Synthesis and reactivity of azepino[3,4-b]indol-5-yl trifluoromethanesulfonate

Article abstract of DOI:10.1016/S0040-4020(00)00374-4

A convenient method for the synthesis of 5-substituted azepino[3,4- b]indol-1-ones 18 - 27 is described. This synthesis was based on palladium mediated cross-coupling reactions of the key intermediate azepino[3,4- b]indol-5-yl trifluoromethanesulfonates 3, obtained from the corresponding azepino[3,4-b]indole-1,5-dione 4. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00374-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4491±4499
Synthesis and Reactivity of Azepino[3,4-b]indol-5-yl
Tri¯uoromethanesulfonate
*
Á Ã Â
Lidwine Chacun-Lefevre, Benoõt Joseph and Jean-Yves Merour
   Â
Institut de Chimie Organique et Analytique, associe au CNRS, Universite d'Orleans, BP 6759, 45067 Orleans Cedex 2, France
Received 6 March 2000; accepted 2 May 2000
AbstractÐA convenient method for the synthesis of 5-substituted azepino[3,4-b]indol-1-ones 18±27 is described. This synthesis was based
on palladium mediated cross-coupling reactions of the key intermediate azepino[3,4-b]indol-5-yl tri¯uoromethanesulfonates 3, obtained
from the corresponding azepino[3,4-b]indole-1,5-dione 4. q 2000 Elsevier Science Ltd. All rights reserved.
A growing collection of marine natural compounds have
been reported in recent years as active leads for new drug
development1 or tools for cell biology.2 A number of cyclic
guanidine compounds containing a pyrrole ring, bio-
Our interest in indolic chemistry11 arose out of our desire to
prepare a diverse set of 5-substituted azepino indoles 2
which can be potential building blocks. The synthetic
approach was based on palladium mediated cross-coupling
reactions (Stille or Suzuki reaction) of the key tri¯ate 3,
prepared from the azepino[3,4-b]indole-1,5-dione 4.
È
genetically derivable from oroõdin, have been extracted
from marine organisms and display a large number of bio-
logical properties.3,4 Our attention has been focused on
Odiline or Stevensine 1 characterised by a pyrroloazepine
skeleton, 6,7-dihydro-1H-pyrrolo[2,3-c]azepin-8-one, con-
nected to a cyclic guanidine. The name Odiline was given
by Potier,5 but Albizati and Faulkner6 in a simultaneous and
independent study, assigned the name Stevensine. This
natural product has been the target of total synthesis
efforts.7±10
The synthesis of compound 4 has been already de-
scribed.12,13 Our synthesis is slightly modi®ed and is
outlined in Scheme 1. Amidi®cation of the commercially
available indole-2-carboxylic acid 5 with b-alanine ethyl
ester hydrochloride in the presence of DMAP and EDCI
gave 6 in 95% yield. For information, the same reaction
on a large scale with 5 (35 mmol) afforded exclusively the
2-indolecarboxylic anhydride 7. To avoid the intramolecu-
lar cyclisation on the indolic nitrogen atom, we decided to
protect it with a methyl group. Thus, reaction of compound
6 with iodomethane resulted in a regioselective methylation
in good yield of the indolic nitrogen atom to give 8.14
Saponi®cation of 8 with lithium hydroxide gave the acid 9
in 96% yield. Final PPA/P2O5 cyclisation provided
azepino[3,4-b]indole-1,5-dione 4 in 86% yield.
Keywords: indole; palladium; catalysis.
* Corresponding author. Tel.: 133-2-3849-4592; fax: 133-2-3841-7281;
e-mail: jean-yves.merour@univ-orleans.fr
The reactivity of the ketone 4 has been thoroughly investigated.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00374-4

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L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4492
Scheme 1. (a) H2NCH2CH2COOEt´HCl, DMAP, EDCI, CH2Cl2, rt, 20 h, 95%; (b) MeI, K2CO3, MeCN re¯ux, 24 h, 90%; (c) LiOH, EtOH, rt, 18 h, 96%;
(d) PPA, P2O5, 1108C, 1 h, 86%.
Table 1.
The Wittig reaction of 4 with (carbethoxymethylene)tri-
phenylphosphorane
or
Horner±Wadsworth±Emmons
reaction with triethylphosphonoacetate failed. The low reac-
tivity of the keto group led us to view the functionalisation
of the position-5 via palladium-catalysed reactions. The
preparation of tri¯ate from 4 was ®rst undergone. Therefore,
treatment of the lactam 4 with tri¯uoromethanesulfonic
anhydride in the presence of sodium carbonate in dichloro-
methane led exclusively to the formation of the O,N-ditri-
¯ate 10 in 70% yield. This structure was supported by IR, 1H
and 13C NMR spectra.15 If the same reaction was carried out
with tri¯uoromethanesulfonic anhydride in the presence of
N,N-dimethylformamide/dichloromethane (in order to
increase the solubility of 4) the formyl compound 11 was
obtained in 52% yield (Scheme 2).
Product
R
Conditions
Yield (%)
12a
12b
Ac
Boc
Ac2O, pyridine re¯ux, 2 h
Boc2O (1 equiv.), DMAP,
MeCN, 24 h
MeI, NaH, DMF, 08C, 15 min
BnCl, NaH, DMF, 08C, 30 min
PMBCl, NaH, DMF, 08C,
40 min
85
40
12c
12d
12e
Me
Bn
PMB
60
72
78
12f
SO2Ph
PhSO2Cl, NaH, DMF, 08C, 1 h
90
Unfortunately, compound 10 engaged in Stille reaction
afforded erratic results, so it was necessary to protect the
nitrogen atom of lactam 4 to solve the problem. In the
pyrrole series, protection of the lactam by acetyl or tosyl
group gave unsatisfactory results.16 In our hands, according
to standard procedures, protection of the amide group of
4 was performed to give the desired compounds 12
(Table 1).
12c (60% yield), the dimethyl derivative 14 (12% yield) and
the trimethyl derivative 15 (3% yield). N-Benzylation of 4
afforded 12d in 72% yield. The two last derivatives 12e and
12f were obtained, respectively, in 78 and 90% yield.
Tri¯ates 3 were easily obtained in fair to good yields, by
reaction of 12 with tri¯uoromethanesulfonic anhydride in
the presence of sodium carbonate in dichloromethane. Other
experimental approaches were unproductive (LDA/tri-
¯imide, 2788C, Hunig base/tri¯imide, NaH/tri¯uoro-
methanesulfonic anhydride). It should be noted that for
12a and 12e, three compounds were isolated: the expected
tri¯ate 3a (21% yield) and 3e (53% yield), the monotri¯ate
16 with the free NH (30% yield from 12a and 20% yield
from 12e) and the ditri¯ate 10 (respectively 13% yield from
12a and 23% yield from 12e) (Scheme 3).
Acetylation in the presence of acetic anhydride gave mainly
the compound 12a (85% yield) with the O,N-diacetylated
derivative 13a in 13% yield. Similarly reaction of 4 with
Boc2O (1 equiv.) gave the compound 12b (40% yield) and
the O,N-diBoc 13b (20% yield). Attempts with 2 equiv. of
Boc2O led to the compound 13b in 66% yield. N-Methyl-
ation or N-benzylation reaction must be carefully controlled
in order to prevent a-alkylation. Reaction of 4 with sodium
hydride and iodomethane in N,N-dimethylformamide at
room temperature afforded the desired N-methyl derivative
Scheme 2. (a) Na2CO3, Tf2O (1.5 equiv.), CH2Cl2, rt, 24 h, 70%; (b) Na2CO3, Tf2O (3 equiv.), DMF/CH2Cl2, rt, 24 h, 52%.

Á
L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4493
Scheme 3. (a) Na2CO3, Tf2O (1.5 equiv.), CH2Cl2, rt, 24 h, 3a RˆAc, 21%, 3c RˆMe, 90%, 3d RˆBn, 95%, 3e RˆPMB, 53%, 3f RˆSO2Ph, 95%.
Scheme 4. Method A: Pd(PPh3)4, A-Sn(R)3, LiCl, DMF, 1008C, 2 h; Method B: Pd(PPh3)4, A-B(OH)2, NaHCO3, EtOH/toluene, 808C, 2 h.
Reaction on the nitrogen atom was exclusively observed if
compound 12b was treated with tri¯uoromethanesulfonic
anhydride; the monotri¯ate 17 was obtained in 82% yield.
tri¯ate 16 and tributyl(2-thiophenyl)stannane gave the
compound 27 (71% yield). Compound 27 was evaluated
for growth inhibitory property, measured as IC50 value,
against the murine leukemia L1210 cell line. Weak in
vitro cytotoxicity was observed (IC50 L1210.10 mM).
Table 2.
Product
A
Yield (%)
90
18
19
20
Me
99
92
Among the different monotri¯ates synthesised, we exam-
ined the reactivity of 3d expecting an easy deprotection of
the lactam nitrogen atom. Reactions of 3e, 3f and the unpro-
tected tri¯ate 16 were also investigated. A range of
palladium mediated cross-coupling reactions with 3d were
carried out in order to introduce various heterocyclic appen-
dages (Scheme 4).
21
22
23
74
90
99
Compounds 18±21 were prepared according to Stille reac-
tion by using commercially available stannanes and freshly
prepared tetrakis(triphenylphosphine)palladium reagent in
N,N-dimethylformamide (Table 2).17 Three arylboronic
acids were also coupled to 3d under Suzuki conditions.18
Compounds 22±24 were obtained in good yields (Table
2). Reaction between 3e and 2-thiophenylboronic acid
afforded compound 25 in 86% yield. Stille reaction between
tri¯ate 3f and tetramethylstannane gave the derivative 26
(76% yield). Under similar conditions, the unprotected
24
86

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L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4494
47.76; H, 3.26; N, 6.96. Found: C, 48.05; H, 3.39; N,
6.80; MS m/z 403 (M11)1.
2,10-Dimethyl-1-oxo-1,2,3,10-tetrahydroazepino[3,4-b]-
indol-5-yl tri¯uoromethanesulfonate (3c). According to
the procedure for the synthesis of 3a, compound 3c was
prepared in 90% yield; mp 112±1138C (ethyl acetate±petro-
leum ether); IR (KBr) n 1623 (CO), 1425 (OSO2), 1200
1
(OSO2) cm21; H NMR (250 MHz, CDCl3) d 3.28 (s, 3H,
CH3), 3.84 (d, 2H, Jˆ7.3 Hz, CH2), 4.12 (s, 3H, CH3), 6.18
(t, 1H, Jˆ7.3 Hz, CH), 7.31±7.35 (m, 1H, HAr), 7.47±7.49
(m, 2H, HAr), 7.98 (d, 1H, Jˆ8.2 Hz, HAr); 13C NMR
(62.90 MHz, CDCl3) d 32.3 (CH3), 35.2 (CH3), 46.1
(CH2), 110.3 (C), 110.5 (CH), 113.2 (CH), 118.4 (q, Jˆ
315 Hz, CF3), 121.7 (CH), 122,1 (CH), 122.6 (C), 125.6
(CH), 133.4 (C), 138.2 (C), 149.3 (C), 160.8 (CO). Anal.
Calcd for C15H13F3N2O4S: C, 48.13; H, 3.50; N, 7.48.
Found: C, 48.49; H, 3.69; N, 7.31. MS m/z 375 (M11)1.
Attempts to debenzylate compound 19 were till now unpro-
ductive (BCl3, Na/NH3, etc.). The introduction of the cyclic
guanidine moiety, found in the Stevensine structure, is
underway using another synthetic approach.
In summary, we have described an easy and versatile
synthesis of 5-substituted azepino[3,4-b]indol-1-ones 18±
27 from tri¯ates 3d, 3e, 3f and 16. These latter compounds
were found to be versatile intermediates for palladium
mediated cross-coupling reactions.
2-Benzyl-10-methyl-1-oxo-1,2,3,10-tetrahydroazepino-
[3,4-b]indol-5-yl tri¯uoromethanesulfonate (3d). Accord-
ing to the procedure for the synthesis of 3a, compound 3d
was prepared in 95% yield; mp 117±1188C (ethyl acetate±
petroleum ether); IR (KBr) n 1631 (CO), 1422 (OSO2),
Experimental
Melting points were determined using a BuÈchi capillary
instrument and are uncorrected. The infrared spectra of
the compounds were recorded on a Perkin±Elmer FTIR
paragon 1000 spectrometer. The NMR spectra were
recorded at 300 K in CDCl3 on a Bruker Avance DPX
250. The chemical shifts are expressed in parts per million
relative to tetramethylsilane (TMS). The mass spectra were
recorded on Perkin±Elmer SCIEX API 300 using ionspray
methodology. Thin-layer chromatography (TLC) was run
on precoated silica gel plates (Merck 60F254) and the spots
visualised using an ultraviolet lamp. Flash chromatography
was carried out on column using ¯ash silica gel 60 Merck
(40±63 mm) as the stationary phase. All the reactions
requiring anhydrous conditions were conducted in a
¯ame-dried apparatus. Stannanes and boronic acids were
purchased from Lancaster or Sigma±Aldrich.
1
1207 (OSO2) cm21; H NMR (250 MHz, CDCl3) d 3.76
(d, 2H, Jˆ7.5 Hz, CH2), 4.12 (s, 3H, CH3), 4.70±4.90 (m,
2H, CH2), 5.79 (t, 1H, Jˆ7.5 Hz, CH), 7.18±7.46 (m, 8H,
HAr), 7.92±7.95 (m, 1H, HAr); 13C NMR (62.90 MHz,
CDCl3) d 32.4 (CH3), 43.8 (CH2), 51.0 (CH2), 110.5
(CH), 114.3 (CH), 121.9 (CH), 122.1 (CH), 122.6 (C),
124.4 (q, Jˆ300 Hz, CF3), 125.7 (CH), 128.1 (CH), 128.2
(2CH), 128.8 (2CH), 132.3 (C), 132.7 (C), 137.3 (C), 138.3
(C), 148.9 (C), 160.9 (CO); Anal. Calcd for C21H17F3N2O4S:
C, 56.00; H, 3.80; N, 6.22. Found: C, 56.37; H, 3.68; N,
3.91; MS m/z 451 (M11)1.
2-(4-Methoxybenzyl)-10-methyl-1-oxo-1,2,3,10-tetra-
hydroazepino[3,4-b]indol-5-yl tri¯uoromethanesulfonate
(3e). According to the procedure for the synthesis of 3a,
compound 3e was prepared in 53% yield. The compounds
10 and 16 were also obtained, respectively, in 23 and 20%
yield (chromatography eluent: petroleum ether±ethyl
acetate 1:1). Mp 125±1268C (ethyl acetate±petroleum
ether); IR (KBr) n 1634 (CO), 1413 (OSO2), 1240 (OSO2)
2-Acetyl-10-methyl-1-oxo-1,2,3,10-tetrahydroazepino-
[3,4-b]indol-5-yl tri¯uoromethanesulfonate (3a). To a
suspension of compound 12a (330 mg, 1.3 mmol) and
sodium carbonate (198 mg, 1.86 mmol) in dry dichloro-
methane (5 mL), was added tri¯uoromethanesulfonic
anhydride (271 mL, 1.9 mmol) in dry dichloromethane
(8 mL). The mixture was stirred for 24 h at room tempera-
ture, then water was added and the mixture was extracted.
The organic layer was dried over MgSO4 and evaporated in
vacuo. The crude residue was puri®ed by column chroma-
tography (eluent: petroleum ether±ethyl acetate 6:4) to
afford 16 (140 mg, 30%), 3a (105 mg, 21%) and the
ditri¯ate 10 (83 mg, 13%). Mp 161±1628C (ethyl acetate±
petroleum ether); IR (KBr) n 1700 (CO), 1672 (CO), 1422
(OSO2), 1209 (OSO2) cm21; 1H NMR (250 MHz, CDCl3) d
2.61 (s, 3H, CH3), 4.15 (s, 3H, CH3), 4.20±4.50 (m, 2H,
CH2), 6.37 (t, 1H, Jˆ7.5 Hz, CH), 7.33±7.40 (m, 1H,
HAr), 7.51±7.55 (m, 2H, HAr), 8.04 (d, 1H, Jˆ8.0 Hz,
HAr); 13C NMR (62.90 MHz, CDCl3) d 27.2 (CH3), 32.9
(CH3), 39.4 (CH2), 110.8 (CH), 112.7 (C), 116.7 (CH),
118.9 (q, Jˆ315 Hz, CF3), 122.6 (C), 122.6 (CH), 122.9
(CH), 127.1 (CH), 131.2 (C), 139.3 (C), 149.0 (C), 162.1
(CO), 172.2 (CO); Anal. Calcd for C16H13F3N2O5S: C,
cm21
;
1H NMR (250 MHz, CDCl3) d 3.79 (d, 2H,
Jˆ7.5 Hz, CH2), 3.85 (s, 3H, CH3), 4.16 (s, 3H, CH3),
4.70±4.80 (m, 2H, CH2), 5.82 (t, 1H, Jˆ7.5 Hz, CH),
6.92±6.96 (m, 2H, HAr), 7.30±7.36 (m, 3H, HAr), 7.48±
7.50 (m, 2H, HAr), 7.98 (d, 1H, Jˆ8.2 Hz, HAr); 13C NMR
(62.90 MHz, CDCl3) d 32.4 (CH3), 43.6 (CH2), 50.3 (CH2),
55.3 (CH3), 110.4 (CH), 110.5 (C), 114.2 (2CH), 114.5
(CH), 118.5 (q, Jˆ315 Hz, CF3), 121.9 (CH), 122.1 (CH),
122.6 (C), 125.6 (CH), 129.5 (2CH), 129.5 (C), 132.8 (C),
138.2 (C), 148.8 (C), 159.3 (C), 160.8 (CO); Anal. Calcd for
C22H19F3N2O5S: C, 55.00; H, 3.99; N, 5.83. Found: C,
54.67; H, 4.14 N, 5.93; MS m/z 481 (M11)1.
10-Methyl-1-oxo-2-phenylsulfonyl-1,2,3,10-tetrahydro-
azepino[3,4-b]indol-5-yl tri¯uoromethanesulfonate (3f).
According to the procedure for the synthesis of 3a,
compound 3f was prepared in 95% yield; mp 119±1208C
(ethyl acetate±petroleum ether); IR (KBr) n 1668 (CO),
1640 (CO), 1409 (OSO2), 1218 (OSO2), 1172 (NSO2)

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4495
1
cm21; H NMR (250 MHz, CDCl3) d 3.99 (s, 3H, CH3),
64.60; H, 6.20; N, 10.76. Found: C, 64.25; H, 6.33; N,
10.89; MS m/z 261 (M11)1.
4.20±4.70 (m, 2H, CH2), 6.43 (t, 1H, Jˆ7.5 Hz, CH),
7.26±7.58 (m, 6H, HAr), 7.93±8.01 (m, 3H, HAr); 13C
NMR (62.90 MHz, CDCl3) d 32.6 (CH3), 41.7 (CH2),
110.7 (CH), 112.2 (C), 115.4 (CH), 118.5 (q, Jˆ330 Hz,
CF3), 122.4 (C), 122.5 (CH), 123.0 (CH), 127.1 (CH),
129.0 (CH), 129.0 (3 CH), 130.2 (C), 134.2 (CH), 137.9
(C), 139.0 (C), 149.6(C), 159.6 (CO); Anal. Calcd for
C20H15F3N2O6S2: C, 48.00; H, 3.02; N, 5.60. Found: C,
48.39; H, 2.86; N, 5.75; MS m/z 501 (M11)1.
1H-2-Indolecarboxylic anhydride (7). Compound 7 was
obtained in 95% yield by upscaling the synthesis of 6
(35 mmol); mp 207±2088C (dichloromethane); IR (KBr) n
1
3363 (NH), 3310 (NH), 1770 (CO), 1694 (CO) cm21; H
NMR (250 MHz, CDCl3) d 7.16 (t, 2H, Jˆ8.0 Hz, HAr),
7.33 (t, 2H, Jˆ8.0 Hz, HAr), 7.46 (s, 2H, H3), 7.54 (d, 2H,
Jˆ8.0 Hz, HAr), 7.69 (d, 2H, Jˆ8.0 Hz, HAr), 11.59 (broad s,
2H, NH); 13C NMR (62.90 MHz, CDCl3) d 111.1 (CH),
112.3 (CH), 120.2 (CH), 122.0 (CH), 125.1 (CH), 125.5
(C), 126.3 (C), 138.2 (C), 156.5 (CO); Anal. Calcd for
C18H12N2O3: C, 71.05; H, 3.97; N, 9.21. Found: C, 71.36;
H, 4.09; N, 9.35; MS m/z 305 (M11)1.
10-Methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indole-
1,5-dione (4). In a dry balloon, phosphorus pentoxide
(1.30 g) and polyphosphoric acid (9.80 g) were stirred at
1108C until complete dissolution of phosphorus pentoxide.
Acid 9 (1.80 g, 7.3 mmol) was added and the ®nal mixture
was stirred at 1108C for 1 h. After cooling, the mixture was
poured into ice, slowly neutralised by saturated sodium
hydrogenocarbonate. Dichloromethane (200 mL) was
added and the mixture was stirred overnight. After extrac-
tion, the aqueous layer was twice extracted with dichloro-
methane. The organic phase was dried over MgSO4 and
evaporated in vacuo to give a brownish solid that was
recrystallised from ethyl acetate±petroleum ether to give
a yellow solid 4 (1.43 g, 86%); mp 201±2028C (ethyl
acetate±petroleum ether, 2088C lit.12); IR (KBr) n 3208
Ethyl 3-{[(1-methyl)-1H-2-indolylcarbonyl]amino}propa-
noate (8). A solution of amide 6 (5.01 g, 19.2 mmol),
K2CO3 (10.63 g, 77.0 mmol) and iodomethane (2.9 mL,
46.5 mmol) in acetonitrile (150 mL) was stirred at re¯ux
for 24 h. The cooled mixture was ®ltered and the ®ltrate
was evaporated in vacuo. The crude residue was puri®ed
by column chromatography (eluent: petroleum ether±ethyl
acetate 9:1) to afford 8 (4.74 g, 90%) as a white solid; mp
75±768C (ethyl acetate±petroleum ether); IR (KBr) n
1
3375±3150 (NH), 1740 (CO), 1629 (CO) cm21; H NMR
(NH), 1661 (CO), 1640 (CO) cm21; H NMR (250 MHz,
(250 MHz, CDCl3) d 1.28 (t, 3H, Jˆ7.2 Hz, CH3), 2.65 (t,
2H, Jˆ6.0 Hz, CH2), 3.73 (dd, 2H, Jˆ5.0, 6.0 Hz, CH2),
4.05 (s, 3H, CH3), 4.15 (q, 2H, Jˆ7.2 Hz, CH2), 6.83 (s,
1H, H3), 6.90 (t, 1H, Jˆ5.0 Hz, NH), 7.10±7.17 (m, 1H,
HAr), 7.39±7.41 (m, 2H, HAr), 7.63 (d, 1H, Jˆ8.0 Hz,
HAr); 13C NMR (62.90 MHz, CDCl3) d 14.2 (CH3), 31.5
(CH3), 34.0 (CH2), 34.9 (CH2), 60.8 (CH2), 103.9 (CH),
110.1 (CH), 120.4 (CH), 121.8 (CH), 124.0 (CH), 126.0
(C), 131.9 (C), 139.0 (C). 162.5 (CO), 172.7 (CO); Anal.
Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found:
C, 65.90; H, 6.47; N, 10.12; MS m/z 275 (M11)1.
1
DMSO-d6) d 2.74±2.79 (m, 2H, CH2), 3.36±3.40 (m, 2H,
CH2), 3.99 (s, 3H, CH3), 7.22±7.44 (m, 2H, HAr), 7.63 (d,
1H, Jˆ8.0 Hz, HAr), 8.27 (d, 1H, Jˆ8.0 Hz, HAr), 8.78
(broad t, 1H, Jˆ4.5 Hz, NH); 13C NMR (62.90 MHz,
DMSO-d6) d 32.4 (CH3), 36.7 (CH2), 45.0 (CH2), 111.0
(CH), 114.8 (C), 122.7 (CH), 123.2 (CH), 124.6 (C),
125.1 (CH), 134.7 (C), 138.0 (C), 162.4 (CO), 195.7
(CO); Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N,
12.27. Found: C, 68.07; H, 5.44; N, 12.39; MS m/z 229
(M11)1.
Ethyl 3-[(1H-2-indolylcarbonyl)amino]propanoate (6).
To a solution of b-alanine ethylester hydrochloride
(1.57 g, 10.2 mmol) and DMAP (1.87 g, 15.3 mmol) in
dry dichloromethane (20 mL) at 08C was added a solution
of indole-2-carboxylic acid 5 (1.50 g, 9.3 mmol) in dry
dichloromethane (20 mL) then EDCI (1.96 g, 10.2 mmol)
in dry dichloromethane (20 mL). The ®nal mixture was
stirred at 08C for 4 h, then at room temperature for 20 h.
After evaporation of the solvent, the solid obtained was
suspended in water and ®ltered. The solid was partitioned
between ethyl acetate (50 mL) and 10% hydrochloric acid
(50 mL) and extracted. The organic phase was dried over
MgSO4 and evaporated to afford 6 (2.30 g, 95%) as white
crystals; mp 159±1608C (ether); IR (KBr) n 3377 (NH),
3-[(1-Methyl-1H-2-indolylcarbonyl)amino]propanoic acid
(9). A solution of ester 8 (4.2 g, 15.31 mmol) and LiOH
(1.29 g, 30.72 mmol) in ethanol (140 mL) was stirred at
room temperature for 18 h. After cooling, the solvent was
evaporated in vacuo. The residue was dissolved in water and
the acidi®cation of the medium led to a white precipitate
which was ®ltered and washed with ethanol to provide 9
(3.62 g, 96%); mp 1618C (ethanol, 1608C lit.12); IR (KBr) n
3392 (NH), 3200±2100 (OH), 1728 (CO), 1700 (CO) cm21
;
1H NMR (250 MHz, CDCl3) d 2.63 (t, 2H, Jˆ6.2 Hz, CH2),
3.69 (dd, 2H, Jˆ5.0, 6.2 Hz, CH2), 4.04 (s, 3H, CH3), 6.87
(s, 1H, H3), 7.12±7.36 (m, 3H, HAr), 7.22 (broad t, 1H,
Jˆ5.0 Hz, NH), 7.61 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR
(62.90 MHz, CDCl3) d 31.2 (CH3), 33.6 (CH2), 34.7
(CH2), 103.7 (CH), 109.7 (CH), 120.0 (CH), 121.4 (CH),
123.6 (CH), 125.7 (C), 131.7 (C), 138.6 (C), 162.2 (CO),
174.3 (CO); Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73;
N, 11.38. Found: C, 63.12; H, 5.83; N, 11.51; MS m/z 247
(M11)1.
3350 (NH), 1718 (CO), 1624 (CO) cm21 1H NMR
;
(250 MHz, DMSO-d6) d 1.18 (t, 3H, Jˆ7.0 Hz, CH3),
2.60 (t, 2H, Jˆ6.7 Hz, CH2), 3.52 (dd, 2H, Jˆ5.2, 6.7 Hz,
CH2), 4.08 (q, 2H, Jˆ7.0 Hz, CH2), 7.06 (t, 1H, Jˆ7.5 Hz,
HAr), 7.08 (s, 1H, H3), 7.17 (t, 1H, Jˆ7.5 Hz, HAr), 7.42 (d,
1H, Jˆ7.5 Hz, HAr), 7.60 (d, 1H, Jˆ7.5 Hz, HAr), 8.53 (t,
1H, Jˆ5.2 Hz, NH), 11.56 (broad s, 1H, NH); 13C NMR
(62.90 MHz, DMSO-d6) d 14.5 (CH3), 34.3 (CH2), 35.5
(CH2), 60.4 (CH2), 102.9 (CH), 112.7 (CH), 120.1 (CH),
122.0 (CH), 123.3 (CH), 127.4 (C), 132.0 (C), 136.8 (C),
161.6 (CO), 171.7 (CO); Anal. Calcd for C14H16N2O3: C,
10-Methyl-1-oxo-2-{[(tri¯uoromethyl)sulfonyl]oxy}-1,2,3,
10-tetrahydroazepino[3,4-b]indol-5-yl tri¯uoromethane-
sulfonate (10). Compound 10 was obtained in 70% yield
according to the method described for the preparation of
tri¯ates 3 (chromatography eluent: petroleum ether±ethyl

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L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4496
acetate 4:6); mp 177±1788C (ethyl acetate±petroleum
4 (200 mg, 0.88 mmol), di-tert-butyl dicarbonate (384 mg,
1.76 mmol) and a catalytic amount of DMAP in acetonitrile
(5 mL) was stirred at room temperature for 24 h. After
evaporation, the crude residue was puri®ed by column chro-
matography (eluent: petroleum ether±ethyl acetate 6:2) to
give 12b (115 mg, 40%), compound 13b (75 mg, 20%) and
starting material 4 (80 mg, 40%). Mp133±1348C (ethyl
acetate±petroleum ether); IR (KBr) n 1729 (CO), 1677
1
ether); IR (KBr) n 1702 (CO) cm21; H NMR (250 MHz,
DMSO-d6) d 4.03 (s, 3H, CH3), 4.50 (broad d, 2H, Jˆ
7.5 Hz, CH2), 6.67 (t, 1H, Jˆ7.5 Hz, CH), 7.34±7.40 (m,
1H, HAr), 7.53±7.59 (m, 1H, HAr), 7.78 (d, 1H, Jˆ8.0 Hz,
HAr), 7.88 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR (62.90 MHz,
DMSO-d6) d 33.3 (CH3), 44.7 (CH2), 112.5 (CH), 112.5 (C),
119.0 (CH), 121.1 (q, Jˆ300 Hz, CF3), 122.0 (CH), 123.5
(CH), 125.9 (C), 127.8 (CH), 129.1 (C), 139.5 (C), 148.5
(C), 159.6 (CO); Anal. Calcd for C15H10F6N2O6S2: C, 36.59;
H, 2.05; N, 5.69. Found: C, 36.20; H, 2.24; N, 5.88; MS m/z
493 (M11)1.
1
(CO), 1643 (CO) cm21; H NMR (250 MHz, CDCl3) d
1.58 (s, 9H, (CH3)3), 2.94±2.96 (m, 2H, CH2), 4.06 (s, 3H,
CH3), 4.17±4.21 (m, 2H, CH2), 7.32±7.42 (m, 3H, HAr),
8.32 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR (62.90 MHz,
CDCl3) d 28.4 (3CH3), 33.1 (CH3), 42.4 (CH2), 43.7
(CH2), 84.3 (C), 110.3 (CH), 116.8 (C), 123.8 (CH), 124.0
(CH), 124.9 (C), 126.6 (CH), 133.9 (C), 139.1 (C), 151.8
(CO), 161.4 (CO), 195.7 (CO); Anal. Calcd for C18H20N2O4:
C, 65.84; H, 6.14; N, 8.53. Found: C, 66.17; H, 6.01; N,
8.65; MS m/z 329 (M11)1.
2-Formyl-10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]-
indole-1,5-dione (11). To a suspension of compound 4
(347 mg, 1.52 mmol) and potassium carbonate (480 mg,
4.52 mmol) in dry dichloromethane±DMF (7 mL, 6:1 v/v)
was added a solution of tri¯uoromethanesulfonic anhydride
(0.76 mL, 4.52 mmol) in dry dichloromethane (6 mL). The
®nal mixture was stirred at room temperature for 24 h.
The mixture was hydrolysed with water and extracted.
The aqueous phase was extracted with dichloromethane
twice. The organic phase was dried over MgSO4 and evapo-
rated in vacuo. The crude residue was triturated with toluene
which led to the crystallisation of the desired compound 11
(202 mg, 52%) as a yellow solid; mp 213±2148C (toluene);
2,10-Dimethyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indole-
1,5-dione (12c). To a solution of 4 (300 mg, 1.31 mmol) in
dry DMF (5 mL) at 08C, NaH (62 mg, 1.55 mmol, 60% oil
dispersion) was added portionwise and the mixture was
stirred for 1 h at room temperature. Iodomethane (90 mL,
1.57 mmol) was added and the ®nal mixture was stirred for
15 min. The mixture was diluted with water (10 mL), and
extracted with ethyl acetate (2£10 mL). The organic phase
was dried over MgSO4 and evaporated. The crude residue
was puri®ed by column chromatography (eluent: petroleum
ether±ethyl acetate 1:1) to give 12c (190 mg, 60%), 14
(40 mg, 12%) and 15 (10 mg, 3%). Mp 168±1698C (ethyl
acetate±petroleum ether); IR (KBr) n 1645 (CO), 1642
1
IR (KBr) n 1702 (CO), 1677 (CO), 1639 (CO) cm21; H
NMR (250 MHz, DMSO-d6) d 2.86±2.91 (m, 2H, CH2),
4.02±4.11 (m, 2H, CH2), 4.08 (s, 3H, CH3), 7.37 (t, 1H,
Jˆ8.0 Hz, HAr), 7.50 (t, 1H, Jˆ8.0 Hz, HAr), 7.76 (d, 1H,
Jˆ8.0 Hz, HAr), 8.29 (d, 1H, Jˆ8.0 Hz, HAr), 9.44 (s, 1H,
CHO); 13C NMR (62.90 MHz, DMSO-d6) d 33.0 (CH3),
42.5 (CH2), 43.1 (CH2), 111.5 (CH), 116.4 (C), 123.2
(CH), 123.9 (CH), 124.4 (C), 126.4 (CH), 132.4 (C),
139.0 (C), 162.3 (CO), 163.5 (CO), 195.5 (CO); Anal.
Calcd for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93.
Found: C, 65.37; H, 4.88; N, 11.12; MS m/z 257 (M11)1.
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 2.95±2.99 (m,
2H, CH2), 3.33 (s, 3H, CH3), 3.81±3.85 (m, 2H, CH2), 4.10
(s, 3H, CH3), 7.39±7.48 (m, 3H, HAr), 8.43±8.47 (m, 1H,
HAr); 13C NMR (62.90 MHz, CDCl3) d 32.6 (CH3), 35.2
(CH3), 43.0 (CH2), 46.7 (CH2), 110.1 (CH), 115.4 (C),
123.5 (CH), 123.7 (CH), 125.0 (C), 125.8 (CH), 134.6
(C), 138.4 (C), 161.4 (CO), 195.4 (CO); Anal. Calcd for
C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.75; H, 5.99; N, 11.40; MS m/z 243 (M11)1.
2-Acetyl-10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]-
indole-1,5-dione (12a). To a solution of 4 (500 mg,
2.19 mmol) in acetic anhydride (25 mL) stirred at 1008C,
was added pyridine (360 mL, 4.38 mmol) and the ®nal
mixture was stirred at 1408C for 2 h. After cooling and
evaporation of the solvents, the crude residue was par-
titioned between water and dichloromethane and extracted.
The organic layer was washed with water twice, dried over
MgSO4 and evaporated in vacuo. The crude residue was
puri®ed by column chromatography (eluent: petroleum
ether±ethyl acetate 4:6) to give successively 12a (503 mg,
85%) and 13a (89 mg, 13%). Mp 185±1868C (ethyl
acetate±petroleum ether); IR (KBr) n 1707 (CO), 1677
2-Benzyl-10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]-
indole-1,5-dione (12d). According to the procedure for the
synthesis of 12c, compound 12d was prepared in 72% yield
using benzyl chloride (chromatography eluent: petroleum
ether±ethyl acetate 4:6). Mp 127±1288C (ethyl acetate±
petroleum ether); IR (KBr) n 1649 (CO), 1637 (CO)
1
cm21; H NMR (250 MHz, CDCl3) d 2.70±2.75 (m, 2H,
CH2), 3.69±3.73 (m, 2H, CH2), 4.10 (s, 3H, CH3), 4.87 (s,
2H, CH2), 7.31±7.44 (m, 8H, HAr), 8.37±8.41 (m, 1H, HAr);
13C NMR (62.90 MHz, CDCl3) d 32.8 (CH3), 43.5 (CH2),
44.2 (CH2), 50.8 (CH2), 110.1 (CH), 115.5 (C), 123.5 (CH),
123.7 (CH), 125.0 (C), 125.6 (CH), 125.9 (C), 128.0 (CH),
128.3 (2CH), 129.0 (2CH), 131.7 (C), 138.6 (C), 162.2
(CO), 174.3 (CO); Anal. Calcd for C20H18N2O2: C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.74; H, 5.86; N, 8.63; MS m/z
319 (M11)1.
1
(CO), 1641 (CO) cm21; H NMR (250 MHz, CDCl3) d
2.63 (s, 3H, CH3), 2.89±2.93 (m, 2H, CH2), 4.07 (s, 3H,
CH3), 4.31±4.35 (m, 2H, CH2), 7.33±7.47 (m, 3H, HAr),
8.35±8.38 (m, 1H, HAr); 13C NMR (62.90 MHz, CDCl3) d
26.3 (CH3), 31.9 (CH3), 38.6 (CH2), 42.3 (CH2), 109.2 (CH),
116.0 (C), 122.9 (CH), 123.1 (CH), 123.7 (C), 125.6 (CH),
131.4 (C), 138.2 (C), 162.2 (CO), 171.2 (CO), 194.6 (CO);
Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36.
Found: C, 66.30; H, 5.38; N, 10.43; MS m/z 271 (M11)1.
2-(4-Methoxybenzyl)-10-methyl-1,2,3,4,5,10-hexahydro-
azepino[3,4-b]indole-1,5-dione (12e). According to the
procedure for the synthesis of 12c, compound 12e was
prepared in 78% yield using 4-methoxybenzyl chloride
tert-Butyl 10-methyl-1,5-dioxo-1,2,3,4,5,10-hexahydro-
azepino[3,4-b]indole-2-carboxylate (12b). A solution of

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L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4497
(chromatography eluent: petroleum ether±ethyl acetate
1:1); mp 136±1378C (ethyl acetate±petroleum ether); IR
indole-1,5-dione (14). Yield: 12%; mp 146±1478C (ethyl
acetate±petroleum ether); IR (KBr) n broad 1638 (CO)
1
(KBr) n 1650 (CO), 1632 (CO) cm21
;
1H NMR
cm21; H NMR (250 MHz, CDCl3) d 1.35 (d, 3H, Jˆ
(250 MHz, CDCl3) d 2.69±2.74 (m, 2H, CH2), 3.71±3.75
(m, 2H, CH2), 3.84 (s, 3H, CH3), 4.11 (s, 3H, CH3), 4.82 (s,
2H, CH2), 6.90±6.93 (m, 2H, HAr), 7.29±7.45 (m, 6H, HAr);
13C NMR (62.90 MHz, CDCl3) d 33.3 (CH3), 44.1 (CH2),
44.5 (CH2), 50.7 (CH2), 55.8 (CH3), 110.0 (CH), 114.2
(2CH), 115.3 (C), 123.4 (CH), 123.5 (CH), 124.9 (C),
125.4 (CH), 128.8 (C), 129.6 (2CH), 134.5 (C), 138.4 (C),
159.2 (C), 161.3 (CO), 195.4 (CO); Anal. Calcd for
C21H20N2O2: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.06;
H, 5.96; N, 8.20; MS m/z 349 (M11)1.
7.8 Hz, CH3), 2.88±2.95 (m, 1H, CH), 3.36 (s, 3H, CH3),
3.76±3.81 (m, 2H, CH2), 4.10 (s, 3H, CH3), 7.36±7.47 (m,
3H, HAr), 8.42±8.46 (m, 1H, HAr); 13C NMR (62.90 MHz,
CDCl3) d 16.2 (CH3), 34.1 (CH3), 37.9 (CH3), 48.4 (CH),
54.2 (CH2), 111.5 (CH); 116.7 (C), 125.0 (2CH), 126.7 (C),
126.9 (CH), 135.5 (C), 139.9 (C), 162.9 (CO), 199.8 (CO);
Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93.
Found: C, 69.91; H, 6.45; N, 11.12; MS m/z 257 (M11)1.
2,4,4,10-Tetramethyl-1,2,3,4,5,10-hexahydroazepino-
[3,4-b]indole-1,5-dione (15). Yield: 3%; mp 105±1068C
(ethyl acetate±petroleum ether); IR (KBr) n 1642 broad
10-Methyl-2-phenylsulfonyl-1,2,3,4,5,10-hexahydroaze-
pino[3,4-b]indole-1,5-dione (12f). According to the pro-
cedure for the synthesis of 12c, compound 12f was
prepared in 90% yield using benzenesulfonyl chloride
(chromatography eluent: petroleum ether±ethyl acetate
8:2); mp 187±1888C (ethyl acetate±petroleum ether); IR
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 1.33 (s, 6H,
(CH3)2), 3.34 (s, 3H, CH3), 3.58±3.78 (m, 2H, CH2), 4.12
(s, 3H, CH3), 7.36±7.47 (m, 3H, HAr), 8.37±8.40 (m, 1H,
HAr); 13C NMR (62.90 MHz, CDCl3) d 23.3 (2CH3), 32.6
(CH3), 37.4 (CH3), 49.5 (C), 58.4 (CH2), 110.2 (CH), 115.4
(C), 123.5 (2CH), 125.5 (CH), 125.9 (C), 133.6 (C), 138.5
(C), 161.6 (CO), 200.7 (CO); Anal. Calcd for C16H18N2O2:
C, 71.09; H, 6.71; N, 10.36. Found: C, 71.43; H, 6.60; N,
10.42; MS m/z 271 (M11)1.
(KBr) n 1672 (CO), 1646 (CO) 1354, 1165 (NSO2) cm21
;
1H NMR (250 MHz, CDCl3) d 3.07±3.11 (m, 2H, CH2),
3.93 (s, 3H, CH3), 4.40±4.44 (m, 2H, CH2), 7.31±7.39 (m,
3H, HAr), 7.56±7.65 (m, 3H, HAr), 8.10 (d, 2H, Jˆ8.0 Hz,
HAr), 8.34 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR (62.90 MHz,
CDCl3) d 32.9 (CH3), 42.3 (CH2), 44.5 (CH2), 110.4 (CH),
117.2 (C), 124.0 (CH), 124.4 (CH), 124.8 (C), 126.8 (CH),
128.8 (2CH), 129.1 (2CH), 131.2 (C), 134.3 (CH), 138.7
(C), 139.1 (C), 160.9 (CO), 194.4 (CO); Anal. Calcd for
C19H16N2O4S: C, 61.94; H, 4.38; N, 7.60. Found: C,
61.63; H, 4.27; N, 7.89; MS m/z 369 (M11)1.
10-Methyl-1-oxo-1,2,3,10-tetrahydroazepino[3,4-b]indol-
5-yl tri¯uoromethanesulfonate (16). Yield: 20±30%; mp
202±2038C (ethyl acetate±petroleum ether); IR (KBr) n
3212 (NH), 1640 (CO), 1407 (OSO2), 1209 (OSO2) cm21
;
1H NMR (250 MHz, CDCl3) d 3.65 (dd (d if D2O
exchange), 2H, Jˆ6.0, 7.5 Hz, CH2), 4.11 (s, 3H, CH3),
6.08 (t, 1H, Jˆ7.5 Hz, CH), 7.24±7.33 (m, 4H, NH1HAr),
7.96±7.99 (m, 1H, HAr); 13C NMR (62.90 MHz, CDCl3) d
32.3 (CH3), 37.2 (CH2), 110.5 (CH), 111.4 (C), 114.7 (CH),
118.4 (q, Jˆ320 Hz, CF3), 122.1 (CH), 122.3 (CH), 122.8
(C), 125.9 (CH), 131.4 (C), 138.5 (C), 148.9 (C), 163.4
(CO); Anal. Calcd for C14H11F3N2O4S: C, 46.67; H, 3.08;
N, 7.77. Found: C, 46.98; H, 2.94; N, 7.92; MS m/z 361
(M11)1.
2-Acetyl-10-methyl-1-oxo-1,2,3,10-tetrahydroazepino-
[3,4-b]indol-5-yl acetate (13a). Yield: 13%; gum; IR (®lm)
1
n 1707 (CO), 1652 (CO), 1641 (CO); H NMR (250 MHz,
CDCl3) d 2.29 (s, 3H, CH3), 3.03 (s, 3H, CH3), 4.06 (s, 3H,
CH3), 4.13±4.53 (m, 2H, CH2), 6.05 (t, 1H, Jˆ7.3 Hz, CH),
7.18±7.26 (m, 1H, HAr), 7.41±7.43 (m, 2H, HAr), 7.85 (d,
1H, Jˆ8.0 Hz, HAr); 13C NMR (62.90 MHz, CDCl3) d 22.1
(CH3), 28.3 (CH3), 33.7 (CH3), 40.3 (CH2), 111.6 (CH),
115.4 (CH), 116.6 (C), 122.9 (CH), 123.2 (CH), 123.8
(C), 127.4 (CH), 131.8 (C), 140.4 (C), 150.0 (C), 163.7
(CO), 169.5 (CO), 173.1 (CO); Anal. Calcd for
C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C, 65.69;
H, 5.28; N, 8.80; MS m/z 313 (M11)1.
10-Methyl-2-(tri¯uoromethylsulfonyl)-1,2,3,4,5,10-hexa-
hydroazepino[3,4-b]indole-1,5-dione (17). According to
the procedure for the synthesis of 3a, compound 17 was
prepared from 12b in 82% yield; mp 192±1938C (ethyl
acetate±petroleum ether); IR (KBr) n 1684 (CO), 1653
(CO), 1407 (NSO2), 1215 (NSO2) cm21
;
1H NMR
tert-Butyl 5-[(tert-butoxycarbonyl)oxy]-10-methyl-1-oxo-
1,2,3,10-tetrahydroazepino[3,4-b]indole-2-carboxylate
(13b). Yield: 20%; mp 123±1248C (ethyl acetate±petro-
leum ether); IR (KBr) n 1758 (CO), 1704 (CO), 1689
(250 MHz, DMSO-d6) d 3.14 (t, 2H, Jˆ5.3 Hz, CH2),
4.08 (s, 3H, CH3), 4.33 (t, 2H, Jˆ5.3 Hz, CH2), 7.40 (t,
1H, Jˆ8.0 Hz, HAr), 7.54 (t, 1H, Jˆ8.0 Hz, HAr), 7.79 (d,
1H, Jˆ8.0 Hz, HAr), 8.26 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR
(62.90 MHz, DMSO-d6) d 33.0 (CH3), 44.1 (CH2), 45.2
(CH2), 111.5 (CH), 117.2 (C), 123.1 (CH), 124.0 (C),
124.1 (CH), 124.4 (q, Jˆ290 Hz, CF3), 126.9 (CH), 130.1
(C), 139.1 (C), 160.4 (CO), 194.1 (CO); Anal. Calcd for
C14H11F3N2O4S: C, 46.67; H, 3.08; N, 7.77. Found: C,
46.32; H, 3.15; N, 7.89; MS m/z 361 (M11)1.
1
(CO) cm21; H NMR (250 MHz, CDCl3) d 1.41 (s, 9H,
(CH3)3), 1.55 (s, 9H, (CH3)3), 4.03 (s, 3H, CH3), 4.14±
4.24 (m, 2H, CH2), 6.08 (t, 1H, Jˆ7.3 Hz, CH), 7.16±7.22
(m, 1H, HAr), 7.35±7.37 (m, 2H, HAr), 7.93 (d, 1H,
Jˆ8.5 Hz, HAr); 13C NMR (62.90 MHz, CDCl3) d 27.4
(3CH3), 27.9 (3CH3), 32.5 (CH3), 41.7 (CH2), 83.2 (C),
83.6 (C), 110.2 (CH), 112.6 (CH), 114.7 (C), 121.5 (CH),
122.2 (CH), 122.5 (C), 125.9 (CH), 130.9 (C), 138.8 (C),
149.6 (C), 150.6 (CO), 151.2 (CO), 160.8 (CO); Anal. Calcd
for C23H28N2O4: C, 69.68; H, 7.12; N, 7.07. Found: C,
70.03; H, 7.28; N, 6.89; MS m/z 397 (M11)1.
General procedure for the Stille reaction with 3d
(method A)
To a suspension of freshly prepared tetrakis(triphenylphos-
phine)palladium (15 mg, 0.013 mmol) and LiCl (26 mg,
0.61 mmol) in dry DMF was added a solution of 3d
2,4,10-Trimethyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]-

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L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4498
(100 mg, 0.22 mmol) and stannane (tributylvinylstannane
for 18, tetramethylstannane for 19, tributyl(1-ethoxyvinyl)-
stannane for 20 or tributyl-2-furanylstannane for 21,
0.33 mmol) in dry DMF under argon. The solution was
stirred at 1008C for 2 h. The solvent was then removed in
vacuo and the crude residue was puri®ed by column
chromatography (eluent: toluene for 18 and 20, toluene±
ethyl acetate 1:1 for 19 and petroleum ether±ethyl acetate
6:4 for 21) to give the desired compounds.
CH), 6.40±6.42 (m, 1H, HAr), 6.46±6.48 (m, 1H, HAr),
7.09±7.13 (m, 1H, HAr), 7.19±7.22 (m, 1H, HAr), 7.29±
7.46 (m, 8H, HAr); 13C NMR (62.90 MHz, CDCl3) d 32.0
(CH3), 44.7 (CH2), 50.3 (CH2), 109.6 (CH), 110.0 (CH),
111.2 (CH), 115.2 (C), 120.2 (CH), 120.4 (CH), 122.5
(CH), 124.3 (C), 124.5 (CH), 127.6 (CH), 128.0 (2CH),
128.7 (2CH), 130.7 (C), 133.2 (C), 137.7 (C), 138.2 (C),
142.1 (CH), 152.7 (C), 162.3 (CO); Anal. Calcd for
C24H20N2O2: C, 78.24; H, 5.47; N, 7.60. Found: C, 78.52;
H, 5.61; N, 7.48; MS m/z 369 (M11)1.
2-Benzyl-10-methyl-5-vinyl-1,2,3,10-tetrahydroazepino-
[3,4-b]indol-1-one (18). Yield: 90%; mp 153±1548C
General procedure for the Suzuki reaction with 3d
(method B)
(methanol); IR (KBr) n 1622 (CO) cm21 1H NMR
;
(250 MHz, CDCl3) d 3.65 (d, 2H, Jˆ7.0 Hz, CH2), 4.08
(s, 3H, CH3), 4.80±4.90 (m, 2H, CH2), 5.29 (dd, 1H, Jˆ
1.3, 10.5 Hz, vCH2), 5.48 (dd, 1H, Jˆ1.3, 17.5 Hz,
vCH2), 5.94 (t, 1H, Jˆ7.0 Hz, CH), 6.07 (dd, 1H, Jˆ
10.5, 17.5 Hz, CH), 7.14±7.20 (m, 1H, HAr), 7.31±7.47
(m, 7H, HAr), 7.84 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR
(62.90 MHz, CDCl3) d 32.1 (CH3), 45.0 (CH2), 50.5
(CH2), 110.1 (CH), 116.1 (C), 117.8 (CH2), 120.1 (CH),
122.7 (CH), 123.0 (CH), 124.5 (C), 124.6 (CH), 127.6
(CH), 128.1 (2CH), 128.7 (2CH), 132.6 (C), 136.2 (CH),
137.9 (C), 138.4 (C), 139.2 (C), 162.4 (CO); Anal. Calcd for
C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.77; H,
6.00; N, 8.69; MS m/z 329 (M11)1.
To a stirred solution of 3d (100 mg, 0.22 mmol) in dry tolu-
ene (5 mL) was added freshly prepared tetrakis(triphenyl-
phosphine)palladium (15 mg, 0.013 mmol). The solution
was stirred for 30 min at room temperature. Boronic acid
(2- or 3-thiophenylboronic acid for 22 or 23 and phenyl-
boronic acid for 24, 0.33 mmol) diluted in absolute ethanol
(2 mL) was then added, followed immediately by saturated
aqueous hydrogenocarbonate (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 (3£5 mL). The
combined organic extracts were dried over MgSO4 and
evaporated in vacuo. The crude residue was puri®ed by
column chromatography (eluent: toluene±ethyl acetate
9:1) to give the desired compound.
2-Benzyl-5,10-dimethyl-1,2,3,10-tetrahydroazepino[3,4-b]-
indol-1-one (19). Yield: 99%; gum; IR (®lm) n 1623 (CO)
1
cm21; H NMR (250 MHz, CDCl3) d 2.42 (s, 3H, CH3),
3.62 (d, 2H, Jˆ7.0 Hz, CH2), 4.11 (s, 3H, CH3), 4.84 (s,
2H, CH2), 5.71 (t, 1H, Jˆ7.0 Hz, CH), 7.17±7.27 (m, 1H,
HAr), 7.31±7.44 (m, 7H, HAr), 7.90 (d, 1H, Jˆ8.2 Hz, HAr);
13C NMR (62.90 MHz, CDCl3) d 21.8 (CH3), 32.1 (CH3),
45.0 (CH2), 50.4 (CH2), 110.1 (CH), 119.3 (C), 120.3 (CH),
120.9 (CH), 122.4 (CH), 124.4 (CH), 124.5 (C), 127.4 (CH),
128.0 (2CH), 128.6 (2CH), 132.0 (C), 136.7 (C), 138.0 (C),
138.6 (C), 162.0 (CO); Anal. Calcd for C21H20N2O: C,
79.72; H, 6.37; N, 8.85. Found: C, 79.38; H, 6.53; N,
8.98; MS m/z 317 (M11)1.
2-Benzyl-10-methyl-5-(2-thienyl)-1,2,3,10-tetrahydroaze-
pino[3,4-b]indol-1-one (22). Yield: 90%; mp 139±1408C
(methanol); IR (KBr) n 1625 (CO) cm21 1H NMR
;
(250 MHz, CDCl3) d 3.74 (d, 2H, Jˆ7.0 Hz, CH2), 4.15
(s, 3H, CH3), 4.65±5.15 (m, 2H, CH2), 6.13 (t, 1H, Jˆ
7.0 Hz, CH), 6.99±7.04 (m, 3H, HAr), 7.20±7.36 (m, 9H,
HAr); 13C NMR (62.90 MHz, CDCl3) d 32.1 (CH3), 44.9
(CH2), 50.4 (CH2), 110.0 (CH), 116.7 (C), 120.1 (CH),
122.0 (CH), 122.7 (CH), 124.4 (C), 124.5 (CH), 125.1
(CH), 127.1 (CH), 127.3 (CH), 127.6 (CH), 128.0 (2CH),
128.7 (2CH), 133.0 (C), 134.8 (C), 137.6 (C), 138.3 (C),
142.7 (C), 162.3 (CO); Anal. Calcd for C24H20N2OS: C,
74.97; H, 5.24; N, 7.29. Found: C, 75.33; H, 5.18; N,
7.47; MS m/z 385 (M11)1.
2-Benzyl-10-methyl-5-(1-ethoxyvinyl)-1,2,3,10-tetrahydro-
azepino[3,4-b]indol-1-one (20). Yield: 92%; mp 129±
1
1308C (methanol); IR (KBr) n 1628 (CO) cm21; H NMR
(250 MHz, CDCl3) d 1.33 (t, 3H, Jˆ7.0 Hz, CH3), 3.71 (d,
2H, Jˆ7.0 Hz, CH2), 3.94 (q, 2H, Jˆ7.0 Hz, CH2), 4.15 (s,
3H, CH3), 4.36 (d, 1H, Jˆ2.0 Hz, vCH2), 4.45 (d, 1H, Jˆ
2.0 Hz, vCH2), 4.75±5.06 (m, 2H, CH2), 6.34 (t, 1H, Jˆ
7.0 Hz, CH), 7.17±7.21 (m, 1H, HAr), 7.36±7.48 (m, 7H,
HAr), 7.81 (d, 1H, Jˆ8.0 Hz, HAr); 13C NMR (62.90 MHz,
CDCl3) d 14.5 (CH3), 32.1 (CH3), 44.9 (CH2), 50.4 (CH2),
63.5 (CH2), 87.1 (CH2), 110.0 (CH), 115.8 (C), 120.1 (CH),
122.6 (CH), 122.8 (CH), 124.5 (CH), 124.6 (C), 127.6 (CH),
128.1 (2CH), 128.7 (2CH), 133.0 (C), 137.8 (C), 137.9 (C),
138.3 (C), 159.6 (C), 162.4 (CO); Anal. Calcd for
C24H24N2O2: C, 77.39; H, 6.49; N, 7.52. Found: C, 77.68;
H, 6.57; N, 7.70; MS m/z 373 (M11)1.
2-Benzyl-10-methyl-5-(3-thienyl)-1,2,3,10-tetrahydro-
azepino[3,4-b]indol-1-one (23). Yield: 99%; mp 97±988C
(methanol); IR (KBr) n 1625 (CO) cm21 1H NMR
;
(250 MHz, CDCl3) d 3.73 (t, 2H, Jˆ6.9 Hz, CH2), 4.13 (s,
3H, CH3), 4.57±5.09 (m, 2H, CH2), 6.07 (t, 1H, Jˆ6.9 Hz,
CH), 6.87±7.05 (m, 3H, HAr), 7.18±7.43 (m, 9H, HAr); 13
C
NMR (62.90 MHz, CDCl3) d 32.1 (CH3), 44.9 (CH2), 50.4
(CH2), 109.9 (CH), 117.2 (C), 119.7 (C), 120.1 (CH), 121.2
(CH), 122.6 (CH), 123.2 (CH), 124.5 (CH), 125.3 (CH),
126.0 (C), 126.3 (CH), 127.5 (CH), 128.0 (2CH), 128.7
(2CH), 136.3 (C), 137.7 (C), 138.4 (C), 141.4 (C), 162.3
(CO); Anal. Calcd for C24H20N2OS: C, 74.97; H, 5.24; N,
7.29; Found: C, 75.23; H, 5.12; N, 7.15; MS m/z 385
(M11)1.
2-Benzyl-10-methyl-5-(2-furanyl)-1,2,3,10-tetrahydroaze-
pino[3,4-b]indol-1-one (21). Yield: 74%; mp 110±1118C
(methanol); IR (KBr) n 1627 (CO) cm21 1H NMR
;
2-Benzyl-10-methyl-5-phenyl-1,2,3,10-tetrahydroazepino-
[3,4-b]indol-1-one (24). Yield: 86%; mp 173±1748C
(250 MHz, CDCl3) d 3.76 (t, 2H, Jˆ7.3 Hz, CH2), 4.14 (s,
(methanol); IR (KBr) n 1622 (CO) cm21 1H NMR
;
3H, CH3), 4.76±4.94 (m, 2H, CH2), 6.33 (t, 1H, Jˆ7.3 Hz,

Á
L. Chacun-Lefevre et al. / Tetrahedron 56 (2000) 4491±4499
4499
(250 MHz, CDCl3) d 3.75 (t, 2H, Jˆ7.5 Hz, CH2), 4,13 (s,
3H, CH3), 4.81±4.90 (m, 2H, CH2), 6.69 (t, 1H, Jˆ7.5 Hz,
CH), 6.65±6.69 (m, 1H, HAr), 6.85±6.88 (m, 1H, HAr),
7.22±7.42 (m, 12H, HAr); 13C NMR (62.90 MHz, CDCl3)
d 32.1 (CH3), 45.1 (CH2), 50.4 (CH2), 109.9 (CH), 117.2
(C), 120.0 (CH), 122.0 (CH), 122.7 (CH), 124.4 (CH), 124.5
(C), 127.5 (CH), 127.9 (CH), 128.0 (2CH), 128.3 (2CH),
128.5 (2CH), 128.7 (2CH), 133.2 (C), 137.7 (C), 138.4 (C),
140.3 (C), 142.0 (C), 162,3 (CO); Anal. Calcd for
C26H22N2O: C, 82.51; H, 5.86; N, 7.40. Found: C, 82.17;
H, 5.96; N, 7.57; MS m/z 379 (M11)1.
eluent: petroleum ether±ethyl acetate 8:2). Mp 194±1958C
1
(ethanol); IR (KBr) n 3168 (NH), 1648 (CO) cm21; H
NMR (250 MHz, CDCl3) d 3.61 (dd (d if D2O exchange),
2H, Jˆ6.0, 7.5 Hz, CH2), 4.12 (s, 3H, CH3), 6.27 (t, 1H,
Jˆ7.5 Hz, CH), 6.94±7.03 (m, 5H, NH1HAr), 7.25±7.41
(m, 3H, HAr); 13C NMR (62.90 MHz, CDCl3) d 32.1
(CH3), 38.8 (CH2), 110.2 (CH), 117.6 (C), 120.3 (CH),
123.0 (CH), 123.1 (CH), 124.7 (C), 124.9 (CH), 125.2
(CH), 127.1 (CH), 127.4 (CH), 131.7 (C), 134.7 (C),
138.6 (C), 143.1 (C), 164.6 (CO); Anal. Calcd for
C17H14N2OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 69.72;
H, 4.58; N, 9.65; MS m/z 295 (M11)1.
2-(4-Methoxybenzyl)-10-methyl-5-(2-thienyl)-1,2,3,10-
tetrahydroazepino[3,4-b]indol-1-one (25). According to
method B, compound 25 was prepared from 3e and 2-thio-
phenylboronic acid in 86% yield (chromatography eluent:
dichloromethane±ethyl acetate 9:1). Mp 111±1128C
Acknowledgements
This work was supported by a grant awarded to L. C.-L. by
Â
the Conseil Regional du Centre.
(methanol); IR (KBr) n 1627 (CO) cm21 1H NMR
;
(250 MHz, CDCl3) d 3.75 (d, 2H, Jˆ7.0 Hz, CH2), 3.84
(s, 3H, CH3), 4.18 (s, 3H, CH3), 4.65±5.00 (m, 2H, CH2),
6.15 (t, 1H, Jˆ7.0 Hz, CH), 6.90±6.94 (m, 2H, HAr), 7.02±
7.07 (m, 4H, HAr), 7.31±7.46 (m, 5H, HAr); 13C NMR
(62.90 MHz, CDCl3,) d 32.0 (CH3), 44.6 (CH2), 49.7
(CH2), 55.2 (CH3), 110.0 (CH), 114.0 (2CH), 116.6 (C),
120.0 (CH), 122.1 (CH), 122.6 (CH), 124.4 (CH), 125.0
(CH), 125.8 (C), 127.0 (CH), 127.3 (CH), 129.4 (2CH),
129.7 (C), 133.1 (C), 134.6 (C), 138.2 (C), 142.7 (C),
159.0 (C), 162.1 (CO); Anal. Calcd for C25H22N2O2S: C,
72.44; H, 5.35; N, 6.76. Found: C, 72.17; H, 5.20; N,
6.92; MS m/z 415 (M11)1.
References
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pino[3,4-b]indol-1-one (26). To a suspension of freshly
prepared tetrakis(triphenylphosphine)palladium (17 mg,
0.015 mmol) and LiCl (28 mg, 0.67 mmol) in dry DMF
was added a solution of 3f (120 mg, 0.24 mmol) and tetra-
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was then removed in vacuo and the crude residue was
puri®ed by column chromatography (eluent: toluene±ethyl
acetate 1:1) to give 26 (67 mg, 76%) as solid; mp 141±
1428C (methanol); IR (KBr) n 1676 (CO), 1354 (NSO2),
5. De Nanteuil, G.; Ahond, A.; Guilhem, J.; Poupat, C.; Tran Huu
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1
1167 (NSO2) cm21; H NMR (250 MHz, CDCl3) d 2.45
Â
11. (a) Joseph, B.; Cornec, O.; Merour, J.-Y. Tetrahedron 1998,
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54, 7765. (b) Joseph, B.; Alagille, D.; Rousseau, C.; Merour, J.-Y.
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(s, 3H, CH3), 3.91 (s, 3H, CH3), 4.60±5.15 (broad s, 2H,
CH2), 6.17 (t, 1H, Jˆ7.0 Hz, CH), 7.13±7.21 (m, 1H, HAr),
7.35±7.39 (m, 2H, HAr), 7.46±7.57 (m, 3H, HAr), 7.88 (d,
1H, Jˆ8.5 Hz, HAr), 7.98±8.04 (m, 2H, HAr); 13C NMR
(62.90 MHz, CDCl3) d 22.1 (CH3), 32.2 (CH3), 43.3
(CH2), 110.4 (CH), 121.0 (CH), 121.1 (C), 121.7 (CH),
122.9 (CH), 124.0 (C), 125.8 (CH), 128.6 (2CH), 128.7
(2CH), 129.5 (C), 133.5 (CH), 138.0 (C), 139.0 (C), 139.2
(C), 161.0 (CO); Anal. Calcd for C20H18N2O3S: C, 65.56; H,
4.95; N, 7.64. Found: C, 65.89; H, 5.11; N, 7.43; MS m/z
367 (M11)1.
Â
Hasnaoui, A.; Merour, J.-Y. Heterocycles 1999, 51, 2127.
È
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indol-1-one (27). According to the procedure for the synth-
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butyl(2-thiophenyl)stannane in 71% yield (chromatography
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