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Synlett 2008(11): 1729-1733  
DOI: 10.1055/s-2008-1078485
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Qiang Wanga,b, Xiaoxue Cuia, Shasha Liua, Lili Suna, 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
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Publication History

Received 29 February 2008
Publication Date:
11 June 2008 (online)

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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

    References and Notes

  • 1a Gupta R. Paul S. Nanda P. J. Indian Chem. Soc.  2005,  82:  573 
    CrossrefGoogle Scholar
  • 1b Winstead MB. Heine HW. J. Am. Chem. Soc.  1955,  77:  1913 
    CrossrefGoogle Scholar
  • 1c Zhong W. Song G. Peng Y. Qian X. Synth. Commun.  2000,  30:  3801 
    CrossrefGoogle Scholar
  • 2a Haisa M. Kashino S. Ueno T. Shinozaki N. Matsuzaki Y. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem.  1980,  36:  2306 
    CrossrefGoogle Scholar
  • 2b Wasserman HJ. Ryan RR. Layne SP. Acta Crystallogr., Sect. C: Cryst. Struct. Commun.  1985,  41:  783 
    CrossrefGoogle Scholar
  • 4

    (a)Cambridge Structural Database, version 1.8 (May 2007).
    Crossref
  • 3b Molcanov K. Stojkovic MR. Piantanida I. Zinic M. Acta Crystallogr., Sect. E: Struct. Rep. Online  2006,  62:  o2666 
    CrossrefGoogle Scholar
  • 3c Balasubramamam V. Mohamed-Abubakar S. Vittal JJ. Valiyaveettil S. CrystEngComm  2004,  6:  284 
    CrossrefGoogle Scholar
  • 3d Klika KD. Janovec L. Lmrich J. Suchar G. Kristian P. Sillanpaa R. Pihlaja K. Eur. J. Org. Chem.  2002,  1248 
    CrossrefGoogle Scholar
  • 5a Royo M. Alsina J. Giralt E. Slomcyznska U. Albericio F. J. Chem. Soc., Perkin Trans. 1  1995,  1095 
    Google Scholar
  • 5b Pianka M. Edwards JD. Smith CBF. J. Sci. Food Agric.  1966,  17:  407 
    Google Scholar
  • 5c Haworth RD. MacGillivary R. Peacock DH. J. Chem. Soc.  1950,  1493 
    Google Scholar
  • 6 Eliel EL. Manoharan M. J. Org. Chem.  1981,  46:  1959 
    CrossrefGoogle Scholar
7

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.