A new synthetic approach to pentacyclic ring, 6,7,14,15-tetrahydro[1,5] diazocino[1,2-a:6,5-a']-8-dihydrodiindole

Article abstract of DOI:10.3987/COM-11-12340

The construction of a new pentacyclic ring system, 6,7,14,15-tetrahydro[1, 5]diazocino[1,2-a:6,5-a']-8-dihydrodiindole (7) from simple precursors through our new synthetic route was presented to be a facile and concise method for an intramolecular N-alkylation of tosylate 12 which was obtained from N-acylation of indoline 4 with indole acid 9, followed by reduction and tosylation. This new synthetic approach can overcome the disadvantage of uncontrollable intermolecular double N-alkylation of the precursor 3 to produce the unexpected ring system 2.

Full text of DOI:10.3987/COM-11-12340

HETEROCYCLES, Vol. 83, No. 11, 2011
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HETEROCYCLES, Vol. 83, No. 11, 2011, pp. 2627 - 2633. © 2011 The Japan Institute of Heterocyclic Chemistry
Received, 18th August, 2011, Accepted, 29th September, 2011, Published online, 6th October, 2011
DOI: 10.3987/COM-11-12340
A NEW SYNTHETIC APPROACH TO PENTACYCLIC RING, 6,7,14,15-
TETRAHYDRO[1,5]DIAZOCINO[1,2-a:6,5-a]-8-DIHYDRODIINDOLE
Kittisak Sripha,1* Darius Paul Zlotos,2 Ulrike Holzgrabe,2 and Somsak
Ruchirawat3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol
University, Bangkok, Thailand, 2Pharmaceutical Institute, University of
3
Wuerzburg, Wuerzburg, Germany, Chulabhorn Research institute, Bangkok,
Thailand; E-mail: pyksp@mahidol.ac.th
Abstract - The construction of a new pentacyclic ring system, 6,7,14,15-
tetrahydro[1,5]diazocino[1,2-a:6,5-a]-8-dihydrodiindole (7) from simple
precursors through our new synthetic route was presented to be a facile and
concise method for an intramolecular N-alkylation of tosylate 12 which was
obtained from N-acylation of indoline 4 with indole acid 9, followed by reduction
and tosylation. This new synthetic approach can overcome the disadvantage of
uncontrollable intermolecular double N-alkylation of the precursor 3 to produce
the unexpected ring system 2.
The synthesis of the derivatives of 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a]diindole was
reported.1 Because of the potent allosteric modulators on muscarinic M2 receptors of bisquaternary
analogs of Strychnos alkaloid caracurine V,2,3 the idea to generate an uncomplicated ring skeleton derived
from caracurine V was explored. This ring system was designed by simplify the complex analog of
Caracurine V to the essential pharmacophore of two positively charged nitrogens at a distance of about 10
Å surrounded by two aromatic ring systems.4 The accomplish construction of the ring system involved
the self-condensation of N,N-disubstituted-ethanamine-2-(2-bromoethyl)-1H-indole. In order to decorate
the varieties of the length of side-chains, the synthesis only pentacyclic ring skeleton without the side
changes was investigated by the dimerization of the 2-(2-tosylethyl)-1H-indole 3. Interestingly, under
strong base condition, the unexpected isomeric hexacylcic ring system, 7,7-a,13,14-tetrahydro-6H-
cyclobuta[b]pyrimido[1,2-a:3,4-a]diindole 2 was found instead of the expected desired ring system 15
(Figure 1).

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HETEROCYCLES, Vol. 83, No. 11, 2011
N
O
N
OTs
2
1
N
H
3
N
N
2
Figure 1
Due to the highly reactive of indole ring at C-3 position toward both intra- and inter-molecular
alkylations, the dimerization of 3 to form 1 could not be controlled. The C-3 indole acted as nucleophile,
so, the intramolecular cyclization was constructed the four-membered ring up, followed by intermolecular
cyclization from another indolyl anion. In fact, the ring with the most strain would be formed difficultly.
Nevertheless, the intramolecular cyclization to form the strained 4-membered ring was favorable because
of the less entropy. Furthermore, the proximity effect should be stated in this case owning to the close
position between C-3 indole which acted as nucleophile and electrophilic carbon of a flexible ethylene
side chain. The formation of 6-membered ring by intermolecular cyclization was favorable more than 8-
membered ring because of the less ring strain and less entropy. The mechanism for the formation of 2 was
proposed by Attia.5 To overcome this uncontrollable dimerization of 3, an idea of new synthesis pathway
involved a connection side by side between indole and indoline derivatives was generated as shown in
Scheme 1.
O
CO2Et
H
N
N
N
N
CO2Et
reducing agent
N
base 2
N
base 1
H
4
N
+
H
N
TsO
6
5
7
3
Scheme 1
The two precursors of this route, tosylate 3 and indoline ethyl ester 4, could be prepared from known
ethyl-indol-2-ylacetate.6 The tosylate 3 was synthesized in two step from ethyl-indol-2-ylacetate using the
reaction sequences describe previously by Attia.5 The reduction of ethyl-indol-2-ylacetate to the
corresponding 4 was carried out by using borane-trimethylamine complex in trifluoroacetic acid.7 N-
substitution of 4 by the tosylate 3 was attempted by using triethylamine in dry tetrahydrofuran (THF) or

HETEROCYCLES, Vol. 83, No. 11, 2011
2629
potassium carbonate in dry acetonitrile (Scheme 2). Unfortunately, no desired product was obtained under
the condition using trimethylamine as reagent, and surprisingly, a complex decacyclic heterocycles 8
(13%) was obtained instead of the expected product 5 when the reaction mixture was refluxed in dry
acetonitrile in the presence of potassium carbonate. Using the data establishment from the experimental
techniques of H,H-COSY, and HMQC with the assistance of NMR analysis data of 2, the structural
feature of 8 comprising of tetrahydro-cyclobutyl indole connected with two indoles was illustrated. So,
under the desired conditions in Scheme 1, the further steps to reach compound 6 and 7 were not carried
out.
N
H
N
EtO2C
K2CO3,
dry MeCN,
reflux
5
NEt3, dry THF, rt
N
H
N
4 + 3
EtO2C
5
N
N
N
8
Scheme 2
The initial formation of the amide 10 was another synthetic strategy to connect the side chain of the
indole acid 9 to the N-atom of indoline 4. The acid 9 was coupled with indoline 4 in the presence of N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI·HCl) to obtain amide 10 in 65% yield.
Simultaneous amide and ester reduction using lithium aluminium hydride (LiAlH4) yielded the unstable
alcohol 11, which was used for the tosylation step without purification to give the tosylate 12 in 72%. The
final formation of the targeted pentacyclic ring system 7 comprising one indole and one indoline moiety
was achieved by means of intramolecular cyclization using potassium hydroxide (KOH) in dry
dimethylformamide in 65% yield (Scheme 3).
From this synthetic pathway, the consecutive connection using ethylene side chain of indole and indoline
derivatives could overcome the drawback involved the entropy effect. The attachment of N-indoline 4
with the side chain of indole acid 9 was carried out by means of N-acylation. After the reduction and

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HETEROCYCLES, Vol. 83, No. 11, 2011
tosylation, in the presence of strong base, the proximity of N-indole and ethylene side chain of indoline
comforted the intramolecular N-alkylation to gain the expected pentacyclic ring system. The complete
NMR assignment of 7 were carried out using H,H-COSY, HMQC, and HMBC. The connecting pathway
in the COSY correlation starting from germinal coupling of H-8b at  = 2.50 ppm and H-8a at  = 3.32
ppm to H-7a, and further to H-7b, H-7a and H-6b, H-6a revealed the alicyclic spin system of indoline and
one side of ethylene groups within the central diazocine ring. The remaining alicyclic signals correspond
to the other side of ethylene protons at C-14 and C-15 revealed as multiplet at  = 3.14 and 3.87 ppm,
respectively. The HMQC data was established a high rigidity of this ring system because of the separately
wide germinal hydrogens of diazocine ring. All new synthesized compounds were also characterized by
IR, 1H NMR, 13C NMR, and MS.
4
3
4
3
5
5
6
8
6
LiAlH4,
N
1
O
.
9
H
N
H
8'
EDCI HCl, CH2Cl2, rt
7
dry THF, rt
1
1'
N
7
EtO2C
1'
HO
N
7'
+
4
7'
6'
3'
9'
N
CO2H
6'
10
3'
H
11
TsCl, CH2Cl2, rt
4'
5'
9
4'
1
5'
4
KOH, dry DMF,
0 oC to rt
16
7
2
3
5
6
15
8
3
14
13
N
9
N
5
1
4
12
7
H
N
1'
6
TsO
N
7'
8'
11
10
9'
3'
8
7
12
6'
9
4'
5'
Scheme 3
In summary,
a
new synthetic route towards the pentacyclic ring system, 6,7,14,15-
tetrahydro[1,5]diazocino[1,2-a:6,5-a]-8-dihydrodiindole was established. Starting from N-acylation of
indoline 4 with indole acid 9, the targeted pentacyclic ring could be achievable in four steps in an overall
yield of 31%. This synthetic route can suppress the production of unexpected ring system from the
uncontrollable intermolecular N-alkylation of its precursor, 2-(2-tosylethyl)-1H-indole 3, due to the
consecutive connection of ethylene side chains of indole and indoline derivatives, The concise synthesis
of this new pentacyclic ring skeleton will be useful for the synthetic methodology in the medicinal
chemistry research of muscarinic receptors. The various side chains of this ring skeleton can be provided
as new investigated analogs of allosteric ligands at the muscarinic receptors.

HETEROCYCLES, Vol. 83, No. 11, 2011
2631
EXPERIMENTAL
Starting compounds and reagents were purchased from commercial suppliers. 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 nm) obtained from Merck. A Bruker AV-
1
400 spectrophotometer was used to obtain H NMR (400 MHz) and 13C NMR (100 MHz) spectra,
respectively. The chemical shifts () were reported in ppm relative to CDCl3 (7.24 for 1H, 77.0 for 13C).
IR spectra were recorded as ATR technique on Bio Rad, PharmalyzIR instrument. Mass spectra using EI
technique were determined on a Finnigan MAT 8200 spectrophotometer. High resolution mass spectra
were obtained using Bruker Micro time-of-flight mass spectrometry.
Starting Materials. 2-(2-tosylethyl)-1H-indole (3),5,7 ethyl-2-(indolin-2-yl)acetate (4),8 2-(1H-indol-
2yl)acetic acid (9)9,10 were prepared followed the report procedures. All other chemicals used in this study
were commercially available.
Ethyl 2-(1-(2-(1H-indol-2-yl)acetyl)indolin-2-yl)acetate (10). To the mixture of 1H-indole-2-acetic acid
(0.8 g, 4.57 mmol) and ethyl-2,3-dihydro-1H-indole-2-acetate (1.03 g, 5.02 mmol) in dry CH2Cl2 (80
mL), under argon, EDCI·HCl (1.31 g, 6.85 mmol) was added. The reaction mixture was allowed to stir at
room temperature for 2 h. The solvent was removed in vacuum to yield an brown oil which was subjected
to chromatograph using EtOAc:Hex/1:2 as an eluent to obtain 1.24 g (74%) of 10 as a brown solid: mp
o
108.7-109.6 C; TLC Rf = 0.4 (SiO2, EtOAc:Hex/1:2); FT-IR (ATR)  (cm-1) 3350, 2928, 1713, 1630,
1595, 1402, 1192, 1152, 746, 687, 666; 1HNMR (400 MHz, CDCl3)  9.13 (brs, 1H, NH), 8.15 (d, 1H, J
= 6.4 Hz, H-4), 7.55 (d, 1H, J = 7.7 Hz, H-4), 7.24 (m, 2H, H-5 and H-6), 7.15 (td, 1H, J = 7.6, 1.1 Hz,
H-6), 7.10-7.07 (m, 2H, H-5 and H-7), 6.41 (s, 1H, H-3), 5.21-4.99 (m, 1H, H-2), 4.20-4.06 (m, 4H,
CH2-CO-N and CH3-CH2-O), 3.42 (dd, 1H, J = 8.7, 8.6 Hz H-3a), 2.84 (d, 1H, J = 16.1 Hz, H-3’b), 2.71-
13
2.58 (m, 2H, CH2-CO-O), 1.27 (t, 3H, J = 7.1 Hz, O-CH2-CH3); C NMR (100 MHz, CDCl3)  170.3
(CO-O), 167.7 (CO-N), 136.4 (C-7a), 131.1 (C-3a), 130.0 (C-7a), 128.1 (C-3a), 127.6 (C-5), 125.1 (C-
5), 124.7 (C-6), 121.6 (C-6), 120 (C-4), 119.7 (C-7), 118.1 (C-4), 110.9 (C-7), 101.4 (C-3), 60.4 (CH3-
CH2-O), 57.2 (C-2), 40.2 (CH2-CO-O), 34.8 (CH2-CO-N), 14.1 (O-CH2-CH3); MS (EI, 70 eV) m/z (rel.
int) 362 [M+] (36), 205 (58), 190 (37), 130 (100), 118 (39). HRMS calcd. for C22H22N2O3, m/z: 362.1630
(M+); Found, m/z: 362.1631.
1-(2-(2-Hydroxyethyl)indolin-1-yl)-2-(1H-indol-2-yl)ethanone (11). To a suspension of LiAlH4 (0.2 g,
5.0 mmol) in dry THF (20 mL) under argon at 0 oC, the solution of 10 (0.53 g, 1.46 mmol) was added
dropwise. The reaction mixture was stirred at room temperature for 3 h and then terminated by adding
o
carefully water (0.4 mL) after cooling down at 0 C. The suspension was stirred vigorously at room
temperature for 1 h and precipitate was filtered out. The filtrate was dried over anhydrous MgSO4 and

2632
HETEROCYCLES, Vol. 83, No. 11, 2011
evaporated in vacuo. The crude product 11 was obtained as a neat pale yellowish liquid (0.34 g, 76%). It
was subsequently used for the further synthesis without purification; TLC Rf = 0.52 (Silica gel,
CHCl3:MeOH/10:0.5); 1HNMR (400 MHz, CDCl3)  8.30 (s, 1H, NH), 7.55 (d, 1H, J = 7.59 Hz, H-4),
7.28 (d, 1H, J = 8.0 Hz, H-4), 7.15-7.06 (m, 4H, H-5, H-5, H-6, H-7), 6.74 (t, 1H, J = 7.31, H-6), 3.86-
3.68 (m, 3H, H-2, H-9), 3.51 (td, 2H, J = 7.36, 3.37 Hz, H-9), 3.15 (dd, 1H, J = 15.60, 8.77 Hz, H-3a),
3.06-2.98 (m, 2H, H-8), 2.79 (dd, 1H, J = 15.57, 9.55 Hz, H3b), 2.03-1.79 (m, 2H, H-8); 13C NMR (100
MHz, CDCl3)  137.3 (C-7a), 136.0 (C-7a), 128.6 (C-3a), 127.6 (C-3a), 124.5 (C-6), 121.2 (C-4),
119.8 (C-6), 119.7 (C-5), 118.7 (C-4), 110.5 (C-5 and C-7), 107.9 (C-7), 62.7 (C-9), 59.7 (C-2), 35.5
(C-8), 34.6 (C-3), 25.9 (C-8).
2-(1-(2-(1H-Indol-2-yl)ethyl)indolin-2-yl)ethyl 4-methylbenzenesulfonate (12). The solution of p-
toluenesulfonyl chloride (0.7 g, 3.5 mmol) in dry CH2Cl2 (30 mL) was added dropwise into a solution of
o
crude product 11 and triethylamine (1.0 mL) in dry CH2Cl2 (30 mL) under argon at 0 C. The reaction
mixture was stirred at room temperature overnight. After removing the organic solvent, the residue was
subjected to chromatograph by using CHCl3:Hex/3:1 as eluting solvent. The pure compound of 12 was
o
obtained as brown solid (0.54 g, 80%); mp 110-113 C; TLC Rf = 0.51 (SiO2, CHCl3); FT-IR (ATR) 
(cm-1) 3393, 3250, 3049, 2956, 2924, 1604, 1484, 1457, 1353, 1173, 1120, 1009, 746, 681, 664; 1HNMR
(400 MHz, CDCl3)  8.37 (brs, 1H, NH), 7.75 (d, 1H, J = 8.3 Hz, H-4), 7.69 (d, 1H, J = 8.3 Hz, H-4),
7.54 (d, 1H, J = 7.47 Hz, H-7), 7.31-7.04 (m, 8H, H-5, H-5, H-6, H-6, H-a, H-b), 6.28 (d, J = 1.0 Hz, H-
3), 4.18-4.06 (m, 2H, H-9), 3.72-3.64 (m, 2H, H-2 and H-7), 3.48 (m, 1H, H-9), 3.07-2.94 (m, 2H, H-8
13
and H-3a), 2.61 (dd, 1H, J = 15.6, 9.2 Hz, H3b), 2.41 (s, 1H, -CH3), 2.03-1.79 (m, 2H, H-8); C NMR
(100 MHz, CDCl3)  136.4 (C-7a), 131.1 (C-3a), 130.0 (C-7a), 128.1 (C-3a), 127.6 (C-5), 125.1 (C-5),
124.7 (C-6), 121.6 (C-6), 120 (C-4), 119.7 (C-7), 118.1 (C-4), 110.9 (C-7), 101.4 (C-3), 67.6 (C-9),
61.5 (C-2), 48.1 (C-9), 34.9 (C-3), 33.2 (C-8), 30.1 (C-2), 25.9 (C-8), 21.6 (-CH3); MS (EI, 70 eV) m/z
(rel. int) 289 (100), 145 (58), 131 (35). HRMS calcd. for C20H20N2, m/z: 460.1821 (M+); Found, m/z:
460.1815.
o
6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a]-8-dihydrodiindole (7). At 0 C, a powder of
potassium hydroxide (0.07 g, 1.3 mmol) was added to a solution of 12 (0.14 g, 0.3 mmol) in dry DMF (6
mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete,
water (30 ml) was added and the dark suspension was extracted with Et2O (4 x 20 ml). The combined
organic phases were washed with water (3 x 20 mL) and brine (20 ml) and dried over anhydrous MgSO4.
The solvent was removed in vacuo to obtain an brown neat residue, which was chromatographed eluting
o
with CHCl3:Hex/1:1 to give the 7 (0.06 g, 68%) as a white solid; mp 144 – 145.8 C (crystallization
from CHCl3 and Hex); TLC Rf = 0.42 (SiO2, CHCl3:Hex/1:1); FT-IR (ATR)  (cm-1) 3019, 2951, 2927,

HETEROCYCLES, Vol. 83, No. 11, 2011
2633
1
1603, 1542, 1482, 1455, 1415, 1354, 1213, 1132, 1018, 897, 784, 734, 724, 676; HNMR (400 MHz,
CDCl3)  7.58 (d, 1H, J = 7.8 Hz, H-4), 7.33 (d, 1H, J = 8.1 Hz, H-1), 7.21-7.08 (m, 3H, H-2, H-3 and H-
12), 7.04 (d, 1H, J = 7.1 Hz, H-9), 6.75 (m, 2H, H-10 and H-11), 6.31 (s, 1H, H-16), 4.62-4.55 (m, 1H, H-
6a), 4.29 (dd, 1H, J = 14.7, 4.0 Hz H-6b), 3.88-3.85 (m, 1H, H-14a), 3.32 (dd, 1H, J = 16.2, 10.3 Hz, H-
8a), 3.17-3.10 (m, 3H, H-14b, H-15a and H-15b), 2.85-2.79 (m, 1H, H-7a), 2.50 (d, J = 16.0 Hz, H-8b),
13
2.17-2.08 (m, 1H, H-7a), 1.84-1.79 (m, 1H, H-7b); C NMR (100 MHz, CDCl3)  153.3 (C-12a), 138.9
(C-15a), 136.1 (C-4a), 135.0 (C-16a), 129.5 (C-8a), 128.2 (C-3), 127.6 (C-9), 124.9 (C-2), 120.8 (C-10),
120.1 (C-12), 119.4 (C-4), 113.1 (C-1), 109.1 (C-1), 99.3 (C-16), 61.2 (C-7a), 58.1 (C-14), 39.1 (C-6),
37.7 (C-7), 36.3 (C-8), 29.7 (C-15); MS (EI, 70 eV) m/z (rel. int) 288 [M+] (100), 172 (45), 158 (16), 144
(83), 130 (68), 115 (13). HRMS calcd. for C20H20N2, m/z: 288.1626 (M+); Found, m/z: 288.1625.
ACKNOWLEDGEMENT
Financial support from the TRF-CHE Research Grant for New Scholar (MRG4880025) and the DAAD is
gratefully acknowledged.
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