Recyclization of Hydrazides of 2-Carboxyphenyldifurylmethanes: Synthesis of Novel 4,10-Dihydro-3H-pyridazino[1,6-b]isoquinolin-10-one System

Abstract

A novel heterocyclic system of 4,10-dihydro-3H-pyr­idazino[1,6-b]isoquinolin-10-one has been synthesized via acid-catalyzed recyclization of hydrazides of 2-carboxyphenyldifurylmethanes as well as by alternative synthesis by interaction of the corresponding isocoumarine ketones with hydrazine hydrate.

furans - ring opening - ring closure - fused-ring systems - pyridazino[1,6-b]isoquinolin-10-one

References and Notes

For reviews, see:

1a Dean FM. Adv. Heterocycl. Chem.  1982,  30:  167 

1b Dean FM. Adv. Heterocycl. Chem.  1982,  31:  237 

1c Piancatelli G. D’Auria M. D’Onofrio F. Synthesis  1994,  867 

2 For a review, see: Butin AV. Abaev VT. Izv. Akad. Nauk Ser. Khim.  2001,  1436 

3a Butin AV. Krapivin GD. Zavodnik VE. Kul’nevich VG. Khim. Geterotsikl. Soedin.  1993,  616 

3b Abaev VT. Gutnov AV. Butin AV. Khim. Geterotsikl. Soedin.  1998,  603 

3c Gutnov AV. Butin AV. Abaev VT. Krapivin GD. Zavodnik VE. Molecules  1999,  4:  204 

4 Butin AV. Stroganova TA. Lodina IV. Krapivin GD. Tetrahedron Lett.  2001,  42:  2031 

5a Dmitriev AS. Podelyakin SA. Abaev VT. Butin AV. Khim. Geterotsikl. Soedin.  2005,  1400 

5b Abaev VT. Dmitriev AS. Gutnov AV. Podelyakin SA. Butin AV. J. Heterocycl. Chem.  2006,  43:  1195 

6 Abaev VT. Osipova AA. Butin AV. Khim. Geterotsikl. Soedin.  2001,  849 

7 Butin AV. Abaev VT. Mel’chin VV. Dmitriev AS. Tetrahedron Lett.  2005,  46:  8439 

See for example:

8a Bezoari MD. Paudler WW. J. Org. Chem.  1980,  45:  4584 

8b Haley JF. Rosenfeld SM. Keehn PM. J. Org. Chem.  1977,  42:  1379 

8c Kharchenko VG. Markushina IA. Voronin SP. Khim. Geterotsikl. Soedin.  1982,  418 

8d Kharchenko VG. Gubina TI. Voronin SP. Markushina IA. Khim. Geterotsikl. Soedin.  1986,  1453 

8e Voronin SP. Gubina TI. Markushina IA. Kharchenko VG. Khim. Geterotsikl. Soedin.  1989,  1333 

9a Butin AV. Gutnov AV. Abaev VT. Krapivin GD. Khim. Geterotsikl. Soedin.  1998,  883 

9b Butin AV. Smirnov SK. Stroganova TA. J. Heterocycl. Chem.  2006,  43:  623 

9c Gutnov AV. Abaev VT. Butin AV. Dmitriev AS. J. Org. Chem.  2001,  66:  8685 

10 For a typical procedure, see: Johnstone RWA. Rose ME. Tetrahedron  1979,  35:  2169.  Preparation of Compounds 9a-f; General Procedure To a suspension of finely powdered KOH (2 g) in anhyd DMSO (40 mL) were added compound 8 (6.76 mmol) and MeI (2 mL, 12.12 mmol) and the mixture was stirred at r.t. for 20 min. The suspension was filtered off and the filtrate was poured into H₂O (500 mL). The resulting emulsion was brought to pH 5-6 with dilute HCl and extracted with CH₂Cl₂ (4 × 30 mL). The combined extract was dried over anhyd Na₂SO₄ and evaporated to dryness. The residue was purified by flash chromatography on silica gel (hexane-CH₂Cl₂, 10:1). Eluate containing the target compound was reduced in volume to 10-20 mL and left for crystallization at temperature below 0 °C.Selected analytical data of 9b: mp 57-58 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.24 (s, 6 H, CH₃), 3.87 (s, 3 H, OCH₃), 5.85 (d, J = 3.3 Hz, 2 H, 4-H_Fur), 5.88 (d, J = 3.1 Hz, 2 H, 3-H_fur), 6.48 (s, 1 H, CH), 7.24 (d, J = 8.5 Hz, 1 H, H_Ar), 7.41 (dd, J = 2.2, 8.5 Hz, 1 H, H_Ar), 7.90 (d, J = 2.2 Hz, 1 H, H_Ar). Anal. Calcd for C₁₉H₁₇ClO₄: C, 66.19; H, 4.97. Found: C, 66.01; H, 5.09

11

Preparation of Compounds 10a-f; General Procedure A mixture of compound 9 (5.81 mmol), NH₂NH₂·H₂O (9 mL) and n-BuOH (9 mL) was refluxed for 20 min. Then it was poured into H₂O (300 mL). The resulting precipitate was filtered off, air-dried and used in the next step as such.

12

Preparation of Compounds 13a-f (Method A); General Procedure To a 15% solution of p-TsOH in benzene (20 mL), prepared by refluxing p-TsOH·H₂O in benzene with azeotropic removal of H₂O, compound 10 (4.19 mmol) was added and the mixture was refluxed for 10 min. The resulting solution was poured into H₂O (300 mL). The slurry was extracted with CH₂Cl₂ (3 × 50 mL). The combined extract was washed with H₂O, dried over anhyd Na₂SO₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane-EtOAc, 4:1). Solvent was stripped off of the eluate and the residue was recrystallized from hexane-EtOAc (10:1) at temperature below 0 °C.
Selected analytical data of 13b: mp 173-174 °C. IR: 1667 (CO) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s, 3 H, CH₃), 2.33 (t, J = 7.5 Hz, 2 H, CH₂), 2.38 (s, 3 H, CH₃), 2.84 (t, J = 7.5 Hz, 2 H, CH₂), 6.15 (d, J = 3.1 Hz, 1 H, 4-H_Fur), 6.31 (d, J = 3.1 Hz, 1 H, 3-H_fur), 7.33 (d, J = 8.7 Hz, 1 H, H_Ar), 7.51 (dd, J = 2.2, 8.7 Hz, 1 H, H_Ar), 8.52 (d, J = 2.2 Hz, 1 H, H_Ar). ¹³C NMR (50 MHz, CDCl₃): δ = 13.82, 22.54, 24.43, 24.65, 105.25, 106.95, 113.16, 126.36, 126.80, 128.09, 132.69, 133.04, 134.63, 135.08, 145.49, 152.92, 158.27, 163.19. MS: m/z (%) = 329, 327 (5, 15) [M⁺ + 1], 328, 326 (28, 83) [M⁺], 293 (28), 292 (100), 249 (18), 208 (15), 43 (20). Anal. Calcd for C₁₈H₁₅ClN₂O₂: C, 66.16; H, 4.63. Found: C, 66.08; H, 4.69.

13a Ferrer S. Naughton DP. Parveen I. Threadgill MD. J. Chem. Soc., Perkin Trans. 1  2002,  335 

13b Ukita T. Nakamura Y. Kubo A. Yamamoto Y. Moritani Y. Saruta K. Higashijima T. Kotera J. Takagi M. Kikkawa K. Omori K. J. Med. Chem.  2001,  44:  2204 

13c Kowalczyk BA. Synthesis  2000,  1113 

13d Yamaguchi S. Uchiuzoh Y. Sanada K. J. Heterocycl. Chem.  1995,  32:  419 

13e Bhide BH. Akolkar VD. Brahmbhatt DI. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1993,  32:  675 

14 Cushman M. Jayaraman M. Vroman JA. Fukunaga AK. Fox BM. Kohlhagen G. Strumberg D. Pommier Y. J. Med. Chem.  2000,  43:  3688 

15 Dusemund J. Arch. Pharm. (Weinheim, Ger.)  1982,  315:  925 

16

Preparation of Compounds 13a-f (Method B); General Procedure A suspension of compound 14 (3.37 mmol) in ethylene glycol (50 mL) with NH₂NH₂·H₂O (1 mL) was stirred at r.t. until complete dissolution of the starting material was observed (30 min, TLC monitoring). The resulting solution was refluxed for 15 min, poured into H₂O (300 mL) and extracted with CH₂Cl₂ (3 × 50 mL). The combined extract was washed with H₂O, dried over anhyd Na₂SO₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane-EtOAc, 4:1). The solvent was stripped off of the eluate and the residue was recrystallized from hexane-EtOAc (10:1) at temperature below 0 °C.

17

Crystal data of compound 13f: C₁₈H₁₅BrN₂O₂, monoclinic, space group C2/c; a = 32.028(6) Å, b = 11.022(2) Å, c = 9.016(2) Å, α = 90°, β = 90.48(3)°, γ = 90°, V = 3182.6(11) ų, Z = 8, D _calcd = 1.550 Mg/m³, F(000) = 1504; 3330 reflections collected, 3116 unique (R _int = 0.0269); final R indices (3116 observed collections I >2σI): R ₁ = 0.0331, wR ₂ = 0.0818; final R indices (all data): R ₁ = 0.1677, wR ₂ = 0.0945. Crystallographic data (excluding structure factors) for the structure in this article have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 614755. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or E-mail: [e-mail]]. Each request should be accompanied by the complete citation of this paper.

18 Veeraraghavan S. Popp FD. J. Heterocycl. Chem.  1981,  18:  71