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A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and their chemoselective hydrogenation to β-fluoroalkyl sulfones
Journal of Fluorine Chemistry 206 (2018) 108–116
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and their chemoselective hydrogenation to β-fluoroalkyl sulfones ⁎
Daniel M. Sedgwicka,b, Raquel Romána,b, Pablo Barrioa, , Cristina Moralesa, Santos Fusteroa,b, a b
T
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Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords: Regioselectivity Alkynyl sulfones β-Fluorovinyl sulfones Hydrogenation Chemoselectivity β-Fluoroalkyl sulfones
A highly regioselective, metal-free hydrofluorination reaction of alkynyl sulfones was developed using TBAF—one of the cheapest and most commonly available fluoride sources. In addition, the reactivity of the resulting β-fluorovinyl sulfones was studied, focusing on their selective hydrogenation reaction. Both β-fluorovinyl sulfones and their hydrogenation products β-fluoroalkyl sulfones may find applications in medicinal and agrochemical sciences.
1. Introduction Fluorine is increasingly relevant in a variety of fields, such as agrochemistry, materials science and medicinal chemistry. The fluorine atom has become a routine addition in the search for new molecular entities in drug development, due to the unique characteristics of the CeF bond [1–3]. Being the most electronegative element, the carbonfluoride bond is among the most polarized in organic chemistry, allowing chemists to modify certain features of bioactive molecules, including metabolic stability, acidity/basicity, and lipophilicity. In certain cases, the effect of the fluorine atom on a functional group can be significant. For example, due to their altered electronic arrangement, vinyl fluorides might be used as bioisosteres for the peptide bond [4–6]. Vinyl fluorides, therefore, are increasingly important in organic and medicinal chemistry due to new applications and their increasing ease of preparation thanks to advances in synthetic fluorine chemistry [7]. Sulfones are similarly versatile synthetic building blocks [8–10]. Their strongly electron-withdrawing nature increases the acidity of the adjacent hydrogen atoms and allows the α carbon to be used as a nucleophile in CeC bond forming processes such as the Julia olefination and the Ramberg-Bäcklund reaction. This same electron-withdrawing character places vinyl sulfones among the most electron-deficient CeC double bonds, making them viable electrophiles in Michael additions and cycloaddition processes. For these reasons, fluorinated vinyl sulfones are expected to be not only useful in chemical synthesis, but also have potential applications in medicinal and agrochemical sciences [11]. However, methods to produce fluorinated vinylsulfones are
⁎
scarce. Although there are several methods to synthesize the related αfluorovinyl sulfones [12,13], to the best of our knowledge only two such reports deal with the synthesis of the β-fluoro analogs (Scheme 1a) [14,15]. A recent report by Hammond and co-workers outlines a strategy to produce the desired products, although their method requires the use of an expensive gold catalyst [15]. Other reports on similar substrates have presented problems with regioselectivity [16]. The selective hydrogenation of vinyl fluorides to alkyl fluorides remains an underrepresented field; only a handful of studies have been reported [17–22]. This could be due to the intrinsic difficulties associated with the transformation: (1) only recently have new advances in fluorine chemistry allowed the facile synthesis of the vinyl fluoride precursors; and (2) the CeX bond has a tendency to undergo hydrodehalogenation, thus resulting in a mixture of the desired product and the dehalogenated derivative. For this reason, vinyl halides are generally seen as poor substrates for hydrogenation reactions. However, of the vinyl halides, fluorides are perhaps the most commonly used given the relative strength of the C—F bond when compared to its chloride, bromide and iodide counterparts. Nevertheless, no examples of hydrogenation of fluorovinyl sulfones have been previously reported. Furthermore, in the vast majority of known examples of this transformation, the fluorine atom is adjacent to a carbonyl group, or a perfluorinated substrate is used. There are very few studies that include substrates presenting the fluorine atom in the β-position [23], with the exception of specific gem-difluorinated acrylic acids [24] and α,β-difluoro-α,β-unsaturated carbonyl compounds [18] (Scheme 1b). Herein we disclose a metal-free and regioselective synthetic
Corresponding authors at: Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain. E-mail addresses: [email protected] (P. Barrio), [email protected] (S. Fustero).
https://doi.org/10.1016/j.jfluchem.2017.12.016 Received 27 November 2017; Received in revised form 20 December 2017; Accepted 21 December 2017 Available online 23 December 2017 0022-1139/ © 2017 Elsevier B.V. All rights reserved.
Journal of Fluorine Chemistry 206 (2018) 108–116
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Scheme 1. a) Previous examples of the synthesis of β-fluorovinyl sulfones. b) Previous examples of hydrogenation of α- fluoro- α, β-unsaturated carbonyl compounds with a heterogeneous palladium catalyst. c) This work: metal-free synthesis of β-fluorovinyl sulfones under mild conditions and their hydrogenation to the corresponding β-fluoroalkyl sulfones.
anhydrous THF, molecular sieves, lower temperatures and other less hygroscopic fluoride sources (TBAT, TMAF, ZnF2, KHF2, NaF, TBAF@ SiO2) all failed to improve the yield of 2a. Therefore, we decided to run several control experiments to understand how the reaction might proceed (Scheme 3). Alkynyl sulfone 1a and fluorovinyl sulfone 2a are both stable in a mixture of THF/water, and 2a does not react further even in the presence of TBAF. However, the addition of 1 equivalent of LiOH to 2a resulted in a 1:1:1 mixture of alkynyl sulfone 1a, unreacted 2a, and βketo sulfone 3a, suggesting that the slightly basic reaction conditions were responsible for the formation of the undesired ketone. Furthermore, given the stability of the fluorovinyl sulfone upon treatment with TBAF in aqueous THF, we deduced that the hydroxide anion may be formed upon protonation of intermediate 4 (Scheme 4). In light of these results, we ran the reaction with the addition of one equivalent NH4Cl to protonate intermediate 4 and hinder the in situ formation of hydroxide, thereby reducing the formation of the ketone side product. To our delight, the reaction proceeded with full conversion and high selectivity, and the desired (Z)-fluorovinyl sulfones 2 were isolated in much higher yields (Table 1). The addition of more equivalents of ammonium chloride—or the addition of a saturated aqueous solution to the solvent mixture (THF:NH4Cl(aq) 10:1)—resulted in much lower conversions, even after 24 h. Similarly, other acids such as p-toluenesulfonic acid inhibited the reaction and no product was detected. We then investigated the scope of the reaction. Several aromatic groups were well tolerated on the alkynyl sulfone starting materials, including electron neutral substituents on the aromatic ring such as alkyl and aryl groupings leading to 2a–e (Table 1) in good yields and chemoselectivities. p-Methoxy and 3,5-dimethoxy substituents were also compatible, affording to 2f–h in similarly good yields and chemoselectivities (Table 1). Bromine-bearing products 2i,j—noteworthy for their potential applicability to further transformations, such as palladium-catalyzed cross-couplings—were also obtained in good yields, albeit somewhat lower selectivities (Table 1). Unfortunately, the use of alkynyl sulfones with electron-withdrawing substituents on the aromatic ring, such as the trifluoromethyl- and 3,5-difluoro-substituted
procedure to afford (Z)-β-fluorovinyl sulfones using cheap and nontoxic starting materials, and the first studies into the chemoselective heterogeneous hydrogenation of these valuable building blocks (Scheme 1c). 2. Results and discussion We first turned our attention to studying the regioselectivity of the hydrofluorination of alkynyl sulfones 1, which were prepared according to literature procedures [25]. Regarding the hydrofluorination of related substrates, Tatro and co-workers reported the selective fluorination of ethyl propiolate, achieving both the α and β regioisomers, albeit in a low 38% yield for the β derivative [16]; Jiang and co-workers reported the successful addition of fluoride solely to the β-position of similar electron-deficient alkynes, although with slight E/Z selectivity issues [26]; and Zhu and co-workers found that the addition of fluoride to ynamides could be α- or β-selective depending on the metal catalyst used [27]. We first attempted metal-catalyzed hydrofluorination using HF as the fluoride source, and we were able to achieve the desired βfluorovinyl sulfones, albeit in moderate to low yields. Thus, we decided to look for a simpler method and take advantage of the inherent electrophilic character of the alkynyl sulfone. In this sense, we observed that the treatment of alkynyl sulfone 1a with TBAF at room temperature in THF gave the corresponding (Z)-βfluorovinyl sulfone 2a in moderate yield (43%) and complete selectivity. The origin of this overwhelming preference for the Z geometry may lie in the formation of a negative charge on the α carbon upon nucleophilic addition. This negatively charged intermediate should adopt the most stable conformation with the lone pair in anti to the fluorine atom, in order to minimize electrostatic repulsion with the fluorine’s lone pairs (see intermediate 4, Scheme 4). However, under these conditions, we also observed the formation of a side product identified as β-keto sulfone 3a [28] (40%) (2a:3a close to 1:1), which we reasoned was due to residual water in the TBAF acting as a competing nucleophile (Scheme 2) [29]. We attempted to minimize the formation of β-keto sulfone 3a by avoiding water exposure. However, the use of freshly distilled
Scheme 2. Preliminary results towards the hydrofluorination of alkynyl sulfones.
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Scheme 3. Control experiments.
1k,1l, resulted in a drop in chemical yield and chemoselectivity (28%, 72:28 for 2k and 30%, 67:33 for 2l) (Table 1). In addition, the heteroaromatic thiophene-derived alkynyl sulfone 1m also worked well, giving 2m in a good yield and selectivity (Table 1). Unfortunately, we found that aliphatic derivatives such as 1n,o failed to give the desired fluorovinyl sulfones 2n,o, both with and without the ammonium chloride additive (Table 1), instead giving rise to the related allenyl sulfones [30]. With the desired β-fluorovinyl sulfones in hand, we then decided to explore their reactivity. Reaction with a diverse range of nucleophiles, including diethyl malonate, primary and secondary amines, nitromethane, and boronic acids all resulted in the loss of fluorine via an addition-elimination mechanism [14]. We then turned our attention to the heterogeneous hydrogenation of the vinyl fluoride moiety, an ambitious transformation given the limited literature surrounding the hydrogenation of fluorinated olefins [17–22]. The process would provide β-fluoroalkyl sulfones 5, which are similarly scarce in the literature. In this context, Liu and co-workers have recently developed a racemic and regioselective Pd-catalyzed intermolecular fluorosulfonylation of styrenes under mild conditions [31]. Lectka and coworkers have also applied their benzylic fluorination methodologies to the synthesis of 5a [32,33]. After testing a variety of known heterogeneous hydrogenation systems—such as PtO2, Pd(OH)2, Pd/C, and NH4HCO2/Pd/C—using the model substrate 2a we found palladium on activated charcoal to be the most suitable. The transformation is highly sensitive to both solvent effects and reaction time (Table 2). Methanol is widely used in hydrogenation reactions, and has been used successfully in several past examples with vinyl fluorides [18,24]; however, we found that methanol promoted the competing hydrodefluorination reaction and resulted in a higher degree of the corresponding defluorinated alkyl sulfones 6 (Table 2, entry 5). Ultimately, we found that the best solvent in terms of
chemoselectivity was toluene (Table 2, entries 7–9). Given the slower reaction rate in toluene, a careful reaction-time optimization could be carried out to maximize conversion and chemoselectivity. Increasing the reaction time to 1.5 h resulted in a significant improvement in conversion with no noticeable effect on the degree of defluorination (Table 2, entry 8). An extra 0.5 h reaction time increase resulted in full conversion at the expense of a chemoselectivity (Table 2, entry 9). Longer reaction times resulted in a greater degree of hydrodefluorinated product (Table 2, entry 10). The conditions shown in entry 9 resulted in the best-isolated yield and were used in the subsequent study into the scope of the reaction. There are three speculated mechanisms for the competing hydrodefluorination reaction: (1) the hydrogenation of the CeC double bond to give the desired 5, followed by the elimination of HF and the hydrogenation of the resulting defluorinated vinyl sulfone; (2) a concerted mechanism as proposed by Hudlicky via a carbene intermediate [17]; and (3) direct cleavage of the CeF bond in 5 promoted by the palladium catalyst. The intermediate defluorinated vinyl sulfone 7 was not observed at any point (Scheme 5). Furthermore, in contrast to Andersson [21] and Hudlicky’s [17] work with α-fluorovinyl carbonyls, we observed that the resulting saturated β-fluoroalkyl sulfone 5 reacted further in the reaction conditions to give 6. These observations lead us to believe that the direct cleavage of the C(sp3)eF bond was responsible for the hydrodefluorination of 5. Alternative reducing agents, such as NaBH4 and Et3SiH, were also explored unsuccessfully. For several substrates the reaction time had to be modified to achieve the best yields of the desired products, but eventually we were able to achieve high yields and acceptable selectivities for a range of substrates (Table 3). Fluorovinyl sulfones with electron-neutral aromatic substituents such as 2a–e, along with electron-rich p-methoxy bearing substrates 2f and 2g, all gave rise to the corresponding βfluoroalkyl sulfones 5a-g in good yields and chemoselectivities Scheme 4. Proposed mechanism of reaction and formation of side products.
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Table 1 Scope of the hydrofluorination reaction of alkynyl sulfones.
Table 2 Optimization for the selective heterogeneous hydrogenation of (Z)-β-fluorovinyl sulfones.
Entrya
Solvent
Time/h
Conversion (%)
5a:6a
1 2 3 4 5 6 7 8 9 10
MTBE Et2O EtOAc Dioxane MeOH Acetone Toluene Toluene Toluene Toluene
1 1 1 1 1 1 1 1.5 2 18
> 98 > 98 > 98 > 98 > 98 > 98 30 80 > 98 > 98
86:14 75:25 50:50 87:13 75:25 25:75 > 98:2 > 98:2 92:8 66:34
a
Standard reaction conditions: 2a (0.05 mmol), Pd/C (10–15 mol%), solvent (1.5 mL), H2 (1 atm).
group with respect to the vinyl fluoride moiety, in accordance with its Hammett coefficient. Similarly, fluorovinyl sulfone 2k with an electronwithdrawing trifluoromethyl group in the para position also required a much longer reaction time, and unfortunately led to a higher degree of defluorination (Table 3, entry 10). In the case of bromine-bearing 2i the only product observed was 2a, arising from the cleavage of the
(Table 3, entries 1–7). Naphthyl-containing fluorovinyl sulfone 2b and the related p-biphenyl derivative 2c resulted in slightly lower selectivities (Table 3, entries 2–3). On the other hand, substrates 2 h and 2l, bearing electronegative atoms in the meta position, required significantly longer reaction times (Table 3, entries 8, 11). This suggests that the m-methoxy substituent behaves as an electron-withdrawing 111
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Scheme 5. Control experiments towards the hydrodefluorination mechanism.
more susceptible to cleavage than in α, and that the aromatic ring plays no role in the loss of fluorine in β.
aromatic CeBr bond; this was not observed with the related aromatic CeF bonds in 5l. Thiophene-based 2m could also be hydrogenated in good yields and chemoselectivities, although a stoichiometric amount of Pd/C was needed, possibly due to catalyst poisoning by the desired product 5m (Table 3, entry 12). We later sought to extend our methodologies to the synthesis of other related compounds. Firstly, we attempted the hydrofluorination of ethyl phenylpropiolate using our metal-free conditions (Scheme 6a). This substrate proved somewhat less reactive than the alkynyl sulfones, and it was necessary to heat the mixture. However, the reaction failed to reach completion even after 16 h at 60 °C. Nevertheless, we obtained the desired β-fluorovinyl ester 8 in a moderate 50% yield. We were pleased to find that the subsequent hydrogenation of 8 to β-fluoro ester 9 (Scheme 6a) resulted in complete conversion after just 1.5 h with a selectivity of 91:9 with respect to the corresponding defluorinated product. Secondly, we validated our hydrogenation procedure with other fluorovinyl sulfones such as the α-fluorinated and aliphatic analogs 11 and 2n, which were synthesized according to the methods described by Prakash [13] and Hammond [15], respectively. Both hydrogenations occurred uneventfully, giving rise to both high yields and selectivities (Scheme 6b,c). It is worth noting that the hydrogenation of α-fluorovinyl sulfone 11 was more selective than that of the β-fluorinated analogue 2a (96:4 vs 92:8), and that minor hydrodefluorination occurred even with aliphatic derivative 2n (for 5n 93:7) (Scheme 6c). These results suggest that the CeF bond in the β-position is inherently
3. Conclusion In conclusion, we have developed a simple, inexpensive, metal-free, and selective procedure for the synthesis of (Z)-β-fluorovinyl sulfones—a new class of compounds only recently introduced in the chemical literature—and investigated the reactivity of such compounds. In this sense, we have described the first studies into the hydrogenation of fluorovinyl sulfones, obtaining a range of hydrogenated products in good yields and selectivities; a challenging reaction given the competing hydrodehalogenation that has hindered the use of similar substrates in hydrogenation processes. Further studies towards an enantioselective version are currently being carried out in our laboratory. 4. Experimental section 4.1. General methods Reactions were carried out under a nitrogen atmosphere unless otherwise indicated. Solvents were purified prior to use: THF was distilled from sodium. The reactions were monitored by TLC on 0.25 mm precoated silica-gel plates. Visualization was carried out with UV light and aqueous ceric ammonium molybdate solution or potassium
Table 3 β-Fluorovinyl sulfone hydrogenation scope.
Entry
Substrate 2a
R1
R2
Product 5
Time (h)
Conversion (%)
Yield 5 (%)b
5:6
1 2 3 4 5 6 7 8 9 10 11 12e
2a 2b 2c 2d 2e 2f 2g 2h 2i 2k 2l 2m
C6H5 2-Naphthyl p-PhC6H4 p-MeC6H4 p-t-BuC6H4 p-MeOC6H4 p-MeOC6H4 3,5-diMeOC6H3 p-BrC6H4 p-CF3C6H4 3,5-diFC6H3 3-Thienyl
p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 C6H5 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4
5a 5b 5c 5d 5e 5f 5g 5h 5ic 5k 5l 5m
2 2.5 3 2 3 2 3 60 16 120 60 2.5
> 98 > 98 > 98 > 98 95 > 98 > 98 > 98 41 80 > 98 > 98
96 97 94 92 96 95 96 95 0 90d 94 85
92:8 87:13 89:11 97:3 96:4 96:4 93:7 95:5 – 78:22 92:8 93:7
a b c d e
Standard reaction conditions: 2 (0.05 mmol), Pd/C (15 mol%), Toluene (1.5 mL), H2 (1 atm). Results shown are the average of a minimum 2–3 experiments. In most cases, compounds 5 contain small amounts of inseparable defluorinated sulfones 6. The only product observed was 2a. Yield corresponds to the mixture of starting 2k, β-fluorovinyl sulfone 5k and defluorinated sulfone 6k. Pd/C (100 mol%) was used.
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Scheme 6. Heterogeneous hydrogenation: other applications.
145.6 (C) ppm. HRMS (EI) calcd. for C15H11BrO2S [M+H+]: 334.9736, found 334.9728.
permanganate stain. Flash column chromatography was performed with the indicated solvents on silica gel 60 (particle size: 0.040−0.063 mm). 1H, 13C and 19F NMR spectra were recorded by a 300 MHz spectrometer. Chemical shifts are given in ppm (δ), referenced to the residual proton resonances of the solvents. Coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, respectively. The letters br indicate that the signal is broad. A QTOF mass analyzer system has been used for the HRMS measurements.
4.2.3. 1,3-Difluoro-5-(tosylethynyl)benzene (1l) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1l as a white solid (67%, 150 mg). Mp 105–107 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 6.93–6.99 (m, 1H; CH), 7.04-7.08 (m, 2H; 2CH), 7.43 (dd, J = 9.0, 0.6 Hz, 2H; 2CH), 7.96 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.8 (CH3), 86.9 (C), 89.2 (C), 107.8 (dd, 2J = 25.0, 25.0 Hz, CH), 115.7 (dd, 2J = 28.0 Hz, 4J = 9.0 Hz, 2CH), 120.0 (dd, 3J = 120, 12.0 Hz, C), 127.7 (2CH), 130.1 (2CH), 138.3 (C), 145.9 (C), 162.1 (d, 1 J = 252.2 Hz, CF), 163.7 (d, 1J = 252.2, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −107.3-(-107.4) (m, 2F; 2CF) ppm. HRMS (EI) calcd. for C15H10F2O2S [M+H+]: 293.0442, found 293.0434.
4.2. Synthesis of alkynylsulfones [25]: general procedure Ceric ammonium nitrate (2.5 mmol) was added portion-wise to a mixture of the corresponding acetylene (1 mmol), sodium p-toluenesulfinate (1.2 mmol) and NaI (1.2 mmol) in CH3CN (15 mL) under a nitrogen atmosphere. After the completion of the reaction (1 h approx.), the reaction mixture was hydrolyzed with H2O and extracted with CH2Cl2. The organic layer was separated, washed with brine (50 mL) and dried over Na2SO4. The solvent was removed and the residue was heated at 60 °C with K2CO3 (3 mmol) in acetone (10 mL) for 16 h. After the completion of the reaction, the reaction mixture was washed with H2O (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo using a rotary evaporator and the residue was purified by column chromatography to afford the desired product. Compounds 1d, 1f-g are described in reference [25]; compounds 1a and 1e in reference [34a]; compounds 1b, 1 h, 1i and 1k in reference [34b]; compound 1 m in reference [34c]; and compound 1n in reference [15].
4.3. Synthesis of (Z)-β-fluorovinyl sulfones 2: general procedure A 1 M solution of TBAF (0.15 mmol) was added to a solution of the corresponding alkynyl sulfone (0.1 mmol) and NH4Cl (0.1 mmol) in THF (0.1 M) under a nitrogen atmosphere at room temperature. After completion of the reaction (1–3 h), the reaction mixture was hydrolyzed with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography affording compounds 2. Compound 2a is described in reference [13]. 4.3.1. (Z)-2-(1-Fluoro-2-tosylvinyl)naphthalene (2b) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2b as a white solid (69%, 28 mg). Mp 130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.69 (d, J = 33.0 Hz, 1H; CH), 7.39 (d, J = 9.0 Hz, 2H; 2CH), 7.52 (d, J = 9.0 Hz, 1H; CH), 7.57–7.62 (m, 2H; 2CH), 7.84–7.89 (m, 3H; 3CH), 8.00 (d, J = 9.0 Hz, 2H; 2CH), 8.12 (s, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 110.0 (d, J = 12.8 Hz, CH), 121.5 (d, J = 7.6 Hz, CH), 125.8 (d, J = 25.7 Hz, C), 127.1 (d, J = 7.6 Hz, CH), 127.3 (CH), 127.7 (CH), 127.8 (CH), 128.5 (CH), 129.0 (CH), 129.8 (CH), 132.5 (C), 134.8 (C), 139.3 (C), 144.6 (C), 164.0 (d, 1 J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.9 (d, J = 31.0, 1F; CF) ppm. HRMS (EI) calcd. for C19H15FO2S [M+H+]: 327.0850, found 327.0852.
4.2.1. 4-(Tosylethynyl)-1,1′-biphenyl (1c) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1c as a white solid (40%, 410 mg). Mp 132–134 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 7.41–7.50 (m, 5H; 5CH), 7.58–7.61 (m, 6H; 6CH), 8.00 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 86.1 (C), 93.1 (C), 116.6 (C), 127.1 (2CH), 127.3 (2CH), 127.5 (2CH), 128.4 (CH), 129.0 (2CH), 130.0 (2CH), 133.2 (2CH), 139.0 (C), 139.5 (C), 144.3 (C), 145.3 (C) ppm. HRMS (EI) calcd. for C21H16O2S [M+H+]: 333.0944, found 333.0941. 4.2.2. 1-Bromo-3-(tosylethynyl)benzene (1j) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1 j as a white solid (44%, 340 mg). Mp 130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.5 (s, 3H; CH3), 7.26 (dd, J = 9.9, 6.0 Hz, 1H; CH), 7.42 (d, J = 9.0 Hz, 2H; 2CH), 7.45–7.49 (m, 1H; CH), 7.59–7.63 (m, 1H; CH), 7.67 (dd, J = 3.0, 3.0 Hz, 1H; CH), 7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.8 (CH3), 86.5 (C), 90.6 (C), 120.0 (C), 122.4 (C), 127.6 (2CH), 130.0 (2CH), 130.1 (CH), 131.2 (CH), 134.5 (CH), 135.2 (CH), 138.6 (C),
4.3.2. (Z)-4-(1-Fluoro-2-tosylvinyl)-1,1′-biphenyl (2c) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2c as a white solid (72%, 27 mg). Mp 196–198 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.60 (d, J = 33.0 Hz, 1H; CH), 7.37–7.50 (m, 5H; 5CH), 7.59-7.65 (m, 6H; 6CH), 7.98 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 109.5 (d, J = 13.6 Hz, CH), 126.4 (d, J = 8.3, 2CH), 127.1 (2CH), 127.2 (C), 127.7 (2CH), 128.4 (CH), 129.0 (2CH), 129.8 (2CH), 113
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139.3 (d, J = 8.3 Hz, C), 144.6 (C), 145.2 (C), 163.3 (d, 1J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.8 (d, J = 32.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C21H17FO2S [M+H+]: 353.1006, found 353.1003.
3
J = 13.6 Hz, CH), 127.7 (2CH), 129.8 (2CH), 130.5 (d, J = 26.4 Hz, C), 139.1 (C), 144.6 (C), 161.1 (C), 163.7 (d, 1 J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.3 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C17H17FO4S [M+H+]: 337.0904, found 337.0895. 2
4.3.3. (Z)-1-((2-Fluoro-2-(4-tolyl)vinyl)sulfonyl)-4-methylbenzene (2d) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2d as a white solid (67%, 28 mg). Mp 100–102 °C. 1H NMR (CDCl3, 300 MHz) δ 2.39 (s, 3H; CH3), 2.46 (s, 3H; CH3), 6.52 (d, J = 33.0 Hz, 1H; CH), 7.23 (d, J = 9.0 Hz, 2H; 2CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.46 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.5 (CH3), 21.6 (CH3), 108.7 (d, J = 13.6 Hz, CH), 125.8 (2CH), 125.9 (2CH), 126.1 (C), 127.6 (2CH), 129.7 (2CH), 139.4 (C), 143.2 (C), 144.4 (C), 164.5 (d, 1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.4 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C16H15FO2S [M+H+]: 291.0850, found 291.0858.
4.3.8. (Z)-1-Bromo-4-(1-fluoro-2-tosylvinyl)benzene (2i) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2i as a white solid (63%, 22 mg). Mp 145–147 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.56 (d, J = 33.0 Hz, 1H; CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.42 (d, J = 9.0 Hz, 2H; 2CH), 7.58 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 110.3 (d, J = 13.6 Hz, CH), 127.2 (CH), 127.3 (CH), 127.6 (d, J = 26.7 Hz, C), 127.7 (CH), 129.9 (CH), 132.3 (C), 144.8 (C), 163.5 (d, J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.2 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H12BrFO2S [M +H+]: 354.9798, found 354.9806.
4.3.4. (Z)-1-(tert-Butyl)-4-(1-fluoro-2-tosylvinyl)benzene (2e) Flash chromatography of the crude reaction product [n-hexaneEtOAc (15:1)] afforded 2e as a white solid (67%, 28 mg). Mp 122–124 °C. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.46 (s, 3H; CH3), 6.52 (d, J = 33 Hz, 1H; CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.44 (d, J = 9.0 Hz, 2H; 2CH), 7.51 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 30.9 (3CH3), 35.1 (C), 108.8 (d, 2J = 13.6 Hz, CH), 125.8 (d, 3 J = 7.5 Hz, 2CH), 126.0 (d J = 2.3 Hz, 2CH), 127.6 (2CH), 129.7 (2CH), 139.4 (C), 144.4 (C); 156.3 (C), 164.2 (d, 1J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.4 (d, J = 31.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C19H21FO2S [M+H+]: 333.1319, found 333.1327.
4.3.9. (Z)-1-Bromo-3-(1-fluoro-2-tosylvinyl)benzene (2j) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2j as a white solid (60%, 20 mg). Mp 81–83 °C. 1 H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.57 (d, J = 30.0 Hz, 1H; CH), 7.33 (d, J = 9.0 Hz, 1H; CH), 7.38 (d, J = 6.0 Hz, 2H; 2CH), 7.50 (d, J = 9.0 Hz, 1H; CH), 7.61–7.64 (m, 1H; CH), 7.69-7.70 (m, 1H; CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 111.2 (d, J = 13.6 Hz, CH), 123.1 (C), 124.4 (d, J = 7.5 Hz, CH), 127.7 (2CH), 128.8 (d J = 8.3 Hz, CH), 129.9 (2CH), 130.5 (CH), 135.2 (CH), 138.8 (C), 144.8 (C), 162.0 (d, 1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.1 (d, J = 31.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H12BrFO2S [M+H+]: 354.9798, found 354.9793.
4.3.5. (Z)-1-(1-Fluoro-2-(phenylsulfonyl)vinyl)-4-methoxybenzene (2f) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2f as a white solid (72%, 40 mg). Mp 78–80 °C. 1 H NMR (CDCl3, 300 MHz) δ 3.86 (s, 3H; OCH3), 6.45 (d, J = 33.0 Hz, 1H; CH), 6.93 (d, J = 9.0 Hz, 2H; 2CH), 7.51–7.65 (m, 5H; 5CH), 8.07 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.5 (OCH3), 107.1 (d, J = 13.6 Hz, CH), 114.5 (2CH), 120.8 (d, J = 25.6 Hz, C), 127.5 (2CH), 127.9 (J = 8.3 Hz, 2CH), 129.1 (2CH), 133.3 (CH), 142.4 (C), 163.0 (C), 164.5 (d, 1J = 273.0 Hz, C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.7 (d, J = 33.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H13FO3S [M + H+]: 293.0642, found 293.0642.
4.3.10. (Z)-1-((2-Fluoro-2-(4-(trifluoromethyl)phenyl)vinyl)sulfonyl)-4methylbenzene (2k) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2k as a white solid (28%, 20 mg). Mp 129–131 °C. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 6.64 (d, J = 32.0 Hz, 1H; CH), 7.37 (dd, J = 8.6, 0.7 Hz, 1H; CH), 7.68 (s, 2H; 2CH), 7.94 (d, J = 8.0 Hz, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 111.9 (d, J = 13.1 Hz, C), 111.9 (d, J = 13.1 Hz, C), 125.9 (q, J = 2.4 Hz, CH), 126.2 (d, J = 7.6 Hz, CH), 127.8 (CH), 129.9 (CH), 132.2 (d, J = 27.4 Hz, C), 133.8 (d, J = 33.1 Hz, C), 138.6 (C), 144.9 (C), 162.1 (d, J = 274.0 Hz, C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.84 (d, J = 31.9 Hz, CF), −63.71 (s, CF3) ppm. HRMS (EI) calcd. for C16H12F4O2S [M+NH4+]: 362.0832, found 362.0825.
4.3.6. (Z)-1-[(2-Fluoro-2-(4-methoxyphenyl)vinyl)sulfonyl]-4methylbenzene (2g) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2g as a white solid (71%, 45 mg). Mp 74–75 °C. 1 H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.84 (s, 3H; OCH3), 6.43 (d, J = 32.8 Hz, 1H; CH), 6.92 (d, J = 9.1 Hz, 1H; CH), 7.36 (d, J = 9.0 Hz, 1H; CH), 7.51 (d, J = 9.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 55.2 (OCH3), 107.4 (d, 2J = 13.4 Hz, CH), 114.5 (2CH), 120.9 (d, 2J = 25.6 Hz, C), 127.5 (2CH), 127.8 (d, 3J = 8.2 Hz, 2CH), 129.7 (2CH), 139.5 (C), 144.3 (C), 162.9 (C), 164.2 (d, 1J = 272.2 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.3 (d, J = 33.9 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C16H15O3S [M+H+]: 307.0799, found 307.0800.
4.3.11. (Z)-1,3-Difluoro-5-(1-fluoro-2-tosylvinyl)benzene (2l) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2l as a white solid (30%, 21 mg). Mp 158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 6.57 (d, J = 30.0 Hz, 1H; CH), 6.92-7.00 (m, 1H; CH), 7.08-7.11 (m, 2H; 2CH), 7.40 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 107.7 (dd, 2J = 24.8, 24.9 Hz, CH), 109.0 (dd, 2J = 27.1, 27.2 Hz, CH), 112.1 (d, J = 12.8 Hz, CH), 127.8 (2CH), 129.9 (2CH), 131.9 (d, 2J = 28.7 Hz, C), 138.5 (C), 145.1 (C), 161.1 (d, 1J = 274.0 Hz, CF), 163.0 (d, 1J = 251.4 Hz, CF), 163.2 (d, 1J = 251.5 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −106.7 (s, 2F; 2CF), −94.2 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H11F3O2S [M+H+]: 313.0505, found 313.0506.
4.3.7. (Z)-1-(1-Fluoro-2-tosylvinyl)-3,5-dimethoxybenzene (2h) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2h as a white solid (70%, 30 mg). Mp 158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.80 (s, 6H; 2OCH3), 6.53 (d, J = 33.0 Hz, 1H; CH), 6.57-6.59 (m, 1H; CH), 6.67 (d, J = 3.0 Hz, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.94 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.6 (OCH3), 103.9 (CH), 104.3 (d, 2J = 52.1 Hz, CH), 110.2 (d,
4.3.12. (Z)-3-(1-Fluoro-2-tosylvinyl)thiophene (2m) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2m as a white solid (70%, 65 mg). Mp 121–123 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.39 (d, J = 33.2 Hz, 1H; CH), 7.15 (d, J = 6.0 Hz, 1H; CH), 7.35-7.38 (m, 3H; 3CH), 7.74 (d, J = 3.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz, 1H; CH) ppm. 114
Journal of Fluorine Chemistry 206 (2018) 108–116
D.M. Sedgwick et al. 13 C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 109.0 (d, J = 12.5 Hz, CH), 124.4 (d, J = 7.5 Hz, CH), 127.6 (2CH), 128.0 (CH), 128.2 (d, J = 6.0 Hz, CH), 129.8 (2CH), 131.0 (d, 2J = 27.9 Hz, C), 139.3 (C), 144.5 (C), 160.0 (d, 1J = 270.9 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.7 (d, J = 32.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C13H11FO2S2 [M+H+]: 283.0257, found 283.0254.
3.43 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H; CHH), 3.77-3.90 (m, 1H; CHH), 5.99 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.35-7.40 (m, 4H; 4CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 31.2 (3CH3), 34.7 (C), 62.7 (d, 2 J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.7, CHF), 125.4 (d, 3J = 6.0 Hz, 2CH), 125.8 (2CH), 128.3 (2CH), 129.8 (2CH), 133.8 (d, 2 J = 13.6 Hz, C), 136.7 (C), 144.9 (C), 152.6 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −171.9 (ddd, J = 48.0, 31.1, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C19H23FO2S [M + NH4+]: 352.1741, found 352.1742.
4.3.13. Ethyl (Z)-3-fluoro-3-phenylacrylate (8) Described in reference [35]. 4.4. Hydrogenation of β-fluorovinylsulfones
4.4.6. 1-(1-Fluoro-2-(phenylsulfonyl)ethyl)-4-methoxybenzene (5f) Crude reaction product 5f (95%, 19 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 3.47 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H; CHH), 3.81 (s, 3H; OCH3), 3.78-3.93 (m, 1H; CHH), 5.97 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.88 (d, J = 9.0 Hz, 2H; 2CH), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.55-7.60 (m, 2H; 2CH), 7.65–7.70 (m, 1H; CH), 7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.3 (OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.3 (d, 1J = 175.2 Hz, CHF), 114.3 (2CH), 127.3 (d, 3J = 5.3 Hz, 2CH), 128.3 (2CH), 128.7 (d, 2 J = 20.4 Hz, C), 129.2 (2CH), 133.9 (CH), 139.7 (C), 160.4 (C) ppm. 19 F NMR (CDCl3, 282.4 MHz) δ −167.8 (ddd, J = 48.0, 31.1, 14.1, 1F; CHF) ppm. HRMS (EI) calcd. for C15H15FO3S [M+NH4+]: 312.1064, found 312.1056.
4.4.1. General procedure for the synthesis of β-fluoro sulfones 5 Pd(C) catalyst (15 mol%) was added to a solution of the corresponding β-fluorovinyl sulfone 2 (0.05 mmol) in toluene (0.033 M), and hydrogen gas was charged by purging the reaction flask several times, without stirring. The reaction was then stirred under H2 (atmospheric pressure) at room temperature for 1–3 h. The mixture was filtered to remove the catalyst, and the solvent was evaporated in vacuo. In most cases, compounds 5 contain small amounts of inseparable defluorinated sulfones 6. Compound 5a has been described in reference [31]. For compounds 10 and 11, see reference [14]. 4.4.2. -(1-Fluoro-2-tosylethyl)naphthalene (5b) Crude reaction product 5b (96%, 20 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.57 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.86-3.98 (m, 1H; CHH), 6.18 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.33-7.38 (m, 3H; 3CH), 7.52-7.55 (m, 2H; 2CH), 7.76–7.87 (m, 6H; 6CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 62.6 (d, 2J = 26.4 Hz, CH2), 88.8 (d, 1J = 177.4 Hz, CHF), 122.5 (d, 3J = 5.3 Hz, CH), 125.3 (d, 3J = 7.5 Hz, CH), 126.8 (CH), 126.9 (CH), 127.7 (CH), 128.1 (CH), 128.3 (2CH), 128.9 (CH), 129.8 (2CH), 132.9 (C), 133.5 (C), 134.1 (d, 2J = 20.4 Hz, C), 136.6 (C), 145.0 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1 (ddd, J = 45.1, 28.2, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C19H17FO2S [M+NH4+]: 346.1272, found 346.1268.
4.4.7. 1-((2-Fluoro-2-(4-methoxyphenyl)ethyl)sulfonyl)-4-methylbenzene (5g) Crude reaction product 5g (96%, 21 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.45 (ddd, J = 30.0, 15.0 3.0 Hz, 1H; CHH), 3.81 (s, 3H; OCH3), 3.78–3.90 (m, 1H; CHH), 5.95 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.89 (d, J = 9.0 Hz, 2H; 2CH), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.84 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.3 (OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.4 (d, 1 J = 175.9 Hz, CHF), 114.2 (2CH), 127.3 (d, 3J = 6.0 Hz, 2CH), 128.3 (2CH), 128.9 (d, 2J = 20.4 Hz, C), 129.8 (2CH), 136.7 (C), 144.9 (C), 160.4 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −168.0 (ddd, J = 45.2, 28.2, 11.3 1F; CHF) ppm. HRMS (EI) calcd. for C16H17FO3S [M +NH4+]: 326.1221, found 326.1215.
4.4.3. 4-(1-Fluoro-2-tosylethyl)-1,1′-biphenyl (5c) Crude reaction product 5c (94%, 16 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.81-3.93 (m, 1H; CHH), 6.08 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.36-7.61 (m, 11H; 11CH), 7.87 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.7 (d, 2 J = 25.7 Hz, CH2), 88.5 (d, 1J = 177.4 Hz, CHF), 126.0 (d, 3 J = 6.8 Hz, 2CH), 127.1 (2CH), 127.6 (2CH), 127.7 (CH), 128.3 (2CH), 128.8 (2CH), 129.9 (2CH), 135.7 (d, 2J = 19.6 Hz, C), 136.7 (C), 140.2 (C), 142.4 (C), 145.0 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1 (ddd, J = 45.1, 31.1, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C21H19FO2S [M+NH4+]: 372.1428, found 372.1426.
4.4.8. 1-(1-Fluoro-2-tosylethyl)-3,5-dimethoxybenzene (5h) Crude reaction product 5h (95%, 12 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 3.45 (ddd, J = 33.5, 15.0, 3.1 Hz, 1H; CHH), 3.72-3.84 (m, 1H; CHH), 3.78 (s, 6H; 2OCH3), 5.90 (ddd, J = 48.1, 9.0, 3.1 Hz, 1H; CHF), 6.41 (s, 3H; 3CH), 7.39 (d, J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.4 (2OCH3), 62.4 (d, 2J = 25.7 Hz, CH2), 88.5 (d, 1J = 180.0 Hz, CHF), 101.0 (CH), 103.2 (d, 3J = 6.8 Hz, 2CH), 128.3 (2CH), 129.9 (2CH), 136.7 (C), 139.3 (d, 2J = 20.4 Hz, C), 145.0 (C), 161.2 (2C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −175.2 (ddd, J = 48.0, 33.5, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C17H19FO4S [M+H+]: 339.1061, found 339.1050.
4.4.4. 1-((2-Fluoro-2-(p-tolyl)ethyl)sulfonyl)-4-methylbenzene (5d) Crude reaction product 5d (92%, 23 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H; CH3), 2.48 (s, 3H; CH3), 3.45 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.76–3.89 (m, 1H; CHH), 7.18 (s, 4H; 4CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.2 (CH3), 21.7 (CH3), 62.7 (d, 2J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.0 Hz, CHF), 125.6 (d, 3 J = 6.0 Hz, 2CH), 128.3 (2CH), 129.5 (2CH), 129.8 (2CH), 133.9 (d, 2 J = 20.4 Hz, C), 136.7 (C), 139.4 (C), 144.9 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −171.7 (ddd, J = 48.0, 31.0, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C16H17FO2S [M+NH4+]: 310.1272, found 310.1269.
4.4.9. 4-(1-Fluoro-2-tosylethyl)-1-trifluoromethylbenzene (5k) Crude reaction product 5k (90%, 9 mg) was obtained as viscous oil. Data taken from the crude mixture. Only the most characteristic signals for 5k are described in the following data, due to the difficulties in isolating this compound (see spectrum 5k). 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 3.48 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.80 (ddd, J = 24.0, 15.0, 9.0 Hz, 1H; CHH), 6.09 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 62.5 (d, 2J = 24.9 Hz, CH2), 87.9 (d, 1J = 179.7 Hz, CHF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −177.0 (ddd, J = 46.0, 30.0, 14.2 Hz, 1F; CHF), −63.1 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C16H14F4O2S [M +NH4+]: 364.0989, found 364.0993.
4.4.5. 1-(tert-Butyl)-4-(1-fluoro-2-tosylethyl)benzene (5e) Crude reaction product 5e (96%, 16 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.47 (s, 3H; CH3), 115
Journal of Fluorine Chemistry 206 (2018) 108–116
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4.4.10. 1,3-Difluoro-5-(1-fluoro-2-tosylethyl)benzene (5l) Crude reaction product 5l (94%, 18 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 2.48 (s, CH3), 3.44 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.75 (ddd, J = 21.0, 15.0, 9.0 Hz, 1H; CHH), 6.00 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 6.77-6.85 (m, 3H; 3CH), 7.40 (d, J = 9.0 Hz, 2H; 2CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.4 (d, 2J = 25.7 Hz, CH2), 87.4 (d, 1 J = 180.4 Hz, CHF), 104.6 (dd, 2J = 25.7 Hz, CH), 108.5 (ddd, J = 25.6, 7.5 Hz, 2CH), 128.2 (2CH), 129.9 (2CH), 136.4 (C), 140.7 (C), 145.3 (C), 163.1 (d, 1J = 252.4 Hz, CF), 163.1 (d, 1J = 252.4 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −176.6 (ddd, J = 45.1, 28.2, 14.0 Hz, 1H; CHF), −107.5 to (−107.4) (m, 2F; 2CF) ppm. HRMS (EI) calcd. for C15H13F3O2S [M+NH4+]: 332.0927, found 332.0926.
[2] D.E. Yerien, S. Bonesi, A. Postigo, Org. Biomol. Chem. 14 (2016) 8398–8427. [3] (a) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Aceña, V.A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 116 (2016) 422–518. [4] J.F. Nadon, K. Rochon, S. Grastilleur, G. Langlois, T.T.H. Dao, V. Blais, B. Guérin, L. Gendron, Y.L. Dory, ACS Chem. Neurosci. 8 (2017) 40–49. [5] B.E. McKinney, J.J. Urban, J. Phys. Chem. A 114 (2010) 1123–1133. [6] M. Drouin, J.F. Paquin, Beilstein J. Org. Chem. 13 (2017) 2637–2658 For a very recent review, see:. [7] O.E. Okoromoba, J. Han, G.B. Hammond, B. Xu, J. Am. Chem. Soc. 136 (2014) 14381–14384. [8] A.-N.R. Alba, X. Companyó, R. Rios, Chem. Soc. Rev. 39 (2010) 2018. [9] D.C. Meadows, J. Gervay-Hague, Med. Res. Rev. 26 (2006) 793–814. [10] N.S. Simpkins, Tetrahedron 46 (1990) 6951–6984. [11] D.C. Meadows, J. Gervay-Hague, Med. Res. Rev. 26 (2006) 793–814 For a review on vinyl sulfones and their used in medicinal chemistry see:. [12] A.K. Ghosh, B. Zajc, Synlett (2008) 999–1004. [13] G.K.S. Prakash, S. Chacko, H. Vaghoo, N. Shao, L. Gurung, T. Mathew, G.A. Olah, Org. Lett. 11 (2009) 1127–1130. [14] C.D. McCune, M.L. Beio, J.M. Sturdivant, R. de la Salud-Bea, B.M. Darnell, D.B. Berkowitz, J. Am. Chem. Soc. 139 (2017) 14077–14089. [15] X. Zeng, S. Liu, G.B. Hammond, B. Xu, J. Chem. Eur. 23 (2017) 11977–11981. [16] T.B. Patrick, J. Neumann, A. Tatro, J. Fluor. Chem. 132 (2011) 779–782. [17] M. Hudlicky, J. Fluor. Chem. 14 (1979) 189–199. [18] R. Sauvetre, J.-F. Normant, P. Martinet, J. Fluor. Chem. 52 (1991) 419–432. [19] M. Saburi, H. Takeuchi, M. Ogasawara, T. Tsukahara, Y. Ishii, T. Ikariya, T. Takahishi, T. Uchida, J. Organomet. Chem. 428 (1992) 155–167. [20] S.W. Krska, J.V. Mitten, P.G. Dormer, D. Mowrey, F. Machrouhi, Y. Sun, T.D. Nelson, Tetrahedron 65 (2009) 8987–8994. [21] M. Engman, J.S. Diesen, A. Paptchikhine, P.G. Andersson, J. Am. Chem. Soc. 129 (2007) 4536–4537. [22] P. Kaukoranta, M. Engman, C. Hedberg, J. Bergquist, P.G. Andersson, Adv. Synth. Catal. 350 (2008) 1168–1176. [23] (a) For the synthesis of other β-halovinyl sulfones, see: Y. Liang, S.H. Suzol, Z. Wen, A.G. Artiles, L. Mathivathanan, R.G. Raptis, S.F. Wnuk, Org. Lett. 18 (2016) 1418–1421; (b) X. Zeng, L. Ilies, E. Nakamura, Org. Lett. 14 (2012) 954–956. [24] T. Kitazume, T. Ohnogi, H. Miyauchi, T. Yamazaki, J. Org. Chem. 54 (1989) 5630–5632. [25] V. Nair, A. Augustine, T.D. Suja, Synthesis 15 (2002) 2259–2265. [26] Y. Li, X. Liu, D. Ma, B. Liu, H. Jiang, Adv. Synth. Catal. 354 (2012) 2683–2688. [27] J. Che, Y. Li, F. Zhang, R. Zheng, Y. Bai, G. Zhu, Tetrahedron Lett. 55 (2014) 6240–6242. [28] (a) Fluorovinyl sulfones 2 and β-keto sulfones 3 were easily separated by flash chromatography. For recent examples of the synthesis of β-keto sulfones, see: S. Handa, J.C. Fennewaald, B.H. Lipshutz, Angew. Chem. Int. Ed. 53 (2014) 3432–3435; (b) Q. Lu, J. Zhang, P. Peng, G. Zhang, Z. Huang, H. Yi, J.T. Miller, A. Lei, Chem. Sci. 6 (2015) 4851–4854; (c) D. Yang, B. Huang, W. Wei, J. Li, G. Lin, Y. Liu, J. Ding, P. Sun, H. Wang, Green Chem. 18 (2016) 5630–5634; (d) L. Xie, X. Zhen, S. Huang, X. Su, M. Lin, Y. Li, Green Chem. 19 (2017) 3530–3534; (e) J. Yu, R. Mao, Q. Wang, J. Wu, Org. Chem. Front. 4 (2017) 617–621. [29] More than ten years ago Sun and DiMagno described a methodology for the preparation of anhydrous TBAF. However, their procedure is somewhat laborious and tedious and therefore its use would not be desirable in this study, which aims to provide a practical and inexpensive alternative for the synthesis of the title compounds: H. Sun, S.G. DiMagno, J. Am. Chem. Soc., 127 (2005) 2050–2051. [30] S.E. Denmark, M.A. Harmata, K.S. White, J. Org. Chem. 52 (1987) 4031–4042. [31] Z. Yuan, H.-Y. Wang, X. Mu, P. Chen, Y.-L. Guo, G. Liu, J. Am. Chem. Soc. 137 (2015) 2468–2471. [32] S. Bloom, S.A. Sharber, M.G. Holl, J.L. Knippel, T. Lectka, J. Org. Chem. 78 (2013) 11082–11086. [33] S. Bloom, M. McCann, T. Lectka, Org. Lett. 16 (2014) 6338–6341. [34] (a) P. Chen, Ch. Zhu, R. Zhu, W. Wu, H. Jiang, Chem. Asian. J. 12 (2017) 1875–1878. [35] S. Peng, F.-L. Qing, Y.-Q. Li, Ch-M. Hu, J. Org. Chem. 65 (2000) 694–700.
4.4.11. 3-(1-Fluoro-2-tosylethyl)thiophene (5m) Crude reaction product 5m (85%, 10 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.79-3.92 (m, 1H; CHH), 6.10 (ddd, J = 6.0 Hz, 1H; CH), 7.30-7.34 (m, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.84 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.0 (d, 2J = 25.7 Hz, CH2), 84.8 (d, 1J = 174.4 Hz, CHF), 123.6 (d, 3J = 7.5 Hz, CH), 124.8 (d, 3J = 3.0 Hz, CH), 127.3 (CH), 128.3 (2CH), 129.9 (2CH), 136.6 (C), 137.8 (d, 2J = 21.9 Hz, C), 145.1 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −167.5 (ddd, J = 45.2, 28.2, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C13H13FO2S2 [M+NH4+]: 302.0679, found 302.0682. 4.4.12. ((2-Fluorooctyl)sulfonyl)benzene (5n) Crude reaction product 5n (94%, 14 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 0.89–1.72 (m, 13H; C6H13), 3.28 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.54-3.60 (m, 1H; CHH), 4.92-5.15 (m, 1H; CHF), 7.57-7.71 (m, 3H; 3CH), 7.95-7.97 (m, 2H; 2CH) ppm. 13 C NMR (CDCl3, 75.5 MHz) δ 13.9 (CH3), 22.4 (CH2), 24.4 (d, 3 J = 4.5 Hz, CH2), 28.7 (CH2), 31.5 (CH2), 34.8 (d, 2J = 20.4 Hz, CH2), 61.0 (d, 2J = 23.4 Hz, CH2), 88.1 (d, 1J = 174.4 Hz, CHF), 128.2 (2CH), 129.2 (2CH), 133.9 (CH), 139.7 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −180.0 to (−179.5) (m, 1F; CHF) ppm. HRMS (EI) calcd. for C14H21FO2S [M+NH4+]: 290.1585, found 290.1578. Acknowledgments We would like to thank the Spanish Ministerio de Economía y Competitividad (CTQ-2013-43310-P) and the Generalitat Valenciana (GV/PrometeoII/2014/073). D. M. S. thanks the Spanish Ministerio de Educación, Cultura y Deporte for a predoctoral fellowship (FPU15/ 01485). The authors are also grateful to Alberto Llobat and Daniel Dávila for assistance in the synthesis of the starting materials. References [1] E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58 (2015) 8315–8359.
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and their chemoselective hydrogenation to β-fluoroalkyl sulfones ⁎
Daniel M. Sedgwicka,b, Raquel Romána,b, Pablo Barrioa, , Cristina Moralesa, Santos Fusteroa,b, a b
T
⁎
Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords: Regioselectivity Alkynyl sulfones β-Fluorovinyl sulfones Hydrogenation Chemoselectivity β-Fluoroalkyl sulfones
A highly regioselective, metal-free hydrofluorination reaction of alkynyl sulfones was developed using TBAF—one of the cheapest and most commonly available fluoride sources. In addition, the reactivity of the resulting β-fluorovinyl sulfones was studied, focusing on their selective hydrogenation reaction. Both β-fluorovinyl sulfones and their hydrogenation products β-fluoroalkyl sulfones may find applications in medicinal and agrochemical sciences.
1. Introduction Fluorine is increasingly relevant in a variety of fields, such as agrochemistry, materials science and medicinal chemistry. The fluorine atom has become a routine addition in the search for new molecular entities in drug development, due to the unique characteristics of the CeF bond [1–3]. Being the most electronegative element, the carbonfluoride bond is among the most polarized in organic chemistry, allowing chemists to modify certain features of bioactive molecules, including metabolic stability, acidity/basicity, and lipophilicity. In certain cases, the effect of the fluorine atom on a functional group can be significant. For example, due to their altered electronic arrangement, vinyl fluorides might be used as bioisosteres for the peptide bond [4–6]. Vinyl fluorides, therefore, are increasingly important in organic and medicinal chemistry due to new applications and their increasing ease of preparation thanks to advances in synthetic fluorine chemistry [7]. Sulfones are similarly versatile synthetic building blocks [8–10]. Their strongly electron-withdrawing nature increases the acidity of the adjacent hydrogen atoms and allows the α carbon to be used as a nucleophile in CeC bond forming processes such as the Julia olefination and the Ramberg-Bäcklund reaction. This same electron-withdrawing character places vinyl sulfones among the most electron-deficient CeC double bonds, making them viable electrophiles in Michael additions and cycloaddition processes. For these reasons, fluorinated vinyl sulfones are expected to be not only useful in chemical synthesis, but also have potential applications in medicinal and agrochemical sciences [11]. However, methods to produce fluorinated vinylsulfones are
⁎
scarce. Although there are several methods to synthesize the related αfluorovinyl sulfones [12,13], to the best of our knowledge only two such reports deal with the synthesis of the β-fluoro analogs (Scheme 1a) [14,15]. A recent report by Hammond and co-workers outlines a strategy to produce the desired products, although their method requires the use of an expensive gold catalyst [15]. Other reports on similar substrates have presented problems with regioselectivity [16]. The selective hydrogenation of vinyl fluorides to alkyl fluorides remains an underrepresented field; only a handful of studies have been reported [17–22]. This could be due to the intrinsic difficulties associated with the transformation: (1) only recently have new advances in fluorine chemistry allowed the facile synthesis of the vinyl fluoride precursors; and (2) the CeX bond has a tendency to undergo hydrodehalogenation, thus resulting in a mixture of the desired product and the dehalogenated derivative. For this reason, vinyl halides are generally seen as poor substrates for hydrogenation reactions. However, of the vinyl halides, fluorides are perhaps the most commonly used given the relative strength of the C—F bond when compared to its chloride, bromide and iodide counterparts. Nevertheless, no examples of hydrogenation of fluorovinyl sulfones have been previously reported. Furthermore, in the vast majority of known examples of this transformation, the fluorine atom is adjacent to a carbonyl group, or a perfluorinated substrate is used. There are very few studies that include substrates presenting the fluorine atom in the β-position [23], with the exception of specific gem-difluorinated acrylic acids [24] and α,β-difluoro-α,β-unsaturated carbonyl compounds [18] (Scheme 1b). Herein we disclose a metal-free and regioselective synthetic
Corresponding authors at: Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain. E-mail addresses: [email protected] (P. Barrio), [email protected] (S. Fustero).
https://doi.org/10.1016/j.jfluchem.2017.12.016 Received 27 November 2017; Received in revised form 20 December 2017; Accepted 21 December 2017 Available online 23 December 2017 0022-1139/ © 2017 Elsevier B.V. All rights reserved.
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Scheme 1. a) Previous examples of the synthesis of β-fluorovinyl sulfones. b) Previous examples of hydrogenation of α- fluoro- α, β-unsaturated carbonyl compounds with a heterogeneous palladium catalyst. c) This work: metal-free synthesis of β-fluorovinyl sulfones under mild conditions and their hydrogenation to the corresponding β-fluoroalkyl sulfones.
anhydrous THF, molecular sieves, lower temperatures and other less hygroscopic fluoride sources (TBAT, TMAF, ZnF2, KHF2, NaF, TBAF@ SiO2) all failed to improve the yield of 2a. Therefore, we decided to run several control experiments to understand how the reaction might proceed (Scheme 3). Alkynyl sulfone 1a and fluorovinyl sulfone 2a are both stable in a mixture of THF/water, and 2a does not react further even in the presence of TBAF. However, the addition of 1 equivalent of LiOH to 2a resulted in a 1:1:1 mixture of alkynyl sulfone 1a, unreacted 2a, and βketo sulfone 3a, suggesting that the slightly basic reaction conditions were responsible for the formation of the undesired ketone. Furthermore, given the stability of the fluorovinyl sulfone upon treatment with TBAF in aqueous THF, we deduced that the hydroxide anion may be formed upon protonation of intermediate 4 (Scheme 4). In light of these results, we ran the reaction with the addition of one equivalent NH4Cl to protonate intermediate 4 and hinder the in situ formation of hydroxide, thereby reducing the formation of the ketone side product. To our delight, the reaction proceeded with full conversion and high selectivity, and the desired (Z)-fluorovinyl sulfones 2 were isolated in much higher yields (Table 1). The addition of more equivalents of ammonium chloride—or the addition of a saturated aqueous solution to the solvent mixture (THF:NH4Cl(aq) 10:1)—resulted in much lower conversions, even after 24 h. Similarly, other acids such as p-toluenesulfonic acid inhibited the reaction and no product was detected. We then investigated the scope of the reaction. Several aromatic groups were well tolerated on the alkynyl sulfone starting materials, including electron neutral substituents on the aromatic ring such as alkyl and aryl groupings leading to 2a–e (Table 1) in good yields and chemoselectivities. p-Methoxy and 3,5-dimethoxy substituents were also compatible, affording to 2f–h in similarly good yields and chemoselectivities (Table 1). Bromine-bearing products 2i,j—noteworthy for their potential applicability to further transformations, such as palladium-catalyzed cross-couplings—were also obtained in good yields, albeit somewhat lower selectivities (Table 1). Unfortunately, the use of alkynyl sulfones with electron-withdrawing substituents on the aromatic ring, such as the trifluoromethyl- and 3,5-difluoro-substituted
procedure to afford (Z)-β-fluorovinyl sulfones using cheap and nontoxic starting materials, and the first studies into the chemoselective heterogeneous hydrogenation of these valuable building blocks (Scheme 1c). 2. Results and discussion We first turned our attention to studying the regioselectivity of the hydrofluorination of alkynyl sulfones 1, which were prepared according to literature procedures [25]. Regarding the hydrofluorination of related substrates, Tatro and co-workers reported the selective fluorination of ethyl propiolate, achieving both the α and β regioisomers, albeit in a low 38% yield for the β derivative [16]; Jiang and co-workers reported the successful addition of fluoride solely to the β-position of similar electron-deficient alkynes, although with slight E/Z selectivity issues [26]; and Zhu and co-workers found that the addition of fluoride to ynamides could be α- or β-selective depending on the metal catalyst used [27]. We first attempted metal-catalyzed hydrofluorination using HF as the fluoride source, and we were able to achieve the desired βfluorovinyl sulfones, albeit in moderate to low yields. Thus, we decided to look for a simpler method and take advantage of the inherent electrophilic character of the alkynyl sulfone. In this sense, we observed that the treatment of alkynyl sulfone 1a with TBAF at room temperature in THF gave the corresponding (Z)-βfluorovinyl sulfone 2a in moderate yield (43%) and complete selectivity. The origin of this overwhelming preference for the Z geometry may lie in the formation of a negative charge on the α carbon upon nucleophilic addition. This negatively charged intermediate should adopt the most stable conformation with the lone pair in anti to the fluorine atom, in order to minimize electrostatic repulsion with the fluorine’s lone pairs (see intermediate 4, Scheme 4). However, under these conditions, we also observed the formation of a side product identified as β-keto sulfone 3a [28] (40%) (2a:3a close to 1:1), which we reasoned was due to residual water in the TBAF acting as a competing nucleophile (Scheme 2) [29]. We attempted to minimize the formation of β-keto sulfone 3a by avoiding water exposure. However, the use of freshly distilled
Scheme 2. Preliminary results towards the hydrofluorination of alkynyl sulfones.
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Scheme 3. Control experiments.
1k,1l, resulted in a drop in chemical yield and chemoselectivity (28%, 72:28 for 2k and 30%, 67:33 for 2l) (Table 1). In addition, the heteroaromatic thiophene-derived alkynyl sulfone 1m also worked well, giving 2m in a good yield and selectivity (Table 1). Unfortunately, we found that aliphatic derivatives such as 1n,o failed to give the desired fluorovinyl sulfones 2n,o, both with and without the ammonium chloride additive (Table 1), instead giving rise to the related allenyl sulfones [30]. With the desired β-fluorovinyl sulfones in hand, we then decided to explore their reactivity. Reaction with a diverse range of nucleophiles, including diethyl malonate, primary and secondary amines, nitromethane, and boronic acids all resulted in the loss of fluorine via an addition-elimination mechanism [14]. We then turned our attention to the heterogeneous hydrogenation of the vinyl fluoride moiety, an ambitious transformation given the limited literature surrounding the hydrogenation of fluorinated olefins [17–22]. The process would provide β-fluoroalkyl sulfones 5, which are similarly scarce in the literature. In this context, Liu and co-workers have recently developed a racemic and regioselective Pd-catalyzed intermolecular fluorosulfonylation of styrenes under mild conditions [31]. Lectka and coworkers have also applied their benzylic fluorination methodologies to the synthesis of 5a [32,33]. After testing a variety of known heterogeneous hydrogenation systems—such as PtO2, Pd(OH)2, Pd/C, and NH4HCO2/Pd/C—using the model substrate 2a we found palladium on activated charcoal to be the most suitable. The transformation is highly sensitive to both solvent effects and reaction time (Table 2). Methanol is widely used in hydrogenation reactions, and has been used successfully in several past examples with vinyl fluorides [18,24]; however, we found that methanol promoted the competing hydrodefluorination reaction and resulted in a higher degree of the corresponding defluorinated alkyl sulfones 6 (Table 2, entry 5). Ultimately, we found that the best solvent in terms of
chemoselectivity was toluene (Table 2, entries 7–9). Given the slower reaction rate in toluene, a careful reaction-time optimization could be carried out to maximize conversion and chemoselectivity. Increasing the reaction time to 1.5 h resulted in a significant improvement in conversion with no noticeable effect on the degree of defluorination (Table 2, entry 8). An extra 0.5 h reaction time increase resulted in full conversion at the expense of a chemoselectivity (Table 2, entry 9). Longer reaction times resulted in a greater degree of hydrodefluorinated product (Table 2, entry 10). The conditions shown in entry 9 resulted in the best-isolated yield and were used in the subsequent study into the scope of the reaction. There are three speculated mechanisms for the competing hydrodefluorination reaction: (1) the hydrogenation of the CeC double bond to give the desired 5, followed by the elimination of HF and the hydrogenation of the resulting defluorinated vinyl sulfone; (2) a concerted mechanism as proposed by Hudlicky via a carbene intermediate [17]; and (3) direct cleavage of the CeF bond in 5 promoted by the palladium catalyst. The intermediate defluorinated vinyl sulfone 7 was not observed at any point (Scheme 5). Furthermore, in contrast to Andersson [21] and Hudlicky’s [17] work with α-fluorovinyl carbonyls, we observed that the resulting saturated β-fluoroalkyl sulfone 5 reacted further in the reaction conditions to give 6. These observations lead us to believe that the direct cleavage of the C(sp3)eF bond was responsible for the hydrodefluorination of 5. Alternative reducing agents, such as NaBH4 and Et3SiH, were also explored unsuccessfully. For several substrates the reaction time had to be modified to achieve the best yields of the desired products, but eventually we were able to achieve high yields and acceptable selectivities for a range of substrates (Table 3). Fluorovinyl sulfones with electron-neutral aromatic substituents such as 2a–e, along with electron-rich p-methoxy bearing substrates 2f and 2g, all gave rise to the corresponding βfluoroalkyl sulfones 5a-g in good yields and chemoselectivities Scheme 4. Proposed mechanism of reaction and formation of side products.
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Table 1 Scope of the hydrofluorination reaction of alkynyl sulfones.
Table 2 Optimization for the selective heterogeneous hydrogenation of (Z)-β-fluorovinyl sulfones.
Entrya
Solvent
Time/h
Conversion (%)
5a:6a
1 2 3 4 5 6 7 8 9 10
MTBE Et2O EtOAc Dioxane MeOH Acetone Toluene Toluene Toluene Toluene
1 1 1 1 1 1 1 1.5 2 18
> 98 > 98 > 98 > 98 > 98 > 98 30 80 > 98 > 98
86:14 75:25 50:50 87:13 75:25 25:75 > 98:2 > 98:2 92:8 66:34
a
Standard reaction conditions: 2a (0.05 mmol), Pd/C (10–15 mol%), solvent (1.5 mL), H2 (1 atm).
group with respect to the vinyl fluoride moiety, in accordance with its Hammett coefficient. Similarly, fluorovinyl sulfone 2k with an electronwithdrawing trifluoromethyl group in the para position also required a much longer reaction time, and unfortunately led to a higher degree of defluorination (Table 3, entry 10). In the case of bromine-bearing 2i the only product observed was 2a, arising from the cleavage of the
(Table 3, entries 1–7). Naphthyl-containing fluorovinyl sulfone 2b and the related p-biphenyl derivative 2c resulted in slightly lower selectivities (Table 3, entries 2–3). On the other hand, substrates 2 h and 2l, bearing electronegative atoms in the meta position, required significantly longer reaction times (Table 3, entries 8, 11). This suggests that the m-methoxy substituent behaves as an electron-withdrawing 111
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Scheme 5. Control experiments towards the hydrodefluorination mechanism.
more susceptible to cleavage than in α, and that the aromatic ring plays no role in the loss of fluorine in β.
aromatic CeBr bond; this was not observed with the related aromatic CeF bonds in 5l. Thiophene-based 2m could also be hydrogenated in good yields and chemoselectivities, although a stoichiometric amount of Pd/C was needed, possibly due to catalyst poisoning by the desired product 5m (Table 3, entry 12). We later sought to extend our methodologies to the synthesis of other related compounds. Firstly, we attempted the hydrofluorination of ethyl phenylpropiolate using our metal-free conditions (Scheme 6a). This substrate proved somewhat less reactive than the alkynyl sulfones, and it was necessary to heat the mixture. However, the reaction failed to reach completion even after 16 h at 60 °C. Nevertheless, we obtained the desired β-fluorovinyl ester 8 in a moderate 50% yield. We were pleased to find that the subsequent hydrogenation of 8 to β-fluoro ester 9 (Scheme 6a) resulted in complete conversion after just 1.5 h with a selectivity of 91:9 with respect to the corresponding defluorinated product. Secondly, we validated our hydrogenation procedure with other fluorovinyl sulfones such as the α-fluorinated and aliphatic analogs 11 and 2n, which were synthesized according to the methods described by Prakash [13] and Hammond [15], respectively. Both hydrogenations occurred uneventfully, giving rise to both high yields and selectivities (Scheme 6b,c). It is worth noting that the hydrogenation of α-fluorovinyl sulfone 11 was more selective than that of the β-fluorinated analogue 2a (96:4 vs 92:8), and that minor hydrodefluorination occurred even with aliphatic derivative 2n (for 5n 93:7) (Scheme 6c). These results suggest that the CeF bond in the β-position is inherently
3. Conclusion In conclusion, we have developed a simple, inexpensive, metal-free, and selective procedure for the synthesis of (Z)-β-fluorovinyl sulfones—a new class of compounds only recently introduced in the chemical literature—and investigated the reactivity of such compounds. In this sense, we have described the first studies into the hydrogenation of fluorovinyl sulfones, obtaining a range of hydrogenated products in good yields and selectivities; a challenging reaction given the competing hydrodehalogenation that has hindered the use of similar substrates in hydrogenation processes. Further studies towards an enantioselective version are currently being carried out in our laboratory. 4. Experimental section 4.1. General methods Reactions were carried out under a nitrogen atmosphere unless otherwise indicated. Solvents were purified prior to use: THF was distilled from sodium. The reactions were monitored by TLC on 0.25 mm precoated silica-gel plates. Visualization was carried out with UV light and aqueous ceric ammonium molybdate solution or potassium
Table 3 β-Fluorovinyl sulfone hydrogenation scope.
Entry
Substrate 2a
R1
R2
Product 5
Time (h)
Conversion (%)
Yield 5 (%)b
5:6
1 2 3 4 5 6 7 8 9 10 11 12e
2a 2b 2c 2d 2e 2f 2g 2h 2i 2k 2l 2m
C6H5 2-Naphthyl p-PhC6H4 p-MeC6H4 p-t-BuC6H4 p-MeOC6H4 p-MeOC6H4 3,5-diMeOC6H3 p-BrC6H4 p-CF3C6H4 3,5-diFC6H3 3-Thienyl
p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 C6H5 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4 p-MeC6H4
5a 5b 5c 5d 5e 5f 5g 5h 5ic 5k 5l 5m
2 2.5 3 2 3 2 3 60 16 120 60 2.5
> 98 > 98 > 98 > 98 95 > 98 > 98 > 98 41 80 > 98 > 98
96 97 94 92 96 95 96 95 0 90d 94 85
92:8 87:13 89:11 97:3 96:4 96:4 93:7 95:5 – 78:22 92:8 93:7
a b c d e
Standard reaction conditions: 2 (0.05 mmol), Pd/C (15 mol%), Toluene (1.5 mL), H2 (1 atm). Results shown are the average of a minimum 2–3 experiments. In most cases, compounds 5 contain small amounts of inseparable defluorinated sulfones 6. The only product observed was 2a. Yield corresponds to the mixture of starting 2k, β-fluorovinyl sulfone 5k and defluorinated sulfone 6k. Pd/C (100 mol%) was used.
112
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Scheme 6. Heterogeneous hydrogenation: other applications.
145.6 (C) ppm. HRMS (EI) calcd. for C15H11BrO2S [M+H+]: 334.9736, found 334.9728.
permanganate stain. Flash column chromatography was performed with the indicated solvents on silica gel 60 (particle size: 0.040−0.063 mm). 1H, 13C and 19F NMR spectra were recorded by a 300 MHz spectrometer. Chemical shifts are given in ppm (δ), referenced to the residual proton resonances of the solvents. Coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, respectively. The letters br indicate that the signal is broad. A QTOF mass analyzer system has been used for the HRMS measurements.
4.2.3. 1,3-Difluoro-5-(tosylethynyl)benzene (1l) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1l as a white solid (67%, 150 mg). Mp 105–107 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 6.93–6.99 (m, 1H; CH), 7.04-7.08 (m, 2H; 2CH), 7.43 (dd, J = 9.0, 0.6 Hz, 2H; 2CH), 7.96 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.8 (CH3), 86.9 (C), 89.2 (C), 107.8 (dd, 2J = 25.0, 25.0 Hz, CH), 115.7 (dd, 2J = 28.0 Hz, 4J = 9.0 Hz, 2CH), 120.0 (dd, 3J = 120, 12.0 Hz, C), 127.7 (2CH), 130.1 (2CH), 138.3 (C), 145.9 (C), 162.1 (d, 1 J = 252.2 Hz, CF), 163.7 (d, 1J = 252.2, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −107.3-(-107.4) (m, 2F; 2CF) ppm. HRMS (EI) calcd. for C15H10F2O2S [M+H+]: 293.0442, found 293.0434.
4.2. Synthesis of alkynylsulfones [25]: general procedure Ceric ammonium nitrate (2.5 mmol) was added portion-wise to a mixture of the corresponding acetylene (1 mmol), sodium p-toluenesulfinate (1.2 mmol) and NaI (1.2 mmol) in CH3CN (15 mL) under a nitrogen atmosphere. After the completion of the reaction (1 h approx.), the reaction mixture was hydrolyzed with H2O and extracted with CH2Cl2. The organic layer was separated, washed with brine (50 mL) and dried over Na2SO4. The solvent was removed and the residue was heated at 60 °C with K2CO3 (3 mmol) in acetone (10 mL) for 16 h. After the completion of the reaction, the reaction mixture was washed with H2O (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo using a rotary evaporator and the residue was purified by column chromatography to afford the desired product. Compounds 1d, 1f-g are described in reference [25]; compounds 1a and 1e in reference [34a]; compounds 1b, 1 h, 1i and 1k in reference [34b]; compound 1 m in reference [34c]; and compound 1n in reference [15].
4.3. Synthesis of (Z)-β-fluorovinyl sulfones 2: general procedure A 1 M solution of TBAF (0.15 mmol) was added to a solution of the corresponding alkynyl sulfone (0.1 mmol) and NH4Cl (0.1 mmol) in THF (0.1 M) under a nitrogen atmosphere at room temperature. After completion of the reaction (1–3 h), the reaction mixture was hydrolyzed with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography affording compounds 2. Compound 2a is described in reference [13]. 4.3.1. (Z)-2-(1-Fluoro-2-tosylvinyl)naphthalene (2b) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2b as a white solid (69%, 28 mg). Mp 130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.69 (d, J = 33.0 Hz, 1H; CH), 7.39 (d, J = 9.0 Hz, 2H; 2CH), 7.52 (d, J = 9.0 Hz, 1H; CH), 7.57–7.62 (m, 2H; 2CH), 7.84–7.89 (m, 3H; 3CH), 8.00 (d, J = 9.0 Hz, 2H; 2CH), 8.12 (s, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 110.0 (d, J = 12.8 Hz, CH), 121.5 (d, J = 7.6 Hz, CH), 125.8 (d, J = 25.7 Hz, C), 127.1 (d, J = 7.6 Hz, CH), 127.3 (CH), 127.7 (CH), 127.8 (CH), 128.5 (CH), 129.0 (CH), 129.8 (CH), 132.5 (C), 134.8 (C), 139.3 (C), 144.6 (C), 164.0 (d, 1 J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.9 (d, J = 31.0, 1F; CF) ppm. HRMS (EI) calcd. for C19H15FO2S [M+H+]: 327.0850, found 327.0852.
4.2.1. 4-(Tosylethynyl)-1,1′-biphenyl (1c) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1c as a white solid (40%, 410 mg). Mp 132–134 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 7.41–7.50 (m, 5H; 5CH), 7.58–7.61 (m, 6H; 6CH), 8.00 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 86.1 (C), 93.1 (C), 116.6 (C), 127.1 (2CH), 127.3 (2CH), 127.5 (2CH), 128.4 (CH), 129.0 (2CH), 130.0 (2CH), 133.2 (2CH), 139.0 (C), 139.5 (C), 144.3 (C), 145.3 (C) ppm. HRMS (EI) calcd. for C21H16O2S [M+H+]: 333.0944, found 333.0941. 4.2.2. 1-Bromo-3-(tosylethynyl)benzene (1j) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 1 j as a white solid (44%, 340 mg). Mp 130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.5 (s, 3H; CH3), 7.26 (dd, J = 9.9, 6.0 Hz, 1H; CH), 7.42 (d, J = 9.0 Hz, 2H; 2CH), 7.45–7.49 (m, 1H; CH), 7.59–7.63 (m, 1H; CH), 7.67 (dd, J = 3.0, 3.0 Hz, 1H; CH), 7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.8 (CH3), 86.5 (C), 90.6 (C), 120.0 (C), 122.4 (C), 127.6 (2CH), 130.0 (2CH), 130.1 (CH), 131.2 (CH), 134.5 (CH), 135.2 (CH), 138.6 (C),
4.3.2. (Z)-4-(1-Fluoro-2-tosylvinyl)-1,1′-biphenyl (2c) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2c as a white solid (72%, 27 mg). Mp 196–198 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.60 (d, J = 33.0 Hz, 1H; CH), 7.37–7.50 (m, 5H; 5CH), 7.59-7.65 (m, 6H; 6CH), 7.98 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 109.5 (d, J = 13.6 Hz, CH), 126.4 (d, J = 8.3, 2CH), 127.1 (2CH), 127.2 (C), 127.7 (2CH), 128.4 (CH), 129.0 (2CH), 129.8 (2CH), 113
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139.3 (d, J = 8.3 Hz, C), 144.6 (C), 145.2 (C), 163.3 (d, 1J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.8 (d, J = 32.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C21H17FO2S [M+H+]: 353.1006, found 353.1003.
3
J = 13.6 Hz, CH), 127.7 (2CH), 129.8 (2CH), 130.5 (d, J = 26.4 Hz, C), 139.1 (C), 144.6 (C), 161.1 (C), 163.7 (d, 1 J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.3 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C17H17FO4S [M+H+]: 337.0904, found 337.0895. 2
4.3.3. (Z)-1-((2-Fluoro-2-(4-tolyl)vinyl)sulfonyl)-4-methylbenzene (2d) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2d as a white solid (67%, 28 mg). Mp 100–102 °C. 1H NMR (CDCl3, 300 MHz) δ 2.39 (s, 3H; CH3), 2.46 (s, 3H; CH3), 6.52 (d, J = 33.0 Hz, 1H; CH), 7.23 (d, J = 9.0 Hz, 2H; 2CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.46 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.5 (CH3), 21.6 (CH3), 108.7 (d, J = 13.6 Hz, CH), 125.8 (2CH), 125.9 (2CH), 126.1 (C), 127.6 (2CH), 129.7 (2CH), 139.4 (C), 143.2 (C), 144.4 (C), 164.5 (d, 1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.4 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C16H15FO2S [M+H+]: 291.0850, found 291.0858.
4.3.8. (Z)-1-Bromo-4-(1-fluoro-2-tosylvinyl)benzene (2i) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2i as a white solid (63%, 22 mg). Mp 145–147 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.56 (d, J = 33.0 Hz, 1H; CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.42 (d, J = 9.0 Hz, 2H; 2CH), 7.58 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 110.3 (d, J = 13.6 Hz, CH), 127.2 (CH), 127.3 (CH), 127.6 (d, J = 26.7 Hz, C), 127.7 (CH), 129.9 (CH), 132.3 (C), 144.8 (C), 163.5 (d, J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.2 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H12BrFO2S [M +H+]: 354.9798, found 354.9806.
4.3.4. (Z)-1-(tert-Butyl)-4-(1-fluoro-2-tosylvinyl)benzene (2e) Flash chromatography of the crude reaction product [n-hexaneEtOAc (15:1)] afforded 2e as a white solid (67%, 28 mg). Mp 122–124 °C. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.46 (s, 3H; CH3), 6.52 (d, J = 33 Hz, 1H; CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.44 (d, J = 9.0 Hz, 2H; 2CH), 7.51 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 30.9 (3CH3), 35.1 (C), 108.8 (d, 2J = 13.6 Hz, CH), 125.8 (d, 3 J = 7.5 Hz, 2CH), 126.0 (d J = 2.3 Hz, 2CH), 127.6 (2CH), 129.7 (2CH), 139.4 (C), 144.4 (C); 156.3 (C), 164.2 (d, 1J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.4 (d, J = 31.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C19H21FO2S [M+H+]: 333.1319, found 333.1327.
4.3.9. (Z)-1-Bromo-3-(1-fluoro-2-tosylvinyl)benzene (2j) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2j as a white solid (60%, 20 mg). Mp 81–83 °C. 1 H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.57 (d, J = 30.0 Hz, 1H; CH), 7.33 (d, J = 9.0 Hz, 1H; CH), 7.38 (d, J = 6.0 Hz, 2H; 2CH), 7.50 (d, J = 9.0 Hz, 1H; CH), 7.61–7.64 (m, 1H; CH), 7.69-7.70 (m, 1H; CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 111.2 (d, J = 13.6 Hz, CH), 123.1 (C), 124.4 (d, J = 7.5 Hz, CH), 127.7 (2CH), 128.8 (d J = 8.3 Hz, CH), 129.9 (2CH), 130.5 (CH), 135.2 (CH), 138.8 (C), 144.8 (C), 162.0 (d, 1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.1 (d, J = 31.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H12BrFO2S [M+H+]: 354.9798, found 354.9793.
4.3.5. (Z)-1-(1-Fluoro-2-(phenylsulfonyl)vinyl)-4-methoxybenzene (2f) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2f as a white solid (72%, 40 mg). Mp 78–80 °C. 1 H NMR (CDCl3, 300 MHz) δ 3.86 (s, 3H; OCH3), 6.45 (d, J = 33.0 Hz, 1H; CH), 6.93 (d, J = 9.0 Hz, 2H; 2CH), 7.51–7.65 (m, 5H; 5CH), 8.07 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.5 (OCH3), 107.1 (d, J = 13.6 Hz, CH), 114.5 (2CH), 120.8 (d, J = 25.6 Hz, C), 127.5 (2CH), 127.9 (J = 8.3 Hz, 2CH), 129.1 (2CH), 133.3 (CH), 142.4 (C), 163.0 (C), 164.5 (d, 1J = 273.0 Hz, C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.7 (d, J = 33.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H13FO3S [M + H+]: 293.0642, found 293.0642.
4.3.10. (Z)-1-((2-Fluoro-2-(4-(trifluoromethyl)phenyl)vinyl)sulfonyl)-4methylbenzene (2k) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2k as a white solid (28%, 20 mg). Mp 129–131 °C. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 6.64 (d, J = 32.0 Hz, 1H; CH), 7.37 (dd, J = 8.6, 0.7 Hz, 1H; CH), 7.68 (s, 2H; 2CH), 7.94 (d, J = 8.0 Hz, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 111.9 (d, J = 13.1 Hz, C), 111.9 (d, J = 13.1 Hz, C), 125.9 (q, J = 2.4 Hz, CH), 126.2 (d, J = 7.6 Hz, CH), 127.8 (CH), 129.9 (CH), 132.2 (d, J = 27.4 Hz, C), 133.8 (d, J = 33.1 Hz, C), 138.6 (C), 144.9 (C), 162.1 (d, J = 274.0 Hz, C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.84 (d, J = 31.9 Hz, CF), −63.71 (s, CF3) ppm. HRMS (EI) calcd. for C16H12F4O2S [M+NH4+]: 362.0832, found 362.0825.
4.3.6. (Z)-1-[(2-Fluoro-2-(4-methoxyphenyl)vinyl)sulfonyl]-4methylbenzene (2g) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2g as a white solid (71%, 45 mg). Mp 74–75 °C. 1 H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.84 (s, 3H; OCH3), 6.43 (d, J = 32.8 Hz, 1H; CH), 6.92 (d, J = 9.1 Hz, 1H; CH), 7.36 (d, J = 9.0 Hz, 1H; CH), 7.51 (d, J = 9.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 55.2 (OCH3), 107.4 (d, 2J = 13.4 Hz, CH), 114.5 (2CH), 120.9 (d, 2J = 25.6 Hz, C), 127.5 (2CH), 127.8 (d, 3J = 8.2 Hz, 2CH), 129.7 (2CH), 139.5 (C), 144.3 (C), 162.9 (C), 164.2 (d, 1J = 272.2 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.3 (d, J = 33.9 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C16H15O3S [M+H+]: 307.0799, found 307.0800.
4.3.11. (Z)-1,3-Difluoro-5-(1-fluoro-2-tosylvinyl)benzene (2l) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2l as a white solid (30%, 21 mg). Mp 158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 6.57 (d, J = 30.0 Hz, 1H; CH), 6.92-7.00 (m, 1H; CH), 7.08-7.11 (m, 2H; 2CH), 7.40 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 107.7 (dd, 2J = 24.8, 24.9 Hz, CH), 109.0 (dd, 2J = 27.1, 27.2 Hz, CH), 112.1 (d, J = 12.8 Hz, CH), 127.8 (2CH), 129.9 (2CH), 131.9 (d, 2J = 28.7 Hz, C), 138.5 (C), 145.1 (C), 161.1 (d, 1J = 274.0 Hz, CF), 163.0 (d, 1J = 251.4 Hz, CF), 163.2 (d, 1J = 251.5 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −106.7 (s, 2F; 2CF), −94.2 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H11F3O2S [M+H+]: 313.0505, found 313.0506.
4.3.7. (Z)-1-(1-Fluoro-2-tosylvinyl)-3,5-dimethoxybenzene (2h) Flash chromatography of the crude reaction product [n-hexaneEtOAc (10:1)] afforded 2h as a white solid (70%, 30 mg). Mp 158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.80 (s, 6H; 2OCH3), 6.53 (d, J = 33.0 Hz, 1H; CH), 6.57-6.59 (m, 1H; CH), 6.67 (d, J = 3.0 Hz, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.94 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.6 (OCH3), 103.9 (CH), 104.3 (d, 2J = 52.1 Hz, CH), 110.2 (d,
4.3.12. (Z)-3-(1-Fluoro-2-tosylvinyl)thiophene (2m) Flash chromatography of the crude reaction product [n-hexaneEtOAc (5:1)] afforded 2m as a white solid (70%, 65 mg). Mp 121–123 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.39 (d, J = 33.2 Hz, 1H; CH), 7.15 (d, J = 6.0 Hz, 1H; CH), 7.35-7.38 (m, 3H; 3CH), 7.74 (d, J = 3.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz, 1H; CH) ppm. 114
Journal of Fluorine Chemistry 206 (2018) 108–116
D.M. Sedgwick et al. 13 C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 109.0 (d, J = 12.5 Hz, CH), 124.4 (d, J = 7.5 Hz, CH), 127.6 (2CH), 128.0 (CH), 128.2 (d, J = 6.0 Hz, CH), 129.8 (2CH), 131.0 (d, 2J = 27.9 Hz, C), 139.3 (C), 144.5 (C), 160.0 (d, 1J = 270.9 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.7 (d, J = 32.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C13H11FO2S2 [M+H+]: 283.0257, found 283.0254.
3.43 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H; CHH), 3.77-3.90 (m, 1H; CHH), 5.99 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.35-7.40 (m, 4H; 4CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 31.2 (3CH3), 34.7 (C), 62.7 (d, 2 J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.7, CHF), 125.4 (d, 3J = 6.0 Hz, 2CH), 125.8 (2CH), 128.3 (2CH), 129.8 (2CH), 133.8 (d, 2 J = 13.6 Hz, C), 136.7 (C), 144.9 (C), 152.6 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −171.9 (ddd, J = 48.0, 31.1, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C19H23FO2S [M + NH4+]: 352.1741, found 352.1742.
4.3.13. Ethyl (Z)-3-fluoro-3-phenylacrylate (8) Described in reference [35]. 4.4. Hydrogenation of β-fluorovinylsulfones
4.4.6. 1-(1-Fluoro-2-(phenylsulfonyl)ethyl)-4-methoxybenzene (5f) Crude reaction product 5f (95%, 19 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 3.47 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H; CHH), 3.81 (s, 3H; OCH3), 3.78-3.93 (m, 1H; CHH), 5.97 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.88 (d, J = 9.0 Hz, 2H; 2CH), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.55-7.60 (m, 2H; 2CH), 7.65–7.70 (m, 1H; CH), 7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.3 (OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.3 (d, 1J = 175.2 Hz, CHF), 114.3 (2CH), 127.3 (d, 3J = 5.3 Hz, 2CH), 128.3 (2CH), 128.7 (d, 2 J = 20.4 Hz, C), 129.2 (2CH), 133.9 (CH), 139.7 (C), 160.4 (C) ppm. 19 F NMR (CDCl3, 282.4 MHz) δ −167.8 (ddd, J = 48.0, 31.1, 14.1, 1F; CHF) ppm. HRMS (EI) calcd. for C15H15FO3S [M+NH4+]: 312.1064, found 312.1056.
4.4.1. General procedure for the synthesis of β-fluoro sulfones 5 Pd(C) catalyst (15 mol%) was added to a solution of the corresponding β-fluorovinyl sulfone 2 (0.05 mmol) in toluene (0.033 M), and hydrogen gas was charged by purging the reaction flask several times, without stirring. The reaction was then stirred under H2 (atmospheric pressure) at room temperature for 1–3 h. The mixture was filtered to remove the catalyst, and the solvent was evaporated in vacuo. In most cases, compounds 5 contain small amounts of inseparable defluorinated sulfones 6. Compound 5a has been described in reference [31]. For compounds 10 and 11, see reference [14]. 4.4.2. -(1-Fluoro-2-tosylethyl)naphthalene (5b) Crude reaction product 5b (96%, 20 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.57 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.86-3.98 (m, 1H; CHH), 6.18 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.33-7.38 (m, 3H; 3CH), 7.52-7.55 (m, 2H; 2CH), 7.76–7.87 (m, 6H; 6CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 62.6 (d, 2J = 26.4 Hz, CH2), 88.8 (d, 1J = 177.4 Hz, CHF), 122.5 (d, 3J = 5.3 Hz, CH), 125.3 (d, 3J = 7.5 Hz, CH), 126.8 (CH), 126.9 (CH), 127.7 (CH), 128.1 (CH), 128.3 (2CH), 128.9 (CH), 129.8 (2CH), 132.9 (C), 133.5 (C), 134.1 (d, 2J = 20.4 Hz, C), 136.6 (C), 145.0 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1 (ddd, J = 45.1, 28.2, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C19H17FO2S [M+NH4+]: 346.1272, found 346.1268.
4.4.7. 1-((2-Fluoro-2-(4-methoxyphenyl)ethyl)sulfonyl)-4-methylbenzene (5g) Crude reaction product 5g (96%, 21 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.45 (ddd, J = 30.0, 15.0 3.0 Hz, 1H; CHH), 3.81 (s, 3H; OCH3), 3.78–3.90 (m, 1H; CHH), 5.95 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.89 (d, J = 9.0 Hz, 2H; 2CH), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.84 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.3 (OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.4 (d, 1 J = 175.9 Hz, CHF), 114.2 (2CH), 127.3 (d, 3J = 6.0 Hz, 2CH), 128.3 (2CH), 128.9 (d, 2J = 20.4 Hz, C), 129.8 (2CH), 136.7 (C), 144.9 (C), 160.4 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −168.0 (ddd, J = 45.2, 28.2, 11.3 1F; CHF) ppm. HRMS (EI) calcd. for C16H17FO3S [M +NH4+]: 326.1221, found 326.1215.
4.4.3. 4-(1-Fluoro-2-tosylethyl)-1,1′-biphenyl (5c) Crude reaction product 5c (94%, 16 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.81-3.93 (m, 1H; CHH), 6.08 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.36-7.61 (m, 11H; 11CH), 7.87 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.7 (d, 2 J = 25.7 Hz, CH2), 88.5 (d, 1J = 177.4 Hz, CHF), 126.0 (d, 3 J = 6.8 Hz, 2CH), 127.1 (2CH), 127.6 (2CH), 127.7 (CH), 128.3 (2CH), 128.8 (2CH), 129.9 (2CH), 135.7 (d, 2J = 19.6 Hz, C), 136.7 (C), 140.2 (C), 142.4 (C), 145.0 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1 (ddd, J = 45.1, 31.1, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C21H19FO2S [M+NH4+]: 372.1428, found 372.1426.
4.4.8. 1-(1-Fluoro-2-tosylethyl)-3,5-dimethoxybenzene (5h) Crude reaction product 5h (95%, 12 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 3.45 (ddd, J = 33.5, 15.0, 3.1 Hz, 1H; CHH), 3.72-3.84 (m, 1H; CHH), 3.78 (s, 6H; 2OCH3), 5.90 (ddd, J = 48.1, 9.0, 3.1 Hz, 1H; CHF), 6.41 (s, 3H; 3CH), 7.39 (d, J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.4 (2OCH3), 62.4 (d, 2J = 25.7 Hz, CH2), 88.5 (d, 1J = 180.0 Hz, CHF), 101.0 (CH), 103.2 (d, 3J = 6.8 Hz, 2CH), 128.3 (2CH), 129.9 (2CH), 136.7 (C), 139.3 (d, 2J = 20.4 Hz, C), 145.0 (C), 161.2 (2C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −175.2 (ddd, J = 48.0, 33.5, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C17H19FO4S [M+H+]: 339.1061, found 339.1050.
4.4.4. 1-((2-Fluoro-2-(p-tolyl)ethyl)sulfonyl)-4-methylbenzene (5d) Crude reaction product 5d (92%, 23 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H; CH3), 2.48 (s, 3H; CH3), 3.45 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.76–3.89 (m, 1H; CHH), 7.18 (s, 4H; 4CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.2 (CH3), 21.7 (CH3), 62.7 (d, 2J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.0 Hz, CHF), 125.6 (d, 3 J = 6.0 Hz, 2CH), 128.3 (2CH), 129.5 (2CH), 129.8 (2CH), 133.9 (d, 2 J = 20.4 Hz, C), 136.7 (C), 139.4 (C), 144.9 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −171.7 (ddd, J = 48.0, 31.0, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C16H17FO2S [M+NH4+]: 310.1272, found 310.1269.
4.4.9. 4-(1-Fluoro-2-tosylethyl)-1-trifluoromethylbenzene (5k) Crude reaction product 5k (90%, 9 mg) was obtained as viscous oil. Data taken from the crude mixture. Only the most characteristic signals for 5k are described in the following data, due to the difficulties in isolating this compound (see spectrum 5k). 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 3.48 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.80 (ddd, J = 24.0, 15.0, 9.0 Hz, 1H; CHH), 6.09 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 62.5 (d, 2J = 24.9 Hz, CH2), 87.9 (d, 1J = 179.7 Hz, CHF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −177.0 (ddd, J = 46.0, 30.0, 14.2 Hz, 1F; CHF), −63.1 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C16H14F4O2S [M +NH4+]: 364.0989, found 364.0993.
4.4.5. 1-(tert-Butyl)-4-(1-fluoro-2-tosylethyl)benzene (5e) Crude reaction product 5e (96%, 16 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.47 (s, 3H; CH3), 115
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4.4.10. 1,3-Difluoro-5-(1-fluoro-2-tosylethyl)benzene (5l) Crude reaction product 5l (94%, 18 mg) was obtained as viscous oil. 1 H NMR (CDCl3, 300 MHz) δ 2.48 (s, CH3), 3.44 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.75 (ddd, J = 21.0, 15.0, 9.0 Hz, 1H; CHH), 6.00 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 6.77-6.85 (m, 3H; 3CH), 7.40 (d, J = 9.0 Hz, 2H; 2CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.4 (d, 2J = 25.7 Hz, CH2), 87.4 (d, 1 J = 180.4 Hz, CHF), 104.6 (dd, 2J = 25.7 Hz, CH), 108.5 (ddd, J = 25.6, 7.5 Hz, 2CH), 128.2 (2CH), 129.9 (2CH), 136.4 (C), 140.7 (C), 145.3 (C), 163.1 (d, 1J = 252.4 Hz, CF), 163.1 (d, 1J = 252.4 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −176.6 (ddd, J = 45.1, 28.2, 14.0 Hz, 1H; CHF), −107.5 to (−107.4) (m, 2F; 2CF) ppm. HRMS (EI) calcd. for C15H13F3O2S [M+NH4+]: 332.0927, found 332.0926.
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4.4.11. 3-(1-Fluoro-2-tosylethyl)thiophene (5m) Crude reaction product 5m (85%, 10 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.79-3.92 (m, 1H; CHH), 6.10 (ddd, J = 6.0 Hz, 1H; CH), 7.30-7.34 (m, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.84 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.0 (d, 2J = 25.7 Hz, CH2), 84.8 (d, 1J = 174.4 Hz, CHF), 123.6 (d, 3J = 7.5 Hz, CH), 124.8 (d, 3J = 3.0 Hz, CH), 127.3 (CH), 128.3 (2CH), 129.9 (2CH), 136.6 (C), 137.8 (d, 2J = 21.9 Hz, C), 145.1 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −167.5 (ddd, J = 45.2, 28.2, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C13H13FO2S2 [M+NH4+]: 302.0679, found 302.0682. 4.4.12. ((2-Fluorooctyl)sulfonyl)benzene (5n) Crude reaction product 5n (94%, 14 mg) was obtained as viscous oil. 1H NMR (CDCl3, 300 MHz) δ 0.89–1.72 (m, 13H; C6H13), 3.28 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.54-3.60 (m, 1H; CHH), 4.92-5.15 (m, 1H; CHF), 7.57-7.71 (m, 3H; 3CH), 7.95-7.97 (m, 2H; 2CH) ppm. 13 C NMR (CDCl3, 75.5 MHz) δ 13.9 (CH3), 22.4 (CH2), 24.4 (d, 3 J = 4.5 Hz, CH2), 28.7 (CH2), 31.5 (CH2), 34.8 (d, 2J = 20.4 Hz, CH2), 61.0 (d, 2J = 23.4 Hz, CH2), 88.1 (d, 1J = 174.4 Hz, CHF), 128.2 (2CH), 129.2 (2CH), 133.9 (CH), 139.7 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −180.0 to (−179.5) (m, 1F; CHF) ppm. HRMS (EI) calcd. for C14H21FO2S [M+NH4+]: 290.1585, found 290.1578. Acknowledgments We would like to thank the Spanish Ministerio de Economía y Competitividad (CTQ-2013-43310-P) and the Generalitat Valenciana (GV/PrometeoII/2014/073). D. M. S. thanks the Spanish Ministerio de Educación, Cultura y Deporte for a predoctoral fellowship (FPU15/ 01485). The authors are also grateful to Alberto Llobat and Daniel Dávila for assistance in the synthesis of the starting materials. References [1] E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58 (2015) 8315–8359.
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