Synthesis of 1,3,1′,5′,6′,7′-hexahydro-3,3′- biindolyl-2,4′-dione derivatives by cyclization of 3-alkylideneoxindoles with enaminone

Article abstract of DOI:10.1007/s11164-012-0974-2

The reaction between 3-alkylideneoxindoles 1 and 3-aminocyclohex-2-enone 2 was studied, and an efficient synthesis of 1,3,1′,5′,6′, 7′-hexahydro-3,3′-biindolyl-2,4′-dione derivatives was developed by a sequential Michael addition followed by intramolecular condensation catalyzed by nickel dichloride hexahydrate. The reaction mechanism is discussed.

Full text of DOI:10.1007/s11164-012-0974-2

Res Chem Intermed
DOI 10.1007/s11164-012-0974-2
Synthesis of 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,
40-dione derivatives by cyclization of 3-alkylideneoxindoles
with enaminone
Peng Hui Yang
Received: 6 November 2012 / Accepted: 8 December 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract The reaction between 3-alkylideneoxindoles 1 and 3-aminocyclohex-2-
enone 2 was studied, and an efficient synthesis of 1,3,10,50,60,70-hexahydro-3,30-
biindolyl-2,40-dione derivatives was developed by a sequential Michael addition
followed by intramolecular condensation catalyzed by nickel dichloride hexahy-
drate. The reaction mechanism is discussed.
Keywords Biindoles ꢀ 3-Alkylideneoxindoles ꢀ Synthesis
Introduction
Biindoles are the core structure of many naturally occurring alkaloids and have
important biological activities including antioxidation activity [1], plant growth-
promoting activity [2], protein kinase C inhibiting activity [3, 4], etc. Among these,
the anticancer activity is the most notable [5, 6]. Therefore, they are the research
targets for many organic and pharmaceutical chemists [7–10].
3-Alkylideneoxindoles are readily available building blocks for construction of
various heterocycles. They are usually attacked by nucleophiles on exocyclic double
bond. Spanish scientists reported controlled generation of three contiguous
stereocenters in the Michael addition of 1-pyrrolidinocyclohexene to N-methyl-3-
phenacylideneoxindole [11]; Bergman and colleague [12] reported efficient
synthesis of highly substituted pyrrole by the reaction between 3-aminocrotonates
and 3-acetonylideneoxindole in refluxing toluene; More recently, Perumal and
colleague [13] reported an InCl3-catalyzed one-pot synthesis of 2-pyrrolo-30-
yloxindoles via three-component reaction of 3-phenacylideneoxindole, b-keto ester,
and ammonium acetate at reflux in ethanol.
P. H. Yang (&)
College of Chemistry and Chemical Engineering, Xi’an Shiyou University, Xi’an 710065, China
e-mail: yaph2001@iccas.ac.cn
123

P. H. Yang
R3
N
H
N
O
R3
R2
H2N
O
R2
NiCl26H2O
EtOH
O
O
O
N
R1
R1
1a-1g
2
3a-3g
Scheme 1 Synthesis of 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione derivatives
As a continuation of our program on the development of new methodologies for
preparation of biologically active heterocycles, we developed an efficient synthesis
of hereto-unknown 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione derivatives by
cyclization of 3-alkylideneoxindole 1 with 3-aminocyclohex-2-enone 2 catalyzed by
nickel dichloride hexahydrate (Scheme 1).
Results and discussion
To optimize the reaction conditions, we first examined the reaction between
3-alkylideneoxindole 1a and 3-aminocyclohex-2-enone 2. When 3-alkylideneoxin-
dole 1a and 3-aminocyclohex-2-enone were heated in ethanol, the expected
1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3a was formed in 66.8 % yield
after 60 h of reflux. Higher reaction temperature when using high-boiling-point
solvents such as n-butanol caused decreased yields due to side-reactions. Perumal
reported that InCl3 was an efficient catalyst for this type of reaction, but InCl3 is
expensive and moisture sensitive. We tried to find a cheap and stable catalyst. After
several trials, we found that nickel dichloride hexahydrate was suitable for the
reaction. As can be seen from Table 1, the reaction of 1a and 3-aminocyclohex-2-
enone 2 catalyzed by nickel dichloride hexahydrate in refluxing ethanol afforded the
expected 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione in 80.7 % yield.
Then, the scope and limitations of the reaction involving various 3-alkylidene-
oxindoles 1 and 3-aminocyclohex-2-enone 2 were explored. The results are
presented in Table 2. It can be seen from Table 2 that 3-alkylideneoxindoles with
various substituents were all good substrates for the reaction. When substituent R3
was phenyl, the reaction yield was high, while when R3 was methyl, the reaction
yield was relatively low.
The proton nuclear magnetic resonance (NMR) spectrum of the products seemed
to be complex because two sets of signals were observed due to the keto–enol
tautomerization. However, the proton signals from different tautomers could be
distinguished after careful study. The ratio of keto to enol varied for different
compounds as indicated in Table 2.
The proposed mechanism of the reaction is shown in Scheme 2. 3-Aminocyclo-
hex-2-enone 2 behaved as a 1,3-dinucleophile when reacted with 3-alkylideneox-
indole. The reaction started with 3-aminocyclohex-2-enone 2 attacking the
3-alkylideneoxindole 1a at the exocyclic methylene carbon via Michael addition
123

Synthesis of 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione derivatives
Table 1 Optimization of reaction conditions
H
N
O
O
O
O
O
H2N
N
H
N
H
1a
2
3a
Entry
Product
Catalyst
Solvent
Time
(h)
Yield
(%)
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3a
3a
None
EtOH
60
30
30
72
24
60
60
66.8
60.9
18.7
80.1
65.8
80.7
Messy
None
Toluene
n-Butanol
EtOH
None
B(OH)3
B(OH)3
NiCl.26H2O
CuCl.22H2O
Toluene
EtOH
EtOH
Table 2 1,3,10,50,60,70-Hexahydro-3,30-biindolyl-2,40-dione 3
Entry
Product (keto:enol)a
R1
R2
R3
Yieldb
(%)
1
2
3
4
5
6
7
a
3a (4:1)
3b (3:1)
3c (4:1)
3d (3:1)
3e (4:5)
3f (2:3)
3g (3:2)
H
H
C6H5
C6H5
C6H5
C6H5
Me
80.7
82.0
84.3
78.4
66.2
65.1
69.5
H
Me
H
Me
Et
H
H
H
H
Me
H
Me
Me
Me
Ratio obtained from 1H nuclear magnetic resonance (NMR) analysis of the NH protons
Isolated yield
b
to give the intermediate 4. The intermediate 4 underwent ring closure followed by
elimination of one molecule of water to afford the 1,3,10,50,60,70-hexahydro-3,30-
biindolyl-2,40-dione 3a.
Conclusions
The reaction between 3-alkylideneoxindoles 1 and 3-aminocyclohex-2-enone 2 was
studied, and an efficient synthesis of 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-
dione derivatives was developed by a sequential Michael addition followed by
intramolecular condensation catalyzed by nickel dichloride hexahydrate. The
reaction mechanism was discussed.
123

P. H. Yang
H2N
O
O
O
NiCl26H2O
O
O
O
H2N
N
H
N
H
2
1a
4
H
N
H
N
H
N
-H2O
keto-enol
tautomerism
HO
O
O
O
O
O
OH
N
H
N
H
N
H
3a
Scheme 2 The proposed mechanism
Experimental
Melting points were uncorrected and determined on a WRS-1A digital melting-
point apparatus. 1H NMR spectra were recorded on an INOVA-400 using
tetramethylsilane (TMS) as internal reference. Elemental analysis was recorded
on a VarioEL III elemental analysis device. All reagents and solvents were obtained
from commercial sources and were used without purification.
General procedure for preparing 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-
dione 3a–h
To a mixture of 3-alkylideneoxindole 1 (1.0 eq.) and 3-aminocyclohex-2-enone 2
(1.2 eq.) in 25 mL of anhydrous EtOH was added nickel dichloride hexahydrate
(0.3 eq.). Then the mixture was stirred and refluxed for 40–82 h. The mixture was
cooled to room temperature. The precipitated product was collected by filtration, or
the mixture was poured into water and extracted with ethyl acetate. The extracts
were dried and evaporated, and the residue was crystallized to give the pure
products.
20-Phenyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3a
M.p.[290 °C; 1H NMR (DMSO-d6) d: 11.70 (s, 1H), 10.27 (s, 1H), 7.46–7.52 (m,
3H), 7.35–7.37 (m, 1H), 7.08–7.12 (m, 2H), 6.78–6.79 (m, 3H), 4.52 (s, 1H), 2.77
(s, 2H), 2.09 (s, 2H), 1.94 (s, 2H). Anal. Calcd. for C22H18N2O2: C, 77.17; H, 5.30;
N, 8.18 %. Found: C, 76.82; H, 5.14; N, 7.90 %.
123

Synthesis of 1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione derivatives
5-Methyl-20-phenyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3b
1
M.p. 253–255 °C; H NMR (DMSO-d6) d: 11.70 (s, 1H), 10.17 (s, 1H), 7.47–7.55
(m, 3H), 7.37 (t, 1H, J = 6.4 Hz), 7.14 (d, 1H, J = 4.8 Hz), 6.90 (d, 1H,
J = 8.0 Hz), 6.65–6.74 (m, 2H), 4.51 (s, 1H), 2.80 (t, 2H, J = 5.2 Hz), 2.16 (s, 3H),
2.11–2.13 (m, 2H), 1.95–1.99 (m, 2H); Anal. Calcd. for C23H20N2O2: C, 77.51; H,
5.66; N, 7.86 %. Found: C, 77.20; H, 5.42; N, 7.59 %.
1-Methyl-20-phenyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3c
M.p. 270–272 °C; 1H NMR (DMSO-d6) d: 11.73 (s, 1H), 7.37–7.58 (m, 4H),
7.13–7.21 (m, 2H), 6.87–6.99 (m, 3H), 4.62 (s, 1H), 3.15 (s, 3H), 2.78 (t, 2H,
J = 6.0 Hz), 2.07–2.13 (m, 2H), 1.92–1.96 (m, 2H); Anal. Calcd. for C23H20N2O2:
C, 77.51; H, 5.66; N, 7.86 %. Found: C, 77.15; H, 5.48; N, 7.85 %.
1-Ethyl-20-phenyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3d
M.p. 269–270 °C; 1H NMR (DMSO-d6) d: 11.74 (s, 1H), 7.46–7.56 (m, 3H), 7.37 (t,
1H, J = 7.2 Hz), 7.10–7.25 (m, 2H), 6.86–7.03 (m, 3H), 4.58 (s, 1H), 3.71 (q, 2H,
J = 7.2 Hz), 2.79 (t, 2H, J = 5.6 Hz), 2.08–2.13 (m, 2H), 1.93–1.96 (m, 2H), 1.23
(t, 3H, J = 6.4 Hz); Anal. Calcd. for C24H22N2O2: C, 77.81; H, 5.99; N, 7.56 %.
Found: C, 77.46; H, 5.83; N, 7.22 %.
20-Methyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3e
M.p.[290 °C; 1H NMR (DMSO-d6) d: 11.10 (s, 1H), 10.44 (s, 1H), 6.67–7.15 (m,
4H), 5.49 (s, 1H), 2.72 (t, 2H, J = 6.0 Hz), 2.35 (t, 1H, J = 6.0 Hz), 1.99–2.05 (m,
2H), 1.87–1.90 (m, 1H), 1.58 (s, 3H); Anal. Calcd. for C17H16N2O2: C, 72.84; H,
5.75; N, 9.99 %. Found: C, 74.42; H, 5.54; N, 9.66 %.
5,20-Dimethyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3f
1
M.p. [290 °C; H NMR (DMSO-d6) d: 11.10 (s, 1H), 10.34 (s, 1H), 6.93 (d, 1H,
J = 8.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 6.68 (s, 1H), 5.45 (s, 1H), 2.72 (t, 2H,
J = 5.2 Hz), 2.35 (t, 1H, J = 5.6 Hz), 2.17 (s, 3H), 2.01–2.05 (m, 2H), 1.86–1.91
(m, 1H), 1.58 (s, 3H); Anal. Calcd. for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52 %.
Found: C, 72.99; H, 5.88; N, 9.19 %.
1,20-Dimethyl-1,3,10,50,60,70-hexahydro-3,30-biindolyl-2,40-dione 3g
M.p. 260–262 °C; 1H NMR (DMSO-d6) d: 11.16 (s, 1H), 7.16 (t, 1H, J = 8.0 Hz),
6.93 (t, 2H, J = 8.0 Hz), 6.75 (d, 1H, J = 8.0 Hz), 4.54 (s, 1H), 3.14 (s, 3H), 2.65
(t, 2H, J = 5.2 Hz), 2.35 (t, 1H, J = 6.0 Hz), 2.27 (s, 3H), 1.98–2.07 (m, 2H),
1.85–1.90 (m, 1H); Anal. Calcd. for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52 %.
Found: C, 73.02; H, 5.96; N, 9.31 %.
123

P. H. Yang
Acknowledgments This work was supported by the Foundation of Xi’an Shiyou University (Z08012).
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