Synthesis of substituted azepino[3,4-b]indole-1,5-diones

Article abstract of DOI:10.1002/ejoc.200400348

Cyclic β-amino esters 4, obtained from lactams, were condensed with indole-2-carbonyl chloride to afford the corresponding amides. Similarly, unusual conditions led to cyclisation at the 3-position of the indole moiety in the presence of pTSA and ethylene glycol to afford previously unknown pentacyclic derivatives 12 and 15. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400348

FULL PAPER
Synthesis of Substituted Azepino[3,4-b]indole-1,5-diones
[a]
[b]
[a]
ˆ
´
Julien Perron, Benoıt Joseph, and Jean-Yves Merour*
Keywords: β-Amino esters / Indoles / Electrophilic cyclisation / Synthesis design
Cyclic β-amino esters 4, obtained from lactams, were con-
of pTSA and ethylene glycol to afford previously unknown
densed with indole-2-carbonyl chloride to afford the corres- pentacyclic derivatives 12 and 15.
ponding amides. Similarly, unusual conditions led to cyclis-
ation at the 3-position of the indole moiety in the presence
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
kinase inhibitors such as paullones,[7,8] hymenialdisine[9Ϫ15]
and 5-(arylhydrazono)-3,4,5,10-tetrahydro-2H-azepino[3,4-
b]indol-1-one.[16,17]
The benzodiazepine scaffold provides access to a large
family of bioactive derivatives.[1] Of these the pyrrolo-
[2,1-c][1,4]benzodiazepine (PDB) antitumor antibiotics are
a well-known class of DNA-binding agents,[2,3] for example,
anthramycin (Figure 1), which have shown significant in vi-
tro cytotoxicity,[4,5] but have not progressed in clinical trials
because of side effects. Recently, Erba and co-workers de-
scribed the preparation of a similar indole analogue A, in
which the pyrrolo[1,2-c][1,4]diazepine moiety was obtained
from 2-amidinylindole-3-carboxaldehyde.[6] The seven-
membered lactam moiety is also encountered in potent gly-
cogen synthase kinase-3 (GSK3) and/or cyclin-dependant
For our part, we have reported the synthesis of the first
pyrrolo[1,2:1Ј,2Ј]azepino[6,5-b]indole-1,5-dione framework
B from indole-2-carboxylic acid and ethyl pyrrolidin-2-yl-
acetate through an unusual cyclisation reaction.[18Ϫ20]
Given the versatility of this synthetic approach, we sought
to extend it to the preparation of new pentacyclic com-
pounds C. The two main aims of this work were (i) the
development of a general preparation of N-heterocycle
acetates from five- or six-membered aromatic and heteroar-
omatic lactams and (ii) the application of our original
cyclisation reaction to various heterocycles.
First, the synthesis required the preparation of N-hetero-
cycle acetates such as ethyl 2-(2,3-dihydro-1H-indol-2-yl)-
acetate, ethyl 2-(1,2,3,4-tetrahydroquinolin-2-yl)acetate,
ethyl 2-(3,4-dihydro-2H-benzo[1,4]benzoxazin-3-yl)acetate
or ethyl 2-(1,2,3,4-tetrahydroquinoxalin-2-yl)acetate. Nu-
merous preparations of these derivatives have been reported
in the literature.[21Ϫ27] Some of them used nitroarenes as
the starting materials and involved tandem sequences
(reduction/reductive amination,[28,29] reduction/lactam
formation[30Ϫ31] and reduction/Michael addition).[32,33] In
our previous paper,[18] an effective synthesis of ethyl pyrroli-
din-2-ylacetate from pyrrolidone was described using a
closed method developed for the pyroglutamate series.[34]
The three-step synthesis was based on the reduction of the
pyrrolidinone followed by a HornerϪWadsworthϪEmmons
olefination and an intramolecular Michael addition
(Scheme 1).
Figure 1. Anthramycin and selected azepinoindoles
[a]
Institut de Chimie Organique et Analytique, UMR-CNRS
´
´
6005, Universite d’Orleans,
´
Results and Discussion
B. P. 6759, 45067 Orleans Cedex 2, France
Fax: (internat.) ϩ 33-2-38417281
E-mail: jean-yves.merour@univ-orleans.fr
[b]
Preparation of β-Amino Esters
Laboratoire de Chimie Organique 1, UMR-CNRS 5181,
´
ˆ
Universite Claude Bernard Ϫ Lyon 1, CPE Ϫ Batiment 308,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne
Cedex, France
Neither the Wittig nor the HornerϪWadsworthϪ
Emmons reaction is useful for the introduction of a two-
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400348
Eur. J. Org. Chem. 2004, 4606Ϫ4613

Synthesis of Substituted Azepino[3,4-b]indole-1,5-diones
FULL PAPER
Table 1. Yields of 2 and 3 in the reduction/olefination/Michael ad-
dition reactions
X
Y
W
n
Yield (%)
Yield (%)
2a[23]
2b
CH2
CH2
O
O
O
CH
CH
N
CH
CH
H
H
H
H
Ph
0
1
1
1
1
72
83
99
99
75
3a
3b
3c
3d
3e
63
76
57
91
89
2c
2d
2e
Scheme 1. Synthesis of ethyl (pyrolidin-2-yl)acetate
we developed an effective reduction/olefination/Michael
addition reaction sequence for the preparation of N-hetero-
cycle acetates.
carbon unit onto a lactam derivative. To do this, it is neces-
sary to increase the electrophilicity of the carbonyl group
in order for the lactam to react with phosphorus ylides re-
agents. One way to achieve this, is to partially reduce the
lactam function to a masked aldehyde such as an aminal
Access to Pentacyclic Indole Derivatives
These β-amino esters are useful precursors in the syn-
(Scheme 2). Lactams 1a, 1b and 1d are commercially avail- thesis of the pentacyclic derivatives C. We chose indolin-2-
able. Starting materials 1c and 1e were prepared according ylacetate 4a as a model starting material for the synthesis
to reported procedures.[35,36] Compounds 1 were first N- of C. Our first attempt to couple 4a and indole-2-carboxylic
protected with Boc2O in the presence of a catalytic amount acid (5) in the presence of 1-ethyl-3-(3-dimethylaminoprop-
of DMAP to afford compounds 2[37Ϫ40] in 72Ϫ99% yield. yl)carbodiimide (EDCI) yielded 9 in only 35% yield owing
The formation of the aminals was achieved by using a super to the low nucleophilicity of the amine 4a (i.e. with pyrroli-
hydride. These aminals were then immediately treated with dine-2-acetate, the yield of amidification was 85%).[18] The
the anion of triethyl phosphonoacetate. This olefination re- use of other added activating agents also proved fruitless.
action was immediately followed by an intramolecular Fortunately, when the crude indole-2-carbonyl chloride (7),
Michael addition to the acrylate chain by a favorable six- obtained by classical treatment of 5 with thionyl chloride,
exo-trig process. The derivatives 3 were obtained in fair was added in excess (3 equiv.) to the sodium salt of the
yields (see Table 1). Boc deprotection of 3 was carried out amino ester 4a (to enhance the nucleophilicity of the nitro-
in TFA to afford derivatives 4[21Ϫ23,32] in quantitative yield. gen atom) at room temperature, the desired amide 9 was
Note that the spontaneous cyclisation reaction was not ob- obtained in 57% yield. Similarly, 1-methylindole-2-carbonyl
served in the pyrrolidone series; instead the HornerϪ chloride (8), prepared from 6, was treated with 4a to give
WadsworthϪEmmons adduct was isolated in good yield amide 10 in excellent yield (96%). In this last reaction, only
(Scheme 1). Deprotection of the nitrogen atom by TFA 1.5 equiv. of the crude acyl chloride was necessary
yielded the salt as an (E) isomer. The enhanced nucleophil- (Scheme 3).
icity of the nitrogen atom in the presence of triethylamine
allowed the intramolecular Michael addition. In this way,
Scheme 2. a) Boc2O (1 equiv.), DMAP (0.1 equiv.), MeCN, room
temp., 48 h; b) LiBEt3H (1.2 equiv.), THF, Ϫ78 °C, 30 min; c)
(EtO)2P(O)CH2CO2Et (2 equiv.), NaH (2 equiv.), THF, 30 min; d)
CF3CO2H, CH2Cl2, room temp., 2 h, quantitative yield
Scheme 3. a) EDCI, DMAP, CH2Cl2, 0 °C to room temp., 24 h
(35%); b) SOCl2, Et3N, THF, 0 °C, 45 min; c) 4a (1 equiv.), NaH
(2 equiv.), THF, room temp., 2 h followed by addition to 7 (3
equiv.) or 8 (1.5 equiv.), 2 h (9 57%; 10 96%)
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FULL PAPER
Saponification of 9 in the presence of lithium hydroxide type A,[18] electrophilic cyclisation of the acid in poly-
in ethanol at room temperature led quantitatively to the phosphoric acid (PPA) was not successful and afforded by-
acid 11. But in contrast to the behavior of compounds of products (Scheme 4). The same result was again observed
when PPA cyclisation was applied to the acid obtained from
14d (see below). Next, we refluxed 9 or 10 in toluene in the
presence of 2 equiv. of para-toluenesulfonic acid (pTSA) for
24 h. In the first case, degradation of the starting material
was again observed, but with 10 we isolated the azepino
derivative 12 in 41% yield. This result and our previous
work on the synthesis of pyrrolo[1,2:1Ј,2Ј]azepino[6,5-
b]indole-1,5-dione[18] led us to investigate the electrophilic
ring closure of ester derivative 10 in the presence of pTSA
and ethylene glycol. Thus, this reaction was performed in
toluene at reflux for 8 h to afford compound 12. An optimal
yield of 87% was obtained in the presence of 2 equiv. of
pTSA monohydrate and 5 equiv.of ethylene glycol.
In order to gain an insight into the role played by ethyl-
ene glycol, the latter was replaced by 2-methoxyethanol.
After heating for 2 h, we observed only the formation of
the 2-methoxyethoxy ester 13 in good yield from 10 with no
trace of the azepino derivative (Scheme 5). A hypothetical
mechanism for the cyclisation reaction involves the initial
formation of an orthoester intermediate which then un-
dergoes electrophilic cyclisation in acidic media. Water
(from pTSA monohydrate) in the medium led to the final
hydrolysis of the acetal into the carbonyl function.
We extended our synthesis to two other β-amino esters
4b and 4d (Scheme 6). Amidification of the indolecarbonyl
Scheme 4. a) LiOH (2 equiv.), EtOH, room temp., 20 h (11 100%);
b) PPA, 120 °C, 2 h; c) pTSA monohydrate (2 equiv.), toluene, re-
flux, 24 h (12 41%); d) pTSA monohydrate (2 equiv.), ethylene gly-
col (5 equiv.), toluene, reflux, 8 h (12 87%)
Scheme 5. a) pTSA (2 equiv.), 2-methoxyethanol (5 equiv.), toluene, reflux, 2 h (13 89%); b) pTSA monohydrate (2 equiv.), ethylene glycol
(5 equiv.), toluene, reflux, 8 h
Scheme 6. a) NaH (2 equiv.), THF, room temp., 2 h followed by the addition of 8, room temp., 2 h; b) pTSA (2 equiv.), ethylene glycol
(5 equiv.), toluene, reflux, 3Ϫ5 h
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Eur. J. Org. Chem. 2004, 4606Ϫ4613

Synthesis of Substituted Azepino[3,4-b]indole-1,5-diones
FULL PAPER
tert-Butyl 2-Oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate (2b):
Compound 2b was prepared in 83% yield from 1b according to the
procedure described above for the synthesis of 2. The physical and
analytical data of 2b are identical in all respects to the data given
in the literature.[38]
chloride 8 with the sodium salt of 4b or 4d afforded com-
pounds 14b and 14d in 77 and 95% yields, respectively. Note
that the coupling reaction between 7 and 4e afforded the
corresponding amide in low yield (15%, not described in
the Expt. Sect.). Compounds 14b and 14d were subjected
to the cyclization reaction to give 15b and 15d respectively,
in good yields (Table 2). Note that the pyridinylamino ester
4c did not react with 8 owing to the low nucleophilicity of
the amine sodium salt.
tert-Butyl
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-4-car-
boxylate (2c): Compound 2c was prepared in 99% yield from 1c
according to the procedure described above for the synthesis of 2.
The physical and analytical data of 2c are identical in all respects
to the data given in the literature.[39]
tert-Butyl
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate
Table 2. Yields of 14 and 15
(2d): Compound 2d was prepared in 99% yield from 1d according
to the procedure described above for the synthesis of 2. The physi-
cal and analytical data of 2d are identical in all respects to the data
given in the literature.[40]
Amine
X
Yield (%)
Yield (%)
4b
4d
CH2
O
14b
14d
77
95
15b
15d
82
76
tert-Butyl 3-Oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-car-
boxylate (2e): Compound 2e was prepared as a yellow oil in 75%
yield from 1e according to the procedure described above for the
synthesis of 2. IR (film): ν˜ ϭ 1748, 1734 cmϪ1 1H NMR
.
Conclusions
(250 MHz, CDCl3, 25 °C): δ ϭ 1.64 (s, 9 H, 3 CH3), 6.10 (s, 1 H,
OCH), 6.89Ϫ7.07 (m, 3 H, HAr), 7.13Ϫ7.27 (m, 5 H, HAr), 7.79
(d, J ϭ 7.9 Hz, 1 H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25
°C): δ ϭ 27.8 (3 CH3), 76.9 (OCH), 84.3 (C), 116.0 (CH), 117.5
(CH), 118.4 (CH), 122.4 (CH), 125.1 (CH), 125.3 (CH), 125.7
(CH), 126.2 (C), 128.2 (CH), 128.7 (CH), 132.3 (C), 145.4 (C),
150.0 (CϭO), 163.9 (CϭO) ppm. ESI MS: m/z ϭ 326 [Mϩ ϩ H].
C19H19NO4 (325.4): calcd. C 70.14, H 5.89, N 4.30; found C 69.95,
H 5.78; N 4.43.
An effective reduction/olefination/Michael addition reac-
tion sequence has been developed for the preparation of N-
heterocycle acetates 4. Similarly, unusual conditions led to
cyclisation at the 3-position of the indole moiety in the pres-
ence of pTSA and ethylene glycol to afford previously un-
known pentacyclic derivatives 12 and 15.
tert-Butyl 2-(2-Ethoxy-2-oxoethyl)-2,3-dihydroindole-1-carboxylate
(3a): Under argon, 1  LiBEt3H in THF (2.60 mL, 2.60 mmol) was
added dropwise to a solution of 2a (500 mg, 2.14 mmol) in anhy-
drous THF (10 mL) at Ϫ78 °C. After stirring at Ϫ78 °C for 30 min,
the mixture was treated with a saturated Na2CO3 solution (3 mL);
then a 35% H2O2 solution (3 mL) was slowly added at Ϫ15 °C. The
mixture was stirred at room temperature for 30 min, then filtered.
The filtrate was concentrated in vacuo and the residue was ex-
tracted with ethyl acetate (2 ϫ 10 mL). The organic phase was
washed with brine, dried with MgSO4 and filtered. The filtrate was
maintained under reduced pressure for 2 h. Then, the remaining
residue was dissolved in THF (5 mL) and added dropwise at 0 °C
to a freshly prepared solution of triethyl phosphonoacetate anion
(4.30 mmol) in THF (5 mL). After stirring at room temperature for
30 min, the mixture was hydrolysed and extracted with ethyl acet-
ate. The organic layer was dried with MgSO4 and the solvents were
evaporated in vacuo. The residue was purified by flash chromatog-
Experimental Section
General Remarks: Melting points were determined with a Büchi
SMP-20 melting point apparatus and are uncorrected. H and 13C
1
NMR spectra were recorded with a Bruker Avance DPX-250 spec-
trometer (250.13 MHz for 1H and 62.9 MHz for 13C). The chemical
shifts are reported in ppm (δ scale) and all J values are in Hz. The
infrared spectra of the compounds were recorded with
a
PerkinϪElmer FTIR PARAGON 1000 PC spectrometer and val-
ues are reported in cmϪ1. Mass spectra (ion spray) were recorded
with a PerkinϪElmer Sciex PI 300 spectrometer. The reactions were
monitored using silica gel TLC plates (silica Merck 60 F254). Spots
were visualised by UV light at 254 and 365 nm. Column chroma-
tography was performed using silica gel 60 (0.063Ϫ0.200 mm,
Merck). All solvents were purified by distillation or otherwise were
analytical grade and used as received.
General Procedure for the Synthesis of Compounds 2: Di-tert-butyl
raphy (petroleum ether/ethyl acetate, 95:5) to afford 3a (410 mg,
1
dicarbonate
(0.89 mmol) were added to a solution of 1 (8.90 mmol) in MeCN
(50 mL). The mixture was stirred at room temperature for 48 h. (s, 9 H, CH3), 2.50 (dd, J ϭ 9.7, 15.8 Hz, 1 H, CH2), 2.79Ϫ2.90
(8.90 mmol)
and
4-(dimethylamino)pyridine 63%) as a colorless oil. IR (film): ν˜ ϭ 1738, 1729 cmϪ1. H NMR
(250 MHz, CDCl3, 25 °C): δ ϭ 1.21 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.57
After concentration, the residue was diluted with ethyl acetate
(40 mL) and water (40 mL) and the final solution was extracted
ethyl acetate. The organic phase was washed with a solution of
2  hydrochloric acid (2 ϫ 20 mL). The organic phase was dried
(MgSO4) and the solvents were evaporated in vacuo. The residue
was purified by column chromatography to afford N-Boc-substi-
tuted lactams 2.
(m, 2 H, CH2), 3.39 (dd, J ϭ 9.7, 15.8 Hz, 1 H, CH2), 4.09 (q, J ϭ
7.1 Hz, 2 H, OCH2), 4.72Ϫ4.80 (m, 1 H, NCH), 6.89Ϫ6.95 (m, 1
H, HAr), 7.10Ϫ7.17 (m, 2 H, HAr), 7.66 (br. s, 1 H, HAr) ppm. 13C
NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.1 (CH3), 28.4 (3 CH3),
33.9 (CH2), 39.2 (CH2), 56.1 (CH), 60.3 (CH2), 81.2 (C), 115.2
(CH), 122.6 (CH), 125.0 (CH), 127.4 (CH), 129.6 (C), 141.6 (C),
151.9 (CϭO), 170.9 (CϭO) ppm. ESI MS: m/z ϭ 328 [Mϩ ϩ Na].
C17H23NO4 (305.4): calcd. C 66.86, H 7.59, N 4.59; found C 66.54,
H 7.77; N 4.48.
tert-Butyl 2-Oxo-2,3-dihydroindole-1-carboxylate (2a): Compound
2a was prepared in 72% yield from 1a according to the procedure
described above for the synthesis of 2. The physical and analytical
data of 2a are identical in all respects to the data given in the litera-
ture.[37]
tert-Butyl
2-(2-Ethoxy-2-oxoethyl)-1,2,3,4-tetrahydroquinoline-1-
carboxylate (3b): Compound 3b was prepared as an oil in 76% yield
from 2b according to the procedure described for the synthesis of
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FULL PAPER
3a; chromatography eluent: petroleum ether/ethyl acetate, 9:1. IR
(CH2)1, 31.5 (CH2)2, 51.6 (NCH)1ϩ2, 60.5 (OCH2)1, 60.9 (OCH2)2,
77.4 (OCH)1, 77.6 (OCH)2, 80.6 (C)1, 81.9 (C)2, 109.8 (CH), 113.2
1
(film): ν˜ ϭ 1744, 1732 cmϪ1. H NMR (250 MHz, CDCl3, 25 °C):
δ ϭ 1.22 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.50 (s, 9 H, 3 CH3), 1.60Ϫ1.74 (CH), 116.8 (CH), 122.4 (2 CH), 123.4 (CH), 124.8 (CH), 125.0
(m, 1 H, CH2), 2.26Ϫ2.40 (m, 2 H, CH2), 2.60Ϫ2.68 (m, 3 H, CH2, (CH), 125.3 (CH), 125.7 (2 CH), 128.2 (CH), 128.4 (CH), 128.6 (4
CH2), 4.09 (q, J ϭ 7.1 Hz, 2 H, OCH2), 4.83Ϫ4.94 (m, 1 H, NCH), CH), 128.8 (CH), 133.9 (C), 136.8 (C), 144.5 (C), 145.4 (C), 150.6
6.97Ϫ7.18 (m, 3 H, HAr), 7.48 (d, J ϭ 8.1 Hz, 1 H, HAr) ppm. 13C (2 C), 152.4 (CϭO), 152.7 (CϭO), 170.4 (CϭO), 171.3 (CϭO)
NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.2 (CH3), 24.9 (CH2), 28.3
ppm. ESI MS: m/z ϭ 398 [Mϩ ϩ H]. C23H27NO5 (397.5): calcd. C
(3 CH3), 29.1 (CH2), 38.8 (CH2), 50.2 (NCH), 60.4 (OCH2), 80.9 69.50, H 6.85, N 3.52; found C 69.84, H 6.74; N 3.63.
(C), 124.0 (CH), 125.8 (CH), 125.9 (CH), 127.8 (CH), 131.3 (C),
Ethyl 2-(2,3-Dihydro-1H-indol-2-yl)acetate (4a):[27] A solution of
136.8 (C), 153.6 (CϭO), 171.1 (CϭO) ppm. ESI MS: m/z ϭ 320
compound 3a (3.30 g, 10.8 mmol) in dichloromethane/trifluoro-
[Mϩ ϩ H]. C18H25NO4 (319.4): calcd. C 67.69, H 7.89, N 4.39;
acetic acid (14 mL, 1:1, v/v) was stirred at 0 °C for 1 h 30 min. The
solution was chilled with ice, treated with a saturated NaHCO3
found C 67.40, H 7.98; N 4.22.
solution and extracted with dichloromethane (25 mL). The organic
phase was dried with MgSO4 and the solvents were evaporated in
tert-Butyl
3-(2-Ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrido[3,2-b]-
[1,4]oxazine-4-carboxylate (3c): Compound 3c was prepared as an
oil in 57% yield from 2c according to the procedure described for
the synthesis of 3a; chromatography eluent: petroleum ether/ethyl
vacuo to give 4a (2.2 g, 100%) as an oil. IR (film): ν˜ ϭ 3375 cmϪ1
.
1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.37 (t, J ϭ 7.3 Hz, 3 H,
CH3), 2.68 (d, J ϭ 6.6 Hz, 2 H, CH2Ph), 2.76 (dd, J ϭ 15.5, 8.4 Hz,
1 H, CH2), 3.24 (dd, J ϭ 15.5, 8.4 Hz, 1 H, CH2), 4.22Ϫ4.30 (q,
J ϭ 7.3 Hz, 2 H, OCH2), 4.22Ϫ4.30 (m, 1 H, CH), 4.57 (br. s, 1
H, NH); 6.66 (d, J ϭ 7.5 Hz, 1 H, HAr), 6.75 (dd, J ϭ 7.7, 7.5 Hz,
1 H, HAr), 7.08Ϫ7.17 (m, 2 H, HAr) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 °C): δ ϭ 14.0 (CH3), 35.5 (CH2), 40.6 (CH2), 55.5
(NCH), 60.2 (OCH2), 108.8 (CH), 118.2 (CH), 124.3 (CH), 127.1
(CH), 127.6 (C), 150.4 (C), 171.9 (CϭO) ppm. ESI MS: m/z ϭ 206
[Mϩ ϩ H]. C12H15NO2 (205.3): calcd. C 70.22, H 7.37, N 6.82;
found C 69.95, H 7.25; N 6.99.
acetate, 6:4. IR (film): ν˜ ϭ 1740, 1732 cmϪ1. H NMR (250 MHz,
1
CDCl3, 25 °C): δ ϭ 1.26 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.56 (s, 9 H, 3
CH3), 2.57 (d, J ϭ 7.3 Hz, 2 H, CH2CO), 4.12 (dd, J ϭ 11.3,
2.9 Hz, 1 H, OCH2), 4.16 (q, J ϭ 7.1 Hz, 2 H, OCH2), 4.38 (dd,
J ϭ 11.3, 1.2 Hz, 1 H, OCH2), 5.00Ϫ5.06 (m, 1 H, NCH),
6.94Ϫ6.99 (m, 1 H, HAr), 7.16Ϫ7.20 (m, 1 H, HAr), 8.09Ϫ8.11 (m,
1 H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.1
(CH3), 28.2 (3 CH3), 34.5 (CH2), 48.2 (NCH), 60.9 (OCH2), 66.9
(OCH2), 82.2 (C), 120.2 (CH), 124.1 (CH), 138.5 (C), 140.8 (CH),
141.2 (C), 151.1 (CϭO), 170.6 (CϭO) ppm. ESI MS: m/z ϭ 323
[Mϩ ϩ H]. C16H22N2O5 (322.3): calcd. C 59.62, H 6.88, N 8.69;
found C 60.00, H 6.74; N 8.53.
Ethyl 2-(1,2,3,4-Tetrahydroquinolin-2-yl)acetate (4b): Compound 4b
was prepared in 99% yield from 3b according to the procedure de-
scribed for the synthesis of 4a. The physical and analytical data of
4b are identical in all respects to the data given in the literature.[32]
tert-Butyl 3-(2-Ethoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-
4-carboxylate (3d): Compound 3d was prepared as an oil in 91%
yield from 2d according to the procedure described for the synthesis
of 3a; chromatography eluent: petroleum ether/ethyl acetate, 9:1.
Ethyl 2-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)acetate (4c):
Compound 4c was prepared as an oil in 99% yield from 3c accord-
ing to the procedure described for the synthesis of 4a. IR (film):
IR (film): ν˜ ϭ 1734, 1728 cmϪ1. H NMR (250 MHz, CDCl3, 25
1
°C): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.54 (s, 9 H, 3 CH3), 2.47
(dd, J ϭ 15.9, 6.1 Hz, 1 H, CH2), 2.59 (dd, J ϭ 15.9, 8.1 Hz, 1 H,
CH2), 4.06Ϫ4.17 (m, 3 H, OCH2CH3, OCH2), 4.32 (dd, J ϭ 11.1,
1.6 Hz, 1 H, OCH2), 4.96Ϫ5.02 (m, 1 H, NCH), 6.83Ϫ6.98 (m, 3
H, HAr), 7.86 (d, J ϭ 7.9 Hz, 1 H, HAr) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 °C): δ ϭ 14.2 (CH3), 28.3 (3 CH3), 34.4 (CH2), 47.3
(NCH), 60.7 (OCH2), 67.0 (OCH2), 81.9 (C), 116.9 (CH), 120.8
(CH), 123.7 (CH), 124.2 (C), 124.3 (CH), 144.9 (C), 152.0 (CϭO),
170.8 (CϭO) ppm. ESI MS: m/z ϭ 322 [M ϩ H]ϩ. C17H23NO5
(321.4): calcd. C 63.54, H 7.21, N 4.36; found C 63.27, H 7.09;
N 4.52.
ν˜ ϭ 3254, 1735 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ
.
1.23 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.56 (d, J ϭ 7.3 Hz, 2 H, CH2CO),
3.93Ϫ4.01 (m, 2 H, OCH2), 4.11Ϫ4.20 (m, 3 H, OCH2, NCH),
5.67 (br. s, 1 H, NH), 6.51Ϫ6.56 (m, 1 H, HAr), 6.93Ϫ6.97 (m, 1
H, HAr), 7.66 (d, 1 H, J ϭ 4.4 Hz, HAr) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 °C): δ 14.2 (CH3), 37.2 (CH2), 46.5 (NCH), 61.1
(OCH2), 67.5 (OCH2), 113.7 (CH), 122.7 (CH), 137.9 (CH), 139.4
(C), 146.4 (C), 170.7 (CϭO) ppm. ESI MS: m/z ϭ 223 [Mϩ ϩ H].
C11H14N2O3 (222.3): calcd. C 59.45, H 6.35, N 12.60; found C
59.11, H 6.50; N 12.43.
Ethyl 2-(3,4-Dihydro-2H-1,4-benzoxazin-3-yl)acetate (4d): Com-
pound 4d was prepared as an oil in 99% yield from 3d according
to the procedure described for the synthesis of 4a. The physical and
analytical data of 4d are identical in all respects to the data given
in the literature.[32,33]
tert-Butyl
3-(2-Ethoxy-2-oxoethyl)-2-phenyl-3,4-dihydro-2H-1,4-
benzoxazine-4-carboxylate (3e): Compound 3e was prepared as a
mixture of diastereomers (50:50 ratio), inseparable by column chro-
matography, as an oil in 89% yield from 2d according to the pro-
cedure described for the synthesis of 3a; chromatography eluent:
petroleum ether/ethyl acetate, 95:5. IR (film): ν˜ ϭ 1755, 1735 cmϪ1
.
Ethyl 2-(2-Phenyl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (4e):
1
Diastereomer 1: H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.11 (t, Compound 4e was prepared as an oil in 99% yield, as a mixture of
J ϭ 7.1 Hz, 3 H, CH3), 1.57 (s, 9 H, 3 CH3), 2.21 (d, J ϭ 6.5 Hz, two diastereomers (50:50 ratio), from 3e according to the procedure
2 H, CH2CO), 4.13 (q, J ϭ 7.1 Hz, 2 H, OCH2), 5.21Ϫ5.24 (m, 1 described for the synthesis of 4a. IR (film): ν˜ ϭ 3374, 1738 cmϪ1
.
H, NCH), 6.64Ϫ6.78 (m, 2 H, OCH, Har), 6.89Ϫ7.05 (m, 2 H, 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.00 (t, J ϭ 7.1 Hz, 3 H,
HAr), 7.24Ϫ7.49 (m, 5 H, HAr), 7.78 (d, J ϭ 8.1 Hz, 1 H, HAr
)
CH3), 1.10 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.01 (dd, J ϭ 17.3, 2.5 Hz,
ppm. Diastereomer 2: 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1 H, CH2CO), 2.34 (dd, J ϭ 17.3, 11.0 Hz, 1 H, CH2CO), 2.59 (t,
1.23 (t, J ϭ 6.9 Hz, 3 H, CH3), 1.56 (s, 9 H, 3 CH3), 3.22 (d, J ϭ J ϭ 6.6 Hz, 1 H, CH2CO), 3.12 (t, J ϭ 6.6 Hz, 1 H, CH2CO),
7.1 Hz, 2 H, CH2CO), 3.92 (q, 2 H, OCH2, J ϭ 6.9 Hz), 5.26Ϫ5.33 3.84Ϫ4.04 (m, 4 H, 2 OCH2), 5.11 (s, 2 H, 2NH), 6.47Ϫ6.77 (m, 4
(m, 1 H, NCH), 6.10 (t, J ϭ 7.0 Hz, 1 H, OCH), 6.89Ϫ7.05 (m, 2
H, HAr), 7.24Ϫ7.49 (m, 6 H, HAr), 8.12 (d, J ϭ 7.9 Hz, 1 H, HAr
ppm. Diastereomers 1 ؉ 2: 13C NMR (62.9 MHz, CDCl3, 25 °C):
H, 2 OCH ϩ2 NCH), 7.08Ϫ7.40 (m, 16 H, HAr), 7.78Ϫ7.86 (m, 2
H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.1, 14.2
(CH3), 32.5, 33.4 (CH2), 51.1 (2 NCH), 60.7, 61.0 (OCH2), 77.3,
)
δ ϭ 14.1 (CH3)1, 14.2 (CH3)2, 28.3 (3 CH3)1, 28.4 (3 CH3)2, 31.1 (2 OCH), 115.6, 115.7 (CH), 116.9 (2 CH), 118.7 (2 CH), 121.7,
4610
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4606Ϫ4613

Synthesis of Substituted Azepino[3,4-b]indole-1,5-diones
FULL PAPER
122.1 (CH), 125.9 (2 CH), 128.0, 128.1 (CH), 128.7, 128.8 (2 CH), MgSO4 and the solvents were evaporated to give 11 (92 mg, 100%)
1
131.8 (2 C), 133.3 (2 CH), 138.0 (2 C), 143.4 (2 C), 172.6, 173.1 as a colorless oil. IR (film): ν˜ ϭ 3363, 3205, 1728, 1627 cmϪ1. H
(CϭO) ppm. ESI MS: m/z ϭ 298 [Mϩ ϩ H]. C18H19NO3 (297.4):
calcd. C 72.71, H 6.44, N 4.71; found C 73.05, H 6.58; N 4.83.
NMR (250 MHz, CDCl3, 25 °C): δ ϭ 2.51Ϫ2.56 (m, 1 H, CH2),
2.69Ϫ2.87 (m, 2 H, CH2Ph), 3.31Ϫ3.39 (m, 1 H, CH2), 5.18Ϫ5.27
(m, 1 H, NCH), 6.84 (s, 1 H, ϭCH), 6.89Ϫ7.43 (m, 7 H, HAr), 7.59
(d, J ϭ 7.9 Hz, 1 H, HAr), 11.51 (br. s, 1 H, NH) ppm. 13C NMR
(62.9 MHz, [D6]DMSO, 80 °C): δ ϭ 34.5 (CH2), 39.4 (CH2), 57.1
(NCH), 104.3 (CH), 112.3 (CH), 117.2 (CH), 120.1 (CH), 121.8
(CH), 124.0 (CH), 124.2 (CH), 125.5 (CH), 127.1 (CH), 127.3 (C),
130.4 (C), 130.8 (C), 136.2 (C), 142.3 (C), 160.2 (CϭO), 171.8 (Cϭ
O) ppm. ESI MS: m/z ϭ 321 [Mϩ ϩ H]. C19H16N2O3 (320.4): calcd.
C 71.24, H 5.03, N 8.74; found C 70.97, H 5.16; N 8.88.
Ethyl 2-[1-(1H-Indol-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]acet-
ate (9): At 0 °C, compound 4a (110 mg, 0.54 mmol), dissolved in
THF (3 mL), was added dropwise to a suspension of sodium hy-
dride (0.04 g, 1.07 mmol, 60% dispersed in oil) in anhydrous THF
(2 mL). The final mixture was stirred at room temperature for 2 h.
Thionyl chloride (0.09 mL, 1.23 mmol) was slowly added at 0 °C
to a solution of indole-2-carboxylic acid (5) (0.13 g, 0.80 mmol)
and triethylamine (0.15 mL, 1.07 mmol) in THF (15 mL). The solu-
tion was stirred at 0 °C for 50 min. The precipitate obtained was
eliminated by filtration (washing with dichloromethane). The fil-
12-Methyl-5a,6-dihydroindolo[3Ј,2Ј:5,6]azepino[1,2-a]indoline-
7,13(5H,12H)-dione (12): A solution of 10 (150 mg, 0.42 mmol),
trate was concentrated to afford 7 as an oil which was kept under pTSA (157 mg, 0.83 mmol) and ethane-1,2-diol (0.11 mL,
reduced pressure. Then, compound 7 was dissolved in anhydrous 2.07 mmol) in toluene (5 mL) was refluxed for 8 h. After cooling,
dichloromethane (5 mL) and added to the solution of the sodium water (10 mL) and ethyl acetate (10 mL) were added. The aqueous
salt of amine 4a at 0 °C. The mixture was stirred at room tempera-
ture for 2 h. A saturated NH4Cl solution was added to the medium
and the resulting mixture was extracted with ethyl acetate (2 ϫ
layer was extracted twice with ethyl acetate (2 ϫ 10 mL). The or-
ganic layers were dried with MgSO4 and the solvents evaporated in
vacuo. The residue was purified by column chromatography (di-
10 mL). The organic layer was dried (MgSO4), and the solvents chloromethane) to afford 12 (115 mg, 87%) as a solid; m.p.
1
were evaporated in vacuo. The crude residue was purified by col-
umn chromatography (petroleum ether/ethyl acetate, 9:1) to give 9
(95 mg, 57%) as a solid; m.p. 135Ϫ137 °C (ethyl acetate/petroleum
ether). IR (KBr): ν˜ ϭ 3381, 1731, 1623 cmϪ1. 1H NMR (250 MHz,
280Ϫ282 °C (toluene). IR (KBr): ν˜ ϭ 1640 (CO) cmϪ1. H NMR
(250 MHz, CDCl3, 25 °C): δ ϭ 2.86Ϫ2.99 (m, 2 H, CH2Ph), 3.31
(dd, J ϭ 17.7, 11.7 Hz, 1 H, CH2), 3.67 (dd, J ϭ 17.7, 10.1 Hz, 1
H, CH2), 4.12 (s, 3 H, NCH3), 4.99Ϫ5.09 (m, 1 H, NCH),
CDCl3, 25 °C): δ ϭ 1.30 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.69 (dd, J ϭ 7.12Ϫ7.18 (m, 1 H, HAr), 7.28Ϫ7.47 (m, 5 H, HAr), 8.38 (d, J ϭ
15.9, 11.5 Hz, 1 H, CH2), 2.97Ϫ3.05 (m, 2 H, CH2Ph), 3.53 (dd,
8.1 Hz, 1 H, HAr), 8.44 (d, J ϭ 8.1 Hz, 1 H, HAr) ppm. 13C NMR
J ϭ 15.9, 8.2 Hz, 1 H, CH2), 4.21 (q, J ϭ 7.1 Hz, 2 H, OCH2), (62.9 MHz, CDCl3, 25 °C): δ ϭ 33.0 (NCH3), 35.5 (CH2), 51.4
5.48Ϫ5.54 (m, 1 H, NCH), 7.07Ϫ7.37 (m, 6 H, 5 HAr, ϭCH), 7.44 (CH2), 56.5 (NCH), 110.3 (CH), 116.2 (C), 117.7 (CH), 123.9 (CH),
(d, J ϭ 8.1 Hz, 1 H, HAr), 7.69 (d, J ϭ 8.1 Hz, 1 H, Har), 8.20 (d, 124.0 (CH), 125.0 (CH), 125.3 (C), 125.4 (CH), 126.0 (CH), 128.2
J ϭ 7.7 Hz, 1 H, HAr), 10.02 (s, 1 H, NH) ppm. 13C NMR (CH), 130.1 (C), 135.2 (C), 138.7 (C), 141.2 (C), 158.8 (CϭO),
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.3 (CH3), 35.2 (CH2), 39.5 (CH2),
193.8 (CϭO) ppm. ESI MS: m/z ϭ 317 [Mϩ ϩ H]. C20H16N2O2
57.5 (NCH), 61.1 (OCH2), 105.8 (CH), 112.0 (CH), 118.6 (CH), (316.4): calcd. C 75.93, H 5.10, N 8.85; found C 76.22, H 5.23;
120.7 (CH), 122.5 (CH), 124.9 (CH), 125.1 (CH), 125.4 (CH), 127.7 N 8.69.
(CH), 128.2 (C), 129.8 (C), 130.3 (C), 136.0 (C), 142.4 (C), 160.2
2-Methoxyethyl
hydro-1H-indol-2-yl}acetate (13):
0.28 mmol), pTSA (110 mg, 0.55 mmol) and 2-methoxyethanol
(0.08 mL, 1.38 mmol) in toluene (3 mL) was refluxed for 2 h. After
cooling, water (10 mL) and ethyl acetate (10 mL) were added. The
2{1-[(1-Methyl-1H-indol-2-yl)carbonyl]-2,3-di-
solution of 10 (100 mg,
(CϭO), 170.7 (CϭO) ppm. ESI MS: m/z ϭ 349 [Mϩ ϩ H].
C21H20N2O3 (348.4): calcd. C 72.40, H 5.79, N 8.04; found C 72.65,
H 5.61; N 8.14.
A
Ethyl 2-{1-[(1-Methyl-1H-indol-2-yl)carbonyl]-2,3-dihydro-1H-in-
dol-2-yl}acetate (10): Compound 10 was prepared as a foam in 96% aqueous layer was extracted twice with ethyl acetate (2 ϫ 10 mL).
yield from 4a and 1-methylindole-2-carboxylic acid (6) according
to the procedure described for the synthesis of 9; chromatography
eluent: petroleum ether/ethyl acetate, 9:1. IR (film): ν˜ ϭ 1740, 1621
The organic layers were dried with MgSO4 and the solvents evapo-
rated in vacuo. The residue was purified by column chromatogra-
phy (dichloromethane) to afford 13 (96 mg, 89%) as a foam. IR
1
cmϪ1. 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.12 (t, J ϭ 6.9 Hz, (film): ν˜ ϭ 1738, 1624 cmϪ1. H NMR (250 MHz, CDCl3, 25 °C):
3 H, CH3), 2.57 (dd, J ϭ 15.6, 9.1 Hz, 1 H, CH2), 2.80Ϫ2.94 (m,
2 H, CH2Ph), 3.47 (dd, J ϭ 15.6, 9.1 Hz, 1 H, CH2), 3.79 (s, 3 H,
δ ϭ 2.53 (dd, J ϭ 15.9, 8.9 Hz, 1 H, CH2), 2.79Ϫ2.90 (m, 2 H,
CH2Ph), 3.44 (dd, J ϭ 15.9, 8.9 Hz, 1 H, CH2), 3.81 (s, 3 H,
NCH3), 3.91Ϫ4.05 (m, 2 H, OCH2), 5.20Ϫ5.25 (m, 1 H, NCH), NCH3), 4.01 (s, 3 H, OCH3), 4.09Ϫ4.16 (m, 4 H, 2 OCH2),
6.79 (s, 1 H, ϭCH), 6.93Ϫ7.35 (m, 7 H, HAr), 7.61 (d, J ϭ 7.8 Hz, 5.21Ϫ5.24 (m, 1 H, NCH), 6.76 (s, 1 H, ϭCH), 6.95Ϫ7.39 (m, 7
1 H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 13.9 H, HAr), 7.61 (d, J ϭ 7.8 Hz, 1 H, HAr) ppm. 13C NMR (62.9 MHz,
(CH3), 30.9 (NCH3), 33.9 (CH2), 38.7 (CH2), 57.8 (NCH), 60.5 CDCl3, 25 °C): δ ϭ 30.9 (NCH3), 34.1 (CH2), 39.5 (CH2), 56.4
(OCH2), 104.0 (ϭCH), 109.9 (CH), 116.0 (CH), 120.3 (CH), 121.9
(NCH), 58.8 (OCH3), 63.8 (OCH2), 67.5 (OCH2), 104.1 (CH),
(CH), 123.6 (CH), 124.1 (CH), 125.4 (CH), 126.4 (C), 127.2 (CH), 109.9 (CH), 116.6 (CH), 120.6 (CH), 121.1 (CH), 123.6 (CH), 123.7
130.9 (C), 132.6 (C), 137.8 (C), 141.3 (C), 161.4 (CϭO), 170.4 (Cϭ
O) ppm. ESI MS (IS): m/z ϭ 363 [Mϩ ϩ H]. C22H22N2O3 (362.4):
calcd. C 72.91, H 6.12, N 7.73; found C 72.67, H 5.94; N 7.86.
(CH), 125.4 (CH), 127.0 (C), 127.3 (CH), 131.0 (C), 132.5 (C),
138.1 (C), 141.0 (C), 160.8 (CϭO), 170.6 (CϭO) ppm. ESI MS:
m/z ϭ 393 [Mϩ ϩ H]. C23H24N2O4 (392.5): calcd. C 70.39, H 6.16,
N 7.14; found C 70.75, H 6.09; N 7.03.
2[1-(1H-Indol-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]acetic Acid
(11): Lithium hydroxide monohydrate (43 mg, 0.57 mmol) was ad-
ded to a solution of compound 9 (100 mg, 0.29 mmol) in ethanol
(5 mL). The mixture was stirred at room temperature for 20 h.
After evaporation of the ethanol, the residue was dissolved in water
Ethyl 2-{1-[(1-Methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydro-
quinolin-2-yl}acetate (14b): Compound 14b was prepared as a foam
in 77% yield from 4b and 1-methylindole-2-carboxylic acid 6 ac-
cording to the procedure described for the synthesis of 10; chroma-
and neutralised with a 1  HCl solution. The mixture was extracted tography eluent: petroleum ether/ethyl acetate, 8:2. IR (film): nu(t-
with ethyl acetate (2 ϫ 10 mL). The organic phase was dried with
ilde) ϭ 1738, 1624 cmϪ1. 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ
Eur. J. Org. Chem. 2004, 4606Ϫ4613
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4611

´
J. Perron, B. Joseph, J.-Y. Merour
FULL PAPER
1.24 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.65Ϫ1.76 (m, 1 H, CH2),
2.40Ϫ2.61 (m, 2 H, CH2, CH2), 2.75Ϫ2.86 (m, 3 H, CH2, CH2),
3.85 (s, 3 H, NCH3), 4.11 (q, J ϭ 7.2 Hz, 2 H, OCH2), 5.14Ϫ5.25
(m, 1 H, NCH), 6.13 (s, 1 H, ϭCH), 6.69Ϫ6.72 (m, 1 H, HAr),
6.83Ϫ6.89 (m, 1 H, HAr), 7.01Ϫ7.07 (m, 2 H, HAr), 7.17Ϫ7.44 (m,
4 H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.3
(CH3), 25.5 (CH2), 30.4 (CH2), 31.4 (NCH3), 39.2 (CH2), 50.4
(NCH), 60.7 (OCH2), 106.2 (CH), 109.9 (CH), 120.1 (CH), 122.0
(CH), 123.6 (CH), 125.7 (CH), 126.2 (CH), 126.3 (C), 126.4 (CH),
127.7 (CH), 132.6 (CH), 133.6 (C), 137.9 (C), 138,0 (C), 163.2 (Cϭ
O), 170.9 (CϭO) ppm. ESI MS: m/z ϭ 377 [Mϩ ϩ H]. C23H24N2O3
(376.5): calcd. C 73.38, H 6.43, N 7.44; found C 73.06, H 6.60;
N 7.58.
Acknowledgments
`
This research work was supported by a grant from the Ministere
´
de l’Enseignement Superieur et de la Recherche to J. P.
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A. Kamal, G. Suresh Kumar Reddy, K. Laxma Reddy, S.
1.26 (t, J ϭ 6.9 Hz, 3 H, CH3), 2.67Ϫ2.71 (m, 2 H, CH2), 3.87 (s,
3 H, NCH3), 4.16 (q, J ϭ 6.9 Hz, 2 H, OCH2), 4.32 (dd, J ϭ
11.3, 2.8 Hz, 1 H, OCH2), 4.52 (dd, J ϭ 11.3, 1.2 Hz, 1 H, OCH2),
5.24Ϫ5.30 (m, 1 H, NCH), 6.63 (s, 1 H, ϭCH), 6.65Ϫ6.69 (m, 1
H, HAr), 6.91Ϫ7.05 (m, 3 H, HAr), 7.08Ϫ7.16 (m, 1 H, HAr),
7.31Ϫ7.38 (m, 2 H, HAr), 7.56 (d, J ϭ 8.2 Hz, 1 H, HAr) ppm. 13C
NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.3 (CH3), 31.5 (NCH3),
34.0 (CH2), 47.4 (NCH), 61.0 (OCH2), 68.1 (OCH2), 106.6 (CH),
110.1 (CH), 117.2 (CH), 120.5 (CH), 120.6 (CH), 122.3 (CH), 123.9
(C), 124.2 (CH), 124.8 (CH), 126.0 (CH), 126.3 (C), 131.6 (C),
138.6 (C), 145.4 (C), 162.0 (CϭO), 170.6 (CϭO) ppm. ESI MS:
m/z ϭ 379 [M ϩ H]ϩ. C22H22N2O4 (378.4): calcd. C 69.83, H 5.86,
N 7.40; found C 70.12, H 5.69; N 7.53.
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D. J. Faulkner, Nat. Prod. Rep. 1999, 16, 155Ϫ198 and earlier
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13-Methyl-6a,7-dihydro-5H-indolo[3Ј,2Ј:5,6]azepino[1,2-a]quinoline-
8,14(6H,13H)-dione (15b): Compound 15b was prepared as a solid
in 82% yield from 14b according to the procedure described for
the synthesis of 12; chromatography eluent: dichloromethane. M.p.
[13]
S. Forenza, L. Minale, R. Riccio, E. Fattorusso, J. Chem. Soc.,
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[14]
263Ϫ264 °C (toluene). IR (KBr): ν˜ ϭ 1640 cmϪ1 1H NMR
.
[15]
(250 MHz, CDCl3, 25 °C): δ ϭ 1.54Ϫ1.70 (m, 1 H, CH2),
2.38Ϫ2.49 (m, 1 H, CH2), 2.64Ϫ2.68 (m, 2 H, CH2), 2.83Ϫ3.08
(m, 2 H, CH2), 4.06 (s, 3 H, NCH3), 4.75Ϫ4.86 (m, 1 H, NCH),
7.13Ϫ7.46 (m, 6 H, HAr), 7.80 (d, J ϭ 8.1 Hz, 1 H, HAr), 8.41 (d,
J ϭ 7.9 Hz, 1 H, HAr) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C):
δ ϭ 21.1 (CH2), 32.4 (CH2), 33.2 (NCH3), 50.9 (CH2), 54.1 (NCH),
110.3 (CH), 116.8 (C), 123.6 (CH), 124.0 (CH), 125.1 (C), 125.7
(CH), 126.0 (CH), 126.2 (CH), 126.8 (CH), 127.6 (CH), 128.1 (C),
130.1 (C), 134.8 (C), 138.9 (C), 161.4 (CϭO), 195.4 (CϭO) ppm.
ESI MS: m/z ϭ 331 [Mϩ ϩ H]. C21H18N2O2 (330.4): calcd. C 76.34,
H 5.49, N 8.48; found C 76.63, H 5.45; N 8.65.
2002, 23, 417Ϫ425.
[16]
M. A. Lago, WO Patent 2001, 0164680 (Chem. Abstr. 2001,
135, 211033).
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Y. Wan, W. Hur, C. Y. Cho, Y. Liu, F. J. Adrian, O. Lozach, S.
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2004, 11, 247Ϫ259.
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[18]
´
6553Ϫ6556.
[19]
[20]
[21]
`
´
L. Chacun-Lefevre, B. Joseph, J.-Y. Merour, Synlett 2001,
848Ϫ850.
L. Chacun-Lefevre, B. Joseph, J.-Y. Merour, Tetrahedron 2000,
56, 4491Ϫ4499.
`
´
R. Nagata, N. Tanno, T. Kodo, N. Ae, H. Yamaguchi, T. Nishi-
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13-Methyl-6a,7-dihydroindolo[3Ј,2Ј:5,6]azepino[2,1-c][1,4]benzoxa-
zine-8,14(6H,13H)-dione (15d): Compound 15d was prepared as a
solid in 76% yield from 14d according to the procedure described
above for the synthesis of 12; chromatography eluent: dichloro-
methane. M.p. 250Ϫ252 °C (toluene). IR (KBr): ν˜ ϭ 1640, 1607
cmϪ1. 1H NMR (250 MHz, [D6]DMSO, 25 °C): δ ϭ 2.88Ϫ3.04 (m,
2 H, CH2), 4.06 (s, 3 H, NCH3), 4.16 (dd, J ϭ 11.2, 3.1 Hz, 1 H,
OCH2), 4.35 (dd, J ϭ 11.2, 2.1 Hz, 1 H, OCH2), 5.08Ϫ5.11 (m, 1
H, NCH), 6.98Ϫ7.12 (m, 3 H, HAr), 7.30Ϫ7.48 (m, 2 H, HAr), 7.72
(d, J ϭ 7.5 Hz, 1 H, HAr), 8.18 (d, J ϭ 8.3 Hz, 1 H, HAr), 8.79 (d,
J ϭ 8.1 Hz, 1 H, HAr) ppm. The 13C NMR spectrum could not be
recorded owing to the very poor solubility of 15d. ESI MS: m/z ϭ
333 [Mϩ ϩ H]. C20H16N2O3 (332.4): calcd. C 72.28, H 4.85, N
8.43; found C 72.57, H 4.98; N 8.32.
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3456Ϫ3463.
4612
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4606Ϫ4613

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Received May 18, 2004
Eur. J. Org. Chem. 2004, 4606Ϫ4613
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4613