K. Sripha et al. / Tetrahedron Letters 44 (2003) 7183–7186
7185
J=15.7, 2.6 Hz, Ha-7), 2.64 (m, 2H, Ha-14 and Hb-15),
2.05 (m, 1H, Ha-15); 13C NMR (100 MHz, CDCl3) l
151.2 (C-4a), 135.3 (C-13a), 134.2 (C-8a), 132.2 (C-
15b), 129.0 (C-12a), 127.7 (C-3), 124.2 (C-1), 120.5
(C-10), 120.3 (C-12), 119.8 (C-11), 118.2 (C-2), 110.9
(C-9), 105.7 (C-4), 98.5 (C-13), 83.4 (C-5a), 48.1 (C-
15a), 36.6 (C-6), 34.2 (C-14), 21.7 (C-7), 21.5 (C-15);
MS (EI, 70 eV) m/z (rel. int.), 286 (3), 285 (3), 258
(100), 257 (26), 129 (15), 128 (16), HREIMS m/z
285.1393 [M−1]+ (calcd for C20H17N2 285.1392).
7: TLC Rf=0.36 (SiO2, CHCl3:MeOH:25%NH3/
1
100:10:1); H NMR (400 MHz, CDCl3) l 7.65 (d, 1H,
J=7.9 Hz, H-9), 7.62 (d, 1H, J=7.9 Hz, H-12), 7.18
(m, 1H, H-10), 7.12 (m, 1H, H-11), 7.07 (dd, 1H,
J=8.0, 7.1 Hz, H-3), 6.98 (d, 1H, J=7.1 Hz, H-1), 6.63
(dd, 1H, J=8.0, 7.1 Hz, H-2), 6.60 (d, 1H, J=8.0 Hz,
1
H-4), H chemical shifts of the remaining protons coin-
cide with the l values of the corresponding atoms of 8
within 0.03 ppm; 13C NMR (100 MHz, CDCl3) l
151.1 (C-4a), 127.7 (C-3), 124.2 (C-1), 118.2 (C-4),
105.7 (C-2), 13C chemical shifts of the remaining carbon
atoms coincide with the l-values of the corresponding
atoms of 8 within 0.2 ppm.
Scheme 3. Reagents and conditions: (i) 40% aq. dimethyl-
amine (3 equiv.), 40% aq. formaldehyde (3 equiv.), acetic acid,
4 h; (ii) methyl iodide and allyl bromide, respectively, rt, 1 h;
(iii) diethyl ether.
8: mp 75–76°C; TLC Rf=0.14 (SiO2, CHCl3:MeOH:
25%NH3/100:10:1); FT-IR (ATR) w (cm−1) 3047, 2940,
2853, 2809, 2716, 1612, 1566, 1485, 1455, 1404, 1320,
1
1239, 1197, 1173, 1146, 1041, 1013, 842, 802, 737; H
9 and 10 exhibited an approximately 4-fold lower M2
binding affinity (EC50, diss 35 and 48 nM, respectively)
NMR (400 MHz, CDCl3) l 7.64 (m, 2H, H-9 and
H-12), 7.19 (t, 1H, J=7.6 Hz, H-10), 7.12 (t, 1H,
J=7.6 Hz, H-11), 6.98 (dd, 1H, J=8.0, 1.5 Hz, H-3),
6.93 (d, 1H, J=1.5 Hz, H-1), 6.54 (d, 1H, J=8.0 Hz,
H-4), 4.68 (t, 1H, J=8.2 Hz, H-15a), 3.92 (ddd, 1H,
J=14.2, 5.1, 2.1 Hz, Hb-6), 3.48 (m, 1H, Ha-6), 3.49 (d,
than the corresponding caracurine
(dimethylcaracurinium diiodide:
V
analogues
8
nM, diallyl-
caracurinium dibromide: 11 nM), which is probably
due to different spatial arrangements of the aromatic
rings, as well as to different internitrogen distances in
both ring systems.
1H, J=13.1 Hz, N-CHaHb
6
at C-13), 3.41 (m, 1H,
Hb-14), 3.40 (d, 1H, J=13.1 Hz, N-CHaHb at C-13),
3.30 (d, 1H, J=12.5 Hz, N-CHaHb
at C-2), 3.20 (d, 1H,
J=12.5 Hz, N-CHaHb at C-2), 2.99 (m, 1H, Hb-7), 2.95
6
6
In conclusion, dimerization of 2-(indol-2-yl)-ethyl tosy-
6
(m, 1H, Ha-7), 2.60 (m, 2H, Ha-14 and Hb-15), 2.19 (s,
6H, 2×N-CH3), 2.17 (s, 6H, 2×N-CH3), 2.03 (m, 1H,
Ha-15); 13C NMR (100 MHz, CDCl3) l 150.3 (C-4a),
134.0 (C-8a), 133.7 (C-13a), 132.3 (C-15b), 129.5 (C-
12a), 128.8 (C-2), 128.6 (C-3), 125.3 (C-1), 120.6 (C-10),
119.6 (C-11), 119.0 (C-12), 110.7 (C-9), 107.4 (C-13),
late provided
a novel pentacycyclic ring system:
6,7,14,15 - tetrahydro - 15aH - azocino[1,2 - a:6,5-b%]-
diindole. The new heterocycle was formed via asymmet-
rical double alkylation of 2-(indol-2-yl)-ethyl tosylate at
nitrogen and C-3-carbon. The N-methyl and N-allyl
salts of the double aminomethylated new ring skeleton
are potent ligands of the allosteric site of muscarinic M2
receptors with an approximately 4-fold lower binding
affinity than the corresponding caracurine V analogues.
105.1 (C-4), 83.5 (C-5a), 64.1 (N-C
6 H2 at C-2), 52.9
(N-CH2 at C-13), 48.1 (C-15a), 45.5 and 45.1 (N-CH3),
6
36.6 (C-6), 34.3 (C-14), 21.6 (C-15), 20.1 (C-7), MS (EI,
70 eV) m/z (rel. int.) 400 [M+] (2), 372 (60), 328 (100),
284 (34), 142 (34).
Analytical data for compounds 6–8
Supplementary material: COSY, HMQC and HMBC
spectra of compound 6, 1H and HMBC spectra of
compound 8.
6: mp 148–149°C; TLC Rf=0.43 (SiO2, CHCl3:hexane
1:3); FT-IR (ATR) w (cm−1) 3042, 2992, 2967, 2946,
2874, 1607, 1557, 1480, 1454, 1387, 1351, 1320, 1245,
1
1225, 1199, 1145, 1906, 1018, 915, 867, 772, 739; H
NMR (400 MHz, CDCl3) l 7.67 (d, 1H, J=8.1 Hz,
H-9), 7.53 (d, 1H, J=7.8 Hz, H-12), 7.17 (m, 1H,
H-10), 7.11 (m, 1H, H-11), 7.09 (m, 1H, H-3), 6.99 (d,
1H, J=7.1 Hz, H-1), 6.64 (m, 1H, H-2), 6.61 (d, 1H,
J=7.8 Hz, H-4), 6.15 (d, 1H, J=0.8 Hz, H-13), 4.73 (t,
1H, J=8.3 Hz, H-15a), 3.92 (dd, 1H, J=14.3, 5.4 Hz,
Hb-6), 3.51 (ddd, 1H, J=14.3, 12.8, 3.3 Hz, Ha-6), 3.41
(m, 1H, Hb-14), 3.11 (m, 1H, Hb-7), 2.87 (dd, 1H,
Acknowledgements
Financial support from the Deutscher Akademischer
Austauschdienst (to K.S.), the Fonds der Chemischen
Industrie (to D.P.Z.), and the Deutsche Forschungsge-
meinschaft (to K.M.) is gratefully acknowledged. We
thank Mechthild Kepe (Bonn) for her skilful technical
assistance.