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Synlett 2008(20): 3177-3179  
DOI: 10.1055/s-0028-1087279
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Three-Component Reaction between 2-Aminopyridines, Aldehydes and Meldrum’s Acid in Water: An Efficient Synthesis of β-Amino Acids

Mehdi Adib*a, Solmaz Fatemia, Meisam Nosratia, Hamid Reza Bijanzadehb
a School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
Fax: +98(21)66495291; e-Mail: madib@khayam.ut.ac.ir;
b Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Further Information

Publication History

Received 30 June 2008
Publication Date:
26 November 2008 (online)

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Abstract

A novel, one-pot, three-component synthesis of β-amino acids is described. Heating an alkaline aqueous solution of a 2-aminopyridine, an aldehyde and Meldrum’s acid afforded β-amino acids in good to excellent yields.

Key words

β-amino acids - 2-aminopyridines - aldehydes - Meldrum’s acid - three-component reactions - synthesis in water

    References and Notes

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9

Procedure for the Preparation of 3-Phenyl-3-(2-pyridylamino)propanoic Acid (8a): A mixture of 2-aminopyridine (0.188 g, 2 mmol), benzaldehyde (0.212 g, 2 mmol), Meldrum’s acid (0.288 g, 2 mmol) and KOH (0.056 g, 1 mmol) in H2O (5 mL) was stirred at 100 ˚C for 1.5 h, then the reaction mixture was cooled to r.t. and left overnight. The product was obtained as colorless crystals. Yield: 0.46 g (95%); mp 94-95 ˚C. IR (KBr): 3250 (NH), 2450-3300 (OH), 1710 (C=O), 1676, 1618, 1543, 1443, 1420, 1356, 1286, 1167, 1086, 962, 764, 700 cm-¹. ¹H NMR (500.1 MHz, DMSO-d 6): δ = 2.69 (dd, ² J = 15.4 Hz, ³ J = 6.3 Hz, 1 H, CH), 2.83 (dd, ² J = 15.4 Hz, ³ J = 8.5 Hz, 1 H, CH), 5.35-5.41 (m, 1 H, CH), 6.46 (dd, J = 6.2, 6.3 Hz, 1 H, CH), 6.51 (d, J = 8.4 Hz, 1 H, CH), 7.08 (d, J = 8.5 Hz, 1 H, NH), 7.20 (t, J = 7.5 Hz, 1 H, CH), 7.30 (dd, J = 7.4, 7.6 Hz, 2 H, 2 × CH), 7.34 (dt, J = 1.7, 7.9 Hz, 1 H, CH), 7.42 (d, J = 7.9 Hz, 2 H, 2 × CH), 7.93 (dd, J = 1.4, 4.5 Hz, 1 H, CH), 12.10 (br, 1 H, OH). ¹³C NMR (125.8 MHz, DMSO-d 6): δ = 41.93 (CH2), 51.26 (CH), 108.41, 111.90, 126.60, 126.67, 128.14, 136.67 (6 × CH), 143.64 (C), 147.36 (CH), 157.86 (NCN), 172.12 (C=O). MS: m/z (%) = 242 (58) [M+], 224 (8), 197 (97), 183 (100), 122 (10), 104 (24), 94 (29), 78 (56), 67 (20), 51 (19). Anal. Calcd for C14H14N2O2 (242.28): C, 69.41; H, 5.82; N, 11.56. Found: C, 69.3; H, 5.9; N, 11.4.
3-(4-Methylphenyl)-3-(2-pyridylamino)propanoic Acid (8d): yield: 0.47 g (92%); colorless crystals; mp 99-100 ˚C. IR (KBr): 3260 (NH), 2500-3350 (OH), 1713 (C=O), 1676, 1620, 1541, 1512, 1462, 1444, 1410, 1364, 1285, 1078, 962, 818, 760, 723 cm-¹. ¹H NMR (500.1 MHz, DMSO-d 6): δ = 2.23 (s, 3 H, Me), 2.63 (dd, ² J = 15.3 Hz, ³ J = 6.3 Hz, 1 H, CH), 2.78 (dd, ² J = 15.3 Hz, ³ J = 8.4 Hz, 1 H, CH), 5.26-5.32 (m, 1 H, CH), 6.43 (dd, J = 5.9, 6.1 Hz, 1 H, CH), 6.47 (d, J = 8.4 Hz, 1 H, CH), 7.01 (d, J = 8.5 Hz, 1 H, NH), 7.07 (d, J = 7.9 Hz, 2 H, 2 × CH), 7.28 (d, J = 7.9 Hz, 2 H, 2 × CH), 7.31 (dt, J = 1.6, 7.8 Hz, 1 H, CH), 7.90 (d, J = 3.9 Hz, 1 H, CH), 12.00 (br, 1 H, OH). ¹³C NMR (125.8 MHz, DMSO-d 6): δ = 20.54 (Me), 41.91 (CH2), 51.01 (CH), 108.34, 111.82, 126.49, 128.66 (4 × CH), 135.66 (C), 136.61 (CH), 140.53 (C), 147.30 (CH), 157.85 (NCN), 172.10 (C=O). MS: m/z (%) = 256 (69) [M+], 238 (17), 211 (94), 197 (100), 178 (9), 117 (25), 105 (20), 98 (13), 91 (28), 78 (56), 65 (11), 51 (13). Anal. Calcd for C15H16N2O2 (256.30): C, 70.29; H, 6.29; N, 10.93. Found: C, 70.3; H, 6.4; N, 10.8.
3-(2-Pyridylamino)hexanoic Acid (8n): yield: 0.33 g (80%); colorless crystals; mp 52-54 ˚C. IR (KBr): 3264 (NH), 2500-3400 (OH), 1707 (C=O), 1676, 1615, 1540, 1443, 1417, 1350, 1282, 1170, 1080, 980 cm-¹. ¹H NMR (300.1 MHz, DMSO-d 6): δ = 0.84 (t, J = 7.2 Hz, 3 H, Me), 1.22-1.40 (m, 2 H, CH2), 1.42-1.54 (m, 2 H, CH2), 2.31 (dd, ² J = 14.9 Hz, ³ J = 6.9 Hz, 1 H, CH), 2.48 (dd, ² J = 14.9 Hz, ³ J = 6.2 Hz, 1 H, CH), 4.18-4.23 (m, 1 H, CH), 6.32 (d, J = 8.0 Hz, 1 H, NH), 6.42 (dd, J = 6.0, 6.2 Hz, 1 H, CH), 6.44 (d, J = 8.0 Hz, 1 H, CH), 7.31 (dt, J = 1.6, 7.9 Hz, 1 H, CH), 7.92 (d, J = 4.3 Hz, 1 H, CH), 11.75 (br, 1 H, OH). ¹³C NMR (75.5 MHz, DMSO-d 6): δ = 14.38 (Me), 19.22, 36.84, 40.15 (3 × CH2), 47.36 (CH), 108.83, 111.71, 136.98, 147.81 (4 × CH), 158.84 (NCN), 173.60 (C=O). MS: m/z (%) = 209 (100) [M+ + 1], 208 (81) [M+], 192 (18), 179 (9), 165 (36), 149 (72), 135 (16), 121 (84), 107 (19), 94 (55), 78 (57), 67 (25). Anal. Calcd for C11H16N2O2 (208.26): C, 63.44; H, 7.74; N, 13.45. Found: C, 63.2; H, 7.8; N, 13.2.