Tetra-n-butylammonium Fluoride1

n-Bu4NF
(TBAF)

[429-41-4]  · C16H36FN  · Tetra-n-butylammonium Fluoride  · (MW 261.53) (TBAF.3H2O)

[87749-50-6]  · C16H42FNO3  · Tetra-n-butylammonium Fluoride  · (MW 315.59) (TBAF.xH2O)

[22206-57-1]

(can be used for most fluoride-assisted reactions; deprotection of silyl groups;1e desilylation;2,3 fluorination;4 used as a base5,6)

Alternate Name: TBAF.

Physical Data: TBAF.xH2O: mp 62-63 °C.

Solubility: sol H2O, THF, MeCN.

Form Supplied in: trihydrate, 1.0 M solution in THF, and 75 wt % solution in water.

Preparative Method: aqueous Hydrofluoric Acid is passed through an Amberlite IRA 410 OH column, followed by an aqueous solution of Tetra-n-butylammonium Bromide. After the resin is washed with water, the combined water fractions are repeatedly evaporated until no water is present. Tetrabutylammonium fluoride is collected as an oil in quantitative yield.

Handling, Storage, and Precautions: use in a fume hood.

Deprotection of Silyl Groups.

Tetrabutylammonium fluoride has been used widely as a reagent for the efficient cleavage of various silyl protecting groups such as O-silyls of nucleosides,7,8 pyrophosphate,9 N-silyls,10,11 CO2-silyl, and S-silyl derivatives.1e These reactions are often carried out under very mild conditions in excellent yields. Thus it has been used in the synthesis of base-sensitive chlorohydrins (eq 1)12 and b-lactams.10,13 2-(Trimethylsilyl)ethoxymethyl groups can also be effectively removed from various substrates (eq 2).14-18 Silyl ethers can be converted to esters in one pot when they are treated with TBAF, followed by exposure to acyl chlorides19,20 or anhydride21 in the presence of base (eq 3). Treatment of triisopropylsilyl enol ethers with Iodosylbenzene/Azidotrimethylsilane, followed by desilylation and elimination with TBAF, gives good yields of the a,b-unsaturated ketones (eq 4).22,23

Cyclobutanone alkyl silyl acetals, obtained from [2 + 2] cycloadditions, can be deprotected with 1 equiv of TBAF in THF to give the open-chain cyano esters in excellent yields (eq 5).24 When 4-chloro-2-cyanocyclobutane alkyl silyl acetals are used as substrates for this reaction, (E/Z) mixtures of 2-cyanocyclopropanecarboxylates are obtained by an intramolecular cyclization (eq 6).

11-Membered pyrrolizidine dilactones have been synthesized by treating a trimethylsilylethyl ester with TBAF in MeCN to form an anion, which then undergoes cyclization by displacement of the mesylate.

Desilylation Reagent.

Cleavage of carbon-silicon bonds with fluoride has been studied very extensively. TBAF is a very powerful reagent for desilylation of a wide range of silicon-containing compounds, such as vinylsilanes,2,25,26 alkynylsilanes,23,27 arylsilanes,28,29 acylsilanes,30 b-silyl sulfones,31-33 and other silane derivatives.3,34-37 It appears that cleavage of sp-C-Si bonds is more facile than that of sp2-C-Si and sp3-C-Si bonds and that substituted groups, such as phenyl and alkoxyl, can often facilitate cleavage. A dimethylphenylsilyl group can be removed from a vinyl carbon by TBAF with retention of the alkene stereochemistry (eq 7).2 This method has been applied to the synthesis of terminal conjugated trienes (eqs 8 and 9).38 The five-membered siloxanes can be desilylated with 3 equiv of TBAF in DMF and this protodesilylation is very sensitive to subtle structure changes (eq 10).39

The anions, generated in situ by desilylation of silylacetylenes,40,41 allylsilanes,42-44 propargylsilanes,45 a-silyloxetanones,46 bis(trimethylsilylmethyl) sulfides,47 and other silane derivatives,48-51 can undergo nucleophilic addition to ketones and aldehydes (eq 11).52 N-(C,C-bis(trimethylsilyl)methyl) amido derivatives can add to aldehydes followed by Peterson alkenation to form acyl enamines.48,53 Treatment of 2-trimethylsilyl-1,3-dithianes can generate dithianyl anions, which are capable of carbocyclization via direct addition to carbonyl or Michael addition (eq 12). The fluoride-catalyzed Michael additions are more general than Lewis acid-catalyzed reactions and proceed well even for those compounds with enolizable protons and/or severe steric hindrance (eq 13).54,55

Direct fluoride-induced trifluoromethylation of a-keto esters (eq 14),56 ketones,57 aldehydes,58,59 and sulfoxides59 have been reported using Trifluoromethyltrimethylsilane with TBAF in THF.

Desilylation of some compounds can generate very reactive species such as benzynes,60 pyridynes,61 xylylenes,62,63 and benzofuran-2,3-xylylenes.64 1,4-Elimination of o-(a-trimethylsilylalkyl)benzyltrimethylammonium halides with TBAF in acetonitrile generates o-xylylenes, which undergo intermolecular and intramolecular cycloadditions (eq 15).62-64 Treatment of a-silyl disulfides with Cesium Fluoride or TBAF forms thioaldehydes, which have been trapped by cycloaddition with cyclopentadiene (eq 16).65

Use as a Base.

TBAF has been widely used for a variety of base-catalyzed reactions such as alkylation,66 elimination,67 halogenation,68 Michael addition,69-71 aldol condensation, and intramolecular cyclizations.5,72-74 It is especially useful when other inorganic bases face solubility problems in organic solvents. The reactions are usually carried out below 100 °C due to the low thermal stability of TBAF.1e

TBAF is very useful for alkylation of nucleic acid derivatives. Methylation75 or benzylation66 of uracil gives almost quantitative yields of alkylated product when using alkyl bromides, dialkyl sulfates (eq 17), trialkyl phosphates, or alkyl chlorides with TBAF. Alkylation of the thiol anions generated from deprotection by 1,2-dibromoethane produces interesting tetrachalcogenofulvalenes.14 Under phase-transfer conditions, selective mono- and dialkylations of malononitrile have been achieved by using neat TBAF with Potassium Carbonate or Potassium t-Butoxide and controlling the amount of alkyl bromides or iodides used (eqs 18 and 19).76

Enol silyl ethers react with aldehydes with a catalytic amount of TBAF to give the aldol silyl ethers in good yields. These reactions generally proceed under very mild conditions and within shorter periods of time than conventional strong acidic or basic conditions. The products from 4-t-butyl-1-methyl-2-(trimethylsilyloxy)cyclohexene and benzaldehyde show very good axial selectivity and a little anti-syn selectivity (eq 20).77 The aldol condensation of ketones and aldehydes can be achieved in one pot when ethyl (trimethylsilyl)acetate is used as a silylation agent with TBAF (eq 21).

Silyl nitronates undergo aldol condensation with aldehydes in the presence of a catalytic amount of anhydrous TBAF to form highly diastereoselective erythro products, which can be elaborated to give synthetically useful 1,2-amino alcohols (eq 22).6,78 A one-pot procedure has been developed for direct aldol condensation of nitroalkanes with aldehydes by using TBAF trihydrate with Triethylamine and t-Butyldimethylchlorosilane.79 It appears that silyl nitronates are not reactive intermediates in this case, and the reactions proceed by a different mechanism.

Miscellaneous.

Fluoride ion from anhydrous TBAF undergoes nucleophilic displacement of tosylates,4,80 halides,80 and aryl nitro compounds81 to give fluorinated products. When used with N-Bromosuccinimide, bromofluorination products are obtained.82

Several important peptide-protecting groups such as 9-fluorenylmethyloxycarbonyl,83 benzyl,84 4-nitrobenzyl,85 2,2,2-trichloroethyl,85 and acetonyl (eq 23)86 can be removed by TBAF under mild conditions.


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Hui-Yin Li

Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA



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