An Expedient Process for the Synthesis of 2-(N-arylamino)benzaldehydes from 2-Hydroxybenzaldehydes via Smiles Rearrangement

Dedicated to Professor Firouz Matloubi Moghaddam on his 62nd birthday

Abstract

This paper describes an efficient Smiles rearrangement process for the synthesis of 2-(N-arylamino)benzaldehyde derivatives with reasonable yields. A mechanism is proposed for the reaction course.

Key words

2-(N-arylamino)benzaldehyde - 2-hydroxybenzaldehyde - Smiles rearrangement - O-alkylation

Publication History

Received: 24 June 2013

Accepted after revision: 21 July 2013

Publication Date:
27 August 2013 (online)

• References and Notes

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• 12 General Procedure for the Synthesis of 2-(N-Arylamino)benzaldehydes 5a–h To a stirred suspension of KF/Al₂O₃ (150 mg) in DMF (5 mL) were added 2-hydroxy benzaldehyde 4 (1 mmol) and 2-chloro-N-arylacetamide 3 (1 mmol), and the reaction mixture was stirred at 120 °C for 14 h with progress of the reaction being monitored by TLC. After completion of the reaction, the mixture was poured into ice cold H₂O, stirred for 15 min, then extracted with CH₂Cl₂ (3 × 10 mL). The organic phase was dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (eluent: PE–EtOAc, 6:1) to afford the desired compound 5a–h. Spectroscopic Data N-(4-Chlorophenyl) 2-(2-Formylphenoxy)acetamide (I) ¹H NMR (400 MHz, CDC1₃): δ = 10.11 (m, 2 H, CHO, NH), 7.87 (dd, J ₁ = 8.80 Hz, J ₂ = 2.0 Hz, 2 H), 7.82 (dd, J ₁ = 9.20 Hz, J ₂ = 1.60 Hz, 1 H), 7.68–7.75 (m, 1 H), 7.37 (dd, J ₁ = 8.80 Hz, J ₂ = 2.0 Hz, 2 H), 7.28 (m, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 4.72 (s, 2 H, CH₂) ppm. 2-(4-Chlorophenylamino)benzaldehyde (5a) ¹H NMR (400 MHz, CDC1₃): δ = 10.00 (br s, 1 H, NH), 9.92 (s, 1 H, CHO), 7.59 (d, J = 8.0 Hz, 1 H), 7.33–7.42 (m, 3 H), 7.19–7.25 (m, 3 H), 6.88 (t, J = 7.80 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 194.35, 147.36, 138.34, 136.70, 135.64 (2 C), 129.53, 124.29, 119.59, 117.61, 112.82 ppm. MS (EI): m/z (%) = 233 (33), 231 (100) [M⁺], 202 (74), 167 (91). Anal. Calcd for C₁₃H₁₀ClNO: C, 67.39; H, 4.35; N, 6.05. Found: C, 67.18; H, 4.40; N, 5.95. 2-(4-Methylphenylamino)benzaldehyde (5b) ¹H NMR (400 MHz, CDC1₃): δ = 9.98 (br s, 1 H, NH), 9.93 (s, 1 H, CHO), 7.58 (d, J = 8.80 Hz, 1 H), 7.38 (t, J = 7.80 Hz, 1 H), 7.17–7.23 (m, 5 H), 6.84 (t, J = 7.40 Hz, 1 H), 2.39 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 194.18, 148.39, 136.93, 136.61, 135.55, 135.35, 130.06, 123.69, 119.15, 116.77, 112.81, 21.00 ppm. MS (EI): m/z (%) = 211 (92) [M⁺], 182 (100), 167 (43). Anal. Calcd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.50; H, 6.09; N, 6.70. 2-(2-Methylphenylamino)benzaldehyde (5c) ¹H NMR (400 MHz, CDC1₃): δ = 9.97 (s, 1 H, CHO), 9.89 (br s, 1 H, NH), 7.60 (dd, J ₁ = 9.20 Hz, J₂ = 1.60 Hz, 1 H), 7.32–7.40 (m, 3 H), 7.26 (t, J = 8.40 Hz, 1 H), 7.17 (t, J = 7.40 Hz, 1 H), 6.92 (t, J = 8.40 Hz, 1 H), 6.83 (t, J = 7.30 Hz, 1 H), 2.33 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 194.31, 148.42, 137.98, 136.49, 135.59, 133.28, 131.22, 126.12, 125.44, 124.75, 119.12, 114.64, 112.89, 18.05 ppm. MS (EI): m/z (%) = 211 (100) [M⁺], 182 (74), 167 (39). Anal. Calcd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.48; H, 6.07; N, 6.56. 2-(3-Acetylphenylamino)benzaldehyde (5d) ¹H NMR (400 MHz, CDC1₃): δ = 10.12 (br s, 1 H, NH), 9.93 (s, 1 H, CHO), 7.89 (d, J = 2.40 Hz, 1 H), 7.71–7.73 (m, 1 H), 7.62 (dd, J ₁ = 7.60 Hz, J ₂ = 1.80 Hz, 1 H), 7.41–7.49 (m, 3 H), 7.27 (t, J = 8.40 Hz, 1 H), 6.91 (t, J = 7.40 Hz, 1 H), 2.63 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 197.21. 194.44, 147.04, 140.34, 138.44, 136.76, 135.74, 129.72, 127.24, 124.08, 122.10, 119.74, 117.91, 112.85, 26.79 ppm. MS (EI): m/z (%) = 239 (100) [M⁺], 210 (39), 196 (32), 168 (55), 167 (44). Anal. Calcd for C₁₅H₁₃NO₂: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.41; H, 5.35; N, 5.69. 2-(4-Chlorophenylamino)-3-methoxybenzaldehyde (5e) ¹H NMR (400 MHz, CDC1₃): δ = 9.99 (s, 1 H, CHO), 8.77 (br s, 1 H, NH), 7.34 (dd, J ₁ = 7.20 Hz, J = 2.40 Hz, 1 H), 7.18 (d, J = 8.80 Hz, 2 H), 7.11–7.13 (m, 2 H), 6.82 (d, J = 8.80 Hz, 2 H), 3.77 (s, 3 H, OCH₃) ppm. MS (EI): m/z (%) = 263 (34), 261 (100) [M⁺], 234 (26), 232 (76) 183 (38). Anal. Calcd for C₁₄H₁₂ClNO: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.30; H, 4.53; N, 5.24. 2-(4-Methylphenylamino)-5-bromobenzaldehyde (5f) ¹H NMR (400 MHz, CDC1₃): δ = 9.91 (br s, 1 H, NH), 9.84 (s, 1 H, CHO), 7.66 (d, J = 2.40 Hz, 1 H), 7.39 (dd, J ₁ = 8.80 Hz, J ₂ = 2.20 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.40 Hz, 2 H), 7.04 (d, J = 8.80 Hz, 1 H), 2.39 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 192.90, 147.33, 138.15, 138.13, 136.35, 134.91, 130.19, 123.62, 120.30, 114.97, 107.62, 21.04 ppm. MS (EI): m/z (%) = 291 (96), 289 (99) [M⁺], 262 (69), 260 (73), 167 (34). Anal. Calcd for C₁₄H₁₂BrNO: C, 57.95; H, 4.17; N, 4.83. Found: C, 57.77; H, 4.10; N, 4.91. 2-(4-Methylphenylamino)naphthalene-1-carbaldehyde (5g) ¹H NMR (400 MHz, CDC1₃): δ = 11.60 (br s, 1 H, NH), 10.92 (s, 1 H, CHO), 8.37 (d, J = 8.40 Hz, 1 H), 7.74 (d, J = 9.20 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.20 Hz, 1 H), 7.21–7.35 (m, 6 H), 2.42 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 189.84, 150.15, 137.21, 136.25, 135.42, 135.02, 130.16, 129.35, 128.11, 126.65, 124.83, 123.13, 118.42, 115.25, 108.19, 21.06 ppm. MS (EI): m/z (%) = 261 (100) [M⁺], 232 (85), 217 (53). Anal. Calcd for C₁₈H₁₅NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 82.85; H, 5.61; N, 5.24. 2-(4-Chlorophenylamino)naphthalene-1-carbaldehyde (5h) ¹H NMR (400 MHz, CDC1₃): δ = 11.57 (br s, 1 H, NH), 10.93 (s, 1 H, CHO), 8.36 (d, J = 6.80 Hz, 1 H), 7.79 (d, J = 9.20 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 7.20 Hz, 1 H), 7.24–7.39 (m, 6 H) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 190.22, 149.11, 137.71, 137.38, 134.84, 130.58, 129.67, 129.40, 129.08, 126.94, 125.61, 123.49, 118.65, 114.84, 108.84 ppm. MS (EI): m/z (%) = 283 (34), 281 (100) [M⁺], 252 (46), 217 (98). Anal. Calcd for C₁₄H₁₂ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C, 72.29; H, 4.38; N, 4.80. N-Phenyl 4-Methylaniline (8) ¹H NMR (400 MHz, CDC1₃): δ = 7.26–7.31 (m, 2 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.04–7.07 (m, 4 H), 6.93 (t, J = 7.40 Hz, 1 H), 5.66 (br s, 1 H, NH), 2.36 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDC1₃): δ = 134.94, 140.28, 131.01, 129.92, 129.37, 120.38, 118.96, 116.93, 20.76 ppm.
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