Chinese Journal of Chemistry, 2007, 25, 1005—1007 Full Paper

* E-mail: peiwen58@zjut.edu.cn; Tel.: 0086-0571-88320629; Fax: 0086-0571-8832629 Received September 12, 2006; revised November 13, 2006; accepted March 20, 2007.

© 2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Researches on a Novel Method for Fluorination of Halopyridazine Derivatives in Ionic Liquid

SUN, Li(孙莉) PEI, Wen*(裴文)

College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China

A novel method for fluorination of halopyridazine derivatives with potassium fluoride was performed using a green chemistry procedure, including ionic liquid as an environmentally benign reaction medium and microwave irradiation with high yield.

Keywords fluorination method, halopyridazine derivatives, ionic liquid, green chemistry procedure, microwave irradiation

Introduction

Fluoropyridazine compounds are an important in-termediate of pharmaceuticals and herbicides for their good biological activities.1 The researches on the pyri-dazine chemistry have been developed rapidly since Fischer obtained a pyridazine compound in 1886.2 However, the fluoropyridazine system has been less thoroughly investigated than other pyridazine systems, especially before the antitumor activity of fluoropyri- midine derivatives was discovered. Following fluoro-pyrimidine research works, the field of fluoropyridazine chemistry has attracted much attention of organic chemists to the biological activities, such as herbicidal, antituberculosis, antitumor activities and so on.

Our recent interest has been in the area of clean syn-thesis using ionic liquids as a green recyclable alterna-tive to classical molecular solvents. As part of a pro-gram to investigate the range of organic reaction possi-ble in ionic liquids, we were interested in the research on fluorination of halogen substituted pyridazine de-rivatives as their structure was similar to the fluoro-pyrimidine derivatives. To the best of our knowledge, since 1960 there has been a series of research works for synthesis of fluoropyridazines, but no report to describe the fluorination process for preparing fluoropyridazine derivatives using ionic liquids as reaction media. Therefore, we herein employed various chloro or bromo substituted pyridazine derivatives as our starting materi-als to investigate the fluorination by potassium fluoride in ionic liquid media based on our previous work (Table 1).3

Firstly, we examined the fluorination of 4,5-dichlo- ro-1,6-dihydro-1-phenylpyridazin-6-one as model sub-strate to react with potassium fluoride in the ionic liquid of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]- [BF4]), and obtained 5-chloro-1,6-dihydro-4-fluoro-1-

Table 1 Results of fluorination of halopyridazine derivatives

Entry Product m.p./℃ Time/h Temp./℃ Yielda/%

1 1a 145—146 3 100 85

2 1b 71—72 3 100 78

3 1c 130—131 3 100 84

4 1d 159—160 3 100 74

5 1e ＞270 2 80 62

6 2 83—84 9 120 80

7 3 237—239 1 reflux 88

8 4 46—47 5 100 73

9 5 98—99 1 reflux 78

10b 1a 145—146 10 80—100 88

11b 1d 159—160 10 80—100 82

12b 2 83—84 10 80—100 89

13b 4 46—47 10 80—100 81 a Isolated yield. b Microwave condition, the power is 70 W, reac-tion time is 10 min.

phenylpyridazin-6-one (1a) in high yield [Eq. (1), Entry 1]. The fluorine nuclear magnetic resonance spectrum (19F NMR) showed that one peak of the C(4) fluorine atom at δ 32. The infrared spectrum showed the clear peak of carbonyl absorption of amide in a range of 1640—1650 cm－1. The elemental analysis and mass spectrum supported the theoretical values for the pro-posed structure. In order to distinguish the fluorination occurred at C(4) or C(5), we employed 4,5-dichloro-1,6- dihydro-1-phenylpyridazin-6-one and 1a to react with the same equivalent of sodium methoxide respectively in methanol, and the same product of 5-chloro-1,6-di- hydro-4-methoxy-1-phenylpyridazin-6-one was ob-tained.4 With this exciting result in hand, the fluorina-tion of a class of 4,5-dichloro-1,6-dihydropyridazin- 6-ones with potassium fluoride was performed (Entry

1006 Chin. J. Chem., 2007, Vol. 25, No. 7 SUN & PEI

© 2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2—5).

In the fluorination of 4-chloro-1,2-dihydro-3,6- pyridazinedione under the same reaction condition, we found some polymeric product was formed and the iso-lation of the fluorinated product was quite difficult. To confirm the substitution product was formed firstly, we treated this reaction mixture with silver nitrate solution and observed the precipitation of silver chloride. Ac-cording to this result we thought the chlorine atom had been successfully replaced by fluorine atom. Then, we changed our reaction route and applied the reaction of 4-chloro-1,2-dihydro-3,6-pyridazinedione with methyl iodide to prepare 4-chloro-3,6-dimethoxypyridazine, followed by the fluorination of 4-chloro-3,6-dimeth- oxypyridazine to give 4-fluoro-3,6-dimethoxypyridazine (2) under the above reaction condition at 120 ℃ in 80% yield (Scheme 1, Entry 6). The 4-fluoro-1,2-dihy- dro-3,6-pyrida-zinedione (3) was obtained by the hy-drolytic cleavage of 4-fluoro-3,6-dimethoxypyridazine treated with hydrobromic acid under the usual condi-tions (Scheme 1, Entry 7).

Scheme 1

4-Fluoro-3,6-dichloropyridazine (4) was also pre-pared by the reaction of 3,4, 6-trichloropyridazine with potassium fluoride in ionic liquid with good yield at 100 ℃ for 5 h. And then, 4-fluoro-6-chloro-3-methoxypyri- dazine (5) was obtained by the reaction with one equivalent of sodium methoxide in methyl alcohol (Scheme 2, Entry 8—9).

Scheme 2

In addition, in an effort to develop a more widely applicable methodology, we examined consequently the possibility that microwave irradiation could facilitatethe fluorination to form the desired product, including an optimized one-pot microwave-assisted reaction provid-ing an efficient route to fluoropyridazine derivatives. The experimentation on reaction system mentioned above was investigated to understand the impact of mi-crowave irradiation on the fluorination. The desired products were obtained, to our delight, when we applied our optimized microwave reaction conditions to a vari-ety of fluorination reactions in high yield (Entry 10—13).

In conclusion, we have developed a new and effi-cient green chemistry synthetic procedure for the syn-thesis of fluoropyridazines using ionic liquid as reaction media. We have also provided an efficient micro-wave-assisted, one-pot synthesis of fluoropyridazines. The results demonstrate that microwave-assisted chem-istry can not only privide increased yield and shortened reaction time, but also expand the accessible chemical space by forming the fluoropyridazines.

Experimental

1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) and 1-butyl-3-methylimidazolium hexa- fluorophosphate ([bmim][PF6]) were prepared according to the literature method.5 Potassium fluoride was anhy-drously prepared by ourselves. 1H NMR spectra were recorded on a Bruker 400 spectrometer with reference to TMS internal standard in CDCl3 or DMSO-d6. Mass spectra were recorded on an HP5998B mass spectrome-ter by electron impact (EI). All the products were satis-factorily characterized by 1H NMR, MS or elemental analysis, and comparison of their NMR spectra has been made with available literature.

General procedure for the fluorination

A three-necked round-bottom flask containing a stir-ring bar was charged with halopyridazine (1.0 mmol), anhydrous potassium fluoride (3 mmol), and [bmim]- [BF4] or ([bmim][PF6]) (10 mL) under nitrogen in 80—120 ℃ for 2—10 h. After being cooled, the mixture was extracted with CH2Cl2 (3×20 mL) or toluene (3×20 mL), and then the organic layer was combined and washed with water, dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel using ethyl acetate and hexane (10/90 to 30/70 in volume ratio) as eluant. The structure of the compound was confirmed by 1H NMR and MS and melting point.

A round-bottom flask was charged with halopyri-dazine (1.0 mmol), anhydrous potassium fluoride (3 mmol), and [bmim][BF4] or ([bmim][PF6]) (10 mL) under nitrogen and irradiated under microwave condi-tions for 10 min. After being cooled, the mixture was

Halopyridazine derivatives Chin. J. Chem., 2007 Vol. 25 No. 7 1007

© 2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

extracted with CH2Cl2 (3×20 mL) or toluene (3×20 mL) and the organic layer was combined and washed with water, dried with MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatog-raphy on silica gel using ethyl acetate and hexane (10/90 to 30/70 in volume ratio) as eluant.

5-Chloro-1,6-dihydro-4-fluoro-1-phenylpyridazin-6- one (1a)

1H NMR (CDCl3) δ: 6.96—7.26 (m, 5H, Ph), 7.91 (s, 1H); 19F NMR (CDCl3) δ: 32; IR (KBr) ν: 1640, 1606 cm－1; MS m/z: 224 (M＋). Anal. calcd for C10H6Cl- FN2O: C 53.57, H 2.68, N 12.50; found C 53.67, H 2.55, N 12.61.

5-Chloro-1,6-dihydro-4-fluoro-1-benzylpyridazin-6- one (1b)

1H NMR (CDCl3) δ: 4.29 (s, 2H), 7.56—7.96 (m, 5H, Ph), 8. 03 (s, 1H); IR (KBr) ν: 1640, 1610 cm－1; MS m/z: 238 (M＋). Anal. calcd for C11H8ClFN2O: C 55.35, H 3.35; found C 55.37, H 3.40.

5-Chloro-1,6-dihydro-4-fluoro-1-totylpyridazin-6- one (1c)

1H NMR (CDCl3) δ: 2.29 (s, 3H), 7.06—7.26 (m, 4H, Ph), 7. 83 (s, 1H); 19F NMR (CDCl3) δ: 32; IR (KBr) ν: 1640, 1610, 1500 cm－1; MS m/z: 238 (M＋). Anal. calcd for C11H8ClFN2O: C 55.35, H 3.35, Cl 14.88; found C 55.27, H 3.45, Cl 14.67.

5-Bromo-1,6-dihydro-4-fluoro-1-phenylpyridazin-6- one (1d)

1H NMR (CDCl3) δ: 7.39—7.56 (m, 5H, Ph), 8.01 (s, 1H); IR (KBr) ν: 1645, 1610 cm－1; MS m/z: 268 (M+). Anal. calcd for C10H6BrFN2O: C 53.57, H 2.67; found C 53.67, H 2.55.

5-Bromo-1,6-dihydro-4-fluoro-1-p-nitrophenylpyri- dazin-6-one (1e)

1H NMR (CDCl3) δ: 7.76—7.90 (m, 4H, Ph), 8.09 (s, 1H); IR (KBr) ν: 1645, 1600 cm－1; MS m/z: 314 (M＋). Anal. calcd for C10H5BrFN3O3: C 38.24, H 1.61; found C 38.37, H 1.75.

4-Fluoro-3,6-dimethoxypyridazine (2) 1H NMR (CDCl3) δ: 3.76 (s, 6H), 7.09 (s, 1H); IR

(KBr) ν: 1640, 1600 cm－1; MS m/z: 158 (M＋). Anal. calcd for C6H7FN2O2: C 45.57, H 4.43; found C 45.67, H 4.75.

4-Fluoro-1,2-dihydro-3,6-pyridazinedione (3) 1H NMR (CDCl3) δ: 7.50 (s, 1H), 11.95 (s, 2H); IR

(KBr) ν: 1640, 1590, 1560, 1490 cm－1; MS m/z: 130 (M＋). Anal. calcd for C4H3FN2O2: C 36.92, H 2.31; found C 36.65, H 2.37.

4-Fluoro-3,6-dichloropyridazine (4) 1H NMR (CDCl3) δ: 8.09 (s, 1H); IR (KBr) ν: 1620,

1536, 1500 cm－1; MS m/z: 166 (M＋). Anal. calcd for C4HCl2FN2: C 28.74, N 16.71; found C 28.67, N 16.35.

6-Chloro-4-fluoro-3-methoxypyridazine (5) 1H NMR (CDCl3) δ: 7.50 (s, 1H), 11.95 (s, 2H); IR

(KBr) ν: 1578, 1559, 1480, 1460 cm－1; MS m/z: 162 (M+). Anal. calcd for C5H4ClFN2O: C 36.92, H 2.46; found C 36.95, H 2.47.

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(E0609121 YANG, X.; FAN, Y. Y.)