Enhanced Nucleophilicity of N-Aryl Amides with peri-CH and Their Condensations with Formaldehyde

Qiang Wang; Xiaoxue Cui; Shasha Liu; Lili Sun; Chunbao Li

doi:10.1055/s-2008-1078485

LETTER

Enhanced Nucleophilicity of N-Aryl Amides with peri-CH and Their Condensations with Formaldehyde

Qiang Wang^a,b, Xiaoxue Cui^a, Shasha Liu^a, Lili Sun^a, Chunbao Li*^a
^a Department of Chemistry, College of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27403475; e-Mail: lichunbao@tju.edu.cn;
^b State Key Laboratory Base of Novel Functional Materials and Preparation Science at Ningbo, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, P. R. of China

Abstract

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Abstract

N-Aryl amides with peri-CH are capable to condense with formaldehyde to yield N-hydroxymethylated N-aryl amides. The enhanced nucleophilicity is attributed to the single conjugation of the amide nitrogen with the acyl group but not the aryl group. Infrared measurements provide additional evidence for the enhanced nucleophilicity of the amides with peri-CH.

Key words

amides - condensation - nucleophilic addition - aldehydes - alcohols

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References and Notes

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Typical Experimental Procedure for Hydroxy-methylation of N -Aryl Amides
A mixture of amides (0.54 mmol, 1 equiv), polyform-aldehyde (5.40 mmol, 10 equiv), K₂CO₃ (0.54 mmol, 1 equiv), and PTC (TBAB, 0.02 mmol, 0.05 equiv) in dry CHCl₃ was stirred for the indicated time (Table [1] ) at r.t. After completion of the reaction, the unreacted polyform-aldehyde was removed by filtration and CHCl₃ was removed under vacuum to obtain the crude products. The crude products were purified by preparative TLC on SiO₂ or analyzed by ¹H NMR to determine the yields.
Spectroscopic Data for Products (Table 1) N -Hydroxymethyl- N -(naphthalen-1-yl)acetamide (1b)
White syrup, EtOAc-CH₂Cl₂ (1:8) as eluant, 93% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.965-7.891 (m, 3 H), 7.613-7.549 (m, 2 H), 7.505 (t, J = 7.5 Hz, 1 H), 7.446 (dd, J ₁ = 7.5 Hz, J ₂ = 1.5 Hz, 1 H), 5.374 (d, J = 10.0 Hz, 1 H), 4.915 (d, J = 10.0 Hz, 1 H), 4.320-4.293 (br m, 1 H), 1.803 (s, 3 H). ESI-MS: m/z (%) = 216.0 (100) [M⁺ + 1]. Anal. Calcd for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.50; H, 6.10; N, 6.55. IR (KBr): 3350.23, 3052.62, 2951.26, 1649.64, 1052.16, 1037.96 cm^-1.
N -Hydroxymethyl- N -(naphthalen-1-yl)acrylamide (2b) White syrup, EtOAc-CH₂Cl₂ (1:8) as eluant, 50% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.941-7.905 (m, 3 H), 7.587-7.565 (m, 2 H), 7.518-7.487 (m, 1 H), 7.428-7.412 (m, 1 H), 6.444 (dd, J ₁ = 17.0 Hz, J ₂ = 2.0 Hz, 1 H), 5.812 (dd, J ₁ = 17.0 Hz, J ₂ = 10.0 Hz, 1 H), 5.478 (dd, J ₁ = 12.0 Hz, J ₂ = 2.0 Hz, 1 H), 5.441 (dd, J ₁ = 10.0 Hz, J ₂ = 7.0 Hz, 1 H), 5.002 (dd, J ₁ = 10.0 Hz, J ₂ = 9.0 Hz, 1 H), 4.329 (t, J = 8.0 Hz, 1 H). ESI-MS: m/z = 228.0 (100) [M⁺ + 1]. Anal. Calcd for C₁₄H₁₃NO₂: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.97; H, 5.79; N, 6.17. IR (KBr): 3398.72, 3055.21, 2928.00, 1653.31, 1049.45, 1029.40 cm^-1.
N -Hydroxymethyl- N -(naphthalen-1-yl)benzamide (3b)
White syrup, Et₂O-CH₂Cl₂ (1:15) as eluant, 20% yield. ¹H NMR (500 MHz, CDCl₃): d = 8.156 (d, J = 8.0 Hz, 1 H), 7.890 (d, J = 8.0 Hz, 1 H), 7.748 (d, J = 13.0 Hz, 1 H), 7.655 (t, J = 7.5 Hz, 1 H), 7.585-7.542 (m, 2 H), 7.299-7.246 (m, 3 H), 7.190 (t, J = 7.5 Hz, 1 H), 7.098-7.045 (m, 3 H), 5.541 (t, J = 9.0 Hz, 1 H), 5.096 (t, J = 9.0 Hz, 1 H), 4.207 (t, J = 9.0 Hz, 1 H). ESI-MS: m/z (%) = 278.0 [M⁺ + 1]. Anal. Calcd for C₁₈H₁₅NO₂: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.97; H, 5.43; N, 5.08. IR (KBr): 3409.95, 3057.77, 2927.19, 1636.20, 1055.98, 1019.09 cm^-1.
N -[4-(Dimethylamino)naphthalen-1-yl]- N -(hydroxy-methyl)acetamide (6b) Colorless syrup, Et₂O-CH₂Cl₂ (1:6) as eluant, 90% yield. ¹H NMR (500 MHz, CDCl₃): d = 8.302-8.283 (m, 1 H), 7.911-7.892 (m, 1 H), 7.583-7.542 (m, 2 H), 7.327 (d, J = 8.0 Hz, 1 H), 7.037 (d, J = 8.0 Hz, 1 H), 5.353-5.325 (m, 1 H), 4.892-4.861 (m, 1 H), 4.048 (br s, 1 H), 2.932 (s, 6 H), 1.811 (s, 3 H). ESI-MS: m/z (%) = 258.9 [M⁺]. Anal. Calcd for C₁₅H₁₈N₂O₂: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.73; H, 7.03; N, 10.83. IR (KBr): 3412.11, 354.34, 2926.98, 1652.68, 1047.83, 970.03 cm^-1.
N -Hydroxymethyl- N -(quinolin-5-yl)acetamide (7b) White solid, CH₂Cl₂-Et₂O (1:2) as eluant, 80% yield. ¹H NMR (500 MHz, CDCl₃): d = 8.980 (dd, J ₁ = 4.5 Hz, J ₂ = 1.5 Hz, 1 H), 8.362 (d, J = 8.5 Hz, 1 H), 8.164 (d, J = 8.5 Hz, 1 H), 7.758-7.726 (m, 2 H), 7.523-7.492 (m, 2 H), 5.187-5.152 (m, 1 H), 5.129-5.094 (m, 1 H), 4.383 (br t, J = 7.0 Hz, 1 H), 1.178 (s, 3 H). ESI-MS: m/z (%) = 216.9 (100) [M⁺]. Anal. Calcd for C₁₂H₁₂N₂O₂: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.64; H, 5.60; N, 12.95. IR (KBr): 3266.71, 3192.02, 2926.37, 1660.64, 1051.17, 1000.55 cm^-1.
N -Hydroxymethyl- N -(isoquinolin-5-yl)acetamide (8b) White syrup, EtOH-CH₂Cl₂ (1:15) as eluant, 69% yield. ¹H NMR (500 MHz, CDCl₃): d = 9.331 (s, 1 H), 8.631 (d, J = 6.0 Hz, 1 H), 8.049 (dd, J ₁ = 7.5 Hz, J ₂ = 1.5 Hz, 1 H), 7.797 (d, J = 6.0 Hz, 1 H), 7.695-7.652 (m, 2 H), 5.300 (d, J = 10.5 Hz, 1 H), 4.989 (d, J = 10.5 Hz, 1 H), 1.791 (s, 3 H). ESI-MS: m/z (%) = 216.9 (100) [M⁺]. Anal. Calcd for C₁₂H₁₂N₂O₂: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.66; H, 5.60; N, 12.95. IR (KBr): 3247.57, 2922.58, 1667.28, 1054.27, 1032.91 cm^-1.
N -(Anthracen-9-yl)- N -(hydroxymethyl)acetamide (10b) Yellow solid, PE-EtOAc (1:1) as eluant, 87% yield. ¹H NMR (500 MHz, CDCl₃): d = 8.537 (s, 1 H), 8.135 (d, J = 8.5 Hz, 2 H), 8.077 (d, J = 8.5 Hz, 2 H), 7.612 (d, J = 7.0 Hz, 2 H), 7.545 (t, J = 7.0 Hz, 2 H), 5.270 (d, J = 8.0 Hz, 2 H), 4.344 (br t, J = 7.5 Hz, 1 H), 1.674 (s, 3 H). ESI-MS: m/z (%) = 266.0 (100) [M⁺ + 1]. Anal. Calcd for C₁₇H₁₅NO₂: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.97; H, 5.71; N, 5.30. IR (KBr): 3331.89, 3056.89, 2951.33, 1645.44, 1051.71, 1005.03 cm^-1.
N -Hydroxymethyl- N -[1-(hydroxymethyl)-2-methyl-1 H -indol-4-yl]acetamide (11b) Light yellow syrup, PE-EtOAc (1:1) as eluant, 86% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.395 (d, J = 8.0 Hz, 1 H), 7.158 (t, J = 7.5 Hz, 1 H), 6.931 (d, J = 7.5 Hz, 1 H), 6.258 (s, 1 H), 5.623-5.614 (m, 2 H), 5.061-5.037 (m, 2 H), 3.861 (br t, J = 6.5 Hz, 1 H), 3.322 (br t, J = 5.5 Hz, 1 H), 2.509 (s, 3 H), 1.787 (s, 3 H). ESI-MS: m/z (%) = 248.9 (100) [M⁺]. Anal. Calcd for C₁₃H₁₆N₂O₃: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.88; H, 6.52; N, 11.27. IR (KBr): 3391.72, 2922.62, 1637.66, 1037.87, 992.20 cm^-1.
Ethyl 1-Hydroxymethyl-3-[ N -(hydroxymethyl)-acetamido]-1 H -indole-2-carboxylate (12b) Colorless syrup, Et₂O-CH₂Cl₂ (1:5) as eluant, 65% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.662 (d, J = 8.0 Hz, 1 H), 7.568 (d, J = 8.5 Hz, 1 H), 7.468 (t, J = 7.5 Hz, 1 H), 7.269 (t, J = 7.5 Hz, 1 H), 5.838-5.753 (m, 2 H), 5.313-5.279 (m, 1 H), 4.854 (t, J = 9.5 Hz, 1 H), 4.568 (t, J = 8.5 Hz, 1 H), 4.445-4.385 (m, 2 H), 3.822 (t, J = 7.5 Hz, 1 H), 1.885 (s, 3 H), 1.392 (t, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) = 329.0 (100) [M⁺ + 23]. Anal. Calcd for C₁₅H₁₈N₂O₅: C, 58.82; H, 5.92; N, 9.1. Found: C, 58.80; H, 5.93; N, 9.15. IR (KBr): 3272.07, 2924.23, 1702.18, 1661.32, 1036.68 cm^-1.
Ethyl 3-Acetamido-1-(hydroxymethyl)-1 H -indole-2-carboxylate (12c) White solid, Et₂O-CH₂Cl₂ (1:5) as eluant, 29% yield. ¹H NMR (500 MHz, CDCl₃): d = 8.538 (s, 1 H), 7.958 (d, J = 7.5 Hz, 1 H), 7.453 (d, J = 8.0 Hz, 1 H), 7.406 (t, J = 6.5 Hz, 1 H), 7.165 (t, J = 6.5 Hz, 1 H), 5.751 (d, J = 8.0 Hz, 2 H), 4.483 (q, J = 7.0 Hz, 2 H), 4.060 (br t, J = 6.0 Hz, 1 H), 2.278 (s, 3 H), 1.487 (t, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) = 277.1 (100) [M⁺ + 1]. Anal. Calcd for C₁₄H₁₆N₂O₄: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.85; H, 5.85; N, 10.13. IR (KBr): 3266.87, 2924.45, 1691.19, 1660.78, 1053.51, 1018.17 cm^-1.
N -(Biphenyl-2-yl)- N -(hydroxymethyl)acetamide (13b) White solid, EtOAc-PE (1:3) as eluant, 80% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.451-7.361 (m, 8 H), 7.305-7.288 (m, 1 H), 5.299-5.271 (m, 1 H), 4.428-4.389 (m, 1 H), 3.753 (br s, 1 H), 1.780 (s, 3 H). ESI-MS: m/z (%) = 263.9 (100) [M⁺ + 23]. Anal. Calcd for C₁₅H₁₅NO₂: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.68; H, 6.26; N, 5.83. IR (KBr): 3323.07, 2953.33, 1642.20, 1050.97, 1010.89 cm^-1.
N -Hydroxymethyl- N -(2-isopropylphenyl)acetamide (14b) Colorless syrup, Et₂O-CH₂Cl₂ (1:5) as eluant, 50% yield. ¹H NMR (500 MHz, CDCl₃): d = 7.404 (dd, J ₁ = 8.0 Hz, J ₂ = 1.5 Hz, 1 H), 7.372 (dt, J ₁ = 7.0 Hz, J ₂ = 1.0 Hz, 1 H), 7.231 (dt, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1 H), 7.162 (dd, J ₁ = 7.5 Hz, J ₂ = 1.0 Hz, 1 H), 5.234 (dd, J ₁ = 10.0 Hz, J ₂ = 7.0 Hz, 1 H), 4.744 (t, J = 10.0 Hz, 1 H), 4.002 (t, J = 8.0 Hz, 1 H), 3.124 (m, 1 H), 1.818 (s, 3 H), 1.231 (d, J = 6.5 Hz, 3 H), 1.203 (d, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) = 208.0 (100) [M⁺ + 1]. Anal. Calcd for C₁₂H₁₇NO₂: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.52; H, 8.28; N, 6.75. IR (KBr): 3326.96, 2963.94, 1652.29, 1048.75, 1027.57 cm^-1.