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Synlett 2002(1): 0073-0076
DOI: 10.1055/s-2002-19334
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Entry to Isoxazolo[4,5-d]pyridazin-4(5H) [and 7(6H)]-ones from Functionalized Vinyl Sulfoxides

J. L. García Ruano*, F. Bercial, A. Fraile, M. Rosario Martín*
Departamento de Química Orgánica (C-1), Universidad Autónoma, Cantoblanco, 28049 Madrid, Spain
Fax: +34(9)13973966; e-Mail: joseluis.garcia.ruano@uam.es; e-Mail: rosario.martin@uam.es;
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Publication History

Received 21 September 2001
Publication Date:
01 February 2007 (online)

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Abstract

Isoxazolo[4,5-d]pyridazin-4(5H) [and 7(6H)]-ones can be respectively synthesised in a one-pot two-step synthetic sequence from 4 or 3-arylsulfinyl-5-alkoxyfuran-2(5H)-ones, involving their reactions with nitrile oxides and subsequent reflux with hydrazine hydrate into a 4:3 mixture of water/acetic acid. The 1,3-dipolar reaction takes place with complete regioselectivity, which is controlled by the position of the sulfinyl group at the dipolarophile, yielding, after desulfinylation and subsequent opening of the lactone ring, the two possible regioisomeric 3-substituted isoxazoles bearing formyl and carboxylic acid moieties at C-4 and C-5. These compounds, as well as their methyl esters, can be independently transformed into the corresponding isoxazolopyridazinones in high yields by reaction with hydrazine hydrate.

Key words

1,3-dipolar cycloadditions - vinyl sulfoxides - lactones - isoxazolo[4,5-d]pyridazin-4(5H) [and 7(6H)]-ones - acetals

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16

Procedure for Addition of Benzonitrile Oxide to Furanone 6: To a stirred mixture of sodium hydroxide solution 1 N (3.12 mL) and ether (6 mL) was added portionwise during 10 min at 0 ºC the benzaldehyde chloroxime (267.5 mg, 1.72 mmol). The ethereal layer was separated, quickly dried over MgSO4 and added to a solution of the sulfinylfuranone 6 (156 mg, 0.43 mmol) in ether (6 mL). After stirring for 2 h the solvent was removed under reduced pressure. 1H NMR (CDCl3) of 8: δ = 2.35-0.80 (m, 18 H), 3.68 (dt, 1 H, J = 10.7 and 4.4), 6.37 (s, 1 H), 7.65-7.35 (m, 3 H), 8.15 (m, 2 H).

17

Following the above procedure after 1 h a 50:40:10 mixture of 8, 7 and 6 was detected. After 2 h a 90:10 mixture of 8 and 7 was obtained. 1H NMR (CDCl3) of 7: δ = 0.80-2.60 (m, 18 H), 3.82 (dt,1 H, J = 10.7 and 4.4), 4.48 (s, 1 H, H-3a), 6.01 (s, 1 H, H-6), 7.50-7.21 (m, 3 H), 7.75 (m, 2 H).

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General Procedure: A mixture of the crude aldehyde-acid 3a-c [obtained in the formolysis of the corresponding t-butyl ester-acetal (0.52 mmol)] or their corresponding methyl esters 3’a-c (0.52 mmol), hydrazine hydrate of 80% (47 µL, 0.77 mmol) and EtOH-HOAc 10:1 (3.85 mL) was refluxed for the time indicated in the Table. After removal of the solvents, the isoxazolopyridazinones were purified by column chromatography. 3-Phenylisoxazolo[4,5-d]pyridazin-7(6H)-one 10a: Eluent: Hexanes-EtOAc 2:1. White solid, mp 259-261 ºC (it decomposed before melting). IR (KBr): 3179, 3103, 1688, 1590 cm-1. 1H NMR (DMSO-d6): δ = 7.63 (m, 3 H), 8.02 (m, 2 H), 8.75 (s, 1 H), 13.58 (bs, 1 H). 13C NMR (DMSO-d6): δ = 119.0 (C), 126.5 (C), 128.2 (CH), 129.8 (CH), 131.6 (CH), 132.5 (CH), 152.3, 157.6, 159.9 (C). MS (FAB): m/z = 214(34) [MH+], 137(70), 136(65), 107(21), 77(17). HRMS (FAB) calcd for C11H8N3O2 [MH+]: 214.06165; found 214.0624. Anal. Calcd for C11H7N3O2: C, 61.97; H, 3.31; N, 19.71. Found: C, 61.79; H, 3.08; N, 20.05. 3-Bromoisoxazolo[4,5-d]pyridazin-7(6H)-one 10b: Eluent: Hexanes-EtOAc 4:1. White solid, which decomposes without melting under 300 ºC. IR (KBr): 3234, 1682, 1588, 1561 cm-1. 1H NMR (DMSO-d6): δ = 8.40 (s, 1 H), 13.62 (bs 1 H). 13C NMR (DMSO-d6): δ = 121.7 (C), 131.3 (CH), 138.0, 151.7, 159.7 (C). MS (FAB): m/z = 216 (2 Br isotopes, 27) [MH+], 136(65), 102(100). HRMS (FAB) calcd for C5H3BrN3O2 [MH+]: 215.94086; found 215.9413.
3-Methylisoxazolo[4,5-d]pyridazin-7(6H)-one 10c: Eluent: Hexanes-EtOAc 3:2. White solid, mp 232-234 º C with descomposition. IR (KBr): 3242, 1680, 1595 cm-1. 1H NMR (DMSO-d6): δ = 2.56 (s, 3 H), 8.48 (s, 1 H), 13.43 (bs, 1 H). 13C NMR (DMSO-d6): δ = 10.0 (CH3), 120.9 (C), 132.7 (C4), 152.4, 156.3, 158.6 (C). Anal. Calcd for C6H5N3O2: C, 47.69; H, 3.33; N, 27.81. Found: C, 47.47; H, 3.05; N, 27.39.

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Data for 11: White solid, mp 221-223 ºC (it decomposed before melting). Anal. Calcd for C11H7N3O2: C, 61.97; H, 3.31; N, 19.71. Found: C, 61.79; H, 3.08; N, 20.05. IR (KBr): 3174, 1683, 1564 cm-1. 1H NMR (DMSO-d6): δ = 7.56 (m, 3 H), 8.31 (m, 2 H), 8.75 (s, 1 H), 13.40 (bs, 1 H). 13C NMR (DMSO-d6): δ = 113.4 (C), 126.2 (CH), 126.4 (C), 129.1 (CH), 129.3 (CH), 131.5 (CH), 158.4, 159.1, 165.4 (C). MS (FAB): m/z = 214(35) [MH+], 137(79), 136(69), 107(24), 77(18). HRMS (FAB) calcd for C11H8N3O2 [MH+]: 214.06165; found 214.0614.

22

5-[(Ethoxy)[(2-isopropyl-5-methylcyclohexyl)oxy]methyl]-3-phenylisoxazole-4-carboxylic acid 12A and B: Isolated by column chromatography (CHCl3-methanol, 60:1). IR (KBr): 3700-2500, 1693, 1602, 1453 cm-1. 1H NMR: δ = 0.58 (d, 3 HB, Me, J = 6.9), 0.79 (d, 3 HA, Me, J = 6.9), 0.85 (d, 3 HB, Me, J = 7.0), 0.89 (d, 3 HA, Me, J = 6.5), 0.93 (d, 3 HA, Me, J = 7.0), 0.95 (d, 3 HB, J = 6.2), 1.26 (t, 3 HA, J = 7.0), 1.28 (t, 3 HB, J = 7.0), 0.78-2.38 (m, 9 HA and 9 HB), 3.42 (dt, 1 HB, J = 4.3 and 10.6), 3.63 (dt, 1 Ha, J = 4.1 and 10.6), 3.76 (m, 2 HA and 2 HB), 6.21 (s, 1 HB), 6.28 (s, 1 Ha), 7.46 (m, 3 HA and 3 HB), 7.64 (m, 2 HA and 2 HB). 13C NMR: δ = 14.9 (CH3), 15.5 (CH3), 15.7 (CH3), 21.0 (CH3), 22.2 (CH3), 22.9 (CH2), 25.0 (CH), 25.1 (CH), 31.4 (CH), 31.6 (CH), 34.1 (CH2), 40.6 (CH2), 41.7 (CH2), 47.9 (CH), 48.1 (CH), 62.7 (CH2), 63.0 (CH2), 77.6 (CH), 79.3 (CH), 92.7 (CH), 94.5 (CH), 108.5 (C), 127.5 (C), 128.1 (CH), 129.4 (CH), 130.0 (CH), 162.4 (C), 162.5 (C), 165.0 (C), 165.2 (C), 173.4 (C), 173.5 (C). MS (FAB): m/z = 402(16) [M+ + 1], 356(13), 246(24), 218(27), 139(45), 57(100). Methyl 5-[(Ethoxy)[(2-isopropyl-5-methylcyclo-hexyl)oxy]methyl]-3-phenylisoxazole-4-carboxylate 13A and B: IR (KBr) 1731, 1594, 1451 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 0.58 (d, 3 HB, Me, J = 6.9), 0.78 (d, 3 HA, Me, J = 6.9), 0.85 (d, 3 HB, Me, J = 7.1), 0.91 (d, 3 HA, Me, J = 6.5), 0.93 (d, 3 HA, Me, J = 7.1), 0.95 (d, 3 HB, Me, J = 6.9), 1.24 (t, 3 HA, Et, J = 7.0), 1,26 (t, 3 HB, Et, J = 6.8), 0.80-1.43 (m, 5 HA and 5 HB, menthyl), 1.65 (m, 2 HA and 2 HB, menthyl), 2.05-2.41 (m, 2 HA and 2 HB, menthyl), 3.39 (dt, menthyl, 1 HB, J = 4.3 and 10.6), 3.59 (dt, 1 HA, menthyl, J = 4.3 and 10.6), 3.72 (m, 2 HA and 2 HB, Et), 3.78 (s, 3 HB, OMe), 3.79 (s, 3 HA, OMe), 6.19 (s, 1 HB, acetalic-H), 6.25 (s, 1 HA, acetalic-H), 7.44 (m, 3 HA and 3 HB, Ph), 7.61 (m, 2 HA and 2 HB, Ph). 13C NMR (CDCl3, 300 MHz): δ = 15.0 (CH3), 15.5 (CH3), 15.7 (CH3), 21.0 (CH3), 21.1 (CH3), 22.3 (CH3), 22.9 (CH2), 25.0 (CH), 25.1 (CH), 31.4 (CH), 31.6 (CH), 34.2 (CH2), 40.6 (CH2), 41.7 (CH2), 48.0 (CH), 48.1 (CH), 52.0 (CH3), 62.4 (CH2), 62.7 (CH2), 77.0 (CH), 78.8 (CH), 92.6 (CH), 94.3 (CH), 109.0 (C), 127.9 (C), 128.1 (CH), 128.2 (CH), 129.1 (CH), 129.2 (CH), 161.7 (C), 161.8 (C), 161.9 (C), 172.6 (C), 172.7 (C).

23

A mixture of the crude reaction of the cycloaddition of benzonitrile oxide to sulfinyl furanones 4 or 6 (0.41 mmol), hydrazine hydrate of 80% (50 µL, 0.82 mmol), H2O (1.7 mL), and HOAc (1.3 mL) was refluxed for 2 or 1 h respectively. After cooling, the solutions were neutralized with a sat. solution of sodium bicarbonate to pH 7, and then extracted with CH2Cl2 (3 × 25 mL). The organic solutions were dried over anhyd Na2SO4 and the solvent removed to give a residue, which was purified by column chromatography (acetone-hexanes 1:4) affording compounds 10a or 11 in 75% yield.