Facile synthesis of cycloalkanoindole derivatives by aza-Claisen rearrangement

Article abstract of DOI:10.1007/s00706-012-0831-4

Carba analogs of physostigmine were prepared from aniline derivatives with BF3 . Et2O catalyzed cyclization. Suzuki coupling reactions of the new compounds are also discussed. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0831-4

Monatsh Chem
DOI 10.1007/s00706-012-0831-4
ORIGINAL PAPER
Facile synthesis of cycloalkanoindole derivatives by aza-Claisen
rearrangement
•
Katalin Kupai Gergely Banoczi Gabor Hornyanszky
•
•
•
Pal Kolonits Lajos Novak
Received: 19 March 2012 / Accepted: 7 August 2012
Ó Springer-Verlag 2012
Abstract Carba analogs of physostigmine were prepared
from aniline derivatives with BF.3Et2O catalyzed cycliza-
tion. Suzuki coupling reactions of the new compounds are
also discussed.
(nivalin) [11–13]—are used for the treatment in the mild to
moderate stages of Alzheimer’s disease.
The alkaloid of the African Calabar bean (Physostigma
venesonum), (-)-physostigmine (eserine) inhibits the ace-
tylcholinesterase. This inhibitory effect comes from the
carbamate moiety of the molecule, which transcarbamylates
the enzyme. The physostigmine’s analog phenserine, a
phenylcarbamoyl derivative, is a highly potent inhibitor of
this enzyme. Furthermore, the above mentioned rivastig-
mine is also an aryl carbamate derivative (Fig. 1) [14–17].
In recent years, we have published two papers about the
easy preparation of carba analogs of physostigmine [18,
19]. In that work the synthesis of potent inhibitors of the
esterase enzyme was based on the aza-Claisen rearrange-
ment of cycloalkenyl-N-methylbenzenamine, followed by
aza-Alder-ene reaction of the intermediate. To test the
scope and limitation of the rearrangement reactions, we
have prepared a series of new carba analogs of physo-
stigmine and studied their reactions.
Keywords Alzheimer’s disease ꢀ Physostigmine analogs ꢀ
Ene reaction ꢀ Cyclization ꢀ Bromination
Introduction
Alzheimer’s disease is the most common brain disorder
that affects older people. This brain disease slowly destroys
memory and ability to learn or recognize new things and
friends. As the disease progresses, bodily functions and the
ability to carry out daily activities are lost and the person
needs total care [1–3].
Alzheimer’s disease cannot be cured, but there are
treatments which can prevent or slow down the progress of
getting worse. The disease is associated with the cholinergic
system. The enzyme acetylcholinesterase rapidly hydro-
lyzes the naturally released acetylcholine causing a shortage
in this neurotransmitter [4, 5]. Most of the researches are
directed to inhibit this enzyme activity, which would
increase the concentration of acetylcholine in the brain.
Nowadays, cholinesterase inhibitors—donepezil (aricept)
[6, 7], rivastigmine (exelon) [8–10], and galanthamine
Results and discussion
Synthesis of new analogs 5 is depicted in Scheme 1. The
reactions of compounds 1 with allyl halides 2 gave the
expected amines 3 in good to excellent yields (Table 1,
entries 1–4). Treatment of compounds 3a, 3b with
BF.3Et2O in sulfolane yielded a mixture of cis- and trans-
isomers of 5a, 5b, which were separated by column chro-
matography (entries 5, 6). In the reaction of the chloro
compound 3c only the cis-isomer was isolated (entry 7).
In the attempted cyclization of 3d, 3e we failed to get
the wanted 5d, 5e. Here, under the forcing condition
(170 °C) some degradation and the reduction of the bro-
mine-carbon bond took place. Therefore, compounds 5d,
K. Kupai ꢀ G. Banoczi ꢀ G. Hornyanszky ꢀ P. Kolonits ꢀ
L. Novak (&)
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics,
Research Group for Alkaloid Chemistry, Hungarian
´
Academy of Sciences, Gellert Ter 4, Budapest 1111, Hungary
e-mail: lnovak@mail.bme.hu
´
123

K. Kupai et al.
Table 1 Compounds prepared
O
Entry Substrate Reagent
X, Y, n
Product
Yield/%
N
O
H
N
O
R
1
2
3
4
5
1a
1a
1c
1d
3a
2a
H, -, 1
H, -, 2
Cl, -, 1
Br, -, 1
H
3a
53
N
2b
3b
69
O
H
N
2a
3c
90
2a
BF.3Et2O
3d
90
N
R = Me (-)-Physostigmine
R = Ph Phenserine
Rivastigmine
cis-5a
trans-5a
5b
14
27
BF.3Et2O H, -, 2
BF.3Et2O Cl, -, 1
30 [12]
41
Fig. 1 Alkaloid of the Calabar bean and its analogs
6
3b
7
3c
cis-5c
cis-5d
trans-5d
cis-5e
trans-5e
Cl
8
cis-5a
NBS
NBS
NBS
NBS
11a
Br, -, 1
Br, -, 1
Br, -, 2
Br, -, 2
69
n
X
9
trans-5a
cis-5b
77
X
. Et2O
NaI
BF3
+
10
11
12
13
14
15
16
17
79
aza-Claisen rearr.
n
N
NH
H
trans-5b
trans-5d
trans-5e
trans-5d
trans-5e
trans-5d
trans-5e
75
1
2
3
H, OPh, 1 trans-12a 71
H, OPh, 2 trans-12b 73
n
11a
n
X
X
11b
11b
11c
H, NO2, 1 trans-12c
24
NH
H, NO2, 2 trans-12d 21
N
4
6
H, CF3, 1
H, CF3, 2
trans-12e
trans-12f
58
59
aza-Alder-ene
reaction
11c
n
X
H
n
X
In our recent paper [19] we suggested a mechanism for
the ring closure reaction (3 ? 5). On the basis of ab initio
calculation of the transition state, a two steps mechanism,
namely aza-Claisen rearrangement followed by aza-Alder-
ene reaction, was recommended (3 ? 4 ? 5). Now we
have found further evidence for this mechanism. In the ring
closure reaction of 8 (Scheme 2) we isolated the side-
product 10, beside compound 9, and treated it with
BF.3Et2O at 170 °C for longer time. However, no ring
closure product 9 could be isolated. We observed only
some degradation.
NH
N
5
7
1
2
a
b
3-7
a
b
c
d
e
X
H
MeO
Cl
Br
n
1
2
X
H
H
Cl
Br
Br
n
1
2
1
1
2
a
b
c
d
Scheme 1
Finally, we investigated the reactivity of the bromo com-
pounds in a Suzuki coupling reaction (Scheme 3). The
reaction of compounds 5d, 5e with 4-phenoxyphenylboronic
acid (11a), in the presence of tetrakis(triphenylphos-
phine)palladium (0) catalyst and in DMF, afforded
compounds 12a, 12b in good yield (entries 12, 13). Using a
similar condition, the reaction between compounds 5d, 5e and
3-nitrophenylboronicacid(11b) affordedthewantedproducts
12c, 12d, but the yields were poor (entries 14, 15). The
reaction of these bromo compounds 5d, 5e with 4-(trifluoro-
methyl)phenylboronic acid (11c) also furnished the coupling
products 12e, 12f in acceptable yields (entries 16, 17).
5e were prepared by the bromination of 5a, 5b using NBS
(entries 8–11). In the bromination of 5a we get some per-
cent of the 1,3-dibromo derivative, too.
The annulations of rings (cis or trans) were determined
by the Nuclear Overhauser Effect Spectroscopy (NOESY)
interaction between the hydrogens of the methyl group
(8a-CH3) and the neighboring CH group. Furthermore, in
the 13C NMR spectra the trans-5 diastereomers showed a
c-effect between the methyl group (8a-CH3) and the
methylene group (C-5). In the spectra of the corresponding
cis-5 the c-effect was missing (8a-CH3 and C-5). This
observation, in accordance with other NMR data, was
found in trans-fused five- and six-membered rings in the
trans-compounds (Table 2).
Experimental
In the cyclization reactions we observed the formation
of side-products 7, but no attempts were made to isolate
them in a pure state. Compounds 7 were obviously formed
through the aromatization of intermediate 4 followed by
the double bond migration in the products 6.
Solvents were used as received from commercial suppliers,
and no further attempts were made to purify or dry them.
Melting points were determined on a Bu¨chi apparatus and
123

Facile synthesis of cycloalkanoindole derivatives
Table 2 Selected data for stereochemical assignments
Compound
1H NMR
13C NMR
Ring fusion
CH3/CH
dCH /ppm
d
CH/ppm
NOESYa
dCH /ppm
dCH /ppm
c-effect
3
3
2
cis-5a
1.24
0.68
1.03
0.83
1.23
0.69
1.03
0.83
2.73
2.52
2.88
3.06
2.75
2.56
2.92
3.08
?
-
?
-
?
-
?
-
21.83
10.73
24.20
12.76
21.74
10.86
24.62
12.86
24.56
21.48
32.02
22.79
24.45
21.24
31.72
22.47
cis
trans-5a
cis-5bb
trans-5bb
cis-5d
trans-5d
cis-5e
?
?
?
?
trans
cis
trans
cis
trans
cis
trans-5e
trans
a
Cross peak in NOESY spectrum
See Ref. [19]
b
TLC and Kieselgel 60 for column chromatography.
N-Methylbenzenamine, 4-methoxy-N-methylbenzenamine,
4-chloro-N-methylbenzenamine, and 4-bromo-N-methyl-
benzenamine were obtained from commercial sources and
were of the higher grade available. The preparation of
compounds 3b and 5b has already been described [19].
O
N
8
H
BF3. Et2O
O
H
General procedure for preparation of cycloalkylmethyl-
N-methylbenzeneamine 3
O
+
N
NH2
H
Compound 2 (16 mmol) was added dropwise to a stirred
mixture of 1 (16 mmol) and 2.5 g NaI in 20 cm3 acetone. The
resultant solution was stirred at rt for 2 h. The NaCl precipi-
tated was filtered off and the filtrate was diluted with 50 cm3
CH2Cl2. After washing with 20 cm3 water, the solution was
dried(MgSO4),concentratedinvacuo,andpurifiedbycolumn
chromatography (hexane:acetone = 9:1).
9
10
Scheme 2
X
Y
n
H
5
+ Y
B(OH)2
N-(1-Cyclohexenylmethyl)-N-methylbenzenamine
(3a, C14H19N)
X
N
Light yellow oil; TLC (hexane:acetone = 9:1): Rf = 0.56;
1H NMR (CDCl3): d = 1.59 (m, 4H, 2 CH2), 2.00 (m, 4H,
2 CH2), 2.90 (s, 3H, CH3), 3.70 (s, 2H, N–CH2), 5.52 (m,
1H, CH=), 6.70 (m, J = 7.95 Hz, 2H, ArH), 6.72 (t,
J = 7.2 Hz, 1H, ArH), 7.22 (t, J = 7.5 Hz, 2H, ArH) ppm;
13C NMR (CDCl3): d = 22.06, 22.76, 22.85, 25.19, 26.67,
38.21, 59.29, 112.34, 116.08, 122.46, 129.24, 134.08 ppm.
11
a
Y
X
12
Y
X
n
1
a
OPh
H
OPh H
b
c
b
c
d
e
H
CF3
NO2
H
OPh
H
H
H
NO2
NO2
2
1
2
CF3
CF3
H
H
1
2
f
4-Chloro-N-(1-cyclohexenylmethyl)-N-methylbenzenamine
(3c, C14H18ClN)
Yellow oil; TLC (hexane:EtOAc = 15:1): Rf = 0.53; GC:
Scheme 3
1
are corrected. 1H NMR and 13C NMR spectra were
obtained on a Bruker DRX-500 spectrometer operating at
500 and 125 MHz, respectively. All NMR spectra are
reported in ppm relative to TMS. MS spectra were con-
ducted on a Agilent 6140 quadrupole LC/MS instrument.
Merck precoated silica gel 60 F254 plates were used for
tR = 10.22 min; H NMR (CDCl3): d = 1.61 (m, 4H, 2
CH2), 1.86 (m, 2H, CH2), 1.98 (m, 2H, CH2), 2.89 (s, 3H,
CH3), 3.71 (s, 2H, N–CH2), 5.48 (m, 1H, CH=), 6.61 (m,
2H, ArH), 7.12 (d, J = 9.0 Hz, 2H, ArH) ppm; 13C NMR
(CDCl3): d = 22.71, 22.79, 25.14, 26.63, 38.62, 59.40,
113.53, 122.89, 128.97, 133.54 ppm.
123

K. Kupai et al.
4-Bromo-N-(1-cyclohexenylmethyl)-N-methylbenzenamine
(3d, C14H18BrN)
cis-3-Chloro-5,6,7,8,8a,9-hexahydro-8a,9-dimethyl-4bH-
carbazole (5c, C14H18ClN)
Light yellow oil; TLC (hexane:EtOAc = 15:1): Rf = 0.55;
GC: tR = 14.2 min; 1H NMR (CDCl3): d = 1.65 (m, 4H, 2
CH2), 1.88 (m, 2H, CH2), 1.98 (m, 2H, CH2), 2.89 (s, 3H,
CH3), 3.73 (s, 2H, N-CH2), 5.49 (m, 1H, CH =), 6.56 (d,
J = 9.0 Hz, 2H, ArH), 7.25 (d, J = 9.0 Hz, 2H, ArH)
ppm; 13C NMR (CDCl3): d = 22.07, 24.31, 25.74, 30.64,
38.68, 57.58, 113.61, 121.25, 131.23, 133.49 ppm.
A mixture of 2 g 3c (8.5 mmol) and 1.31 g BF.3Et2O
(1.1 cm3, 8.5 mmol) in 40 cm3 sulfolane was heated at
160 °C for 2 h under Ar. After cooling 40 cm3 water was
added and the reaction mixture was extracted three times
with CH2Cl2 (40 cm3 each). The combined organic extracts
were dried (MgSO4), concentrated in vacuo, and purified
by column chromatography to give a mixture of 5c and 7c.
This mixture was dissolved in 50 cm3 ether and after
adding 9.8 g phenyl isocyanate (9 cm3, 7.5 mmol) the
resulting solution was stirred at rt overnight. The excess of
phenyl isocyanate was decomposed by 20 cm3 adding
water, the layers were separated, and the organic layer was
dried (MgSO4), concentrated in vacuo, and the residue was
purified by column chromatography to give 5c (0.84 g,
41 %). 1H NMR (CDCl3): d = 1.36 (s, 3H, CH3),
1.40–2.15 (m, 8H, 4 CH2), 2.61 (s, 3H, CH3), 6.30 (d,
J = 3.3 Hz, 1H, ArH), 6.94 (m, 2H, ArH) ppm; 13C NMR
(CDCl3): d = 21.79, 22.20, 23.47, 25.04, 28.44, 30.14,
47.38, 68.18, 107.86, 122.73, 127.03, 134.76, 150.55 ppm;
MS: m/z (%) = 235 (M?, 100), 101 (M?-C6H13ClN, 15).
5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-4bH-carbazole
(5a, C14H19N)
To a hot solution (160 °C) of 1 g 3a (4.8 mmol) in 30 cm3
sulfolane was added 0.69 g BF.3Et2O (0.6 cm3, 4.8 mmol)
and the resulting mixture was stirred at 170 °C for 1.5 h.
After cooling, 30 cm3 water was added and the reaction
mixture was extracted three times with CH2Cl2 (60 cm3
each). The combined organic extracts were dried (MgSO4),
concentrated in vacuo, and purified by column chromatog-
raphy to yield a mixture of compounds 5a and 7a. This
mixture was dissolved in 30 cm3 ether and 0.5 cm3 phenyl
isocyanate (4.3 mmol) was added, and the reaction mixture
was stirred for overnight. The excess of phenyl isocyanide
was decomposed by addition of 10 cm3 water. The layers
were separated and the organic layer was dried (MgSO4),
the solvent was evaporated, and the residue was purified by
column chromatography to give cis- and trans-isomers of
compound 5a.
3-Bromo-5,6,7,8,8a,9-hexahydro-8a,9-dimethyl-4bH-
carbazole (5d, C14H18BrN)
To a cooled (-20 °C) solution of 1 g compound 5a
(5 mmol) in 20 cm3 ether was added 0.89 g N-bromosuc-
cinimide (5 mmol) and the resulting mixture was stirred at
rt for 0.5 h. The reaction mixture was partitioned between
water and dichloromethane. The organic layer was dried
and evaporated in vacuo, and the residue was purified by
column chromatography to yield 5d.
cis-Isomer: yield 0.14 g (14 %); light yellow oil; 1H
NMR (DMSO-d6): d = 1.14 (m, 1H, C3–H), 1.20 (m, 1H,
C2–H), 1.24 (s, 3H, CH3), 1.27 (m, 1H, C1–H), 1.40 (m, 2H,
C1–H, C3–H), 1.42 (m, 1H, C2–H), 1.68 (m, 1H, C4–H), 1.91
(m, 1H, C4–H), 2.55 (s, 3H, N–CH3), 2.73 (t, J = 4.5 Hz,
1H, C4a–H), 6.37 (d, J = 7.5 Hz, 1H, C8–H), 6.58 (t,
J = 7.5 Hz, 1H, C6-H), 6.96 (d, J = 7.0 Hz, 1H, C5-H),
6.98 (t, J = 7.5 Hz, 1H, C7-H) ppm; 13C NMR (DMSO-d6):
d = 21.55 (C-2), 21.83 (CH3), 22.04 (C-3), 24.56 (C-4),
28.05 (CH3), 29.60 (C-1), 46.79 (C-4a), 67.18 (C-9a), 106.99
(C-8), 117.08 (C-6), 121.89 (C-5), 127.24 (C-7), 132.10 (C-
4b), 151.62 (C-8a) ppm; MS: m/z (%) = 201 (M?, 23), 186
(M?-CH3, 36), 158 (M?-C3H7, 100), 144 (M?-C4H9, 30).
cis-Isomer: yield 0.96 g (69 %); light yellow oil; TLC
(hexane:EtOAc = 15:1): Rf = 0.44; 1H NMR (DMSO-d6):
d = 1.13 (m, 1H, C6–H), 1.17 (m, 1H, C7–H), 1.23 (s, 3H,
CH3), 1.27 (m, 1H, C8–H), 1.41 (m, 3H, C6–H, C7–H, C8–
H), 1.67 (m, 1H, C5–H), 1.88 (m, 1H, C5–H), 2.55 (s, 3H,
N–CH3), 2.75 (t, J = 4.5 Hz, 1H, C4b–H), 6.33 (d,
J = 8.0 Hz, 1H, C1–H), 7.10 (s, 1H, C4–H), 7.12 (d,
J = 8.0 Hz, 1H, C2–H) ppm; 13C NMR (DMSO-d6):
d = 21.34 (C-7), 21.74 (CH3), 22.00 (C-6), 24.45 (C-5),
27.94 (N–CH3), 29.72 (C-8), 46.69 (C-4b), 67.59 (C-8a),
107.87 (C-3), 108.62 (C-1), 124.90 (C-4), 129.67 (C-2),
135.09 (C-4a), 150.83 (C-9a) ppm; MS: m/z (%) = 279
(M?, 26), 264 (M?-CH3, 15), 236 (M?-C3H7, 100), 157
(M?-C3H7Br, 60).
1
trans-Isomer: yield 0.27 g (27 %); yellow oil; H NMR
(DMSO-d6): d = 0.68 (s, 3H, CH3), 1.38 (m, 1H, C3–H),
1.42 (m, 1H, C2–H), 1.46 (m, 1H, C4–H), 1.58 (m, 1H, C1–
H), 1.70 (m, 1H, C2–H), 1.82 (m, 1H, C3–H), 1.94 (m, 1H,
C1–H), 2.06 (m, 1H, C4–H), 2.52 (br. s, 1H), 2.55 (s, 3H,
N–CH3), 6.41 (d, J = 7.5 Hz, 1H, C8–H), 6.59 (t,
J = 7.5 Hz, 1H, C6–H), 6.93 (d, J = 7.0 Hz, 1H, C5–H),
6.98 (t, J = 7.5 Hz, 1H, C7–H) ppm; 13C NMR (DMSO-
d6): d = 10.73 (CH3), 21.48 (C-2), 22.01 (C-2), 25.63
(C-3), 28.93 (CH3), 35.21 (C-1), 51.33 (C-4a), 69.90
(C-9a), 106.91 (C-8), 117.21 (C-6), 120.29 (C-5), 126.85
(C-7), 132.12 (C-4b), 151.91 (C-8a) ppm.
trans-Isomer: yield 1.08 g (77 %); yellow oil; TLC
(hexane:EtOAc = 15:1): Rf = 0.42; 1H NMR (DMSO-d6):
d = 0.69 (s, 3H, CH3), 1.36 (m, 1H, C6–H), 1.43 (m, 2H,
C5–H, C7–H), 1.57 (m, 1H, C8–H), 1.68 (m, 1H, C7–H),
1.81 (m, 1H, C6–H), 1.93 (m, 1H, C8–H), 2.06 (m, 1H, C5–
H), 2.55 (s, 3H, N–CH3), 2.56 (m, 1H, C4b–H), 6.37 (d,
J = 8.0 Hz, 1H, C1–H), 7.06 (s, 1H, C4–H), 7.13 (d,
123

Facile synthesis of cycloalkanoindole derivatives
J = 8.0 Hz, 1H, C2–H) ppm; 13C NMR (DMSO-d6):
d = 10.86 (CH3), 21.24 (C-5), 21.92 (C-7), 25.51 (C-6),
28.83 (CH3), 35.08 (C-8), 51.33 (C-4b), 70.34 (C-8a),
108.32 (C-3), 108.62 (C-1), 124.03 (C-4), 129.26 (C-2),
135.02 (C-4a), 151.17 (C-9a) ppm.
6.97 (s, 1H, C1–H), 7.09 (dd, J = 8.2, 1.0 Hz, 1H, C3–H)
ppm; 13C NMR (DMSO-d6): d = 12.86 (C5a–CH3), 22.47
(C-10), 25.28 (C-8), 25.46 (C-9), 26.58 (C-7), 28.38
(N–CH3), 38.72 (C-6), 47.77 (C-10a), 73.11 (C-5a),
107.38 (C-4), 107.59 (C-2), 124.61 (C-1), 129.53 (C-3),
135.60 (C-10b), 150.64 (C-4a) ppm.
As a side product 1,3-dibromo-5,6,7,8,8a,9-hexahydro-
8a,9-dimethyl-4bH-carbazole (C14H17Br2N) has been
obtained as light green gum. cis-Isomer: 1H NMR
(DMSO-d6): d = 1.18 (m, 2H, C6–H, C7–H), 1.24 (s, 3H,
CH3), 1.32 (m, 1H, C8–H), 1.42 (m, 2H, C6–H, C7–H), 1.50
(m, 1H, C8–H), 1.67 (m, 1H, C5–H), 1.88 (m, 1H, C5–H),
2.75 (m-t, J = 5 Hz, 1H, C4b–H), 2.96 (s, 3H, CH3), 7.14
(br. s, 1H, C4–H), 7.29 (br. s, 1H, C2–H) ppm; 13C NMR
(DMSO-d6): d = 21.26 (C-7), 21.75 (CH3), 21.79 (C-6),
24.25 (C-5), 30.11 (C-8), 30.57 (CH3), 46.54 (C-4b), 68.47
(C-8a), 100.85 (C-1), 108.24 (C-4), 124.52 (C-4), 133.97
(C-2), 138.37 (C-4a), 146.99 (C-9a). trans-Isomer: 1H
NMR (DMSO-d6): d = 0.77 (s, 3H, CH3), 1.33 (m, 1H,
C6–H), 1.43 (m, 2H, C7–H), 1.52 (m, 1H, C8–H), 1.70 (m,
1H, C7–H), 1.81 (m, 1H, C6–H), 1.94 (m, 1H, C8–H), 2.06
(m, 1H, C5–H), 2.54 (br. s, 1H, C4b–H), 2.96 (s, 3H, CH3),
7.08 (br. s, 1H, C4–H), 7.29 (br. s, 1H, C2–H) ppm; 13C
NMR (DMSO-d6): d = 11.50 (CH3), 21.15 (C-5), 21.99
(C-7), 25.32 (C-6), 31.20 (CH3), 34.70 (C-8), 51.10 (C-4b),
70.95 (C-8a), 101.05 (C-1), 108.57 (C-3), 123.53 (C-4),
133.54 (C-2), 138.26 (C-4a), 147.08 (C-9a) ppm.
General procedure for the preparation of compounds
12
To a mixture of boronic acid 11 (1.07 mmol, 1.2 equiv.) and
58 mg tetrakis(triphenylphosphine) palladium (0) catalyst
(0.05 mmol, 0.05 equiv.) in 2 cm3 2 M K2CO3 solution was
added the corresponding bromo compound 5 (0.89 mmol) in
2 cm3 DMF and the resultant mixture was heated under
reflux for 2 h. After cooling, 5 cm3 saturated NaHCO3 was
added and the reaction mixture was extracted three times
with ether (15 cm3 each). The combined ethereal solution
was dried (MgSO4), the solvent evaporated in vacuo, and the
residue was purified by column chromatography.
trans-5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-3-
(4-phenoxyphenyl)-4bH-carbazole (12a, C26H27NO)
Light yellow crystals; m.p.: 91–92 °C; TLC (hex-
ane:EtOAc = 15:1): Rf = 0.64; 1H NMR (CDCl3):
d = 0.80 (s, 3H, CH3), 1.46 (m, 2H, C6–H, C7–H), 1.56
(m, 1H, C5–H), 1.72 (m, 1H, C8–H), 1.77 (m, 1H, C7–H),
1.91 (m, 1H, C6–H), 1.96 (m, 1H, C8–H), 2.15 (m, 1H, C5–
H), 2.68 (s, 3H, CH3), 2.72 (m, 1H, C4b–H), 6.49 (d,
2-Bromo-5,5a,6,7,8,9,10,10a-octahydrocyclohepta-
[b]indole (5e, C15H20BrN)
0
J = 8.0 Hz, 1H, C1–H), 7.03 (d, J = 8.5 Hz, 4H, C3 –H,
To a stirred solution of 1 g 5b (4.7 mmol) in 40 cm3 ether
was added 0.83 g N-bromosuccinimide (4.7 mmol) at
-20 °C and the resultant mixture was stirred at rt for
0.5 h. The precipitate was filtered off, the solvent was
evaporated in vacuo, and the residue was purified by
column chromatography to give 5e.
0
00
00
C5 –H, C2 –H, C6 –H), 7.08 (t, J = 8.0 Hz, 1H, C4 –H),
00
7.20 (br. s, 1H, C4–H), 7.29 (d, J = 8.0 Hz, 1H, C2–H),
00
00
7.33 (t, J = 8.0 Hz, 2H, C3 –H, C5 –H), 7.50 (d,
J = 8.5 Hz, 2H, C2 –H, C6 –H) ppm; 13C NMR (CDCl3):
d = 11.04 (CH3), 21.84 (C-5), 22.40 (C-7), 25.96 (C-6),
29.15 (CH3), 35.61 (C-8), 51.69 (C-4b), 70.63 (C-8a),
107.24 (C-1), 118.58 (C-200, C-600), 119.27 (C-30, C-50),
119.91 (C-4), 122.95 (C-400), 125.49 (C-2), 127.67 (C-20,
C-60), 129.68 (C-300, C-500), 129.79 (C-3), 133.44 (C-4a),
137.46 (C-10), 151.30 (C-9a), 155.46 (C-40), 157.66 (C-100)
ppm; MS: m/z (%) = 369 (M?, 44), 354 (M?-CH3, 100),
312 (M?-C4H9, 13).
0
0
cis-Isomer: yield 1.1 g (79 %); yellow oil; TLC (hex-
ane:EtOAc = 15:1): Rf = 0.43; 1H NMR (DMSO-d6):
d = 1.03 (s, 3H, C5a-CH3), 1.41 (m, 6H, C7–H, C8–H,
C9–H), 1.60 (m, 1H, C10–H), 1.72 (m, 3H, C6–H, C10–H),
2.57 (s, 3H, N–CH3), 2.92 (m, 1H, C10a–H), 6.20 (d,
J = 8.2 Hz, 1H, C4–H), 7.05 (s, 1H, C1–H), 7.07 (dd,
J = 8.2, 1.0 Hz, 1H, C3–H) ppm; 13C NMR (DMSO-d6):
d = 23.72 (C-7), 24.62 (C5a–CH3), 27.12 (C-9), 27.60
(N–CH3), 30.89 (C-8), 31.72 (C-10), 35.62 (C-6), 52.38
(C-10a), 69.37 (C-5a), 106.39 (C-2), 106.42 (C-4), 126.51
(C-1), 129.95 (C-3), 135.02 (C-10b), 150.16 (C-4a) ppm.
trans-Isomer: yield 1.04 g (75 %); yellow oil; TLC
(hexane:EtOAc = 15:1): Rf = 0.40; 1H NMR (DMSO-d6):
d = 0.83 (s, 3H, C5a-CH3), 1.30 (m, 1H, C7–H), 1.48 (m,
3H, C8–H, C9–H, C10–H), 1.51 (m, 1H, C6–H), 1.67 (m,
1H, C8–H), 1.85 (m, 1H, C7–H), 1.89 (m, 1H, C9–H), 2.06
(m, 1H, C6–H), 2.18 (m, 1H, C10–H), 2.52 (s, 3H, N–CH3),
3.08 (m, 1H, C10a–H), 6.24 (d, J = 8.2 Hz, 1H, C4–H),
trans-5,5a,6,7,8,9,10,10a-Octahydro-5,5a-dimethyl-2-
(4-phenoxyphenyl)-cyclohepta[b]indole
(12b, C27H29NO)
White solid; m.p.: 95–96 °C; TLC (hexane:EtOAc = 15:1):
Rf = 0.64; 1H NMR (CDCl3): d = 0.95 (s, 3H, CH3), 1.37
(m, 1H, C7–H), 1.56 (m, 2H, C8–H, C9–H), 1.68 (m, 2H,
C6–H, C10–H), 1.76 (m, 1H, C8–H), 1.96 (m, 1H, C7–H),
2.01 (m, 1H, C9–H), 2.12 (m, d-t, J = 13.0, 4.0 Hz, 1H, C6–
H), 2.31 (m, 1H, C10–H), 2.65 (s, 3H, CH3), 3.23 (dd,
J = 12.0, 4.5 Hz, 1H, C10a–H), 6.37 (d, J = 8.0 Hz, 1H,
0
C4–H), 7.02 (d, J = 8.5 Hz, 2H, C3 –H, C5 –H), 7.08 (t,
0
123

K. Kupai et al.
00
J = 8.0 Hz, 1H, C4 –H), 7.16 (br. s, 1H, C1–H), 7.27 (br. s,
d = 0.82 (s, 3H, CH3), 1.47 (m, 1H, C6–H), 1.51 (m, 1H,
C7–H), 1.61 (m, 1H, C5–H), 1.69 (m, 1H, C8–H), 1.78 (m,
1H, C7–H), 1.92 (m, 1H, C6–H), 2.03 (m, 1H, C8–H), 2.21
(m, 1H, C5–H), 2.68 (m, 1H, C4b–H), 2.70 (s, 3H, N–CH3),
6.54 (d, J = 8.0 Hz, 1H, C1–H), 7.31 (s, 1H, C4–H), 7.44
00
00
1H, C3–H), 7.32 (t, J = 8.0 Hz, 2H, C3 –H, C5 –H), 7.48
(d, J = 8.5 Hz, 2H, C2 –H, C6 –H) ppm; 13C NMR
(CDCl3): d = 13.15 (CH3), 23.12 (C-10), 25.78 (C-8),
26.06 (C-9), 27.07 (C-7), 28.69 (CH3), 39.40 (C-6), 48.22
(C-10a), 73.41 (C-5a), 106.03 (C-4), 118.58 (C-200, C-600),
119.25 (C-300, C-500), 120.67 (C-1), 122.93 (C-400), 125.89
(C-3), 127.40 (C-20, C-60), 129.67 (C-300, C-500), 129.76 (C-
2), 133.86 (C-10b), 137.54 (C-10), 150.83 (C-4a), 155.35
(C-40), 157.67 (C-100) ppm; MS: m/z (%) = 383 (M?, 50),
368 (M?-CH3, 100), 312 (M?-C5H11, 13).
0
0
0
(d, J = 8.0 Hz, 1H, C2–H), 7.69 (d, J = 8.2 Hz, 2H, C3 –H,
C5 –H), 7.79 (d, J = 8.2 Hz, 2H, C2 –H, C6 –H) ppm; 13C
NMR (acetone-d6): d = 11.37 (CH3), 22.48 (C-5), 23.13
(C-7), 26.78 (C-6), 29.13 (N–CH3), 36.36 (C-8), 52.66 (C-
4b), 71.34 (C-8a), 107.92 (C-1), 120.68 (C-4), 125.83 (CF3,
q, 1JC-F = 270 Hz), 126.44 (q, 3JC-F = 3.6 Hz, C-30, C-50),
127.12 (C-2), 127.27 (C-20), 127.94 (q, 2JC-F = 31.7, C-40),
129.19 (C-3), 134.43 (C-4a), 146.76 (C-10), 153.66 (C-9a)
ppm; MS: m/z (%) = 345 (M?, 25), 330 (M?-CH3, 100),
312 (M?-C3H7, 10), 288 (M?-C4H9, 22).
0
0
0
trans-5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-3-
(3-nitrophenyl)-4bH-carbazole (12c, C20H22N2O2)
1
Yellow oil; TLC (hexane:EtOAc = 15:1): Rf = 0.28; H
NMR (CDCl3): d = 0.82 (s, 3H, CH3), 1.49 (m, 1H, C7–H),
1.59 (m, 1H, C5–H), 1.73 (m, 1H, C8–H), 1.80 (m, 1H, C7–
H), 1.94 (m, 1H, C6–H), 1.98 (m, 1H, C8–H), 2.19(m, 1H, C5–
H), 2.70 (s, 3H, CH3), 2.73 (m, 1H, C4b–H), 6.51 (d,
J = 8.0 Hz, 1H, C1–H), 7.25 (d, J = 2.8 Hz, 1H, C4–H),
trans-5,5a,6,7,8,9,10,10a-Octahydro-5,5a-dimethyl-2-
[4-(trifluoromethyl)phenyl]cyclohepta[b]indole
(12f, C22H24F3N)
Yellow solid; m.p.: 42–43 °C; TLC (hexane:EtOAc =
1
0
7.36 (d, J = 8.0 Hz, 1H, C2–H), 7.51(t, J = 8.0 Hz, 1H, C5 –
15:1): Rf = 0.43; H NMR (DMSO-d6): d = 0.89 (s, 3H,
0
H), 7.86 (d, J = 8.0 Hz, 1H, C6 –H), 8.06 (d, J = 8.0 Hz, 1H,
CH3), 1.33 (m, 1H, C8–H), 1.54 (m, 2H, C7–H, C9–H), 1.57
(m, 2H, C6–H, C10–H), 1.70 (m, 1H, C7–H), 1.90 (m, 1H,
C8–H), 1.95 (m, 1H, C9–H), 2.12 (m, 1H, C6–H), 2.35 (m,
1H, C10–H), 2.62 (s, 3H, N–CH3), 3.16 (m, 1H, C10a–H),
6.42 (d, J = 8.0 Hz, 1H, C4–H), 7.30 (br. s, 1H, C1–H),
7.40 (d, J = 8.0 Hz, 1H, C3–H), 7.68 (d, J = 8.2 Hz, 2H,
C4 –H), 8.40 (s, 1H, C2 –H) ppm; 13C NMR (CDCl3):
d = 11.19 (CH3), 21.81 (C-5), 22.36 (C-7), 25.93 (C-6),
28.96 (CH3), 35.55 (C-8), 51.69 (C-4b), 70.72 (C-8a), 107.17
(C-1), 119.92 (C-4), 120.41 (C-40), 120.94 (C-20), 126.16 (C-
2), 127.87 (C-3), 129.38 (C-50), 132.13 (C-60), 133.79 (C-4a),
143.73 (C-10), 148.77 (C-30), 152.49 (C-9a) ppm.
0
0
0
0
0
0
C3 –H, C5 –H), 7.77 (d, J = 8.2 Hz, 2H, C2 –H, C6 –H)
ppm; 13C NMR (DMSO-d6): d = 13.23 (CH3), 22.68 (C-
10), 25.36 (C-7), 25.56 (C-9), 26.66 (C-8), 28.38 (N–CH3),
38.80 (C-6), 47.79 (C-10a), 73.08 (C-5a), 106.04 (C-4),
trans-5,5a,6,7,8,9,10,10a-Octahydro-5,5a-dimethyl-2-(3-
nitrophenyl)cyclohepta[b]indole (12d, C21H24N2O2)
Light yellow oil; TLC (hexane:EtOAc = 15:1): Rf = 0.28;
1H NMR (CDCl3): d = 0.97 (s, 3H, CH3), 1.38 (m, 1H, C7–
H), 1.58 (m, 2H, C8–H, C9–H), 1.70 (m, 2H, C6–H, C10–H),
1.78 (m, 1H, C8–H), 1.96 (m, 1H, C7–H), 2.03 (m, 1H, C9–
H), 2.12 (m, 1H, C6–H), 2.32 (m, 1H, C10–H), 2.68 (s, 3H, N–
CH3), 3.25 (dd, J = 12.5, 4.8 Hz, 1H, C10a–H), 6.39 (d,
J = 8.0 Hz, 1H, C4–H), 7.21 (s, 1H, C1–H), 7.35 (d,
1
120.47 (C-1), 124.78 (q, JCF = 271 Hz, CF3), 125.67 (q,
2
3JCF = 3.6 Hz, C-30, C-50), 125.75 (q, JCF = 30.3 Hz,
C-40), 126.12 (C-20, C-60), 126.54 (C-3), 127.04 (C-2),
133.79 (C-10b), 145.20 (C-10), 151.95 (C-4a) ppm.
Attempted cyclization of compound 10
0
J = 8.0 Hz, 1H, C3–H), 7.50 (t, J = 8.0 Hz, 1H, C5 –H),
Compound 10 was treated with an equivalent amount of
BF.3Et2O in sulfolane at 170 °C for 5 h. After cooling
water was added and the mixture was extracted with
CH2Cl2. The solvent was evaporated in vacuo and the
residue was purified by column chromatography to get
back the unchanged starting compound 10 (82 %).
0
7.83 (d, J = 8.0 Hz, 1H, C6 –H), 8.04 (dd, J = 8.0, 1.2 Hz,
1H, C4 –H), 8.37 (s, 1H, C2 –H) ppm; 13C NMR (CDCl3):
d = 13.35 (CH3), 23.08 (C-10), 25.71 (C-8), 25.97 (C-9),
27.00 (C-7), 28.51 (N–CH3), 39.26 (C-6), 48.14 (C-10a),
73.56 (C-5a), 106.03 (C-4), 120.26 (C-40), 120.63 (C-1),
120.77 (C-20), 126.54 (C-3), 127.38 (C-2), 129.36 (C-50),
131.98 (C-60), 134.29 (C-10b), 143.72 (C-10), 148.75 (C-30),
151.92 (C-4a) ppm; MS: m/z (%) = 336 (M?, 15), 247 (M?-
C3H7NO2, 100), 245 (10), 145 (15), 126 (22), 105 (15).
0
0
¨
¨
Acknowledgments We are grateful to Laszlo Konczol, Department
of Inorganic and Analytical Chemistry, Budapest University of
Technology and Economics, for helpful discussion on the reaction
mechanism.
trans-5,6,7,8,8a,9-Hexahydro-8a,9-dimethyl-3-
[4-(trifluoromethyl)phenyl]-4bH-carbazole
(12e, C21H22F3N)
References
Light yellow crystals; m.p.: 45–47 °C; TLC (hex-
ane:EtOAc = 15:1): Rf = 0.42; 1H NMR (acetone-d6):
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