E. Guénin, M. Monteil, N. Bouchemal, T. Prangé, M. Lecouvey
FULL PAPER
NaOH (0.1 ). The organic layer were then dried on magnesium
3
NCH2CH2CH2CH2CH2COOH), 3.66 (t, JH,H = 7.3 Hz, 2 H,
sulfate, filtered and the solvents evaporated.
NCH2CH2CH2CH2CH2COOH), 7.67–7.82 (m, 4 H, C6H4) ppm.
13C{1H} NMR (CDCl3, 125.7 MHz, 298 K):
δ = 24.3 (s,
Benzyl N-(3-Dimethylcarbamoylpropyl)carbamate (7): Yield 422 mg
NCH2CH2CH2CH2CH2COOH), 26.4 (s, NCH2CH2CH2CH2-
CH2COOH), 28.4 (s, NCH2CH2CH2CH2CH2COOH), 33.9 (s,
NCH2CH2CH2CH2CH2COOH), 37.9 (s, NCH2CH2CH2CH2-
CH2COOH), 123.4, 132.3, 134.1 (s, C6H4), 168.6 [s, NC(O)], 179.3
(s, COOH) ppm.
(80%). IR (film): ν = 3315, 3064, 3032, 2954, 2930, 1717, 1634,
˜
1532, 1499, 1455, 1401, 1294, 1259, 1138, 1041, 1025, 753, 698,
1
3
666 cm–1. H NMR (CDCl3, 200 MHz, 298 K): δ = 1.84 (qt, JH,H
3
= 6.9 Hz, 2 H, NHCH2CH2CH2CON), 2.34 (t, JH,H = 6.9 Hz, 2
H, NHCH2CH2CH2CON), 2.90 (s, 3 H, NCH3), 2.94 (s, 3 H,
NCH3), 3.23 (dt, 3JH,H = 6.9 Hz, 2 H, NHCH2CH2CH2CON), 5.07
Synthesis of 11a–c: In a 50 mL round-bottom flask, oxalyl chloride
[s, 2 H, CH2OC(O)NH], 5.21–5.35 (m, 1 H, NH), 7.20–7.45 (m, 5 (3.75 mL, 25 mmol) was added under N2 to a solution of 10a–c
H, C6H5) ppm.
(10 mmol) in dichloromethane (25 mL). The solution was refluxed
for 6 h. The reaction mixture was then evaporated under vacuum
(0.1 Torr) to yield quantitatively a pale yellow powder of 11a–c.
Deprotection of Benzyl 2-Oxopyrrolidine-1-carboxylate: In a 50 mL
round-bottom flask connected to a hydrogenation apparatus, palla-
dium (10 wt.-%) on activated carbon (1 g) was added to a solution
of 6 (4 mmol) in methanol (50 mL). The flask was purged several
times with hydrogen, and the reaction was stirred for 24 h. The
palladium on activated carbon was filtered, and the solvent was
evaporated under reduced pressure (0.1 Torr). After washes with
diethyl ether (3ϫ10 mL), compound 6a was obtained quantita-
3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propionyl Chloride (11a): M.p.
97 °C. IR (film): ν = 2956, 2934, 1802, 1710, 1466, 1437, 1398,
˜
1368, 1289, 1246, 1171, 1109, 1090, 1053, 1053, 993, 965, 868, 753,
718, 656 cm–1. 1H NMR (CDCl3, 200 MHz, 298 K): δ = 3.33 (t,
3
3JH,H = 7.0 Hz, 2 H, NCH2CH2COCl), 4.03 (t, JH,H = 7.0 Hz, 2
H, NCH2CH2COCl), 7.67–7.73 (m, 2 H, C6H4), 7.78–7.84 (m, 2
H, C6H4) ppm. 13C{1H} NMR (CDCl3, 125.7 MHz, 298 K): δ =
33.3 (s, NCH2CH2COCl), 45.0 (s, NCH2CH2COCl), 123.6, 131.9,
134.3 (s, C6H4), 167.8 [s, NC(O)], 171.5 (s, COCl) ppm.
tively as a yellow oil. Pyrrolidin-2-one (6a): IR (KBr): ν = 3219,
˜
2987, 1669, 1498, 1456, 1421, 1292, 1208, 1138, 996 cm–1. 1H NMR
(CD3OD, 200 MHz, 298 K):
δ
=
2.21–2.25 (m,
2
H,
NHCH2CH2CH2CO), 2.58–2.62 (m, 2 H, NHCH2CH2CH2CO),
3.50–3.77 (m, 2 H, NHCH2CH2CH2CO), 8.29–8.31 (m, 1 H,
NHCH2CH2CH2CO) ppm. 13C{1H} NMR (CD3OD, 125.7 MHz,
298 K): δ = 21.7 (s, NHCH2CH2CH2CO), 31.9 (s, NHCH2CH2-
CH2CO), 45.4 (s, NHCH2CH2CH2CO), 174.8 (s, OCNH) ppm.
4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyryl Chloride (11b): M.p.
69 °C. IR (film): ν = 2940, 1805, 1708, 1468, 1438, 1398, 1360,
˜
1338, 1314, 1286, 12487, 1192, 1117, 1087, 1065, 1033, 950, 894,
1
3
720 cm–1. H NMR (CDCl3, 200 MHz, 298 K): δ = 2.08 (qt, JH,H
= 7.0 Hz, 2 H, NCH2CH2CH2COCl), 2.99 (t, 3JH,H = 7.0 Hz, 2 H,
Synthesis of 10a–c: Phthalic anhydride (5.92 g, 40 mmol) and
amino acid (40 mmol) were heated at 170 °C for 6 h in a 100 mL
round-bottomed flask equipped with a condenser. The reaction
mixture was cooled, the resulting solid was dissolved in dichloro-
NCH2CH2CH2COCl), 3.77 (t, 3JH,H
=
7.0 Hz,
2
H,
NCH2CH2CH2COCl), 7.70–7.74 (m, 2 H, C6H4), 7.83–7.87(m, 2
H, C6H4) ppm. 13C{1H} NMR (CDCl3, 50.3 MHz, 298 K): δ =
24.3 (s, NCH2CH2CH2COCl), 36.5 (s, NCH2CH2CH2COCl), 44.5
methane (50 mL) and washed with HCl solution (0.1 , (s, NCH2CH2CH2COCl), 123.4, 132.1, 134.2 (s, C6H4), 168.4 [s,
3ϫ20 mL). The organic layer was dried, and the solvents were
NC(O)], 173.3 (s, COCl) ppm.
evaporated under vacuum to yield quantitatively a white solid.
6-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)hexanoyl Chloride (11c): M.p.
3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propionic Acid (10a): M.p.
58 °C. IR (film): ν = 2936, 2867, 1798, 1709, 1465, 1437, 1397,
˜
152 °C. IR (KBr): ν = 2981, 2969, 1770, 1700, 1466, 1440, 1408, 1369, 1333, 1286, 1208, 1186, 1051, 1018, 943, 872, 719 cm–1.
˜
1378, 1296, 1284, 1254, 1212, 1103, 1088, 1072, 1031, 1001, 910,
1H NMR (CDCl3, 500 MHz, 298 K): δ = 1.31–1.42 (m, 2 H,
873, 824, 730, 615 cm–1. H NMR (CDCl3, 200 MHz, 298 K): δ = NCH2CH2CH2CH2CH2COCl),
1.60–1.75 (m, H,
NCH2CH2CH2CH2CH2COCl), 2.85 (t, JH,H = 7.3 Hz, 2 H,
1
4
3
3
3
2.80 (t, JH,H = 7.0 Hz, 2 H, NCH2CH2COOH), 4.00 (t, JH,H
=
3
7.0 Hz, 2 H, NCH2CH2COOH), 7.65–7.76 (m, 2 H, C6H4), 7.80– NCH2CH2CH2CH2CH2COCl), 3.64 (t, JH,H = 7.3 Hz, 2 H
7.89 (m, 2 H, C6H4) ppm. 13C{1H} NMR (CDCl3, 125.7 MHz, NCH2CH2CH2CH2CH2COCl), 7.66–7.81 (m, 4 H, C6H4) ppm.
298 K): δ = 33.8 (s, NCH2CH2COOH), 33.6 (s, NCH2CH2COOH), 13C{1H} NMR (CDCl3, 125.7 MHz, 298 K):
δ = 24.7 (s,
123.6 (s, C6H4), 132.1 (s, C6H4), 134.3 (s, C6H4), 168.2 [s, NC(O)],
176.7 (s, COOH) ppm.
NCH2CH2CH2CH2CH2COCl), 25.8 (s, NCH2CH2CH2CH2-
CH2COCl), 28.3 (s, NCH2CH2CH2CH2CH2COCl), 37.7 (s,
NCH2CH2CH2CH2CH2COCl), 47.0 (s, NCH2CH2CH2CH2-
CH2COCl), 123.4, 132.2, 134.1 (s, C6H4), 168.6 [s, NC(O)], 173.8
(s, COCl) ppm.
4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyric Acid (10b): M.p.
117 °C. IR (KBr): ν = 2958, 2940, 1767, 1705, 1469, 1437, 1396,
˜
1358, 1338, 1314, 1285, 1249, 1195, 1121, 1033, 1020, 945, 894,
1
781, 720 cm–1. H NMR (CDCl3, 200 MHz, 298 K): δ = 2.02 (qt,
Synthesis of 12a–c, 13a–c, 14a–c: In a 50 mL round-bottom three-
neck flask equipped with a thermometer, acid chloride 11a–c
3
3JH,H = 7.0 Hz, 2 H, NCH2CH2CH2COOH), 2.44 (t, JH,H
=
3
7.0 Hz, 2 H, NCH2CH2CH2COOH), 3.75 (t, JH,H = 7.0 Hz, 2 H, (2.5 mmol) was added dropwise, under Ar, at –5 °C, to silylated
NCH2CH2CH2COOH), 7.65–7.80 (m, 2 H, C6H4), 7.81–7.86 (m, 2 phosphite (5 mmol). When the addition was completed, reaction
H, C6H4) ppm. 13C{1H} NMR (CDCl3, 50.3 MHz, 298 K): δ =
mixture was allowed to stand at room temperature for 4 h [6 h for
23.7 (s, NCH2CH2CH2COOH), 31.4 (s, NCH2CH2CH2COOH), the reaction with phenyl bis(trimethylsilyl) phosphite]. The evol-
37.2 (s, NCH2CH2CH2COOH), 123.3 (s, C6H4), 134.0 (s, C6H4), ution of the reaction was monitored by 31P{1H} NMR. The volatile
168.4 [s, NC(O)], 178.4 (s, COOH) ppm.
fractions were evaporated under reduced pressure (0.1 Torr) before
being hydrolyzed with methanol. After evaporation, the crude
products were purified as follows.
6-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)hexanoic Acid (10c): M.p.
109 °C. IR (KBr): ν = 2932, 2864, 1773, 1725, 1465, 1438, 1395,
˜
1363, 1336, 1313, 1255, 1206, 1188, 1111, 1050, 952, 875, 721,
[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-1-hydroxy-1-phosphonopro-
pyl]phosphonic Acid (12a): After solvent removal in vacuo, the resi-
H, due was precipitated from methanol/diethyl ether (60:40). The
1
712 cm–1. H NMR (CDCl3, 500 MHz, 298 K): δ = 1.30–1.42 (m,
2
H, NCH2CH2CH2CH2CH2COOH), 1.61–1.72 (m,
4
3
NCH2CH2CH2CH2CH2COOH), 2.32 (t, JH,H = 7.3 Hz, 2 H, white powder was then lyophilised. Yield 545 mg (60%). M.p.
3386
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Eur. J. Org. Chem. 2007, 3380–3391