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Synlett 2008(6): 813-816  
DOI: 10.1055/s-2008-1042929
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Approach for the Synthesis of Highly Fluorescent Pyrrolo[1,2-b]pyridazines

Florea Dumitraşcua, Mino R. Caira*b, Bogdan Drăghicia, Miron Teodor Căproiua, Dan G. Dumitrescua
a Centre of Organic Chemistry ‘C. D. Nenitzescu’, Romanian Academy, Spl. Independentei 202B, 060023 Bucharest, Romania
b Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax: +27(21)6897499; e-Mail: Mino.Caira@uct.ac.za;
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Publikationsverlauf

Received 26 June 2007
Publikationsdatum:
11. März 2008 (online)

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Abstract

Pyrrolo[1,2-b]pyridazine derivatives were synthesized for the first time by 1,3-dipolar cycloaddition reaction between mesoionic 1,3-oxazolo[3,2-b]pyridazinium-2-oxides and acetylenic dipolarophiles. The isolation and characterization of the stable mesoionic oxazolo[3,2-b]pyridazines are also presented.

Key words

1,3-dipolar cycloaddition - mesoionic oxazolopyr­idazine - pyrrolo[1,2-b]pyridazines - Michael addition - hydrogenation

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General Procedure for the Synthesis of Compounds 5 3 (2H)-Pyridazinone acid 2 (5 mmol) were suspended with stirring in Ac2O (5 mL) and then DMAD (5.5 mmol) was added.The reaction mixture was kept at ca. 90 °C for 3-4 h. The pyrrolopyridazine derivatives 5 were isolated by filtration or by evaporation of the solvent. In the latter case, the crude product was purified by recrystallization or by column chromatography using CH2Cl2 as eluent. Dimethyl 2,7-Dimethylpyrrolo[1,2- b ]pyridazine-5,6-dicarboxylate (5a)
Colorless crystals from EtOH with mp 135-136 °C; yield 60%. Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.87; H, 5.70; N, 10.93. 1H NMR (300 MHz, CDCl3): δ = 2.52 (s, 3 H, 2-Me), 2.61 (s, 3 H, 7-Me), 3.89, 3.95 (2 s, 6 H, 2 MeO), 6.76 (d, 1 H, J = 9.3 Hz, H-3), 8.27 (d, 1 H, J = 9.3 Hz, H-4). 13C NMR (75 MHz, CDCl3): δ = 9.7 (7-Me), 21.8 (2-Me), 51.3, 52.2 (2 MeO), 101.6 (C-5), 116.3 (C-3), 117.7, 127.6, 128.3 (C-4a, C-6, C-7), 127.5 (C-4), 152.4 (C-2), 163.8, 166.3 (2 COO).

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General Procedure for the Synthesis of Compounds 3 Acid 6b or 6d (1 g) in Ac2O (3 mL) was kept at ca. 90 °C for 3 h. The yellow precipitate was filtered and washed with Ac2O and then with anhyd Et2O.
3-Methyl-6-phenyloxazolo[3,2- b ]pyridazinium-2-oxide (3b)
Yellow crystals from Ac2O with mp 199-202 °C; yield 72%. Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.43; H, 4.78; N, 12.70. 1H NMR (300 MHz, CDCl3): δ = 2.36 (s, 3 H, 3-Me), 7.31, 7.36 (2 d, 2 H, J = 8.8 Hz, H-7, H-8), 7.48-7.53, 7.89-7.94 (2 m, 5 H, H-2′, H-3′, H-4′, H-5′, H-6′). 13C NMR (75 MHz, CDCl3): δ = 6.9 (3-Me), 94.7 (C-3), 110.0, 112.3 (C-7, C-8), 126.7, 129.0 (C-2′, C-3′, C-5′, C-6′), 130.2 (C-4′) 134.6 (C-1′), 138.4 (C-8a), 153.9 (C-6), 160.4 (2-CO).

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General Procedure for the Synthesis of 7 and 8 The experimental procedure for compounds 7 and 8 was similar to those for pyrrolopyridazines 5. The two compounds were isolated by column chromatography using neutral alumina (Merck 200-20 mesh) and CH2Cl2 as eluent.
Dimethyl 2-Methylpyrrolo[1,2- b ]pyridazine-5,6-dicarboxylate (7a)
Colorless crystals from EtOH with mp 89-91 °C; yield 22%. Anal. Calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29. Found: C, 59.34; H, 5.21; N, 10.50. 1H NMR (300 MHz, CDCl3): δ = 2.52 (s, 3 H, 2-Me), 3.91, 3.92 (2 s, 6 H, 2 MeO), 6.75 (d, 1 H, J = 9.3 Hz, H-3), 7.92 (s, 1 H, H-7), 8.26 (d, 1 H, J = 9.3 Hz, H-4). 13C NMR (75 MHz, CDCl3): δ = 21.7 (2-Me), 51.4, 52.1 (2 MeO), 103.4 (C-5), 117.3 (C-3), 117.9, 128.7 (C-4a, C-6, C-7), 121.0 (C-7), 128.2 (C-4), 153.4 (C-2), 163.7, 164.5 (2 COO).
Dimethyl 3-[( E )-(Buten-2-yl-1,4-dioate)]-6-methyloxazolo[3,2- b ]pyridazinium-2-oxide (8a)
Yellow crystals from MeCN with mp 180-183 °C; yield 39%. Anal. Calcd for C13H12N2O6: C, 53.43; H, 4.14; N, 9.59. Found: C, 53.59; H, 4.33; N, 9.74. 1H NMR (300 MHz, CDCl3): δ = 2.65 (s, 3 H, 6-Me), 3.76, 3.99 (2 s, 6 H, 2 MeO), 6.97 (s, 1 H, =CHCOO), 7.21 (d, 1 H, J = 8.8 Hz, H-7), 7.45 (d, 1 H, J = 9.3 Hz, H-8). 13C NMR (75 MHz, CDCl3): δ = 21.6 (6-Me), 51.7, 52.9 (2 MeO), 94.2 (C-3), 109.5 (C-10), 113.1 (C-8), 121.5 (C-7), 135.6 (C-9), 140.8 (C-8a), 155.4 (C-6), 156.8 (2-CO), 166.1, 166.7 (2 COO). Off-resonance NMR experiment: J C-3-H-10 = 6.3 Hz; J 9-CO-H-10 = 11.5 Hz.

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General Procedure for the Synthesis of Compounds 9 Esters 5 or 6 (2 mmol) were dissolved in AcOH (10 mL) and under reflux was added Zn powder (3 mmol) over a period of 3 h. The reaction was monitored by 1H NMR or TLC. In the case when the reaction was found to be incomplete, Zn (1 mmol) was added and refluxing was continued for ca. 2 h. The hot reaction mixture was filtered and the precipitate was washed with AcOH. The AcOH was removed and the residue was purified by column chromatography.
Dimethyl 2-Phenyl-3,4-dihydropyrrolo[1,2- b ]pyri-dazine-5,6-dicarboxylate (9b)
Colorless crystals from EtOH with mp 145-147 °C; yield 77%. Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C, 65.72; H, 5.33; N, 9.21. 1H NMR (300 MHz, CDCl3): δ = 2.92 (t, 2 H, J = 8.1, 8.0 Hz, 3-CH2), 3.26 (t, 2 H, J = 8.1, 8.0 Hz, 4-CH2), 3.84, 3.87 (2 s, 6 H, 2 MeO), 7.46-7.48 (m, 3 H, H-3′, H-4′, H-5′), 7.54 (s, 1 H, H-7), 7.85-7.88 (m, 2 H, H-2′, H-6′). 13C NMR (75 MHz, CDCl3): δ = 17.5 (4-CH2), 21.2 (3-CH2), 51.4, 51.5 (2 MeO), 109.7, 113.9, 127.2 (C-4a, C-5, C-6), 125.5 (C-7), 126.4, 128.7 (C-2′, C-3′, C-5′, C-6′), 131.0 (C-4′), 135.2 (C-1′), 160.0 (C-2), 164.0, 165.5 (2 COO).

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Crystal data for 9b (R1 = Ph, R2 = H): C17H16N2O4; colorless plate; M = 312.32, orthorhombic, Pbca, a = 8.1844(2) Å, b = 13.4925(3) Å, c = 27.0683(6) Å, V = 2989.1(1) Å3, Z = 8, T = 113(2) K, F 000 = 1312, R1 = 0.0440, wR2 = 0.1089. The CCDC deposition number is 651836.