THE SYNTHESIS OF HETEROCYCLES FROM INDOLIN-2-ONE DERIVATIVES AND ACTIVE METHYLENE REAGENTS

Full text of DOI:10.1135/cccc19941235

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THE SYNTHESIS OF HETEROCYCLES FROM INDOLIN-2-ONE
DERIVATIVES AND ACTIVE METHYLENE REAGENTS*
a
a
b
Fathy F. ABDEL-LATIF , Ramadan A. MEKHEIMER , Mohamed M. MASHALY
a
and Essam Kh. AHMED
a Chemistry Department, Faculty of Science, El-Minia University, El-Minia, Egypt
b Chemistry Department, Faculty of Science, El-Mansoura University, Damietta, Egypt
Received May 4, 1993
Accepted October 19, 1993
Indole and some of its derivatives have been reported to possess interesting biological
activities (e.g. ref.1). In continuation to our research2 – 5 it was interesting to investigate
the synthesis of multifunctionalized heterocyclic spiro derivatives via the reaction of
isatin, ethyl cyanoacetate and an other active methylene compound. The synthesis is
realized as a one-pot reaction.
It has been found that refluxing of an ethanolic piperidine solution of equimolar
ratios of isatin (Ia), ethyl cyanoacetate (II) and barbituric acid (IIIa) or thiobarbituric
acid (IIIb) afforded a solid product whose structure was assumed, in accordance with
elemental analysis and IR and 1H NMR spectra, to be VIIIa and VIIIb (Scheme 1).
Confirmation of the structures VIIIa and VIIIb follows from their preparation from
compound IV, synthesized separately, and barbituric acids IIIa and IIIb in 1 : 1 molar
ratio under the same reaction conditions.
Further condensation reactions were carried out under the same experimental condi-
tions (Scheme 2). Isatin (Ia), ethyl cyanoacetate (II) and active methylene compounds
IX – XI afforded spiropyran-4-yl indolidene derivatives XIII; spiro[indoline-3,4′(1H)-
pyrano[2,3-c]pyrazol]-2-one derivatives XIVa and spiropyridin-4-yl indolidene deriva-
tive XV. Structures XIII – XV were proven by an independent synthesis by reaction of
the compound IV with the appropriate active methylene compound IX – XII under the
same reaction conditions.
Although it has been reported that certain ethyl arylidenecyanoacetate derivatives
could not react with 8-hydroxyquinoline6, we found that the condensation of the
isatines I, ethyl cyanoacetate (II) and 8-hydroxyquinoline (XII) had afforded the corre-
sponding spiro compounds XVIa and XVIb (Scheme 2).
* Part 7; Part 6 see ref.4.
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Abdel-Latif, Mekheimer, Mashaly, Ahmed:
SCHEME 1
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SCHEME 2
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Abdel-Latif, Mekheimer, Mashaly, Ahmed:
EXPERIMENTAL
All melting points are uncorrected. IR spectra (ν, cm−1) were recorded in the KBr pellet on a Shi-
madzu-470 spectrophotometer. 1H NMR spectra (δ, ppm) were measured on a Varian EM-390 spec-
trophotometer (90 MHz) in CD3SOCD3 solutions using tetramethylsilane as an internal standard.
Microanalytical data were obtained from the Microanalytical Data Unit at Cairo University. Com-
pound IV was prepared according to the described procedure7, m.p. 215 °C (ethanol).
Sythesis of VIIIa, VIIIb, XIIIa – XIIId, XIVa, XIVb, XV, XVIIa, XVIIb. General Procedure
Method A. An equimolar (0.01 mol) mixture of each of isatin, ethyl cyanoacetate and active
methylene compound IIIa, IIIb, IXa – IXd, Xa, Xb, XI or XII in ethanol (50 ml) was treated with
piperidine (0.1 ml). The reaction mixture was heated for 3 – 5 h, the product separated or it was
obtained after concentration and trituration with cold water. The products were collected by filtration,
dried and recrystallized from an appropriate solvent.
Method B. An equimolar mixture of IV and active methylene compound IIIa, IIIb, IXa – IXd, Xa,
Xb, XI or XII in ethanol (50 ml) was treated with piperidine (0.1 ml). The reaction mixture was
heated for 3 – 6 h and worked up as described in method A.
7′-Amino-6′-ethoxycarbonyl-4′-hydroxy-2′-oxospiro-
[indoline-3,5′(1H)-pyrano[2,3-d]pyrimidin]-2-one (VIIIa)
Yellow crystals from ethanol, yield 90%. M.p. 260 °C (dec.). IR spectrum: 3 300 – 3 100 (OH, NH,
1
NH2); 1 730 (ester CO). H NMR spectrum: 1.68 t, 3 H (CH3); 2.60 q, 2 H (CH2); 6.94 – 7.97 m, 6 H
(arom. + NH2). For C17H14N4O6 (370.3) calculated: 55.13% C, 3.81% H, 15.13% N; found: 55.18% C,
3.76% H, 15.14% N.
7′-Amino-6′-ethoxycarbonyl-4′-hydroxy-2′-mercaptospiro-
[indoline-3,5′(1H)-pyrano[2,3-d]pyrimidin]-2-one (VIIIb)
Brown crystals from ethanol, yield 80%. M.p. > 300 °C. IR spectrum: 3 300 – 3 100 (OH, NH,
NH2); 1 730 (ester CO). For C17H14N4O5S (386.4) calculated: 52.84% C, 3.65% H, 14.50% N;
8.30% S; found: 52.89% C, 3.60% H, 14.46% N, 8.34% S.
5′-Acetyl-2′-amino-3′-ethoxycarbonyl-6′-methylspiro-
[indoline-3,4′(1H)-pyran]-2-one (XIIIa)
Pale yellow crystals from ethanol, yield 72%. M.p. 232 °C. IR spectrum: 3 350, 3 150 (NH, NH2);
1 730 (ester CO); 1 675 (acetyl CO). For C18H18N2O5 (342.3) calculated: 63.15% C, 5.30% H, 8.18% N,
found: 63.20% C, 5.29% H, 8.15% N.
2′-Amino-5′-benzoyl-3′-ethoxycarbonyl-6′-methylspiro[indoline-3,4′(1H)-pyran]-2-one (XIIIb)
Colourless crystals from ethanol, yield 70%. M.p. 236 – 238 °C. IR spectrum: 3 300, 3 250, 3 200,
3 100 (NH, NH2); 1 720 (ester CO); 1 680 (benzoyl CO). For C23H20N2O5 (404.4) calculated:
68.30% C, 4.99% H, 6.93% N; found: 68.27% C, 5.00% H, 6.88% N.
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2′-Amino-3′,5′-diethoxycarbonyl-6′-methylspiro[indoline-3,4′(1H)-pyran]-2-one (XIIIc)
Pale yellow crystals from ethanol, yield 75%. M.p. 176 °C. IR spectrum: 3 350, 3 200 (NH, NH2);
1
1 730 (ester CO). H NMR spectrum: 0.57 – 0.97 tt, 6 H (2 CH3); 2.06 s, 3 H (CH3); 3.66 – 3.94 qq,
4 H (2 CH2); 6.94 – 8.05 m, 6 H (arom. + NH2). For C19H20N2O6 (372.4) calculated: 61.28% C,
5.41% H, 7.52% N; found: 61.24% C, 5.45% H, 7.57% N.
2′-Amino-5′-cyano-3′-ethoxycarbonyl-6′-phenylspiro[indoline-3,4′(1H)-pyran]-2-one (XIIId)
Pale buff crystals from ethanol, yield 70%. M.p. 205 – 207 °C. IR spectrum: 3 400, 3 300, 3 200
(NH, NH2); 2 200 (CN); 1 730 (CO). For C22H17N3O4 (387.4) calculated: 68.21% C, 4.42% H,
10.85% N; found: 68.25% C, 4.38% H, 10.80% N.
6′-Amino-5′-ethoxycarbonyl-3′-methylspiro[indoline-3,4′(1H)-pyrano[2,3-c]pyrazol]-2-one (XIVa)
Buff crystals from ethanol, yield 85%. M.p. 284 – 286 °C (ref.8 gives 285 – 286 °C). IR spectrum:
1
3 400, 3 150 (NH, NH2); 1 730 (ester CO). H NMR spectrum: 0.85 t, 3 H (ester CH3); 1.23 s, 3 H
(pyrazole CH3); 3.83 q, 2 H (ester CH2); 6.72 – 7.42 m, 6 H (arom. + NH2); 11.53 s, 1 H (NH);
11.80 s, 1 H (NH). 13C NMR spectrum: 179.7 (indole C-2), 168.2 (ester CO), 162.9 (pyran C-2),
154.4 (pyran C-6), 141.9 (pyrazole C-3), 136.6 (indole C-7a), 134.7 (indole C-3a), 127.2 (indole C-4),
122.6 (indole C-5), 121.6 (indole C-6), 108.7 (indole C-7), 97.1 (pyran C-5), 74.3 (pyran C-3), 58.6
(ester CH2), 11.1 (ester CH3), 8.9 (pyrazole CH3). For C17H16N4O4 (340.3) calculated: 59.99% C,
4.74% H, 16.46% N; found: 60.04% C, 4.70% H, 16.44% N.
6′-Amino-5′-ethoxycarbonyl-3′-methyl-1′-phenylspiro-
[indoline-3,4′(1H)-pyrano[2,3-c]pyrazol]-2-one (XIVb)
Buff crystals from ethanol, yield 70%. M.p. 232 – 234 °C (dec.) (ref.8 gives 235 °C). IR spectrum:
3 300, 3 200 (NH, NH2); 1 730 (ester CO). 1H NMR spectrum: 0.77 t, 3 H (ester CH3); 1.6 s, 3 H
(pyrazole CH3); 3.73 q, 2 H (ester CH2); 6.73 – 8.20 m, 11 H (arom. + NH2); 11.4 s, 1 H (NH).
13C NMR spectrum: 179.1 (indole C-2), 167.8 (ester CO), 161.2 (pyran C-2), 144.1 (pyran C-6),
143.8 (pyrazole C-3), 142.8 (indole C-7a), 137.3 (phenyl C-1), 135.7 (indole C-3a), 129.1 (phenyl
C-3,5), 127.5 (phenyl C-4), 126.1 phenyl C-2,6), 122.9 (indole C-4), 121.5 (indole C-5), 119.8 (in-
dole C-6), 108.7 (indole C-7), 98.1 (pyran C-5), 74.6 (pyran C-3), 58.8 (ester CH2), 47.4 (spiro carbon),
12.9 (pyrazole CH3), 11.5 (ester CH3). For C23H20N4O4 (416.4) calculated: 66.33% C, 4.84% H, 13.46% N;
found: 66.30% C, 5.80% H, 13.42% N.
2′-Amino-3′,5′-diethoxycarbonyl-6′-cyano(ethoxycarbonyl)methylspiro-
[indoline-3,4′(1H)-pyridin]-2-one (XV)
Orange crystals from ethanol, yield 90%. M.p. 196 – 197 °C. IR spectrum: 3 350 – 3 150 (NH, NH2);
1
2 200 (CN); 1 740, 1 720 (esters, CO). H NMR spectrum: 1.10 – 1.31 ttt, 9 H (3 CH3); 3.97 – 4.26 qqq,
6 H (3 CH2); 5.77 s, 1 H (CH); 7.14 – 7.86 m, 6 H (arom. + NH2). For C23H24N4O7 (468.4) calcu-
lated: 58.97% C, 5.16% H, 11.96% N; found: 58.91% C, 5.20% H, 11.97% N.
9′-Amino-8′-ethoxycarbonylspiro[indoline-3,7′(1H)-pyrano[3,2-h]quinolin]-2-one (XVIa)
Colourless crystals from dimethylformamide–ethanol, yield 75%. M.p. 279 – 280 °C. IR spectrum:
3 400 – 3 200 (NH, NH2); 1 730 (ester CO). 13C NMR spectrum: 180.9 (indole C-2), 161.1 (ester
CO), 150.5 (pyran C-6), 142.8 (pyran C-2), 142.1 (indole C-7a), 136.0 (indole C-3a), 129 – 122
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Abdel-Latif, Mekheimer, Mashaly, Ahmed:
(arom.), 109.4 (pyran C-3), 58.9 (ester CH2), 50.7 (spiro carbon), 13.3 (CH3). For C22H17N3O4
(387.4) calculated: 68.21% C, 4.42% H, 10.85% N; found: 68.25% C, 4.40% H, 10.81% N.
9′-Amino-5-bromo-8′-ethoxycarbonylspiro-
[indoline-3,7′(1H)-pyrano[3,2-h]quinolin]-2-one (XVIb)
Grey crystals from ethanol, yield 67%. M.p. 266 – 268 °C. IR spectrum: 3 300 – 3 200 (NH, NH2);
1 730 (ester CO). For C22H16N3O4Br (466.3) calculated: 56.67% C, 3.46% H, 9.01% N; found:
56.62% C, 3.50% H, 8.98% N.
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