6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole. Synthesis of a novel pentacyclic ring system

Article abstract of DOI:10.1016/S0040-4020(02)01530-2

In search of new lead structures for potent allosteric enhancers of antagonist binding to muscarinic M₂ receptors, the first representative of a novel heterocyclic ring system, 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole, has been synthesized. The new pentacyclic ring skeleton is obtained from [3-(2-dibenzylaminoethyl)indol-2-yl]-acetic acid methyl ester in three steps.

Full text of DOI:10.1016/S0040-4020(02)01530-2

Tetrahedron 59 (2003) 391–394
6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a0]diindole.
Synthesis of a novel pentacyclic ring system
*
Kittisak Sripha and Darius Paul Zlotos
¨ ¨ ¨ ¨
Institut fur Pharmazie und Lebensmittelchemie, Universitat Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
Received 7 June 2002; revised 28 October 2002; accepted 19 November 2002
Abstract—In search of new lead structures for potent allosteric enhancers of antagonist binding to muscarinic M2 receptors, the first
representative of a novel heterocyclic ring system, 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a0]diindole, has been synthesized. The new
pentacyclic ring skeleton is obtained from [3-(2-dibenzylaminoethyl)indol-2-yl]-acetic acid methyl ester in three steps. q 2003 Published by
Elsevier Science Ltd.
1. Introduction
Many structurally different compounds belonging to various
pharmacological groups have been reported to retard the
dissociation of antagonists from the muscarinic acetyl-
choline receptor.1,2 This effect is based on an allosteric
modulation of the antagonist-receptor complex caused by a
modulator occupying a site apart from the common
antagonist binding area.3,4 The inhibition of ligand dis-
sociation may result in a receptor subtype-specific increase
of ligand binding which opens various therapeutic perspec-
tives such as for the therapy of dementia or pain.1
Figure 1. Structural relationship between caracurine V and the desired ring
system.
Bisquaternary analogs of the Strychnos alkaloid caracurine
V are among the most potent allosteric modulators of
muscarinic M2 receptors.5 The very rigid caracurine V ring
skeleton satisfies the pharmacophore model of two
positively charged nitrogens at a distance of ca. 10 A
surrounded by two aromatic ring systems.6,7
reduction to an alcohol. An alternative route for the critical
dimerization step involves the intermolecular lactame
formation from the corresponding acid (Fig. 2).
˚
Reduction of the caracurine V skeleton to structural features
responsible for good allosteric potency provides the
following pentacyclic ring system (Fig. 1).
2. Results and discussion
In this article we describe the synthesis of the first
representative of the novel ring system employing the
double alkylation strategy.
This novel ring skeleton could become a new lead structure
in search of muscarinic active compounds.
The synthesis pathway of the desired ring system is
illustrated in Scheme 1.
Retrosynthetic analysis suggested that the desired hetero-
cyclic ring system could be formed by intermolecular
N-alkylation of bromoethylindole, which should be easily
obtained from the corresponding methylacetate after
The starting material was the known ester 1, which was
prepared according to the procedure described previously
by Kuehne.8 Thus, chlorination of N,N-dibenzyltryptamine
and reaction of the resulting chloroimine with thallium
dimethyl malonate, followed by monodecarbomethoxyl-
ation with lithium iodide hydrate in dimethylacetamide led
to ester 1 in an overall yield of 42%. Reduction of 1 was
Keywords: 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a0]diindole; novel
pentacyclic ring system; muscarinic active compounds; dimerization of
bromoethylindole.
*
Corresponding author. Tel.: þ49-931-8885489, fax: þ49-931-8885494;
e-mail: zlotos@pharmazie.uni-wuerzburg.de
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01530-2

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K. Sripha, D. P. Zlotos / Tetrahedron 59 (2003) 391–394
column chromatography on silica gel. Another possible
four-ring by-product resulting from the intramolecular
N-alkylation of 3 could not be observed.
We also investigated the other route for building the title
ring system via the corresponding eight-membered ring
dilactame. After saponification of ester 1 to the correspond-
ing acid, several coupling attempts were made to obtain the
desired dilactame. Unfortunately, no dimerization product
could be isolated after treatment of the acid with DCC,
Mukaiyama’s reagent,9 2-ethoxy-1-ethoxycarbonyl-1,2-
dihydroquinoline (EEDQ)10 and 1[3-(dimethylamino)pro-
pyl]-3-ethylcarbodiimide hydrochloride (EDCI)/(dimethyl-
amino)pyridine (DMAP).11 Finally, we reduced the indole
double bond of 1 with NaBH4, CF3COOH, expecting that
the increased nucleophilic character of the indole nitrogen
would facilitate the lactame formation.
Disappointingly, no cyclization product could be observed
after coupling attempts of the corresponding indoline acid
with coupling reagents mentioned above.
All new compounds were characterized by IR, 1H NMR, 13
C
NMR and MS. The NMR assignments were made using
H,H-COSY and HMQC experiments. For the compound 4,
HMBC and ROESY experiments were necessary for a
complete assignment.
Figure 2. Retrosynthetic analysis of the desired ring system.
carried out with lithium aluminium hydride in THF giving
alcohol 2 in 81% yield. Conversion of 2 to the correspond-
ing alkyl bromide 3 could be achieved using carbontetra-
bromide (CBr4) and tris-(dimethylamino)phosphine in 87%
yield. The targeted ring system was prepared via dimeriza-
tion of 3 in DMF with sodium hydride as base giving the
bis(dibenzylethylamine) analog 4 in 47%. A side-reaction
involving a HBr elimination from 3 gave 2-vinylindole 5 in
22% yield. Compounds 4 and 5 could be separated by
Unlike caracurine V which is a highly symmetrical ring
system with a 2-fold symmetry axis,7 the novel ring skeleton
showed no symmetry, as indicated by NMR spectroscopy.
1
Both H and 13C NMR spectra of compound 4 revealed
double sets of signals, each for half the molecule.
Furthermore, methylene hydrogen atoms at C-6, C-7, C-14,
C-17,C-19, C-20,C-21, C-22, C-23andC-24appearedastwo,
widely separated resonances. The non-equivalence of the
Scheme 1. (i) LiAlH4, dry THF, room temperature, 3 h, (ii) CBr4, P(NMe2)3, dry CH2Cl2, room temperature, 16 h, (iii) NaH, dry DMF, 08C, 15 min, room
temperature, 20 min.

K. Sripha, D. P. Zlotos / Tetrahedron 59 (2003) 391–394
393
methylene hydrogen atoms suggested a high rigidity of the
novel ring system.
CDCl3) d 139.5 (C-7a), 135.3 (C-3a), 133.0 (C-2), 128.92,
128.94, 128.7, 128.1 (benzene rings), 126.8 (C-3), 121.1
(C-5), 118.9 (C-4), 118.1 (C-6), 110.3 (C-7), 62.3 (–CH2–
CH2–OH), 58.5 (2£–CH2–Ph), 54.0 (–CH2–CH2–N),
28.8 (–CH2–CH2–OH), 22.1 (–CH2–CH2–N); MS (EI,
70 eV) m/z (rel. int) 384 [Mþ] (1), 210 (60), 91 (100). Anal.
calcd for C26H28N2O: C, 81.21; H, 7.34; N, 7.29. Found: C,
81.06; H, 7.02; N, 7.22.
3. Conclusion
In conclusion, we have presented a short route towards the
new 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a0]-
diindole ring skeleton. Starting from the known [3-(2-
dibenzylaminoethyl)indol-2-yl]-acetic acid methyl ester,
the first member of this new heterocyclic class could be
achieved in three steps in an overall yield of 33%. This
method opens an easy route to many new analogs with
various N-substituents.
4.2.2. 2-(2-Bromoethyl)-3-(2-dibenzylaminoethyl)indole
(3). The solution of P(NMe2)3 (2.61 g, 16 mmol) in dry
CH2Cl2 (30 ml) was added dropwise to the mixture of
alcohol 2 (1.52 g, 4.0 mmol) and CBr4 (2.62 g, 8.0 mmol) in
dry CH2Cl2 (60 ml) at 08C. After stirring for 16 h at room
temperature, the reaction mixture was washed with water
(3£50 ml) and brine 30 ml, dried over anhydrous Na2SO4
and evaporated. Purification by column chromatography
(SiO2, EtOAc/hexane, 1/5), gave the compound 3 (1.55 g,
87%) as a pale yellow solid. Crystallization from ether/
hexane afforded an analytical sample: mp 1308C; TLC
4. Experimental
4.1. General
Rf¼0.32 (SiO2, EtOAc/hexane, 1/5); FT-IR (ATR) n (cm21
)
All melting points were determined using a capillary
melting point apparatus (Gallenkamp, Sanyo) and are
uncorrected. Column chromatography was carried out on
silica gel 60 (0.063–0.200 mm) obtained from Merck. A
3221, 2900, 1456, 750, 698, 654; 1H NMR (400 MHz,
CDCl3) d 8.02 (br, 1H, NH), 7.61–6.95 (m, 14H), 3.75 (s,
4H, 2£–CH2–Ph), 3.34 (t, 2H, J¼7.1 Hz, –CH2–CH2–
Br), 3.10 (t, 2H, J¼7.1 Hz –CH2–CH2–Br), 2.85 (m, 2H,
–CH2–CH2–N), 2.67 (m, 2H, –CH2–CH2–N); 13C NMR
(100 MHz, CDCl3) d 135.4 (C-7a), 133.2 (C-3a), 129.3,
129.0, 128.9, 128.3 (benzene rings), 127.2 (C-2), 121.6
(C-5), 119.2 (C-4), 118.4 (C-6), 110.6 (C-7), 108.0 (C-3),
59.1 (2£–CH2–Ph), 54.4 (–CH2–CH2–N), 32.0 (–CH2–
CH2–Br), 30.1 (–CH2–CH2–Br), 22.5 (–CH2–CH2–N);
MS (CI, NH3 gas, 150 eV) m/z (rel. int) 449 (10), 447 (9)
[Mþ1]þ (8), MS (EI, 70 eV) m/z (rel. int) 367 (6), 210
(100), 91 (92). Anal. calcd for C26H27BrN2: C, 69.48; H,
6.50; N, 6.23. Found: C, 69.22; H, 6.42; N, 5.82.
1
Bruker AV-400 spectrometer was used to obtain H NMR
(400 MHz) and 13C NMR (100 MHz) spectra, respectively.
1
The H NMR spectrum of 4 was recorded at 600 MHz on
Bruker AV-600 spectrometer. The chemical shifts (d) are
1
reported in ppm relative to CDCl3 (7.24 for H, 77.0 for
13C). Mass spectra were determined on a Finnigan MAT
8200 spectrometer. IR spectra, recorded as ATR, were
obtained by using a Bio Rad, PharmalyzIR instrument.
Elemental analyses were performed by the microanalytical
section of the Institute of Anorganic Chemistry, University
of Wu¨rzburg.
4.2.3. 8,16-Bis-(2-dibenzylaminoethyl)-6,7,14,15-tetra-
hydro[1,5]diazocino[1,2-a:6,5-a0]diindole (4) and
2-vinyl-3-(2-dibenzylaminoethyl)-indole (5). The suspen-
sion of NaH (0.07 g, 2.9 mmol) in dry DMF (10 ml) was
added dropwise to the solution of 3 (0.5 g, 1.1 mmol) in dry
DMF (20 ml) at 08C. The reaction mixture was stirred for
20 min at 08C and then for 15 min at room temperature.
Diethylether (30 ml) and cold water (30 ml) were added and
the aqueous phase was extracted with diethylether
(2£30 ml). The combined ether extracts were washed with
water (2£15 ml) and brine (15 ml), dried over anhydrous
Na2SO4 and evaporated. Purification by column chroma-
tography (SiO2, EtOAc/hexane, 1/3), gave the desired dimer
compound 4 (0.2 g, 47%) as a colorless solid and compound
5 (0.09 g, 22%) as a yellow solid. Crystallization of 4 from
ether/hexane afforded an analytical sample: mp 1308C; TLC
4.2. Materials
Starting materials and reagents were obtained from
commercial suppliers. Ester 1 was prepared according to
the procedure of Kuehne.8
4.2.1. 2-[3-(2-Dibenzylaminoethyl)indol-2-yl]ethanol (2).
The solution of ester 1 (1.72 g, 4.2 mmol) in dry THF
(20 ml) was added dropwise to the suspension of LiAlH4
(0.23 g, 6.3 mmol) in dry THF (30 ml) at 08C under argon.
The mixture was stirred at room temperature for 3 h. After
cooling to 08C, 2 ml of water was slowly added, followed by
the careful addition of 2 ml of 15% NaOH and 4 ml of
water. The reaction mixture was stirred at room temperature
for 1 h and filtered. The precipitant was washed with THF
and the combined THF solutions were dried over anhydrous
Na2SO4 and evaporated. Purification by column chroma-
tography (SiO2, CHCl3/MeOH, 10/1), gave 1.30 g (81%) of
alcohol 2 as a pale yellow solid. Crystallization from
ether/hexane afforded an analytical sample: mp 77–788C;
TLC Rf¼0.56 (SiO2, CHCl3/MeOH, 10/1); FT-IR (ATR) n
(cm21) 3348, 3052, 2889, 1456, 1356, 1063, 1015, 735,
Rf¼0.56 (SiO2, EtOAc/hexane, 1/3); FT-IR (ATR) n (cm21
)
3221, 2900, 1456, 750, 698, 654; 1H NMR (600 MHz,
CDCl3) d 7.89 (d, 1H, J¼8.5 Hz, H-4), 7.36 (d, 4H,
J¼7.0 Hz), 7.23–7.09 (m, 14H), 7.03 (ddd, 1H, J¼8.3, 7.1,
1.0 Hz, H-11), 7.00–6.97 (m, 5H), 6.49 (d, 1H, J¼8.3 Hz,
H-12), 6.48 (dd, 1H, J¼7.2, 1.0 Hz, H-9), 6.43 (t, 1H,
J¼7.2 Hz, H-10), 3.79–3.72 (m, 2H, Hb-14 and Hb-6), 3.70
(d, 2H, J¼13.7 Hz, Hb-19 and Hb-20), 3.63 (d, 2H,
J¼13.7 Hz, Ha-19 and Ha-20), 3.17 (ddd, 1H, J¼13.8,
12.1, 3.3 Hz, Ha-14), 2.90 (d, 2H, J¼13.9 Hz, Hb-23 and
Hb-24), 2.81 (ddd, 1H, J¼13.9, 10.1, 6.1 Hz, Hb-17), 2.74
1
699; H NMR (400 MHz, CDCl3) d 8.25 (br, 1H, NH),
7.40–6.97 (m, 14H), 3.72 (s, 4H, 2£–CH2–Ph), 3.71 (t, 2H,
J¼5.8 Hz, –CH2–CH2–OH), 2.87 (m, 2H, –CH2–CH2–
N), 2.75 (t, 2H, J¼5.8 Hz, –CH2–CH2–OH), 2.67 (m, 2H,
–CH2–CH2–N), 1.79 (br, 1H, OH); 13C NMR (100 MHz,

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K. Sripha, D. P. Zlotos / Tetrahedron 59 (2003) 391–394
(ddd, 1H, J¼13.9, 9.7, 6.1 Hz, Ha-17), 2.64 (ddd, 1H,
J¼13.7, 10.2, 6.5 Hz, Ha-6), 2.61–2.51 (m, 4H, CH2-15
and CH2-18), 2.54 (d, 2H, J¼13.9 Hz, Ha-23 and Ha-24),
2.40–2.48 (m, 2H, Hb-7 and Hb-21), 2.13 (ddd, 1H, J¼12.5,
10.2, 6.6 Hz, Ha-7), 1.99 (ddd; 1H, J¼14.1, 11.9, 4.5 Hz,
Ha-21), 1.86 (ddd, 1H, J¼12.5, 12.5, 4.5 Hz, Hb-22), 0.85
(m, 1H, Ha-22); 13C NMR (100 MHz, CDCl3) d 149.4
(C-12a), 140.0, 139.9, 128.7, 128.4, 128.2, 127.9, 126.8,
126.3 (benzene rings), 135.0 (C-4a), 134.6 (C-8a), 132.8
(C-15a), 129.3 (C-16a), 127.6 (C-11), 122.7 (C-9), 120.5
(C-3), 119.5 (C-2), 118.4 (C-1), 117.9 (C-10), 112.3 (C-4),
109.6 (C-16), 106.2 (C-12), 85.5 (C-7a), 59.7 (C-8), 58.6
(C-19 and C-20), 57.4 (C-23 and C-24), 54.0 (C-18), 48.5
(C-22), 38.4 (C-14), 35.0 (C-6), 30.7 (C-21), 29.7 (C-7),
21.9 (C-17), 21.7 (C-15); MS (CI, NH3 gas, 150 eV) m/z
(rel. int) 733 [Mþ] (39), MS (EI, 70 eV) m/z (rel. int), 641
(51), 522 (33), 210 (70); 91 (100). Anal. calcd for C52H52N4:
C, 85.21; H, 7.15; N, 7.64. Found: C, 85.00; H, 7.32; N,
7.61. Crystallization of 5 from CHCl3/hexane afforded an
analytical sample: mp 111–1138C; TLC Rf¼0.45 (SiO2,
EtOAc/hexane, 1/3); FT-IR (ATR) n (cm21) 3411, 3010,
2818, 1450, 1026, 881, 737, 696; 1H NMR (400 MHz,
CDCl3) d 7.92 (br, 1H, NH), 7.44–6.98 (m, 14H), 6.70 (dd,
1H, J¼17.5, 11.5 Hz, –CHvCH2), 5.41 (d, 1H,
J¼17.5 Hz, –CHvCH aHb), 5.22 (d, 1H, J¼11.5 Hz,
–CHvCHaH b), 3.74 (s, 4H, 2£–CH2–Ph), 2.98, (m, 2H,
–CH2–CH2–N), 2.74 (m, 2H, –CH2–CH2–N); 13C NMR
(100 MHz, CDCl3) d 139.8 (C-7a), 136.1 (C-3a), 132.2
(C-2), 128.8, 128.7, 128.1 (benzene rings), 126.8 (C-3),
125.4 (–CHvCH2), 122.9 (C-5), 119.3 (C-4), 119.0 (C-6),
110.7 (–CHvCH2), 110.4 (C-7), 58.6 (2£–CH2–Ph), 54.2
(–CH2–CH2–N), 22.1 (–CH2–CH2–N); MS (EI, 70 eV)
m/z (rel. int) 366 [Mþ] (2), 210 (100), 149 (33), 91 (97).
Anal. calcd for C26H26N2: C, 84.74; H, 7.66; N, 7.60.
Found: C, 84.37; H, 7.37; N, 7.22.
Acknowledgements
Financial support from the Deutscher Akademischer
Austauschdienst and the Fonds der Chemischen Industrie
is gratefully acknowledged. We would like to thank Dr
Matthias Gru¨ne and Elfriede Ruckdeschel, Institute of
Organic Chemistry, University of Wu¨rzburg for recording
600 MHz NMR spectra.
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