A Combinatorial Thiohydantoin Library
J . Org. Chem., Vol. 62, No. 10, 1997 3235
stirred for 1 h, followed by chromatography on silica gel
[hexane:ethyl acetate (75:25 to 0:100)] to yield the thiohydan-
toin as a low-melting white foam (82 mg, 96%): IR νmax (CHCl3)
gel [hexane:ethyl acetate (50:50)] to yield the thioxopyrimidi-
none as a pale yellow foam (75 mg, 73%): mp 68-75 °C; IR
ν
max (KBr) 1717 cm-1; 1H NMR δ 3.14 (dd, 1H, J ) 1.88, 16.18
1
1752 cm-1; H NMR δ 3.32 (dd, 1H, J ) 3.93, 14.49 Hz, CH2-
Hz, C5-H2), 3.57 (dd, 1H, J ) 6.95, 16.21 Hz, C5-H2), 4.49 (d,
1H, J ) 15.17 Hz, CH2Py), 5.45-5.51 (br d, 1H, J ) 6 Hz,
C6-H), 6.26 (d, 1H, J ) 15.17 Hz, CH2Py), 7.22-8.59 (m, 13H,
ArH); 13C NMR δ 38.61, 58.41, 58.89, 122.29, 122.94, 123.35,
125.57, 128.66, 129.38, 130.85, 132.12, 136.39, 136.83, 138.31,
149.52, 155.20, 165.10, 181.44; HRMS calcd for C22H18BrN3-
OS 451.0354 (M+), found 451.0349; HPLC purity 95%.
Gen er a l P r oced u r e for Libr a r y Syn th esis. A solution
of R-amino acid ester in the form of an acid salt (2 mmol),
triethylamine (1.1 molar equiv), aldehyde (1.1 molar equiv),
and sodium triacetoxyborohydride (1.5 molar equiv) in CH2-
Cl2 was stirred overnight at rt and then quenched with water.
The organic phase was washed with water (2×) and dried over
MgSO4, and aliquots (each containing 0.1 mmol of secondary
amine based on theoretical yield) were distributed into 1.5 mL
vials. Triethylamine (14 µL, 0.1 mmol) and isothiocyanate
(0.11 mmol) were added into each vial, and the solution was
shaken for 1 h. Glycine (1 mmol) was added and the mixture
shaken vigorously for 2 h, followed by addition of water and
further shaking for 1 h. After separation, the organic phase
was washed with water (1.5 mL) and finally evaporated to
yield the crude thiohydantoin.
Ph), 3.50 (dd, 1H, J ) 4.42, 14.46 Hz, CH2Ph), 4.69 (d, 1H, J
) 15.13 Hz, CH2Py), 4.83 (t, 1H, J ) 4.16 Hz, C5-H), 5.89 (d,
1H, J ) 15.13 Hz, CH2Py), 6.74-8.61 (m, 13H, ArH); 13C NMR
δ 34.60, 49.78, 63.26, 115.81, 116.11, 123.14, 123.44, 127.71,
128.69, 129.51, 130.01, 130.12, 133.46, 137.04, 149.65, 154.59,
160.84, 164.13, 172.38, 182.74; HRMS calcd for C22H18FN3OS
391.1155 (M+), found 391.1160. HPLC purity 83%. Anal.
Calcd for C22H18FN3OS: C, 67.33; H, 5.07; N, 11.06; S, 8.02;
F, 4.92. Found: C, 67.50; H, 4.63; N 10.73; S, 8.19; F, 4.85.
(S)-1-(3-Th ien ylm eth yl)-3-p h en yl-5-(3-in d olylm eth yl)-
2,4-im id a zolid in ed ion e (8). To a solution of L-tryptophan
methyl ester hydrochloride (50 mg, 196 µmol) in CH2Cl2 (0.5
mL) was added triethylamine (30 µL, 217 µmol), 3-thiophen-
ecarboxaldehyde (22 µL, 251 µmol), and sodium triacetoxy-
borohydride (63 mg, 297 µmol). The reaction mixture was
stirred at rt for 24 h. Phenyl isocyanate (28 µL, 257 µmol)
was then added and the mixture stirred for 1 h, followed by
chromatography on silica gel [hexane:ethyl acetate (60:40)] to
yield the hydantoin as a white solid (73 mg, 97%): mp 152-
1
153 °C; IR νmax (KBr): 1710 cm-1; H NMR δ 3.40 (dd, 1H, J
) 4.42, 15.3 Hz, CH2Ind), 3.48 (dd, 1H, J ) 4.65, 15.25 Hz,
CH2Ind), 4.13 (d, 1H, J ) 15.19 Hz, CH2Th), 4.24 (t, 1H, J )
4.53 Hz, C5-H), 5.06 (d, 1H, J ) 15.16 Hz, CH2Th), 6.88-8.29
(m, 14H, ArH); 13C NMR δ 25.49, 39.96, 58.80, 108.24, 111.33,
118.77, 119.84, 122.34, 123.25, 123.96, 126.07, 127.04, 127.13,
127.48, 128.07, 128.90, 131.52, 136.00, 136.08, 155.66, 171.90;
HRMS calcd for C23H19N3O2S 401.1198 (M+), found 401.1184;
HPLC purity 97%. Anal. Calcd for C23H19N3O2S: C, 68.81;
H, 4.77; N, 10.47; S, 7.99. Found: C, 68.17; H, 4.99; N 10.63;
S, 8.05.
Ack n ow led gm en t. We are grateful to attachment
students from Ngee Ann and Singapore Polytechnic for
assistance with library synthesis and HPLC analysis
and the Central Facility Laboratory, Department of
Chemistry, and the Centre for Natural Product Re-
search of the National University of Singapore for
micronanalysis, NMR, IR, and MS data. This work was
supported by grants from the National Science and
Technology Board of Singapore.
1-(2-P yr idylm eth yl)-3,6-(diph en yl)-tetr ah ydr o-2-th ioxo-
4(3H)-p yr im id in on e (9). To a solution of DL-3-amino-3-
phenylpropionic acid methyl ester (49 mg, 227 µmol) in CH2Cl2
(0.5 mL) was added triethylamine (100 µL, 684 µmol), 2-py-
ridinecarboxaldehyde (32 µL, 336 µmol), and sodium triace-
toxyborohydride (87 mg, 410 µmol). The reaction mixture was
stirred at rt until all the amino acid ester had been consumed.
4-Bromophenyl isothiocyanate (58 mg, 271 µmol) was then
added and the mixture stirred for 1 h, followed by addition of
triethylamine (200 µL) and heating at 80 °C for 2 days. The
reaction mixture was cooled to rt, diluted with CH2Cl2, washed
with water, dried over MgSO4, and chromatographed on silica
Su p p or tin g In for m a tion Ava ila ble: Characterization
(1H NMR, HPLC, MS) for the crude thiohydantoins in Table
2; 1H and 13C NMR spectra for compounds 7-9 (46 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O962376U