Highly efficient, one-pot synthesis of novel bis-spirooxindoles with skeletal diversity: Via sequential multi-component reaction in PEG-400 as a biodegradable solvent

Article abstract of DOI:10.1039/c7ra06017c

A green and efficient one-pot, sequential, multi-component protocol has been developed for the synthesis of some novel symmetrical bis-spirooxindole derivatives from the reaction of isatins, dihalides, malono derivatives and C-H activated carbonyl compoun

Full text of DOI:10.1039/c7ra06017c

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Highly efficient, one-pot synthesis of novel bis-
spirooxindoles with skeletal diversity via sequential
multi-component reaction in PEG-400 as
a biodegradable solvent†
Cite this: RSC Adv., 2017, 7, 39502
Ensieh Safari, Ammar Maryamabadi and Alireza Hasaninejad
*
A green and efficient one-pot, sequential, multi-component protocol has been developed for the synthesis
of some novel symmetrical bis-spirooxindole derivatives from the reaction of isatins, dihalides, malono
derivatives and C–H activated carbonyl compounds or ketene aminal derivatives in the presence of
2 3
potassium carbonate (K CO ) in polyethylene glycol 400 (PEG-400) as a biodegradable polymeric
Received 29th May 2017
Accepted 6th August 2017
solvent at room temperature. In this research, a variety of bis-spiro-indoline-pyranopyranes, bis-spiro-
indoline-chromenes, bis-spiro-indoline-pyrido-pyrimidines, bis-spiro-indoline-imidazo-pyridines and
bis-spiro-indoline-pyridines were obtained with excellent yields within short reaction time and without
chromatographic separation.
DOI: 10.1039/c7ra06017c
rsc.li/rsc-advances
widely in bio-conjugates as tools for diagnostics and in drug
delivery.
Development of efficient chemical reaction sequences in
Introduction
10,11
Public concern over the effects of chemical release into the
environment has grown steadily due to the potential threats to green media that provide a molecular diversity and structural
human health and indirect harm arising through disruptions of complexity with a minimum number of synthetic steps could be
1
12
natural ecosystems. The introduction of green processes into major challenge. As a solution for these challenges, multi-
chemistry has helped to reduce chemical related impact on component reactions (MCRs) are considered to be one of the
2
human health and the environment. Since most organic reac- most efficient strategies in modern organic synthesis and
tions occur in the liquid phase, selection of solvent is one of the employing green solvents may inuence the course of reaction,
13
most active areas of research in green chemistry, because it yields, selectivity and the reaction rates. MCRs are well known
makes up by far the greatest proportion of waste and a signi- for their simplicity of operation, reduction of isolation and
cant part of the hazard issues and energy intensity of purication steps, and minimization of energy, time, costs, and
3,4
14–17
a process. Green solvents should meet some basic require- waste production.
The efforts to combine the advantages of
ments such as low toxicity, non-ammability, non- MCRs and eco-friendly solvents through conducting MCRs in
5
,6
18
mutagenicity, non-volatility and widespread availability.
such solvents has been comprehensively reviewed. Conduct-
19
20
21
Recently, polyethylene glycol (PEG) has been found to be ing MCRs in water, ionic liquids, polyethylene glycol (PEG),
7,8
22
23
a novel, powerful and interesting green solvent system. PEG super critical carbon dioxide (scCO
), bio-derived solvents,
2
24
25
covers many requirements of a green solvent such as thermal peruorinated solvents and neat systems has attracted more
stability over a wide range of temperatures, recovery, non- attention in recent decade.
8,9
explosiveness, commercial availability and non-toxicity.
Isatin and bis-isatin spiro derivatives (including bis-
PEGs are readily soluble in polar solvents such as water, DMF spirooxindoles) have been synthesized using different meth-
and methanol but are insoluble in non-polar solvents such as odologies and have been utilized successfully in many biolog-
diethyl ether and n-hexane; this unequalled property permits ical processes as antimicrobial, anticancer and enzyme
26–28
the recovery of PEGs by precipitation and ltration, which is inhibitor agents.
However, many of the synthetic routes
extremely signicant in soluble polymer-supported chemistry. toward bis-spirooxindoles include the use of toxic solvents and
Furthermore, PEG is a biological polymer that has been used catalysts or they have been conducted in harsh conditions like
29–31
reuxing for long times.
Furthermore, biological studies
demonstrate that the presence of an aliphatic chain in a mole-
Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr, cule decreases the polarity and lead to increases in lipophilicity
7
†
1
516913817, Iran . E-mail: a_hasaninejad@yahoo.com
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra06017c
of the compound. Therefore, this property enables the
compound to cross the biological membrane which cause
39502 | RSC Adv., 2017, 7, 39502–39511
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appropriate reaction medium for the synthesis of bis-
spirooxindoles. Different solvents, catalysts and reaction
temperatures were explored in this investigation. Water,
methanol, ethanol, acetonitrile, DMF, DMSO and PEG-400 were
examined as solvent and the effects of temperature, the type and
the amount of catalyst have been checked (Table 1). Aer this
vast study, the results have depicted that the highest value for
yield of desired bis-spirooxindole has been obtained in PEG-400
2 3
in the presence of 2 mmol of K CO at room temperature.
Initially, this reaction was carried out in PEG-400 without any
catalyst at room temperature. It was observed that the reaction
did not proceed even aer 24 hours (Table 1, entry 1). Different
3 2 3
catalysts including L-proline, DABCO, DBU, NaHCO , Na CO ,
Table 1 Synthesis of bis-spiroindoline chromene 7a through one-pot
sequential condensation reaction between isatin 1a (2 mmol), 1,6-
dibromohexane 2a (1 mmol), malononitrile 4a (2 mmol) and dimedone
5a (2 mmol) using different amounts of basic catalysts in various
solvents and temperatures
Scheme 1 The one-pot, multi-component synthesis of bis-spiroox-
indoles in PEG-400/K CO at room temperature.
2 3
increasing the biological activity of the compound. On the basis
of the above hypothesis and according to the biological activity
32
of spirooxindoles, we would like to report an efficient one-pot,
multi-component synthesis of novel bis-spirooxindole deriva-
tives in green medium (Scheme 1).
a
Catalyst
(mmol)
Temperature
( C)
Time
(h)
Yield
(%)
Results and discussion
ꢀ
Entry
Solvent
Initially, the sequential condensation of isatin 1a (2 mmol), 1,6-
dibromohexane 2a (1 mmol), malononitrile 4a (2 mmol) and
dimedone 5a (2 mmol) (Scheme 2) was investigated to nd an
1
2
3
4
5
6
7
8
9
—
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
24
24
24
24
24
24
24
24
24
24
9
—
—
—
—
Trace
42
—
30
73
—
91
80
91
90
91
—
—
—
L-Proline (2)
DABCO (2)
DBU (2)
NaHCO
Na CO
NaOH (2)
CaCO (2)
Cs CO (2)
KOH (2)
3
(2)
(2)
2
3
3
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
(2)
(1.5)
(3)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
12
9
9
80
9
H
2
O
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
100
24
24
24
24
18
15
24
24
MeOH
EtOH
CH
3
CN
Trace
80
85
—
—
DMF
DMSO
—
—
a
Scheme 2 Regioselectivity in ketene aminal reactions with bis-isatin-
Isolated yield.
malononitrile aggregate.
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NaOH, CaCO
3
, Cs
2
CO
3
, KOH and K
2
CO
3
in PEG-400 at room
On the basis of biological studies, the existence of two or
temperature were tested (Table 1, entries 2–11) and K CO was more different heterocyclic moieties in a single molecule oen
2
3
34,35
the best catalyst for this transformation (Table 1, entry 11). enhances the biological activity dramatically.
Increasing the amount of K CO did not improve the reaction methods are available for the synthesis of bis-spirooxindoles
A few synthetic
2
3
results whereas; decreasing the amount of catalyst decreased derivatives. However, survey of the literature data show that
the reaction yield (compare entries 11–13 Table 1). Increasing of the majority of these methods suffer from one or more draw-
the reaction temperature did not affect the reaction process (for backs, such as multistep sequences, toxic solvents like DMSO
comparison see Table 1, entries 11, 14 and 15). The model and DMF, application of hazardous and toxic agents like NaH
29–31,36
reaction was also examined in the presence of K
2
CO
3
in other and long reaction times.
Considering the aforementioned
solvents including H O, MeOH, EtOH, CH CN, DMF and drawbacks, producing of N-alkyl-linked bis-isatins and then
2
3
DMSO. In protic solvents (H O, EtOH, and MeOH) the reaction obtaining the corresponding bis-spirooxindole compounds in
2
did not proceed at all, whereas change of solvent from protic to our introduced reaction model have merits such as green
aprotic (CH
3
CN, DMF, DMSO) resulted in the formation of the solvent, non-toxic reagent, room temperature conditions, low
desired product. This observations could be related to the cost, and easy work-up.
solubility of starting materials and activation of catalyst in
aprotic solvents. The reaction was also tested in neat conditions 400/K
Having found the basic conditions for model reaction (PEG-
CO ), we then directed our attention toward the reaction
2
3
2 3
in the presence of K CO at different temperatures but did not scope for the synthesis of bis-spirooxindoles and the results
proceed even aer 24 h (Table 1, entries 22, 23). The reason have been shown in Table 2.
behind this performance of PEG-400 could be related to its
As shown in Table 2, all reactions proceeded efficiently,
unique property in solving and gathering reactants and the affording the corresponding products in good to excellent
catalyst together to react more efficiently in comparison to other yields. Considering different substitutions on starting isatins,
33
solvents.
malono-derivatives and enolizable ketones, the obtained
2 3
Table 2 One-pot, multi-component synthesis of bis-spirooxindoles (7a–7u) in the presence of K CO in PEG-400 at room temperature
a
Entry
R
Y
X
Z
Ketone
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(p-C
(p-C
(p-C
(p-C
(p-C
(p-C
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
4
4
4
4
4
4
4
4
4
2
4
4
4
2
2
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
CN
CO
CO
CO
CO
CO
CN
CO
CO
CO
CN
CO
CO
CO
CO
CN
CO
CN
CO
CO
CN
5a
5a
5a
5d
5c
5b
5a
5c
5c
5e
5a
5b
5d
5c
5b
5a
5b
5b
5a
5a
5a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
9
91
90
88
89
90
90
93
89
92
90
89
90
89
88
90
95
90
90
88
90
91
2
2
2
2
2
Me
Et
Me
Et
10
12
12
12
11
9
11.5
9
10
9
10
8
9
10
8
8
Me
Me
Br
Br
Me
F
H
Me
H
H
H
H
Br
Br
Br
Me
H
Et
2
2
2
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
2
2
2
2
Me
Et
Et
Me
6
6
6
6
6
6
H
4
4
4
4
4
4
)
)
)
)
)
)
H
H
H
H
H
2
Et
9
2
2
Et
Et
7s
7t
7u
10
10
9
H
a
Isolated yield.
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compounds are representative for all possible 180 possible
combinations.
Ketene aminals (KAs) are powerful and versatile intermedi-
ates in heterocyclic synthesis. Reactions of ketene aminals with
It is well known that the presence of indole substructure in a number of bis-electrophilic reagents have been successfully
heterocyclic compounds such as spirooxindloes, makes them used to give ve- and six-membered and fused heterocyclic
3
7–39
41
biologically active.
can be found in many natural active compounds with anti- synthesized according to literature.
Spirooxindoles are fascinating cores that compounds during the past years. Ketene aminals were
21,42
Briey, 1,1-
bis(methylthio)-2-nitroethylene (1 mmol) and diamines
40
proliferative, antibacterial, antifungal and antiviral activities.
Therefore, as a future plan, it is worthy to evaluate the effect of (1 mmol) or primary amines (2 mmol) have been reacted in
the additional spiro core on the biological activity of the ob- EtOH at reux for 2–4 h. The precipitate has been ltered and
tained bis-spiro compounds by comparing with mono-spiro washed by cold ethanol (82–95% yield) (Table 3).
activities.
Subsequently, we expanded the scope of the performed
condensation reaction by investigating the use of ketene ami-
nals as alternatives for enolizable ketones. Under the same
conditions for model reaction, the condensation reaction of
isatins, dihalides, malono derivatives and ketene aminals in the
Table 3 Synthesis of ketene aminal derivatives
2 3
presence of K CO in PEG-400 at room temperature have been
conducted, affording the corresponding products 8a–8n in good
yields and in short reaction times (Table 4).
As shown in Table 4, different types of alkyl dihalides, which
some of them have aromatic ring in their structure, have been
effectively utilized as linker between two isatin molecules. Also
isatins with electron withdrawing and electron donating
substitutions on their aromatic ring have been successfully
used for synthesis of these complex structures. It turned out
that the electronic effects of substitution on aromatic ring of
isatin has negligibly affected the time and yield of bis-
spirooxindole. Various aliphatic cyclic and acyclic ketene
a
Entry
R
1
Product
Time (h)
Yield (%)
1
2
3
4
–(CH
–(CH
–CH
2
)
)
2
3
–
–
6a
6b
6c
6d
2.5
4
2.5
2
82
93
94
95
2
2
C(CH
3
)
2
2
CH –
PhCH
2
–
a
Isolated yield.
Table 4 One-pot, multi-component synthesis of bis-spirooxindole derivatives (8a–8n) in the presence of K
2
CO
3
in PEG-400 at room
temperature
a
Entry
R
Y
X
Z
Ketene aminal
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
NO
NO
NO
CH
CH
CH
F
(CH
(CH
(p-C
2
2
)
)
2
Br
Br
Cl
Br
Br
Cl
Br
Br
Cl
Br
Cl
Br
Br
Cl
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
6a
6b
6c
6b
6d
6a
6c
6a
6b
8b
6d
6a
6c
6d
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
11
12
11
13
10
10
9
73
74
69
73
75
70
72
69
71
67
69
72
71
77
4
6
H
4
4
)
)
2
2
2
3
3
3
(CH
2
)
2
(CH
(p-C
(CH
(o-C
(p-C
(CH
(p-C
(CH
(o-C
(o-C
2
6
)
H
4
2
6
6
)
H
H
4
4
)
)
11
9
4
10
11
12
13
14
2
)
2
12
10
12
13
10
F
6
H
4
)
Br
Br
Br
2
)
4
6
6
H
H
4
)
)
4
a
Isolated yield.
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aminals were successfully utilized to prepare the corresponding
bis-spiro-indoline-pyrido-pyrimidines,
bis-spiro-indoline-
imidazo-pyridines and bis-spiro-indoline-pyridines derivatives
in high yields. Noteworthy, as a result of the greater nucleo-
philicity of the a-carbon atom in comparison with nitrogen
43
atom, attack of a-carbon leads to the reaction between ketene
aminals (6a–6d) and bis-isatin-malononitrile aggregate to form
the corresponding spiro-dihydropyridine ring in the target
compounds (8a–8n) in moderate to good yields (67–75%) (upper
pathway of Scheme 2). Recent studies on mono-spiro counter-
parts of bis-spirooxindoles that contain dihydropyridine rings
have approved their ability in inhibition of acetyl cholinesterase
and butyryl cholinesterase enzymes which are well known for
they role in Alzheimer disease that it makes these bis-spiro
molecules an attractive subjects of further biological
Chart 1 The reaction of: isatin 1a (2 mmol) with 1,6-dibromohexane
2a (1 mmol), malononitrile 4a (2 mmol) and dimedone 5a (2 mmol) in
2 3
the presence of recovered PEG-400/K CO (2 mmol) at room
temperature.
2 3
In another study, reusability of PEG and K CO were studied.
For this propose, the reaction of isatin 1a (2 mmol) with 1,6-
dibromohexane 2a (1 mmol), malononitrile 4a (2 mmol) and
21
investigation.
It should be mentioned that the reaction failed when ethyl-2-
cyanoacetate and methyl-2-cyanoacetate were used instead of
malononitrile which could be related to lower tendency of
ketene aminals to undergo condensation reactions when
compared to enolizable ketones.
dimedone 5a (2 mmol) was performed in the presence of K
2 3
CO
(2 mmol) in PEG-400 (3 mL) at room temperature. Aer
completion of the reaction, as monitored by TLC, water (3 mL)
was added to the reaction mixture to precipitate the product
and separate it. Aer isolation of product, water was removed by
A
plausible mechanism for the synthesis of bis-
spirooxindole derivatives 7 and 8 in the presence of K CO is
2
3
ꢀ
direct distillation at 100 C and the mixture of PEG-400 and
shown on Scheme 3. The rst step involves the formation of
product 3 from condensation reaction between 2 eq. of isatin 1
K
2
2
CO
3
was washed with diethyl ether (two times, every time with
CO were successfully used
mL). The regenerated PEG and K
2
3
with 1 eq. dihalide 2. In the PEG-400/K CO system, because of
2
3
for the next run under identical reaction conditions. The reus-
ability results are summarized in Chart 1. As Chart 1 indicates,
PEG/K CO system was successfully recycled and reused in four
the coordination of the cationic centre of K CO with the
2
3
2
ꢁ
oxygen of polyethylene glycol, the CO
anion could be pre-
3
2
3
44
2ꢁ
sented in solution and the reaction of CO
3
anion with isatin
cycles with almost unchanged yields (Chart 1).
derivatives was elevated by increasing the nucleophilicity of
nitrogen atom to attack to dihalide. Then, fast Knoevenagel
condensation occurs between
3 and acidic protons of
Experimental
compound 4 for the formation of olen A. In the presence of
K CO , ketene aminal 6 converts to its corresponding enolate,
2
3
All reagents were purchased from commercial suppliers and
used without any further purication. All the reactions were
carried out under air atmosphere. H and C NMR spectra were
recorded on a Bruker Avance (400 and 100 MHz) NMR spec-
trometer in DMSO as solvent. The following abbreviations are
used to indicate the multiplicity in NMR spectra: s—singlet; d—
doublet; t—triplet; q—quartet; quint.—quintet; dd—double
doublet; m—multiplet; br—broad signal and coupling
constants (J values) in hertz (Hz). Melting points were recorded
on a B u¨ chi B-545 apparatus in open capillary tubes. Elemental
analyses were performed by using a Leco Analyzer 932 (Leco
Corp., St. Joseph, MI).
which easily reacts with olen A to produce intermediate B,
which followed by proton transfer and tautomerization to form
the desired product 8.
General procedure for the synthesis of ketene aminals
A solution of bis(methylthio)-2-nitroethylene (1 mmol) and
diamine derivatives (1 mmol) or benzyl amine (2 mmol) were
added in a 25 mL round-bottomed ask contained ethanol
ꢀ
(
4.0 mL), and the resulting mixture was reux at 80 C. Aer
completion of the reaction conrmed by TLC, the reaction
mixture was cooled to room temperature. Then, the precipitated
product was ltered, and washed with cool ethanol (two times,
every time with 4 mL) to give the pure product.
Scheme 3 The proposed mechanism for the synthesis of bis-spi-
rooxindole in the presence of K CO in PEG-400.
2 3
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General procedure for the synthesis of bis-spirooxindole
derivatives
d ¼ 0.73 (t, J ¼ 8 Hz, 6H), 1.46–1.47 (m, 4H), 1.63–1.65 (m, 4H),
2.20 (s, 6H), 2.21 (s, 6H) 3.45–3.52 (m, 2H), 3.63–3.68 (m, 2H),
3
8
1
1
1
.70–3.75 (m, 4H), 6.31 (s, 2H), 6.78–6.82 (m, 4H), 6.98 (d, J ¼
A solution of isatin derivates (2 mmol) and K
2
2
was stirred for 6 h at room temperature. Aer completion of the
reaction conrmed by TLC, malono derivative (2 mmol) and
enolizable carbonyl compound (5a–5d, 2 mmol) or ketene
aminal derivative (6a–6d, 2 mmol) were added to the reaction
mixture. Aer completion of the reaction, 3 mL of water was
added to the reaction mixture; the precipitate was ltrated and
washed with ethanol (two times, every time with 5 mL) to give
2
CO
mmol) in PEG (3 mL) was stirred at room temperature. Aer
h, di-halide derivates (1 mmol) was added, and the mixture
3
(276 mg,
13
Hz, 2H), 8.07 (br, 4H, NH ); C NMR (100 MHz, DMSO-d ): d ¼
2
6
4.0, 19.6, 21.0, 26.8, 27.2, 44.6, 46.6, 59.3, 75.9, 98.1, 101.3,
07.4, 123.9, 128.5, 130.7, 134.5, 143.1, 159.4, 159.5, 159.9, 163.6,
67.7, 177.4.
0
000
0
0
Diethyl-1 ,1 -(hexane-1,6-diyl)bis(2-amino-5 -bromo-2 ,5-
0
dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-car-
boxylate) (7f). Cream solid; mp > 290 C; H NMR (400 MHz,
ꢀ
1
DMSO-d ): d ¼ 0.71–0.74 (m, 6H), 1.47–1.49 (m, 4H), 1.64–1.66
6
(m, 4H), 1.88–1.89 (m, 4H), 2.17–2.22 (m, 4H), 2.64–2.67 (m,
4H), 3.47–3.50 (m, 2H), 3.62–3.65 (m, 2H), 3.67–3.77 (m, 4H),
the pure product. The recovered PEG-400 and K
for another time without loss of its activity.
2
CO
3
were used
6.84–6.87 (m, 2H), 7.12–7.13 (m, 2H), 7.29–7.33 (m, 2H), 7.99
1
3
0
000
0
(br, 4H, NH
2
); C NMR (100 MHz, DMSO-d
6
): d ¼ 14.1, 20.0,
1
,1 -(Hexane-1,6-diyl)bis(2-amino-7,7-dimethyl-2 ,5-dioxo-
0
26.7, 27.0, 27.4, 37.4, 44.6, 46.84, 59.2, 76.0, 109.3, 113.2, 113.9,
125.7, 130.4, 138.3, 144.8, 159.7, 165.4, 167.8, 178.1, 195.5.
5
,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-carbonitrile)
ꢀ
7a). Cream solid; mp > 290 C; H NMR (400 MHz, DMSO-d ):
6
1
(
0
000
0
1
,1 -(Hexane-1,6-diyl)bis(2-amino-5 -bromo-7,7-dimethyl-
d (ppm) ¼ 1.02 (s, 6H), 1.04 (s, 6H), 1.41–1.44 (m, 4H), 1.59–1.63
0
0
2
,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-
(m, 4H), 2.09–2.19 (m, 4H), 3.04 (s, 4H), 3.59–3.67 (m, 4H), 6.86–
ꢀ
1
1
3
carbonitrile) (7g). White solid, mp > 290 C; H NMR (400 MHz,
DMSO-d
1
3
NH
2
6.88 (m, 4H), 7.02–7.04 (m, 2H), 7.25 (br, 4H, NH ); C NMR
6
): d ¼ 1.02 (s, 6H), 1.07 (s, 6H), 1.40–1.42 (m, 4H), 1.58–
.60 (m, 4H), 2.13–1.16 (m, 4H), 2.59 (s, 4H), 2.64 (s, 4H), 3.57–
.71 (m, 4H), 6.97–6.99 (m, 2H), 7.29–7.30 (m, 2H), 7.39 (br, 4H,
(
5
1
100 MHz, DMSO-d
6
): d ¼ 26.5, 27.5, 28.1, 32.4, 45.2, 46.8, 50.4,
7.7, 108.8, 111.2, 117.7, 122.6, 123.4, 128.8, 134.2, 143.5, 159.3,
64.7, 176.8, 195.3.
1
3
0
000
2
); C NMR (100 MHz, DMSO-d
6
): d ¼ 26.3, 27.1, 27.7, 28.0,
Dimethyl-1 ,1 -(hexane-1,6-diyl)bis(2-amino-7,7-dimethyl-
,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-
0
0
32.5, 47.0, 50.0, 57.0, 61.5, 110.6, 110.8, 114.4, 118.9, 126.3,
131.5, 136.6, 142.9, 148.3, 155.2, 159.4, 165.2, 176.5, 195.6.
2
ꢀ
1
carboxylate) (7b). Cream solid; mp > 290 C; H NMR (400 MHz,
DMSO-d
): d (ppm) ¼ 0.94 (s, 6H), 1.01 (s, 6H), 1.26 (s, 4H), 1.50–
.54 (m, 4H), 1.66–1.68 (m, 4H), 1.97–2.01 (m, 2H), 2.13–2.17
m, 2H), 3.21 (s, 6H), 3.61–3.63 (m, 4H), 6.86–6.90 (m, 6H), 7.13
0
0
0
0
Dimethyl-1,1 -(hexane-1,6-diyl)bis(2 -amino-5,7 -dimethyl-
6
0
0
0
0
2,5 -dioxo-5 H-spiro[indoline-3,4 -pyrano[4,3-b]pyran]-3 -carbox-
1
ꢀ
1
ylate) (7h). Light brown solid, mp > 290 C; H NMR (400 MHz,
DMSO-d
6
6
(
(
1
3
6
): d ¼ 1.47–1.49 (m, 4H), 1.61–1.64 (m, 4H), 2.20 (s,
s, 2H), 7.87 (br, 4H, NH
2
); C NMR (100 MHz, DMSO-d
6
): d ¼
H), 2.21 (s, 6H), 3.24 (s, 6H), 3.60–3.72 (m, 4H), 6.31 (s, 2H),
2
1
1
0.0, 27.5, 31.2, 37.4, 44.3, 47.0, 59.2, 76.2, 108.7, 109.9, 113.7,
1
3
2
.79–6.81 (m, 4H), 6.96–98 (m, 2H), 8.02 (br, 4H, NH ); C NMR
25.7, 128.2, 130.3, 136.0, 138.3, 144.7, 150.2, 159.7, 165.8,
67.7, 178.7, 196.4.
(100 MHz, DMSO-d
6
): d ¼ 19.6, 21.0, 26.7, 27.2, 27.4, 44.5, 46.6,
0
000
0
50.9, 59.3, 76.0, 101.3, 107.5, 123.9, 128.6, 130.7, 134.3, 142.9,
158.8, 159.4, 163.6, 167.859, 177.4.
Diethyl-1 ,1 -(hexane-1,6-diyl)bis(2-amino-7,7-dimethyl-2 ,5-
0
dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-car-
0
0
0
0
ꢀ
1
Dimethyl-1,1 -(hexane-1,6-diyl)bis(2 -amino-5-uoro-7 -
boxylate) (7c). Cream solid; mp > 290 C; H NMR (400 MHz,
DMSO-d
0
0
0
methyl-2,5 -dioxo-5 H-spiro[indoline-3,4 -pyrano[4,3-b]pyran]-
6
): d ¼ 0.68–0.72 (m, 6H), 0.93–0.97 (s, 6H), 1.02 (s, 6H),
.26 (s, 4H), 1.50–1.52 (m, 4H), 1.67–1.69 (m, 4H), 2.02–2.13 (m,
H), 3.35–3.67 (m, 4H), 3.71–3.73 (m, 4H), 6.86–6.91 (m, 6H),
0
ꢀ
1
3
-carboxylate) (7i). White solid, mp > 290 C; H NMR (400
MHz, DMSO-d
): d ¼ 1.48–1.50 (m, 4H), 1.64–1.66 (m, 4H), 2.21
(s, 6H), 3.23 (s, 6H), 3.52–3.74 (m, 4H), 6.32 (s, 2H), 6.86–6.93
m, 2H), 6.99–7.01 (m, 2H), 7.16–7.20 (m, 2H), 8.03 (br, 4H,
1
4
7
6
1
3
.14 (s, 2H), 7.92 (br, 4H, NH2); C NMR (100 MHz, DMSO-d6):
(
d ¼ 14.0, 19.6, 26.7, 27.2, 27.4, 31.2, 44.6, 46.5, 50.9, 53.4, 59.3,
1
3
NH2); C NMR (100 MHz, DMSO-d ): d ¼ 19.9, 27.0, 27.4, 27.5,
6
7
1
5.9, 101.2, 107.7, 128.4, 134.3, 145.4, 158.4, 159.4, 159.5, 159.9,
63.7, 167.8, 177.5.
44.6, 46.4, 51.1, 59.1, 75.9, 101.4, 107.9, 124.1, 128.6, 130.7,
00
0
0
134.5, 143.1, 158.6, 159.4, 163.6, 167.9, 177.5.
Dimethyl-1,1 -(hexane-1,6-diyl)bis(2 -amino-6 -(hydroxy-
00 0 0 0
Dimethyl-1,1 -(butane-1,4-diyl)bis(2 -amino-2,5 -dioxo-5 H-
0
0
0
methyl)-5-methyl-2,8 -dioxo-8 H-spiro[indoline-3,4 -pyrano[3,2-
0
0
0
ꢀ
1
spiro[indoline-3,4 -pyrano[3,2-c]chromene]-3 -carboxylate) (7j).
b]pyran]-3 -carboxylate) (7d). Cream solid; mp > 290 C; H NMR
400 MHz, DMSO-d
ꢀ
1
Light brown solid, mp > 290 C, H NMR (400 MHz, DMSO-d
d ¼ 1.77–1.85 (m, 4H), 3.05 (s, 6H), 3.66–3.83 (m, 4H), 6.82–6.90
m, 2H), 7.02–7.25 (m, 6H), 7.48 (d, J ¼ 8 Hz, 2H), 7.54–7.57 (m,
);
6
):
(
6
): d ¼ 1.44–1.48 (m, 4H), 1.64–1.66 (m, 4H),
.23 (s, 6H), 3.25 (s 6H), 3.67–3.73 (m, 4H), 3.93–4.06 (m, 4H),
.64 (br, 2H, OH), 6.33 (s, 2H), 6.96–7.01 (m, 4H), 7.07–7.09 (m,
H), 8.11 (br, 4H, NH2); C NMR (100 MHz, DMSO-d ): d ¼ 26.2,
2
5
2
2
1
1
(
1
3
2H), 7.75–7.84 (m, 2H), 8.07 (d, J ¼ 8 Hz, 2H), 8.21 (br, 4H, NH
2
6
1
3
C NMR (100 MHz, DMSO-d ): d ¼ 31.2, 49.0, 58.3, 113.0, 116.0,
6
7.2, 31.2, 45.1, 51.1, 59.4, 73.9, 73.9, 108.7, 111.8, 124.4, 129.8,
31.9, 133.5, 136.8, 141.4, 148.3, 160.4, 167.5, 168.8, 169.8,
75.7.
1
1
17.3, 121.3, 123.4, 125.7, 126.9, 127.9, 128.2, 130.7, 134.5,
35.4, 137.1, 137.4, 147.4, 152.6, 155.4, 158.5, 159.1, 162.4.
0
000
0
0
00
0
0
0
1 ,1 -(Hexane-1,6-diyl)bis(2-amino-5 ,7,7-trimethyl-2 ,5-
Diethyl-1,1 -(hexane-1,6-diyl)bis(2 -amino-5,7 -dimethyl-2,5 -
0
0
0
0
dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-car-
bonitrile) (7k). Cream solid, mp > 290 C; H NMR (400 MHz,
DMSO-d
dioxo-5 H-spiro[indoline-3,4 -pyrano[4,3-b]pyran]-3 -carboxylate)
ꢀ
1
ꢀ
7e). Cream solid; mp > 290 C; H NMR (400 MHz, DMSO-d ):
6
1
(
6
): d ¼ 1.02 (s, 6H), 1.04 (s, 6H), 1.41–1.44 (m, 4H), 1.59–
RSC Adv., 2017, 7, 39502–39511 | 39507
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Paper
1
3
.63 (m, 4H), 2.09–2.19 (m, 4H), 2.25 (s, 6H), 3.04 (s, 4H), 3.59– 7.18 (m, 2H), 7.25–7.28 (m, 2H), 7.56 (s, 4H), 8.03 (br, 4H, NH
2
);
13
.67 (m, 4H), 6.86–6.88 (m, 4H), 7.02–7.05 (m, 2H), 7.45 (br, 4H,
C NMR (100 MHz, DMSO-d ): d ¼ 13.9, 20.0, 28.9, 35.9, 42.1,
6
1
3
NH2); C NMR (100 MHz, DMSO-d ): d ¼ 21.1, 26.5, 27.2, 27.7, 50.8, 51.1, 60.8, 81.1, 109.7, 11.7, 124.4, 129.9, 130.9, 133.5, 136.9,
6
2
1
7.9, 32.4, 44.5, 46.9, 50.4, 57.9, 108.5, 111.3, 117.7, 124.0, 129.0, 141.4, 148.3, 160.4, 167.5, 168.9, 169.8, 175.9.
31.5, 134.3, 141.1, 159.2, 159.3, 164.6, 176.7, 195.3.
0
000
0
1 ,1 -(1,4-Phenylenebis(methylene))bis(2-amino-5 -bromo-
0
000
0
0
0
Dimethyl-1 ,1 -(hexane-1,6-diyl)bis(2-amino-2 ,5-dioxo- 2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-
0
ꢀ
1
5
,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-carboxylate) carbonitrile) (7r). Cream solid, mp > 290 C; H NMR (400 MHz,
ꢀ
1
(
7l). Cream solid, mp > 290 C; H NMR (400 MHz, DMSO-d
6
): DMSO-d
6
): d ¼ 1.95–1.98 (m, 4H), 2.25–2.29 (m, 4H), 2.70–2.85
d ¼ 1.50–1.52 (m, 4H), 1.66–1.68 (m, 4H), 1.86–1.88 (m, 4H), 2.11 (m, 4H), 4.90 (s, 4H), 6.69–6.71 (m, 2H), 6.97–6.99 (m, 2H), 7.11–
1
3
(s, 6H), 2.64–2.66 (m, 4H), 3.19–3.21 (m, 4H), 3.62–3.71 (m, 4H), 7.14 (m, 4H), 7.32 (s, 2H), 7.45 (br, 4H, NH2); C NMR (100
6
7
2
1
.82–6.85 (m, 4H), 6.91–6.93 (d, J ¼ 7 Hz, 2H), 7.11–7.14 (m, 2H), MHz, DMSO-d ): d ¼ 20.1, 27.3, 36.7, 43.5, 44.6, 47.3, 57.0,
6
13
.86 (r, 4H, NH ); C NMR (100 MHz, DMSO-d ): d ¼ 14.1, 20.1, 111.3, 111.5, 114.9, 117.8, 126.6, 127.6, 131.5, 135.2, 136.6,
2
6
6.8, 27.4, 31.2, 37.4, 46.7, 50.7, 76.6, 107.3, 114.6, 121.5, 122.8, 142.3, 159.2, 159.3, 167.5, 176.9, 195.9.
0
000
27.9, 135.6, 145.2, 159.5, 164.9, 168.1, 178.5, 195.3.
Diethyl-1 ,1 -(1,4-phenylenebis(methylene))bis(2-amino-
00
0
0
0
0
Diethyl-1,1 -(hexane-1,6-diyl)bis(2 -amino-6 -(hydroxymethyl)- 5 ,7,7-trimethyl-2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-
0 0 0 0 0 ꢀ
1
2,8 -dioxo-8 H-spiro[indoline-3,4 -pyrano[3,2-b]pyran]-3 -carboxy- 4,3 -indoline]-3-carboxylate) (7s). Cream solid, mp > 290 C; H
ꢀ
1
late) (7m). Light brown solid, mp > 290 C; H NMR (400 MHz, NMR (400 MHz, DMSO-d
6
): d ¼ 0.53–0.61 (m, 6H), 0.99 (s, 6H),
DMSO-d ): d ¼ 0.68–0.72 (m, 6H), 1.43–1.45 (m, 4H), 1.64–1.66 1.04 (s, 6H), 1.26 (s, 4H), 2.11 (s, 4H), 2.17 (s, 6H), 3.47–3.51 (m,
6
(
4
7
m, 4H), 3.57–3.70 (m, 4H), 3.71–3.85 (m, 4H), 3.97–3.98 (m, 2H), 3.75–3.79 (m, 2H), 4.66 (d, J ¼ 16 Hz, 2H), 4.97 (d, J ¼ 16 Hz,
H), 5.63 (t, J ¼ 6.4 Hz, 2H, OH), 6.35 (s, 2H), 7.08–7.10 (m, 2H), 2H), 6.52–6.54 (m, 2H), 6.75 (s, 2H), 6.85–6.86 (m, 2H), 7.57 (s,
1
3
1
3
.49–7.50 (m, 4H), 8.20 (br, 4H, NH
): d ¼ 14.0, 26.2, 27.2, 44.0, 51.2, 59.4, 73.3, 80.0, 110.0, 24.8, 27.1, 27.3, 32.5, 42.8, 44.8, 50.9, 51.1, 79.1, 108.8, 113.3,
11.9, 114.7, 126.9, 132.2, 135.7, 137.1, 143.2, 147.2, 160.6, 122.11, 122.7, 127.4, 127.9, 128.1, 134.9, 135.5, 145.3, 159.5,
67.2, 168.8, 169.9, 175.7. 159.6, 163.5, 168.1, 179.5.
2
); C NMR (100 MHz, 4H), 7.94 (br, 4H, NH
2
); C NMR (100 MHz, DMSO-d
6
): d ¼ 14.1,
DMSO-d
1
1
6
00
0
0
0
0 000
0
Diethyl-1,1 -(butane-1,4-diyl)bis(2 -amino-7 -methyl-2,5 -
Diethyl-1 ,1 -(1,4-phenylenebis(methylene))bis(2-amino-7,7-
0
0
0
0
dioxo-5 H-spiro[indoline-3,4 -pyrano[4,3-b]pyran]-3 -carboxy- dimethyl-2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -
ꢀ
1
ꢀ
1
late) (7n). Cream solid, mp > 290 C; H NMR (400 MHz, DMSO- indoline]-3-carboxylate) (7t). Cream solid, mp > 290 C; H NMR
d ): d ¼ 0.63–0.68 (m, 6H), 1.80 (m, 4H), 2.23 (s, 6H), 3.59–3.66 (400 MHz, DMSO-d ): d ¼ 0.53–0.55 (m, 6H), 0.98 (s, 6H), 1.05 (s,
6
6
(m, 4H) 3.73–3.80 (m, 4H), 6.34 (s, 2H), 6.86–6.90 (m, 2H), 6.98– 6H), 1.26 (s, 4H), 2.11 (s, 4H), 3.40–3.45 (m, 2H), 3.77–3.79 (m,
1
3
7.02 (m, 4H), 7.14–7.20 (m, 2H), 8.07 (br, 4H, NH
2
); C NMR 2H), 4.71 (d, J ¼ 16 Hz, 2H) 4.97 (d, J ¼ 16 Hz, 2H), 6.67 (d, J ¼
(100 MHz, DMSO-d
6
): d ¼ 14.0, 19.7, 25.2, 46.6, 59.2, 75.8, 98.2, 8 Hz, 2H), 6.86 (d, J ¼ 8 Hz, 2H), 6.94–6.95 (m, 2H), 7.06–7.08
13
1
1
2
01.2, 107.9, 121.9, 123.2, 128.3, 134.6, 145.4, 158.8, 159.5, (m, 2H), 7.59 (s, 4H), 7.96 (br, 4H, NH ); C NMR (100 MHz,
60.0, 163.7, 167.7, 177.7.
DMSO-d
6
): d ¼ 14.1, 27.2, 27.3, 32.5, 41.9, 44.9, 51.9, 52.0, 80.1,
0
000
0
Dimethyl-1 ,1 -(butane-1,4-diyl)bis(2-amino-2 ,5-dioxo- 108.8, 113.2, 122.1, 122.6, 127.4, 127.9, 128.2, 134.9, 136.5,
,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-carboxylate) 145.5, 159.3, 159.5, 164.7, 168.1, 178.7.
0
5
ꢀ
1
0
000
(
7o). White solid, mp > 290 C; H NMR (400 MHz, DMSO-d ):
1 ,1 -(1,4-Phenylenebis(methylene))bis(2-amino-7,7-dimethyl-
6
0
0
d ¼ 1.78–1.80 (m, 4H), 1.87–1.89 (m, 4H), 2.15–2.24 (m, 4H), 2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-3-
ꢀ
1
2
2
.66–2.68 (m, 4H), 3.19 (s, 6H), 3.70–3.75 (m, 4H), 6.81–6.86 (m, carbonitrile) (7u). Cream solid, mp > 290 C; H NMR (400 MHz,
H), 6.91–6.95 (m, 4H), 7.09–7.14 (m, 2H), 7.89 (br, 4H, NH ); DMSO-d
): d ¼ 1.04 (s, 6H), 1.07 (s, 6H), 2.12–2.26 (m, 4H), 2.57–
): d ¼ 20.2, 26.1, 28.3, 38.0, 43.2, 2.63 (m, 4H), 4.90 (s, 4H), 6.69–6.71 (m, 2H), 6.98–7.00 (m, 2H),
2
6
1
3
C NMR (100 MHz, DMSO-d
5.3, 59.2, 75.8, 107.1, 113.1, 114.0, 124.9, 130.4, 138.3, 145.1, 7.01–7.15 (m, 4H), 7.34 (br, 4H, NH
59.7, 165.3, 168.2, 178.2, 194.9.
DMSO-d ): d ¼ 27.5, 27.7, 28.0, 31.2, 32.5, 43.5, 47.2, 50.3, 56.9,
6
1
3
4
1
2
); C NMR (100 MHz,
6
0
0
0
0
0
1
,1 -(1,4-Phenylenebis(methylene))bis(2-amino-5 -bromo- 110.5, 111.4, 114.9, 117.8, 126.4, 127.6, 131.5, 135.2, 136.4,
0
0
7
,7-dimethyl-2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 - 142.4, 159.5, 165.5, 176.8, 195.8.
ꢀ
1
0
000
0
indoline]-3-carbonitrile) (7p). Cream solid, mp > 290 C;
NMR (400 MHz, DMSO-d
4
H
1 ,1 -(Butane-1,4-diyl)bis(5-amino-8-nitro-2 -oxo-2,3-dihy-
0
6
): d ¼ 1.04 (s, 6H), 1.06 (s, 6H), 2.21 (s, dro-1H-spiro[imidazo[1,2-a]pyridine-7,3 -indoline]-6-carbonitrile)
ꢀ
1
H), 2.60–2.68 (m, 4H), 4.91 (s, 4H), 6.67–6.71 (m, 2H), 7.34–7.36 (8a). Cream powder; mp > 290 C; H NMR (400 MHz, CDCl
3
): d ¼
N), 4.15 (4H, m,
2
N), 6.99 (2H, d, Ar), 7.44 (4H, m, Ar),
1
3
(m, 4H), 7.43 (s, 4H), 7.46 (br, 4H, NH
2
); C NMR (100 MHz, 1.75 (4H, m, CH
): d ¼ 27.5, 27.7, 28.0, 31.2, 32.6, 43.6, 47.2, 50.3, 56.9, CH NH), 4.65 (4H, m, CH
10.5, 111.4, 114.9, 117.8, 126.4, 127.6, 131.5, 135.2, 136.4, 7.87 (2H, d, Ar), 8.4–8.75 (br, NH ), 9.88 (2H, s, NH). C NMR (100
2 2 2
CH N), 3.90 (4H, m, CH
DMSO-d
1
1
6
2
1
3
2
42.4, 159.5, 165.5, 176.8, 195.8.
MHz, CDCl ): d ¼ 29.0, 47.3, 50.0, 51.6, 65.4, 112.7, 117.1, 120.5,
3
0
000
0
Diethyl-1 ,1 -(1,4-phenylenebis(methylene))bis(2-amino-5 - 125.2, 127.3, 128.6, 132.5, 138.9, 146.8, 186.8. Anal. calcd for
0
0
bromo-2 ,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3 -indoline]-
34 30 12 6
C H N O : C, 58.12; H, 4.03; N, 23.92%. Found: C, 58.11; H,
ꢀ
1
3-carboxylate) (7q). Cream solid, mp > 290 C; H NMR (400 MHz, 4.09; N, 23.93%.
00 0 0 0 0 0 0
1,1 -(Hexane-1,6-diyl)bis(6 -amino-9 -nitro-2-oxo-1 ,2 ,3 ,4 -
DMSO-d
6
): d ¼ 0.54–0.62 (m, 6H), 1.91–1.94 (m, 4H), 2.21–2.35 (m,
0
0
4H), 2.68–2.70 (m, 4H), 3.42–4.49 (m, 2H), 3.77–3.83 (m, 2H), 4.70 tetrahydrospiro[indoline-3,8 -pyrido[1,2-a]pyrimidine]-7 -car-
ꢀ
1
(d, J ¼ 16 Hz, 2H), 4.97 (d, J ¼ 16 Hz, 2H), 6.63–6.65 (m, 2H), 7.17– bonitrile) (8b). White powder; mp > 290 C; H NMR (400 MHz,
39508 | RSC Adv., 2017, 7, 39502–39511
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CDCl
3
): d ¼ 1.89–2.35 (16H, m, aliph), 4.2–4.35 (8H, m, CH
2
N), 137.6, 143.8, 150.1, 154.5, 174.8. Anal. calcd for C44
H
50
N
12
O
6
: C,
5
8
.5–6.5 (br, NH ), 7.84–7.95 (2H, dd, Ar), 7.95–8.10 (2H, dd, Ar), 62.69; H, 5.98; N, 19.94%. Found: C, 62.72; H, 6.04; N, 20.00%.
.10–8.25 (2H, dd, Ar), 8.25–8.38 (2H, dd, Ar), 9.94 (2H, s, NH).
2
0
000
0
1 ,1 -(1,2-Phenylenebis(methylene))bis(5-amino-5 -methyl-
1
3
0
0
C NMR (100 MHz, CDCl ): d ¼ 25.7, 31.2, 32.7, 43.2, 47.0, 48.6, 8-nitro-2 -oxo-2,3-dihydro-1H-spiro[imidazo[1,2-a]pyridine-7,3 -
3
ꢀ
1
5
1
5
0.0, 66.9, 112.7, 120.5, 124.0, 127.3, 128.6, 131.1, 132.5, 138.9, indoline]-6-carbonitrile) (8h). Cream powder; mp > 290 C; H
43.9, 146.8, 186.8. Anal. calcd for C38 : C, 60.15; H, NMR (400 MHz, CDCl
): d ¼ 3.03 (6H, s, Me), 3.77 (8H, m,
.05; N, 22.15%. Found: C, 60.22; H, 5.06; N, 22.19%. CH N), 6.78 (4H, d, CH Ar), 7.10 (2H, t, Ar), 7.17 (2H, d, Ar), 7.29
,1 -(1,4-Phenylenebis(methylene))bis(6 -amino-3 ,3 - (2H, t, Ar), 7.40 (2H, t, Ar), 8.70–9.30 (br, NH ), 9.78 (2H, d, NH).
): d ¼ 21.6, 42.1, 42.7, 50.2, 53.0,
H
38
N
12
O
6
3
2
2
00
0
0
0
0
1
2
0
0
0
0
0
13
dimethyl-9 -nitro-2-oxo-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-3,8 -
pyrido[1,2-a]pyrimidine]-7 -carbonitrile) (8c). White powder; 115.3, 117.2, 126.8, 127.1, 127.6, 128.7, 129.3, 131.6, 133.0,
C NMR (100 MHz, CDCl
3
0
ꢀ
1
mp > 290 C; H NMR (400 MHz, CDCl ): d ¼ 1.97 (12H, s, CH ), 134.1, 137.4, 143.3, 150.3, 155.2, 174.4. Anal. calcd for
3
3
3.80 (8H, t, CH N), 6.82 (2H, d, CH Ar), 7.35 (8H, m, Ar), 7.43 C H N O : C, 61.69; H, 4.40; N, 21.58%. Found: C, 61.61; H,
2 2 40 34 12 6
1
3
(
(
1
1
4H, d, Ar), 9.70–10.10 (br, NH
100 MHz, CDCl
2
), 10.16 (2H, s, NH). C NMR 4.35; N, 21.58%.
00 0 0
1,1 -(1,4-Phenylenebis(methylene))bis(6 -amino-5-methyl-9 -
3
): d ¼ 23.9, 36.5, 42.3, 53.6, 55.2, 61.1, 112.3,
15.2, 120.3, 123.8, 127.4, 129.0, 129.6, 133.5, 136.3, 137.3, nitro-2-oxo-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-3,8 -pyrido[1,2-a]
0
0
0
0
0
0
ꢀ
43.0, 150.8, 154.1, 177.1. Anal. calcd for C44H N O : C, 63.30; pyrimidine]-7 -carbonitrile) (8i). Yellow powder; mp > 290 C;
42 12 6
1
H, 5.07; N, 20.13%. Found: C, 63.30; H, 5.09; N, 22.19%.
H NMR (400 MHz, CDCl
3
): d ¼ 1.65 (4H, m, aliph), 3.59 (4H, t,
00
0
0
0
0
1
,1 -(Butane-1,4-diyl)bis(6 -amino-5,9 -dinitro-2-oxo-1 ,2 , CH N), 3.73 (4H, t, CH NH), 3.85 (6H, s, CH ), 6.47 (2 H, d,
2
2
3
0
0
0
0
3
,4 -tetrahydrospiro[indoline-3,8 -pyrido[1,2-a]pyrimidine]-7 - CH Ar), 7.05 (2H, dt, Ar), 7.15 (2H, m, Ar), 7.35 (2H, dt, Ar), 7.45
2
ꢀ
1
13
carbonitrile) (8d). Pale yellow powder; mp > 290 C; H NMR (2H, t, Ar), 7.54 (2H, dt, Ar), 10.03 (2H, s, NH). C NMR (100
400 MHz, CDCl ): d ¼ 18.1, 20.1, 23.8, 42.6, 48.3, 49.0, 53.2, 115.8,
): d ¼ 1.41–1.57 (4H, m, aliph), 1.80–2.02 (4H, MHz, CDCl
m, aliph), 2.92–3.07 (4H, m, CH N), 3.17–3.26 (4H, m, CH N), 117.1, 127.7, 127.9, 128.8, 129.0, 133.7, 134.4, 136.1, 137.2,
.81–3.94 (4H, m, CH N), 7.54–7.6 (4H, m, Ar), 7.94–8.01 (2H, d, 143.7, 150.3, 153.3, 154.0, 175.6. Anal. calcd for C42 : C,
): d ¼ 23.5, 25.5, 62.65; H, 4.75; N, 20.83%. Found: C, 62.61; H, 4.72; N, 20.79%.
(
3
3
2
2
3
2
38 12 6
H N O
1
3
Ar), 9.8 (2H, d, NH). C NMR (100 MHz, CDCl
3
00 0 0 0
1,1 -(Butane-1,4-diyl)bis(6 -amino-5-uoro-7 -isocyano-9 -
4
1
3
2.2, 49.5, 115.7, 116.1, 116.9, 129.2, 133.5, 137.1, 140.1, 143.8,
50.7, 154.5, 175.6. Anal. calcd for C H N O : C, 52.68; H, nitro-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-3,8 -pyrido[1,2-a]
.93; N, 23.89%. Found: C, 52.72; H, 3.93; N, 23.94%.
0
0
0
0
0
3
6
32 14 10
ꢀ
1
pyrimidin]-2-one) (8j). Cream powder; mp > 290 C; H NMR
00
0
0
0
1
,1 -(Hexane-1,6-diyl)bis(2 -amino-1 -benzyl-6 -(benzy- (400 MHz, CDCl ): d ¼ 0.87 (4H, m, aliph), 1.01 (4H, m, aliph),
3
0
0
0
0
lamino)-5,5 -dinitro-2-oxo-1 H-spiro[indoline-3,4 -pyridine]-3 - 4.23 (8H, m, CH
2
N), 4.50 (4H, t, NCH
carbonitrile) (8e). Yellow powder; mp > 290 C; H NMR (400 (2H, d, Ar), 7.70 (2H, t, Ar), 10.03 (2H, s, NH). C NMR (100
MHz, CDCl ): d ¼ 23.7, 25.5, 38.0, 42.3, 49.8, 114.2, 114.7, 117.2,
): d ¼ 0.70–0.82 (4H, m, aliph), 1.85–1.94 (4H, m, MHz, CDCl
aliph), 4.04–4.12 (4H, m, CH N), 6.26–6.33 (2H, t, CH Ar), 7.45– 133.5, 136.8, 137.2, 143.9, 150.6, 161.1, 161.4, 176.3. Anal. calcd
.51 (20H, m, Ar), 7.53–7.59 (2H, m, Ar), 8.5–9.5 (br, NH ), 9.98 for C36 : C, 56.39; H, 4.21; N, 21.92%. Found: C,
2H, d, NH). C NMR (100 MHz, CDCl ): d ¼ 26.7, 27.6, 42.4, 56.49; H, 4.28; N, 21.86%.
2
), 7.25 (2 H, d, Ar), 7.58
ꢀ
1
13
3
3
2
2
7
(
4
1
1
1
2
32 2 12 6
H F N O
1
3
3
00 0 0 0
1,1 -(1,4-Phenylenebis(methylene))bis(2 -amino-1 -benzyl-6 -
8.6, 49.4, 53.2, 115.2, 116.0, 117.0, 127.1, 127.6, 128.4, 128.9,
29.2, 133.7, 136.8, 137.2, 139.0, 140.2, 143.2, 150.6, 155.4, (benzylamino)-5-uoro-5 -nitro-2-oxo-1 H-spiro[indoline-3,4 -
0
0
0
0
ꢀ
1
74.8. Anal. calcd for C60
H
52
N
14
O
10: C, 63.82; H, 4.64; N, pyridine]-3 -carbonitrile) (8k). White powder; mp > 290 C; H
NMR (400 MHz, CDCl Ar), 6.28 (4H, t,
): d ¼ 7.76 (8H, dd, CH
,1 -(1,4-Phenylenebis(methylene))bis(5-amino-5 ,8- CH Ar), 7.21 (2H, d, Ar), 7.34 (2H, d, Ar), 7.43–7.60 (20H, m, Ar),
dinitro-2 -oxo-2,3-dihydro-1H-spiro[imidazo[1,2-a]pyridine-7,3 - 7.57 (2H, t, Ar), 7.92 (4H, m, Ar), 8.60–9.10 (br, NH ), 10.00 (2H,
): d ¼ 19.0, 42.0, 49.3, 49.5,
NMR (400 MHz, CDCl ): d ¼ 3.89–4.00 (4H, dt, CH N), 4.08–4.21 53.2, 114.2, 114.6, 115.6, 117.6, 127.4, 127.7, 128.1, 128.5, 129.2,
7.37%. Found: C, 63.86; H, 4.61; N, 17.34%.
3
2
0
000
0
1
2
0
0
2
ꢀ
1
13
indoline]-6-carbonitrile) (8f). Cream powder; mp > 290 C; H d, NH). C NMR (100 MHz, CDCl
3
3
2
(
4H, dt, CH NH), 6.34 (4H, dd, CH Ar), 6.69 (2H, d, Ar), 7.16 (2H, 133.8, 136.3, 136.9, 139.5, 143.2, 150.8, 153.6, 154.0, 161.2,
2 2
d, Ar), 7.29 (4H, m, Ar), 7.40 (2H, t, Ar), 8.91–9.52 (br, NH ), 9.98 173.9. Anal. calcd for C H F N O : C, 68.00; H, 4.42; N,
2
62 48 2 12 6
1
3
(
2H, d, NH). C NMR (100 MHz, CDCl
3
): d ¼ 42.4, 42.9, 48.7, 15.35%. Found: C, 68.03; H, 4.36; N, 15.41%.
0
000
0
5
1
5
3.1, 115.8, 116.3, 117.0, 127.7, 128.2, 133.8, 136.4, 137.1, 140.7,
43.2, 150.3, 154.4, 175.9. Anal. calcd for C38
1 ,1 -(Butane-1,4-diyl)bis(5-amino-5 -bromo-6-isocyano-8-
10: C, nitro-2,3-dihydro-1H-spiro[imidazo[1,2-a]pyridine-7,3 -indolin]-
0
H
28
N
14
O
0
ꢀ
1
4.29; H, 3.36; N, 23.32%. Found: C, 54.35; H, 3.31; N, 23.38%. 2 -one) (8l). White powder; mp > 290 C; H NMR (400 MHz,
00
0
0
0
0
1
,1 -(Hexane-1,6-diyl)bis(6 -amino-3 ,3 ,5-trimethyl-9 -nitro- CDCl
3
): d ¼ 1.15 (4H, m, aliph), 3.94 (4H, m, CH
2
N), 4.13 (4H, m,
0
0
0
0
0
2
-oxo-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-3,8 -pyrido[1,2-a] CH NH), 4.40 (4H, m, CH N), 7.2–7.6 (br, NH ), 7.70–7.85 (4H,
2
2
2
0
ꢀ
1
13
pyrimidine]-7 -carbonitrile) (8g). White powder; mp > 290 C; H m, Ar), 7.93–7.99 (2H, m, Ar), 9.77 (1 H, s, NH). C NMR (100
NMR (400 MHz, CDCl ): d ¼ 0.81 (4 H, m, CH ), 0.91 (6H, s, Me), MHz, CDCl ): d ¼ 25.5, 42.2, 42.7, 48.8, 49.8, 117.2, 117.7, 126.2,
3
2
3
1
.04 (6H, s, Me), 1.19 (4H, m, aliph), 2.93 (6H, s, MeAr), 4.04 (4H, 133.0, 134.6, 136.4, 137.1, 143.0, 151.6, 160.2, 175.5. Anal. calcd
d, NCH
2 2 2 2 12 6
), 4.26 (4H, d, NHCH ), 4.55 (4H, m, CH N), 7.08 (2 H, d, for C34H28Br N O : C, 47.46; H, 3.28; N, 19.53%. Found: C,
1
3
Ar), 7.20 (2H, t, Ar), 7.31 (2H, t, Ar), 10.22 (2H, d, NH). C NMR 47.40; H, 3.25; N, 19.46%.
00 0
1,1 -(1,2-Phenylenebis(methylene))bis(6 -amino-5-bromo-
(100 MHz, CDCl
3
): d ¼ 20.1, 23.1, 26.4, 27.0, 36.9, 42.1, 49.0,
0
0
0
0
0
0
0
55.8, 61.2, 115.0, 115.6, 126.3, 127.1, 128.1, 129.2, 133.8, 134.7, 3 ,3 -dimethyl-9 -nitro-2-oxo-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-
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Paper
0
0
3
,8 -pyrido[1,2-a]pyrimidine]-7 -carbonitrile)
(8m).
Yellow
5 J. Song and B. Han, Natl. Sci. Rev., 2015, 1–2.
6 C. Capello, U. Fisher and K. Kungerb u¨ hler, Green Chem.,
2007, 9, 927–934.
ꢀ
1
powder; mp > 290 C; H NMR (400 MHz, CDCl
6H, s, CH ), 1.85 (6H, s, CH ), 3.45 (4H, m, CH
CH NH), 4.70–5.04 (4H, dd, CH
Ar), 7.76 (2H, t, Ar), 8.06 (2H, d, Ar), 8.22 (2H, d, Ar), 9.90–10.20
3
): d ¼ 1.80
(
3
3
2
N), 3.83 (4H, m,
Ar), 7.29 (2H, t, Ar), 7.47 (2H, d,
7 A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725–748.
8 (a) J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers,
Green Chem., 2005, 7, 64–82; (b) J. Bi, Z. Zhang, Q. Liu and
G. Zhang, Green Chem., 2012, 14, 1159; (c) J. M. Khurana,
A. Chaudhary, A. Lumb and B. Nand, Green Chem., 2012,
14, 2321; (d) Y. Zou, Q. Huang, T. K. Huang, Q. C. Ni,
E. S. Zhang, T. L. Xu, M. Yuand and J. Lie, Org. Biomol.
Chem., 2013, 11, 6967; (e) G. D. Yadav and B. G. Motirale,
Org. Process Res. Dev., 2009, 13, 341; (f) M. Vafaeezadeh and
M. Mahmoodi Hashemi, J. Mol. Liq., 2015, 207, 73–79.
9 C. C. A. Cariou, G. J. Clarkson and M. Shipman, J. Org. Chem.,
2008, 73, 9762–9764.
2
2
1
3
(
2
1
br, NH ), 10.26 (2H, s, NH). C NMR (100 MHz, CDCl ): d ¼
2
3
3.8, 36.6, 42.8, 53.2, 55.1, 61.3, 115.1, 117.1, 117.5, 126.2, 127.6,
29.5, 131.1, 133.4, 134.5, 137.5, 143.1, 151.2, 151.5, 175.5. Anal.
calcd for C44
C, 53.16; H, 4.11; N, 16.91%.
2 12 6
H40Br N O : C, 53.24; H, 4.06; N, 16.93%. Found:
00 0 0 0
,1 -(1,4-Phenylenebis(methylene))bis(2 -amino-1 -benzyl-6 -
1
0
0
0
(
benzylamino)-5-bromo-5 -nitro-2-oxo-1 H-spiro[indoline-3,4 -
0
ꢀ
1
pyridine]-3 -carbonitrile) (8n). Cream powder; mp > 290 C; H
NMR (400 MHz, CDCl ): d ¼ 6.00 (8H, dd, CH Ar), 6.28 (4H, dt,
3
2
CH Ar), 7.15 (12H, m, Ar), 7.42 (4H, m, Ar), 7.63 (2H, t, Ar), 7.88
2
(
2H, t, Ar), 8.02 (2H, d, Ar), 8.21 (4H, m, Ar), 8.31 (2H, d, Ar), 10 L. Zhou, D. S. Bohle, H. F. Jiang and C. J. Li, Synlett, 2009,
1
3
1
4
1
1
0.11 (2H, d, NH). C NMR (100 MHz, CDCl
8.4, 48.7, 53.4, 115.4, 117.1, 117.6, 126.3, 127.2, 127.7, 128.5, 11 G. Ren, J. Zhang, Z. Duan, M. Cui and Y. Wu, Aust. J. Chem.,
28.9, 129.5, 133.1, 134.4, 136.4, 139.5, 143.7, 150.3, 153.6,
2009, 62, 75–81.
53.9, 174.4. Anal. calcd for C62
: C, 61.19; H, 3.98; 12 S. L. Schreiber, Science, 2000, 287, 1964–1969.
3
): d ¼ 20.6, 43.0,
937–940.
2 12 6
H48Br N O
N, 13.81%. Found: C, 61.16; H, 4.03; N, 13.86%.
13 R. C. Cioc, E. Ruijter and R. V. A. Orru, Green Chem., 2014, 16,
958–2975.
2
1
4 M. Zolgol, A. Khazaei, A. Zare, M. Mokhlesi, T. Hekmat-
Zadeh, A. Hasaninejad, F. Derakhshan-Panah, A. Moosavi-
Zare, H. Keypour, A. Deghani-Firouzabadi and
M. Merajoddin, J. Chem. Sci., 2012, 124, 501–508.
Conclusions
In summary, a highly efficient and green method for one-pot
multi-component synthesis of bis-spirooxindoles has been re-
ported. The described procedure takes advantage of PEG-400 as 15 A. Zare, R. Khanivar, M. Hatami, M. Mokhlesi, M. Zolgol,
an inexpensive, biodegradable, commercially available and
reusable solvent. Non-toxic and environmentally friendly
A. Moosavi-Zare, A. Hasaninejad, A. Khazaei and
V. Khakyzadeh, J. Mex. Chem. Soc., 2012, 4, 56.
reagent, K CO , was used to promote the reaction toward 16 A. Hasaninejad, S. Firoozi and F. Mandegani, Tetrahedron
2
3
completion. The generality of the method has been investigated
Lett., 2013, 54, 2791–2794.
using ketene aminals as well as enolizable ketones to form 17 (a) P. Helene, Adv. Synth. Catal., 2012, 354, 237–294; (b)
a library of complex structure of bis-spiro compounds.
J. G. Hernandez and E. Juaristi, Chem. Commun., 2012, 48,
396–5409; (c) D. Bonne, T. Constantieux, Y. Coquerel and
5
J. Rodriguez, Org. Biomol. Chem., 2012, 10, 3969–3973.
8 Y. Gu, Green Chem., 2012, 14, 2091–2128.
Conflicts of interest
1
There are no conicts to declare.
19 G. R. Khabibullin, E. S. Fedotov, V. R. Akhmetov,
E. S. Mesheryakov, L. M. Khalilov and A. G. bragimov, Mol.
Diversity, 2016, 2, 557–565.
Acknowledgements
20 S. K. Panja and S. Saha, RSC Adv., 2013, 3, 14495–14500.
The authors thank Persian Gulf University Research Councils 21 A. Maryamabadi, A. Hasaninejad, N. Nowrouzi,
for the nancial support of this work.
G. H. Mohebbi and B. Asghari, Bioorg. Med. Chem., 2016, 6,
408–1417.
1
2
2 P. Licence, J. Ke, M. Sokolova, S. K. Rossb and M. Poliakoff,
Green Chem., 2003, 5, 99–104.
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39510 | RSC Adv., 2017, 7, 39502–39511
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Paper
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