Synthesis of indolo[2,1-a][2]benzazepine and indolo[2,1-a][2]-benzazocine

Article abstract of DOI:10.1055/s-0029-1217168

The synthesis of functionalised 6,7-dihydro-5H-indolo[ 2,1-a][2]benzazepine and 5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine from methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate, involving RCM as the key step to generate the tetracyclic indolo[2,1-a][2]benzazepine and indolo[2,1-a][2] benzazocine core structure, is outlined. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217168

LETTER
1395
Synthesis of Indolo[2,1-a][2]benzazepine and Indolo[2,1-a][2]-benzazocine
Synthesis of In
i
dolo[2
m
,1-
a
][2]benzazepineona Ponzi,* Jörg Habermann, Maria del Rosario Rico Ferreira, Frank Narjes
Department of Medicinal Chemistry, IRBM ‘P. Angeletti’ S.p.A., Merck Research Laboratories Rome,
Via Pontina km 30,600, 00040 Pomezia, Rome, Italy
Fax +39(06)91093225; E-mail: simona_ponzi@merck.com
Received 13 February 2009
O
NR1
O
2
NR1
( )n
Abstract: The synthesis of functionalised 6,7-dihydro-5H-indo-
2
O
lo[2,1-a][2]benzazepine and 5,6,7,8-tetrahydroindolo[2,1-a][2]benz-
azocine from methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate,
involving RCM as the key step to generate the tetracyclic indo-
lo[2,1-a][2]benzazepine and indolo[2,1-a][2]benzazocine core
structure, is outlined.
N
HO
O
( )n
N
HO
3a (n = 2)
3b (n = 1)
3c (n = 1)
3d (n = 1)
Key words: hepatitis C, HCV NS5B polymerase inhibitor,
5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine, 6,7-dihydro-5H-
indolo[2,1-a]benzazepine, ring-closing metathesis
4a (n = 2)
4b (n = 1)
4c (n = 1)
R2
N
NR1
O
2
NR1
( )n
2
R2N
( )n
N
HO
Recent research identified substituted 5,6,7,8-tetra-
hydroindolo[2,1-a][2,5]benzodiazocines (1) and 6,7-di-
hydro-5H-indolo[1,2-d][1,4]benzodiazepines (2) as novel
RNA-dependent RNA polymerase inhibitors of hepatitis
C virus (HCV)1 (Figure 1).
O
N
HO
5a (n = 2)
5b (n = 1)
5c (n = 1)
5d (n = 1)
6a (n = 2)
6b (n = 1)
6c (n = 1)
R
R
N
Figure
2
6,7-Dihydro-5H-indolo[2,1-a][2]benzazepines
and
O
O
N
5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocines
N
N
HO
HO
( )n
H
( )n
N
N
(a)
Br
+
1
2
Br
Br
Figure 1 5,6,7,8-Tetrahydroindolo[2,1-a][2,5]benzodiazocines (1)
and 6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepines (2)
(b)
( )n
N
In the process of carrying out structure–activity relation-
ship studies we became interested in the preparation of
(c)
N
( )n
Br
functionalized
6,7-dihydro-5H-indolo[2,1-a][2]benz-
azepines and 5,6,7,8-tetrahydroindolo[2,1-a][2]benzazo-
cines (3–6, Figure 2).
Scheme
1
Reagents and conditions: (a) KOH, DMSO; (b)
Pd(PPh3)4, KOAc, DMA, reflux; (c) Pd2(dba)3, SIPr, NaOt-Bu, tolue-
ne.
Earlier research had addressed the tethering via alkylation
processes and cyclisation via aromatic cross-coupling or
via Buchwald–Hartwig coupling to construct the indole2–7
(Scheme 1). However, all of these methods leave an un-
functionalised alkyl chain as tethering group.
To this end methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-
indole-6-carboxylate (8) was prepared from methyl 2-
bromo-3-cyclohexyl-1H-indole-6-carboxylate (7) by
Suzuki8 reaction with 2-vinylbenzene boronic acid. This
was followed by N-alkylation with 4-bromo-1-butene or
allylbromide to furnish the intermediates 9a and 9b in ex-
cellent yield (Scheme 2). Treatment of 9a,b with Zhannan
catalyst I9 in dichloromethane resulted in a clean cyclisa-
tion to 10a,b. In the benzazepine series hydroboration fol-
lowed by oxidative workup yielded a 4:1 mixture of 11b
and the isomeric homobenzylic alcohol 12b, while in the
benzazocine series only benzylic alcohol 11a was formed.
Products of type 3 and 4 were readily obtained by direct
Therefore, we chose to construct the tether between the
indole nitrogen and the aryl group via a ring-closure
metathesis leaving a double bond. This approach allowed
for the functionalisation of the positions of interest and
gave access to the tetracyclic indolobenzazocines 3–6a
and indolobenzazepines 3b–d, 4b,c, 5b–d, 6b,c).
SYNLETT 2009, No. 9, pp 1395–1400
x
x.
x
x.
2
0
0
9
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217168; Art ID: D05309ST
© Georg Thieme Verlag Stuttgart · New York

1396
S. Ponzi et al.
LETTER
O
O
O
( )n
H
H
N
N
N
MeO
MeO
MeO
Br
(a)
(b)
7
8
9a (n = 2)
9b (n = 1)
OH
OH
O
O
O
( )n
( )n
( )n
N
N
N
(c)
MeO
(d)
MeO
MeO
10a (n = 2)
10b (n = 1)
11a (n = 2)
11b (n = 1)
12a (n = 2)
12b (n = 1)
NR2
O
O
NR2
O
O
( )n
( )n
(e)
N
N
HO
HO
3a (n = 2)
3b (n = 1)
3c (n = 1)
3d (n = 1)
4b (n = 1)
4c (n = 1)
Scheme 2 Reagents and conditions: (a) 2-vinylbenzene boronic acid, PdCl2(PPh3)2, 2 M Na2CO3, dioxane, 110 °C, 91%; (b) NaH, 4-bromo-
1-butene, DMF, 40 °C, 60% or NaH, allylbromide, DMF, r.t., 98%; (c) Zhannan catalyst I, CH2Cl2, 35 °C, 68–84%; (d) BH3·DMS, THF, then
(3 N) NaOH, H2O2, 0 °C; (e) NaOH (40%), TBAB, toluene, N,N-dialkylamino ethyl chloride, 70 °C.
Table 1 Synthesis of Compounds 3 and 413 (continued)
alkylation of the benzylic and homobenzylic alcohols 11
and 12 (Scheme 2). The yields obtained for the last two
steps are reported in Table 1.
Compd
Structurea
Yield (%)b
O
NEt2
O
N
HO
Table 1 Synthesis of Compounds 3 and 413
3d (n = 1)
49
Compd
Structurea
Yield (%)b
O
O
N
N
N
HO
N
N
O
3a (n = 2)
63
O
4b (n = 1)
N
42
HO
O
N
O
HO
3b (n = 1)
29
18
NEt2
O
O
N
HO
4c (n = 1)
18
O
NMe2
O
HO
3c (n = 1)
a All compounds were obtained as a racemic mixture.
b Yield for steps d,e for compounds obtained as TFA salts after HPLC
purification.
Synlett 2009, No. 9, 1395–1400 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolo[2,1-a][2]benzazepine
1397
NR1
2
O
O
O
OH
NR2
O
N
N
N
MeO
HO
MeO
(a)
(b), (e)
11a
13
5a
(c)
O
O
NR2
OMs
N
N
MeO
NR1
HO
2
(d), (e)
14
5a
Scheme 3 Reagents and conditions: (a) DMP, CH2Cl2, quant.; (b) amine, NaBH(OAC)3, DCE, r.t. to 50 °C or TiCl4, NaCNBH3, MeOH; (c)
MsCl, Et3N, CH2Cl2, quantit. as crude; (d) amine, CH2Cl2; (e) 1 M KOH, dioxane, 70 °C.
To access the benzylic amine analogues 5 the benzylic al- To gain reasonable access to the homobenzylic alcohols,
cohol 11a was oxidised with DMP in dichloromethane both in the benzazepine and the benzazocine series, an al-
yielding the corresponding ketone 13 (Scheme 3).
ternative approach needed to be developed.
Surprisingly, this ketone did not react with selected First attempts to access the homobenzylic alcohols 12a,b,
amines under any reductive amination conditions attempt- either via the bromohydrin10 or by inducing regioselectiv-
ed (Scheme 3). Also the approach via the treatment of the ity in the hydroboration step11 using a bulky borane were
alcohol 11a with mesyl chloride and triethylamine in unsuccessful. Also the approach to form the epoxide using
dichloromethane followed by nucleophilic displacement MCPBA in chloroform failed, giving rise to opening of
with the selected amine was not successful. This was due the indole ring (Scheme 5). We observed this same side
to the instability of the mesylate 14 which underwent fac- reaction under various oxidative conditions [e.g.,
ile elimination to 10a.
CrO3(pyridine)3; SeO2, t-BuOOH; CuCl2·2H2O, t-
BuOOH, O2; Pd(OH)2/C, K2CO3, t-BuOOH; CrO3, 3,5-
DMP, t-BuOOH]. To circumvent this problem we decided
to proceed via the treatment of alkene (10a,b) with osmi-
um tetroxide in THF–acetone–water to access diols 17a
and 17b. These intermediates opened the route to the
cyclic carbonates 18a and 18b obtained by reaction with
triphosgene and triethylamine in dichloromethane.12 The
To resolve this issue the benzylic alcohols 11a,b were
brominated with phosphorus tribromide and the resulting
bromides 15a,b were reacted with different amines
(Scheme 4). A subsequent reductive amination with form-
aldehyde gave products 16a–d (Scheme 4). Hydrolysis of
the methyl ester was achieved by heating at 70 °C in 1 M
KOH. The results obtained are reported in Table 2.
OH
Br
O
O
( )n
( )n
N
N
MeO
MeO
(a)
15a (n = 2)
15b (n = 1)
11a (n = 2)
11b (n = 1)
(b), (c)
R2
N
R2
N
NR1
NR1
O
O
2
2
( )n
( )n
N
N
HO
MeO
(d)
16a (n = 2, R2 = H)
16b (n = 1, R2 = H)
16c (n = 1, R2 = Me)
16d (n = 1, R2 = Me)
5a (n = 2, R2 = H)
5b (n = 1, R2 = H)
5c (n = 1, R2 = Me)
5d (n = 1, R2 = Me)
Scheme 4 Reagents and conditions: (a) PBr3, CH2Cl2, 0 °C to r.t.; (b) N,N-dialkyl ethylenediamine, MeCN, 55 °C; (c) HCHO, AcOH,
NaCNBH3, CH2Cl2; (d) 1 M KOH, dioxane, 70 °C.
Synlett 2009, No. 9, 1395–1400 © Thieme Stuttgart · New York

1398
S. Ponzi et al.
LETTER
Table 2 Synthesis of Compounds 514
Compd
Structurea
Yield (%)b
O
O
O
N
H
N
O
MeO
MeO
N
oxidation
N
O
HO
N
5a (n = 2)
53
24
Scheme 5 Oxidative ring opening
H
N
N
O
OH
N
HO
OH
5b (n = 1)
O
O
( )n
N
( )n
N
MeO
(a)
MeO
Me
10a (n = 2)
10b (n = 1)
17a (n = 2)
17b (n = 1)
N
NMe2
O
(b)
N
O
O
HO
5c (n = 1)
49
OH
O
O
O
( )n
N
( )n
N
MeO
MeO
(c)
Me
N
N
O
18a (n = 2)
18b (n = 1)
12a (n = 2)
12b (n = 1)
N
HO
5d (n = 1)
29
Scheme 6 Reagents and conditions: (a) NMO, OsO4 (4% wt in
H2O), acetone–THF–H2O; (b) Et3N, CO(OCCl3)2, CH2Cl2, –50 °C to
r.t.; (c) H2, Raney/Ni, acetone–MeOH, quant. as crude for steps a–c.
a All compounds were obtained as a racemic mixture.
Raney nickel mediated reduction of the cyclic carbonate
gave access to the homobenzylic alcohols 12a,b in a very
clean fashion (Scheme 6). Products of type 4a16 were
readily obtained by direct alkylation of the homobenzylic
alcohol 12a (Scheme 7).
To gain access to the amine analogues of the type 6b,15
which could not be obtained by nucleophilic displacement
of the corresponding bromide as was possible in the case
of benzylic analogues, the homobenzylic alcohol 12b was
oxidised with DMP in dichloromethane (Scheme 8).
b Yield for steps a–d for compounds obtained as TFA salts after HPLC
purification.
In summary, we have reported a novel synthesis of two
scaffolds, 6,7-dihydro-5H-indolo[2,1-a][2]benzazepines
and 5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocines ap-
plying a highly efficient ring-closure metathesis reaction.
As shown, this new approach allowed the wide and facile
functionalisation both in the benzylic and the homoben-
zylic positions. In order to do so, two main synthetic strat-
egies were successfully employed. The versatility of the
double bond installed via RCM creates a synthetic advan-
tage and makes our synthesis a favourable and interesting
alternative to other ways.
The ketone 19 was treated with the selected amine in
reductive amination conditions. After base-mediated (1 M
KOH) hydrolysis the desired acid 6b was efficiently
obtained (Scheme 8).
OH
O
N
O
O
N
N
(a)
MeO
HO
12a
4a
Scheme 7 Reagents and conditions: (a) NaOH (40%), TBAB, toluene, 1-(2-chloroethyl)pyrrolidine, 70 °C.
Synlett 2009, No. 9, 1395–1400 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolo[2,1-a][2]benzazepine
1399
was isolated by chromatography (PE–EtOAc); yield 91%.
To a 0.3 M soln of methyl 3-cyclohexyl-2-(2-vinylphenyl)-
1H-indole-6-carboxylate (8) in dry DMF, 60% NaH (1.5
equiv) in mineral oil was added at 0 °C, after 1 h allyl
bromide (1.5 equiv) or 4-bromo-1-butene (2 equiv) were
added, and the suspension was stirred at r.t. for 2 h or at
40 °C for 5 h. The mixture was diluted with EtOAc, washed
with 1 N HCl, H2O and brine, dried over Na2SO4, and
concentrated in vacuo to give methyl 1-allyl-3-cyclohexyl-
2-(2-vinylphenyl)-1H-indole-6-carboxylate (9b, 98%) or
methyl 1-buten-3-en-1-yl-3-cyclohexyl-2-(2-vinylphenyl)-
1H-indole-6-carboxylate (9a, 60%). Methyl 1-allyl-3-
cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate(9b)
or methyl 1-buten-3-en-1-yl-3-cyclohexyl-2-(2-vinyl-
phenyl)-1H-indole-6-carboxylate (9a) were dissolved in
CH2Cl2 (0.02 M) and treated with Zhannan catalyst I (0.3
equiv) at 35 °C for 1 h. After removal of solvent the residue
was purified by chromatography (PE–EtOAc) to afford
methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-
carboxylate (10b) or methyl 14-cyclohexyl-7,8-dihydro-
indolo[2,1-a][2]benzazocine-11-carboxylate (10a) in 84%
and 80% yield. BH3·SMe2 (1.6 equiv, 2 M soln in THF) was
added to a 0.2 M solution of methyl 13-cyclohexyl-7H-
indolo[2,1-a][2]benzazepine-10-carboxylate (10b) in THF
or methyl 14-cyclohexyl-7,8-dihydroindolo[2,1-a][2]benz-
azocine-11-carboxylate (10a), and the mixture was stirred
for 2 h at r.t.; 3 M aq NaOH (3 equiv) and 35% H2O2 (3
equiv) were added at 0 °C, and stirring was continued
overnight at r.t. After dilution with sat. NaHCO3 the aqueous
phase was extracted with EtOAc, the organic phase was
washed with H2O and brine, dried over Na2SO4, and
concentrated in vacuo to give a 4:1 mixture of methyl 13-
cyclohexyl-5-hydroxy-6,7-dihydro-5H-indolo[2,1-
a][2]benzazepine-10-carboxylate (11b) and methyl 13-
cyclohexyl-6-hydroxy-6,7-dihydro-5H-indolo[2,1-
a][2]benzazepine-10-carboxylate (12b) or methyl 14-
cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo[2,1-
a][2]benzazocine-11-carboxylate (11a). The foregoing
crude was dissolved in toluene (20 mL/mmol), 40% aq
NaOH (15 equiv) and TBAB (0.25 equiv) were added, and
the mixture was stirred for 30 min. Selected dialkylamino-
ethyl chloride (3 equiv) was then added and the resulting
mixture heated at 70 °C for 1 d; evaporation to dryness gave
a residue which was purified by RP-HPLC to give products
3a–d, 4b,c.
O
OH
O
O
N
N
MeO
(a)
MeO
12b
19
(b)
NMe2
NMe2
HN
HN
O
O
N
N
MeO
HO
(d)
20
6b
Scheme 8 Reagents and conditions: (a) DMP, CH2Cl2, 0 °C to r.t.;
(b) N,N-dimethyl ethylenediamine, AcOH, NaCNBH3, DCE; (c) 1 M
KOH, dioxane, 70 °C, 31% for steps a–c.
References and Notes
(1) (a) Stansfield, I.; Ercolani, C.; Mackay, A.; Conte, I.;
Pompei, M.; Koch, U.; Gennari, N.; Giuliano, C.; Rowley,
M.; Narjes, F. Bioorg. Med. Chem. Lett. 2009, 19, 627.
(b) Hirashima, S.; Oka, T.; Ikegashira, K.; Noji, S.;
Yamanaka, H.; Hara, Y.; Goto, H.; Mizojiri, R.; Nima, Y.;
Noguchi, T.; Ando, I.; Ikeda, S.; Hashimoto, H. Bioorg.
Med. Chem. Lett. 2007, 17, 3181. (c) Ikegashira, K.; Oka,
T.; Hirashima, S.; Noji, S.; Yamahaka, H.; Hara, Y.; Adachi,
T.; Tsuruha, J.-I.; Doi, S.; Hase, Y.; Noguchi, T.; Ando, I.;
Ogura, N.; Ikeda, S.; Hashimoto, H. J. Med. Chem. 2006, 49,
6950.
(2) Kozikowski, A. P.; Me, D. Tetrahedron Lett. 1991, 32, 3317.
(3) Kozikowski, A. P.; Me, D.; Brewer, J.; Sun, S.; Costa, E.;
Romeo, E.; Guidotti, A. J. Med. Chem. 1993, 36, 2908.
(4) Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41, 4209.
(5) Vincze, Z.; Biro, A. B.; Csekei, M.; Timari, G.; Kotschy, A.
Synthesis 2006, 1375.
(6) Ikegashira, K.; Oka, T.; Hirashima, S.; Noji, S.; Yamanaka,
H.; Hara, Y.; Adachi, T.; Tsuruha, J.; Doi, S.; Hase, Y.;
Noguchi, T.; Ando, I.; Ogura, N.; Ikeda, S.; Hashimoto, H.
J. Med. Chem. 2006, 49, 6950.
Selected Data for 3a
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d = 1.16–
2.30 (20 H, m), 2.61–2.72 (1 H, m), 2.93–3.05 (2 H, m),
3.15–3.30 (3 H, m), 3.41–3.52 (2 H, m), 3.78 (1 H, d, J = 9.0
Hz), 4.40–4.45 (1 H, m), 7.38 (1 H, d, J = 7.4 Hz), 7.47–7.50
(1 H, m), 7.62–7.71 (3 H, m), 7.85 (1 H, d, J = 8.3 Hz), 8.07
(1 H, s), 9.31 (1 H, br s), 12.59 (1 H, br s). MS (ES+): m/z =
487 [M + H]+.
(7) Lautens, M. J. Org. Chem. 2008, 73, 1888.
(8) Suzuki, A. Pure Appl. Chem. 1991, 63, 419.
(9) (a) Ettari, R.; Micale, N. J. Organomet. Chem. 2007, 692,
3574. (b) The catalyst was purchased from Zhannan Pharma
Ltd., Shanghai, China: Zhan, Z.-Y. WO 2007003135 A1,
2007.
(10) Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059.
(11) Brown, H. C. J. Org. Chem. 1986, 51, 439.
(12) Corey, E. J. Org. Lett. 2003, 5, 2465.
(13) Typical Procedure for Compounds 3a–d, 4b,c
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (7)
and (2-vinylphenyl)boronic acid (1.5 equiv) were dissolved
in dioxane (0.07 M) and 2 M aq Na2CO3 (6 equiv) was
added. The soln was degassed by bubbling argon,
Pd(PPh3)2Cl2 (0.2 equiv) was added, and the reaction
mixture was refluxed for 1 h; after cooling, EtOAc was
added, and the solution washed with H2O and brine,
dried over Na2SO4 and concentrated in vacuo. Methyl 3-
cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (8)
Selected Data for 3d
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d = 0.58–
0.67 (1 H, m), 0.79–0.82 (1 H, m), 1.16–1.23 (6 H, m), 1.38–
1.49 (2 H, m), 1.58–2.06 (8 H, m), 2.62–2.90 (3 H, m), 3.05–
3.80 (7 H, m), 4.23–4.28 (1 H, m), 4.58–4.71 (1 H, m), 7.43–
7.64 (5 H, m), 7.83–7.87 (1 H, d, J = 8.4 Hz), 8.13 (1 H, s).
MS (ES+): m/z = 475 [M + H]+.
(14) Typical Procedure for Compounds 5a–d
Phosphorus tribromide (0.5 equiv) was added at 0 °C to a 0.2
M soln of methyl 13-cyclohexyl-5-hydroxy-6,7-dihydro-
5H-indolo[2,1-a][2]benzazepine-10-carboxylate (11b) or
methyl 14-cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo-
[2,1-a][2]benzazocine-11-carboxylate (11a) in CH2Cl2, and
the mixture was stirred at r.t. for 2 h. The reaction mixture
Synlett 2009, No. 9, 1395–1400 © Thieme Stuttgart · New York

1400
S. Ponzi et al.
LETTER
cyclohexyl-2-oxo-3a,14b-dihydro-4H-[1,3]dioxolo[4,5-
was diluted with EtOAc, washed with H2O and brine, dried
over Na2SO4, and concentrated in vacuo to give methyl 5-
bromo-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-
a][2]benzazepine-10-carboxylate (15b) or methyl 5-bromo-
14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-
d]indolo[2,1-a][2] benzazepine-7-carboxylate (18b) in
acetone–MeOH (3:1) was treated with Raney-Ni (slurry in
H2O), and the vigorously stirred reaction mixture was
hydrogenated at 1 atm H2. After 48 h the solid was filtered
and the filtrates evaporated in vacuo to leave the clean
methyl 13-cyclohexyl-6-hydroxy-6,7-dihydro-5H-
indolo[2,1-a] [2]benzazepine-10-carboxylate (12b). A
solution (0.05 M) of methyl 13-cyclohexyl-6-hydroxy-6,7-
dihydro-5H-indolo[2,1-a][2] benzazepine-10-carboxylate
(12b) in CH2Cl2 was treated with DMP (1.3 equiv) at 0 °C
and left warming to r.t. and then stirred for 2 h under
nitrogen. The solution was then diluted with EtOAc and
washed with sat. NaHCO3, H2O, brine, dried over Na2SO4,
and evaporated in vacuo to afford methyl 13-cyclohexyl-6-
oxo-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-
carboxylate (19). The crude material was dissolved in DCE
(0.05 M), 2-dimethylaminoethylamine was added, the pH
adjusted to 6 with AcOH, and the soln left stirring for 30
min. NaBH(OAc)3 was added, and the soln was left stirring
at r.t. overnight. After diluting with EtOAc, the organic
phase was washed with NaOH (1 N), H2O, brine, dried over
Na2SO4, and evaporated in vacuo to afford methyl 13-
cyclohexyl-6-{[2-(dimethylamino)ethyl]amino}-6,7-
dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate
(20). Hydrolysis of the foregoing methyl ester was done with
1 M aq KOH (6 equiv) in dioxane (0.1 M) at 60 °C; the
reaction was complete in 2 h, and the title compound was
obtained after RP-HPLC purification.
a][2]benzazocine-11-carboxylate (15a) that were dissolved
in MeCN and treated with the selected N,N-
dialkylethylenediamine (8 equiv) at 55 °C for 3 h;
evaporation in vacuo to dryness gave crude products 16a,b,
an amount of which was dissolved in CH2Cl2 and pH
adjusted to 6 with AcOH; 37% aq HCHO and NaCNBH3 (3
equiv, after 30 min) were added, and the mixture was stirred
at r.t. overnight. The reaction mixture was diluted with
EtOAc and washed with 1 N NaOH and brine, dried, and
evaporated affording compounds 16c,d. Hydrolysis of the
foregoing methyl esters was done with 1 M aq KOH (6
equiv) in dioxane (0.1 M) at 60 °C; the reaction was
complete in 2 h, and the title compounds 5a–d were obtained
after RP-HPLC purification.
Selected Data for 5b
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d = 1.15–
1.77 (7 H, m), 1.90–2.17 (10 H, m), 2.78–2.91 (2 H, m),
3.40–3.59 (7 H, m), 4.11–4.16 (1 H, m), 4.75–4.81 (1 H, m),
7.51–7.66 (5 H, m), 7.92 (1 H, d, J = 8.5 Hz), 8.20 (1 H, s).
MS (ES+): m/z = 472 [M + H]+.
Selected Data for 5d
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d = 1.16–
1.77 (8 H, m), 1.80–2.11 (8 H, m), 2.19–2.31 (2 H, m), 2.61–
2.87 (5 H, m), 2.98–3.41 (7 H, m), 4.54–4.66 (1 H, m), 7.42
(1 H, d, J = 8.1 Hz), 7.47–7.54 (2 H, m), 7.63 (1 H, d, J = 8.3
Hz), 7.69–7.75 (1 H, m), 7.86 (1 H, d, J = 8.3 Hz), 8.12 (1 H,
s). MS (ES+): m/z = 486 [M + H]+.
Selected Data for 6b
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d = 1.16–
1.59 (4 H, m), 1.61–2.12 (6 H, m), 2.74–2.98 (8 H, m), 3.12–
3.43 (7 H, m), 4.69–4.73 (1 H, m), 7.49–7.58 (4 H, m), 7.67–
7.73 (1 H, m), 7.90–7.93 (1 H, m), 8.24 (1 H, br s).
MS (ES+): m/z = 446.4 [M + H]+.
(15) Typical Procedure for Compounds 6b
A soln (0.11 M) of methyl 13-cyclohexyl-7H-indolo[2,1-
a][2]benzazepine-10-carboxylate (10b) in acetone–THF–
H2O (1:1:1) was treated with N-methylmorpholine-N-oxide
(1.2 equiv), followed by OsO4 (4% wt in H2O; 0.1 equiv) and
left stirring at r.t. overnight. The clear soln was then treated
with 10% wt Na2SO3 and left stirring for 30 min, then diluted
with H2O, and extracted with EtOAc. The organic phase was
washed with brine, dried over Na2SO4, and evaporated in
vacuo to give methyl 13-cyclohexyl-5,6-dihydroxy-6,7-
dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate
(17b). A soln (0.05 M) of methyl 13-cyclohexyl-5,6-
dihydroxy-6,7-dihydro-5H-indole[2,1-a][2]benzazepine-
10-carboxylate (17b) in CH2Cl2 was treated with Et3N (4
equiv), and cooled to –50 °C. Triphosgene (0.4 equiv) was
added, and the soln was allowed to warm to r.t. over 30 min.
After 2 h at r.t., sat. NaHCO3 was added and the solution
extracted with EtOAc. The organic phase was washed with
H2O, brine, dried over Na2SO4, and evaporated in vacuo to
leave methyl 10-cyclohexyl-2-oxo-3a,14b-dihydro-4H-
[1,3]dioxolo[4,5-d]indolo[2,1-a][2]benzazepine-7-
(16) Typical Procedure for Compounds 4a
Methyl 14-cyclohexyl-6-hydroxy-5,6,7,8-tetrahydro-
indolo[2,1-a][2]benzazocine-11-carboxylate (12a),
prepared as its seven-membered ring analogue as reported
above, was dissolved in toluene (20 mL/mmol), 40% aq
NaOH (15 equiv), and TBAB (0.25 equiv) were added, and
the mixture was stirred for 30 min. 1-(2-chloroethyl)-
pyrrolidine (3 equiv) was then added and the resulting
mixture heated at 70 °C for 1 d; evaporation to dryness gave
a residue which was purified by RP-HPLC to give product
4a; yield 23% from the alkene 10a.
Selected Data for 4a
1H NMR (TFA salt, 400 MHz, DMSO-d6, 300 K): d =
1.16–1.39 (3 H, m), 1.43–1.58 (2 H, m), 1.64–1.75 (2 H, m),
1.82–2.18 (9 H, m), 2.18–2.34 (1 H, m), 2.57–2.68 (1 H, m),
2.99–3.11 (3 H, m), 3.12–3.29 (2 H, m), 3.50–3.65 (4 H, m),
3.73–3.94 (2 H, m), 4.26–4.45 (1 H, m), 7.31–7.56 (4 H, m),
7.66–7.68 (1 H, d, J = 8.4 Hz), 7.86–7.88 (1 H, d, J = 8.4
Hz), 8.08 (1 H, s). MS (ES+): m/z = 487 [M + H]+.
carboxylate (18b). A solution (0.02 M) of methyl 10-
Synlett 2009, No. 9, 1395–1400 © Thieme Stuttgart · New York

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