Grindstone chemistry: one-pot synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones

Article abstract of DOI:10.1016/j.tetlet.2009.11.041

A one-pot, pseudo four-component, and simple synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones via the reaction of 1,3-indandione, aromatic amines and isatins or acenaphthylene-1,2-dione using a 'Grindstone Chemistry' method is reported.

Full text of DOI:10.1016/j.tetlet.2009.11.041

Tetrahedron Letters 51 (2010) 499–502
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Tetrahedron Letters
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Grindstone chemistry: one-pot synthesis of spiro[diindenopyridine-indoline]
triones and spiro[acenaphthylene-diindenopyridine]triones
*
Ramin Ghahremanzadeh, Somayeh Ahadi, Ghazaleh Imani Shakibaei, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, pseudo four-component, and simple synthesis of spiro[diindenopyridine-indoline]triones and
spiro[acenaphthylene-diindenopyridine]triones via the reaction of 1,3-indandione, aromatic amines and
isatins or acenaphthylene-1,2-dione using a ‘Grindstone Chemistry’ method is reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 September 2009
Revised 4 November 2009
Accepted 10 November 2009
Available online 14 November 2009
Keywords:
Isatin
Spirooxindole
Grindstone
Spiro[diindenopyridine-indoline]trione,
Acenaphthylen-1,2-dione
Indenopyridine derivatives represent important biological and
medicinal scaffolds. The indenopyridine skeleton is present in the
4-azafluorenone group of alkaloids, represented by its simplest
member onychnine (Fig. 1).1 Indenopyrazoles A and indenopyrida-
zines B have been investigated as cyclin-dependent kinase2 and
selective monoamine oxidase B (MAO-B)3 inhibitors, respectively.
Indenopyridines C exhibit cytotoxic,4a phosphodiesterase inhibi-
tory,4b adenosine A2a receptor antagonistic,4c antiinflammatory/
antiallergic,4d coronary dilating4e, and calcium-modulating activi-
ties.4f These compounds have also been investigated for the treat-
ment of hyperlipoproteinemia and arteriosclerosis4g as well as
neurodegenerative diseases.4h
pounds.18,19 The ‘Grindstone Chemistry’ procedure is a slight mod-
ification of a method described by Toda et al. who demonstrated
that many reactions can be performed in high yields by simply
grinding two or more solids together.20 These reactions were usu-
ally carried out on a very small scale in an agate mortar and grind-
ing with a pestle. Bose et al. extended this approach to chemical
reactions on large scale, a method they termed a ‘Grindstone
Chemistry’ modified approach.18
Y
Indole and indoline are important fragments of a large number
of natural products and medicinal agents,5 and several indolines,
spiro-annulated with heterocycles at the 3-position, have shown
good biological activity.6–8 The spirooxindole system is the core
structure of many pharmacological agents and natural alka-
loids.9–11 For example, spirotryprostatins A and B, two natural
alkaloids isolated from the fermentation broth of Aspergillus fumig-
atus, have been identified as novel inhibitors of microtubule
assembly.11 As a consequence, a number of methods have been re-
O
O
O
Y
X
X
NH
N
N
N
N
onychnine
B
A
O
X
Y
N
N
O
O
O
O
N
N
ported for the preparation of spirooxindole-fused heterocycles.12–
N
C
17
O
Recently, the ‘Grindstone Chemistry’ technique has been used
as a green and rapid method for the synthesis of organic com-
O
N
N
MeO
H
H
spirotryprostatin B
spirotryprostatin A
* Corresponding author. Fax: +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
Figure
spirooxindoles.
1. Representative
important
indenone-fused
heterocycles
and
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.041

500
R. Ghahremanzadeh et al. / Tetrahedron Letters 51 (2010) 499–502
NR
X
O
O
O
O
O
X
Grindstone
O +
Ar-NH2
2
+
p-TSA
3-4 min
N
R
N
O
Ar
1a-d
2a-e
3
4a-t
Scheme 1. One-pot synthesis of spirodiindenopyridine-indolines 4.
a catalytic amount of p-toluenesulfonic acid (p-TSA) (an inexpen-
sive and readily available catalyst) was ground using a mortar
and pestle of appropriate size (Scheme 1). Grinding for about
3–4 min led to red colored 5-phenyl-5H-spiro[diindeno[1,2-
b:20,10-e]pyridin-11,30-indoline]-20,10,12-trione 4a in 85% yield.
The reaction was performed at ambient temperature during which
almost a 10 °C increase in temperature was observed. This increase
in reaction temperature indicated that spirodiindenopyridine-ind-
oline formation was an exothermic process.
Next, to delineate the scope of this approach, particularly with
regard to library construction, this method was evaluated using
four substituted isatins 1a–d, five substituted anilines 2a–e, and
1,3-indanedione 3. The corresponding spiro[diindeno[1,2-b:20,10-
e]pyridin-11,30-indoline]-20,10,12-triones 4a–t were obtained in
good yields under similar conditions, (Table 1). The reaction pro-
ceeds very cleanly under mild conditions and is compatible with
a wide range of functional groups.
Table 1
Spiro[diindenopyridine-indoline]triones 4
Product
Ar
X
R
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
85
82
87
89
90
81
84
80
88
86
83
84
90
91
87
90
86
87
91
82
4-Br–C6H4
4-O2N–C6H4
4-Me–C6H4
4-MeO–C6H4
C6H5
4-Br–C6H4
4-O2N–C6H4
4-Me–C6H4
4-MeO–C6H4
C6H5
4-Br–C6H4
4-O2N–C6H4
4-Me–C6H4
4-MeO–C6H4
C6H5
4-Br–C6H4
4-O2N–C6H4
4-Me–C6H4
4-MeO–C6H4
H
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
4j
4k
4l
Br
Br
Br
Br
Br
NO2
NO2
NO2
NO2
NO2
4m
4n
4o
4p
4q
4r
4s
4t
H
H
H
H
The 1H and 13C NMR spectra of the crude products indicated the
formation of spirooxindole-fused diindenopyridines 4. The nature
of these compounds as 1:1:2 adducts was apparent from their
mass spectra, which displayed, in each case, the molecular ion peak
at the appropriate m/z value. Compounds 4a–t are stable solids
whose structures were established by IR, 1H and 13C NMR spectros-
copy, and elemental analysis.
H
a
Isolated yield, reaction time = 3–4 min.
In ‘Grindstone Chemistry’, exothermic reactions can be per-
The results were good in terms of yields and product purity in
the presence of p-TSA, while without p-TSA, the yields of products
were low (<40%) even after 30 min.
When this reaction was carried out with aliphatic amines such
as n-propylamine or ethylamine under the same conditions, the
TLC and 1H NMR spectra of the reaction mixtures showed the pres-
ence of a combination of starting materials and numerous by-prod-
ucts, the yield of the expected product being very poor.
We have not established an exact mechanism for the formation
of spiro[diindenopyridine-indoline]triones 4, however, a reason-
able possibility is shown in Scheme 2. It is thought that product
4 results from initial addition of 1,3-indanedione 3 to the isatin 1
formed by grinding the reactants together for a few minutes with-
out using any organic solvent; apparently this method is not very
effective for endothermic reactions. Since spirodiindenopyridine-
indoline formation is an exothermic reaction, and as part of our
program aimed toward the preparation of heterocyclic com-
pounds,21–29 especially spirooxindoles,30–34 we report herein the
synthesis of spiro[diindenopyridine-indoline]triones and spiro
[acenaphthylene-diindenopyridine]triones via ‘Grindstone Chem
istry’.
In a pilot experiment,35 a mixture of isatin 1a (10 mmol), aniline
2a (10 mmol), and 1,3-indanedione 3 (20 mmol) in the presence of
O
NR
NR
O
O
O
X
X
O
X
O
O
O
1
p-TSA
O
O
HO
O
+
N
R
5
O
O
O
3
1
6
NR
O
X
NR
ArNH2
2
X
O
O
O
O
-H2O
O
O
NHAr
N
Ar
4
Scheme 2. Proposed mechanism for the synthesis of spirodiindenopyridine-indolines 4.

R. Ghahremanzadeh et al. / Tetrahedron Letters 51 (2010) 499–502
501
O
O
O
O
O
O
O
Grindstone
+
Ar-NH2
2
+
p-TSA
3-4 min
N
Ar
7
2a-e
3
8a-e
Product
8a
Ar
Yield (%) a
C6H5
87
88
82
86
89
8b
4-Br-C6H4
4-O2N-C6H4
4-Me-C6H4
4-MeO-C6H4
8c
8d
8e
a Isolated yield
Scheme 3. One-pot synthesis of spiro[acenaphthylene-diindenopyridine]triones 6.
Bremm, K.-D.; Bischoff, H.; Schmidt D.; Schuhmacher, J. Ger. Offen. DE
19627430 A1 19980115, 1998; Chem. Abstr. 1998, 129, p148914q; (h)
Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest, K. T.; Tang Y.;
Jackson, P. F. PCT Int. Appl. WO 2003088963 A1 20031030, 2003; Chem. Abstr.
139, 137, p650637c.
to yield intermediate 5, which reacted further with another mole-
cule of 3. Finally, addition of the substituted aniline 2 to the inter-
mediate 6, followed by cyclization afforded the product 4.
A large-scale synthesis of spiro[diindenopyridine-indoline]tri-
one 4a was carried out on 100 mmol scale (a total of 60 g) in a large
glass bowl. The reaction mixture was ground by a mechanical stir-
rer for just under five minutes and the desired product was ob-
tained in 85% yield.
To further explore the potential of this protocol for spirooxin-
dole synthesis, we investigated the reaction of anilines 2 and
1,3-indanedione 3 with acenaphthylen-1,2-dione 7. Spiro[ace-
naphthylene-diindenopyridine]triones 8a–e were obtained in good
yields (Scheme 3).
In conclusion, we have described an efficient, one-pot, and
pseudo four-component method for the synthesis of spiro[diinde-
nopyridine-indoline]triones and spiro[acenaphthylene-diindeno-
pyridine]triones using ‘Grindstone chemistry’. Prominent among
the advantages of this new method are operational simplicity, good
yields of products in short reaction times, and easy work-up
procedures.
5. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1996.
6. Joshi, K. C.; Chand, P. Pharmazie 1982, 37.
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8. Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; El-Bady, Sh. M. Bioorg. Med.
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Watanabe, H. Eur. J. Pharmacol. 2002, 444, 39.
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17. Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; El-Bady, Sh. M. Bioorg. Med.
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20. Toda, F.; Tanaka, K.; Sekikawa, A. J. Chem. Soc., Chem. Commun. 1987, 279.
21. Bazgir, A.; Mohammadi Khanaposhtani, M.; Abolhasani Soorki, A. Bioorg. Med.
Chem. Lett. 2008, 18, 5800.
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44, 1009.
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti, University.
References and notes
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30. Bazgir, A.; Noroozi Tisseh, Z.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5165.
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Safak, C.; Simsek, R.; Altas, Y.; Boydag, S.; Erol, K. Bull. Chim. Farm. 1997, 136,
665; (g) Brandes, A.; Loegers, M.; Schmidt, G.; Angerbauer, R.; Schmeck, C.;
35. Typical procedure for the preparation of 5-phenyl-5H-spiro[diindeno[1,2-b:20,10-
e]pyridin-11,30-indoline]-20,10,12-trione (4a):
A mixture of 1,3-indandione
(2.92 g, 20 mmol), aniline (0.93 g, 10 mmol), isatin (1.47 g, 10 mmol), and p-
TSA (0.62 g, 3 mmol) was ground for 3–4 min using a mortar and pestle. After
storage at rt for 10 min, the solid was washed with H2O (20 mL) and EtOH
(15 mL) to afford the pure product 4a as a red powder (4.06 g, 85%); mp
>300 °C. IR (KBr) (
m
max, cmꢀ1): 3437, 3132, 1703, 1624. 1H NMR (300 MHz,
3
DMSO-d6): dH = 5.46 (2H, d, JHH = 6.0 Hz, H-Ar), 6.45–8.14 (15H, m, H-Ar),

502
R. Ghahremanzadeh et al. / Tetrahedron Letters 51 (2010) 499–502
10.65 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): dC = 46.1, 109.5, 111.9, 121.8,
for C32H17BrN2O3: C, 68.95; H, 3.07; N, 5.03. Found: C, 68.83; H, 3.13; N, 5.10.5-
121.9, 122.7, 124.9, 125.9, 128.5, 129.0, 130.7, 132.1, 132.8, 134.8, 136.5, 138.2,
142.6, 156.2, 178.0, 190.0. Anal. Calcd for C32H18N2O3: C, 80.32; H, 3.79; N,
5.85. Found: C, 80.41; H, 3.71; N, 5.76.Selected characterization data:5-
(4-Bromophenyl)-5H-spiro[diindeno[1,2-b:20,10-e]pyridin-11,30-indoline]-20,10,12-
(4-Methoxyphenyl)-50-nitro-5H-spiro[diindeno[1,2-b:20,10-e]pyridin-11,30-indoline]-
20,10,12-trione (4t): Red powder (yield 82%); mp >300 °C. IR (KBr) ( max/cmꢀ1):
m
3301, 3064, 1740, 1698. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.96 (3H, s,
OCH3), 5.61 (2H, d, 3JHH = 6.6 Hz, H-Ar), 7.08–8.43 (13H, m, H-Ar), 11.40 (1H, s,
NH). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 46.2, 56.2, 109.6, 110.5, 115.5,
115.7, 120.9, 122.0, 122.3, 126.6, 130.6, 131.0, 131.2, 131.7, 132.7, 133.1, 135.4,
136.6, 143.0, 149.2, 157.6, 161.5, 190.1. Anal. Calcd for C33H19N3O6: C, 71.61; H,
3.46; N, 7.59. Found: C, 71.70; H, 3.52; N, 7.65.50-Phenyl-50,5a’-dihydro-2H,4b0H-
spiro[acenaphthylene-1,110-diindeno[1,2-b:20,10-e]pyridin]-2,100,120(10a0H,11a0H)-
trione (4b): Red powder (yield 82%); mp >300 °C. IR (KBr) (m
max/cmꢀ1): 3495,
1708, 1629. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.56 (2H, d, 3JHH = 6.0 Hz,
H-Ar), 6.84–8.15 (14H, m, H-Ar), 10.65 (1H, s, NH). Anal. Calcd for
C32H17BrN2O3: C, 68.95; H, 3.07; N, 5.03. Found: C, 68.92; H, 3.02; N,
4.96.Due to the very low solubility of 4b, we were unable to obtain 13C NMR
data.10-Methyl-5-p-tolyl-5H-spiro[diindeno[1,2-b:20,10-e]pyridin-11,30-indoline]-
trione (8a): Red powder (yield 87%); mp >300 °C. IR (KBr) (m
max/cmꢀ1): 3442,
20,10,12-trione (4i): Red powder (yield 88%); mp >300 °C. IR (KBr) (
m
max /cmꢀ1):
1725, 1687, 1621. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.48 (2H, d,
3JHH = 7.2 Hz, H-Ar), 7.09–8.32 (17H, m, H-Ar). Anal. Calcd for C36H19NO3: C,
84.20; H, 3.73; N, 2.73. Found: C, 84.33; H, 3.67; N, 2.65.Due to the very low
3059, 1702, 1614. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 2.57 (3H, s, CH3),
3
3.25 (3H, s, NCH3), 5.54 (2H, d, JHH = 7.4 Hz, H-Ar), 6.97–8.03 (14H, m, H-Ar).
13C NMR (75 MHz, DMSO-d6): dC (ppm) 21.5, 26.9, 45.6, 108.4, 111.6, 121.9,
122.0, 122.7, 124.6, 129.2, 130.1, 130.8, 131.2, 132.7, 132.9, 133.9, 135.6, 136.6,
142.0, 144.0, 156.5, 176.5, 190.0. Anal. Calcd for C34H22N2O3: C, 80.62; H, 4.38;
N, 5.53. Found: C, 80.53; H, 4.31; N, 5.44.50-Bromo-5-phenyl-5H-
spiro[diindeno[1,2-b:20,10-e]pyridin-11,30-indoline]-20,10,12-trione (4k): Red
solubility of 8a, we were unable to obtain C NMR data.50-p-Tolyl-50,5a0-
13
dihydro-2H,4b0H-spiro[acenaphthylene-1,110-diindeno[1,2-b:20,1’-e]pyridin]-2,100,
120(10a0H,11a0H)-trione (8d): Red powder (yield 86%); mp >300 °C. IR (KBr)
(m
max /cmꢀ1): 3500, 1697, 1619, 1610. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
2.57 (3H, s, CH3), 5.56 (2H, d, 3JHH = 7.4 Hz, H-Ar), 7.14–8.33 (16H, m, H-Ar). 13
C
powder (yield 83%); mp >300 °C. IR (KBr) (
m
max/cmꢀ1): 3342, 3064, 1729,
NMR (75 MHz, DMSO-d6): dC (ppm) 21.3, 50.9, 109.7, 113.1, 113.5, 117.3,
121.1, 121.8, 122.0, 125.2, 128.9, 129.2, 129.9, 130.6, 131.0, 131.8, 132.6, 132.8,
135.7, 136.7, 141.2, 142.0, 156.6, 158.0, 158.6, 159.1, 159.6, 190.3, 204.5, 206.7.
Anal. Calcd for C37H21NO3: C, 84.23; H, 4.01; N, 2.65. Found: C, 84.10; H, 3.94;
N, 2.71.
1694. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.45 (2H, d, 3JHH = 7.2 Hz, H-Ar),
6.83–8.24 (14H, m, H-Ar), 10.80 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 46.3, 111.2, 111.4, 113.9, 121.9, 122.0, 127.8, 130.2, 130.7, 130.9, 131.7,
132.1, 132.7, 132.9, 136.5, 136.9, 138.2, 142.0, 156.6, 177.7, 190.0. Anal. Calcd