Acta Chim. Slov. 2005, 52, 13–26 13 Review Article Selectfluor™ F-TEDA-BF4 as a Versatile Mediator or Catalyst in Organic Chemistry Stojan Stavber"* and Marko Zupan"6 " »Jožef Štefan« Institute, Jamova 39, 1000 Ljubljana, Slovenia, E-mail: stojan.stavber@ijs.si b Department of Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia Received 22-02-2005 Abstract Selectfluor™ F-TEDA-BF4 1 (l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetra-fluoroborate)) is not only one of the most valuable reagents for electrophilic fluorination but also a versatile mediator or catalvst for various other functionalisations of organic compounds. Its application for selective and effective iodination, bromination, chlorination, nitration and thiocyanation of a comprehensive range of organic compound is revievved. Benzylic functionalisation of hexamethylbenzene mediated with F-TEDA-BF4 in the presence of various sources of nucleophiles is described and a method for the synthesis of /?ara-quinols or/?ara-quinol ethers emphasised. F-TEDA-BF4 is also useful for the promotion of allylstannation of aldehydes and imines, cleavage of/?-methoxy-benzylidene (PMP), tetrahydropyranyl (THP) or 1,3-dithiane protection, and rearrangements of bicyclic iodides, as well as for catalysis of the regioselective ring opening of epoxides or [4+2] cycloaddition reactions betvveen imines and cyclic enol ethers. Key words: Selectfluor™ F-TEDA-BF4, iodination, bromination, hexametylbenzene, allylstannation, deprotection Contents INTRODUCTION ....................................................................................................13 FUNCTIONALISATION OF ORGANIC COMPOUNDS IN THE PRESENCE OF F-TEDA-BF4..................................................................................15 Oxidation of primary alcohols .............................................................................15 Oxidation of some phenols ..................................................................................15 Iodination of arenas..............................................................................................16 Iodination of ketones............................................................................................18 Bromination of unsaturated carbon-carbon bonds ...............................................19 Other types of oxidative functionalisation of arenas............................................20 Functionalisation at a benzylic carbon atom........................................................21 Allylation of aldehydes and imines......................................................................24 Cleavage of p-methoxybenzylidene (PMP), tetrahydropyranyl (THP) and 1,3-dithiane protecting groups.......................................................................24 Rearrangements of bicvclic iodides .....................................................................24 Regioselective ring opening of epoxides .............................................................24 Cycloaddition reactions........................................................................................25 CONCLUSIONS AND PERSPECTIVES................................................................25 REFERENCES .........................................................................................................25 Introduction Selective fluorination of organic compounds under mild reaction conditions through an electrophilic reac-tion process is one of the most important strategies for accomlishing this task of wide interest to the basic and applied research community.1–6 The group of chemicals enabling this type of fluorofunctionalisation are usually called electrophilic fluorinating reagents. Indicating the type of reactive bond through which an active fluorine atom is connected with the ligand part of a reagent, the group consists of three main families of reagents: xenon fluorides,1 fluoroxy reagents,6 and N-F reagents. One of the most important breakthroughs in modern organofluorine chemistrv was accomplished in the late eighties of the last century by the scientific introduction and quickly following broad svnthetic application of organic molecules incorporating a reactive N-F bond Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 14 Acta Chim. Slov. 2005, 52, 13–26 CH2CI N + F (BF4")2 1 l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) Selectfluor™ F-TEDA-BF4 as mild fluorinating reagents.912 N-F reagents have practically revolutionised the common perception of selective synthesis of fluorinated organic compounds, which is no longer limited to specialised laboratories with sophisticated equipment and specially trained staff complying with strict safety precautions, but is an ordinary experimental protocol, convenient for routine work in any organic chemistry laboratory. These eas-ily-handled “bench-top” materials, usually with optimal stability/reactivity characteristics and reasonable cost, are divided into three main groups: neutral N-fluoro amines (R1R2NF), N-fluoropyridinium and related salts, and quaternary N-F salts ( F-N+RJR2R3Y). The most widely used members of the last group are N-fluoro derivatives of l,4-diazabicyclo[2.2.2]octane and 1-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1, known under the trade name Selectfluor™ F-TEDA-BF4 the most representative in the series. Since its invention13 and introduction in the scien-tific literature,14 Selectfluor™ F-TEDA-BF4 quickly be-came one of the most popular reagents for electrophilic fluorofunctionalization of organic compounds,1518 used as an ordinary bench-top material in research laboratories, as well as a multi-ton scale produced chemical for several industrial applications.19 Some basic characteristics of F-TEDA-BF4 are collected in Table 1. The material is a white solid decom-posing at its melting point or lower, having complicated thermal behaviour. The compound is soluble, or at least moderateh/ soluble, in acetonitrile, slightly soluble in methanol and acetone, insoluble in dichloromethane and very soluble in water. The stability of F-TEDA-BF4 in water and some organic solvents has been studied.20 It was established that its neutral or acidic water solutions are stable, while its fast decomposition takes plače in alkaline water solutions. F-TEDA-BF4 decomposes in DMSO (rapidly and exothermically) and DMF (slowly on heating), but is stable in acetonitrile or methanol solutions. Acetonitrile and methanol are thus accepted as the most convenient solvents for its reactions with organic compounds, while until very recenth/,21 the corresponding chemistry in aqueous media was almost neglected. Table 1. Some characteristics of F-TEDA-BF4 (1). Characteristic Data Molecular formula C7Hi4B2ClF9N2 Molecular weight (g/mol) 354.26 Active fluorine (g/kg N-F) 53.6 (mmol /g N-F) 2.82 Melting point 170 oC (dec.) NMR data (solvent): D20; 19F (? in ppm from CCl3F) 43.5, -152.0; 1H (? in ppm from TMS) 4.5, 5.0, 5.5 Solubilitya) : MeCN s. MeOH s.s Me2CO s.s. CH2C12 is. H20 s. E1/2 (V, SCE) 0.33 Commercial availability Yes " more than 0.05 g/L: soluble (s); 0.01g/L-0.05g/L: moderately soluble (m.s.); less than O.Olg/L: slightly soluble (s.s.); insoluble (is.). A very important characteristic of F-TEDA-BF4, which considerably affects its convenience as a reagent for various transformations of organic compounds, is its oxidative power. As evident from Table 1 its half-wave potential (E1/2)22 characterises it as strong oxidant, one of the strongest in the series of N-F reagents.23 Selec- Biographical Sketches Marko Zupan (left), boni in Ljubljana in 1947, completed his PhD in organic chemistry (mentor Alfred Pollak) in 1974. Since 1970 he has been a member of University of Ljubljana and in 1987 has been nominated as Professor of Organic Chemistry at the Faculty of Chemistry and Chemical Technology. Since 1972 he has been an associate member of the Jožef Štefan Institute, and Scientific Adviser there since 1987. Stojan Stavber (right) was born in Maribor in 1951 and completed his PhD in 1987 (mentor Marko Zupan). As the undergraduate študent he has joined Zupan’s group at Jožef Štefan Institute in 1974, has been nominated as Scientific Adviser there in 2000 and actually as Head of Department for Physical and Organic Chemistry. The scientific work of Zupan and Stavber published in more than 200 original scientific articles is dealing mainly with organohalogene chemistry, especially organofluorine chemistry, the photochemistry of fluoro-organic molecules and polymer-supported reagents. The chemistry of Zupan-Stavber group has been awarded by the Republic of Slovenia with B. Kidrič Fund Award for Important Discoveries on Fluorination of Organic Molecules (1981), B.Kidrič Fund Awards for Patent and Innovations (1983, 1985, 1987), and Zois Award for research excellence in the field of Organic Chemistry (2000). Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 15 fluor™ F-TEDA-BF4 is thus one of the most powerful electrophilic fluorinating reagent from the N-F farnih/ and a potential multipurpose chemical suitable for me-diation of other functionalisations or transformations of organic compounds. The literature data concerning its use as a fluorinating reagent have been comprehen-sively documented during the last decade,9"12'15-18 while a review of its applications as a reagent or catalyst for “other-than-fluorine” functionalisation of organic compounds is the subject of the present account. Functalisation of Organic Compounds in the Presence of F-TEDA-BF4 Oxidation of primary alcohols The hydroxy functional group is an oxidisable structural moiety ordinarily sensitive to the presence of chemicals having a certain oxidising power. Reac-tions of benzylic alcohols with F-TEDA-BF4 were studied and their oxidation to benzaldehyde derivatives established.24 Reactions in acetonitrile were found, at least for derivatives bearing a deactivated aromatic ring, to be relatively slow (Table 2) and have limited synthetic importance, but nevertheless the protection of this functional moiety is required when 1 is used for fluorination of organic molecules bearing a benzylic hydroxy group. Aliphatic primary alcohols are also readily oxidised to corresponding aldehydes by 1 in MeCN.25 Table 2. Reaction of benzylic alcohols 2 with Selectfluor™ F-TEDA-BF4 (1). OH O OH R 1, MeCN, refl. R H _ Time (h) Yield (%) H 18 43 4-N02 65 62 2-NO2 435 56 2-C1 45 42 4-C1 15 37 Oxidation of some phenols Reactions of phenols with F-TEDA-BF4 were extensively studied. These derivatives, substituted by an additional hydroxy substituent on ortho 4 or para 6 position, were readily oxidized to the corresponding quinones 5 or 7 (Scheme 1) by 1 in MeCN.25 The course of reactions of l,3,5-trialkyl substituted phenols 8 (Scheme 2) with 1 were found to be considerably dependent on the structure of the target substrates and the solvent used.26 The reaction of 8 in pure acetonitrile gave fluorinated products while in the OH 1, MeCN OH OH 6 1, MeCN O 7 a: R = H b: R = Bu' c: 1,4-naphthalenedione Scheme 1 OH Buk Jk, „Bu' O Bu' 9a: R1 = H 9b:Rl = Me 11 10 CH2NHCOMe Scheme 2 presence of alcohols or water para quinols 9a or para quinol ethers 9b were formed. However, the presence of more acidic nucleophile-like trifluoroacetic acid (TFA) caused quite different transformations of the target phenols. The reaction of 8a with 1 in MeCN/TFA 9:1 solvent mixture resulted in the formation of 2,6-di-tert-butyl-4-methylacetamidophenol 10 as the main product (70%), accompanied by small amounts of ring and side chain trifluoroacetoxy and/or acetamido substituted phenols. The similar reaction of 2,4,6-tri-tert-butyl-phenol 8b gave 2-methyl-5,7-di-tert-butylbenzoxazole 11 as the main product (65%), accompanied by small amounts of 2- and 4-acetamido derivatives of di-tert-butylphenol, 2,6-di-tert-butylquinone, various isomers of trifluoroacetoxy-substituted derivatives and N-tert-butylacetamide. It is obvious that, under these condi-tions, the reaction intermediates reacted with MeCN o o 4 5 O R R R R O 2 3 R . R Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 16 Acta Chim. Slov. 2005, 52, 13–26 OH Buk /-k -Buf © R 12 -H R = Bu' Buk /k -Bu' O R = Me -H OH Buk JL _Bu' Y •CH2 OH ©CH2 Bu' O Buk A ,Bu' l + )\ TFA MeCN e Me N Bu' Bu' TFA MeCN -Bu' OH Buk Jk -Buf o Bu' 10 CH2NHCOMe Me 11 Bu' Scheme 3 following a Ritter-type reaction as the main process, instead of being quenched with TFA as an external nucleophile. The reaction rates were shown to obey simple second-order kinetics and the values of the second-order rate constants (k2) were found to be dependent on the structure of the target phenol and decreased with the bulkiness of the substrate.26 Methanol slightly increased the rate, while water decreased it consider-ably. Activation enthalpies (betvveen 72 and 78 kJmor"1) and activation entropies (betvveen -5 to -42 Jmol_1K_1) were obtained. Activation entropies were found to be higher for less hindered substrates, indicating that the rate-determining steps were mainly regulated by steric factors. An electron transfer-type process thus forming cation-radical species 12 as the key intermediates, which were further transformed to products 9, 10 or 11, was postulated as the reaction pathway (Scheme 3). A method for efficient synthesis of various types of />ara-quinols or/>ara-quinol ethers was developed27 on the basis of the above mentioned investigations and the corresponding results are collected in Table 3. Table 3. Synthesis of para-quinols and para-quinol ethers medi-ated by F-TEDA-BF4 (l).27 OH O Rk /k ^ Rk A .R1 R2 MeCN/ R4oH(9/1) 30 °C; 3-6 h R^O R2 Phenol R4 Product Yield (%) Bu'. OH h Bu' OH Bu' Bu' Bu' Me OH Me. Me Me H Me Et Pr HOC2H4 H Me Et HOC2H4 MeOC2H4 H Me Et CF3CH2 HOC2H4 MeOC2H4 Bu' Bu' R^O Bu' Bu' Bu' R^O Me Me Me R^O Me 19 79 75 77 79 78 82 75 81 78 76 85 82 38 76 79 Iodination of arenes Iodo substituted aromatic molecules have been recognised for a long tirne as valuable synthetic tools, above ali in carbon-carbon bond formation, mainly through metal catalysed coupling reactions. In addi-tion, many iodinated aromatic derivatives are used in medicine as drugs or diagnostic aids, contrasting agents, and radioactively labelled markers. The chemistry dealing with selective iodination of arenes has thus at-tracted broad interest in the wider scientific community. Electrophilic iodination using a variety of electrophilic iodine species has been accepted as the most convenient general synthetic approach. Elemental iodine should be certainly the most convenient iodination reagent for this task but a certain activation in order to increase its weak electrophilicity is typically necessary. Hydrogen iodide, liberated during iodo the substitution process, ordinary interferes with the selectivity and efficiency of these reactions, while one iodine atom is lost in this čase for iodofunctionalisation of the target compound. The activation of electrophilicity of elemental iodine could be achieved by polarisation of the I-I bond or by oxida-tive formation of I+ species and it was first demonstrated in our laboratory that Selectfluor™ F-TEDA-BF4 is an appropriate mediator for this task. As shown in Scheme 4 room temperature re-gioselective iodination of aromatic ethers 13 could be efficiently performed using the I2 / F-TEDA-BF4 tandem.28 Only a half-equivalent of I2 and 1 was nec-essary for conversion of the starting material into the O R - e O O - e o Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 17 Table 4. Iodination of methyl-substituted benzenes 16 mediated by F-TEDA - BF4 (l).29 F-TEDA-BF4 (1) l2, MeCN,T = 55-65°C 16 17 Methyl benzene 16 Reaction conditions 16 : I2: 1 Reaction tirne (h) 1 : 0.6 : 0.6 3 1:5:5 24 1 : 1.5 : 1.5 5 1:5:5 24 1 : 0.6 : 0.6 1 1 : 1.1 : 1.1 3 1:3:3 24 1 : 0.75 : 0.75 1.5 1:4:4 24 1 : 0.6 : 0.6 1.5 1:4:4 24 1 : 0.75 : 0.75 1.5 1:2:2 2.5 1 : 0.75 : 0.75 1 1:2:2 2.5 1 : 0.75 : 0.75 1 1:2:2 2.5 Iodo methylbenzene (17) Yield (%) l-iodo-2,4-dimethylbenzene l,3,5-triiodo-2,4-dimethylbenzene 1,4-diiodo-2,5-dimethylbenzene l,3,4-triiodo-2,5-dimethylbenzene 2-iodo-l,3,5-trimethylbenzene 2,4-diodo-1,3,5-trimethylbenzene l,3,5-triiodo-2,4,6-trimethylbenzene l-iodo-2,4,5-trimethylbenzene l,2,4-triiodo-3,5,6-trimethylbenzene l-iodo-2,3,4-trimethylbenzene l,2,3-triiodo-4,5,6-trimethylbenzene 3-iodo-l,2,4,5-tetramethylbenzene l,4-diiodo-2,3,5,6-tetramethylbenzene l-iodo-2,3,4,5-tetramethylbenzene l,2-diiodo-3,4,5,6-tetramethylbenzene 2-iodo-l,3,4,5-tetramethylbenzene l,3-diiodo-2,4,5,6-tetramethylbenzene 85 65 81 65 88 80 83 88 68 88 69 88 68 85 67 88 68 OR1 OR1 R = H 0.5 l2; 0.5 1 MeCN, 22 °C, 3-30 h 13 R Scheme 4 14a: R1 = Me 14b: R1 = Bn 14C: R1 = Ph 15a: R = F, R1 = Me 15b:R = CI,Rl = Me 15c: R = Br, R1 = Me 15d: R = I, R1 = Me 15e:R = CHO, Rl = Me 15f: R = Bu', R1 = Me 4-iodo substituted derivatives 14a-c, or the 2-iodo products 15a-f when the para position in the substrate was already occupied. This very useful synthetic approach was further applied for the selective transformation of a series of methyl substituted benzene derivatives 16 to the cor-responding mono-, di- and even tri-iodo substituted derivatives 17, depending on the ratio betvveen target substrate, iodine, and F-TEDA-BF4.29 The results are collected in Table 4. As evident from the data in Table 5, the method was also efficient in the čase of sterically hindered alkyl substituted benzene derivatives where selective progres- R R R Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 18 Acta Chim. Slov. 2005, 52, 13–26 Table 5. Iodination of sterically hindered alkyl-substituted arenes 18 mediated by F-TEDA-BF4 (l).30 F-TEDA-BF4 (1) l2, MeCN, T = 55-65 °C 18 19 Alkyl benzene (18) Reaction conditions 18:I2: 1 Reaction tirne (h) Iodo alkylbenzene 19 Yield (%) Me Pr' Pr' Pr' 6 Bu> 6 Pr' Bu> Bu> Me'' ^-^ "Me Pr' 1 : 0.6 : 0.6 1 :2.5 :2.5 1 : 0.75 : 0.75 1 :2.5 :2.5 1 : 0.6 : 0.6 1 : 2.2 : 2.2 1 : 0.6 : 0.6 1 : 0.6 : 0.6 1 : 0.75 : 0.75 1:5:5 1 : 0.75 : 0.75 4.5 1.5 5 24 4-terf-butyl-2-iodo-l-methylbenzene 5-terf-butyl-l,3-diiodo-2-methylbenzene 2-iodo-1,4-diisopropylbenzene l,4-diiodo-2,5-diisopropylbenzene 1 -iodo-2,4-diisopropylbenzene l,5-diiodo-2,4-diisopropylbenzene l,3-di-ferf-butyl-5-iodobenzene 5-terf-butyl-2-iodo-l,3-dimethylbenzene l,5-di-fert-butyl-2-iodo-3-methylbenzene 5-terf-butyl-l,2-diiodo-3-methylbenzene 2-iodo-l,3,5-triisopropylbenzene 88 80 77 81 89 71 83 88 58 77 90 ~~ sive iodination could be achieved using the I2 / F-TEDA-BF4 tandem in acetonitrile reaction media.30 A varietv of aromatic compounds was regiose-lectively iodinated with iodine and F-TEDA-BF4 in imidazolium- and pyridinium-based ionic liquids, l-butyl-3-methylimidazolium hexafluorophosphate ( [brnim][PF6] ) and l-butylpyrodinium tetrafluorobo-rate ( [bpyr][BF4] ). Iodination v/as para- directed when possible, othenvise it occurred in the ort/zo-position.31 The corresponding results of these 1 mediated iodi-nations under “eco-friendly” reaction conditions are shown in Table 6. Iodination of ketones An iodine atom bonded at the position a to the carbonyl group makes the molecule a convenient synthon for further functionalisation. For the prepara-tion of a-iodinated ketones various indirect methods like halogen interchange reactions or electrophilic iodination of silyl enol ethers or enol acetates are common synthetic procedures, while direct methods of iodofunctionalisation are stili scarce. Activation of elemental iodine by F-TEDA-BF4 has been found to be an excellent synthetic procedure of direct iodofunctionalisation of ketones a to the carbonyl group. As shown R R . 2 _ Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 19 Table 6. Iodination of aromatic compounds with I2 / F-TEDA-BF4a in ionic liquids.31 Aromatic substrate Solvent Product distribution (mol %) Yield*(%) Toluene [brnim] [PF6] 4-Iodotoluene (65); 2-iodotoluene(35) 40 1,4-Dimethylbenzene [bpyr][BF4] [brnim] [PF6] 2-Iodo-l,4-dimethylbenzene 90 90 1,3,5-Trimethylbenzene [bpyr][BF4] [brnim] [PF6] 2-Iodo-1,3,5-trimethylbenzene 90 95 1,2,4,5-Tetramethylbenzene [brnim] [PF6] 3-Iodo-l,2,4,5-tetramethylbenzene 43 Anisole [bpyr][BF4] [brnim] [PF6] 4-Iodoanisole 57 56 4-Methylphenol [bpyr][BF4] [brnim] [PF6] 2-Iodo-4-methylphenol 48 66 Phenol [brnim] [PF6] 4-Iodophenol(90);2-iodophenol(10) 72 2,6-Di-iso-propylphenol [bpyr][BF4] [brnim] [PF6] 2,6-Di-iso-propyl-4-iodophenol 40 50 Aniline [bpyr][BF4] [bpyr][BF4] [brnim] [PF6] 4-Iodoaniline 25 56c 40 4-Nitrophenol [bpyr][BF4] 2-Iodo-4-nitrophenol 13 3,4-Dimethoxyacetophenone [bpyr][BF4] [brnim] [PF6] a-Iodo-3,4-dimethoxyacetophenone 81 27 " Reaction conditions: I2 (0.9 mmol); F-TEDA-BF4 (0.9 mmol); arene(1.8 mmol); solvent 3 mL; 24 h; 80 °C; b Calcd. on the starting material; c> Aniline/I2/1 1.2 : 0.6 : 0.6. in Scheme 5 reactions of aryl methyl ketones 20 in a methanol solution of I2 / 1 resulted in the formation of the corresponding a-iodo substituted ketones32 21a-k in high yield. In the čase of compounds 22 bearing an activated aryl ring, the regioselectivity of iodination depended on the solvent used. In MeOH, iodination at the a-carbonyl was found to be exclusive (23, 25, 27, and 29), while in MeCN selective ring iodination was achieved (24, 26, 28, and 30). The synthetic importance of the method has been proven by its application for selective iodofunctionali-zation of different types of acetyl substituted aromatic and heteroaromatic derivatives33 as shown in Table 7, as well as a variety of indanone and tetralone derivatives,34 as becomes evident from the data collected in Table 8. Bromination of unsaturated carbon-carbon bonds Oxidative bromination of various alkenes using potassium bromide as the source of the electrophilic bromine species and F-TEDA-BF4 as the oxidant was re-ported. The course of the reaction was found to depend crucially on the structure of the alkene substrate.35 Derivatives of styrene (31a,b, Scheme 6) were al-most quantitatively transformed to vicinal bromohydrins or methyl ethers 32 using the 1 / KBr / MeCN system in the presence of water or methanol. The bromination of phenyacetylene 33 under F-TEDA-BF4 mediation in water resulted in the formation of a,a-dibromoac-etophenone 34 when a neutral aqueous solution of 1 and KBr was used; in the presence of a weak base (E)-l,2-dibromostyrene 35 was formed, while under acidic conditions (Z)-l,2-dibromostyrene 36 was the predominant product.35 For a system having a double bond conjugated with a carbonyl group (37, 39, Scheme 7) a-bromo-conjugated products 38 or 40 were obtained. When a carbonyl was conjugated with a phenyl group on the P-position (41), oxidative bromination, using the 1 / KBr / aqueous MeCN system, gave stereoselectively erythro-dibromo products 42a-c, while in the čase of a chalcone target (41, R3=Ph, R4=H) using dry MeCN the bromoamidation process resulted in 43. On the oth-er hand, derivatives of trans-cinnamic acid undenvent decarboxylic bromination, yielding p-bromostyrene Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 20 Acta Chim. Slov. 2005, 52, 13–26 o x ArXH3 l2/1/MeOH 22 °C, 1-24 h 20 Ar = O x ArXH2-l 21 70-95% ~W R: H (a), p-OMe (b), p-Me (c), p-F (d), m-CF3 (e), m-N02 (f) or Ar = 1-naphthyl (g), 2-naphthyl (h), 9-phenanthryl (i), 3-phenanthryl (j), 1-pyrenyl(k) O 22 Ar^ChV l2/1 MeCN COCH3 24 (27%) [Tjl 26 (68%) OH COCH3 OMe MeOH COCH2l [Cj\ 23 (78%) OH COCH2l ^.OMe co; OMe 25 (78%) OMe COCH3 COCH2l MeO^ /-L _,OMe MeO^ X^ _,OMe 28 (62%) \^^ 30 (68%) fO OMe Q 27 (75%) O >-' 0Me 29 (86%) Scheme 5 derivatives 44a-c with very high E/Z stereoselectivity. Bromination followed by intramolecular ring closure in the čase of a target like 45 also proceeded smoothly but lacked diastereoselectivity, thus forming 46 in high yield.35 Other types of oxidative functionalisation of arenes Electrophilic functionalization of benzene derivatives with various electrophilic species generated in situ from their anionic precursors by reaction of F-TEDA-BF4 in MeCN solution at room temperature was reported and the results are collected in Table 9.36 It was established that different anionic precursors could be Table 7. Iodination of aryl ketones" by I2 activated with F-TEDA-BF4.33 Ketone a-Iodo ketone Yield" (%) COCH3 6 0CH3 coch2i 6 0CH3 85 OCH3 OCH3 COCH3 Js. ,OCH3 Y^ 0CH3 0CH3 C0CH3 CH30' y^ "0CH3 0CH3 coch2i Js. ,OCH3 Y^ 0CH3 0CH3 C0CH3 82 CH30' y^ "0CH3 0CH3 83 OCH3 HO. OCH3 HO. COCH3 84 COCH2l H OL) H 75 C0CH3 coch2i 70 (Cjf J^COCH3 KZ/ir /^COCH2| " Reaction conditions: ketone (2 mmol), F-TEDA-BF4 (1.2 mmol), I2 (1 mmol), methanol (20 mL), 22 "C, reaction time 20-48 hours; b Refers to the isolated pure products. P h R 1/KBr MeCN/RlOH 31a: R = H 31b: R = Me Ph R—UcH2Br 32 (80-98%) OR1 Rl=Me Ph- Na2C03 = 33 1/KBr / H20 AcOH Br O Br Br Br Ph Br Ph-^CH2Br2 Ph Ph Br 35 (67%) 34 (92%) 36 35 (6.5 : 1; 61 %) Scheme 6 O Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 21 Table 8. Iodination of substituted 1-indanones and 1-tetralones by I2 activated with F-TEDA-BF4. 3 Ketone Time (h) a-Iodo ketone Yield"(%) Me 24 O Me 86 (CH2)n OR R2. R1- (CH2)n a:n = 1;R1 = H b: n = 2; R1 = H c:n = 2;R1 = Me a:n = 2;R1 = OH, R2 = H b:n = 1;R1 = OMe,R2 = H c:n = 1;R1 = H,R2 = OMe d:n = 2;R1 = H, R2 = OMe e:n = 1;R1 = R2 = OMe e: n = 2; R1 = R2 = OMe MeO' O OMe OMe O a: n = 1 (CH2)n b: n = 2 20 20 20 20 20 5 6 6 6 (CH2)n OR R2. R} (CH2)n MeO' OMe p OMe OMe O I (CH2)n OMe 64 69 87 73 86 85 86 84 85 86 85 87 24 63 a Reaction conditions: ketone (2 mmol), F-TEDA-BF4 (1.1 mmol), I2 (1 mmol), methanol (20 mL), 20 "C, reaction time 5-24 hours. b Refers to the isolated pure products. oxidised by 1 to active electrophilic species which read-ily functionalised the benzene ring. The reactivity in a group of easily oxidizable anions decreases in the order Br > Cl" > SCN~ > N02", the second group includes anions like AcO and TfO which are difficult to oxidize to their cationic forms, while the third group which includes cyanide, cyanate, methoxide or thiomethoxide anions, could not be oxidized with 1 under the reaction conditions used. The reaction of sodium, potassium or ammonium salts of the anions from the first group with an activated benzene ring in the presence of equimolar or slightly excess amounts of 1 resulted in the forma-tion of bromo, chloro, thiocyano or nitro-substituted benzene derivatives. From the comparative studies it was established that potassium salts gave the best results and that F-TEDA-BF4 afforded the highest yields of substituted products in the shortest reaction time. The best choice of solvent for this valuable reaction was found to be MeCN, while reactions did not proceed in MeOH.36 Functionalisation at a benzvlic carbon atom In the functionalizations described in the sections 2.2. to 2.6., F-TEDA-BF4 acted as an oxidant to produce electrophilic species from various sources (I+ from I2 or I" ,Br+ from Br or N02+ from N02~ etc). In this section a few additional examples of functionalization are described when 1 acts mainly as an oxidant for a o o o o o o o 6 o o _ Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 22 Acta Chim. Slov. 2005, 52, 13–26 R2 37a: R2 = Me 37b: R2 = OMe O 1/Br2 MeCN / H20 R2 38(81-84%) Br 1/Br2 n(CH2)-^ 39a: n = 1 39b: n = 2 Br MeCN / H20 * J 40a: 91 % 40b: 87% 2eq. of1;2.5eq. ofKBr Ac O Br 42a: R3=Me; 87% a: R4=H; E/Z=95:5; 84% 42b: R3=OMe; 89% 43: R3=Ph b: R4=3-CI; E/Z=97:3; 86% 42c R3=Prr 83% c: R4=4-OH; E/Z=99:9; 82% OH Cl 45 D 46 (83%) ""Br CH2NHCORl 50a: R1 = Et; 82% 50b: R1 = i-Pr; 75% 50c: R1 = c-Pr; 86% 50d: R1 = Ph; 75% 50e: R1 = Bn; 90% TFA/R1CN 47 ROH CH2OR 48a: R = n-hexyl; 90% 48b: R = i-Pr; 88% 48c: R = c-pentyl; 98% 48d: R = C2H4OMe; 93% 48e: R = CH2CF3; 75% 48F: R = Bn; 75% CH2OCOR2 51a:R2 = Me;97% 51b:R2 = CF3;80% VCOOH CH2CI N + IS J (BF4")2 F MeCN TMSR3 CH2R3 49a: R3 = N3; 96% 49b: R3 = Cl; 80% Scheme 8 Scheme 7 chosen substrate, thus forming an electron deficient reactive intermediate which reacts with an external nucleophile. An example of this kind is derivatisation of a ben-zylic carbon atom in hexamethylbenzene (HMB) 47 is shown in Scheme 8. Reactions of HMB with F-TEDA-BF4 in MeCN solvent in the presence of alcohols result-ed in the formation of pentamethylbenzylalkyl ethers 48a-f in high to excellent yield, while in the presence of trimethylsilyl derivatives like TMS-azide or TMS-chlo-ride, the corresponding pentamethylbenzyl-substituted derivatives 49a,b were readily formed. Reactions in TFA or in acetic acid gave pentamethylbenzyl acetate 51a or trifluoroacetate 51b, while transformation in TFA in the presence of various nitriles resulted in Ritter-type benzylic amidation and the corresponding pentame-thylbenzyl amides 50a-e were isolated.37 It was also established that by using appropriate reaction conditions and 1 as mediator, selective func-tionalisation of HMB can also be obtained in the presence of compounds bearing two different nucleophilic centres (Scheme 9). When TFA was used as the solvent, 2-cyanoethanol yielded selective ly the benzyl amide de-rivative 52, while in MeCN it gave benzylic ether 53. On the other hand, cyanoacetic acid as a source of external nucleophile was activated at its cyanide moiety if TFA was used as solvent and the corresponding benzyl amide 54 was formed, while in MeCN, potassium cyanoacetate acted as a carboxy nucleophile and pentamethylbenzyl cyanoacetate 55 was formed.37 O o o + o Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 23 Table 9. Qxidative functionalization of benzene derivatives a mediated by F-TEDA-BF4. 36 R R Na®Xe/F-TEDA-BF4 MeCN/20°C X _ Aromatics X" Time (h) Conversion (%) Product distribution (mol%)a benzene phenol anisole acetanilide l,4-dimethoxybenzene 4-nitrophenol Br 72 100 Cl 72 100 N02 72 100 Br 3 90 Cl 42 42 N02 68 98 Br 21 100 Cl 42 58 SCN 21 67 N02 97 43 Br 3 87 Br 113 100 Cl 113 100 SCN 160 60 N02 184 100 N02 45 95 bromobenzene (100) chlorobenzene(97), dichlorobenzenes(3) nitrobenzene(lOO) bromophenols(87), 2,4-dibromophenol(12) chlorophenols (25), fluorophenols (67) nitrophenol (81), fluoronitrophenol (16) 4-bromoanisole (100) chloroanisoles (67), fluoroanisoles (31) SCN-anisoles (94) nitroanisoles (13), fluoroanisoles (87) bromoacetanilide (99) 2-bromo-l,4-dimethoxybenzene(100) 2-chloro-1,4-dimethoxybenzene (100) 2-SCN-l,4-dimethoxybenzene (100) 2-nitro- l,4-dimethoxybenzene (100) 2,4-dinitrophenol (100) ' In some cases regioselectivity not determined. CH2NHCOCH2COOH 54; 95% CH2OCOCH2CN 55; 60% TFA R = H MeCN R = K NC-CH2-COOR 47 HOCH2CH2CN TFA CH2NHCOCH2CH2OTf 52; 90% C CH2CI N + N + F (BF4~)2 MeCN CH2OCH2CH2CN 53; 80% Scheme 9 47 1/MeCN R-Y-Rf CH2-Y-Rf 1 / TFA C6F5CN CH2NHCOC6F5 57 (81 %) 56a: R=H, Y=0, Rf =CF3CH2; 75% 56b: R=H, Y=0, Rf =C2F5CH2; 70% 56c: R=H, Y=0, Rf =C3F7CH2; 70% 56d: R=H, Y=0, Rf =(CF3)2CH; 71% 56e: R=K, Y=OC(0), Rf =C2F5; 97% 56f: R=K, Y=OC(0), Rf =C4Fn; 96% 56g: R=K, Y=OC(0), Rf =n-C7F15; 90% Scheme 10 A similar synthetic protocol was applied for direct introduction of a perfluoroalkyl moiety containing func-tional groups at the benzylic position in HMB (Scheme 10). The reaction of HMB with an acetonitrile solution of 1 in the presence of perfluoroalcohols or potassium salts of perfluoroalkanoic acids resulted in a high yield formation of the corresponding R( benzylic ethers 56a-d or esters 56e-g, while benzylic amidation in TFA failed Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 24 Acta Chim. Slov. 2005, 52, 13–26 except in the čase of pentafluorobenzonitrile, where the corresponding perfluoro substituted benzyl benzamide 57 could be isolated in high yield.38 Allylation of aldehydes and imines Allystannanes have been widely used for the con-version of aldehydes or ketones to homoallylic alcohols or of imines to homoallylic amines. Promotion of these transformations using strong Lewis acids or rare earth metals is necessary, and the processes are very sensitive to moisture and difficult to handle on a large-scale. It has been found that F-TEDA-BF4 could be an efficient promotor for these functionalisations with excellent moisture and air tolerance.39 Aryl and alkyl adehydes 58 were readily allylated to 59 with tributylallyltin in the presence of a stoichiometric amount of F-TEDA-BF4 (Scheme 11). O x R H 58 -SnBu3 1 / MeCN OH deprotection usually requires strong acidic or oxidative conditions, which could cause incovenience when multi-functional groups are present in target derivatives. It has been shown that 1 can smoothly and efficiently cleave PMP 63 and THP 65 protective groups under mild reaction conditions (Scheme 13). 1,3-Dithiane protec-tion of carbonyl is often used in synthetic procedures, but its removal is relatively difficult and requires harsh conditions. It has been demonstrated that F-TEDA-BF4 could easily cleavage 1,3-dithiane protection 67 in a few minutes reaction at room temperature.40 —i )—PMP \— R1- -O 63 OTHP OTHP 1/MeCN r.t.; 5 h * 1/MeCN r.t.; 5 h ' R OH -OH 64 (90%) OH R1- 59 65 -OH 66 (90-95%) a: R = Ph (76%); b: R = 1-naphthyl (90%); c: R = n-heptyl (83%) OH d:R=|( )l (93%); e:R = [Qj (86%) Scheme 11 Using 1 as the promoter, one-pot allylation of imines with tributylallyltin thus forming homoallylic amines 62 was achieved in moderate to good yield (Scheme 12). Aldehyde 60 (0.8 mmol), amine 61 (1.2 mmol) and 1 (0.8 mmol), were stirred in MeCN solution at room temperature for a few minutes, the first portion of tributylallyltin was then added (1.2 mmol), stirred for 30 min and the second portions of 1 (0.4 mmol) and tributylallyltin (1.2 mmol) were added in order to carry the reaction to completition.39 o 1 +R1NH2 R H 60 61 ^SnBu3 1 Scheme 12 NHR1 MeCN R ^ 62 (46-87%) Cleavage of p-methoxybenzylidene (PMP), tetrahydropyranyl (THP) and 1,3-dithiane protecting groups A new and efficient method for cleavage of PMP, THP and 1,3-dithiane protecting groups with F-TEDA-BF4 has been discovered and developed.40 PMP and THP are very useful protecting groups for diols. Their R2. 67 1/MeCN r.t.; 5 min* Scheme 13 R2. 68 (80-95%) Rearrangements of bicyclic iodides Stereoselective synthesis of 5,6-difunctionalized-2-azabicyclo[2.1.1] hexanes containing 5-araft-fluoro or hydroxyl in one methano bridge (70, Scheme 13) was performed by rearrangement of the iodo-substituted precursors 69 induced by an aqueous MeCN solution of F-TEDA-BF4.41 y/^N-Ri Y 69 MeCN H20 R- OH N-R1 R = H or Me R1 = COOBn Y = ForOH Y Scheme 14 70 Regioselective ring opening of epoxides A variety of epoxides 71, Scheme 15 undenvent rapid ring opening with ammonium thiocyanate in the presence of 10 mol% of F-TEDA-BF4 in MeCN at room temperature, thus regioselectively affording the corresponding P-hydroxy thiocyanates 72 in excel-lent yields. Cycloakyl oxides 73 under similar reaction conditions gave P-hydroxy thiocyanates 74 with anty-stereoselectivity.42 R O 1 Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry Acta Chim. Slov. 2005, 52, 13–26 25 + NH4SCN 1 (10%) MeCN, r.t* HO SCN 71 72 a: R = Ph; 80% b: R = n-Bu; 75% c: R = CH2OPh; 90% d: R = CH2COPh; 86% e: R = CH2ONaph; 90% f: R = CH2(p-OMe)Ph; 95% 73 + NH4SCN 1 (10%) MeCN, r.t* >^ ,OH 'SCN 74a: n = 1; 89% 74b: n = 2; 85% Scheme 15 Cycloaddition reactions Aryl imines 75, Scheme 16 undenvent smooth [4+2] cycloaddition reactions with cyclic enol ethers like 3,4-dihydro-2H-pyran and 3,4-dihydrofuran in the presence of 10 mol% of 1 in MeCN at room temperature to afford pyrano- (76, n=2) or furanotetrahydro-quinoline (76, n=l) derivatives in high yield and with erado-selectivity.43 fk r h, ^ Ar 75 1 (10%) MeCN NH )n H Ar 76 endo/exo from 80:20 to 94:4; yields 85-94% Scheme 16 Conclusions and Perspectives 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2 ]octane bis(tetrafluoroborate); SelectfluorF-TEDA-BF4 is one of the most popular modern reagents for selective fluorination of organic compounds under mild reaction conditions. As evident from the present compilation of the corresponding literature reports, it also can act as a versatile mediator or catalyst for several other types of functionalization or transformations of organic deriva-tives, thus opening up new and interesting prospects. References 1. Organofluorine Chemistry: Principles and Commercial Applications; R. E Banks, B. E. Smart, J. C. Tatlow, Eds.; Plenum Press: New York, 1994. 2. Chemistry of Organic Fluorine Compounds II: A Critical Revievv; M. Hudlicky, A. E. Pavlath, Eds.; ACS Monograph 187, American Chemical Society: Washington, DC, 1995. 3. Biomedicinal Frontiers of Fluorine Chemistry; I. Ojima, J. R. McCarthy, J. T. Welch, Eds.; ACS Symposium Series 693; American Chemical Society: Washington, DC, 1996. 4. Methods of Organic Chemistry (Houben-Weyl), 4th edition, Voh. E lOa-c: Organo-Fluorine Compounds; B. Baasner, H. Hagemann, J. C. Tatlow, Eds.; Thieme: Stuttgart, 1999. 5. Modem Fluoroorganic Chemistry. Synthesis, Reactivity, Applications; P. Kirsch, Ed.; Wiley: Weinheim, 2004. 6. M. Shimizu, T. Hiyama, Angew. Chem., Int. Ed. 2004, 44, 214-231. 7. M. Zupan. In Chemistry of Functional groups, Supplement D2: The Chemistry of Halides, pseudo-halides and azides, S. Patai, Z. Rappoport, Eds.; Wiley&Sons: New York, 1995; Chapter 15, 821-860. 8. S. Rožen, Chem Rev. 1996, 96, 1717-1736. 9. G. S. Lal, P. G. Pez, G. R. Syvret, Chem. Rev. 1996, 96, 1737-1755. 10. D. S. Taylor, C. C. Kotoris, G. Hum, Tetrahedron 1999, 55, 12431-12477. 11. G. G. Furin, A. A. Fainzilberg, Rz«s. Chem. Rev. 1999, 68, 653-684. 12. G. G. Furin, In Methods of Organic Chemistry (Houben-Weyl), 4th edition, Vol. E lOa: Organo-Fluorine Compounds; B. Baasner, H. Hagemann, C. J. Tatlow, Eds.; Thieme: Stuttgart, 1999, 432-498. 13. R. E. Banks, U.S. Patent 5 086 178, 1992. 14. R. E. Banks, N. S. Mohialdin-Khaffaf, G. S. Lal, I. Sharif, G. R. Syvret, Chem. Commun. 1992, 595-596. 15. M. Zupan, S. Stavber, in Trends in Organic Chemistry; Research Trends: Trivandrum, India, 1995, 5, 11-36. 16. R. E. Banks, /. Fluorine Chem. 1998, 87, 1-17. 17. R. P. Singh, J. M. Shreeve, Acc. Chem. Res. 2004, 37, 31-44. 18. P. T. Nyffeler, S. G. Duron, M. D. Burkart, S. P. Vmcent, C-H. Wong, Angew. Chem., Int. Ed. 2004, 44, 192-212. 19. J. J. Hart, G. R. Syvret, /. Fluorine Chem. 1999, 100, 157-161. 20. M. Zupan, M. Papež, S. Stavber,/. Fluorine Chem. 1996, 78, 137-140. 21. G. Stavber, M. Zupan, M. Jereb, S. Stavber, Org. Lett. 2004, 6, 4973-4976. 22. G. P. Girina, A. A. Fainzirberg, L. G. Feoktistov, Russ. I. Electrochem. 2000, 36, 162-163. 23. A. G. Gilicinski, G. P. Pez, R. G. Svvret, G. S. Lal, /. Fluorine Chem. 1992, 59, 157-162. 24. R. E. Banks, N. J. Lavvrence, A. L. Popplevvell, Synlett 1994, 831-832. O R R O R N Stavber and Zupan F-TEDA-BF4 as a Versatile Reagent in Organic Chemistry 26 Acta Chim. Slov. 2005, 52, 13–26 25. M. Zupan, J. Iskra, S. Stavber, Buli. Chem. Soc. 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Povzetek SelectfluorTM F-TEDA-BF4 (1-klorometil-4-fluoro-1,4-diazoniabiciklo[2.2.2]oktan bis(tetrafluoroborat) ) ni samo eden najbolj koristnih reagentov za elektrofilno fluoriranje ampak tudi vsestranski mediator ali katalizator za mnoge druge funkcionalizacije ali pretvorbe organskih spojin. Opisana je njegova uporaba pri številnih reakcijah jodiranja, bromiranja, kloriranja, nitriranja ali uvedbe tiocianatne skupine v različne vrste organskih spojin. Funkcionalizacijo heksametilbenzena na benzilno mesto je moč izvesti zelo uspešno z F-TEDA-BF4 ob prisotnosti različnih nukleofilov. F-TEDA-BF4 je odličen reagent za pripravo para-kinolov ali para-kinol etrov iz ustreznih fenolov, uporabili so ga za aliliranje aldehidov in iminov, za PMP ali THP deprotekcijo glikolov ali odstranitev 1,3-ditianske zaščite karbonilne skupine, pri nekaterih premestitvah v skupini bicikličnih jodidov, ugotovili pa so tudi, da katalizira regioselektivno odpiranje epoksidnih obročev in nekatere [4+2] cikloadicijske reakcije med imini in cikličnimi enolnimi etri. 35. C. Ye, J. M. Shreeve, /. Org. Chem. 2004, 69, 8561-8563. 36. R. G. Syvret, K. M. Butt, T. P. Nguyen, V. L. Bulleck, R. D. Rieth,/. Org. Chem. 2002, 67, 4487–4493. 37. S. Stavber, P. Kralj, M. Zupan, Synlett 2001, 1152-1154. 38. S. Stavber, P. Kralj, M. Zupan, Acta. Chim. Slov. 2002, 49, 553-560. 39. J. Liu, C-H. Wong, Tetrahedron Lett. 2002, 43, 3915-3919. 40. J. Liu, C-H. Wong, Tetrahedron Lett. 2002, 43, 4037-4039. 41. G. R. Krow, G. Lin, K. P. Moore, A. M. Thomas, C. DeBrosse, C. W. Ross, H. G. Ramjit, Org. Lett. 2004, 6, 1669-1672. 42. J. S. Yadav, B. V S. Reddy, C. S. Reddy, Tetrahedron Lett. 2004, 45, 1291-1293. 43. J. S. Yadav, B. V S. Reddy, V Sunitha, C. S. Reddy,^4