An Improved Synthesis of Amidoalkyl Phenols Involving a Ritter-Type Reaction [1]

Abstract

Three-component condensation of phenols, aromatic aldehydes and alkyl nitriles in the presence of a catalytic amount of triflic acid yielded the corresponding amidoalkyl phenols involving a Ritter-type reaction. The products were formed in high yields and in short reaction times.

Keywords

amidoalkyl phenol - three-component condensation - ortho-quinone methide - Ritter reaction

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Part 118 in the series ‘Studies on novel synthetic methodologies’.

References and Notes

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1

Part 118 in the series ‘Studies on novel synthetic methodologies’.

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General Experimental Procedure: To a mixture of a phenol (1 mmol) and aromatic aldehyde (1 mmol) in MeCN or acrylonitrile (5 mL), triflic acid (10 mol%) was added. The mixture was heated under reflux and the reaction was monitored by TLC. After completion of the reaction, H₂O (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The extract was dried and concentrated. The residue was subjected to column chromatography (silica gel; eluent: hexane-EtOAc, 4:1) to obtain the pure amido-alkyl phenol.
The spectral (IR, ¹H and ¹³C NMR and MS) data of some representative products are given below.
Compound 4a: IR (KBr): 3422, 1654, 1511, 1460, 1376, 1269 cm^-1. ¹H NMR (200 MHz, CDCl₃ + DMSO-d ₆): δ = 8.99 (br s, 1 H), 8.01 (m, 1 H), 7.90 (br s, 1 H), 7.44-7.52 (m, 2 H), 6.84 (d, J = 8.0 Hz, 3 H), 6.68 (d, J = 8.0 Hz, 3 H), 1.92 (s, 3 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 23.0, 55.4, 115.8, 121.8, 122.3, 129.3, 130.4, 132.2, 134.4, 146.1, 148.2, 157.1, 169.3. MS (FAB): m/z (%) = 278 (2), 276 (6) [M + H]⁺·, 184 (33), 182 (100).
Compound 4i: IR (KBr): 3409, 1644, 1537, 1370, 1330, 1272 cm^-1. ¹H NMR (200 MHz, CDCl₃ + DMSO-d ₆): δ = 9.82 (br s, 1 H), 8.26 (m, 1 H), 8.02 (m, 1 H), 6.62-7.76 (m, 6 H), 7.32-7.41 (m, 3 H), 7.18-7.25 (m, 4 H), 2.06 (s, 3 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 22.9, 48.0, 118.4, 119.1, 122.5, 123.3, 123.4, 123.9, 125.1, 125.3, 126.4, 126.7, 127.2, 127.9, 128.7, 128.8, 128.9, 131.3, 132.2, 132.9, 140.6, 153.2, 169.1. MS (FAB): m/z (%) = 342 (2) [M + H]⁺·, 198 (100).
Compound 4k: IR (KBr): 3425, 1647, 1513, 1462, 1274 cm^-1. ¹H NMR (200 MHz, CDCl₃ + DMSO-d ₆): δ = 9.65 (br s, 1 H), 9.12 (d, J = 8.0 Hz, 1 H), 8.00 (m, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.36 (m, 1 H), 7.06-7.22 (m, 5 H), 6.64 (d, J = 8.0 Hz, 2 H), 3.64 (s, 3 H), 2.02 (s, 3 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 23.2, 48.2, 55.5, 113.9, 119.0, 119.5, 122.9, 126.8, 127.8, 129.0, 129.6, 132.8, 134.9, 153.6, 158.2, 169.6. MS (FAB): m/z (%) = 322 (3) [M + H]⁺·, 178 (100).
Compound 4m: IR (KBr): 3446, 1657, 1622, 1514, 1337, 1276 cm^-1. ¹H NMR (200 MHz, CDCl₃ + DMSO-d ₆): δ = 9.61 (br s, 1 H), 8.22 (m, 1 H), 8.00 (m, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.41 (m, 1 H), 7.10-7.28 (m, 7 H), 6.21-6.38 (m, 2 H), 5.61 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 47.5, 117.5, 118.0, 121.8, 122.2, 125.0, 125.8, 127.0, 127.2, 127.5, 128.5, 128.7, 130.6, 130.9, 131.9, 140.1, 152.4, 164.0. MS (FAB): m/z (%) = 340 (2), 338 (6) [M + H]⁺·, 196 (33), 194 (100).