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

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.

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

References and Notes

1 Ruxer JM. Lachoux C. Ousset JB. Torregrosa JL. Mattioda GJ. J. Heterocycl. Chem.  1994,  31:  409 

2 Ungureanu M. Mangalagiu I. Grosu G. Petrovanu M. Ann. Pharm. Fr.  1997,  55:  69 

3 Nasir AI. Gundersen L.-L. Rise F. Antonsen Ø. Kristensen T. Langhelle B. Bast A. Custers I. Haenen GRMM. Wikström H. Bioorg. Med. Chem. Lett.  1998,  8:  1829 

4 Østby OB. Dalhus B. Gundersen L.-L. Rise F. Bast A. Haenen GRMM. Eur. J. Org. Chem.  2000,  3763 

5 Østby OB. Gundersen L.-L. Rise F. Antonsen Ø. Fosnes K. Larsen V. Bast A. Custers I. Haenen GRMM. Arch. Pharm. Pharm. Med. Chem.  2001,  334:  21 

6a Ohtani M, Fuji M, Fukui Y, and Adachi M. inventors; WO  059999. 

6b Salvati ME, Illig CR, Wilson KJ, Chen J, Meegalla SK, and Wall MJ. inventors; US  7030112. 

6c Fu J.-M. inventors; US  7074791. 

7 Cheng Y. Ma B. Wudl F. J. Mater. Chem.  1999,  9:  2183 

8 Mitsumori T. Bednikov M. Sedo J. Wudl F. Chem. Mater.  2003,  15:  3759 

9 Mitsumori T. Craig IM. Martini IB. Schwartz BJ. Wudl F. Macromolecules  2005,  38:  4698 

10 Swamy KMK. Park MS. Han SJ. Kim SK. Kim JH. Lee C. Bang H. Kim Y. Kim S.-J. Yoon J. Tetrahedron  2005,  61:  10227 

11 Zbancioc GN. Mangalagiu II. Synlett  2006,  804 

12 Kuhla DE. Lombardino JG. Adv. Heterocycl. Chem.  1977,  21:  50 

13 Satoh K. Miyasaka T. Arakawa K. Yakugaku Zasshi  1977,  97:  422 

14 Stetter H. Landscheidt A. J. Heterocycl. Chem.  1979,  16:  839 

15 Abdelrazek FM. Synth. Commun.  2005,  35:  2251 

16a Ohsawa A. Abe Y. Igeta H. Bull. Chem. Soc. Jpn.  1980,  53:  3273 

16b Ohsawa A. Abe Y. Igeta H. Chem. Pharm. Bull.  1980,  28:  3488 

17 Khlebnikov AF. Kostik EI. Kostikov RR. Synthesis  1993,  568 

18 Veeraraghavan S. Bhattacharjee D. Popp FD.
J. Heterocycl. Chem.  1981,  18:  443 

19 Siriwardana AI. Nakamura I. Yamamoto Y. J. Org. Chem.  2004,  69:  3202 

20 Flitsch W. Kramer U. Tetrahedron Lett.  1968,  12:  1479 

For reviews on mesoionic compounds including münchnones, see:

21a Palmer DC. In Oxazoles: Synthesis, Reactions and Spectroscopy   Part A:  John Wiley and Sons; New Jersey: 2003.  p.473-576  

21b Gribble GW. In Synthetic Applications of Dipolar Cycloaddition Chemistry towards Heterocycles and Natural Product   Padwa A. Pearson WH. John Wiley and Sons; New York: 2002.  p.681-754  

21c Potts KT. In 1,3-Dipolar Cycloaddition Chemistry   Vol. 2:  Padwa A. Wiley; New York: 1984.  p.1-81  

21d Ollis WD. Stanforth SP. Ramsden CA. Tetrahedron  1985,  41:  2239 

21e Ramsden CA. Newton CG. Tetrahedron  1982,  38:  2965 

21f Ramsden CA. In Comprehensive Organic Chemistry   Vol. 4:  Barton DHR. Ollis WD. Academic Press; New York: 1979.  p.1171-1228  

21g Ollis WD. Ramsden CA. Adv. Heterocycl. Chem.  1976,  19:  1 

22a Huisgen R. Gotthardt H. Bayer HO. Angew. Chem., Int. Ed. Engl.  1964,  3:  135 

22b Huisgen R. Gotthardt H. Bayer HO. Chem. Ber.  1970,  103:  2356 

23a King JA. McMillan FH. J. Am. Chem. Soc.  1952,  74:  3222 

23b McMillan FH. McMillan GB. Kun KA. King JA. J. Am. Chem. Soc.  1956,  78:  407 

23c McMillan FH. McMillan GB. Kun KA. King JA. J. Am. Chem. Soc.  1956,  78:  2642 

23d Sayed AA. Jahine H. Zaher H.-A. Sherif O. Indian J. Chem.  1975,  13:  1142 

23e Ismail MF. Shams NA. Abdel Rahman SE. Fateen AK. Rev. Roum. Chim.  1979,  24:  899 

23f Jahine H. Zaher HA. Akhnookh Y. El-Gendy Z. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1978,  16:  1000 

24a Tišler M. Stanovnik B. Adv. Heterocycl. Chem.  1968,  9:  211 

24b Tišler M. Stanovnik B. Adv. Heterocycl. Chem.  1979,  24:  365 

24c Tišler M. Stanovnik B. Adv. Heterocycl. Chem.  1990,  49:  385 

24d Csende F. Szabo Z. Bérnath G. Stáger G. Synthesis  1995,  1240 

25

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).

26

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).

27

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.

28a Pleininger H. Wild D. Chem. Ber.  1966,  99:  3070 

28b Fried F. Taylor JB. Westwood R. J. Chem. Soc., Chem. Commun.  1971,  226 

28c Kon Thoo Lin PVS. Buchan R. Fraser M. McHattie D. Heterocycles  1990,  31:  1459 

28d Tighineanu E. Rãileanu D. Rev. Roum. Chim.  1992,  37:  1307 

28e Tighineanu E. Rãileanu D. Simonov Yu. Bouroº P. Tetrahedron  1996,  52:  12475 

28f Cavdar H. Saracoglu N. J. Org. Chem.  2006,  71:  7793 

28g Jones RA. Sepulveda Arques J. Tetrahedron  1981,  37:  1597 

29a Vogeli U. von Philipsborn W. Org. Magn. Reson.  1975,  7:  617 

29b Barillier D. Strobel MP. Morin L. Paquer D. Tetrahedron  1983,  39:  767 

29c Gregory B. Hinz W. Jones RA. Sepulveda Arques J. J. Chem. Res., Synop.  1984,  311 

30a Vasilescu M. Dumitraºcu F. Lemmetyinen H. Tkachenko N. J. Fluoresc.  2004,  14:  443 

30b Vasilescu M. Dumitraºcu F. Bandula R. Drãghici C. Lemmetyinen H. Rev. Roum. Chim.  2004,  49:  905 

31

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).

32

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) ų, Z = 8, T = 113(2) K, F ₀₀₀ = 1312, R1 = 0.0440, wR2 = 0.1089. The CCDC deposition number is 651836.

33 Caira MR. Dumitraºcu F. Drãghici C. Dumitrescu D. Cristea M. Molecules  2005,  10:  360