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

Article abstract of DOI:10.1016/S0040-4020(03)00979-7

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.

Full text of DOI:10.1016/S0040-4020(03)00979-7

Tetrahedron 59 (2003) 6659–6666
Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones
a
Julien Perron, Benoıt Joseph and Jean-Yves Merour
b
a
,
*
ˆ
´
a
´
´
´
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite d’Orleans, BP 6759, 45067 Orleans Cedex 2, France
´ ˆ
Laboratoire de Chimie Organique 1, Universite Claude Bernard-Lyon 1, UMR-CNRS 5622, CPE-Batiment 308, 43 Boulevard du 11
b
Novembre 1918, 69622 Villeurbanne Cedex, France
Received 3 January 2003; revised 8 May 2003; accepted 12 June 2003
Abstract—Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-
dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-
methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6–14 were synthesised in good yields from 4 via palladium-mediated cross-coupling
reactions.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
dione 1 was reported in the literature.3a–6 Reactivity studies
on compound 1 reveal that electrophilic attack in a-position
of the ketone in position-5 of the azepino ring was effective.3a
Thus, dibromo derivative 2a was prepared in 93% yield from
1a in the presence of LiHMDS (3 equiv.) in THF at 2788C,
followed by addition of dibromine (2 equiv.). The modifi-
cation of the experimental procedure (LiHMDS (1.8 equiv.)
then Br2 (1 equiv.) afforded compounds 2a and 3a in 7 and
88% yield, respectively (Scheme 1).
Azepino[3,4-b]pyrrole scaffold is found in natural products
such as hymenialdisine, stevensine or hymenin and displays
several biological properties (Fig. 1).1 Among the related
indole derivatives prepared, azepino[3,4-b]indole com-
pounds I were published as potent myt 1 kinase inhibitors.2
For our part, we have developed the syntheses of a,b-
unsaturated ester II and 5-substituted azepino[3,4-b]indole-
1-ones III through palladium-mediated cross-coupling
reactions (Fig. 1).3
Compound 2b was also prepared from 1b in the presence of
1,2-dibromotetrachloroethane in 90% yield. It should be
noted that when LDA was used as base, the corresponding
anion was not stable and the a-bromination yield was
always low.
Following a similar synthetic approach based on palladium
cross-coupling reactions, we have prepared a new series of
4-substituted azepino[3,4-b]indole-1,5-diones IV and
derivatives with potential biological properties (Fig. 1).4
To the best of our knowledge, this 4-substituted tricyclic
skeleton has not been yet described in the literature.
Nevertheless, a closed structure V was elaborated, using
an other pathway, by Troschutz and Hoffman.5
Attempts of nucleophilic substitution followed by intramo-
lecular addition-elimination reaction on 2a and 3a with
diamines such as 1,2-diaminoethane or 1,2-phenylene-
diamine failed to afford new derivatives with a supplemen-
tary fused aza ring between position-4 and -5 of azepino
moiety. In all cases, elimination of hydrogen bromide on 2a
or 3a was observed to give derivatives 4a or 5a.
2. Results and discussion
The elimination reaction was optimised by replacement of
amines by DBU as base. Thus, treatment of bromo
derivatives 2a,b or 3a with DBU (1 equiv.) in DMF led to
4a,b or 5a in good yields (93–95%) (Scheme 2). The PMB
group of 4a and 5a was readily removed by treatment with
TFA providing the corresponding azepino derivatives 4a
and 5a (51 and 68% yield).7 Boc protection on 4b was
carried out in the presence of Boc2O and DMAP in
acetonitrile to afford 4c in 61% yield.
In this paper, we reported our results concerning the
reactivity of derivatives 2–5 and the synthesis of a new
family of compounds with an indole nucleus and different
heterocycles or alkenyl chains around a central seven-
membered ring. The synthesis of azepino[3,4-b]indole-1,5-
Keywords: elimination; cross-coupling reactions; seven-membered ring.
*
Corresponding author. Tel.: þ33-2-38-494592; fax: þ33-2-38-417281;
e-mail: jean-yves.merour@univ-orleans.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00979-7

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J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
Figure 1.
Suzuki and Stille coupling reactions8,9 were performed on
protected (PMB, Boc) or unprotected a-bromo-a,b-
unsaturated ketones 4 to give access to 4-substituted
derivatives 6–14. According to the Suzuki procedure, the
desired compounds 6–12 were prepared from commer-
cially available boronic acids (1.5 equiv.), Pd(PPh3)4
(10% mol) and saturated aqueous hydrogenocarbonate
as inorganic base in toluene–ethanol. The phenyl
derivatives 6a–c were prepared from 4a–c. The best
coupling reaction yield was observed from the PMB
protected starting material 6a (84% yield). The com-
pounds 7–12 were prepared from their corresponding
boronic acids in 68–97% yield (Scheme 3).
Stille reaction was also investigated. Vinyltributyl- stannane
and 1-ethoxyvinyltributylstannane (2 equiv.) were coupled
Scheme 2. (a) DBU (1 equiv.), DMF, rt, 30 min; (b) TFA, reflux, 24 h; (c)
DMAP, Boc2O (2 equiv.), CH3CN, rt, 24 h.
Scheme 1. (a) (i) LiHMDS (3 equiv.), THF, 2788C, 1 h (ii) Br2 (2 equiv.),
15 min, 2788C or 1,2-dibromotetrachloroethane (2.5 equiv.), 30 min,
2788C; (b) (i) LiHMDS (1.8 equiv.), THF, 2788C, 1 h (ii) Br2
(1 equiv.), 2788C, 15 min.
Scheme 3. (a) Pd(PPh3)4 (10% mol), A–B(OH)2 (1.5 equiv.), toluene–
EtOH–aq. sat. NaHCO3, 808C, 1 h; (b) Pd(PPh3)4 (10% mol), A-SnBu3
(2 equiv.), DMF, 1008C, 1 h.

J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
6661
to 4a to give 13a and 14a in 87–95% yield. The compounds
13b and 14b were obtained in 28–31% yield from 4c.
Coupling reaction yields were always better when protected
ketone 4a-b were used. The difference of yields observed
betweenbothprotectivegroupsisexplainedbyBoc hydrolysis
of coupling derivatives (6b, 10b) in the reaction medium
Compound
Entry
a
R
A
Yield (%)a
84
6a
PMB
6b
6c
7
a
a
a
a
a
Boc
H
66
44
85
76
82
Scheme 4. (a) N-methylmaleimide (2 equiv.), toluene, sealed tube, 1808C,
1 h; (b) maleic anhydride (2 equiv.), toluene, sealed tube, 1808C, 1 h;
(c) DMAD (2 equiv.), toluene, sealed tube, 1808C, 3 h; (d) 2,2-dimethyl-
aminoethylamine, 1008C, 24 h.
PMB
PMB
PMB
maleic anhydride to afford unknown tetracyclic compounds
16–18 in 53–87% yield. Amide 19 was prepared from 18 in
the presence of 2,2-dimethylaminoethylamine in 66% yield
(Scheme 4).
8
9
10a
10b
11
a
a
a
a
PMB
Boc
97
68
77
96
3. Conclusion
In summary, we have developed an efficient route to 4-
substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-
diones 6–14 from the corresponding bromides 4 through
palladium-catalysed reactions.
PMB
PMB
12
4. Experimental
4.1. Chemistry
13a
13b
14a
b
b
b
PMB
H
PMB
87
31
95
Melting point were determined using a Bu¨chi SMP-20
1
melting point apparatus and are uncorrected. H and 13C
14b
b
H
28
NMR spectra were recorded at 300 K in CDCl3 or DMSO-
d6 on a Bruker Avance DPX 250. The chemical shifts are
reported in ppm (d scale) and all J values are in Hz. The
infrared spectra of compounds were recorded on a Perkin–
Elmer FTIR PARAGON 1000 PC and values were reported
in cm21. MS spectra (Ion Spray) were performed on a
Perkin–Elmer Sciex PI 300. Monitoring of the reactions
was performed using silica gel TLC plates (silica Merck 60
F254). Spots were visualised by UV light at 254 and 365 nm.
Column chromatography were performed using silica gel 60
(0.063–0.200 mm, Merck). Stannanes and boronic acids
were purchased from Lancaster or Sigma-Aldrich
companies.
a
Yield isolated.
Vinylethers 14a,b were hydrolysed in acidic medium (10%
HCl, acetone, room temperature, 1 h) to afford the diketo
derivatives 15a,b in quantitative yield.
4.1.1. 4,4-Dibromo-2-(4-methoxybenzyl)-10-methyl-3,4-
dihydro-2H,10H-azepino[3,4-b]indole-1,5-dione
(2a).
Under argon, solution of LiHMDS (3.62 mL,
a
3.62 mmol, 1 M in THF) was added dropwise to a stirred
solution of 1a (420 mg, 1.21 mmol) in dry THF (20 mL) at
2788C. After 1 h, a solution of bromine (0.12 mL,
2.41 mmol) in THF (10 mL) was slowly added to the
mixture. After 15 min, hydrolysis was performed by
The vinyl compound 13a was engaged in [4þ2] cycloaddi-
tion reactions with various dienophiles such as dimethyl
acetylenedicarboxylate (DMAD), N-methyl-maleimide or

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J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
addition of aq. sat. NH4Cl. After extraction with ethyl
acetate (50 mL), the combined organic extracts were dried
over MgSO4 and evaporated in vacuo. The crude residue
was purified by column chromatography on silica gel
(petroleum ether–ethyl acetate 7:3) to afford compound 2a
as a yellow solid (560 mg, 93%). Mp 158–1608C (ethyl
acetate–petroleum ether); IR (KBr) n 1651 (CO), 1610
6.91 (d, 2H, J¼8.5 Hz, HAr), 7.34–7.47 (m, 5H, HAr), 8.39
(d, 1H, J¼8.0 Hz, HAr).
4.1.4. 4-Bromo-2-(4-methoxybenzyl)-10-methyl-2H,10H-
azepino[3,4-b]indole-1,5-dione (4a). DBU (0.30 mL,
1.96 mmol) was added to a solution of 2a (1.00 g,
1.96 mmol) in DMF (10 mL). The solution was stirred at
room temperature for 30 min followed by addition of 10%
HCl solution. After filtration, the residue was washed with
water. The solid obtained was partitioned between dichlor-
omethane (30 mL) and water. After extraction, organic
layers were dried over MgSO4, filtered and evaporated in
vacuo. The crude residue was recrystallised from toluene to
afford 4a (0.81 mg, 93%) as a yellow solid. Mp 178–1808C
1
(CO) cm21; H NMR (CDCl3, 250 MHz) d 3.82 (s, 3H,
CH3), 4.11 (s, 3H, CH3), 4.34 (br s, 2H, CH2), 5.73 (br s, 2H,
CH2), 6.93 (d, 2H, J¼8.5 Hz, HAr), 7.32–7.47 (m, 5H, HAr),
8.31 (d, 1H, J¼7.7 Hz, HAr); 13C NMR (CDCl3,
62.90 MHz) d 33.2 (CH3), 51.4 (CH2), 55.5 (CH3), 58.3
(CH2), 67.9 (C), 110.6 (CH), 114.5 (2CH), 114.0 (C), 123.5
(CH), 124.5 (CH), 126.0 (C), 126.5 (CH), 128.0 (C), 130.0
(2CH), 132.9 (C), 139.0 (C), 159.7 (C), 161.6 (CO), 184.0
(toluene); IR (KBr) n 1640 (CO), 1608 (CO) cm21 1H
;
81
(CO); MS (IS) m/z 527 (79Br, MþNa)þ, 529 (79Brþ Br,
NMR (CDCl3, 250 MHz) d 3.80 (s, 3H, CH3), 4.25 (s, 3H,
CH3), 5.15 (s, 2H, CH2), 6.91 (d, 2H, J¼8.5 Hz, HAr), 7.26–
7.55 (m, 5H, HAr), 7.82 (s, 1H, HAr), 8.88 (d, 1H, J¼8.3 Hz,
HAr); 13C NMR (CDCl3, 62.90 MHz) d 34.4 (CH3), 55.4
(CH3), 56.0 (CH2), 110.3 (CH), 112.9 (C), 114.5 (2CH),
118.6 (C), 124.1 (CH), 125.2 (C), 125.4 (CH), 126.0 (C),
127.8 (CH), 129.5 (2CH), 130.8 (C), 135.9 (CH), 139.9 (C),
159.7 (C), 159.8 (CO), 175.4 (CO); MS (IS) m/z 425 (79Br,
MþH)þ, 427 (81Br, MþH)þ. Anal. calcd for
C21H17BrN2O3: C, 59.31; H, 4.03; N, 6.59. Found: C,
59.55; H, 4.17; N, 6.42.
MþNa)þ, 531 (81Br, MþNa)þ. Anal. calcd for
C21H18Br2N2O3: C, 49.83; H, 3.58; N, 5.53. Found: C,
49.58; H, 3.67; N, 5.69.
4.1.2. 4,4-Dibromo-10-methyl-3,4-dihydro-2H,10H-aze-
pino[3,4-b]indole-1,5-dione (2b). Under argon, a solution
of LiHMDS (15.8 mL, 15.8 mmol, 1 M in THF) was added
dropwise to a stirred solution of 1b (0.80 g, 3.51 mmol) in
dry THF (50 mL) at 2788C. After 1 h, a solution of
1,2-dibromotetrachloroethane (2.85 g, 8.77 mmol) in THF
(10 mL) was slowly added to the mixture. After 30 min,
hydrolysis was performed by addition of aq. sat. NH4Cl.
After extraction with ethyl acetate (3£50 mL), the com-
bined organic extracts were dried over MgSO4, filtered and
evaporated in vacuo. The crude product was recrystallised
from ethyl acetate–petroleum ether to afford 2b (1.21 g,
90%) as a yellow solid. Mp 186–1888C (ethyl acetate–
petroleum ether); IR (KBr) n 3310 (NH), 1670 (CO), 1625
(CO) cm21; 1H NMR (DMSO-d6, 250 MHz) d 4.03 (s, 3H,
CH3), 4.10 (br s, 2H, CH2), 7.32–7.51 (m, 2H), 7.74 (d, 1H,
J¼8.2 Hz), 8.15 (d, 1H, J¼8.0 Hz), 9.48 (t, 1H, J¼4.2 Hz);
13C NMR (DMSO-d6, 62.90 MHz) d 32.7 (CH3), 52.6
(CH2), 70.5 (C), 108.9 (C), 111.7 (CH), 122.1 (CH), 124.1
(CH), 125.2 (C), 125.9 (CH), 134.0 (C), 138.4 (C), 161.8
(CO), 184.3 (CO); MS (IS) m/z 385 (79Br, MþH)þ, 387
4.1.5. 4-Bromo-10-methyl-2H,10H-azepino[3,4-b]indole-
1,5-dione (4b). Method 1: DBU (1.28 mL, 8.42 mmol) was
added to a solution of 2b (1.30 g, 3.37 mmol) in DMF
(10 mL). The solution was stirred at room temperature for
30 min followed by addition of 10% HCl solution. After
filtration, the residue was washed with water and ether.
Compound 4b was obtained as a yellow solid (920 mg,
89%).
Method 2: Under argon, a solution of 4a (200 mg,
0.47 mmol) in trifluoroacetic acid (3 mL) was stirred at
reflux for 24 h. After cooling, the mixture was poured
into ice and neutralised by 10% NaOH solution. After
filtration, the crude product was recrystallised once from
ethyl acetate–petroleum ether to give 4b as a yellow
solid (73 mg, 51%). Mp 196–1988C (ethyl acetate–
petroleum ether); IR (KBr) n 3260 (NH), 1630 (CO),
81
(79Brþ Br, MþH)þ, 389 (81Br, MþH)þ. Anal. calcd for
C13H10Br2N2O2: C, 40.45; H, 2.61; N, 7.26. Found: C,
40.77; H, 2.44; N, 7.43.
1
1612 (CO) cm21; H NMR (DMSO-d6, 250 MHz) d 4.24
4.1.3. 4-Bromo-2-(4-methoxybenzyl)-10-methyl-3,4-
dihydro-2H,10H-azepino[3,4-b]indole-1,5-dione
(s, 3H, CH3), 7.38–7.44 (m, 1H, HAr), 7.55–7.61 (m, 2H,
HAr), 7.80–7.83 (m, 1H, HAr), 8.72–8.75 (d, 1H,
J¼8.2 Hz, HAr), 11.50 (br s, 1H, NH); 13C NMR
(DMSO-d6, 62.90 MHz) d 33.8 (CH3), 110.6 (C), 111.4
(CH), 118.4 (C), 123.7 (CH), 124.3 (CH), 124.8 (C),
125.5 (C), 127.5 (CH), 133.4 (CH), 139.5 (C), 161.0 (C),
175.2 (CO); MS (IS) m/z 305 (79Br, MþH)þ, 307 (81Br,
MþH)þ. Anal. calcd for C13H19BrN2O2: C, 51.17; H,
2.97; N, 9.18. Found: C, 50.84; H, 3.09; N, 9.29.
(3a).
Under argon, solution of LiHMDS (0.77 mL,
a
0.77 mmol, 1 M in THF) was added dropwise under argon
to a stirred solution of 1a (150 mg, 0.43 mmol) in dry THF
(20 mL) at 2788C. After 1 h, a solution of bromine
(0.02 mL, 0.43 mmol) in THF (1 mL) was slowly added to
the mixture. After 15 min, hydrolysis was performed by
addition of aq. sat. NH4Cl. After extraction with ethyl
acetate (50 mL), the combined organic extracts were dried
over MgSO4 and evaporated in vacuo. The crude residue
was purified by column chromatography on silica gel
(petroleum ether–EtOAc 7:3) to afford 2a (15 mg, 7%) and
3a (160 mg, 88%) as a yellow oil. Compound 3a was
4.1.6. 4-Bromo-10-methyl-1,5-dioxo-5,10-dihydro-1H-
azepino[3,4-b]indole-2-carboxylic acid tert-butyl ester
(4c). Under argon, a solution of 4b (0.80 g, 2.62 mmol),
Boc2O (1.14 g, 5.24 mmol) and DMAP (32 mg, 0.26 mmol)
in acetonitrile (25 mL) was stirred at room temperature for
24 h. The resulting precipitate was filtered and recrystallised
once from ethyl acetate–petroleum ether to give the
desired compound 4c as a yellow solid (0.65 g, 61%). Mp
1
unstable and was used directly in the next step. H NMR
(CDCl3, 250 MHz) d 3.82 (s, 3H, CH3), 3.95 (m, 2H, CH2),
4.12 (s, 3H, CH2), 4.36 (br d, 1H, J¼14.0 Hz, CH2), 4.57 (br
t, 1H, J¼4.0 Hz, CH), 5.48 (br d, 1H, J¼14.0 Hz, CH2),

J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
6663
126–1288C (ethyl acetate–petroleum ether); IR (KBr) n
1773 (CO), 1657 (CO), 1612 (CO) cm21; 1H NMR (CDCl3,
250 MHz) d 1.64 (s, 9H, 3CH3), 4.20 (s, 3H, CH3), 7.40–
7.60 (m, 3H, HAr), 8.01 (s, 1H, HAr), 8.85 (d, 1H, J¼7.9 Hz,
HAr); 13C NMR (CDCl3, 62.90 MHz) d 27.7 (3CH3), 33.7
(CH3), 87.7 (C), 110.4 (CH), 112.4 (C), 118.5 (C), 124.5
(CH), 125.0 (C), 125.4 (C), 125.5 (CH), 128.2 (CH), 130.1
(CH), 140.0 (C), 151.5 (CO), 159.6 (CO), 175.5 (CO); MS
(IS) m/z 405 (79Br, MþH)þ, 407 (81Br, MþH)þ. Anal. calcd
for C18H17BrN2O4: C, 53.35; H, 4.23; N, 6.91. Found: C,
53.73; H, 4.05; N, 7.03.
added, following immediately by saturated aqueous
NaHCO3 (2 mL). The heterogeneous solution was stirred
at 808C for 1 h. Brine solution was then added, the two
layers were separated and the aqueous phase was extracted
with dichloromethane (2£5 mL). The combined organic
extracts were dried over MgSO4 and evaporated in vacuo.
The residue was purified by column chromatography on
silica gel (dichloromethane) to give the desired compound.
4.2.1. 2-(4-Methoxybenzyl)-10-methyl-4-phenyl-
2H,10H-azepino[3,4-b]indole-1,5-dione (6a). Yield: 84%.
Mp 164–1668C (ethyl acetate–petroleum ether); IR (KBr) n
1641 (CO), 1606 (CO) cm21; 1H NMR (CDCl3, 250 MHz)
d 3.78 (s, 3H, CH3), 4.25 (s, 3H, CH3), 5.16 (s, 2H, CH2),
6.87 (d, 2H, J¼8.6 Hz, HAr), 7.18 (s, 1H, vCH), 7.24–7.48
(m, 8H, HAr), 7.48–7.50 (m, 2H, HAr), 8.84 (d, 1H,
J¼8.3 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d 34.1
(CH3), 55.4 (CH3), 55.8 (CH2), 110.2 (CH), 114.4 (2CH),
122.4 (C), 123.7 (CH), 125.4 (CH), 125.5 (C), 127.3 (C),
127.5 (CH), 127.6 (CH), 128.3 (2CH), 128.4 (C), 129.3
(2CH), 130.0 (2CH), 131.2 (C), 135.9 (CH), 138.6 (C),
139.9 (C), 159.5 (C), 160.3 (CO), 181.5 (CO); MS (IS) m/z
423 (MþH)þ. Anal. calcd for C27H22N2O3: C, 76.76; H,
5.25; N, 6.63. Found: C, 77.01; H, 5.11; N, 6.52.
4.1.7. 2-(4-Methoxybenzyl)-10-methyl-2H,10H-azepino-
[3,4-b]indole-1,5-dione (5a). DBU (0.04 mL, 0.23 mmol)
was added to a solution of 3a (100 mg, 0.23 mmol) in DMF.
The solution was stirred at room temperature for 1 h.
Hydrolysis was performed by addition of 10% HCl solution.
After filtration, the residue was washed with water and
ether. The solid obtained was partitioned between dichlor-
omethane (30 mL) and water. After extraction, organic
layers were dried over MgSO4, filtered and evaporated in
vacuo. Compound 5a was obtained as a yellow solid
(78 mg, 95%). Mp 144–1468C (toluene); IR (KBr) n 1647
(CO), 1628 (CO) cm21; 1H NMR (CDCl3, 250 MHz) d 3.79
(s, 3H, CH3), 4.25 (s, 3H, CH3), 5.12 (s, 2H, CH2), 5.98 (d,
1H, J¼11.0 Hz, vCH), 6.85–6.90 (m, 3H, HAr), 7.27–7.53
(m, 5H, HAr), 8.86 (d, 1H, J¼8.1 Hz, HAr); 13C NMR
(CDCl3, 62.90 MHz) d 34.5 (CH3), 55.3 (CH3), 55.4 (CH2),
110.3 (CH), 114.4 (2CH), 114.6 (CH), 121.5 (C), 123.8
(CH), 125.0 (C), 125.4 (CH), 127.5 (CH), 128.4 (C), 129.3
(2CH), 129.8 (C), 134.9 (CH), 140.0 (C), 159.6 (C), 161.1
(CO), 182.6 (CO); MS (IS) m/z 347 (MþH)þ. Anal. calcd
for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.57; H, 5.07; N, 7.92.
4.2.2. 10-Methyl-1,5-dioxo-4-phenyl-5,10-dihydro-1H-
azepino[3,4-b]indole-2-carboxylic acid tert-butyl ester
(6b). Yield: 66%. Mp 174–1768C (ethyl acetate–petroleum
ether); IR (KBr) n 1758 (CO), 1668 (CO), 1614 (CO) cm21
;
1H NMR (CDCl3, 250 MHz) d 1.63 (s, 9H, CH3), 4.26 (s,
3H, CH3), 7.34 (s, 1H, vCH), 7.36–7.57 (m, 8H, HAr), 8.83
(d, 1H, J¼8.2 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d
27.7 (3CH3), 33.6 (CH3), 87.0 (C), 110.3 (CH), 122.0 (C),
124.0 (CH), 125.5 (CH), 125.6 (C), 126.6 (C), 127.7 (CH),
127.8 (CH), 128.3 (2CH), 129.7 (CH), 130.0 (2CH), 130.8
(C), 137.8 (C), 139.9 (C), 152.6 (CO), 160.0 (CO), 181.6
(CO); MS (IS) m/z 403 (MþH)þ. Anal. calcd for
C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.30;
H, 5.69; N, 6.83.
4.1.8. 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-dione
(5b). Under argon, a solution of 5a (300 mg, 0.86 mmol) in
trifluoroacetic acid (5 mL) was stirred at reflux for 15 h.
After cooling, the mixture was poured into ice and
neutralised by 10% NaOH solution. After filtration, the
crude product was recrystallised once from ethyl acetate–
petroleum ether to give 5b as a white solid (132 mg,
68%). Mp 130–1328C (ethyl acetate–petroleum ether);
4.2.3. 10-Methyl-4-phenyl-2H,10H-azepino[3,4-b]-
indole-1,5-dione (6c). Yield: 44%. Mp 139–1418C (ethyl
acetate–petroleum ether); IR (KBr) n 3365 (NH), 1652
1
1
IR (KBr) n 3320 (NH), 1650 (CO), 1618 (CO) cm21; H
(CO), 1618 (CO) cm21; H NMR (DMSO-d6, 250 MHz) d
NMR (DMSO-d6, 250 MHz) d 4.24 (s, 2H, CH3), 5.84 (d,
1H, J¼10.0 Hz, vCH), 6.81 (t, 1H, J¼10.0 Hz, vCH),
7.37 (t, 1H, J¼7.3 Hz, HAr), 7.55 (t, 1H, J¼7.4 Hz, HAr),
7.79 (d, 1H, J¼7.8 Hz, HAr), 8.74 (d, 1H, J¼8.1 Hz,
HAr), 11.18 (br s, 1H, NH); 13C NMR (DMSO-d6,
62.90 MHz) d 33.7 (CH3), 111.2 (CH), 112.4 (CH), 121.0
(C), 123.2 (CH), 124.4 (CH), 124.6 (C), 127.1 (CH),
131.1 (C), 132.1 (CH), 139.9 (C), 161.1 (CO), 182.3
(CO); MS (IS) m/z 227 (MþH)þ. Anal. calcd for
C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C,
69.35; H, 4.60; N, 12.47.
4.25 (s, 3H, CH3), 7.25–7.48 (m, 3H, vCHþHAr), 7.85–
7.92 (m, 6H, HAr), 8.77 (d, 1H, J¼8.1 Hz, HAr), 11.48 (br s,
1H, NH); 13C NMR (DMSO-d6, 62.90 MHz) d 33.9 (CH3),
110.1 (CH), 122.8 (C), 123.8 (CH), 124.1 (CH), 124.5 (CH),
125.0 (C), 126.5 (C), 127.7 (CH), 128.3 (2CH), 128.8
(2CH), 129.6 (CH), 130.2 (C), 138.6 (C), 139.8 (C), 161.2
(CO), 182.7 (CO); MS (IS) m/z 303 (MþH)þ. Anal. calcd
for C19H14N2O2: C, 75.48; H, 4.67; N, 9.27. Found: C,
75.72; H, 4.84; N, 9.45.
4.2.4. 2-(4-Methoxybenzyl)-10-methyl-4-thiophen-2-yl-
2H,10H-azepino[3,4-b]indole-1,5-dione (7). Yield: 85%.
Mp 168–1698C (ethyl acetate–petroleum ether); IR (KBr)
4.2. General procedurefor the Suzukireactionwith 4(a–c)
n 1642 (CO), 1594 (CO) cm21
;
1H NMR (CDCl3,
To a stirred solution of compound 4 (1.31 mmol) in dry
toluene (5 mL) was added freshly prepared tetrakis-
(triphenylphosphine)palladium (0.014 mmol). The solution
was stirred at room temperature for 15 min. Boronic acid
(1.97 mmol) diluted in absolute ethanol (2 mL) was then
250 MHz) d 3.80 (s, 3H, CH3), 4.28 (s, 3H, CH3), 5.22
(s, 2H, CH2), 6.90 (d, 2H, J¼8.5 Hz, HAr), 7.00–7.11 (m,
2H, HAr), 7.31 (s, 1H, vCH), 7.35–7.42 (m, 4H, HAr),
7.52–7.54 (m, 2H, HAr), 8.87 (d, 1H, J¼8.2 Hz, HAr); 13C
NMR (CDCl3, 62.90 MHz) d 34.1 (CH3), 55.4 (CH3), 56.1

6664
J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
(CH2), 110.2 (CH), 114.5 (2CH), 120.2 (C), 121.7 (C),
123.7 (CH), 125.0 (CH), 125.2 (CH), 125.3 (C), 126.1
(CH), 127.2 (CH), 127.5 (CH), 128.3 (C), 129.5 (2CH),
130.9 (C), 134.5 (CH), 139.2 (C), 139.8 (C), 159.6 (C),
159.9 (CO), 180.3 (CO); MS (IS) m/z 429 (MþH)þ. Anal.
calcd for C25H20N2O3S: C, 70.07; H, 4.70; N, 6.54.
Found: C, 69.84; H, 4.85; N, 6.63.
(s, 9H, CH3), 4.24 (s, 3H, CH3), 7.30–7.45 (m, 4H, HAr),
7.53 (s, 1H, vCH), 7.54–7.56 (m, 1H, HAr), 7.78 (s, 1H,
HAr), 7.79–7.86 (m, 2H, HAr), 8.87 (d, 1H, J¼8.2 Hz, HAr);
13C NMR (CDCl3, 62.90 MHz) d 27.7 (3CH3), 33.7 (CH3),
87.4 (C), 110.4 (CH), 120.3 (C), 121.7 (C), 122.0 (CH),
122.8 (CH), 123.6 (CH), 124.3 (CH), 124.4 (CH), 125.2 (C),
125.5 (CH), 125.6 (CH), 128.0 (CH), 129.3 (CH), 130.1 (C),
139.1 (C), 139.3 (C), 140.1 (C), 141.2 (C), 152.4 (CO),
159.8 (CO), 180.8 (CO); MS (IS) m/z 459 (MþH)þ. Anal.
calcd for C26H22N2O4S: C, 68.11; H, 4.84; N, 6.11. Found:
C, 68.37; H, 4.67; N, 5.93.
4.2.5. 4-Furan-2-yl-2-(4-methoxybenzyl)-10-methyl-
2H,10H-azepino[3,4-b]indole-1,5-dione (8). Yield: 76%.
Mp 127–1298C (ethyl acetate–petroleum ether); IR (KBr) n
1642 (CO), 1622 (CO) cm21; 1H NMR (CDCl3, 250 MHz)
d 3.77 (s, 3H, CH3), 4.20 (s, 3H, CH3), 5.21 (s, 2H, CH2),
6.48–6.50 (m, 1H, HAr), 6.86–6.89 (m, 2H, HAr), 7.24–
7.50 (m, 7H, vCHþHAr), 7.82 (s, 1H, vCH), 8.86 (d, 1H,
J¼8.2 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d 34.0
(CH3), 55.4 (CH3), 56.6 (CH2), 110.2 (CH), 110.8 (CH),
112.1 (CH), 114.4 (2CH), 116.9 (C), 122.2 (C), 123.6 (CH),
125.3 (CH), 125.5 (C), 127.5 (CH), 128.4 (C), 129.4 (2CH),
130.7 (C), 133.6 (CH), 139.8 (C), 141.0 (C), 149.3 (C),
159.6 (C), 159.9 (CO), 179.8 (CO); MS (IS) m/z 413
(MþH)þ. Anal. calcd for C25H20N2O4: C, 72.80; H, 4.89; N,
6.79. Found: C, 72.54; H, 4.70; N, 6.67.
4.2.9. 4-Benzofuran-2-yl-2-(4-methoxybenzyl)-10-
methyl-2H,10H-azepino[3,4-b]indole-1,5-dione (11).
Yield: 77%. Mp 199–2018C (ethyl acetate–petroleum
1
ether); IR (KBr) n 1642 (CO), 1621 (CO) cm21; H NMR
(CDCl3, 250 MHz) d 3.79 (s, 3H, CH3), 4.27 (s, 3H, CH3),
5.31 (s, 2H, CH2), 6.91 (d, 2H, J¼8.8 Hz, HAr), 7.20–7.30
(m, 3H, HArþvCH), 7.39–7.45 (m, 3H, HAr), 7.53–7.61
(m, 3H, HAr), 7.75 (s, 1H, HAr), 8.15 (s, 1H, HAr), 8.83 (d,
1H, J¼8.2 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d 34.1
(CH3), 55.4 (CH3), 56.9 (CH2), 107.5 (CH), 110.3 (CH),
110.6 (CH), 114.5 (2CH), 114.6 (C), 116.2 (C), 121.4 (CH),
122.4 (C), 123.0 (CH), 123.9 (CH), 124.4 (CH), 125.4 (CH),
125.5 (C), 127.6 (CH), 128.3 (C), 129.5 (2CH), 130.0 (C),
130.7 (C), 135.1 (CH), 140.0 (C), 153.6 (C), 159.7 (C),
160.0 (CO), 179.9 (CO); MS (IS) m/z 463 (MþH)þ. Anal.
calcd for C29H22N2O4: C, 75.31; H, 4.79; N, 6.06. Found: C,
75.01; H, 4.92; N, 6.23.
4.2.6. 2-(4-Methoxybenzyl)-10-methyl-4-thiophen-3-yl-
2H,10H-azepino[3,4-b]indole-1,5-dione (9). Yield: 82%.
Mp 171–1728C (ethyl acetate–petroleum ether); IR (KBr) n
1650 (CO), 1645 (CO) cm21; 1H NMR (CDCl3, 250 MHz)
d 3.80 (s, 3H, CH3), 4.29 (s, 3H, CH3), 5.20 (s, 2H, CH2),
6.90 (d, 2H, J¼8.8 Hz, HAr), 7.30–7.41 (m, 7H, vCHþ
HAr), 7.52–7.54 (m, 2H, HAr), 8.85 (d, 1H, J¼8.2 Hz, HAr);
13C NMR (CDCl3, 62.90 MHz) d 34.1 (CH3), 55.4 (CH3),
55.7 (CH2), 110.2 (CH), 114.5 (2CH), 122.1 (C), 122.2 (C),
123.6 (CH), 123.7 (CH), 125.0 (CH), 125.2 (CH), 125.4 (C),
127.4 (CH), 128.4 (C), 129.1 (CH), 129.4 (2CH), 131.0 (C),
135.1 (CH), 138.5 (C), 139.9 (C), 159.6 (C), 160.1 (CO),
181.3 (CO); MS (IS) m/z 429 (MþH)þ. Anal. calcd for
C25H20N2O3S: C, 70.07; H, 4.70; N, 6.54. Found: C, 70.36;
H, 4.89; N, 6.38.
4.2.10. 2-[2-(4-Methoxybenzyl)-10-methyl-1,5-dioxo-
1,2,5,10-tetrahydroazepino[3,4-b]indol-4-yl]benzaldehy-
de (12). Yield: 96%. Mp 224–2268C (ethyl acetate–
petroleum ether); IR (KBr) n 1699 (CO), 1636 (CO), 1585
1
(CO) cm21; H NMR (CDCl3, 250 MHz) d 3.79 (s, 3H,
CH3), 4.30 (s, 3H, CH3), 5.21 (br s, 2H, CH2), 6.89 (d, 2H,
J¼8.8 Hz, HAr), 7.18 (s, 1H, vCH), 7.21–7.38 (m, 4H,
HAr), 7.48–7.63 (m, 4H, HAr), 7.98 (d, 1H, J¼7.6 Hz, HAr),
8.76 (d, 1H, J¼8.2 Hz, HAr), 9.92 (s, 1H, CHO); 13C NMR
(CDCl3, 62.90 MHz) d 34.3 (CH3), 55.5 (CH3), 55.9 (CH2),
110.3 (CH), 114.5 (C), 114.6 (2CH), 121.8 (C), 124.0 (CH),
124.7 (C), 125.5 (CH), 127.8 (CH), 128.2 (C), 128.6 (CH),
129.0 (CH), 129.3 (2CH), 129.4 (C), 131.7 (CH), 134.0
(CH), 135.5 (C), 136.0 (CH), 140.1 (C), 140.7 (C), 159.7
(C), 160.4 (CO), 181.4 (CO), 191.6 (CO); MS (IS) m/z 451
(MþH)þ. Anal. calcd for C28H22N2O4: C, 74.65; H, 4.92; N,
6.22. Found: C, 74.39; H, 5.06; N, 6.41.
4.2.7. 4-Benzo[b]thiophen-2-yl-2-(4-methoxybenzyl)-10-
methyl-2H,10H-azepino[3,4-b]indole-1,5-dione (10a).
Yield: 97%. Mp 175–1768C (ethyl acetate–petroleum
1
ether); IR (KBr) n 1642 (CO), 1591 (CO) cm21; H NMR
(CDCl3, 250 MHz) d 3.77 (s, 3H, CH3), 4.18 (s, 3H, CH3),
5.16 (s, 2H, CH2), 6.90 (d, 2H, J¼8.7 Hz, HAr), 7.24–7.53
(m, 8H, vCHþHAr), 7.53 (s, 1H, HAr), 7.66–7.82 (m, 2H,
HAr), 8.84 (d, 1H, J¼8.2 Hz, HAr); 13C NMR (CDCl3,
62.90 MHz) d 34.1 (CH3), 55.4 (CH3), 56.1 (CH2), 110.2
(CH), 114.5 (2CH), 121.7 (C), 121.9 (CH), 122.1 (CH),
122.4 (C), 123.4 (CH), 123.8 (CH), 124.2 (CH), 125.2
(CH), 125.2 (CH), 125.4 (C), 127.5 (CH), 128.2 (C),
129.6 (2CH), 130.8 (C), 135.7 (CH), 139.2 (C), 139.8 (C),
140.2 (C), 140.9 (C), 159.7 (C), 159.9 (CO), 180.3
(CO); MS (IS) m/z 479 (MþH)þ. Anal. calcd for
C29H22N2O3S: C, 72.78; H, 4.63; N, 5.85. Found: C,
73.05; H, 4.76; N, 5.70.
4.3. General procedure for the Stille reaction with 4(a-b)
To a suspension of freshly prepared tetrakis-(triphenylpho-
sphine)palladium (0.02 mmol) in dry DMF (5 mL) was
added, under argon, a solution of 4 (0.23 mmol) and
stannane (tributylvinylstannane for 13a-13b, tributyl(1-
ethoxyvinyl)stannane for 14a-14b) (0.46 mmol) in dry
DMF (2 mL). The solution was stirred at 1008C for 1 h.
The solvent was then evaporated in vacuo and the crude
residue was purified by column chromatography (dichlor-
omethane for 13a-13b and dichloromethane–triethylamine
98:2 for 14a-14b) to afford the desired products.
4.2.8. 4-Benzo[b]thiophen-2-yl-10-methyl-1,5-dioxo-
5,10-dihydro-1H-azepino[3,4-b]indole-2-carboxylic acid
tert-butyl ester (10b). Yield: 68%. Mp 166–1688C (ethyl
acetate–petroleum ether); IR (KBr) n 1730 (CO), 1640
(CO), 1622 (CO) cm21; 1H NMR (CDCl3, 250 MHz) d 1.65
4.3.1. 2-(4-Methoxybenzyl)-10-methyl-4-vinyl-2-yl-
2H,10H-azepino[3,4-b]indole-1,5-dione (13a). Yield:

J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
6665
87%. Mp 108–1108C (ethyl acetate–petroleum ether); IR
1
4.3.5. 2-(4-Methoxybenzyl)-10-methyl-4-acetyl-2-yl-
2H,10H-azepino[3,4-b]indole-1,5-dione (15a). A solution
of 14a (200 mg, 0.48 mmol) in acetone/10% HCl (14 mL, 5/
2) was stirred at room temperature for 1 h. After
evaporation, the residue was partitioned between dichlor-
omethane (10 mL) and water. After extraction, organic
layers were dried over MgSO4, filtered and evaporated in
vacuo. Compound 15a was obtained as a yellow solid
(177 mg, 95%). Mp 159–1608C (ethyl acetate–petroleum
(KBr) n 1644 (CO), 1613 (CO) cm21; H NMR (CDCl3,
250 MHz) d 3.77 (s, 3H, CH3), 4.19 (s, 3H, CH3), 5.15 (s,
2H, CH2), 5.19 (dd, 1H, J¼1.2, 10.5 Hz, vCH2), 5.43 (dd,
1H, J¼1.2, 17.5 Hz, vCH2), 6.87 (d, 2H, J¼8.5 Hz, HAr),
6.98 (dd, 1H, J¼10.5, 17.5 Hz, vCH), 7.23–7.49 (m, 6H,
vCHþHAr), 8.79 (d, 1H, J¼7.9 Hz, HAr); 13C NMR
(CDCl3, 62.90 MHz) d 34.1 (CH3), 55.4 (CH3), 55.8
(CH2), 110.2 (CH), 114.3 (CH2), 114.4 (2CH), 121.8 (C),
123.7 (CH), 123.9 (C), 125.2 (CH), 125.3 (C), 127.4 (CH),
128.4 (C), 129.4 (2CH), 131.2 (C), 133.2 (CH), 134.2 (CH),
139.8 (C), 159.6 (C), 160.2 (CO), 181.4 (CO); MS (IS) m/z
373 (MþH)þ. Anal. calcd for C23H20N2O3: C, 74.18; H,
5.41; N, 7.52. Found: C, 73.83; H, 5.60; N, 7.68.
ether); IR (KBr) n 1680 (CO), 1664 (CO), 1610 (CO) cm21
;
1H NMR (CDCl3, 250 MHz) d 2.66 (s, 3H, CH3), 3.79 (s,
3H, CH3), 4.17 (s, 3H, CH3), 5.16 (s, 2H, CH2), 6.87 (d, 2H,
J¼8.5 Hz, HAr), 7.31–7.50 (m, 5H, vCHþHAr), 8.01 (s,
1H, HAr), 8.74 (d, 1H, J¼8.1 Hz, HAr); 13C NMR (CDCl3,
62.90 MHz) d 31.2 (CH3), 34.0 (CH3), 55.3 (CH3), 56.8
(CH2), 110.3 (CH), 114.4 (2CH), 123.2 (C), 123.8 (CH),
124.1 (C), 124.9 (CH), 125.0 (C), 127.8 (CH), 128.4 (C),
129.6 (2CH), 130.1 (C), 139.9 (C), 142.1 (CH), 159.7 (C),
160.4 (CO), 181.2 (CO), 199.3 (CO); MS (IS) m/z 411
(MþNa)þ. Anal. calcd for C23H20N2O4: C, 71.12; H, 5.19;
N, 7.21. Found: C, 71.43; H, 5.10; N, 7.05.
4.3.2. 10-Methyl-4-vinyl-2H,10H-azepino[3,4-b]-indole-
1,5-dione (13b). Yield: 31%. Mp 135–1378C (ethyl
acetate–petroleum ether); IR (KBr) n 3260 (NH), 1654
1
(CO), 1623 (CO) cm21; H NMR (DMSO-d6, 250 MHz) d
4.29 (s, 3H, CH3), 5.26 (dd, 1H, J¼1.4, 10.4 Hz, vCH2),
5.69 (dd, 1H, J¼1.4, 16.8 Hz, vCH2), 6.90 (dd, 1H, J¼
10.4, 16.8 Hz, vCH), 7.52–7.64 (m, 4H, vCHþHAr), 8.77
(d, 1H, J¼8.1 Hz, HAr), 11.34 (br s, 1H, NH); 13C NMR
(DMSO-d6, 62.90 MHz) d 33.9 (CH3), 110.5 (CH), 114.8
(CH2), 121.8 (C), 123.1 (CH), 123.2 (CH), 124.5 (C), 127.0
(CH), 127.3 (C), 130.8 (C), 132.0 (CH), 133.1 (CH), 139.5
(C), 161.0 (CO), 178.2 (CO); MS (IS) m/z 253 (MþH)þ.
Anal. calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.67; H, 4.62; N, 11.25.
4.3.6. 10-Methyl-4-acetyl-2-yl-2H,10H-azepino[3,4-b]-
indole-1,5-dione (15b). Yield 96%. Mp 118–1208C (ethyl
acetate–petroleum ether); IR (KBr) n 3243 (NH), 1680
1
(CO), 1664 (CO), 1610 (CO) cm21; H NMR (DMSO-d6,
250 MHz) d 2.48 (s, 3H, CH3), 4.19 (s, 3H, CH3), 7.34–7.43
(m, 2H, vCHþHAr), 7.52–7.58 (m, 1H, HAr), 7.76–7.79
(m, 1H, HAr), 8.67 (d, 1H, J¼8.3 Hz, HAr), 11.63 (br s, NH);
13C NMR (DMSO-d6, 62.90 MHz) d 30.8 (CH3), 33.5
(CH3), 111.4 (CH), 122.3 (C), 123.2 (C), 123.5 (CH), 124.3
(CH), 124.8 (C), 127.4 (CH), 129.5 (C), 137.8 (CH), 139.4
(C), 160.4 (CO), 181.0 (CO), 199.0 (CO); MS (IS) m/z 269
(MþH)þ. Anal. calcd for C15H12N2O3: C, 67.16; H, 4.51; N,
10.44. Found: C, 67.41; H, 4.40; N, 10.57.
4.3.3. 2-(4-Methoxybenzyl)-10-methyl-4-(1-ethoxy-
vinyl)-2-yl-2H,10H-azepino[3,4-b]indole-1,5-dione
(14a). Yield: 95%. Mp 154–1568C (ethyl acetate–pet-
roleum ether); IR (KBr) n 1644 (CO), 1613 (CO) cm21; 1H
NMR (CDCl3, 250 MHz) d 1.34 (t, 3H, J¼6.9 Hz, CH3),
3.79 (s, 3H, CH3), 3.88 (q, 2H, J¼6.9 Hz, CH2), 4.21 (s, 3H,
CH3), 4.36 (d, 1H, J¼2.1 Hz, vCH2), 4.54 (d, 1H, J¼
2.1 Hz, vCH2), 5.13 (s, 2H, CH2), 6.88 (d, 2H, J¼7.2 Hz,
HAr), 7.29–7.47 (m, 6H, vCHþHAr), 8.81 (d, 1H, J¼
8.1 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d 14.7 (CH3),
34.0 (CH3), 55.4 (CH3), 55.7 (CH2), 63.7 (CH2), 87.5 (CH2),
110.2 (CH), 114.4 (2CH), 122.7 (C), 123.6 (CH), 123.7 (C),
125.3 (CH), 125.5 (C), 127.4 (CH), 128.4 (C), 129.5 (2CH),
130.9 (C), 135.7 (CH), 139.8 (C), 158.5 (C), 159.6 (C),
160.5 (CO), 181.1 (CO); MS (IS) m/z 439 (MþNa)þ. Anal.
calcd for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found: C,
71.72; H, 5.67; N, 6.59.
4.4. General procedure for the Diels–Alder reaction
with 13a
To a solution of 13a (0.27 mmol) in toluene (3 mL) was
added dienophile (0.54 mmol). The mixture was stirred in a
sealed tube at 1808C for 3 h (DMAD) or 1 h (N-
methylmaleimide and maleic anhydride). The solvent was
then evaporated in vacuo and the crude residue was purified
by column chromatography (ethyl acetate/ petroleum ether
7:3 for 16, ethyl acetate–petroleum ether 6:4 for 17 and
ethyl acetate–petroleum ether 4:6 for 18) to give the desired
compound.
4.3.4. 4-(1-Ethoxyvinyl)-10-methyl-2H,10H-azepino-
[3,4-b]-1,5-dione (14b). Yield: 28%. Mp 181–1838C
(ethyl acetate–petroleum ether); IR (KBr) n 3266 (NH),
1677 (CO), 1642 (CO) cm21; 1H NMR (CDCl3, 250 MHz)
d 1.37 (t, 3H, J¼6.9 Hz, CH3), 3.92 (q, 2H, J¼6.9 Hz, CH2),
4.29 (s, 3H, CH3), 4.41 (d, 1H, J¼1.8 Hz, vCH2), 4.68 (d,
1H, J¼1.8 Hz, vH2), 7.16 (d, 1H, J¼4.5 Hz, HAr), 7.36–
7.58 (m, 3H, vCHþHAr), 8.69 (br s, 1H, NH), 8.91 (d, 1H,
J¼7.9 Hz, HAr); 13C NMR (CDCl3, 62.90 MHz) d 14.5
(CH3), 54.7 (CH3), 62.4 (CH2), 86.9 (CH2), 110.3 (CH),
122.1 (C), 123.2 (C), 124.0 (CH), 125.2 (CH), 126.9 (CH),
125.5 (C), 130.1 (C), 136.0 (CH), 140.8 (C), 159.1 (C),
160.9 (CO), 181.2 (CO); MS (IS) m/z 297 (MþH)þ. Anal.
calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C,
68.60; H, 5.60; N, 9.53.
4.4.1. N-Methyl-7-(4-methoxybenzyl)-5-methyl-6,12-
dioxo-5,6,7,7a,8,9,10,12-octahydrobenzo[2,3]azepino
[6,5-b]indole-8,9-dicarboximide (16). Yield: 87%. Mp
139–1418C (ethyl acetate–petroleum ether); IR (KBr) n
1702 (CO), 1636 (CO), 1610 (CO) cm21; 1H NMR (DMSO-
d6, 808C, 250 MHz) d 2.11 (s, 3H, CH3), 2.29–2.38 (m, 1H,
CH2), 2.69–2.78 (m, 1H, CH2), 3.27–3.35 (m, 1H, CH),
3.43–3.49 (m, 1H, CH), 3.74 (s, 3H, CH3), 4.07 (s, 3H,
CH3), 4.59 (d, 1H, J¼15.3 Hz, CH2), 4.74 (m, 1H, CH), 5.15
(d, 1H, J¼15.3 Hz, CH2), 6.59 (m, 1H, vCH), 6.89 (d, 2H,
J¼8.5 Hz, HAr), 7.22–7.42 (m, 4H, HAr), 7.62 (d, 1H,
J¼8.5 Hz, HAr), 7.95 (d, 1H, J¼7.9 Hz, HAr); 13C NMR
(DMSO-d6, 808C, 62.90 MHz) d 23.1 (CH3), 23.2 (CH2),
31.9 (CH3), 39.7 (CH), 42.5 (CH), 50.3 (CH2), 54.8 (CH3),

6666
J. Perron et al. / Tetrahedron 59 (2003) 6659–6666
56.6 (CH), 110.2 (CH), 113.7 (2CH), 114.5 (C), 121.1 (CH),
122.3 (CH), 122.9 (C), 124.9 (CH), 128.4 (2CH), 129.0 (C),
132.8 (C), 134.1 (CH), 135.0 (C), 137.8 (C), 158.4 (C),
161.8 (CO), 176.0 (CO), 177.4 (CO), 183.5 (CO); MS (IS)
m/z 484 (MþH)þ. Anal. calcd for C28H25N3O5: C, 69.55; H,
5.21; N, 8.69. Found: C, 69.73; H, 5.06; N, 8.81.
CH3), 2.49 (t, 2H, J¼6.5 Hz, CH2), 2.59 (t, 2H, J¼6.5 Hz,
CH2), 3.43–3.47 (m, 2H, CH2), 3.68 (s, 3H, CH3), 3.72–
3.81 (m, 2H, CH2), 3.98 (s, 3H, CH3), 4.37 (br s, 2H, CH2),
6.67 (d, 2H, J¼8.0 Hz, HAr), 7.03 (d, 1H, J¼7.5 Hz, HAr),
7.10–7.19 (m, 3H, HAr), 7.29–7.61 (m, 3H, HAr), 7.56 (d,
1H, J¼7.5 Hz, HAr), 8.24 (br s, 1H, NH), 8.37 (br s, 1H,
NH); 13C NMR (CDCl3, 62.90 MHz) d 32.3 (CH3), 35.9
(CH2), 37.6 (CH2), 45.3 (2CH3), 45.6 (2CH3), 50.5 (CH2),
55.2 (CH3), 57.3 (CH2), 57.7 (CH2), 110.7 (CH), 114.1
(2CH), 122.1 (C), 122.3 (CH), 123.0 (CH), 123.6 (C), 124.4
(C), 124.5 (CH), 129.3 (2CH), 130.2 (CH), 130.4 (C), 130.9
(CH), 135.7 (C), 137.0 (C), 138.7 (C), 145.6 (C), 159.1 (C),
161.0 (C), 161.7 (CO), 169.7 (CO), 170.0 (CO), 191.3 (CO);
MS (IS) m/z 625 (MþH)þ. Anal. calcd for C35H40N6O5: C,
67.29; H, 6.45; N, 13.45. Found: C, 67.60; H, 6.61; N, 13.63.
4.4.2. 7-(4-Methoxybenzyl)-5-methyl-6,12-dioxo-
5,6,7,7a,8,9,10,12-octahydrobenzo[2,3]azepino[6,5-b]-
indole-8,9-dicarboxylic anhydride (17). Yield: 57%; IR
(film) n 1716 (CO), 1642 (CO), 1612 (CO) cm21; 1H NMR
(CDCl3, 250 MHz) d 2.16 (br s, 1H, CH2), 2.90 (br s, 1H,
CH2), 3.28–3.43 (m, 2H, CH), 3.79 (s, 3H, CH3), 4.12 (s,
3H, CH3), 4.44 (br s, 1H, CH2), 4.96 (m, 2H, CHþCH2),
6.78 (m, 1H, vCH), 6.88 (d, 2H, J¼8.5 Hz, HAr), 7.28–
7.44 (m, 5H, HAr), 8.16 (d, 1H, J¼8.1 Hz, HAr); 13C NMR
(DMSO-d6, 808C, 62.90 MHz) d 23.5 (CH2), 32.0 (CH3),
36.4 (CH), 44.0 (CH), 50.4 (CH2), 54.8 (CH3), 55.1 (CH),
110.5 (CH), 113.8 (2CH), 114.7 (C), 121.3 (CH), 122.6
(CH), 123.0 (C), 125.1 (CH), 128.4 (2CH), 128.8 (C), 132.8
(C), 134.8 (CH), 135.4 (C), 138.0 (C), 158.5 (C), 161.5
(CO), 171.4 (CO), 173.1 (CO), 182.7 (CO); MS (IS) m/z 471
(MþH)þ. Anal. calcd for C27H22N2O6: C, 68.93; H, 4.71; N,
5.95. Found: C, 68.59; H, 4.87; N, 6.12.
Acknowledgements
This research work was supported by a grant from the
‘MESNR’ to J. P.
References
4.4.3. 7-(4-Methoxybenzyl)-5-methyl-6,12-dioxo-
5,6,7,12-tetrahydrobenzo[2,3]azepino[6,5-b]indole-8,9-
dicarboxylic acid dimethyl ester (18). Yield: 53%. Mp
199–2018C (toluene); IR (KBr) n 1722 (CO), 1708 (CO),
1652 (CO), 1618 (CO) cm21; 1H NMR (CDCl3, 250 MHz)
d 3.68 (s, 3H, CH3), 3.93 (s, 3H, CH3), 4.06 (s, 3H, CH3),
4.08 (s, 3H, CH3), 4.42 (d, 1H, J¼14.0 Hz, NCH2), 5.58 (d,
1H, J¼14.0 Hz, NCH2), 6.69 (d, 2H, J¼8.6 Hz, HAr), 6.99
(d, 2H, J¼8.6 Hz, HAr), 7.28–7.41 (m, 3H, HAr), 7.83–7.93
(m, 2H, HAr), 8.16 (d, 1H, J¼7.9 Hz, HAr); 13C NMR
(CDCl3, 62.90 MHz) d 32.8 (CH3), 53.2 (CH3), 53.7 (CH3),
55.0 (CH2), 55.3 (CH3), 110.5 (CH), 114.1 (2CH), 122.4
(CH), 122.6 (C), 123.9 (C), 124.0 (CH), 124.2 (C), 126.6
(CH), 128.1 (CH), 128.2 (C), 129.5 (2CH), 129.5 (CH),
132.5 (C), 132.8 (C), 139.0 (C), 143.7 (C), 159.3 (C), 159.7
(C), 162.2 (CO), 165.7 (CO), 167.5 (CO), 185.0 (CO); MS
(IS) m/z 513 (MþH)þ. Anal. calcd for C29H24N2O7: C,
67.96; H, 4.72; N, 5.47. Found: C, 68.29; H, 4.88; N, 5.63.
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´
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1
1660 (CO), 1640 (CO), 1622 (CO), 1602 (CO) cm21; H
NMR (CDCl3, 250 MHz) d 2.26 (s, 6H, CH3), 2.30 (s, 6H,