One-pot of three-component synthesis of novel amino-spiroindene derivatives

Article abstract of DOI:10.1007/s13738-013-0332-3

A facile and efficient one-pot three-component synthesis of the amino-spiroindene derivatives was achieved, via the reaction of ninhydrin, malononitrile or ethylcyanoacetate and various reagents including 1, 2- and 1,3-dicarbonyl compounds/enols. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-013-0332-3

J IRAN CHEM SOC (2014) 11:623–629
DOI 10.1007/s13738-013-0332-3
ORIGINAL PAPER
One-pot of three-component synthesis of novel amino-spiroindene
derivatives
•
Ali Darehkordi Zahra Karimi-Taleghani
•
Omid Ali Pouralimardan
Received: 17 May 2013 / Accepted: 25 August 2013 / Published online: 5 October 2013
Ó Iranian Chemical Society 2013
Abstract A facile and efficient one-pot three-component
synthesis of the amino-spiroindene derivatives was
achieved, via the reaction of ninhydrin, malononitrile or
ethylcyanoacetate and various reagents including 1, 2- and
1,3-dicarbonyl compounds/enols.
In recent years, the synthesis of combinatorial small-
molecule heterocyclic libraries has emerged as a valuable
tool in the search for novel lead structures [7, 8]. Thus, the
success of combinatorial chemistry in the drug discovery
process is considerably dependent on further advances in
heterocyclic MCR methodology and, according to the
current synthetic requirements; environmentally benign
multi-component procedures are particularly welcome.
(1,3-Dioxo-2,3-dihydro-1H-inden-2-ylidene) propanedi-
nitrile (I, also referred to as 2-(dicyanomethylene)-1,3-
indanedione, Scheme 1) may be considered to be analo-
gous to ethenetetracarbonitrile (2) in its reactions [9]. This
compound can be considered as an intermediate for the
synthesis of pyran rings.
Keywords Ninhydrin ꢀ Amino-spiroindene
derivatives ꢀ Multi-component reactions
Introduction
In multi-component reactions (MCRs), three or more
reactants come together in a single reaction vessel to form
new products that contain structural units of all the
components.
Heterocycles containing the pyran ring are important
targets in synthetic and medicinal chemistry because
this fragment is a key moiety in numerous biologically
active compounds and natural products [10, 11]. Spiro
compounds represent an important class of naturally
occurring substances characterized by highly pro-
nounced biological properties. The spiro functionality
has been known for a long time to be present in phy-
tochemicals either in alkaloids, lactones or terpenoids
[12]. Biological activities of spiro compounds contain-
ing pyrans have also been proved. They also show good
activity as hypertensive agents [13]. They have been the
subject of great interest as potential novel analgesic
agents [14].
The development of MCRs designed to produce elabo-
rate biologically active compounds has become an impor-
tant area of research in organic, combinatorial, and
medicinal chemistry [1–4]. The MCR strategy offers sig-
nificant advantages over conventional linear-type synthesis
due to its flexible, convergent, and atom efficient nature [5,
6].
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0332-3) contains supplementary
material, which is available to authorized users.
Spiro-cyclic systems containing one sp3 carbon atom
common to two rings are structurally interesting [15]. One
of the important criteria of the biological activities of
asymmetric structure spiro-molecule, is chiral spiro-carbon
atom [16, 17]. The presence of the sterically constrained
spiro structure in various natural products also adds to the
interest in the investigations of spiro compounds [18].
A. Darehkordi (&) ꢀ Z. Karimi-Taleghani
Department of Chemistry, Faculty of Sciences, Vali-e-Asr
University of Rafsanjan, 77176 Rafrsanjan, Iran
e-mail: adarehkordi@yahoo.com; darehkordi@vru.ac.ir
O. A. Pouralimardan
Department of Chemistry, Faculty of Sciences, Payame Noor
University of Bandar Abbas, Bandar Abbas, Iran
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O
(0.3 ml) were added to the mixture; upon completion,
monitored by TLC (n-hexane/ethyl acetate), the reaction
mixture was allowed to cool to room temperature. The
solid was filtered off, washed with ether or ethanol several
times, and was purified with EtOH to give the desired
products.
O
O
N
N
C
N
N
C
N
N
N
N
C
C
C
C
C
C
O
I
III
II
Scheme 1 Carbonitrile derivatives: a 2-(1,3-dioxo-1H-inden-2(3H)-
ylidene) malononitrile I; b ethene-1,1,2,2-tetracarbonitrile II; c 1,4-
dioxo-1,4-dihydronaphthalene-2,3-dicarbonitrile III
20-amino-1,3,50-trioxo-1,3-dihydro-50H-spiro[indene-
2,40indeno[1,2-b]pyran]-30-carbonitrile (5a)
The synthesis of heterocycles by MCRs often involves
classic carbonyl condensation chemistry [19, 20] and basic
catalysts play an important role in MCRs. Triethylamine is
an efficient and inexpensive base and its efficiency as a
basic catalyst has been explored frequently [21, 22].
As we were synthesizing new amino-spiroindene deriv-
atives using 2-(dicyanomethylene)-1, 3-indanedione deriv-
atives and cyclic ketone, 1, 2 and 1, 3-bicarbonyl, cumarin
and 1-naphthol, we were interested in the synthesis of spiro
and spiroindene rings and their properties. The reaction was
carried out in ethanol or dioxin under reflux conditions. The
results of 1H- NMR, 13C- NMR, FT-IR and elemental
analysis confirmed the formation of these products.
Brown powder, M.P = 335–339 °C. Yield = 70 %. IR
KBr (tmax, cm-1): 3,395 (NH2, broad), 3,045 (C–H aro-
matic), 2,194 (CN), 1,705, 1,680 (C=O). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 7.31 (1H, H-aro-
matic(1,3-indandione), d, J = 10.0 Hz), 7.37 (1H, H-aro-
matic(1,3-indandione), d, J = 10.0 Hz), 7.45 (1H,
H-aromatic(1,3-indandione), t, J = 10 Hz), 7.57 (1H,
H-aromatic(1,3-indandione), t, J = 10.0 Hz),7.93–8.11
(2H, NH2), 8.13 (4H, H-aromatic) ppm. 13C-NMR
(DMSO-d6, 125.77 MHz): d (ppm) = 52.18 (1C, C–CN),
53.23 (1C, C-spiro), 105.57 (C–C=O), 116.81 (1C, CN),
119.17, 122.59, 122.92, 123.07, 123.77, 129.92, 131.73,
133.94, 134.60, 136.26, 136.52, 137.64, 140.63 (C-aro-
matic), 161.39 (1C, C–NH2), 169.05 (1C, C–CO), 189.32
(1C, C=O(1,3-indandione)), 198.41 (2C, C=O).
Experimental
General
2-amino-10,30,5-trioxo-10,30,5,6,7,8-hexahydrospiro
[chromene-4,20-indene]-3-carbonitrile (5b)
Chemicals and solvents such as EtOAc, EtOH, DMF, and
MeOH obtained from Merck Chemical. Co. were used
without further purification. Melting points were deter-
mined on a Melt-Tem II melting point apparatus and were
uncorrected. IR spectra were obtained on a Matson-1000
FT-IR spectrometer. Peaks are reported in wave numbers
(cm-1). All of the NMR spectra were recorded on a Bruker
model DRX-500 avance (1H: 500 MHz) (13C: 125 MHz)
and Bruker model DRX-400 AVANCE (1H: 400 MHz)
(13C: 100 MHz) NMR spectrometer. Chemical shifts are
reported in parts per million (ppm) from tetramethylsilane
(TMS) as an internal standard in DMSO-d6 as a solvent.
Elemental analyses (C, H, and N) were performed with a
Heracus CHN-O-Rapid analyzer. Purity of the compounds
is checked by thin layer chromatography (TLC) on Merck
silica gel 60 F254 pre-coated sheets in n-Hexane/ethyl
acetate mixture and spots were developed using either
iodine or ultraviolet light as visualizing agent.
Yellow powder, M.P = 295–298 °C. Yield = 69 % IR
KBr (tmax, cm-1): 3,401 (NH2, broad), 3,085 (C–Haromatic),
2,922 (C–Haliphatic), 2,203 (CN), 1,711, 1,675 (C=O) cm-1
.
1H-NMR (DMSO-d6, 500 MHz): d (ppm) = 1.94 (2H,
CH2, t, J = 5.0 Hz), 2.27 (2H, CH2, t, J = 5.0 Hz), 2.69
(2H, CH2, t, J = 4.0 Hz), 7.64 (2H, NH2, s), 8.01 (4H,
aromatic) ppm. 13C-NMR (DMSO-d6, 125.77 MHz): d
(ppm) = 19.81 (1C, CH2), 26.37 (1C, CH2), 35.27 (1C,
CH2), 51.89 (1C, C–CN), 53.18 (1C, C-spiro), 111.04 (1C,
C=C spiro ring), 116.89 (1C, C–CN), 123.13 (2C, C-aro-
matic), 136.59 (2C, C-aromatic), 140.55 (2C, C-aromatic),
159.79 (1C, C–O), 168.31 (1C, C–NH2),196.11 (2C, C=O),
199.76 (1C, C=O, 1,3-diketon).
2-amino-7,7-dimethyl-10,30,5-trioxo-10,30,5,6,7,8-
hexahydrospiro [chromene-4,20-indene]-3-carbonitrile
(5c)
General procedure
Brown powder, M.P = 297 °C. Yield = 63 %. IR KBr
(tmax, cm-1): 3,398 (NH2, broad), 3,058 (C–Haromatic),
2,912 (C–Haliphatic), 2,199 (CN), 1,713, 1,668 (C=O),
A mixture of ninhydrin (2 mmol, 0.36 g), malononitrile
(2 mmol, 0.13 g), or ethyl cyanoacetate (2 mmol, 0.23 g),
in EtOH (10 ml) was stirred at 60 °C for 15 min. Then, the
desired ketone (2 mmol) EtOH (4 ml) and piperidine
1
cm-1. H-NMR (DMSO-d6, 500 MHz): d (ppm) = 1.05
(6H, CH3), 2.21 (2H, CH2, s), 2.63 (2H, CH2, s), 7.66 (2H,
NH2, s), 8.03 (4H, H-aromatic) ppm. 13C-NMR (DMSO-d6,
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J IRAN CHEM SOC (2014) 11:623–629
625
125.77 MHz): d (ppm) = 28.06 (2C, CH3), 33.31 (1C),
40,90 (1C, CH2), 49.82 (1C, CH2), 52.68 (1C, C–CN),
54.01 (1C, C-spiro), 110.89 (1C, C=C, spiro ring), 117.70
(1C, CN), 124.03, 137.48, 141.45 (6C, C-aromatic), 160.76
(1C, C–O), 167.34 (1C, C-NH2), 196.91 (2C, C=O), 200.59
(1C, C=O).
NMR (DMSO-d6, 500 MHz) d: 3.10 (s, 3H, CH3), 3.39 (s,
3H, CH3), 7.89 (s, 2H, NH2), 8.08–8.13 (m, 4H, ArH), MS
m/z (%): 364 (M?, 17.23).
20-amino1,3,50-trioxo-1,3-dihydro-50H-spiro[indene-
2,40-pyrano[3,2-c]chromene]-30-carbonitrile (5g)
2-amino-10,30,8-trioxo-10,30,5,6,7,8-hexahydrospiro
[chromene-4,20-indene]-3-carbonitrile (5d)
Brown
Yield = 75 % IR KBr (tmax, cm-1): 3,398 (NH2, broad),
3,039 (C–Haromatic), 2,201(CN), 1,700, 1,682(C=O), cm-1
powder,
M.P = 215 °C
(Decompose).
.
Brown powder, M.P = 240 °C. Yield = 79 %. IR KBr
(tmax, cm-1): 3,375 (NH2, broad), 3,029 (C–Haromatic),
1H-NMR (DMSO-d6, 500 MHz): d (ppm) = 7.51 (1H-aro-
matic, d, J = 8.4 Hz), 7.54 (1H, H- aromatic, t,
J = 7.65 Hz), 7.78 (1H, H-aromatic, t, J = 7.4 Hz), 7.90
(1H, H-aromatic, d, J = 7.75 Hz), 8.09–8.13 (m, NH2,
H-aromatic) ppm. 13C-NMR (DMSO-d6, 125.77 MHz): d
(ppm) = 52.89 (1C, C–CN), 65.39 (1C, C-spiro), 99.76 (1C,
C- C-spiro), 111.9 (1C, CN), 115.57, 116.50, 117.02, 122.23,
122.99, 123.83, 120.57, 125.33, 125.43, 134.28, 137.32,
140.53, 152.22, 156.74, 159.61, 159.74 (C-aromatic), 160.00
(C=O, C-cumarin), 198.78 (2C=O, 1,3-indandione ring).
2,203 (CN), 2,913 (C–Haliphatic), 1,726, 1,715 (C=O) cm-1
.
1H-NMR (DMSO-d6, 500 MHz): d (ppm) = 1.96 (2H,
CH2, t, J = 5.0 Hz), 2.28 (2H, CH2, t, J = 5.0 Hz), 2.71
(2H, CH2, t, J = 5.0 Hz), 7.63 (2H, NH2, S), 8.00 (2H,
H-aromatic), 8.03 (2H, H-aromatic) ppm. 13C-NMR
(-DMSO-d6, 125.77 MHz): d (ppm) = 19.79 (1C, CH2),
26.35 (1C, CH2), 35.25 (2H, CH2), 51.87 (1C, C–CN),
53.17 (1C, C-spiro), 111.01 (1C, CN), 116.84 (1C, C=C),
123.10, 136.57, 140.52 (C-aromatic), 159.76 (1C, C–O),
168.28 (1C, C–NH2), 196.08 (1C, C = O 1,2-cyclohexa-
none), 199.72 (2C, C=O).
Ethyl-20-amino-1,3,50-trioxo-1,3-dihydro-50H-
spiro[indene-2,40-pyrano[3,2-c]chromene]-30-
carboxylate (5g’)
70-amino-1,20,3,40-tetraoxo-1,10,20,3,30,40-
hexahydrospiro[indene-2,50-pyrano[2,3-d]pyrimidine]-
60-carbonitrile (5e)
IR KBr (tmax, cm-1): 3,398 (NH2, broad), 3,039 (C–
H
aromatic), 2,201(CN), 1,700, 1,682(C=O), cm-1. H-NMR
Yield = 88 %.IR (KBr, tmax, cm-1): 3,316(NH2, broad),
3,183 (NH), 3,096, 2,206 (CN), 1,724, 1,699 (C=O).1H-
NMR (DMSO-d6, 500 MHz) d:7.68 (s, 2H, NH2),
8.15–8.22 (m, 4H, ArH), 11.27 (s, 1H, NH), 12.35 (s, 1H,
NH); MS m/z(%): 336 (M?, 38.64).
(DMSO-d6, 500 MHz): d (ppm) 1.10 (m, 3H, CH3), 4.20 (m,
2H, CH2), 7.51 (1H-aromatic, d, J = 8.4 Hz), 7.54 (1H, H-
aromatic, t, J = 7.65 Hz), 7.78 (1H, H-aromatic, t,
J = 7.4 Hz), 7.90 (1H, H-aromatic, d, J = 7.75 Hz),
8.09–8.13 (m, NH2, H-aromatic) ppm 13C-NMR (DMSO-d6,
125.77 MHz): d (ppm) = 14.00 (CH3), 65.00 (CH2–O),
52.89 (1C, C–CN), 65.39 (1C, C-spiro), 99.76 (1C,
C- C-spiro), 111.9 (1C, CN), 115.57, 116.50, 117.02,
122.23, 122.99, 123.83, 120.57, 125.33, 125.43, 134.28,
137.32, 140.53, 152.22, 156.74, 159.61, 159.74 (C-aro-
matic), 160.00 (C=O, C=O esteric), 198.78 (2C=O, 1, 3-in-
dandione ring).
70-amino-10,30-dimethyl-1,20,3,40-tetraoxo-
1,10,20,3,30,40-hexahydrospiro[indene-2,50-pyrano[2,3-
d]pyrimidine]-60-carbonitrile (5f)
Yield = 89 %. IR (KBr, tmax, cm-1): 3,384 (NH2, broad),
3,321, 3,253, 3,210, 2,193 (CN), 1,731, 1,680 (C=O). H-
1
Scheme 2 Three-component
synthesis of amino-spiroindene
derivatives
O
O
Et
H
O
H
H
O
-
-
H
C
2
+
N
C
N
C
O
O
O
N Et
(
)
3
NH2
O
O
N
C
re ux
fl
2
4
a-
5
f
1
O
O
O
O
O
O
=
H
C
O
d
H
3
3C
:
b
a :
O
N
N
c :
HN
NH
e:
:
O
:
f
O
O
O
O
O
O
H
3C
H
C
3
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J IRAN CHEM SOC (2014) 11:623–629
Scheme 3 A plausible
mechanism for synthesis of
2-amino-10,30,8-trioxo-
10,30,5,6,7,8-
hexahydrospiro[chromene-4,20-
indene]-3-carbonitrile
Scheme 4 Three-component
reaction of ninhydrin/
malonitrile and 2-naphthol or
4-hydroxy cumarin
Scheme 5 Synthesis of ethyl
2-amino-10,30,8-trioxo-
10,30,5,6,7,8-
hexahydrospiro[chromene-4,20-
indene]-3-carboxylate
2-amino-10,30-dioxo-10,30-dihydrospiro
[benzo[h]chromene-4,20-indene]-3-carbonitrile (5h’)
3,068
(C–Haromatic),
2,926
(C–Haliphatic),
1,709
(C=O), 1,620 (C=C) cm-1
.
1H -NMR (DMSO-
d6, 500 MHz) d: 7.90 (s, 2H, NH2), 8.14–8.18
(m, 10H, ArH); MS m/z (%): 352 (M?, 19.23), 180
(100.00).
Brown powder, M.P = 319 °C Decompose. Yield =
88 %. IR (KBr, tmax, cm-1): 3,399 (NH2, broad),
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J IRAN CHEM SOC (2014) 11:623–629
627
Ethyl-3-amino-10,30-dioxo-10,30-
dihydrospiro[benzo[f]chromene-1,20-indene]-2-
carboxylate (5h)
CH3), 19.46 (1C, CH2), 27.23 (1C, CH2), 35.11 (2C, CH2),
52.07 (1C, C–CN), 53.63 (1C, C-spiro), 62.17 (1C, OCH2),
112.05 (1C, CN), 117.55 (1C, C=C), 123.79, 138.61, 140.82
(C-aromatic), 160.96 (1C, C–O), 169.98 (1C, C–NH2), 197.04
(1C, C=O 1,2-cyclohexanone),178, 199.72 (3C, C=O).
IR (KBr, tmax, cm-1): 3,410 (NH2, broad), 1,718 (C=O),
1,648, cm-1. H-NMR (DMSO-d6, 500 MHz) d: 1.09 (m, 3H,
CH3), 4.18 (m, 2H, CH2), 7.57 (s, 2H, NH2), 7.86–9.08 (m,
10H, ArH); MS m/z (%): 399 (M?, 23.05), 327 (100.00).
Results and discussion
2-amino-3-(2-methoxyacetyl)-6,7-dihydrospiro
[chromene-4,20-indene]-10,30,8(5H)-trione (i)
We have developed an efficient protocol for the solution
phase synthesis of new amino- spiroindene derivatives
through the three-component condensation of ninhy-
drin, malononitrile/ethylcyanoacetate and various reagents
including a-methylencarbonyl compounds/enols (Scheme 2).
In a closely relevant study Khurana et al. [23] reported the
synthesis of a series of Spiropyrans derivatives through the
three-component condensation of ninhydrin, malononitrile
and different 1,3-dicarbonyl compounds in the presence of
polyethylene glycol (PEG)-stabilized Ni nanoparticles. But
the present study revealed the results, using a wide variety
Yield = 69 %. IR (KBr, tmax, cm-1): 3,395 (NH2, broad),
3,064 (C–Haromatic), 2,209 (CN), 2917 (C–Haliphatic), 1,726,
1,715, 1,687 (C=O) cm-1
.
1H-NMR (DMSO-d6,
500 MHz): d (ppm) = d: 1.12 (m, 3H, CH3), 4.21 (m, 2H,
CH2) 1.96 (2H, CH2, t, J = 5.0 Hz), 2.28 (2H, CH2, t,
J = 5.0 Hz), 2.71 (2H, CH, t, J = 5.0 Hz), 7.63 (2H, NH2,
s), 8.00 (2H, H-aromatic), 8.03 (2H, H-aromatic) ppm. 13C-
NMR (DMSO-d6, 125.77 MHz): d (ppm) = 14.53 9 (1C,
Table 1 Structures, yield and conditions synthesis of amino-spiroindene derivatives 5a–f, 5g, 5g’, 5h, 5h’ and i
Entry
1
Dicarbonyl compounds
Product
Time (h)
8
Isolated yield (%)
70
2
4
69
3
6
63
4
5
79
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J IRAN CHEM SOC (2014) 11:623–629
Table 1 continued
Entry
Dicarbonyl compounds
Product
Time (h)
8
Isolated yield (%)
88
5
6
8
89
7
7
75
8
6
88
9
10
69
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J IRAN CHEM SOC (2014) 11:623–629
629
Acknowledgments We gratefully acknowledge, the Vali-e-Asr
University of Rafsanjan Faculty Research Grant for financial support.
of compounds 4, 4-hydroxy cumarin and 2-naphthol by a
straightforward procedure in the absence of complex and
expensive catalyst.
The synthesis of 5a-f includes a two-step reaction:
Knoevenagel condensation to obtain unsaturated nitriles
I from ninhydrin 1 and malononitrile 2 and interaction of
I with the active a-methylencarbonyl compounds/enols 4
catalyzed by triethylamine or piperazine (Et3N or C5H11N).
A plausible mechanism for the reaction is shown in
Scheme 3. Compound 1 undergoes Knoevenagel conden-
sation with malononitrile/ethyl cyanoacetate. Unsaturated
nitriles I are formed very easily in ethanol even in the
absence of Et3N. Reactant I undergoes Michael addition to
reagent 4, followed by cycloaddition onto the nitrile.
Eventually, after tautomeric proton shift compound 5 is
formed.
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In summary, we have developed a new facile protocol for
the synthesis of new amino-spiroindene derivatives from
the reaction of ninhydrin, malononitrile/ethylcyanoacetate
and a-methylencarbonyl compounds/enols.
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