Synthesis of iodo-indoloazepinones in an iodine-mediated three-component domino reaction via a regioselective 7-endo-dig iodo-cyclization pathway ±

Article abstract of DOI:10.1021/jo201228t

An efficient and rapid synthetic strategy for the naturally occurring indoloazepinone scaffold via a three-component reaction of indole-2- carboxamides, 1,3-disubstituted propargyl alcohols, and I₂ is described. The strategy involves a C-H functionalization-alkyne activation-intramolecular hydroamidation-deprotonation domino sequence. The salient feature of this sequence is regioselective electrophilic 7-endo-dig iodo-cyclization during the intramolecular hydroamidation to afford a seven-membered azepinone ring annulated to the indole.

Full text of DOI:10.1021/jo201228t

ARTICLE
pubs.acs.org/joc
Synthesis of Iodo-Indoloazepinones in an Iodine-Mediated
Three-Component Domino Reaction via a Regioselective 7-endo-dig
Iodo-Cyclization Pathway(
Sudhir K. Sharma,† Anil K. Mandadapu,† Brijesh Kumar,‡ and Bijoy Kundu*,†
†Medicinal & Process Chemistry Division and ‡Sophisticated Analytical and Instrument Facility, Central Drug Research Institute, CSIR,
Lucknow 226001, India
S Supporting Information
b
ABSTRACT: An efficient and rapid synthetic strategy for the
naturally occurring indoloazepinone scaffold via a three-
component reaction of indole-2-carboxamides, 1,3-disubstituted
propargyl alcohols, and I2 is described. The strategy involves
a CÀH functionalizationÀalkyne activationÀintramolecular
hydroamidationÀdeprotonation domino sequence. The salient feature of this sequence is regioselective electrophilic 7-endo-dig
iodo-cyclization during the intramolecular hydroamidation to afford a seven-membered azepinone ring annulated to the indole.
’ INTRODUCTION
The motivation for our endeavor stemmed from the fact that
internal alkynes tethered to an intramolecular nucleophilic center
tend to undergo electrophilic 5-, 6-, or 7-endo/exo cyclizations14
following Baldwin’s cyclization principles.15 The strategy gen-
erally involves initial activation of the alkyne either in the
presence of iodine-derived electrophilic reagents16 or in the
presence of Brønsted acids/Lewis acids17/metals as a catalyst18,
which is then followed by the attack of a nucleophile on the
electron-deficient carbon of the alkyne to afford polycyclic
structures. Indeed, most of these reactions have been carried
out in multistep format and their application to a multicompo-
nent format remains limited to electrophilic 5-/6-endo-dig path-
ways.19 To the best of our knowledge, there is no report available
on the application of electrophilic 7-endo-dig format20 to multi-
component domino reactions.
In recent years, multicomponent domino reactions (MCRs)1
involving condensation of three or more reactants to furnish
polyheterocyclic frameworks have received increasing atten-
tion, due to their high importance in drug discovery.2 Unlike
traditional multistep processes, these reactions allow formation
of several bonds via a cascade of irreversible chemical reactions
in a single step without the isolation of intermediate(s). The
attractive features of these reactions are simplicity, efficiency,
atom economy, shortened reaction times, and diversity-
oriented synthesis in one pot.3 Although the strategy has been
successfully applied to the synthesis of five-, six-, and seven-
membered heterocycles,4 the design of new multicomponent
domino reactions continues to remain a challenge for organic
chemists. As part of our continuing effort on the development
of new routes for the synthesis of indole-based natural
products5 as well as polyheterocycles, via multicomponent6/
multistep reaction formats,7 we embarked on a search for a
three-component domino reaction involving indole-2-carbox-
amides and 1,3-disubstituted propargyl alcohols as two of the
reactants for the generation of indole-annulated azepine rings.
In recent years, although multicomponent domino reactions for
the synthesis of polyheterocycles using alkynes as one of the
participating components8 have received much attention, the
use of 1,3-disubstituted propargyl alcohols, despite their versa-
tility as building blocks,9 has remained underexplored.6b Simi-
larly, in case of the second reactant, although the synthesis
of indoles10 and C-3-functionalized indoles11 has been exten-
sively carried out in multicomponent format, reports on the
use of functionalized indoles for the synthesis of polyhetero-
cycles in multicomponent format are scarce,12,6 despite being a
privileged13 pharmaceutical template.
’ RESULTS AND DISCUSSION
In our endeavor to develop a three-component strategy in-
volving an electrophilic 7-endo-dig cyclization pathway, we en-
visaged that treating bifunctional indole-2-carboxamide (with
C-3 and amidic N as nucleophilic options) with the three-carbon
1,3-disubstituted propargyl alcohol derivatives in the presence of
an electrophilic reagent as a third component may lead to a seven-
membered ring annulated to the indole via a CÀH functionali-
zationÀalkyne activationÀintramolecular hydroamidation21À
deprotonation domino sequence. To effect this one-pot domino
sequence, we proposed the use of molecular iodine instead of
metal catalyst, as the former may not only serve as an electrophile
but also act as the third component in the multicomponent
format. Such iodo-cyclizations leave an iodine atom attached to
Received: June 15, 2011
Published: July 06, 2011
( CDRI Communication No. 8094
r
2011 American Chemical Society
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the product that is amenable to further manipulation using
palladium-catalyzed coupling reactions (Scheme 1).
58% isolated yield. The structure of the product was elucidated
by the combined use of various homo- and heteronuclear two-
dimensional NMR experiments coupled with the presence of a
CO band in the FTIR at 1673 cmÀ1 that led to the identification
of the 4-iodoindoloazepinone 3a as the product arising from
intramolecular hydroamidation via 7-endo-dig iodo-cyclization
pathway. As envisaged, the halo reactant not only acted as an
electrophile but also became part of the cyclized product.
Recently, the synthesis of 3-benzazepinones, analogous to 3a,
has been reported24 in multistep format via Au/Ag cocatalyzed
intramolecular hydroamidation of 2-(1-alkynyl)phenylacet-
amide; however, the strategy involved harsh reaction conditions
such as high temperature and long reaction times. Figure 1
depicts a few selected HMBC and NOESY correlations required
for the confirmation of structure 3a.
Mechanistically, formation of 3a via a three-component domino
process may have occurred initially via iodine-catalyzed nucleo-
philic substitution6b,25 of 1-(3,4-dimethoxyphenyl)-3-phenylprop-
2-yn-1-ol at the alcoholic carbon by the nucleophilic C-3 of the
indole to afford the C-3 functionalized intermediate 4 (Figure 2).
The alkyne in 4 then forms an iodonium complex by co-
ordinating with I+, thereby enhancing the electrophilicity of the
alkyne to generate intermediate 5. The activated (electron-
deficient) triple bond then undergoes nucleophilic attack by
the amidic nitrogen (intramolecular hydroamidation) to form
the protonated intermediate 6 via electrophilic 7-endo-dig iodo-
cyclization. This is then followed by deprotonation of the amidic
proton in the intermediate 6 to afford 3a. Thus, the internal alkyne
in the intermediate 4, instead of undergoing 6-exo-dig cyclization
(E1 carbon; Figure 2), preferred the 7-endo-dig cyclization format
(E2 carbon; Figure 2) to furnish indoloazepinone 3a as a single
regioisomer. Thus, the three-component reaction proceeds
via a CÀH functionalizationÀalkyne activationÀintramolecular
hydroamidationÀdeprotonation domino sequence in one pot.
In addition, it is interesting to note that regioselectivity was
also observed during the intramolecular iodo-cyclization of the
intermediate 4 despite the availability of each of the two electro-
philic (E1 and E2 alkyne carbons) and nucleophilic centers (O
and N). In addition to 3a, the other three possible regioisomers
are structures 7 and 8, expected to arise from 6-exo-dig cyclization
by involving carbon E1 of the alkyne and the amidic O and N as
nucleophiles and in cyclization, respectively, whereas structure 9
is likely to arise from 7-endo cyclization with the involvement of
O as the nucleophile and alkyne carbon E2 as an electrophile
(Figure 3). In contrast, 3a is formed as a result of preferential
nucleophilic attack by the amidic nitrogen at the alkyne carbon
E2 instead of nucleophilic oxygen in the 7-endo-dig format.
Once regioselectivity and a probable mechanism were estab-
lished, we then proceeded to optimize the reaction conditions
with a view to enhance the yield of 3a, and the results have been
In this report, we describe a rapid three-component domino
reaction comprising indole-2-carboxamides/1,3-disubstituted
propargyl alcohols/I2 leading to the synthesis of indoloazepi-
nones, a skeleton present in the natural product hymenialdisine
(HMD) and its annulated derivatives, which exhibit kinase-
inhibiting properties.22 In addition, the synthetically generated
seven-membered azepinone templates are ubiquitously present
in natural products as well as in clinically used drugs associated
with diverse CNS/CVS activities and thus remain target struc-
tures of interest to synthetic chemists.23
In our initial experiments, we treated the mixture of N-(4-
methylbenzyl)-1H-indole-2-carboxamide (1a; 1.0 equiv) and
1-(3,4-dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (2a; 1.0 equiv)
with molecular iodine (5.0 equiv) in acetonitrile at room temper-
ature. The progress of the reaction was monitored by TLC, and
within 30 min we observed the complete disappearance of 1a and
2a followed by the appearance of a fast-moving new spot on
TLC. After workup and purification by column chromatography,
we isolated a new product with a molecular weight of 640.9 Da in
Scheme 1. MCR Involving Indole-2-carboxamide, 1,3-Di-
substituted Propargyl Alcohol, and I2
Figure 1. Some important HMBC and NOESY correlations for the
confirmation of 3a.
Figure 2. Plausible mechanism for the formation of 3a from iodine-mediated three-component domino reaction.
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summarized in Table 1. Carrying out MCR at 0 °C for 30 min had
a negligible effect on the yield (60%, entry 2) in comparison to
the reaction carried out at room temperature (entry 1); however,
increasing the reaction time to 45 min enhanced the yield to 68%
(entry 3). On the basis of the observation of a slow reaction rate
at lower temperatures, initiating reaction at 0 °C and then
proceeding to room temperature marginally enhanced the yield
to 71% (entry 4). Switching the solvent from acetonitrile to
DCM, MeOH, THF, and nitromethane furnished the product in
reduced yield (entries 5À8). Replacing molecular iodine with
other iodo-based electrophiles such as NIS and ICl failed to
furnish title compounds (entries 9 and 10), as these strongly
electrophilic iodo reagents may be leading to the formation of
3-iodoindole and thus interfering with the functionalization of
C-3. This gets further support from the observation that reducing
the concentration of molecular iodine to 2.5 equiv from 5 equiv
furnished 3a in reduced yield (entry 11). Thus, the optimal
reaction conditions could be either carrying out the reaction at
0 °C for 45 min or initiating the reaction at 0 °C and then
proceeding to room temperature for 30 min. It is interesting to
note that molecular iodine played an important role in our
multicomponent domino reaction with three-tier involvement:
(1) it catalyzed nucleophilic substitution of propargyl alcohol at
the alcoholic carbon by the nucleophilic carbon C-3 of the indole,
(2) it acted as an electrophile and activated the alkyne in the
intermediate 4 by forming an iodonium complex, thereby allow-
ing hydroamidation, and (3) it acted as a third component in the
multicomponent format and became part of the final product to
afford 4-iodoindoloazepinone 3a. The scope and limitation of the
optimized reaction conditions were examined by studying the
effect of different substituents on the amidic nitrogen (R1; 1aÀf)
and on the propargyl alcohols (R2 and R3; 2aÀf). The substrates
1aÀf were subjected to multicomponent reactions by treating
them with the structurally diverse propargyl alcohol derivatives
2aÀf and I2. The requisite propargyl derivatives can be readily
prepared in quantitative yields using a procedure published in the
literature.26 In all cases, the substrates underwent electrophilic
7-endo-dig iodo-cyclization to furnish 18 compounds as single
regioisomers in 55À72% yields (Table 2). In general, reactions
were not sensitive to the electronic properties of the aliphatic
amines used for derivatizing the 1H-indole-2-carboxylic acid.
The synthesis of indole-2-carboxamides using aliphatic amines
was carried out by using the standard DCC/HOBt method.
Replacing aliphatic amine with aromatic amine in the 2-indole-
carboxamide failed to initiate cyclization, probably due to the
electronic nature of the substituent. Further, use of a substituted
phenyl ring such as R2 in 2 with both electron-donating and -
withdrawing groups had no effect on the yield of 4-iodoindolo-
azepinone 3; however, when aliphatic moiety was employed as R2,
the resulting propargyl alcohol derivatives 2 failed to undergo
nucleophilic substitution by C-3 of the indole 2-carboxamide 1.
Similarly, employing a phenyl ring with both electron-donating
and -withdrawing substituents such as R3 had no effect on the
yield but employing an aliphatic moiety as R3 led to a slight
reduction in the yield of 3 (entries 9, 11, 14, and 18). As described
elsewhere,25 propargyl alcohol (R2 = R3 = H) failed to undergo
nucleophilic substitution by C-3 of the indoles to afford 3.
’ CONCLUSION
In conclusion, we have developed an efficient synthetic
strategy toward the synthesis of the naturally occurring indolo-
azepinone scaffold via a three-component reaction involving
indole-2-carboxamide, 1,3-disubstituted propargyl alcohols, and
I2 under mild conditions. The strategy follows an iodine-
mediated CÀH functionalizationÀalkyne activationÀintramole-
cular hydroamidationÀdeprotonation domino sequence to af-
ford 4-iodoindoloazepinones. The salient feature of the strategy
Figure 3. Three other alternatives for the formation of regioisomeric
products (7À9) from the intermediate 4 via either 6-exo- or 7-endo-dig
iodo-cyclizations.
Table 1. Optimization of Reaction Conditions for the Formation of 3a
entry
electrophilic reagent
temp (°C)
time (min)
yield of 3a (%)a
1
iodine (5 equiv) in CH3CN
iodine (5 equiv) in CH3CN
iodine (5 equiv) in CH3CN
iodine (5 equiv) in CH3CN
iodine (5 equiv) in DCM
room temp
0
30
30
45
30
45
30
30
30
60
60
30
58
60
2
3
0
68
4
0Àroom temp
0Àroom temp
0Àroom temp
0Àroom temp
0Àroom temp
0Àroom temp
0Àroom temp
0Àroom temp
71
5
55b
27b
41b
20b
0
6
iodine (5 equiv) in CH3OH
iodine (5 equiv) in THF
7
8
iodine (5 equiv) in CH3NO2
N-iodosuccinimide (5 equiv) in CH3CN
ICl (5 equiv) in CH3CN
9
10
0
30b
11
iodine (2.5 equiv) in CH3CN
a Isolated yields. b Yields based on HPLC.
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Table 2. Synthesis of 4-Iodoindoloazepinone 3 from 1, 2, and I2 in Three-Component Domino Format
entry
1
R1
2
R2
R3
product
yield (%)a
1
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1e
1e
1e
1e
1f
4-CH3C6H4CH2
4-CH3C6H4CH2
4-CH3OC6H4CH2
4-CH3OC6H4CH2
4-CH3OC6H4CH2
C6H5 CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)3C
2a
2b
2c
2a
2d
2a
2b
2d
2e
2a
2e
2a
2b
2e
2d
2f
3,4-(CH3O)2C6H4
4-C2H5OC6H4
4-CH3C6H4
C6H5
3a
3b
3c
3d
3e
3f
71
63
72
66
68
68
64
67
57
60
55
69
62
56
63
59
55
52
2
4-CH3C6H4
C6H5
3
4
3,4-(CH3O)2C6H4
4-ClC6H4
C6H5
5
4-CH3C6H4
C6H5
6
3,4-(CH3O)2C6H4
4-C2H5OC6H4
4-ClC6H4
7
4-CH3C6H4
4-CH3C6H4
C6H9
3g
3h
3i
8
9
4-C2H5OC6H4
3,4-(CH3O)2C6H4
4-C2H5OC6H4
3,4-(CH3O)2C6H4
4-C2H5OC6H4
4-C2H5OC6H4
4-ClC6H4
10
C6H5
3j
11
(CH3)3C
C6H9
3k
3l
12
C5H9
C6H5
13
C5H9
4-CH3C6H4
C6H9
3m
3n
3o
3p
3q
3r
14
C5H9
15
C5H9
4-CH3C6H4
4-(CH3)3C6H4
4-CH3C6H4
C6H9
16
C3H5
4-C2H5OC6H4
4-ClC6H4
17
1f
C3H5
2d
2e
18
1f
C3H5
4-C2H5OC6H4
a Isolated yields.
involves regioselective electrophilic 7-endo-dig iodo-cycliza-
tion wherein a nitrogen nucleophile from the amidic moiety
preferentially attacks the activated alkyne rather than the oxygen
nucleophile. Haloheterocycles have been documented to play
an important role as intermediates, due to their ability to under-
go numerous palladium-catalyzed reactions for the substitution of
the halide atom. Further studies are in progress to extend the iodine-
mediated MCR format to the synthesis of other haloheterocycles.
addition of the corresponding amine (1.0 mmol) to the reaction mixture,
and stirring was continued at room temperature for 24 h. After this the
reaction mixture was passed through a bed of Celite, and the filtrate was
evaporated to dryness. The oily residue was extracted with EtOAc
(50 mL Â 3) and sequentially washed with 5% NaHCO3 and 5%
KHSO4 and finally with brine (10 mL). The organic layer was dried over
anhydrous sodium sulfate and evaporated to dryness under reduced
pressure. The crude product so obtained was purified by triturating with
ethanol to afford 1aÀf.
N-(4-Methylbenzyl)-1H-indole-2-carboxamide (1a): white solid;
yield 93%; mp >250 °C; FT-IR (KBr) 2926, 1637, 1564, 1413, 1309,
’ EXPERIMENTAL SECTION
1
I. General Information. All reagents and solvents were purchased
from commercial sources and used without purification. NMR spectra
were recorded with 200 and 300 MHz spectrometers for 1H NMR and
50 and 75 MHz spectrometers for 13C NMR. Chemical shifts δ are given
in ppm relative to the residual signals of tetramethylsilane in CDCl3 or
1012 cmÀ1; H NMR (200 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.02
(s, 1H), 7.63À7.04 (m, 9H), 4.50 (s, 2H), 2.27 (s, 3H), ppm; 13C NMR
(50 MHz, DMSO-d6) δ 161.2, 136.6, 135.9, 131.8, 128.9, 127.3, 123.3,
121.5, 119.8, 112.4, 102.7, 42.0, 20.7 ppm; exact mass for C17H16N2O
264.13 [M], HR-MS (ESI) found 265.134 07 [M + H]+.
1
deuterated solvent CDCl3/DMSO-d6 for H and 13C NMR. Multi-
N-(4-Methoxybenzyl)-1H-indole-2-carboxamide (1b): white solid;
yield 89%; mp >250 °C; FT-IR (KBr) 3281, 1628, 1546, 1512, 1244,
1028 cmÀ1; 1H NMR (200 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.96 (t, J =
5.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.29À7.13
(m, 4H), 7.06À6.96 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 4.43 (d, J = 5.9
Hz, 2H), 3.72 (s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 161.2,
158.4, 136.6, 131.8, 131.7, 128.7, 127.3, 123.5, 121.6, 119.9, 113.8, 112.4,
102.8, 55.2, 41.8 ppm; exact mass for C17H16N2O2 280.12 [M], HR-MS
(ESI) found 281.129 00 [M + H]+.
N-Benzyl-1H-indole-2-carboxamide (1c): white solid; yield 95%; mp
194À196 °C (lit.27 mp 192À193 °C); FT-IR (KBr) 3269, 2933, 1633,
1545, 1418, 1312 cmÀ1; 1H NMR (200 MHz, DMSO-d6) δ 11.61 (s,
1H), 9.05 (t, J = 6.0 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.1 Hz,
1H), 7.35À7.14 (m, 7H), 7.03 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 6.0 Hz,
plicities are reported as follows: singlet (s), doublet (d), doublet of
doublets (dd), doublet of triplets (dt), triplet (t), quartet (q), multiplet
(m). High-resolution mass spectra were taken with a mass spectrometer.
Columnchromatographywas performed usingsilica gel(100À200 mesh)
as the stationary phase. All reactions were monitored by thin-layer chro-
matography (TLC). The purity and characterization of these com-
pounds were further established using HR/ESI (+ve) mass spectroscopy.
Melting points were measured on a capillary melting point apparatus and
are uncorrected.
II. General Experimental Procedure for Indole-2-carboxamides
1aÀf. To a stirred solution of indole-2-carboxalic acid (1.0 mmol) in
THF at 0 °C was added DCC (1.0 mmol) and HOBT (1.0 mmol), and
the reaction mixture was stirred for 30 min. This was followed by
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2H) ppm; 13CNMR(50MHz,DMSO-d6) δ161.2, 139.7, 136.6, 131.7, 128.4,
127.3, 127.2, 126.8, 123.4, 121.4, 119.8, 112.4, 102.7, 42.3 ppm; exact mass for
C16H14N2O 250.11 [M], HR-MS (ESI) found 251.118 44 [M + H]+.
N-(tert-Butyl)-1H-indole-2-carboxamide (1d): white solid; yield
78%; mp 108À110 °C; FT-IR (KBr) 3230, 2829, 1635, 1542,
1-(4-Chlorophenyl)-3-(4-methylphenyl)prop-2-yn-1-ol (2d): white
solid; yield 80%; mp 78À80 °C; FT-IR (KBr) 3032, 2923, 1489, 1091,
1016, 818 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 8.3 Hz,
2H), 7.36À7.33 (m, 4H), 7.53 (d, J = 8.2 Hz, 2H), 5.64 (s, 1H), 2.40
(brs, 1H), 2.34 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.3,
138.9, 134.1, 131.7, 129.2, 128.7, 128.2, 119.2, 87.8, 87.2, 64.4, 21.5 ppm;
exact mass for C16H13ClO 256.07 [M], HR-MS (ESI) found 257.14505
[M + H]+.
1
1452 cmÀ1; H NMR (200 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.71
(s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.19À7.11 (m,
2H), 7.05À6.97 (m, 1H), 1.40 (s, 9H) ppm; 13C NMR (50 MHz,
CDCl3) δ 160.8, 136.3, 132.7, 127.1, 123.1, 121.4, 119.6, 112.2, 102.8,
50.9, 28.8 ppm; exact mass for C13H16N2O 216.13 [M], HR-MS (ESI)
found 217.13409 [M + H]+.
N-Cyclopentyl-1H-indole-2-carboxamide (1e): white solid; yield
86%; mp 220À224 °C; FT-IR (KBr) 3252, 2951, 1619, 1558, 1417,
1310, 1225 cmÀ1; 1H NMR (200 MHz, DMSO-d6): δ 11.55 (s, 1H),
8.29 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41À7.39 (m, 1H),
7.20À7.11 (m, 2H), 7.05À6.97 (m, 1H), 4.30À4.20 (m, 1H),
1.98À1.52 (m, 8H) ppm; 13C NMR (50 MHz, DMSO-d6) δ 160.7,
136.4, 132.1, 127.1, 123.1, 121.4, 119.6, 112.3, 102.7, 50.6, 32.2, 23.4
ppm; exact mass for C14H16N2O 228.13 [M], HR-MS (ESI) found
229.13409 [M + H]+.
3-Cyclohex-1-en-1-yl-1-(4-ethoxyphenyl)prop-2-yn-1-ol (2e): white
oil; yield 76%; FT-IR (neat) 2914, 1737, 1413, 1012 cmÀ1; 1H NMR
(300 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H),
6.15 (s, 1H), 5.50 (d, J = 5.6 Hz, 1H), 4.01 (q, J = 6.9 Hz, 2H), 2.18À2.08
(m, 5H), 1.62À1.57 (m, 4H), 1.40 (t, J = 6.9 Hz, 3H) ppm; 13C NMR
(50 MHz, DMSO-d6) δ 158.9, 135.5, 133.4, 128.1, 120.2, 114.5, 114.4,
88.3, 86.5, 64.6, 63.6, 29.2, 25.7, 22.3, 21.5, 14.8 ppm; exact mass for
C17H20O2 256.15 [M], HR-MS (ESI) found 257.15415 [M + H]+.
3-[4-(tert-Butyl)phenyl]-1-(3,4-dimethoxyphenyl)prop-2-yn-1-ol
(2f): white oil; yield 85%; FT-IR (neat) 3032, 2923, 1489, 1091, 1016,
818 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 7.45À7.32 (m, 4H),
7.17À7.13 (s, 1H), 6.88À6.81 (s, 2H), 5.63 (s, 1H), 3.83 (s, 3H),
3.87 (s, 3H), 1.79 (s, 1H), 1.30 (s, 9H), ppm; 13C NMR (75 MHz,
CDCl3) δ 149.3, 149.2, 131.5, 125.4, 119.2, 118.3, 111.1, 111.0, 110.9,
110.1, 109.1, 88.4, 86.6, 64.9, 56.0, 55.9, 34.8, 31.2 ppm; exact mass for
C21H24O3 324.17 [M], HR-MS (ESI) found 325.02504 [M + H]+.
IV. General Procedure for Synthesis of the Iodo-Indolo-
azepinone Derivatives 3aÀr. To a solution of indole-2-carboxamide
1 (0.200 g, 0.73 mmol) and 1,3-diphenylprop-2-yn-1-ol 2 (0.73 mmol)
in acetonitrile (10 mL) was added iodine (5.0 mmol) at 0 °C, and the
reaction mixture was stirred for 30 min at room temperature. After
completion of the reaction as analyzed by TLC, the reaction mixture was
diluted with saturated sodium thiosulfate solution and extracted with
EtOAc (20 mL Â 3). The separated organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, and evaporated to
dryness under reduced pressure. The crude product so obtained was
purified on a silica gel column using hexane/ethyl acetate (1/19, v/v) as
eluent to afford 4-iodoindoloazepinones 3aÀr.
N-Cyclopropyl-1H-indole-2-carboxamide (1f): white solid; yield
83%; mp 220À224 °C; FT-IR (KBr) 3416, 2926, 1626, 1539, 1420,
1310, 1267 cmÀ1; 1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.43
(s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18À6.99 (m,
3H), 2.87À2.84 (m, 1H), 0.72 (d, J = 4.7 Hz, 2H), 0.60 (d, J = 4.7 Hz,
2H) ppm; 13C NMR (50 MHz, DMSO-d6) δ 162.5, 136.5, 131.8, 127.2,
123.4, 121.6, 119.8, 112.4, 102.7, 22.8, 5.9 ppm; exact mass for
C12H12N2O 200.09 [M], HR-MS (ESI) found 201.10279 [M + H]+.
III. General Experimental Procedure for 1,3-Disubstituted
Propargyl Alcohols 2aÀf. To a degassed solution of terminal alkyne
(1.0 mmol) in dry THF at À78 °C under a nitrogen atmosphere was
added n-BuLi (1.6 M solution in hexane, 2.0 mmol), and the reaction
mixture was stirred for 0.5 h at À78 °C. Next the corresponding
aldehyde (1.0 mmol) was added to the reaction mixture, and after
completion of the reaction as analyzed by TLC, the reaction mixture was
diluted with an aqueous solution of ammonium chloride. The mixture
was extracted with EtOAc (20 mL Â 3), and the separated organic layer
was washed with brine (10 mL), dried over anhydrous sodium sulfate,
and evaporated to dryness under reduced pressure. The crude product
so obtained was purified on a silica gel column using hexane/ethyl
acetate (1/19, v/v) as eluent to afford 2aÀf.
2-(4-Methylbenzyl)-3-phenyl-4-iodo-5-(3,4-dimethoxyphenyl)-
5,10-dihydroazepino[3,4-b]indol-1(2H)-one (3a): yellow solid; yield
71%; mp 96À98 °C; FT-IR (KBr) 3054, 2931, 1673, 1510, 1449, 1325,
1258, 1022 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.21 (brs, 1H), 7.59
(d, J = 8.6 Hz, 1H), 7.31À7.21 (m, 7H), 7.12À6.93 (m, 7H), 6.78 (d, J =
8.3 Hz, 1H), 5.87 (s, 1H), 4.26 (q, J = 14.8 Hz, 2H), 3.83 (s, 3H), 3.77 (s,
3H), 2.30 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 150.2, 149.2,
148.4, 145.8, 140.2, 138.0, 136.8, 136.2, 132.3, 129.7, 129.0, 128.3, 128.2,
127.8, 125.3, 124.8, 123.9, 120.6, 120.1, 119.9, 118.4, 112.2, 111.3, 110.8,
84.2, 55.9, 55.8, 49.5, 44.5, 21.2 ppm; exact mass for C34H29IN2O3
640.12 [M], HR-MS (ESI) found 641.1393 [M + H]+.
2-(4-Methylbenzyl)-3-(4-methylphenyl)-4-iodo-5-(4-ethoxyphenyl)-
5,10-dihydroazepino[3,4-b]indol-1(2H)-one (3b): yellow solid; yield
63%; mp 104À106 °C; FT-IR (KBr) 3289, 2928, 1605, 1438, 1245,
1174, 1042 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.79 (brs, 1H), 7.60
(d, J = 8.0 Hz, 1H), 7.39À7.35 (m, 4H), 7.24À7.07 (m, 5H), 6.98 (s,
4H), 6.82À6.79 (m, 2H), 5.60 (s, 1H), 4.48 (q, J = 14.8 Hz, 2H), 3.98 (q,
J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 157.9, 151.1, 148.2, 139.1, 136.6, 136.3,
136.1, 135.6, 132.6, 129.2, 128.9, 128.8, 128.2, 127.9, 126.7, 125.8, 124.9,
121.2, 120.3, 119.2, 114.5, 111.8, 90.6, 63.4, 53.5, 50.6, 21.4, 21.1, 14.9
ppm; exact mass for C35H31IN2O2 638.14 [M], HR-MS (ESI) found
639.1474 [M + H]+.
1-(3,4-Dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (2a): orange so-
lid; yield 83%; mp 82À83 °C; FT-IR (KBr) 3429, 2959, 1514, 1263,
1141, 1027 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 7.49À7.45 (m, 2H),
7.33À7.31 (s, 3H), 7.17À7.15 (m, 2H), 6.89À6.86 (m, 1H), 5.64
(s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.27 (brs, 1H), ppm; 13C NMR
(75 MHz, CDCl3) δ 149, 133.5, 131.8, 128.7, 128.4, 122.6, 119.2, 111.1,
110.1, 89.0, 86.6, 64.9, 56.0, 55.9 ppm; exact mass for C17H16O3 268.11
[M], HR-MS (ESI) found 269.12807 [M + H]+.
1-(4-Ethoxyphenyl)-3-(4-methylphenyl)prop-2-yn-1-ol (2b): white
1
oil; yield 76%; FT-IR (neat) 3452, 2835, 1761, 1612, 1011 cmÀ1; H
NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.10 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.60 (s, 1H), 4.01
(q, J = 6.9 Hz, 2H), 2.52 (s, 1H), 2.32 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H)
ppm; 13C NMR (50 MHz, CDCl3) δ 159.0, 138.6, 133.1, 131.7, 129.1,
128.2, 119.6, 114.6, 88.5, 86.6, 64.7, 63.6, 21.5, 14.8 ppm; exact mass for
C18H18O2 266.13 [M], HR-MS (ESI) found 267.01272 [M + H]+.
1-(4-Methylphenyl)-3-phenylprop-2-yn-1-ol (2c): white oil; yield
78%; FT-IR (neat) 3401, 3021, 1632, 1444, 1291, 1215, 1032 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 8.1 Hz, 1H), 7.72À7.69 (m,
1H), 7.51À7.33 (m, 7H), 5.68 (s, 1H), 2.39 (s, 3H), 2.37 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 138.1, 137.9, 131.7, 129.3, 128.7. 128.3,
126.8, 122.6, 89.2, 86.4, 64.8, 21.2 ppm; exact mass for C16H14O 222.10
[M], HR-MS (ESI) found 223.10226 [M + H]+.
2-(4-Methoxybenzyl)-3-phenyl-4-iodo-5-(4-methylphenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3c): yellow solid; yield 72%;
mp 102À104 °C; FT-IR (KBr) 3056, 2946, 1680, 1544, 1231, 1120,
1042 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.51 (brs, 1H), 7.56 (d, J =
7.8 Hz, 1H), 7.42À7.36 (m, 4H), 7.31À7.21 (m, 5H), 7.11À7.07 (m,
6802
dx.doi.org/10.1021/jo201228t |J. Org. Chem. 2011, 76, 6798–6805

The Journal of Organic Chemistry
ARTICLE
3H), 6.96 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 5.88 (s, 1H), 4.28
(s, 2H), 3.74 (s, 3H), 2.29 (s, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ
158.5, 158.1, 145.9, 140.2, 138.1, 137.1, 136.8, 131.9, 129.7, 129.6, 129.1,
128.3, 128.2, 127.6, 125.4, 123.7, 120.7, 120.2, 118.8, 112.3, 84.3, 55.4,
49.1, 44.7, 21.2 ppm; exact mass for C33H27IN2O2 610.11 [M], HR-MS
(ESI) found 611.1179 [M + H]+.
1H NMR (300 MHz, CDCl3) δ 10.94 (brs, 1H), 7.66 (d, J = 8.1 Hz, 1H),
7.52 (t, J = 8.0 Hz, 2H), 7.43À7.38 (m, 2H), 7.31À7.23 (m, 3H),
7.19À7.16 (m, 3H), 6.75 (d, J = 8.7 Hz, 2H), 5.93 (s, 1H), 5.58 (s, 1H),
4.74 (s, 2H), 3.99 (q, J = 6.9 Hz, 2H), 2.13À1.62 (s, 8H), 1.40 (t, J =
6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 157.9, 153.2, 148.7,
139.9, 136.5, 136.3, 132.8, 132.1, 128.4, 128.1, 127.9, 126.8, 126.7, 125.8,
124.9, 121.5, 120.3, 119.3, 114.8, 114.5, 111.8, 88.6, 63.4, 52.8, 50.6, 25.9,
24.9, 22.4, 21.8, 14.9 ppm; exact mass for C33H31IN2O2 614.14 [M],
HR-MS (ESI) found 615.1493 [M + H]+.
2-(4-Methoxybenzyl)-3-phenyl-4-iodo-5-(3,4-dimethoxyphenyl)-
5,10-dihydroazepino[3,4-b]indol-1(2H)-one (3d): yellow solid; yield
66%; mp 103À105 °C; FT-IR (KBr) 3031, 2924, 1663, 1442, 1224,
1
1046 cmÀ1; H NMR (200 MHz, CDCl3) δ 9.67 (brs, 1H), 7.58
2-tert-Butyl-3-phenyl-4-iodo-5-(3,4-dimethoxyphenyl)-5,10-dihydro-
azepino[3,4-b]indol-1(2H)-one (3j): brown solid; yield 60%; mp
106À108 °C; FT-IR (KBr) 3071, 2926, 1598, 1517, 1260, 1134,
(d, J = 7.9 Hz, 1H), 7.44À7.22 (m, 7H), 7.14À7.07 (m, 2H),
6.98À6.90 (m, 3H), 6.78À6.70 (m, 3H), 5.88 (s, 1H), 4.26 (s, 2H),
3.77 (s, 3H), 3.74 (s, 6H) ppm; 13C NMR (50 MHz, CDCl3) δ 158.7,
149.3, 149.3, 148.5, 147.8, 139.9, 138.6, 131.8, 130.8, 129.5, 129.2,
128.4, 128.3, 126.2, 124.4, 122.3, 120.9, 120.3, 119.9, 113.8, 112.6,
111.4, 110.7, 85.3, 55.9, 55.3, 48.5, 44.4 ppm; exact mass for
C34H29IN2O4 656.12 [M], HR-MS (ESI) found 657.1264 [M + H]+.
2-(4-Methoxybenzyl)-3-(4-methylphenyl)-4-iodo-5-(4-chlorophenyl)-
5,10-dihydroazepino[3,4-b]indol-1(2H)-one (3e): yellow solid; yield
68%; mp 95À97 °C; FT-IR (KBr) 3330, 2924, 1659, 1437, 1245,
1081 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 10.22 (brs, 1H), 7.55 (d, J =
8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.36À7.27 (m, 7H), 7.15 (d, J = 7.9
Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.92 (s, 1H),
4.28 (d, J = 14.5 Hz, 2H), 3.76 (s, 3H), 2.34 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3) δ 159.0, 150.2, 147.7, 139.3, 138.9, 137.4, 136.4, 133.7,
129.6, 129.5, 129.2, 129.1, 129.0, 128.9, 128.8, 127.3, 123.9, 121.5, 120.3,
113.9, 113.1, 87.9, 55.3, 47.8, 44.3, 21.4 ppm; exact mass for C33H26ClI-
N2O2 644.07 [M], HR-MS (ESI) found 645.0809 [M + H]+.
1025 cmÀ1 1H NMR (300 MHz, CDCl3) δ 9.67 (brs, 1H), 7.59
;
(d, J = 8.0 Hz, 1H), 7.32À7.20 (m, 7H), 7.11À6.96 (m, 3H), 6.77 (d, J =
8.3 Hz, 1H), 5.85 (s, 1H), 3.83 (s, 6H), 0.97 (s, 9H) ppm; 13C NMR (75
MHz, CDCl3) δ 150.5, 149.1, 148.2, 142.2, 141.2, 137.6, 132.9, 129.7,
129.3, 128.3, 128.1, 128.0, 124.8, 124.7, 124.6, 120.3, 119.9, 119.8, 117.0,
111.9, 111.2, 110.5, 81.9, 55.8, 54.0, 44.1, 29.7 ppm; exact mass for
C30H29IN2O3 592.12 [M], HR-MS (ESI) found 593.1291 [M + H]+.
2-tert-Butyl-3-cyclohex-1-enyl-4-iodo-5-(4-ethoxyphenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3k): yellow solid; yield 55%;
mp 98À100 °C; FT-IR (KBr) 3253, 2928, 1718, 1631, 1505, 1442, 1244,
1075 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.81 (brs, 1H), 7.57 (d, J =
8.0 Hz, 1H), 7.47À7.40 (m, 1H), 7.34À7.25 (m, 4H), 7.11À7.06 (m,
1H), 6.80 (d, J = 8.6 Hz, 2H), 5.84 (s, 1H), 5.72 (s, 1H), 3.98 (q, J = 7.0
Hz, 2H), 2.29À2.09 (m, 4H), 1.74À1.72 (m, 4H), 1.58À1.44 (s, 9H),
1.38 (t, J = 7.0 Hz, 2H), ppm; 13C NMR (75 MHz, CDCl3) δ 158.0,
148.4, 143.4, 137.7, 137.5, 136.6, 132.5, 128.5, 127.9, 125.4, 124.8, 124.7,
122.5, 120.3, 120.0, 117.8, 114.8, 114.6, 112.0, 89.3, 63.4, 54.3, 43.6, 30.3,
29.0, 27.6, 25.3, 22.3, 14.9 ppm; exact mass for C30H33IN2O2 580.16
[M], HR-MS (ESI) found 581.1667 [M + H]+.
2-Benzyl-3-phenyl-4-iodo-5-(3,4-dimethoxyphenyl)-5,10-dihydro-
azepino[3,4-b]indol-1(2H)-one (3f): brown solid; yield 68%; mp
112À114 °C; FT-IR (KBr) 3058, 2934, 1673, 1509, 1447, 1257,
1
1138, 1076 cmÀ1; H NMR (300 MHz, CDCl3) δ 9.36 (brs, 1H),
2-Cyclopentyl-3-phenyl-4-iodo-5-(3,4-dimethoxyphenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3l): yellow solid; yield 69%;
mp 99À101 °C; FT-IR (KBr) 3257, 2938, 1638, 1568, 1447, 1261,
1020 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.55 (brs, 1H), 7.58 (d, J =
8.0 Hz, 1H), 7.40À7.21 (m, 7H), 7.13À7.08 (m, 2H), 6.93 (dd, J = 8.2,
1.8 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.85 (s, 1H), 3.83 (s, 7H),
7.46 (d, J = 8.0 Hz, 1H), 7.44À7.18 (m, 10H), 7.14À7.00 (m, 4H),
6.96À6.93 (m, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 4.30 (q, J =
14.8 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H) ppm; 13C NMR (50 MHz,
CDCl3) δ 150.2, 149.2, 148.5, 145.8, 140.2, 139.9, 138.0, 132.3, 129.7,
129.3, 128.4, 128.2, 127.9, 126.7, 125.4, 124.8, 123.9, 120.7, 120.2, 120.0,
118.5, 112.2, 111.3, 110.9, 84.3, 55.9, 49.8, 44.5 ppm; exact mass for
C33H27IN2O3 626.11 [M], HR-MS (ESI) found 627.1111 [M + H]+.
2-Benzyl-3-(4-methylphenyl)-4-iodo-5-(4-ethoxyphenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3g): yellow solid; yield 64%;
mp 101À103 °C; FT-IR (KBr) 3270, 2925, 1604, 1440, 1244, 1173,
1040 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.05 (brs, 1H), 7.63 (d, J =
8.0 Hz, 1H), 7.41À7.13 (m, 14H), 6.82 (d, J = 8.7 Hz, 2H), 5.60 (s, 1H),
4.50 (q, J = 15.3 Hz, 2H), 3.98 (q, J = 6.9 Hz, 2H), 2.37 (s, 3H), 1.38
(t, J = 6.9 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ 158.1, 151.2,
148.1, 139.8, 139.2, 136.3, 135.7, 132.6, 129.3, 128.9, 128.4, 128.3, 127.9,
126.8, 126.7, 125.9, 125.1, 121.2, 120.4, 119.4, 114.6, 111.8, 90.6, 63.5,
53.6, 50.9, 21.5, 15.0 ppm; exact mass for C34H29IN2O2 624.13 [M],
HR-MS (ESI) found 625.1324 [M + H]+.
1.76À1.57 (m, 2H), 2.29À2.09 (m, 4H), 1.74À1.72 (m, 2H), ppm; 13
C
NMR (50 MHz, CDCl3) δ 150.4, 149.2, 148.4, 144.9, 140.3, 137.9,
132.5, 129.7, 128.0, 127.9, 125.1, 124.8, 124.0, 120.0, 119.8, 117.9, 112.2,
111.3, 110.9, 83.6, 56.5, 55.9, 44.4, 34.2, 34.0, 24.2, 24.1 ppm; exact mass
for C31H29IN2O3 604.12 [M], HR-MS (ESI) found 605.1272 [M + H]+.
2-Cyclopentyl-3-(4-methylphenyl)-4-iodo-5-(4-ethoxyphenyl)-5,
10-dihydroazepino[3,4-b]indol-1(2H)-one (3m): yellow solid; yield
62%; mp 107À109 °C; FT-IR (KBr) 3342, 2944, 2589, 1672, 1535,
1053, 741 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 10.05 (brs, 1H), 7.53
(d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.29À7.19 (m, 4H),
7.11À7.03 (m, 3H), 6.80 (d, J = 8.6 Hz, 2H), 5.84 (s, 1H), 3.99À3.86
(m, 3H), 2.33 (s, 3H), 1.77À1.44 (s, 5H). 1.35 (t, J = 6.9 Hz, 3H),
1.25À1.19 (m, 2H), 0.89À0.85 (m, 1H) ppm; 13C NMR (50 MHz,
CDCl3) δ 158.3, 149.5, 147.5, 138.5, 138.1, 137.1, 131.5, 129.4, 128.6,
125.9, 124.4, 122.2, 120.8, 120.3, 114.8, 112.5, 85.2, 63.4, 56.5, 44.0, 33.7,
33.4, 24.0, 21.3, 14.9 ppm; exact mass for C32H31IN2O2 602.14 [M],
HR-MS (ESI) found 603.1529 [M + H]+.
2-Benzyl-3-(4-methylphenyl)-4-iodo-5-(4-chlorophenyl)-5,10-dihydro-
azepino[3,4-b]indol-1(2H)-one (3h): brown solid; yield 67%; mp
109À111 °C; FT-IR (KBr) 2925, 1676, 1488, 1218, 1155, 1087 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 9.55 (brs, 1H), 7.48 (d, J = 8.0 Hz, 1H),
7.39À7.30 (m, 4H), 7.28À7.24 (m, 1H), 7.21À7.10 (m, 6H),
7.08À6.99 (m, 5H), 5.82 (s, 1H), 4.28 (s, 2H), 2.26 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 159.1, 150.8, 148.7, 147.4, 138.9, 138.4,
138.0, 136.8, 133.4, 129.4, 129.3, 129.1, 129.0, 128.9, 128.8, 128.4, 127.9,
126.9, 124.4, 121.0, 120.0, 112.6, 86.2, 49.3, 44.4, 21.4 ppm; exact
mass for C32H24ClIN2O 614.06 [M], HR-MS (ESI) found 615.0688
[M + H]+.
2-Cyclopentyl-3-cyclohex-1-enyl-4-iodo-5-(4-ethoxyphenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3n): yellow solid; yield 56%;
mp 103À105 °C; FT-IR (KBr) 3248, 2926, 1630, 1507, 1245,
1045 cmÀ1 1H NMR (300 MHz, CDCl3) δ 9.97 (brs, 1H), 7.60
;
(d, J = 8.0 Hz, 1H), 7.36À7.25 (m, 5H), 6.82 (d, J = 8.7 Hz, 2H), 5.90 (s,
1H), 5.49 (s, 1H), 4.42-.4.35 (m, 1H), 4.00 (q, J = 6.9 Hz, 2H),
2.32À2.17 (m, 4H), 1.76À1.00 (m, 13H), 0.96À0.89 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ 157.9, 153.4, 147.0, 136.5, 136.1, 132.8,
131.8, 128.2, 126.9, 126.1, 124.8, 120.9, 119.3, 114.5, 111.7, 88.6, 63.4,
2-Benzyl-3-cyclohex-1-enyl-4-iodo-5-(4-ethoxyphenyl)-5,10-di-
hydroazepino[3,4-b]indol-1(2H)-one (3i): yellow solid; yield 57%; mp
113À115 °C; FT-IR (KBr) 2927, 1660, 1487, 1440, 1218, 1090 cmÀ1
;
6803
dx.doi.org/10.1021/jo201228t |J. Org. Chem. 2011, 76, 6798–6805

The Journal of Organic Chemistry
ARTICLE
56.9, 52.9, 34.9, 34.3, 29.8, 25.9, 25.0, 22.5, 21.9, 14.9 ppm; exact mass
for C31H33IN2O2 592.16 [M], HR-MS (ESI) found 593.1519 [M + H]+.
2-Cyclopentyl-3-(4-methylphenyl)-4-iodo-5-(4-chlorophenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3o): white solid; yield 63%;
mp 110À112 °C; FT-IR (KBr) 3212, 2921, 1656, 1489, 1331, 1219,
1088 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.62 (brs, 1H), 7.55 (d, J =
8.1 Hz, 1H), 7.45À7.38 (m, 4H), 7.34À7.28 (m, 4H), 7.16À7.11 (m,
3H), 5.89 (s, 1H), 3.85À3.84 (m, 1H), 2.37 (s, 3H), 1.81À0.85 (m, 8H)
ppm; 13C NMR (50 MHz, CDCl3) δ 149.3, 145.4, 138.5, 138.2, 138.0,
137.1, 133.3, 129.6, 129.1, 129.0, 128.6, 128.3, 125.5, 124.6, 123.6, 120.8,
119.9, 117.9, 112.3, 85.1, 56.3, 44.3, 34.0, 33.8, 24.1, 24.0, 21.4 ppm;
exact mass for C30H26ClIN2O 592.08 [M], HR-MS (ESI) found
593.1496 [M + H]+.
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2-Cyclopropyl-3-(4-tert-butylphenyl)-4-iodo-5-(3,4-dimethoxyphenyl)-
5,10-dihydroazepino[3,4-b]indol-1(2H)-one (3p): yellow oil; yield
59%; FT-IR (neat) 3342, 2944, 2589, 1672, 1535, 1053, 741 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 9.55 (brs, 1H), 7.60 (d, J = 7.9 Hz, 1H),
7.43À7.20 (m, 7H), 7.13 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.05 (s,
1H), 1.30 (s, 9H), 0.71 (m, 4H) ppm; 13C NMR (50 MHz, CDCl3) δ
151.2, 150.0, 149.1, 148.4, 147.0, 137.9, 136.9, 132.2, 129.5, 125.3, 124.9,
124.7, 123.6, 120.7, 120.1, 119.8, 118.1, 112.1, 111.3, 111.1, 84.9, 55.9,
55.8, 44.3, 34.6, 31.3, 28.3, 8.5, 8.4 ppm; exact mass for C33H33IN2O3
632.15 [M], HR-MS (ESI) found 633.1590 [M + H]+.
2-Cyclopropyl-3-(4-methylphenyl)-4-iodo-5-(4-chlorophenyl)-5,10-
dihydroazepino[3,4-b]indol-1(2H)-one (3q): yellow solid; yield 55%;
mp 116À118 °C; FT-IR (KBr) 3192, 2923, 1623, 1486, 1443, 1270,
1088 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 9.29 (brs, 1H), 7.55 (d, J =
8.1 Hz, 1H), 7.47À7.28 (m, 7H), 7.23À7.13 (m, 4H), 5.88 (s, 1H),
3.09À3.05 (s, 1H), 2.37 (s, 3H), 0.88À0.60 (s, 4H) ppm; 13C NMR (50
MHz, CDCl3) δ 149.2, 146.8, 138.4, 138.1, 137.9,136.9,133.3. 131.8,
129.8, 129.1, 129.0, 128.6, 125.5, 124.7, 123.7, 120.8, 119.9, 117.5, 112.3,
85.8, 44.6, 29.8, 21.4, 8.8, 8.7 ppm; exact mass for C28H22ClIN2O 564.05
[M], HR-MS (ESI) found 565.0527 [M + H]+.
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1
IR (neat) 3247, 2927, 1662, 1503, 1441, 1244, 1174, 1083 cmÀ1; H
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NMR (300 MHz, CDCl3) δ 9.54 (brs, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.39À7.25 (m, 4H), 7.09 (t, J= 7.4 Hz, 1H), 6.78 (d, J= 8.6 Hz, 2H), 5.86 (s,
1H), 5.70 (s, 1H), 2.95 (q, J = 6.9 Hz, 2H), 3.51 (t, J = 5.2 Hz, 2H),
2.19À2.06 (m, 4H), 1.70À1.57 (m, 4H), 1.36 (t, J = 6.9 Hz, 2H), 0.86À0.85
(m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 158.2, 148.5, 138.2, 136.9,
131.8, 128.7, 125.5, 124.8, 123.2, 120.7, 120.2, 119.2, 114.7, 112.4, 90.3, 63.5,
43.6, 29.8, 28.4, 28.0, 25.6, 22.8, 22.1, 14.9, 8.4 ppm; exact mass for
C29H29IN2O2 564.13 [M], HR-MS (ESI) found 565.1327 [M + H]+.
’ ASSOCIATED CONTENT
Supporting Information. Figures giving 1H and 13C
S
b
NMR and HRMS spectra of all final compounds and 2D spectra
of 3a,p. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +91 522 2612411-18, ext. 4383. Fax: +91 522 2623405.
E-mail: bijoy_kundu@yahoo.com, b_kundu@cdri.res.in.
(11) (a) Zhao, J. L.; Liu, L.; Zhang, H. B.; Wu, Y. C.; Wang, D.;
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Tetrahedron Lett. 2011, 52, 568. (e) Qiu, G.; Ding, Q.; Jie, P. Y.; Wu, J.
’ ACKNOWLEDGMENT
S.K.S. and A.K.M. are grateful to the CSIR, New Delhi, India,
for fellowships. We thank the SAIF, CDRI, India, for providing
analytical data.
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