Journal of Medicinal Chemistry
Article
(s, 2 H); 13C NMR (125 MHz, CDCl3): 181.4, 169.8, 150.1, 139.2,
138.4, 129.9, 128.7, 128.4, 128.2, 126.8, 125.6, 124.1 (q, J = 270.8
Hz), 46.2, 31.9; HRMS (ESI): calcd for C18H15F3N4OS2 (M + H)+,
425.0712; found, 425.0713.
(CN), 1699 (CO), 3363; 1H NMR (200 MHz, DMSO): 9.52 (s,
1 H), 8.60 (d, J = 3.6 Hz, 2 H), 8.18 (d, J = 3.6 Hz, 2 H), 7.94 (d, J =
3.0 Hz, 2 H), 7.89−7.83 (m, 5 H), 7.75−7.70 (m, 2 H), 6.83−6.82
(m, 1 H), 4.94, 4.92 (ABq, J = 5.6 Hz, 2 H).·13C NMR (50 MHz,
DMSO): 167.6, 164.1, 154.0, 146.7, 141.5, 137.2, 136.9, 129.5, 129.4,
129.1, 129.0, 128.2, 127.8, 125.6, 117.7, 50.4, 36.4; HRMS (ESI):
calcd for C23H19N5O4S (M + H)+, 462.1230; found, 462.1230.
1-((5-(Benzylthio)-1,3,4-oxadiazol-2-yl)methyl)-3-(4-
nitrophenyl)thiourea (3c). White solid; yield = 136 mg (68%); mp
193.8−194.2 °C; IR (neat) νmax, cm−1: 1688 (CS),1635 (CN),
(d, J = 8.5 Hz, 2 H), 4.50 (s, 2 H), 3.93 (s, 2 H); 13C NMR (125
MHz, CDCl3): 181.4, 170.1, 149.9, 146.8, 140.9, 139.5, 130.7, 129.1,
128.8, 127.2, 124.1, 46.6, 32.3; HRMS (ESI): calcd for C17H15N5O3S2
(M + H)+, 402.0689; found, 402.0680.
1
3154; H NMR (500 MHz, CDCl3): 8.30 (d, J = 8.5 Hz, 2 H), 7.67
General Procedure for Synthesis of Compounds 4a−4i (Schemes
1 and 2). Trifluoroacetic acid (0.5 mL) was dropwise added to a
stirred solution of 2a−c (0.5 mmol) in dry dichloromethane (2 mL).
After 2 h, the volatiles were removed under reduced pressure to afford
the trifluoroacetate salt. A solution of the crude trifluoroacetate salt
(0.5 mmol) in dichloromethane (5 mL) was cooled in an ice-water
bath. To it was added Et3N (0.1 mL, 0.55 mmol), followed by the
addition of respective isocyanates (0.5 mmol). After 15 min of stirring
at room temperature, the mixture was concentrated under reduced
pressure and the residue was taken in ethyl acetate. The solution was
washed with water and concentrated under reduced pressure. The
crude product was purified by column chromatography to afford
compounds 4a−i.
1-((S)-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)(phenyl)methyl)-3-p-
tolylurea (4d). White solid; yield = 125 mg (58%); mp 118.1−119.0
°C; [α]2D5 = −16.5 (c 1.05, CHCl3); IR (neat) νmax, cm−1: 1592 (C
1
N), 1638 (CO), 3300; H NMR (200 MHz, CDCl3): 8.06 (s, 1
H), 7.31−7.29 (m, 10 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 8.4
Hz, 2 H), 6.53−6.48 (m, 1 H), 4.37 (s, 2 H), 2.28 (s, 3 H); 13C NMR
(50 MHz, CDCl3): 168.1, 165.0, 155.0, 137.2, 136.1, 134.9, 132.8,
129.5, 129.1, 129.0, 128.9, 128.6, 128.2, 127.1, 120.3, 50.5, 37.0, 20.8;
HRMS (ESI): calcd for C24H22N4O2S (M + H)+, 431.1563; found,
431.1536.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(5-(benzylthio)-1,3,4-ox-
adiazol-2-yl)(Phenyl)Methyl)urea (4a). Yield: 207 mg (75%), white
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-1-(5-(benzylthio)-1,3,4-
oxadiazol-2-yl)-2phenylethyl)urea (4e). Colorless crystal; yield =
220 mg (78%); mp 167−168 °C; [α]2D5 = −53.0 (c 1.01, CHCl3); IR
(neat) νmax, cm−1: 1581 (CN), 1658 (CO), 3304; 1H NMR (500
MHz, CDCl3): 8.48 (s, 1 H), 7.75 (s, 2 H), 7.37 (t, J = 7.5 Hz, 3 H),
7.34−7.26 (m, 3 H), 7.18 (br s, 3 H), 6.96 (d, J = 4.0 Hz, 2 H), 6.85
(d, J = 8.5 Hz, 1 H), 5.6−5.5 (m, 1 H), 4.41 (ABq, J = 17.5,13.0 Hz, 2
H), 3.05 (dd, J = 13.5, 6.0 Hz, 1 H), 2.87 (dd, J = 13.5, 6.0 Hz, 1 H);
13C NMR (125 MHz, CDCl3): 169.1, 165.4, 153.9, 140.7, 134.8,
solid; mp 128−129 °C; [α]2D5 = −2.5 (c 1.06, CHCl3); IR (neat) νmax
,
cm−1: 1622 (CN), 1694 (CO), 3360; 1H NMR (500 MHz,
CDCl3): 8.85 (s, 1 H), 7.95−7.88 (m, 2 H), 7.58, (d, J = 7.5 Hz, 1
H), 7.45 (s, 1 H), 7.36−7.27 (m, 5 H), 7.26−7.24 (m, 5 H), 6.55 (d, J
= 7.5 Hz, 1H), 4.38 (br s, 2 H); 13C NMR (125 MHz, CDCl3): 168.6,
165.5, 153.9, 140.9, 136.6, 134.5, 132.3 (q, J = 33.0 Hz), 129.4, 129.1,
128.9, 128.8, 128.4, 126.8, 123.3 (q, J = 270.8 Hz), 118.3, 115.6, 50.3,
37.3; HRMS (ESI): calcd for C25H18F6N4O2S (M + H)+, 553.1127;
found, 553.1124.
134.7, 131.8 (q, J = 29.7 Hz), 129.3, 129.0, 128.9, 128.7, 128.5, 127.5,
123.2 (q, J = 269.0 Hz), 118.0, 115.5, 47.8, 40.2, 37.0; HRMS (ESI):
calcd for C26H20F6N4O2S (M + H)+, 567.1283; found, 567.1284.
1-((S)-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)(phenyl)methyl)-3-(4-
methoxyphenyl)urea (4b). White solid; yield = 123 mg (55%); mp
158.3−159.1 °C; [α]D25.2 = +17.6 (c 1.05, CHCl3); IR (neat) νmax
,
1-((S)-1-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)-2-phenylethyl)-3-
(4-methoxyphenyl)urea (4f). White solid; yield = 126 mg (55%); mp
163−164 °C; [α]D25.1 = −17.05 (c 1.33, CHCl3); IR (neat) νmax, cm−1:
cm−1: 1596 (CN), 1666 (CO), 3347; 1H NMR (500 MHz,
CDCl3): 7.76 (s, 1 H), 7.29 (br s, 5 H), 7.25−7.24 (m, 3 H), 7.20 (d,
J = 9.0 Hz, 2 H), 6.98 (br s,1 H), 6.76 (d, J = 9.0 Hz, 2 H), 6.46 (d, J
= 8.5 Hz, 1 H), 4.34 (ABq, J = 19.0, 13.0 Hz, 2 H), 3.73 (s, 3 H): 13C
NMR (125 MHz, CDCl3): 167.9, 164.9, 156.4, 155.2, 137.2, 135.1,
131.3, 129.1, 128.9, 128.8, 128.6, 128.1, 127.1, 123.0, 114.4, 55.5,
50.7, 37.0; HRMS (ESI): calcd for C24H22N4O3S (M + H)+,
447.1485; found, 447.1485.
1
1631 (CN), 1660 (CO), 3334; H NMR (500 MHz, CDCl3):
7.37 (d, J = 7 Hz, 2 H), 7.33−7.27 (m, 3 H), 7.20−7.17 (m, 4 H),
7.12 (d, J = 9 Hz, 2 H), 7.02−7.00 (m, 2 H), 6.77 (d, J = 9.0 Hz, 2
H), 6.04 (d, J = 6.5 Hz, 1 H), 5.53 (dd, J = 15.0, 6.5 Hz, 1 H), 4.4−
4.36 (m, 2 H), 3.76 (s, 3 H), 3.15 (dd, J = 14.0, 6.5 Hz, 1 H), 3.06
(dd, J = 14.0, 6.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): 168.2,
164.5, 156.8, 155.3, 135.4, 135.3, 130.9, 129.4, 129.0, 128.8, 128.6,
128.2, 127.2, 123.8, 114.5, 55.5, 47.9, 40.0, 36.9; HRMS (ESI): calcd
for C25H24N4O3S (M + H)+, 461.1641; found, 461.1642.
1-((S)-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)(phenyl)methyl)-3-(4-
nitrophenyl)urea (4c). White solid; yield = 160 mg (70%); mp 186−
187 °C; [α]2D5.8 = +28.2 (c 0.96, EtOAc); IR (neat) νmax, cm−1: 1603
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J. Med. Chem. 2021, 64, 1524−1544