A peculiar selective rearrangement during the NiS-catalysed dehydrogenation of 4,5-dihydro-1H-benz[g]indole

Article abstract of DOI:10.1016/j.mencom.2007.09.017

The dehydrogenation of 4,5-dihydro-1H-benz[g]indole on NiS/Al₂O₃ (350 °C) is accompanied by a peculiar rearrangement to give 3H-benz[e]indole (71%).

Full text of DOI:10.1016/j.mencom.2007.09.017

Mendeleev
Communications
Mendeleev Commun., 2007, 17, 296–298
A peculiar selective rearrangement during the NiS-catalysed
dehydrogenation of 4,5-dihydro-1H-benz[g]indole
Boris A. Trofimov,*a Alexander M. Vasil’tsov,a Igor’ A. Ushakov,a Andrey V. Ivanov,a
Elena Yu. Schmidt,a Al’bina I. Mikhaleva,a Nadezhda I. Protsuka and Vladimir B. Kobychevb
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russian Federation. Fax: +7 3952 41 9346; e-mail: boris_trofimov@irioch.irk.ru
b Institute of Mathematics, Economics and Information Science, Irkutsk State University, 664033 Irkutsk,
Russian Federation. Fax: +7 3952 42 6856; e-mail: gimli@cc.isu.ru
DOI: 10.1016/j.mencom.2007.09.017
The dehydrogenation of 4,5-dihydro-1H-benz[g]indole on NiS/Al2O3 (350 °C) is accompanied by a peculiar rearrangement to
give 3H-benz[e]indole (71%).
Among indole antibiotics (CC-1065 and duocarmycins), which
are strong cytotoxins and potential anticancer drugs,1 benz[e]-
indole analogues are more stable and pharmacologically active,2
though a number of benz[g]indoles are also used for the
therapeutic purposes.3 Recently, carbocyanine and 4,4-difluoro-
4-bora-3a,4a-diaza-s-indacene dyes with benz[e]indole4 and
benz[g]indole5 moieties, showing fluorescence in the near-
infrared spectral region, have been synthesised for biomonitoring.
So far the syntheses of unsubstituted benzindoles are of low
to moderate yieding multistep procedures based on inaccessible
starting materials.6–9
In order to elaborate a novel expedient synthesis of 1H-benz-
[g]indole 2, we studied the dehydrogenation of 4,5-dihydro-1H-
benz[g]indole 1, which is readily available from 1-tetralone10 or
1-tetralonoxime11 and acetylene using the KOH/DMSO catalytic
system (the yield of 1 was 72%).10
It would be expected that the dehydrogenation of indole 1
proceeds easily. This can be seen, for example, during the
aromatizations of tetraline,12 indolines13 and a 4,5-dihydro-
1H-benz[g]indole moiety (in BODIPY dyes),5 which takes
place quantitatively. However, under these conditions, indole 1
was inactive.
The successful catalytic dehydrogenation of indole 1 has been
achieved in the presence of NiS on granular alumina at 350 °C.
Unexpectedly, on the ‘fresh’ catalyst, 3H-benz[e]indole 3 was
detected as the major product (its concentration in the catalysate
reached 71%). As the reaction time was increased, the con-
centration of indole 3 decreased and that of target indole 2
increased. Finally, after 2.5 h, the overall yield of indoles
2 and 3 in 2.5 h reached 88% (70% 2 + 18% 3) (Scheme 1).†
Pure crystalline g-isomer 2 can be easily isolated from the
catalysate due to its low solubility in cold n-hexane, whereas
e-isomer 3 is soluble in n-hexane, benzene and diethyl ether.
†
NMR spectra were recorded on a Bruker DPX 400 spectrometer
(400.13 MHz for H; 101.61 MHz for 13C) with HMDS as an internal
1
standard. The assignments of 1H and 13C NMR spectra were performed by
COSY, NOESY, HSQC and HMBC experiments. IR spectra were obtained
on a Bruker IFS 25 instrument in KBr pellets. GLC analysis was carried
out on Agilent 6890N, HMS – on Shimadzu GCMS-QP5050A.
Catalyst Preparation. Granulated Al2O3 (50 g) in 110 ml of an aqueous
solution of Ni(OAc)2 (21.18 g) was stirred for 1 h and then kept overnight.
Afterwards, H2S (100 ml min–1) was passed through the mixture for 30 min.
The catalyst was filtered off, washed with a 3% aqueous solution of
NaOH (200 ml) and then washed with distilled water to pH 7 and dried
in air at 100 °C for 5 h.
Dehydrogenation of 4,5-dihydro-1H-benz[g]indole 1. Method A:
4,5-Dihydro-1H-benz[g]indole 1 (0.50 g, 3 mmol) in 10 ml of benzene
was passed in N2 flow (3 dm3 h–1) dropwise through the quartz reactor
(a 10 mm diameter tube filled with a catalyst: NiS/Al2O3, 0.44% Ni,
alumina particles, 2×3 mm; catalyst layer, 8.5 cm) at 350 °C for 2.5 h.
Afterwards, another portion of neat benzene (10 ml) was passed through
the reactor at the same temperature for 1.5 h. Benzene was evaporated
from the reaction mixture to give 0.45 g of a solid (mixture of indoles
2 and 3). The mixture was dissolved in boiling n-hexane and after
cooling to ambient temperature, kept at 6–8 °C overnight. The crystals
precipitated were washed with cold n-hexane to give 0.35 g (70% yield)
of g-isomer 2 as light-gray crystals with metallic luster, mp 181 °C
(lit.,6 mp 177–178 °C). After the evaporation of n-hexane, 0.10 g of
3H-benz[e]indole 3 (90% purity, 18% yield) was isolated as viscous
1
yellow oil (lit.,6 mp 34–35 °C; yellow oil7). H and 13C NMR spectral
data of 2 and 3 are in a good accordance with literature data.9
Method B: 4,5-Dihydro-1H-benz[g]indole 1 (1.50 g, 9 mmol) in 30 ml
of benzene was passed in N2 flow (3 dm3 h–1) dropwise through the
same reactor with the fresh catalyst at 350 °C for 8.5 h. Afterwards,
the reactor was washed with 10 ml of neat benzene at the same tem-
perature for 1.5 h. After evaporation of benzene, 1.01 g of a mixture of
indoles 2 and 3 was obtained (the indole 3 content of the mixture was
41%, yield 28%).
NiS/Al2O3, – H2
350 °C, 2.5 h
N
H
1
Method C: 4,5-Dihydro-1H-benz[g]indole 1 (1.50 g, 9 mmol) in 30 ml
of benzene was passed in N2 flow (3 dm3 h–1) dropwise through the
reactor with granulated Al2O3 (catalyst layer of 8.5 cm) at 350 °C
for 8.5 h. After the evaporation of benzene, 0.22 g of a mixture of
indoles 1 (recovered 9.8%), 2 (yield 0.9%), 3 (yield 3.6%) and, possibly,
deprotonated 4 and dihydro derivative 5 (yields of 0.3 + 0.4%) was
obtained. MS (EI) for benzindoles 2 and 3: m/z (%), 167 ([M+], 100),
139 (32), 84 (30). MS (EI) for isomers 1, 5 and deprotonated 4: m/z (%),
168 ([(M – H)+], 100), 139 (13), 115 (10), 83 (55).
H
N
+
N
H
2
70%
3
18%
Scheme 1
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Mendeleev Commun., 2007, 17, 296–298
H+
HC CH
1
H
H
2
N
N
KOH/DMSO
129–132 °C, 7 h
N
H
H
H
H
H
6
78%
[1,2]
[1,2]
Scheme 3
N
design. The rearrangement described, apart from its synthetic
utility, unveils novel facets of basic benzindoles chemistry
under heterogeneous catalysis conditions.
H
H
4
This work was supported by the Presidium of the Russian
Academy of Sciences (grant nos. 10002-251/P-25/155-305/
200404-072 and 10104-71/P-25/155-305/090605-003) and the
Russian Science Support Foundation.
H
3
– H+
– H2
N
H
H
N
H
5
References
Scheme 2
1
D. L. Boger, J. Desharnais and K. Capps, Angew. Chem., Int. Ed. Engl.,
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The rearrangement of 1 to 3 is likely to involve spiro-inter-
mediate 4, which undergoes further substituent migration over
the pyrrolenine ring to give 4,5-dihydro-3H-benz[e]indole 5,
which is dehydrogenated to indole 3 (Scheme 2). These substi-
tuent migrations are presumed to be of a carbocationic nature
due to the remaining acidic centres of Al2O3(H2O)n, which
are gradually quenched by the basic products of pyrrole ring
oligomerization.
2
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The proposed mechanism is confirmed by an experiment on
the pure carrier Al2O3 performed under the same conditions
as with NiS/Al2O3. In this case, in the catalysate, apart from
starting indole 1 (the main component, recovery is 9.8%)
among the reaction products (over 10) isomers 2 and 3 (in 0.9
and 3.6% yields, respectively) were identified using MS and GLC
techniques. Obviously, the dehydrogenation in the absence of
NiS occurs owing to the energy gain due to the aromatization
of tricyclic ensembles. However, the process becomes less
selective and 85% of the products remain on alumina because
of the pyrrole ring oligomerization in the presence of acids.14
Upon GLC and MS analysis of the product mixture, two other
isomers of the starting material were detected, which may cor-
respond to dihydro derivative 5 and deprotonated spiro-inter-
mediate 4. Thus, the NiS deposition on Al2O3 secures the selective
dehydrogenation 1 ® 2 suppressing isomerization processes.
A comparison of the quantum-chemical calculations (the
B3LYP hybrid functional15 with 6-31G* basis set, 2:3 = 44:56
at 625 K; MP2/6-311G**, 2:3 = 42:58 at equilibrium) with the
experimental results confirms that the reaction mixture does not
reach an equilibrium and the indole ratio 2:3 is controlled by
kinetic factors such as the concentration of protogenic centres
of a catalyst and their evolution during the reaction.
A synthetic advantage of the catalytic method developed
is that it allows parent benz[e]- and benz[g]indoles, so far
practically inaccessible, to be synthesised from readily available
1-tetralone oxime in only two simple steps.
So far these heterocycles have been a challenge to synthesise,
but functionalizations on the ring are a matter of appropriate
experimental technique. For example, indole 2 is readily vinylated
with acetylene under atmospheric pressure in the superbase
catalytic system KOH/DMSO (129–132 °C, 7 h) to afford
1-vinyl-1H-benz[g]indole 6 in 78% yield (85% conversion of 2)
(Scheme 3).‡
5
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‡
Vinylation of benz[g]indole 2. 1H-benz[g]indole 2 (1.90 g, 11.3 mmol),
KOH·0.5H2O (2.50 g, 38.5 mmol) and DMSO (20 ml) were placed in a
50 ml flask furnished with a magnetic stirrer, a thermometer and a tube
for acetylene introduction. The mixture was heated (129–132 °C) and
acetylene was fed for 7 h with stirring. GLC was used for the reaction
control. The cooled reaction mixture (20 °C) was extracted by n-hexane
(6×20 ml); the combined extracts were washed with water (3×20 ml)
and dried over K2CO3. Hexane was removed, and the crude product was
column chromatographed (basic Al2O3; eluent, n-hexane) to give 1.71 g
(8.8 mmol, 78% yield) of 1-vinyl-1H-benz[g]indole 6, yellowish viscous
oil, soluble in organic solvents.
1
1-Vinyl-1H-benz[g]indole 6. H NMR (CDCl3) d: 8.36 (d, 1H, H-9,
J 8.5 Hz), 7.91 (d, 1H, H-6, J 8.1 Hz), 7.74 (dd, 1H, HX, JB–X 15.6 Hz,
JA–X 9.0 Hz), 7.61 (d, 1H, H-4, J 8.5 Hz), 7.52 (d, 1H, H-5, J 8.1 Hz),
7.50 (t, 1H, H-8, J 8.1 Hz, J 1.2 Hz), 7.40 (t, 1H, H-7, J 8.5 Hz, J 1.2 Hz),
7.31 (d, 1H, H-2, J 3.1 Hz), 6.68 (d, 1H, H-3, J 3.1 Hz), 5.43 (d, 1H, HB,
JB–X 15.6 Hz), 5.11 (d, 1H, HA, JA–X 9.0 Hz). 13C NMR (CDCl3) d:
134.73, 131.79, 129.41, 129.28, 126.27, 125.91, 125.62, 123.45, 123.12,
122.02, 121.38, 120.91, 105.12, 104.61. IR (KBr, n/cm–1): 3097, 3056,
3017, 2957, 2922, 2851, 1639, 1587, 1563, 1527, 1503, 1457, 1419, 1403,
1355, 1343, 1321, 1298, 1273, 1231, 1203, 1073, 1046, 980, 967, 942, 880,
868, 810, 783, 766, 745, 727, 693, 680, 589, 561, 422. Found (%): C, 86.99;
H, 6.01; N, 7.15. Calc. for C14H11N (%): C, 87.01; H, 5.74; N 7.25.
New vinyl derivative 6, is a structural isomer of N-vinyl-
carbazole, which is a widely used monomer and precursor of
active materials in the manufacture of light emitting diodes and
lasers.16 Thus, 6 may be expected to find similar application
in optoelectronics, as well as a useful intermediate in drug
– 297 –

Mendeleev Commun., 2007, 17, 296–298
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Received: 2nd March 2007; Com. 07/2885
– 298 –