1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate)

[140681-55-6]  · C7H14B2ClF9N2  · 1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate)  · (MW 354.26)

(easily handled, cost-effective, site-selective electrophilic fluorinating agent applicable to a wide variety of organic substrates possessing overt or masked carbanionic character1-4)

Alternate Names: F-TEDA-BF4; Selectfluor™.

Physical Data: apparent mp 190 °C (thermal behavior is complicated; exothermic decomposition can occur at temperatures >80 °C); d 1.731 g cm-3.

Solubility: v sol cold H2O (176 g L-1 at 20 °C), dil HCl (decomposed by dil NaOH); sol MeCN; sl sol MeOH, EtOH, Me2CO; sol DMF (reacts slowly on heating), pyridine (reacts), and DMSO (reacts rapidly and exothermically).

Form Supplied in: free-flowing, virtually nonhygroscopic, white solid. Available commercially.

Analysis of Reagent Purity: NMR (1H, 19F; soln. in D2O);1 iodimetric titration [acidified (HCl) soln. in H2O-Me2CO (1:1) + excess KI; I2 determined with thiosulfate/starch (1 I2 &ident; 1 +NF)]. Note that the reagent (known as F-TEDA-BF4;3 TEDA = triethylenediamine) oxidizes aqueous bromide ion to bromine at rt but not chloride to chlorine.5

Handling, Storage, and Precautions: store below 38 °C (lower temperatures are advisable for bulk storage); use in solution or suspension; do not heat the solid reagent above 80 °C. Take standard precautions to avoid breathing dust or vapors (evolved during reaction), contact with eyes or skin (dust or its solutions), and contamination of clothing. F-TEDA-BF4 is moderately toxic (male rat oral LD50 640 mg kg-1; female rat 350-500 mg kg-1), and is an irritant to the eye and respiratory system. Always use approved dust mask (or respirator), gloves, and safety glasses when handling the solid. Carry out solubility tests on a sensible scale when seeking alternative solvents (note the problem with DMSO referred to above). An MSDS (Material Safety Data Sheet) and further information is available from Air Products and Chemicals, Inc., Speciality Gases Dept., 7201 Hamilton Boulevard, Allentown, PA 18195-1501, USA.

Fluorination of Stabilized Carbanions.

Highly stabilized carbanions [e.g. alkali metal salts of substituted malonates (eq 1), phosphonates (eq 2)] react rapidly and efficiently with this reagent.2-4 Only low yields (<20%) of a-fluoro ketones can be obtained from highly reactive ketone-derived metal enolates; this drawback can be overcome by using enol acetate or silyl enol ether derivatives of ketones as substrates (see below).3

Fluorination of Enols, Enol Acetates, Silyl Enol Ethers, and Enamines.

Numerous enolizable substrates of the 1,3-dicarbonyl class (RCOCH2COR´) have been monofluorinated efficiently under mild conditions with an equimolar proportion of F-TEDA-BF4 (e.g. eqs 3-6); difluorination can be achieved (e.g. eq 6; yields here estimated by NMR), but efficient introduction of the second fluorine may require a two-step procedure (depending on the equilibrium enol content of the monofluoride) (eq 7).4

F-TEDA-BF4 is highly effective for introducing fluorine selectively at positions 6 or 16 in steroids via attack on enol acetate or silyl enol ether derivatives.2,3 High yields of 16-fluoro targets can be achieved with excellent stereoselectivity (e.g. eq 8). Fluorination at position 6 (e.g. eq 9) proceeds cleanly and more rapidly (typically, reactions are complete within 15 min at rt in MeCN).

Fluorination of the prototypical enamine 1-morpholinocyclohex-1-ene with a suspension of the 1,1,1-trifluoroethyl analog of F-TEDA-BF4, CF3CH2+N(CH2CH2)3+NF (CF3SO3-)2,1 in CH2Cl2 at 20 °C gives 2-fluorocyclohexanone in 81% yield.2 [Note that within the Selectfluor range of 1-alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane salts, ease of F+ transfer increases as the electronegativity of the 1-alkyl group increases (CF3CH2 > CH2Cl > CH3).1] Fluorination of enamines of D4- or D1,4-3-keto steroids with F-TEDA-BF4 is said to produce a mixture of 4-fluoro and 6-fluoro products.3

Fluorination of Alkenes.

Alkenes capable of producing highly stabilized carbocations through notional addition of F+ (e.g. styrene, a-methylstyrene, trans-stilbene, 1-phenylcyclohexene) react smoothly with F-TEDA-BF4 at room temperature in the presence of weak nucleophiles (e.g. H2O, MeOH, AcOH, HF-pyridine) (e.g. eq 10).3

Fluorination of Aromatic Compounds.

Benzene resists attack by F-TEDA-BF4 under normal conditions. The introduction of electron-releasing (+I, +M) ring substituents facilitates fluorination (e.g. eqs 11-13).1,2,3,6

Organosulfur Compounds.

The first step in the sequence RSCH2R1 -> R+S(F)CH2R1 -> RSCHFR1 -> RS(O)xCHFR´ (x = 1, 2) can be effected smoothly with F-TEDA-BF4, the Pummerer-like rearrangement of the fluorosulfonium salt (not isolated) being effected with a nitrogenous base (Triethylamine or 1,8-Diazabicyclo[5.4.0]undec-7-ene) (e.g. eqs 14-16).3

Fluorination of Carbon-Metal Bonds.

Grignard reagents react slowly with suspensions of F-TEDA-BF4 in dry diethyl ether or THF at rt to provide the corresponding monofluorides (eqs 17 and 18).3

The availability of F-TEDA-BF4 has at last made possible the synthesis of 5-fluorocyclopentadiene, the fugitive nature of which requires it to be trapped in situ (eq 19).7 Treatment of Thallium(I) Cyclopentadienide with positive halogen sources such as NBS and NCS is a known route to other 5-halogenocyclopentadienes.

Electrophilic fluorination of vinylstannanes with F-TEDA-BF4 provides easy access to fluoroalkenes carrying a variety of functional groups (e.g. eqs 20 and 21).8

Fluorination of Quinuclidine.

Quantitative transfer of F+ occurs from F-TEDA-BF4 to quinuclidine at rt in acetonitrile (eq 22).9 This method provides easy access to N-fluoroquinuclidinium tetrafluoroborate (NFQNBF4), one of a family of N-fluoroammonium salts (fluoride,10 triflate,11 tetrafluoroborate,11 perfluoroalkanecarboxylate11) originally developed in response to worldwide demand for more generally acceptable (less aggressive, nonexplosive, less toxic, inexpensive) site-selective electrophilic fluorinating agents than Perchloryl Fluoride, O-F reagents (e.g. Trifluoromethyl Hypofluorite, Cesium Fluoroxysulfate), Xenon(II) Fluoride, and Fluorine itself.12

F-TEDA salts arose out of research aimed at the development of a similar yet more powerful family of N-fluoroammonium salts than NFQN salts; tunable fluorinating ability and considerably greater commercial prospects were also targets. [Fluorinating power can be adjusted via the electronegativity of the quaternizing alkyl group (see earlier).2] In-house synthesis of both NFQN and F-TEDA salts is an unwelcome prospect in many laboratories since fluorine is required;1,10,11 the commercial availability of F-TEDA-BF4 has resolved this major problem, making possible renewed interest in NFQN salts.

At present, not enough information is available to provide a proper appraisal of advantages to be gained by using an NFQN salt rather than its F-TEDA analog; given the current relative costs and availability of quinuclidine and TEDA, F-TEDA-BF4 will normally be preferred. Limited data indicate that highly basic carbanions give better yields of C-F products with NFQN salts than with F-TEDA salts.

Some Comparisons.

Electrochemical measurements (reduction potentials),5 supported by practical experience, indicate the following order of fluorinating power for N-fluoro reagents: (CF3SO2)2NF, ClCH2+N(CH2CH2)3+NF (BF4-)2 (F-TEDA-BF4; A), Me+N(CH2CH2)3+NF (TfO-)2, HC(CH2CH2)3+NF TfO-, pyF+ TfO- (A), (PhSO2)2NF (A), p-MeC6H4SO2NFMe (A) (TfO- = CF3SO3-; A = available commercially). The electrophilic fluorination power of F-TEDA-BF4 falls not far short of that of the powerful so-called DesMarteau N-F reagent,13 N-fluoro[bis(trifluoromethyl)sulfonyl]imide, (CF3SO2)2NF, the only liquid in this group (bp 90-91 °C). This reagent is not available commercially, and its preparation entails a costly multistep synthesis terminating in a direct fluorination procedure [(CF3SO2)2NH + F2 -> (CF3SO2)2NF + HF] requiring considerable expertise and special equipment.14 Not all power-variable Meinert-Umemoto15 N-fluoropyridinium salts (e.g. N-Fluoropyridinium Triflate) are available commercially, and sensitivity to attack by moisture or bases can be a drawback.16 N-Fluorobenzenesulfonimide, (PhSO2)2NF (Differding's reagent),17 and N-fluoro-N-alkylarenesulfonamides (Barnette reagents),18 developed for the fluorination of carbanions, seem too unreactive to be viewed as general-purpose reagents.

Overall, F-TEDA-BF4 is probably the best general-purpose electrophilic fluorinating agent available at the time of writing: it fluorinates a wide variety of electron-rich carbon centers rapidly under mild conditions with high efficiency and selectivity, and no special apparatus or handling techniques are required. Soluble in a number of useful reaction solvents (including aqueous systems), F-TEDA-BF4 is compatible with common reactor materials and offers the additional advantage of being degradable into manageable waste products.19 A most welcome alternative to the use of highly toxic and potentially explosive electrophilic fluorinating agents such as F2, FClO3, and CF3OF, F-TEDA-BF4 was already in commercial use just four years after its design and synthesis by Banks and Sharif.2,19


1. Banks, R. E.; U.S. Patent 5 086 178, 1992.
2. Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. CC 1992, 595.
3. Lal, G. S. JOC 1993, 58, 2791.
4. Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. CC 1994, 343.
5. Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lal, G. S. JFC 1992, 59, 157.
6. Banks, R. E.; Sharif, I. in preparation.
7. McClinton, M. A.; Sik, V. JCS(P1) 1992, 1891.
8. Matthews, D. P.; Miller, S. C.; Jarvi, E. T.; Sabol, J. S.; McCarthy, J. R. TL 1993, 34, 3057.
9. Abdul-Ghani, M; Banks, R. E.; Besheesh, M. K.; Sharif, I; Syvret, R. G. JFC 1995, in press.
10. Banks, R. E.; Du Boisson, R. A.; Morton, W. D.; Tsiliopoulos, E. JCS(P1) 1988, 2805.
11. Banks, R. E.; Sharif, I. JFC 1991, 55, 207.
12. For recent reviews of electrophilic fluorination, see New Fluorinating Agents in Organic Synthesis; German, L.; Zemskov, S. Eds.; Springer: Berlin, 1989; and Purrington, S. T.; Kagen, B. S.; Patrick, T. B. CRV 1986, 86, 997.
13. See, for example, Xu, Z.-Q.; DesMarteau, D. D.; Gotoh, Y. JFC 1992, 58, 71 and references cited therein.
14. DesMarteau, D. D.; Witz, M. JFC 1991, 52, 7.
15. (a) Meinert, H.; Cech, D. ZC 1972, 12, 292. (b) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. JACS 1990, 112, 8563.
16. Umemoto, T.; Harasawa, K.; Tomizawa, G.; Kawada, K.; Tomita, K. BCJ 1991, 64, 1081.
17. (a) Differding, E.; Ofner, H. SL 1991, 187. (b) Differding, E.; Duthaler, R. O.; Krieger, A.; Rüegg, G. M.; Schmit, C. SL 1991, 395.
18. (a) Barnette, W. E. JACS 1984, 106, 452. (b) Lee, S. H.; Schwartz, J. JACS 1986, 108, 2445.
19. Chem. Eng. News 1993, 71 (36), 29.

R. Eric Banks & Vincent Murtagh

University of Manchester Institute of Science and Technology, UK



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