Journal of Medicinal Chemistry
Article
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47%. Rf = 0.70 (n-hexane/ethyl acetate, 2:8); H NMR (300 MHz,
DMSO-d6) δ = 1.03 (m, 4H, CH2-CH2), 2.60 (m, 1H, CH), 4.91 (s,
2H, NH2), 6.54 (dd, 1H, J = 3.62 Hz and J = 0.57 Hz, 3-H), 6.57 (dd,
1H, J = 8.77 Hz and J = 2.09 Hz, 6-H), 6.71 (d, 1H, J = 2.09 Hz, 4-H),
7.98 (d, 1H, J = 3.24 Hz, 2-H), 8.00 ppm (dd, 1H, J = 8.77 Hz and J =
0.57 Hz, 7-H); 13C NMR (75 MHz, DMSO-d6) δ = 15.95 (CH2CH2),
28.44 (CH), 101.15 (3-C), 104.33 (4-C), 112.77 (7-C), 113.24 (6-C),
128.06 (2-C), 128.94 (3a-C), 129.74 (7a-C), 142.52 (5-C), 171.61
ppm (NC(O)CHCH2CH2). HRMS (ESI-MS, 140 eV): m/z [M + H+]
calculated for C12H13N2O+, 201.2439; found, 201.2482.
by reacting 2.148 g (11.60 mmol) of 5-aminoindole derivative 3c and
3.01 mL (17.7 mmol) of ethyl benzoylacetate, obtaining after column
chromatography (d = 3 cm, l = 30 cm, 230−400 mesh, eluent n-
hexane/ethyl acetate, 1:1) 2.54 g of a dark red solid. Yield 71%; Rf =
0.72 (n-hexane/ethyl acetate, 1:1); 1H NMR (400 MHz, DMSO-d6) δ
= 1.24 (t, 3H, J = 6.92 Hz, CHCOOCH2CH3), 2.97 (t, 2H, J = 6.34
Hz, NCH2CH2CN), 4.14 (q, 2H, J = 6.92 Hz,, CHCOOCH2CH3),
4.39 (t, 2H, J = 6.34 Hz, NCH2CH2CN), 4.85 (s, 1H,
CHCOOCH2CH3), 6.28 (dd, 1H, J = 3.19 Hz and J = 0.69 Hz, 3-
H), 6.66 (dd, 1H, J = 8.71 Hz and J = 2.08 Hz, 6-H), 6.98 (m, 1H, J =
2.08 Hz, 4-H), 7.29 (m, 1H, 2-H), 7.29 (m, 1H, 4′-H), 7.35 (m, 1H, 7-
H), 7.37 (m, 2H, 2′-H and 6′-H), 7.35 (m, 2H, 3′-H and 5′-H), 10.27
ppm (s, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ = 14.94
(CHCOOCH2CH3), 19.01 (NCH2CH2CN), 41.71 (NCH2CH2CN),
59.14 (CHCOOCH2CH3), 89.12 (CHCOOCH2CH3), 101.68 (3-C),
110.44 (7-C), 115.25 (4-C), 118.75 (6-C), 119.29 (CN), 128.64 (3a-
C), 128.89 (2′-C and 6′-C), 128.59 (5′-C and 3′-C), 129.85 (4′-C),
129.87 (2-C), 132.93 (7a-C), 133.06 (1′-C), 136.31 (5-C), 160.50
(NHCCH), 169.79 ppm (CHCOOCH2CH3). HRMS (ESI-MS, 140
General Procedure for the Synthesis of Acrylate Derivatives
4a−f and 7f. As a typical procedure, the synthesis of acrylate
derivative 4a is described in detail. In a 100 mL round-bottomed flask,
1.234 g (7.00 mmol) of 3-substituted aminoindole 3a in 25 mL of
absolute ethanol was condensed with 1.82 mL (10.5 mmol; d = 1.11 g/
mL) of commercial ethyl benzoylacetate and 0.5 mL of glacial acetic
acid in the presence of 100 mg of Drierite. The mixture was refluxed
for about 24 h, the reaction being monitored by TLC analysis (n-
hexane/ethyl acetate, 3:7). Even though the reaction was not complete
after 24 h, the mixture was cooled and filtered to remove the Drierite;
the resulting solution was evaporated to dryness under vacuum and the
residue (2.420 g) purified by silica gel chromatography (d = 3 cm, l =
35 cm, 230−400 mesh, eluent n-hexane/ethyl acetate, 3:7) to yield
1.47 g of a semisolid yellow product.
+
eV): m/z [M + H+] calculated for C22H22N3O2 , 360.4284; found,
360.4242.
(E,Z)-Ethyl 3-(1-((Ethoxycarbonyl)methyl)-1H-indol-5-ylami-
no)-3-phenylacrylate (4d). Compound 4d was prepared as for
compound 4a by reacting 0.800 g (3.66 mmol) of 5-aminoindole 3d,
to yield after silica gel column chromatography (d = 2.5 cm, l = 30 cm,
230−400 mesh, eluent n-hexane/ethyl acetate, 1:1) 1.024 g of a
semisolid red product. Yield 70%; Rf = 0.54 (n-hexane/ethyl acetate,
(E,Z)-Ethyl 3-(1-(2-Hydroxyethyl)-1H-indol-5-ylamino)-3-
phenylacrylate (4a). Yield 60%; Rf = 0.58 (n-hexane/ethyl acetate,
3:7); H NMR (300 MHz, DMSO-d6) δ = 1.11 (t, 3H, J = 7.05 Hz,
1
1
CH2CH3), 3.89 (q, 2H, J = 7.05 Hz, CH2CH2OH), 4.13 (q, 2H, J =
7.05 Hz, CH2CH3), 4.61 (t, 2H, J = 7.05 Hz, CH2CH2OH), 4.83 (s,
1H, CH), 5.15 (t, 1H, J = 7.05 Hz, OH), 7.16 (d, 1H, J = 3.05 Hz, 3-
H), 7.67 (m, 5H, 2′-H, 3′-H, 4′-H, 5′-H, 6′-H), 7.71 (dd, 1H, J = 8.77
and J = 2.10 Hz, 6-H), 8.02 (d, 1H, J = 2.10 Hz, 4-H), 8.07 (d, 1H, J =
3.05 Hz, 2-H), 8.13 (d, 1H, J = 8.77 Hz, 7-H), 10.25 ppm (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) δ = 14.75 (CHCOOCH2CH3),
46.94 (NCH2CH2OH), 60.24 (CHCOOCH2CH3), 61.56
(NCH2CH2OH), 89.44 (CHCOOCH2CH3), 102.62 (3-C), 110.75
(7-C), 114.73 (4-C), 118.12 (6-C), 127.22 (3a-C), 128.94 (2′-C and
6′-C), 129.44 (5′-C and 3′-C), 129.87 (4′-C), 130.44 (2-C), 132.03
(7a-C), 133.76 (1′-C), 137.42 (5-C), 159.92 (NHCCH), 169.84 ppm
(CHCOOCH2CH3). HRMS (ESI-MS, 140 eV): m/z [M + H+]
1:1); H NMR (300 MHz, DMSO-d6) δ = 1.11 (t, 3H, J = 7.05 Hz,
CH2CH3), 1.16 (t, 3H, J = 7.05 Hz, CH2CH3), 4.01 (q, 2H, J = 7.05
Hz, CH2CH3), 4.13 (q, 2H, J = 7.05 Hz, CH2CH3), 4.83 (s, 1H, CH),
4.95 (s, 2H, CH2) 6.20 (d, 1H, J = 3.05 Hz, 3-H), 6.60 (dd, 1H, J =
8.77 Hz and J = 2.10 Hz, 6-H), 6.97 (d, 1H, J = 2.10 Hz, 4-H), 7.30
(m, 7H, 2-H, 7-H, 2′-H, 3′-H, 4′-H, 5′-H, and 6′-H), 10.25 ppm (s,
1H, NH); 13C NMR (75 MHz, DMSO-d6)
δ = 14.33
(CHCOOCH2CH3), 15.64 (NCH2COOCH2CH3), 46.55
(NCH2COOCH2CH3), 60.24 (CHCOOCH2CH3), 61.15
(NCH2COOCH2CH3), 88.95(CHCOOCH2CH3), 102.36 (3-C),
110.82 (7-C), 114.46 (4-C), 118.25 (6-C), 127.16 (3a-C),
128.77(2′-C and 6′-C), 129.41 (5′-C and 3′-C), 129.82 (4′-C),
130.11 (2-C), 132.09 (7a-C), 133.24 (1′-C), 137.77 (5-C), 160.14
(NHCCH), 168.88 (CHCOOCH2 CH3 ), 169.76 ppm
(NCH2COOCH2CH3);HRMS (ESI-MS, 140 eV): m/z [M + H+]
+
calculated for C21H23N2O3 , 351.4184; found, 351.4194.
(E,Z)-Ethyl 3-(1-(Cyclopropylmethyl)-1H-indol-5-ylamino)-3-
(3,4-dimethoxyphenyl)acrylate (4b). Compound 4b was prepared
as for compound 4a by reacting 0.500 g (2.68 mmol) of 5-aminoindole
3b, obtaining after column chromatography 0.387 g of a semisolid
+
calculated for C23H25N2O4 , 393.4551; found, 393.4577.
(E,Z)-Ethyl 3-(1-Propionyl-1H-indol-5-ylamino)-3-phenyla-
crylate (4e). Compound 4e was prepared as for compound 4a by
reacting 0.240 g (1.28 mmol) of 5-aminoindole 3e and 0.332 mL of
ethyl benzoyl acetate (1.92 mmol, d = 1.11 g/mL). An amount of
0.525 g of a crude product was obtained, and this was purified by silica
gel column chromatography (d = 2 cm, l = 15 cm, 230−400 mesh,
eluent n-hexane/ethyl acetate/toluene, 1:1:1), giving 0.250 g of a
semisolid yellow product. Yield 53%; Rf = 0.72 (ethyl acetate/n-
1
product. Yield 87%; Rf = 0.76 and Rf = 0.70 (ethyl acetate); H NMR
(300 MHz, DMSO-d6) including NMR signals of both isomers δ =
0.32 (dd, 2H, J = 4.95 Hz and J = 1.14 Hz, CH2-CH2), 0.46 (dd, 2H, J
= 8.20 Hz and J = 1.90 Hz, CH2-CH2), 1.17 (t, 3H, J = 7.05 Hz,
CH2CH3), 1.23 (t, 3H, J = 7.05 Hz, CH2CH3), 1.29 (m, 1H, CH), 3.54
and 3.68 (s, 6H, -OCH3), 3.81 and 3.85 (s, 6H, -OCH3), 4.09 (m, 2H,
J = 6.29 Hz, CH2CH3), 4.13 (m, 2H, J = 7.05 Hz, CH2CH3), 4.88 (s,
1H, CH), 6.10 and 6.25 (dd, 2H, J = 2.86 Hz and J = 0.76 Hz, J = 3.05
Hz, J = 0.57 Hz, 3-H), 6.51 (dd, 2H, J = 9.15 Hz and J = 2.09 Hz, 6-
H), 6.64 (dd, 2H, J = 8.39 and J = 1.90 Hz, 6′-H), 6.82 (d, 1H, J = 8.96
Hz, 5′-H), 7.02 (d, 1H, J = 0.90 Hz, 2′-H), 7.12 (d, 1H, J = 8.58 Hz, 7-
H), 7.18 (dd, 2H, J = 6.29 Hz and J = 3.05 Hz, 4-H), 7.31 and 7.36 (d,
2H, J = 8.77 Hz and J = 3.05 Hz, 5-H), 7.44 (d, 1H, J = 2.09 Hz, 2-H),
7.61 (dd, 1H, J = 8.58 Hz and J = 2.28 Hz, 6-H), 10.19 ppm (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) δ = 8.24 (CH2CH2), 13.07
(CH), 14.34 (CHCOOCH2CH3), 60.24 (CHCOOCH2CH3), 62.04
(OCH3), 62.61 (OCH3), 88.78 (CHCOOCH2CH3), 101.91 (3-C),
111.77 (7-C), 114.97 (4-C), 115.85 (2′-C), 117.24 (6-C), 119.82 (5′-
C), 122.45 (6′-C), 126.92 (3a-C), 130.44 (2-C), 132.03 (7a-C),
135.62 (1′-C), 137.23 (5-C), 160.44 (NHCCH), 163.03 (3′-C),
164.24 (4′-C), 169.84 ppm (CHCOOCH2CH3). HRMS (ESI-MS,
1
hexane/toluene, 1:1:1); H NMR (400 MHz, DMSO-d6) δ = 1.16 (t,
3H, J = 7.33 Hz, C(O)CH2CH3), 1.24 (t, 3H, J = 6.92 Hz,
COOCH2CH3), 2.96 (q, 2H, J = 7.33 Hz, C(O)CH2CH3), 4.14 (q,
2H, J = 6.92 Hz, COOCH2CH3), 4.85 (s, 1H, CH), 6.28 (dd, 1H, J =
3.19 Hz and J = 0.69 Hz, 3-H), 6.66 (dd, 1H, J = 8.70 Hz and J = 2.08
Hz, 6-H), 6.97 (m, 1H, J = 2.08 Hz, 4-H), 7.28 (d, 1H, J = 3.19 Hz, 2-
H), 7.29 (m, 1H, 4′-H), 7.34 (m, 2H, 3′-H and 5′-H), 7.35 (dd, 1H, J
= 8.70 Hz and J = 0.69 Hz, 7-H), 7.37 (m, 2H, 2′-H and 6′-H), 10.26
ppm (bs, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ = 9.36
(C(O)CH2CH3), 14.94 (COOCH2CH3), 28.45 (C(O)CH2CH3),
59.14 (COOCH2CH3), 89.11 (CH), 101.68 (3-C), 110.44 (7-C),
115.25 (4-C), 118.76 (6-C), 128.59 (3′-C and 5′-C), 128.64 (3a-C),
128.89 (2′-C and 6′-C), 129.84 (4′-C), 129.87 (2-C), 132.93 (7a-C),
133.06 (1′-C), 136.31 (5-C), 160.51 (C-CH), 169.79
(COOCH2CH3), 174.80 ppm (COCH2CH3). HRMS (ESI-MS, 140
+
+
140 eV): m/z [M + H+] calculated for C25H29N2O4 , 421.5082; found,
eV): m/z [M + H+] calculated for C22H23N2O3 , 363.4291; found,
421.5095.
363.4273.
(E,Z)-Ethyl 3-(1-(2-Cyanoethyl)-1H-indol-5-ylamino)-3-phe-
nylacrylate (4c). Compound 4c was prepared as for compound 4a
(E,Z)-Ethyl 3-(1-Cyclopropylmethanone-1H-indol-5-ylami-
no)-3-phenylacrylate (4f). Compound 4f was prepared as for
M
J. Med. Chem. XXXX, XXX, XXX−XXX