Article
6-(Naphthalene-2-yl)-2H-chromene-2-one (4j). Yield: 63.8%.
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19 5945
J = 14.7 Hz, 7.5 Hz, CH2), 2.51 (2H, t, J = 7.5 Hz,
CH2CH2CH3), 1.586 (2H, m, CH2CH2CH3), 1.32 (3H, t, J =
6.9 Hz, COOCH2CH3), 1.156 (3H, t, J = 6.9 Hz, COO-
CH2CH3), 0.904 (3H, t, J = 7.2 Hz, CH2CH2CH3). 13C NMR
(75 MHz, CDCl3): δ 171.96, 169.25, 161.83, 148.13, 138.84,
128.25, 127.75, 125.35, 115.58, 76.94. 60.26, 59.57, 43.90, 37.45,
31.44, 24.73, 14.72, 14.22, 13.81. HRMS-ESI (positive) calcd for
(C19H25NO5þNa)þ 370.1632; found 370.1652 (MþNa)þ. Anal.
(C19H25NO5) C, H, N. Calcd C, 65.69; H, 7.25; N, 4.03. Found
C, 65.23; H, 7.11; N, 3.90.
1H NMR (CDCl3): δ 8.04 (1H, d, J = 1.6 Hz, 5-H), 7.97-7.94
(1H, d, J=8.8 Hz, 4H), 7.93-7.88 (3H, m, Ar), 7.83-7.80 (2H,
m, Ar), 7.72 (1H, dd, J = 1.6, 8.4 Hz, 7-H), 7.55-7.51 (2H, m,
Ar), 7.45 (1H, d, J = 8.4 Hz, 8-H), 6.49 (1H, d, J = 9.6 Hz,
CHCO). 13C NMR (100 MHz, CDCl3): δ 206.89, 160.65,
153.48, 143.51, 136.67, 133.58, 132.72, 131.00, 128.82, 128.16,
127.71, 126.64, 126.35, 126.31, 125.92, 125.12. 119.13, 117.40,
117.11. ESI-MS (positive): m/z 295.3 (M þNa)þ
General Procedure for the Synthesis of Substituted Ethyl-4H-
chromene-3-carboxylate Compounds (5a-5h). Freshly cut so-
dium (0.096 mmol) was added to anhydrous ethanol (2 mL),
followed by the addition of ethyl cyanoacetate (0.192 mmol).
The reaction mixture was stirred at room temperature under an
inert atmosphere for 30 min, followed by the addition of a
solution of the corresponding coumarin (0.08 mmol) in anhy-
drous ethanol (1 mL). The resulting reaction mixture was stirred
at room temperature. Upon consumption of the coumarin, the
reaction mass was concentrated, diluted with water (30 mL), and
extracted using methylene chloride (3 ꢀ 20 mL). The organics
were combined, dried (MgSO4), and the solvent removed under
vacuum to afford an oil. This crude oil was subjected to column
chromatography to afford the pure product.
Ethyl 2-Amino-6-(4-tert-butylphenyl)-4-(2-ethoxy-2-oxoethyl)-
4H-chromene-3-carboxylate (5e). Yield: 56%. H NMR (CD-
1
Cl3): δ 7.45 (6H, m, Ar), 7.01 (1H, d, J=8.7 Hz, 8-H), 6.34 (2H,
br s, NH2), 4.35 (1H, dd, J=4.5, 6.6 Hz, 4-H), 4.24 (2H, q, J=
7.2 Hz, COOCH2CH3), 4.02 (2H, q, J=7.2 Hz, COOCH2CH3),
2.69 (1H, dd, J=5.1, 15.0 Hz, HCHCO), 2.62 (1H, dd, J=6.6,
15.0 Hz, HCHCO), 1.33 (12H, m, C(CH3)3 and COOCH2CH3),
1.13 (3H, t, J = 7.2 Hz, COOCH2CH3). 13C NMR (75 MHz,
CDCl3): δ 171.88, 169.23, 161.63, 150.32, 149.38, 137.50, 137.43,
126.98, 126.60, 126.35, 125.94, 125.87, 116.19, 76.82, 60.33,
59.66, 43.77, 35.08, 34.66, 31.49, 14.74, 14.21. HRMS-ESI
(positive) calcd for (C26H31NO5 þ Na)þ 460.2120; found
460.2106 (M þ Na)þ. Anal. (C26H31NO5) C, H, N. Calcd C,
71.37; H, 7.14; N, 3.2. Found C, 69.72; H, 7.16; N, 3.12.
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-5-phenyl-4H-chromene-
3-carboxylate (5f). Yield: 51%. 1H NMR (CDCl3): δ 7.44 (7H,
m, Ar), 7.03 (1H, d, J=8.4 Hz, 8-H), 6.32 (2H, br s, NH2), 4.36
(1H, dd, J = 4.5, 6.9 Hz, 4-H), 4.23 (2H, q, J = 7.2 Hz,
COOCH2CH3), 4.02 (2H, q, J = 7.2 Hz, COOCH2CH3), 2.69
(1H, dd, J=4.5, 14.7 Hz, HCHCO), 2.62 (1H, dd, J=6.9, 14.7
Hz, HCHCO), 1.33 (3H, t, J=6.9 Hz, COOCH2CH3), 1.12 (3H,
t, J = 7.2 Hz, COOCH2CH3). 13C NMR (75 MHz, CDCl3): δ
171.98, 169.29, 161.71, 149.68, 140.53, 137.71, 129.01, 127.40,
127.28, 127.08, 126.60, 126.14, 116.36, 76.95, 60.44, 59.77, 43.90,
31.59, 14.82, 14.29. HRMS-ESI (positive) calcd for (C22H23-
NO5 þ Na)þ 404.1468; found 404.1464 (M þ Na)þ. Anal.
(C22H23NO5) C, H, N. Calcd C, 69.28; H, 6.08; N, 3.67. Found
C, 68.88; H, 6.05; N, 3.41.
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-7-phenyl-4H-chromene-
3-carboxylate (5g). Yield: 56%. 1H NMR (CDCl3): δ 7.41 (6H,
m, Ar), 7.21 (1H, s, Ar), 7.15 (1H, s, Ar), 6.28 (2H, br s, NH2),
4.28 (1H, dd, J = 4.5, 7.2 Hz, 4-H), 4.19 (2H, q, J = 6.9 Hz,
COOCH2CH3), 4.00 (2H, q, J = 6.9 Hz, COOCH2CH3), 2.64
(1H, dd, J=4.5, 15 Hz, HCHCO), 2.56 (1H, dd, J=6.9, 15 Hz,
HCHCO), 1.28 (3H, t, J =7.2 Hz, COOCH2CH3), 1.12 (3H, t,
J = 7.2 Hz, COOCH2CH3). 13C NMR (75 MHz, CDCl3): δ
172.03, 169.29, 161.74, 150.46, 141.93, 140.25, 129.05, 128.97,
127.82, 127.19, 124.77, 123.32, 114.52, 76.99, 60.45, 59.77, 43.84,
31.20, 14.83, 14.33. HRMS-ESI (positive) calcd for (C22H23-
NO5 þ Na)þ 404.1468; found 404.1452 (M þ Na)þ. Anal.
(C22H23NO5) C, H, N. Calcd C, 69.28; H, 6.08; N, 3.67. Found
C, 70.00; H, 6.25; N, 3.62.
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-
3-carboxylate (5a). Yield: 53%. 1H NMR (CDCl3): δ 7.44 (7H,
m, Ar), 7.03 (1H, d, J=8.4 Hz, 8-H), 6.32 (2H, br s, NH2), 4.36
(1H, dd, J = 4.5, 6.9 Hz, 4-H), 4.24 (2H, q, J = 7.2 Hz,
COOCH2CH3), 4.02 (2H, q, J = 7.2 Hz, COOCH2CH3), 2.70
(1H, dd, J=4.8, 15.0 Hz, HCHCO), 2.62 (1H, dd, J=6.9, 15.0
Hz, HCHCO), 1.34 (3H, t, J=6.9 Hz, COOCH2CH3), 1.12 (3H,
t, J = 7.2 Hz, COOCH2CH3). 13C NMR (75 MHz, CDCl3): δ
171.88, 169.21, 161.61, 149.58, 140.43, 137.61, 128.92, 127.31,
127.19, 126.99, 126.52, 126.03, 116.276, 60.36, 59.69, 43.79,
31.48, 14.74, 14.21. HRMS-ESI (positive) calcd for (C22H23-
NO5 þ Na)þ 404.1468; found 404.08 (M þ Na)þ. Anal.
(C22H23NO5) C, H, N. Calcd C, 69.28; H, 6.08; N, 3.67. Found
C, 69.86; H, 6.24; N, 3.44.
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-car-
1
boxylate (5b). Yield: 54%. H NMR (CDCl3): δ 7.21 (2H, m,
Ar), 7.07 (1H, dt, J=1.5, 7.5, 8.7 Hz, Ar H), 6.96 (1H, dd, J=
1.2, 8.1 Hz) 6.34 (2H, br s, NH2), 4.29 (1H, dd, J=4.8, 7.5 Hz,
4-H), 4.22 (2H, q, J=6.9 Hz, COOCH2CH3), 4.03 (2H, q, J=
7.2 Hz, COOCH2CH3), 2.64 (1H, dd, J = 4.8, 15.0 Hz,
HCHCO), 2.57 (1H, dd, J =7.2, 14.7 Hz, HCHCO), 1.32 (3H,
t, J=7.2 Hz, COOCH2CH3), 1.15 (3H, t, J=7.2 Hz, COOCH2-
CH3). 13C NMR (75 MHz, CDCl3): δ 171.69, 169.03, 161.38,
149.29, 131.38, 130.84, 128.03, 117.78, 116.87, 76.51, 60.59,
59.87, 43.56, 31.31, 14.79, 14.35. HRMS-ESI (positive) calcd
for (C16H19NO5 þNa)þ: 328.1155; found 328.1128 (MþNa)þ.
Anal. (C16H19NO5) C, H, N. Calcd C, 62.94; H, 6.27; N, 4.59.
Found C, 62.94; H 6.19; N, 4.52.
Ethyl 2-Amino-6-bromo-4-(2-ethoxy-2-oxoethyl)-4H-chromene-
3-carboxylate (5c). Yield: 52%. 1H NMR (CDCl3): δ 7.38 (1H,
d, J=2.4 Hz, 5-H), 7.29 (1H, dd, J=2.4, 8.4 Hz, 7-H), 6.84 (1H,
d, J=9.0 Hz, 8-H), 6.30 (2H, br s, NH2), 4.22 (3H, m, 4-H and
COOCH2CH3), 4.05 (2H, q, J = 7.2 Hz, COOCH2CH3), 2.64
(1H, dd, J=4.8, 15 Hz, HCHCO), 2.57 (1H, dd, J=6.9, 15 Hz,
HCHCO), 1.31 (3H, t, J= 7.2 Hz, COOCH2CH3), 1.18 (3H, t,
J = 7.2 Hz, COOCH2CH3). 13C NMR (CDCl3): δ 171.69,
169.03, 161.38, 149.29, 131.38, 130.84, 128.03, 117.78, 116.87,
76.51, 60.59, 59.87, 43.56, 31.31, 14.79, 14.35. HRMS-ESI
(positive) calcd for (C16H18BrNO5 þ Naþ): 406.0261; found,
406.0266 (MþNa) þ. Anal. (C16H18BrNO5) C, H, N. Calcd C,
50.02; H, 4.72; N, 3.65. Found C, 50.54; H, 5.06; N, 3.64.
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-6-propyl-4H-chromene-
3-carboxylate (5d). Yield: 53%. 1H NMR (CDCl3): δ 7.03
(1H, d, J = 1.8 Hz, 5-H), 6.98 (1H, dd, J = 2.1 Hz, 8.4 Hz,
7-H), 6.86 (1H, d, J = 8.4 Hz, 8-H), 6.28 (2H, br s, NH2), 4.23
(3H, m, 4-H, COOCH2CH3), 4.02 (2H, q, J = 6.9 Hz, COO-
CH2CH3), 2.63 (1H, J = 14.7 Hz, 7.5 Hz, CH2), 2.54 (1H,
Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)-8-phenyl-4H-chromene-
3-carboxylate (5h). Yield: 54%. 1H NMR (CDCl3): δ 7.44 (5H,
m, Ar), 7.22 (2H, m, Ar), 7.15 (1H, t, J=7.2 Hz, Ar), 6.22 (2H,
br s, NH2), 4.36 (1H, dd, J=4.8, 7.5 Hz, 4-H), 4.23 (2H, q, J=
7.5 Hz, COOCH2CH3), 4.06 (2H, q, J=7.5 Hz, COOCH2CH3),
2.67 (1H, dd, J=4.2, 14.7 Hz, HCHCO), 2.58 (1H, dd, J=7.5,
14.7 Hz, HCHCO), 1.33 (3H, t, J=7.2 Hz, COOCH2CH3), 1.17
(3H, t, J=7.2 Hz, COOCH2CH3). 13C NMR (75 MHz, CDCl3):
δ 171.98, 169.16, 161.72, 146.93, 137.42, 129.74, 129.41, 128.38,
128.01, 127.56, 126.53, 124.51, 77.21, 60.44, 59.74, 44.07, 31.87,
14.82, 14.35. HRMS-ESI (positive) calcd for (C22H23NO5 þ
Na)þ 404.1468; found 404.1471 (MþNa)þ. Anal. (C22H23NO5)
C, H, N. Calcd C, 69.28; H, 6.08; N, 3.67. Found C, 68.80; H,
6.64; N, 3.56.
Ethyl 2-Acetamido-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chro-
mene-3-carboxylate (5i). Compound 5a (0.030 g, 0.078 mmol)
was taken in acetic anhydride (2 mL). The resultant reaction
mixture was heated under reflux for 8 h. Following this, the