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Cocatalysis in phase-transfer catalyzed fluorination of alkyl halides and sulfonates
Journal of Fluorine Chemistry 126 (2005) 209–216 www.elsevier.com/locate/fluor
Cocatalysis in phase-transfer catalyzed fluorination of alkyl halides and sulfonates M. Ma˛kosza*, R. Bujok Institute of Organic Chemistry PAS, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland Received 7 December 2004; accepted 9 December 2004 Available online 15 January 2005
Abstract Phase-transfer catalyzed (PTC) fluorination of alkyl halides and sulfonates with solid KF proceeds efficiently when cocatalyst triphenyltin fluoride is used. The cocatalytic action of the tin compound consists in continuous formation of difluorotriphenylstannate anion that as the tetraalkyloammonium salt enter the solution where it reacts with alkyl halides to produce alkyl fluorides. The cocatalytic system was used to synthesis of 1,1-difluoroalkanes in two steps from aldehydes. A new kind of PTC was elaborated in which Ph3SnF acts as phase transfer catalyst via continuous formation of potassium salts of diflurotriphenylstannate anions soluble in dipolar aprotic solvents. A new, simple and general method of synthesis of tetraalkylammonium and potassium salts of difluorotriorgano-tin, silicon and germanium anions is reported. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluorination; Phase-transfer catalysis; Tin compounds; Cocatalysis hypervalent anions of tin; Silicon; Germanium
1. Introduction Many pharmaceuticals, plant protection agents and other practically important compounds contain fluorinated substituents, thus methods of introduction of this halogen into organic molecules are of great interest [1]. Amongst many ways of introduction of fluorine into organic compounds the most widely used is nucleophilic substitution of halogen or other nucleofugal groups with fluoride anion [2]. This reaction, although widely used, encounters serious problems connected with the insolubility of KF, the common source of F anions, in the majority of solvents used in such processes. Additionally, due to high basicity of F anions, the substitution process is often accompanied with b-elimination resulting in formation olefinic side products [2a,3] (Scheme 1). Nucleophilic substitution of halogen in organic compounds with inorganic anions is most efficiently executed using phase-transfer catalysis, PTC, methodology [4]. The high charge density of * Corresponding author. Tel.: +48 22 631 87 88; fax: +48 22 632 66 81. E-mail address: [email protected] (M. Ma˛kosza). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.12.003
F , consequently the high energy of its solvation in protic solvents [5] and low lipophilicity makes use of the typical liquid–liquid PTC, with tetraalkylammonium salts, TAA, catalysts a procedure of low efficiency for the nucleophilic fluorination process [3a,6]. The most common procedure in this case is solid–liquid PTC with anhydrous KF and TAA or crown ethers catalysts, however due to the high energy of crystalline lattice of KF and low lipophilicity of F anions the ion exchange equilibrium proceeding on the surface of solid KF, that determines the concentration of F in the organic phase is very unfavourable [6] (Scheme 2). Moreover, the high basicity of F anions often results in partial decomposition of the most common PT catalysts tetraalkylammonium salts along the Hoffmann degradation pathway [7]. It appeared to us that these problems encountered in PTC fluorination, could be partially solved by use of an additional compound able to react rapidly with KF to form reversibly an anionic complex or covalently bonded anionic addition products of higher lipophilicity than F anions. As a result F ions should be transferred readily into the organic phase where they enter irreversible reaction with alkyl halides or
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Scheme 1.
Scheme 2.
[9], however, due to high price and molecular weight of this salt (630) its use for practical synthesis is infeasible. We expected that Ph3SnF, being a moderately active Lewis acid when added to a suspension of KF in an appropriate solvent, should react with solid KF at a reasonably high rate assuring formation of the hypervalent Ph3SnF2 anions. These anions should enter the organic solution in form of lipophilic TAA salts where the reaction with alkyl halides resulting in formation of fluorides takes place, whereas liberated 1 reacts with KF so continuous formation of the Ph3SnF2 anions results in the cocatalytic effect (Scheme 4).
2. Results and discussion
sulfonates to give alkyl fluorides. Thus, such compound A acts as a cocatalyst in the PTC reactions of F with alkyl halides carried out in a two-phase liquid–solid system. The concept of cocatalysis in PTC fluorination of alkyl halides is presented in Scheme 3. A related concept of cocatalysis in PTC base induced b-elimination reactions was formulated and executed earlier [8]. It is known that Ph3SnF (1) reacts with Bu4N+F giving a stable, crystalline salt of hypervalent pentacoordinated stannate anions Bu4N+Ph3SnF2 [9]. This salt can act as a source of F anions in some reactions, such as, for instance, conversion of silyl enol ethers to enolates [9]. It reacts also with benzyl bromide leading to formation of benzyl fluoride
We observed the cocatalytic effect of Ph3SnF (1) in a model reaction of PhCH2Br with KF suspended in acetonitrile carried out in the presence of Bu4N+ HSO4 . In this system, under arbitrally chosen conditions assuring moderate conversion (shown in Scheme 5), conversion of PhCH2Br in PhCH2F catalyzed by the PT catalyst was in a range of a few percent, whereas upon addition of 1 it exceed 42%. These results indicate that Ph3SnF does react with solid suspended KF to form lipophilic Ph3SnF2 anions that are able to enter the organic solution as ion pairs with lipophilic Bu4N+ cations, and that in the organic solution the hypervalent tin anion transfers F to the haloalkane. Similar, cocatalytic effects of 1 was observed in sulfolane. Interestingly, in this solvent the fluorination was efficiently catalyzed by 1, even in the absence of the TAA salt because the potassium salt of the hypervalent anion Ph3SnF2 is soluble in this solvent at elevated temperature. The positive results of these preliminary experiments promoted detailed studies of this cocatalytic process. It should be clarified whether the Ph3SnF2 anion reacts directly with R–X giving R–F or it dissociates, at least to a low degree, in the organic solution producing free F anions where they enter fast reaction with R–X. This question was answered in two ways. First, we have found that indeed in the suspension of K+F in acetonitrile or other polar aprotic
Scheme 4.
Scheme 5.
Scheme 3.
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211
Scheme 6.
solvents, containing Ph3SnF and Bu4N+HSO4 there is complete conversion of Ph3SnF into the complex Ph3SnF2 anion existing in the solution in form of tetrabutylammonium salt. This salt can be isolated from the organic solution almost quantitatively. The known isolated salt exhibit high thermal stability (mp 192–193 8C without decomposition). The 119Sn and 19F NMR spectra of this salt in acetonitrile solution at room and elevated temperature show the absence of signals of F anions and tetra-coordinated Sn, indicating that under these conditions dissociation of the hypervalent stannate anions does not occur. One should therefore accept that the substitution proceeds via direct reaction between the hypervalent anions and R–X. This conclusion is confirmed independently taking into account expected differences in the reactivity pattern of F and Ph3SnF2 anions. The reaction of sec-alkyl halides with the highly basic F anions proceeds to a substantial degree along an b-elimination pathway, so formation of alkenes is a substantial side reaction, whereas the basicity of Ph3SnF2 anions should be much lower, thus the side process of belimination should be less pronounced. The data in Scheme 6 show that the reaction of 2-octyl mesylate and 1-(p-nitrophenyl)-ethyl bromide with fluoride anions under typical PTC conditions gave major quantities the elimination products, whereas the reaction cocatalyzed by Ph3SnF gave mostly the substitution products. These results confirmed that the cocatalytic PTC fluorination does not proceed via reaction with free fluoride anions but with the less basic Ph3SnF2 anions. Initially we used commercially available Ph3SnF. In fact less expensive, very convenient and more soluble Ph3SnCl, was found to be an equally good cocatalyst, because in the presence of KF it is rapidly converted into Ph3SnF, but in these cases benzyl chloride was formed as byproduct. Many other tetravalent tin compounds of general structure R3SnF,
able to form hypervalent anions by addition of F should exhibit the cocatalytic activity in the PTC fluorination with KF. We selected a few triorganotin fluorides, R3SnF, containing various R groups for screening their cocatalytic activities in the PT catalyzed model reaction of PhCH2Br with KF. Results obtained, when the reactions were carried out under identical conditions are shown in Scheme 7. The cocatalytic action of the tin compounds embraces two major steps: formation of the hypervalent anions and the reactions of these anions with alkylating agents, thus the overall cocatalytic activity of R3SnF should depend on the rates of these both processes. Substituents R in R3SnF should exert different effects on the rates. In the reaction with KF, R3SnF act as Lewis acids, so this process should be accelerated when R is an electron withdrawing substituents. On the other hand, the activity of R3SnF2 as F donors should be higher when R are electron donating substituents. As the consequence the electronic effects of R on cocatalytic activity of R3SnF are in opposite directions, hence, there should be an optimum between such effects assuring sufficiently fast rates of both of these two processes involved. Rates constants of the reactions of PhCH2Br with a series of Bu4N+R3SnF2 prepared separately were measured by GLC analysis of the samples taken periodically and relative
Scheme 7.
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Scheme 10. Scheme 8.
rate constants for various R, in relation to R = Ph are given in Scheme 8. These data confirm our expectations concerning effect of R on the reactivity of R3SnF2 . Direct measurements of the rates of formation of R3SnF2 in the reaction of R3SnF with solid KF cannot give reliable data due to the heterogenity of the system. The observation that the cocatalytic activities of various R3SnF under identical, arbitrally chosen conditions, do not parallel the activities of the corresponding R3SnF2 prepared in advance in the reaction with PhCH2Br indicates that the overall cocatalytic effectiveness is indeed a superposition of opposite effects. We have tested also cocatalytic action of tin compounds having two or three halogen substituents at tin. Treatment of R2SnCl2 and RSnCl3 with KF results in the exchange of halogens to produce R2SnF2 and RSnF3. These compounds are much stronger Lewis acids than the corresponding R3SnF, thus add readily one or even two fluoride anions to produce hypervalent pentacoordinated anions or even hexacoordinated dianions [10]. These anions are however poor donors of F in the reaction with benzyl bromide thus they exhibit only moderate cocatalytic action (R2SnF42 ) or are unable to act as cocatalyst (RSnF52 ) as can be seen in Scheme 9. The results presented of screening of some tin compounds as potential cocatalysts in PTC fluorination have shown that the most efficient are trialkyl and triaryltin halides. Taking into account rather moderate toxicity (LD50 486 mg/kg, oral, rats data given in Gelest catalogue 1998) we recommend triphenyltin fluoride as a convenient cocatalyst, which can be obtained with excellent yield from the inexpensive chloride. Compounds of other elements of group 14: silicon, germanium and lead are able, similarly to that of tin, to add fluoride anions to form hypervalent anions. This is
particularly characteristic for compounds of silicon. In fact, such anions have found wide use in organic synthesis as fluoride anion sources, e.g. TASF [11], Bu4N+R3SiF2 (R = Ph [12a] or R = PhMe2, BuMe2 [12b]. Screening of some compounds of silicon as potential cocatalysts in the PTC fluorination, under conditions analogous to those used for tin compounds has shown that in general, they are not efficient as cocatalysts. Degree of conversion in these experiments are shown in Scheme 10. On the other hand, tetraalkylammonium salts of difluorotriorganosilicate anions are active donors of fluoride anions [12]. As shown in Scheme 11 they react with benzyl bromide even somewhat faster than the analogous difluorotriorganostannate anions. It is therefore evident that inability of the silicon compounds to act as cocatalysts in PTC fluorination is due to low the rate of their reaction with solid KF to give triorganodifluorosilicate anions. This correlates with known low Lewis acidity of triorganohalosilanes. Triphenylgermanium bromide and triphenyllead chloride show some cocatalytic activity in the fluorination process, however substantially weaker than that of the tin compound. Cocatalytic activities of triphenyl haloderivatives of silicon, germanium, tin and lead compounds are compared in Scheme 12. On the basis of these studies we have selected triphenyltin fluoride as a convenient and efficient cocatalysts in the PTC fluorination of alkyl halides and sulfonates. The value of this approach can be seen from results presented in Table 1 obtained under conditions specified in Scheme 13. The cocatalytic methodology is of particular value for synthesis of secondary alkyl fluorides when, contrary to the reaction with fluoride anions, the undesired side reaction of b-elimination does not affect yields of the products.
Scheme 9.
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213
Scheme 11. Scheme 15.
Scheme 12.
Table 1 Yields of alkyl fluorides obtained in cocatalytic PTC system Entry
Substrate
Time (h)
Yield R–Fa (%)
1 2 3 4 5 6 7 8 9
PhCH2Br PhCOCH2Br EtOOCCH2Br CH3(CH2)7OMs (2,4-di-NO2C6H3)SO3(CH2)7CH3 PhSO2(CH2)3OTs CH3(CH2)5CH(OMs)CH3 EtOOCCH(OMs)CH3 4-NO2PhCH(OMs)CH3
14 6 24 72 19b 40 24 96 8
100 99 100 90 94 82c 82 89 92
a b c
Yield determined by GC. Reaction carried-out at room temperature. Yield of isolated product.
Scheme 13.
The cocatalytic methodology elaborated is also an efficient tool in synthesis of 1,1-difluoroalkanes from aldehydes via bis-triflates as shown in Scheme 14 [13]. In our preliminary experiments we have observed that triphenyltin fluoride itself catalyse the fluorination process
when carried out in sulfolane. Obviously difluorotriphenylstannate anions form potassium salt soluble in this solvent. This effect does not operate in acetonitrile, because potassium difluorotriphenylstannate does not dissolve in this solvent. On the basis of this observation we developed a new type of phase-transfer catalysis concept in the liquid– solid system. The new phase-transfer catalyst: triphenyltin halide reacts with solid KF to produce potassium salt of the lipophilic hypervalent anions soluble in polar aprotic solvents (DMF, sulfolane) transferring in this way covalently bonded F anions into the organic phase. These lipophilic hypervalent anions react in the organic phase with R–X so R–F are formed and regenerate triphenyltin fluoride that reacts again with solid KF, etc. Thus, the concept of new PTC consists in continous conversion of nonlipophilic F anions into highly lipophilic hypervalent anions that are able to enter organic solution as potassium salt, whereas the classical concept of PTC consists in transferring the reacting anions into organic phase in form of lipophilic salts of lipophilic cations thanks to lipophilicity of the latter. The concept and some results obtained under the new PTC condition are presented in Scheme 15 [14]. Observation, that triorganotin halides and tetrabutyloammonium salt react with solid KF suspended in an aprotic solvent giving solutions of tetrabutylammonium salts of triorganodifluorostannate anions let us to elaborate of new method of synthesis of such salts. These salts used as such or generated in situ are convenient starting materials delivering anions X for the synthesis of alkyl fluorides [9,11a,12], nitriles [15] or azides [15], as a source of fluoride anions for the conversion vinyl silyl ethers into enolates [9], etc. The main field of application of these salts are Pd catalyzed coupling reactions with aryl halides or triflates [16]. In these reactions
Scheme 14.
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Ar3SnF2 and Ar3SiF2 anions behave as sources of nucleophilic aryl groups. Stirring of the equimolar amounts of R3SnF and Q+X with an excess of KF suspended in acetonitrile, DMF etc, results in formation of solutions of Q+R3SnF2 . Removal of the excess of KF and other solid inorganic salts by filtration, evaporation of the solvent and/or precipitation of the salt with ether give the product of high purity and in good yield [17]. Even more, similar approach was applicable to synthesis of potassium salts of such anions [17]. These salts were not reported in literature, but can be readily prepared by simple stirring of triorganotin or triorganosilyl fluorides with an excess of KF in DMF. Upon removal of solid salts the solution of K+R3SnF2 in DMF was evaporated and the salts separated by precipitation with diethyl ether.
3. Experimental 1
H, 13C, 19F and 119Sn NMR spectra were obtained on a Varian Geminini AC—200 MHz spectrometer or Varian Mercury—400BB spectrometer. Tetramethylsilane (TMS) was used as an internal standard for 1H and 13C NMR spectra, CFCl3 for 19F NMR spectra and tetramethyltin for 119 Sn NMR spectra. Acetonitrile and DMF were distilled from calcium hydride and dried over molecular sieves 4A. Sulfolane was distilled under reduced pressure and dried over molecular sieves 4A. Other reagents were purchased from Aldrich Co. and used without purification. 3.1. Synthesis of alkyl fluorides in cocatalytic system. typical procedure Freshly dried KF (14.52 g, 250 mmol), Ph3SnF (1.84 g, 5 mmol), Bu4N+HSO4 (1.68 g, 5 mmol) and an alkyl mesylate, tosylate or bromide (50 mmol) were stirred in acetonitrile (35 mL) at 85 8C (bath temperature) till the reaction was completed (6–96 h). The reaction mixture was diluted with diethyl ether (60 mL) and treated with water (200 mL). The organic layer was removed and the inorganic phase with an insoluble solid (Ph3SnF) was extracted with ether (5 35 mL). The solid was filtered-off and dried. Triphenyltin fluoride was recovered with 60–80% yield. The combined extracts were dried and the solvent was distilled using a 20 cm Vigreux column. The products were purified by column chromatography (silica gel, n-pentane or n-pentane/ CH2Cl2). 1-Fluorooctane: a corresponding mesylate was used as a substrate. Yield: 63%. Colourless liquid. 1H NMR d: (200 MHz, CDCl3): 0.90 (t, J = 6.7 Hz, 3H), 1.26–1.32 (m, 10H), 1.55–1.82 (m, 2H), 4.43 (dt, J [19F–1H] = 46 Hz, J[1H–1H] = 6.2 Hz, 2H) ppm. 19F NMR d: (178 MHz, CDCl3): 218.5 (m) ppm. MS (LSIMS(+), GLY): 133
[M + H]+. Analysis: found: C, 72.6%; H, 13.1%. Calculated for C8H17F (132.22): C, 72.7%; H, 13.0%. Ethyl fluoroacetate: a corresponding bromide was used as a substrate. Due to the high toxicity of this compound, it was not isolated. The structure was confirmed by GC–MS analysis: m/z (ion, rel. int.): 105 (M+ 1, 2), 91 (9), 79 (10), 78 (18), 61 (100), 45 (13), 43 (12), 42 (13). Benzyl fluoride: a corresponding bromide was used as a substrate. Yield: 72 %. A colourless liquid. 1H NMR d: (200 MHz, CDCl3): 5.35 (d, J[19F–1H] = 48 Hz, 2H), 7.36 (bs, 5H) ppm. 19F NMR d: (178 MHz, CDCl3): 207.2 (t, J[19F–1H] = 48 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 110 (M+, 48), 109 (100), 83 (17). Analysis: found: C, 75.9%; H, 6.4%. Calculated for C7H7F (110.13): C, 76.3%; H, 6.4%. 2-Fluoroacetophenone: a corresponding bromide was used as a substrate. Yield: 62 %. An orange liquid. 1H NMR d: (200 MHz, CDCl3): 5.54 (d, J[19F–1H] = 47 Hz, 2H), 7.45–7.54 (m, 2H), 7.59–7.68 (m, 1H), 7.87–7.92 (m, 2H) ppm. 19F NMR d: (178 MHz, CDCl3): 231.3 (t, J[19F–1H] = 47 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 138 (M+, 8), 106 (10), 105 (100), 77 (76), 51 (25). Analysis: found: C, 69.3%; H, 4.9%. Calculated for C8H7FO (138.14): C, 69.5%; H, 5.1%. 3-Fluoropropyl phenyl sulfone: a corresponding tosylate was used as a substrate. Yield: 82 %. A colourless oil. 1H NMR d: (CDCl3, 400 MHz): 2.08–2.21 (m, 2H), 3.22–3.26 (m, 2H), 4.52 (dt, J[19F–1H] = 47 Hz; J[1H–1H] = 5.7 Hz, 2H), 7.57–7.62 (m, 2H), 7.66–7.70 (m, 1H), 7.91–7.95 (m, 2H) ppm. 19F NMR d: (CDCl3, 376 MHz): 220.9 (tt, J[19F–1H] = 47 Hz; J[19F–1H] = 23 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 202 (M+, 6), 156 (10), 141 (35), 118 (40), 94 (15), 78 (39a), 77 (100), 51 (26), 41 (12). Analysis: found: C, 53.2%; H, 5.5%; S, 15.9%. Calculated for C9H11F2OS (202.25): C, 53.4%; H, 5.5%; S, 15.8%. 2-Fluorooctane: a corresponding tosylate was used as a substrate. Yield: 63%. A colourless liquid. 1H NMR d: (CDCl3, 400 MHz): 0,89 (t, J = 6.5 Hz, 3H), 1.23–1.80 (m, 14H), 4.51–4.75 (m, 1H) ppm. 19F NMR d: (CDCl3, 376 MHz): 172.6 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 112 (M+–HF, 5), 111 (12), 97 (22), 95 (11), 85 (30), 84 (12), 83 (27), 81 (14), 71 (56), 70 (22), 69 (41), 67 (11), 57 (100), 56 (22), 55 (46), 44 (30a), 43 (40), 41 (20), 40 (19). Analysis: found: C, 72.5%; H, 13.1%. Calculated for C8H17F (132.22): C, 72.7%; H, 12.9%. Ethyl 2-fluoropropionate: a corresponding mesylate was used as a substrate. Yield: 55 %. A colourless liquid. 1H NMR d: (200 MHz, CDCl3): 1.32 (t, J = 7.2 Hz, 3H), 1.59 ˜ 4.26 (k, (dd, J[19F–1H] = 24 Hz; J[1H–1H] = 6.9 Hz, 3H), J = 7.1 Hz, 2H), 5.00 (dk, J[19F–1H] = 49 Hz, ˜ ppm. 19F NMR d: (178, CDCl3): J[1H–1H] = 7.0 Hz, 1H) 185.1 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 120 (M+, 2), 61 (10), 47 (100), 46 (42), 45 (28). Analysis: found: C, 49.1%; H, 7.9%. Calculated for C5H9FO2 (120.12): C, 49.9%; H, 7.5%. 1-(p-Nitrophenyl)ethyl fluoride: a corresponding mesylate was used as a substrate. Yield: 80%. Yellow solid, mp
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35–37 8C. 1H NMR d: (200 MHz, CDCl3): 1.67 (dd, J[19F–1H] = 24 Hz, J[1H–1H] = 6.5 Hz, 3H), 5.74 (dk, J[19F–1H] = 47 Hz, J[1H–1H] = 6.5 Hz, 1H), 7.54 and 8.24 (AA‘XX’, 4H) ppm. 19F NMR d: (178 MHz, CDCl3): 173.1 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 169 (M+, 100), 154 (59), 152 (29), 124 (23), 123 (54), 122 (21), 108 (14), 107 (19), 103 (45), 101 (11), 96 (24), 77 (70), 51 (22), 50 (30). Analysis: found: C, 57.0%; H, 4.6%; N, 8.1%. Calculated for C8H8FNO2 (169.16): C, 56.8%; H, 4.8%; N, 8.3%. 3.2. Synthesis of alkyl fluorides in the absence of tetrabutylammonium salts. typical procedure. Freshly dried KF (14.52 g, 250 mmol), Ph3SnF (1.84 g, 5 mmol) and an alkyl mesylate, tosylate or bromide (50 mmol) were stirred in sulfolane (35 mL) at 85–105 8C (bath temperature) till the reaction was completed (4–48 h). The reaction mixture was diluted with diethyl ether (60 mL) and treated with water (200 mL). The organic layer was removed and the inorganic phase with an insoluble solid (Ph3SnF) was extracted with ether (5 35 mL). The solid was filtered-off and dried. The combined extracts were washed with water (2 50 mL), dried and the solvent was distilled using a 20 cm Vigreux column. The products were purified by column chromatography (silica gel, n-pentane or n-pentane/CH2Cl2). 3.3. Synthesis of 1,1-difluoroalkanes Typical procedure: dried powdered KF (3.094 g, 53.3 mmol), Ph3SnF (98 mg, 0.27 mmol) Bu4N+ HSO4 (91 mg, 0.27 mmol) and a freshly prepared solution of RCH(OTf)2 in CH2Cl2 (2.7 mmol in 4.5 mL) were vigorously stirred at room temperature till the reaction was completed (16–48 h). The reaction mixture was diluted with ether (25 mL), the solid was filtered off, washed with ether (3 8 mL). The ether extracts were combined and the solvent was distilled using a 20 cm Vigreux column. The products were purified by chromatography (silica gel, n-pentane or n-pentane/CH2Cl2). 3.4. Kinetics of the reactions of tetrabutylammonium salts of hypervalent anions with benzyl bromide A solution of a hypervalent salt Q+R3MF2 (1 mmol) and biphenyl (50 mg, an internal standard) in acetonitrile (8 mL) was stirred at the defined temperature for 20 min then benzyl bromide (0.171 g, 1.0 mmol) was added via micro syringe. Samples of the mixtures were taken every 20 min and a concentration of benzyl bromide and benzyl fluoride were determined by GLC analysis. 3.5. Synthesis of tetrabutylammonium salts. Potassium fluoride (10–20 equiv.), R3MX (3.0 mmol), tetrabutylammonium hydrogensulfate (3.0 mmol) and sol-
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vent (MeCN or DMF; 7.5 mL) were placed in flask and heated with stirring at 60 8C for 24 h. The solid was filtered off and washed with the solvent used in the reaction (4 5 mL). The combined filtrates were evaporated and the residue was recrystallized from MeCN/Et2O. 3.6. Synthesis of potassium salts Potassium fluoride (10–20 equiv.), R3MX (1.0 mmol) and DMF (2.5 mL) were placed in flask and heated with stirring at 60 8C for 24 h. The solid was filtered off and washed with DMF (4 3 mL). The combined filtrates were evaporated and the residue was recrystallized from DMF/ Et2O. 3.7. Determining of rate constants of the reactions hypervalent salts with benzyl bromide Hypervalent salt Q+ R3MF2 (1.0 mmol) and biphenyl (0.050 g; an internal standard) were placed in a flask. Acetonitrile (8.0 mL) was added and the solution was stirred at corresponding temperature (temperature of the bath = 60 or 85 8C) for 20 min, to heat the solution to desired temperature. Then benzyl bromide (0.171 g; 1.0 mmol) was added via microsyringe. Samples were taken every 20 min in initial stage of the reactions (120 min), then once an hour. Concentrations of benzyl bromide and benzyl fluoride were determined by GC analysis.
Acknowledgements This work was generously supported by Bayer Pharma, Wuppertal, Germany. We thank Professor W. Dmowski for helpful discussion.
References [1] (a) R. Filler, Organofluorine compounds in medicinal chemistry and biomedical applications, in: R. Filler (Ed.), Studies in Organic Chemistry, vol. 48, Elsevier, New York, 1993, pp. 1–23; (b) R.L. Powell, 4th ed. Methods of Organic Chemistry, Additional and Suppl.vol, vol. E10a, Houben-Weyl, 1999(Chapter 6). [2] (a) L. Subramanian, R. Siegemund, 4th ed. Methods of Organic Chemistry, Additional and Suppl.vol, vol. E10a, Houben-Weyl, 1999 (Chapter A.14); (b) J.A. Wilkinson, Chem Rev. 92 (1992) 505–519. [3] (a) D. Landini, F. Montanari, F. Rolla, Synthesis (1974) 428–430; (b) C.L. Liotta, H.P. Harris, J. Am. Chem. Soc. 96 (1974) 225–2250. [4] (a) E.V. Dehmlow, S.S. Dehmlow, Phase Transfer Catalysis Principles, VCH, Weinheim, New York, 1978, Basel, Cambridge, Tokyo, 1993.; (b) M. Ma˛ kosza, M. Fedoryn´ ski, Adv. Catal. 35 (1987) 373–422; (c) M. Ma˛ kosza, M. Fedoryn´ ski, Catal. Rev. 45 (2003) 321–367. [5] W.A. Sheppard, C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969, pp. 9–17. [6] S. Dermeik, Y. Sasson, J. Org. Chem. 50 (1985) 879–882. [7] D. Landini, A. Maia, A. Rampoldi, J. Org. Chem. 54 (1989) 328–332.
216
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[8] (a) M. Ma˛ kosza, A. Chesnokov, Tetrahedron 56 (2000) 3553–3558; (b) M. Ma˛ kosza, A. Chesnokov, Tetrahedron 58 (2002) 7295–7301. [9] M. Gingras, Tetrahedron Lett. 32 (1991) 7381–7384. [10] L.A. Hobbs, P.J. Smith, J. Organomet. Chem. 206 (1981) 59–67. [11] (a) L.A. Mulard, P. Kovac, P.J. Glaudemans, Carbohydr. Res. 259 (1994) 117–129; (b) R. Noyori, I. Nishida, J. Sakata, J. Am. Chem. Soc. 105 (1983) 1598–1608. [12] (a) A.S. Pilcher, H.L. Ammon, P. DeShong, J. Am. Chem. Soc. 117 (1995) 5166–5167; (b) J. Kvı´cˇ ala, P. Mysı´k, O. Paleta, Synlett (2001) 547–549.
[13] R. Bujok, M. Ma˛ kosza, Synlett (2002) 1285–1286. [14] M. Ma˛ kosza, R. Bujok, Tetrahedron Lett. 45 (2004) 1385–1386. [15] E. Soli, A. Manoso, M. Patterson, P. De Shong, D. Favor, R. Hirschmann, A. Smith, J. Org. Chem. 64 (1999) 3171–3177. [16] (a) A. Garcı´a Martı´nez, J. Osı´o Barcina, M. del Rosario Colorado Heras, A. de Fresno Cereso, Org. Lett. 2 (2000) 1377–1378; (b) M.-R. Brescia, P. DeShong, J. Org. Chem. 63 (1998) 3156– 3157; (c) M.E. Movery, P. DeShong, J. Org. Chem. 64 (1999) 3266– 3270. [17] M. Ma˛ kosza, R. Bujok, Synlett (2004) 371–373.
Cocatalysis in phase-transfer catalyzed fluorination of alkyl halides and sulfonates M. Ma˛kosza*, R. Bujok Institute of Organic Chemistry PAS, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland Received 7 December 2004; accepted 9 December 2004 Available online 15 January 2005
Abstract Phase-transfer catalyzed (PTC) fluorination of alkyl halides and sulfonates with solid KF proceeds efficiently when cocatalyst triphenyltin fluoride is used. The cocatalytic action of the tin compound consists in continuous formation of difluorotriphenylstannate anion that as the tetraalkyloammonium salt enter the solution where it reacts with alkyl halides to produce alkyl fluorides. The cocatalytic system was used to synthesis of 1,1-difluoroalkanes in two steps from aldehydes. A new kind of PTC was elaborated in which Ph3SnF acts as phase transfer catalyst via continuous formation of potassium salts of diflurotriphenylstannate anions soluble in dipolar aprotic solvents. A new, simple and general method of synthesis of tetraalkylammonium and potassium salts of difluorotriorgano-tin, silicon and germanium anions is reported. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluorination; Phase-transfer catalysis; Tin compounds; Cocatalysis hypervalent anions of tin; Silicon; Germanium
1. Introduction Many pharmaceuticals, plant protection agents and other practically important compounds contain fluorinated substituents, thus methods of introduction of this halogen into organic molecules are of great interest [1]. Amongst many ways of introduction of fluorine into organic compounds the most widely used is nucleophilic substitution of halogen or other nucleofugal groups with fluoride anion [2]. This reaction, although widely used, encounters serious problems connected with the insolubility of KF, the common source of F anions, in the majority of solvents used in such processes. Additionally, due to high basicity of F anions, the substitution process is often accompanied with b-elimination resulting in formation olefinic side products [2a,3] (Scheme 1). Nucleophilic substitution of halogen in organic compounds with inorganic anions is most efficiently executed using phase-transfer catalysis, PTC, methodology [4]. The high charge density of * Corresponding author. Tel.: +48 22 631 87 88; fax: +48 22 632 66 81. E-mail address: [email protected] (M. Ma˛kosza). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.12.003
F , consequently the high energy of its solvation in protic solvents [5] and low lipophilicity makes use of the typical liquid–liquid PTC, with tetraalkylammonium salts, TAA, catalysts a procedure of low efficiency for the nucleophilic fluorination process [3a,6]. The most common procedure in this case is solid–liquid PTC with anhydrous KF and TAA or crown ethers catalysts, however due to the high energy of crystalline lattice of KF and low lipophilicity of F anions the ion exchange equilibrium proceeding on the surface of solid KF, that determines the concentration of F in the organic phase is very unfavourable [6] (Scheme 2). Moreover, the high basicity of F anions often results in partial decomposition of the most common PT catalysts tetraalkylammonium salts along the Hoffmann degradation pathway [7]. It appeared to us that these problems encountered in PTC fluorination, could be partially solved by use of an additional compound able to react rapidly with KF to form reversibly an anionic complex or covalently bonded anionic addition products of higher lipophilicity than F anions. As a result F ions should be transferred readily into the organic phase where they enter irreversible reaction with alkyl halides or
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Scheme 1.
Scheme 2.
[9], however, due to high price and molecular weight of this salt (630) its use for practical synthesis is infeasible. We expected that Ph3SnF, being a moderately active Lewis acid when added to a suspension of KF in an appropriate solvent, should react with solid KF at a reasonably high rate assuring formation of the hypervalent Ph3SnF2 anions. These anions should enter the organic solution in form of lipophilic TAA salts where the reaction with alkyl halides resulting in formation of fluorides takes place, whereas liberated 1 reacts with KF so continuous formation of the Ph3SnF2 anions results in the cocatalytic effect (Scheme 4).
2. Results and discussion
sulfonates to give alkyl fluorides. Thus, such compound A acts as a cocatalyst in the PTC reactions of F with alkyl halides carried out in a two-phase liquid–solid system. The concept of cocatalysis in PTC fluorination of alkyl halides is presented in Scheme 3. A related concept of cocatalysis in PTC base induced b-elimination reactions was formulated and executed earlier [8]. It is known that Ph3SnF (1) reacts with Bu4N+F giving a stable, crystalline salt of hypervalent pentacoordinated stannate anions Bu4N+Ph3SnF2 [9]. This salt can act as a source of F anions in some reactions, such as, for instance, conversion of silyl enol ethers to enolates [9]. It reacts also with benzyl bromide leading to formation of benzyl fluoride
We observed the cocatalytic effect of Ph3SnF (1) in a model reaction of PhCH2Br with KF suspended in acetonitrile carried out in the presence of Bu4N+ HSO4 . In this system, under arbitrally chosen conditions assuring moderate conversion (shown in Scheme 5), conversion of PhCH2Br in PhCH2F catalyzed by the PT catalyst was in a range of a few percent, whereas upon addition of 1 it exceed 42%. These results indicate that Ph3SnF does react with solid suspended KF to form lipophilic Ph3SnF2 anions that are able to enter the organic solution as ion pairs with lipophilic Bu4N+ cations, and that in the organic solution the hypervalent tin anion transfers F to the haloalkane. Similar, cocatalytic effects of 1 was observed in sulfolane. Interestingly, in this solvent the fluorination was efficiently catalyzed by 1, even in the absence of the TAA salt because the potassium salt of the hypervalent anion Ph3SnF2 is soluble in this solvent at elevated temperature. The positive results of these preliminary experiments promoted detailed studies of this cocatalytic process. It should be clarified whether the Ph3SnF2 anion reacts directly with R–X giving R–F or it dissociates, at least to a low degree, in the organic solution producing free F anions where they enter fast reaction with R–X. This question was answered in two ways. First, we have found that indeed in the suspension of K+F in acetonitrile or other polar aprotic
Scheme 4.
Scheme 5.
Scheme 3.
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211
Scheme 6.
solvents, containing Ph3SnF and Bu4N+HSO4 there is complete conversion of Ph3SnF into the complex Ph3SnF2 anion existing in the solution in form of tetrabutylammonium salt. This salt can be isolated from the organic solution almost quantitatively. The known isolated salt exhibit high thermal stability (mp 192–193 8C without decomposition). The 119Sn and 19F NMR spectra of this salt in acetonitrile solution at room and elevated temperature show the absence of signals of F anions and tetra-coordinated Sn, indicating that under these conditions dissociation of the hypervalent stannate anions does not occur. One should therefore accept that the substitution proceeds via direct reaction between the hypervalent anions and R–X. This conclusion is confirmed independently taking into account expected differences in the reactivity pattern of F and Ph3SnF2 anions. The reaction of sec-alkyl halides with the highly basic F anions proceeds to a substantial degree along an b-elimination pathway, so formation of alkenes is a substantial side reaction, whereas the basicity of Ph3SnF2 anions should be much lower, thus the side process of belimination should be less pronounced. The data in Scheme 6 show that the reaction of 2-octyl mesylate and 1-(p-nitrophenyl)-ethyl bromide with fluoride anions under typical PTC conditions gave major quantities the elimination products, whereas the reaction cocatalyzed by Ph3SnF gave mostly the substitution products. These results confirmed that the cocatalytic PTC fluorination does not proceed via reaction with free fluoride anions but with the less basic Ph3SnF2 anions. Initially we used commercially available Ph3SnF. In fact less expensive, very convenient and more soluble Ph3SnCl, was found to be an equally good cocatalyst, because in the presence of KF it is rapidly converted into Ph3SnF, but in these cases benzyl chloride was formed as byproduct. Many other tetravalent tin compounds of general structure R3SnF,
able to form hypervalent anions by addition of F should exhibit the cocatalytic activity in the PTC fluorination with KF. We selected a few triorganotin fluorides, R3SnF, containing various R groups for screening their cocatalytic activities in the PT catalyzed model reaction of PhCH2Br with KF. Results obtained, when the reactions were carried out under identical conditions are shown in Scheme 7. The cocatalytic action of the tin compounds embraces two major steps: formation of the hypervalent anions and the reactions of these anions with alkylating agents, thus the overall cocatalytic activity of R3SnF should depend on the rates of these both processes. Substituents R in R3SnF should exert different effects on the rates. In the reaction with KF, R3SnF act as Lewis acids, so this process should be accelerated when R is an electron withdrawing substituents. On the other hand, the activity of R3SnF2 as F donors should be higher when R are electron donating substituents. As the consequence the electronic effects of R on cocatalytic activity of R3SnF are in opposite directions, hence, there should be an optimum between such effects assuring sufficiently fast rates of both of these two processes involved. Rates constants of the reactions of PhCH2Br with a series of Bu4N+R3SnF2 prepared separately were measured by GLC analysis of the samples taken periodically and relative
Scheme 7.
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Scheme 10. Scheme 8.
rate constants for various R, in relation to R = Ph are given in Scheme 8. These data confirm our expectations concerning effect of R on the reactivity of R3SnF2 . Direct measurements of the rates of formation of R3SnF2 in the reaction of R3SnF with solid KF cannot give reliable data due to the heterogenity of the system. The observation that the cocatalytic activities of various R3SnF under identical, arbitrally chosen conditions, do not parallel the activities of the corresponding R3SnF2 prepared in advance in the reaction with PhCH2Br indicates that the overall cocatalytic effectiveness is indeed a superposition of opposite effects. We have tested also cocatalytic action of tin compounds having two or three halogen substituents at tin. Treatment of R2SnCl2 and RSnCl3 with KF results in the exchange of halogens to produce R2SnF2 and RSnF3. These compounds are much stronger Lewis acids than the corresponding R3SnF, thus add readily one or even two fluoride anions to produce hypervalent pentacoordinated anions or even hexacoordinated dianions [10]. These anions are however poor donors of F in the reaction with benzyl bromide thus they exhibit only moderate cocatalytic action (R2SnF42 ) or are unable to act as cocatalyst (RSnF52 ) as can be seen in Scheme 9. The results presented of screening of some tin compounds as potential cocatalysts in PTC fluorination have shown that the most efficient are trialkyl and triaryltin halides. Taking into account rather moderate toxicity (LD50 486 mg/kg, oral, rats data given in Gelest catalogue 1998) we recommend triphenyltin fluoride as a convenient cocatalyst, which can be obtained with excellent yield from the inexpensive chloride. Compounds of other elements of group 14: silicon, germanium and lead are able, similarly to that of tin, to add fluoride anions to form hypervalent anions. This is
particularly characteristic for compounds of silicon. In fact, such anions have found wide use in organic synthesis as fluoride anion sources, e.g. TASF [11], Bu4N+R3SiF2 (R = Ph [12a] or R = PhMe2, BuMe2 [12b]. Screening of some compounds of silicon as potential cocatalysts in the PTC fluorination, under conditions analogous to those used for tin compounds has shown that in general, they are not efficient as cocatalysts. Degree of conversion in these experiments are shown in Scheme 10. On the other hand, tetraalkylammonium salts of difluorotriorganosilicate anions are active donors of fluoride anions [12]. As shown in Scheme 11 they react with benzyl bromide even somewhat faster than the analogous difluorotriorganostannate anions. It is therefore evident that inability of the silicon compounds to act as cocatalysts in PTC fluorination is due to low the rate of their reaction with solid KF to give triorganodifluorosilicate anions. This correlates with known low Lewis acidity of triorganohalosilanes. Triphenylgermanium bromide and triphenyllead chloride show some cocatalytic activity in the fluorination process, however substantially weaker than that of the tin compound. Cocatalytic activities of triphenyl haloderivatives of silicon, germanium, tin and lead compounds are compared in Scheme 12. On the basis of these studies we have selected triphenyltin fluoride as a convenient and efficient cocatalysts in the PTC fluorination of alkyl halides and sulfonates. The value of this approach can be seen from results presented in Table 1 obtained under conditions specified in Scheme 13. The cocatalytic methodology is of particular value for synthesis of secondary alkyl fluorides when, contrary to the reaction with fluoride anions, the undesired side reaction of b-elimination does not affect yields of the products.
Scheme 9.
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213
Scheme 11. Scheme 15.
Scheme 12.
Table 1 Yields of alkyl fluorides obtained in cocatalytic PTC system Entry
Substrate
Time (h)
Yield R–Fa (%)
1 2 3 4 5 6 7 8 9
PhCH2Br PhCOCH2Br EtOOCCH2Br CH3(CH2)7OMs (2,4-di-NO2C6H3)SO3(CH2)7CH3 PhSO2(CH2)3OTs CH3(CH2)5CH(OMs)CH3 EtOOCCH(OMs)CH3 4-NO2PhCH(OMs)CH3
14 6 24 72 19b 40 24 96 8
100 99 100 90 94 82c 82 89 92
a b c
Yield determined by GC. Reaction carried-out at room temperature. Yield of isolated product.
Scheme 13.
The cocatalytic methodology elaborated is also an efficient tool in synthesis of 1,1-difluoroalkanes from aldehydes via bis-triflates as shown in Scheme 14 [13]. In our preliminary experiments we have observed that triphenyltin fluoride itself catalyse the fluorination process
when carried out in sulfolane. Obviously difluorotriphenylstannate anions form potassium salt soluble in this solvent. This effect does not operate in acetonitrile, because potassium difluorotriphenylstannate does not dissolve in this solvent. On the basis of this observation we developed a new type of phase-transfer catalysis concept in the liquid– solid system. The new phase-transfer catalyst: triphenyltin halide reacts with solid KF to produce potassium salt of the lipophilic hypervalent anions soluble in polar aprotic solvents (DMF, sulfolane) transferring in this way covalently bonded F anions into the organic phase. These lipophilic hypervalent anions react in the organic phase with R–X so R–F are formed and regenerate triphenyltin fluoride that reacts again with solid KF, etc. Thus, the concept of new PTC consists in continous conversion of nonlipophilic F anions into highly lipophilic hypervalent anions that are able to enter organic solution as potassium salt, whereas the classical concept of PTC consists in transferring the reacting anions into organic phase in form of lipophilic salts of lipophilic cations thanks to lipophilicity of the latter. The concept and some results obtained under the new PTC condition are presented in Scheme 15 [14]. Observation, that triorganotin halides and tetrabutyloammonium salt react with solid KF suspended in an aprotic solvent giving solutions of tetrabutylammonium salts of triorganodifluorostannate anions let us to elaborate of new method of synthesis of such salts. These salts used as such or generated in situ are convenient starting materials delivering anions X for the synthesis of alkyl fluorides [9,11a,12], nitriles [15] or azides [15], as a source of fluoride anions for the conversion vinyl silyl ethers into enolates [9], etc. The main field of application of these salts are Pd catalyzed coupling reactions with aryl halides or triflates [16]. In these reactions
Scheme 14.
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Ar3SnF2 and Ar3SiF2 anions behave as sources of nucleophilic aryl groups. Stirring of the equimolar amounts of R3SnF and Q+X with an excess of KF suspended in acetonitrile, DMF etc, results in formation of solutions of Q+R3SnF2 . Removal of the excess of KF and other solid inorganic salts by filtration, evaporation of the solvent and/or precipitation of the salt with ether give the product of high purity and in good yield [17]. Even more, similar approach was applicable to synthesis of potassium salts of such anions [17]. These salts were not reported in literature, but can be readily prepared by simple stirring of triorganotin or triorganosilyl fluorides with an excess of KF in DMF. Upon removal of solid salts the solution of K+R3SnF2 in DMF was evaporated and the salts separated by precipitation with diethyl ether.
3. Experimental 1
H, 13C, 19F and 119Sn NMR spectra were obtained on a Varian Geminini AC—200 MHz spectrometer or Varian Mercury—400BB spectrometer. Tetramethylsilane (TMS) was used as an internal standard for 1H and 13C NMR spectra, CFCl3 for 19F NMR spectra and tetramethyltin for 119 Sn NMR spectra. Acetonitrile and DMF were distilled from calcium hydride and dried over molecular sieves 4A. Sulfolane was distilled under reduced pressure and dried over molecular sieves 4A. Other reagents were purchased from Aldrich Co. and used without purification. 3.1. Synthesis of alkyl fluorides in cocatalytic system. typical procedure Freshly dried KF (14.52 g, 250 mmol), Ph3SnF (1.84 g, 5 mmol), Bu4N+HSO4 (1.68 g, 5 mmol) and an alkyl mesylate, tosylate or bromide (50 mmol) were stirred in acetonitrile (35 mL) at 85 8C (bath temperature) till the reaction was completed (6–96 h). The reaction mixture was diluted with diethyl ether (60 mL) and treated with water (200 mL). The organic layer was removed and the inorganic phase with an insoluble solid (Ph3SnF) was extracted with ether (5 35 mL). The solid was filtered-off and dried. Triphenyltin fluoride was recovered with 60–80% yield. The combined extracts were dried and the solvent was distilled using a 20 cm Vigreux column. The products were purified by column chromatography (silica gel, n-pentane or n-pentane/ CH2Cl2). 1-Fluorooctane: a corresponding mesylate was used as a substrate. Yield: 63%. Colourless liquid. 1H NMR d: (200 MHz, CDCl3): 0.90 (t, J = 6.7 Hz, 3H), 1.26–1.32 (m, 10H), 1.55–1.82 (m, 2H), 4.43 (dt, J [19F–1H] = 46 Hz, J[1H–1H] = 6.2 Hz, 2H) ppm. 19F NMR d: (178 MHz, CDCl3): 218.5 (m) ppm. MS (LSIMS(+), GLY): 133
[M + H]+. Analysis: found: C, 72.6%; H, 13.1%. Calculated for C8H17F (132.22): C, 72.7%; H, 13.0%. Ethyl fluoroacetate: a corresponding bromide was used as a substrate. Due to the high toxicity of this compound, it was not isolated. The structure was confirmed by GC–MS analysis: m/z (ion, rel. int.): 105 (M+ 1, 2), 91 (9), 79 (10), 78 (18), 61 (100), 45 (13), 43 (12), 42 (13). Benzyl fluoride: a corresponding bromide was used as a substrate. Yield: 72 %. A colourless liquid. 1H NMR d: (200 MHz, CDCl3): 5.35 (d, J[19F–1H] = 48 Hz, 2H), 7.36 (bs, 5H) ppm. 19F NMR d: (178 MHz, CDCl3): 207.2 (t, J[19F–1H] = 48 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 110 (M+, 48), 109 (100), 83 (17). Analysis: found: C, 75.9%; H, 6.4%. Calculated for C7H7F (110.13): C, 76.3%; H, 6.4%. 2-Fluoroacetophenone: a corresponding bromide was used as a substrate. Yield: 62 %. An orange liquid. 1H NMR d: (200 MHz, CDCl3): 5.54 (d, J[19F–1H] = 47 Hz, 2H), 7.45–7.54 (m, 2H), 7.59–7.68 (m, 1H), 7.87–7.92 (m, 2H) ppm. 19F NMR d: (178 MHz, CDCl3): 231.3 (t, J[19F–1H] = 47 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 138 (M+, 8), 106 (10), 105 (100), 77 (76), 51 (25). Analysis: found: C, 69.3%; H, 4.9%. Calculated for C8H7FO (138.14): C, 69.5%; H, 5.1%. 3-Fluoropropyl phenyl sulfone: a corresponding tosylate was used as a substrate. Yield: 82 %. A colourless oil. 1H NMR d: (CDCl3, 400 MHz): 2.08–2.21 (m, 2H), 3.22–3.26 (m, 2H), 4.52 (dt, J[19F–1H] = 47 Hz; J[1H–1H] = 5.7 Hz, 2H), 7.57–7.62 (m, 2H), 7.66–7.70 (m, 1H), 7.91–7.95 (m, 2H) ppm. 19F NMR d: (CDCl3, 376 MHz): 220.9 (tt, J[19F–1H] = 47 Hz; J[19F–1H] = 23 Hz) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 202 (M+, 6), 156 (10), 141 (35), 118 (40), 94 (15), 78 (39a), 77 (100), 51 (26), 41 (12). Analysis: found: C, 53.2%; H, 5.5%; S, 15.9%. Calculated for C9H11F2OS (202.25): C, 53.4%; H, 5.5%; S, 15.8%. 2-Fluorooctane: a corresponding tosylate was used as a substrate. Yield: 63%. A colourless liquid. 1H NMR d: (CDCl3, 400 MHz): 0,89 (t, J = 6.5 Hz, 3H), 1.23–1.80 (m, 14H), 4.51–4.75 (m, 1H) ppm. 19F NMR d: (CDCl3, 376 MHz): 172.6 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 112 (M+–HF, 5), 111 (12), 97 (22), 95 (11), 85 (30), 84 (12), 83 (27), 81 (14), 71 (56), 70 (22), 69 (41), 67 (11), 57 (100), 56 (22), 55 (46), 44 (30a), 43 (40), 41 (20), 40 (19). Analysis: found: C, 72.5%; H, 13.1%. Calculated for C8H17F (132.22): C, 72.7%; H, 12.9%. Ethyl 2-fluoropropionate: a corresponding mesylate was used as a substrate. Yield: 55 %. A colourless liquid. 1H NMR d: (200 MHz, CDCl3): 1.32 (t, J = 7.2 Hz, 3H), 1.59 ˜ 4.26 (k, (dd, J[19F–1H] = 24 Hz; J[1H–1H] = 6.9 Hz, 3H), J = 7.1 Hz, 2H), 5.00 (dk, J[19F–1H] = 49 Hz, ˜ ppm. 19F NMR d: (178, CDCl3): J[1H–1H] = 7.0 Hz, 1H) 185.1 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 120 (M+, 2), 61 (10), 47 (100), 46 (42), 45 (28). Analysis: found: C, 49.1%; H, 7.9%. Calculated for C5H9FO2 (120.12): C, 49.9%; H, 7.5%. 1-(p-Nitrophenyl)ethyl fluoride: a corresponding mesylate was used as a substrate. Yield: 80%. Yellow solid, mp
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35–37 8C. 1H NMR d: (200 MHz, CDCl3): 1.67 (dd, J[19F–1H] = 24 Hz, J[1H–1H] = 6.5 Hz, 3H), 5.74 (dk, J[19F–1H] = 47 Hz, J[1H–1H] = 6.5 Hz, 1H), 7.54 and 8.24 (AA‘XX’, 4H) ppm. 19F NMR d: (178 MHz, CDCl3): 173.1 (m) ppm. MS (EI, 70 eV): m/z (ion, rel. int.): 169 (M+, 100), 154 (59), 152 (29), 124 (23), 123 (54), 122 (21), 108 (14), 107 (19), 103 (45), 101 (11), 96 (24), 77 (70), 51 (22), 50 (30). Analysis: found: C, 57.0%; H, 4.6%; N, 8.1%. Calculated for C8H8FNO2 (169.16): C, 56.8%; H, 4.8%; N, 8.3%. 3.2. Synthesis of alkyl fluorides in the absence of tetrabutylammonium salts. typical procedure. Freshly dried KF (14.52 g, 250 mmol), Ph3SnF (1.84 g, 5 mmol) and an alkyl mesylate, tosylate or bromide (50 mmol) were stirred in sulfolane (35 mL) at 85–105 8C (bath temperature) till the reaction was completed (4–48 h). The reaction mixture was diluted with diethyl ether (60 mL) and treated with water (200 mL). The organic layer was removed and the inorganic phase with an insoluble solid (Ph3SnF) was extracted with ether (5 35 mL). The solid was filtered-off and dried. The combined extracts were washed with water (2 50 mL), dried and the solvent was distilled using a 20 cm Vigreux column. The products were purified by column chromatography (silica gel, n-pentane or n-pentane/CH2Cl2). 3.3. Synthesis of 1,1-difluoroalkanes Typical procedure: dried powdered KF (3.094 g, 53.3 mmol), Ph3SnF (98 mg, 0.27 mmol) Bu4N+ HSO4 (91 mg, 0.27 mmol) and a freshly prepared solution of RCH(OTf)2 in CH2Cl2 (2.7 mmol in 4.5 mL) were vigorously stirred at room temperature till the reaction was completed (16–48 h). The reaction mixture was diluted with ether (25 mL), the solid was filtered off, washed with ether (3 8 mL). The ether extracts were combined and the solvent was distilled using a 20 cm Vigreux column. The products were purified by chromatography (silica gel, n-pentane or n-pentane/CH2Cl2). 3.4. Kinetics of the reactions of tetrabutylammonium salts of hypervalent anions with benzyl bromide A solution of a hypervalent salt Q+R3MF2 (1 mmol) and biphenyl (50 mg, an internal standard) in acetonitrile (8 mL) was stirred at the defined temperature for 20 min then benzyl bromide (0.171 g, 1.0 mmol) was added via micro syringe. Samples of the mixtures were taken every 20 min and a concentration of benzyl bromide and benzyl fluoride were determined by GLC analysis. 3.5. Synthesis of tetrabutylammonium salts. Potassium fluoride (10–20 equiv.), R3MX (3.0 mmol), tetrabutylammonium hydrogensulfate (3.0 mmol) and sol-
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vent (MeCN or DMF; 7.5 mL) were placed in flask and heated with stirring at 60 8C for 24 h. The solid was filtered off and washed with the solvent used in the reaction (4 5 mL). The combined filtrates were evaporated and the residue was recrystallized from MeCN/Et2O. 3.6. Synthesis of potassium salts Potassium fluoride (10–20 equiv.), R3MX (1.0 mmol) and DMF (2.5 mL) were placed in flask and heated with stirring at 60 8C for 24 h. The solid was filtered off and washed with DMF (4 3 mL). The combined filtrates were evaporated and the residue was recrystallized from DMF/ Et2O. 3.7. Determining of rate constants of the reactions hypervalent salts with benzyl bromide Hypervalent salt Q+ R3MF2 (1.0 mmol) and biphenyl (0.050 g; an internal standard) were placed in a flask. Acetonitrile (8.0 mL) was added and the solution was stirred at corresponding temperature (temperature of the bath = 60 or 85 8C) for 20 min, to heat the solution to desired temperature. Then benzyl bromide (0.171 g; 1.0 mmol) was added via microsyringe. Samples were taken every 20 min in initial stage of the reactions (120 min), then once an hour. Concentrations of benzyl bromide and benzyl fluoride were determined by GC analysis.
Acknowledgements This work was generously supported by Bayer Pharma, Wuppertal, Germany. We thank Professor W. Dmowski for helpful discussion.
References [1] (a) R. Filler, Organofluorine compounds in medicinal chemistry and biomedical applications, in: R. Filler (Ed.), Studies in Organic Chemistry, vol. 48, Elsevier, New York, 1993, pp. 1–23; (b) R.L. Powell, 4th ed. Methods of Organic Chemistry, Additional and Suppl.vol, vol. E10a, Houben-Weyl, 1999(Chapter 6). [2] (a) L. Subramanian, R. Siegemund, 4th ed. Methods of Organic Chemistry, Additional and Suppl.vol, vol. E10a, Houben-Weyl, 1999 (Chapter A.14); (b) J.A. Wilkinson, Chem Rev. 92 (1992) 505–519. [3] (a) D. Landini, F. Montanari, F. Rolla, Synthesis (1974) 428–430; (b) C.L. Liotta, H.P. Harris, J. Am. Chem. Soc. 96 (1974) 225–2250. [4] (a) E.V. Dehmlow, S.S. Dehmlow, Phase Transfer Catalysis Principles, VCH, Weinheim, New York, 1978, Basel, Cambridge, Tokyo, 1993.; (b) M. Ma˛ kosza, M. Fedoryn´ ski, Adv. Catal. 35 (1987) 373–422; (c) M. Ma˛ kosza, M. Fedoryn´ ski, Catal. Rev. 45 (2003) 321–367. [5] W.A. Sheppard, C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969, pp. 9–17. [6] S. Dermeik, Y. Sasson, J. Org. Chem. 50 (1985) 879–882. [7] D. Landini, A. Maia, A. Rampoldi, J. Org. Chem. 54 (1989) 328–332.
216
M. Ma˛ kosza, R. Bujok / Journal of Fluorine Chemistry 126 (2005) 209–216
[8] (a) M. Ma˛ kosza, A. Chesnokov, Tetrahedron 56 (2000) 3553–3558; (b) M. Ma˛ kosza, A. Chesnokov, Tetrahedron 58 (2002) 7295–7301. [9] M. Gingras, Tetrahedron Lett. 32 (1991) 7381–7384. [10] L.A. Hobbs, P.J. Smith, J. Organomet. Chem. 206 (1981) 59–67. [11] (a) L.A. Mulard, P. Kovac, P.J. Glaudemans, Carbohydr. Res. 259 (1994) 117–129; (b) R. Noyori, I. Nishida, J. Sakata, J. Am. Chem. Soc. 105 (1983) 1598–1608. [12] (a) A.S. Pilcher, H.L. Ammon, P. DeShong, J. Am. Chem. Soc. 117 (1995) 5166–5167; (b) J. Kvı´cˇ ala, P. Mysı´k, O. Paleta, Synlett (2001) 547–549.
[13] R. Bujok, M. Ma˛ kosza, Synlett (2002) 1285–1286. [14] M. Ma˛ kosza, R. Bujok, Tetrahedron Lett. 45 (2004) 1385–1386. [15] E. Soli, A. Manoso, M. Patterson, P. De Shong, D. Favor, R. Hirschmann, A. Smith, J. Org. Chem. 64 (1999) 3171–3177. [16] (a) A. Garcı´a Martı´nez, J. Osı´o Barcina, M. del Rosario Colorado Heras, A. de Fresno Cereso, Org. Lett. 2 (2000) 1377–1378; (b) M.-R. Brescia, P. DeShong, J. Org. Chem. 63 (1998) 3156– 3157; (c) M.E. Movery, P. DeShong, J. Org. Chem. 64 (1999) 3266– 3270. [17] M. Ma˛ kosza, R. Bujok, Synlett (2004) 371–373.