V. H. J. Frade et al. / Tetrahedron 63 (2007) 1654–1663
1661
1H, 3-H), 7.40–7.50 (m, 2H, 6-H and 7-H), 7.76–7.86
(m, 2H, 8-H and 5-H). 13C NMR (CDCl3, 75.4 MHz):
dC¼23.9 (NCH2CH2CH2), 31.9 (NCH2CH2CH2), 43.6
(NCH2CH2CH2), 104.5 (C-4), 117.6 (C-2), 119.9 (C-5),
123.5 (C-4a), 124.7 (C-7), 125.7 (C-6), 126.5 (C-3), 128.6
(C-8), 134.3 (C-8a), 143.0 (C-1), 179.5 (CO2H). IR (Nujol,
cmꢀ1): n¼3418, 2954, 2924, 2854, 1694, 1651, 1581,
1526, 1463, 1455, 1378, 1349, 1290, 1220, 1126, 1093,
1036, 1015. HRMS (FAB) calcd for C14H15NO2 [M+]:
229.1103; found: 229.1102.
4b, respectively, in DMF by a standard DCC/HOBt cou-
pling. After evaporation of the solvent and dry chromato-
graphy, the required derivatives Bza–Val–OMe (5a) and
Bza–Gly–OMe (5b) were obtained. N-tert-Butyloxycarbo-
nylvaline, Boc–Val–OH (6a) or N-tert-butyloxycarbonyl
glycine, Boc–Gly–OH (6b) was reacted in the same con-
ditions with fluorophores Bzh–H (1c) and Bzn–H (1e) to
give compounds Boc–Val–Bzh (7a) and Boc–Gly–Bzh
(7b) and Boc–Val–Bzn (8), respectively.
4.4.1. Bza–Val–OMe (5a). The product of the reaction of
Bza–OH (1b) (0.043 g, 1.10ꢂ10ꢀ4 mol) with H–Val–OMe
(4a) (0.042 g, 2.48ꢂ10ꢀ4 mol) was chromatographed using
dichloromethane/methanol, 5.5:0.5 as the eluent, to produce
Bza–Val–OMe (5a) (0.043 g, 75%). Mp¼188.0–190.0 ꢁC.
TLC (dichloromethane/methanol, 5.5:0.5): Rf¼0.39. 1H
NMR (CDCl3, 300 MHz): d¼0.80–1.0 (m, 6H, g-CH3 Val),
1.40 (t, J¼6.9 Hz, 3H, NCH2CH3), 1.90–2.0 (m, 1H, b-CH
Val), 2.20–2.30 (m, 2H, NHCH2CH2CH2), 2.36 (s, 3H,
CH3), 2.64 (t, J¼5.7 Hz, 2H, NHCH2CH2CH2), 3.02 (s,
3H, OCH3), 3.30–3.50 (m, 2H, NHCH2CH3), 3.73 (br s,
1H, a-CH Val), 3.80–3.90 (m, 2H, NHCH2CH2CH2), 6.0
(br s, 1H, a-NH Val), 6.46 (s, 1H, 8-H), 6.94 (s, 1H, 6-H),
7.47 (s, 1H, 11-H), 7.76–7.80 (m, 2H, 2-H and 3-H), 8.75–
8.85 (m, 1H, 1-H), 9.0–9.10 (m, 1H, 4-H), 11.43 (br s, 1H,
NH). 13C NMR (CD3OD, 75.4 MHz): dC¼14.1 (NHCH2CH3
and g-CH3 Val), 17.7 (CH3), 23.4 (NHCH2CH2CH2), 30.6
(NHCH2CH2CH2), 35.6 (OCH3), 38.7 (NHCH2CH3), 44.6
(NHCH2CH2CH2), 58.0 (a-CH Val), 93.7 (C-6 and C-8),
123.5 (Ar–C), 124.2 (C-4), 125.1 (Ar–C), 125.5 (C-1),
129.2 (C-10), 130.5 (C-2), 131.3 (C-11 and Ar–C), 131.6
(C-3), 135.2 (Ar–C), 146.8 (Ar–C), 151.3 (Ar–C), 153.4
(C-9), 158.3 (C-5), 166.6 (CONH), 172.6 (CO2CH3). IR
(Nujol, cmꢀ1): n¼3408, 2954, 2924, 2854, 1742, 1639,
1592, 1463, 1377, 1318. HRMS (FAB) calcd for
C29H36N4O4 [M+]: 504.2737; found: 504.2718.
4.3.3. 3-(Naphthalen-1-ylamino)propanol (3c). The
product of the reaction of 1-naphthylamine (2.0 g, 1.4ꢂ
10ꢀ2 mol) with 3-bromo-1-propanol (1.33 mL, 1.47ꢂ
10ꢀ2 mol) in ethanol (5 mL), according to the procedure
describedaboveforthepreparationofcompound3a,waschro-
matographed with chloroform and chloroform/methanol,
5.8:0.2 as the eluent, to produce compound 3c as a pinkish
oil (2.07 g, 70%). TLC (chloroform/methanol, 5.7:0.3):
1
Rf¼0.30. H NMR (CDCl3, 300 MHz): d¼1.96–2.10 (m,
2H, NCH2CH2CH2), 3.10–3.50 (m, 1H, NH), 3.44 (t,
J¼6.0 Hz, 2H, NCH2CH2CH2), 3.90 (t, J¼5.7 Hz, 2H,
NCH2CH2CH2), 6.67 (d, J¼7.0 Hz, 1H, 4-H), 7.28 (d, J¼
6.6 Hz, 1H, 2-H), 7.38 (t, J¼7.5 Hz, 1H, 3-H), 7.43–7.51
(m, 2H, 6-H and 7-H), 7.78–7.86 (m, 2H, 8-H and 5-H).
13C NMR (CDCl3, 75.4 MHz): dC¼31.2 (NCH2CH2CH2),
42.5 (NCH2CH2CH2), 61.8 (NCH2CH2CH2), 104.7 (C-4),
117.6 (C-2), 120.0 (C-5), 123.5 (C-4a), 124.7 (C-7), 125.7
(C-6), 126.5 (C-3), 128.5 (C-8), 134.2 (C-8a), 143.3 (C-1).
IR (neat, cmꢀ1): n¼3529–3109, 3046, 2953, 2914, 2846,
1624, 1581, 1524, 1468, 1406, 1368, 1337, 1274, 1249,
1205, 1174, 1124, 1061. HRMS (FAB) calcd for
C13H15NO [M+]: 201.1154; found: 201.1157.
4.3.4. 3-(Naphthalen-1-ylamino)chloromethyl (3d). Thio-
nyl chloride (0.015 mL, 1.99ꢂ10ꢀ4 mol) was added to a
solution of compound 3c (0.044 g, 2.19ꢂ10ꢀ4 mol) in di-
chloromethane (1 mL) and the reaction mixture was stirred
for 22 h at room temperature. The solvent was removed under
reduced pressure and the crude mixture was purified by chro-
matography with dichloromethane/n-hexane, 3:7 as the elu-
ent, to produce compound 3d as a colourless oil (0.015 g,
31%). TLC (chloroform/methanol, 4:6): Rf¼0.71. 1H NMR
(CDCl3, 300 MHz): d¼2.20–2.30 (m, 2H, NCH2CH2CH2),
3.54 (t, J¼6.9 Hz, 2H, NCH2CH2CH2), 3.75 (t, J¼6.0 Hz,
2H, NCH2CH2CH2), 4.30–4.70 (br s, 1H, NH), 6.68 (d, J¼
7.5 Hz, 1H, 4-H), 7.26 (d, J¼8.1 Hz, 1H, 2-H), 7.37 (t, J¼
7.5 Hz, 1H, 3-H), 7.42–7.50 (m, 2H, 6-H and 7-H), 7.78–
7.86 (m, 2H, 8-H and 5-H). 13C NMR (CDCl3, 75.4 MHz):
dC¼31.7 (NCH2CH2CH2), 41.3 (NCH2CH2CH2), 49.2
(NCH2CH2CH2), 104.4 (C-4), 117.6 (C-2), 119.7 (C-5),
123.4 (C-4a), 124.7 (C-7), 125.8 (C-6), 126.5 (C-3), 128.7
(C-8), 134.3 (C-8a), 142.9 (C-1). IR (neat, cmꢀ1): n¼3440,
3054, 2959, 2926, 1623, 1582, 1480, 1409, 1377, 1345,
1279, 1254, 1219, 1121. HRMS (FAB) calcd for
C13H14N35Cl [M+]: 219.0815; found 219.0811. Calcd for
C13H14N37Cl [M+]: 221.0785; found: 221.0795.
4.4.2. Bza–Gly–OMe (5b). The product of the reaction of
Bza–OH (1b) (0.057 g, 1.46ꢂ10ꢀ4 mol) with H–Gly–OMe
(4b) (0.055 g, 4.38ꢂ10ꢀ4 mol) was chromatographed using
dichloromethane/methanol, 5.5:0.5 as the eluent, to produce
the amide Bza–Gly–OMe (5b) (0.066 g, 98%). Mp¼160.0–
162.0 ꢁC. TLC (dichloromethane/methanol, 5.5:0.5): Rf¼
0.56. 1H NMR (CDCl3, 300 MHz): d¼1.71 (br s, 3H,
NCH2CH3), 2.02–2.21 (m, 2H, NHCH2CH2CH2,), 2.36 (s,
3H, CH3), 2.60–2.72 (m, 4H, NHCH2CH2CH2 and
NHCH2CH2CH2), 3.07 (s, 3H, OCH3), 3.40–3.60 (m, 2H,
NHCH2CH3), 3.60–3.70 (m, 2H, CH2 Gly), 3.90–4.10
(2H, m, NHCH2CH2CH2), 6.0 (br s, 1H, a-NH Gly), 6.60
(1H, br s, 8-H), 7.0 (1H, br s, 6-H), 7.40 (1H, br s, 11-H),
7.70 (1H, br s, 3-H), 7.80 (1H, br s, 2-H), 8.40 (1H, br s,
1-H), 8.80 (1H, br s, 4-H), 11.60 (1H, br s, NH). 13C NMR
(CDCl3, 75.4 MHz): dC¼14.1 (NHCH2CH3 and CH3),
24.2 (NHCH2CH2CH2), 29.6 (NHCH2CH2CH2), 33.3
(OCH3), 40.0 (NHCH2CH3), 41.2 (CH2 Gly), 47.4
(NHCH2CH2CH2), 93.2 (C-6), 93.7 (C-8), 124.0 (Ar–C),
125.57 (C-4), 126.1 (Ar–C), 127.0 (C-1), 129.3 (C-10),
130.6 (C-2), 130.9 (C-3), 131.6 (C-11 and Ar–C), 139.9
(Ar–C), 144.8 (Ar–C), 151.3 (Ar–C), 151.5 (C-9), 157.0
(C-5), 166.7 (CONH), 173.6 (CO2CH3). IR (Nujol, cmꢀ1):
n¼3400, 2954, 2924, 2854, 1742, 1657, 1463, 1377, 1302.
HRMS (FAB) calcd for C26H29N4O4 [M+]: 461.2189; found:
461.2194.
4.4. General method for the synthesis of fluorescently
labelled L-amino acids 5a,b, 7a,b and 8
Carboxylic acid derivative Bza–OH (1b) was reacted with
L-valine or L-glycine methyl ester hydrochloride 4a and