R. Gust et al.
MED
1-Propyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole (5c): 1-Propyl-
2,3,5-tris(4-methoxyphenyl)-1H-pyrrole (4c) (0.5 mmol, 220 mg) and
BBr3 (2.6 mmol, 645 mg). Orange solid, mp: 1198C, yield:
Experimental Section
General: IR spectra (KBr pellets): ATI Mattson Genesis. 1H NMR:
Avance DPX 400 spectrometer (Bruker, Karlsruhe, Germany) at
400 MHz (internal standard: (CH3)4Si). Elemental analysis: Vario EL
(Elementar, Hanau, Germany). HPLC: Bio-Tek Kontron Instruments,
Germany; column: Eurospher 100-5 C18, 250ꢂ4 mm, Knauer GmbH,
Germany. In C, H, and N analysis, compounds 5a–h showed ac-
ceptable purity (within 0.4% of the calculated values), and in HPLC
studies they showed purity ranging from 95 to 100%. Mass spec-
trometry: CH-7A (Varian MAT, Bremen, Germany). Microplate
reader: Flashscan S12 (Analytik Jena, Germany) and Wallac Victor2
1420 multilabel counter (PerkinElmer, USA). Scintillation counter:
Wallac Microbeta TriLux (PerkinElmer, USA).
1
0.28 mmol (111 mg), 58%. H NMR (400 MHz, [D6]DMSO]): d=9.56
(s, 1H, OH), 9.51 (s, 1H, OH), 9.08 (s, 1H, OH), 7.26 (d, 2H, J=
8.5 Hz, ArH), 7.09 (d, 2H, J=8.5 Hz, ArH), 6.91 (d, 2H, J=8.6 Hz,
ArH), 6.81 (m, 4H, ArH), 6.54 (d, 2H, J=8.7 Hz, ArH), 6.16 (s, 1H,
CH), 3.71 (t, 2H, J=7.6 Hz, NCH2CH2CH3), 1.15 (m, 2H, J=7.5 Hz,
NCH2CH2CH3), 0.43 ppm (t, 3H, J=7.4 Hz, NCH2CH2CH3); MS (EI,
1508C): m/z (%)=385 [M]+· (43), 356 (6), 342 (6), 330 (3), 121 (14),
43 (100); IR (KBr): n˜ =3399(b,s), 2962(w), 1892(w), 1702(w), 1613(m),
1567(m), 1519(s), 1500(s), 1343(m), 1232(b,s), 1171(m), 1100(w),
836(m) cmꢁ1; Anal. calcd for C25H23NO3·0.4EtOAc: C 75.94, H 6.28, N
3.33, found: C 76.02, H 6.48, N 3.28.
Molecular modeling and docking studies: Initial 3D coordinates
of the compounds were generated with the software CORINA by
Molecular Networks (Erlangen, Germany) and subsequently docked
using GOLD, version 4.11 (CCDC, UK). Ensemble docking of com-
pounds 5a–h, PPT, and E2 was done using PDB complexes 3DT3,
3ERD, 3L03 and 2QZO (for ERa), and 2NV7, 2QTU, 3OLL and 3OLS
(for ERb). For pose ranking, the PPT 3D pharmacophore was used
in an analogous manner as reported previously,[22] by following the
already known 3D pharmacophore pattern of PPT. Pharmacophore
creation and visualization were performed using the program Li-
gandScout version 3.02.[23–25]
1-(2-Methylpropyl)-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole (5d):
1-(2-Methylpropyl)-2,3,5-tris(4-methoxyphenyl)-1H-pyrrole
(4d)
(0.45 mmol, 200 mg) and BBr3 (2.3 mmol, 567 mg). Orange solid,
mp: 2108C, yield: 0.31 mmol (125 mg), 70%. 1H NMR (400 MHz,
[D6]DMSO]): d=9.54 (s, 1H, OH), 9.49 (s, 1H, OH), 9.08 (s, 1H, OH),
7.26 (d, 2H, J=8.5 Hz, ArH), 7.07 (d, 2H, J=8.4 Hz, ArH), 6.92 (d,
2H, J=8.6 Hz, ArH), 6.82 (d, 2H, J=8.6 Hz, ArH), 6.79 (d, 2H, J=
8.6 Hz, ArH), 6.54 (d, 2H, J=8.6 Hz, ArH), 6.16 (s, 1H, CH), 3.66 (d,
2H, J=7.4 Hz, NCH2CH(CH3)2), 1.32 (m, 1H, J=6.9 Hz, NCH2CH-
(CH3)2), 0.36 ppm (d, 6H, J=6.7 Hz, NCH2CH(CH3)2); MS (EI, 1508C):
m/z (%)=399 [M]+ (75), 356 (21), 199 (5), 121 (28), 43 (100); IR
(KBr): n˜ =3400(b,s), 2958(m), 1892(w), 1703(w), 1613(m), 1567 (m),
Synthesis: Solvents were purified according to published proce-
dures or purchased pure. Syntheses of precursors are described in
the Supporting Information.
1519(s), 1500(s), 1333(m), 1229(b, s), 1171(m), 1100(w), 836(s) cmꢁ1
;
Anal. calcd for C26H25NO3·0.5EtOAc: C 75.82, H 6.54, N 3.16, found:
C 75.42, H 6.28, N 3.44.
Ether cleavage: BBr3 dissolved in CH2Cl2 (5 mL) was added slowly
under inert gas (Ar) to a solution of the respective 2,3,5-tris(4-me-
thoxyphenyl)-1H-pyrrole (4a–h) in dry CH2Cl2 (15 mL) at 08C. The
reaction was allowed to warm to room temperature and stirred
overnight. The solvent was evaporated, and the residue was taken
up in MeOH several times. Purification was performed with silica
gel column chromatography using CH2Cl2/MeOH (9:1 v/v).
2,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrrole (5e): 2,3,5-Tris
(4-methoxyphenyl)-4-propyl-1H-pyrrole (4e) (0.19 mmol, 80 mg)
and BBr3 (0.94 mmol, 88 mL). Cream-colored solid, mp: 1978C,
1
yield: 0.15 mmol (59 mg), 82%. H NMR (400 MHz, [D6]DMSO]): d=
10.52 (s, 1H, NH), 9.36 (s, 1H, OH), 9.23 (s, 1H, OH), 9.21 (s, 1H,
OH), 7.31 (d, 2H, J=8.5, ArH), 7.04 (d, 2H, J=8.6, ArH), 6.95 (d, 2H,
J=8.4, ArH), 6.79 (d, 2H, J=8.6, ArH), 6.66 (d, 2H, J=8.4, ArH), 6.55
(d, 2H, J=8.6, ArH), 2.37 (t, 2H, J=7.9, CH2CH3CH3), 1.21 (m, 2H,
CH2CH2CH3), 0.66 ppm (t, 3H, J=7.3, CH2CH2CH3); Anal. calcd for
C25H23NO3: C 77.90, H 6.01, N 3.63, found: C 78.29, H 6.08, N 3.99.
1-Methyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole (5a): 1-Methyl-
2,3,5-tris(4-methoxyphenyl)-1H-pyrrole (4a) (0.45 mmol, 180 mg)
and BBr3 (2.3 mmol, 564 mg). Yellow solid, mp: 1368C, yield:
0.3 mmol (109 mg), 68%; 1H NMR (400 MHz, [D6]DMSO]): d=9.55
(s, 1H, OH), 9.51 (s, 1H, OH), 9.10 (s, 1H, OH), 7.30 (d, 2H, J=
8.5 Hz, ArH), 7.10 (d, 2H, J=8.5 Hz, ArH), 6.93 (d, 2H, J=8.6 Hz,
ArH), 6.83 (d, 2H, J=8.6 Hz, ArH), 6.79 (d, 2H, J=8.6 Hz, ArH), 6.56
(d, 2H, J=8.6 Hz, ArH), 6.20 (s, 1H, CH), 3.30 ppm (s, 3H, NCH3); MS
(EI, 308C): m/z (%)=357 [M]+· (100), 327 (4), 280 (4), 178 (7), 121
(5); IR (KBr): n˜ =3389(b,s), 3043(w), 1892(w), 1702(w), 1567(m),
1-Methyl-2,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrrole
1-Methyl-2,3,5-tris(4-methoxyphenyl)-4-propyl-1H-pyrrole
(5 f):
(4 f)
(0.32 mmol, 142 mg) and BBr3 (1.6 mmol, 403 mg). Yellow solid,
mp: 1358C, yield: 0.05 mmol (20 mg), 15%. 1H NMR (400 MHz,
[D6]DMSO]): d=9.53 (s, 1H, OH), 9.40 (s, 1H, OH), 9.13 (s, 1H, OH),
7.21 (d, 2H, J=8.6 Hz, ArH), 7.00 (d, 2H, J=8.6 Hz, ArH), 6.88 (d,
2H, J=8.6 Hz, ArH), 6.85 (d, 2H, J=8.6 Hz, ArH), 6.67 (d, 2H, J=
8.6 Hz, ArH), 6.61 (d, 2H, J=8.6 Hz, ArH), 3.20 (s, 3H, NCH3), 2.29 (t,
2H, J=7.2 Hz, CH2CH2CH3), 1.10 (m, 2H, CH2CH2CH3), 0.58 ppm (t,
3H, J=7.3 Hz, CH2CH2CH3); MS (EI, 1708C): m/z (%)=399 [M]+·
(100), 370 (77), 343 (20), 199 (6), 184 (5), 134 (13); IR (KBr): n˜ =
3387(b,m), 2957(m), 2927(m), 1666(m), 1608(s), 1511(s), 1438(m),
1519(s), 1500(s), 1377(m), 1235(b,s), 1102(m), 1144(w), 836(m) cmꢁ1
;
Anal. calcd for C23H19NO3·1.1EtOAc: C 71.60, H 6.01, N 3.08, found:
C 71.66, H 6.27, N 3.20.
1-Ethyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole (5b): 1-Ethyl-2,3,5-
tris(4-methoxyphenyl)-1H-pyrrole (4b) (0.61 mmol, 250 mg) and
BBr3 (3.0 mmol, 757 mg). Orange solid, mp: 1278C, yield:
1368(m), 1266(s), 1239(s), 1169(m), 1106(m), 1050(w), 836(m) cmꢁ1
;
1
0.45 mmol (166 mg), 74%. H NMR (400 MHz, [D6]DMSO]): d=9.58
Anal. calcd for C26H25NO3·1.4H2O: C 73.53, H 6.60, N 3.30, found: C
73.36, H 6.88, N 3.35.
(s, 1H, OH), 9.53 (s, 1H, OH), 9.08 (s, 1H, OH), 7.27 (d, 2H, J=
8.5 Hz, ArH), 7.11 (d, 2H, J=8.4 Hz, ArH), 6.91 (d, 2H, J=8.6 Hz,
ArH), 6.82 (m, 4H, ArH), 6.54 (d, 2H, J=8.6 Hz, ArH), 6.17 (s, 1H,
CH), 3.77 (q, 2H, J=6.8 Hz, NCH2CH3), 0.77 ppm (t, 3H, J=7.0 Hz,
NCH2CH3); MS (EI, 1508C): m/z (%)=371 [M]+· (100), 343 (12), 316
(7), 185 (7), 121 (2); IR (KBr): n˜ =3392(b,s), 2976(w), 1891(w),
1702(w), 1613(m), 1567(m), 1519(m), 1500(s), 1341(m), 1229(b,m),
1171(m), 1118(w), 836(m) cmꢁ1; Anal. calcd for C24H21NO3·0.5EtOAc:
C 75.16, H 6.06, N 3.37, found: C 75.16, H 6.21, N 3.56.
1-Ethyl-2,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrrole
1-Ethyl-2,3,5-tris(4-methoxyphenyl)-4-propyl-1H-pyrrole
(5g):
(4g)
(0.35 mmol, 170 mg) and BBr3 (1.8 mmol, 447 mg). Yellow solid,
mp: 1488C, yield: 0.11 mmol (43 mg), 30%. 1H NMR (400 MHz,
[D6]DMSO]): d=9.51 (s, 1H, OH), 9.39 (s, 1H, OH), 9.08 (s, 1H, OH),
7.18 (d, 2H, J=8.5 Hz, ArH), 7.00 (d, 2H, J=8.5 Hz, ArH), 6.87 (d,
2H, J=8.5 Hz, ArH), 6.84 (d, 2H, J=8.5 Hz, ArH), 6.67 (d, 2H, J=
2060
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 2055 – 2062