(S)-Proline as a Neutral and Efficient Catalyst for the One-Pot Synthesis of Tetrahydrobenzo[b]pyran Derivatives in Aqueous Media

Abstract

(S)-Proline has been used as a mild, efficient and neutral catalyst for synthesis of various 4H-benzo[b]pyran derivatives via a one-pot three-component condensation of aromatic aldehydes, ­active methylene compounds, and dimedone in aqueous media. This method offers the advantages of proceeding and neutral and mild conditions, giving high to excellent yields of the products and simple workup.

4H-benzo[b]pyrans - 4H-chromene - aqueous media - (S)-proline - Knoevenagel-cyclocondensation reaction

References and Notes

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16

General Experimental Procedure: Method A. A solution of an aromatic aldehyde 1 (1 mmol), malono-nitrile (2, 1.2 mmol), 5,5-dimethyl-1,3-cyclohexanedione (3, 1.1 mmol) and (S)-proline (5 mol%) in H₂O (20 mL) was stirred at r.t. for 0.5 h (in the case of 4p, the reaction mixture was stirred in refluxing H₂O for 2 h). Then, the mixture was cooled in a refrigerator overnight; the solid compound obtained was filtered off and washed with H₂O (30 mL). The crude products were purified by recrystallization from EtOH (96%).
General Experimental Procedure: Method B.
A mixture of aromatic aldehyde 1 (1 mmol), alkyl cyano-acetate (2, 1.2 mmol), 5,5-dimethyl-1,3-cyclohexanedione (3, 1.1 mmol) and (S)-proline (5 mol%) in a mixture of H₂O (15 mL) and EtOH (15 mL) was stirred at 50 °C for 2 h. After completion of the reaction, the volume of the solution was reduced to half, and H₂O (15 mL) was added. Then the mixture was cooled in a refrigerator overnight and the solid compound was collected by filtration. The crude products were recrystallized from EtOH (96%). IR spectra were obtained on a Shimadzu IR-460 and Perkin-Elmer FT-IR Spectrum 1 spectrometer. ¹H NMR spectra were run on a Bruker DRX-500 (500 MHz) AVANCE instrument using TMS as internal standard and DMSO-d ₆ or CDCl₃ as solvent. Data of selected compounds are given below:
Compound 4d: ¹H NMR (DMSO-d ₆): δ = 0.95 (3 H, s, Me), 1.04 (3 H, s, Me), 2.10 (1 H, d, H-6, J = 16.0 Hz), 2.24 (1 H, d, H-6′, J = 16.0 Hz), 2.51 (2 H, br s, H-8), 4.29 (1 H, s, H-4), 7.16 (2 H, br s, NH₂), 7.37 (2 H, d, J = 8.05 Hz, ArH), 7.76 (2 H, d, J = 8.05 Hz, ArH).
Compound 4j: ¹H NMR (DMSO-d ₆): δ = 0.94 (3 H, s, Me), 1.03 (3 H, s, Me), 2.01 (3 H, s, COMe), 2.08 (1 H, d, J = 16.0 Hz, H-6), 2.24 (1 H, d, J = 16.0 Hz, H-6′), 2.50 (2 H, br s, H-8), 4.11 (1 H, s, H-4), 6.99 (2 H, br s, NH₂), 7.04 (2 H, d, J = 8.4 Hz, ArH), 7.45 (2 H, d, J = 8.4 Hz, ArH), 9.87 (1 H, s, NHCO).
Compound 4q: IR (KBr): ν_max = 3429, 3313, 1694, 1653 cm^-1. ¹H NMR (CDCl₃): δ = 1.00 (3 H, s, Me), 1.14 (3 H, s, Me), 2.20 (1 H, d, J = 16.0 Hz, H-6), 2.27 (1 H, d, J = 16.0 Hz, H-6′), 2.45 (2 H, br s, H-8), 3.65 (3 H, s, OMe), 4.73 (1 H, s, H-4), 6.20 (2 H, br s, NH₂), 7.21 (2 H, d, J = 8.4 Hz, ArH), 7.24 (2 H, d, J = 8.4 Hz, ArH).
Compound 4r: IR (KBr): ν_max = 3431, 3315, 1696, 1656, 1532, 1352 cm^-1. ¹H NMR (CDCl₃): δ = 0.98 (3 H, s, Me), 1.12 (3 H, s, Me), 2.16 (1 H, d, J = 16.0 Hz, H-6), 2.26 (1 H, d, J = 16.0 Hz, H-6′), 2.48 (2 H, br s, H-8), 3.64 (3 H, s, OMe), 4.80 (1 H, s, H-4), 6.30 (2 H, br s, NH₂), 7.39 (1 H, t, J = 13.0 Hz, ArH), 7.68 (1 H, dt, J = 13.0, 3.2 Hz, ArH), 8.00 (1 H, m, ArH), 8.08 (1 H, t, J = 3.2 Hz, ArH).
Compound 4s: IR (KBr): ν_max = 3404, 3291, 1691, 1655 cm^-1. ¹H NMR (CDCl₃): δ = 1.00 (3 H, s, Me), 1.13 (3 H, s, Me), 1.19 (3 H, t, J = 7.08 Hz, Me), 2.20 (1 H, d, J = 16.0 Hz, H-6), 2.26 (1 H, d, J = 16.0 Hz, H-6′), 2.46 (2 H, br s, H-8), 4.06 (2 H, m, OCH₂), 4.73 (1 H, s, H-4), 6.22 (2 H, br s, NH₂), 7.14 (1 H, t, J = 7.2 Hz, ArH), 7.24 (2 H, t, J = 7.2 Hz, ArH), 7.30 (2 H, d, J = 7.5 Hz, ArH).
Compound 4t: IR (KBr): ν_max = 3477, 3317, 1692, 1669 cm^-1. ¹H NMR (CDCl₃): δ = 0.98 (3 H, s, Me), 1.11 (3 H, s, Me), 1.17 (3 H, t, J = 7.1 Hz, Me), 2.17 (1 H, d, J = 16.0 Hz, H-6), 2.27 (1 H, d, J = 16.0 Hz, H-6′), 2.44 (2 H, br s, H-8), 4.05 (2 H, m, OCH₂), 4.68 (1 H, s, H-4), 6.20 (2 H, br s, NH₂), 7.19 (2 H, d, J = 8.1 Hz, ArH), 7.21 (2 H, d, J = 8.1 Hz, ArH).
Compound 4x: IR (KBr): ν_max = 3476, 3338, 1687, 1659 cm^-1. ¹H NMR (CDCl₃): δ = 1.00 (3 H, s, Me), 1.15 (3 H, s, Me), 1.17 (3 H, t, J = 7.1 Hz, Me), 2.20 (1 H, d, J = 16.0 Hz, H-6), 2.28 (1 H, d, J = 16.0 Hz, H-6′), 2.49 (1 H, d, J = 16.0 Hz, H-8), 2.50 (1 H, d, J = 16.0 Hz, H-6′), 4.06 (2 H, m, OCH₂), 4.83 (1 H, s, H-4), 6.32 (2 H, br s, NH₂), 7.48 (2 H, d, J = 8.8 Hz, ArH), 8.12 (2 H, d, J = 8.8 Hz, ArH).

17 List B. Synlett  2001,  1675