Environmental friendly synthesis of novel isatin ketal and isatin schiff base derivatives using michael addition reaction under solvent-free conditions

Article abstract of DOI:10.1002/cjoc.201100351

An efficient and simple procedure for the synthesis of novel isatin derivatives is described. Michael addition of aniline Schiff bases of isatin or p-toluidine Schiff bases of isatin to fumaric esters affords the Michael adduct compounds in good to high y

Full text of DOI:10.1002/cjoc.201100351

FULL PAPER
DOI: 10.1002/cjoc.201100351
Environmental Friendly Synthesis of Novel Isatin Ketal and
Isatin Schiff Base Derivatives Using Michael Addition Reaction
under Solvent-Free Conditions
Imanzadeh, Gholamhassan*
Zamanloo, Mohammadreza
Soltanizadeh, Zahra
Mansoori, Yagoub
Khodayari, Ali
Salehzadeh, Jaber
Department of Chemistry, Faculty of Science, University of Mohaghegh Ardabili, 56199-11367, Ardabil, Iran
An efficient and simple procedure for the synthesis of novel isatin derivatives is described. Michael addition of
aniline Schiff bases of isatin or p-toluidine Schiff bases of isatin to fumaric esters affords the Michael adduct com-
pounds in good to high yields in the presence of K2CO3 and tetrabutylammonium bromide (TBAB) under sol-
vent-free conditions. Repeating of this reaction about spiro[1,3-dioxolane-2,3'-indol]-2'(1'H)-one, as a Michael do-
nor, in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) gives Michael adducts in remarkable yields under
the same conditions.
Keywords Michael addition, isatin ketal, isatin Schiff base, fumaric ester, acrylic ester, solvent-free conditions
Introduction
this reaction. However, to the best of our knowledge, no
datum is available on the addition of the Schiff base of
isatin 2 or 3 and dioxolane ketal 4 to α,β-unsaturated
esters. Having the above points in mind and also in con-
tinuing our previous studies on aza-Michael reac-
tion,[42,43] this work investigates the aza-Michael addi-
tion reaction of isatin Schiff bases 2, 3 and isatin ketal 4
with α,β-unsaturated esters under solvent-free condi-
tions (Schemes 1 and 2).
Isatin 1 (1H-indol-2,3-diones) is a versatile molecule
in the synthesis of many products with pharmacologic
activity.[1] In 1841, this compound was obtained by oxi-
dation of Indigo with nitric and chromic acid.[2] In na-
ture, isatin has been identified in blood and urine of
mammalian,[3] in rat brain,[4] in plants of genus Isatis[5]
and in coal tar.[6] Studies show that isatin readily crosses
the blood-brain barrier and acts on the central nervous
system (CNS).[7] This compound has been identified as
a selective inhibitor of monoamine oxidas B (MAOB)[8]
and therefore it has been suggested to be an alternative
for the treatment of Parkinson’s disease, by increasing
dopamine levels in the striatum.[9,10] Numerous investi-
gations show isatin has anxiogenic effects.[11-16] Schiff
bases and Mannich bases of isatin are reported to show
a variety of biological activities like antibacterial,[17-19]
antifungal,[20-22] antiviral,[23-25] anti-HIV,[26-28] antipro-
tozoal[29,30] and antihelimithic properties.[31,32] Some of
Schiff bases of isatin show that they have a potent anti-
cancer activity against human cancer.[33] Isatin ketals
have anxiolytic,[34] psychotropic,[35] and anticonvulsant
activity.[36] For instance spiro[1,3-dioxolane-2,3'-indol]-
2'(1'H)-one 4 (as a dioxolane ketal) has sedative, hyp-
notic and anesthetic properties.[37]
Scheme 1 Addition of isatin Schiff bases to α,β-unsaturated
esters
R
O
N
R = Tol
2
R
NH2
+
N
H
O
N
H
O
R = Ph
3
1
O
OR'
R'O
O
N
R
R = Tol
2a - 2e
N
O
R = Ph
Aza-Micheal addition reaction is one of the most
famous methods for forming a carbon-nitrogen bond in
organic synthesis.[38] Different Michael donors such as
amines,[39] amides,[40] and imides[41] have been used in
O
3a - 3d
O
OR'
OR'
*
E-mail: Imanzad2000@yahoo.com
Received September 16, 2011; accepted November 27, 2011.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100351 or from the author.
Chin. J. Chem. 2012, 30, 891—899 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
891

Imanzadeh et al.
FULL PAPER
Scheme 2 Addition of isatin ketal to α,β-unsaturated esters
troscopy. The progress of the reactions was followed by
TLC using silica gel SILIG/UV 254 plates. H NMR
1
O
OH
(400 MHz) and 13C NMR (100 MHz) spectra were re-
corded on a Bruker 300 MHz instrument. FT-IR spectra
were recorded on a Perkin-Elmer RX-1 instrument.
Mass spectra were recorded on a Shimadzu GC-MS-QP
1000PX. Elemental analysis for C, H, and N were per-
formed using a Heraeus CHN-O-Rapid analyzer. The
melting points were determined in open capillaries with
a Stuart Melting Point Apparatus and are uncorrected.
HO
N
O
H
O
O
1
O
O
OR
RO
O
N
O
OR
O
OR
O
O
General procedure for addition of isatin Schiff bases
2 or 3 to symmetrical fumaric esters
5a - 5f
N
O
To a well ground mixture of isatin Schiff base (1.0
mmol), K2CO3 (1.0 mmol), and TBAB (0.5 mmol), fu-
maric ester (1.2 mmol) was added and mixed thor-
oughly with a glass rod. The resulting mixture was kept
in an oil bath at 90—100 ℃ for appropriate time (Ta-
ble 1). The progress of reaction was monitored by TLC.
After the completion of reaction the mixture was sus-
pended in chloroform (30 mL), filtered and the filtrate
was washed with water (10 mL×3) and dried with
MgSO4. The solvent was removed under reduced pres-
sure and the resulting crude material was purified on
short silica-gel column with ethyl acetate∶n-hexane
(1∶9) as the eluent.
H
O
O
N
O
O
OR
4
OR
O
6a - 6f
Experimental
Spiro[1,3-dioxolane-2,3'-indol]-2'(1'H)-one 4, and all
α,β-unsaturated esters were synthesized in our labora-
tory according to the literature procedures[37,45] and their
1
structures were confirmed by IR and H NMR spec-
Table 1 Michael addition of isatin Schiff bases 2, 3 to fumaric esters in the presence of K2CO3
Entry
Ester
Product
Time/min
Yielda/%
N
O
O
O
O
1
40
85
O
N
O
O
O
H
H
H
O
2a
N
O
O
O
O
2
60
85
O
N
O
O
O
H
H
H
O
2b
N
O
O
O
O
4
300
75
N
O
O
O
O
H
H H
O
2d
892
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 891—899

Environmental Friendly Synthesis of Novel Isatin Ketal and Isatin Schiff Base Derivatives
Continued
Yielda/%
Entry
Ester
Product
Time/min
N
O
O
O
O
5
60
85
80
80
80
O
N
O
O
O
H
H H
3a
O
N
O
O
O
O
6
7
8
120
100
150
O
N
O
O
O
H
H H
3b
O
N
O
O
O
O
O
N
O
O
O
H
H H
O
3c
N
O
O
O
O
O
N
8
8
O
O
O
6
H
6
H H
3d
O
a Isolated yields.
General procedure for addition isatin ketal 4 to
symmetrical fumaric ester and acrylic esters
Physical and spectroscopic data of isolated products
Diethyl 2-(3-(p-tolylimino)-2-oxoindolin-1-yl)-
1
A mixture of isatin ketal 4 (1.0 mmol), DABCO (1.0
mmol), TBAB (0.5 mmol), fumaric esters or acrylic es-
ter (1.2 mmol) was kept in the oil bath for the stipulated
time (Table 2) at 80—90 ℃. The progress of the reac-
tion was monitored by TLC. After completion of reac-
tion the reaction mixture was cooled to room tempera-
ture and dissolved in chloroform (40 mL). TBAB was
recovered by the addition of water (15 mL), then col-
lected and dried under vacuum. The chloroform layer
was washed with water (15 mL×3). The organic layer
was dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the resulting crude
material was purified on short silica-gel column with
ethyl acetate∶n-hexane (2∶8) as the eluent.
succinate (2a) Orange oil; H NMR (400 MHz,
CDCl3) δ: 1.20—1.26 (m, 6H), 2.39 (s, 3H), 3.20 (dd,
J＝16.9, 8.0 Hz, 1H), 3.43 (dd, J＝16.9, 6.3 Hz, 1H),
4.13—4.25 (m, 4H), 5.41 (dd, J＝8.0, 6.3 Hz, 1H),
6.99—7.42 (m, 8H); 13C NMR (100 MHz, CDCl3) δ:
12.92, 32.69, 49.62, 60.13, 61.36, 108.92, 114.83,
116.53, 122.21, 124.27, 125.25, 128.30, 132.96, 148.9,
152.27, 161.81, 167.11, 169.08; IR (KBr) ν: 2982, 2935,
1735, 1652, 1606, 1466, 1367, 1260, 1096, 1025, 858,
－
＋
1
752, 697 cm ; MS (70 eV) m/z (%): 408 (M , 32.28).
Anal. calcld for C23H24N2O5: C 67.64, H 5.88, N 6.86;
found C 67.48, H 5.90, N 6.64.
Dipropyl 2-(3-(p-tolylimino)-2-oxoindolin-1-yl)-
1
succinate (2b) Orange oil; H NMR (400 MHz,
CDCl3) δ: 0.82—0.93 (m, 6H), 1.58—1.64 (m, 4H),
Chin. J. Chem. 2012, 30, 891—899
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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893

Imanzadeh et al.
FULL PAPER
Table 2 Michael addition of isatin ketal 4 to α,β-unsaturated esters in the presence of DABCOa
Entry
Ester
Product
Time/min
Yieldb/%
O
O
O
O
O
N
1
180
85
83
O
O
O
O
O
O
5a
O
O
O
O
N
O
2
O
180
O
O
O
O
O
5b
O
O
O
O
O
O
O
3
180
78
N
O
2
2
O
O
3 O
3
5c
O
O
O
O
N
O
4
5
6
240
240
240
60
75
73
70
90
O
O
O
O
O
O
O
5d
O
O
O
N
O
O
O
2
2
O
O
O
2
2
O
5e
O
O
O
O
N
O
O
4
O
4
O
O
5O
5
O
5f
O
O
O
O
N
7
O
O
O
6a
894
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Chin. J. Chem. 2012, 30, 891—899

Environmental Friendly Synthesis of Novel Isatin Ketal and Isatin Schiff Base Derivatives
Continued
Yieldb/%
Entry
8
Ester
Product
Time/min
60
O
O
O
O
89
89
87
88
87
N
O
3
O
3
O
6b
O
O
O
O
9
60
60
60
60
N
5
O
O
5
O
6c
O
O
O
O
N
10
11
12
O
O
3
3
O
6d
O
O
O
O
N
O
7
O
7
O
6e
O
O
O
O
N
O
O
9
9
O
6f
a Ethyl fumarate or acrylic ester, isatin ketal 4, DABCO and TBAB with molar ratios 1.2∶1.0∶1.0∶0.5 were used respectively. b After
purification by column chromatography.
2.39 (s, 3H), 3.13 (dd, J＝16.8, 7.9 Hz, 1H), 3.45 (dd,
J＝16.8, 6.4 Hz, 1H), 4.09—4.15 (m, 4H), 5.43 (dd, J＝
7.9, 6.4 Hz, 1H), 6.80—7.34 (m, 8H); 13C NMR (100
MHz, CDCl3) δ: 9.13, 19.88, 20.66, 32.65, 49.59, 65.66,
108.80, 114.88, 116.74, 121.88, 125.05, 128.79, 132.78,
134.08, 146.31, 151.96, 161.89, 167.19, 169.15; IR
(KBr) ν: 2969.47, 2939.72, 1739.03, 1654.34, 1606.59,
1468.44, 1364.24, 1269.94, 1179.27, 751.5, 576.08
167.41, 169.18; IR (KBr) ν: 2961, 2936, 1736, 1654,
－
1
1606, 1468, 1364, 1239, 1119, 1057, 750, 653 cm ;
MS (70 eV) m/z (%): 492 (M＋, 21.50). Anal. calcld for
C29H36N2O5: C 70.73, H 7.31, N 5.69; found C 70.55, H
7.38, N 5.82.
Dicyclohexyl 2-(3-(p-tolylimino)-2-oxoindolin-1-
1
yl)succinate (2d) Orange oil; H NMR (400 MHz,
CDCl3) δ: 1.25—1.38 (m, 12H), 1.49—1.75 (m, 8H),
2.39 (s, 3H), 3.06 (dd, J＝16.7, 8.1 Hz, 1H), 3.38 (dd,
J＝16.7, 6.3 Hz, 1H), 4.73—4.76 (m, 2H), 5.43 (dd, J＝
8.1, 6.3 Hz, 1H), 6.81—7.35 (m, 8H); 13C NMR (100
MHz, CDCl3) δ: 19.97, 22.63, 24.19, 30.37, 33.11,
49.94, 72.69, 109.06, 114.17, 116.86, 121.62, 125.09,
128.86, 132.75, 134.12, 146.43, 152.11, 161.99, 166.62,
168.55; IR (KBr) ν: 2937, 2860, 1733, 1651, 1608, 1517,
－
＋
1
cm ; MS (70 eV) m/z (%): 436 (M , 18.68). Anal.
calcld for C25H28N2O5: C 68.80, H 6.42, N 6.42; found
C 68.62, H 6.55, N 6.81.
Dippentan-2-yl 2-(3-(p-tolylimino)-2-oxoindolin-
1
1-yl)succinate (2c) Orange oil; H NMR (400 MHz,
CDCl3) δ: 0.68—0.80 (m, 6H), 1.05—1.26 (m, 14H),
2.28 (s, 3H), 2.91—3.01 (m, 1H), 3.28—3.32 (m, 1H),
4.85—4.91 (m, 2H), 5.28—5.37 (m, 1H), 6.65—6.83
(m, 5H), 7.10—7.25 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ: 13.72, 17.54, 22.45, 21.80, 37.61, 38.10,
39.77, 49.59, 65.66, 108.00, 114.71, 116.43, 121.54,
125.10, 129.02, 132.71, 133.97, 145.33, 151.96, 162.01,
－
1
1468, 1361, 1259, 1188, 1013, 958, 751, 643 cm ; MS
(70 eV) m/z (%): 516 (M＋, 32.63). Anal. calcld for
C31H36N2O5: C 72.09, H 6.97, N 5.42; found C 72.13, H
6.71, N 5.63.
Dipropyl 2-(3-(phenylimino)-2-oxoindolin-1-
Chin. J. Chem. 2012, 30, 891—899
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Imanzadeh et al.
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1
yl)succinate (3a) Orange oil; H NMR (400 MHz,
CDCl3) δ: 0.83—0.95 (m, 6H), 1.58—1.67 (m, 4H),
3.12 (dd, J＝16.8, 8.9 Hz, 1H), 3.45 (dd, J＝16.8, 6.3
Hz, 1H), 4.05—416 (m, 4H), 5.43 (dd, J＝8.9, 6.3 Hz,
1H), 6.76—7.45 (m, 9H); 13C NMR (100 MHz, CDCl3)
δ: 9.24, 20.77, 32.76, 49.73, 65.69, 108.95, 114.9,
116.58, 121.81, 124.31, 125.33, 128.38, 133.02, 149.19,
152.33, 161.91, 167.27, 169.28; IR (KBr) ν: 2965, 2875,
1736, 1656, 1612, 1468, 1364, 1269, 1180, 1120, 1067,
17.0, 7.5 Hz, 1H), 4.14—4.27 (m, 4H), 4.30—4.34 (m,
2H), 4.53—4.59 (m, 2H), 5.26 (dd, J＝7.5, 7.3 Hz, 1H),
6.87 (d, J＝8.0 Hz, 1H), 7.10 (t, J＝7.5 Hz, 1H),
7.34—7.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ:
13.94, 13.96, 33.70, 50.13, 61.14, 62.20, 65.69, 65.80,
101.54, 109.34, 123.49, 123.83, 125.12, 131.60, 142.81,
168.41, 170.12, 172.99; IR (KBr) ν: 2936, 2912, 1732,
－
1
1620, 1468, 1420, 1369, 1277, 1187 cm ; MS (70 eV)
m/z (%): 363 (M＋, 28.63). Anal. calcld for C18H21NO7:
C 59.50, H 5.78, N 3.85; found C 59.53, H 5.41, N 3.91.
Diisopropyl 2-(spiro(1,3-dioxolane-2,3'-indolin-2'-
－
＋
1
1022, 752, 697 cm ; MS (70 eV) m/z (%): 422 (M ,
44.53). Anal. calcld for C24H26N2O5: C 68.24, H 6.16, N
6.63; found C 68.33, H 6.28, N 6.81.
1
one-1'-yl))succinate (5b) Yellow oil; H NMR (400
Dibutyl 2-(3-(phenylimino)-2-oxoindolin-1-yl)-
succinate (3b) Orange oil; 1H NMR (400 MHz,
CDCl3) δ: 0.84 (t, J＝7.8 Hz, 3H), 0.91 (t, J＝7.5 Hz,
3H), 1.18—1.24 (m, 2H), 1.26—1.39 (m, 2H),
1.45—1.55 (m, 2H), 1.57—1.66 (m, 2H), 2.92 (dd, J＝
16.5, 7.5 Hz, 1H), 3.38 (dd, J＝16.5, 7.0 Hz, 1H),
4.09—4.16 (m, 4H), 5.27 (dd, J＝7.5, 7.0 Hz, 1H),
6.80—7.43 (m, 9H); 13C NMR (100 MHz, CDCl3) δ:
12.25, 17.62, 28.93, 32.39, 49.44, 63.65, 108.71, 114.51,
116.19, 121.46, 123.98, 124.91, 128.05, 132.78, 148.82,
152.05, 161.55, 166.87, 168.86; IR (KBr) ν: 2961, 2875,
1736, 1656, 1609, 1468, 1364, 1276, 1180, 1116, 1067,
MHz, CDCl3) δ: 1.12 (d, J＝6.5 Hz, 3H), 1.18 (d, J＝
6.5 Hz, 3H), 1.22 (d, J＝6.5 Hz, 6H), 2.88 (dd, J＝
17.25, 7.5 Hz, 1H), 3.32 (dd, J＝17.25, 7.0 Hz, 1H),
4.31—4.35 (m, 2H), 4.57—4.59 (m, 2H), 5.98—5.10
(m, 2H), 5.23 (t, J＝7 Hz, 1H), 6.87 (d, J＝8.1 Hz, 1H),
7.10 (t, J＝7.40 Hz, 1H), 7.34—7.40 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ: 21.42, 21.60, 34.12, 50.40, 65.66,
65.82, 101.23, 109.43, 123.42, 123.88, 125.09, 131.53,
142.98, 167.93, 169.66, 172.99; IR (KBr) ν: 2983, 2905,
1735, 1620, 1490, 1470, 1376, 1286, 1188 cm ; MS
(70 eV) m/z (%): 391 (M＋, 77.64). Anal. calcld for
C20H25NO7: C 61.38, H 6.39, N 3.58; found C 61.41, H
6.22, N 3.79.
－
1
－
＋
1
1022, 752, 697 cm ; MS (70 eV) m/z (%): 450 (M ,
67.14). Anal. calcld for C26H30N2O5: C 69.33, H 6.66, N
6.22; found C 69.65, H 6.40, N 6.14.
Dibutyl 2-(spiro(1,3-dioxolane-2,3'-indolin-2'-
1
one-1'-yl))succinate (5c) Yellow oil; H NMR (400
Diisopentyl 2-(3-(phenylimino)-2-oxoindolin-1-
yl)succinate (3c) Orange oil; H NMR (400 MHz,
MHz, CDCl3) δ: 0.83 (t, J＝7.5 Hz, 3H), 0.91 (t, J＝7.5
Hz, 3H), 1.20—1.37 (m, 4H), 1.50—1.60 (m, 4H), 2.92
(dd, J＝7.5, 16.5 Hz, 1H), 3.38 (dd, J＝7.2, 16.5 Hz,
1H), 4.07—4.14 (m, 2H), 4.17—4.23 (m, 2H),
4.30—4.34 (m, 2H), 4.54—4.60 (m, 2H), 5.27 (dd, J＝
7.2, 7.5 Hz, 1H), 6.87 (d, J＝8.0 Hz, 1H), 7.10 (t, J＝
1
CDCl3) δ: 0.80—0.90 (m, 12H), 1.47—1.53 (m, 6H),
3.11 (dd, J＝16.8, 7.9 Hz, 1H), 3.43 (dd, J＝16.8, 6.3
Hz, 1H), 4.08—4.22 (m, 4H), 5.42 (dd, J＝7.9, 6.3 Hz,
1H), 6.76—7.42 (m, 9H); 13C NMR (100 MHz, CDCl3)
δ: 21.17, 23.72, 32.59, 35.85, 49.58, 62.71, 108.80,
114.71, 116.37, 121.66, 124.16, 125.14, 128.23, 132.90,
148.97, 152.18, 161.72, 161.81, 167.07, 169.08; IR
(KBr) ν: 2959, 2872, 1740, 1654, 1607, 1468, 1367,
13
7.5 Hz, 1H), 7.35—7.41 (m, 2H); C NMR (100 MHz,
CDCl3) δ: 13.33, 13.48, 18.63, 18.85, 30.16, 30.31,
33.60, 50.04, 64.89, 65.56, 65.66, 65.83, 101.45, 109.17,
123.33, 123.80, 125.02, 131.45, 142.77, 168.38, 170.07,
172.90; IR (KBr) ν: 2964, 2876, 1738, 1620, 1489, 1470,
－
1
1183, 949, 750, 695 cm ; MS (70 eV) m/z (%): 478
(M＋, 51.27). Anal. calcld for C28H34N2O5: C 70.29, H
7.11, N 5.85; found C 70.20, H 7.42, N 5.39.
－
＋
1
1366, 1262, 1187 cm ; MS (70 eV) m/z (%): 419 (M ,
57.89). Anal. calcld for C22H29NO7: C 63.00, H 6.92, N
3.34; found C 63.19, H 7.15, N 3.54.
Didecyl 2-(3-(phenylimino)-2-oxoindolin-1-yl)-
succinate (3d) Orange oil; 1H NMR (400 MHz,
CDCl3) δ: 0.85—0.88 (m, 6H), 1.20—1.26 (m, 28H),
1.57—1.60 (m, 4H), 3.11 (dd, J＝16.8, 7.9 Hz, 1H),
3.44 (dd, J＝16.8, 6.2 Hz, 1H), 4.07—4.17 (m, 4H),
5.35 (dd, J＝7.9, 6.2 Hz, 1H), 6.76—7.45 (m, 9H); 13C
NMR (100 MHz, CDCl3) δ: 12.95, 21.51, 24.65, 28.06,
28.12, 28.32, 30.71, 32.63, 49.61, 64.28, 108.86, 114.78,
116.48, 121.68, 124.21, 125.21, 128.25, 132.90, 149.02,
152.22, 161.77, 167.15, 169.13; IR (KBr) ν: 2926, 2855,
1740, 1653, 1607, 1468, 1362, 1230, 1178, 981, 749,
Bis(2-methylbutyl) 2-(spiro(1,3-dioxolane-2,3'-
1
indolin-2'-one-1'-yl))succinate (5d) Yellow oil; H
NMR (400 MHz, CDCl3) δ: 0.77—0.82 (m, 6H),
0.88—0.91 (m, 6H), 1.00—1.20 (m, 2H), 1.36—1.42
(m, 2H), 1.59—1.63 (m, 1H), 1.64—1.69 (m, 1H), 2.93
(dd, J＝17.0, 8.0 Hz, 1H), 3.41 (dd, J＝17.0, 7.0 Hz,
1H), 3.87—3.93 (m, 2H), 3.95—4.05 (m, 2H),
4.30—4.36 (m, 2H), 4.54—4.60 (m, 2H), 5.29—5.31
(m, 2H), 6.86 (d, J＝7.1 Hz, 1H), 7.10 (t, J＝7.5 Hz,
1H), 7.35—7.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ: 10.92, 11.11, 16.11, 16.23, 25.70, 25.90, 33.72, 33.81,
33.88, 50.12, 65.69, 65.77, 69.82, 70.66, 101.59, 109.24,
123.48, 123.90, 125.17, 131.59, 142.91, 168.59, 170.28,
173.05; IR (KBr) ν: 2965, 2879, 1736, 1620, 1490, 1469,
－
＋
1
653 cm ; MS (70 eV) m/z (%): 618 (M , 32.63). Anal.
calcld for C38H54N2O5: C 73.79, H 8.74, N 4.53; found
C 73.68, H 8.79, N 4.49.
Diethyl 2-(spiro(1,3-dioxolane-2,3'-indolin-2'-
one-1'-yl))succinate (5a) Colorless oil; 1H NMR (400
MHz, CDCl3) δ: 1.18 (t, J＝7.1 Hz, 3H), 1.22 (t, J＝7.5
Hz, 3H), 2.85 (dd, J＝17.0, 7.3 Hz,1H), 3.35 (dd, J＝
－
＋
1
1366, 1229,1187 cm ; MS (70 eV) m/z (%): 447 (M ,
27.14). Anal. calcld for C24H33NO7: C 64.42, H 7.38, N
3.13; found C 64.72, H 7.43, N 3.18.
896
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 891—899

Environmental Friendly Synthesis of Novel Isatin Ketal and Isatin Schiff Base Derivatives
Di-sec-butyl 2-(spiro(1,3-dioxolane-2,3'-indolin-
2'-one-1'-yl))succinate (5e) Yellow oil; H NMR
64.11, H 6.87, N 4.52.
Hexyl 3-(spiro(1,3-dioxolane-2,3'-indolin-2'-one-
1'-yl))propionate (6c) Yellow oil; H NMR (400
1
1
(400 MHz, CDCl3) δ: 0.75 (t, J＝7.5 Hz, 3H), 0.85 (t,
J＝7.5 Hz, 3H), 0.92 (m, 4H), 1.08 (d, J＝6.5 Hz, 3H),
1.13 (d, J＝6.4 Hz, 3H), 1.20—1.26 (m, 4H),
2.86—2.94 (m, 1H), 3.30—3.37 (m, 1H), 4.32—4.38
(m, 2H), 4.53—4.61 (m, 2H), 4.90—4.95 (m, 2H),
5.25—5.29 (m, 1H), 6.86 (d, J＝8.0 Hz, 1H), 7.10 (t,
J＝7.4 Hz, 1H), 7.34—7.40 (m, 2H); 13C NMR (100
MHz, CDCl3) δ: 13.79, 13.86, 18.00, 18.43, 19.48,
19.73, 37.70, 37.83, 37.89, 50.37, 65.66, 65.79, 71.90,
73.27, 101.13, 109.41, 123.41, 123.88, 125.10, 131.52,
142.97, 168.06, 169.79, 172.94; IR (KBr) ν: 2962, 2875,
MHz, CDCl3) δ: 0.88 (t, J＝6.5 Hz, 3H), 1.00—1.38 (m,
4H), 1.47—1.50 (m, 2H), 1.57—1.59 (m, 2H), 2.68 (t,
J＝7.5 Hz, 2H), 3.97 (t, J＝7.5 Hz, 2H), 4.05 (t, J＝6.5
Hz, 2H), 4.32—4.38 (m, 2H), 4.53—4.59 (m, 2H), 6.90
(d, J＝8.0 Hz, 1H), 7.08 (t, J＝7.5 Hz, 1H), 7.36—4.39
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 13.19, 23.33,
24.66, 30.55, 31.33, 34.85, 51.61, 64.29, 65.02, 101.12,
108.15, 123.26, 124.16, 127.55, 130.91, 142.67, 170.24,
172.43; IR (KBr) ν: 2958, 2860, 1733, 1620, 1492, 1470,
－
＋
1
1293, 1192, 1132 cm ; MS (70 eV) m/z (%): 347 (M ,
36.06). Anal. calcld for C19H25NO5: C 65.70, H 7.20, N
4.03; found C 65.49, H 7.32, N 3.89.
2-Ethylhexy-3-(spiro(1,3-dioxolane-2,3'-indolin-
2'-one-1'-yl))propionate (6d) Yellow oil; H NMR
－
1
1737, 1621, 1490, 1470, 1387, 1287, 1189 cm ; MS
(70 eV) m/z (%): 447 (M＋, 2.18). Anal. calcld for
C24H33NO7: C 64.42, H 7.38, N 3.13; found C 64.39, H
7.72, N 3.51.
1
Bis(2-methylbutyl) 2-(spiro(1,3-dioxolane-2,3'-
indolin-2'-one-1'-yl))succinate (5f) Yellow oil; H
(400 MHz, CDCl3) δ: 0.85—0.89 (m, 4H), 1.03 (t, J＝
7.5 Hz, 3H), 1.24 (t, J＝7.5 Hz, 3H), 1.46—1.49 (m,
2H), 1.50—1.59 (m, 1H), 1.69—1.71 (m, 2H), 2.70 (t,
J＝7.5 Hz, 2H), 3.93 (t, J＝7.5 Hz, 2H), 4.01 (t, J＝7.5
Hz, 2H), 4.32—4.38 (m, 2H), 4.53—4.59 (m, 2H), 6.90
(d, J＝7.5 Hz, 1H), 7.09 (t, J＝7.5 Hz, 1H), 7.37—7.39
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 10.86, 13.98,
22.85, 24.17, 30.22, 32.06, 35.55, 38.52, 59.04, 65.73,
66.89, 67.37, 101.98, 108.82, 123.28, 123.93, 124.94,
131.64, 143.47, 171.20, 173.23; IR (KBr) ν: 2961, 2875,
1
NMR (400 MHz, CDCl3) δ: 0.90—1.00 (m, 12H),
1.28—1.70 (m, 12H), 2.68 (dd, J＝16.5, 7.5 Hz, 1H),
3.37 (dd, J＝16.5, 7.1 Hz, 1H), 4.08—4.15 (m, 4H),
4.30—4.40 (m, 2H), 4.50—4.57 (m, 2H), 5.27 (m, 1H),
6.86 (d, J＝7.8 Hz, 1H), 7.09 (t, J＝7.5 Hz, 1H),
7.34—7.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ:
13.43, 13.58, 22.33, 22.44, 25.39, 25.47, 30.41, 30.47,
31.20, 31.32, 33.70, 50.12, 65.34, 65.45, 65.76, 65.96,
101.22, 109.28, 123.44, 123.87, 125.13, 131.55, 142,85,
168.51, 170.21, 173.01; IR (KBr) ν: 2962, 2875, 1734,
－
1
1732, 1621, 1492, 1469, 1365, 1293, 1193 cm ; MS
(70 eV) m/z (%): 375 (M＋, 32.59). Anal. calcld for
C21H29NO5: C 67.20, H 7.73, N 3.73; found C 67.77, H
7.29, N 3.32.
－
1
1621, 1490, 1470, 1369, 1296,1156 cm ; MS (70 eV)
m/z (%): 475 (M＋, 3.75). Anal. calcld for C26H37NO7: C
65.68, H 7.78, N 2.94; found C 65.29, H 7.55, N 2.48.
Ethyl 3-(spiro(1,3-dioxolane-2,3'-indolin-2'-
one-1'-yl))propionate (6a) Yellow oil; 1H NMR (400
MHz, CDCl3) δ: 1.02 (t, J＝7.5 Hz, 3H), 2.68 (t, J＝7.0
Hz, 2H), 3.93 (t, J＝7.0 Hz, 2H), 4.13 (q, J＝7.5 Hz,
2H), 4.32—4.38 (m, 2H), 4.53—4.59 (m, 2H), 6.90 (d,
J＝8.0 Hz, 1H), 7.10 (t, J＝7.5 Hz, 1H), 7.36—7.39 (m,
2H); 13C NMR (100 MHz, CDCl3) δ: 13.38, 35.27,
58.62, 60.59, 65.47, 101.58, 108.58, 123.00, 123.65,
124.63, 131.37, 143.16, 170.66, 172.90; IR (KBr) ν:
2979, 2904, 1733, 1619, 1491, 1470, 1369, 1292, 1195
Octyl 3-(spiro(1,3-dioxolane-2,3'-indolin-2'-one-
1
1'-yl))propionate (6e) Yellow oil; H NMR (400
MHz, CDCl3) δ: 0.90 (t, J＝7.5 Hz, 3H), 1.25—1.29 (m,
12H), 2.69 (t, J＝7.5 Hz, 2H), 3.93 (t, J＝7.5 Hz, 2H),
4.07 (t, J＝7.5 Hz, 2H), 4.32—4.38 (m, 2H),
4.53—4.59 (m, 2H), 6.90 (d, J＝7.5 Hz, 1H), 7.09 (t,
J＝7.5 Hz, 1H), 7.37—7.39 (m, 2H); 13C NMR (100
MHz, CDCl3) δ: 14.06, 22.60, 25.80, 28.43, 29.10,
29.15, 31.74, 35.65, 65.15, 65.77, 76.73, 101.93, 108.88,
123.28, 124.02, 124.98, 131.65, 143.59, 171.12, 173.27;
IR (KBr) ν: 2929, 2857, 1734, 1621, 1492, 1469, 1366,
－
＋
－
＋
1
1
cm ; MS (70 eV) m/z (%): 291 (M , 4.37). Anal.
calcld for C15H17NO5: C 61.85, H 5.84, N 4.81; found C
61.91, H 5.46, N 4.63.
1293, 1193 cm ; MS (70 eV) m/z (%): 375 (M , 62.29).
Anal. calcld for C21H29NO5: C 67.20, H 7.73, N 3.73;
found C 67.85, H 7.28, N 3.91.
Butyl 3-(spiro(1,3-dioxolane-2,3'-indolin-2'-one-
1'-yl))propionate (6b) Yellow oil; H NMR (400
Decyl 3-(spiro(1,3-dioxolane-2,3'-indolin-2'-one-
1'-yl))propionate (6f) Yellow oil; H NMR (400
1
1
MHz, CDCl3) δ: 0.9 (t, J＝7.5 Hz, 3H), 1.26—1.36 (m,
2H), 1.57—1.69 (m, 2H), 2.70 (t, J＝7 Hz, 2H), 3.92 (t,
J＝7.5 Hz, 2H), 4.07 (t, J＝6.5 Hz, 2H), 4.32—4.38 (m,
2H), 4.53—4.59 (m, 2H), 6.90 (d, J＝8.0 Hz, 1H), 7.09
MHz, CDCl3) δ: 0.89 (t, J＝7.5 Hz, 3H), 1.27 (m, 14H),
1.55—1.59 (m, 2H), 2.69 (t, J＝7.3 Hz, 2H), 3.92 (t,
J＝7.3 Hz, 2H), 4.06 (t, J＝7.5 Hz, 2H), 4.32—4.38 (m,
2H), 4.53—4.59 (m, 2H), 6.90 (d, J＝8.0 Hz, 1H), 7.09
13
13
(t, J＝7.5 Hz, 1H), 7.37—7.39 (m, 2H); C NMR (100
(t, J＝7.5 Hz, 1H), 7.37—7.39 (m, 2H); C NMR (100
MHz, CDCl3) δ: 13.63, 19.01, 32.10, 35.61, 59.13,
64.83, 65.76, 76.75, 101.90, 108.87, 123.29, 123.94,
124.95, 131.66, 143.53, 171.13, 173.24; IR (KBr) ν:
2962, 2875, 1733, 1620, 1491, 1469, 1366, 1291, 1193
cm ; MS (70 eV) m/z (%): 319 (M , 37.19). Anal.
calcld for C17H21NO5: C 63.94, H 6.58, N 4.38; found C
MHz, CDCl3) δ: 14.06, 22.63, 25.88, 28.58, 29.18,
29.25, 29.44, 29.47, 31.84, 35.63, 62.98, 64.68, 65.14,
65.76, 101.92, 108.86, 123.27, 124.00, 124.96, 131.63,
143.57, 171.11, 173.25; IR (KBr) ν: 2927, 2856, 1734,
－
＋
－
1
1
1621, 1492, 1469, 1366, 1262, 1192 cm ; MS (70 eV)
m/z (%): 403 (M＋, 82.00). Anal. calcld for C23H33NO5:
Chin. J. Chem. 2012, 30, 891—899
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
897

Imanzadeh et al.
FULL PAPER
C 68.48, H 8.18, N 3.47; found C 68.52, H 8.43, N 3.21.
achieved by carrying out the reaction with acrylic esters,
despite containing only one carbonyl electron-with-
drawing group, as Michael acceptor. The results allow
the conclusion that the steric effects of substitutes on
β-carbon atom are more important than their electronic
effects. These effects caused that fumaric esters were
more sensitive to the size of alkoxy groups than acrylic
esters. We see that the bulkiness of alkoxy group, when
the Michael acceptors are acrylic esters, has no signifi-
cant effect on the yields and the reaction times (Table 2,
Entries 7—12). But, in contrast to these results, when
fumaric esters are used as Michael acceptor, the sterical
hindrance of alkoxy groups influence the yields and
reaction times under the same conditions (Table 2, En-
tries 1—6).
Results and Discussion
As a first step, we decided to extend our previous
work[44] concerning the synthesis of novel derivatives of
isatin Schiff bases by applying the solvent-free system
conditions. Therefore, aza-Michael addition of
p-toluidine Schiff base of isatin 2 to ethyl fumarate, as a
model reaction, was investigated in the presence of
tetrabutylammonium bromide TBAB and various or-
ganic and inorganic bases to evaluate their capabilities
and selectivities. This study showed that the best results
were obtained when K2CO3 was applied as a base at 100
℃ under solvent-free conditions. In the absence of
TBAB, in the reaction media, no progressing was ob-
served for model reaction at all. It was also observed
that using ethyl fumarate, p-toluidine Schiff base of
isatin, K2CO3 and TBAB with molar ratios 1.2∶1.0∶
1.0∶0.5, respectively, gives the desired product in high
yield and in short reaction time. We varied the amount
of K2CO3 and TBAB loading in the reaction and there
was no improvement in yield with the decrease or in-
crease of loading. Using this method, p-toluidine Schiff
base of isatin 2 was added to four different fumaric es-
ters (Table 1, Entries 1—4), and aniline Schiff base of
isatin 3 was also added to four different fumaric esters
under model reaction conditions (Table 1, Entries 5—8).
According to these results the method is applicable to
primary fumaric esters (Table 1, Entries 1, 2, 5, 6, 8) as
well as to secondary fumaric esters (Table 1, Entries 3,
4, 7). All reactions were very clean and the products
were obtained in very good to excellent yields within 40
to 300 min. It is important to note that, when the fu-
maric esters containing sterically hindered alkoxy
groups were used, the reaction proceeded slowly (Table
1, Entries 8, 9). Since a large variety of primary amines
can be coupled to isatin, this method is suitable for
various scaffolds.
Conclusions
In summary, we developed a new, effective and
environment friendly procedure for the Michael addition
of aniline Schiff bases of isatin, p-toluidine Schiff bases
of isatin, as well as spiro[1,3-dioxolane-2,3'-indol]-
2'(1'H)-one to α,β-unsaturated esters in the presence of
TBAB under solvent-free conditions. It was found that
among the various organic and inorganic bases, K2CO3
is a more suitable base for former reactions, while
DBCO effectively catalyzes the latter reaction. We, also,
observed that in both reactions, when Michael acceptor
is fumaric ester, the structure of alkoxy group has sig-
nificant effect on the yield and reaction time. Lower
yields of products and longer reaction times were ob-
tained when sterically hindered fumaric esters were
used as α,β-unsaturated systems.
Acknowledgement
The authors are thankful to University of Mo-
haghegh Ardabili for the financial suport and the Labo-
ratories of Tehran University for the product analysis.
In another study, we extended this reaction to
spiro[1,3-dioxolane-2,3'-indol]-2'(1'H)-one 4 as Michael
donor. But when 4 was treated with ethyl fumarate, in
the presence of potassium carbonate and TBAB, we
faced the problem of getting product in low yield.
Therefore we decided to try the reaction in the presence
of various organic and inorganic bases as well as in the
presence of various solvents. The obtained results from
this test indicated that DABCO is the reasonable base
for catalysis of the reaction in the presence of TBAB
under solvent-free conditions at 100 ℃. Using solvents
such as DMSO, DMF, EtOH and H2O, in the reflux
conditions, the product was isolated in very low yields.
Therefore, the solvent-free reaction in the presence of
TBAB is more efficient.
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chin. J. Chem. 2012, 30, 891—899
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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