Ando Takashi

Cork David G.

Fujita Mitsue

Kimura Takahide

Departmental Bulletin Paperdepartmental bulletin pape

Cork, David G.

Kimura, Takahide

Fujita, Mitsue

Ando, Takashi

Shiga University of Medical Science Repository BI WAKO / 滋賀医科大学機関リポジトリ

Improved fluorination with supported fluoridereagents著者 Cork David G., Kimura Takahide, Fujita Mitsue,Ando Takashijournal orpublication title滋賀医科大学基礎学研究volume 4page range 7-11year 1993-03その他の言語のタイトル種々のフッ化物担持試薬によるフッ素化シュシュ ノ フッカブツ タンジ シヤク ニ ヨル フッソカURL http://hdl.handle.net/10422/1195Bulletin of Shiga University of Medical Science (General Education)4 : 7-ll (1993)Improved Fluorination with Supported Fluoride ReagentsDavid G.Cork*, Takahide Kimura**, Mitsue Fuiita**, and Takashi Ando*Received February 23 , 1993Potassium and tetrabutylammonium fluorides dispersed on nonsurface-hydroxylated supportmaterials, such as Teflon beads and Nafion cation exchange resin, were found to show enhancedreactivity and/or easy handling for fluorination reactions.Potassium fluoride is a popular source of fluorine for preparation of organofluonne com-pounds, due to its stability and cost, thus a variety of methods have been tried to improve itseffectiveness for uncleophilic fluormation. Spray dried KF has been shown to have increasedreactivity for fluorination of some organic halides compared to ordinary KF and this has beenrelated to the increase in surface area. As an alternative, the surface area of KF may beincreased by dispersion on an inorganic support. Alumina supported KF has been shown to havehigh basicity but poor fluorinating ability, presumably due to its hydroxylated surface. Calciumfluoride, on the other hand, has been reported as a support that allows the fluorinating abilityof KF2 and AgF3 to be exploited. Finely powdered CaF2 has a surface area of ca. lOmyg andKF dispersed over this surface shows good fluorinating ability, consistent with the increasedsurface area on going from KF(O.lmvg) to spray dried KF(1.3mvg). Inert polystyrene beadshave similarly been used to improve the reactivity of KF. 4Tetrabutylammonium fluoride(TBAF) is another well known and valuable source of fluorideion, and is soluble in a variety of common organic solvents. Unfortunately, however, its use issometimes limited by its physical properties. Thus the commercially available trihydrate isexceedingly hygroscopic and notably 'sticky', preventing it from being easily and rapidly handledduring weighing procedures. Resort to drybox conditions maybe necessary for quantitativeweighing or for maintaining high reactivity. Furthermore, the reagent has limited thermalstability and readily decomposes if reaction or drying conditions exceed 70-80 C. However,careful drying of the trihydrate under vacuum has been shown to give a highly reactive oil , usefulfor fluoro-denitration reaction. 5In this paper we wish to report our investigation on the use of some high-surface-area non-surface-hydroxylated support materials, such as Teflon and perfluorinated cation exchangepolymers, to enhance the reactivity and improve handling of KF and TBAF for fluorinationreactions.'Present address: Institute for Biofunctional Research, Suita, Osaka 565, Japan.**木村隆英,藤田光恵,安藤喬志: Department of Chemistry, Shiga University of Medical Sci-ence, Otsu, Shiga 520-21, Japan.-　7　-D.G. Cork・T. Kimura・M. Fujita・T. AndoEXPERIMENTALChromosorb T and Fluoropak 80(Teflon polymers) were obtained from Gasukuro Kogyo,Inc. , Japan and were dried at 80-C/O.lmmHg before use. Nafion cation-exchange powder andTBAF trihydrate were from Aldrich Chemicals Ltd. Nafion was converted to the potassium formby treatment with KOH-methanol before being dried at 80。C/O. lmm Hg. Activated charcoal(No.2186) was from Merck and was washed with ether several times before being dried at 60-C/20mmHg. Polystyrene beads, XAD2, were from Amberlite, and were dried at 50-C/0.lmmHgbefore use. Anhydrous methanol was obtained from Nacalai Tesque, Inc. , Japan. Potassiumfluoride was from Morita Kagaku Kogyo, Co. , Ltd. , Japan and was used untreated.KF-supported ReagentsThe supported reagents were prepared by adding the dry support(5-10g) to a solution of KFin methanol(20-30ml) , keeping the KF/support ratio at 2mmol/g, followed by rotary evaporationand drying at ca. 80-C/O.lmmHg.Reactions with solvent: Typically, KF-support(2mmolF-) was added to sulfolane (5-10ml) in around-bottomed flask. Tetradecane(30/*L) was added as an internal standard, a reflux con-denser fitted, and the mixture magnetically stirred while being heated to the reaction tempera-ture. After temperature had equilibrated benzyl bromide(115//L, l.Ommol) was added and themixture was kept efficiently stirred. Samples of reaction solvent were intermittently removed forGLC analysis.Reactions without solvent: When no solvent was used the reagent(2-3mmolF~) was rapidly addedto a glass ampoule containing benzyl bromide(45/*L, 0.4mmol). The ampoule was sealed andimmersed m an oil bath thermostatted at the required temperature. After the stated time theampoule was removed, cooled and cleaned before being placed in a screw-capped test tube with5ml of MeCN containing tetradecane(30 /*L). The ampoule was broken by shaking the test tube,the contents thoroughly mixed, and then the solvent was analyzed by GLC.TBAF-supported Reagen tsThe reagents were prepared by dissloving TBAF-3H2O (1.0g, 3mmol) in dry methanol (10-15ml)and then adding support(Fluoropak 80 or XAD2 (3. 0g) ). The mixture was evaporated to drynesson a rotary evaporator with a water bath at ca. 30 C. A further portion of dry methanol wasadded and the evaporation repeated. After continued drying of the reagent for 30min on therotary evaporator it was transferred to a drying pistol and further dried at 50 C under vacuum(O.lmmHg) for 24h or 48h. The resulting reagents(TBAF-FP80, TBAF-XAD2) were white,free-flowing granular powders.The water contents of the final reagents were measured by the Karl Fischer titration.Duplicate weighed samples were shaken for 30min in screw-capped test tubes with 5. Oral of dryMeCN. The water contents of the solvents were then compared with identical aliquots of MeCNshaken without added reagent. Samples of the TBAF-FP80 reagent dried for 24h at 0.1mmHg-　8　-Improved Fluorination with Supported Fluoride Reagents(reagent A) were found to have water contents corresponding to ca. 0. 3mol/molF- , whereas 48h drying gave reagent C, with no detectable water. A sample of reagent A was measured forwater after storage for several weeks in a screw-capped sample tube(which had been openedseveral times for removal of reagent) , this showed 1.3-1.4molH20/molF∴ A sample of TBAFimpregnated on polystyrene (TBAF-XAD2) showed no detectable water after 24h drying at 50。C/O.lmmHg.In a typical reaction TBAF-FP80 (0.63g, 0.5m皿olF-) was added to 2-chlor0-6-nitrobenzonitrile(0.046g, 0.25mmol) dissolved in solvent(5ml) containing tetradecane(30/*L) as an internal stan-dard. The mixture, in a screw-capped test tube, was shaken in a water bath at 20-C with aMini-vapor shaking apparatus. Small samples of the reaction solvent were rapidly withdrawnat intervals for GLC analysis. All reactions were run along side control experiments usingcommercial TBAFォ3H20.RESULTS AND DISCUSSIONThe activation of KF by dispersion on Teflon polymers(Fluoropak 80 0r Chromosorb T) , aperfluorinated ion-exchange resin(Nafion-K) or charcoal, was investigated using the fluorina-tion of benzyl bromide(reaction A) as shown in Table 1. When no solvent was employed thepre-supported KF-FP80 reagent was found to be superior to the simple mixture of KF and thesupport(runs 1 and 2) , or the use of other support materials. However, when reactions were runm sulfolane, KF-FP80 showed no activation as compared to the reported 36% yield in 2h usingKF alone. 2α The only reagent which did show increased fluorinating ability was KF-Nafion-K(run 4) , which gave 69% yield in 3h. The ionic sites on the surface of this ion-exchange resin mayenable KF to be dispersed more evenly than on the non-functionalized polymer surfaces. Alsoshown in Table 1 are some results for an aryl chloro-fluoro exchange reaction, but the KF-Nafionreagent was less effective than KF-FP80 for this(runs 10 and ll).Table 1. Fluonnation with KF-support reagentsrun reaenta reaction13　solven【 T/-C GLC(dme)cKF-FP8 02　KF+FP80eKF-ChT4　KF-NafionKKF- C6　　KトFP8 0KF-ChT8　KF-NafionKKF-C10 KF-NafionK1 1 KF-FP80none　116　32(3.5h)dnone　116　-(3.5h)dnone　116　2(3h)dnone　112　8(3h)none　120　21(3h)sulfolane 120sulfolane 115sulfolane 108sulfolane　80sulfolane 180sulfolane 18036( h16(2h), 61(24h)69(3h , 76(4h)23(16h8(45m), 13(3h), 19(7h)16(45m), 35(3h), 35(7h)fa) KF-FP80 - KF on Fluoropak 80, KF-ChT = KF on Chromosorb T, KFC・ KF on charcoal b) A - benzyl bromide to benzyl fluoride, B - 2,6-蝣dichlorobenzonitrile to 2-chlor0-6-fluorobenzonitrile c) compare forreaction A, sulfolane, 120 -C; KF (36%, 2 h), KF-CaF2 (92%, 2h), ref. 2ad) with up to 25% benzyl ether e) KF and Fluoropa上80 mixed inquantities as for run 1 f) with 4% 2,6-difluorobenzoni亡rile.-　9　-D.G. Cork・T. Kimura・M. Fujita・T. AndoThe efficiency of the KF dispersion was found to be rather variable when using the Teflonpolymers and some reagents showed low activity. During preparation it was important to keepthe support in the KF solution for as long as possible during rotary evaporation in order tomaximize salt dispersion on the support surface. It was noted that although the reagents werewell dried before use benzyl ether was formed as a byproduct in yields of up to 25% for reactionA, suggesting that some water was tenaciously held by the reagents. The use of solvent greatlyreduced this side reaction. The perfluorinated polymer supports have surface areas of 7-lOrrf/gand are thus comparable to CaF2. Charcoal has a much higher surface area than the othersupports but the results suggest that KF is not efficiently dispersed over the surface.The high cost of the Nafion resin does not make it appear to be a useful alternative to CaF2for activation of KF for fluorination, but the results help confirm that fluorinating abilityincreases with the effective surface area of the salt.Table 2 shows that the TBAF-FP80 (reagent A) gave enhanced reaction rate for heterogeneousfluorination in hydrocarbon solvent (xylene) compared to the commercial TBAF* 3H20 , althoughlittle difference in final conversion was observed(runs 1,2; 9,10; ll,12; 16,17). The moreextensively dried TBAF-FP80 (reagent C) showed decreased heterogeneous reactivity (run 3) andthe extremely dry TBAF-XAD2 was also less effective(run 4) , suggesting a trace of water isimportant for activation of fluoride. 6 During the course of these reactions a dark-colored immisci-ble phase was formed, presumably due to reaction byproducts, which appeared to limit the finalreaction yields to ca. 50% or less. In several cases acetonitrile was added to make the finalreaction mixture homogeneous, and then further analysis by GLC showed that rapid reactionresumed. Thus suggesting that although the TBAF was poisoned for heterogeneous reaction itwas not totally inactivated.Table 2. Fluorinations Comparing TBAF-FP80, TBAF-XAD2, alid TBAF-3H20substrate solvent reta T/-C productsGLC45 ,-(5m);5,-(5m);25,-(30m);1 0,-(30m);75,2(30m);rield/% (time)45 -(30m); 50,-(lh)43 -(30m); 50,-(lh)40,-(lh); 88,12(lh)b14,-(lh); 43,2(lh)1)80,2(lh)c??。?????????????xylene A　　20xylene B　　20xylene C　　20xylene D　　20THF　　　　　20MeCN C　　20MeCN B　　20MeCN D　　20トC8H17I xylene A　　50¥-CgHnl xylene B　　50碩'2xylenexylenexyleneMeCNMeCN褒cn (3-cnI-OrHi tF1-QHi tF自陣(S- -???????????????????????70,2(5m); 77,3(30m); 78,3(lh)c58,5(5m); 56,6(30m)52,3(5m); 52,3(30m)34(5m); 37(30m); 35(lh)b22(5m); 36(30m); 35(lh)b38,12(2h); 28,4(3h); 41,15(5h)"i18,2(3h); 26,4(5h); 39,30(5h)d12,l(30m); 30,4(3h)<128,2(4h); 31,2(7h); 47,7(llh)e40,13(4h); 41,14(7h); 10,9(1lh)ec¥ci;7,(;0-);25(m);8(90芸T,主57(90-)d5(90m)dCICla) A = TBAF-FP80 dried 24 h, B = commercial TBAF-3H20, C = TBAF-FP80 dried 48 h, D =TBAF-XAD2 dried 24 h b) with 32% ocト1-ene c) compare ref. 5, anhydrous TBAF, THF,room temp., 75,25(90 m) d) after addition of MeCN to make the reaction mixturehomogeneous e) after further reaction with a fresh batch of reagent at 7 h (ca. 0.5 mmol F-).-10-Improved Fluorination with Supported Fluoride ReagentsFor homogeneous fluorination in THF or MeCN, the TBAF-FP80 reagents were again moreeffective than TBAF-XAD2 0r the commercial trihydrate for fluoro-denitration of 2-chlor0-6-nitrobenzonitrile (runs 5-8). The reaction was more selective with the "anhydrous" TBAF-FP80 than with the previously reported "anhydrous" TBAF oil5 (runs 5, 6). The fluorination of2 , 6-dichlorobenzonitrile to give 2-chlor0-6-fluorobenzonitrile was also achieved with improved・selectivity using TBAF-FP80, although at a slower rate (runs 14 , 15).Our results indicate that the simple impregnation of TBAF'3H2O on to a high-surface-areainert Teflon polymer(7-10m7g) enables it to be efficiently dried and handled as a freeflowingpowder. The increased surface area of the reagent leads to faster reaction for heterogeneousfluorination, especially when a trace of water remains, but byproduct poisoning of the reagentlimits the extent of reaction. We believe that the advantages of improved reaction rate as wellas handling and drying make the TBAF-FP80 reagent useful. Furthermore, the Teflon polymercan easily be removed from the reaction for reuse or used in the form of a column.REFERENCES1. N.Ishikawa, T.Kitazume, T.Yamazaki, Y.Mochida, and T.Tatsuno, Chem.Lett. ,7611981).2. a) J.H.Clark, A.J.Hyde, and D.K.Smith, J.Chem.Soc., Chem.Commun., 791(1986);b) J.Ichihara, T.Matsuo, T.Hanafusa, and T.Ando, J.Chem.Soc. , Chem.Commun.,793(1986).3. T.Ando, D.G.Cork, M.Fujita, T.Kimura, and T.Tatsuno, Chem.Lett. , 1877(1988).4. H.Liu, P.Wang, and P.Sun, J.Fluorine Chem., 43, 429,(1989).5. J.H.Clark and D.K.Smith, Tetrahedron Lett., 2233(1985).6. S.Dermeik and Y.Sasson, J.Org.Chem., 50, 879(1985).- ilil -

Improved fluorination with supported fluoride reagents

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シュシュ ノ フッカブツ タンジ シヤク ニ ヨル フッソカ

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