Month 2019
DHODH Inhibitory Activity of Novel Coumarin Derivatives
3.08–3.16 (m, 1H CH2), 3.59 (s, 3H, CO2CH3), 3.71 (s, 2H,
CH2), 4.5 (q, Ј = 5.24 Hz, 1H, CH), 6.34 (s, 1H, C3–H), 7.37
(t, Ј = 7.2 Hz, 1H, Ar–H), 7.42–7.56 (m, 6H, Ar–H), 7.63 (t,
Ј = 6.8 Hz, 1H, Ar–H), 7.78 (d, Ј = 8.0 Hz, 1H, Ar–H), 8.81
H), 7.3 (t, Ј = 8.4 Hz, 1H, Ar–H), 7.44 (d, Ј = 8.4 Hz,
1H, Ar–H), 7.55 (s, 1H, Ar–H), 8.75 (d, Ј = 7.6 Hz, 1H,
CONH); LCMS: m/z 376 [M+1]+.
Methyl 2-(2-(6-methoxy-2-oxo-2H-chromen-4-yl)acetamido)-
Pale yellow solid, 1H NMR
(d, Ј = 7.6 Hz, 1H, CO–NH); LCMS: m/z 366.4 [M+1]+.
3-phenylpropanoate (4g).
(400 MHz, DMSO-d6): δ 2.87–2.93 (m, 1H of CH2),
3.03–3.08 (m, 1H of CH2), 3.58 (s, 3H, OCH3), 3.72 (d,
Ј = 8.08 Hz, 2H, CH2), 3.78 (s, 3H, CO2Me), 4.47–4.52
(m, 1H, CH), 6.37 (s, 1H, C3–H), 7.15–7.24 (m, 7H, Ar–
H), 7.34 (d, Ј = 9.2 Hz, 1H, Ar–H), 8.81 (d, Ј = 8.0 Hz,
1H, CONH); LCMS: m/z 394.0 [M-1]+.
Methyl 3-methyl-2-(2-(2-oxo-2H-chromen-4-yl)acetamido)
1
pentanoate (4b). Off white solid, H NMR (400 MHz,
DMSO-d6): δ 0.85 (dd, Ј = 2.8 Hz, 6.8 Hz, 6H, 2 CH3),
1.21–1.26 (m, 1H), 1.37–1.44 (m, 1H), 3.63 (s, 3H,
CO2CH3), 3.85 (s, 2H, CH2), 4.24 (t, Ј = 7.6 Hz, 1H,
NH–CH), 6.46 (s, 1H, C3 H), 7.37 (t, Ј = 7.2 Hz, 1H,
Ar–H), 7.42 (d, Ј = 8.0 Hz, 1H, Ar–H), 7.63 (t,
Ј = 6.8 Hz, 1H, Ar–H), 7.78 (d, Ј = 8.0 Hz, 1H, Ar–H),
8.69 (d, Ј = 8.0 Hz, 1H, –CONH); 13C NMR (400 MHz,
DMSO-d6): δ 11.1 (CH3), 15.5 (CH3), 24.7 (CH2), 36.2
(CH), 38.2 (CH), 51.8 (CH2), 56.6 (CH3), 116, 116, 119
(Ar–C), 124.3, 125.4, 132 (C-4), 151 (Ar–C), 153.1 (Ar–
C), 159.7 (C═O), 168.1 (C═O), 171.9 (N–C═O); LCMS:
m/z 332.2 [M+1]+.
Methyl 2-(2-(6-methoxy-2-oxo-2H-chromen-4-yl)acetamido)-
3-methylpentanoate (4h).
Off white solid, 1H NMR
(300 MHz, DMSO-d6): δ 0.85 (m, 6H, 2-CH3), 1.17–1.27
(m, 1H of CH2), 1.39–1.44 (m, 1H of CH2), 1.84–1.89
(m, 1H, CH), 3.62 (s, 3H, Ar–OMe), 3.83 (s, 3H,
CO2Me), 3.85 (s, 2H, CH2), 4.24 (t, Ј = 6.3 Hz, 1H,
NHCH), 6.45 (s, 1H, C3–H), 7.23 (d, Ј = 7.47 Hz, 1H,
Ar–H), 7.26 (s, 1H, Ar–H), 7.36 (d, Ј = 9.45 Hz, 1H,
Ar–H), 8.72 (d, Ј = 7.53 Hz, 1H, CONH); LCMS: m/z
362.2 [M+1]+.
Dimethyl
pentanedioate (4c).
2-(2-(2-oxo-2H-chromen-4-yl)acetamido)
Pale yellow solid, 1H NMR
(300 MHz, DMSO-d6): δ 1.83–1.93 (m, 1H of CH2),
1.98–2.07 (m, 1H of CH2), 2.4 (t, Ј = 7.5 Hz, 2H, CO–
CH2), 3.6 (s, 6H, 2 CO2Me), 3.8 (s, 2H, CH2), 4.3 (q,
Ј = 7.5 Hz, NH–CH), 6.49 (s, 1H, C3H), 7.37 (t,
Ј = 8.2 Hz, 1H, Ar–H), 7.41 (d, Ј = 8.4 Hz, 1H, Ar–H),
7.64 (t, Ј = 8.4 Hz, 1H, Ar–H), 7.7 (d, Ј = 7.8 Hz, 1H,
Ar–H), 8.75 (d, Ј = 7.2 Hz, 1H, CONH); LCMS: m/z
362.2 [M+1]+.
2-[2-(6-Methoxy-2-oxo-2H-chromen-4-yl)-acetylamino]-
pentanedioic acid dimethyl ester (4i). Off white solid, H
1
NMR (400 MHz, DMSO-d6): δ 1.83–1.9 (m, 1H of
CH2), 2.00–2.07 (m, 1H of CH2), 2.4 (q, Ј = 7.6 Hz,
2H, CH2), 3.5 (s, 3H, OCH3), 3.61 (s, 3H, CO2CH3),
3.62 (s, 3H, OCH3), 3.78 (s, 2H, CH2), 4.27–4.33 (m,
1H, NHCH), 6.43 (s, 1H, C3–H), 7.06 (s, 1H, Ar–H),
7.2 (d, Ј = 2.9 Hz, 1H, Ar–H), 7.34 (d, Ј = 3.0 Hz,
1H, Ar–H), 8.75 (d, Ј = 7.6 Hz, 1H, CONH); LCMS:
m/z 392.4 [M+1]+.
Methyl 2-(2-(6-methyl-2-oxo-2H-chromen-4-yl)acetamido)-
3-phenylpropanoate (4d).
Pale yellow solid, 1H NMR
(400 MHz, DMSO-d6): δ 2.34 (s, 3H, Ar CH3), 2.88–
2.93 (m, 1H of CH2), 3.08–3.16 (m, 1H of CH2), 3.59
(s, 3H, CO2CH3), 3.71 (d, Ј = 8.4 Hz, 2H, Ar CH2),
4.5 (q, Ј = 5.24 Hz, 1H, CH), 6.34 (s, 1H, C3–H),
7.16–7.24 (m, 5H, Ar–H), 7.28 (d, Ј = 8.4 Hz, 1H, Ar–
H), 7.42 (d, Ј = 8.4 Hz, 1H, Ar–H), 7.49 (s, 1H, Ar–
H), 8.81 (d, Ј = 7.6 Hz, 1H, CO–NH); LCMS: m/z
380.4 [M+1]+.
Methyl
carboxylate (4j).
1-(2-(2-oxo-2H-chromen-4-yl)acetyl)piperidine-2-
Pale yellow solid, 1H NMR
(400 MHz, CD3OD): δ 1.39–1.45 (m, 2H, CH2), 1.69–
1.85 (m, 4H, 2-CH2), 2.29–2.33 (m, 2H, CH2), 3.78 (s,
3H, CO2CH3), 4.07 (s, 2H, CH2), 5.28 (t, Ј = 5.60 Hz,
1H, CH), 6.42 (s, 1H, C3H), 7.37 (d, Ј = 7.6 Hz, 2H,
Ar–H), 7.6 (t, Ј = 11.2 Hz, 2H, Ar–H); LCMS: m/z
330.3 [M+1]+.
Methyl
1-(2-(6-methyl-2-oxo-2H-chromen-4-yl)acetyl)
Methyl
3-methyl-2-(2-(6-methyl-2-oxo-2H-chromen-4-yl)
1
Off white solid, 1H NMR
piperidine-2-carboxylate (4k). Pale yellow solid, H NMR
(400 MHz, DMSO-d6): δ 1.29–1.36 (m, 1H, CH), 1.65–
1.76 (m, 3H, H of CH2), 2.19–2.39 (m, 1H, CH2), 2.43
(s, 3H, Ar–Me), 3.22–3.28 (m, 1H, CH), 3.82 (s, 3H,
CO2CH3), 3.94–3.97 (m, 1H of CH2), 4.04–4.08 (m, 1H
of CH2), 4.23 (m, 1H of CH2), 5.11–5.24 (m, 1H, CH),
6.46 (s, 1H, C3–H), 7.37 (d, Ј = 8.4 Hz, 1H, Ar–H), 7.47
(s, 1H, Ar–H), 7.5 (d, Ј = 8.0 Hz, 1H, Ar–H); LCMS: m/
z 344.4 [M+1]+.
acetamido)pentanoate (4e).
(400 MHz, DMSO-d6): δ 0.82–0.87 (m, 6H, 2 CH3),
1.22–1.27 (m, 1H, CH), 1.40–1.42 (m, 1H, CH), 1.82–
11.84 (m, 1H, CH), 2.37 (s, 3H, Ar–CH3), 3.54 (s, 3H,
CO2CH3), 3.84 (s, 2H, CH2), 4.26 (t, Ј = 1.6 Hz, 1H,
NH–CH), 6.43 (s, 1H, C3–H), 7.31 (t, Ј = 8.4 Hz, 1H,
Ar–H), 7.42 (d, Ј = 8.4 Hz, 1H, Ar–H), 7.58 (s, 1H,
Ar–H), 8.72 (d, Ј = 8.12 Hz, 1H, CONH); LCMS: m/z
346.2 [M+1]+.
Methyl
1-(2-(6-methoxy-2-oxo-2H-chromen-4-yl)acetyl)
Dimethyl 2-(2-(6-methyl-2-oxo-2H-chromen-4-yl)acetamido)
1
1
piperidine-2-carboxylate (4l).
Off white solid, H NMR
pentanedioate (4f). Off white solid, H NMR (400 MHz,
(400 MHz, DMSO-d6): δ 1.22–1.28 (m, 1H of CH2),
1.43–1.48 (m, 1H of CH2), 1.60–1.68 (m, 3H, CH2 and
1H of CH2), 2.12–2.20 (m, 1H of CH2), 3.16–3.32 (m,
1H of CH2), 3.67 (s, 3H, Ar–OMe), 3.8 (s, 3H,
DMSO-d6): δ 1.83–1.9 (m, 1H of CH2), 2.00–2.07 (m,
1H of CH2), 2.3 (s, 3H, Ar–CH3), 2.4 (q, Ј = 7.6 Hz, 2H,
CH2), 3.5 (s, 3H, OCH3), 3.61 (s, 3H, CO2CH3), 3.78 (s,
2H, CH2), 4.27–4.33 (m, 1H, NH–CH), 6.43 (s, 1H, C3–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet