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Simple preparations of condensed furan, perhydropyridazine and pyrrolidine derivatives from three components

Yoshinari Okamoto, Tadashi Okawara* and Mitsuru Furukawa

Faculty of Pharmaceutical Sciences, Kumamoto University, Oe-hon-machi, Kumamoto 862, Japan

Abstract

4-Methyl-4-dimethoxymethylpyrans (5b and c) prepared from 1,3-cyclohexanedione (2), pyruvic aldehyde dimethyl acetal (3b), and malononitrile (4) were subjected to HCl hydrolysis affording fused furofuranones (6), which were treated with amines and hydrazines to give the condensed pyrrolopyrrolidinones (9) and pyridazinones (10, 11).

Introduction

Naturally occurring analogues of (-)-physostigmine having perhydropyrrolo[2,3-b]indole alkaloids (1) as a main structural component have received much attention as inhibitors of acetylcholinesterase [1] and therapeutic agents for treating Alzheimer's disease.[2]
Consequently a number of approaches [3] to these compounds have been reported. However, most of these methods require several steps. It is known that a three component reaction using cyclohexane-1,3-dione (2), ketone (3a), and malononitrile (4) produce fused pyran derivatives (5a).[4] In the course of our work [5] on simple preparations of saturated polyheterocycles using dicarbonyl, we attempted to apply this reaction to the preparation of condensed furan, perhydropyridazine and pyrrolidine derivatives by replacing of 3a with pyruvic aldehyde dimethyl acetal (3b). Herein we wish to report a simple and unique preparation of the title compounds.

Results and discussion

A solution of 2, 3b and 4 in benzene was heated under reflux in the presence of a catalytic amount of piperidine to give the fused 4H-pyranes (5b and 5c) in yields of 64 and 87% (Scheme 1).



The structure of 5c was based on the characteristic acetal methine proton and carbon at d 4.51 and 109 in the 1H and 13C NMR spectra, respectively, and a molecular ion peak at m/z 306 in the mass spectrum. Hydrolysis of compound 5b and c with 2 M hydrochloric acid gave the fused furo[2,3-b]furanone (6a and b) in yields of 62 and 64% (Scheme 2). [6]



The structure of 6b was determined as follows: The 1H NMR spectrum showed the acetal methine proton at d 6.23 ppm and the 13C NMR spectrum indicated the acetal methine carbon at d 112 ppm with quaternary carbons at d 34, 48, 116 and 173 ppm, respectively. The mass spectrum indicated a molecular ion at m/z 236. The IR spectrum showed carbonyl absorptions at 1650 and 1790 cm-1. This reaction mechanism can be deduced as follows: Compound 5b and c is subject to HCl hydrolysis affording intermediate (7). This is followed by formation of the hemiacetal (8), which undergoes intramolecular cyclization and decarboxylation to 6.

Conversion of 6 to the fused pyrrolopyrrolidinones (9) were achieved in 47-89% yields by heating with ammonia and primary amines in EtOH. Structural assignment was based on 1H and 13C NMR spectra, mass spectra, and elemental analyses. [7]

Reaction of 6 with 1 equiv. of methylhydrazine in EtOH gave the furopyridazinones (10). Their spectral data strongly supported the structure. Treatment of 6 with 2 equiv. of the hydrazines afforded the pyrrolopyridazinone (11).[8]

As an application of this three component reaction, we attempted to react with 4-hydroxy-6-methyl-2-pyrone (12) and 4-hydroxycoumarin (15) producing the pyranopyranes (13 and 16) followed by hydrolysis with HCl to the furofuranones (14 and 17). These compounds were characterized by MS and 1H and 13C NMR spectra. All spectral data were consistent with the proposed structure. Compound 17 was heated in a sealed tube with ammonia affording compound 19 via formation of intermediate 18 followed by decarboxylation. Another possible enamine structure 20 was eliminated by presence of two methylenes in 1H and 13C NMR spectra. [9]


A short approach to pyrrolopyrrolidinone and pyrrolopyridazine derivatives using three components has been established. Reduction of compound 6 to the pyrrolopyrrolidines and preparation of optically active derivatives are being investigated.

References

  1. S. Takano and K. Ogasawara, The Alkaloids, vol. 36, ed. by A. Brossi, Academic Press, New York, 1989, pp. 224-251.
  2. 2. Cf. S. A. Beller, J. E. Overall and A. C. Swann, Psychopharmacology, 1987, 87, 145.
  3. 3. A. Brossi. X-. F. Pei and N. H. Greig, Aust. J. Chem., 1996, 49, 171 and cited therein; Q-. S. Yu and B-. Y.Lu, Heterocycles, 1994, 39, 519; P. F. Santos, A. M. Lobo and S. Prabhakar, Tetrahedron Lett., 1995, 36, 8099; X-. F. Pei and A. Brossi, Heterocycles, 1995, 41, 2823.
  4. 4. F. F. A-. Latif, M. M. Mashaly and E. H. E-. Gawish, J. Chem. Res. (S), 1995, 178.
  5. 5. T. Okawara, K. Uchiyama, Y. Okamoto, T. Yamasaki and M. Furukawa, J. Chem. Soc. Chem. Commun. 1990, 1385; ibem. J. Chem. Research, 1992, 264; T. Okawara, S. Ehara, S. Matsumoto, Y. Okamoto and M. Furukawa, J. Chem. Soc. Perkin Trans I, 1990, 2615; T. Okawara, S. Ehara, M. Eto, K. Harano and M. Furukawa, Tetrahedron Lett., 1993, 34, 4231.
  6. 6. A suspended solution of 5b (2 mmol) in 2 M HCl (20 ml) was refluxed for 12 h. The reaction mixture was extracted with CH2Cl2 (4 x 25 ml). The CH2Cl2 layer was washed with water (20 ml) and dried over MgSO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (CH2Cl2: MeOH = 50 : 1).
  7. 6b: yield 0.35 g (64%); mp 85-87 oC; IR (KBr) 1790, 1650 cm-1; 1H NMR [(CD3)2SO) 1.02 (3H, s, CH3), 1.03 (3H, s, CH3), 1.38 (3H, s, CH3), 2.12 (1H, d, J = 16.17 Hz, CHH), 2.25 (1H, d, J = 16.17 Hz, CHH), 2.37 (1H, d, J = 18.14 Hz, CHH), 2.48 (1H, d, J = 18.14 Hz, CHH), 2.76 (1H, d, J = 18.14 Hz, CHH), 2.84 (1H, d, J = 18.14 Hz, CHH), 6.23 (1H, s, OCHO); 13C NMR [(CD3)2SO) 20.91, 27.25, 28.25 (CH3), 36.15, 37.82, 50.64 (CH2), 33.92, 47.92 (C), 111.97 (CH), 116.42, 173.11 (C=C), 173.38, 193.45 (C=O); MS-EI m/z 236 (M+)
  8. 7. A solution of 6 (2 mmol) and amine (10 mmol) in EtOH (20 ml) was heateded in a sealed tube at 80 oC for 12 h. The EtOH was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (CH2Cl2: MeOH = 20 : 1).
  9. 9b: yield 0.42 g (89%); mp 270-272 oC; IR (KBr) 1690, 1680 cm-1; 1H NMR [(CD3)2SO) 0.96 (3H, s, CH3), 0.98 (3H, s, CH3), 1.26 (3H, s, CH3), 1.91 (1H, d, J = 15.83 Hz, CHH), 2.05 (1H, d, J = 15.83 Hz, CHH), 2.14 (1H, d, J = 16.83 Hz, CHH), 2.21 (1H, d, J = 17.15 Hz, CHH), 2.23 (1H, d, J = 16.83 Hz, CHH), 2..53 (1H, d, J = 17.15 Hz, CHH), 4.83 (1H, s, NCHN), 7.94 (1H, s, NH), 8.21 (1H, s, NH); 13C NMR [(CD3)2SO) 23.74, 27.49, 28.71 (CH3), 36.42, 41.36, 50.62 (CH2), 33.80, 46.73 (C), 77.84 (CH), 112.05, 164.53 (C=C), 175.83, 188.89 (C=O); MS-EI m/z 234 (M+).
  10. 8. A solution of 6 (2 mmol) and hydrazine (10 mmol) in EtOH (10 ml) was refluxed for 12 h. The EtOH was evaporated under reduced pressure. The solid was obtained by trituration with Et2O, filtered by washing with isopropyl ether and recrystallized from EtOH.
  11. 12a: yield 0.24 g (45%); mp 251-253 oC; 1H NMR [(CD3)2SO) d 0.92 (3H, s, CH3), 0.98 (3H, s, CH3), 1.28 (3H, s, CH3), 1.81 (1H, d, J = 15.84 Hz, CHH), 1.96 (1H, d, J = 15.84 Hz, CHH), 2.24 (1H, d, J = 17.15 Hz, CHH), 2.25 (1H, d, J = 13.52 Hz, CHH), 2.34 (1H, d, J = 17.15 Hz, CHH), 2.67 (1H, d, J = 13.52 Hz, CHH), 4.26 (1H, d, J = 2.31 Hz, CH), 4.36 (2H, s, NH2), 5.88 (1H, d, J = 2.31 Hz, NH), 8.21 (1H, s, NH); 13C NMR [(CD3)2SO) d 33.19, 45.16, 106.16, 167.73, 174.90, 187.52 (C), 86.21 (CH), 35.27, 38.28, 50.78 (CH2), 25.13, 27.69, 28.99 (CH3); MS-EI m/z 264 (M+).
  12. 9. A suspended solution of 17 (2 mmol) in ammonia solution (10 ml) was heated at 80 oC in a sealed tube for 2 h. The solid was filtered and recrystallized from EtOH: yield 0.29g (63%); mp 218-219 oC; 1H NMR [(CD3)2SO) 1.34 (3H, s, CH3), 2.14 (1H, d, J 17.49 Hz, CHH), 2.40 (1H, d, J 17.49 Hz, CHH), 3.02 (1H, d, J 17.82 Hz, CHH), 3.37 (1H, d, J 17.82 Hz, CHH), 5.30 (1H, s, CH), 6.90-6.97 (2H, m, Ar-H), 7.37-7.50 (1H, m, Ar-H), 8.69 (1H, s, NH), 13.26 (1H, br, OH); 13C NMR [(CD3)2SO) 24.74 (CH3), 43.87, 48.08 (CH2), 41.77 (C), 90.66 (CH), 116.29, 160.29 (=C),116.58, 118.63, 130.37, 133.26 (=CH), 175.40, 177.48 (C=O and C=N); MS-EI m/z 230 (M+)