, ArH), 7.21 (d, J = 7.5 Hz, 2 H, ArH), 7.47–7.52 (m, 2 H, ArH), 7.72 (t, J = 7.5 Hz, 1 H, ArH), 8.00 (d, J = 7.5 Hz, 1 H, ArH), 10.39 (d, J = 5.5 Hz, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 21.1, 29.2, 37.5, 107.3, 108.3, 113.1, 117.1, 123.3, 125.5, 128.8, 129.1, 133.6, 136.8, 138.8, 152.2, 152.4, 157.2, 159.7. ESI–MS: 365 [M⁺ + 1]. Anal. Calcd for C₂₀H₁₆N₂O₅: C, 65.93; H, 4.43; N, 7.69. Found: C, 65.87; H, 4.49; N, 7.74.