Diazepines[1,4] annelated with indoline and maleimide from 3-(di)alkylamino-4-(indol-1-yl)maleimides: Mechanism of rearrangement and cyclization

Article abstract of DOI:10.1016/j.tet.2005.01.005

The mechanism of cyclization of 3-(di)alkylamino-4-(indol-1-yl)maleimides to diazepine[1,4] derivatives was elucidated using deuterium labeled precursors.

Full text of DOI:10.1016/j.tet.2005.01.005

Tetrahedron 61 (2005) 2017–2020
Diazepines[1,4] annelated with indoline and maleimide from
3-(di)alkylamino-4-(indol-1-yl)maleimides: mechanism of
rearrangement and cyclization
*
Sergey A. Lakatosh, Yuri N. Luzikov and Maria N. Preobrazhenskaya
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, Moscow 119021, Russian Federation
Received 4 August 2004; revised 22 November 2004; accepted 5 January 2005
Available online 22 January 2005
Abstract—The mechanism of cyclization of 3-(di)alkylamino-4-(indol-1-yl)maleimides to diazepine[1,4] derivatives was elucidated using
deuterium labeled precursors.
q 2005 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
In our previous paper1 we have described an unusual
cyclization of 3-(di)alkylamino-4-(indol-1-yl)maleimides
(1) by protic acids leading to the diazepines[1,4] with
annelated indoline and maleimide nuclei (2) (Fig. 1).
Treatment of 3-diethylamino-4-(indol-1-yl)-1-methyl-
maleimide 8 with TFA in CH2Cl2 gave diazepine derivative
9.1 Similarly, the dideuterated product 10 was obtained in
80% yield when CF3CO2D was used (Fig. 3).
The 1H and 13C NMR spectra of compounds 9 and 10 were
compared (Table 1).
The 1H NMR spectrum of 10 was more straightforward than
that obtained for 9. Instead of a three hydrogen multiplet in
the range d 3.1–3.25 the single hydrogen multiplet at d 3.17
was present. The latter was coupled with three hydrogen
triplet at d 1.08. This fact allows us to identify this signal as
one of the hydrogens of the methylene group attached to N7.
The signals corresponding to the hydrogens at C2 (position-
3 of the indoline subfragment) were absent. The signal
corresponding to the hydrogens at C1 (position-2 of indoline
subfragment) at d 4.44 was a broad singlet instead of
complex multiplet at d 4.43–4.49 in the spectrum of 9. The
Figure 1.
We assumed that the cyclization proceeds via three steps
(Fig. 2): (1) protonation of the indole nucleus at position 3
(4); (2) hydride shift from the carbon atom adjacent to the
nitrogen atom to position 2 of the protonated indole nucleus.
This shift leads to the formation of indoline and iminium ion
moieties (5); (3) electrophilic attack of the iminium ion at
position 7 of the indoline nucleus resulting in protonated
diazepine derivative 6. Presented herein are the results of
the experiments performed to test this hypothesis.
1
other parameters of H NMR spectra of 9 and 10 were
similar. In the 13C NMR spectrum of 9 the singlet signal of
C2 atom at d 28.2 was present; in contrast, in the 13C NMR
spectrum of 10 a multiplet (a doublet of triplets JZ30.5,
19.8 Hz) at d 27.4–28.1 was detectable. Thus, we conclude
that the product of cyclization of indolylmaleimide 8 by
CF3CO2D (compound 10) has two deuterium atoms at
position 2 (position 3 of indoline subfragment). This finding
supports the hypothesis that the first step of cyclization is the
protonation of the indole nucleus at position 3.
Keywords: Cyclization; Hydride shift; Mechanism; Indole.
* Corresponding author. Tel.: C7 095 245 3753; fax: C7 095 245 0295;
e-mail: mnp@space.ru
We next set out to find the source of hydrogen at C1 in the
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.01.005

2018
S. A. Lakatosh et al. / Tetrahedron 61 (2005) 2017–2020
Figure 2.
Thus the percentage of deuterium incorporation in 12, 13,
and 14 can be evaluated as more than 97%.
The synthesis of indolinodiazepine derivative 17 from
indolomaleimide 16 was described previously.1 Indolo-
maleimide 15 was treated with TFA in CH2Cl2 and the
cyclization product 18 was isolated as described for
1
compound 17.1 The H and 13C NMR spectra of 18 were
compared with the spectra of non-deuterated indolino-
diazepine 17 (Table 2) and demonstrate that compound 18
contains as an admixture about 15% of non-deuterated
1
compound 17. H NMR spectra of compounds 17 and 18
were very close. However, in H NMR spectrum of 18 the
1
signals of an admixture of 17 [hydrogen atom at C6 (one
hydrogen quadruplet at d 5.31), methyl group at C6 (three
hydrogen doublet at d 1.42) and one of the signals
corresponding to hydrogens at C1 (doublet of triplets at d
4.55)] were observed with the relative intensity of 15%; and
the signal of another C1–H hydrogen at d 4.35 was a triplet
whereas in compound 17 it was a quadruplet. In the 13C
NMR spectrum of 18 C6–CH3 methyl carbon signal, as well
as the signals of C6 and C1, were observed as multiplets at d
21.1, 50.2, and 56.7 instead of singlets at d 20.3, 48.3 and
55.1, respectively. The signals of carbon atoms of non-
deuterated product were also detectable as low intensity
singlets at d 22.3, 50.5 and 57.1. EI-MS data show that
compound 18 contains the admixtures of the corresponding
tetra-deutero derivative (w25%) and non-deutero
compound 17 (w13%) (Fig. 4).
Figure 3.
cyclization products 2. 1-Benzyl-3-[(d5-ethyl)anilino]-4-
(1H-indol-1-yl)-1H-pyrrole-2,5-dione 15 was used as a
model compound in this experiment. Sodium d5-ethylate
prepared from d6-ethanol 11 and NaH in THF was treated
with TosCl to give d5-ethyl tosylate 12. N-(d5-Ethyl)aniline
13 was obtained by the reaction of 12 with an excess of
aniline. The reaction of 13 with 3-bromo-4-(indole-1-
yl)maleimide 14 in DMF in the presence of Huenig base
yielded 15. According to the EI-MS spectrum and 1H NMR
data of 15 the percentage of deuterium incorporation was
97%. The signals corresponding to the carbon atoms of the
ethyl group of non-deuterated 15 were observed in the 13C
NMR spectrum as low intensity singlets at d 13.7 and 46.6.
Altogether, our data demonstrate that, in the cyclization of
compound 15, the deuterium atom migrates from the
position adjacent to nitrogen of N-(d5-ethyl)aniline residue
to position-2 of the indole nucleus. This model confirms the
mechanism of the cyclization process suggested in our
previous study.1

S. A. Lakatosh et al. / Tetrahedron 61 (2005) 2017–2020
Table 1. The differences in NMR spectra of compounds 9 and 10a
2019
Compound 9
Commentary
Compound 10
Commentary
1H NMR, d, ppm
3.1–3.25, 3H, m
4.43–4.49, 2H, m
C2–H2 and one of the hydrogens of N7–CH2 group
C1–H2
3.17, 1H, m
4.44, 2H, br s
One of the hydrogens of N7–CH2 group
C1–H2
13C NMR, d, ppm
28.2, s
C2
27.4–28.1, m
C2
a The spectra were registered in CDCl3.
3. Experimental
3.1. General
Table 2. Differences in NMR spectra of compounds 17 and 18a
NMR spectra were recorded with Varian VXR-400 instru-
ment at 400 MHz (1H NMR) or at 75 MHz (13C NMR) with
internal references. Chemical shifts are given in ppm and
coupling constants in Hz. Assignment of the signals was
based on the decoupling experiments for 1H NMR and APT-
experiments for 13C NMR spectra, the signals correspond-
ing to the quaternary carbon atoms are marked (q). Electron
impact mass-spectra (EI-MS) were obtained on an SAQ 710
Finnigan instrument at 70 eV (direct introduction, ion
source temperature 150 8C). HRMS mass spectra were
registered on a MAT 8430 Finnigan instrument with data
operating system SS-300 (EI, 70 eV, direct introduction, ion
source temperature 250 8C). Analytical TLC was performed
on Kieselgel F254 plates (Merck) and column chromato-
graphy on Silica Gel Merck 60. Mps were determined on a
Buchi SMP-20 apparatus and are uncorrected. Extracts were
dried over anhydrous Na2SO4 and evaporated under reduced
pressure. Solvents and reagents were obtained from
commercial suppliers unless otherwise specified.
Compound 17
Compound 18
Commentary
1H NMR
1.42, 3H, d
4.45, 1H, q
4.55, 1H, dt
5.31, 1H, q
13C NMR
20.3, s
48.3, s
55.1, s
Less intensive
4.34, 1H, t
Less intensive
Less intensive
C6–CH3
C1–Ha
C1–Hb
C6–H
21.1, m
50.2, m
56.7, m
C6–CH3 (C6–CD3)
C1
C6
a The spectra were registered in DMSO-d6.
3.1.1. d5-Ethyl tosylate (12). d6-Ethanol (5.1 ml,
77.5 mmol) was added dropwise at 0 8C to the stirred
suspension of NaH (2.4 g, 100 mmol) in THF (35 ml). The
resulting suspension was stirred for 30 min at ambient
temperature and treated with TosCl (19 g, 100 mmol)
dissolved in THF (20 ml). The reaction mixture was stirred
overnight, and the solvent was evaporated. The residue was
dissolved in Et2O–1 N HCl mixture (1:1, 100 ml). Organic
phase was washed with NaHCO3 solution (30 ml), water
(30 ml), brine (30 ml) dried over Na2SO4 and evaporated.
The residue was chromatographed (n-heptane–EtOAc,
20:1) to give 12 as an oil that crystallized upon standing
at 0 8C for 7 days as colorless crystals (12.4 g, 61 mmol,
70%); mp 32–34 8C (n-heptane–EtOAc, 20:1); Rf 0.35
(n-heptane–EtOAc, 5:1); dH (CDCl3) 2.4 (3H, s, PhCH3),
7.3 (2H, d, Ph), 7.74 (2H, d, Ph); dC (CDCl3) 13.2–13.9 (m,
–CD2CD3), 21.4 (PhCH3) 65.7–66.1 (m, –CD2CD3), 127.6
(2C), 129.6 (2C), 133.0 (q), 144.5 (q) m/z (EI-MS) MC 205
(100), MCKOCD2CD3 155 (85), 91 MCKC2D5OSO2
(40%).
3.1.2. N-(d5-Ethyl)aniline (13). The mixture of aniline (5 g,
54 mmol) and 12 (5.5 g, 27 mmol) was stirred at ambient
temperature until no starting 12 could be detected by TLC.
The reaction mixture was diluted with Et2O (100 ml) and
extracted with 2 N HCl (2!50 ml). The extracts were
washed with CHCl3 (50 ml), pH was adjusted to 12 with 2 N
NaOH solution, and the amines were extracted with Et2O
Figure 4.

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S. A. Lakatosh et al. / Tetrahedron 61 (2005) 2017–2020
(2!75 ml). The extracts were dried over NaOH and
evaporated. 13 was separated from the starting aniline by
column chromatography (n-heptane/n-heptane–Et3N,
20:1) to give 13 as a dark oil (2.3 g, 18.4 mmol, 50%); dH
(CDCl3) 3.5 (1H, br s, NH), 6.66 (3H, d, Ph), 6.76 (2H, t,
Ph), 7.24 (3H,t, Ph); dC (CDCl3) 13.6–14.1 (m, –CD2CD3),
37.1–37.5 (m, –CD2CD3), 112.5 (2C), 117.0, 129.0 (2C),
148.3 (q).
3.1.5. 9-Benzyl-1,6-dideutero-2-hydro-6-(d3-methyl)-7-
phenyl-6H-pyrrolo[30,40:2,3][1,4]diazepino [6,7,1-hi]in-
dole-8,10(7H,9H)-dione (18). To the stirred solution of
15 (200 mg, 0.48 mmol) in CH2Cl2 (20 ml) was added TFA
(2 ml) and the mixture was left to stir for 8 h. The reaction
mixture was diluted with EtOAc (60 ml) and washed with
aq NaHCO3 (3!20 ml), water (20 ml) and brine; dried and
evaporated, the residue was chromatographed (n-heptane/
n-heptane–acetone, 10:1) to give 18 as a dark violet solid
(120 mg, 60%); mp 139–141 8C (cyclohexane), Rf 0.24
(n-heptane–EtOAc 6:1); m/z (EI HRMS) MC 426.2085
(C27H18D5N3O2 requires 426.2099) (100%), m/z (EI-MS)
MC 426 (100), MC (non-deuterated) 421 (15), MCKCD3
408 (30), MC (non-deuterated) KCH3 406 (9%).
3.1.3. 2-Dideutero-1,2-dihydro-7-ethyl-6,9-dimethyl-6H-
pyrrolo[30,40:2,3][1,4]diazepino[6,7,1-hi]indole-8,10-
(7H,9H)-dione (10). A solution of 3-(diethylamino)-4-(1H-
indol-1-yl)-1-methyl-1H-pyrrole-2,5-dione 8 (300 mg,
1 mmol) in CH2Cl2 (5 ml) was treated with CF3CO2D
(1 ml). The reaction mixture was left to stir overnight and
then poured into a mixture of EtOAc (50 ml) and aq
NaHCO3 (30 ml), the organic layer was separated, washed
with aq NaHCO3 (30 ml), water (30 ml), brine (30 ml) dried
over Na2SO4 and evaporated. The residue was purified by
column chromatography (n-heptane/n-heptane–acetone,
10:1) to give 10 as a dark violet solid (240 mg, 0.8 mmol,
80%); mp 80–82 8C (cyclohexane); Rf 0.41 (n-heptane–
EtOAc, 3:1); m/z (EI HRMS) MC 299.1614
(C17H17D2N3O2 requires 299.1601) (100), MCKCH3 284
(80), MCKNCH2CH3 256 (28), MCKC(O)NCH3 241
(50%).
Acknowledgements
This work was supported by Russian Foundation for Basic
Research, grant No. 03-03-32090-a. S. A. Lakatosh was also
supported by the Regional Social Fund for Support of
Russian Medical Science.
3.1.4. 1-Benzyl-3-[N-(d5-ethyl)aniline]-4-(1H-indol-1-yl)-
1H-pyrrole-2,5-dione (15). To the solution of 1-benzyl-3-
bromo-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione 14 (1.1 g,
2.7 mmol) in DMF (10 ml) were added N-(d5-ethyl)aniline
(0.5 g, 3.9 mmol) and ethyldiisopropylamine (1 ml). The
reaction mixture was stirred at 60 8C for 72 h and diluted
with EtOAc (50 ml) and water (20 ml). The organic layer
was separated and washed with 1 N HCl (2!10 ml), aq
NaHCO3 (10 ml), water (10 ml), brine (10 ml), dried and
evaporated. The residue was purified by chromatography
(n-heptane–EtOAc, 15:1) to give 15 as red crystals (0.8 g,
1.9 mmol, 70%); mp 112–114 8C (n-heptane–EtOAc); Rf
0.42 (n-heptane–EtOAc, 6:1); m/z (EI HRMS) MC
426.2087 (C27H18D5N3O2 requires 426.2099) (100),
MCKCD3 408 (11%).
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tet.2005.
01.005
References and notes
1. Lakatosh, S. A.; Luzikov, Y. N.; Preobrazhenskaya, M. N. Org.
Biomol. Chem. 2003, 1, 826–833.