Practical and efficient palladium-promoted synthesis of indole systems containing medium- and large-ring-fused heterocycles

Article abstract of DOI:10.1055/s-2006-942398

The synthesis of indolo-benzazepine, indolo-benzazocine and indolo-benzazonine derivatives using a palladium-catalyzed coupling reaction is described. The polycyclic systems were obtained in a few steps directly from commercially available materials. The

Full text of DOI:10.1055/s-2006-942398

2404
PAPER
Practical and Efficient Palladium-Promoted Synthesis of Indole Systems
Containing Medium- and Large-Ring-Fused Heterocycles
P
alladium-Prom
g
ote
d
Synthe
l
sis of
I
n
e
dole System
s
Co
M
ntaining Medium- and
.
Large-Fused
B
Heterocycles eccalli,*a Gianluigi Broggini,b Michela Martinelli,a Giuseppe Paladino,a Elisabetta Rossia
a
Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, Università di Milano, via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
Fax +39(02)50314476; E-mail: egle.beccalli@unimi.it
b
Received 1 March 2006; revised 10 March 2006
indoles (i.e., azakenpaullones) showed improved action as
GSK-3b inhibitors.5 The indoloazocine derivatives, such
as compound B (Figure 1), showed acetylcholinesterase
(AChE) inhibitory activities6 which at present represents
Abstract: The synthesis of indolo-benzazepine, indolo-benzazo-
cine and indolo-benzazonine derivatives using a palladium-cata-
lyzed coupling reaction is described. The polycyclic systems were
obtained in a few steps directly from commercially available mate-
rials. The coupling of substrates containing aryl bromides was im- a major pharmacological approach to the treatment of
Alzheimer’s disease.7 Indoloazocines have also been pat-
proved by microwave irradiation.
ented as a central nervous system depressant.8 Many in-
Key words: palladium catalyst, fused-ring systems, indoles, lac-
tams, intramolecular cyclization
dole alkaloid families (i.e., iboga, vinca, aspidosperma)
include large, indolo-fused, heterocyclic rings.9
Following our studies on the wide applicability of palladi-
um-catalyzed intramolecular coupling reactions, we re-
ported previously the palladium-catalyzed ring
cyclization of 2- and 3-carboxamide-substituted indoles
resulting in the formation of b- and g-carbolinones.10
General syntheses of medium- and large-ring heterocy-
cles have been difficult to develop. However, because of
their occurrence, nitrogen-containing seven- and eight-
membered ring systems, as well as larger fused-ring sys-
tems, are worthy of detailed investigation. In particular,
the development of synthetic methods for the synthesis of
seven-membered heterocycles fused to indole nucleus has
received much attention.1 General syntheses for larger-
ring heterocycles, indoloazocines and indoloazonines, are
not available; only some synthetic paths to particular in-
doloazocines have been described.2 We describe here a
novel sequence to obtain indolo-benzazepines, indolo-
benzazocines, and indolo-benzazonines in only three
steps, which involves amide functionalization of indole
derivatives and palladium-catalyzed intramolecular car-
bon–carbon bond formation. The formed heteropolycy-
clic systems constitute the skeleton of some important
pharmaceutical building blocks. Their relevance is due to
the activity of indolo-benzazepines as cyclin-dependant
kinase (CDK) inhibitors3 and as glycogen synthase ki-
nase-3b (GSK-3b) inhibitors4 and also their promising an-
titumoral properties (a representative example is
compound A, Figure 1). Moreover, the pyrido-azepino-
To achieve larger heterocycles fused to the indole nucle-
us, we envisaged indole-3-acetic acid 1 and indole-3-pro-
pionic acid 2 as starting materials for the reaction
sequence depicted in Scheme 1. The amides 4 obtained
from indole-3-acetic acid and indole-3-propionic acid are
collected in Tables 1 and 2, respectively, and are given
with the cyclization times and yields of 5.
The synthesis of the intermediate amides 3 was dependent
on the reactivity of the different starting amines. In the
case of benzylamine or 2-phenylethylamine (Table 1, en-
tries f, g and Table 2, entry k) the amidation was per-
formed via the acyl chloride. In the case of anilines and
aminopyridines (Table 1, entries a–e and Table 2, entries
h–j) the coupling was achieved using a complex of phenyl
dichlorophosphate and N,N-dimethylformamide.11
The subsequent N-methylation step, affording intermedi-
ates 4, was necessary to avoid complexation of palladium
to the amide nitrogen and was carried out with sodium hy-
dride and iodomethane in tetrahydrofuran solution. It
should be emphasized that the 1H NMR spectra of the de-
rivatives 4f, 4g, and 4k, in CDCl3 solution, display the ex-
istence of 1:1 ratio of rotational isomers caused by
restricted rotation about the amide bond. Obtaining the 1H
NMR spectrum of 4f in DMSO-d6 at room temperature a
3:5 mixture of rotamers was revealed, while on raising the
temperature to 110 °C the coalescence of the signals was
observed.
O
CO2Me
CO2Me
NH
N
N
Et
H
N
H
A
B
Figure 1
Optimization studies for the intramolecular ring closure of
the amides 4 with various palladium sources, bases, and
solvents were undertaken. The use of palladium(II) ace-
tate in the absence of a phosphine ligand or tetrakis(tri-
SYNTHESIS 2006, No. 14, pp 2404–2412
Advanced online publication: 16.05.2006
DOI: 10.1055/s-2006-942398; Art ID: Z04606SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

PAPER
Palladium-Promoted Synthesis of Indole Systems Containing Ring-Fused Heterocycles
2405
phenylphosphine)palladium resulted in a low conversion, Melting points were determined on a Büchi B-540 heating appara-
1
tus and are uncorrected. H NMR and 13C NMR spectra were ob-
as did the use of potassium carbonate or cesium carbonate
tained on a Bruker Avance 400. Chemical shifts are given in ppm
as bases. The investigation of the use of different solvents
downfield from TMS. 13C NMR spectra are 1H-decoupled and the
determination of the multiplicities was achieved by the APT pulse
sequence. IR spectra were recorded on a Jasco FT–IR 5300 spectro-
(MeCN and DMF) resulted in only moderate yields of 5.
The treatment of the amides 4 with palladium(II) acetate
as catalyst, triphenylphosphine as ligand, potassium ace-
tate as base, tetrabutylammonium chloride as additive, in
N,N-dimethylacetamide (DMA) at 110 °C constitutes the
best conditions for the synthesis of the target indolo-ben-
zazepines, indolo-benzazocines, indolo-benzazonines,
and aza-analogues thereof 5 in good to excellent yields.
photometer.
Amides 3; General Procedure
Method A: To DMF (0.15 mL, 1.95 mmol), PhOP(O)Cl2 (0.18 mL,
1.2 mmol) was added at 0 °C. The mixture was stirred for 5 min,
then 1 or 2 (1 mmol) in CH2Cl2 (15 mL) was added and the soln was
stirred for 10 min. Pyridine (0.32 mL, 4 mmol) was added and, after
The nature of the aryl halides was fundamental to evaluate 10 min, the appropriate amine (1.2 mmol) was added always at
0 °C. After stirring at r.t. for the reported time, the mixture was di-
luted with brine (15 mL) and extracted with CH2Cl2 (3 × 20 mL).
The organic layer was dried (Na2SO4) and evaporated under re-
duced pressure. The residue was chromatographed on a silica gel
column to give the amide 3.
the yields of the intramolecular cyclization step. Aryl io-
dides usually gave better results than aryl bromides
(Table 1, entries a and b compared with entry c), but bro-
mopyridine derivatives gave quantitative yields (Table 1,
entries d and e).
Method B: To a soln of 1 or 2 (1 mmol) in anhyd THF (10 mL), ox-
In the case of the less reactive aryl bromides, microwave
irradiation was tested to improve the cyclization step,
since metal-catalyzed processes are ideal candidates for
acceleration by microwaves. Heating the reacting mole-
cules by means of absorption of microwave energy by a
polar solvent effectively affords high temperatures in a
short time and in uniform way. The reaction mixture was
irradiated in a multimode oven equipped with temperature
control at 600 W for the reported time and in this period
the solution temperature reached 120 °C or 160 °C. The
irradiation time for each experiment was determined by
TLC control. This procedure gave better results compared
with traditional heating as showed in Tables 1 and 2 (en-
tries c, f, g, and k).
alyl chloride (0.21 mL, 2.5 mmol) was added at 0 °C. The mixture
was stirred at r.t. for 2 h. The solvent was evaporated under reduced
pressure and the residue was taken up with anhyd CH2Cl2 (15 mL).
A soln of the appropriate amine (2.2 mmol) and Et3N (8 mmol) in
anhyd CH2Cl2 (5 mL) was added dropwise. The mixture was stirred
for 18 h, then washed with 5% HCl (10 mL). The organic layer was
dried (Na2SO4) and evaporated under reduced pressure. The residue
was chromatographed on a silica gel column (eluent indicated be-
low) to give the amide 3.
N-(2-Iodophenyl)-2-(1-methyl-1H-indol-3-yl)acetamide (3a)
Method A; stirring for 4 h; eluent: CH2Cl2–MeOH, 20:1; yield:
74%; mp 113–114 °C (cream powder from Et2O–hexane).
IR (Nujol): 1680, 3350 cm–1.
1H NMR (CDCl3): d = 3.85 (s, 3 H), 3.95 (s, 2 H), 6.76 (t, J = 7.5
Hz, 1 H), 7.16–7.23 (m, 2 H), 7.30–7.40 (m, 3 H), 7.61–7.67 (m, 2
H), 7.85 (br s, 1 H, absent after deuteration), 8.32 (d, J = 8.0 Hz, 1
H).
In conclusion, we have developed an efficient synthesis of
unusual indolo-fused nitrogenated heterocycles of various
sizes via palladium-catalyzed intramolecular cyclization
of readily accessible amides 4.
O
(CH2)m
(CH2)m
COOH
W
(CH2)n
X
NH2
i
+
HN
X
(CH2)n
N
N
Y
Z
Me
Me
n = 0, 1
W
1 : m = 1
2 : m = 2
Z
3
Y
O
(CH2)m
O
(CH2)m
Me
N
ii
iii
N
(CH2)n
N
Me
(CH2)n
N
Me
X
Me
Z
Y
W
W
Z
Y
4
5
Scheme 1 Reagents and conditions: (i) When n = 0: PhOP(O)Cl2, DMF, py, CH2Cl2, r.t.; When n = 1, 2: (COCl)2, THF, r.t.; (ii) NaH, MeI,
THF, r.t.; (iii) Pd(OAc)2 (5 mol%), Ph3P (10 mol%), AcOK, TBACl, DMA, 110 °C.
Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York

2406
E. M. Beccalli et al.
PAPER
Table 1 Compounds 4 and 5 Obtained from Indole-3-acetic Acid 1
Entry
Amine
Amide 4
Cyclization time (h) Product 5
Yielda of 5 (%)
a
I
O
30
85
O
N
Me
I
N
Me
Me
NH2
N
N
Me
Me
b
c
5
76
O
O
Cl
I
N
Me
I
N
NH2
N
N
Me
Me
Cl
Cl
35 (2)b
55 (70)c
Me
Br
O
O
N
Me
N
Me
Br
NH2
N
N
Me
Me
Me
Me
d
e
17
17
99
99
O
O
N
Br
N
Me
N
Me
Me
NH2
Br
N
N
Me
Me
N
N
Me
Br
O
O
N
Me
N
N
NH2
Br
N
N
N
N
Me
Me
Me
Me
O
f
48 (1)b
30 (45)c
O
Br
Br
Me
Me
Me
NH2
N
N
N
N
Me
Me
Br
g
72 (2)b
20 (51)c
O
O
Me
N
N
NH2
N
N
Me
Me
Br
a Starting from 4.
b MW irradiation time.
c In brackets the yield obtained using MW irradiation.
13C NMR (CDCl3): d = 33.3 (q), 34.9 (t), 89.5 (s), 107.2 (s), 109.9
(d), 119.5 (d), 120.3 (d), 121.6 (d), 122.9 (d), 126.1 (d), 128.1 (s),
129.2 (d), 129.5 (d), 137.9 (s), 138.6 (s), 139.2 (d), 170.5 (s).
N-(4-Chloro-2-iodophenyl)-2-(1-methyl-1H-indol-3-yl)acet-
amide (3b)
Method A; stirring for 4 h; eluent: from CH2Cl2 to CH2Cl2–Et2O,
10:1; yield: 72%; mp 162–163 °C (white crystals from Et2O–hex-
ane).
IR (Nujol): 1670, 3278 cm–1.
Anal. Calcd for C17H15IN2O: C, 52.33; H, 3.87; N, 7.18. Found: C,
52.05; H, 4.08; N, 7.01.
Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York

PAPER
Palladium-Promoted Synthesis of Indole Systems Containing Ring-Fused Heterocycles
2407
Table 2 Compounds 4 and 5 Obtained from Indole-3-propionic Acid 2
Entry
Amine
Amide 4
Cyclization time (h) Product 5
Yielda of 5 (%)b
h
24
99
I
O
O
N
N
N
N
Me
Me
I
N
NH2
N
Me
Me
i
24
99
Cl
I
O
O
Me
Me
I
NH2
N
N
Me
Me
Cl
Cl
j
48
78
N
Br
O
O
N
N
Me
Me
NH2
N
N
Br
Me
Me
N
N
k
72 (2)b
26 (55)c
Br
O
O
NH2
N
Me
Me
N
N
N
Me
Me
Br
a Starting from 4.
b MW irradiation time.
c In brackets the yield obtained using MW irradiation.
1H NMR (CDCl3): d = 3.85 (s, 3 H), 3.94 (s, 2 H), 7.16 (s, 1 H), 7.19
(m, 1 H), 7.26–7.34 (m, 2 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.59 (s, 1
H), 7.63 (d, J = 7.9 Hz, 1 H), 7.83 (br s, 1 H, absent after deutera-
tion), 8.27 (d, J = 8.9 Hz, 1 H).
N-(2-Bromopyridin-3-yl)-2-(1-methyl-1H-indol-3-yl)acetamide
(3d)
Method A; stirring for 24 h; eluent: from CH2Cl2 to CH2Cl2–Et2O,
10:1; yield: 78%; mp 115–116 °C (white powder from i-Pr2O).
13C NMR (CDCl3): d = 33.3 (q), 34.9 (t), 89.1 (s), 107.0 (s), 110.0
(d), 119.5 (d), 120.4 (d), 121.8 (d), 123.0 (d), 128.0 (s), 129.3 (d),
129.5 (d), 129.8 (s), 137.5 (s), 137.9 (s), 138.2 (d), 170.5 (s).
IR (Nujol): 1670, 3325 cm–1.
1H NMR (CDCl3): d = 3.86 (s, 3 H), 3.96 (s, 2 H), 7.16 (s, 1 H), 7.20
(dd, J = 8.2, 7.3 Hz, 1 H), 7.23 (dd, J = 4.4, 8.1 Hz, 1 H,), 7.31 (dd,
J = 7.3, 7.9 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.62 (d, J = 7.9 Hz,
1 H), 8.02 (dd, J = 1.7, 4.4 Hz, 1 H), 8.09 (br s, 1 H, absent after
deuteration), 8.71 (dd, J = 1.7, 8.1 Hz, 1 H).
Anal. Calcd for C17H14ClIN2O: C, 48.08; H, 3.32; N, 6.60. Found:
C, 47.91; H, 3.57; N, 6.39.
N-(2-Bromo-4-methylphenyl)-2-(1-methyl-1H-indol-3-yl)acet-
amide (3c)
Method A; stirring for 24 h; eluent: from CH2Cl2 to CH2Cl2–Et2O,
10:1; yield: 68%; mp 101–102 °C (white powder from i-Pr2O).
13C NMR (CDCl3): d = 33.3 (q), 35.0 (t), 106.7 (s), 110.1 (d), 119.2
(d), 120.4 (d), 123.0 (d), 123.8 (d), 127.7 (s), 128.6 (d), 129.0 (d),
133.3 (s), 133.9 (s), 137.8 (s), 144.7 (d), 170.9 (s).
Anal. Calcd for C16H14BrN3O: C, 55.83; H, 4.10; N, 12.21. Found:
C, 55.81; H, 3.88; N, 12.43.
IR (Nujol): 1680, 3350 cm–1.
1H NMR (CDCl3): d = 2.26 (s, 3 H), 3.84 (s, 3 H), 3.93 (s, 2 H), 7.09
(d, J = 8.4 Hz, 1 H), 7.14 (s, 1 H), 7.19 (dd, J = 7.2, 7.9 Hz, 1 H),
7.22 (s, 1 H), 7.31 (dd, J = 7.2, 8.2 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1
H), 7.65 (d, J = 7.9 Hz, 1 H), 7.94 (br s, 1 H, absent after deutera-
tion), 8.23 (d, J = 8.4 Hz, 1 H).
N-(3-Bromo-5-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-
yl)acetamide (3e)
Method A; stirring for 4 h; eluent: CH2Cl2–MeOH, 20:1; yield:
71%; mp 159–160 °C (yellow crystals from CH2Cl2–hexane).
13C NMR (CDCl3): d = 20.9 (q), 33.3 (q), 34.9 (t), 107.3 (s), 109.9
(d), 113.6 (s), 119.4 (d), 120.2 (d), 121.8 (d), 122.8 (d), 127.9 (s),
129.0 (d), 129.2 (d), 132.8 (d), 133.5 (s), 135.4 (s), 137.7 (s), 170.2
(s).
IR (Nujol): 1660, 3275 cm–1.
1H NMR (CDCl3): d = 2.25 (s, 3 H), 3.80 (s, 3 H), 3.98 (s, 2 H), 7.09
(s, 1 H), 7.17 (dd, J = 7.3, 8.2 Hz, 1 H), 7.28 (dd, J = 7.3, 7.9 Hz, 1
H), 7.34 (d, J = 8.2 Hz, 1 H), 7.60 (s, 1 H), 7.68 (d, J = 7.9 Hz, 1 H),
8.10 (br s, 1 H, absent after deuteration), 8.15 (s, 1 H).
13C NMR (CDCl3): d = 17.8 (q), 33.2 (q), 34.6 (t), 107.2 (s), 109.9
(d), 112.7 (s), 119.5 (d), 120.1 (d), 122.7 (d), 128.0 (s), 129.1 (d),
131.9 (s), 137.7 (s), 142.0 (d), 146.5 (s), 147.8 (d), 170.1 (s).
Anal. Calcd for C18H17BrN2O: C, 60.52; H, 4.80; N, 7.84. Found: C,
60.75; H, 4.63; N, 7.99.
Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York

2408
E. M. Beccalli et al.
PAPER
Anal. Calcd for C17H16BrN3O: C, 57.00; H, 4.50; N, 11.73. Found:
C, 56.72; H, 4.73; N, 11.49.
7.22–7.35 (m, 4 H, after deuteration m, 3 H), 7.65 (d, J = 7.8 Hz, 1
H), 7.70 (d, J = 2.3 Hz, 1 H), 8.18 (d, J = 8.6 Hz, 1 H).
13C NMR (CDCl3): d = 21.6 (t), 33.1 (q), 39.1 (t), 89.7 (s), 109.8 (d),
113.1 (s), 119.1 (d), 119.4 (d), 122.2 (d), 122.7 (d), 127.1 (d), 127.8
(s), 129.6 (d), 130.1 (s), 137.4 (s), 137.7 (s), 138.2 (d), 171.5 (s).
N-(2-Bromobenzyl)-2-(1-methyl-1H-indol-3-yl)acetamide (3f)
Method B; eluent: CH2Cl2–Et2O, 5:1; yield: 85%; mp 128–129 °C
(cream powder from CH2Cl2–hexane).
IR (Nujol): 1640, 3250 cm–1.
1H NMR (CDCl3): d = 3.78 (s, 3 H), 3.80 (s, 2 H), 4.44 (d, J = 6.1
Hz, 2 H), 6.25 (br s, 1 H, absent after deuteration), 7.02 (s, 1 H), 7.10
(dd, J = 7.3, 8.2 Hz, 1 H), 7.14 (dd, J = 7.3, 7.9 Hz, 1 H), 7.19–7.32
(m, 2 H), 7.28 (dd, J = 7.4, 7.9 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H),
7.48 (d, J = 7.9 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H).
13C NMR (CDCl3): d = 33.2 (q), 33.7 (t), 44.1 (t), 107.7 (s), 109.9
(d), 119.3 (d), 120.0 (d), 122.6 (d), 123.8 (s), 127.9 (d), 128.7 (d),
129.3 (d), 130.1 (d), 131.9 (s), 133.1 (d), 137.6 (s), 145.7 (s), 172.0
(s).
Anal. Calcd for C18H16ClIN2O: C, 49.28; H, 3.68; N, 6.39. Found:
C, 49.02; H, 3.91; N, 6.26.
N-(2-Bromopyridin-3-yl)-3-(1-methyl-1H-indol-3-yl)propion-
amide (3j)
Method A; eluent: CH2Cl2–Et2O, 5:1; light yellow oil; yield: 39%.
IR (Nujol): 1645, 3300 cm–1.
1H NMR (CDCl3): d = 1.86 (t, J = 7.1 Hz, 2 H), 3.22 (t, J = 7.1 Hz,
2 H), 3.73 (s, 3 H), 6.92 (s, 1 H), 7.10–7.30 (m, 4 H), 7.53 (br s, 1
H, absent after deuteration), 7.62 (d, J = 7.6 Hz, 1 H), 8.04 (dd,
J = 1.8, 4.8 Hz, 1 H), 8.66 (dd, J = 1.8, 8.4 Hz, 1 H).
Anal. Calcd for C18H17BrN2O: C, 60.52; H, 4.80; N, 7.84. Found: C,
60.70; H, 4.72; N, 7.89.
13C NMR (CDCl3): d = 21.5 (t), 33.1 (q), 39.2 (t), 109.8 (d), 112.9
(s), 119.1 (d), 119.4 (d), 122.3 (d), 123.9 (d), 127.1 (d), 127.7 (s),
129.2 (d), 133.2 (s), 133.9 (s), 137.7 (s), 144.7 (d), 171.9 (s).
N-[2-(2-Bromophenyl)ethyl]-2-(1-methyl-1H-indol-3-yl)acet-
amide (3g)
Method B; eluent: CH2Cl2–Et2O, 5:1; yield: 59%; mp 100–101 °C
Anal. Calcd for C17H16BrN3O: C, 57.00; H, 4.50; N, 11.73. Found:
C, 57.19; H, 5.33; N, 11.98.
(cream powder from Et2O–hexane).
IR (Nujol): 1640, 3300 cm–1.
N-(2-Bromobenzyl)-3-(1-methyl-1H-indol-3-yl)propionamide
(3k)
Method B; eluent: CH2Cl2–MeOH, 20:1; yield: 51%; mp 121–
122 °C (yellow crystals from CH2Cl2–hexane).
IR (Nujol): 1640, 3300 cm–1.
1H NMR (CDCl3): d = 2.62 (t, J = 7.2 Hz, 2 H), 3.13 (t, J = 7.2 Hz,
2 H), 3.70 (s, 3 H), 4.45 (d, J = 6.0 Hz, 2 H), 5.90 (br s, 1 H, absent
after deuteration), 6.81 (s, 1 H), 7.09–7.32 (m, 6 H), 7.51 (d, J = 7.9
Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H).
13C NMR (CDCl3): d = 21.6 (t), 33.0 (q), 37.9 (t), 44.1 (t), 109.7 (d),
113.7 (s), 119.2 (d), 119.3 (d), 122.0 (d), 124.0 (s), 127.0 (d), 127.9
(s), 128.0 (d), 129.4 (d), 130.6 (d), 133.1 (d), 137.5 (s), 137.7 (s),
173.0 (s).
1H NMR (CDCl3): d = 2.86 (t, J = 6.8 Hz, 2 H), 3.47 (q, J = 6.8 Hz,
2 H), 3.71 (s, 2 H), 3.78 (s, 3 H), 5.76 (br s, 1 H, absent after deu-
teration), 6.90 (dd, J = 2.5, 6.7 Hz, 1 H), 7.00 (s, 1 H), 7.01–7.05
(m, 2 H), 7.15 (dd, J = 7.3, 8.2 Hz, 1 H), 7.28 (dd, J = 7.3, 7.9 Hz,
1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7.45 (dd, J = 1.8, 7.4 Hz, 1 H), 7.51
(d, J = 7.9 Hz, 1 H).
13C NMR (CDCl3): d = 33.1 (q), 33.7 (t), 36.0 (t), 39.5 (t), 107.8 (s),
109.8 (d), 119.2 (d), 120.0 (d), 122.6 (d), 124.8 (s), 127.8 (d), 127.9
(s), 128.5 (d), 128.7 (d), 131.3 (d), 133.2 (d), 137.6 (s), 138.6 (s),
172.0 (s).
Anal. Calcd for C19H19BrN2O: C, 61.47; H, 5.16; N, 7.55. Found: C,
61.59; H, 5.01; N, 7.83.
Anal. Calcd for C19H19BrN2O: C, 61.47; H, 5.16; N, 7.55. Found: C,
61.52; H, 4.91; N, 7.34.
N-(2-Iodophenyl)-3-(1-methyl-1H-indol-3-yl)propionamide
(3h)
Amides 4; General Procedure
Method A; stirring for 4 h; eluent: from CH2Cl2 to CH2Cl2–Et2O,
10:1; yield: 65%; mp 124–125 °C (cream needles from CH2Cl2–
hexane).
IR (Nujol): 1640, 3250 cm–1.
1H NMR (CDCl3): d = 2.86 (t, J = 7.3 Hz, 2 H), 3.26 (t, J = 7.3 Hz,
2 H), 3.75 (s, 3 H), 6.84 (ddd, J = 1.2, 7.4, 8.0 Hz, 1 H), 6.95 (s, 1
H), 7.16 (dd, J = 7.1, 7.8 Hz, 1 H), 7.26 (dd, J = 6.9, 7.4 Hz, 1 H),
7.32 (d, J = 8.1 Hz, 1 H), 7.35 (m, 2 H, after deuteration dd, J = 7.1,
8.1 Hz, 1 H,), 7.66 (d, J = 7.8 Hz, 1 H), 7.74 (dd, J = 1.0, 8.0 Hz, 1
H), 8.25 (dd, J = 1.2, 6.9 Hz, 1 H).
To a soln of the amide 3 (1 mmol) in anhyd THF (10 mL), 60% NaH
(60 mg, 1.5 mmol) was added portionwise under N2 at 0 °C. After
stirring for 15 min at r.t., MeI (0.5 mL, 8 mmol) was added. The
mixture was stirred at 50 °C for 18 h (Tables 1 and 2, entries a, e,
and g) or at r.t. (other entries), then the mixture was concentrated.
The residue was diluted with 1 M HCl and extracted with CH2Cl2
(2 × 20 mL). The organic layer was dried (Na2SO4), the solvent
evaporated and the residue purified by chromatography (CH2Cl2–
Et2O, 5:1) or crystallization (entry h).
N-(2-Iodophenyl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acet-
amide (4a)
Pale yellow oil; yield: 76%.
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 3.20 (s, 3 H), 3.49 (d, J = 3.0 Hz, 2 H), 3.71
(s, 3 H), 6.85 (s, 1 H), 7.04 (m, 2 H), 7.10–7.38 (m, 5 H), 7.95 (dd,
J = 1.4, 7.6 Hz, 1 H).
13C NMR (CDCl3): d = 31.5 (t), 32.9 (q), 36.5 (q), 100.1 (s), 107.7
(s), 109.3 (d), 119.1 (d), 193.3 (d), 121.7 (d), 128.1 (s), 128.2 (d),
129.6 (d), 130.0 (d), 130.1 (d), 137.0 (s), 140.4 (d), 146.5 (s), 171.4
(s).
13C NMR (CDCl3): d = 21.6 (t), 30.0 (q), 39.1 (t), 90.2 (s), 109.7 (d),
113.3 (s), 119.1 (d), 119.3 (d), 122.1 (d), 122.4 (d), 126.2 (d), 127.1
(d), 127.9 (s), 129.5 (d), 137.6 (s), 138.6 (s), 139.1 (d), 171.4 (s).
Anal. Calcd for C18H17IN2O: C, 53.48; H, 4.24; N, 6.93. Found: C,
53.37; H, 4.17; N, 6.98.
N-(4-Chloro-2-iodophenyl)-3-(1-methyl-1H-indol-3-yl)propi-
onamide (3i)
Method A; stirring for 4 h; eluent: CH2Cl2–MeOH 20:1. Yield: 48%;
mp 151–152 °C (white powder from CH2Cl2–hexane).
IR (Nujol): 1650, 3250 cm–1.
1H NMR (CDCl3): d = 2.85 (t, J = 7.2 Hz, 2 H), 3.24 (t, J = 7.2 Hz,
2 H), 3.75 (s, 3 H), 6.94 (s, 1 H), 7.15 (dd, J = 7.3, 7.8 Hz, 1 H),
Anal. Calcd for C18H17IN2O: C, 53.48; H, 4.24; N, 6.93. Found: C,
53.66; H, 3.95; N, 7.19.
Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York

PAPER
Palladium-Promoted Synthesis of Indole Systems Containing Ring-Fused Heterocycles
2409
N-(4-Chloro-2-iodophenyl)-N-methyl-2-(1-methyl-1H-indol-3-
yl)acetamide (4b)
Yield: 72%; mp 77–80 °C (yellow crystals from Et2O–hexane).
N-(2-Bromobenzyl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acet-
amide (4f)
Yellow oil; yield: 64%.
IR (Nujol): 1650 cm–1.
IR (Nujol): 1644 cm–1.
1H NMR (CDCl3): d = 3.19 (s, 3 H), 3.48 and 3.55 (system AB,
J = 15.7 Hz, 2 H), 3.74 (s, 3 H), 6.85 (s, 1 H), 7.03 (d, J = 8.2 Hz, 1
H), 7.06 (dd, J = 6.0, 7.5 Hz, 1 H), 7.20 (dd, J = 7.5, 7.8 Hz, 1 H),
7.24–7.35 (m, 3 H), 7.93 (d, J = 2.2 Hz, 1 H).
13C NMR (CDCl3): d = 31.9 (t), 33.1 (q), 36.7 (q), 100.5 (s), 107.6
(s), 109.5 (d), 119.3 (d), 119.5 (d), 121.9 (d), 128.2 (d), 130.3 (d),
130.4 (d), 134.9 (s), 137.1 (s), 137.5 (s), 139.8 (d), 145.4 (s), 171.4
(s).
1H NMR (CDCl3, mixture 1:1 of rotamers): d = 3.06 (s, 6 H), 3.67
(s, 3 H), 3.72 (s, 5 H), 3.92 (s, 2 H), 4.60 (s, 2 H), 4.74 (s, 2 H), 6.91–
7.79 (m, 18 H); (400 MHz, DMSO-d6, mixture 5:3 of rotamers):
major rotamer d = 3.05 (s, 3 H), 3.77 (s, 3 H), 3.89 (s, 2 H), 4.53 (s,
2 H), 6.91–7.79 (m, 9 H); minor rotamer d = 2.86 (s, 3 H), 3.67 (s,
3 H), 3.71 (s, 2 H), 4.67 (s, 2 H), 6.91–7.79 (m, 9 H); (400 MHz,
DMSO-d6, 110 °C): d = 2.95 (s, 6 H), 3.74 (s, 2 H), 3.84 (s, 1 H),
4.65 (s, 1 H), 6.80–7.70 (m, 9 H).
13C NMR (CDCl3, mixture 1:1 of rotamers): d = 31.4 (t), 32.9 (q),
33.0 (q), 34.9 (q), 36.1 (q), 51.2 (t), 54.6 (t), 107.5 (s), 107.6 (s),
109.3 (d), 109.5 (d), 119.1 (d), 119.3 (d), 119.4 (d), 121.9 (d), 122.0
(d), 122.6 (s), 123.8 (s), 127.0 (d), 127.7 (d), 127.9 (d), 128.9 (d),
129.0 (d), 129.2 (d), 133.0 (d), 133.1 (d), 135.9 (s), 136.5 (s), 137.1
(s), 137.2 (s), 140.5 (s), 172.3 (s), 172.7 (s).
Anal. Calcd for C18H16ClIN2O: C, 49.28; H, 3.68; N, 6.39. Found:
C, 49.21; H, 3.91; N, 6.28.
N-(2-Bromo-4-methylphenyl)-N-methyl-2-(1-methyl-1H-indol-
3-yl)acetamide (4c)
Light yellow oil; yield: 78%.
Anal. Calcd for C19H19BrN2O: C, 61.47; H, 5.16; N, 7.55. Found: C,
61.39; H, 4.86; N, 7.32.
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 2.41 (s, 3 H), 3.22 (s, 3 H), 3.52 (s, 2 H), 3.74
(s, 3 H), 6.91 (s, 1 H), 7.02–7.15 (m, 3 H), 7.19 (dd, J = 7.2, 7.9 Hz,
1 H), 7.26 (d, J = 8.7 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 1 H), 7.53 (s, 1
H).
N-[2-(2-Bromophenyl)ethyl]-N-methyl-2-(1-methyl-1H-indol-
3-yl)acetamide (4g)
Yellow oil; yield: 68%.
13C NMR (CDCl3): d = 21.2 (q), 31.1 (t), 33.1 (q), 36.6 (q), 108.0
(s), 109.4 (d), 113.4 (s), 119.1 (d), 119.3 (d), 121.8 (d), 123.5 (s),
128.3 (d), 129.6 (d), 129.9 (d), 134.6 (d), 135.0 (s), 137.1 (s), 140.6
(s), 171.9 (s).
IR (Nujol): 1640 cm–1.
1H NMR (CDCl3, mixture 1:1 of rotamers): d = 2.92 (t, J = 7.6 Hz,
2 H), 2.96 (s, 3 H) 3.02 (t, J = 7.6 Hz, 2 H), 3.04 (s, 3 H), 3.58 (t,
J = 7.6 Hz, 2 H), 3.65 (t, J = 7.6 Hz, 2 H), 3.69 (s, 2 H), 3.75 (s, 3
H), 3.78 (s, 3 H), 3.84 (s, 2 H), 6.94 (d, J = 7.9 Hz, 2 H), 6.99 (s, 2
H), 7.02–7.58 (m, 11 H), 7.55 (m, 1 H) 7.60 (d, J = 7.9 Hz, 1 H),
7.65 (d, J = 7.9 Hz, 1 H).
13C NMR (CDCl3, mixture 1:1 of rotamers): d = 31.0 (t), 31.7 (t),
31.1 (q), 34.1 (q), 34.3 (t), 35.6 (t), 37.1 (q), 48.8 (t), 50.5 (t), 107.9
(s), 108.3 (s), 109.6 (d), 119.2 (d), 119.3 (d), 119.4 (d), 119.5 (d),
122.1 (d), 124.7 (s), 124.8 (s), 124.7 (s) 124.8 (s) 126.6 (d), 126.7
(d), 128.0 (d), 128.2 (d), 128.5 (d), 129.0 (d), 131.6 (d), 131.7 (d),
133.1 (d), 133.4 (d), 137.3 (s), 137.9 (s), 138.9 (s), 171.2 (s), 172.1
(s).
Anal. Calcd for C19H19BrN2O: C, 61.47; H, 5.16; N, 7.55. Found: C,
61.44; H, 5.04; N, 7.81.
N-(2-Bromopyridin-3-yl)-N-methyl-2-(1-methyl-1H-indol-3-
yl)acetamide (4d)
Light yellow oil; yield: 85%.
IR (Nujol): 1650 cm–1.
1H NMR (CDCl3): d = 3.24 (s, 3 H), 3.51 and 3.60 (AB system,
J = 15.7 Hz, 2 H), 3.72 (s, 3 H), 6.78 (s, 1 H), 7.05 (dd, J = 7.3, 7.9
Hz, 1 H), 7.16–7.23 (m, 2 H), 7.26 (d, J = 8.2 Hz, 1 H), 7.30 (d,
J = 7.9 Hz, 1 H), 7.35 (dd, J = 1.8, 7.7 Hz, 1 H), 8.35 (dd, J = 1.8,
4.7 Hz, 1 H).
Anal. Calcd for C20H21BrN2O: C, 62.35; H, 5.49; N, 7.27. Found: C,
62.09; H, 5.72; N, 7.11.
13C NMR (CDCl3): d = 32.0 (t), 33.1 (q), 36.6 (q), 107.4 (s), 109.6
(d), 119.2 (d), 119.5 (d), 122.1 (d), 123.9 (d), 127.9 (s), 128.0 (d),
137.1 (s), 138.6 (d), 140.7 (s), 144.0 (s), 150.0 (d), 171.5 (s).
N-(2-Iodophenyl)-N-methyl-3-(1-methyl-1H-indol-3-yl)propi-
onamide (4h)
Yield: 99%; mp 95 °C (light yellow crystals from Et2O–hexane).
IR (Nujol): 1650 cm–1.
Anal. Calcd for C17H16BrN3O: C, 57.00; H, 4.50; N, 11.73. Found:
C, 56.86; H, 4.29; N, 11.47.
1H NMR (CDCl3): d = 2.36 (m, 2 H), 3.10 (m, 2 H), 3.21 (s, 3 H),
3.71 (s, 3 H), 6.81 (s, 1 H), 6.98–7.07 (m, 3 H), 7.20 (ddd, J = 1.3,
7.2, 7.8 Hz, 1 H), 7.26 (d, J = 8.1 Hz, 1 H), 7.28 (ddd, J = 1.4, 7.6,
8.1 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.90 (dd, J = 1.3; 7.8 Hz, 1
H).
N-(3-Bromo-5-methylpyridin-2-yl)-N-methyl-2-(1-methyl-1H-
indol-3-yl)acetamide (4e)
Yellow oil; yield: 89%.
IR (Nujol): 1660 cm–1.
13C NMR (CDCl3): d = 21.4 (t), 32.9 (q), 35.9 (t), 36.3 (q), 100.1 (s),
109.4 (d), 114.2 (s), 119.0 (d), 119.3 (d), 121.8 (d), 126.8 (d), 128.0
(s), 129.4 (d), 130.0 (d), 130.2 (d), 137.3 (s), 140.5 (d), 146.4 (s),
172.8. (s).
1H NMR (CDCl3): d = 2.35 (s, 3 H), 3.26 (s, 3 H), 3.58 (s, 2 H), 3.72
(s, 3 H), 6.90 (s, 1 H), 7.02 (dd, J = 7.3, 8.2 Hz, 1 H), 7.16 (dd,
J = 7.3, 7.9 Hz, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 7.9 Hz,
1 H), 7.73 (s, 1 H), 8.28 (s, 1 H).
13C NMR (CDCl3): d = 17.9 (q), 31.5 (t), 33.0 (q), 35.1 (q), 107.6
(s), 109.3 (d), 119.0 (d), 119.1 (d), 119.5 (s), 121.7 (d), 128.1 (d),
128.2 (s), 135.5 (s), 137.0 (s), 143.1 (d), 149.1 (d), 152.4 (s), 171.8
(s).
Anal. Calcd for C19H19IN2O: C, 54.56; H, 4.58; N, 6.70. Found: C,
54.50; H, 4.66; N, 6.47.
N-(4-Chloro-2-iodophenyl)-N-methyl-3-(1-methyl-1H-indol-3-
yl)propionamide (4i)
Yellow oil; yield: 89%.
IR (Nujol): 1660 cm–1.
Anal. Calcd for C18H18BrN3O: C, 58.08; H, 4.87; N, 11.29. Found:
C, 57.81; H, 5.10; N, 11.51.
Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York

2410
E. M. Beccalli et al.
PAPER
2-Chloro-5,12-dimethyl-7,12-dihydroindolo[3,2-d][1]benza-
zepin-6(5H)-one (5b)
Yield: 76%; mp 171–172 °C (light yellow crystals from Et2O–hex-
ane).
1H NMR (CDCl3): d = 2.34 (t, J = 7.9 Hz, 2 H), 3.03–3.14 (m, 2 H),
3.16 (s, 3 H), 3.73 (s, 3 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.81 (s, 1 H),
7.06 (dd, J = 7.3, 7.9 Hz, 1 H), 7.16–7.22 (m, 2 H), 7.27 (d, J = 6.9
Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.87 (d, J = 2.1 Hz, 1 H).
13C NMR (CDCl3): d = 21.5 (t), 32.9 (q), 35.9 (t), 36.3 (q), 100.4 (s),
109.5 (d), 114.1 (s), 119.1 (d), 119.2 (d), 121.9 (d), 126.9 (d), 128.0
(s), 129.9 (d), 130.4 (d), 134.9 (s), 137.3 (s), 139.7 (d), 145.2 (s),
172.8 (s).
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 3.07 and 3.99 (AB system, J = 14.1 Hz, 2 H),
3.35 (s, 3 H), 3.92 (s, 3 H), 7.23 (dd, J = 7.2, 7.5 Hz, 1 H), 7.35 (dd,
J = 7.2, 7.9 Hz, 1 H), 7.40–7.44 (m, 3 H), 7.53 (s, 1 H), 7.75 (d,
J = 7.9 Hz, 1 H).
13C NMR (CDCl3): d = 32.2 (q), 32.6 (t), 38.1 (q), 110.2 (d), 113.5
(s), 119.3 (d), 120.6 (d), 123.7 (d), 125.9 (s), 126.0 (d), 126.9 (s),
128.3 (d), 128.4 (d), 130.4 (s), 132.8 (s), 139.8 (s), 140.5 (s), 172.8
(s).
Anal. Calcd for C19H18ClIN2O: C, 50.41; H, 4.01; N, 6.19. Found:
C, 50.66; H, 3.72; N, 6.36.
N-(2-Bromopyridin-3-yl)-N-methyl-3-(1-methyl-1H-indol-3-
yl)propionamide (4j)
Yield: 96%; mp 197–198 °C (cream crystals from Et2O–hexane).
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 2.37 (m, 2 H), 3.09 (m, 2 H), 3.20 (s, 3 H),
3.72 (s, 3 H), 6.81 (s, 1 H), 7.01–7.09 (m, 3 H), 7.21 (ddd, J = 0.8,
7.1, 8.1 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1
H), 8.30 (dd, J = 2.0, 4.6 Hz, 1 H).
Anal. Calcd for C18H15ClN2O: C, 69.57; H, 4.86; N, 9.01. Found: C,
69.74; H, 5.11; N, 8.72.
2,5,12-Trimethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-
6(5H)-one (5c)
Pale yellow oil; yield: 55%; 70% using MW irradiation.
13C NMR (CDCl3): d = 21.5 (t), 32.9 (q), 35.7 (t), 36.2 (q), 109.5
(d), 109.6 (d), 113.8 (s), 119.2 (d), 122.0 (d), 124.1 (d), 126.9 (d),
127.9 (s), 137.3 (s), 138.4 (d), 140.5 (s), 143.9 (s), 149.6 (d), 172.8
(s).
IR (Nujol): 1635 cm–1.
1H NMR (CDCl3): d = 2.49 (s, 3 H), 3.08 and 3.97 (AB system,
J = 14.0 Hz, 2 H), 3.35 (s, 3 H), 3.92 (s, 3 H), 7.22 (dd, J = 7.2, 7.9
Hz, 1 H), 7.27 (d, J = 8.1 Hz, 1 H), 7.32 (dd, J = 7.2, 8.0 Hz, 1 H),
7.35–7.42 (m, 3 H), 7.75 (d, J = 8.1 Hz, 1 H).
13C NMR (CDCl3): d = 21.5 (q), 32.2 (q), 32.7 (t), 38.0 (q), 110.1
(d), 112.6 (s), 119.1 (d), 120.3 (d), 123.1 (d), 124.5 (d), 125.2 (s),
126.1 (s), 129.1 (d), 129.3 (d), 134.2 (s), 134.8 (s), 139.6 (s), 139.8
(s), 173.2 (s).
Anal. Calcd for C18H18BrN3O: C, 58.08; H, 4.87; N, 11.29. Found:
C, 58.02; H, 5.08; N, 11.13.
N-(2-Bromobenzyl)-N-methyl-3-(1-methyl-1H-indol-3-yl)pro-
pionamide (4k)
Brownish oil; yield: 99%.
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3, mixture 1:1 of rotamers): d = 2.65 (t, J = 8.1 Hz,
2 H), 2.80 (t, J = 8.1 Hz, 2 H), 2.89 (s, 3 H), 3.00 (s, 3 H), 3.02–3.20
(m, 4 H), 3.71 (s, 3 H), 3.74 (s, 3 H), 4.46 (s, 2 H), 4.72 (s, 2 H), 6.85
(s, 1 H), 6.92 (s, 1 H), 6.96–7.35 (m, 12 H), 7.44–7.64 (m, 4 H).
Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C,
78.87; H, 6.01; N, 9.40.
5,12-Dimethyl-7,12-dihydropyrido[3¢,2¢:2,3]azepino[4,5-b]in-
dol-6(5H)-one (5d)
Yield: 99%; mp 150–152 °C (red crystals from CH2Cl2–hexane).
13C NMR (CDCl3, mixture 1:1 of rotamers): d = 20.9 (t), 21.2 (t),
32.8 (q), 34.3 (t), 34.5 (q), 34.6 (t), 35.5 (q), 51.1 (t), 54.0 (t), 109.4
(d), 109.5 (d), 114.0 (s), 114.1 (s), 118.9 (d), 119.0 (d), 121.7 (d),
121.8 (d), 122.8 (s) 123.8 (s), 126.7 (d), 126.9 (d), 127.0 (d), 127.8
(d), 128.1 (d), 128.9 (d), 129.0 (d), 129.2 (d), 133.0 (d), 133.3 (d),
135.8 (s), 136.5 (s), 137.2 (s), 137.3 (s), 173.3 (s), 173.8 (s).
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 3.11 and 4.08 (AB system, J = 14.0 Hz, 2 H),
3.36 (s, 3 H), 4.13 (s, 3 H), 7.21 (dd, J = 7.2, 7.7 Hz, 1 H), 7.33–7.38
(m, 2 H), 7.45 (d, J = 8.3 Hz, 1 H), 7.74–7.78 (m, 2 H), 8.61 (d,
J = 4.5 Hz, 1 H).
13C NMR (CDCl3): d = 32.0 (q), 32.7 (t), 37.7 (q), 110.3 (d), 114.6
(s), 119.4 (d), 120.3 (d), 122.0 (d), 124.0 (d), 125.7 (s), 131.8 (d),
132.6 (s), 138.5 (s), 139.9 (s), 144.6 (s), 145.7 (d), 172.4 (s).
Anal. Calcd for C20H21BrN2O: C, 62.35; H, 5.49; N, 7.27. Found: C,
62.08; H, 5.70; N, 7.12.
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.58; H, 5.22; N, 14.99.
Cyclization of the Amides 4; General Procedure
Thermal heating. A soln of 4 (1 mmol), Pd(OAc)2 (12 mg, 0.05
mmol), Ph3P (26 mg, 0.1 mmol), AcOK (196 mg, 2 mmol), and
TBACl (278 mg, 1 mmol) in DMA (5 mL) was stirred at 110 °C for
the time reported in Tables 1 and 2. After cooling to r.t., the mixture
was diluted with brine (15 mL) and extracted with Et2O. The organ-
ic layer was dried (Na2SO4) and evaporated under reduced pressure.
The residue was chromatographed on a silica gel column (light pe-
troleum ether–Et2O, 1:1) to give compound 5.
2,5,12-Trimethyl-7,12-dihydropyrido[2¢,3¢:2,3]azepino[4,5-
b]indol-6(5H)-one (5e)
Yield: 99%; mp 163–164 °C (light yellow crystals from CH2Cl2–
hexane).
IR (Nujol): 1675 cm–1.
1H NMR (CDCl3): d = 2.49 (s, 3 H), 3.12 and 4.04 (AB system,
J = 14.2 Hz, 2 H), 3.46 (s, 3 H), 3.87 (s, 3 H), 7.22 (dd, J = 7.2, 7.8
Hz, 1 H), 7.34 (dd, J = 7.2, 8.1 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H),
7.70 (s, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 8.40 (s, 1 H).
13C NMR (CDCl3): d = 18.4 (q), 32.1 (q), 32.8 (t), 35.6 (q), 110.2
(d), 112.9 (s), 119.3 (d), 119.7 (s), 120.6 (d), 123.6 (d), 125.9 (s),
129.5 (s), 132.2 (s), 137.3 (d), 140.1 (s) 148.3 (d), 151.0 (s), 172.8
(s).
Microwave irradiation. A soln of the amide 4c, 4f, 4g, or 4k (1
mmol), Pd(OAc)2 (12 mg, 0.05 mmol), Ph3P (26 mg, 0.1 mmol),
AcOK (196 mg, 2 mmol), and TBACl (278 mg, 1 mmol) in DMA
(5 mL) was heated in a microwave oven (600 W) at 160 °C for 2 h
for 4c and 4g and at 120 °C for the time reported in Tables 1 and 2
for 4f and 4k. The mixture was elaborated as indicated above.
5,12-Dimethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-
Anal. Calcd for C18H17N3O: C, 74.21; H, 5.88; N, 14.42. Found: C,
74.33; H, 6.10; N, 14.19.
one (5a)
Yield: 85%.1f
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Palladium-Promoted Synthesis of Indole Systems Containing Ring-Fused Heterocycles
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6,13-Dimethyl-5,6,8,13-tetrahydroindolo[3,2-e][2]benzazocin-
7-one (5f)
Brownish oil; yield: 30%; 45% using MW irradiation.
5,13-Dimethyl-5,7,8,13-tetrahydropyrido[3¢,2¢:2,3]azocino[4,5-
b]indol-6-one (5j)
Yield: 78%; mp 199–201 °C (cream powder from Et2O).
IR (Nujol): 1620 cm–1.
IR (Nujol): 1660 cm–1.
1H NMR (CDCl3): d = 2.97–4.65 (m, 4 H), 3.18 (s, 3 H), 3.77 (s, 3
H), 7.15 (m, 1 H), 7.23 (dd, J = 7.1, 7.4 Hz, 1 H), 7.33 (dd, J = 7.1,
7.6 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.47–7.52 (m, 2 H), 7.58 (d,
J = 6.4 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H).
1H NMR (CDCl3): d = 2.47 (m, 1 H), 2.81 (m, 1 H), 3.10 (m, 1 H),
3.21 (s, 3 H), 3.56 (m, 1 H), 3.59 (s, 3 H), 7.16 (m, 1 H), 7.30–7.33
(m, 2 H), 7.42 (m, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.74 (d, J = 8.1
Hz, 1 H), 8.75 (d, J = 4.0 Hz, 1 H).
13C NMR (CDCl3): d = 31.4 (q), 34.8 (t), 39.2 (q), 54.6 (t), 108.5 (s),
110.0 (d), 119.3 (d), 120.4 (d), 122.8 (d), 127.8 (s), 128.6 (d), 129.3
(d), 129.6 (d), 131.3 (d), 131.7 (s), 137.5 (s), 137.6 (s), 138.1 (s),
170.3 (s).
13C NMR (CDCl3): d = 23.2 (t), 31.3 (q), 31.3 (t), 36.6 (q), 109.7
(d), 114.7 (s), 119.5 (d), 119.6 (d), 123.5 (d), 127.6 (s), 128.3 (d),
132.2 (d), 133.7 (s), 138.4 (s), 140.4 (s), 148.4 (d), 149.4 (s), 173.3
(s).
Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C,
78.78; H, 6.56; N, 9.41.
Anal. Calcd for C18H17N3O: C, 74.21; H, 5.88; N, 14.42. Found: C,
74.02; H, 6.11; N, 14.16.
7,14-Dimethyl-6,7,9,14-tetrahydroindolo[3,2-f][3]benzazonin-
8(5H)-one (5g)
Yellow oil; yield: 20%; 51% using MW irradiation.
IR (Nujol): 1630 cm–1.
1H NMR (CDCl3): d = 2.51–2.57 (m, 2 H), 2.86–3.03 (m, 3 H), 3.25
(m, 1 H), 3.41 (m, 1 H), 3.56–3.89 (m, 5 H), 7.13–7.45 (m, 7 H),
8.21 (d, J = 7.6 Hz, 1 H).
13C NMR (CDCl3): d = 30.1 (t), 30.7 (q), 35.2 (t), 36.2 (q), 53.2 (t),
108.0 (s), 109.4 (d), 120.0 (d), 123.0 (d), 123.4 (d), 126.6 (d), 129.4
(d), 130.0 (d), 130.1 (s), 132.3 (d), 136.5 (s), 137.3 (s), 137.9 (s),
142.8 (s), 172.0 (s).
6,14-Dimethyl-6,8,9,14-tetrahydroindolo[3,2-f][2]benzazonin-
7(6H)-one (5k)
Yield: 26%; 55% using MW irradiation; mp 209–210 °C (ochre
powder from Et2O).
IR (Nujol): 1630 cm–1.
1H NMR (CDCl3): d = 2.27 (m, 1 H), 2.60 (m, 1 H), 3.12 (m, 1 H),
3.30 (s, 3 H), 3.39 (m, 1 H), 3.57 (s, 3 H), 4.10 and 4.71 (AB system,
J = 15.1 Hz, 2 H), 7.23 (t, J = 7.2 Hz, 1 H), 7.30–7.40 (m, 3 H),
7.43–7.53 (m, 2 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 7.2 Hz,
1 H).
13C NMR (CDCl3): d = 14.5 (q), 23.1 (t), 31.7 (q), 32.3 (t), 52.4 (t),
109.9 (d), 115.5 (s), 117.0 (s), 119.0 (d), 120.1 (d), 122.7 (d), 127.0
(s), 128.0 (d), 129.2 (d), 130.5 (d), 132.0 (d), 135.6 (s), 137.4 (s),
138.2 (s), 175.0 (s).
Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62; N, 9.20. Found: C,
79.25; H, 6.39; N, 9.02.
5,13-Dimethyl-5,7,8,13-tetrahydroindolo[3,2-e][1]benzazocin-
6-one (5h)
Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62; N, 9.20. Found: C,
78.80; H, 6.85; N, 9.13.
Yield: 99%; mp 188–189 °C (red crystals from CH2Cl2–hexane).
IR (Nujol): 1650 cm–1.
Acknowledgment
1H NMR (CDCl3): d = 2.45 (m, 1 H), 2.91 (m, 1 H), 3.10 (m, 1 H),
3.23 (s, 3 H), 3.52 (m, 1 H), 3.53 (s, 3 H), 7.19 (ddd, J = 1.4, 6.7,
7.9 Hz, 1 H), 7.29–7.34 (m, 2 H), 7.36–7.53 (m, 4 H), 7.61 (d,
J = 7.9 Hz, 1 H).
The authors gratefully acknowledge the MIUR (Cofin 2003) for fi-
nancial support.
13C NMR (CDCl3): d = 22.9 (t), 31.2 (q), 31.6 (t), 36.6 (q), 109.7
(d), 113.6 (s), 119.3 (d), 119.8 (d), 123.0 (d), 126.8 (d), 127.4 (d),
128.2 (s), 129.7 (d), 130.4 (s), 132.6 (s), 132.9 (d), 138.2 (s), 143.8
(s), 173.8 (s).
References
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Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C,
78.61; H, 6.07; N, 9.82.
2-Chloro-5,13-dimethyl-5,7,8,13-tetrahydroindolo[3,2-
e][1]benzazocin-6-one (5i)
Yield: 99%; mp 198–199 °C (ochre powder from Et2O–hexane).
IR (Nujol): 1660 cm–1.
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1H NMR (CDCl3): d = 2.45 (m, 1 H), 2.92 (m, 1 H), 3.07 (m, 1 H),
3.19 (s, 3 H), 3.50 (m, 1 H), 3.54 (s, 3 H), 7.19 (t, J = 6.3 Hz, 1 H),
7.28–7.37 (m, 4 H), 7.47 (d, J = 8.3 Hz, 1 H), 7.59 (d, J = 7.7 Hz,
1 H).
13C NMR (CDCl3): d = 22.9 (t), 31.4 (q), 31.5 (t), 36.7 (q), 109.8
(d), 114.4 (s), 119.5 (d), 120.1 (d), 123.5 (d), 127.0 (s), 128.1 (d),
129.8 (d), 131.2 (s), 132.2 (s), 132.6 (d), 133.0 (s), 138.5 (s), 142.4
(s), 173.7 (s).
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70.33; H, 5.54; N, 8.39.
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Synthesis 2006, No. 14, 2404–2412 © Thieme Stuttgart · New York