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

doi:10.1055/s-0028-1087558

LETTER

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

Abstract

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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

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References and Notes

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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.

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⁺].

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.

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⁺].

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⁺].

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⁺].