General synthesis procedure
Amino acid (dipeptide) (1 mmol) and DTBBQ (1 mmol) were dissolved in ethanol (50 mL, 60 - 96%) and heated for 5 hrs at 50 °C. The solvent was removed and the residue separated by column chromatography or repeatedly by preparative TLC on 20 x 20 cm plates developed with mixtures of ethyl acetate-petroleum ether (EA-PE), ethyl acetate- toluene (EA-Tol) or petroleum ether-diethyl ether (PE-E) in the appropriate ratios. Purity of isolated layers was checked by TLC using a minimum of two types of developing solvents.
5,7-Di-tert-butylbenzoxazole (
2a). C
15H
21NO = 231.33; Yield 45 %; m.p. 50 °C (lit [
15] m.p. 53-55 °C); prep. TLC (EA-PE 1:9) R
f = 0.32, TLC (CHCl
3-MeOH 9:1) R
f = 0.71;
; IR (CHCl
3) ν
max 2961, 2908, 2870 (C-H), 1616, 1520 (C=N), 1482 (C=C), 1392, 1365 (CH
3) cm
-1;
1H-NMR (CDCl
3) δ 8.08 (s, 1H, Ar); 7.66 (d, 1H,
J=1.65 Hz, Ar), 7.34 (d, 1H,
J=1.65 Hz, Ar); 1.49 (s, 9H, CH
3), 1.39 (s, 9H, CH
3);
13C-NMR (CDCl
3) δ 152.02, 147.70, 140.27, 134.09, 119.86, 114.56, 35.02, 34.37, 31.80, 29.83; UV (EtOH) 211, 236, 275 nm; cLogP 5.068.
5,7-Di-tert-butyl-2-methylbenzoxazole (2b). C16H23NO = 245.18; Yield 72 %; m.p. 58-61 °C; prep. TLC PE-E (1:1) Rf = 0.64; TLC CH2Cl2 Rf = 0.13, CHCl3-MeOH (9:1) Rf = 0.75, EA-PE (9:1) Rf = 0.28; IR (KBr) νmax 2955, 2906, 2869 (C-H), 1608, 1582 (C=N), 1483, 1466 (C=C), 1394, 1363 (CH3), 873, 843 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.51 (d, 1H, J=1.92 Hz, Ar), 7.23 (d, 1H, J=1.92 Hz, Ar), 2.63 (s, 3H, CH3), 1.47 (s, 9H, CH3), 1.38 (s. 9H, CH3); 13C-NMR (CDCl3) δ 163.10, 147.11, 141.67, 133.35, 118.66, 113.59, 34.96, 34.36, 31.82, 29.88, 14.63; M+ = 245 m/e; UV(EtOH) 208, 236, 274 nm; cLogP 5.336.
5,7-Di-tert-butyl-2-phenylbenzoxazole (
2c)
. C
21H
25NO = 307.43; Yield 68 %; m.p. 59-60 °C (EtOH), lit [
16] m.p. 60-61 °C (MeOH); prep. TLC EA-PE (1:9) R
f = 0.52; TLC EA-Tol (1:4) R
f = 0.80; IR (KBr) ν
max 2957, 2907, 2868 (C-H), 1624, 1557 (C=N), 1482 (C=C), 1391, 1362 (CH
3), 863, 706 (Ar- H) cm
-1;
1H-NMR (CDCl
3) δ 8.30–8.23 (m, 2H, Ar); 7.67 (d, 1H,
J = 1.79 Hz, Ar); 7.57–7.50 (m, 3H, Ar); 7.32 (d, 1H,
J=1.79 Hz, Ar); 1.56 (s, 9H, CH
3); 1.41 (s, 9H, CH
3);
13C-NMR (CDCl
3) δ 162.45, 147.72, 146.91, 142.28, 133.70, 131.17, 128.86, 127.51, 127.38, 119.54, 114.20, 35.07, 34.46, 31.81, 30.01; UV (EtOH) 207, 239, 296 nm; cLogP 7.165.
5,7-Di-tert-butyl-2-benzylbenzoxazole (2d). C22H27NO = 321.46; Yield 73 %; oil; prep. TLC EA-PE (1:9) Rf = 0.18; IR (Nujol) νmax 1605, 1575 (C=N), 1582 (C=C), 1391, 1360 (CH3), 868, 849, 722 (Ar- H) cm-1; 1H-NMR (CDCl3) δ 7.55 (d, 1H, J=1.92 Hz, Ar), 7.42-7.27 (m, 5H, Ar), 7.25 (d, 1H, J=1.93 Hz, Ar), 4.27 (s, 2H, CH2), 1.45 (s, 9H, SH3), 1.36 (s, 9H, CH3); 13C-NMR (CDCl3) δ 164.65, 147.32, 147.21, 142.86, 135.28, 133.58, 128.91, 127.13, 119.00, 113.92, 35.29, 34.35, 31.79, 31.57, 29.60; UV (EtOH) 211, 238, 276 nm; cLogP 6.904.
5,7-Di-tert-butyl-2-(1-methyl)ethylbenzoxazole (2e). C18H27NO = 273.21; Yield 52.6 %; oil; prep. TLC EA-PE (1:9) Rf = 0.55, then PE-E (1:1) Rf = 088; IR (KBr) νmax 2958, 2907, 2871 (C-H), 1608, 1574 (C=N), 1482 (C=C), 1390, 1363 (CH3), 869, 837 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.58 (d, 1H, J=1.79 Hz, Ar), 7.25 (d, 1H, J=1.79 Hz, Ar), 3.34-3.18 (m, 1H, CH), 1.48 (s, 9H, CH3), 1.46 (d, 6H, J=7.69, CH3), 1.37 (s, 9H, CH3); 13C-NMR (CDCl3) δ 170.75, 147.24, 146.86, 141.02, 133.48, 118.75, 113.75, 34.99, 34.36, 31.82, 29.87, 28.79, 20.35; UV (EtOH) 208, 236, 276 nm; cLogP 6.264.
5,7-Di-tert-butyl-2-(2-methyl)propylbenzoxazole (2f). C19H29NO = 287.44; Yield 34 %; oil; prep. TLC EA-PE (1:9) Rf = 0.87; IR (CHCl3) νmax 2959, 2908, 2871 (C-H), 1607, 1575 (C=N), 1482 (C=C), 1392, 1364 (CH3), 868 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.54 (d, 1H, J=1.79 Hz, Ar), 7.24 (d, 1H, J=1.79 Hz, Ar), 2.81 (d, 2H, J=7.14 Hz, CH2), 2.38-2.19 (m, 1H, CH), 1.48 (s, 9H, CH3), 1.37 (s, 9H, CH3), 1.05 (d, 6H, J=6.6 Hz, CH3); 13C-NMR (CDCl3) δ 165.95, 147.07, 141.52, 133.42, 118.64, 113.72, 37.58, 34.98, 34.35, 31.83, 29.87, 27.56, 22.42; UV (EtOH) 212, 237, 275 nm; cLogP 6.793.
5,7-Di-tert-butyl-2-(2-methylthioethyl)-benzoxazole (2g). C18H27NOS = 305.48; Yield 67.3 %; m.p. 95 °C; column chromatography EA-PE (0.5:9.5), then prep. TLC EA-PE (2:8) Rf = 0.45; IR (CHCl3) νmax 2966, 2921, 2910, 2871 (C-H), 1606, 1574 (C=N), 1482 (C=C), 1393, 1365 (CH3) cm-1; 1H-NMR (CDCl3) δ 7.55 (d, 1H, J=1.92 Hz, Ar), 7.25 (d, 1H, J=1.92 Hz, Ar), 3.28-3.20 (m, 2H, CH2), 3.07- 2.99 (m, 2H, CH2), 2.17 (s, 3H, CH3), 1.47 (s, 9H, CH3), 1.36 (s, 9H, CH3); 13C-NMR (CDCl3) δ 142.13, 142.07, 140.54, 135.59, 115.95, 110.36, 34.89, 34.40, 31.63, 29.74, 15.60; UV (EtOH) 213, 238, 275 nm; cLogP 5.634.
4-(5,7-Di-tert-butylbenzoxazol-2-yl-methyl)-phenol (2h). C22H27NO2 = 337.46; Yield 35.7 %; m.p. 121-123 °C (EtOH/H2O); TLC EA-PE (1:9) Rf = 0.64; IR (KBr) νmax 3440 (O-H), 2959, 2906, 2869 (C-H), 1615, 1517(C=N), 1479 (C=C), 1392, 1363 (CH3), 834, (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.53 (d, 1H, J=1.92 Hz, Ar), 7.26 (d, 1H, J=1.92 Hz, Ar), 7.17-7.10 (m AA´BB´, 2H, Ar), 6.73-6.67 (m, AA´BB´, 2H, Ar), 4.18 (s, 2H, CH2), 1.47 (s, 9H, CH3), 1.34 (s, 9H, CH3); 13C-NMR (CDCl3) δ 165.72, 155.51, 147.64, 147.01, 140.84, 133.73, 130.05, 126.13, 119.20, 115.91, 113.58, 35.01, 34.38, 34.35, 31.47, 29.89; UV (EtOH) 217, 279, 328 nm; cLogP 6.237.
5,7-Di-tert-butyl-2-[1H-indol-3-yl(methyl)]-benzoxazole (2i). C24H28N2O = 360.49; Yield 82%; M.p.: 159-161 °C (EtOH/H2O); column chromatography PE-CH2Cl2 (2:8), then EA-PE (1:9) Rf = 0.57; IR (KBr) νmax 3390 (N-H), 2963, 2906, 2870 (C-H), 1617, 1575 (C=N), 1481, 1458 (C=C), 1391, 1363 (CH3), 871, 845 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 8.28 (bs, 1H, NH), 7.75 (d, 1H, J=7.7 Hz, Ar), 7.55 (d, 1H, J=1.9 Hz, Ar), 7.37-7.32 (m, 1H, Ar), 7.24 (d, 1H, J=1.9 Hz, Ar), 7.23-7.10 (m, 3H, Ar), 4.44 (s, 2H, CH2), 1.46 (s, 9H, CH3), 1.35 (s, 9H, CH3); 13C-NMR (CDCl3) δ 165.21, 147.27, 147.09, 141.30, 136.16, 133.56, 126.99, 122.89, 122.23, 119.64, 118.92, 113.81, 111.17, 109.48, 34.98, 34.35, 31.80, 29.90, 25.38; UV (EtOH) 223, 242, 276 nm; cLogP 6.894.
5,7-Di-tert-butylbenzoxazole-2-carboxamide (2j). C16H22N2O2= 274.17; Yield 61 %; m.p. 193-194 °C (EtOH); column chromatography in Tol, then EA-Tol (1:4), TLC Rf = 0.2; TLC EA-PE (1:9) Rf = 0.52; IR (KBr) νmax 2961, 2907, 2871(C-H), 1701(C=N), 1619, 1600 (C=N), 1546 (C=N), 1483 (C=C), 1395, 1364 (CH3), 870, 841 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.63 (d, 1H, J=1.64 Hz, Ar), 7.44 (d, 1H, J=1.64 Hz, Ar), 7.25 (bs, 1H, NH2), 6.42 (bs, 1H, NH2), 1.51 (s, 9H, CH3), 1.38 (s, 9H, CH3); 13C-NMR (CDCl3) δ 157.70, 154.50, 148.96, 140.51, 135.20, 122.11, 115.04, 35.150, 34.57, 31.68, 29.92; UV (EtOH) 213, 231, 274 nm; cLogP 4.566.
1,3-Bis(5,7-di-tert-butylbenzoxazol-2-yl)propane (2k). C33H46N2O2=502,73; Yield 38 %; m.p. 155-157 °C (EA-PE); prep. TLC EA-PE (1:9) Rf = 0.68; TLC Tol-EA (4:1) Rf = 0.83; IR (KBr) νmax 2957, 2906, 2869 (C-H), 1607, 1574 (C=N), 1482 (C=C), 1403, 1363 (CH3), 869, 769 (Ar-H) cm-1; 1H-NMR (CDCl3) δ: 7.55 (d, 2H, J=2.29 Hz, Ar), 7.25 (d, 2H, J=2.29 Hz, Ar), 3.13 (t, 4H, J=7.41 Hz, CH2), 2.56-2.44 (m, 2H, CH2), 1.46 (s, 18H, CH3), 1.37 (s, 18H, CH3); 13C-NMR (CDCl3) δ 165.38, 147.25, 147.03, 141.44, 133.52, 118.88, 113.80, 34.99, 34.36, 31.82, 29.90, 27.88, 23.93; UV (EtOH) 216, 239, 275 nm; cLogP 9.978.
(5,7-Di-tert-butylbenzoxazol-2-yl)phenylmethanol (2l). C22H27NO2 = 337.20; Yield 33 %; m.p. 112 – 114 °C; column chromatography in CH2Cl2 followed by MeOH; TLC CHCl3-MeOH (9:1) Rf = 0.65; IR (KBr) νmax 2961, 2907, 2869 (C-H), 1624, 1570 (C=N), 1482 (C=C), 1403, 1364 (CH3), 869, 855 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 7.57-7.52 (m, 3H Ar), 7.42-7.28 (m, 3H Ar), 7.28-7.25 (m, 1H Ar), 6.03 (d, 1H, J=5.2 Hz, CH), 3.75 (d, 1H, J=5.5 Hz, OH); 1.41 (s, 9H, CH3), 1.36 (s, 9H, CH3); 13C-NMR (CDCl3) δ 166.08, 147.78, 147.29, 140.48, 139.18, 133.98, 128.66, 128.56, 126.61, 119.60, 114.21, 70.47, 35.04, 34.34, 31.77, 29.83; M+ = 337 m/e; UV (EtOH) 209, 242, 277 nm; cLogP 4.029.
5,7-Di-tert-butylbezoxazol-2-methylcarbonate (2m). C17H23NO3 = 289.37; Yield 17 %; oil; preparative TLC CHCl3-MeOH (9:1) Rf = 0.78; IR (CHCl3) νmax 2967, 2908, 2872 (C-H), 1746 (CO-ester), 1616, 1544 (C=N), 1483 (C=C), 1365 (CH3) cm-1; 1H-NMR (CDCl3) δ 7.69 (d, 1H, J=1.92 Hz, Ar); 7.46 (d, 1H, J=1.92 Hz, Ar); 4.07 (s, 3H, CH3); 1.51 (s, 9H, CH3); 1.38 (s, 9H, CH3); 13C-NMR (CDCl3) δ 157.07, 152.19, 149.10, 147.42, 140.85, 135.01, 122.66, 115.71, 53.43, 35.14, 34.53, 31.64, 29.85; UV (EtOH) 213, 233, 275 nm; cLogP 4.789.
[(5,7-di-tert-butylbenzoxazole-2-carbonyl)-amino]-acetic acid (2n). C18H24N2O4 = 332.39; Yield 80 %; m.p. 182-183 °C; isolation by extraction with PE. Insoluble crystalline part recrystallized from EA-PE; TLC CHCl3-MeOH (9:1) Rf = 0.26, 1-butanol-formic acid-water (75:15:10) Rf = 0.87; IR (KBr) νmax 3410 (O-H), 2961, 2908, 2872 (C-H), 1740 (COOH), 1694 (CONH2), 1618, 1559 (C=N), 1482 (C=C), 1391, 1365 (CH3), 869, 845 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 8.27 (t, 1H, J=5.63 Hz, NH), 7.61 (d, 1H, J=1.79 Hz, Ar), 7.43 (d, 1H, J=1.79 Hz, Ar), 4.37 (d, 2H, J=5.77 Hz, CH2), 1.50 (s, 9H, CH3), 1.37 (s, 9H, CH3); 13C-NMR (CDCl3) δ 172.73, 156.15, 154.47, 149.23, 147.37, 139.73, 135.21, 122.27, 114.66, 41.27, 35.12, 34.46, 31.60, 29.77; UV (EtOH) 217, 231, 264 nm; cLogP 4.673.
2-[(5,7-Di-tert-butylbenzoxazole-2-carbonyl)-amino]-4-methylpentanoic acid (2o). C22H32N2O4 = 388.50; Yield 41.3 %; m.p. 183-184 °C; isolation by extraction with PE. Insoluble crystalline part recrystallized from EA-PE; TLC CHCl3-MeOH (9:1) Rf=0.32, 1-butanol-formic acid-water (75:15:10) Rf = 0.62; [α]D25 = 39.32 °(c = 0.9; EA); IR (KBr) νmax 3408 (O-H), 2961, 2907, 2869 (C-H), 1725 (COOH), 1685 (CONH2), 1618, 1557 (C=N), 1482 (C=C), 1391, 1364 (CH3), 869 cm-1; 1H-NMR (CDCl3) δ 7.85 (d, 1H, J=8.52 Hz, NH), 7.62 (d, 1H, J=1.79 Hz, Ar), 7.42 (d, 1H, J=1.79 Hz, Ar), 6.72 (bs, 1H, COOH), 4.92-4.82 (m, 1H, CH), 1.91-1.72 (m, 3H, CH, CH2), 1.50 (s, 9H, CH3), 1.37 (s, 9H, CH3), 1.00 (d overlapped, 3H, J=6.05 Hz, CH3), 0.99 (d, overlapped, 3H, J=6.05 Hz, CH3); 13C-NMR (CDCl3) δ 176.35, 155.76, 154.62, 149.06, 147.61, 140.10, 135.23, 122.09, 114.83, 51.04, 41.08, 35.15, 34.53, 31.67, 29.89, 24.92, 21.68; UV (EtOH) 212, 233, 279 nm; cLogP 6.439.
2-[(5,7-Di-tert-butylbenzoxazole-2-carbonyl)-amino]-3-(4-hydroxyphenyl)propionic acid (2p). C25H30N2O5 = 438.52; Yield 64 %; m.p.: 126 -128 °C; isolation by extraction with PE. Insoluble crystalline part recrystallized from E-PE; [α]D25 = 36.58 °(c=0.8; EA); TLC EA-Tol (1:4) Rf = 0.1, CHCl3-MeOH (7:3) Rf = 0.85; IR (KBr) νmax 3405 (O-H), 2962, 2909, 2871(C-H), 1724 (COOH), 1678 (CONH2), 1616, 1558 (C=N), 1483 (C=C), 1392 , 1365 (CH3), 877 ,837(Ar-H) cm-1; 1H-NMR (CDCl3) δ 9.20 (bs, 1H, OH), 9.12 (d, 1H, J=8.24 Hz), 7.66 (d, 1H, J=1.64 Hz, Ar), 7.41 (d, 1H, J=1.92 Hz, Ar), 7.11-7.04 (m AA´BB´, 2H, Ar), 6.67-6.60 (m AA´BB´, 2H, Ar), 4.67-4.52 (m, 1H, CH), 3.14-3.01 (m, 2H, CH2), 1.44 (s, 9H, CH3), 1.34 (s, 9H, CH3); 13C-NMR (CDCl3) δ 172.42, 156.16, 155.38, 155.13, 148.63, 146.75, 140.44, 134.58, 130.29, 127.80, 121.59, 115.26, 115.16, 54.50, 40.54, 35.23, 34.36, 31.67, 29.83; UV (EtOH) 209, 242, 277 nm; cLogP 5.733.
(2-Oxo-propionylamino)acetic acid (
3a). C
5H
7NO
4 = 145.11; Yield 65 %. M.p.: 88 °C (EA-PE), lit. [
17] m.p. 90 °C; TLC 1-butanol-formic acid-water (75:15:10) R
f = 0.63; IR (KBr) ν
max 3283 (N-H), 1734 (CO-COOH), 1683 (CO), 1663 (amide-I), 1538 (amide II), 1412, 161 (CH
3), 1183 (C-O) cm
-1;
1H NMR (D
2O) δ 4.1 (s, 2H, CH
2), 2.2 (s, 3H, CH
3);
13C-NMR (D
2O) δ 200.00, 177.93, 165.10, 43.61, 26.95
2-(2-Oxo-3-phenyl-propionylamino)-3-pheyl-propionic acid (3b). C18H17NO4 = 311.33; Compound was isolated as 4b
4-Methyl-2-oxo-pentanoylamino)-acetic acid (3c). C8H13NO4 = 187.19; Yield 20 %; oil, TLC CHCl3- MeOH (9:1) Rf=0,21; IR (CHCl3) νmax 3404 (O-H), 2963, 2935, 2874 (C-H), 1732 (COOH), 1689 (CONH2), 1526, 1467, 1438, 1370 cm-1; 1H-NMR (DMSO) δ 7.51 (bs, 1H, NH), 7.13 (d, 2H, J=5.49, CH2), 2.80 (d, 2H, J=6.87 Hz, CH2) 2,35-1.98 (m, 1H, CH), 0.95 (d, 6H, J=6.6 Hz, CH3)
{2-[(2,4-dinitrophenyl)-hydrazono]-propionylamino}acetic acid (
4a) C
11H
11N
5O
7 = 325.23; Yield 45 %; m.p.: 245 – 246 °C (EtOH/H
2O), lit. [
18] m.p.: 245-246 °C; IR (KBr) ν
max 3314 (N-H); 3108, 3095 (=C-H), 1737 (-CO-C=N); 1654 (CONH
2); 1619, 1341 (NO
2); 848, 833(Ar-H) cm
-1;
1H-NMR (CDCl
3) δ 11.22 (bs, 1H, OH), 9.18 (d, 1H,
J=2.47 Hz, H3´), 8.44 (ddd, 1H,
J=9.48 Hz,
J=2.47 Hz,
J=0.55 Hz, H5´), 8.00 (d, 1H,
J=9.48 Hz, H6´), 7.47 (t, 1H,
J=4.94 Hz, NH), 4.19 (d, 2H,
J=5.22 Hz, CH
2), 2.32 (s, 3H, CH
3);
13C-NMR (CDCl
3) δ 169.76, 163.08, 146.53, 143.92, 139.60, 139.60, 123.28, 116.62, 61.84, 41.52, 14.16; UV (EtOH) 207, 264, 351 nm.
2{2-[(2,4-dinitrophenyl)-hydrazono]-3-phenyl-propionylamino}-3-phenylpropionic acid (4b) C24H21N5O7 = 491.45; Yield 35 %; m.p. 131-133 °C (EtOH); IR (KBr) νmax 3420 (N-H); 1736 (-CO-C=N); 1671 (CONH2); 1618, 1339 (NO2); 742, 702 (Ar-H) cm-1; 1H-NMR (CDCl3) δ 11.24 (bs, 1H, OH), 9.10 (d, 1H, J=2.48 Hz, H3´), 8.33 (dd, 1H, J=9.62 Hz, J=2.48, H5´), 7.67 (d, 1H, J=9.62 Hz, H6´), 7.57-7.29 (m, 10H), 5.06-4.97 (m, 1H, CH), 4.13 (d, 2H, CH2), 3.28 (d, 2H, J=5.49 Hz, CH2); 13C NMR (CDCl3) δ 14.18, 30.67, 37.85, 61.84, 116.78, 123.10, 127.31, 127.49, 128.69, 129.23, 129.48, 130.07, 131.09, 133.18, 135.65, 139.63, 143.75, 147.76, 162.86, 171.26; UV (EtOH) 210, 253, 352 nm.