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Synlett 2009(4): 625-627  
DOI: 10.1055/s-0028-1087558
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Novel Spiro Cyclic 2-Oxindole Derivatives of 6-Amino-4H-Pyridazine via [3+3] Atom Combination Utilizing Chitosan as a Catalyst

Ismail Abdelshafy Abdelhamid*a,b
a Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Fax: 002(02)35727556; e-Mail: ismail_shafy@yahoo.com;
b Institut für Organische Chemie der Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Further Information

Publication History

Received 5 November 2008
Publication Date:
16 February 2009 (online)

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Abstract

Azaenamines were reacted with 3-cyanomethylidene-2-oxindoles using chitosan catalyst to yield spirocyclic 2-oxindole derivatives of 6-amino-4H-pyridazine and fused pyridazinoquinazolines.

Key words

aza-enamine - chitosan - Michael addition - 3-spiro­pyridazines-2-oxindoles

    References and Notes

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14

General Procedures for Compounds 8a,b and 12 Method A: A mixture of aza-enamine 4 (10 mmol) and 3-cyanomethylidene-2-oxindoles 3 was refluxed in EtOH (20 mL) in the presence of piperidine (0.1 mL) for 3 h. The solvent was evaporated under vacuum, and the crude product was collected and crystallized from EtOH or EtOH-dioxane.
Method B: A mixture of arylhydrazone 4 (10 mmol) and 3-cyanomethylidene-2-oxindoles 3 was refluxed in EtOH (20 mL) in the presence of chitosan (0.2 g) for 3 h. The solvent was evaporated under vacuum, and the crude product was collected and crystallized from EtOH or EtOH-dioxane. The catalyst chitosan was removed by filtration prior or during the crystallization process.

15

4,3′-Spiro(3-acetyl-6-amino-1-phenyl-1 H ,4 H -pyridazine-5-carbonitrile)-2′-oxindole (8a) Mp 262-264 ˚C. IR (KBr): ν = 3444, 3359, 3220 (NH2 and NH), 2190 (CN), 1724, 1623 (2 CO) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.18 (s, 3 H, CH3-CO), 6.14 (br s, 2 H, NH2), 6.83-7.58 (m, 9 H, Ar H), 10.57 (br s, 1 H, indole NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 24.7 (CH3), 48.5 (spiro C), 59.7 (CCN), 109.5, 118.0 (CN), 122.1, 123.8, 126.6, 128.7, 129, 129.7, 134.4, 139.9, 140.6 (Ar CH), 141.3 (CCOCH3), 149.7 (CNH2), 177 (CONH), 194.8 (CO). MS (EI): m/z (%) = 357 [M+].

16

General Method for the Synthesis of Compounds 9 and 10 A solution of each of 4c or 4d (10 mmol) was treated with compound 3a (10 mmol) in pyridine (10 mL). The solution was refluxed for 5 h, then poured onto H2O and acidified with dilute HCl. The solid product obtained was crystallized from EtOH or EtOH-dioxane.

17

4,3′-Spiro{2-acetyl-6-oxo-3-phenyl-3,5,6,11-tetrahydropyridazino[1,6- a ]quinazoline-4-carbonitrile}-2′-oxindole (9) Mp >300 ˚C. IR (KBr): ν = 3376, 3189 (2 NH), 2196 (CN), 1735, 1693, 1633 (3CO) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.46 (s, 3 H, CH3CO), 6.86-8.00 (m, 8 H, Ar H), 10.78 (br s, 1 H, indole NH), 11.79 (br s, 1 H, pyrimidine NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 25.5 (CH3), 49.6 (spiro C), 66.4 (CCN), 109.7, 114.4, 114.9, 115.7 (CN), 122.3, 124.8, 126.8, 127.3, 129.9, 133.5, 139.7, 141.2, 142,5, (Ar CH), 141.3 (CCOCH3), 149.7 (CNH2), 162, 176.2 (2 CONH), 194.0 (CO). MS (EI): m/z (%) = 383 [M+].

18

4,3′-Spiro(ethyl 3-acetyl-6-amino-1-phenyl-1 H ,4 H -pyridazine-5-carboxylate)-2′-oxindole (12) Mp 244-246 ˚C. IR (KBr): ν = 3496, 3428, 3237 (NH2 and NH), 1720, 1644, 1608 (3 CO) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 0.87 (t, 3 H, CH3, J = 7.2 Hz), 2.11 (s, 3 H, CH3CO), 4.2 (q, 2 H, CH2, J = 7.2 Hz), 6.71 (br s, 2 H, NH2), 6.86-7.89 (m, 9 H, Ar H), 10.31 (br s, 1 H, indole NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.2 (CH3), 25.4 (CH3), 48.6 (CH2), 56.9 (spiro C), 76.5 (CCN), 108.5, 119.3, 126.9, 128.7, 129.9, 132.8, 136,9, 141.1, 142.9, 143.1 (Ar CH), 144.5 (CCOCH3), 149.4 (CNH2), 167.9 (CONH), 179.1 (CO2Et), 194.8 (CO). MS (EI): m/z (%) = 404 [M+].

19

Spectral Data of Compound 13 Mp 285 -287 ˚C. IR (KBr): ν = 3120, 3245, 1646 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.21 (t, 3 H, CH3, J = 7.2 Hz), 2.62 (s, 3 H, CH3CO), 4.25 (q, 2 H, CH2, J = 7.2 Hz) 6.84-7.84 (m, 9 H, Ar H), 9.00 (s, 1 H), 13.40 (br s,
1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 14.1, 15.5, 63.8, 73, 116.8, 118.6, 119.6, 120.9, 121, 123.3, 123.9, 124.5, 125.5, 128.1, 128.8, 136.3, 139.8, 145.6, 155.7, 165.8. MS (EI): m/z (%) = 386 [M+].