Synthesis of cycloalkanoindoles, the carba analogs of physostigmine

Article abstract of DOI:10.3987/COM-07-11154

The title compounds 9 were prepared by combined aza-Claisen rearrangement/intramolecular ring-closure reaction of N-allylaniline derivatives 3, followed by BBr₃ mediated cleavage of methoxy group and subsequent formation of the phenylcarbamyl d

Full text of DOI:10.3987/COM-07-11154

HETEROCYCLES, Vol. 75, No. 1, 2008
43
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 43 - 56. © The Japan Institute of Heterocyclic Chemistry
Received, 27th June, 2007, Accepted, 5th September, 2007, Published online, 10th September, 2007. COM-07-11154
SYNTHESIS OF CYCLOALKANOINDOLES, THE CARBA ANALOGS
OF PHYSOSTIGMINE
Imre Kiraly, Gabor Hornyanszky, Katalin Kupai, and Lajos Novak*
Department of Organic Chemistry and Technology, Budapest University of
Technology and Economics, Research Group for Alkaloid Chemistry of the
Hungarian Academy of Sciences, Gellért tér 4, 1111 Budapest, Hungary. Fax
+36(1)4633297; E-mail: lnovak@mail.bme.hu
Abstract – The title compounds 9 were prepared by combined aza-Claisen
rearrangement/intramolecular ring-closure reaction of N-allylaniline derivatives 3,
followed by BBr3 mediated cleavage of methoxy group and subsequent formation
of the phenylcarbamyl derivatives.
INTRODUCTION
Alzheimer’s disease is one of the leading cause of death in the Western societies. The disease is a
progressive dementia associated with the cholinergic system. Acetylcholinesterase enzyme rapidly
metabolizes the naturally released acetylcholine causing a lack in this neurotransmitter.1-3 An alkaloid of
the African Calabar bean (Physostigma venesonum), (-)-physostigmine, inhibits the acetylcholinesterase
by transcarbamylation. This inhibition reduces the rate of hydrolysis of acetylcholine in the brain and
increases its colinerg activity. Physostigmine has been used medically to improve memory and relief in
Alzheimer’s disease.4-6 Phenserine, in which the methylcarbamyl group of physostigmine was substituted
by phenylcarbamyl group, is highly potent in inhibiting acetylcholinesterase due to its increased ability to
cross the blood-brain barrier.
The growing need for new acetylcholinesterase inhibitors in clinical trials and applications had focused
interest on the preparation of physostigmine congeners.7-9 For instance, the pyrrolo[2,3-b]indole skeleton
had been replaced by furo[2,3-b]indole and furo[2,3-b]benzofuran ring.10 However, the carba analogs, in
which one of the nitrogen-containing ring had been substituted by cycloalkano skeleton, have not got
attention.

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HETEROCYCLES, Vol. 75, No. 1, 2008
Our general interest in the preparation of new heterocyclic compounds, which might be promising in the
treatment of mental diseases, prompted us to elaborate methods for the synthesis of the carba analogs of
pyrrolo[2,3-b]indole. In this report we present methods for the preparation of the cycloalkano-indole
derivatives (Scheme 1, 5 and 6).11
H
N
H
N
O
O
O
O
N
N
N
N
(-)-physostigmine
phenserine
RESULTS AND DISCUSSION
Our synthesis was based on combined aza-Claisen rearrangement/intramolecular ring-closing reaction of
N-allylaniline derivatives 3.12 Treatment of aniline with 1-(chloromethyl)cyclohex-1-ene (2a) afforded
N-(cyclohexenylmethyl)benzeneamine (3a), which was subjected to thermal rearrangement using
.
BF3 OEt2 as a catalyst. A mixture of three products (5a, 6a and 7a) were formed, which was easily
separated by column chromatography, in (20 %, 7 %, and 6 %) yields, respectively (Table 1, Entries 1
and 8).
The structure of these compounds were determined based on their spectroscopic properties. The
stereochemistry of 5a and 6a were established on the basis of NOE difference experiments. Irradiation of
CH3-8a of 5a (1.24 ppm) showed NOE on H-4b (2.67 ppm, 1.9 %), indicating a cis relationship between
H-4b/CH3-8a. Furthermore, irradiation of H-4b (2.67 ppm) also showed an increase (5 %) in the intensity
of methyl signal. However, in the case of 6a irradiation of CH3-8a (0.87 ppm) did not give significant
change of the H-4b signal (2.49 ppm). Likewise, irradiation of H-4b (2.49 ppm) resulted only a moderate
increase of the intensity of CH3-8a signal (2 %), indicating a trans relationship between these groups.
Compound 7a was formed from the product of rearrangement reaction (4a) by double bond migration.
Likewise, reaction between aniline and (E)-1-(chloromethyl)cyclohept-1-ene (2b) afforded compound 3b.
Thermal rearrangement of the latter, followed by ring-closure, furnished 5b and 6b in (27 % and 9 %)
yields, respectively. Here the side product 7b was formed in 9 % yield (Entries 2 and 9).

HETEROCYCLES, Vol. 75, No. 1, 2008
45
n
Cl
R1
R1
.
BF3 Et2O
+
NH
R2
N
n
1
3
2
R2
n
n
R1
R1
NH
R2
N
4
R2
n
R1
H
R1
H
R1
n
n
+
+
R2
N
NH
N
6
7
R2
5
R2
Scheme 1
Attempted reaction of 1a with 1-(chloromethyl)cyclopent-1-ene (2c) afforded compound 3c. Thermal
rearrangement of this compound, followed by ring-closure reaction, furnished only the cis-isomer (5c)
and the side-product (7c) in 50% and 8% yields, respectively (Entries 3 and 10).
Having achieved the synthesis of 5a,b and 6a,b, we turned our attention to obtain substituted analogs, too.
Reaction of 1b with 2a afforded 3d in 65 % yield. However, the attempted rearrangement of the latter
failed. From the reaction mixture we could isolate only the unchanged starting compound and some
degradation products (Entries 4 and 11).
In the case of alkylation of compound 1b with 2c gave the wanted product 3e in moderate yield (44 %).
Then 3e underwent thermal rearrangement followed by ring closure to afford the single stereoisomer 5e
and the side-product 7e (Entries 5 and 12).

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HETEROCYCLES, Vol. 75, No. 1, 2008
H
HO
n
BBr3
N
C O
5
N
8
R2
H
N
H
O
n
O
N
9
R2
Scheme 2
Table 1. Compounds Prepared
Entry Substrate Reagent
R1
H
H
H
R2
H
H
H
n
1
2
0
1
0
0
1
1
2
0
1
0
0
1
Product(s)
Yields (%)
1
1a
1a
1a
1b
1b
1c
1c
3a
3b
3c
3d
3e
3f
2a
2b
2c
2a
2c
2c
2a
3a
68
2
3b
71
3
3c
59
4
OMe H
OMe H
OMe Me
OMe Me
3d
65
5
3e
44
6
3f
36
7
3g
78
.
8
BF3 Et2O
H
H
H
H
H
H
5a, 6a, 7a
5b, 6b, 7b
5c, 7c
-
20, 7, 6
27, 9, 9
50, 8
-
.
9
BF3 Et2O
.
10
11
12
13
14
BF3 Et2O
.
BF3 Et2O OMe H
.
BF3 Et2O OMe H
5e, 7e
7f
40, 11
53
.
BF3 Et2O OMe Me
.
3g
BF3 Et2O OMe Me
5g, 7g
51, 18
During the synthesis of compounds 3 we got a dialkylated side-product in all cases. In order to overcome
this difficulty, 4-methylaminoanisole (1c) was prepared and treated by the 5 and 6-membered cyclic
alkylatig agents (2a, 2c) to obtain the products 3g and 3f, respectively.

HETEROCYCLES, Vol. 75, No. 1, 2008
47
However the ring-closure reaction of 3f was unsuccessful, we got only the rearranged form (7f) of the
expected product (Entry 13). Finally we could prepare 5f from 5e with the reaction of NaH and methyl
iodide (Table 2, Entry 1).
.
Fortunately 3g underwent ring-closure reaction in the high boiling sulfolane, in the presence of BF3 OEt2
catalyst, providing two main compounds, such as the cis-isomer of the product (5g) and the rearranged
derivative (7g) (Entry 14). Presumably the sterical hindrance of the methyl group could be attributed to
the absence of trans-isomer (6g).
Table 2. Compounds Prepared
Entry Substrate Reagent
R1
R2
n
Product(s)
Yields (%)
1
2
3
4
5
5e
5g
5f
NaH, MeI OMe Me
0
5f
71
73
93
48
58
BBr3
OH
OH
-
Me
Me
Me
Me
1
0
1
0
8a
8b
9a
9b
BBr3
8a
8b
PhNCO
PhNCO
-
To finish the synthesis, 5g and 5f had been treated with BBr3 and the hydroxyl derivatives 8a,b formed
were then reacted with phenyl isocyanate to afford the carba analog of physostigmine 9b and its
congeners 9a (Scheme 2. Table 2, Entries 2-5).
In summary, we have developed a straightforward approach to the analogs of physostigmine based on the
combined aza-Claisen rearrangement/intramolecular ring-closure reaction of the N-allylaniline derivatives,
followed by BBr3 mediated cleavage of methoxy group and subsequent formation of the phenylcarbamyl
derivatives.
EXPERIMENTAL
IR spectra were recorded on Spekord 75 IR spectrometer. 1H and 13C NMR spectra were obtained with a
Bruker DRX-500 spectrometer; internal standard TMS. All solvents were dried by means of standard
methods. Reactions were followed by TLC on Merck pre-coated silica gel 60F254 plates. Merck
Kieselgel® 60 was employed for column chromatography.
1-(Chloromethyl)cyclohex-1-ene
(2a)13
was
prepared
by
known
procedure.
1-(Chloromethyl)cyclohept-1-ene (2b) was prepared from cycloheptanone according to the procedure

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HETEROCYCLES, Vol. 75, No. 1, 2008
used for the preparation of 2a, in 30 % overall yield. 1-(Chloromethyl)cyclopent-1-ene (2c) was prepared
from methyl-2-oxocyclopentanecarboxylate by LiAlH4-reduction14 followed by the chlorination step
according to that of 2a and 2b, in 54 % overall yield.
1
1-(Chloromethyl)cyclohept-1-ene (2b). Yellowish oil. TLC (CH2Cl2): Rf = 0.77. H NMR (CDCl3): δ
1.53 (m, 4H, 2 CH2), 1.75 (m, 2H, CH2), 2.15 (m, 2H, CH2), 2.26 (m, 2H, CH2), 4.02 (s, 2H, CH2-Cl),
13
5.95 (t, J = 6.4 Hz, 1H, HC=). C NMR (CDCl3): δ 24.20, 25.12, 28.71, 31.35, 32.61, 53.22 (CH2Cl),
132.54, 140.61.
1
1-(Chloromethyl)cyclopent-1-ene (2c). TLC (hexane/EtOAc 9:1): Rf = 0.66. H NMR (CDCl3): δ 1.87
(m, 2H, CH2), 2.42 (m, 4H, 2 CH2), 4.29 (s, 2H, CH2-Cl), 5.75 (s, 1H, HC=). 13C NMR (CDCl3): δ 22.88,
32.05, 32.42, 43.53, 129.82, 140,14.
N-(Cyclohexenylmethyl)benzenamine (3a). A mixture of 2a (0.5 g, 3.8 mmol) and freshly distilled
aniline (1.43 g, 15 mmol) in water (3 mL) was vigorously stirred at rt for 1 h. The reaction mixture was
extracted with ether, the ethereal extract was dried (MgSO4) and then concentrated in vacuo. The residue
was purified by column chromatography using hexane/EtOAc (9:1) as eluent to yield 3a as yellow oil
(0.49 g, 68 %). TLC (hexane/EtOAc 9:1): Rf = 0.4. 1H NMR (CDCl3): δ 1.59 (m, 4H, 2 CH2), 2.00 (br. s,
4H, 2 CH2), 3.60 (s, 2H, N-CH2), 4.35 (br. s, 1H, NH), 5.67 (m, 1H, HC=), 6.64 (d, J = 7.95 Hz, 2H,
13
ArH), 6.71 (t, J = 7.2 Hz, 1H, ArH), 7.50 (t, J = 7.50 Hz, 2H,ArH). C NMR (CDCl3): δ 22.50, 22.71,
26.83, 50.80 (N-CH2), 113.32, 117.74, 119.32, 123.50, 129.16, 134.80, 148.00. Anal. Calcd for C13H17N:
C, 83.37; H, 9.15; N, 7.48. Found: C, 83.20; H, 8.91; N, 7.36.
N-(Cycloheptenylmethyl)benzenamine (3b). Compound 2b (0.4 g, 2.8 mmol) was added dropwise to a
mixture of aniline (1.03 g, 11 mmol) and water (3 mL). The two phase system was vigorously stirred at rt
for 2.5 h and then extracted with ether. The organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by column chromatography using hexane/EtOAc (9:1) as eluent to afford 3b as
light yellow liquid (0.39 g, 71 %). TLC (hexane/EtOAc 9:1): Rf = 0.61. 1H NMR (CDCl3): δ 1.48 (m, 4H,
2 CH2), 1.73 (m, 2H, CH2), 2.11 (m, 2H, CH2), 2.16 (m, 2H, CH2), 3.60 (br.s, 1H, NH), 3.61 (s, 2H, CH2),
5.80 (t, J = 6.3 Hz, 1H, HC=), 6.60 (d, J = 8.5 Hz, 2H, ArH), 6.68 (t, J = 7.2 Hz, 1H, ArH), 7.15 (t, J =
8.5 Hz, 2H, ArH). 13C NMR (CDCl3): δ 26.85, 27.11, 28.19, 31.12, 32.47, 51.90, 112.93, 117.18, 127.79,
129.12, 141.29, 148.41. Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.27; H, 9.29; N,
7.02.

HETEROCYCLES, Vol. 75, No. 1, 2008
49
N-(Cyclopentenylmethyl)benzenamine (3c). This compound was prepared accordingly to the method
applied for 3b, using 1a and 2c as starting materials. 3c was yielded as a yellowish oil in 59 %. TLC
(CH2Cl2/MeOH 99:1): Rf = 0,71. 1H NMR (CDCl3): δ 1.93 (m, 2H, CH2), 2,36 (m, 4H, 2 CH2), 3.78 (br.s,
1H, NH), 3.81 (s, 2H, N-CH2), 5.62 (br.s, 1H, HC=), 6.68 (d, J = 8.0 Hz, 2H, ArH), 6.74 (t, J = 7.4 Hz,
1H, ArH), 7.20 (t, J = 7.7 Hz, 2H, ArH). 13C NMR (CDCl3): δ 23.58, 32.55, 33.89, 45.19, 113.29, 117.73,
125.98, 129.07, 141.60, 147.78
N-(Cyclohexenylmethyl)-4-methoxybenzenamine (3d). This compound was prepared using the same
procedure as for the preparation of 3b and compounds 1b and 2a as starting materials: yield 65 %. Light
1
yellow liquid. TLC (hexane/EtOAc 4:1): Rf = 0.49. H NMR (CDCl3): δ 1.60 (m, 4H, 2 CH2), 2.01 (m,
4H, 2 CH2), 3.58 (s, 2H, N-CH2), 3.76 (s, 3H, OCH3), 3.90 (s, 1H, NH), 5.68 (s, 1H, HC=), 6.57 (d, J =
8.45 Hz, 2H, ArH), 6.79 (d, J = 8.8 Hz, 2H, ArH). 13C NMR (CDCl3): δ 22.60, 22.93, 25.32, 27.10, 52.21
(N-CH2), 56.00 (OCH3), 115.02, 115.20, 123.90, 135.11, 141.91, 152.80. Anal. Calcd for C14H19NO: C,
77.38; H, 8.81; N, 6.45. Found: C, 77.27; H, 9.05; N, 6.22.
N-(Cyclopentenylmethyl)-4-methoxybenzenamine (3e). This compound was prepared accordingly to
that method applied for 3b, using 1b and 2c as starting materials and was yielded as a yellowish oil in
44%.TLC (hexane/EtOAc 9:1): Rf = 0.51. 1H NMR (CDCl3): δ 1.90 (m, 2H, CH2), 2,33 (m, 4H, 2 CH2),
3,74 (s, 5H, N-CH2 + CH3), 4.10 (s, 1H, NH), 5.59 (s, 1H, HC=), 6.61 (d, J = 8.5 Hz, 2H, ArH), 6.77 (d, J
= 9.0 Hz, 2H, ArH). 13C NMR (CDCl3): δ 23.57, 32.57, 33.94, 46.07, 56.01, 114.66, 115.03, 125.94,
142.39, 142.65, 152.46
N-(Cyclopentenylmethyl)-4-methoxy-N-methylbenzenamine (3f). Compound 2c (2.87 g, 25 mmol)
was added dropwise to a mixture of 1c (3.43 g, 25 mmol), triethylamin (5.06 g, 50 mmol) and water (25
mL). The two phase system was vigorously stirred at rt for 1.5 h and then extracted with dichloromethane.
The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography using hexane/EtOAc (7:3) as eluent to afford 3f as light yellow
liquid (1.95 g, 36 %). TLC (hexane/EtOAc 7:3): Rf = 0.73. 1H NMR (CDCl3): δ 1.87 (m, 2H, CH2), 2.22
(m, 2H, CH2), ), 2.30 (m, 2H, CH2), 2.86 (s, 3H, CH3), 3.75 (s, 3H, CH3), 3.84 (s, 2H, N-CH2), 5.47 (s,
13
1H, HC=), 6.71 (d, J = 8.4 Hz, 2H, ArH), 6.82 (d, J = 8.7 Hz, 2H, ArH). C NMR (CDCl3): δ 23.66,
32.44, 33.85, 39.12, 54.75, 56.00, 114.5, 114.85, 126.71, 141.60, 141.64, 151.77
N-(Cyclohexenylmethyl)-4-methoxy-N-methylbenzenamine (3g). To a suspension of 1c (0.5 g, 3.6
mmol) in water (5 mL) were added successively compound 2a (0.47 g, 3.6 mmol) and triethylamine (1

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HETEROCYCLES, Vol. 75, No. 1, 2008
mL), and the resulting mixture was stirred at rt for 3 h. The reaction mixture was extracted with ether
(2x20 mL), the ethereal extracts were dried (MgSO4), and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography using hexane/acetone (7:3) as eluent to afford 3f as light
yellow oil (0.63 g, 78 %). TLC (hexane/EtOAc 7:3): Rf = 0.67. 1H NMR (CDCl3): δ 1.60 (m, 4H, 2 CH2),
1.9 (m, 2H, CH2), 2.82 (s, 3H, N-CH3), 3.64 (s, 2H, N-CH2), 3.74 (s, 3H, OCH3), 5.53 (s, 1H, =CH), 6.69
(m, 2H, ArH), 6.80 (m, 2H, ArH). 13C NMR (CDCl3): δ 2.66, 22.75, 25.07, 26.58, 38.55 (N-CH3), 55.84
(O-CH3), 60.42 (N-CH2), 114.15, 114.69, 122.76 (=CH), 134.53 (=C), 145.14, 151.48. Anal. Calcd for
C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.59; H, 8.82; N, 6.21.
5,6,7,8,8a,9-Hexahydro-8a-methyl-4bH-carbazole (5a and 6a). To a solution of compound 3a (0.48 g,
.
2.6 mmol) in sulfolane (10 mL) was added BF3 OEt2 (0.33 mL, 2.6 mmol) and the resulting mixture was
o
stirred at 170-175 C for 2 h under Ar. After cooling, water (10 mL) was added and the mixture was
extracted with chloroform. The organic extract was dried (MgSO4), concentrated in vacuo, and the
sulfolane was removed by column chromatography (using hexane/EtOAc 9:1 as eluent). The crude
product was purified by preparative thin layer chromatography to give 5a (95 mg, 20 %), 6a (32 mg, 7 %),
and 7a (30 mg, 6 %).
1
Compound 5a: yellow oil. TLC (hexane/EtOAc 9:1): Rf = 0.29. H NMR (DMSO-d6): δ 1.20 (m, 2H,
C6-H and C7-H), 1.24 (s, 3H, CH3), 1.39 (m, 2H, C6-H and C7-H), 1.42 (m, 2H, C8-H), 1.67 (m, 1H,
C5-H), 1.82 (m, 1H, C5-H), 2.67 (m, 1H, C4b-H), 5.31 (s, 1H, NH), 6.47 (d, J = 7.6 Hz, 1H, C1-H), 6.53 (t,
J = 7.4 Hz, 1H, C3-H), 6.88 (t, J = 7.6 Hz, 1H, C2-H), 6.95 (d, J = 7.3 Hz, 1H, C4-H). 13C NMR
(DMSO-d6): δ 21.94 (C-7), 21.96 (C-6), 25.05 (C-5), 25.93 (CH3), 35.11 (C-8), 46.98 (C-4b), 63.08
(C-8a), 108.83 (C-1), 116.69 (C-3), 122.38 (C-4), 126.65 (C-2), 132.11 (C-4a), 150.42 (C-9a). Anal.
Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.44; H, 9.02; N, 7.21.
Compound 6a: yellow oil. TLC (hexane/EtOAc 9:1): Rf = 0.23. 1H NMR (DMSO-d6): δ 0.87 (s, 3H, CH3),
1.35 (m, 1H, C7-H), 1.40 (m, 1H, C5-H), 1.47 (m, 1H, C6-H), 1.64 (m, 2H, C6-H and C7-H), 1.80 (m, 2H,
C7-H and C8-H), 2.05 (m, 1H, C5-H), 2.49 (m, 1H, C4b), 5.40 (s, 1H, NH), 6.54 (d, J = 7.7 Hz, 1H, C1-H),
13
6.55 (t, J = 7.4 Hz, 1H, C3-H), 6.89 (t, J = 7.6 Hz, 1H, C2-H), 6.92 (d, J = 7.0 Hz, 1H, C4-H). C NMR
(DMSO-d6): δ 17.74 (CH3), 21.77 (C-5), 22.52 (C-6), 25.68 (C-7), 37.70 (C-8), 51.42 (C-4b), 65.84
(C-8a), 109.28 (C-1), 117.01 (C-3), 121.34 (C-4), 126.27 (C-2), 131.32 (C-4a), 150.84 (C-9a). Anal.
Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.09; H, 8.87; N, 7.57.
1
Compound 7a: light yellow oil. TLC (hexane/CH2Cl2 1:1): Rf = 0.27. H NMR (DMSO-d6): δ 1.40 (s,
3H, CH3), 1.68 (m, 4H, 2 CH2), 2.05 (m, 4H, 2 CH2), 4.50 (br.s, 2H, NH2), 6.16 (t, J = 7.5 Hz, 1H, ArH),
6.64 (d, J = 8.0 Hz, 1H, ArH), 6.75 (d, J = 6.5 Hz, 1H, ArH), 6.91 (t, J = 6.5 Hz, 1H, ArH).13C NMR

HETEROCYCLES, Vol. 75, No. 1, 2008
51
(DMSO-d6): δ 21.29 (CH3), 23.87, 24.16, 31.47, 31.73, 115.00, 117.02, 128.94, 129.31, 129.83, 130.69,
145.31. Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.57; H, 8.93; N, 7.52.
5a-Methyl-5,5a,6,7,8,9,10,10a-octahydrocyclohepta[b]indole (5b and 6b). To a solution of 3b (0.35 g,
.
1.7 mmol) in sulfolane (13 mL) was added BF3 OEt2 (0.22 mL, 1.7 mmol) and the resultant mixture was
stirred at 160-170 oC for 40 min under Ar. After cooling, water (15 L) was added and the reaction mixture
was extracted with chloroform. The organic layer was dried (MgSO4), concentrated in vacuo, and the
sulfolane was removed by column chromatography using hexane/EtOAc (9:1) as eluent. The crude
product was purified by preparative thin layer chromatography to yield 5b (93 mg, 27 %), 6b (31 mg,
9 %), and 7b (30 mg, 9 %).
Compound 5b: colorless semisolid. TLC (hexane/EtOAc 9:1): Rf = 0.51. 1H NMR ( CDCl3): δ 1.27 (s, 3H,
CH3), 1.38 (m, 1H, C7-H), 1.40 (m, 1H, C8-H), 1.42 (m, 1H, C9-H), 1.63 (m, 1H, C8-H), 1.70 (m, 1H,
C7-H), 1.74 (m, 1H, C6-H), 1.76 (m, 2H, C9-H and C10-H), 1.80 (m, 2H, C6-H and C10-H), 2.95 (dd, J = 8
and 2 Hz, 1H, C10a-H), 3.1 (br.s, 1H, NH), 6.53 (d, J = 7.8 Hz, 1H, C4-H), 6.68 (t, J = 7.4 Hz, 1H, C2-H),
13
7.00 (t, J = 7.4 Hz, 1H, C3-H), 7.01 (d, J =7.4 Hz, 1H, C1-H). C NMR (CDCl3): δ 24.65 (C-7), 28.50
(C-9), 30.81 (CH3), 31.37 (C-8), 32.33 (C-10), 40.39 (C-6), 53.96 (C-10a), 65.94 (C-5a), 108.75 (C-4),
118.07 (C-2), 124.64 (C-1), 127.38 (C-3), 133.28 (C-10b), 149.08 (C-4a). Anal. Calcd for C14H19N: C,
83.53; H, 9.51; N, 6.96. Found: C, 83.36; H, 9.27; N, 7.05.
Compound 6b: colorless semisolid. TLC (hexane/EtOAc 9:1): Rf = 0.42. 1H NMR ( CDCl3): δ 1.12 (s, 3H,
CH3), 1.37 (m,1H, C7-H), 1.52 (m, 1H, C8-H), 1.55 (m, 1H, C9-H), 1.63 (m, 1H, C10-H), 1.75 (m, 1H,
C8-H), 1.80 (m, 1H, C6-H), 1.91 (m, 2H, C6-H and C7-H), 2.00 (m, 2H, C9-H), 2.25 (m, 1H, C10-H),
3.19 (dd, J = 12.5 and 5.5 Hz, 1H, C10a-H), 3.3 (br.s, 1H, NH), 6.55 (d, J = 7.6 Hz, 1H, C4-H), 6.70(t, J =
13
7.5Hz, 1H, C2-H), 6.95 (t, J = 7.5 Hz, 1H, C3-H), 6.98 (d, J = 8 Hz, 1H, C1-H). C NMR (CDCl3): δ
20.48 (CH3), 23.55 (C-10), 25.76 (C-8), 26.05 (C-9), 27.49 (C-7), 42.58 (C-6), 48.12 (C-10a), 69.38
(C-5a), 109.02 (C-4), 118.37 (C-2), 122.75 (C-1), 126.90 (C-3), 133.32 (C-10b), 149.76 (C-4a). Anal.
Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.42; H, 9.32; N, 6.68.
Compound 7b: yellow oil. TLC hexane/EtOAc 9:1): Rf = 0.47. 1H NMR (CDCl3): δ 1.55 (m, 1H, CH2),
1.56 (s, 3H, CH3), 1.60 (m, 3H, CH3), 1.77 (m, 1H, CH2), 1.85 (m, 1H, CH2), 2.22 (m, 1H, CH2), 2.32 (m,
1H, CH2), 2.34 (m, 1H, CH2), 2.42 (m, 1H, CH2), 3.60 (br.s, 2H, NH2), 6.68 (d, J = 8.3 Hz, 1H, ArH),
6.71 (t-d, J = 7.5 and 1 Hz, 1H, ArH), 6.90 (dd, J = 7.5 and 1 Hz, 1H, ArH, 7.02 (t-d, J = 7.5 and 1.5 Hz,
13
1H, ArH). C NMR (CDCl3): δ 22.63(CH3), 26.36, 27.39, 32.48, 35.09, 35.39, 114.93, 118.30, 127.03,
128.77, 131.95, 134.60, 138.15, 142.58. Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C,
83.72; H, 9.39; N, 7.16.

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HETEROCYCLES, Vol. 75, No. 1, 2008
3a-Methyl-1,2,3,3a,4,8b-hexahydrocyclopent[b]indole and 2-(2-methylcyclopent-1-enyl)benzen-
.
amine (5c and 7c) To a solution of 3c (0.155 g, 0.9 mmol) in sulfolane (6 mL) was added BF3 OEt2 (0.14
mL, 1.1 mmol) and the resultant mixture was stirred at 160-170 oC for 100 min under Ar. After cooling,
water (10 L) was added and the reaction mixture was extracted with chloroform. The organic layer was
dried (MgSO4), concentrated in vacuo, and the sulfolane was removed by column chromatography on
Al2O3 gel using hexane/EtOAc (9:1) as eluent. The crude product was purified by preparative thin layer
chromatography to yield 5c (77 mg, 50 %), 7c (12 mg, 8 %).
Compound 5c: yellow oil. TLC (hexane/EtOAc 9:1): Rf = 0.45. 1H NMR (DMSO-d6): δ 1.28 (s, 3H, CH3),
1.45 (m, 1H, CH2), 1,55 (m, 3H, CH2), 1,72 (m, 1H, CH2), 2,00 (m, 1H, CH2), 3,13 (d, J = 8.5 Hz, 1H,
CH), 5.50 (br.s, 1H, NH), 6.32 (d, J = 7.5 Hz, 1H, ArH), 6.44 (t, J = 7.0 Hz, 1H, ArH), 6.84 (t, J = 7.5 Hz,
13
1H, ArH), 6.89 (d, J = 7.0 Hz, 1H, ArH). C NMR (DMSO-d6): δ 25.35, 28.04, 35.39, 42.41, 53.42,
70.59, 107.03, 116.21, 124.28, 127.23, 132.28, 151.43.
Compound 7c: yellow oil. TLC hexane/EtOAc 9:1): Rf = 0.36. 1H NMR (DMSO-d6): δ 1.53 (s, 3H, CH3),
1.88 (m, 2H, CH2), 2.42 (m, 2H, CH2), 2.53 (m, 2H, CH2), 4.54 (br.s, 2H, NH2), 6.50 (t, J = 7.5 Hz, 1H,
13
ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 6.81 (d, J = 7.5 Hz, 1H, ArH), 6.92 (t, J = 8.0 Hz, 1H, ArH). C
NMR (DMSO-d6): δ 15.11, 22.0, 37.19, 38.22, 114.51, 115.96, 122.95, 127.38, 128.84, 133.47, 135.31,
145.27.
7-Methoxy-3a-methyl-1,2,3,3a,4,8b-hexahydrocyclopent[b]indole
and
4-metoxy-2-(2-methyl-
cyclopent-1-enyl)benzenamine (5e and 7e) These compounds were prepared accordingly to the method
applied for 5c and 7c using 3e as a starting material.
Compound 5e: yellow oil, yielded in 40%. TLC (hexane/EtOAc 9:1): Rf = 0.48. 1H NMR (CDCl3): δ 1.40
(s, 3H, CH3), 1.63 (m, 3H, CH2), 1,17 (m, 2H, CH2), 2,00 (m, 1H, CH2), 3,00 (br.s, 1H, NH), 3,25 (d, J =
7.8 Hz, 1H, CH), 3.74 (s, 3H, CH3), 6.55 (d, J = 20.4 Hz, 1H, ArH), 6.62 (d, J = 20.4 Hz, 1H, ArH), 6.65
13
(br.s, 1H, ArH). C NMR (CDCl3): δ 25.77, 28.26, 35.23, 43.19, 54.72, 56.17, 72.05, 110.03, 111.53,
112.77, 135.40, 144.33, 153.85.
Compound 7e: yellow oil, yielded in 11%. TLC (hexane/EtOAc 9:1): Rf = 0.41. 1H NMR (CDCl3): δ 1.61
(s, 3H, CH3), 1.95 (m, 2H, CH2), 2,45 (m, 2H, CH2), 2,62 (m, 2H, CH2), 3,77 (br.s, 5H, NH2+CH3), 6.57
(s, 1H, ArH), 6.68 (m, 2H, ArH). 13C NMR (CDCl3): δ 15.27, 22.65, 37.98, 38.86, 55.91, 113.59, 114.71,
116.77, 126.65, 133.45, 137.00, 137.32, 152.74.
4-Metoxy-N-methyl-2-(2-methylcyclopent-1-enyl)benzenamine (7f) The preparation of 7f was similar
to that of 5c and 7c using 3f as a starting material.
Compound 7f: yellow oil, yielded in 53%. TLC (hexane/EtOAc 9:1): Rf = 0.61. 1H NMR (CDCl3): δ 1.57

HETEROCYCLES, Vol. 75, No. 1, 2008
53
(s, 3H, CH3), 1.94 (m, 2H, CH2), 2,47 (m, 2H, CH2), 2,59 (m, 2H, CH2), 2.81 (s, 3H, N-CH3), 3,18 (br.s,
1H, NH), 3.74 (s, 3H, O-CH3), 6.59 (s, 2H, ArH), 6.76 (m, 1H, ArH). 13C NMR (CDCl3): δ 15.17, 22.60,
32.03, 38.04, 38.83, 56.00, 111.00, 113.02, 115.31, 123.23, 133.33, 137.46, 141.04, 151.51.
5,6,7,8,8a,9-Hexahydro-3-methoxy-8a,9-dimethyl-4bH-carbazole (5g). To a solution of 3g (0.5 g, 2.2
.
mmol) in sulfolane (6 mL) was added BF3 Et2O (0.28 mL, 2.2 mmol) and the resulting mixture was
heated at 185-190 oC for 30 min. After cooling, the reaction mixture was diluted with water (20 mL) and
extracted with CH2Cl2 (3x50 mL). The combined extracts were dried (MgSO4), the solvent was
evaporated in vacuo, and the sulfolane was removed by column chromatography on Al2O3 gel using
hexane/EtOAc (9:1) as eluent. The resulting mixture of 5g and side product 7g (R1= OMe, R2= Me, n= 1)
was dissolved in ether (15 mL) and treated with phenylisocyanate (0.185 mL). After stirring at rt for 18 h,
the solvent was evaporated in vacuo, and the residue was purified by chromatography on Al2O3 gel (using
hexane/EtOAc 9:1 as eluent) to afford 5g (0.26 g, 51 %) and the phenylcarbamate of 7g (0.14 g, 18 %).
1
Compound 5g: light yellow oil. TLC (hexane/EtOAc 9:1, Al2O3): Rf = 0.62. H NMR (DMSO-d6): δ
1.19 (s, 3H, CH3), 1.50 (m, 8H, 4 CH2), 2.7 (s, 3H, N-CH3), 3.66 (s, 3H, O-CH3), 6.28 (d, J = 4.05 Hz, 1H,
ArH), 6.66 (s, 1H, ArH), 6.72 (m, 1H, ArH). 13C NMR (DMSO-d6): δ 21.49, 21.58, 21.94, 24.29, 28.38,
29.07 (CH3), 46.83 (O-CH3), 67.06 (N-CH3), 106.91, 109.89, 110.86, 133.56, 145.76, 152.12. Anal.
Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.60; H, 9.02; N, 5.86.
Compound phenylcarbamate of 7g: yellow oil. TLC (hexane/EtOAc 7:3): Rf = 0.41. 1H NMR (CDCl3): δ
1.42 (s, 3H, CH3), 1.66 (m, 4H, 2 CH2), 2.04 (br.s, 3H, 2 CH2), 2.10 (br.s, 1H,CH2), 3.12 (s, 3H, N-CH3),
3.84 (s, 3H, O-CH3), 6.18 (s, 1H, NH), 6.71 (d, J = 3.0 Hz, 1H, ArH), 6.86 (dd, J =8.5 and 3.0 Hz, 1H,
ArH), 6.96 (t, J =6.5 Hz, 1H, ArH), 7.23 (m, 5H, ArH). 13C NMR (CDCl3): δ 21.14 (CH3), 22.96, 23.29,
30.95, 31.28, 36.23 (N-CH3), 55.55 (O-CH3), 113.55, 116,79, 119.14, 122.65, 128.78, 129.29, 130.32,
130.72, 132.83, 139.11, 144.87, 154.79 (CO), 159.19.
7-Methoxy-3a,4-dimethyl-1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (5f). To a solution of 5e (0,54 g ,
2,7 mmol) in dry DMF (5 mL) sodium-hydride (0,19 g, 8 mmol) was added and the resulting mixture was
cooled down to 0 °C and stirred for 10 minutes. Methyl iodide was added dropwise to the mixture at 0 °C,
then it was allowed to reach the ambient temperature and stirred 1 h additionally. The mixture was
quenched by water (40 mL) and extracted three times with Et2O (30 mL). The combined ethereal phases
were dried and the solvent was evaporated in vacuo. The crude product 5f (0,54 g, 93%) was used without
further purification.
1
Compound 5f: light yellow oil. TLC (hexane/EtOAc 9/1): Rf = 0,63. H NMR (DMSO-d6): δ 1.22 (s,
3H, CH3), 1.38 (m, 1H, CH2), 1.44 (m, 1H, CH2), 1.59 (m, 1H, CH2), 1.62 (m, 1H, CH2), 1.79 (m, 1H,

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HETEROCYCLES, Vol. 75, No. 1, 2008
CH2), 2.05 (m, 1H, CH2), 2.59 (s, 3H, N-CH3), 3.10 (m, 1H, CH), 3.62 (s, 3H, OCH3), 6.14 (d, J= 8.3 Hz,
1H, ArH), 6.54 (dd, J= 8.3 and 2.4 Hz, 1H, ArH), 6.60 (d, J= 2.4 Hz, 1H, ArH).
13C NMR (DMSO-d6): δ 23.34, 25.20, 29.15, 34.19, 36.43, 52.91, 55.67, 75.55, 104.97, 11.49, 111.92,
133.81, 146.15, 151.62. Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.22; H, 8.57;
N, 6.30.
5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-4bH-carbazol-3-ol (8a). To a solution of 5g (0.25 g, 1.13 mmol)
in chloroform (6 mL) was added BBr3 (0.3 mL) and the resulting mixture was stirred at rt for 1 h. The
reaction mixture was then treated with MeOH (15 mL) and concentrated in vacuo. The residue was
dissolved in aqueous NaHCO3 solution (25 mL) and extracted with Et2O (3x15 mL). The combined
ethereal extracts were dried (MgSO4), the solvent was evaporated in vacuo, and the residue was purified
by column chromatography using CH2Cl2/MeOH (20:1) as eluent to afford 8a (0.18 g, 73 %), light
1
yellow oil. TLC (CH2Cl2/MeOH 20:1): Rf =0.58. H NMR (DMSO-d6): δ 1.13 (m, 1H, CH2), 1.15 (m,
1H, CH2), 1.21 (s, 3H, CH3), 1.23 (m, 1H, CH2), 1.35 (m,2H, CH2), 1.40 (m, 1H, CH2), 1.65 (m, 1H,
CH2), 1.84 (m, 1H, CH2), 2.45 (s, 3H, N-CH3), 2.66 (m, 1H, CH), 6.18 (d, J = 8.1 Hz, 1H, ArH), 6.40 (dd,
J = 8.1 and 1.9 Hz, 1H, ArH), 6.48 (br.s, 1H, ArH), 8.40 (br.s, 1H, OH). 13C NMR (DMSO-d6): δ 21.78,
22.15, 24.58, 28.71 (CH3), 29.14, 47.06, 67.08, 107.49, 110.66, 112.57, 133.47, 144.62, 149.71. Anal.
Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.57; H, 8.62; N, 6.21.
5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-4bH-carbazol-3-yl phenylcarbamate (9a). To a stirred solution
of 8a (0.45 g, 2 mmol) in dry THF (30 mL) was added phenyl isocyanate (0.24 mL, 2.2 mmol) and the
resulting mixture was refluxed for 36 h. The solvent was evaporated in vacuo and the residue was purified
by column chromatography using hexane/EtOAc (7:3) as eluent to yield 9a as a gray semisolid (0.32 g,
1
48 %). TLC (hexane/EtOAc 7:3): Rf = 0.20. H NMR (DMSO-d6): δ 1.16 (m, 1H, CH2), 1.23 (m, 1H,
CH2), 1.27 (s-m, 4H, CH3, CH2), 1.43 (m, 2H, CH2), 1.44 (m, 1H, CH2), 1.68 (m, 1H, CH2), 1.94 (m, 1H,
CH2), 2.56 (s, 3H, CH3), 2.76 (m, 1H, CH), 6.35 (d, J = 8.2 Hz, 1H, ArH), 6.80 (d, J = 8.2 Hz, 1H, ArH),
6.85 (s, 1H, ArH), 7.02 (t, J = 7.3 Hz, 1H, ArH), 7.30 (t, J = 7.7 Hz, 2H, ArH), 7.49 (d, J = 7.9 Hz, 2H,
ArH), 10.02 (s, 1H, NH). 13C NMR (DMSO-d6): δ 21.52, 21.89 (CH3), 22.04, 24.35, 28.33 (CH3), 29.59,
46.80, 67.65, 106.58, 116.57, 118.49, 120.02, 122.85, 128.97, 133.15, 139.08, 142.24, 149.25, 152.76
(CO).
7-Hydroxy-3a,4-dimethyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (8b). This compound was
prepared accordingly to the method applied for 8a, using 5f as a starting material. The crude 8b was
yielded as a yellowish oil in 93 % and was used without further purification. TLC (hexane/EtOAc 7:3): Rf

HETEROCYCLES, Vol. 75, No. 1, 2008
55
=0.51. 1H NMR (DMSO-d6): δ 1.21 (s, 3H, CH3), 1.36 (m, 1H, CH2), 1.45 (m, 1H, CH32), 1.59 (m, 2H,
CH2), 1.77 (m, 1H, CH2), 2.04 (m, 1H, CH2), 2.55 (s, 3H, CH3), 3.05 (m, 1H, CH), 6.05 (d, J = 8,2 Hz,
13
1H, ArH), 6.38 (dd, J = 8,2 and 1,8 Hz, 1H, ArH), 6.42 (br.s, 1H, ArH), 8.29 (s, 1H, OH). C NMR
(DMSO-d6): δ 23.32, 25.18, 29.45, 33.99, 36.23, 52.95, 75.46, 105.52, 112.15, 113.16, 133.65, 144.85,
149.04.
Phenylcarbamate of 8b (9b). This compound was prepared accordingly to the method applied for 9a,
1
using 8b as a starting material and yielded in 58 %. TLC (hexane/EtOAc 7:3): Rf =0.30. H NMR
(DMSO-d6): δ 1.26 (s, 3H, CH3), 1.44 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.85 (m, 1H, CH2), 2.07 (m, 1H,
CH2), 2.66 (s, 3H, CH3), 3.17 (m, 1H, CH), 6.19 (d, J = 8.2 Hz, 1H, ArH), 6.75 (dd, J = 8.2 and 2,1 Hz,
1H, ArH), 6.78 (br.s, 1H, ArH), 7.02 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.7 Hz, 2H, ArH), 7.49 (d, J =
7.9 Hz, 2H, ArH), 10.00 (br.s, 1H, NH). 13C NMR (DMSO-d6): δ 23.67, 25.23, 28.63, 34.69, 36.90, 52.58,
75.67, 104.04, 118.06, 118.44, 120.44, 122.80, 128.96, 133.13, 139.11, 141.20, 149.21, 152.84.
ACKNOWLEDGEMENTS
Financial support from the Hungarian OTKA Foundation (F 034544 and T 42515) is gratefully
acknowledged.
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