992
A. Bourry, R. Akué-Gédu, B. Rigo, J.-P. Hénichart, G. Sanz and D. Couturier
Vol. 40
ml) and triethylamine (218 g, 2.16 mol). The solution was cooled
below 0 °C then sodium borohydride (4.75 g, 125 mmol) was
added slowly while keeping the temperature of the reaction mix-
ture below 0 °C. The solution was stirred at room temperature for
90 min, then the pH was adjusted to 3 with 37 % hydrochloric acid.
The precipitate of diacid 4a was washed with cold water then
2.23 (m, 1H), 2.23-2.4 (m, 1H), 2.40-2.67 (m, 2H), 3.75 (s, 3H),
3.76 (s, 3H), 4.7 (bs, D O exchangeable, 1H), 4.11 (dd, J = 9, 4
2
Hz, 1H), 4.20 (d, J = 14.5 Hz, 1H), 4.90 (d, J = 14.5 Hz, 1H), 6.79
(d, J = 2.0 Hz, 2H), 6.84 (d, J = 2Hz, 1H).
Anal. Calcd. For C
H NO : C, 60.21; H, 6.14; N, 5.02; O,
14 17 5
28.64. Found: C, 60.49; H, 6.47; N, 5.39; O, 28.33.
dried, mp 148-149 °C (H O); IR: 3490, 1720, 1625, 1595, 1575,
2
N-(1H-Indol-3-ylmethyl)glutamic Acid (4d) and 1-(1H-Indol-3-
ylmethyl)-5-pyroglutamic Acid (2d).
-1
1
1510, 1460, 1125 cm ; H NMR (D O/NaOD): δ 1.7-1.9 (m, 2H),
2
2.15 (t, J = 6.7 Hz, 2H), 3.04 (dd, J = 7.8, 6.2 Hz, 1 H), 3.54 (d, J =
Indole-3-carbaldehyde (50 g, 344 mmol) was added to a well
stirred solution of glutamic acid (105 g, 714 mmol) in methanol
(600 ml) and triethylamine (200 ml, 145 g, 1434 mmol). The
solution was cooled below -5 °C then sodium borohydride (5 g,
104 mmol) was added slowly while keeping the temperature of
the reaction mixture between -5 and 0 °C. The solution was
stirred at room temperature for 90 min then the solvents were
evaporated. Water (1000 ml) was added and the solution was
extracted 3 times with ethyl acetate. The pH was adjusted to 3 by
a very slow addition of 1 N hydrochloric acid. The precipitate of
diacid 4d was washed with cold water then dried, mp 195-200 °C
12.8 Hz, 1H), 3.72 (d, J = 12.8 Hz, 1H), 3.77 (s, 3H), 3.87 (s, 6H),
13
6.73 (s, 2H). C NMR (D O/NaOD): δ 23.4, 31.3, 47.5, 53.3,
2
58.1, 58.9, 104.6, 124.6, 134.5, 150.0, 170.8, 178.5.
Anal. Calcd. For C
H NO , H O: C, 52.17; H, 6.71; N, 4.06;
15 21 7 2
O, 37.06. Found: C, 52.06; H, 6.47; N, 4.15; O, 36.69.
The crude compound 4a was refluxed for 5 hours in a 95/5
ethanol/water solution (4000 ml). After cooling at room tempera-
ture the mixture was filtered in order to remove unreacted pyrog-
lutamic acid. The filtrate was evaporated then partitioned
between water and dichloromethane. The pH of the aqueous
phase was adjusted to 1 with 37 % hydrochloric acid; this phase
then was extracted with dichloromethane. The organic phase was
dried, then evaporated, leading to 90 % of acid 2a, mp 160-161
-1
1
(H O); IR: 3420, 1705, 1615, 1585, 1550, 1455, 1175 cm ;
H
2
NMR (D O/NaOD): δ 1.63-1.99 (m, 2H), 2.19 (t, J = 8.4 Hz,
2
-1
2H), 3.16 (dd, J = 7.7, 5.9 Hz, 1 H), 3.79 (d, J = 13.1 Hz, 1H),
3.94 (d, J = 13.1 Hz, 1H), 7.18 (t, J = 6.7 Hz, 1H), 7.26 (t, J = 6.7
Hz, 1H),7.33 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.94 (d, J = 7.4 Hz,
°C (EtOH); IR: 3305, 1710, 1605, 1550, 1495, 1460, 1150 cm ;
1
H NMR (CDCl ): δ 2.11-2.47 (m, 2H), 2.47-2.75 (m, 2H), 3.83
3
(s, 3H), 3.84 (s, 6H), 3.95 (d, J = 14.7 Hz, 1H), 4.07 (dd, J = 9, 3.3
13
1H); C NMR (D O/NaOD): δ 29.7, 34.1, 41.6, 62.9, 111.6,
Hz, 1H) 5.04 (d, J = 14.7 Hz, 1H), 6.46 (s, 2H), 6.68 (bs, D O
2
2
13
112.1, 118.3, 119.1, 121.7, 124.3, 126.6, 135.9, 182.0, 182.5.
exchangeable, 1H); C NMR (CDCl ): δ 22.9, 29.6, 46.0, 56.1,
3
Anal. Calcd. For C
H N O : C, 60.86; H, 5.84; N, 10.14; O,
58.6, 60.7, 105.5, 130.6, 137.2, 153.1, 174.0, 176.0.
14 16 2 4
23.16. Found: C, 60.49; H, 5.93; N, 5.48; O, 22.85.
N-(1,3-Benzodioxol-5-ylmethyl)glutamic Acid (4b) and N-(1,3-
Benzodioxol-5-ylmethyl)-5-pyroglutamic Acid (2b).
The crude compound 4d was refluxed for 5 hours in ethanol
(1000 ml). After cooling at room temperature the mixture was fil-
tered in order to remove unreacted pyroglutamic acid. The filtrate
was evaporated then dried, leading to 61 % of acid 2d, mp 176-2
These compounds were obtained in the same way as for 2a and
4a. Acid 4b: mp 172-3 °C (H O); IR: 1710, 1615, 1505, 1480, 1445,
2
-1
1
-1
1
(EtOH); IR: 1720, 1620, 1500 cm ; H NMR (CDCl ): δ 1.79-
1040 cm ; H NMR (D O/NaOD): δ 1.64-1.90 (m, 2H), 2.15 (t, J =
3
2
1.97 (m, 1H), 2.04-2.29 (m, 1H), 2.27-2.69 (m, 2H), 3.74 (dd, J =
9.2, 5.2 Hz, 1H), 4.18 (d, J = 15.2 Hz, 1H), 5.15 (d, J = 15.2 Hz,
1H), 7.17 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.33 (s,
8.8 Hz, 2H), 3.04 (dd, J = 7.7, 5.8 Hz, 1 H), 3.48 (d, J = 12.5 Hz, 1H),
3.65 (d, J = 12.5 Hz, 1H), 5.98 (s, 2H), 6.79-6.90 (m, 3H).
Anal. Calcd. For C
H NO : C, 55.51; H, 5.38; N, 4.98; O,
13 15 6
13
1H), 7.53 (d, J = 5.8 Hz, 1H), 7.56 (d, J = 5.8 Hz, 1H); C NMR
34.13. Found: C, 55.15; H, 5.35; N, 5.34; O, 34.43.
(CDCl ): δ 22.5, 30.0, 37.4, 58.0, 109.2, 111.7, 118.7, 119.3,
Acid 2b was obtained in 82 % yield, mp 138-9 (AcOEt); IR:
3
-1
1
121.7, 125.0, 126.7, 136.7, 174.0, 174.8.
1715, 1635, 1500, 1470, 1450, 1040 cm ; H NMR (CDCl ): δ
3
2.06-2.45 (m, 2H), 2.45-2.73 (m, 2H), 3.90 (d, J = 15 Hz, 1H),
4.04 (dd, J = 8.9, 3.2 Hz, 1H), 5.04 (d, J = 15 Hz, 1H), 5.95 (s,
2H), 6.68 (dd, J = 7.8, 1.5 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.75
Iminoether Method.
5-(Chloromethyl)-1,3-benzodioxole.
13
(d, J = 7.8 Hz, 1H), 7.88 (bs, D O exchangeable, 1H); C NMR
A mixture of piperonyl alcohol (100 g, 0.66 mol) and 37 %
HCl was strongly stirred for 20 min, then the product was
extracted with dichloromethane. After drying the chloride was
obtained in 98 % yield. H NMR (CDCl ): δ 4.51 (s, 2H), 5.94 (s,
2H), 6.74 (dd, J = 7.8, 0.5 Hz, 1H), 6.83 (dd, J = 7.8, 1.8 Hz, 1H),
6.86 (dd, J = 1.8, 0.5 Hz, 1H).
2
(CDCl ): δ 22.9, 29.6, 45.4, 58.3, 101.0, 108.1, 108.7, 121.9,
3
128.8, 147.1, 147.8, 174.7, 175.7.
1
Anal. Calcd. For C
H NO : C, 59.31; H, 4.98; N, 5.32; O,
13 13 5
3
30.39. Found: C, 59.58; H, 4.97; N, 5.45; O, 30.39.
N-(2,5-Dimethoxybenzyl)glutamic Acid (4c) and N-(2,5-
Dimethoxybenzyl)pyroglutamic Acid (2c).
Methyl 1-(1,3-Benzodioxol-5-ylmethyl)pyroglutamate.
These compounds were obtained in the same way as for 2a and
A 1000 ml round bottom flask equipped with a high surface
Graham condenser connected to a water pump was charged with
a mixture of 5-(chloromethyl)-1,3-benzodioxole (167 g, 0.98
mol) and methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxy-
late [10] (183 g, 1.16 mol). A good magnetic stirring was applied,
then the water pump vacuum was applied (in order to remove all
the methyl chloride formed during the reaction) and the solution
was refluxed for 8 hours, yielding 90 % in methyl 1-(1,3-benzo-
dioxol-5-ylmethyl)pyroglutamate, mp 94-7 °C (AcOEt); IR:
4a. Acid 4c: mp 164-5 °C (H O); IR: 1715, 1575, 1505, 1455,
2
-1
1
1045 cm ; H NMR (D O/NaOD): δ 1.68-1.94 (m, 2H), 2.18 (t,
2
J = 8.5 Hz, 2H), 3.04 (dd, J = 7.4, 6.2 Hz, 1 H), 3.58 (d, J = 13.1
Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H), 3.82 (s, 3H), 6.91
(d, J = 9.2 Hz, 1H), 6.93 (s, 1H), 7.0 (d, J = 9.2 Hz, 1H).
Anal. Calcd. For C
H NO : C, 56.56; H, 6.44; N, 4.71; O,
14 19 6
32.29. Found: C, 56.73; H, 6.67; N, 4.50; O, 31.91.
Acid 2c was obtained in 81 % yield, mp 151-2 (AcOEt); IR:
-1
1
-1
1
1740, 1635, 1505, 1460, 1040 cm ; H NMR (CDCl ): δ 2.01-
1735, 1680, 1495, 1445, 1035 cm ; H NMR (CDCl ): δ 1.98-
3
3