M. Pintea et al. / Tetrahedron 64 (2008) 8851–8870
8865
CH2OH), 3.66 (dd, 2JH,H¼10.8 Hz, 3JH,H¼5.8 Hz, 4H, 1-, 10-H, CH2OH),
4.46 (br s, 4H, 4ꢄOH), 6.37 (br s, 2H, N-, N0-H) ppm. 13C NMR
d, 3JH,H¼6.0, 6.8 Hz, respectively, 2H, 2-, 20-H), 4.83–4.90 (m, 2H, 3-,
30-OH), 4.97–5.02 (br m, 2H, 1-, 10-H), 5.61, 5.72, 5.80, 5.83 (4ꢄd,
3JH,H¼5.3, 5.3, 4.9, 5.3 Hz, respectively, 2H, 1-, 10-OH), 6.82, 6.88,
7.07, 7.10 (4ꢄd, 3JH,H¼9.0, 9.4, 9.1, 8.3 Hz, respectively, 2H, N-, N0-H),
(75 MHz, DMSO-d6, 25 ꢀC):
d
¼7.7, 7.8, 8.0 (2C, C-4, -40), 22.4, 23.0
(2C, C-3, -30), 60.9, 61.0, 61.2, 61.3, 61.6 (6C, C-1, -10, C-2, -20,
2ꢄCH2OH), 164.5, 165.0, 165.2 (2C, C-4, -6, s-triazine), 167.1, 167.2
(1C, C-2, s-triazine) ppm. MS (FABþ, 3-nitrobenzylalcohol): m/z
(%)¼350 (33) [Mþ], 245 (45), 219 (20), 165 (20).
3
7.45, 7.54, 7.58, 7.64 (4ꢄd, JH,H¼8.6, 8.7, 8.7, 8.7 Hz, respectively,
3
4H, 2-, 20-, 6-, 60-H, p-NPh), 8.00, 8.13, 8.21 (3ꢄd, JH,H¼8.7, 8.7,
8.7 Hz, respectively, 2H, 3-, 30-, 5-, 50-H, p-NPh) ppm. 1H NMR
(400 MHz, DMSO-d6, 80 ꢀC):
d
¼3.37–3.42 (br m, 2H, 3-, 30-H), 3.59
4.3.1.3. 2-Chloro-4,6-bis[1,3-dihydroxy-2-(hydroxymethyl)prop-2-
ylamino]-s-triazine (2c). Yield 47%, white crystalline powder, mp
86–88 ꢀC (direct trituration from acetone/ligroin). Anal. Calcd for
(br s, 2H, 3-, 30-H), 4.13 (br s, 2H, 2-, 20-H), 4.61 (br s, 2H, 3-, 30-OH),
5.03 (s, 2H, 1-, 10-H), 5.45, 5.59 (2ꢄbr s, 2H, 1-, 10-OH), 6.51, 6.74
(2ꢄbr s, 2H, N-, N0-H), 7.56 (br m, 4H, 2-, 20-, 6-, 60-H, p-NPh), 8.09
(br m, 4H, 3-, 30-, 5-, 50-H, p-NPh) ppm. 13C NMR (75 MHz, DMSO-
C
11ClH20N5O6 (353.76): C, 37.34; H, 5.70; N, 19.80. Found: C, 36.99;
H, 5.25; N, 20.04. Rf (75% acetone/ligroin)¼0.30. IR (KBr): non-
d6, 25 ꢀC):
d
¼57.3, 57.6 (2C, C-2, -20), 60.5, 60.6 (2C, C-3, -30), 69.9,
depositable on KBr, insoluble in appropriate IR solvents. 1H NMR
70.0, 70.1 (2C, C-1, -10), 122.9, 123.1, (4C, C-2, -20 -6, -60, p-NPh),
127.7, 127.9 (4C, C-3, -30, -5, -50, p-NPh), 146.6 (2C, C-1, -10, p-NPh),
151.9, 152.0, 152.2 (2C, C-4, -40, p-NPh), 165.26, 165.34, 165.9 (2C, C-
4, -6, s-triazine), 167.6, 168.0 (1C, C-2, s-triazine) ppm. MS (FABþ, 3-
nitrobenzylalcohol): m/z (%)¼536 (40) [Mþ], 520 (<10), 355 (<10),
335 (<10), 273 (<10), 261 (40), 245 (100), 230 (10), 213 (15), 192
(10), 176 (15), 165 (13). MS (FABþ, glycerol): m/z (%)¼536 (90), 520
(25), 502 (17), 488 (<10), 461 (<10), 446 (<10), 427 (<10), 413
(<10), 402 (<10), 383 (40), 369 (25), 341 (12), 315 (10), 301 (12),
(300 MHz, DMSO-d6, 25 ꢀC):
d
¼3.65 [s, 12H, 2ꢄ(1-, 10-, 3-, 30-H,
3
CH2OH)], 4.51, 4.57, 4.82, 5.20 (4ꢄt, JH,H¼5.2, 6.0, 6.0 Hz, re-
spectively, br s at 5.20 ppm, 6H, 6ꢄOH), 6.29, 6.50, 6.52, 6.57 (4ꢄbr
s, 2H, N-, N0-H) ppm. 1H NMR (400 MHz, DMSO-d6, 80 ꢀC):
d¼3.70
[s, 12H, 2ꢄ(1-, 10-, 3-, 30-H, CH2OH)], 4.43 (br s, 6H, 6ꢄOH), 6.30 (br
s, 2H, N-, N0-H) ppm. 13C NMR (75 MHz, DMSO-d6, 25 ꢀC):
d¼59.8,
59.9, 60.3 (6C, C-1, -10, -3, -30, 2ꢄCH2OH), 62.0, 62.3, 62.4 (2C, C-2,
-20), 164.6, 165.1 (2C, C-4, -6, s-triazine), 167.1 (1C, C-2, s-tri-
azine) ppm. MS (FABþ, glycerol): m/z (%)¼354 (90) [Mþ], 336 (20),
320 (23), 306 (10), 262 (53), 250 (25), 232 (15), 223 (25), 217 (100),
201 (25), 192 (35).
285 (20), 277 (100), 263 (915), 251 (11), 245 (22), 230 (21), 225 (68),
20
214 (28), 203 (27). [
a
]
ꢁ8.37 (c 1, DMSO); ꢁ28.4 (c 0.05, MeOH).
D
4.4. Typical procedure for the synthesis of compounds 3d
and 3e (Scheme 2, Route 3, Table 1)
4.3.1.4. 2-Chloro-4,6-bis[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yla-
mino]-s-triazine (2d). Yield 96%, white crystalline powder, mp 78–
80 ꢀC (flash column chromatography; eluent toluene/isopropanol,
3:1 or direct trituration from Et2O/ligroin, Table 1). Anal. Calcd for
4.4.1. Preparation of compound 3d
To a dry 1,4-dioxane (50 mL) solution containing (1S,2S)-2-
amino-1-phenyl-1,3-propanediol D (1.00 g, 5.98 mmol) and cya-
nuric chloride (0.350 g, 1.90 mmol), anhyd K2CO3 (0.828 g,
6.00 mmol) was added with vigorous stirring. The resulted sus-
pension was first kept at room temperature for 24 h when TLC
monitoring indicated formation of a mixture containing the
unreacted D, intermediate 2d and the desired 3d in traces. The
reaction mixture was then heated at reflux until TLC control
(dichloromethane/ethanol 4:1 v/v) showed no more evolution
(about 60 h) and then cooled at room temperature. After filtering
off and washing minerals well with dry 1,4-dioxane (50 mL), the
combined filtrate was evaporated under reduced pressure to dry-
ness yielding the crude reaction mixture, which was submitted to
column chromatography on silica gel. The following fractions were
isolated using gradient of eluents: intermediate 2d (0.192 g, 23%
partial conversion of cyanuric chloride, eluent dichloromethane/
ethanol 4:0.75 v/v) and the desired 3d (0.820 g, 75% conversion of
cyanuric chloride, eluent dichloromethane/ethanol 3.25:1 v/v).
C
21ClH24N5O4 (445.90): C, 56.57; H, 5.42; N, 15.71. Found: C,
56.44; H, 5.61; N, 15.99. Rf (75% toluene/isopropanol)¼0.30. IR
(KBr):
¼3308 (s), 3029 (s), 2929 (m), 2873 (m), 1729 (w), 1581
(s), 1528 (s), 1496 (s), 1454 (s), 1419 (s), 1291 (m), 1128 (m), 1042
n
(m), 988 (m), 803 (m), 756 (w), 700 (s), 571 (m) cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6, 25 ꢀC):
d
¼3.31–3.38 (m, 2H, 3-, 30-H), 3.48–
3.61 (m, 2H, 3-, 30-H), 4.07–4.14 (br m, 2H, 2-, 20-H), 4.82–4.89
3
(m, 2H, 1-, 10-H), 4.78, (dd, JH,H¼4.9, 4.9 Hz, 2H, 3-, 30-OH), 5.35,
3
5.43, 5.53, 5.54 (4ꢄd, JH,H¼5.7, 5.7, 4.9, 3.4 Hz, respectively, 2H,
3
1-, 10-OH), 6.71, 6.81, 7.01, 7.05 (4ꢄd, JH,H¼9.0, 9.1, 9.4, 9.0 Hz,
respectively, 2H, N-, N0-H), 7.10–7.40 (m, 10H, Ph) ppm. 1H NMR
(400 MHz, DMSO-d6, 80 ꢀC):
d
¼3.38 (ddd, 2JH,H¼10.5 Hz,
3JH,H¼5.2, 5.2 Hz, 2H, 3-, 30-H), 3.56 (dd, JH,H¼10.5 Hz,
3JH,H¼6.2 Hz, 2H, 3-, 30-H), 4.12–4.18 (m, 2H, 2-, 20-H), 4.46 (br s,
2H, 3-, 30-OH), 4.89 (s, 2H, 1-, 10-H), 5.11, 5.23 (2ꢄbr s, 2H, 1-, 10-
OH), 6.45, 6.64 (2ꢄbr s, 2H, N-, N0-H), 7.14–7.33 (m, 10H, Ph) ppm.
2
13C NMR (75 MHz, DMSO-d6, 25 ꢀC):
d¼58.0, 58.1, 58.2 (2C, C-2,
-20), 60.4, 60.6 (2C, C, C-3, -30), 70.2, 70.3, 70.5 (2C, C-1, -10), 126.5,
126.55, 126.61, 127.0, 127.2, 128.06, 128.10, 128.6, 129.2 (10C, CH,
Ph), 143.6, 143.67, 143.73 (2C, C-1, -10, Ph), 165.4, 165.6, 166.0 (2C,
C-4, -6, s-triazine), 167.7, 168.2 (1C, C-2, s-triazine) ppm. MS
4.4.1.1. 2,4,6-Tris[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-ylamino]-s-
triazine (3d). Yield 75%, white crystalline powder, mp 104–108 ꢀC
(flash column chromatography; dichloromethane/ethanol, 3.25:1).
Anal. Calcd for C30H36N6O6 (576.65): C, 62.49; H, 6.29; N, 14.57.
Found: C, 62.79; H, 5.95; N, 14.88. Rf (80% dichloromethane/
(FABþ, 3-nitrobenzylalcohol): m/z (%)¼446 (40) [Mþ], 391 (55),
20
338 (15), 279 (15), 235 (15), 219 (20), 167 (33). [
THF).
a]
ꢁ3.0 (c 0.5,
D
ethanol)¼0.60. IR (KBr):
n
¼3400 (s), 2937 (w), 2834 (w), 1562 (s),
1509 (s), 1451 (m), 1197 (w), 1162 (w), 1053 (m), 810 (m), 701
4.3.1.5. 2-Chloro-4,6-bis[(1S,2S)-1,3-dihydroxy-1-(4-nitrophenyl)-
prop-2-ylamino]-s-triazine (2e). Yield 88%, yellowish crystalline
powder, mp 137.9–138.6 ꢀC (flash column chromatography; eluent
toluene/isopropanol, 3:1 or direct trituration from Et2O, Table 1).
Anal. Calcd for C21ClH22N7O8 (535.90): C, 47.07; H, 4.14; N, 18.30.
Found: C, 46.95; H, 4.41; N, 18.18. Rf (75% toluene/isopropanol)¼
(m) cmꢁ1
.
1H NMR (300 MHz, DMSO-d6, 25 ꢀC):
d
¼3.32 (d,
3JH,H¼4.1 Hz, 3H, 3-, 30-, 300-H), 3.41 (s, 3H, 3-, 30-, 300-H), 3.94, 4.06
(br s, 3H, 2-, 20-, 200-H), 4.74 (br s, 3H, 3-, 30-, 300-OH), 4.88 (s, 3H, 1-,
3
10-, 100-H), 5.48 (d, JH,H¼4.9 Hz, 3H, 1-, 10-, 100-OH), 5.54, 5.66, 5.78
3
(3ꢄd, JH,H¼6.8, 6.8, 7.5 Hz, respectively, 3H, N-, N0-, N00-H), 7.20–
7.60 (m, 15H, Ph) ppm. 1H NMR (400 MHz, DMSO-d6, 80 ꢀC):
d
¼3.37
2
3
0.75. IR (KBr):
n
¼3338 (s), 2942 (w), 2885 (w), 1579 (s), 1516 (s),
(dd, JH,H¼10.5 Hz, JH,H¼5.2 Hz, 3H, 3-, 30-, 300-H), 3.51 (dd,
2JH,H¼10.5 Hz, 3JH,H¼6.6 Hz, 3H, 3-, 30-, 300-H), 4.05 (dddd, 3JH,H¼5.8,
5.8, 5.8, 6.0 Hz, 3H, 2-, 20-, 200-H), 4.46 (br s, 3H, 3-, 30-, 300-OH), 4.88
(d, 3JH,H¼3.6 Hz, 3H, 1-, 10-, 100-H), 5.26 (br s, 3H, 1-, 10-, 100-OH), 5.53
1417 (m), 1348 (s), 1130 (m), 1109 (m), 1068 (m), 1014 (m), 987 (m),
854 (m), 804 (m), 726 (w), 701 (m), 566 (w) cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6, 25 ꢀC):
d
¼3.23 (dd, 2JH,H¼9.8 Hz, 3JH,H¼4.9 Hz,
3
3
2H, 3-, 30-H), 3.55 (br d, 3JH,H¼6.4 Hz, 2H, 3-, 30-H), 4.05, 4.21 (2ꢄbr
(d, JH,H¼5.6 Hz, 3H, N-, N0-, N00-H), 7.19 (dd, JH,H¼7.2, 7.2 Hz, 3H,