Marian Dryzhakov

Joseph Moran

Autocatalytic Friedel-Crafts Reactions of Tertiary Aliphatic Fluorides Initiated by B(C6F5)3 H2O

Keywords: Friedel-Crafts, aliphatic fluoride, carbocations, Brønsted acid, autocatalysis

ABSTRACT:

The C-F bond is the strongest single bond to carbon, constituting an intrinsic challenge for selective catalytic activation in the presence of other functional groups. Existing methods for the activation of tertiary aliphatic fluorides in volve stoichiometric abstraction with fluorophilic Lewis acids or by Lewis acid catalysed trapping with Si reagents. Herein, we describe a B(C6F5)3•H2O catalyzed Friedel-Crafts reaction of tertiary alkyl fluorides that proceeds rapidly at room temperature without trapping reagents. The method is completely selective for F -over traditionally better leaving groups and displays an autocatalytic kinetic profile.

The use of organofluorine compounds in medicinal chemistry, polymer chemistry and material science is widespread owing to the unique nature of the C-F bond. 1 Possessing the highest electronegativity value (χ = 4 by the Pauling scale), 2 a fluorine atom forms the strongest single bond to carbon. 3 This bond is characterized by a short interatomic length (rW = 1.47 Å) as well as a high polarity. [START_REF] O'hagan | [END_REF] The electrostatic character and thermodynamic stability of the C-F bond makes it relatively inert and renders its selective cleavage in the presence of less robust functional groups challenging. Moreover, its low nucleofugality makes fluoride a poor leaving group. 5 The growing interest in densely functionalized organofluorine compounds as well as concerns associated with the environmental accumulation of persistent organofluorine compounds has generated interest in the selective cleavage of C-F bonds. Consequently, a variety of methods for the transformation of polyfluorinated molecules, mono-and polyfluorinated aromatics, as well as benzylic and allylic fluorides have recently been reported. [START_REF] Ahrens | transition metal catalyzed functionalization of polyfluorinated molecules[END_REF] Despite these advances, selective functionalization of C(sp 3 )-F bonds in simple unactivated aliphatic substrates is much less explored. [START_REF] Terao | For metal catalyzed coupling of primary alkyl fluorides with Grignard reagents[END_REF][START_REF] Matsubara | For low-yielding coupling with Grignard reagents in the absence of a metal catalyst[END_REF] A typical approach for the activation of fluoride as a leaving group relies on the stoichiometric use of fluorophilic B, Al or Ga Lewis acids or stoichiometric Si trapping reagents, a constraint apparently grounded in the thermodynamic need to form strong covalent bonds to fluorine. [START_REF] Stahl | For a review on main-group Lewis acid mediated activation of organofluorides[END_REF][START_REF] Ooi | For activation of organofluorides with stoichiometric Al Lewis acids[END_REF][START_REF] Namavari | For activation with stoichiometric B Lewis acid[END_REF][START_REF] Hirano | For activation with substoichiometric B Lewis acid in the presence of stoichiometric Si[END_REF][13] In a representative example from Olah and co-workers, stoichiometric amounts of boron trihalides or pseudohalides were used to abstract fluoride and to generate carbocations under cryogenic conditions en route to Friedel-Crafts reactions. 14 The harsh conditions did not discriminate between primary, secondary and tertiary aliphatic fluoride substitution patterns. The development of alternative and catalytic activation modes for aliphatic fluorides could open new possibilities for their chemoselective functionalization (Figure 1).

We recently disclosed that the presence of electron-rich nitro compounds as co-catalyst or as solvent leads to increased catalytic activity of strong Brønsted acids such as B(C6F5)3•H2O by inducing aggregation of the latter. 15 Although the existence of H-bonds to fluorine continues to be debated, 16 a growing number of reports on the use of H-bond donors to activate C-F bonds have recently appeared. 17 Inspired by the work of Paquin and co-workers on the activation of benzylic fluorides by high concentrations of H-bond donors, 17c we hypothesized that our more strongly H-bond donating system could enable the selective activation of the C(sp 3 )-F bond in tertiary aliphatic fluorides at low concentrations and with catalytic turnover. Gratifyingly, just 1 mol% of B(C6F5)3•H2O in nitromethane promotes the efficient Friedel-Crafts reaction of tertiary aliphatic fluoride 1a with 1,3-dimethoxybenzene in 10 min at ambient temperature (eq 1). 18 Reducing the catalyst loading to 0.2 mol% also led to complete conversion after 1 h under otherwise identical conditions.

Chemoselectivity is of vital importance when it is desirable to activate one strong covalent bond in the presence of others that are weaker. With suitable reaction conditions in hand, we speculated that the H-bond accepting nature of tertiary alkyl fluorides could make their selective activation possible over traditionally better leaving groups. Thus, a library of tertiary aliphatic halides, ethers and esters was prepared and tested. Indeed, the B(C6F5)3•H2O catalyst showed complete selectivity for the activation of the fluoride over other leaving groups even after prolonged reaction time, emphasizing the importance of the acid-fluorine interactions (Table 1, entries 1-7). We next set out to evaluate the influence of substitution pattern on reactivity. To the best of our knowledge, studies on the relative reactivity of mono-and difluorides have only been carried out for benzylic fluorides, 17c and there are no such studies for unactivated aliphatic systems. Furthermore, prior studies by Olah on the use of stoichiometric fluoride abstracting agents did not discriminate between primary, secondary and tertiary aliphatic fluorides. 14 To attack this problem, a library of mono-and disubstituted alkyl fluorides was synthesized and tested under our standard reaction conditions (Table 1, entries 8-11). Primary and secondary fluorides, as well as difluorinated analogues, were unreactive under the catalytic conditions, suggesting the intermediacy of a carbocation. a Determined by 1 H NMR using an internal standard. b Isolated yield.

The scope of suitable nucleophiles was next examined (Table 2). As a rule, common electron rich Friedel-Crafts nucleophiles were well tolerated, furnishing substitution products in good to high yields. Phenol and naphthol derivatives furnished products 2b-d. Halogen bearing arenes could be used as nucleophiles to deliver compounds 2l and 2m. Addition of hexafluoroisopropanol (HFIP) as a co-solvent was in some cases beneficial to the reaction outcome, as in the case of 2i and 2j. Indole nucleophiles furnished products 2e and 2h, albeit under elevated temperatures. Interestingly, in the case of 2h, C-and N-alkylated products could be isolated separately in an 11:1 ratio. Thiophene and furan could also be employed in this transformation to deliver 2f and 2g, though a diminished yield of the latter was obtained as a result of the fast competitive polymerization of furan under the acidic reaction conditions. Only trace quantities of bisalkylation were observed in the described reactions.

Table 2. Arene scope.

a Isolated yield after Kugelrohr distillation. b Isolated yield after silica gel chromatography. c MeNO2/HFIP (1:1) was used as a solvent d 5 equiv of nucleophile was used. e Reaction carried out at 90 °C. f Combined yield of C-and N-alkylation products, isolated separately in an 11:1 ratio. HFIP = 1,1,1,3,3,3-Hexafluoro-2propanol. (eq 1)

1a 2a, >95% GC yield 90% isolated yield (1 h) X R 2 R 1 B(C 6 F 5 ) 3 •H 2 O (1 mol%) 1,3-Dimethoxybenzene (5 equiv) MeNO 2 (1 M) 23 °C, 1 h R 2 R 1
OMe OMe Next, efforts were undertaken to test the range of tertiary aliphatic fluorides compatible with the productive Friedel-Crafts reaction. After accomplishing the synthesis of the novel fluorinated starting materials by deoxygenative fluorination of the corresponding alcohols, 19 we subjected them to standard catalytic conditions with 1,3-dimethoxybenzene as nucleophile. Halogen-bearing products 3b and 3c could be obtained in good yields as well as the more sterically demanding 3h. Alkyl fluoride 1d, prone to elimination, furnished the desired product 3d in 76% yield. Adamantyl fluoride 1i reacted well to give product 3i, just as substrates with elongated aliphatic chains were successfully coupled to furnish compounds 3e-g. Cyclohexyl-derived product 3j could also be obtained from the corresponding fluoride (Table 3).

Table 3. Tertiary aliphatic fluoride scope. a a Isolated yields after Kugelrohr distillation. Time-dependent NMR studies were carried out in order to gain insight into the nature of the catalytically active species in the Friedel-Crafts reaction. Reactions were carried out at 4 °C to ensure that their rates were sufficiently slow to effectively compare different conditions. In all cases, the reactions display an induction period and a sigmoid kinetic profile characteristic of autocatalytic systems. [START_REF] Bissette | For a review of mechanisms of autocatalysis[END_REF] Increasing the catalyst loading from 1 to 10 mol% decreased the induction period from about 220 to 60 minutes, but resulted in a comparable kinetic profile once the induction period had expired (Figure 2, green vs. maroon points). For comparison with B(C6F5)3•H2O (pKa = 8.6 in MeCN 21 ), initiating the reaction with 1 mol% TfOH (pKa = 0.7 in MeCN 22 ) and HF (calculated pKa = 25.2 in MeCN 23 ) resulted in induction periods of about 25 minutes and 200 minutes, respectively (Figure 1, blue and red points). Thus, despite the fact that the reaction is autocatalytic in HF, the initiating Brønsted acid catalyst plays an essential role. Autocatalytic reaction kinetics were previously observed by Paquin and co-workers for Friedel-Crafts reactions of benzylic fluorides using HFIP solvent as an H-bond donor to initiate the reaction after several hours. 17c Though the comparable kinetic profiles of B(C6F5)3•H2O and HF might initially be viewed as surprising since the former is a stronger acid by more than 14 orders of magnitude, HF is well known to undergo concentration-dependent homoassociation in organic solvents to form higher order aggregates that are much stronger Brønsted acids than the monomeric species. 24 A plausible set of catalytic cycles that accounts for all observations is shown in Figure 3. Alk methodology allows for the selective reaction of fluorides over other halides or oxygen-based leaving groups. The synthetic utility of this method is highlighted by that fact that, despite the nearly 140-year history of the Friedel-Crafts reaction, more than 90% of the simple products synthesized herein are new compounds. The observed autocatalytic kinetics are likely due to aggregation of in situ generated HF to generate a highly active Brønsted acid catalyst.

Figure 1 .

 1 Figure 1. Stoichiometric versus catalytic methods for Friedel-Crafts reactions of aliphatic fluorides.

Figure 2 .

 2 Figure 2. Time-dependent NMR study at 4 °C revealing an autocatalytic kinetic profile.

Figure 3 .

 3 Figure 3. Proposed autocatalytic mechanism.In conclusion, the Friedel-Crafts reaction of tertiary aliphatic fluorides has been rendered catalytic for the first time by using a Brønsted acid to initiate an autocatalytic reaction. A range of tertiary aliphatic fluorides was successfully coupled with a variety of electron rich arenes and heterocyclic compounds. Tertiary aliphatic fluorides react rapidly at room temperature in contrast to other aliphatic substitution patterns, pointing to an SN1-type mechanism. The user-friendly

Table 1 . Selectivity with respect to leaving group and substitution pattern.

 1

	Entry	X	R 1	R 2	Yield [%] a
	1	F	Me	Me	90 b
	2	Cl	Me	Me	<1
	3	Br	Me	Me	<1
	4	OH	Me	Me	<1
	5	OMe	Me	Me	<1
	6	OBn	Me	Me	<1
	7	OAc	Me	Me	<1
	8	F	Me	H	<1
	9	F	H	H	<1
	10	F	F	H	<1
	11	F	F	Me	<1

ACKNOWLEDGMENT

This work was supported in part by a LabEx CSC "Chemistry of Complex Systems" grant and the Marie Curie Actions FP7-PEOPLE Program (CIG-2012-326112). M.D. thanks the Région Alsace for a fellowship. We thank Stéphanie Kouaho (Service de Spectrométrie de masse, Université de Strasbourg), Yann Simon and Benedicte Gauriat (Thermo Fisher Scientific) for HRMS analysis.

ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

General experimental procedures, characterization data, 1 H, 13 C and 19 F spectra of products and new starting materials (PDF)

AUTHOR INFORMATION Corresponding Author

* E-mail: moran@unistra.fr

Notes

The authors declare no competing financial interest.


Marian Dryzhakov

Edward Richmond

Guang Li

Joseph Moran
email: moran@unistra.fr

Catalytic B(C6F5

Keywords: Aliphatic fluoride, Brønsted acid, catalysis, carbocation, alkyl azide, thioether Highlights

published or not. The documents may come

Introduction

The unique properties of organic molecules that bear fluorine atoms in their structures have long been appreciated by researchers in the fields of synthetic chemistry, medicine and material science [1]. This is primarily due to the impact of the strong and highly polar C-F bond on the stability, as well as lipophilicity, of such organofluorides [START_REF] O'hagan | [END_REF]. However, the great demand for fluorinated materials has also generated significant concern regarding their high resistance to decomposition and consequently their accumulation in the environment [START_REF] Neilson | Organofluorines[END_REF]. With fluorine forming the strongest and a notably short (rW = 1.47 Å) single bond to carbon [START_REF] Luo | Handbook of Bond Dissociation Energies in Organic Compounds[END_REF], the fluoride ion is traditionally considered a poor leaving group [START_REF] Nolte | [END_REF], thus explaining the chemical inertness of fluorinated substrates and the sluggishness of their environmental degradation. Although a number of methods have been developed to break C(sp 2 )-F bonds in mono-and polyfluorinated aromatics [6], as well as benzylic and allylic fluorides [7], the efficient cleavage of unactivated C(sp 3 )-F bonds in simple aliphatic substrates remains underdeveloped [START_REF] Terao | For couplings of alkyl fluorides with Grignard reagents in the presence of metal catalyst[END_REF]. Such transformations typically rely on the use of stoichiometric fluorophilic main group Lewis acids or the use of a Lewis acidic catalyst accompanied by stoichiometric fluoride-trapping silicon reagents (Figure 1 -Top) [START_REF]For a review on the topic[END_REF]. Thus, in addition to the high kinetic barrier for functionalization of unactivated C(sp 3 )-F bonds, competitive elimination processes from the intermediate carbocation often decrease the efficiency of target transformations [START_REF] Olah | Carbocation Chemistry[END_REF].

Our research group has recently engaged in efforts toward the generation and utilization of aliphatic carbocations from the corresponding alcohol precursors; transformations that can be catalyzed by the strong Brønsted acid tris(pentafluorophenyl)borane hydrate (B(C6F5)3•H2O) [11]. Using this commercially available catalyst, we subsequently disclosed the first catalytic [12] Friedel-Crafts reaction of tertiary aliphatic fluorides with activated (hetero)arenes [13], a transformation that previously required the use of stoichiometric fluorophilic reagents [14]. Herein we disclose the extension of this concept to the direct catalytic substitution of tertiary aliphatic fluorides with a range of heteroatomic nucleophiles, under benign reaction conditions that do not require stoichiometric activation (Figure 1 -Bottom).

Figure 1: Previous studies towards the catalytic substitution of tertiary aliphatic fluorides (top) and this work; the practical, catalytic substitution of tertiary aliphatic fluorides with a variety of nucleophile classes (bottom).

Results and discussion

As an entry point to the heteroatomic substitution of tertiary aliphatic fluorides, we elected to focus on the preparation of organic azides employing trimethylsilyl azide (TMSN3) as a functionalization agent. As well as being a potent nucleophile, we reasoned that the trimethylsilyl group would have the added benefit of acting as a fluoride trap in this transformation, thus favoring the accompanied formation of the target azide product. Catalytic methods to produce alkyl azides remain scarce [11b] and to the best of our knowledge, a single study on the catalytic azidation of tertiary alkyl fluorides using TMSN3 has been documented [9e], with the exception of a study specific to adamantyl fluoride [9c]. In all of three reported reactions, a minimum of 10 mol% of pyrophoric trialkylaluminium catalyst was used at cryogenic temperatures to provide alkyl azides, typically in less than 65% isolated yield, presumably due to competitive side reactions. With this in mind, we were delighted when our initial investigations into this reaction revealed that as little as 1 mol% of B(C6F5)3•H2O in nitromethane is enough to obtain synthetically useful yields of aliphatic azide products at room temperature (Table 1). Thus, homobenzylic tertiary aliphatic azides (2a-c) could be conveniently obtained after only 2 hours of reaction time, followed by a simple chromatographic purification. Elimination-prone substrates could also be employed, furnishing the desired products in good yield (2d). Conformationally restricted and cyclic aliphatic azides (2e and 2f, respectively) were also smoothly prepared according to the optimized conditions. Additionally, more complex structures, such as bisabolol-derived azide product (2g), are facile to obtain without noticeable competitive azidation or isomerization of acid-sensitive double bonds [15].

Table 1

Scope of defluorinative azidation reaction. a,b a Reagents and conditions: 1 (0.25 mmol), TMS-N3 (0.50 mmol), MeNO2 (0.125 mL), and B(C6F5)3•H2O (1 mol%). Reaction stirred at r.t. for 1 h. b Isolated yields after column chromatography.

Thioethers, the prototypical sulfur(II) compounds which have versatile applications in synthetic, biological and medicinal chemistry [START_REF] Cremlyn | An Introduction to Organosulfur Chemistry[END_REF], are another class of substrates that could conceivably be accessed through the interception of tertiary carbocations. Surprisingly, despite the utility of such substrates, synthetic methods to access tertiary thioethers appear to be rather limited compared to other substitution patterns [START_REF] Clayden | [END_REF]. Additionally, to the best of our knowledge, to date there are no reports that describe the catalytic preparation of such compounds from the corresponding fluorinated precursors [START_REF] Cain | For the use of stoichiometric Lewis or Brønsted acids for thioetherifaction of alcohol precursors[END_REF]. Applying our standard reaction conditions to the substitution of tertiary aliphatic fluorides with a variety of thiol nucleophiles yielded an array of tertiary aliphatic thioethers (Table 2). Typically, high yields of substitution products were obtained most probably as a result of the higher nucleophilicity of such S-centered nucleophiles. , as well as cyclic (3e, 3g) and fully saturated (3f) thioethers could be easily synthesized. In addition to thiophenol (3a-f), p-methoxyphenyl (PMP) thiol (3g) proved a competent nucleophile in this reaction. As a further demonstration of the B(C6F5)3•H2O-initiated functionalization of fluorinated substrates, we next sought to employ increasingly weaker nucleophiles. Surprisingly, to the best of our knowledge, little to no literature evidence exists for the substitution of tertiary alkyl fluorides to produce heteroatom-substituted products, such as alkyl ethers, carbamates and sulfonamides [START_REF]A Scifinder search[END_REF]. To this end, a series of O-, N-and C-centered nucleophiles were tested in this reaction manifold under our otherwise identical reaction conditions (Table 3). Thus, substitution of 1-fluoroadamantane with a variety of nucleophiles furnished a suite of adamantanes bearing synthetically useful functional groups (4a-e). As would be expected, silylated nucleophiles such as silyl enol ethers (4d) and allyltrimethylsilane (4g) proved competent reaction partners in this catalytic transformation. Oxygen-bearing nucleophiles were also well tolerated providing the corresponding ethers (4a and 4h) in moderate to excellent yields. Additionally, it was also possible to employ benzyl carbamate as a nucleophile in such transformations, although the corresponding acid-labile products (4f and 4i) were isolated in slightly diminished yield.

Table 3 Scope of defluorinative substitution with various nucleophiles. a, b a Reagents and conditions: 1 (0.25 mmol), NuH or TMSNu (0.50 mmol), MeNO2 (0.125 mL), and B(C6F5)3•H2O (1 mol%). Reaction stirred at r.t. for 1 h. b Isolated yields after column chromatography. c Reaction stirred at 50 °C for 1 h.

Our previous kinetic study on the closely related Friedel-Crafts reaction of tertiary aliphatic fluorides initiated by substoichiometric B(C6F5)3•H2O, revealed an autocatalytic reaction profile characterized by a short induction period at room temperature followed by rapid product formation once the induction period has expired [13]. Such an observation is consistent with the stoichiometric HF-byproduct being involved in the formation of a superior HF-derived Brønsted acid catalysts in solution [START_REF] Champagne | For the use of strong H-bond donors at high concentrations for activation of benzylic fluorides[END_REF]. In accordance with this knowledge, we suggest that the reactions described herein employing non-silylated nucleophiles also proceed by a similar B(C6F5)3•H2O-initiated autocatalytic pathway. However, in cases where silylated nucleophiles are employed, such as TMS-N 3 (Table 1), the reaction is not autocatalytic, as the fluoride anion is trapped by silicon. Thus, activation of the tertiary aliphatic fluoride by B(C6F5)3•H2O initiates heterolytic cleavage to generate the tertiary aliphatic carbocation which is intercepted by the silylated nucleophile. Concomitantly, the liberated fluoride is scavenged by the silyl group giving the TMS-F byproduct and allowing the regenerated B(C6F5)3•H2O to re-enter the catalytic cycle (Figure 2). However, an alternative pathway involving activation of TMS-N3 by the Brønsted acid with subsequent silylation-abstraction of fluoride by electrophilic silicon cannot be excluded. In conclusion, the catalytic defluorinative substitution of tertiary aliphatic fluorides with a variety of nucleophiles has been described. Proceeding at ambient temperature and employing only 1 mol% of a commercially available Brønsted acid catalyst, the generality of this simple and highly tractable methodology has been exemplified through the preparation of a range of S-, O-, N-, and C-substituted products. To the best of our knowledge, this is the first study where such functionalized products (thioethers, ethers, carbamates, sulfonamides) have been accessed via simple catalytic substitution of a fluorinated tertiary C(sp 3 ) center. In other cases, for example azidation and alkylation reactions, prior routes have relied on the use of pyrophoric activation reagents and cryogenic reaction conditions. The described methodology therefore provides an immensely simplified and attractive variant to such substitution reactions with much practical appeal.

Experimental

3.1 General Information. All reagents and solvents were used as received without purification unless otherwise stated. General laboratory techniques were used throughout, and no special precautions were taken to exclude air or moisture from the reactions unless otherwise stated. Elevated temperatures were achieved by way of a stirrer-hotplate, heating block and thermocouple. Where applicable, analytical thin layer chromatography was performed on pre-coated aluminium plates (Kieselgel 60 F254 silica). TLC visualisation was carried out with ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO4 solution. Flash column chromatography was performed on Kieselgel 60 silica eluting with the solvent system stated. 1 H, 13 C and 19 F nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance II 400 (400 MHz 1 H, 100 MHz 13 C, 376 MHz 19 F) spectrometer at ambient temperature in the deuterated solvent stated. All chemical shifts are quoted in parts per million (ppm) relative to the residual solvent as the internal standard. Data are reported as: multiplicity (ap = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, oct = octet, non = nonet, m = multiplet), integration and coupling constant(s) in Hz. Melting points were obtained on a Büchi Melting Point B-450 apparatus, and high resolution mass spectra were obtained on an Agilent Technologies LCMS (ESI) or (EI) system.

Materials.

Unless otherwise noted, all commercial materials were purchased from Sigma-Aldrich and used without further purification. The substrates 3-bromo-3-methyl-1-phenylbutane [21], 3-chloro-3-methyl-1phenylbutane [21], 3-methoxy-3-methyl-1-phenylbutane [22], benzyl 1,1-dimethyl-3-phenylpropyl ether [11b], 1,1-dimethyl-3-phenylpropyl acetate [ 23 ] were prepared according to a literature procedure. Tris(pentafluorophenyl)borane B(C6F5)3 was purchased from Alfa Aesar and used under air, without any precaution to exclude moisture or air. B(C6F5)3 is known to rapidly hydrate to B(C6F5)3•H2O under these conditions [24].

Preparation of Tertiary Aliphatic Fluorides

Aliphatic fluorides 1a-i were prepared as previously reported according to the general procedures outlined below with identical spectral data [13].

General Procedure A To a solution of alcohol (9.75 mmol) in dry CH2Cl2 (30 mL) at -78 °C, was added (diethylamino)sulfur trifluoride (2.60 mL, 3.14 g, 19.5 mmol, 2.00 equiv). The mixture was slowly warmed to room temperature and stirred for 2 h. The reaction was diluted with CH2Cl2, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo (< 20 °C). The residue was purified by silica gel chromatography (Petroleum ether) to afford the desired product.

Characterization Data for Novel Starting Materials

4-(2-Fluoro-6-methylhept-5-en-2-yl)-1-methylcyclohex-1-ene 1g

The title compound was prepared as an inconsequential, inseparable mixture of diastereomers according to General Procedure A from (-)-α-bisabolol (1454 mg, 6.5 mmol). Isolated (1000 mg, 69%) as a colorless oil after column chromatography (Petroleum ether 100%). Rf = 0.3 (100% Petroleum ether). Diastereomeric ratio [2.5:1]. 1 H NMR (400 MHz, CDCl3)  5.42(1H, m), 5.17

Defluorinative Substitution Reaction Procedure

General Procedure B To a 2 mL disposable vial containing the requisite aliphatic fluoride 1 (0.25 mmol, 1 equiv) in nitromethane (0.125 mL, 2.0 M) was added the requisite nucleophile (0.50 mmol, 2 equiv), followed by B(C6F5)3•H2O (1.3 mg, 2.5 µmol, 1.0 mol%). The vial was capped and the mixture allowed to stir for 1 h at room temperature (23 °C), unless another temperature is specified in the procedure. At completion, the reaction mixture was directly dry loaded onto silica and purified by column chromatography over silica according to the conditions given. For reactions at elevated temperatures, an identical procedure was followed, however the reaction was performed in a 10 mL screw-top vial. The desired temperature was achieved using a heating block and contact thermometer.

Characterization Data for Substitution Products (3-Azido-3-methylbutyl)benzene 2a

The title compound was prepared according to General Procedure B from fluoride 1a (42 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (41 mg, 87%) as a colorless oil after column chromatography over silica (Petroleum ether 95%, Et2O 5%). Rf = 0.39 (Petroleum ether 95%, Et2O 5%). 1 H NMR (400 MHz, CDCl3)  7.37-7.24 (5H,m), 2.77-2.71 (2H, m), 1.88-1.83 (2H, m), 1.40 (s, 6H); 13 C NMR (100 MHz, CDCl3)  141. 9, 128.5, 128.3, 126.0, 61.5, 43.6, 30.8, 26.1. Analytical data are in accordance with the literature [11b].

1-(3-Azido-3-methylbutyl)-4-chlorobenzene 2b

The title compound was prepared according to General Procedure B from fluoride 1b (50 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (48 mg, 86%) as a colorless oil after column chromatography over silica (Petroleum ether 99.8%, Et2O 0.2%). Rf = 0.18 (Petroleum ether 99.8%, Et2O 0.2%). 1 H NMR (400 MHz, CDCl3)  7.30 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.3 Hz), 2.73-2.68 (2H, m), 1.83-1.78 (2H, m), 1.39 (6H, s); 13 C NMR (100 MHz, CDCl3)  140. 3, 131.7, 129.7, 128.6, 61.3, 43.4, 30.1, 26.1. Analytical data are in accordance with the literature [11b].

1-(3-Azido-3-methylbutyl)-4-bromobenzene 2c

The title compound was prepared according to General Procedure B from fluoride 1c (61 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (56 mg, 84%) as a colorless oil after column chromatography over silica (Petroleum ether 99.8%, Et2O 0.2%). Rf = 0.35 (Petroleum ether 99.8%, Et2O 0.2%). 1 H NMR (400 MHz, CDCl3)  7.40 (2H, d, J = 8.2 Hz), 7.07 (2H, d, J = 8.2 Hz), 2.66-2.61 (2H, m), 1.77-1.73 (2H, m), 1.33 (6H, s); 13 C NMR (100 MHz, CDCl3)  140. 8, 131.5, 130.1, 119.7, 61.3, 43.4, 30.2, 26.1. Analytical data are in accordance with the literature [11b].

(2-Azido-2-methylpropyl)benzene 2d

The title compound was prepared according to General Procedure B from fluoride 1d (38 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (33 mg, 74%) as a colorless oil after column chromatography over silica (Petroleum ether 99%, Et 2 O 1%). R f = 0.15 (Petroleum ether 99%, Et 2 O 1%). 1 H NMR (400 MHz, CDCl3)  7.40-7.26 (5H, m), 2.83 (2H, s), 1.33 (6H, s); 13 C NMR (100 MHz, CDCl3)  136. 8, 130.5, 128.1, 126.8, 61.8, 47.6, 26.0. Analytical data are in accordance with the literature [11b].

1-Azidoadamantane 2e

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (34 mg, 77%) as a white solid after column chromatography over silica (Petroleum ether 99.5%, Et2O 0.5%). Rf = 0.23 (Petroleum ether 99.5%, Et2O 0.5%).

1 H NMR (400 MHz, CDCl3)  2.20 (3H, s), 1.84 (6H, app. d. J = 2.7 Hz), 1.71 (6H, q, J = 10.8 Hz); 13 C NMR (100 MHz, CDCl3)  59.0, 41. 5, 35.9, 29.8. Analytical data are accordance with the literature [11b].

1-Azido-1-butylcyclohexane 2f

The title compound was prepared according to General Procedure B from fluoride 1f (40 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (40 mg, 89%) as a colorless liquid after column chromatography over silica (Petroleum ether 100%). Rf = 0.38 (Petroleum ether 100%). 1 H NMR (400 MHz, CDCl3)  1. 68-1.50 (10H, m), 1.39-1.22 (6H, m), 0.92 (3H, t, J = 6.8 Hz); 13 C NMR (100 MHz, CDCl3)  64. 2, 40.0, 34.7, 25.6, 25.5, 23.2, 22.3, 14.1. Analytical data are in accordance with the literature [11b].

4-(2-Azido-6-methylhept-5-en-2-yl)-1-methylcyclohex-1-ene 2g

The title compound was prepared as an inseparable mixture of diastereomers according to General Procedure B from fluoride 1g (56 mg, 0.25 mmol) and trimethylsilyl azide (0.066 mL, 0.50 mmol). Isolated (42 mg, 68%) as colorless oil after column chromatography over silica (Petroleum ether 99.7%, Et2O 0.3%). Rf = 0.25 (Petroleum ether 99.7%, Et2O 0.3%). Diastereomeric ratio [1:1]. Due to the overlapping signals, the NMR data is reported cumulatively for both diastereomers. 1 H NMR (400 MHz, CDCl3)  5.39 (ap. d, 1H, J = 5.1 Hz), 5.12 (ap. t, 1H, J = 6.9 Hz), 2.08-2.00 (m, 5H), 1.89-1.78 (m, 2H), 1.71 (3H, s), 1.67 (3H, s), 1.64 (3H, s), 1. 61-1.54 (2H, m), 1.36-1.22 (5H, m). Analytical data are accordance with the literature [11b].

(2-Methyl-4-phenylbutan-2-yl)(phenyl)sulfane 3a

The title compound was prepared according to General Procedure B from fluoride 1a (42 mg, 0.25 mmol) and thiophenol (0.052 mL, 0.50 mmol). Isolated (60 mg, 94%) as a white solid after column chromatography over silica (Petroleum ether 99%, Et2O 1%). Rf = 0.20 (Petroleum ether 99%, Et2O 1%). 1 H NMR (400 MHz, CDCl3)  7.58 (2H, dd, J = 7.6, 1.4 Hz), 7.39-7.26 (5H, m), 7.22-7.19 (3H, m), 2.87-2.83 (m, 2H), 1.82-1.78 (m, 2H), 1.34 (s, 6H); 13 C NMR (100 MHz, CDCl3)  142. 5, 137.5, 132.3, 128.8, 128.6, 128.4, 128.4, 125.8, 49.2, 44.3, 31.4, 29.0. Analytical data are in accordance with the literature [25].

(4-(4-Chlorophenyl)-2-methylbutan-2-yl)(phenyl)sulfane 3b

The title compound was prepared according to General Procedure B from fluoride 1b (50 mg, 0.25 mmol) and thiophenol (0.052 mL, 0.50 mmol). Isolated (67 mg, 92%) as a white solid after column chromatography over silica (Petroleum ether 99%, Et 2 O 1%). R f = 0.14 (Petroleum ether 99%, Et 2 O 1%). mp 45-47 °C; 1 H NMR (400 MHz, CDCl3)  7.59 (2H, d, J = 6.8 Hz), 7.44-7.37 (3H, m), 7.29 (2H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.2 Hz), 2.87-2.83 (m, 2H), 1.80-1.76 (m, 2H), 1.36 (s, 6H); 13 C NMR (100 MHz, CDCl3)  140.9, 137. 5, 132.1, 131.5, 129.7, 128.8, 128.6, 128.5, 49.1, 44.1, 30.8, 29.0; HRMS (ESI) for [M+K] C17H19 35 ClSK found 329.0554, calcd. 329.0528 (-7.9 ppm).

(4-(4-Bromophenyl)-2-methylbutan-2-yl)(phenyl)sulfane 3c

The title compound was prepared according to General Procedure B from fluoride 1c (61 mg, 0.25 mmol) and thiophenol (0.052 mL, 0.50 mmol). Isolated (72 mg, 87%) as a white solid after column chromatography over silica (Petroleum ether 99%, Et2O 1%). Rf = 0.15 (Petroleum ether 99%, Et2O 1%). mp 49-50 °C; 1 H NMR (400 MHz, CDCl3) m),m),m),2.79 (2H,dt,J = 8.1,4.3 Hz),m), 1.32 (s, 6H); 13 C NMR (100 MHz, CDCl3)  141. 4, 137.5, 132.1, 131.5, 130.2, 128.8, 128.6, 119.5, 49.1, 44.0, 30.8, 29.0; HRMS (ESI) for [M+K] C17H19 79 BrSK found 373.0025, calcd. 373.0022 (-0.58 ppm).

(2-Methyl-1-phenylpropan-2-yl)(phenyl)sulfane 3d

The title compound was prepared according to General Procedure B from fluoride 1d (38 mg, 0.25 mmol) and thiophenol (0.052 mL, 0.50 mmol). Isolated (55 mg, 90%) as a colorless oil after column chromatography over silica (Petroleum ether 99%, Et2O 1%). Rf = 0.13 (Petroleum ether 99%, Et2O 1%). 1 H NMR (400 MHz, CDCl3)  7.63 (2H, d, J = 6.4 Hz), 7.44-7.37 (3H, m), 7.35-7.28 (3H, m), 7.23-7.21 (2H, m), 2.95 (m, 2H), 1.26 (s, 6H); 13 C NMR (100 MHz, CDCl3)  137. 8, 137.7, 132.1, 130.8, 128.8, 128.6, 127.9, 126.4, 49.3, 49.0, 28.1; HRMS (ESI) for [M+K] C16H18SK found 281.0761, calcd. 281.0761 (+0.06 ppm).

1-Adamantanyl(phenyl)sulfane 3e

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and thiophenol (0.052 mL, 0.50 mmol). Isolated (57 mg, 94%) as a white solid after column chromatography over silica (Petroleum ether 99%, Et2O 1%). Rf = 0.27 (Petroleum ether 99%, Et2O 1%). 1 H NMR (400 MHz, CDCl3)  7.52-7.48 (2H, m), 7.38-7.26 (3H, m), 2.01 (s, 3H), 1.84-1.80 (m, 6H), 1.66-1.58 (m, 6H); 13 C NMR (100 MHz, CDCl3)  131. 7, 130.6, 128.6, 128.3, 47.9, 43.6, 36.2, 30.0. Analytical data are in accordance with the literature [13].

(2,6-Dimethylheptan-2-yl)(phenyl)sulfane 3f

The title compound was prepared according to General Procedure B from fluoride 1h (40 mg, 0.25 mmol) and thiophenol (0.051 mL, 0.50 mmol). Isolated (50 mg, 85%) as a colorless liquid after column chromatography over silica (100% Petroleum ether). Rf = 0.30 (100% Petroleum ether). 1 H NMR (400 MHz, CDCl3)  7.52-7.50 (2H, m), 7.38-7.29 (3H, m), 1.59-1.51 (1H, m), 1.49-1.40 (4H, m), 1.23 (6H, s), 1.17-1.12 (2H, m), 0.90 (3H, s), 0.88 (3H, s); 13 C NMR (100 MHz, CDCl3)  137. 7, 132.6, 128.7, 128.5, 49.6, 42.8, 39.5, 28.9, 28.1, 22.8, 22.7. Analytical data are in accordance with the literature [26].

(1-Butylcyclohexyl)(4-methoxyphenyl)sulfane 3g

The title compound was prepared according to General Procedure B from fluoride 1f (40 mg, 0.25 mmol) and 4-methoxythiophenol (0.061 mL, 0.50 mmol). Isolated (55 mg, 95%) as a colorless liquid after column chromatography over silica (100% petroleum ether). Rf = 0.27 (Petroleum ether 99%, Et2O 1%). 1 H NMR (400 MHz, CDCl 3 )  7. 41-7.37 (2H, m), 6.86-6.82 (2H, m), 3.82 (3H, s), 1.79-1.76 (2H, m), 1.58-1.41 (8H, m), 1.36-1.27 (6H, m), 0.94 (3H, t, J = 7.3 Hz); 13 C NMR (100 MHz, CDCl3)  160. 2, 139.0, 122.9, 114.1, 55.4, 53.9, 38.7, 36.2, 26.2, 25.8, 23.3, 22.4, 14.4; HRMS (ESI) for [M+K] C17H26OSK calcd. 317.1336, found 317.1292.

1-Phenethoxyadamantane 4a

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and 2-phenylethanol (0.060 mL, 0.50 mmol), however the reaction was performed at 50 °C. Isolated (59 mg, 92%) as a colorless oil after column chromatography over silica (95% Petroleum ether, 5% EtOAc). Rf = 0.29 (Petroleum ether 97%, EtOAc 3%). 1 H NMR (400 MHz, CDCl3)  7. m),3.61 (2H,t,J = 7.6 Hz),2.83 (2H,t,J = 7.6 Hz),2.13 (3H,br s),1.74 (6H,ap. d,J = 2.8 Hz),m); 13 C NMR (100 MHz, CDCl3)  139. 5, 129.1, 128.3, 126.2, 72.3, 61.4, 41.7, 37.7, 36.6, 30.6; HRMS (ESI) for [M+Na] C18H24ONa found 279.1730, calcd. 279.1719 (-3.9 ppm).

N-(Adamantan-1-yl)-4-methylbenzenesulfonamide 4b

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and p-toluenesulfonamide (86 mg, 0.50 mmol). Isolated (72 mg, 95%) as a white solid after column chromatography over silica (90% Petroleum ether, 10% EtOAc). Rf = 0.15 (Petroleum ether 90%, EtOAc 10%). mp 167-168 °C; 1 H NMR (400 MHz, CDCl3)  7.78 (2H,d,J = 8.4 Hz),m), 4.44 (1H, br s), 2.42 (3H, s), 2.01 (3H, br s), 1.79 (6H, d, J = 2.7 Hz), 1.62-1.54 (6H, m); 13 C NMR (100 MHz, CDCl3)  142. 8, 141.3, 129.5, 127.0, 55.1, 43.1, 36.0, 29.6, 21.6. Analytical data are in accordance with the literature [27].

1-Allyladamantane 4c

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and allyltrimethylsilane (0.057 mL, 0.50 mmol). Isolated (31 mg, 70%) as a colorless liquid after column chromatography over silica (100% petroleum ether). As with previous literature preparations of the material, the NMR spectra show traces of impurities [28]. Rf = 0.83 (Petroleum ether 100%). 1 H NMR (400 MHz, CDCl3)  5.84 (1H, ddtd, J = 16.9, 10.1, 7.5, 0.7 Hz), 5.03-4.94 (2H, m), 1.95 (3H, br s), 1.82 (1H, d, J = 7.5 Hz), 1.72-1.60 (6H, m), 1.49-1.47 (6H, m); 13 C NMR (100 MHz, CDCl3)  135. 1, 116.6, 49.2, 42.6, 37.3, 33.0, 28.8. Analytical data are in accordance with the literature [28].

2-(Adamantan-1-yl)-1-phenylethanone 4d

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and 1-phenyl-1-trimethylsiloxyethylene (96 mg, 0.50 mmol). Isolated (60 mg, 94%) as a colorless oil after column chromatography over silica (Petroleum ether 99%, Et2O 1%). Rf = 0.29 (Petroleum ether 100%). 1 H NMR (400 MHz, CDCl3)  7.97-7.94 (2H, m), 7.57-7.53 (1H, m), 7.48-7.43 (2H, m), 2.73 (2H, s), 1.95 (3H, br s), 1.71-1.61 (12H, m); 13 C NMR (100 MHz, CDCl3)  200. 4, 139.0, 132.8, 128.5, 128.5, 51.3, 43.1, 36.9, 34.1, 28.8. Analytical data are in accordance with the literature [29].

2-(Adamantan-1-yl)-1,3-diphenylpropane-1,3-dione 4e

The title compound was prepared according to General Procedure B from fluoride 1e (39 mg, 0.25 mmol) and dibenzoylmethane (112 mg, 0.50 mmol). Isolated (70 mg, 78%) as a white solid after column chromatography over silica (96% Petroleum ether, 4% EtOAc). Rf = 0.24 (Petroleum ether 95%, EtOAc 5%). mp 212-214 °C; 1 H NMR (400 MHz, CDCl3)  8.01 -7.98 (4H, m), 7.56-7.52 (2H, m), 7.47-7.43 (4H, m), 5.47 (1H, s), 1.97 (3H, br s), 1.88 (6H, ap. d. J = 2.8 Hz), 1.66 (6H, br s); 13 C NMR (100 MHz, CDCl 3 )  194. 3, 138.7, 133.1, 128.9, 128.5, 64.1, 41.2, 39.7, 36.8, 28.9. Analytical data are in accordance with the literature [30].

Benzyl (1-butylcyclohexyl)carbamate 4f

The title compound was prepared according to General Procedure B from fluoride 1f (40 mg, 0.25 mmol) and benzyl carbamate (76 mg, 0.50 mmol). Isolated (39 mg, 54%) as a pale yellow liquid after column chromatography over silica (95% Petroleum ether, 5% EtOAc). Rf = 0.43 (Petroleum ether 95%, EtOAc 5%). 1 H NMR (400 MHz, CDCl3)  7.37-7.31 (5H, m), 5.06 (2H, s), 4.50 (1H, br s), 1.97-1.92 (2H, m), 1.71-1.66 (2H, m), 1.58-1.15 (12H, m), 0.88 (3H, t, J = 7.1 Hz); 13 C NMR (100 MHz, CDCl3)  154. 5, 137.1, 128.6, 128.1, 66.0, 55.0, 38.2, 35.1, 25.9, 25.4, 23.2, 21.8, 14.3; HRMS (ESI) for [M+K] C18H27NO2K found 328.1676, calcd. 328.1673 (-0.69 ppm).

4,4-Dimethyldodec-1-ene 4g

The title compound was prepared according to General Procedure B from fluoride 1i (44 mg, 0.25 mmol) and trimethylallylsilane (0.057 mL, 0.50 mmol). Isolated (22 mg, 43%) as a colourless liquid (>90% purity) after column chromatography over silica (100% Petroleum ether). Rf = 0.90 (Petroleum ether 100%). 1 H NMR (400 MHz, CDCl3)  5.82 (1H,ddt,J = 16.7,10.4,7.4 Hz),m), 1.94 (2H, dt, J = 7.5, 1.1 Hz), 1. 31-1.17 (14H, m), 0.92-0.88 (3H, m), 0.87-0.85 (6H, m); 13 C NMR (100 MHz, CDCl3)  136. 2, 116.5, 46.6, 42.1, 33.2, 32.1, 30.8, 29.8, 29.5, 27.2, 24.1, 22.8, 14.3. Analytical data are in accordance with the literature [31].

1-Chloro-4-(3-methyl-3-(3-phenylpropoxy)butyl)benzene 4h

The title compound was prepared according to General Procedure B from fluoride 1b (50 mg, 0.25 mmol) and 3-phenylpropan-1-ol (0.068 mL, 0.50 mmol). Isolated (46 mg, 58%) as a colorless oil after column chromatography over silica (97% Petroleum ether, 3% EtOAc). Rf = 0.32 (Petroleum ether 97%, EtOAc 3%). 1 H NMR (400 MHz, CDCl3)  7. 30-7.19 (7H, m), (2H, d, J = 8.3 Hz), 3.36 (2H, t, J = 6.4 Hz), 2.71 (2H, t, J = 7.7 Hz), 2.64-2.59 (2H, m), 1.92-1.85 (2H, m), 1.75-1.70 (2H, m), 1.20 (6H, s); 13 C NMR (100 MHz, CDCl3)  142. 3, 141.6, 131.4, 129.8, 128.6, 128.5, 128.4, 125.8, 74.1, 60.4, 42.5, 32.7, 32.2, 29.8, 25.7; HRMS (ESI) for [M+Na] C20H25 35 ClONa found 339.1488, calcd. 339.1486 (-0.52 ppm).

Benzyl (4-(4-bromophenyl)-2-methylbutan-2-yl)carbamate 4i

The title compound was prepared according to General Procedure B from fluoride 1c (61 mg, 0.25 mmol) and benzyl carbamate (76 mg, 0.50 mmol). Isolated (37 mg, 39%) as a colorless oil after column chromatography over silica (95% Petroleum ether, 5% EtOAc). Rf = 0.21 (Petroleum ether 95%, EtOAc 5%). 1 H NMR (400 MHz, CDCl3)  7.38-7.30 (7H, m), 7.02 (2H, d, J = 7.4 Hz), 5.06 (2H, s), 4.66 (1H, br s), 2.54-2.50 (2H, m), 1.99-1.95 (2H, m), 1.34 (6H, s); 13 C NMR (100 MHz, CDCl 3 )  154. 5, 141.2, 136.7, 131.4, 130.2, 128.6, 128.1, 128.1, 119.4, 66.1, 52.8, 41.7, 30.2, 27.3

Figure 2

 2 Figure 2 Plausible catalytic cycles.

  (1H, ap. t, J = 7.0 Hz), 2.19-1.81 (9H, m), 1.73 (3H, s), 1.70 (3H, s), 1.66 (3H, s), 1.39-1.27 (5H, m); 13 C NMR (100 MHz, CDCl3)  133.8, 131.8, 124.2, 120.5, 98.5 (d, 1 JCF = 168.7 Hz), 42.2 (d, 2 JCF = 22.2 Hz), 37.3 (d, 2 JCF = 22.2 Hz),30.8, 26.1 (d, 3 JCF = 6.1 Hz),25.7, 23.9 (d, 3 JCF = 7.3 Hz), 23.4, 22.0 (d, 3 JCF = 4.6 Hz), 21.4 (d, 2 JCF = 25.3 Hz); 19 F NMR (376 MHz, CDCl3; CF3CO2Hext. std.)  -150.7 (m); HRMS (EI) for C15H25F [M + ]: calcd. 224.1940; found 224.1934.

Table 2

 2 Scope of defluorinative thioether formation. a, b

;

  HRMS (ESI) for [M+K] C19H22 79 BrNO2K found 414.0446, calcd. 414.0465 (+4.7 ppm).

Acknowledgements

This work was supported in part by a LabEx CSC "Chemistry of Complex Systems" grant and the Marie Curie Actions FP7-PEOPLE Program (No. CIG-2012-326112). M.D. and E.R. thank the Région Alsace and the Leverhulme Trust for fellowships, respectively.