Journal of the Arkansas Academy of Science

Volume 52 Article 24

1998 Preparation of Methyl 5-Chloro-6-Fluoronicotinate by Fluoride- Exchange Frank L. Setliff University of Arkansas at Little Rock

Leslie B. Coop University of Arkansas at Little Rock

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Recommended Citation Setliff, Frank L. and Coop, Leslie B. (1998) "Preparation of Methyl 5-Chloro-6-Fluoronicotinate by Fluoride-Chloride Exchange," Journal of the Arkansas Academy of Science: Vol. 52 , Article 24. Available at: http://scholarworks.uark.edu/jaas/vol52/iss1/24

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The Preparation ofMethyl 5-Chloro-6-Fluoronicotinate by Fluoride- Chloride Exchange Frank L.Setliff* and Leslie B. Coop Department of Chemistry University of Arkansas at LittleRock Little Rock, AR 72204

*Corresponding Author

Several chloro and fluoronicotinic have been nicotinate as depicted inFig. 1. examined for hypolipidemic activity indogs (Carlson et. al., We previously attempted the fluoride exchange with 1972). It was demonstrated that 5-fluoronicotinic , 6- various chloronicotinic acids, but the results were totally fluoronicotinic acid, and 5-chloronicotinic acid were unrewarding. Only tars or intractable resins were obtained effective for the supresssion of elevated free fatty acid levels, (Coop, 1996). with the fluoroacids having longer duration. A few simple Melting points were determined on a Mel Temp II alkyl esters of these acids also showed some activity, pre- apparatus and are uncorrected. Elemental analysis was sumably due to in vivo hydrolysis to the acids. While it performed by Desert Analytics Organic Microanalysis, would seem feasible to study possible hypolipidemic activi- Tuscon, AZ. NMR spectra were determined on a ties of nicotinic acids and esters with a dual combination of Bruker AC-F 200 MHz superconducting FT spectrometer and chlorine on the pyridine ring, such studies have with chloroform-d as solvent and tetramethylsilane as inter- been limited by the relative nonavailability of these com- nal standard. Infrared spectra were obtained on a Nicolet pounds. 500 Magna FT-IRspectrophotometer, with samples deposit- In connection with our previous studies involving ed as films evaporated from chloroform onto a KBrplate. exchange of fluorine for chlorine in the pyridine 2- or 6- Methyl 5,6-dichloronicotinate was prepared as described position by nucleophilic displacement (Setliff and DeFoggi, previously (Setliff and Huie 1981). (fine 1978), we saw the opportunity to prepare methyl 5-chloro-6- powder) was purchased from Aldrich Chemical Company fluoronicotinate (a heretofore unknown compound) from and was oven-dried at 110°C for several days prior to use. methyl 5,6-dichloronicotinate, which is readily accessible. It Dimethylformamide (Aldrich) was dried over neutral alumi- has been known for decades that chlorine in the 2-or 6- na for several days and distilled immediately before use position of pyridine is displaced easily by fluoride inboiling (b.p. 158°C.) anhydrous dimethylformamide (DMF), provided a very The synthesis of methyl 5-chloro-6-fluoronicotinate was strong electron withdrawing group (e.g. nitro or ammoni- accomplished as follows. Methyl 5,6-dichloronicotinate um) is located at the para position (Finger and Starr, 1959). 0.0049 mole) was placed in a 25 mL round-bottom flask and However, the more weakly electron withdrawing car- dissolved inDMF(2.5 mL). Drypotassium fluoride powder bomethoxy group, although shown to be sufficiently acti- (0.6 g, 0.0098 mole) was quickly added, and a reflux con- vating to induce displacement of chloride by fluoride in the denser equipped with a drying tube was benzene system if a nitro group is also present (Finger and attached to the flask. The reaction mixture was stirred under Cruse, 1956), had not been tested in a pyridine system. gentle reflux for 1hr withoilbath heating. The oilbath tem- Thus, we attempted and were successful in the conversion of perature was maintained at 155-158°C. The dark reaction methyl 5,6-dichloronicotinate to methyl 5-chloro-6-fluoro- mixture was cooled and transferred to a 250 mL 3-necked

COOMe

KF/DMF

Fig. 1. Nucleophilic displacement of chloride by fluoride at 158°C

Journal of the Arkansas Academy of Science, Vol. 52, 1998 Published by Arkansas Academy of Science, 1998 138

138 Journal of the Arkansas Academy of Science, Vol. 52 [1998], Art. 24 The Preparation of Methyl 5-Chloro-6-Fluoronicotinate by Fluoride- Chloride Exchange

lask, 10 mL of water was added, and the mixture was indi- the chlorine in the 5- position significantly aided activation ectly steam distilled. A white solid (0.30 g, m.p. 47-57°C) since in a control experiment we observed that methyl 2- was filtered from the steam distillate. This material, shown chloronicotinate gave only spectral traces of the fluoroester. >y proton NMR to be a mixture of starting material and >roduct, was returned to the reflux flask and once again leated withpotassium fluoride (0.6 g) in DMF (2.5 mL) for Literature Cited an additional hour. Indirect steam distillation yielded the pure chlorofluoro ester as a fluffy white solid, 0.22 g,24% Carlson, L.A.,C. Hedbom, E. Helgstrand, A.Misiorny, yield, m.p. 66-68°C. IR:v 1724 (C=O), 1068 (CO) cm 1. B. Sjoberg, N. Stjernstrom, and G. Westin. 1972. iHNMR: 5 8.75 (m), H2 ;[8.45, 8.44 and 8.41,8.40] (d Potential hypolipedimic agents III.heterocyclic com- of d), H4;3.97 (s) CH3.The pyridine ring proton signals of pounds affecting free fatty acid mobilization in vivo. he starting dichloro ester [H2 at 8.89 ppm (d) and H4 at 8.36 Acta. Pharm. Suec. 9:221-228. jpm (d)] were not visible at high amplification, indicating Coop, L.B. 1996. The preparation of 2,5- and 5,6difluoron- reasonable purity. Anal. Calcd. for C7H5NO2FC1: C, 44.35; icotinic acid and related compounds. Unpublished M.S. H. 2.66; N, 7.39. Found: C, 44.13; H,2.51; N. 7.41. thesis, University of Arkansas at LittleRock. 100 pp. Although methyl 5-chloro-6-fluoronicotinate was Finger, G.C. and C.W. Cruse. 1956. Aromatic fluorine sucessfully prepared and characterized, the low yield could compounds VII.replacement of aromatic Cl groups by not be improved upon due to a competitive reaction of the F. J. Am. Chem. Soc. 78:6034-6037. dichloroester with DMF. After the initial reflux of 1hr and Finger, G.C. and L.D. Starr. 1959. Aromatic fluorine com- after the volatile solid was removed by steam distillation, pounds IX.2-fluoropyridines. J. Am. Chem. Soc. 81: cooling of the steam distillation pot afforded a nonvolatile 2674-2675. organic material (0.20 g) of m.p. 147-150°C. Preliminary Finger, G.C, L.D. Starr, D.R. Dickinson, H. Gutowsky, ndications based on infrared and 'HNMR data suggest a and J. Hamer. 1963. Aromatic XI. )ossible imminium structure (Fig. 2). Replacement of chlorine by fluorine inhalopyridines. J. Org. Chem. 28:1666-1668. Setliff,F.L. and D.DeFoggi. 1978. 2-Fluoro-5-nitro-3-pico- line and 6-fluoro-5-nitro-3picoline by fluoride-chloride exchange. Org. Prep, and Proc. Int. 10: 83-84. " Setliff, 2,5-and 5,6- F F.L. and W.R. Huie. 1981. Some methyl dihalonicotinates. J. Chem. Eng. Data 26: 332-333.

Fig. 2. Likely structure of the imminium salt formed com- petitively.

This material was not characterized further. Reaction longer than 1 hr led to increased amounts of the pre- imed imminium salt and virtually no steam volatile ester; hereas shorter reaction times and lower reaction mperatures resulted in recovery of mostly unconverted arting material. Enes Although Finger (Finger et al., 1963) had demonstrated le superiority of dimethyl sulfone over DMFas a solvent in uoride-chloride exchanges inpyridine systems, no exam- )les of chloroester substrates were mentioned. With the lope that the use of dimethyl sulfone would eliminate our ompetitive reaction, we employed this solvent under a vari- tyof conditions. However, no pure steam volatile products ould be isolated. conclusion itappears that the ester group offers only ry weak activation to chloride displacement in the kinsence of strongly electron withdrawing groups. Actually,

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