M. Jansen, G. Dannhardt / European Journal of Medicinal Chemistry 38 (2003) 855ꢀ
/865
863
a mixture of sodium acetate trihydrate (9 g) and ice (12
g) and stirring at 4 8C overnight. The product separated
as a solid and is collected by filtration. Light beige
crystals were obtained (4.4 g, 16.1 mmol, 79%), Rf (n-
5.1.13.3. 5-tert-Butyl-3-{[3-(4-methoxyphenyl)-2,4-
dioxo-1-imidazolidinyl]methyl}-1H-indole-2-carboxylic
acid ethyl ester (16c). 1.17 mmol 15 and 4-methoxyphe-
nylisocyanate were used. Column chromatography (n-
hexaneꢀ
/
ethyl acetateꢃ
/
3/2): 0.57; m.p.: 206 8C; IR
hexaneꢀ
dichloromethaneꢀ
/
ethyl acetateꢃ
/
3/1) and crystallisation from
(KBr) (cmꢂ1): 3140, 2940, 1710, 1620; H-NMR (300
MHz) (DMSO-d6) d: 1.32 (m, 12H, C(CH3)3, CH2CH3),
/
n-hexane afforded the pure product
1
(0.34 g, 0.73 mmol, 73%): m.p.: 205 8C; IR (KBr)
1
4.31 (q, Jꢃ
/6.8 Hz, 2H, CH2CH3), 7.49 (m, 2H, Ind-
(cmꢂ1): 3220, 2920, 1740, 1680, 1490; H-NMR (300
H6,7), 8.23 (m, 1H, Ind-H4), 10.60 (s, 1H, CHO), 12.71
(s, 1H, NH); MS m/z: 273 [Mꢁ].
MHz) (DMSO-d6) d: 1.29 (s, 9H, C(CH3)3), 1.38 (t, Jꢃ
7.2 Hz, 3H, CH2CH3), 3.77 (s, 3H, OCH3), 3.92 (s, 2H,
NCH2CO), 4.38 (q, Jꢃ7,2 Hz, 2H, CO2CH2), 5.04 (s,
2H, ArCH2N), 7.01 (d, Jꢃ8.82 Hz, 2H, Ph-H3,5), 7.21
(d, Jꢃ8.82 Hz, 2H, Ph-H2,6), 7.39 (m, 2H, Ind-H6,7),
/
/
5.1.13. General procedure for the synthesis of the
/
hydantoin derivatives 16ꢀ
/
18
/
The glycine ethyl ester hydrochloride (1.5 equiv.) was
suspended in dry dichloromethane (10 mL) and triethyl-
amine (1.8 equiv.) was added. The indole-3-carbalde-
hyde derivative (2.0 equiv.) was added and the mixture
left at room temperature for 20 min. After the addition
of sodium triacetoxyborohydride (2.3 equiv.) the mix-
ture was stirred at room temperature for 24 h. Pheny-
lisocyanate (2.0 equiv) was added, and after another
hour triethylamine (1.8 equiv.). Subsequently the reac-
tion mixture was refluxed for 12 h. After dissolving in
ethyl acetate the organic layer was washed with 5% HCl,
saturated NaHCO3 solution and water, dried (MgSO4)
and concentrated under reduced pressure.
7.82 (m, 1H, Ind-H4), 11.73 (s, 1H, NH); MS m/z: 462
[Mꢁ].
5.1.13.4. 3-[(2,4-Dioxo-3-phenyl-1-
imidazolidinyl)methyl]-1H-indole-2-carboxylic acid ethyl
ester (17a). 2.0 mmol 3-formyl-indole-2-carboxylic acid
ethyl ester and phenylisocyanate were used. Column
chromatography (n-hexaneꢀ
/
ethyl acetateꢃ3/1) and
/
crystallisation from methanol afforded the pure product
(0.37 g, 0.98 mmol, 65%); m.p.: 192 8C; IR (KBr)
(cmꢂ1): 3200, 1750, 1690; 1H-NMR (300 MHz)
(DMSO-d6) d: 1.39 (t, Jꢃ
/
7.2 Hz, 3H, CH3), 3.96 (s,
7.2 Hz, 2H, CH2CH3), 5.05
7.84 (m, 9H, Ph-H, Ind-H),
2H, NCH2CO), 4.40 (q, Jꢃ
/
(s, 2H, IndCH2N), 7.07ꢀ
/
5.1.13.1. 5-tert-Butyl-3-[(2,4-dioxo-3-phenyl-1-
11.90 (s, 1H, NH); MS m/z: 376 [Mꢁ].
imidazolidinyl)methyl]-1H-indole-2-carboxylic acid ethyl
ester (16a). 2.0 mmol carbaldehyde 15 and phenyliso-
cyanate were used. Column chromatography (n-
5.1.13.5. 4,6-Dichloro-3-[(2,4-dioxo-3-phenyl-1-
imidazolidinyl)methyl]-1H-indole-2-carboxylic acid ethyl
ester (18a) and the derivatives 18b and 18c. Were
prepared as described previously [25].
hexaneꢀ
/
ethyl acetateꢃ
/
3/1) and crystallisation from
n-hexane afforded the pure product
dichloromethaneꢀ
/
(0.4 g, 0.93 mmol, 62%), Rf (n-hexaneꢀ
/
ethyl acetateꢃ3/
/
2): 0.08; m.p.: 178 8C; IR (KBr) (cmꢂ1): 3250, 2930,
1750, 1680, 1540; H-NMR (300 MHz) (DMSO-d6) d:
5.1.14. General procedure for the hydrolysis of the esters
to yield acids 19 21
1
/
ꢀ
1.29 (s, 9H, C(CH3)3), 1.38 (t, Jꢃ
CH2CH3), 3.95 (s, 2H, NCH2CO), 4.38 (q, Jꢃ
/
7.15 Hz, 3H,
The ethyl ester (1 equiv.) was dissolved in THF (15
mL) and a solution of LiOH monohydrate (1.2 equiv.)
in water (7 mL) was added. Subsequently the reaction
mixture was stirred at room temperature until the ester
disappeared (TLC). Then the solution was cooled in an
icebath and acidified with 10% HCl and extracted with
several portions of ethyl acetate. The combined organic
extracts were dried (MgSO4) and evaporated to dryness.
/
7.15
7.83
Hz, 2H, CH2CH3), 5.05 (s, 2H, ArCH2N), 7.30ꢀ
/
(m, 8H, Ar-H), 11.75 (s, 1H, NH); MS m/z: 434 [Mꢁ].
5.1.13.2. 5-tert-Butyl-3-{[3-(4-methylphenyl)-2,4-
dioxo-1-imidazolidinyl]methyl}-1H-indole-2-carboxylic
acid ethyl ester (16b). 1.17 mmol 15 and 4-methylphe-
nylisocyanate were used. Column chromatography (n-
hexaneꢀ
dichloromethaneꢀ
/
ethyl acetateꢃ
/
3/1) and crystallisation from
n-hexane afforded the pure product
5.1.14.1. 5-tert-Butyl-3-[(2,4-dioxo-3-phenyl-1-
imidazolidinyl)methyl]-1H-indole-2-carboxylic
/
acid
(19a). Ethyl ester 16a (0.35 g, 0.81 mmol) was hydro-
lysed according to the general procedure. Crystallisation
(0.35 g, 0.78 mmol, 78%): m.p.: 189 8C; IR (KBr)
(cmꢂ1): 3300, 2960, 1710; 1H-NMR (300 MHz)
(DMSO-d6) d: 1.29 (s, 9H, C(CH3)3), 1.38 (t, Jꢃ
Hz, 3H, CH2CH3), 2.32 (s, 3H, Ph-CH3); 3.93 (s, 2H,
NCH2CO), 4.38 (q, Jꢃ7.15 Hz, 2H, CH2CH3), 5.05 (s,
2H, ArCH2N), 7.19 (d, Jꢃ8.35 Hz, 2H, Ph-H3,5), 7.27
(d, Jꢃ8.35 Hz, 2H, Ph-H2,6), 7.39 (m, 2H, Ind-H6,7),
/
7.15
from dichloromethaneꢀ
product as white crystals (0.28 g, 0.7 mmol, 86%),
m.p.: 237 8C; IR (KBr) (cmꢂ1): 3400ꢀ
2300, 3180, 2920,
1750, 1685, 1640, 1530; H-NMR (300 MHz) (DMSO-
d6) d: 1.28 (s, 9H, C(CH3)3), 3.93 (s, 2H, NCH2CO),
/
n-hexane afforded the pure
/
/
1
/
/
7.83 (m, 1H, Ind-H4), 11.73 (s, 1H, NH); MS m/z: 448
[Mꢁ].
5.06 (s, 2H, ArCH2N), 7.30ꢀ
/
7.80 (m, 8H, Ar-H), 11.63
(s, 1H, NH), 13.24 (bs, 1H, COOH); 13C-NMR (75