E.G. Koutsandrea et al.: New paullone derivativesꢀ
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Ethyl 1-benzyloxymethyl-4-{tert-butoxycarbonyl[(1-(benzyloxy-
methyl)-1H-indol-3-yl)methyl]carbamoyl}-5-iodo-1H-pyrrole-
2-carboxylate (24c)ꢀYield 62%; oil; 1H NMR (CDCl3): δ 1.28 (t, J = 6.1
Hz, 3H), 1.25 (s, 9H), 4.24 (q, J = 7.1 Hz, 2H), 4.78 (s, 2H), 4.84 (s, 2H),
Hz, 2H), 7.02 (t, J = 7.5 Hz, 2H), 7.06–7.11 (m, 2H), 7.27–7.39 (m, 5H), 7.46
(d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.82 (d, J = 7.1 Hz, 1H); 13C NMR (CDCl3): δ
164.1, 160.5, 151.5, 139.5, 136.4, 136.1, 131.5, 129.7, 128.5 (2C), 128.2 (2C),
127.9, 127.8, 127.72 (2C), 127.6 (2C), 126.5, 126.4, 125.8, 124.5, 122.9, 122.0,
5.15 (s, 2H), 5.49 (s, 2H), 5.61 (s, 2H), 7.07 (s, 1H), 7.34–7.46 (m, 13H), 7.51 119.6, 119.2, 111.8, 83.1, 75.8, 74.8, 70.7, 70.4, 60.8, 39.5, 28.1 (3C), 14.3;
(d, J = 3.8 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3): δ 165.95,
159.7, 153.2, 136.9, 136.9, 136.3, 129.0, 128.4 (2C), 128.4 (2C), 128.2, 127.9,
127.9, 127.9 (2C), 127.8 (2C), 127.7, 126.3, 122.2, 120.2, 120.1, 120.0, 112.4,
109.9, 88.9, 82.9, 74.9, 72.0, 70.5, 70.4, 60.6, 40.0, 27.6 (3C), 14.2; MS:
m/z 799.91 [M+Na]+, 816.03 [M+K]+.
MS: m/z 672.18 [M+Na]+, 688.18 [M+K]+.
General procedure for the synthesis
of tetracylic derivatives 12a–c
General procedure for the synthesis Το a solution of the appropriate N-Boc protected amide 25a–c (0.11
mmol) in dry DCM (4 mL), a solution of trifluoroacetic acid (0.91
of tetracylic derivatives 25a–c
mmol) in dry DCM (1 mL) was added and the mixture was stirred
at room temperature for 1 h under argon atmosphere. Then it was
To a solution of the appropriate N-protected amide 24a–c (230 μmol)
in anhydrous DMF (5 mL), Ph3P (12.11 mg, 46.2 μmol), Pd(AcO)2 (5.15
mg, 23.0 μmol) and Ag2CO3 (253 mg, 918 μmol) was added and the
mixture was stirred for 0.5 h at 135°C under argon atmosphere. Then
it was diluted with water and extracted three times with ethyl acetate.
The combined organic phases were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column chro-
matography (0–20% EtOAc in n-hexane) to afford the corresponding
tetracylic derivative 25a–c.
poured to ice-aqueous NH3 solution (25%). The aqueous phase was
washed three times with DCM and the combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate, fil-
tered and concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (20% EtOAc in
n-hexane) to afford the tetracylic derivative 12a–c.
Ethylꢁꢁꢁ1,11-bis(ethoxymethyl)-4-oxo-4,5,6,11-tetrahydro-1H-pyr-
rolo[2′,3′:5,6]azepino [4,3-b]indole-2-carboxylate (12a)ꢀYield 66%;
white powder; mp 194–197°C; 1H NMR (CDCl3): δ 0.97 (t, J = 7.0 Hz, 3H),
1.11 (t, J = 7.0 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H), 3.14 (q, J = 7.0 Hz, 2H), 3.31
(q, J = 7.0 Hz, 2H), 4.19 (dd, J = 15.3, 3.0 Hz, 1H), 4.29–4.44 (m, 2H), 4.49
(dd, J = 15.2, 6.7 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 5.52 (d, J = 10.4 Hz, 1H),
5.61 (d, J = 9.8 Hz, 1H), 6.23 (d, J = 9.8 Hz, 1H), 6.97 (br s, 1H), 7.29 (t, J =
7.1 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.65–7.67 (m, 2H);
13C NMR (CDCl3): δ 167.3, 160.6, 139.5, 132.0, 129.4, 125.8, 125.7, 124.2, 121.7,
121.4, 120.5, 118.7, 118.6, 111.8, 76.8, 75.5, 64.4, 64.2, 60.7, 35.9, 14.8, 14.7,
14.3; MS: m/z 426.31 [M+H]+, 448.29 [M+Na]+, 464.22 [M+K]+.
5 - tert-Butyl 2-ethyl 1,11-bis(ethoxymethyl)-4-oxo-6,11-dihydro-
1H-pyrrolo[2′,3′:5,6] azepino[4,3-b]indole-2,5(4H)-dicarboxylate
(25a)ꢀYield 32%; oil; 1H NMR (CDCl3): δ 0.96 (t, J = 7.0 Hz, 3H), 1.15 (t,
J = 7.0 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.49 (s, 9H), 3.10 (dq, J = 7.0, 1.3
Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 15.4 Hz, 1H), 4.32–4.43 (m,
2H), 5.36 (d, J = 10.2 Hz, 1H), 5.50 (d, J = 10.2 Hz, 1H), 5.61 (d, J = 10.5
Hz, 1H), 5.64 (d, J = 5.0 Hz, 1H), 6.18 (d, J = 9.9 Hz, 1H), 7.27–7.32 (m,
1H), 7.35–7.40 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.80 (d, J = 7. 8
Hz, 1H); 13C NMR (CDCl3): δ 164.1, 160.5, 151.5, 139.6, 131.6, 129.5, 126.3,
125.8, 124.5, 122.8, 121.9, 121.8, 119.6, 118.7, 111.6, 83.1, 76.9, 75.8, 64.4,
64.3, 60.8, 39.6, 28.1 (3C), 14.8, 14.7, 14.3; MS: m/z 548.24 [M+Na]+,
564.17 [M+K]+.
Ethyl 1,11-bis[2-(trimethylsilyl)ethoxymethyl]-4-oxo-4,5,6,11-tet-
rahydro-1H-pyrrolo [2′,3′:5,6]azepino[4,3-b]indole-2-carboxylate
1
(12b)ꢀYield 45%; oil; H NMR (CDCl3): δ -0.20 (s, 9H), -0.10 (s, 9H),
0.55–0.73 (m, 2H), 0.79–0.98 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 3.13 (t, J =
8.2 Hz, 2H), 3.33 (t, J = 8.2 Hz, 2H), 4.17 (d, J = 17.6 Hz, 1H), 4.30–4.48
(m, 3H), 5.31 (d, J = 10.1 Hz, 1H), 5.51 (d, J = 10.4 Hz, 1H), 5.59 (d, J =
10.0 Hz, 1H), 6.26 (d, J = 9.8 Hz, 1H), 6.38 (br s, 1H), 7.25–7.32 (m, 1H),
7.36 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.64–7.70 (m, 2H); 13C NMR
(CDCl3): δ 167.2, 160.6, 139.5, 132.1, 129.6, 126.0, 125.8, 124.2, 121.8, 121.6,
120.5, 118.7, 118.6, 111.9, 8.19, 7.13, 7.2 (2C), 60.7, 35.9, 17.8, 17.4, 14.3, -1.54
(3C), -1.6 (3C); MS: m/z 570.03 [M+H]+, 591.88 [M+Na]+, 608.07 [M+K]+.
5 - tert-Butyl 2-ethyl 1,11-bis[2-(trimethylsilyl)ethoxymethyl]-
4-oxo-6,11-dihydro-1H-pyrrolo[2′,3′:5,6] azepino[4,3-b]indole-
2,5(4H)-dicarboxylate (25b)ꢀYield 41%; oil; 1H NMR (CD3OD): δ
-0.22 (s, 9H), -0.21 (s, 9H), 0.50–0.76 (m, 4H), 1.40 (t, J = 7.1 Hz, 3H),
1.50 (s, 9H), 3.02–3.14 (m, 2H), 3.15–3.27 (m, 2H), 4.16 (d, J = 15.6 Hz,
1H), 4.37 (dq, J = 7.1, 1.1 Hz, 2H), 5.44 (d, J = 11.1 Hz, 1H), 5.58–5.65 (m,
2H), 5.78 (d, J = 11.1 Hz, 1H), 6.29 (d, J = 10.2 Hz, 1H), 7.29 (t, J = 7.4 Hz,
1H), 7.36–7.41 (m, 1H), 7.64 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.9
Ethylꢁꢁꢁ1,11-bis(benzyloxymethyl)-4-oxo-4,5,6,11-tetrahydro-
Hz, 1H); 13C NMR (CDCl3): δ 164.1, 160.5, 151.5, 139.5, 131.7, 129.6, 126.3, 1H-pyrrolo[2′,3′:5,6]azepino [4,3-b]indole-2-carboxylate (12c)ꢀ
1
125.8, 124.4, 122.9, 121.8, 121.7, 119.5, 118.5, 111.6, 83.1, 76.6, 75.6, 66.2, Yield 30%; oil; H NMR (CDCl3): δ 1.40 (t, J = 7.1 Hz, 3H), 4.15 (d, J =
66.1, 60.8, 39.5, 28.1 (3C), 17.8, 17.3, -1.5 (3C), -1.7 (3C); MS: m/z 692.15 9.4 Hz, 1H), 4.21 (d, J = 3.6 Hz, 1H), 4.29–4.47 (m, 2H), 5.31 (d, J = 10.5
[M+Na]+, 708.90 [M+K]+.
Hz, 1H), 5.49 (d, J = 10.5 Hz, 1H), 5.56 (d, J = 9.9 Hz, 1H), 6.16 (d, J =
10.0 Hz, 1H), 6.51 (br s, 1H), 6.87 (d, J = 7.2 Hz, 2H), 7.01–7.06 (m, 4H),
7.21–7.26 (m, 3H), 7.27–7.39 (m, 3H), 7.47 (d, J = 8.1 Hz, 1H), 7.66 (d, J =
7.7 Hz, 1H), 7.70 (s, 1H); 13C NMR (CDCl3): δ 167.1, 160.5, 139.5, 136.5,
136.2, 131.8, 129.7, 128.5 (2C), 128.2 (2C), 128.0, 127.8, 127.7 (2C), 127.7
5 - tert-Butyl 2-ethyl 1,11-bis(benzyloxymethyl)-4-oxo-6,11-dihy-
dro-1H-pyrrolo[2′,3′:5,6] azepino[4,3-b]indole-2,5(4H)-dicarbo-
1
xylate (25c)ꢀYield 40%; oil; H NMR (CD3OD): δ 1H NMR (CDCl3): δ
1.40 (t, J = 7.1 Hz, 3H), 1.49 (s, 9H), 4.20 (d, J = 4.8 Hz, 1H), 4.22 (d, J = (2C), 126.1, 125.8, 124.2, 121.8, 121.7, 121.0, 119.2, 118.7, 112.0, 75.7, 74.5,
4.9 Hz, 1H), 4.29–4.40 (m, 2H), 5.33 (d, J = 10.3 Hz, 1H), 5.47 (d, J = 10.3 70.6, 70.4, 60.7, 35.8, 14.3; MS: m/z 550.13 [M+H]+, 572.11 [M+Na]+,
Hz, 1H), 5.63 (d, J = 9.5 Hz, 1H), 6.14 (d, J = 10.0 Hz, 1H), 6.85 (d, J = 7. 3
588.10 [M+K]+.
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