Synthesis of 1-iodo-1,2,3,4,4a,9a-hexahydrocarbazole, 2a,3,4,5,5a,10a- hexahydrooxazolocarbazolium iodide and 4-bromo-1,2,3,4,4a,11b- hexahydrodibenzoxazepine from N-benzoyl-2-(cyclohex-2-en-1-yl)aniline

Article abstract of DOI:10.1070/MC2004v014n05ABEH001924

The reaction of N-benzoyl-2-(cyclohex-2-en-1-yl)aniline 1 with molecular oxygen in the presence of NaHCO₃ results in N-benzoyl-1-iodo-1,2,3,4, 4a-hexahydrocarbazole, which was isomerised to 1-phenyl-2a,3,4,5,5a,10a- hexahydro[1,3]oxazolo-[5,4,3

Full text of DOI:10.1070/MC2004v014n05ABEH001924

, 2004, 14(5), 219–221
Synthesis of 1-iodo-1,2,3,4,4a,9a-hexahydrocarbazole, 2a,3,4,5,5a,10a-hexa-
hydrooxazolocarbazolium iodide and 4-bromo-1,2,3,4,4a,11b-hexahydro-
dibenzoxazepine from N-benzoyl-2-(cyclohex-2-en-1-yl)aniline
Rail R. Gataullin,* Razida R. Ishberdina, Olga V. Shitikova, Leonid V. Spirikhin, Tat’jana V. Kazhanova and
Ildus B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa, Russian Federation.
Fax: +7 3472 35 6066; e-mail chemorg@anrb.ru
DOI: 10.1070/MC2004v014n05ABEH001924
The reaction of N-benzoyl-2-(cyclohex-2-en-1-yl)aniline 1 with molecular oxygen in the presence of NaHCO3 results in
N-benzoyl-1-iodo-1,2,3,4,4a,9a-hexahydrocarbazole, which was isomerised to 1-phenyl-2a,3,4,5,5a,10a-hexahydro[1,3]oxazolo-
[5,4,3-j,k]carbazol-10-ium iodide, whereas the reaction of amide 1 with molecular bromine results in dibromide, but the interaction
with NBS leads to 4-bromo-6-phenyl-1,2,3,4,4a,11b-hexahydrodibenzo[d,f][1,3]oxazepine.
Benzo-condensed heterocyclic systems are used in the synthesis
of alkaloids or for medical purposes. Because of this, these
systems are of great interest to scientists. The cyclization of
ortho-alkenyl anilines affected by electrophilic reagents is used
for producing benzo-condensed heterocyclic systems.1 The use
of halogens2 or organoselenium compounds3 allows one not
only to construct a heterocyclic fragment but also to introduce a
good living group into a molecule. The cyclization of ortho-
alkenylanilines with electrophilic reagents is known to give
indoline and quinoline compounds. The following transforma-
tion of heterocycles to other systems, as well as the formation
of a 7-exo-cyclization product, is rarely observed.
4, benzoate 9 was produced from quinoline 8. Its spectral
characteristics were compared with those of compound 4
(Scheme 2).
Bz
H
Br
NH
6'
3'
Br
Ar
H
Br
2'
1'
H
3'
2'
H
NH2
Br
2
11
5
i
iv
Ph
O
H
N
We found that the reaction leads to different compounds
depending on the conditions and nature of the halogenating
agent.
NHBz
NHBz
ii or iv
or v
Thus, benzamide 1 obtained from amine 25 forms hexa-
hydrocarbazole 3 in the reaction with molecular iodine. The
cyclization proceeds over a long period of time. Compound 3 is
unstable. Being left in a solvent for a long time or boiled in
benzene for a short time, it isomerises to tricyclic compound 4
in practically quantitative yield.
The reaction of amide 1 with Br2 gives a mixture of reaction
products, from which dibromide 5 was isolated. The latter is a
basic reaction product, which precipitates in a cryctalline form
from solution after the completion of bromination.
However, the u se of N-bromosuccinimide in the hetero-
cyclization of benzamide 1 leads to benzoxazepine 6. The
cyclization proceeds rapidly in contrast to that with I2.
It has been found earlier that 2-hexahydrocarbazole 74 and
its analogues6 undergo isomerization to propane tetrahydro-
quinoline 84 in solution. To confirm the structure of tetracycle
X
X
1
10a X = Br
X = I
12a,b
10b
ii
v
Ph
1
Bz
Ph
O
I
I
6
H
H
iii
H
Hax
10 N
N
N
O5
7
2a
1
3
9
6
8
5
8
7a
11a
8
7
3
10a
5a
9a
4a
9a
9
10
1
5b
4b
4
4
11
5
4
H
4a H
11b
H
H
Br
H
4
3
6
Scheme 1 Reagents and conditions: i, BzCl, 10% aqueous NaOH solu-
tion; ii, I2, NaHCO3, CH2Cl2, 20° C; iii, > 30 days in CH2Cl2, 20 °C or
reflux in benzene; iv, Br2, CH2Cl2, 20 °C; v, NBS, CH2Cl2, 20 °C.
Mendeleev Commun. 2004 219

, 2004, 14(5), 219–221
H-11b proton is axial; it has a high spin–spin coupling constant
with the axial H-1 proton (~12 Hz). The oxygen and bromine
atoms are disposed most distant axially, and owing to that H-4
and H-4a protons are equatorial.
Probably, the dihedral angle between H-11b and H-4a
protons is close to 90°; in this situation, the spin–spin coupling
constant is practically equal to 0 because the H-4a proton
doublet signal transforms to a singlet at the suppression of the
H-4 proton signal.
H
H
H
H
I
I
4
ref. 5,7
i
3
2
N
H
N
H
N
H
H
I
Bz
7
8
9
Scheme 2
The formation of onium complexes in the reactions of olefins
with halogens is a conventional supposition. Halogen onium
complexes 10a,b, formed in the reactions with Br2 or NBS in
the presence of Br– anions lead to dibromide 5 as a result of the
attack of this anion on C-2' or C-3' carbons (11, Scheme 1). In
the reaction with NBS, the Br– anion is absent; probably, by
this reason, an oxygen atom of the amide fragment is a nucleo-
philic particle, and that leads to compound 6.
Two negative bromine atoms of compound 5 are disposed
distinct axial due to the mutual repulsion. Owing to that, the
spin–spin coupling constants are low, in the 1H NMR spectrum
they are observed as narrow multiplets. The H-1' proton signal
has a high diaxial spin-spin coupling constant with the H-6'
proton (J 12.0 Hz).
1
In the H NMR spectrum, the signals of H-2, H-3 and H-4
protons are observed as narrow multiplets owing to the low
spin–spin coupling constant caused by their equatorial disposi-
tion in tetrahydroquinoline derivative 9.
The structure of the compounds obtained was determined
using spectral methods and elemental analysis.† The assignment
of signals in the 1H and 13C NMR spectra of compounds 5 and
6 was made using the CH correlation and the double resonance.
Thus, the H-1 proton of hexahydrocarbazole 3 is axial, as
confirmed by a high spin–spin coupling constant (12.0 Hz) in
4-Bromo-1,2,3,4,4a,11b-hexahydrodibenzoxazepine 6: a solution of
compound 1 (0.2 g, 0.7 mmol) and NBS (0.125 g, 0.7 mmol) was stirred
in CH2Cl2 (5 ml). The progress of the reaction was monitored by TLC.
After the disappearance of the starting amide, the mixture was diluted
with 50 ml of CH2Cl2 and washed with a 10% Na2S2O3 solution
(2×20 ml) and water (2×50 ml). The organic phase was dried over
Na2SO4; the solvent was evaporated in vacuo. The yield of the crude
product was 0.25 g (97%). Rf 0.84 (C6H6–EtOAc, 85:15). The product
was subjected to chromatography on silica gel. The yield of an amorphous
white powder was 0.2 g. An attempt to recrystallise it from hot 95%
ethanol lead to hydrolysis. 1H NMR (CDCl3) d: 1.70–1.80 (m, 2H, Heq-1,
Heq-2), 1.88 (dk, 1H, Hax-1, J1 2.0 Hz, J2 12.0 Hz, Jgem 12.0 Hz), 2.05
(m, 2H, Heq-3, Hax-2), 2.45 (m, 1H, Hax-3), 3.73 (dd, 1H, H-11b,
J1 3.4 Hz, J2 12.0 Hz), 4.59 (ddd, 1H, H-4, J1 1.7 Hz, J2 2.0 Hz,
J3 3.2 Hz), 4.80 (d, 1H, H-4a, J 3.2 Hz), 7.01–7.22 (m, 3H, ArH),
7.31–7.39 (m, 2H, ArH), 8.05 (dd, 2H, J1 2.0 Hz, J2 8.1 Hz). MS, m/z:
355 [M]+, 105 [PhCºO]+, 276 [M – Br]+, 234 [M – C3H6Br]+, 250
[M – PhC=O]+. Found (%): C, 63.94; H, 5.00; Br, 22.35; N, 3.84. Calc.
for C19H18BrNO (%): C, 64.06; H, 5.09; Br, 22.43; N, 3.93.
2-[(1R,2S,3S)-2,3-Dibromocyclohexyl]-1-phenylcarboxamidobenzene
5: to a solution of compound 1 (0.3 g, 1.1 mmol) in 10 ml of CH2Cl2 a
solution of Br2 (0.176 g, 1.1 mmol) in 1 ml of CH2Cl2 was added drop-
wise with stirring. After 72 h, crystals were precipitated. The precipitate
was filtered off, the yield of the resulting compound was 0.02 g;
mp 180–183 °C (CH2Cl2). 1H NMR ([2H6]DMSO) d: 1.55–2.45 (m, 6H,
3CH2), 3.92 (dt, 1H, H-1', J1 2.4 Hz, J2 12.0 Hz), 4.91 (m, 1H, H-2'),
4.99 (m, 1H, H-3'), 7.20-7.60 (m, 7H, ArH), 8.00 (dd, 2H, ArH, J1
1.6 Hz, J2 8.4 Hz), 10.00 (s, 1H, NH). 13C NMR ([2H6]DMSO) d: 20.5
(C-5'), 24.6 (C-4'), 27.5 (C-6'), 35.6 (C-1'), 54.8 (C-3'), 60.6 (C-2'),
126.6 (C-3), 127.1 (C-5), 128.2 (C-4), 128.7 (C-6), 131.4 (C-4''), 127.7
(C-2''), 128.1 (C-3''), 134.0 (C-2), 135.8 (C-1), 139.5 (C-1''), 166.1
(C=O). Fou nd (%): C, 52.06; H, 4.28; Br, 36.47; N, 3.11. Calc. for
C19H19Br2NO (%): C, 52.20; H, 4.38; Br, 36.55; N, 3.20. The residue
was diluted in 50 ml of CH2Cl2 and washed with a 10% Na2SO3 solution
and water (2×50 ml). The organic phase was dried over Na2SO4. The
solvent was removed in vacuo. The yield of the crude mixture was 0.4 g.
Dissolving the mixture in benzene yielded dibromide 5 (0.09 g). 1H and
13C NMR spectra confirm the presence of compound 5 (40%) in a
master batch (0.31 g).
1
the H NMR spectrum of this compound. In oxazepine 6, the
†
1
IR spectra were recorded on a UR-20 instrument. H and 13H NMR
spectra (internal TMS) were measured on a Bruker AM-300 spectro-
1
meter (300.13 and 75.45 MHz for H and 13H, respectively). Elemental
analysis was performed on a C-H-N Analyzer M-185 B. Column
chromatography was performed over silica gel 60 (0.040–0.063 mm;
230–400 mesh, Lancaster). For quantitative TLC, Sorbil UV 254 plates
were used (Luminofor, Russia) detecting the compounds with iodine and
a UV detector (l 254 nm). Mass spectra were recorded on an MX 1320
device (70 eV).
N-Benzoyl-2-(cyclohex-2-en-1-yl)aniline 1: 100 ml of a 1% aqueous
NaOH solution and a solution of aniline 2 (1.73 g, 10 mmol) in benzene
(20 ml) were mixed in a 250 ml flask; benzoyl chloride (1.55 g,
11 mmol) in benzene (10 ml) was added through a dropping funnel. An
exothermic reaction was observed. The reaction mixture cooled to 30 °C
was stirred for 1 h. After completion of the reaction, the aqueous phase
was removed; the organic phase was washed with water (2×20 ml) and
dried with Na2SO4. The yield of the crude product was 2.7 g. The
recrystallization from ethanol alcohol gave 2.5 g (90%), mp 127–130 °C.
Found (%): C, 82.19; H, 6.80; N, 4.98. Calc. for C19H19NO (%): C,
82.28; H, 6.90; N, 5.05.
N-Benzoyl-1-iodo-1,2,3,4,4a,9a-hexahydrocarbazole 3: a mixture of
amide 1 (0.89 g, 3 mmol), I2 (1.52 g, 6 mmol) and NaHCO3 (9 g, 30 mmol)
in CH2Cl2 (30 ml) was stirred for 72 h. The progress of the reaction was
monitored by TLC. After the disappearance of the starting compound,
the mixture was diluted with CH2Cl2 (50 ml). The organic solution was
washed with a 10% Na2S2O3 solution (2×20 ml) and water (2×20 ml)
and dried (Na2SO4). The solvent was removed in vacuo. The residue was
subjected to column chromatography on silica gel. The yield was 0.63 g
(50%); mp 152–155 °C. 1H NMR (CDCl3) d: 1.30–2.40 (m, 6H, 3CH2),
3.70 (m, 1H, H-4a), 4.18 (ddd, 1H, H-1, J1 3.8 Hz, J2 8.8 Hz, J3
12.0 Hz), 5.00 (dd, 1H, H-9a, J1 7.5 Hz, J2 8.8 Hz), 7.05–7.60 (m, 9H,
ArH). IR (n/cm–1): 1650, 1470, 1390, 1280, 1180, 1120, 770, 730, 430.
Found (%): C, 56.38; H, 4.29; I, 31.26; N, 3.28. Calc. for C19H18INO
(%): C, 56.59; H, 4.50; I, 31.47; N, 3.47.
N-Benzoyl-3-iodo-2,4-propano-1,2,3,4-tetrahydroquinoline 9: 100 ml
of a 10% aqueous NaOH solution and compound 8 (0.4 g, 1.33 mmol) in
benzene (20 ml) was mixed in a 250 ml flask. A solution of benzoyl
chloride (0.2 g, 1.46 mmol) in benzene (10 ml) was added with intense
stirring. An exothermic reaction was observed. The mixture was cooled
to 30 °C and stirred for 1 h. After completion of the reaction, the organic
phase was separated, washed with water (2×20 ml) and dried with
Na2SO4. The solvent was removed in vacuo; the residue was subjected to
silica gel chromatography on a short column to produce product 9 as
amorphous white powder in 92% yield (0.5 g). 1H NMR (CDCl3) d: 1.30
(m, 1H, Hax-2'), 1.50 (d, 1H, Heq-2', Jgem 14.3 Hz), 1.7 (d, 1H, Heq-1',
Jgem 12.8 Hz), 2.05 (d, 1H, Heq-3', Jgem 13.7 Hz), 2.45 (m, 1H, Hax-1',
Hax-3'), 3.24–3.28 (m, 1H, H-4), 4.77–4.81 (m, 1H, H-2), 4.87–4.91 (m,
1H, H-3), 6.88–7.07 (m, 4H, ArH), 7.35–7.50 (m, 5H, ArH). 13C NMR
(CDCl3) d: 17.0, 26.1, 29.9 (3CH2), 30.1 (C-4), 42.2 (C-3), 55.8 (C-2),
123.0 (C-8), 123.5 (C-6), 126.2 (C-7), 128.1 (C-2'', C-6''), 128.5 (C-3'',
C-5''), 129.4 (C-4a), 130.7 (C-5, C-4''), 136.4 (C-8a), 138.7 (C-1''),
171.1 (C=O). Found (%): C, 56.47; H, 4.39; I, 31.38; N, 3.37. Calc. for
C19H18INO (%): C, 56.59; H, 4.50; I, 31.47; N, 3.47.
1-Phenyl-2a,3,4,5,5a,10a-hexahydro[1,3]oxazolo[5,4,3-j,k]carbazol-
10-ium iodide 4. Hexahydrocarbazole 3 (1.1 g, 3 mmol) was refluxed in
benzene for 5–7 min. The solvent was evaporated in vacuo. The residue
was washed with benzene (1 ml). The yield of the crude product was
1.09 g. The recrystallization from ethanol gave 0.56 g (51%) of com-
pound 4, which is insoluble in C6H6, CH2Cl2 or CHCl3; mp 157–159 °C
1
(EtOH). H NMR ([2H6]DMSO) d: 1.20–2.00 (m, 6H, 3CH2), 3.50 (dt,
1H, H-5a, J1 6.2 Hz, J2 8.0 Hz), 4.25 (dd, 1H, H-10a, J1 4.6 Hz, J2
6.2 Hz), 5.35 (ddd, 1H, H-2a, J1 4.6 Hz, J2 4.9 Hz, J3 9.2 Hz), 7.05–7.12
(m, 2H, ArH), 7.22 (t, 1H, ArH, J 7.3 Hz), 7.32 (d, 1H, ArH, J 7.2 Hz),
7.51 (t, 2H, ArH, J 7.4 Hz), 7.67 (t, 1H, ArH, J 7.4 Hz), 7.90 (d, 1H,
ArH, J 7.2 Hz). 13C NMR ([2H6]DMSO) d: 19.6 (C-4), 25.6 (C-3), 27.4
(C-5), 40.3 (C-5a), 60.8 (C-10a), 70.1 (C-2a), 118.2 (C-8), 124.2 (C-6),
127.7 (C-9), 128.1 (C-7), 128.5 (C-3'), 129.2 (C-5b), 129.4 (C-2'), 133.5
(C-4'), 137.8 (C-9a), 139.1 (C-1'), 164.5 (N+=C–O). IR (n/cm–1): 1725,
1475, 1375, 1270, 1115, 1035, 775, 725. UV (MeCN): lmax 365 nm,
l
min 330 nm. Found (%): C, 56.41; H, 4.32; Anionic iodine, 31.00; N,
3.26. Calc. for C19H18INO (%): C, 56.59; H, 4.50; Anionic iodine, 31.47;
N, 3.47.
220 Mendeleev Commun. 2004

, 2004, 14(5), 219–221
6 R. R. Gataullin, F. F. Minnigulov, T. V. Khakimova, A. A. Fatykhov,
L. V. Spirikhin and I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim.,
2002, 1227 (Russ. Chem. Bull., Int. Ed., 2002, 51, 1329).
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Received: 7th April 2004; Com. 04/2250
Mendeleev Commun. 2004 221