Organic reaction in water: A highly efficient and environmentally friendly synthesis of spiro compounds catalyzed by L -proline

Article abstract of DOI:10.1002/hlca.201000307

We have developed a clean, simple and efficient method for the synthesis of spiro compounds by three-component reaction of isatins (=1H-indole-2,3-diones) or acenaphthylene-1,2-dione, 1,3-diphenyl-1H-pyrazoles-5-amines, and tetronic acid (=furan-2,4-(3H,5

Full text of DOI:10.1002/hlca.201000307

824
Helvetica Chimica Acta – Vol. 94 (2011)
Organic Reaction in Water: A Highly Efficient and Environmentally Friendly
Synthesis of Spiro Compounds Catalyzed by l-Proline
by Minoo Dabiri, Zeinab Noroozi Tisseh, Mohsen Nobahar, and Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, G. C. Tehran 1983963113, Iran
(e-mail: a_bazgir@sbu.ac.ir)
We have developed a clean, simple and efficient method for the synthesis of spiro compounds by
three-component reaction of isatins (¼1H-indole-2,3-diones) or acenaphthylene-1,2-dione, 1,3-diphenyl-
1H-pyrazoles-5-amines, and tetronic acid (¼ furan-2,4-(3H,5H)-dione or 2-hydroxy-1,4-naphthoquinone
in the presence of a catalytic amount of l-proline in aqueous media. The advantages of this procedure are
mild reaction conditions, high yields of products, operational simplicity, and easy workup procedures
employed.
Introduction. – Multicomponent reactions (MCRs), because of their efficiency,
simple procedures, convergence, and facile execution, are among the best tools for the
synthesis of organic compounds. Therefore, the design of novel MCRs for the synthesis
of different groups of compounds, especially of those which are biologically active, have
attracted great attention. Different research groups active in the areas such as drug
discovery, material science, natural products, and organic synthesis have used this
synthetic method [1 – 5]. Indole and dihydroindol are important moieties of a large
number of natural products and medicinal agents [6], and several dihydroindoles, spiro-
connected with heterocycles at C(3), have shown high biological activities [7 – 9]. The
spiro-oxindole system is the core structure of many pharmacological agents and natural
alkaloids [10 – 13]. For example, spirotryprostatins A and B, two natural alkaloids
isolated from the fermentation broth of Aspergillus fumigatus, have been identified as
novel inhibitors of microtubule assembly. Other cytostatic alkaloids such as pteropo-
dine and isopteropodine have been shown to modulate the function of muscarinic
serotonin receptors [14] (Fig.).
Figure. Representatives of Spirooxindole-Containing Compounds
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
825
As a consequence, several methods have been reported for the preparation of spiro-
oxindole-containing heterocycles [15 – 17].
As small organic molecules like cinchona alkaloids, l-proline has been used as an
inexpensive, nontoxic, readily available catalyst for various transformations under mild
and convenient conditions, affording the corresponding products in excellent yields and
with high selectivity [18]. On the other hand, recently, l-proline has been found to be
very effective in enamine-based direct catalytic asymmetric aldol [19], Mannich [20],
Michael [21], DielsꢀAlder [22], and Knoevenagel reactions [23]. More recently, l-
proline and its derivatives have been used in MCRs.
Considering the reports mentioned above, development of new and simple MCRs
for synthesis of spiro compounds catalyzed by l-proline emerged as an interesting field
to study.
Results and Discussion. – We have recently reported several novel synthesis of
spirooxindoles via isatin based MCRs [24 – 28]. Here, we report an environmentally
benign three-component reaction for the synthesis of new spiro-oxindoles catalyzed by
l-proline.
In a pilot experiment, a mixture of isatin (¼1H-indole-2,3-dione; 1a), 1,3-diphenyl-
1H-pyrazol-5-amine 2a and tetronic acid (¼ furan-2,4(3H,5H)-dione; 3) in the
presence of a catalytic amount of l-proline in refluxing H2O was stirred for 6 h. After
completion of the reaction (monitored by TLC), the crude product was separated from
the mixture by filtration and washed with EtOH (5 ml) to afford product 4a in 91%
yield (Scheme 1).
Scheme 1
We examined this reaction in the absence and presence of several catalysts. The
results are collected in Table 1. After screening a number of catalysts, it should be
mentioned, that, when reactions were carried out in the absence of catalyst, the product
was detected only in trace amounts (Table 1, Entry 1). The best result was obtained
with 10 mol-% of l-proline as the catalyst in refluxing H2O (Entry 3). Using lower
amounts of catalyst resulted in lower yields, while higher amounts of catalyst did not
affect the reaction times and yields (Table 1). To study the effect of temperature, we
also performed three experiments at 708 and 808, and under reflux conditions. It was
observed that a lower reaction temperature led to a lower yield (Table 1).
To investigate the scope and limitations of this reaction, the procedure was
extended to various isatins 1a – 1e and 1H-pyrazol-5-amines 2a – 2d. As compiled in
Table 2, the reactions proceeded very efficiently, leading to the formation of the

826
Helvetica Chimica Acta – Vol. 94 (2011)
Table 1. Optimization of Reaction Conditions
Entry
Catalyst [mol-%]
Conditions
Time [h]
Yield [%]
1
2
3
4
5
8
9
10
11
12
13
None
reflux
reflux
reflux
reflux
708
10
6
6
6
6
trace
76
91
92
78
84
54
47
68
l-Proline (5%)
l-Proline (10%)
l-Proline (15%)
l-Proline (10%)
l-Proline (10%)
InCl3 (10%)
808
6
reflux
reflux
reflux
reflux
reflux
10
10
10
10
10
SSA (10%)a)
HPAs (10%)b)
AcOH (10%)
ZnCl2(10%)
43
trace
a) SSA ¼ Silica sulfuric acid. b) HPAs ¼ Heteropoly acids.
corresponding highly functionalized spiro-oxindoles 4a – 4k in excellent yields (Ta-
ble 2).
To further study the potential of this protocol for spiro-oxindole synthesis, we
investigated the reaction of 2-hydroxy-1,11-naphthoquinone 5 and isatins 1 with 1H-
pyrazol-5-amines 2, and obtained 1,11-dihydro-spiro[benzo[g]pyrazolo[3,4-b]quino-
line-4,3’-indole]-2’,5,10(1’H)-triones 6 in 73 – 82% yields under the same reaction
conditions (Table 3).
Table 2. Synthesis of Spiro-oxindoles 4
Product
X
R
Z
Time [h]
Yield [%]
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
Br
Br
Br
NO2
NO2
NO2
Me
H
H
H
H
Et
Et
Et
H
H
H
H
Br
NO2
H
Br
NO2
H
MeO
NO2
H
6
6.5
7
90
88
91
78
83
76
79
86
77
82
91
6
6.5
6.5
6
6
6.5
6
4j
4k
H
Bn
H
7.5

Helvetica Chimica Acta – Vol. 94 (2011)
Table 3. Synthesis of Spiro-oxindoles 6
827
Product
X
R
Z
Time [h]
Yield [%]
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
H
H
Br
Br
Br
Br
NO2
NO2
Me
H
H
H
H
H
Et
Et
Et
Et
H
H
H
Bn
Bn
H
MeO
Br
NO2
H
MeO
Br
NO2
H
NO2
H
H
Br
6
6.5
6
6
6
6.5
7.5
6.5
6
6
7
93
81
92
93
90
81
79
86
80
82
90
91
85
6j
6k
6l
7.5
7
6m
H
As expected, when isatin 1 was replaced by acenaphthylene-1,2-dione 7, spiro com-
pounds 8 were obtained in good yield under the same reaction conditions (Table 4).
The workup of these very clean reactions involves only a filtration and a simple
washing step with EtOH. Using this simple purification protocol, the desired products
are obtained in good purity. Compounds 4, 6, and 8 are stable solids structures which
1
were established by IR, and H- and 13C-NMR spectroscopy, and elemental analysis.
This method, based on a three-component l-proline-catalyzed reaction in H2O, is the
most simple and convenient procedure, and would be applicable to the synthesis of
different types of spiro-oxindole-containing heterocycles.
Although the mechanism of this reaction has not been established experimentally,
the proposed mechanism is depicted in Scheme 2.
In brief, a convenient, clean, and environmentally friendly method was developed
for the synthesis of spiro compounds in the presence of l-proline in aqueous media.
The simple experimental procedure and purification, and good yields are the
advantages of the present method.
Experimental Part
General. The chemicals used in this work were obtained from Acros and Merck, and were used
without purification. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: Bomem MB-Series

828
Helvetica Chimica Acta – Vol. 94 (2011)
Table 4. Synthesis of Spiro Compounds 8
Product
Z
Time [h]
Yield [%]
8a
8b
8c
8d
8e
H
MeO
Br
H
NO2
6
7
7
6.5
8
80
76
77
82
77
Scheme 2

Helvetica Chimica Acta – Vol. 94 (2011)
829
FT-IR spectrophotometer. 1H-NMR Spectra: Bruker DRX-300 Avance spectrometer at 300.13 MHz.
MS: Finnigan-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental
analyses: Heracus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Spiro Compounds: A mixture of isatins or acenaphthylene-
1,2-dione (1 mmol), 1H-pyrazol-5-amines (1 mmol), tetronic acid or hydroxynaphthoquinone (1 mmol),
and l-proline (0.1 mmol) in refluxing H2O (5 ml) was stirred for 6 – 7 h. The progress of reaction was
monitored by TLC. After completion of reaction, the mixture was filtered, and the precipitate was
washed with H2O and then EtOH (5 ml) to afford the pure products.
1,8-Dihydro-1,3-diphenylspiro[furo[3,4-b]pyrazolo[4,3-e]pyridine-4,3’-indole]-2’,5(1’H,7H)-dione
(4a). Yellow powder. M.p. 258 – 2618. IR (KBr): 3383, 3205, 1721, 1669. 1H-NMR ((D6)DMSO): 4.98 (s,
CH2); 6.81 – 8.32 (m, 14 arom. H); 10.94 (s, NH); 11.07 (s, NH). 13C-NMR ((D6)DMSO): 46.9; 66.4; 96.1;
96.7; 100.3; 108.8; 120.3; 124.3; 126.3; 128.2; 128.4; 128.6; 130.1; 132.4; 135.4; 137.6; 139.5; 143.4; 149;
149.8; 160.6; 170.2; 177.4. Anal. calc. for C27H18N4O3: C 72.64, H 4.06, N 12.55; found: C 72.58, H 4.01, N
12.49.
5’-Bromo-1’-ethyl-1,8-dihydro-1,3-diphenylspiro[furo[4,3-b]pyrazolo[4,3-e]pyridine-4,3’-indole]-
2’,5(1’H,7H)-dione (4d). Cream powder. M.p. > 3008. IR (KBr): 3179, 1763, 1669. 1H-NMR
((D6)DMSO): 0.82 (s, Me); 3.32 (s, CH2); 4.93 (s, CH2); 6.75 – 7.66 (13 arom. H); 10.79 (s, NH).13C-NMR
((D6)DMSO): 12.1; 34.7; 52.1; 66.1; 99.3; 100.3; 110.7; 114.6; 124.2; 127.8; 128.2; 128.5; 130.1; 131.8;
132.8; 137.4; 137.7; 139.6; 141.9; 149.7; 158.8; 159.1; 160.5; 170; 175.6. Anal. calc. for C29H21BrN4O3: C
62.94, H 3.82, N 10.12; found: C 62.86, H 3.88, N 10.04.
1,8-Dihydro-1-(4-methoxyphenyl)-5’-nitro-3-phenylspiro[furo[4,3-b]pyrazolo[4,3-e]pyridine-4,3’-in-
dole]-2’,5(1’H,7H)-dione (4h). White powder. M.p. 275 – 2778. IR (KBr): 3305, 3067, 1738, 1705.
1H-NMR ((D6)DMSO): 3.86 (s, MeO); 4.98 (s, CH2); 6.65 – 8.47 (m, 12 arom. H); 10.33 (s, NH); 10.94 (s,
NH).13C-NMR ((D6)DMSO): 47.5; 65.9; 99.1; 102.2; 109.8; 122.3; 124; 125.1; 125.6; 128.1; 128.3; 128.8;
129.1; 132.4; 135.7; 140; 142.1; 142.8; 146.2; 151.5; 159.3; 169.9; 177.9. Anal. calc. for C28H19N5O6: C 64.49,
H 3.67, N 13.43; found: C 64.57, H 3.60, N 13.50.
1’-Benzyl-1,8-dihydro-1,3-diphenylspiro[furo[3,4-b]pyrazolo[4,3-e]pyridine-4,3’-indole]-2’,5(1’H,
7H)-dione (4k). Yellow powder. M.p. > 3008. IR (KBr): 3426, 1755, 1694. 1H-NMR ((D6)DMSO): 4.19,
4.86 (AB, J ¼ 16, CH2); 6.49 – 8.48 (m, 23 arom. H); 11.08 (s, NH). 13C-NMR ((D6)DMSO): 43.8; 47.2;
66.1; 98.6; 102.3; 109.2; 123.2; 124.1; 125; 125.7; 127.3; 127.5; 128.1; 128.4; 128.8; 129.1; 132.1; 134.7; 136;
139.9; 142.5; 142.8; 146.3; 151.5; 159.8; 170.1; 176. Anal. calc. for C34H24N4O3: C 76.11, H 4.51, N 10.44;
found: C 76.05, H 4.47, N 10.51.
1,11-Dihydro-1,3-diphenylspiro[benzo[g]pyrazolo[3,4-b]quinoline-4,3’-indole]-2’,5,10(1’H)-trione
(6a). Red powder. M.p. 267 – 2708. IR (KBr): 3426, 3343, 1755, 1727, 1678. 1H-NMR ((D6)DMSO): 6.61 –
8.57 (m, 18 arom. H); 10.46 (s, NH); 11.47 (s, NH). 13C-NMR ((D6)DMSO): 51.4; 105.6; 109.9; 114.8;
120.9; 122.5; 123.3; 124; 125.9; 126.2; 127.5; 128; 128.6; 128.9; 129.5; 129.7; 131.8; 132.7; 133.2; 134.3;
134.7; 138.8; 143.9; 149.2; 152.4; 153.5; 176.3; 179.3; 181. Anal. calc. for C33H20N4O3: C 76.14, H 3.87, N
10.76; found: C 76.05, H 3.81, N 10.71.
5’-Bromo-1-(4-bromophenyl)-1’-ethyl-1,11-dihydro-3-phenylspiro[benzo[g]pyrazolo[3,4-b]quino-
line-4,3’-indole]-2’,5,10(1’H)-trione (6g). Red powder. M.p. 268 – 2718. IR (KBr): 3255, 1722, 1705, 1677.
1H-NMR ((D6)DMSO): 0.83 (s, Me); 3.15 (s, CH2); 6.63 – 8.05 (m, 16 arom. H); 9.98 (s, NH). 13C-NMR
((D6)DMSO): 11.8; 34.7; 50; 101;110.4; 114.6; 123.8; 124.1; 125; 126.5; 127.4; 128; 128.6; 128.9; 129;
129.3; 130.07; 131.4; 132.2; 132.6; 133.8; 135.6; 138.5; 139.5; 142.2; 146.1; 149.7; 152.1; 154.3; 176.3; 176.9;
181. Anal. calc. for C35H22Br2N4O3: C 59.51, H 3.14, N 7.93; found: C 59.46, H 3.08, N 7.99.
1,11-Dihydro-5’-methyl-1,3-diphenylspiro[benzo[g]pyrazolo[3,4-b]quinoline-4,3’-indole]-2’,5,10(1’H)-
trione (6k). Red powder. M.p. > 3008. IR (KBr): 3194, 3056, 1716, 1678. 1H-NMR ((D6)DMSO): 2.17 (s,
Me); 6.49 – 8.05 (m, 17 arom. H); 10.02 (s, NH); 10.07 (s, NH). 13C-NMR ((D6)DMSO): 50.6; 101.2;
111.4; 113.5; 123.8; 126.4; 127.3; 127.9; 128.2; 128.6; 129; 130; 130.3; 133.8; 135.7; 136.9; 138.5; 140.3;
141.7; 178.9; 181. Anal. calc. for C34H22N4O3: C 76.39, H 4.15, N 10.48; found: C 76.31, H 4.19, N 10.53.
1’-Benzyl-1-(4-bromophenyl)-1,11-dihydro-3-phenylspiro[benzo[g]pyrazolo[3,4-b]quinoline-4,3’-
indole]-2’,5,10(1’H)-trione (6m). Red powder. M.p. > 3008. IR (KBr): 3194, 1705, 1678, 1617. 1H-NMR
((D6)DMSO): 3.88, 4.77 (AB, J ¼ 16, CH2); 6.43 – 8.07 (m, 23 arom. H); 10.01 (s, NH). 13C-NMR
((D6)DMSO): 43.5; 47.6; 98.6; 101.5; 102.8; 109.2; 121.2; 122.1; 123; 125.1; 125.3; 125.8; 127.3; 127.6;

830
Helvetica Chimica Acta – Vol. 94 (2011)
128;128.3; 128.5; 128.9; 129.1; 129.4; 129.7; 131; 131.3; 132.1; 133; 134.7; 136; 139.9; 142.3; 142.8; 146;
151.3; 159.8; 160.3; 176; 178.3; 179; 181. Anal. calc. for C40H26N4O3: C 78.67, H 4.29, N 9.17; found: C
78.60, H 4.24, N 9.10.
1’,11’-Dihydro-1’,3’-diphenylspiro[2H-acenaphthylene-1,4’-benzo[g]pyrazolo[3,4-b]quinoline]-
1
2,5’,10’-trione (8a). Powder. M.p. 252 – 2558. IR (KBr): 3205, 1718, 1670, 1607. H-NMR ((D6)DMSO):
6.16 – 8.12 (m, 20 arom. H); 10.05 (s, NH). 13C-NMR ((D6)DMSO): 55; 103.4; 117.4; 123.7; 124.9; 126.3;
126.5; 127.1; 127.9; 128.1; 128.4; 128.6; 129.2; 130; 130.4; 131; 132; 133.9; 138.6; 140.6; 146.5; 149.8; 179.8;
181.3; 203.9. Anal. calc. for C37H21N3O3: C 79.99, H 3.81, N 7.56; found: C 79.91, H 3.88, N 7.62.
5’,8’-Dihydro-1’-(4-nitrophenyl)-3’-phenylspiro[2H-acenaphthylene-1,4’-furo[3,4-b]pyrazolo[4,3-
e]pyridine]-2,7’(1’H)-dione (8e). Cream powder. M.p. 230 – 2328. IR (KBr): 3383, 1750, 1723. 1H-NMR
((D6)DMSO): 5.00 (s, CH2); 6.31 – 8.20 (m, 15 arom. H); 10.84 (s, NH); 10.81 (s, NH). 13C-NMR
((D6)DMSO): 52; 66.3; 99.9; 103.7; 121.8; 122.3; 124; 125.2; 125.7; 127.3; 128; 128.2; 128.8; 129.4; 130;
131.6; 132; 132.7; 139.9; 141.4; 142.8; 143.7; 146.3; 151.5; 159.8; 170.4; 203.9. Anal. calc. for C31H18N4O5: C
70.72, H 3.45, N 10.64; found: C 70.67, H 3.39, N 10.57.
REFERENCES
[1] R. V. A. Orru, M. de Greef, Synthesis 2003, 1471.
[2] S. L. Schreiber, Science 2000, 287, 1964.
´
[3] J. Zhu, H. Bienayme, ꢂMulticomponent Reactionsꢃ, Wiley-VCH, Weinheim, Germany, 2005.
[4] A. Dçmling, Chem. Rev. 2006, 106, 17.
[5] L. Weber, Curr. Med. Chem. 2002, 9, 2085.
[6] R. J. Sundberg, ꢂThe Chemistry of Indolesꢃ, Academic, New York, NY, 1996.
[7] K. C. Joshi, P. Chand, Pharmazie 1982, 37, 1.
[8] J. F. M. Da Silva, S. J. Garden, A. C. Pinto, J. Braz. Chem. Soc. 2001, 12, 273.
[9] A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna, Sh. M. El-Bady, Bioorg. Med. Chem. 2004, 12,
2483.
[10] T.-H. Kang, K. Matsumoto, M. Tohda, Y. Murakami, H. Takayama, M. Kitajima, N. Aimi, H.
Watanabe, Eur. J. Pharmacol. 2002, 444, 39.
[11] J. Ma, S. M. Hecht, Chem. Commun. 2004, 1190.
[12] S.-L. Zhu, S.-J. Ji, Y. Zhang, Tetrahedron 2007, 63, 9365.
[13] R. S. Kumar, S. Perumal, Terahedron Lett. 2007, 48, 7164.
[14] R. G. Redkin, L. A. Shemchuk, V. P. Chernykh, O. V. Shishkin, S. V. Shishkina, Tetrahedron 2007, 63,
11444.
[15] G. Shanthi, G. Subbulakshmi, P. T. Perumal, Tetrahedron 2007, 63, 2057.
[16] A. A. Mohammadi, M. Dabiri, H. Qaraat, Tetrahedron 2009, 65, 3804.
[17] S. Chandrasekhar, N. R. Reddy, S. S. Sultana, C. Narsihmulu, K. V. Reddy, Tetrahedron 2006, 62,
338; H. Li, B. Wang, L. Deng, J. Am. Chem. Soc. 2006, 128, 732.
[18] B. Alcaide, P. Almendros, A. Luna, M. R. Torres, J. Org. Chem. 2006, 71, 4818.
[19] J. M. Janey, Y. Hsiao, J. D. Armstrong III, J. Org. Chem. 2006, 71, 390.
[20] M. S. Rasalkar, M. K. Potdar, S. S. Mohile, M. M. Salunkhe, J. Mol. Catal. A: Chem. 2005, 235, 267.
[21] D. B. Ramachary, N. S. Chowdari, C. F. Barbas III, Angew. Chem. 2003, 115, 4365.
[22] H. A. Oskooie, E. Roomizadeh, M. M. Heravi, J. Chem. Res. 2006, 246.
[23] A. Kumar, R. A. Maurya, Tetrahedron 2007, 63, 1946; C.-L. Shi, D.-Q. Shi, S. H. Kim, Z.-B. Huang,
S.-J. Ji, M. Ji, Tetrahedron 2008, 64, 2425; C.-L. Shi, D.-Q. Shi, S. H. Kim, Z.-B. Huang, M. Ji, Aust. J.
Chem. 2008, 61, 547.
[24] A. Bazgir, Z. N. Tisseh, P. Mirzaei, Terahedron Lett. 2008, 49, 5165.
[25] K. Jadidi, R. Ghahremanzadeh, A. Bazgir, Tetrahedron 2009, 65, 2005.
[26] M. Dabiri, S. C. Azimi, H. R. Khavasi, A. Bazgir, Tetrahedron 2008, 64, 7307.
[27] K. Jadidi, R. Ghahremanzadeh, A. Bazgir, J. Comb. Chem. 2009, 11, 341.
[28] R. Ghahremanzadeh, M. Sayyafi, S. Ahadi, A. Bazgir, J. Comb. Chem. 2009, 11, 393.
Received August 14, 2010