Synthesis of novel fluorophenylaryl / heteroaryl ether derivatives

A detailed syntheses of some fluorophenylaryl / heteroaryl ether derivatives 1a, b–4a, b have been described which was accomplished by using a variety of convenient phenolic coupling methods and subsequent Pd-C catalyzed hydrogenation of the coupled intermediates. The compounds synthesized are structurally similar to a number of anti-inflammatory agents.


Introduction
Earlier we published a research article where we described briefly the existence of intramolecular C-F---H-N hydrogen bonding using compounds 1-4, which were designed as covalently-linked base pair models of F (difluorotoluene deoxynucleoside) and A (adenine deoxynucleoside) (Figure 1). 1,2Although our study failed to find any C-F---H-N intramolecular hydrogen bonding and supported Kool's theory that shape complementarities between the base pairs play the major role in DNA replication fidelity, 3 several papers have been published subsequently showing intramolecular C-F--H-N interactions and the role of organic fluorine in hydrogen bonding by means of density functional theory, ab initio and MMFF force field calculations. 4We couldn't explain definitely the reason of not finding intramolecular C-F---H-N hydrogen bonding and it was assumed that the problem might be the design of the compounds.Therefore we didn't proceed for further investigation.Later on we found that our compounds are structurally similar to a number of biologically interesting fluorophenylaryl ether type compounds (Figure 2). 5,6,7The most promising compounds belonging this class is Flosulide (I) and its sulfone analogue (II), which have already been proven as selective cyclo-oxygenase-2 (COX-2) inhibitors 6,7 .Besides these, 5'-cyano-2'(2,4-difluorophenoxy)-biphenyl-4-sulfonamide (III), 2-benzyl-6-cyclohexylsulfanyl-5-(3-fluoro-phenoxy)-1H-benzimidazole (IV) have antiinflammatory properties 8,9 and 4-(biphenyl-4-yloxy)-3-fluorobenzoic acid (V) is a potent human prostatic 5-α-reductase inhibitor. 10Therefore these compounds are therapeutically important as analgesic, antipyretic, antiarthritic (especially rheumatoid arthritis) and anticancer agents.The compounds 1-4 are expected to have similar biological activities due to their structural similarities with these compounds (Figure 2).In this paper we disclose the detailed synthetic procedures with characterization of these compounds.These compounds can be utilized as the lead compound for the design of some biologically active compounds.The synthesis of compounds 1-4 was accomplished by using a variety of phenol coupling methods as key steps (Scheme 1 and 2).4-Fluoro-1,2-phenylenediamine 5 11 was first converted into 5-fluorobenzimidazole 6 by heating in formic acid solution.Nitration of 6 under relatively mild conditions gave a mixture of two regioisomers 5-fluoro-4-nitrobenzimidazole 7 and 5fluoro-6-nitrobenzimidazole 8.The 4-nitro compound 7 was subjected to KF-Al 2 O 3 12 mediated coupling with o-fluorophenol and p-fluorophenol in the presence of catalytic amount of 18crown-6-ether 13 in MeCN to give fluorophenyl benzimidazole (heteroaryl) ethers 9a-9b.Pd-C catalyzed hydrogenation of 9a-9b at atmospheric pressure afforded compounds 1a-1b, respectively in excellent yields.However, KF-Al 2 O 3 mediated coupling reaction 12,13 of 6-nitro compound 8 with fluorophenols failed unexpectedly.We then investigated an alternative procedure.The coupling reaction of 8 with o-fluorophenol and p-fluorophenol was performed in the presence of K 2 CO 3 in DMSO at 100-120 °C10a affording the fluorophenyl benzimidazole (heteroaryl) ethers 10a-10b, which on hydrogenation gave the desired compounds 2a-2b, respectively in good yields.
Preparation of the model compounds 3 and 4 required different phenolic coupling conditions.Coupling of commercially available 2-chloronitrobenzene 11 with the potassium salt of ofluorophenol at 110-120 °C5b yielded the fluorophenylaryl ether compound 12a which on Pd-C catalyzed hydrogenation gave 3a.The compound 4a was prepared from NaH based coupling 14 of 13 15 with o-fluorophenol to afford the fluorophenyl phenyl pyridyl (heteroaryl) ether 14a with subsequent Pd/C catalyzed hydrogenation.p-Fluorinated compounds 3b and 4b were prepared in similar sequences from 12 and 14, respectively in good yields (Scheme 2).

Scheme 2
In summary, we have demonstrated the detailed syntheses of some novel fluorophenylaryl / heteroaryl ether derivatives which are structurally similar to some potent anti-inflammatory agents like Flosulide.The synthetic procedures are more straightforward and convenient than the traditional multi-step syntheses.These synthetic studies are expected to be helpful to generate some highly potent compounds of similar biological activities.The biological activity studies of the synthesized compounds are in progress.

Experimental Section
General Procedures.All melting points were determined with a Yanagimoto Micro Melting Point apparatus and are uncorrected.IR spectra (cm -1 ) were recorded on a Perkin-Elmer 1600 spectrometer. 1 and chemical shifts are expressed in ppm relative to internal Me 4 Si (0.00 ppm) and were recorded on a JEOL GX-270 (270 MHz) spectrometer. 19F-NMR spectra were measured with CFCl 3 as an internal standard and were taken with a JEOL GX-270 (254 MHz) spectrometer.Upfield shifts were quoted as negative δ values. 13C NMR spectra were recorded at 125.76, 75.46 and 68 MHz using Unity plus 500, Varian Gemini 300 and JEOL GX-270 instruments.Chemical shifts are quoted in ppm and are referenced to CDCl 3 .Electron ionization (EI) mass spectra were taken with a JEOL JMS-D300 spectrometer.Column chromatography and preparative TLC were performed on BW-200 (Fuji Silysia) and Kieselgel 60 (Merck, art.7748), respectively.All reactions were carried out under a dry N 2 atmosphere.Unless otherwise noted, reagents were added by syringe.MeOH was distilled from CaO and DMF was distilled over CaH 2 immediately prior to use.Commercially available dehydrated THF [stabilized with butylated hydroxytoluene (BHT)] was used for reaction.

5-Fluoro-4-nitrobenzimidazole (7) and 5-Fluoro-6-nitrobenzimidazole (8).
To a solution of 6 (5.5 g, 40.4 mmol) in concentrated sulphuric acid (6.4 ml, 120 mmol) was added concentrated nitric acid (5.1 ml, 120 mmol) slowly and the whole mixture was stirred at room temperature for 3h.The solution was poured into ice-water.A solid was formed which was filtered and subsequently washed with water and saturated sodium bicarbonate solution.The liquid portion was neutralized by adding KOH pellets.The solid still present was filtered off and the mother liquid was extracted with ethyl acetate (100 ml x 2).The total solids were taken and the organic portion was concentrated in vacuo.The residue was chromatographed on silica gel (3-5% methanol in dichloromethane) to give 7 (2.2 g, 30%) and 8 (4.07 g, 56%), both as a yellowish solid.Data for 7: mp 191-192 °C (from dichloromethane);

5-(2-Fluorophenyl)-4-aminobenzimidazole ether (1a).
To a solution of 9a (107 mg, 0.391 mmol) in MeOH (10 ml) under N 2 was added Pd/C (20 mg) and H 2 gas was allowed to pass through the solution with stirring for 4 h until completion of the reaction by TLC.The reaction mixture was filtered off through a plug of celite and the filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (chloroform-methanol 9:1) to yield 1a (91 mg, 96%) as a grey crystalline solid; mp 127-128 °C (from dichloromethane); Anal.Calcd

2-(2-Fluorophenyl) phenylamine ether (3a).
To a solution of 12a (200 mg, 0.858 mmol) in anhydrous methanol (10 ml) under nitrogen was added Pd/C (50.0 mg).The flask was evacuated and hydrogen gas was allowed to pass through the solution overnight.After being ensured of the completion of the reaction by TLC, the reaction mixture was filtered through a plug of celite to remove Pd/C and the filtrate was concentrated and purified by column chromatography on silica gel (hexane-ethyl acetate 9:1) to give 3a (151 mg, 87%) as a yellow oil; IR (neat, cm -1 ) 3364, 3333 (NH 2 ), 3038, 2868, 1308, 782;
Scheme 1 H-NMR spectra were measured as solutions in CDCl 3, CD 3 OD, D 2 O or DMSO-d 6 ARKAT USA, Inc.