New synthesis of 9-methanesulfonyl-1,2,3,9a-tetrahydro- and 1,2,3,4-tetrahydrocarbazoles from N-methanesulfonyl-2-(cyclohex-1-enyl)aniline

Article abstract of DOI:10.1070/MC2003v013n05ABEH001699

The reaction of N-methanesulfonyl-2-(cyclohex-1-en-1-yl)aniline with Br₂ in the presence of NaHCO₃ in MeCN results in N-methanesulfonyl-2-(6-bromocyclohex-1-en-1-y)aniline, which was cyclised to 9-methanesulfonyl-1,2,3,4-tetrahydrocarbazole, and the effect of NH₃ leads to 9-methanesulfonyl-1,2,3,9a-tetrahydrocarbazole. The reaction of the latter with molecular bromine in the presence of pyridine results in 1-(9-methanesulfonyl-1,2,3,4-tetrahydro-4-carbazolyl)pyridinium bromide in a good yield.

Full text of DOI:10.1070/MC2003v013n05ABEH001699

,
2003, 13(5), 235–236
New synthesis of 9-methanesulfonyl-1,2,3,9a-tetrahydro- and 1,2,3,4-tetra-
hydrocarbazoles from N-methanesulfonyl-2-(cyclohex-1-enyl)aniline
Rail R. Gataullin,* Alexander M. Sotnikov, Ildus B. Abdrakhmanov and Genrikh A. Tolstikov
Institute of Organic Chemistry, Ufa Reseach Centre of the Russian Academy of Sciences, 450054 Ufa, Russian Federation.
Fax: +7 3472 35 606; e-mail: chemorg@anrb.ru
1
0.1070/MC2003v013n05ABEH001699
The reaction of N-methanesulfonyl-2-(cyclohex-1-en-1-yl)aniline with Br in the presence of NaHCO in MeCN results in
2
3
N-methanesulfonyl-2-(6-bromocyclohex-1-en-1-yl)aniline, which was cyclised to 9-methanesulfonyl-1,2,3,4-tetrahydrocarbazole,
and the effect of NH leads to 9-methanesulfonyl-1,2,3,9a-tetrahydrocarbazole. The reaction of the latter with molecular bromine
3
in the presence of pyridine results in 1-(9-methanesulfonyl-1,2,3,4-tetrahydro-4-carbazolyl)pyridinium bromide in a good yield.
Tetrahydrocarbazoles are used in the synthesis of alkaloids1 or
,2
quaternary salt of 6 was obtained from tetrahydrocarbazole 5
¶
3
for medical purposes. The production of these heterocycles
in the reaction with Br in the presence of Py in MeCN in a
2
4
,5
was reviewed in the literature. Here we propose a new method
for the production of 1,2,3,9a- and 1,2,3,4-tetrahydrocarbazole
N-mesylates from 2-(cyclohex-1-enyl)aniline N-mesylate 1.
62.5% yield (Scheme 1). Probably, one of the key stages of this
process is the formation of halide A with an extraordinarily
mobile bromine atom (Scheme 1).
6
The interaction of amine 2 with MsCl in pyridine gives
Probably, allyl bromide 3 is formed as a result of the trans-
amide 1; its reaction with Br in the presence of NaHCO in
addition of Br to sulfonyl amide 1 leading to dibromide 1b.
2
3
2
†
MeCN leads to allyl bromide 3. Compound 3 transforms
Compound 1b underwent trans-elimination according to Zaitsev’s
7
,8
spontaneously to tetrahydrocarbazole 4 within ~5 days at
‡
†
1H and 13C NMR spectra were recorded on a Bruker AM-300 spectro-
room temperature practically in a quantitative yield. The inter-
action of bromide 3 with NH in MeOH or MeCN yielded
meter at 300.13 and 75.47 MHz, respectively (internal standard was
TMS). IR spectra were recorded on a UR-20 spectrophotometer. Mass
spectra were measured on a MX-1320 instrument (70 ev). Thin layer
chromatography was carried out using Silufol UV 254 plates (Czech
3
§
,8
8
tetrahydrocarbazole 5. Earlier, compound 5 was obtained in
a mixture with isomer 4 using tributyltin hydride as a reagent
for radical cyclization. This reagent cannot be used for medical
purposes because of its toxicity and difficulties in the separation
Republic) (CHCl as an eluent).
3
N-Methanesulfonyl-2-(cyclohex-1-en-1-yl)aniline 1. MsCl (1.71 g,
5 mmol) was added dropwise to a solution of compound 2 (1.73 g,
0 mmol) in Py (20 ml) and stirred. The reaction mixture was allowed to
9
of by-products from a reaction mixture. The treatment of com-
6
1
1
pound 5 with an HBr solution leads to heterocycle 4. A
stand for 18 h at room temperature, diluted with 2 ml of H O and stirred
2
for 1 h; the solvent was evaporated in a vacuum. The residue was
Br
dissolved in 100 ml of CH Cl , washed with water (2×10 ml), 5% HCl
2
2
solution, and then with water (10 ml). The organic phase was dried with
i
MgSO . The solvent was removed in a vacuum; the residue was re-
4
crystallised from EtOH. The yield of sulfonylamide 1 was 2.28 g (93%),
mp 89–90 °C (EtOH). Found (%): C, 61.83; H, 6.48; N, 5.22; S, 12.34.
Calc. for C H NO S (%): C, 62.12; H, 6.82; N, 5.57; S, 12.76.
NH2
NHMs
NHMs
1d
1
3
17
2
2
1
vi
N-Methanesulfonyl-2-(6-bromocyclohex-1-en-1-yl)aniline 3. To a solu-
ii
tion of sulfonylamide 1 (0.125 g, 0.5 mmol) and NaHCO (0.42 g, 5 mmol)
3
Br
Br
in 10 ml of MeCN a solution of Br (0.08 g, 0.5 mmol) in 3 ml of the
2
2'
6'
Br
Br
above solution was added with intense stirring. The reaction mixture was
stirred for 3 h, the residue was filtered off, the solvent was evaporated in
1
'
2
'
2
1
1
'
a vacuum. Transparent glassy compound 3 was obtained. The yield was
1
0
.152 g (92%), amorphous mass, R 0.4 (C H –EtOAc, 4:1). H NMR
NHMs
NHMs
NHMs
1a
Br–
f
6
6
(
CDCl ) d: 1.70–3.00 (m, 6H, 3CH ), 3.05 (s, 3H, Me), 4.99–5.03 (m,
3
2
7
3
1
H, H-6'), 5.88 (ddd, 1H, H-2', J 0.8 Hz, J 2.8 Hz, J 4.8 Hz), 6.90 (s,
1 2 3
–
HBr
1H, NH), 7.10–7.14 (m, 2H, Ar), 7.28–7.35 (m, 1H, Ar), 7.68 (dt, 1H,
Ar, J 0.8 Hz, J 8.2 Hz). C NMR (CDCl ) d: 16.6, 25.0, 32.7 (3CH ),
–
HBr
iii
13
1
2
3
2
3
9.5 (Me), 53.5 (CH–Br), 118.0, 123.8, 128.6, 134.0 (C-6, C-4, C-3,
4
b
iv
4
1
Br
6
7
3
2
C-5), 129.0 (C-2'), 131.4, 134.5, 135.2 (C-2, C-1, C-1'). Found (%): C,
4
9a
a
8a
46.93; H, 4.47; Br, 24.02; N, 3.90; S, 9.44. Calc. for C H BrNO S (%):
8
9
13 16
2
N
N
C, 47.28; H, 4.88; Br, 24.20; N, 4.24; S, 9.71.
‡
NHMs
1b
9-Methanesulfonyl-1,2,3,4-tetrahydrocarbazole 4.
Ms
Ms
a. Amide 3 (0.16 g, 0.49 mmol) was left for 96 h at room temperature;
resulting compound 4 was dissolved in CH Cl (15 ml) and washed with
4
5
2
2
1
0% NaHCO (15 ml). The organic phase was dried with Na SO , and the
3
2
4
solvent was evaporated in a vacuum. The residue was subjected to silica
4'
5
'
3'
2'
v
gel column chromatography (0.5 g, CH Cl as an eluent), which yielded
6
'
2
2
0
.12 g (98%) of carbazole 4.
b. A solution of AcBr (0.03 ml, 0.32 mmol) and (0.05 ml, 0.32 mmol)
N
Br
Br–
Br
5
4
of H2O in 1 ml of CH2Cl2 was added to a solution of 5 (0.04 g,
0.16 mmol) in 2 ml of CH Cl . After 72 h, the reaction mixture was
diluted with 30 ml of CH Cl and washed with 20 ml of a 10% NaHCO
solution. The organic phase was dried with Na2SO4; the solvent was
evaporated in a vacuum. The yield of heterocycle 4 was 0.039 g (97.5%).
R 0.75 (C H –EtOAc, 9:1). H NMR (CDCl ) d: 1.25–2.75 (m, 8H,
4
O
S
2
2
O
N
Ms
6
N
2
2
3
N
Ms
A
Me
1
1c
f
6
6
3
1
3
CH ), 3.00 (s, 3H, Me), 7.15–8.20 (m, 4H, Ar). C NMR (CDCl ) d:
2
3
Scheme 1 Reagents and conditions: i, MsCl, Py, 20 °C; ii, Br , NaHCO ,
20.9, 21.9, 23.0, 24.3 (4CH2), 40.1 (Me), 113.6, 118.0, 123.2, 123.8
(C-8, C-5, C-6, C-7), 118.4, 130.2, 135.2, 135.8 (C-4a, C-4b, C-9a,
C-8a). Found (%): C, 62.45; H, 6.03; N, 5.21; S, 12.59. Calc. for
C H NO S (%): C, 62.63; H, 6.06; N, 5.62; S, 12.86.
2
3
MeCN, 20 °C; iii, NH /H O, MeCN or MeOH; iv, HBr, CH Cl ; v, Br , Py,
3
2
2
2
2
2
0 °C; vi, NBS, MeCN or CH Cl , 20 °C or NBS, NaHCO , MeCN or
2
2
3
CH Cl , 20 °C.
2
2
13 15
2
–
235 –

,
2003, 13(5), 235–236
rule. In this process, the participation of the methane sulfonyl
References
group is possible with the formation, for example, of 1c because
1
2
J.-C. Gramain, H.-P. Husso and Y. Troin, J. Org. Chem., 1985, 50, 5517.
A. G. Mustafin, I. N. Khalilov, I. B. Abdrakhmanov and G. A. Tolstikov,
Khim. Prir. Soedin., 1989, 816 [Chem. Nat. Compd. (Engl. Transl.), 1989,
693].
1
0
like reactions are known. However, this supposition was not
confirmed by the interaction of sulfonyl amide 1 with NBS,
where the formation of cyclic 1c can occur. In this case, only
vinyl bromide 7†† was obtained, which can be the stabilization
product of carbocation 1d.
3
N. I. Andreeva, G. A. Bogdanova, A. I. Bokanov, P. Yu. Ivanov, M. D.
Mashkovski and V. I. Shvedov, Khim.-Farm. Zh., 1992, 4 (in Russian).
G. W. Gribble, J. Chem, Soc., Perkin Trans. 1, 2000, 1045.
Comprehensive Organic Chemistry, eds. D. Barton and W. D. Ollis,
Pergamon Press, Oxford–New York–Toronto–Sydney–Paris–Frankfurt,
4
5
The composition and structure of the compounds obtained
were determined by NMR spectroscopy (two-dimensional HH-
cosy, CH-corr) and JMOD and confirmed by elemental analysis.
One-dimensional NOE studies show intramolecular Overhauser
interaction between H-4, H-5 and H-4, H-2',6' as well as
1979, p. 8.
6
R. R. Gataullin, I. S. Afon’kin, A. A. Fatykhov, L. V. Spirikhin and
I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000, 118 (Russ.
Chem. Bull., Int. Ed., 2000, 49, 122).
1
between H-5 and H-2',6', in the H NMR spectrum of 6. It was
found that the saturation of the H-4 proton gives rise to an
7
8
9
M. Kizil, C. Lampard and J. R. Murphy, Tetrahedron Lett., 1996, 37,
2511.
J. A. Murphy, K. A. Scot, R. S. Sinclan and N. Lewis, Tetrahedron
Lett., 1997, 38, 7295.
B. Patro, M. C. Merret, S. D. Makin, J. A. Murphy and K. E. B. Parkes,
Tetrahedron Lett., 2000, 41, 421.
increase in the intensity of H-5 and H-2',6' bands by 5.4 and
1
7.0%, respectively. Similar irradiation of H-5 causes H-2',6'
pattern intensity growth by 2.9%. These facts indicate the spatial
proximity of the above protons.
§
-Methanesulfonyl-1,2,3,9a-tetrahydrocarbazole 5.8
10 J. I. G. Cadogan, D. K. Cameron, I. Gosney, R. M. Highcock and S. F.
9
Newlands, J. Chem. Soc., Chem. Commun., 1986, 10, 766.
a. 30 ml of a 1.5 NNH solution in MeOH was added to 1.0 g (3.03 mmol)
3
of 3 in 20 ml of MeOH. After 24 h, the solvent was evaporated in a
vacuum; the residue was dissolved in 100 ml of CH Cl and washed
2
2
with H O (50 ml). The organic phase was dried with Na SO . The
2
2
4
solvent was evaporated in a vacuum. Recrystallization from EtOH
yielded 0.6 g (79%) of compound 5, mp 106–108 °C (EtOH).
b. To a solution of sulfonylamide 1 (0.8 g, 3.1 mmol) and NaHCO3
(
2.52 g, 31 mmol) in 30 ml of MeCN a solution of Br (0.5 g, 3.1 mmol)
2
in 10 ml of the above solution was added with intense stirring. Then, the
reaction mixture was stirred for 3 h, and the precipitate was filtered off.
This process was carried out two times with the same quantities of amide
1
and bromine. The filtrates were combined and evaporated to a volume
of ~20 ml. The addition of 30 ml of an aqueous 25% NH3 solution
resulted in carbazole 5 in 20–30 min, which was filtered off, washed
with 10 ml of water and dried in a vacuum. The yield was 1.97 g (85%),
1
mp 106–108 °C. H NMR (CDCl ) d: 1.55–2.75 (m, 6H, 3CH ), 2.90 (s,
3
2
3
H, Me), 4.35 (dq, 1H, H-9a, J 3.6 Hz, J 10.0 Hz), 5.98 (q, 1H, H-4,
1 2
J 3.6 Hz), 7.06 (dt, 1H, H-7, J 0.9 Hz, J 7.5 Hz), 7.23 (dd, 1H, H-6,
1
2
J 7.5 Hz, J 8.1 Hz), 7.38 (d, 1H, H-8, J 7.5 Hz), 7.51 (dd, 1H, H-5,
1
2
13
J 0.6 Hz, J 8.1 Hz). C NMR (CDCl ): 19.9, 24.4, 29.1 (3CH ), 33.8
1
2
3
2
(
1
6
Me), 64.7 (C-9a), 114.3 (C-8), 118.7 (C-6), 120.2 (C-5), 124.0 (C-4),
35.3 (C-7), 129.1, 129.3, 143.2 (C-4b, C-4a, C-8a). Found (%): C,
2.24; H, 5.81; N, 5.43; S, 12.43. Calc. for C H NO S (%): C, 62.63;
1
3
15
2
H, 6.06; N, 5.62; S, 12.86.
¶
1
-(9-Methanesulfonyl-1,2,3,4-tetrahydro-4-carbazolyl)pyridinium bromide
. 0.96 g (5.9 mmol) of Br2 in 10 ml of MeCN was added slowly to
tetrahydrocarbazole 5 (1.47 g, 5.9 mmol) in 20 ml of MeCN and 1.5 g
18 mmol) of Py with intense stirring. After 1 h, the solvent was evapo-
6
(
rated in a vacuum. The residue was dissolved in hot H O (10 ml), the
2
solution was decanted and then cooled. The precipitated crystals of the
quaternary salt of 7 were filtered off. The yield was 1.5 g (62.5%),
1
2
mp 129–130 °C. H NMR ([ H ]DMSO) d: 1.85–3.37 (m, 6H, 3CH ),
6
2
3
7
.52 (s, 3H, Me), 6.48 (t, 1H, H-4, J 4.7 Hz), 6.98 (d, 1H, H-5, J 7.7 Hz),
.15 (t, 1H, H-6, J 7.7 Hz), 7.35 (dt, 1H, H-7, J 1.0 Hz, J 8.4 Hz), 7.95
1
2
(
d, 1H, H-8, J 8.4 Hz), 8.18 (t, 2H, H-3', H-5', J 7.5 Hz), 8.70 (t, 1H,
1
3
H-4', J 7.7 Hz), 9.31 (dd, 2H, H-2', H-6', J 1.0 Hz, J 5.2 Hz). C NMR
1
2
2
(
(
1
[ H ]DMSO) d: 17.9, 23.4, 30.6 (3CH ), 41.60 (Me), 63.9 (C-4), 109.9
6
2
C-4a), 113.6 (C-8), 117.9 (C-5), 123.5 (C-6), 124.6 (C-7), 126.3 (C-4b),
28.2 (C-3', C-5'), 135.4 (C-8a), 142.3 (C-9a), 143.9 (C-2', C-6'), 146.3
C-4'). Found (%): C, 52.91; H, 4.53; Br, 19.27; N, 6.41; S, 7.49. Calc.
for C H BrN O S (%): C, 53.08; H, 4.70; Br, 19.62; N, 6.88; S, 7.87.
(
18
19
2
2
†
†
N-Methanesulfonyl-2-(2-bromocyclohex-1-en-1-yl)aniline 7. The mix-
ture of mesilate 1 (0.25 g, 1 mmol) with NBS (0.53 g, 3 mmol) in 20 ml
of CH Cl was stirred in the presence of NaHCO (1 g) for 4 h. Then, the
2
2
3
reaction mixture was added to a 12% Na SO solution (10 ml), stirred
2
3
for 10 min and extracted with 50 ml of CH Cl . The organic phase was
2
2
washed with water (10 ml) and dried over Na SO . The solvent was
2
4
evaporated in a vacuum; the residue was recrystallised from ethanol, the
yield of compound 7 was 0.3 g (91%), mp 148–150 °C (EtOH). IR
–1
1
(
n/cm ): 490, 514, 530 (C–Br), 3262 (NH). H NMR (CDCl ) d: 1.75–
3
1
3
.95 (m, 4H, 2CH ), 2.25–2.40 (m, 2H, CH ), 2.60–2.80 (m, 2H, CH ),
2 2 2
.10 (s, 3H, SO Me), 6.40 (s, 1H, NH), 7.06 (dd, 1H, H-6, J 1.6 Hz,
2
1
J 7.6 Hz), 7.15–7.35 (m, 2H, H-4, H-5), 7.60 (d, 1H, H-3, J 8.1 Hz).
2
3
1
C NMR (CDCl ) d: 22.4, 24.4, 33.5, 36.2 (C-3', C-4', C-5', C-6'), 39.9
Me), 118.5, 124.8, 128.6, 128.7 (C-3, C-4, C-5, C-6), 131.6, 133.2, 133.6,
3
(
1
3
34.3 (C-1, C-1', C-2, C-2'). Found (%): C, 46.84; H, 4.45; Br, 23.82; N,
.81; S, 9.29. Calc. for C H BrNO S (%): C, 47.28; H, 4.88; Br, 24.20;
1
3
16
2
N, 4.24; S, 9.71.
Received: 18th December 2002; Com. 02/2025
–
236 –