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Synlett 2007(4): 0603-0606  
DOI: 10.1055/s-2007-967965
LETTER
© Georg Thieme Verlag Stuttgart · New York

Unprecedented 1,1′-Carbonyldiimidazole-Mediated Amidation of ­Unprotected α-Amino Acids in Water

Rohit K. Sharma, Rahul Jain*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India
Fax: +91(172)2214692; e-Mail: rahuljain@niper.ac.in;
Further Information

Publication History

Received 7 November 2006
Publication Date:
21 February 2007 (online)

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Abstract

The first amidation reaction of unprotected α-amino ­acids in water under neutral conditions with various aliphatic, aromatic and heteroaromatic amines in the presence of coupling reagent 1,1′-carbonyldiimidazole at ambient temperature is described.

Key words

amidation - 1,1′-carbonyldiimidazole (CDI) - α-amino acids - amidation reaction in water

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General Experimental Procedure.
To a solution of α-amino acid 1a-e (1.73 mmol) in H2O (4 mL), CDI (2.08 mmol) was added at ambient temperature and the reaction mixture was stirred for 30 min. Aliphatic or aromatic amine 2a-f (2.08 mmol) was then added and the stirring continued for another 7.5-23.5 h at ambient temperature. The solvent was evaporated under reduced pressure to afford crude product. Column chromatographic purification of crude product on basic alumina using CHCl3-MeOH as eluent produced amides 3a-m in 27-73% yield.

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Analytical Data of N 1-Benzyl-(2 S )-2-amino-5-amino(imino)methylaminopentanamide ( 3a)
Yield 73%; white solid; mp 176-178 °C. MS (APCI): 264.1 [M + 1]+. 1H NMR (300 MHz, D2O): δ = 1.61 (m, 2 H), 1.89 (m, 2 H), 3.16 (t, 2 H, J = 7.3 Hz), 3.69 (t, 1 H, J = 6.8 Hz), 4.39 (s, 2 H), 7.23-7.29 (m, 5 H). 13C NMR (75 MHz, D2O): δ = 25.53, 30.14, 41.47, 43.59, 54.88, 127.70, 128.15, 128.90, 139.14, 158.44, 175.21. IR (KBr): 3445, 3326, 3033, 2923, 2872, 1685, 1573, 1458 cm-1. Anal. Calcd for C13H21N5O: C, 59.32; H, 7.98; N, 26.62. Found: C, 59.24; H, 7.93; N, 26.58.

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Analytical Data of N 1-(3-Quinolyl)-(2 S )-2-amino-5-amino(imino)methylaminopentanamide ( 3f).
Yield 50%; yellow solid; mp 217-219 °C. MS (APCI): 301.1 [M + 1]+. 1H NMR (300 MHz, D2O): δ = 1.66 (m, 2 H), 1.83 (m, 2 H), 3.09 (t, 2 H, J = 7.1 Hz), 3.69 (t, 1 H, J = 6.4 Hz), 7.25 (m, 1 H), 7.61 (m, 2 H), 7.79 (m, 1 H), 7.87 (m, 1 H), 8.55 (m, 1 H). 13C NMR (75 MHz, D2O): δ = 25.14, 31.97, 41.25, 55.90, 118.21, 127.03, 127.69, 127.92, 137.50, 143.95, 157.34, 173.46. IR (KBr): 3414, 3293, 3019, 2912, 2849, 1679, 1552, 1470, 1386 cm-1. Anal. Calcd for C15H20N6O: C, 60.00; H, 6.67; N, 28.00. Found: C, 59.96; H, 6.65; N, 27.95.

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Analytical Data of N 1-Benzyl-(2 S )-2-amino-3-(1 H -4-imidazolyl)propanamide ( 3g).
Yield 60%; white solid; mp 193-195 °C. MS (APCI): 245.2 [M + 1]+. 1H NMR (300 MHz, D2O): δ = 3.26 (d, 2 H, J = 7.2 Hz), 4.08 (t, 1 H, J = 7.2 Hz), 4.36 (s, 2 H), 6.85 (s, 1 H), 7.18-7.22 (m, 5 H), 7.48 (s, 1 H). 13C NMR (75 MHz, D2O): δ = 33.81, 46.73, 58.87, 122.15, 126.95, 127.07, 127.38, 128.15, 128.46, 133.90, 134.78, 143.56, 176.41. IR (KBr): 3458, 3331, 3046, 2948, 2883, 1692, 1638, 1573, 1535, 1370 cm-1. Anal. Calcd for C13H16N4O: C, 63.93; H, 6.56; N, 22.95. Found: C, 63.88; H, 6.52; N, 22.90.

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Analytical Data of N 1-Methyl-(2 S )-2-amino-3-(1 H -4-imidazolyl)propanamide ( 3h).
Yield 56%; off-white solid; mp 127-128 °C. MS (APCI): 169.2 [M + 1]+. 1H NMR (300 MHz, D2O): δ = 2.77 (s, 3 H), 3.38 (d, 2 H, J = 7.2 Hz), 4.18 (t, 1 H, J = 7.2 Hz), 6.91 (s, 1 H), 7.59 (s, 1 H). 13C NMR (75 MHz, D2O): δ = 28.13, 36.58, 55.11, 117.74, 131.43, 136.37, 174.72. IR (KBr): 3421, 3305, 2960, 2893, 1694, 1638, 1584, 1541 cm-1. Anal. Calcd for C7H12N4O: C, 50.00; H, 7.14; N, 33.33. Found: C, 49.94; H, 7.09; N, 33.30.

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Analytical Data of N 1-Benzyl-2-aminoacetamide ( 3m).
Yield 52%; off-white solid; mp 142-144 °C. MS (APCI): 165.3 [M + 1]+. 1H NMR (300 MHz, D2O): δ = 3.67 (s, 2 H), 4.41 (s, 2 H), 7.14-7.19 (m, 5 H). 13C NMR (75 MHz, D2O): δ = 42.57, 49.60, 126.33, 127.17, 128.41, 143.89, 173.70. IR (KBr): 3454, 3319, 2971, 2888, 1687, 1578, 1453 cm-1. Anal. Calcd for C9H12N2O: C, 65.85; H, 7.32; N, 17.07. Found: C, 65.78; H, 7.26; N, 16.99.

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The optical purity of amide analogues was assessed on HPLC using CHIRALPAK WH chiral column (ID 0.46 cm, particle size 10 µm), and results indicate presence of ≤1.0% of the d-enantiomer in all cases.