690 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Elokdah et al.
7.31 (m, 2H), 7.19-7.23 (m, 3H), 4.23 (s, 2H), 3.83-3.87 (m,
2H), 3.73 (q, 2H, J ) 7.25 Hz), 2.83-2.87 (m, 2H), 1.14 (t, 3H,
J ) 7.25 Hz); MS (EI, M•+) m/z 248. Anal. for C13H16N2OS: C,
H, N.
1-Eth yl-3-(2-eth yl-6-m eth ylp h en yl)-2-th ioxoim id a zoli-
d in -4-on e (2.46): light peach solid (66%); mp 82-84 °C; H
NMR δ 7.30 (t, 1H, J ) 7.58 Hz), 7.18 (t, 2H, J ) 7.80 Hz),
4.58 (s, 2H), 3.78-3.84 (m, 2H), 2.33-2.39 (m, 2H), 2.03 (s,
3H), 1.22 (t, 3H, J ) 7.25 Hz), 1.08 (t, 3H, J ) 7.58 Hz); MS
(EI, M•+) m/z 262. Anal. for C14H18N2OS: C, H, N.
3-(2,4-Dich lor op h en yl)-1-eth yl-2-th ioxoim id a zolid in -4-
on e (2.47): light peach solid (74%); mp 144-146 °C; 1H NMR
δ 7.79 (dd, 1H, J ) 8.02 and 1.65 Hz), 7.52 (t, 1H, J ) 8.02
Hz), 7.46 (dd, 1H, J ) 7.91 and 1.76 Hz), 4.61 (d, 1H, J )
20.21 Hz), 4.48 (d, 1H, J ) 19.99 Hz), 3.77-3.83 (m, 2H), 1.22
(t, 3H, J ) 7.25 Hz); MS (CI, [M + H]+) m/z 289/291/293. Anal.
for C11H10Cl2N2OS: C, H, N.
1
1-Eth yl-3-[1-(4-flu or op h en yl)eth yl]-2-th ioxoim id a zol-
id in -4-on e (2.10): light yellow solid (87%); mp 93-95 °C; 1H
NMR δ 7.39-7.43 (m, 2H), 7.11-7.17 (m, 2H), 5.89 (q, 1H, J
) 7.25 Hz), 4.22 (d, 2H, J ) 1.98 Hz), 3.68-3.78 (m, 2H), 1.73
(d, 3H, J ) 7.25 Hz), 1.14 (t, 3H, J ) 7.25 Hz); MS (EI, M•+
m/z 266. Anal. for C13H15FN2OS: C, H, N.
)
1-Eth yl-3-(2-tolyl)-2-th ioxoim idazolidin -4-on e (2.14): off-
1
white solid (83%); mp 105-108 °C; H NMR δ 7.26-7.35 (m,
3H), 7.15 (d, 1H, J ) 7.47 Hz), 4.53 (d, 1H, J ) 19.99 Hz),
4.43 (d, 1H, J ) 19.99 Hz), 3.77-3.83 (m, 2H), 2.08 (s, 3H),
1.21 (t, 3H, J ) 7.25 Hz); MS (EI, M•+) m/z 234. Anal. for
3-(2,4-Dim eth ylp h en yl)-1-eth yl-2-th ioxoim id a zolid in -
4-on e (2.48): light peach solid (87%); mp 161-162 °C; 1H
NMR δ 7.14 (s, 1H), 7.08 (dd, 1H, J ) 12.0 and 3.20 Hz), 7.01
(d, 1H, J ) 13.2 Hz), 4.52 (d, 1H, J ) 22.0 Hz), 4.42 (d, 1H, J
) 21.2 Hz), 3.72-3.87 (m, 1H), 2.32 (s, 3H), 2.03 (s, 3H), 1.21
(t, 3H, J ) 8.00 Hz); MS (EI, M•+) m/z 248. Anal. for
C
12H14N2OS: C, H, N.
3-(2,6-Dich lor op h en yl)-1-eth yl-2-th ioxoim id a zolid in -4-
on e (2.16): tan solid (90%); mp 170-172 °C; 1H NMR δ 7.67
(dd, 2H, J ) 8.13 and 0.66 Hz), 7.54-7.58 (m, 1H), 4.70 (s,
2H), 3.80 (q, 2H, J ) 7.18 Hz), 1.22 (t, 3H, J ) 7.14 Hz); MS
(EI, M•+) m/z 288/290/292. Anal. for C11H10Cl2N2OS: C, H, N.
3-(2-Ch lor o-6-m e t h ylp h e n yl)-1-e t h yl-2-t h ioxoim id -
C
13H16N2OS: C, H, N.
3-(2,5-Dim eth ylp h en yl)-1-eth yl-2-th ioxoim id a zolid in -
4-on e (2.49): off-white solid (85%); mp 176-178 °C; 1H NMR
δ 7.21 (d, 1H, J ) 7.91 Hz), 7.14-7.17 (m, 1H), 6.96 (m, 1H),
4.51 (d, 1H, J ) 19.99 Hz), 4.42 (d, 1H, J ) 19.99 Hz), 3.74-
3.84 (m, 2H), 2.28 (s, 3H), 2.02 (s, 3H), 1.20 (t, 3H, J ) 7.25
Hz); MS (EI, M•+) m/z 248. Anal. for C13H16N2OS: C, H, N.
1-Eth yl-2-th ioxo-3-(2,4,5-tr im eth ylph en yl)im idazolidin -
4-on e (2.50): off-white solid (95%); mp 162-164 °C; 1H NMR
δ 7.09 (s, 1H), 6.89 (s, 1H), 4.49 (d, 1H, J ) 19.99 Hz), 4.40 (d,
1H, J ) 19.99 Hz), 3.73-3.84 (m, 2H), 2.19 (d, 6H, J ) 13.62
Hz), 1.99 (s, 3H), 1.20 (t, 3H, J ) 7.14 Hz); MS (EI, M•+) m/z
262. Anal. for C14H18N2OS: C, H, N.
1
a zolid in -4-on e (2.19): tan solid (67%); mp 124-126 °C; H
NMR δ 7.33-7.47 (m, 3H), 4.62 (s 2H), 3.77-3.83 (m, 2H),
2.14 (s, 3H), 1.22 (t, 3H, J ) 7.25 Hz); MS (EI, M•+) m/z 268/
270. Anal. for C12H13ClN2OS: C, H, N.
3-(2,6-Dim eth ylp h en yl)-1-eth yl-2-th ioxoim id a zolid in -
4-on e (2.37): tan solid (57%); mp 128-131 °C; 1H NMR δ
7.22-7.26 (m, 1H), 7.15-7.17 (m, 2H), 4.57 (s, 2H), 3.80 (q,
2H, J ) 7.25 Hz), 2.04 (s, 6H), 1.21 (t, 3H, J ) 7.25 Hz); MS
(EI, M•+) m/z 248. Anal. for C13H16N2OS: C, H, N.
3-(4-Dim eth yla m in op h en yl)-1-eth yl-2-th ioxoim id a zol-
id in -4-on e (2.38): light pink solid (80%); mp 159-161 °C; 1H
NMR δ 7.01-7.03 (m, 2H), 6.72-6.74 (m, 2H), 4.37 (s, 2H),
3.78 (q, 2H, J ) 7.25 Hz), 2.92 (s, 6H), 1.19 (t, 3H, J ) 7.25
Hz); MS (EI, M•+) m/z 263. Anal. for C13H17N3OS: C, H, N.
1-E t h yl-3-(4-flu or op h e n yl)-2-t h ioxoim id a zolid in -4-
on e (2.40): pink solid (75%); mp 149-151 °C; 1H NMR δ 7.28-
7.36 (m, 4H), 4.40 (s, 2H), 3.80 (q, 2H, J ) 7.18 Hz), 1.20 (t,
1-Eth yl-3-(2-isop r op ylp h en yl)-2-th ioxoim id a zolid in -4-
on e (2.51): white solid (86%); mp 125-127 °C; 1H NMR δ
7.40-7.46 (m, 2H), 7.25-7.29 (m, 1H), 7.09-7.11 (m, 1H), 4.55
(d, 1H, J ) 19.99 Hz), 4.43 (d, 1H, J ) 19.99 Hz), 3.73-3.86
(m, 2H), 2.69-2.74 (m, 1H), 1.21 (t, 3H, J ) 7.25 Hz), 1.14 (d,
3H, J ) 6.81 Hz), 1.07 (d, 3H, J ) 6.81 Hz); MS (EI, M•+) m/z
262. Anal. for C14H18N2OS: C, H, N.
1-Eth yl-3-(2-m eth ylsu lfa n ylp h en yl)-2-th ioxoim id a zol-
id in -4-on e (2.52): tan solid (66%); mp 128-131 °C; 1H NMR
δ 7.43-7.48 (m, 2H), 7.26-7.30 (m, 1H), 7.19-7.21 (m, 1H),
4.54 (d, 1H, J ) 20.21 Hz), 4.43 (d, 1H, J ) 20.21 Hz), 3.76-
3.82 (m, 2H), 2.39 (s, 3H), 1.21 (t, 3H, J ) 7.14 Hz); MS (EI,
M•+) m/z 266. Anal. for C12H14N2S2O: C, H, N.
3H, J ) 7.25 Hz); MS (EI, M•+) m/z 238. Anal. for C11H11
FN2OS: C, H, N.
-
3-(5-Ch lor o-2-m et h oxyp h en yl)-1-et h yl-2-t h ioxoim id -
a zolid in -4-on e (2.41): tan solid (7%); mp 171-174 °C; 1H
NMR δ 7.50 (dd, 1H, J ) 9.01 and 2.64 Hz), 7.33 (d, 1H, J )
2.64 Hz), 7.19 (d, 1H, J ) 9.01 Hz), 4.52 (d, 1H, J ) 19.99
Hz), 4.39 (d, 1H, J ) 20.21 Hz), 3.71-3.84 (m, 5H), 1.20 (t,
1-Ben zyl-3-(2,6-d ich lor op h en yl)-2-th ioxoim id a zolid in -
4-on e (2.15): light yellow solid (79%); mp 124-125 °C; 1H
NMR δ 7.71 (d, 1H, J ) 0.88 Hz), 7.69 (s, 1H), 7.56-7.60 (m,
1H), 7.39-7.42 (m, 2H), 7.31-7.36 (m, 3H), 5.06 (s, 2H), 4.58
3H, J ) 7.25 Hz); MS (EI, M•+) m/z 284/286. Anal. for C12H13
ClN2O2S: C, H, N.
-
1-E t h yl-2-t h ioxo-3-(4-t r iflu or om et h oxyp h en yl)im id -
1
(s, 2H); MS (EI, M•+) m/z 350/352/354. Anal. for C16H12
-
a zolid in -4-on e (2.42): tan solid (46%); mp 116-119 °C; H
NMR δ 7.39-7.46 (m, 4H), 4.38 (s, 2H), 3.76 (q, 2H, J ) 7.2
Cl2N2OS: C, H, N.
Hz), 1.17 (t, 3H, J ) 7.2 Hz); MS (EI, M•+) m/z 304. Anal. for
1-Bu tyl-3-(2-ch lor o-6-m eth ylp h en yl)-2-th ioxoim id a zol-
id in -4-on e (2.20). 2-Chloro acetic acid (47.3 g) was added
portionwise while stirring to n-butylamine (500.0 g) over a
period of 30 min. The mixture was stirred at room temperature
for 18 h. The excess n-butylamine was evaporated, leaving a
viscous clear oil (120.0 g), which solidified upon standing. The
crude product consisted of a 1:1 mixture of N-butylglycine and
butylamine hydrochloride. The mixture of crude N-butylglycine
(8.5 g, 0.035 mol), 2-chloro-6-methylphenyl isothiocyanate (6.5
g, 0.035 mol), triethylamine (14 mL), and methylene chloride
(150 mL) was heated at reflux for 5 h. The solvent was
evaporated and the residue was chromatographed on silica gel
using methylene chloride as an eluant. Crystallization from
ethanol afforded 3.85 g of the title compound (74%) as a light
pink solid: mp 97-100 °C; MS (FAB, [M + H]+) m/z 297/299.
1H NMR δ 7.33-7.47 (m, 3H), 4.60 (s, 2H), 3.73-3.85 (m, 2H),
2.14 (s, 3H), 1.62-1.69 (m, 2H), 1.28-1.38 (m, 2H), 0.92 (t,
3H, J ) 7.36 Hz). Anal. for C14H17ClN2OS: C, H, N.
C
12H11F3N2O2S: C, H, N.
1-Eth yl-3-(5-flu or o-2-m eth ylp h en yl)-2-th ioxoim id a zol-
id in -4-on e (2.43): pink solid (83%); mp 98-100 °C; 1H NMR
δ 7.36-7.40 (m, 1H), 7.23 (td, 1H, J ) 8.50 and 2.79 Hz), 7.13
(dd, 1H, J ) 9.35 and 2.75 Hz), 4.54 (d, 1H, J ) 19.99 Hz),
4.40 (d, 1H, J ) 19.99 Hz), 3.75-3.84 (m, 2H), 2.06 (s, 3H),
1.21 (t, 3H, J ) 7.14 Hz); MS (EI, M•+) m/z 252. Anal. for
C
12H13FN2OS: C, H, N.
1-Eth yl-2-th ioxo-3-(2-tr iflu or om eth ylp h en yl)im id a zol-
1
id in -4-on e (2.44): light pink solid (51%); mp 82-85 °C; H
NMR δ 7.81-7.88 (m, 2H), 7.69-7.73 (m, 1H), 7.50 (d, 1H, J
) 7.91 Hz), 4.59 (d, 1H, J ) 20.21 Hz), 4.44 (d, 1H, J ) 20.21
Hz), 3.71-3.87 (m, 2H), 1.20 (t, 3H, J ) 7.25 Hz); MS (EI,
M•+) m/z 288. Anal. for C12H11F3N2OS: C, H, N.
1-E t h yl-3-(2-et h yl-6-isop r op ylp h en yl)-2-t h ioxoim id -
1
a zolid in -4-on e (2.45): white solid (52%); mp 77-79 °C; H
NMR δ 7.38 (t, 1H, J ) 7.69 Hz), 7.28 (dd, 1H, J ) 7.80 and
1.38 Hz), 7.18 (m, 1H), 4.61 (s, 2H), 3.72-3.87 (m, 2H), 2.60-
2.66 (m, 1H), 2.28-2.38 (m, 2H), 1.22 (t, 3H, J ) 7.25 Hz),
1.14 (d, 3H, J ) 6.81 Hz), 1.08 (t, 3H, J ) 7.47 Hz), 1.04
(d, 3H, J ) 6.81 Hz); MS (EI, M•+) m/z 290. Anal. for
3-(2,6-Dim eth ylp h en yl)-1-isop r op yl-2-th ioxoim id a zol-
id in -4-on e (2.23). Reaction of 2,6-dimethylphenyl isothio-
cyanate (50 mmol) with N-isopropylglycine43 (50 mmol) in the
manner described for compound 2.39 afforded the title com-
pound as a white solid (94%): mp 135-137 °C; 1H NMR δ
C
16H22N2OS: C, H, N.