2024 Volume 72 Issue 10 Pages 884-889
As an easy-to-handle reagent for the in situ generation of outstandingly electrophilic Tf2C=CH2 (Tf=CF3SO2), we have designed and synthesised a novel 4-substituted 2-fluoropyridinium zwitterion, in which a partially fluorinated alkyl group is attached to the pyridinium 4-position. Its zwitterionic nature has been well characterised by quantum chemical bonding analysis. By using this reagent, a wide variety of organic compounds, including commercial bioactive agents, were successfully decorated by the strongly acidic or ionic functionality. Remarkably, the 4-substituted 2-fluoropyridine derivative, which results from the zwitterion with the generation of Tf2C=CH2, can be rapidly separated and recovered from the reaction mixture appropriately using distillation, organic solvent extraction, or fluorous solid phase extraction techniques. Such multi-optionality for the purification methods favours in the isolation of the strongly acidic and/or ionic products.
Electron-deficient alkenes, exemplified by α,β-unsaturated carbonyl compounds, have been a focus of organic chemistry for a long time. A number of the applications to conjugate addition and cycloaddition reactions have been reported. However, extremely electron-deficient alkenes are less studied due to their poor handling. For example, 1,1-bis(triflyl)ethylene, in which the triflyl group (Tf=CF3SO2) is one of the strongest electron withdrawing groups,1) rapidly yields a mixture of Tf2CH2 and formaldehyde through hydrolysis by moisture under an air atmosphere. To overcome such annoyance of Tf2C=CH2, the following in situ generation methods have been reported: 1) Self-promoting condensation of Tf2CH2 and formaldehyde,2,3) 2) retro-Michael reaction of Tf2CHCH2CHTf2,4) and 3) dissociation reaction of 2-fluoropyridinium zwitterion 1a5–7) (Fig. 1). Nowadays, the third option has been recognised as the most convenient and effective one because the reagent 1a is a shelf-stable and easy-to-handle crystalline compound without deliquescency, but once dissolved in organic solvents, immediately releases Tf2C=CH2.8,9) Such achievement has also stimulated active developments of new synthetic reactions using Tf2C=CH2. For example, we reported that Tf2C=CH2 smoothly reacted with neutral nucleophiles H–Nu including electron-rich arenes,4) heterocycles,10,11) and active methylenes12) to give the corresponding carbon acids depicted as Tf2CHCH2Nu, which exhibited high acidity comparable to sulfuric acid molecule.13) In addition, such carbon acids showed higher catalyst performance than structurally related TfOH and Tf2NH in Mukaiyama aldol chemistry.14–24) The reaction of Tf2C=CH2 with amines25) and phosphines26) produced stable carbanion-containing zwitterions. Alcaide and Almendros reported several cyclisation reactions.2,27–31) In particular, it should be remarkable that gem-bis(triflyl)cyclobutenes were synthesised by the (2 + 2) cycloaddition of arylalkynes with Tf2C=CH2 without light irradiation.32–36) In these applications, highly volatile nature of 2-fluoropyridine 2a, which is formed as a by-product with the formation of Tf2C=CH2, is one of the advantages in the purification, but brings about a difficulty in recovering. An efficient alternative, which is easily removable but recyclable, is strongly required. In continuation of the project, we have devised a compound 1b linked to a perfluorooctyl chain by a non-fluorinated hydrocarbon spacer. The high molecular weight and lipophilic labelling in 4-substituted 2-fluoropyridine 2b would contribute to easy purification of the products by distillation or simple washing with organic solvents. Furthermore, fluorous solid phase extraction (FSPE) technique using FluoroFlash® silica gel would be a potent purification method as well.37–39) We have expected that such multi-optionality for the purification methods gives an advantage in the synthesis of the strongly acidic and/or ionic products.
The desired 4-substituted 2-fluoropyridine 2b and zwitterion 1b were easily synthesised (Chart 1). The iodine-selective Mizoroki–Heck reaction40) of 1-bromo-4-iodobenzene 3 with heptadecafluoro-1-decene proceeded by microwave heating (125 °C) to give the coupling product 4 in 63% yield. The desired pyridine 2b was obtained in good overall yield by the desilylative Sonogashira cross coupling reaction of 4 with 2-fluoro-4-(trimethylsilylethynyl)pyridine (TMS-alkyne 5)41) followed by hydrogenation over Pd/C. The weight percentage (F) of fluorine atoms in 2b is 52.8%. The zwitterion forming reaction using Tf2C=CH2 in-situ generated from Tf2CH2 and paraformaldehyde gave the desired zwitterion 1b bearing the carbanion moiety in 84% yield.5) The present protocol was scalable and we obtained 3.1 g of 1b from 2.6 g of 2b in one batch operation.
As shown in Fig. 2, this new 2-fluoropyridinium zwitterion 1b is a stable crystalline compound, allowing storage in bench side at least during several months without any special requirements. In addition, notably advantageous for handling are non-hygroscopic and non-fuming properties. A variable temperature (VT) NMR study of 1b (a 10 mmol L−1 solution in acetonitrile-d3) revealed its dynamic behaviour in the solution. Similar to the original reagent 1a,6) zwitterion 1b exhibited a remarkable downfield shift of methylene hydrogens Ha by increasing the measurement temperature (Figs. 3a, 3b). This phenomenon can be attributed to a very rapid formation of Tf2C=CH2 and 2b over the NMR time scale. The van’t Hoff plot based on the NMR data showed a clear linear relationship (Fig. 3c). Here, thermodynamic parameters ΔrS and ΔrH were calculated to be 282 J K−1 mol−1 and 111 kJ, respectively (for details, see Supplementary Materials). The obtained ΔrG298 K value (27.1 kJ mol−1) for the dissociation of 1b to afford a mixture of Tf2C=CH2 and 2b was slightly higher than that for the dissociation of 1a (18.6 kJ mol−1).6)
These NMR data of 1b implies that it serves as a useful precursor of Tf2C=CH2, and it was demonstrated by the reaction with naphthalen-2-ol (7a) as a model nucleophile (Chart 2). When 1.0 equivalent (equiv.) of 1b was applied instead of the original reagent 1a, the reaction was completed in 5 h, and the desired product 8a (F = 26.1%) and 4-substituted 2-fluoropyridine 2b were isolated in 96 and 94% yields, respectively, by the FSPE technique. After some attempts, we found that the use of highly polar 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP) as the solvent accelerated the reaction, leading to a complete consumption of 7a in 30 min at room temperature to give 8a in 99% yield along with an excellent recovery of 2b. The recovered 2b was reusable for production of the reagent 1b.
With the optimised conditions, the reactions using the reagent 1b enabled the C–H acid functionalisation of a wide variety of nucleophiles (Fig. 4). For example, the phenol moiety in estrone (7b) was selectively reacted with the in situ generated Tf2C=CH2 to give ortho-substituted product 8b in 99% yield. Likewise, N-tosylindole 7c and 1,3-diketone 7d were converted to the desired 2,2-bis(triflyl)ethylation products 8c and 8d. The outstandingly high electrophilicity of Tf2C=CH2 allowed double reactions by using more than 2 equiv. of the reagent 1b; the reaction of 4-tert-butylphenol (7e) with 2.3 equiv. of 1b cleanly afforded 2,6-disubstituted product 9a in 97% yield. In the case of chiral biphenyl 7f, the use of acetonitrile gave diacid 9b with better purity. Likewise, the disubstituted fluorescence dye 9c was obtained in an excellent yield by the C–H acid decoration of BODIPY 493/503 (7g) in HFIP. In all the cases, the FSPE technique using FluoroFlash®, which were reusable without any treatment, was successfully utilised to isolate the superacidic carbon acids.
As shown in Chart 3, the bulb-to-bulb distillation using a Kugelrohr oven was effective for the synthesis of low boiling point carbon acids. For instance, acid molecule 11 derived from acetone 10 and the reagent 1b was isolated as distillate in 92% yield. From the residue, 4-substituted 2-fluoropyridine 2b was obtained in 98% yield.
In the cases where ionic products are formed, simple two-step operation consisting of evaporation of the reaction mixture and washing of the residue with hexane was effective to isolate the desired products. For instance, sufficiently pure anilinium zwitterions 13a, 13b were obtained in excellent yields after washing the crude materials with hexane (Fig. 5). Here, the 4-substituted 2-fluoropyridine 2b was recovered in excellent yields from the hexane phase. Likewise, not only quinuclidinium zwitterion 13c but also relatively lipophilic triphenylphosphonium zwitterion 13d were isolated. Notably, biologically active pyrazolones such as antipyrine 12e and edaravone 12f served nicely as the reaction partners. In these cases, the corresponding C-alkylated pyrazolium type zwitterions 13e, 13f were also obtained in excellent yields after washing the crude materials with hexane.
Moreover, we found that the reagent 1b was effective for the structural decoration of cefdinir (14), one of the third-generation cephalosporin antibiotics.42) Upon the treatment with an equimolar amount of the reagent 1b in HFIP, cefdinir (14) underwent selective alkylation at the 5-position of the thiazole nucleus (Chart 4). After washing the crude material with hexane, the additional purification by reversed-phase column chromatography allowed effective isolation of the corresponding zwitterion 15 in 91% yield. Here, the 4-substituted 2-fluoropyridine 2b was recovered in 95% yield from the hexane phases. This finding clearly demonstrates a high level of chemoselectivity in the electrophilic attack of Tf2C=CH2. Unfortunately, in our preliminary study on the antimicrobial activity against a standard strain of Staphylococcus aureus (JCM2874), the relative potency of 15 significantly decreased to 1.7–3.4% of the parent antibiotic 14 (the Supplementary Materials), though we previously reported that such structural decoration by the carbanionic substituent improves the lipophilicity of the compounds as well as their water solubility.10,11)
The characteristic VT-NMR profile of 1b and its synthetic applications motivated us to conduct theoretical investigation of molecular structure and bonding behaviour between the pyridinium and ethanide moieties (Fig. 6). In the picture of Natural Bond Orbital (NBO) analysis,43) which is closely linked with traditional Lewis structure, a model derivative 1c, in which the perfluorooctyl group in 1b was replaced by a trifluoromethyl group, showed clear zwitterionic character as follows; 1) pronounced negative charge of the C1 atom (−0.94 e) and distributed positive charge in the pyridinium ring (N1, −0.38 e; C3, +0.74 e; C7, +0.11 e) in Natural Population Analysis (NPA), 2) a LPC1 orbital with 1.68 e of occupancy, which corresponds an occupied p orbital of the C1 atom, and 3) relatively large second perturbation energies (E2) from the LPC1 to the adjacent σ* orbitals (LPC1/BD*C2–N1, 24.2 kcal mol−1; LPC1/BD*S–CF3, 22.0 and 21.4 kcal mol−1), which imply delocalisation of negative charge of the C1 atom, called negative hyperconjugation.44) In comparison with density functional theory (DFT)-optimised structure of 1a,45) the model 1c demonstrated an elongated C1–C2 bond (148.3 vs. 146.5 pm) and a shortened C2–N1 bond (152.8 vs. 156.4 pm). Such geometric insight was also consistent with the experimental observation that the dissociation of 4-substituted derivative 1b required somewhat harsh conditions.
In summary, we have successfully developed a novel 2-fluoropyridinium reagent 1b connected with a perfluoroalkyl group by a non-fluorinated hydrocarbon spacer at the 4-position of the pyridinium ring. The present reagent readily released the highly electrophilic Tf2C=CH2 in HFIP. In addition, the 4-substituted 2-fluoropyridine 2b formed as a by-product could be effectively recovered from the reaction mixture by distillation of the products, organic solvent extraction, and FSPE techniques. Quantum chemical bonding analysis of this zwitterion fully supports its zwitterion structure, where the pyridinium moiety is connected with the anionic carbon atom by well-characterised C–C covalent bonds.
All reactions were carried out under Ar atmosphere. The reactions under microwave irradiation were carried out by using a Biotage initiator+ reactor and the temperatures were measured with an internal infrared sensor. Melting points were uncorrected. IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer equipped with an Attenuated Total Reflection (ATR) attachment. NMR spectra were recorded on a Bruker Avance III Nanobay 400 MHz, Avance III HD 500 MHz spectrometer in CDCl3, CD3CN, acetone-d6 or dimethyl sulfoxide (DMSO)-d6. Data are reported as follows: chemical shifts, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad) and coupling constants. Chemical shifts (in ppm) in 1H- and 13C{1H}-NMR spectra were referenced to the solvent signal (CDCl3, 7.26 ppm for 1H and 77.0 ppm for 13C; CD3CN, 1.93 ppm for 1H and 117.7 ppm for 13C; acetone-d6, 2.04 ppm for 1H and 29.8 ppm for 13C; DMSO-d6, 2.50 ppm for 1H-NMR and 39.5 ppm for 13C-NMR). Chemical shifts in 19F-NMR spectra were reported in ppm using (trifluoromethyl)benzene (−63.7 ppm) as a standard. Coupling constants (J) are given in Hz. High resolution mass spectra (HRMS) were measured on a Waters Xevo G2-XS TOF mass spectrometer using electrospray ionisation-time of flight (ESI-TOF) mode. Column chromatography was performed on neutral silica gel (Kanto Chemical, Silica gel 60N, 63–210 µm). FSPE was performed on fluorous silica gel (Sigma-Aldrich, FluoroFlash® silica gel 40 µm).46) Tf2CH2 was supplied from Central Glass Co. and this compound can be also prepared by Waller’s procedure in the laboratory.47,48) Caution: Exposure to perfluroalkyl compounds is a potential risk to adverse health outcomes, therefore such chemicals must be handled with sufficient care and protection against exposure.
2-(2-Fluoro-4-(4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)phenethyl)pyridin-1-ium-1-yl)-1,1-bis((trifluoromethyl)sulfonyl)ethan-1-ide (1b)To a solution of 2-fluoropyridine 2b (2.60 g, 4.02 mmol) in 1,2-dichloroethane (20 mL), Tf2CH2 (1.11 g, 3.96 mmol) and paraformaldehyde (240 mg, 8.00 mmol) were added at room temperature. After being stirred at 60 °C for 4 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was washed sequentially with hexane (2.0 mL × 5) and Et2O (2.0 mL × 5) to give the product 1b in 84% yield (3.14 g, 3.34 mmol). Colorless crystals (from CHCl3); Mp. 111–112 °C, IR (ATR) ν 1645, 1577, 1469, 1351, 1241, 1216, 1192, 1174, 1146, 1127, 1085, 1057, 865, 706, 622, 602, 568, 508 cm−1; 1H-NMR (500 MHz, CD3CN) δ: 2.38–2.50 (2H, m), 2.85–2.90 (2H, m), 2.98 (2H, t, J = 7.7 Hz), 3.19 (2H, t, J = 7.7 Hz), 5.50 (2H, br s), 7.13 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.46–7.50 (1H, m), 7.62 (1H, d, J = 6.4 Hz), 8.70–8.74 (1H, m); 13C{1H}-NMR (100 MHz, CD3CN) δ: 26.4 (t, JC–F = 4.1 Hz), 33.1 (t, JC–F = 44.0 Hz), 35.3, 37.9 (d, JC–F = 1.1 Hz), 56.8, 68.0, 114.2 (d, JC–F = 21.4 Hz), 121.6 (q, JC–F = 326 Hz), 125.5 (d, JC–F = 2.7 Hz), 129.5, 129.7, 138.6, 138.7, 141.9 (d, JC–F = 5.1 Hz), 159.2 (q, JC–F = 276 Hz), 169.4 (d, JC–F = 9.3 Hz); 19F-NMR (471 Hz, CD3CN) δ: −80.9 (6F, s), −81.8 to −82.5 (3F, m), −82.6 (1F, s), −115.2 to −115.4 (2F, m), −122.6 (2F, br s), −122.8 (4F, br s), −123.6 (2F, br s), −124.4 (2F, br s), −127.0 (2F, br s); HRMS (ESI-TOF) Calcd for C23H16F18N [M–(Tf2C = CH2) + H]+, 648.0995. Found 648.0995; Anal. Calcd for C27H17F24NO4S2: C, 34.52; H, 1.82; N, 1.49. Found: C, 34.40; H, 1.94; N, 1.49.
1-(2,2-Bis((trifluoromethyl)sulfonyl)ethyl)naphthalen-2-ol (8a)To a solution of naphthalen-2-ol 7a (28.9 mg, 0.200 mmol) in HFIP (2.0 mL), 2-fluoropyridinium reagent 1b (192 mg, 0.204 mmol) was added at room temperature. After being stirred for 0.5 h at the same temperature, the reaction mixture was concentrated under reduced pressure. Thus obtained residue was purified by column chromatography on FluoroFlash® silica gel (MeOH/H2O = 4 : 1) to give the product 8a in 99% yield (86.8 mg, 0.199 mmol). 2-Fluoropyridine 2b was recovered in 97% yield (128 mg, 0.198 mmol) by washing the column with MeOH. The structure of this compound was confirmed by comparison with the reported NMR data.4) 1H-NMR (400 MHz, CDCl3) δ: 4.24 (2H, d, J = 6.9 Hz), 5.60 (1H, s), 6.05 (1H, t, J = 6.9 Hz), 7.03 (1H, d, J = 8.8 Hz), 7.38–7.44 (1H, m), 7.57–7.63 (1H, m), 7.76–7.83 (2H, m), 8.01 (1H, d, J = 8.8 Hz); 13C{1H}-NMR (100 MHz, CDCl3) δ: 22.3, 76.0, 110.4 116.8, 119.2 (q, JC–F = 330 Hz), 122.3, 124.1, 127.7, 129.0, 129.5, 131.0, 132.8, 151.3; 19F-NMR (376 MHz, CDCl3) δ: −74.1 (6F, s).
1-Methyl-4,4-bis((trifluoromethyl)sulfonyl)butan-1-one (11)A solution of 2-fluoropyridinium reagent 1b (186 mg, 0.198 mmol) in acetone 10 (2.0 mL, 27 mmol) was stirred for 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. Thus obtained residue was purified by bulb-to-bulb distillation (140–160 °C at 7 mmHg) using a Kugelrohr oven to give the product 11 in 92% yield (63.5 mg, 0.181 mmol) as a distillate. From the remaining residue, 2-fluoropyridine 2b was recovered in 98% yield (126 mg, 0.195 mmol). The structure of 11 was confirmed by comparison with the reported NMR data.6) 1H-NMR (400 MHz, CDCl3) δ: 2.22 (3H, s), 2.69 (2H, q, J = 6.4 Hz), 3.01 (2H, t, J = 6.4 Hz), 5.55 (1H, t, J = 6.4 Hz); 13C{1H}-NMR (100 MHz, CDCl3) δ: 20.3, 29.7, 37.9, 75.2, 119.2 (q, JCF = 329 Hz), 206.6; 19F-NMR (376 MHz, CDCl3) δ: −74.1 (6F, s).
2-(4-(Diethylammonio)phenyl)-1,1-bis((trifluoromethyl)sulfonyl)ethan-1-ide (13a)To a solution of N,N-diethylaniline 12a (29.8 mg, 0.200 mmol) in HFIP (2.0 mL), 2-fluoropyridinium reagent 1b (189 mg, 0.201 mmol) was added at room temperature. After being stirred for 2 h at the same temperature, the reaction mixture was concentrated under reduced pressure. Thus obtained residue was purified by washing with hexane (5 mL × 4) to give the product 13a in 88% yield (78.0 mg, 0.177 mmol) and the filtrate was concentrated to give 2-fluoropyridine 2b in 94% yield (123 mg, 0.190 mmol). The structure of this compound was confirmed by comparison with the reported NMR data.25) 1H-NMR (400 MHz, acetone-d6) δ: 1.19 (6H, t, J = 7.2 Hz), 3.74 (2H, s), 3.82–3.93 (2H, m), 3.93–4.04 (2H, m), 7.58 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 9.63 (1H, br s); 13C{1H}-NMR (100 MHz, acetone-d6) δ: 10.7, 33.9, 55.1, 66.4, 122.3, 122.4 (q, JC–F = 329 Hz), 131.6, 135.3, 147.0; 19F-NMR (376 MHz, acetone-d6) δ: −80.4 (6F, s).
This work was partially supported by a Grant-in-Aid for Scientific Research (C) from JSPS (No. 23K06031) and Takeda Science Foundation. The authors thank Mr. Kenji Watanabe (TUPLS) for his technical assistance.
The authors declare no conflict of interest.
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