An efficient one-pot synthesis of novel pyrazolophthalazinyl spirooxindoles

Article abstract of DOI:10.1007/s12039-010-0047-2

A simple and efficient method for the synthesis of novel pyrazolophthalazinyl spirooxindoles by L-proline catalysed one-pot three-component reaction is described. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0047-2

J. Chem. Sci., Vol. 122, No. 3, May 2010, pp. 415–421. © Indian Academy of Sciences.
An efficient one-pot synthesis of novel pyrazolophthalazinyl
spirooxindoles
GNANAMANI SHANTHI and PARAMASIVAN T PERUMAL*
Organic Chemistry Division, Central Leather Research Institute, Chennai 600 020
e-mail: ptperumal@gmail.com
MS received 25 August 2008; revised 31 October 2009; accepted 26 November 2009
Abstract. A simple and efficient method for the synthesis of novel pyrazolophthalazinyl spirooxindoles
by L-proline catalysed one-pot three-component reaction is described.
Keywords. L-proline; pyrazolophthalazinyl spirooxindoles; three-component.
1. Introduction
class of spirooxindoles have made them attractive
synthetic targets (figure 1).
Multicomponent reactions (MCRs) are special types
of synthetically useful organic reactions in which
three or more different starting materials react to a
final product in a one-pot procedure. MCRs are
powerful tools in the modern drug discovery process
and allow the fast, automated, and high-throughput
2. Experimental
2.1 Materials and methods
Malononitrile, isatin, NH SO H, SnCl ⋅2H O, K CO
2
3
2
2
2
3
1
generation of organic compounds. In the past
and basic alumina were obtained from S.D. Fine
Chemicals Indium(III) chloride, CAN, L-proline
and phthalhydrazide were purchased from Aldrich.
All melting points were uncorrected. IR spectra were
recorded on a Perkin Elmer FT–IR spectro-
decade, there have been tremendous developments
in three- and four-component reactions and efforts
2
are still being made to find and develop new MCRs.
The indole template is generally recognized as an
important structure in medicinal chemistry, and in
particular, oxindoles that incorporate a quaternary
stereogenic centre at C3 are attractive targets in or-
ganic synthesis because of their significant biologi-
1
13
photometer. H and C NMR spectra were recorded
in DMSO-d using TMS as an internal standard on a
6
JEOL spectrometer at 500 MHz and 125 MHz and
Bruker spectrometer at 300 MHz and 75 MHz
respectively. Mass spectra were recorded on a JEOL
3
cal activities. The spirooxindole system is the core
structure of many pharmacological agents and natu-
ral alkaloids. For example, spirotryprostatin A, a
natural alkaloid isolated from the fermentation broth
of Aspergillus fumigatus, has been identified as a
4
novel inhibitor of microtubule assembly, and ptero-
podine and isopteropodine have been shown to
modulate the function of muscarinic serotonin
5
receptors (figure 1). In addition to the naturally
occurring pyrrolidino-spiro-3′-oxindoles, synthetic
pyrrolino- and piperidino-spiro-3′-oxindoles have
been shown to exhibit local anaesthetic properties.
The unique structural array and the highly pro-
nounced pharmacological activity displayed by the
Figure 1. Representatives of spirooxindole-containing
*For correspondence
compounds.
415

416
Gnanamani Shanthi and Paramasivan T Perumal
Table 1. Synthesis of pyrazolophthalazinyl spiro-3′-oxindoles 4a–j.
a
Entry
R
X
Product (4)
Time (h)
Yield (%)
R′
1
H
H
CN
2.0
90
2
H
H
CO Et
2
2.2
88
3
CH
H
CN
2.0
92
3
4
Butyl
H
CN
2.2
91
5
Butyl
H
CO Et
2
2.5
88
6
Benzyl
H
CN
2.0
92
7
Benzyl
H
CO Et
2
2.2
90
8
Allyl
H
CN
2.2
87
(Contd…)

An efficient one-pot synthesis of novel pyrazolophthalazinyl spirooxindoles
Table 1. (Contd…)
417
a
Entry
R
X
Product (4)
Time (h)
Yield (%)
R′
9
Allyl
H
CO Et
2
2.5
86
10
H
NO
CN
2.0
90
2
a
Isolated yield
DX 303 HF spectrometer. Elemental analyses were Anal. Calcd. For C H N O : C, 63⋅87; H, 3⋅10; N,
19 11
5
3
recorded using a Thermo Finnigan FLASH EA 1112 19⋅60%. Found: C, 63⋅83; H, 3⋅06; N, 19⋅55 %.
CHN analyser. Analytical TLC was performed on
pre-coated plastic sheets of silica gel G/UV-254 of 2.2b Ethyl 3-amino-5,10-dioxo spiro[(3′H)-indol-
0⋅2 mm thickness (Macherey–Nagel, Germany).
3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b) phthalazin]-
(1′H)-2′-one-2-carboxylate (4b) (table 1, entry 2):
yellow solid. m.p.: 284–286°C. νmax (KBr): 3438,
2.2 General procedure for the synthesis of pyra-
zolophthalazinyl spirooxindoles (4a–j)
–1
1
3328, 1742, 1701, 1665, 1527, 1294, 1140 cm . H
NMR (DMSO-d , 500 MHz): δ 0⋅84 (t, 3H, J =
6
7⋅65 Hz), 3⋅81 (m, 2H), 6⋅80 (d, 1H, J = 7⋅65 Hz),
6⋅84 (t, 1H, J = 6⋅85 Hz), 7⋅18 (t, 1H, J = 7⋅65 Hz),
7⋅27 (d, 1H, J = 7⋅65 Hz), 7⋅52 (br s, 2H, NH , D O
L-proline (20 mol%) was added to a stirred mixture
of isatin (1 mmol), malononitrile (1 mmol) and
phthalhydrazide (1 mmol) in ethanol (5 mL), and re-
fluxed for the appropriate time (table 1). After com-
plete conversion as indicated by TLC, water was
added and the product was extracted with ethyl ace-
tate (2 × 15 mL). The combined extracts were dried
over anhydrous Na SO and concentrated in vacuo.
2
2
exchangeable), 7⋅94 (m, 3H), 8⋅25 (d, 1H, J =
13
9⋅15 Hz), 10⋅73 (s, 1H, NH, D O exchangeable). C
2
NMR (DMSO-d , 125 MHz): δ 14⋅2, 59⋅3, 70⋅7,
6
81⋅3, 109⋅9, 122⋅2, 124⋅3, 127⋅3, 127⋅5, 128⋅0,
128⋅6, 129⋅1, 130⋅0, 134⋅7, 135⋅5, 143⋅9, 151⋅2,
2
4
+
152⋅6, 157⋅0, 163⋅7, 173⋅5. MS (m/z): 404 (M ).
Anal. Calcd. For C H N O : C, 62⋅37; H, 3⋅99; N,
13⋅85 %. Found: C, 62⋅28; H, 3⋅94; N, 13⋅78%.
The resulting product was recrystallized from etha-
21 16
4
5
nol to afford pure product (4a–j).
2.2a 3-Amino-5,10-dioxo spiro[(3′H)-indol-3′,1-
5,10-dihydro-1(H)-pyrazolo(1,2-b)phthalazin]-(1′H)-
2′-one-2-carbonitrile (4a) (table 1, entry 1): yel-
low solid. m.p.: 269–270°C. νmax (KBr): 3439, 3350,
2209, 1756, 1678, 1653, 1465, 1364, 1257,
2.2c 3-Amino-1′-methyl-5,10-dioxo
spiro[(3′H)-
indol-3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthala-
zin]-(1′H)-2′-one-2-carbonitrile (4c) (table 1, entry
3): pale yellow solid. m.p.: 282–284°C. νmax (KBr):
3453, 3327, 2197, 1728, 1664, 1611, 1472, 1371,
–1
1
1163 cm . H NMR (DMSO-d , 500 MHz): δ 6⋅90
6
–1
1
698 cm . H NMR (DMSO-d , 500 MHz): δ 3⋅22 (s,
6
(d, 1H, J = 7⋅65 Hz), 6⋅97 (t, 1H, J = 7⋅65 Hz), 7⋅27
(t, 1H, J = 7⋅6 Hz), 7⋅44 (d, 1H, J = 7⋅65 Hz), 7⋅96
(m, 3H), 8⋅25 (d, 1H, J = 7⋅65 Hz), 8⋅32 (br s, 2H,
NH , D O exchangeable), 10⋅92 (s, 1H, NH, D O
3H), 7⋅05 (t, 1H, J = 7⋅65 Hz), 7⋅11 (d, 1H,
J = 7⋅65 Hz), 7⋅37 (t, 1H, J = 8⋅4 Hz), 7⋅51 (d, 1H,
J = 6⋅9 Hz), 7⋅95 (m, 3H), 8⋅26 (d, 1H, J = 8⋅4 Hz),
2
2
2
13
13
8⋅37 (br s, 2H, NH , D O exchangeable). C NMR
exchangeable). C NMR (DMSO-d , 125 MHz): δ
6
2
2
(DMSO-d , 125 MHz): δ 27⋅3, 60⋅0, 69⋅9, 109⋅7,
6
114⋅9, 123⋅8, 124⋅9, 125⋅3, 127⋅5, 128⋅1, 128⋅3, 129⋅2,
131⋅2, 135⋅0, 135⋅6, 144⋅2, 152⋅4, 153⋅1, 156⋅8, 171⋅6.
60⋅6, 70⋅3, 110⋅9, 114⋅9, 123⋅1, 125⋅2, 125⋅9, 127⋅5,
128⋅1, 128⋅3, 129⋅2, 131⋅0, 134⋅9, 135⋅6, 142⋅7,
152⋅2, 153⋅1, 156⋅9, 173⋅0. MS (m/z): 357 (M )⋅
+

418
Gnanamani Shanthi and Paramasivan T Perumal
+
MS (m/z): 371 (M ). Anal. Calcd. for C H N O : 1H, J = 6⋅85 Hz), 7⋅26 (d, 2H, J = 6⋅9 Hz), 7⋅30
20 13
5
3
C, 64⋅69; H, 3⋅53; N, 18⋅86%. Found: C, 64⋅63; H, (t, 2H, J = 7⋅65 Hz), 7⋅42 (d, 2H, J = 7⋅6 Hz), 7⋅56
3⋅48; N, 18⋅81%.
(d, 1H, J = 7⋅65 Hz), 7⋅97 (m, 2H), 8⋅05 (d, 1H,
J = 6⋅85 Hz), 8⋅28 (d, 1H, J = 9⋅15 Hz), 8⋅41 (br s,
2.2d 3-Amino-1’-butyl-5,10-dioxo spiro[(3’H)-indol- 2H, NH , D O exchangeable). C NMR (DMSO-d ,
2
13
2
6
3’,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthalazin]-
125 MHz): δ 44⋅0, 60⋅3, 70⋅0, 110⋅3, 115⋅0, 123⋅9,
(1′H)-2′-one-2-carbonitrile (4d) (table 1, entry 4): 125⋅1, 125⋅4, 127⋅5, 127⋅6, 128⋅0, 128⋅2, 129⋅1,
pale yellow solid. m.p.: 222–223°C. νmax (KBr): 129⋅3, 131⋅0, 135⋅0, 135⋅6, 136⋅0, 143⋅1, 152⋅4,
+
3382, 3260, 2937, 2196, 1668, 1610, 1562, 1467, 153⋅2, 156⋅9, 171⋅8. MS (m/z): 447 (M ). Anal.
1432, 1374, 1257, 1146 cm . H NMR (DMSO-d , Calcd. for C H N O : C, 69⋅79; H, 3⋅83; N,
–1
1
6
26 17
5
3
500 MHz): δ 0⋅87 (t, 3H, J = 6⋅9 Hz), 1⋅33 (m, 2H), 15⋅.65%. Found: C, 69⋅72; H, 3⋅78; N, 15⋅60%.
1⋅59 (m, 2H), 3⋅70 (m, 2H), 7⋅03 (t, 1H, J =
7⋅65 Hz), 7⋅14 (d, 1H, J = 7⋅65 Hz), 7⋅35 (t, 1H, J = 2.2g Ethyl 3-amino-1′-benzyl-5,10-dioxo spiro
7⋅6 Hz), 7⋅51 (d, 1H, J = 6⋅85 Hz), 7⋅94 (t, 2H, [(3′H)-indol-3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-
J = 7⋅6 Hz), 8⋅00 (d, 1H, J = 8⋅45 Hz), 8⋅26 (d, 1H, b)phthalazin]-(1′H)-2′-one-2-carboxylate (4g) (table
J = 7⋅6 Hz), 8⋅35 (br s, 2H, NH , D O exchange- 1, entry 7): pale yellow solid. m.p.: 290–291°C. νmax
2
2
13
able). C NMR (DMSO-d , 125 MHz): δ 14⋅2, 19⋅8, (KBr): 3426, 3316, 1702, 1697, 1528, 1428, 1383,
6
–1
1
29⋅5, 60⋅4, 70⋅0, 109⋅9, 114⋅8, 123⋅5, 125⋅0, 125⋅4, 1298, 1263, 1143, 700 cm . H NMR (DMSO-d ,
6
127⋅5, 128⋅1, 128⋅3, 129⋅2, 131⋅1, 134⋅9, 135⋅6, 500 MHz): δ 0⋅65 (m, 3H), 3⋅40 (m, 2H), 4⋅88 (ABq,
143⋅5, 152⋅3, 153⋅1, 156⋅9, 171⋅4. MS (m/z): 413 2H, J = 16⋅05 Hz), 6⋅80 (d, 1H, J = 7⋅65 Hz), 6⋅91 (t,
+
(M ). Anal. Calcd. for C H N O : C, 66⋅82; H, 1H, J = 7⋅65 Hz), 7⋅18 (t, 1H, J = 7⋅65 Hz), 7⋅26 (t,
23 19
5
3
4⋅63; N, 16⋅94%. Found: C, 66⋅93; H, 4⋅58; N, 1H, J = 6⋅85 Hz), 7⋅32 (t, 2H, J = 7⋅65 Hz), 7⋅38 (d,
16⋅88%.
1H, J = 7⋅65 Hz), 7⋅52 (d, 2H, J = 7⋅65 Hz), 7⋅96 (m,
3H), 8⋅15 (br s, 2H, NH , D O exchangeable), 8⋅28
2
2
13
2.2e Ethyl 3-amino-1′-butyl-5,10-dioxo spiro[(3′H)- (d, 1H, J = 9⋅15 Hz).
C
NMR (DMSO-d ,
6
indol-3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthala-
125 MHz): δ 14⋅3, 43⋅8, 56⋅6, 59⋅2, 70⋅2, 109⋅3,
zin]-(1′H)-2′-one-2-carboxylate (4e) (table 1, entry 123⋅1, 124⋅1, 127⋅6, 127⋅8, 127⋅9, 128⋅1, 128⋅9,
5): pale yellow solid. m.p.: 258–260°C. νmax (KBr): 129⋅2, 130⋅0, 134⋅8, 135⋅6, 136⋅6, 144⋅4, 152⋅8,
+
3427, 3319, 2933, 1731, 1704, 1674, 1610, 1527, 157⋅1, 163⋅7, 172⋅3. MS (m/z): 494 (M ). Anal.
–1
1468, 1428, 1378, 1298, 1263, 1141, 757, 699 cm . Calcd. for C H N O : C, 68⋅01; H, 4⋅48; N,
28 22
4
5
1
H NMR (DMSO-d , 500 MHz): δ 0⋅77 (m, 3H), 11⋅33%. Found: C, 67⋅95; H, 4⋅42; N, 11⋅28%.
6
0⋅89 (t, 3H, J = 6⋅85 Hz), 1⋅37 (m, 2H), 1⋅60 (m,
2H), 3⋅67 (t, 2H, J = 7⋅65 Hz), 3⋅81 (m, 2H), 6⋅91 (t, 2.2h 3-Amino-1′-allyl-5,10-dioxo spiro[(3′H)-indol-
1H, J = 7⋅6 Hz), 7⋅02 (d, 1H, J = 8⋅4 Hz), 7⋅26 (t, 3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthalazin]-
1H, J = 7⋅65 Hz), 7⋅33 (d, 1H, J = 7⋅65 Hz), 7⋅95 (m, (1′H)-2′-one-2-carbonitrile (4h) (table 1, entry 8):
3H), 7⋅62 (br s, 2H, NH , D O exchangeable), 8⋅26 pale yellow solid. m.p.: 276–277°C. νmax (KBr):
2
2
13
(d, 1H, J = 6⋅85 Hz).
125 MHz): δ 14⋅1, 14⋅3, 20⋅0, 29⋅7, 59⋅2, 70⋅1, 80⋅2, 1469, 1437, 1376, 1285, 1255, 1170, 698 cm . H
C
NMR (DMSO-d , 3382, 3261, 2200, 1712, 1690, 1667, 1612, 1561,
6
–1
1
108⋅8, 122⋅7, 124⋅1, 126⋅8, 127⋅6, 128⋅0, 128⋅6, NMR (DMSO-d , 500 MHz): δ 4⋅34 (ABq, 2H,
6
129⋅1, 130⋅2, 134⋅8, 135⋅5, 144⋅7, 151⋅4, 152⋅7, J = 13⋅0 Hz), 5⋅15 (d, 1H, J = 10⋅7 Hz), 5⋅31 (d, 1H,
+
157⋅2, 163⋅6, 171⋅8. MS (m/z): 460 (M ). Anal. J = 16⋅8 Hz), 5⋅82 (m, 1H), 7⋅00 (d, 1H, J = 7⋅6 Hz),
Calcd. for C H N O : C, 65⋅21; H, 5⋅25; N, 7⋅06 (t, 1H, J = 7⋅65 Hz), 7⋅33 (t, 1H, J = 8⋅4 Hz),
25 24
4
5
12⋅17%. Found: C, 65⋅27; H, 5⋅20; N, 12⋅12%.
7⋅53 (d, 1H, J = 7⋅65 Hz), 7⋅95 (m, 3H), 8⋅26 (d, 1H,
J = 6⋅85 Hz), 8⋅37 (br s, 2H, NH , D O exchange-
2.2f 3-Amino-1′-benzyl-5,10-dioxo spiro[(3′H)- able). C NMR (DMSO-d , 125 MHz): δ 42⋅6, 60⋅3,
2
2
13
6
indol-3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthala-
70⋅0, 110⋅3, 114⋅9, 117⋅0, 123⋅8, 125⋅0, 125⋅3,
zin]-(1′H)-2′-one-2-carbonitrile (4f) (table 1, entry 127⋅6, 128⋅1, 128⋅2, 129⋅2, 131⋅0, 131⋅6, 135⋅0,
6): pale yellow solid. m.p.: 266°C. νmax (KBr): 3373, 135⋅6, 143⋅1, 152⋅3, 153⋅1, 156⋅9, 171⋅4. MS (m/z):
3258, 2197, 1666, 1611, 1468, 1371, 1163, 698 cm . 397 (M ). Anal. Calcd. for C H N O : C, 66⋅49; H,
–1
+
22 15
5
3
1
H NMR (DMSO-d , 500 MHz): δ 4⋅96 (ABq, 2H, 3⋅80; N, 17⋅62%. Found: C, 66⋅57; H, 3⋅75; N,
6
J = 16⋅05 Hz), 6⋅87 (d, 1H, J = 8⋅4 Hz), 7⋅03 (t, 17⋅58%.

An efficient one-pot synthesis of novel pyrazolophthalazinyl spirooxindoles
419
2.2i Ethyl 3-amino-1′-allyl-5,10-dioxo spiro[(3′H)- zolophthalazinyl spiro-3’-oxindoles. Heterocyclic
indol-3′,1-5,10-dihydro-1(H)-pyrazolo(1,2-b)phthala- fused phthalazines have been found effective for the
zin]-(1′H)-2′-one-2-carboxylate (4i) (table 1, entry inhibition of p38 MAP kinase, selective binding of
6
7
8
9): pale yellow solid. m.p.: 254–256°C. νmax (KBr): GABA receptor, antianxiety drug, antitumour
3385, 3252, 1735, 1708, 1668, 1608, 1570, 1455, agent, high affinity ligands to the α2δ – 1 subunit of
9
–1
1
10
1423, 1376, 1285, 1255, 1178, 692 cm . H NMR calcium channel.
(DMSO-d , 500 MHz): δ 0⋅80 (s, 3H), 3⋅79 (q, 2H, Recently, L-proline has been effectively used as a
6
J = 6⋅9 Hz), 4⋅27 (ABq, 2H, J = 17⋅55 Hz), 5⋅18 (d, versatile organocatalyst in various organic transfor-
1H, J = 9⋅95 Hz), 5⋅48 (d, 1H, J = 17⋅55 Hz), 5⋅82 mations. In an extension of our continuing efforts
11
(m, 1H), 6⋅91 (t, 1H, J = 7⋅6 Hz), 6⋅94 (d, 1H, on the application of malononitrile based multicom-
J = 7⋅65 Hz), 7⋅25 (t, 1H, J = 7⋅65 Hz), 7⋅35 (d, 1H, ponent reactions in heterocyclic synthesis and in the
12
J = 6⋅85 Hz), 7⋅86 (br s, 2H, NH , D O exchange- synthesis of spirooxindoles, we report here a sim-
2
2
able), 7⋅95 (t, 2H, J = 7⋅65 Hz), 8⋅02 (d, 1H, ple and efficient method for the synthesis of pyra-
13
J = 9⋅15 Hz), 8⋅27 (d, 1H, J = 7⋅9 Hz). C NMR zolophthalazinyl spiro-3’-oxindoles, through the
(DMSO-d , 125 MHz): δ 14⋅4, 43⋅8, 59⋅4, 70⋅5, three-component condensation of isatin, malo-
6
79⋅7, 111⋅5, 117⋅9, 122⋅9, 124⋅2, 125⋅3, 127⋅1, nonitrile and phthalhydrazide using L-proline as a
127⋅3, 127⋅9, 128⋅6, 130⋅1, 132⋅2, 134⋅8, 135⋅6, catalyst (scheme 1).
152⋅8, 153⋅2, 157⋅1, 162⋅8, 171⋅8. MS (m/z): 444
Initially, a model one-pot three-component reac-
+
(M ). Anal. Calcd. for C H N O : C, 64⋅86; H, tion of isatin 1a (1 mmol), malononitrile 2a (1 mmol)
24 20
4
5
4⋅54; N, 12⋅61%. Found: C, 64⋅75; H, 4⋅51; N, and phthalhydrazide 3 (1 mmol) was investigated.
12⋅55%. Various catalysts, including InCl , CAN, NH SO H,
3
2
3
SnCl ⋅2H O, L-proline, K CO and basic alumina
2
2
2
3
2.2j 3-Amino-5′-nitro-5,10-dioxo spiro[(3′H)-indol- were screened in our model reaction (table 2). The
3′,1-5,10-dihydro-1(H)-pyrazolo (1,2-b)phthalazin]- best overall yield (90%) was obtained with L-proline
(1′H)-2′-one-2-carboxylate (4j) (table 1, entry 10): in ethanol. Optimum results were obtained using
Yellow solid. m.p.: 280–282°C. νmax (KBr): 3378, 20 mol% of L-proline.
3255, 2208, 1710, 1692, 1667, 1608, 1552, 1469,
Table 1 summarizes our results on the one-pot re-
–1
1
1437, 1376, 1285, 1255, 1165, 698 cm . H NMR action of various isatin derivatives and malononitrile/
(DMSO-d , 500 MHz): δ 7⋅12 (d, 1H, J = 8⋅4 Hz), ethyl cyanoacetate with phthalhydrazide (scheme 2).
6
7⋅96 (m, 3H), 8⋅24 (m, 2H), 8⋅44 (br s, 2H, NH , All the completed reactions afforded the correspond-
2
D O exchangeable), 8⋅60 (d, 1H, J = 7⋅65 Hz), 11⋅65 ing pyrazolophthalazinyl spiro-3′-oxindoles in good
2
13
(s, 1H, NH, D O exchangeable). C NMR (DMSO- yields.
2
d , 125 MHz): δ 64⋅0, 69⋅6, 111⋅2, 114⋅8, 121⋅6,
6
The structures of compounds 4a–j were confirmed
1
13
127⋅5, 128⋅0, 128⋅1, 129⋅5, 135⋅0, 135⋅6, 143⋅6, by IR, H and C NMR spectroscopy, mass spec-
148⋅7, 152⋅7, 153⋅1, 157⋅0, 173⋅7. MS (m/z): 402 trometry and elemental analysis. The mass spectrum
(M ). Anal. Calcd. for C H N O : C, 56⋅72; H, of 4a displayed the molecular ion (M ) peak at m/z
+
+
19 10
6
5
1
2⋅51; N, 20⋅89%. Found: C, 56⋅80; H, 2⋅47; N, 357. The H NMR spectrum of 4a exhibited a broad
20⋅82%.
singlet at δ 8⋅32 (D O exchangeable) due to –NH , a
2
2
3. Results and discussion
Table 2. One-pot, three-component synthesis of 4a
using various catalysts.
As part of our endeavour to discover new spirooxin-
doles of biocidal interest, and guided by the obser-
vation that the presence of two or more different
heterocyclic moieties in a single molecule often en-
hances the biocidal profile remarkably, we investi-
gated a three-component reaction of isatin with
malononitrile and phthalhydrazide, in order to syn-
thesize a new class of spirooxindoles with fused
phthalazines. To the best of our knowledge, there
have been no reports on the synthesis of pyra-
a
Yield (%)
Entry
Catalyst
No cat.
Time (h)
1
2
3
4
5
6
7
8
24
6
–
InCl
45
–
3
CAN
10
9
NH SO H
2 3
10
34
90
30
20
SnCl ⋅2H O
8
2
2
L-proline
2
K CO
2
6
3
Basic alumina
6

420
Gnanamani Shanthi and Paramasivan T Perumal
Scheme 1.
Scheme 2.
Scheme 3.
13
singlet at δ 10⋅92 (D O exchangeable) due to –NH (isatin –C=O group) were observed in the C NMR
2
isatin and aromatic protons in the range δ 6⋅90–8⋅25. spectrum. Furthermore, the structure of 4b was
Resonances at δ 70⋅3 (spiro carbon), δ 153⋅1 and established by X-ray crystallographic analysis (fig-
13
156⋅9 (–C=O groups of phthalazine) and δ 173⋅0 ure 2).

An efficient one-pot synthesis of novel pyrazolophthalazinyl spirooxindoles
421
A and Werner B 2000 J. Heterocycl. Chem. 37 647;
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Figure 2. ORTEP diagram of compound 4b.
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El-Agrody A M 2002 Farmaco 57 715; (b) Sebahar P
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5666
A possible mechanism for the formation of 4a–j is
proposed in scheme 3. The process represents a
typical cascade reaction in which the isatin 1 first
condenses with malononitrile/ethyl cyanoacetate 2
to afford isatylidene malononitrile derivative 5. This
step can be regarded as a fast Knoevenagel addition.
Then, the subsequent Michael type addition of the
phthalhydrazide 3 to 5 followed by cyclization af-
fords the corresponding product 4a–j.
5. Kang T H, Matsumoto K, Murakami Y, Takayama H,
Kitajima M, Aimi N and Watanabe H 2002 Eur. J.
Pharmacol. 444 39
6. Mavel S, Thery I and Gueiffier A 2002 Arch. Pharm.
Med. Chem. 335 7
7. (a) Atack J R 2010 Pharmacology and Therapeutics
125 11; (b) Carling R W, Moore K W, Street L J,
Wild D, Isted C, Leeson P D, Thomas S, O’Connor
D, McKernan R M, Quirk K, Cook S M, Atack J R,
Wafford K A Thompson S A, Dawson G R, Ferris P
and Castro J L 2004 J. Med. Chem. 47 1807
4. Conclusion
8. Imamura Y, Noda A, Imamura T, Ono Y, Okawara T
and Noda H 2003 Life Sci. 74 29
In conclusion, we have developed a simple and
clean procedure for the synthesis of new pyra-
zolophthalazinyl spiro-3′-oxindoles starting from
commercially available starting materials. The use
of inexpensive and readily available L-proline has
made this procedure simple, convenient and practi-
cal.
9. Kim J S, Rhee H-K, Park H J, Lee S K, Lee C-O and
Choo H-Y P 2008 Bioorg. Med. Chem. 16 4545
10. Lebsack A D, Gunzner J, Wang B, Pracitto R,
Schaffhauser H, Santini A, Aiyar J, Bezverkov R,
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Med. Chem. Lett. 14 2463
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Chem. 74 7974; (b) Zhou Y and Shan Z 2007 J. Org.
Chem. 72 686; (c) Dodda R and Zhao C-G 2006 Syn-
thesis 19 3238; (d) Wang Y, Shang Z-C, Wu T-X,
Fan J-C and Chen X 2006 J. Mol. Catal. A: Chem.
253 212; (e) Shen Z, Li B, Wang L and Zhang Y
2005 Tetrahedron Lett. 46 8785
Acknowledgement
One of the authors, G S thanks the Council of Scien-
tific and Industrial Research, New Delhi, India for
the research fellowship.
12. (a) Shanthi G, Subbulakshmi G and Perumal P T
2007 Tetrahedron 63 2057; (b) Shanthi G and Peru-
mal P T 2007 Tetrahedron Lett. 48 6785; (c) Shanthi
G and Perumal P T 2008 Tetrahedron Lett. 49 7139;
(d) Shanthi G and Perumal P T 2008 Synlett. 2791;
(e) Jayashree P, Shanthi G and Perumal P T 2009
Synlett. 917
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