Journal of Medicinal Chemistry
Article
5-(3,4-Dihydroxybenzylidene)-2-thioxothiazolidin-4-one
(18R). 18R was synthesized according to procedure D in 88% yield.
1H NMR (300 MHz, CD3OD): δ = 6.86 (d, J = 8.2 Hz, 1H), 6.94
(R)-5-Benzylimidazolidine-2,4-dione (53). A mixture of
L-phenylalanine (3.03 mmol) and sodium cyanate (6.06 mmol) in
water (20 mL) was heated to 50 °C and stirred for 30 min. The
solution was evaporated to 5 mL, and 1 M HCl was added dropwise
until a precipitate remained. Afterward 2 M HCl (10 mL) was added
and the suspension was refluxed for 2 h. The reaction mixture was
allowed to cool to room temperature and the resulting precipitate was
collected, washed with water, and dried under vacuum to obtain 53.
Yield 72%. 1H NMR (300 MHz, DMSO-d6): δ = 2.92 (dd, 2H, J = 4.8
Hz, J = 2.2 Hz), 4.32 (t, 1H, J = 5.1 Hz), 7.22 (m, 5H), 7.91 (bs, 1H),
10.4 (bs, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 36.2, 58.3, 126.5,
127.9, 129.6, 135.5, 157.0, 175.1. HRMS (ESI, [M − H]−) calcd
(C10H9N2O2) 189.0742; found 189.0667.
(dd, J = 8.2 Hz, J = 1.8 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 7.41 (s, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 116.4, 116.5, 120.7, 124.3, 124.9,
132.7, 145.9, 149.1, 169.5, 195.5. HRMS (ESI, [M − H]−) calcd
(C10H7NO3S2) 251.9795; found 251.9797.
5-(3,4-Dihydroxybenzylidene)imidazolidine-2,4-dione
(18H). 18H was synthesized according to procedure E in 35% yield.
1H NMR (300 MHz, acetone-d6): δ = 6.40 (s, 1H), 6.86 (d, J = 8.2 Hz,
1H), 7.01 (dd, J = 8.2 Hz, J = 2.1 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 109.8, 115.8, 117.2, 121.4, 124.3,
125.5, 145.3, 146.4, 155.9, 165.6. HRMS (ESI, [M − H]−) calcd
(C10H8N2O4) 219.0411; found 219.0413.
5-Benzylthiazolidine-2,4-dione (54). To a solution of 2,4-
thiazolidinedione (4.20 mmol) at −78 °C was added n-butyllithium
(8.40 mmol) dropwise and stirred for 15 min. The reaction mixture
was then placed in an ice bath for 30 min. When the mixture was
cooled to −78 °C, benzyl bromide (4.20 mmol) was added and the
mixture was stirred for 30 min. The reaction mixture was allowed to
warm to room temperature and stirred for additional 90 min. The
reaction was quenched with 5% sulfuric acid and the aqueous phase
extracted with ethyl acetate. The organic layer was dried and
5-(3,4-Dihydroxybenzylidene)thiazolidine-2,4-dione
(18Td). 18Td was synthesized according to procedure F in 67% yield.
1H NMR (300 MHz, CD3OD): δ = 6.86 (d, J = 8.2 Hz, 1H), 6.95
(dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H).
13C NMR (75 MHz, CD3OD): δ = 117.2, 117.7, 120.6, 125.4, 126.5,
134.3, 147.2, 149.8, 169.2, 169.8. HRMS (ESI, [M − H]−) calcd
(C10H7NO4S) 236.0023; found 236.0024.
5-((3-Chlorothiophen-2-yl)methylene)-2-thioxoimidazoli-
1
concentrated. Column chromatography furnished 54. Yield 52%. H
din-4-one (24T). 24T was synthesized according to procedure C in
NMR (300 MHz, DMSO-d6): δ = 3.12 (dd, 1H, J = 14.1 Hz, J = 9.2
Hz), 3.39 (dd, 1H, J = 14.1 Hz, J = 4.4 Hz), 4.92 (dd, 1H, J = 9.3 Hz,
J = 4.4 Hz), 7.29 (m, 5H), 10.4 (bs, 1H). 13C NMR (75 MHz, DMSO-
d6): δ = 37.0, 52.6, 126.9, 128.3, 129.1, 136.8, 171.5, 175.6. HRMS
(ESI, [M − H]−) calcd (C10H8NO2S) 206.0354; found 206.0277.
5-Benzyl-2-thioxothiazolidin-4-one (55). An amount of 1.87 mL
ammonia (7 M in MeOH) was added to 10 mL of EtOH and cooled
to 0 °C. To this solution was added dropwise a precooled mixture
of carbon disulfide (26.2 mmol) in 5 mL of ether. The reaction mix-
ture was stirred for 2 h at 0 °C and overnight at room temperature.
The resulting precipitate was collected, sucked dry, and transferred to a
solution of 2-bromo-3-phenylpropanoic acid (2.24 mmol) in water and
stirred for 2 h. The solution was transferred to 6 M HCl (80 °C) and
was heated to 95 °C. The reaction mixture was allowed to cool to room
temperature and the resulting precipitate was collected and dried under
1
45% yield. H NMR (300 MHz, CD3OD): δ = 6.78 (s, 1H), 7.13 (d,
J = 5.4 Hz, 1H), 7.75 (d, J = 5.4 Hz, 1H). 13C NMR (75 MHz,
CD3OD): δ = 101.9, 128.9, 129.5, 129.6, 130.4, 130.7, 167.2, 180.5.
HRMS (ESI, [M − H]−) calcd (C8H5ClN2OS2) 242.9459; found
242.9457.
5-((3-Chlorothiophen-2-yl)methylene)-2-thioxothiazolidin-
4-one (24R). 24R was synthesized according to procedure D in 31%
yield. 1H NMR (300 MHz, DMSO-d6): δ = 7.39 (d, J = 5.3 Hz, 1H),
7.63 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6):
δ = 119.9, 125.9, 129.8, 130.6, 130.8, 134.2, 169.4, 194.5. HRMS
(ESI, [M − H]−) calcd (C8H4ClNOS3) 259.9071; found 259.9071.
5-((3-Chlorothiophen-2-yl)methylene)imidazolidine-2,4-
dione (24H). 24H was synthesized according to procedure E in 25%
yield. 1H NMR (300 MHz, CD3OD): δ = 6.81 (s, 1H), 7.09 (d, J = 5.4
Hz, 1H), 7.67 (d, J = 5.4 Hz, 1H). 13C NMR (75 MHz, CD3OD): δ =
112.0, 127.9, 129.0, 129.1, 129.4, 130.7, 166.6, 173.4. HRMS (ESI,
[M − H]−) calcd (C8H5ClN2O2S) 226.9687; found 226.9690.
5-((3-Chlorothiophen-2-yl)methylene)thiazolidine-2,4-dione
(24Td). 24Td was synthesized according to procedure F in 26% yield.
1H NMR (300 MHz, CD3OD): δ = 7.19 (d, J = 5.4 Hz, 1H), 7.88 (d,
1
vacuum to obtain 55. Yield 61%. H NMR (300 MHz, DMSO-d6):
δ = 3.17 (dd, 1H, J = 14.1 Hz, J = 8.9 Hz), 3.37 (dd, 1H, J = 14.1 Hz,
J = 4.6 Hz), 5.04 (dd, 1H, J = 8.9 Hz, J = 4.6 Hz), 7.27 (m, 5H), 13.2
(bs, 1H). 13C NMR (75 MHz, acetone-d6): δ = 27.8, 46.9, 118.4,
119.8, 120.5, 127.9, 169.2, 194.6. HRMS (ESI, [M − H]−) calcd
(C10H8NOS2) 222.0126; found 222.0061.
5-(3,4-Dihydroxybenzyl)-2-thioxoimidazolidin-4-one (56). 56
was synthesized according to procedures A and B. Yield 15%. 1H NMR
(300 MHz, acetone-d6): δ = 2.82 (dd, 1H, J = 14.1 Hz, J = 6.9 Hz),
3.04 (dd, 1H, J = 14.1 Hz, J = 6.8 Hz), 4.38 (dt, 1H, J = 5.7 Hz, J = 1.2
Hz), 6.53 (dd, 1H, J = 8.1 Hz, J = 1.9 Hz), 6.68 (d, 1H, J = 5.5 Hz),
6.60 (d, 1H, J = 8.0 Hz), 8.81 (bs, 1H), 10.3 (bs, 1H). 13C NMR (75
MHz, DMSO-d6): δ = 29.7, 60.9, 125.3, 126.7, 126.9, 135.9, 175.3,
182.6. HRMS (ESI, [M − H]−) calcd (C10H9N2O3S) 237.0412; found
237.0334.
J = 5.4 Hz, 1H), 6.98 (s, 1H). 13C NMR (75 MHz, DMSO-d6): δ =
120.9, 124.0, 129.4, 130.3, 130.8, 132.6, 167.2, 167.5. HRMS (ESI,
[M − H]−) calcd (C8H4ClNO2S2) 243.9282; found 243.9280.
(S)-1-Acetyl-5-benzyl-2-thioxoimidazolidin-4-one (47). 47
was synthesized according to procedure A. Yield 93%. 1H NMR
(300 MHz, DMSO-d6): δ = 2.69 (s, 3H), 3.12 (m, 1H), 3.40 (m, 1H),
4.99 (m, 1H), 6.97 (m, 2H), 7.77 (m, 3H), 12.42 (s, 1H). 13C NMR
(75 MHz, DMSO-d6): δ = 27.8, 34.9, 63.9, 127.7, 128.8, 129.7, 134.6,
170.5, 172.9, 182.7. MS (EI): m/z = 248.10 g/mol [M+].
(S)-5-Benzyl-2-thioxoimidazolidin-4-one (47a). 47a was syn-
5-(3,4-Dihydroxybenzyl)imidazolidine-2,4-dione (57). See
1
1
thesized according to procedure B out of 47. Yield 87%. H NMR
procedure for 53. Yield 81%. H NMR (300 MHz, DMSO-d6): δ =
(300 MHz, DMSO-d6): δ = 2.95 (d, 2H, J = 5.0 Hz), 4.54 (m, 1H),
7.20 (m, 5H), 10.04 (s, 1H), 11.41 (s, 1H). 13C NMR (75 MHz,
DMSO-d6): δ = 35.6, 61.3, 126.7, 128.0, 129.5, 134.9, 175.6, 182.1. MS
(EI): m/z = 206.10 g/mol [M+].
2.73 (d, 2H, J = 4.3 Hz), 4.19 (t, 1H, J = 4.3 Hz), 6.42 (dd, 1H, J = 8.0
Hz, J = 2.1 Hz), 6.65 (d, 1H, J = 2.0 Hz), 6.60 (d, 1H, J = 8.0 Hz), 7.81
(bs, 1H), 10.4 (bs, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 35.7,
58.6, 120.4, 126.1, 143.8, 144.6, 157.1, 175.2. HRMS (ESI, [M − H]−)
calcd (C10H9N2O4) 221.0641; found 221.0575.
(S)-5-(4-Hydroxybenzyl)-2-thioxoimidazolidin-4-one (51a). 51a
was synthesized according to procedures A and B. Yield 88%. 1H NMR
(300 MHz, acetone-d6): δ = 2.98 (d, J = 4.0 Hz, 2H), 4.07 (t, J =
4.0 Hz, 1H), 6.71 (d, J = 4.0 Hz, 2H), 7.04 (d, J = 4.0 Hz, 2H). HRMS
(ESI, [M − H]−) calcd (C10H10N2O2S) 221.0363; found 221.0363.
(S)-5-Benzylimidazolidine-2,4-dione (52). See procedure for
53. Yield 61%. 1H NMR (300 MHz, DMSO-d6): δ = 2.92 (dd, 2H, J =
4.8 Hz, J = 2.2 Hz), 4.32 (t, 1H, J = 5.1 Hz), 7.22 (m, 5H), 7.91 (bs,
1H), 10.4 (bs, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 36.2, 58.3,
126.5, 127.9, 129.6, 135.5, 157.0, 175.1. HRMS (ESI, [M − H]−) calcd
(C10H9N2O2) 189.0742; found 189.0668.
5-(Thiophen-2-ylmethyl)-2-thioxoimidazolidin-4-one (58). 58
1
was synthesized according to procedures A and B Yield 40%. H NMR
(300 MHz, DMSO-d6): δ = 3.21 (ddd, 2H, J = 15.3 Hz, J = 10.5 Hz, J =
4.3 Hz), 4.54 (dt, 1H, J = 4.6 Hz, J = 1.1 Hz), 6.85 (dd, 1H, J = 3.4 Hz,
J = 0.9 Hz), 6.94 (dd, 1H, J = 5.1 Hz, J = 3.4 Hz), 7.37 (dd, 1H, J = 5.1
Hz, J = 1.2 Hz), 10.1 (bs, 1H), 11.5 (bs, 1H). 13C NMR (75 MHz,
DMSO-d6): δ = 29.7, 60.9, 125.3, 126.7, 126.9, 135.9, 175.3, 182.6.
HRMS (ESI, [M − H]−) calcd (C8H7N2OS2) 211.0078; found 211.0005.
5-(Thiophen-2-ylmethyl)imidazolidine-2,4-dione (59). See
1
procedure for 53. Yield 62%. H NMR (300 MHz, DMSO-d6): δ =
751
dx.doi.org/10.1021/jm201243p | J. Med. Chem. 2012, 55, 743−753