Water-accelerated cationic π-(7-endo) cyclisation: Application to indole-based peri-annulated polyheterocycles

Article abstract of DOI:10.1002/ejoc.201000596

An efficient and versatile method for the synthesis of indolebased polycyclic indolo-benzazepine and its derivatives through water-accelerated cationic π-cyclisation is described. The strategy involves condensation of arylamine moieties linked to C-4 in i

Full text of DOI:10.1002/ejoc.201000596

FULL PAPER
DOI: 10.1002/ejoc.201000596
Water-Accelerated Cationic π-(7-endo) Cyclisation: Application to
Indole-Based Peri-Annulated Polyheterocycles[‡]
Mohammad Saifuddin,[a] Piyush K. Agarwal,[a] Sudhir K. Sharma,[a] Anil K. Mandadapu,[a]
Sahaj Gupta,[a] Vimal K. Harit,[a] and Bijoy Kundu*[a]
Keywords: Nitrogen heterocycles / Medicinal chemistry / Cyclization / Cations
An efficient and versatile method for the synthesis of indole-
based polycyclic indolo-benzazepine and its derivatives
through water-accelerated cationic π-cyclisation is described.
The strategy involves condensation of arylamine moieties
linked to C-4 in indole/azaindole systems with arylaldehydes
in water containing catalytic amount of Brønsted acids. The
C–C bond formation in water is complete within 10–30 min,
furnishing the title compounds in excellent yields and purit-
ies, whereas in organic solvents 10–12 h are required.
Furthermore, aldehydes both with electron-donating and-
withdrawing substituents facilitate the π-cyclisation equally.
as protein kinase C inhibitors, as 5-HT agonists, as melato-
nin agonists and as glucocorticoid receptor modulators,
displaying cytotoxic, antiviral, antimicrobial, antiparasitic,
antiinflammatory, antiserotonin, Ca2þ, calmodulin-
antagonistic and antitopoisomerase-I activities.[2] These
polyheterocycles frequently feature structurally diverse
Introduction
Indole-based fused heterocycles belong to the most widely
distributed naturally occurring compounds, isolated from
plants, fungi and marine organisms.[1] The range of applica-
tions for these therapeutically relevant compounds includes
Figure 1. Structures of naturally occurring indole-based peri-annulated frameworks and the target molecule.
novel frameworks and remain a source of new natural-
[‡] CDRI Communication No. 7938
[a] Division of Medicinal Chemistry, Central Drug Research
Institute, CSIR,
product-inspired[3] chemical entities for chemical biology-
research.
Lucknow 226001, India
Of the myriad reactions devoted to the synthesis of in-
dole-based polyheterocycles, π-cyclisation reactions have re-
mained a method of choice, and chemists continue to de-
velop efficient and practical variants of these reactions to
Fax: +91-0522-2223405, -2223938
E-mail: bijoy_kundu@yahoo.com
b_kundu@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000596.
View this journal online at
wileyonlinelibrary.com
5108
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Eur. J. Org. Chem. 2010, 5108–5117

Water-Assisted Synthesis of Indole-Fused Heterocycles
make use of mild reaction conditions, substrate manipula- 3e, however, was synthesised through the coupling of 4-
tion, and environmentally friendly catalysts/conditions.[4] In (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1c)
continuation of our ongoing studies relating to the synthesis with 2-bromopyridin-3-amine.
of indole-based polyheterocycles indolo-quinolines[5] and
azepino-indoles[6] through π-cyclisations, coupled with our
interest in carrying out organic reactions in water,[7] we were
prompted to use π-cyclisation reactions in aqueous media
for the generation of indole-based polyheterocycles. In re-
cent years, water has been demonstrated as an ideal medium
for many organic transformations even if the starting mate-
rials and products appear to be insoluble.[8] In fact, ever
since the application of water as a solvent in organic chem-
istry was rediscovered by Breslow,[9] a variety of organic
reactions, including allylation, the Diels–Alder reaction,[10]
the Wittig reaction,[11] the aldol reaction,[12] Mannich-type
reactions,[13] the Michael reaction,[14] the Claisen rearrange-
ment,[15] Sonogashira coupling,[16] Tsuji–Trost-type reac-
tions,[17] the Heck reaction[18] and even dehydration reac-
tions,[19] have been achieved in water with significant en-
hancements of the reaction rates.[20] This has been attrib-
uted to hydrophobic packing,[9] solvent polarity,[21] hy-
dration[22] and hydrogen bonding.[23] Here we describe the
water-accelerated synthesis of indolo[3,4-cd][1]benzazepine
and its derivatives through π-cyclisation reactions.
For our studies involving π-cyclisation reactions in aque-
ous media, the target structure indolo[3,4-cd][1]benzazepine
Scheme 1. Reagents and conditions: i) PdCl2(PPh3)2, Na2CO3,
80 °C, DMF, 4 h.
(Figure 1) was inspired by several naturally occurring in-
dole-based peri-fused frameworks in which the indole rings
The boronates were in general prepared by treatment of
are fused through C-3 and C-4 to six-, seven- and eight- bromo compounds with bis[pinacolato]diboron by the pro-
membered rings.[24] To the best of our knowledge this is the cedure published elsewhere[26] and were used in situ for the
first report dealing with the cationic π-(7-endo-trig) cycli- Suzuki coupling. Similarly, 4-bromo-7-azaindole, required
sation in water. Literature reports dealing with the synthesis for the synthesis of substrates 3c and 3d, was obtained by
of peri-fused indoles are scarce and have been predomi- treatment of 7-azaindole with mCPBA in ethyl acetate to
nantly reported in organic solvents.[25]
give the N-oxide, which was then treated with methane-
sulfonic anhydride and tetramethylammonium bromide in
DMF at room temp. to give the desired product.[27]
Once we had the desired substrates 3a–e to hand, we next
investigated their abilities to undergo cationic π-(7-endo)
Results and Discussion
The synthetic strategy for the indolo-benzazepines in- cyclisation when condensed with aldehydes both in water
volved the preparation of a key intermediate of type 3 and in organic solvent. Because Pictet–Spengler reactions
(Scheme 1) in which an arylamine is tethered to the indole are in general more favoured with aldehydes bearing elec-
at C-4. We envisaged that condensation of intermediates of tron-withdrawing groups as substituents than with alde-
type 3 with aldehydes might facilitate cationic π-cyclisation hydes bearing electron-donating groups, we initially exam-
in the resulting aldimines to furnish indole-annulated seven- ined the capability of the substrate 3a to undergo 7-endo
membered rings through the involvement of the nucleo- cyclisation (Table 1) with aldehydes bearing either an elec-
philic indole C-3, which is in the “meta” position relative tron-donating or an electron-withdrawing substituent.
to C-4. The substrates of type 3 differ from our previous Interestingly, the cationic π-cyclisation occurred both in or-
indole-based arylamine substrates[4] with respect to the lo- ganic and in aqueous media through the attack of the elec-
cation of the arylamine, which is generally “ortho”-oriented tron-rich C-3 nucleophile of the indole ring on the iminium
instead of “meta” with respect to the nucleophilic carbon ion, thereby resulting in a seven-membered ring annulated
(C-2/C-3). Our studies commenced with the synthesis of the to the indole ring. The final compound after crystallisation
substrate 3a (Scheme 1), required as a key intermediate for was characterised by NMR and ESMS as the indolo-benz-
the Pictet–Spengler reaction, which was carried out by azepine 4b. Interestingly, out of the different acidic protocols
means of a Suzuki coupling reaction between 4-bromo- (Table 1) used, the best results were obtained when the sub-
indole (1a) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- strate 3a was treated with 4-nitrobenzaldehyde in TFA in
yl)phenylamine (2a, Scheme 1). In order to increase the di- water (5%) at room temp. for 10 min, which effected com-
versity in compounds 3, the strategy was then successfully plete conversion of 3a and afforded 4b with Ͼ95% purity
also applied to the synthesis of substrates 3b–d. Compound based on HPLC and in Ͼ90% isolated yield. Out of the
Eur. J. Org. Chem. 2010, 5108–5117
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B. Kundu et al.
FULL PAPER
Table 1. Optimisation of reaction conditions for the conversion of 3a into 4b and 4f.
Entry Reaction conditions
Temp (°C)
Time
4-Nitrobenzaldehyde
4-Ethoxybenzaldehyde
1
2
3
4
5
6
7
TFA in CH3CN (2%)
Yb(OTf)3 in CH3CN
p-TsOH in CH3CN (1%)
triflic acid in DMF (1%)
TFA in DCM (2%)
TFA in water (5%)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24 h
24 h
24 h
24 h
12 h
10 min
12 h
46
35
36
36
90
41
30
28
29
83
87
n.r.
94
Yb(OTf)3 in water
n.r.[a]
[a] n.r. = no reaction.
Table 2. Optimisation of reaction conditions for the conversion of 3c into 6c and 6e.
Entry
Reaction conditions
Temp. [°C]
Time
4-Nitrobenzaldehyde
3,4-Dimethoxybenzaldehyde
1
2
3
4
5
TFA in water (1%)
TFA in water (2%)
TFA in water (5%)
TFA in water (5%)
TFA in water (10%)
room temp.
room temp.
room temp.
80 °C
30 min
30 min
30 min
30 min
30 min
33
42
93
90
94
21
29
37
82
85
80 °C
organic solvents studied, TFA in dry DCM (2%) at room nating groups and electron-withdrawing groups being suc-
temp. for 12 h effected complete conversion of 3a into 4b. cessfully employable with equal ease. The isolated yields of
The use of water as a reaction medium had thus signifi- the final compounds varied from 83–95%.
cantly enhanced the rate of cationic π-cyclisation relative to
the organic solvent protocol.
Table 3. Synthesis of indolo-benzazepines 4, 5, 8 and benzoazulenes
6, 7.
Similarly, condensation of 4-ethoxybenzaldehyde with
the substrate 3a furnished the peri-fused product 4f in the
presence of TFA in water (5%) at room temp. in 10 min
(Method A) whereas in organic solvents such as TFA in dry
DCM (2%) at room temp. it took 12 h for completion of
the reaction. The use of other acid/Lewis acid catalysts tra-
ditionally used under Pictet–Spengler protocols, such as
pTsOH and Yb(OTf)3 either at room temp. or in the com-
plete absence of an acid catalyst, failed to produce endo-
cyclised products both in the organic solvent and in water.
We next examined the efficacy of the 7-azaindole-based
substrate 3c in undergoing π-cyclisation under aqueous
conditions. Surprisingly, treatment of 3c with 4-nitrobenzal-
dehyde or with 3,4-dimethoxybenzaldehyde in TFA in water
(5%) at room temp. failed to result in complete cyclisation,
furnishing the desired products 6c and 6e only in poor
yield. This prompted us to optimise the reaction conditions
through variation of the concentration of TFA and of the
temperature (Table 2). The best results were obtained when
condensation of 3c with the aldehydes bearing electron-do-
nating or electron-withdrawing groups was carried out in
the presence of TFA in water (10%) at 80 °C for 30 min
(Method B).
After successfully optimizing the reaction conditions for 27
the indole- and 7-azaindole-based substrates 3, we exam-
ined the scope and limitations of the strategy by treating
the substrates 3a–e with 11 different arylaldehydes and ali-
phatic aldehydes. In all cases, the substrates efficiently
underwent π-cyclisation when condensed with aromatic al-
dehydes to yield 34 compounds (4a–g, 5a–i, 6a–f, 7a–f and
8a–j) in excellent yields (Table 3, Scheme 2). In general, the
reactions were not sensitive to the electronic properties of
the substituent on the phenyl ring, with both electron-do-
Entry
Substrate
R2
Product
Yield [%]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
3d
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
4-Cl-C6H4
4-NO2-C6H4
4-Br-C6H4
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
93
94
91
89
86
87
85
90
92
88
87
84
86
83
45
54
90
91
94
86
85
88
89
87
90
88
86
85
91
93
95
90
88
86
85
87
51
63
4-F-C6H4
4-CH3-C6H4
4-C2H5O-C6H4
2-OH-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-Br-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-F-C6H4
4-CH3-C6H4
4-C2H5O-C6H4
4-N(CH3)2-C6H4
CH3CH2
(CH3)3C
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
2-OH-C6H4
3,4-di-OCH3-C6H3
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-F-C6H4
4-C2H5O-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-F-C6H4
28
29
30
31
32
33
34
35
36
37
38
4-C2H5O-C6H4
4-CH3-C6H4
2-OH-C6H4
3,4-di-OCH3-C6H3
CH3 CH2
8g
8h
8i
(CH3)3C
8j
5110
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Eur. J. Org. Chem. 2010, 5108–5117

Water-Assisted Synthesis of Indole-Fused Heterocycles
General Procedure for the Synthesis of Substrates 3a–e by Suzuki
Coupling: A solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenylamine (2a, 1.00 g, 4.56 mmol) and 4-bromo-1H-indole
(1a, 0.89 g, 4.56 mmol) in DMF (5 mL) was degassed with nitrogen
for 15 min, followed by addition of Na2CO3 (1.45 g, 2  in water)
under
a continuous flow of nitrogen. PdCl2(PPh3)2 (0.32 g,
0.45 mmol) was added under nitrogen and the reaction mixture was
stirred at 80 °C for 4 h. The solution was diluted with H2O (5 mL)
and the product was extracted three times with EtOAc (10 mL).
The combined organic layer was dried with Na2SO4 and the solvent
was removed in vacuo. The crude product was purified with a silica
gel column and with hexane/ethyl acetate (90:10, v/v) as eluent to
afford 2-(1H-indol-4-yl)aniline (3a) in 71% yield.
Scheme 2. Reagents and conditions, Method A: R2CHO, TFA in
H2O (5%) at room temp., 10 min; Method B: R2CHO, TFA in H2O
(10%) at 80 °C, 30 min.
General Procedure for the Synthesis of 2-(4,4,5,5-Tetramethyl-
[1,3,2]dioxaborolan-2-yl)-phenylamine (2a): A solution of bis[pina-
colato]diboron (3.24 g, 12.78 mmol), 2-bromoaniline (2.0 g,
11.62 mmol), tricyclohexylphosphane (0.39 g, 1.39 mmol) and po-
tassium acetate (1.7 g, 17.43 mmol) in dry dioxane (15 mL) was
purged with nitrogen for 15 min, followed by the addition of tris[di-
benzylideneacetone]dipalladium(0) (0.53 g, 0.58 mmol). The reac-
tion mixture was heated at 80 °C for 16 h, filtered through celite,
washed with ethyl acetate and concentrated to provide the product,
which was used without further purification.
Condensation of the substrates 3b and 3e with aliphatic
aldehydes (Entries 15, 16, 37 and 38) furnished the endo
cyclised products in moderate yields (45–63%). Ketones
failed to undergo cationic π-(7-endo) cyclisation generally,
with ketimines remaining the only products isolated even
after three days of heating. This may be attributed to the
lower electrophilicities of ketimines than their aldimine
counterparts,[28] because the electrophilicities of imines have
been documented as the driving force for cationic π-cycli-
sation.[29]
General Procedure for the Pictet–Spengler Reaction Leading to the
Synthesis of the Indolo-benzazepine and Benzoazulene Derivatives 4,
5, 6, 7 and 8: A solution of a compound 3 (1 equiv.) and a corre-
sponding aldehyde R2 (1.1. equiv.) was treated with a solution of
trifluoroacetic acid in H2O (5%, 5 mL). The reaction mixture was
stirred at room temp. for 10 min. After completion of the reaction,
NaHCO3 solution was added and the product was extracted three
times with EtOAc (5 mL). The combined organic layer was dried
with Na2SO4 and the solvent was removed in vacuo. The crude
product was purified by trituration with Et2O in hexane, (5%) to
afford the pure compound.
Conclusions
We have developed a mild and efficient method for the
synthesis of indole-based perifused polycycles through
water-accelerated cationic π-cyclisation in water. The
workup procedure was effortless and purification of the
products did not require column chromatography, which
proved to be an additional advantage for the synthesis of
indolo-benzazepine and benzoazulene motifs.
2-(1H-Indol-4-yl)phenylamine (3a): Yield 1.51 g (71%), light yellow
1
solid, m.p. 135–136 °C, Rf = 0.83 (EtOAc/hexane, 1:1). H NMR
(300 MHz, [D6]DMSO): δ = 11.17 (br. s, 1 H, ArNH), 7.39 (d, J =
8.1 Hz, 1 H, ArH), 7.35–7.33 (m, 1 H, ArH), 7.16 (t, J = 7.3 Hz,
1 H, ArH), 7.10–7.04 (m, 2 H, ArH), 6.95 (d, J = 7.1 Hz, 1 H,
ArH), 6.80–6.77 (m, 1 H, ArH), 6.68–6.63 (m, 1 H, ArH), 6.18–
6.17 (m, 1 H, ArH), 4.57 (br. s, 2 H, NH2) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 145.1, 136.1, 131.2, 130.3, 126.7,
125.5, 125.3, 125.2, 110.5, 110.3, 100.7 ppm. IR (KBr): ν
=
˜
Experimental Section
max
3393, 1603, 1481 cm–1. MS (ES+): m/z = 209.3 [M + 1]+. C14H12N2
(208.26): calcd. C 80.74, H 5.81, N 13.45; found C 80.65, H 5.92,
N 13.51.
General: All solvents were commercially available and were used
without purification. All products were characterised by 1H NMR,
13C NMR, ESMS, HRMS, IR and HPLC. Analytical TLC was
performed with 2.5ϫ5 cm plates coated (0.25 mm) with silica gel
60F-254 and visualisation was accomplished with UV light and
iodine. Column chromatography was performed with silica gel
(100–200 mesh). 1H NMR spectra (300 MHz and 200 MHz) are
reported as follows: chemical shifts in ppm downfield from TMS
as internal standard (δ scale), multiplicity [br. s = broad singlet, s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, o =
overlapped, integration and coupling constant (Hz)]. All 13C NMR
spectra (75 MHz and 50 MHz) were determined with complete pro-
ton decoupling and are reported in ppm. Analytical HPLC was
performed with a reversed-phase C-18 column (250 mmϫ4.6 mm).
2-(1H-Indol-4-yl)-4-methylphenylamine (3b): Yield 1.52 g (67%),
brown liquid, Rf = 0.78 (EtOAc/hexane, 1:1). 1H NMR (200 MHz,
[D6]DMSO): δ = 11.18 (br. s, 1 H, ArNH), 7.37 (d, J = 8.8 Hz, 2
H, ArH), 7.14 (t, J = 7.7 Hz, 1 H, ArH), 6.94–6.90 (m, 3 H, ArH),
6.71 (t, J = 6.8 Hz, 1 H, ArH), 6.17 (s, 1 H, ArH), 4.38 (br. s, 2 H,
NH2), 2.19 (s, 3 H, CH3) ppm. 13C NMR (50 MHz, [D6]DMSO):
δ = 142.6, 136.1, 131.4, 130.7, 128.3, 126.2, 125.4, 125.3, 124.6,
121.2, 119.3, 115.2, 110.4, 100.7, 24.9 ppm. IR (neat): νmax = 3382,
˜
1614, 1494 cm–1. MS (ES+): m/z = 223.2 [M + 1]+. C15H14N2
(222.29): calcd. C 81.05, H 6.35, N 12.60; found C 81.10, H 6.29,
N 12.57.
Retention time on HPLC (C18 reversed-phase column; 2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)phenylamine (3c): Yield 1.49 g
150ϫ4.6 mm; 5 µm) with a linear gradient of 10–100% CH3CN in (70%), yellow solid, m.p. 159–163 °C, Rf = 0.16 (EtOAc/hexane,
water over 30 min, flow rate of 1.0 mLmin–1 and UV detection at 1:1). H NMR (200 MHz, CDCl3): δ = 10.70 (br. s, 1 H, ArNH),
1
220/254 nm. Mass spectra were recorded with a electron-spray mass
spectrometer.
8.40 (d, J = 4.5 Hz, 1 H, ArH), 7.39–7.16 (m, 4 H, ArH), 6.91–
6.82 (m, 2 H, ArH), 6.47 (s, 1 H, ArH), 3.83 (br. s, 2 H, NH2) ppm.
Eur. J. Org. Chem. 2010, 5108–5117
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Kundu et al.
13C NMR (50 MHz, [D6]DMSO): δ = 148.9, 145.2, 142.8, 139.5, MS (ES+): m/z = 375.2 [M + 1]+. C21H15BrN2 (375.27): calcd. C
FULL PAPER
130.1, 128.9, 125.9, 122.5, 118.2, 116.4, 115.5, 115.4 ppm. IR
67.21, H 4.03, N 7.47; found C 67.20, H 4.07, N 7.46.
(KBr): νmax = 3454, 3379, 2365, 1608 cm–1. MS (ES+): m/z = 210.4
˜
6-(4-Fluorophenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine
(4d): Yield 0.134 g (89%), purple solid, m.p. 155–157 °C, Rf = 0.20
(EtOAc/hexane, 1:4), tR = 12.98 min. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.96 (s, 1 H, ArNH), 7.79 (d, J = 7.5 Hz, 1 H, ArH),
7.38 (d, J = 7.5 Hz, 1 H, ArH), 7.33 (d, J = 7.8 Hz, 1 H, ArH),
[M + 1]+. C13H11N3 (209.25): calcd. C 74.62, H 5.30, N 20.08;
found C 74.56, H 5.38, N 20.05.
4-Methyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (3d): Yield
1.48 g (65%), pale yellow solid, m.p. 196–198 °C, Rf = 0.13 (EtOAc/
1
hexane, 1:1). H NMR (200 MHz, [D6]DMSO): δ = 11.69 (br. s, 1 7.26–7.17 (m, 3 H, ArH), 7.08–6.88 (m, 5 H, ArH), 6.76 (s, 1 H,
H, ArNH), 8.31–8.22 (m, 1 H, ArH), 7.46 (s, 1 H, ArH), 7.04–6.95
(m, 3 H, ArH), 6.73 (d, J = 8.5 Hz, 1 H, ArH), 6.26 (s, 1 H, ArH),
4.59 (br. s, 2 H, NH2), 2.19 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 148.9, 142.8, 142.7, 139.6, 130.4, 129.5, 125.9,
ArH), 5.90 (s, 1 H, NH), 5.50 (s, 1 H, CH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 147.9, 140.1, 136.7, 130.6, 129.7, 129.6,
129.1, 128.2, 127.2, 125.5, 123.3, 121.8, 121.4, 120.7, 118.9, 117.1,
114.8, 114.3, 109.9, 58.8 ppm. IR (KBr): ν
= 3405, 1605,
˜
max
124.8, 122.7, 118.2, 115.7, 115.6, 99.6, 20.1 ppm. IR (KBr): ν
=
1467 cm–1. MS (ES+): m/z = 315.3 [M + 1]+. C21H15FN2 (314.36):
˜
max
3357, 3141, 2916, 1602 cm–1. MS (ES+): m/z = 224.3 [M + 1]+.
C14H13N3 (223.28): calcd. C 75.31, H 5.87, N 18.82; found C 75.25,
H 5.90, N 18.75.
calcd. C 80.24, H 4.81, N 8.91; found C 80.23, H 4.80, N 8.90.
6-(4-Methylphenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine
(4e): Yield 0.128 g (86%), brown solid, m.p. 133–134 °C, Rf = 0.82
(EtOAc/hexane, 1:1), tR = 13.45 min. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.91 (s, 1 H, ArNH), 7.79 (d, J = 7.4 Hz, 1 H, ArH),
2-(1H-Indol-4-yl)pyridin-3-amine (3e): Yield 1.62 g (76%), light
1
brown solid, m.p. 167–169 °C, Rf = 0.22 (EtOAc/hexane, 1:1). H
NMR (200 MHz, [D6]DMSO): δ = 11.21 (br. s, 1 H, ArNH), 7.93 7.38–7.30 (m, 2 H, ArH), 7.21–7.16 (m, 1 H, ArH), 7.12–7.03 (m,
(dd, J = 4.3, 1.7 Hz, 1 H, ArH), 7.44 (d, J = 7.4 Hz, 1 H, ArH), 4 H, ArH), 7.00–6.87 (m, 3 H, ArH), 6.67 (d, J = 1.9 Hz, 1 H,
7.35 (t, J = 2.8 Hz, 1 H, ArH), 7.23–7.05 (m, 4 H, ArH), 6.27–6.25 ArH), 5.79 (s, 1 H, NH), 5.41 (s, 1 H, CH), 2.23 (s, 3 H, CH3) ppm.
(m, 1 H, ArH), 3.39 (br. s, 2 H, NH2) ppm. 13C NMR (50 MHz, 13C NMR (75 MHz, [D6]DMSO): δ = 141.0, 138.5, 136.7, 136.5,
[D6]DMSO): δ = 143.8, 141.7, 137.3, 136.3, 130.6, 125.9, 125.5,
130.7, 129.8, 129.6, 128.8, 128.7, 128.5, 128.4, 127.7, 127.2, 125.6,
125.3, 123.3, 121.7, 117.1, 116.9, 109.8, 59.5, 20.6 ppm. IR (KBr):
122.7, 121.5, 120.9, 119.3, 111.2, 101.1 ppm. IR (KBr): ν
=
˜
max
3453, 3151, 1610 cm–1. MS (ES+): m/z = 210.4 [M + 1]+. C13H11N3
(209.25): calcd. C 74.62, H 5.30, N 20.08; found C 74.56, H 5.34,
N 20.12.
ν
= 3422, 2922, 1637, 1450 cm–1. MS (ES+): m/z = 311.2 [M +
max
˜
1]+. C22H18N2 (310.40): calcd. C 85.13, H 5.85, N 9.03; found C
85.10, H 5.90, N 9.09.
6-(4-Chlorophenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine 6-(4-Ethoxyphenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine
(4a): Yield 0.148 g (93%), dark brown solid, m.p. 136–138 °C, Rf
= 0.20 (EtOAc/hexane, 1:4), tR = 15.76 min. H NMR (300 MHz,
(4f): Yield 0.142 g (87%), grey solid, m.p. 229–231 °C, Rf = 0.83
1
(EtOAc/hexane, 1:1), tR = 15.60 min. 1H NMR (200 MHz, [D6]-
[D6]DMSO): δ = 10.96 (s, 1 H, ArNH), 7.78 (d, J = 7.5 Hz, 1 H, DMSO): δ = 10.89 (s, 1 H, ArNH), 7.79 (d, J = 7.5 Hz, 1 H, ArH),
ArH), 7.39–7.18 (m, 7 H, ArH), 7.02–6.81 (m, 4 H, ArH), 5.96 (d,
J = 2.8 Hz, 1 H, NH), 5.52 (d, J = 2.4 Hz, 1 H, CH) ppm. 13C
NMR (50 MHz, [D6]DMSO): δ = 147.8, 143.0, 136.7, 131.1, 130.6,
129.6, 129.1, 128.2, 127.8, 127.3, 125.5, 123.4, 121.9, 121.4, 120.8,
7.38–7.29 (m, 2 H, ArH), 7.22–7.11 (m, 3 H, ArH), 7.05–6.86 (m,
3 H, ArH), 6.79 (d, J = 8.6 Hz, 2 H, ArH), 6.66 (d, J = 2.1 Hz, 1
H, ArH), 5.73 (d, J = 2.6 Hz, 1 H, NH), 5.41 (d, J = 2.1 Hz, 1 H,
CH), 3.93 (q, J = 6.9 Hz, 2 H, CH2), 1.28 (t, J = 6.9 Hz, 3 H,
58.7 ppm. IR (KBr): νmax = 3159, 1596, 1468 cm–1. MS (ES+): m/z CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 157.3, 148.5,
˜
= 331.2 [M + 1]+. C21H15ClN2 (330.82): calcd. C 76.24, H 4.57, N
8.47; found C 76.21, H 4.58, N 8.49.
136.7, 136.0, 130.7, 128.9, 128.3, 127.3, 125.6, 123.3, 121.8, 121.2,
120.6, 119.7, 117.1, 113.8, 109.8, 62.8, 59.2, 14.8 ppm. IR (KBr):
ν
= 3177, 1617, 1439 cm–1. MS (ES+): m/z = 341.3 [M + 1]+.
˜
max
6-(4-Nitrophenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine (4b):
Yield 0.154 g (94 %), green solid, m.p. 231–233 °C, Rf = 0.63
(EtOAc/hexane, 1:1), tR = 15.23 min. 1H NMR (300 MHz, [D6]-
C23H20N2O (340.42): calcd. C 81.15, H 5.92, N 8.23; found C
81.01, H 5.98, N 8.23.
DMSO): δ = 11.04 (s, 1 H, ArNH), 8.06 (d, J = 8.7 Hz, 2 H, ArH), 2-(6,7-Dihydro-4H-indolo[3,4-cd][1]benzazepin-6-yl)phenol (4g):
7.78 (d, J = 7.4 Hz, 1 H, ArH), 7.42–7.39 (m, 3 H, ArH), 7.35 (d,
Yield 0.128 g (85 %), green solid, m.p. 180–181 °C, Rf = 0.80
J = 7.7 Hz, 1 H, ArH), 7.22 (t, J = 7.7 Hz, 1 H, ArH), 7.00–6.95 (EtOAc/hexane, 1:1), tR = 12.55 min. 1H NMR (200 MHz, [D6]-
(m, 2 H, ArH), 6.91–6.87 (m, 2 H, ArH), 6.22 (d, J = 4.1 Hz, 1 H, DMSO): δ = 10.92 (s, 1 H, ArNH), 9.65 (br. s, 1 H, OH), 7.78 (d,
NH), 5.71 (d, J = 3.8 Hz, 1 H, CH) ppm. 13C NMR (50 MHz, [D6]-
DMSO): δ = 151.9, 147.1, 146.0, 136.7, 130.4, 129.2, 128.9, 128.3,
127.3, 125.5, 124.2, 123.4, 123.0, 121.9, 121.6, 121.2, 117.3, 117.0,
J = 7.1 Hz, 1 H, ArH), 7.35 (t, J = 8.1 Hz, 2 H, ArH), 7.02–6.80
(m, 5 H, ArH), 6.75–6.65 (m, 2 H, ArH), 6.54 (t, J = 7.4 Hz, 2 H,
ArH), 5.74 (br. s, 1 H, NH), 5.40 (s, 1 H, CH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 154.4, 148.3, 136.7, 130.7, 130.0, 129.1,
128.4, 128.3, 127.8, 127.2, 126.0, 123.1, 121.7, 121.5, 120.6, 118.7,
110.0, 58.5 ppm. IR (KBr): ν
= 3399, 1602, 1516 cm–1. MS
˜
max
(ES+): m/z = 342.3 [M + 1]+. C21H15N3O2 (341.37): calcd. C 73.89,
H 4.43, N 12.31; found C 73.87, H 4.45, N 12.31.
118.4, 117.1, 114.8, 109.9, 54.1 ppm. IR (KBr): ν
= 3368, 1611,
˜
max
1467 cm–1. MS (ES+): m/z = 313.2 [M + 1]+. C21H16N2O (312.37):
6-(4-Bromophenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine
(4c): Yield 0.164 g (91%), grey solid, m.p. 139–140 °C, Rf = 0.80
(EtOAc/hexane, 1:1), tR = 14.21 min. 1H NMR (300 MHz, [D6]-
calcd. C 80.75, H 5.16, N 8.97; found C 80.73, H 5.17, N 8.95.
6-(4-Chlorophenyl)-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
DMSO): δ = 10.99 (s, 1 H, ArNH), 7.78 (d, J = 7.8 Hz, 1 H, ArH), azepine (5a): Yield 0.139 g (90%), off-white solid, m.p. 150–152 °C,
7.42–7.31 (m, 4 H, ArH), 7.20 (d, J = 7.7 Hz, 1 H, ArH), 7.13 (d,
J = 8.3 Hz, 2 H, ArH), 7.01 (d, J = 7.0 Hz, 1 H, ArH), 6.93–6.87
(m, 2 H, ArH), 6.80 (d, J = 2.0 Hz, 1 H, ArH), 6.00 (d, J = 3.3 Hz,
Rf = 0.76 (EtOAc/hexane, 1:1), tR = 21.35 min. 1H NMR
(200 MHz, [D6]DMSO): δ = 10.90 (s, 1 H, ArNH), 7.58 (s, 1 H,
ArH), 7.40–7.15 (m, 7 H, ArH), 6.81 (s, 3 H, ArH), 5.86 (s, 1 H,
1H,NH),5.50(d,J=3.0 Hz,1H,CH) ppm.13CNMR(50 MHz,[D6]- NH), 5.48 (s, 1 H, CH), 2.24 (s, 3 H, CH3) ppm. 13C NMR
DMSO): δ = 147.7, 143.4, 136.7, 132.3, 130.7, 130.6, 129.9, 129.1,
(75 MHz, [D6]DMSO): δ = 145.2, 143.2, 136.8, 131.2, 131.1, 130.7,
128.2, 127.2, 125.5, 123.4, 121.8, 121.4, 120.8, 119.7, 118.1, 117.1,
129.9, 129.6, 129.4, 129.0, 128.7, 128.1, 127.8, 125.6, 123.5, 121.9,
109.9, 58.7 ppm. IR (KBr): ν
= 3422, 3159, 1653, 1466 cm–1.
120.8, 118.5, 117.1, 109.9, 58.8, 20.5 ppm. IR (KBr): ν
= 3430,
˜
˜
max
max
5112
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5108–5117

Water-Assisted Synthesis of Indole-Fused Heterocycles
3171, 1649 cm–1. MS (ES+): m/z = 345.2 [M + 1]+. C22H17ClN2
(344.84): calcd. C 76.63, H 4.97, N 8.12; found C 76.50, H 5.01, N
8.00.
ArH), 7.18 (t, J = 7.7 Hz, 1 H, ArH), 7.09 (d, J = 8.5 Hz, 2 H,
ArH), 6.81 (s, 2 H, ArH), 6.76 (d, J = 8.6 Hz, 2 H, ArH), 6.64 (d,
J = 2.0 Hz, 1 H, ArH), 5.50 (d, J = 2.0 Hz, 1 H, NH), 5.34 (s, 1
H, CH), 3.93 (q, J = 6.9 Hz, 2 H, CH2), 2.23 (s, 3 H, CH3), 1.26
(t, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 157.5, 146.0, 136.9, 136.3, 131.0, 130.0, 129.1, 128.9, 128.4,
125.9, 123.6, 122.0, 120.8, 119.9, 117.3, 114.0, 110.1, 63.1, 59.5,
10-Methyl-6-(4-nitrophenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepine (5b): Yield 0.147 g (92%), yellow solid, m.p. Ͼ250 °C, Rf =
0.74 (EtOAc/hexane, 1:1), tR = 20.56 min. 1H NMR (300 MHz,
[D6]DMSO): δ = 11.06 (d, J = 1.6 Hz, 1 H, ArNH), 8.18–8.15 (m,
1 H, ArH), 8.07 (d, J = 8.7 Hz, 2 H, ArH), 7.58 (d, J = 4.0 Hz, 1
H, ArH), 7.41–7.36 (m, 3 H, ArH), 7.33 (s, 1 H, ArH), 7.26–7.19
(m, 1 H, ArH), 6.96 (d, J = 2.1 Hz, 1 H, ArH), 6.78 (s, 1 H, ArH),
6.12 (d, J = 3.9 Hz, 1 H, NH), 5.67 (d, J = 3.7 Hz, 1 H, CH), 2.22
(s, 3 H, CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 145.3,
143.6, 136.8, 132.3, 131.3, 130.8, 130.0, 129.8, 129.0, 128.7, 128.1,
125.6, 123.5, 121.9, 120.8, 119.7, 118.3, 117.1, 109.9, 58.8,
20.7, 14.9 ppm. IR (KBr): νmax = 3183, 1610, 1460 cm–1. MS (ES+):
˜
m/z = 355.3 [M + 1]+. C24H22N2O (354.45): calcd. C 81.33, H 6.26,
N 7.90; found C 81.37, H 6.21, N 7.85.
N,N-Dimethyl-4-(10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepin-6-yl)aniline (5g): Yield 0.132 g (83%), orange yellow solid,
m.p. 197–199 °C, Rf = 0.60 (EtOAc/hexane, 1:1), tR = 21.13 min.
1H NMR (300 MHz, [D6]DMSO): δ = 10.83 (s, 1 H, ArNH), 7.61
(s, 1 H, ArH), 7.37 (d, J = 7.3 Hz, 1 H, ArH), 7.29 (d, J = 7.8 Hz,
1 H, ArH), 7.17 (t, J = 7.7 Hz, 1 H, ArH), 7.07 (d, J = 8.6 Hz, 2
H, ArH), 6.91–6.82 (m, 2 H, ArH), 6.63 (d, J = 8.7 Hz, 2 H, ArH),
6.58 (s, 1 H, ArH), 5.40 (s, 1 H, NH), 5.23 (s, 1 H, CH), 2.84 [s, 6
H, N(CH3)2], 2.26 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 145.5, 143.9, 136.9, 130.6, 130.0, 128.8, 127.2, 124.9,
123.6, 122.8, 119.1, 117.7, 113.9, 112.9, 112.7, 111.1, 58.6, 20.8,
20.5 ppm. IR (KBr): νmax = 3434, 3188, 1704, 1610, 1517 cm–1. MS
˜
(ES+): m/z = 356.2 [M + 1]+. C22H17N3O2 (355.40): calcd. C 74.35,
H 4.82, N 11.82; found C 74.01, H 5.00, N 11.50.
6-(4-Bromophenyl)-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepine (5c): Yield 0.153 g (88%), white solid, m.p. 225–226 °C, Rf
1
= 0.83 (EtOAc/hexane, 1:1), tR = 21.78 min. H NMR (300 MHz,
[D6]DMSO): δ = 10.98 (d, J = 1.9 Hz, 1 H, ArNH), 7.84 (s, 1 H,
ArH), 7.58 (s, 1 H, ArH), 7.41–7.36 (m, 3 H, ArH), 7.31 (d, J =
7.8 Hz, 1 H, ArH), 7.19 (t, J = 7.8 Hz, 1 H, ArH), 7.12 (d, J =
8.4 Hz, 2 H, ArH), 6.80 (s, 2 H, ArH), 5.87 (d, J = 3.4 Hz, 1 H,
NH), 5.46 (d, J = 3.2 Hz, 1 H, CH), 2.24 (s, 3 H, CH3) ppm. 13C
NMR (50 MHz, [D6]DMSO): δ = 152.2, 146.1, 144.6, 136.8, 130.7,
130.6, 130.0, 129.2, 128.9, 128.7, 128.2, 125.6, 124.3, 123.1, 121.9,
20.0 ppm. IR (KBr): ν
= 3435, 2844, 1672, 1604 cm–1. MS
˜
max
(ES+): m/z = 354.3 [M + 1]+. C24H23N3 (353.47): calcd. C 81.55, H
6.56, N 11.89; found C 81.49, H 6.62, N 11.85.
6-Ethyl-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine (5h):
Yield 0.053 g (45%), yellow liquid, Rf = 0.38 (EtOAc/hexane, 2:8),
1
tR = 20.03 min. H NMR (300 MHz, [D6]DMSO): δ = 10.84 (s, 1
121.2, 117.3, 117.2, 110.0, 58.6, 20.5 ppm. IR (KBr): ν
= 3422,
˜
max
H, ArNH), 7.63 (s, 1 H, ArH), 7.34 (d, J = 4.7 Hz, 1 H, ArH),
7.27 (d, J = 7.5 Hz, 1 H, ArH), 7.18–7.15 (m, 1 H, ArH), 7.09 (d,
J = 2.0 Hz, 1 H, ArH), 6.98–6.91 (m, 2 H, ArH), 5.44 (s, 1 H, NH),
4.13 (t, J = 4.8 Hz, 1 H, CH), 2.30 (s, 3 H, CH3), 1.62–1.53 (m, 2
H, CH2), 0.97 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 145.3, 136.6, 130.7, 129.2, 128.9, 128.5, 128.0,
125.4, 123.0, 121.5, 119.8, 119.0, 116.7, 109.5, 56.9, 29.2, 20.4,
3174, 1579 cm–1. MS (ES+): m/z = 389.2 [M + 1]+. C22H17BrN2
(389.29): calcd. C 67.88, H 4.40, N 7.20; found C 67.50, H 4.81, N
6.88.
6-(4-Fluorophenyl)-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepine (5d): Yield 0.128 g (87%), light blue solid, m.p. 144–146 °C,
Rf = 0.20 (1:4 EtOAc/hexane), tR = 19.90 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 10.91 (s, 1 H, ArNH), 7.59 (s, 1 H,
ArH), 7.38 (d, J = 7.4 Hz, 1 H, ArH), 7.31 (d, J = 7.8 Hz, 1 H,
ArH), 7.24–7.16 (m, 3 H, ArH), 7.04 (t, J = 8.8 Hz, 2 H, ArH),
6.85–6.79 (m, 2 H, ArH), 6.73 (d, J = 1.8 Hz, 1 H, ArH), 5.71 (d,
J = 2.8 Hz, 1 H, NH), 5.45 (d, J = 2.4 Hz, 1 H, CH), 2.25 (s, 3 H,
CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 145.6, 140.4,
140.3, 136.7, 130.7, 129.8, 129.6, 129.0, 128.7, 128.1, 125.6, 123.4,
121.8, 120.75, 119.0, 117.1, 114.8, 114.4, 109.9, 58.9, 20.5 ppm. IR
10.9 ppm. IR (neat): ν
= 3423, 2930, 1649 cm–1. MS (ES+): m/z
˜
max
= 263.3 [M + 1]+. C18H18N2 (262.35): calcd. C 82.41, H 6.92, N
10.68; found C 81.03, H 6.30, N 11.00.
6-tert-Butyl-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benzazepine
(5i): Yield 0.070 g (54%), brown solid, m.p. 112–113 °C, Rf = 0.38
(EtOAc/hexane, 2:8), tR = 19.23 min. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.90 (s, 1 H, ArNH), 7.57 (s, 1 H, ArH), 7.34–7.24
(m, 2 H, ArH), 7.15–7.06 (m, 2 H, ArH), 6.91 (s, 2 H, ArH), 5.74
(d, J = 4.2 Hz, 1 H, NH), 4.05 (s, 1 H, CH), 2.28 (s, 3 H, CH3),
0.77 [s, 9 H, (CH3)3] ppm. 13C NMR (50 MHz, [D6]DMSO): δ =
145.4, 136.4, 130.7, 128.6, 128.4, 128.3, 126.6, 122.5, 121.5, 121.2,
(KBr): νmax = 3172, 1606, 1501 cm–1. MS (ES+): m/z = 329.2 [M +
˜
1]+. C22H17FN2 (328.39): calcd. C 80.47, H 5.22, N 8.53; found C
80.50, H 5.12, N 8.61.
10-Methyl-6-(4-methylphenyl)-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepine (5e): Yield 0.122 g (84%), brown solid, m.p. 140–142 °C, Rf
116.7, 115.8, 109.4, 64.6, 27.7, 20.4 ppm. IR (KBr): ν
= 3407,
˜
max
2949, 1618, 1479 cm–1. MS (ES+): m/z = 291.3 [M + 1]+. C20H22N2
(290.41): calcd. C 82.72, H 7.64, N 9.65; found C 83.01, H 6.50, N
8.75.
1
= 0.80 (EtOAc/hexane, 1:1), tR = 20.56 min. H NMR (300 MHz,
[D6]DMSO): δ = 10.86 (s, 1 H, ArNH), 7.60 (s, 1 H, ArH), 7.39–
7.29 (m, 2 H, ArH), 7.21–7.03 (m, 5 H, ArH), 6.87–6.82 (m, 2 H,
ArH), 6.65 (s, 1 H, ArH), 5.59 (s, 1 H, NH), 5.36 (s, 1 H, CH),
2.25 (s, 3 H, CH3), 2.24 (s, 3 H, CH3) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 145.9, 141.1, 136.7, 135.7, 130.8, 129.6, 128.9,
128.6, 128.0, 127.8, 125.6, 123.4, 121.7, 120.6, 119.5, 117.0, 109.8,
6-(4-Chlorophenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo[cd,f]azulene
(6a): Yield 0.142 g (90%), pale yellow solid, m.p. Ͼ250 °C, Rf =
0.13 (EtOAc/hexane, 1:1), tR = 14.26 min. 1H NMR (300 MHz,
[D6]DMSO): δ = 11.50 (d, J = 1.5 Hz, 1 H, ArNH), 8.26 (d, J =
5.2 Hz, 1 H, ArH), 7.91 (d, J = 7.4 Hz, 1 H, ArH), 7.40 (d, J =
5.4 Hz, 1 H, ArH), 7.27 (d, J = 8.5 Hz, 2 H, ArH), 7.17 (d, J =
8.4 Hz, 2 H, ArH), 7.14–7.09 (m, 1 H, ArH), 7.00–6.91 (m, 3 H,
ArH), 6.33 (d, J = 3.7 Hz, 1 H, NH), 5.57 (d, J = 3.4 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 149.3, 148.8,
143.2, 142.5, 137.9, 131.2, 129.5, 129.3, 128.2, 128.0, 126.0, 123.7,
59.6, 20.7, 20.5 ppm. IR (KBr): νmax = 3428, 2930, 2359, 1657 cm–1.
˜
MS (ES+): m/z = 325.3 [M + 1]+. C23H20N2 (324.42): calcd. C
85.15, H 6.21, N 8.63; found C 85.10, H 6.27, N 8.50.
6-(4-Ethoxyphenyl)-10-methyl-6,7-dihydro-4H-indolo[3,4-cd][1]benz-
azepine (5f): Yield 0.137 g (86%), brown solid, m.p. 182–183 °C, Rf
1
= 0.73 (EtOAc/hexane, 1:1), tR = 22.27 min. H NMR (300 MHz,
[D6]DMSO): δ = 10.83 (d, J = 1.9 Hz, 1 H, ArNH), 7.58 (s, 1 H, 121.1, 120.4, 117.8, 116.8, 111.8, 58.1 ppm. IR (KBr): νmax = 2867,
˜
ArH), 7.36 (d, J = 7.4 Hz, 1 H, ArH), 7.30 (d, J = 7.7 Hz, 1 H,
1598, 1461 cm–1. MS (ES+): m/z = 332.3 [M + 1]+. C20H14ClN3
Eur. J. Org. Chem. 2010, 5108–5117
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5113

B. Kundu et al.
FULL PAPER
(331.80): calcd. C 72.40, H 4.25, N 12.66; found C 71.10, H 4.50,
N 12.80.
(KBr): νmax = 3125, 2875, 1595 cm–1. MS (ES+): m/z = 316.4 [M +
˜
1]+. C20H14FN3 (315.35): calcd. C 76.18, H 4.47, N 13.33; found C
76.23, H 4.38, N 13.35.
6-(4-Bromophenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo[cd,f]azulene
(6b): Yield 0.163 g (91%), yellow solid, m.p. Ͼ250 °C, Rf = 0.16
(EtOAc/hexane, 1:1), tR = 13.49 min. 1H NMR (300 MHz, [D6]-
6-(4-Chlorophenyl)-10-methyl-6,7-dihydro-4H-3,4,7-triazadibenzo-
[cd,f]azulene (7a): Yield 0.137 g (89%), brown solid, m.p. Ͼ250 °C,
DMSO): δ = 11.49 (s, 1 H, ArNH), 8.26 (d, J = 5.2 Hz, 1 H, ArH), Rf = 0.16 (EtOAc/hexane, 1:1), tR = 15.14 min. 1H NMR
7.91 (d, J = 7.5 Hz, 1 H, ArH), 7.42–7.39 (m, 3 H, ArH), 7.11 (d,
J = 8.3 Hz, 3 H, ArH), 6.99–6.91 (m, 3 H, ArH), 6.32 (d, J =
3.6 Hz, 1 H, NH), 5.55 (d, J = 3.4 Hz, 1 H, CH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 149.4, 148.8, 143.3, 142.9, 137.9, 130.9,
129.9, 129.4, 128.3, 126.0, 123.8, 121.3, 120.5, 119.9, 117.8, 116.7,
(300 MHz, [D6]DMSO): δ = 11.44 (s, 1 H, ArNH), 8.25 (d, J =
5.2 Hz, 1 H, ArH), 7.71 (s, 1 H, ArH), 7.40 (d, J = 5.4 Hz, 1 H,
ArH), 7.27 (d, J = 8.4 Hz, 2 H, ArH), 7.16 (d, J = 8.4 Hz, 2 H,
ArH), 6.98–6.86 (m, 3 H, ArH), 6.14 (d, J = 3.7 Hz, 1 H, NH),
5.52 (d, J = 3.4 Hz, 1 H, CH), 2.25 (s, 3 H, CH3) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 149.4, 146.2, 143.1, 142.6, 137.9, 131.2,
130.2, 129.7, 129.5, 128.4, 127.9, 125.9, 123.7, 120.3, 117.8, 116.9,
111.9, 58.2 ppm. IR (KBr): ν
= 3438, 3100, 2867, 1593,
˜
max
1465 cm–1. MS (ES+): m/z = 376.3 [M + 1]+. C20H14BrN3 (376.25):
calcd. C 63.84, H 3.75, N 11.17; found C 64.40, H 3.95, N 12.20.
111.7, 58.1, 20.2 ppm. IR (KBr): ν
= 3141, 2861, 1590,
˜
max
1466 cm–1. MS (ES+): m/z = 346.3 [M + 1]+. C21H16ClN3 (345.83):
6-(4-Nitrophenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo[cd,f]azulene
(6c): Yield 0.154 g (94%), yellow solid, m.p. Ͼ250 °C, Rf = 0.12
(EtOAc/hexane, 1:1), tR = 12.98 min. 1H NMR (200 MHz, [D6]-
calcd. C 72.93, H 4.66, N 12.15; found C 72.93, H 4.66, N 12.15.
6-(4-Bromophenyl)-10-methyl-6,7-dihydro-4H-3,4,7-triazadibenzo-
DMSO): δ = 11.56 (br. s, 1 H, ArNH), 8.27 (d, J = 4.0 Hz, 1 H, [cd,f]azulene (7b): Yield 0.152 g (87%), white solid, m.p. Ͼ250 °C,
ArH), 8.06 (d, J = 7.1 Hz, 2 H, ArH), 7.90 (d, J = 7.7 Hz, 1 H,
ArH), 7.38 (d, J = 8.0 Hz, 3 H, ArH), 7.10 (s, 2 H, ArH), 6.94 (d,
Rf = 0.16 (EtOAc/hexane, 1:1), tR = 14.21 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.45 (s, 1 H, ArNH), 8.25 (d, J =
J = 7.1 Hz, 2 H, ArH), 6.53 (s, 1 H, NH), 5.74 (s, 1 H, CH) ppm. 5.2 Hz, 1 H, ArH), 7.71 (s, 1 H, ArH), 7.41–7.38 (m, 3 H, ArH),
13C NMR (75 MHz, [D6]DMSO): δ = 151.3, 149.5, 148.2, 146.2, 7.10 (d, J = 8.3 Hz, 2 H, ArH), 6.97–6.85 (m, 3 H, ArH), 6.15 (d,
143.4, 137.8, 129.5, 128.9, 128.3, 126.2, 123.7, 123.2, 121.5, 120.9,
J = 3.3 Hz, 1 H, NH), 5.51 (d, J = 3.2 Hz, 1 H, CH), 2.25 (s, 3 H,
CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 149.4, 146.2,
143.1, 143.0, 137.9, 130.8, 130.2, 129.9, 129.8, 128.4, 125.9, 123.7,
117.8, 115.7, 111.9, 58.1 ppm. IR (KBr): ν
= 3343, 3102, 1595,
˜
max
1510 cm–1. MS (ES+): m/z = 343.3 [M + 1]+. C20H14N4O2 (342.36):
calcd. C 70.17, H 4.12, N 16.37; found C 71.10, H 3.98, N 18.12.
120.3, 119.8, 117.8, 116.7, 111.7, 58.1, 20.2 ppm. IR (KBr): ν
=
˜
max
3141, 2864, 1583, 1468 cm–1. MS (ES+): m/z = 390.3 [M + 1]+.
C21H16BrN3 (390.28): calcd. C 64.63, H 4.13, N 10.77; found C
64.70, H 4.08, N 10.74.
2-(6,7-Dihydro-4H-3,4,7-triazadibenzo[cd,f]azulen-6-yl)phenol (6d):
Yield 0.129 g (86%), light pink solid, m.p. 235–238 °C, Rf = 0.10
(EtOAc/hexane, 1:1), tR = 11.20 min. 1H NMR (300 MHz, [D6]-
DMSO): δ = 11.42 (s, 1 H, ArNH), 9.73 (s, 1 H, OH), 8.26 (s, 1 10-Methyl-6-(4-nitrophenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo-
H, ArH), 7.92 (d, J = 7.4 Hz, 1 H, ArH), 7.41 (d, J = 5.2 Hz, 1 H, [cd,f]azulene (7c): Yield 0.144 g (90%), yellow solid, m.p. Ͼ250 °C,
ArH), 7.12–6.83 (m, 6 H, ArH), 6.63–6.52 (m, 2 H, ArH), 5.79 (d,
J = 2.1 Hz, 1 H, NH), 5.69 (s, 1 H, CH) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 154.5, 149.3, 143.1, 137.9, 129.5, 129.2, 128.2,
128.0, 126.0, 123.5, 121.3, 120.1, 118.7, 117.0, 114.9, 53.6 ppm. IR
Rf = 0.12 (EtOAc/hexane, 1:1), tR = 15.35 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.54 (s, 1 H, ArNH), 8.28–8.24 (m,
1 H, ArH), 8.07 (d, J = 8.6 Hz, 2 H, ArH), 7.71 (s, 1 H, ArH),
7.44–7.36 (m, 3 H, ArH), 7.10 (d, J = 2.0 Hz, 1 H, ArH), 6.92 (d,
J = 8.1 Hz, 1 H, ArH), 6.84 (d, J = 8.0 Hz, 1 H, ArH), 6.38 (d, J
= 4.2 Hz, 1 H, NH), 5.70 (d, J = 3.8 Hz, 1 H, CH), 2.23 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 151.6, 149.5,
146.4, 145.8, 143.5, 138.1, 130.8, 130.5, 130.3, 128.9, 128.7, 126.3,
124.4, 124.0, 123.9, 123.3, 120.9, 117.9, 115.9, 58.2, 20.4 ppm. IR
(KBr): ν
= 3042, 1592 cm–1. MS (ES+): m/z = 314.3 [M + 1]+.
˜
max
C20H15N3O (313.36): calcd. C 76.66, H 4.82, N 13.41; found C
76.68, H 4.83, N 13.39.
6-(3,4-Dimethoxyphenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo[cd,f]-
azulene (6e): Yield 0.133 g (85%), yellow solid, m.p. 150–152 °C, Rf
(KBr): νmax = 2862, 2361, 1590, 1510 cm–1. MS (ES+): m/z = 357.3
˜
1
= 0.13 (EtOAc/hexane, 1:1), tR = 11.87 min. H NMR (300 MHz,
[M + 1]+. C21H16N4O2 (356.38): calcd. C 70.77, H 4.53, N 15.72;
found C 70.74, H 4.58, N 15.74.
[D6]DMSO): δ = 11.42 (s, 1 H, ArNH), 8.24 (d, J = 5.2 Hz, 1 H,
ArH), 7.92 (d, J = 7.8 Hz, 1 H, ArH), 7.39 (d, J = 5.4 Hz, 1 H,
ArH), 7.16–7.05 (m, 2 H, ArH), 6.99–6.92 (m, 2 H, ArH), 6.88 (d,
J = 1.9 Hz, 1 H, ArH), 6.71 (d, J = 8.2 Hz, 1 H, ArH), 6.59–6.56
6-(4-Fluorophenyl)-10-methyl-6,7-dihydro-4H-3,4,7-triazadibenzo-
[cd,f]azulene (7d): Yield 0.130 g (88%), brown solid, m.p. Ͼ250 °C,
(m, 1 H, ArH), 6.12 (d, J = 2.8 Hz, 1 H, NH), 5.44 (d, J = 2.3 Hz, Rf = 0.16 (EtOAc/hexane, 1:1), tR = 14.98 min. 1H NMR
1 H, CH), 3.34 (s, 6 H, 2ϫOCH3) ppm. 13C NMR (75 MHz, [D6]- (200 MHz, [D6]DMSO): δ = 11.47 (s, 1 H, ArNH), 8.25 (d, J =
DMSO): δ = 156.7, 149.3, 146.2, 140.0, 142.5, 136.9, 133.3, 130.5,
5.2 Hz, 1 H, ArH), 7.71 (s, 1 H, ArH), 7.40 (d, J = 5.5 Hz, 1 H,
ArH), 7.25–7.19 (m, 2 H, ArH), 7.04 (t, J = 8.9 Hz, 2 H, ArH),
125.6, 124.0, 120.9, 117.9, 116.4, 113.3, 112.0, 111.6, 59.5,
55.9 ppm. IR (KBr): νmax = 3117, 2834, 1594 cm–1. MS (ES+): m/z 6.91 (m, 3 H, ArH), 6.12 (d, J = 3.8 Hz, 1 H, NH), 5.51 (d, J =
˜
= 358.3 [M + 1]+. C22H19N3O2 (357.41): calcd. C 73.93, H 5.36, N
11.76; found C 73.93, H 5.36, N 11.76.
3.0 Hz, 1 H, CH), 2.25 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 149.4, 146.5, 143.1, 139.8, 137.8, 130.1, 129.7,
129.6, 129.5, 128.4, 125.9, 123.7, 120.2, 117.8, 117.4, 114.8, 114.5,
6-(4-Fluorophenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo[cd,f]azulene
(6f): Yield 0.145 g (88%), yellow solid, m.p. Ͼ250 °C, Rf = 0.14
(EtOAc/hexane, 1:1), tR = 13.15 min. 1H NMR (200 MHz, [D6]-
DMSO): δ = 11.47 (br. s, 1 H, ArNH), 8.25 (d, J = 5.3 Hz, 1 H,
ArH), 7.91 (d, J = 7.8 Hz, 1 H, ArH), 7.40 (d, J = 5.5 Hz, 1 H,
ArH), 7.25–7.16 (m, 2 H, ArH), 7.12–6.97 (m, 4 H, ArH), 6.92–
6.91 (m, 2 H, ArH), 6.25 (d, J = 3.5 Hz, 1 H, NH), 5.55 (d, J =
111.7, 58.3, 20.2 ppm. IR (KBr): ν
= 3141, 2873, 1639,
˜
max
1441 cm–1. MS (ES+): m/z = 330.4 [M + 1]+. C21H16FN3 (329.38):
calcd. C 76.58, H 4.90, N 12.76; found C 76.60, H 4.83, N 12.71.
6-(4-Ethoxyphenyl)-10-methyl-6,7-dihydro-4H-3,4,7-triazadibenzo-
[cd,f]azulene (7e): Yield 0.137 g (86 %), pale yellow solid, m.p.
Ͼ250 °C, Rf = 0.16 (EtOAc/hexane, 1:1), tR = 13.57 min. 1H NMR
3.0 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = (200 MHz, [D6]DMSO): δ = 11.39 (s, 1 H, ArNH), 8.24 (d, J =
149.4, 149.0, 143.2, 139.7, 137.9, 129.6, 129.5, 129.3, 128.2, 125.9,
123.6, 121.2, 120.3, 117.8, 117.3, 114.8, 114.5, 111.7, 58.2 ppm. IR
5.2 Hz, 1 H, ArH), 7.71 (s, 1 H, ArH), 7.39 (d, J = 5.4 Hz, 1 H,
ArH), 7.09 (d, J = 8.6 Hz, 2 H, ArH), 6.93 (s, 2 H, ArH), 6.82–
5114
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5108–5117

Water-Assisted Synthesis of Indole-Fused Heterocycles
6.75 (m, 3 H, ArH), 5.95 (d, J = 2.6 Hz, 1 H, NH), 5.40 (d, J =
2.2 Hz, 1 H, CH), 3.93 (q, J = 6.9 Hz, 2 H, CH2), 2.26 (s, 3 H,
CH3), 1.27 (t, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 157.3, 149.4, 146.9, 143.0, 138.0, 135.5, 130.1,
129.6, 128.8, 128.4, 125.8, 123.7, 120.0, 118.1, 117.9, 113.8, 111.7,
6-(4-Fluorophenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
cd]indole (8d): Yield 0.135 g (90%), brown solid, m.p. 185–186 °C,
Rf = 0.40 (EtOAc/hexane, 1:1), tR = 17.07 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.02 (s, 1 H, ArNH), 8.15 (dd, J =
4.3, 1.3 Hz, 1 H, ArH), 8.07 (d, J = 7.7 Hz, 1 H, ArH), 7.39 (d, J
62.8, 58.6, 20.3, 14.7 ppm. IR (KBr): ν
= 3133, 2900, 1593, = 7.4 Hz, 1 H, ArH), 7.18 (dd, J = 8.0, 1.4 Hz, 1 H, ArH), 7.25–
˜
max
1465 cm–1. MS (ES+): m/z = 356.3 [M + 1]+. C23H21N3O (355.44):
7.18 (m, 3 H, ArH), 7.07–6.99 (m, 3 H, ArH), 6.88 (d, J = 1.9 Hz,
1 H, ArH), 6.20 (d, J = 3.3 Hz, 1 H, NH), 5.58 (d, J = 2.9 Hz, 1
H, CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 145.2, 143.9,
141.3, 136.8, 131.4, 130.4, 129.9, 129.6, 128.8, 125.4, 121.9, 121.5,
calcd. C 77.72, H 5.96, N 11.82; found C 77.69, H 5.94, N 11.88.
10-Methyl-6-(4-methylphenyl)-6,7-dihydro-4H-3,4,7-triazadibenzo-
[cd,f]azulene (7f): Yield 0.124 g (85%), yellow solid, m.p. Ͼ250 °C,
Rf = 0.29 (EtOAc/hexane, 1:1), tR = 14.53 min. 1H NMR
(200 MHz, [D6]DMSO): δ = 11.40 (s, 1 H, ArNH), 8.24 (d, J =
5.2 Hz, 1 H, ArH), 7.71 (s, 1 H, ArH), 7.39 (d, J = 5.4 Hz, 1 H,
ArH), 7.10–7.00 (m, 4 H, ArH), 6.92 (s, 2 H, ArH), 6.84 (d, J =
121.2, 118.6, 117.8, 114.8, 114.6, 111.0, 57.7 ppm. IR (KBr): ν
˜
max
= 2925, 2363, 1647, 1609, 1435 cm–1. MS (ES+): m/z = 316.4 [M +
1]+. C20H14FN3 (315.35): calcd. C 76.18, H 4.47, N 13.33; found C
76.19, H 4.43, N 13.30.
2.2 Hz, 1 H, ArH), 6.00 (d, J = 3.3 Hz, 1 H, NH), 5.43 (d, J = 6-(4-Ethoxyphenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
3.0 Hz, 1 H, CH), 2.25 (s, 3 H, CH3), 2.22 (s, 3 H, CH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 149.4, 146.8, 143.0, 140.6, 138.0,
135.8, 130.1, 129.6, 128.6, 128.4, 127.6, 125.8, 123.7, 120.0, 117.8,
cd]indole (8e): Yield 0.128 g (88%), orange solid, m.p. 235–236 °C,
Rf = 0.12 (EtOAc/hexane, 1:9), tR = 14.26 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 10.98 (s, 1 H, ArNH), 8.15 (dd, J =
4.3, 1.4 Hz, 1 H, ArH), 8.06 (dd, J = 7.6, 0.8 Hz, 1 H, ArH), 7.40–
111.6, 58.8, 20.6, 20.3 ppm. IR (KBr): ν
= 3117, 2900, 1588,
˜
max
1464 cm–1. MS (ES+): m/z = 326.3 [M + 1]+. C22H19N3 (325.41): 7.34 (m, 2 H, ArH), 7.22 (t, J = 7.8 Hz, 1 H, ArH), 7.10 (d, J =
calcd. C 81.20, H 5.89, N 12.91; found C 81.25, H 5.83, N 12.87.
8.6 Hz, 2 H, ArH), 7.05–7.01 (m, 1 H, ArH), 6.82–6.76 (m, 3 H,
ArH), 6.11 (s, 1 H, NH), 5.49 (s, 1 H, CH), 3.94 (q, J = 6.9 Hz, 2
H, CH2), 1.28 (t, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 157.4, 145.0, 144.4, 141.0, 136.8, 135.8, 130.3,
130.0, 128.8, 125.4, 122.0, 121.4, 121.1, 118.6, 118.4, 113.8, 111.0,
6-(4-Chlorophenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
cd]indole (8a): Yield 0.144 g (91%), light yellow solid, m.p. 180–
1
181 °C, Rf = 0.60 (EtOAc/hexane, 1:1), tR = 14.87 min. H NMR
(300 MHz, [D6]DMSO): δ = 11.07 (d, J = 1.6 Hz, 1 H, ArNH),
8.15–8.05 (m, 1 H, ArH), 8.06 (d, J = 7.6 Hz, 1 H, ArH), 7.40 (d,
J = 7.4 Hz, 1 H, ArH), 7.30–7.20 (m, 4 H, ArH), 7.15 (d, J =
8.4 Hz, 2 H, ArH), 7.03–6.99 (m, 1 H, ArH), 6.96 (d, J = 2.2 Hz,
62.8, 58.0, 14.7 ppm. IR (KBr): νmax = 3145, 1611, 1403 cm–1. MS
˜
(ES+): m/z = 342.3 [M + 1]+. C22H19N3O (341.41): calcd. C 77.40,
H 5.61, N 12.31; found C 77.43, H 5.62, N 12.33.
1 H, ArH), 6.30 (d, J = 3.7 Hz, 1 H, NH), 5.60 (d, J = 3.5 Hz, 1 6-(4-Methylphenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
H, CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 143.8, 143.0,
141.4, 136.8, 131.6, 131.5, 131.3, 129.9, 129.5, 128.9, 128.7, 128.0,
cd]indole (8f): Yield 0.144 g (86%), brown solid, m.p. 195–196 °C,
Rf = 0.63 (EtOAc/hexane, 1:1), tR = 17.53 min. 1H NMR
(200 MHz, [D6]DMSO): δ = 11.01 (s, 1 H, ArNH), 8.12–8.04 (m,
2 H, ArH), 7.40–7.17 (m, 3 H, ArH), 7.04 (s, 5 H, ArH), 6.84 (s, 1
H, ArH), 617 (s, 1 H, NH), 5.51 (s, 1 H, CH), 2.21 (s, 3 H,
CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 144.3, 140.9,
136.8, 135.8, 130.5, 129.9, 128.6, 127.6, 125.5, 121.9, 121.4, 121.1,
125.4, 122.0, 121.5, 118.7, 117.3, 111.0, 57.7 ppm. IR (KBr): ν
˜
max
= 3250, 2930, 1598, 1423 cm–1. MS (ES+): m/z = 332.3 [M + 1]+.
C20H14ClN3 (331.80): calcd. C 72.40, H 4.25, N 12.66; found C
72.43, H 4.21, N 12.65.
6-(4-Bromophenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
cd]indole (8b): Yield 0.167 g (93%), orange solid, m.p. 135–137 °C,
Rf = 0.77 (EtOAc/hexane, 1:1), tR = 15.45 min. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.07 (d, J = 2.0 Hz, 1 H, ArNH),
8.14 (dd, J = 4.3, 1.4 Hz, 1 H, ArH), 8.06 (dd, J = 7.4, 0.6 Hz, 1
H, ArH), 7.42–7.38 (m, 3 H, ArH), 7.28 (dd, J = 8.0, 1.4 Hz, 1 H,
ArH), 7.23 (d, J = 7.8 Hz, 1 H, ArH), 7.10 (d, J = 8.4 Hz, 2 H,
118.6, 118.1, 110.9, 58.3, 20.7 ppm. IR (KBr): ν
= 3414, 3258,
˜
max
1579 cm–1. MS (ES+): m/z = 312.4 [M + 1]+. C21H17N3 (311.39):
calcd. C 81.00, H 5.50, N 13.49; found C 81.03, H 5.52, N 13.45.
2-(6,7-Dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-cd]indol-6-yl)-
phenol (8g): Yield 0.127 g (85%), brown solid, m.p. 220–222 °C, Rf
1
= 0.50 (EtOAc/hexane, 1:1), tR = 13.85 min. H NMR (200 MHz,
ArH), 7.04–6.99 (m, 1 H, ArH), 6.95 (d, J = 2.3 Hz, 1 H, ArH), [D6]DMSO): δ = 11.01 (d, J = 1.4 Hz, 1 H, ArNH), 9.76 (br. s, 1
6.31 (d, J = 3.8 Hz, 1 H, NH), 5.58 (d, J = 3.7 Hz, 1 H, CH) ppm. H, OH), 8.14 (dd, J = 4.3, 1.4 Hz, 1 H, ArH), 8.08–8.04 (m, 1 H,
13C NMR (50 MHz, [D6]DMSO): δ = 145.2, 143.8, 143.4, 141.3, ArH), 7.41–7.37 (m, 1 H, ArH), 7.29–7.19 (m, 2 H, ArH), 7.02–
136.8, 131.6, 131.4, 130.9, 129.8, 128.8, 128.6, 125.3, 122.0, 121.5,
6.94 (m, 2 H, ArH), 6.87–6.81 (m, 2 H, ArH), 6.59–6.51 (m, 2 H,
121.3, 119.8, 118.6, 117.2, 111.0, 57.7 ppm. IR (KBr): νmax = 3254, ArH), 5.81 (d, J = 2.9 Hz, 1 H, NH), 5.69 (d, J = 3.4 Hz, 1 H,
˜
2930, 1585, 1423 cm–1. MS (ES+): m/z = 376.4 [M + 1]+. CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 154.4, 145.3,
C20H14BrN3 (376.25): calcd. C 63.84, H 3.75, N 11.17; found C
63.81, H 3.76, N 11.13.
144.3, 141.4, 136.8, 130.5, 129.8, 128.1, 127.8, 125.9, 121.9, 121.4,
120.9, 118.6, 117.5, 114.9, 111.0, 53.0 ppm. IR (KBr): νmax = 3155,
˜
2938, 1625, 1410 cm–1. MS (ES+): m/z = 314.4 [M + 1]+.
C20H15N3O (313.36): calcd. C 76.66, H 4.82, N 13.41; found C
76.67, H 4.81, N 13.43.
6-(4-Nitrophenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-
cd]indole (8c): Yield 0.155 g (95%), brown solid, m.p. 206–209 °C,
Rf = 0.43 (EtOAc/hexane, 1:1), tR = 15.89 min. 1H NMR
(200 MHz, [D6]DMSO): δ = 11.16 (s, 1 H, ArNH), 8.31 (s, 1 H,
6-(3,4-Dimethoxyphenyl)-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino-
ArH), 8.10–8.06 (m, 3 H, ArH), 7.44–7.35 (m, 3 H, ArH), 7.24 (t, [3,4,5-cd]indole (8h): Yield 0.148 g (87%), white solid, m.p. 236–
1
J = 7.7 Hz, 2 H, ArH), 7.07–6.97 (m, 2 H, ArH), 6.52 (d, J =
4.3 Hz, 1 H, NH), 5.78 (d, J = 4.1 Hz, 1 H, CH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 151.8, 146.2, 145.4, 143.3, 141.5, 136.8,
131.5, 131.4, 130.2, 129.9, 128.8, 125.3, 123.3, 122.1, 121.7, 121.6,
238 °C, Rf = 0.38 (EtOAc/hexane, 1:1), tR = 15.01 min. H NMR
(200 MHz, [D6]DMSO): δ = 11.01 (s, 1 H, ArNH), 8.16–8.03 (m,
2 H, ArH), 7.38 (d, J = 7.6 Hz, 2 H, ArH), 7.21 (t, J = 7.8 Hz, 1
H, ArH), 7.06–7.01 (m, 2 H, ArH), 6.85 (s, 1 H, ArH), 6.75 (d, J
= 8.1 Hz, 1 H, ArH), 6.53 (d, J = 8.4 Hz, 1 H, ArH), 6.14 (s, 1 H,
NH), 5.47 (d, J = 1.6 Hz, 1 H, CH), 3.66 (s, 6 H, 2ϫOCH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 148.5, 147.7, 145.2, 144.3,
118.3, 116.2, 111.2, 57.6 ppm. IR (KBr): ν
= 3163, 1676, 1591,
˜
max
1510 cm–1. MS (ES+): m/z = 343.3 [M + 1]+. C20H14N4O2 (342.36):
calcd. C 70.17, H 4.12, N 16.37; found C 70.15, H 4.13, N 16.35.
Eur. J. Org. Chem. 2010, 5108–5117
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5115

B. Kundu et al.
FULL PAPER
Fernández-Carvajal, W. V. D. Nest, C. Carreño, A. Ferrer-
Montiel, F. Albericio, J. Med. Chem. 2007, 50, 6133–6143; k)
M. G. Ferlin, G. Chiarelotto, V. Gasparotto, L. D. Via, V.
Pezzi, L. Barzon, G. Palù, I. Castagliuolo, J. Med. Chem. 2005,
48, 3417–3427.
a) R. Frank, Curr. Opin. Biotechnol. 2004, 15, 573–575, and
references cited therein; b) K. Kumar, H. Waldmann, Angew.
Chem. Int. Ed. 2009, 48, 3224–3242.
a) V. M. Muzalevskiy, V. G. Nenajdenko, A. V. Shastin, E. S.
Balenkova, G. Haufe, Tetrahedron 2009, 65, 7553–7561; b)
R. T. Sawant, S. B. Waghmode, Tetrahedron 2009, 65, 1599–
1602; c) I. Ortín, J. F. González, E. d. l. Cuesta, C. Avendaño,
Tetrahedron 2009, 65, 2201–2211; d) X. W. Liao, W. Liu, W. F.
Dong, B. H. Guan, S. Z. Chen, Z. Z. Liu, Tetrahedron 2009,
65, 5709–5715; e) W. Phakhodee, P. Ploypradith, P. Sahakit-
pichan, S. Ruchirawat, Tetrahedron 2009, 65, 351–356; f) P. D.
Bailey, M. A. Beard, T. R. Phillips, Tetrahedron Lett. 2009, 50,
3645–3647; g) X. Shi, S. Liu, W. Xu, Y. Xu, Tetrahedron: Asym-
metry 2008, 19, 435–442; h) Y. Ma, S. Nam, R. Jove, K. Yaku-
shijin, D. A. Horne, Bioorg. Med. Chem. Lett. 2010, 20, 83–86;
i) A. Kulkarni, M. Abid, B. Török, X. Huang, Tetrahedron
Lett. 2009, 50, 1791–1794; j) T. Ito, M. Kitajima, H. Takay-
ama, Tetrahedron Lett. 2009, 50, 4506–4508.
P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu, Eur. J. Org.
Chem. 2009, 2, 292–303.
S. K. Sharma, S. Sharma, P. K. Agarwal, B. Kundu, Eur. J.
Org. Chem. 2009, 9, 1309–1312.
a) B. Saha, S. Sharma, D. Sawant, B. Kundu, Tetrahedron Lett.
2007, 48, 1379–1383; b) B. Saha, S. Sharma, D. Sawant, B.
Kundu, Synlett 2007, 1591–1594.
For a review see a) M. C. Pirrung, K. D. Sarma, Tetrahedron
2005, 61, 11456–11472; b) H. C. Kolb, M. G. Finn, K. B.
Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004–2021.
D. C. Rideout, R. L. Breslow, J. Am. Chem. Soc. 1980, 102,
7816–7817.
a) S. Tiwari, A. Kumar, Angew. Chem. Int. Ed. 2006, 118, 4942–
4943; b) R. Breslow, U. Maitra, Tetrahedron Lett. 1984, 25,
1239–1240; c) R. Breslow, U. Maitra, Tetrahedron Lett. 1983,
24, 1901–1904; d) H. Yanai, A. Saito, T. Taguchi, Tetrahedron
2005, 61, 7087–7093; e) S. D. Larsen, P. A. Grieco, J. Am.
Chem. Soc. 1985, 107, 1768–1769.
J. Dambacher, W. Zhao, A. El-Batta, R. Anness, C. Jiang, M.
Bergdahl, Tetrahedron Lett. 2005, 27, 4473–4477.
M. Wang, C. J. Li, Tetrahedron Lett. 2002, 43, 3589–3591.
T. P. Loh, L. L. Wei, Tetrahedron Lett. 1998, 39, 323–326.
M. K. Chaudhuri, S. Hussain, M. L. Kantamb, B. Neelimab,
Tetrahedron Lett. 2005, 46, 8329–8331.
a) J. J. Gajewski, Acc. Chem. Res. 1997, 30, 219–225; b) P. R.
Andrews, G. D. Smith, I. G. Young, Biochemistry 1973, 12,
3492–3948.
M. Bakherad, A. Keivanloo, B. Bahramian, M. Hashemi, Tet-
rahedron Lett. 2009, 50, 1557–1559.
141.1, 136.8, 136.3, 130.5, 129.8, 125.4, 121.9, 121.3, 121.1, 119.7,
118.5, 118.3, 111.7, 111.1, 110.9, 58.4, 55.4 ppm. IR (KBr): ν
=
˜
max
3180, 1594, 1419 cm–1. MS (ES+): m/z = 358.3 [M + 1]+.
C22H19N3O2 (357.41): calcd. C 73.93, H 5.36, N 11.76; found C
73.95, H 5.33, N 11.72.
[3]
[4]
6-Ethyl-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-cd]indole (8i):
Yield 0.060 g (51 %), brown solid, m.p. 148–149 °C, Rf = 0.38
(EtOAc/hexane, 2:8), tR = 15.32 min. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.91 (s, 1 H, ArNH), 8.18 (s, 1 H, ArH), 8.04–8.01
(m, 1 H, ArH), 7.41–7.31 (m, 2 H, ArH), 7.17–7.10 (m, 3 H, ArH),
5.90 (s, 1 H, NH), 4.23 (s, 1 H, CH), 1.62–1.52 (m, 2 H, ArH), 0.92
(d, J = 3.3 Hz, 3 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 145.1, 143.8, 140.8, 136.8, 130.4, 129.5, 125.0, 122.0, 121.2,
119.7, 118.7, 118.3, 110.7, 56.0, 29.7, 10.8 ppm. IR (KBr): ν
=
˜
max
3300, 2930, 2367, 1641, 1429 cm–1. MS (ES+): m/z = 250.3 [M +
1]+. C16H15N3 (249.31): calcd. C 77.08, H 6.06, N 16.85; found C
76.50, H 6.70, N 16.10.
6-tert-Butyl-6,7-dihydro-4H-pyrido[2Ј,3Ј:6,7]azepino[3,4,5-cd]indole
(8j): Yield 0.083 g (63%), light green solid, m.p. 174–176 °C, Rf =
0.40 (EtOAc/hexane, 2:8), tR = 14.03 min. 1H NMR (300 MHz,
[D6]DMSO): δ = 11.00 (s, 1 H, ArNH), 8.11–8.05 (m, 2 H, ArH),
7.35–7.31 (m, 2 H, ArH), 7.18–7.06 (m, 3 H, ArH), 6.09 (d, J =
5.0 Hz, 1 H, NH), 4.13 (d, J = 5.0 Hz, 1 H, CH), 0.77 [s, 9 H,
(CH3)3] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 144.4, 144.4,
139.5, 136.4, 130.4, 128.2, 126.3, 122.1, 121.9, 120.8, 118.2, 114.8,
[5]
[6]
[7]
110.5, 63.8, 27.6 ppm. IR (KBr): ν
= 3407, 2930, 2375,
˜
max
1649 cm–1. MS (ES+): m/z = 278.3 [M + 1]+. C18H19N3 (277.37):
[8]
calcd. C 77.95, H 6.90, N 15.15; found C 77.43, H 6.23, N 15.20.
Supporting Information (see also the footnote on the first page of
[9]
1
this article): H- and 13C-NMR spectra of compounds 4a–f, 5a–d,
5h, 6a–c,7a–c, 7e–f, 8b, 8e, 8g–h, 8j.
[10]
Acknowledgments
The authors are grateful to SAIF, CDRI, Lucknow for supplying
spectroscopic data. M. S., P. K. A., S. K. S., A. K. M. and S. G. are
grateful to the Council of Scientific and Industrial Research
(CSIR), New Delhi, for fellowships.
[11]
[12]
[13]
[14]
[1] D. J. Faulkner, Nat. Prod. Rep. 2001, 18, 1–49, and references
cited therein.
[15]
[2] a) G. Xie, J. Zimmermann, T. Meyer, J. W. Lown, Bioorg. Med.
Chem. Lett. 1995, 5, 497–500; b) M. S. Chambers, L. J. Street,
S. Goodacre, S. C. Hobbs, P. Hunt, R. A. Jelley, V. G. Matassa,
A. J. Reeve, F. Sternfeld, M. S. Beer, J. A. Stanton, D.
Rathbone, A. P. Watt, A. M. MacLeod, J. Med. Chem. 1999,
42, 691–705; c) R. Faust, P. J. Garratt, R. Jones, L. Yeh, J.
Med. Chem. 2000, 43, 1050–1061; d) S. L. Roach, R. I. Higu-
chi, M. E. Adams, Y. Liu, D. S. Karanewsky, K. B. Marschke,
D. E. Mais, J. N. Miner, L. Zhi, Bioorg. Med. Chem. Lett. 2008,
18, 3504–3508; e) V. S. P. Chaturvedula, S. Sprague, J. K. Schil-
ling, D. G. I. Kingston, J. Nat. Prod. 2003, 66, 528–531; f) Z.
Zhao, S. E. Wolkenberg, M. Lu, V. Munshi, G. Moyer, M.
Feng, A. V. Carella, L. T. Ecto, L. J. Gabryelski, M. Lai, S. G.
Prasad, Y. Yan, G. B. McGaughey, M. D. Miller, C. W.
Lindsley, G. D. Hartman, J. P. Vacca, T. M. Williams, Bioorg.
Med. Chem. Lett. 2008, 18, 554–559; g) A. Scribner, J. A.
Moore III, G. Ouvry, M. Fisher, M. Wyvratt, P. Leavitt, P. Lib-
erator, A. Gurnett, C. Brown, J. Mathew, D. Thompson, D.
Schmatz, T. Biftu, Bioorg. Med. Chem. Lett. 2009, 19, 1517–
1521; h) K. J. Doebel, J. W. F. Wasley, J. Med. Chem. 1972, 15,
1081–1082; i) D. C. Remy, K. E. Rittle, C. A. Hunt, P. S. An-
derson, E. L. Engelhardt, B. V. Clineschmidt, A. Scriabine, J.
Med. Chem. 1977, 20, 1681–1684; j) M. Quintanar-Audelo, A.
[16]
[17]
[18]
[19]
[20]
C. Chevrin, J. L. Bras, F. Henin, J. Muzart, Tetrahedron Lett.
2003, 44, 8099–8102.
D. Schönfelder, O. Nuyken, R. Weberskirch, J. Organometallic.
Chem. 2005, 690, 4648–4655.
S. Kobayashi, S. Iimura, K. Manabe, Chem. Lett. 2002, 31, 10–
11.
a) J. E. Klijn, J. B. F. N. Engberts, Nature 2005, 435, 746–747;
b) C.-J. Li, Chem. Rev. 1993, 93, 2023–2035; c) K. C. Majum-
dar, A. Taher, S. Ponra, Tetrahedron 2010, 51, 147–150; d) A.
Lubineau, Chem. Ind. 1996, 123–127; e) Z. Shen, S. Ji, T. Loh,
Tetrahedron 2008, 64, 8159–8163; f) N. Zotova, A. Franzke, A.
Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2007, 129,
15100–15101; g) B. Liang, M. Dai, J. Chen, Z. Yang, J. Org.
Chem. 2005, 70, 391–393; h) F. Fringuelli, O. Piermatti, F.
Pizzo, in: Targets in Heterocyclic Systems (Eds.: O. Attanasi,
D. Spinelli), Italian Society of Chemistry, Rome, 1997, vol. 1,
pp. 57; i) Organic Synthesis in Water (Ed.: P. A. Grieco),
Blackie Academic and Professional, London, 1998; j) A. Me-
5116
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5108–5117

Water-Assisted Synthesis of Indole-Fused Heterocycles
ijer, S. Otto, J. B. F. N. Engberts, J. Org. Chem. 1998, 63, 8989–
8994, and references cited therein; k) R. Breslow, Acc. Chem.
Res. 1991, 24, 159–164.
[26]
[27]
a) G. André, Y. Han, P. Prasit, Tetrahedron Lett. 1997, 38,
3841–3844; b) B. Oliver, O. Baudoin, D. Guénard, F. Guéritte,
J. Org. Chem. 2000, 65, 9268–9271.
C. Thibault, A. L’Heureux, R. S. Bhide, R. Ruel, Org. Lett.
2003, 5, 5023–5025.
[21] C. Reichardt, Solvent Effects in Organic Chemistry, Verlag
Chemie, Weinheim, 1979, pp. 1–139.
[22] a) W. Blokzijl, J. B. F. N. Engberts, Angew. Chem. Int. Ed. Engl.
1993, 32, 1545–1579; b) T. Rispens, J. B. F. N. Engberts, J. Org.
Chem. 2002, 67, 7369–7377; c) W. Blokzijl, J. B. F. N. Engberts,
M. J. Blandamer, J. Am. Chem. Soc. 1990, 112, 1197–1201; d)
W. Blokzijl, J. B. F. N. Engberts, J. Am. Chem. Soc. 1991, 113,
5440–5442.
[28] S. J. Connon, Angew. Chem. Int. Ed. 2008, 47, 1176–1178.
[29] a) D. Soerens, J. Sandrin, F. Ungemach, P. Mokry, G. S. Nu,
E. Yamanaka, L. Hutchkins, M. DiPierro, J. M. Cook, J. Org.
Chem. 1979, 44, 535–545; b) J. Sandrin, D. Soerens, P. Mokry,
J. M. Cook, Heterocycles 1977, 6, 1133–1139; c) W. M. Dai,
H. J. Zhu, X. J. Hao, Tetrahedron Lett. 1996, 37, 5971–5974; d)
K. M. Czerwinski, L. Deng, J. M. Cook, Tetrahedron Lett.
1994, 33, 4721–4724; e) L. H. Zhang, Y. Z. Bi, F. X. Yu, G.
Menzia, J. M. Cook, Heterocycles 1992, 34, 517–547; f) F. Un-
gemach, M. DiPierro, R. Weber, J. M. Cook, J. Org. Chem.
1981, 46, 164–168; g) M. Jawdosiuk, J. M. Cook, J. Org. Chem.
1984, 49, 2699–2701; h) D. Bonnet, A. Ganesan, J. Comb.
Chem. 2002, 4, 546–548; i) H. Wang, A. Ganesan, Org. Lett.
1999, 1, 1647–1649; j) A. Zawadzka, A. Leniewski, J. K. Mau-
rin, K. Wojtasiewicz, Z. Czarnocki, Org. Lett. 2001, 3, 997–
999; k) C. Gremmen, M. J. Wanner, G. J. Koommen, Tetrahe-
dron Lett. 2001, 42, 8885–8888; l) C. Gremmen, B. Willemse,
M. J. Wanner, G. J. Koomen, Org. Lett. 2000, 2, 1955–1958.
Received: April 29, 2010
[23] J. F. Blake, W. L. Jorgensen, J. Am. Chem. Soc. 1991, 113,
7430–7432.
[24] a) R. J. Capon, F. Rooney, L. M. Murray, E. Collins, A. T. R.
Sim, J. A. P. Rostas, M. S. Butler, A. R. Carrol, J. Nat. Prod.
1998, 61, 660–662; b) A. G. Kozolovskii, T. F. SolovЈeva, V. G.
Sahkarovskii, V. M. Adanin, Dokl. Akad. Nauk SSSR 1981,
260, 230–233; c) S. Krishnan, J. T. Bagdanoff, D. C. Ebner,
Y. K. Ramtohul, U. K. Tambar, B. M. Stoltz, J. Am. Chem.
Soc. 2008, 130, 13745–13754; d) C. L. Schardl, D. G. Panac-
cione, P. Tudzynski, Ergot alkaloids – biology and molecular
biology, in: The Alkaloids: Chemistry and Biology, 2006, vol. 63,
pp. 45–86; e) Y. Nishizuka, Nature 1984, 308, 693–697.
[25] a) J. Kraxner, H. Hübner, P. Gmeiner, Arch. Pharm. Pharm.
Med. Chem. 2000, 333, 287–292; b) A. V. Samet, A. N. Yam-
skov 1, Y. A. Strelenko, V. V. Semenov, Tetrahedron 2009, 65,
6868–6872.
Published Online: July 20, 2010
Eur. J. Org. Chem. 2010, 5108–5117
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5117