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Versatile and chemoselective synthesis of fluorinated methyl ethers from methoxymethyl ethers
Journal of Fluorine Chemistry 201 (2017) 1–6
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Versatile and chemoselective synthesis of fluorinated methyl ethers from methoxymethyl ethers
MARK
Reiya Ohta, Yuichi Kuboki, Yuki Yoshikawa, Yasuyuki Koutani, Tomohiro Maegawa, ⁎ Hiromichi Fujioka Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords: Monofluoromethyl ether Trifluoromethylthiomethyl ether Pyridinium-type salt Nucleophilic addition One-pot reaction
A versatile and chemoselective route has been developed for the synthesis of aliphatic fluorinated methyl ethers (ROCH2RF), specifically monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3), through pyridinium-type salt intermediates derived from methoxymethyl (MOM) ethers. The addition of a fluorine source (F− or SCF3−) to the pyridinium-type salts afforded the corresponding fluorinated methyl ethers in good yields under mild conditions. Notably, the synthesis of monofluoromethyl ethers proceeded within just 5 min.
1. Introduction Fluorinated organic compounds are useful scaffolds for pharmaceutical agents and biologically active compounds. This is mainly the result of the strong electron-withdrawing effect and high lipophilicity of the fluorine atoms or fluorinated groups [1]. Fluorine, trifluoromethyl (CF3), and trifluoromethylthio (SCF3) groups have received particular attention because they can dramatically improve the chemical and biological properties of organic molecules. There is no doubt that fluorine and fluorinated groups play an important role in medicinal chemistry [2]. Today, the overall percentage of fluorinated compounds on the pharmaceutical market is almost 25%, with the top-selling drugs atorvastatin (Lipitor®), lansoprazole (Prevacid®), and rosuvastatin (Crestor®) being representative examples [3]. Even now, drugs and drug candidates are often derived from natural products, but natural products containing fluorine or fluorinated groups are rare [4]. Organic synthesis is thus the key means for developing new fluorinated organic compounds that have the potential to be used as drugs. In recent years, various synthetic methods have been developed for incorporating fluorinated groups into organic compounds. However, although synthetic methods for fluorination [5] and trifluoromethylthiolation [6] are effective and have been well explored, those for the incorporation of fluorinated methyl ethers, such as monofluoromethyl ether (ROCH2F) [7] or trifluoromethylthiomethyl ether (ROCH2SCF3) [8], remain almost entirely unexplored. Interestingly, most reports on the synthesis of these compounds are related to the formation of aromatic fluorinated methyl ethers (ArOCH2RF), and there are few reported synthetic
⁎
Corresponding author. E-mail address: [email protected] (H. Fujioka).
http://dx.doi.org/10.1016/j.jfluchem.2017.07.007 Received 2 May 2017; Received in revised form 15 July 2017; Accepted 18 July 2017 Available online 20 July 2017 0022-1139/ © 2017 Published by Elsevier B.V.
methods for the formation of the aliphatic equivalents (ROCH2RF). Moreover, most of these methods for the formation of all types of fluorinated methyl ethers require a complicated procedure and multiple steps, and their overall efficiency is poor [7,8]. We thus presumed that these synthetic methods must have some limitations, or that some of their motifs are unstable. In medicinal chemistry, easier access to a wide variety of fluorinated compounds is required [2], and, from this point of view, a new, versatile synthetic method for the preparation of fluorinated methyl ethers is needed. We previously developed a mild and efficient method for the deprotection of methoxymethyl (MOM) ethers with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,2′-bipyridyl (Scheme 1, Eq. (1)) [9]. This reaction proceeds under mild conditions through pyridinium-type salt intermediates, has a high chemoselectivity, and allows various acid/base-labile functional groups, including halogens, esters, amides, and trityl- and tert-butyldimethylsilyl ethers, to remain intact [10]. We also recently reported the synthesis of alkyl ethers from MOM ethers, which also proceeds through pyridinium-type salt intermediates (Scheme 1, Eq. (2)) [11]. Addition of C-nucleophiles (RCM), such as organocuprates, to the pyridinium-type salts afforded the corresponding alkyl ethers in high yields. The reaction was also suitable for the synthesis of highly crowded ethers. We predicted that reaction of the pyridinium-type salt intermediates derived from MOM ethers with F-nucleophiles (RFM), such as fluorine and trifluoromethylthio groups, in place of RCM, would be a facile route to the corresponding fluorinated compounds (Scheme 1, Eq. (3)). In addition, the starting MOM ethers are easily prepared from the corresponding hydroxyl
Journal of Fluorine Chemistry 201 (2017) 1–6
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Scheme 1. Our previous mild and efficient methods for the deprotection of methoxymethyl (MOM) ethers (eq. 1), the synthesis of alkyl ethers through pyridinium-type salt intermediates (eq. 2) and the new strategy for the synthesis of fluorinated methyl ethers (Eq. (3)).
(ROCH2F) is shown in Table 2. Various types of MOM ethers served as substrates, and benzyloxy (BnO) (Table 2, Entry 1), triphenylmethyloxy (TrO) (Table 2, Entry 2), acetoxy (AcO) (Table 2, Entry 3), benzoyloxy (BzO) (Table 2, Entry 4), and bromide (Br) (Table 2, Entry 5) groups were unreactive under the reaction conditions. The Lewis and Brønsted acid-labile group (TrO) and the base-labile ester moieties (AcO and BzO) were tolerated under the reaction conditions. Furthermore, this reaction could be applied to primary, secondary, and tertiary (bulky) MOM ethers to give corresponding monofluoromethyl ethers 2 without any problems (Table 2, Entries 6–9). It is especially noteworthy that the reaction proceeded within 5 min when TBAF was used as the fluorine source.
compounds. This method may therefore be useful for the incorporation of various fluorinated groups into various substrates. Herein, we report a versatile method for the synthesis of monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3). 2. Results and discussion 2.1. Synthesis of monofluoromethyl ethers (ROCH2F) First, considering the above ideas, we examined the synthesis of monofluoromethyl ethers (ROCH2F) by nucleophilic addition of fluorine with the pyridinium-type salt intermediates. As shown in Table 1, we treated model substrate MOM ether 1a with a combination of TMSOTf and various pyridines in CH2Cl2. The pyridinium-type salts generated in situ at room temperature from 2,6-lutidine, 2,4,6-collidine, or 2-bromopyridine with tetrabutylammonium fluoride (TBAF) as the fluorine source gave a trace amount of desired monofluoromethyl ether 2a (Table 1, Entries 1–3). However, when electron-withdrawing 2substituted pyridines 2-phenylpyridine and 2,2′-bipyridyl were used as the base, 2a was obtained in moderate yield (Table 1, Entries 4–5). The use of tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF) gave the desired product in better yield than that obtained with TBAF (Table 1, Entry 6); however, other fluorine sources, namely KF, N,Ndiethylaminosulfur trifluoride (DAST), and tetrabutylammonium difluorotriphenylsilicate (TBAT), did not react with the pyridinium-type salt intermediates (Table 1, Entries 7–9). In addition of product 2a, we have observed decomposition products (e.g. deprotected alcohol of MOM ether) of either substrate 1a or product 2a. So, the product was obtained in moderate yield (Table 1, Entries 4–6) The scope of the synthesis of the monofluoromethyl ethers
2.2. Synthesis of trifluoromethylthiomethyl ethers (ROCH2SCF3) To extend the reaction, we next examined the synthesis of trifluoromethylthiomethyl ethers (ROCH2SCF3), which are obtained by nucleophilic addition of the trifluoromethylthio group to the pyridinium-type salt intermediates. First, we converted MOM ether 1f to the pyridinium-type salt intermediate with a combination of TMSOTf and 2,2′-bipyridyl. The pyridinium-type salt generated in situ was then reacted with two equivalents of (trifluoromethylthio)copper(I) (CuSCF3) at room temperature. In CH2Cl2, desired trifluoromethylthiomethyl ether 3f was obtained in only 34% (Table 3, Entry 1). We suspected that the low yield was the result of the low solubility of CuSCF3 in this solvent, and therefore examined other solvents for this reaction. When THF and DMF were used in place of CH2Cl2, we observed a slight decrease in the yield of 3f (Table 3, Entries 2–3). Although the use of CH3CN drastically improved the solubility of CuSCF3, the yield of the reaction was still low (Table 3, Entry 4). In reflux condition, 3f was obtained in a slightly higher yield when using CH2Cl2 (Table 3, Entry 5). On the other hand, in CH3CN, the yield of 3a was decreased in reflux condition (Table 3, Entry 6). In the case of using 5 equivalents of 2,2′-bipyridyl as the base in CH3CN increased the efficiency of this reaction (Table 3, Entry 7). Finally, the desired product 3f was obtained in 82% when using 10 equivalents of 2,2′-bipyridyl as the base in CH3CN (Table 3, Entry 8). The reason for the improved yield is likely the increased nucleophilicity of the trifluoromethylthio anion owing to the formation of a complex between CuSCF3 and the large amount of base [12]. However, when the use of 2 equiv. of pre-synthesized 2,2′-bipyridyl-CuSCF3 complex as trifluoromethylthiomethyl source, we obtained the product in just only about 30% yield. We then decided the use of in situ generated complex between 2 equiv. of CuSCF3 and 10 equiv, of 2,2′-bipyridyl. With the optimized conditions in hand, we investigated the scope of the reaction using a variety of MOM ethers as substrates. The substrates were the same those in Table 2. As shown in Table 4, the reaction displayed high chemoselectivity. Importantly, all compounds (3a–3i) are unprecedented trifluoromethylthiomethyl ethers. We expect that our synthetic method will provide access to the as yet unexplored trifluoromethylthiomethyl ether unit for drug discovery in medicinal chemistry.
Table 1 Optimization of the reaction conditions for the synthesis of monofluoromethyl ether 2a.a
Entry
Pyridine
F source (Y equiv.)
Yield (%)b
1 2 3 4 5 6 7 8 9
2,6-lutidine 2,4,6-collidine 2-bromopyridine 2-phenylpyridine 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl
TBAFc (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TASFd (3 equiv.) KF (8 equiv.) DASTe (3 equiv.) TBATf (3 equiv.)
trace trace trace 43 57 66 N.R.g N.R. N.R.
a Reaction conditions: Methoxymethyl (MOM) ether 1a was treated with the pyridine (3 equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. The fluorine source (Y equiv.) was then added, and the resulting mixture was stirred at room temperature for 1 h. b Isolated yield. c TBAF: tetrabutylammonium fluoride. d TASF: tris(dimethylamino)sulfur trimethylsilyl difluoride. e DAST: N,N-diethylaminosulfur trifluoride. f TBAT: tetrabutylammonium difluorotriphenylsilicate. g N.R.: no reaction.
2
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Table 2 Reaction of pyridinium-type salt intermediates from various methoxymethyl (MOM) ethers 1 with a fluorine source.a
Entry
Product
F source
Yield (%)d
Entry
Product
F source
Yield (%)d
1
2a (R = OBn)
2f
A B
74 58
2b (R = OTr)
3
2c (R = OAc)
7
2g
A B
74 58
4
2d (R = OBz)
66 60 78 65 80 64 63 66
6
2
A B A B A B A B
5
2e (R = Br)
A B
68 62
8
2h
A B
58 47
9
2i
A B
75 64
a Reaction conditions: Methoxymethyl (MOM) ethers 1 were treated with 2,2′-bipyridyl (3 equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. The fluorine source (A: TASF (3 equiv.), B: TBAF (5 equiv.)) was then added, and the resulting mixture was stirred for 1–1.5 h (A) or 5 min (B). b TASF: tris(dimethylamino)sulfur trimethylsilyl difluoride. c TBAF: tetrabutylammonium fluoride. d Isolated yield.
solvents. All reactions were monitored by thin-layer chromatography (TLC) using Merck silica gel 60F254 (0.25 mm). The products were purified by column chromatography over silica gel [Kieselgel 60 (70–230 mesh ASTM) purchased from Merck, or Silica Gel 60N (40–50 μm, spherical neutral) purchased from Kanto Chemical]. 1H, 13 C, and 19F NMR spectra were recorded at 25 °C on JEOL JNM-AL300 (at 300, 75, and 282 MHz, respectively), JEOL JNM-ECS 400 (at 400, 100, and 376 MHz, respectively), or JEOL JNM-LA 500 (at 500, 125, and 470 MHz, respectively) spectrometers, and the chemical shifts are reported relative to an internal standard: tetramethylsilane (TMS; 1H, δ = 0.00 ppm), CDCl3 (1H, δ = 7.26 ppm, 13C, δ = 77.0 ppm), CD3OD (1H, δ = 3.31 ppm), or C6F6 (19F, δ = −165.9 ppm). IR spectra were recorded with Shimadzu FTIR-8400 or Shimadzu IRAffinity-1 spectrometers by diffuse reflectance measurement of samples dispersed in KBr powder. High resolution mass spectrometric measurements were performed by JEOL, using DART® (Direct Analysis in Real Time) mass analysis. MALDI-TOF MS and FAB MS were performed by the Elemental Analysis Section of Graduate School of Pharmaceutical Science in Osaka University. Compounds 1a–1d , 1e [13], 1f [14], 1 g [15], 1 h [16], 1i [11], and 2f are known compounds.
Table 3 Optimization of the reaction conditions for the synthesis of trifluoromethylthiomethyl ether 3f.a
Entry
2,2′-bipyridyl (X equiv.)
Solvent
Temp.
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8
3 3 3 3 3 3 5 10
CH2Cl2 THF DMF CH3CN CH2Cl2 CH3CN CH3CN CH3CN
r.t.c r.t. r.t. r.t. reflux reflux r.t. r.t.
5 3 5 16 5 5 6 5
34 20 20 30 37 19 78 82
a Reaction conditions: Methoxymethyl (MOM) ether 1f was treated with 2,2′-bipyridyl (X equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. CuSCF3 (2 equiv.) was then added, and the resulting mixture was stirred. b Isolated yield. c r.t.: room temperature.
4.2. General procedure for the synthesis of monofluoromethyl ethers (ROCH2F) 2 (Table 2)
3. Conclusion In summary, we have developed a versatile and chemoselective synthesis of fluorinated methyl ethers, specifically monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3). Our method is a simple-to-operate one-pot reaction that uses commercially available fluorinating reagents. We expect that this method will provide a new approach to the synthesis of fluorinated compounds.
[Method A] TMSOTf (72.0 μL, 0.40 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.20 mmol, 1.0 equiv.) and 2,2′-bipyridyl (93.7 mg, 0.60 mmol, 3.0 equiv.) in CH2Cl2 (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then TASF (165.0 mg, 0.60 mmol, 3.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 1 h, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography (n-hexane/EtOAc = 15/1) to give corresponding monofluoromethyl ether (RCOCH2F) 2.
4. Experimental section 4.1. General information All reagents were purchased from commercial sources and used without further purification, unless otherwise noted. Reactions were performed under a nitrogen atmosphere using purchased anhydrous 3
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Table 4 Reaction of pyridinium-type salt intermediates from various MOM ethers 1 with CuSCF3.a
Entry
Product
Yield (%)b
Entry
Product
Yield (%)b
1 2
3a (R = OBn) 3b (R = OTr)
71 97
6
3f
82
3 4
3c (R = OAc) 3d (R = OBz)
80 63
7
3g
94
5
3e (R = Br)
68c
8
3h
86
9
3i
93
a Reaction conditions: Methoxymethyl (MOM) ethers 1 were treated with 2,2′-bipyridyl (10 equiv.) and TMSOTf (2 equiv.) in CH3CN at 0 °C for 0.5 h. CuSCF3 (2 equiv.) was then added, and the resulting mixture was stirred. b Isolated yield. c Reaction was performed at 0 °C.
J = 57.8 Hz); HRMS (FAB): Anal. for C15H29O3FNa [M + Na]+ Calcd.: 299.1998, Found: 299.1996.
[Method B] TMSOTf (72.0 μL, 0.40 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.20 mmol, 1.0 equiv.) and 2,2′-bipyridyl (93.7 mg, 0.60 mmol, 3.0 equiv.) in CH2Cl2 (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol, 5.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 5 min, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography (n-hexane/EtOAc = 15/1) to give corresponding monofluoromethyl ether (RCOCH2F) 2.
4.2.4. 12-(Fluoromethoxy)dodecyl benzoate (2d) Colorless oil; IR (KBr): 2929, 2856, 1717, 1467, 1389, 1176, 951 cm−1; 1H NMR (500 MHz, CDCl3) δ: 8.05–8.03 (2H, m), 7.56–7.53 (1H, m), 7.45–7.42 (2H, m), 5.26 (2H, d, J = 56.7 Hz), 4.31 (2H, t, J = 6.9 Hz), 3.71 (2H, td, J = 6.9, 1.8 Hz), 1.79–1.73 (2H, m), 1.65–1.59 (2H, m), 1.46–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 166.7, 132.8, 130.5, 129.5, 128.3, 103.8 (d, J = 211.1 Hz), 70.8, 65.1, 29.53, 29.49, 29.3, 29.2, 28.7, 26.0, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.8 Hz); HRMS (MALDI-TOF): Anal. for C20H31O3FNa [M + Na]+ Calcd.: 361.2149, Found: 361.2147. 4.2.5. 1-Bromo-12-(fluoromethoxy)dodecane (2e) Colorless oil; IR (KBr): 2928, 2854, 1466, 1175, 951 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.27 (2H, d, J = 56.7 Hz), 3.71 (2H, td, J = 6.9, 1.7 Hz), 3.40 (2H, t, J = 6.9 Hz), 1.88–1.82 (2H, m), 1.65–1.59 (2H, m), 1.44–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 103.8 (d, J = 211.0 Hz), 70.9, 34.1, 32.8, 29.54, 29.49, 29.40, 29.3, 28.7, 28.1, 25.9; 19F NMR (282 MHz, CDCl3) δ: −149.25 (t, J = 56.7 Hz).
4.2.1. 1-Benzyloxy-12-(fluoromethoxy)dodecane (2a) Colorless oil; IR (KBr): 2925, 2855, 1496, 1454, 1174, 944 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 7.35–7.27 (5H, m), 5.27 (2H, d, J = 56.7 Hz), 4.51 (2H, s), 3.72 (2H, td, J = 6.9, 1.7 Hz), 3.47 (2H, t, J = 6.9 Hz), 1.64–1.59 (4H, m), 1.37–1.27 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 138.7, 128.3, 127.6, 127.4, 103.8 (d, J = 211.1 Hz), 86.2, 72.8, 70.9, 70.5, 29.7, 29.54, 29.50, 29.45, 29.3, 26.2, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.7 Hz); HRMS (MALDI-TOF): Anal. for C20H33O2FNa [M + Na]+ Calcd.: 347.2357, Found: 347.2355.
4.2.6. 1-(Fluoromethoxy)decane (2f) Colorless oil; 1H NMR (300 MHz, CDCl3) δ: 5.27 (2H, d, J = 56.7 Hz), 3.71 (2H, td, J = 6.9, 1.7 Hz), 1.67–1.58 (2H, m), 1.37–1.22 (14H, m), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 103.8 (d, J = 211.0 Hz), 70.9, 31.9, 29.6, 29.5, 29.33, 29.31, 25.9, 22.7, 14.1. Spectroscopic data for 2f were consistent with those previously reported for this compound.
4.2.2. 1-(Fluoromethoxy)-12-(triphenylmethyloxy)dodecane (2b) Colorless oil; IR (KBr): 2903, 1598, 1490, 1390, 913 cm−1; 1H NMR (300 MHz, CDCl3) δ: 7.46–7.19 (15H, m), 5.26 (2H, d, J = 56.7 Hz), 3.70 (2H, td, J = 6.5, 2.0 Hz), 3.04 (2H, t, J = 6.5 Hz), 1.66–1.57 (4H, m), 1.39–1.22 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 144.5, 128.7, 127.6, 126.8, 103.8 (d, J = 211.0 Hz), 70.9, 63.6, 30.0, 29.6, 29.5, 29.3, 26.2, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.8 Hz); HRMS (MALDI-TOF): Anal. for C32H41O2FNa [M + Na]+ Calcd.: 499.2983, Found: 499.2985.
4.2.7. 1-(Fluoromethoxy)undec-10-ene (2 g) Colorless oil; IR (KBr): 2928, 1466, 1175, 951 cm−1; 1H NMR (400 MHz, CD3OD) δ: 5.81 (1H, ddt, J = 17.4, 10.5, 6.8 Hz), 5.24 (2H, d, J = 56.8 Hz), 5.01–4.89 (2H, m), 3.70 (2H, dt, J = 6.8, 1.8 Hz), 2.08–2.02 (2H, m), 1.64–1.57 (2H, m), 1.42–1.29 (14H, m); 13C NMR (125 MHz, CDCl3) δ: 139.2, 114.1, 103.8 (d, J = 211.0 Hz), 70.9, 33.8, 29.54, 29.46, 29.37, 29.29, 29.1, 28.9, 25.9; 19F NMR (282 MHz, CDCl3) δ: −145.12 (t, J = 60.9 Hz).
4.2.3. 12-(Fluoromethoxy)dodecyl acetate (2c) Colorless oil; IR (KBr): 2926, 2854, 1739, 1464, 1389, 1175, 952 cm−1; 1H NMR (300 MHz, CDCl3) δ: 5.27 (2H, d, J = 57.0 Hz), 4.04 (2H, t, J = 6.9 Hz), 3.71 (2H, td, J = 6.9, 2.0 Hz), 2.04 (3H, s), 1.67–1.56 (4H, m), 1.37–1.21 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 171.3, 103.8 (d, J = 211.0 Hz), 70.9, 64.6, 29.7, 29.6, 29.5, 29.3, 29.2, 28.6, 25.9, 21.0; 19F NMR (376 MHz, CDCl3) δ: −154.15 (t,
4.2.8. 2-(Fluoromethoxy)decane (2 h) Colorless oil; IR (KBr): 2926, 2856, 1466, 1376, 1107, 983 cm−1; 1 H NMR (400 MHz, CD3OD) δ: 5.28 (2H, ddd, J = 57.3, 18.5, 2.7 Hz), 4
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7.57–7.54 (1H, m), 7.45–7.42 (2H, m), 5.05 (2H, d, J = 1.1 Hz), 4.31 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.9 Hz), 1.79–1.73 (2H, m), 1.62–1.56 (2H, m), 1.46–1.41 (2H, m), 1.38–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 166.7, 132.8, 130.5 (q, J = 305.2 Hz), 130.48, 129.5, 128.3, 72.2, 69.5, 65.1, 29.5, 29.28, 29.25, 29.0, 28.7, 26.02, 25.95; 19F NMR (376 MHz, CDCl3) δ: −43.86; HRMS (DART): Anal. for C21H32O3F3S+1 [M + H]+ Calcd.: 421.2019, Found: 421.2023.
3.80–3.72 (1H, m), 1.60–1.23 (14H, m), 1.20–1.19 (3H, d, J = 6.0 Hz), 0.92–0.89 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 102.7 (d, J = 211.1 Hz), 36.9, 31.9, 29.6, 29.5, 29.3, 25.3, 22.7, 20.6, 14.1; 19F NMR (282 MHz, CDCl3) δ: −149.96 (t, J = 60.9 Hz); HRMS (MALDITOF): Anal. for C11H23OFNa [M + Na]+ Calcd.: 213.1625, Found: 213.1620. 4.2.9. 2-(Fluoromethoxy)-2-methyldecane (2i) Colorless oil; IR (KBr): 2927, 2856, 1468, 1378, 1111, 911 cm−1; 1 H NMR (300 MHz, CDCl3) δ: 5.36 (2H, d, J = 57.7 Hz), 1.68–1.43 (2H, m), 1.27–1.21 (20H, m), 0.88 (3H, t, J = 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ: 98.4 (d, J = 209.5 Hz), 41.7, 31.9, 30.1, 29.6, 29.3, 26.2, 23.9, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ: −144.82 (d, J = 57.8 Hz).
4.3.5. 1-Bromo-12-(trifluoromethylthiomethoxy)dodecane (3e) Colorless oil; IR (KBr): 2926, 2855, 1466, 1133, 1084 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.05 (2H, s), 3.56 (2H, t, J = 6.9 Hz), 3.40 (2H, t, J = 6.9 Hz), 1.88–1.82 (2H, m), 1.64–1.56 (2H, m), 1.45–1.39 (2H, m), 1.37–1.27 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 130.5 (d, J = 305.2 Hz), 72.2, 70.9, 69.6, 34.0, 32.8, 29.47–29.40 (3C), 29.3, 29.0, 28.7, 28.2, 26.0; 19F NMR (376 MHz, CDCl3) δ: −39.07; HRMS (DART): Anal. for C14H30NOF3SBr+1 [M + NH4]+ Calcd.: 396.1178, Found: 396.1189.
4.3. General procedure for the synthesis of trifluoromethylthiomethyl ether (ROCH2SCF3) 3 (Table 4) TMSOTf (36.0 μL, 0.20 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.10 mmol, 1.0 equiv.) and 2,2′-bipyridyl (156.2 mg, 1.00 mmol, 10.0 equiv.) in CH3CN (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then CuSCF3 (32.9 mg, 0.20 mmol, 2.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 1 h, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography to give corresponding trifluoromethylthiomethyl ether (ROCH2SCF3) 3.
4.3.6. 1-(Trifluoromethylthiomethoxy)decane (3f) Colorless oil; IR (KBr): 2925, 2857, 1468, 1134, 1085 cm−1; 1H NMR (300 MHz, CDCl3) δ: 5.05 (2H, q, J = 1.1 Hz), 3.56 (2H, t, J = 6.5 Hz), 1.64–1.55 (2H, m), 1.37–1.22 (14H, m), 0.88 (3H, t, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.5 (d, J = 305.2 Hz), 72.2 (d, J = 2.4 Hz), 69.6, 31.9, 29.5, 29.3, 29.0, 26.0, 22.7, 14.1; 19F NMR (282 MHz, CDCl3) δ: −43.86; HRMS (DART): Anal. for C12H27NOF3S+1 [M + NH4]+ Calcd.: 290.1760, Found: 290.1764. 4.3.7. 1-(Trifluoromethylthiomethoxy)undec-10-ene (3 g) Colorless oil; IR (KBr): 2928, 2857, 1133, 1084, 910, 756 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.81 (1H, ddt, J = 17.2, 10.3, 6.9 Hz), 5.05 (2H, s), 5.01–4.91 (2H, m), 3.56 (2H, t, J = 6.9 Hz), 2.06–2.02 (2H, m), 1.62–1.56 (2H, m), 1.40–1.26 (14H, m); 13C NMR (125 MHz, CDCl3) δ: 139.2, 130.5 (d, J = 305.2 Hz), 129.3, 114.1, 72.2 (q, J = 2.4 Hz), 69.5, 33.8, 29.5, 29.4, 29.3, 29.1, 29.0, 28.9, 26.0; 19F NMR (376 MHz, CDCl3) δ: −43.87; HRMS (DART): Anal. for C13H24OF3S+1 [M + H]+ Calcd.: 285.1495, Found: 285.1496.
4.3.1. 1-Benzyloxy-12-(trifluoromethylthiomethoxy)dodecane (3a) Colorless oil; IR (KBr): 2924, 2855, 1454, 1316, 1127, 1082 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 7.35–7.28 (5H, m), 5.04 (2H, s), 4.51 (2H, s), 3.56 (2H, t, J = 6.6 Hz), 3.46 (2H, t, J = 6.6 Hz), 1.64–1.57 (4H, m), 1.42–1.20 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 138.7, 130.5 (d, J = 305.2), 128.3, 127.6, 127.4, 72.8, 72.2, 70.5, 69.5, 29.7, 29.6–29.5 (5C), 29.3, 29.0, 26.2, 26.0; 19F NMR (376 MHz, CDCl3) δ: −43.88; HRMS (DART): Anal. for C21H37NO2F3S+1 [M + NH4]+ Calcd.: 424.2492, Found: 424.2499.
4.3.8. 2-(Trifluoromethylthiomethoxy)decane (3 h) Colorless oil; IR (KBr): 2927, 2857, 1468, 1378, 1130, 1072, 756, 658 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.12 (A in ABq, 1H, J = 12.0 Hz),5.00 (B in ABq, 1H, J = 12.0 Hz), 3.77–3.70 (1H, m), 1.56–1.53 (2H, m), 1.44–1.21 (14H, m), 1.16 (3H, d, J = 6.3 Hz), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.6 (q, J = 305.2 Hz), 74.2, 69.6 (q, J = 2.4 Hz), 36.1, 31.9, 29.6, 29.5, 29.2, 25.2, 22.6, 19.0, 14.1; 19F NMR (376 MHz, CDCl3) δ: −43.90; HRMS (DART): Anal. for C12H27NOF3S+1 [M + NH4]+ Calcd.: 290.1760, Found: 290.1752.
4.3.2. 1-(Trifluoromethylthiomethoxy)-12-(triphenylmethyloxy)dodecane (3b) Colorless oil; IR (KBr): 3059, 2930, 2856, 1133, 1084 cm−1; 1H NMR (500 MHz, CDCl3) δ: 7.68–7.66 (6H, m), 7.53–7.43 (9H, m), 5.26 (1H, s), 3.78 (2H, t, J = 6.3 Hz), 3.26 (2H, t, J = 6.3 Hz), 1.87–1.79 (4H, m), 1.60–1.42 (16H, m); 13C NMR (100 MHz, CDCl3) δ: 144.5, 130.5 (d, J = 306.1 Hz), 128.7, 127.6, 126.8, 86.2, 72.2 (q, J = 1.9 Hz) 69.5, 63.7, 30.0, 29.55–29.50 (5C), 29.3, 29.0, 26.2, 26.0; 19 F NMR (376 MHz, CDCl3) δ: −43.89; HRMS (DART): Anal. for C33H41O2F3S+1 [M]+ Calcd.: 558.2774, Found: 558.2749.
4.3.9. 2-(Trifluoromethylthiomethoxy)-2-methyldecane (3i) Colorless oil; IR (KBr): 2925, 2855, 1467, 1370, 1132, 1068 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 4.94 (2H, s), 1.49–1.46 (2H, m), 1.34–1.25 (14H, m), 1.21 (6H, s), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.7 (d, J = 305.2 Hz), 78.5, 64.0, 40.8, 31.9, 30.0, 29.5, 29.3, 25.3, 23.7, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ: −44.33; HRMS (DART): Anal. for C13H29NOF3S+1 [M + NH4]+ Calcd.: 304.1917, Found: 304.1911.
4.3.3. 12-(Trifluoromethylthiomethoxy)dodecyl acetate (3c) Colorless oil; IR (KBr): 2931, 2857, 1739, 1241, 1133, 1085 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 5.05 (2H, s), 4.05 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.9 Hz), 2.04 (3H, s), 1.64–1.56 (4H, m), 1.37–1.21 (16H, m); 13C NMR (100 MHz, CDCl3) δ: 171.3, 130.5 (q, J = 310.3 Hz), 72.2 (q, J = 1.9 Hz), 69.5, 64.6, 29.49–29.46 (4C), 29.27–29.22 (2C), 29.0, 28.6, 25.94, 25.87, 21.0; 19F NMR (376 MHz, CDCl3) δ: −43.89; HRMS (DART): Anal. for C16H30O3F3S+1 [M + H]+ Calcd.: 359.1862, Found: 359.1858.
Acknowledgments This work was financially supported by JSPS KAKENHI grant number JP15H04632 and the Platform for Drug Discovery, Informatics, and Structural Life Science. We are also grateful to JEOL Ltd. for the measurement of MS spectra.
4.3.4. 12-(Trifluoromethylthiomethoxy)dodecyl benzoate (3d) Colorless oil; IR (KBr): 2927, 2856, 1718, 1452, 1316, 1131, 1083 cm−1; 1H NMR (500 MHz, CDCl3) δ: 8.06–8.04 (2H, m), 5
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[6] (a) For a review of trifluoromethylthiolation, see: X.-H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 115 (2015) 731; (b) J. Charpentier, N. Früh, A. Togni, Chem. Rev. 115 (2015) 650. [7] (a) O.S. Ascenso, E.P.T. Leitao, W. Heggie, M.R. Ventura, C.D. Maycock, Tetrahedron 73 (2017) 1165; (b) Q.-W. Zhang, A.T. Brusoe, V. Mascitti, K.D. Hesp, D.C. Blakemore, J.T. Kohrt, J.F. Hartwig, Angew. Chem. Int. Ed. 55 (2016) 9758; (c) G.M. Leung, Eur. J. Org. Chem. (2015) 2197; (d) M. Kunigami, S. Hara, J. Fluorine Chem. 167 (2014) 101; (e) X. Shen, M. Zhou, C. Ni, W. Zhang, J. Hu, Chem. Sci. 5 (2014) 117; (f) C. Park, B.S. Lee, D.Y. Chi, Org. Lett. 15 (2013) 4346; (g) Y. Nomura, E. Tokunaga, N. Shibata, Angew. Chem. Int. Ed. 50 (2011) 1885; (h) B. Manteau, S. Pazenok, J.-P. Vors, F.R. Leroux, J. Fluorine Chem. 131 (2010) 140; (i) J. Hu, W. Zhang, F. Wang, Chem. Commun. (2009) 7465; (j) G.K.S. Prakash, I. Ledneczki, S. Chacko, G.A. Olah, Org. Lett. 10 (2008) 557; (k) W. Zhang, L. Zhu, J. Hu, Tetrahedron 63 (2007) 10569. [8] (a) B. He, Z. Xiao, H. Wu, Y. Guo, Q.-Y. Chen, C. Liu, RSC Adv. 7 (2017) 880; (b) C.-H. Park, H.-K. Lim, M.-J. Lim, J.-W. Lee, J.-Y. Chung, C.-H. Ryu, Y.-J. Yoon, M.-K. Ji, J.-Y. Park, WO 2010/098600 A2. (c) S. Ohata, K. Kato, K. Toriyabe, Y. Ito, R. Hamaguchi, Y. Nakano, WO 2009/ 051245 A1. [9] (a) H. Fujioka, Y. Minamitsuji, O. Kubo, K. Senami, T. Maegawa, Tetrahedron 67 (2011) 2949; (b) H. Fujioka, O. Kubo, K. Senami, Y. Minamitsuji, T. Maegawa, Chem. Commun. (2009) 4429. [10] T. Maegawa, H. Fujioka, J. Synth. Org. Chem. Jpn. 71 (2013) 694. [11] Y. Minamitsuji, A. Kawaguchi, O. Kubo, Y. Ueyama, T. Maegawa, H. Fujioka, Adv. Synth. Catal. 354 (2012) 1861. [12] Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem. Int. Ed. 52 (2013) 1548. [13] G. Villorbina, L. Roura, F. Camps, J. Joglar, G. Fabriás, J. Org. Chem. 68 (2003) 2820. [14] A.S.-Y. Lee, Y.-J. Hu, S.-F. Chu, Tetrahedron 57 (2001) 2121. [15] J.R. Vyvyan, J.A. Meyer, K.D. Meyer, J. Org. Chem. 68 (2003) 9144. [16] B.P. Bandgar, C.T. Hajare, P. Wadgaonkar, J. Chem. Res. Synop. (1996) 90.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2017.07.007. References [1] (a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2013; (b) K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006; (c) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004; (d) J.A. Gladysz, D.P. Curran, I.T. Horv́ath, Handbook of Fluorous Chemistry, Wiley-VCH, Weinheim, 2004; (e) T. Hiyama, Organofluorine Compounds. Chemistry and Applications, Springer, Berlin, 2000. [2] (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; (b) E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58 (2015) 8315; (c) L. Xing, D.C. Blakemore, A. Narayanan, R. Unwalla, F. Lovering, R.A. Denny, H. Zhou, M.E. Bunnage, ChemMedChem 10 (2015) 715; (d) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008) 320. [3] (a) J. Wang, M.S. Roselló, J.L. Aceña, C. d. Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432; (b) N. Inoue, Pharmacia 50 (2014) 14; (c) T. Furuya, A.S. Kamlet, T. Ritter, Nature 473 (2011) 470; (d) J.-P. Bégué, D. B.-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley-VCH, Weinheim, 2008; (e) K. Muller, C. Faeh, F. Diederch, Science 317 (2007) 1881. [4] (a) J.-P. Bégué, D.B. Delpon, J. Fluorine Chem. 127 (2006) 992; (b) D. O'Hagan, D.B. Harper, J. Fluorine Chem. 100 (1999) 127. [5] (a) For a review of fluorination, see: A.C. Sather, S.L. Buchwald, Acc. Chem. Res. 49 (2016) 2146; (b) C. Ni, M. Hu, J. Hu, Chem. Rev. 115 (2015) 765; (c) X. Yang, T. Wu, R.J. Phipps, F.D. Toste, Chem. Rev. 115 (2015) 826.
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Versatile and chemoselective synthesis of fluorinated methyl ethers from methoxymethyl ethers
MARK
Reiya Ohta, Yuichi Kuboki, Yuki Yoshikawa, Yasuyuki Koutani, Tomohiro Maegawa, ⁎ Hiromichi Fujioka Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords: Monofluoromethyl ether Trifluoromethylthiomethyl ether Pyridinium-type salt Nucleophilic addition One-pot reaction
A versatile and chemoselective route has been developed for the synthesis of aliphatic fluorinated methyl ethers (ROCH2RF), specifically monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3), through pyridinium-type salt intermediates derived from methoxymethyl (MOM) ethers. The addition of a fluorine source (F− or SCF3−) to the pyridinium-type salts afforded the corresponding fluorinated methyl ethers in good yields under mild conditions. Notably, the synthesis of monofluoromethyl ethers proceeded within just 5 min.
1. Introduction Fluorinated organic compounds are useful scaffolds for pharmaceutical agents and biologically active compounds. This is mainly the result of the strong electron-withdrawing effect and high lipophilicity of the fluorine atoms or fluorinated groups [1]. Fluorine, trifluoromethyl (CF3), and trifluoromethylthio (SCF3) groups have received particular attention because they can dramatically improve the chemical and biological properties of organic molecules. There is no doubt that fluorine and fluorinated groups play an important role in medicinal chemistry [2]. Today, the overall percentage of fluorinated compounds on the pharmaceutical market is almost 25%, with the top-selling drugs atorvastatin (Lipitor®), lansoprazole (Prevacid®), and rosuvastatin (Crestor®) being representative examples [3]. Even now, drugs and drug candidates are often derived from natural products, but natural products containing fluorine or fluorinated groups are rare [4]. Organic synthesis is thus the key means for developing new fluorinated organic compounds that have the potential to be used as drugs. In recent years, various synthetic methods have been developed for incorporating fluorinated groups into organic compounds. However, although synthetic methods for fluorination [5] and trifluoromethylthiolation [6] are effective and have been well explored, those for the incorporation of fluorinated methyl ethers, such as monofluoromethyl ether (ROCH2F) [7] or trifluoromethylthiomethyl ether (ROCH2SCF3) [8], remain almost entirely unexplored. Interestingly, most reports on the synthesis of these compounds are related to the formation of aromatic fluorinated methyl ethers (ArOCH2RF), and there are few reported synthetic
⁎
Corresponding author. E-mail address: [email protected] (H. Fujioka).
http://dx.doi.org/10.1016/j.jfluchem.2017.07.007 Received 2 May 2017; Received in revised form 15 July 2017; Accepted 18 July 2017 Available online 20 July 2017 0022-1139/ © 2017 Published by Elsevier B.V.
methods for the formation of the aliphatic equivalents (ROCH2RF). Moreover, most of these methods for the formation of all types of fluorinated methyl ethers require a complicated procedure and multiple steps, and their overall efficiency is poor [7,8]. We thus presumed that these synthetic methods must have some limitations, or that some of their motifs are unstable. In medicinal chemistry, easier access to a wide variety of fluorinated compounds is required [2], and, from this point of view, a new, versatile synthetic method for the preparation of fluorinated methyl ethers is needed. We previously developed a mild and efficient method for the deprotection of methoxymethyl (MOM) ethers with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,2′-bipyridyl (Scheme 1, Eq. (1)) [9]. This reaction proceeds under mild conditions through pyridinium-type salt intermediates, has a high chemoselectivity, and allows various acid/base-labile functional groups, including halogens, esters, amides, and trityl- and tert-butyldimethylsilyl ethers, to remain intact [10]. We also recently reported the synthesis of alkyl ethers from MOM ethers, which also proceeds through pyridinium-type salt intermediates (Scheme 1, Eq. (2)) [11]. Addition of C-nucleophiles (RCM), such as organocuprates, to the pyridinium-type salts afforded the corresponding alkyl ethers in high yields. The reaction was also suitable for the synthesis of highly crowded ethers. We predicted that reaction of the pyridinium-type salt intermediates derived from MOM ethers with F-nucleophiles (RFM), such as fluorine and trifluoromethylthio groups, in place of RCM, would be a facile route to the corresponding fluorinated compounds (Scheme 1, Eq. (3)). In addition, the starting MOM ethers are easily prepared from the corresponding hydroxyl
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Scheme 1. Our previous mild and efficient methods for the deprotection of methoxymethyl (MOM) ethers (eq. 1), the synthesis of alkyl ethers through pyridinium-type salt intermediates (eq. 2) and the new strategy for the synthesis of fluorinated methyl ethers (Eq. (3)).
(ROCH2F) is shown in Table 2. Various types of MOM ethers served as substrates, and benzyloxy (BnO) (Table 2, Entry 1), triphenylmethyloxy (TrO) (Table 2, Entry 2), acetoxy (AcO) (Table 2, Entry 3), benzoyloxy (BzO) (Table 2, Entry 4), and bromide (Br) (Table 2, Entry 5) groups were unreactive under the reaction conditions. The Lewis and Brønsted acid-labile group (TrO) and the base-labile ester moieties (AcO and BzO) were tolerated under the reaction conditions. Furthermore, this reaction could be applied to primary, secondary, and tertiary (bulky) MOM ethers to give corresponding monofluoromethyl ethers 2 without any problems (Table 2, Entries 6–9). It is especially noteworthy that the reaction proceeded within 5 min when TBAF was used as the fluorine source.
compounds. This method may therefore be useful for the incorporation of various fluorinated groups into various substrates. Herein, we report a versatile method for the synthesis of monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3). 2. Results and discussion 2.1. Synthesis of monofluoromethyl ethers (ROCH2F) First, considering the above ideas, we examined the synthesis of monofluoromethyl ethers (ROCH2F) by nucleophilic addition of fluorine with the pyridinium-type salt intermediates. As shown in Table 1, we treated model substrate MOM ether 1a with a combination of TMSOTf and various pyridines in CH2Cl2. The pyridinium-type salts generated in situ at room temperature from 2,6-lutidine, 2,4,6-collidine, or 2-bromopyridine with tetrabutylammonium fluoride (TBAF) as the fluorine source gave a trace amount of desired monofluoromethyl ether 2a (Table 1, Entries 1–3). However, when electron-withdrawing 2substituted pyridines 2-phenylpyridine and 2,2′-bipyridyl were used as the base, 2a was obtained in moderate yield (Table 1, Entries 4–5). The use of tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF) gave the desired product in better yield than that obtained with TBAF (Table 1, Entry 6); however, other fluorine sources, namely KF, N,Ndiethylaminosulfur trifluoride (DAST), and tetrabutylammonium difluorotriphenylsilicate (TBAT), did not react with the pyridinium-type salt intermediates (Table 1, Entries 7–9). In addition of product 2a, we have observed decomposition products (e.g. deprotected alcohol of MOM ether) of either substrate 1a or product 2a. So, the product was obtained in moderate yield (Table 1, Entries 4–6) The scope of the synthesis of the monofluoromethyl ethers
2.2. Synthesis of trifluoromethylthiomethyl ethers (ROCH2SCF3) To extend the reaction, we next examined the synthesis of trifluoromethylthiomethyl ethers (ROCH2SCF3), which are obtained by nucleophilic addition of the trifluoromethylthio group to the pyridinium-type salt intermediates. First, we converted MOM ether 1f to the pyridinium-type salt intermediate with a combination of TMSOTf and 2,2′-bipyridyl. The pyridinium-type salt generated in situ was then reacted with two equivalents of (trifluoromethylthio)copper(I) (CuSCF3) at room temperature. In CH2Cl2, desired trifluoromethylthiomethyl ether 3f was obtained in only 34% (Table 3, Entry 1). We suspected that the low yield was the result of the low solubility of CuSCF3 in this solvent, and therefore examined other solvents for this reaction. When THF and DMF were used in place of CH2Cl2, we observed a slight decrease in the yield of 3f (Table 3, Entries 2–3). Although the use of CH3CN drastically improved the solubility of CuSCF3, the yield of the reaction was still low (Table 3, Entry 4). In reflux condition, 3f was obtained in a slightly higher yield when using CH2Cl2 (Table 3, Entry 5). On the other hand, in CH3CN, the yield of 3a was decreased in reflux condition (Table 3, Entry 6). In the case of using 5 equivalents of 2,2′-bipyridyl as the base in CH3CN increased the efficiency of this reaction (Table 3, Entry 7). Finally, the desired product 3f was obtained in 82% when using 10 equivalents of 2,2′-bipyridyl as the base in CH3CN (Table 3, Entry 8). The reason for the improved yield is likely the increased nucleophilicity of the trifluoromethylthio anion owing to the formation of a complex between CuSCF3 and the large amount of base [12]. However, when the use of 2 equiv. of pre-synthesized 2,2′-bipyridyl-CuSCF3 complex as trifluoromethylthiomethyl source, we obtained the product in just only about 30% yield. We then decided the use of in situ generated complex between 2 equiv. of CuSCF3 and 10 equiv, of 2,2′-bipyridyl. With the optimized conditions in hand, we investigated the scope of the reaction using a variety of MOM ethers as substrates. The substrates were the same those in Table 2. As shown in Table 4, the reaction displayed high chemoselectivity. Importantly, all compounds (3a–3i) are unprecedented trifluoromethylthiomethyl ethers. We expect that our synthetic method will provide access to the as yet unexplored trifluoromethylthiomethyl ether unit for drug discovery in medicinal chemistry.
Table 1 Optimization of the reaction conditions for the synthesis of monofluoromethyl ether 2a.a
Entry
Pyridine
F source (Y equiv.)
Yield (%)b
1 2 3 4 5 6 7 8 9
2,6-lutidine 2,4,6-collidine 2-bromopyridine 2-phenylpyridine 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl 2,2′-bipyridyl
TBAFc (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TBAF (5 equiv.) TASFd (3 equiv.) KF (8 equiv.) DASTe (3 equiv.) TBATf (3 equiv.)
trace trace trace 43 57 66 N.R.g N.R. N.R.
a Reaction conditions: Methoxymethyl (MOM) ether 1a was treated with the pyridine (3 equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. The fluorine source (Y equiv.) was then added, and the resulting mixture was stirred at room temperature for 1 h. b Isolated yield. c TBAF: tetrabutylammonium fluoride. d TASF: tris(dimethylamino)sulfur trimethylsilyl difluoride. e DAST: N,N-diethylaminosulfur trifluoride. f TBAT: tetrabutylammonium difluorotriphenylsilicate. g N.R.: no reaction.
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Table 2 Reaction of pyridinium-type salt intermediates from various methoxymethyl (MOM) ethers 1 with a fluorine source.a
Entry
Product
F source
Yield (%)d
Entry
Product
F source
Yield (%)d
1
2a (R = OBn)
2f
A B
74 58
2b (R = OTr)
3
2c (R = OAc)
7
2g
A B
74 58
4
2d (R = OBz)
66 60 78 65 80 64 63 66
6
2
A B A B A B A B
5
2e (R = Br)
A B
68 62
8
2h
A B
58 47
9
2i
A B
75 64
a Reaction conditions: Methoxymethyl (MOM) ethers 1 were treated with 2,2′-bipyridyl (3 equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. The fluorine source (A: TASF (3 equiv.), B: TBAF (5 equiv.)) was then added, and the resulting mixture was stirred for 1–1.5 h (A) or 5 min (B). b TASF: tris(dimethylamino)sulfur trimethylsilyl difluoride. c TBAF: tetrabutylammonium fluoride. d Isolated yield.
solvents. All reactions were monitored by thin-layer chromatography (TLC) using Merck silica gel 60F254 (0.25 mm). The products were purified by column chromatography over silica gel [Kieselgel 60 (70–230 mesh ASTM) purchased from Merck, or Silica Gel 60N (40–50 μm, spherical neutral) purchased from Kanto Chemical]. 1H, 13 C, and 19F NMR spectra were recorded at 25 °C on JEOL JNM-AL300 (at 300, 75, and 282 MHz, respectively), JEOL JNM-ECS 400 (at 400, 100, and 376 MHz, respectively), or JEOL JNM-LA 500 (at 500, 125, and 470 MHz, respectively) spectrometers, and the chemical shifts are reported relative to an internal standard: tetramethylsilane (TMS; 1H, δ = 0.00 ppm), CDCl3 (1H, δ = 7.26 ppm, 13C, δ = 77.0 ppm), CD3OD (1H, δ = 3.31 ppm), or C6F6 (19F, δ = −165.9 ppm). IR spectra were recorded with Shimadzu FTIR-8400 or Shimadzu IRAffinity-1 spectrometers by diffuse reflectance measurement of samples dispersed in KBr powder. High resolution mass spectrometric measurements were performed by JEOL, using DART® (Direct Analysis in Real Time) mass analysis. MALDI-TOF MS and FAB MS were performed by the Elemental Analysis Section of Graduate School of Pharmaceutical Science in Osaka University. Compounds 1a–1d , 1e [13], 1f [14], 1 g [15], 1 h [16], 1i [11], and 2f are known compounds.
Table 3 Optimization of the reaction conditions for the synthesis of trifluoromethylthiomethyl ether 3f.a
Entry
2,2′-bipyridyl (X equiv.)
Solvent
Temp.
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8
3 3 3 3 3 3 5 10
CH2Cl2 THF DMF CH3CN CH2Cl2 CH3CN CH3CN CH3CN
r.t.c r.t. r.t. r.t. reflux reflux r.t. r.t.
5 3 5 16 5 5 6 5
34 20 20 30 37 19 78 82
a Reaction conditions: Methoxymethyl (MOM) ether 1f was treated with 2,2′-bipyridyl (X equiv.) and TMSOTf (2 equiv.) in CH2Cl2 at 0 °C for 0.5 h. CuSCF3 (2 equiv.) was then added, and the resulting mixture was stirred. b Isolated yield. c r.t.: room temperature.
4.2. General procedure for the synthesis of monofluoromethyl ethers (ROCH2F) 2 (Table 2)
3. Conclusion In summary, we have developed a versatile and chemoselective synthesis of fluorinated methyl ethers, specifically monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3). Our method is a simple-to-operate one-pot reaction that uses commercially available fluorinating reagents. We expect that this method will provide a new approach to the synthesis of fluorinated compounds.
[Method A] TMSOTf (72.0 μL, 0.40 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.20 mmol, 1.0 equiv.) and 2,2′-bipyridyl (93.7 mg, 0.60 mmol, 3.0 equiv.) in CH2Cl2 (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then TASF (165.0 mg, 0.60 mmol, 3.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 1 h, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography (n-hexane/EtOAc = 15/1) to give corresponding monofluoromethyl ether (RCOCH2F) 2.
4. Experimental section 4.1. General information All reagents were purchased from commercial sources and used without further purification, unless otherwise noted. Reactions were performed under a nitrogen atmosphere using purchased anhydrous 3
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Table 4 Reaction of pyridinium-type salt intermediates from various MOM ethers 1 with CuSCF3.a
Entry
Product
Yield (%)b
Entry
Product
Yield (%)b
1 2
3a (R = OBn) 3b (R = OTr)
71 97
6
3f
82
3 4
3c (R = OAc) 3d (R = OBz)
80 63
7
3g
94
5
3e (R = Br)
68c
8
3h
86
9
3i
93
a Reaction conditions: Methoxymethyl (MOM) ethers 1 were treated with 2,2′-bipyridyl (10 equiv.) and TMSOTf (2 equiv.) in CH3CN at 0 °C for 0.5 h. CuSCF3 (2 equiv.) was then added, and the resulting mixture was stirred. b Isolated yield. c Reaction was performed at 0 °C.
J = 57.8 Hz); HRMS (FAB): Anal. for C15H29O3FNa [M + Na]+ Calcd.: 299.1998, Found: 299.1996.
[Method B] TMSOTf (72.0 μL, 0.40 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.20 mmol, 1.0 equiv.) and 2,2′-bipyridyl (93.7 mg, 0.60 mmol, 3.0 equiv.) in CH2Cl2 (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol, 5.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 5 min, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography (n-hexane/EtOAc = 15/1) to give corresponding monofluoromethyl ether (RCOCH2F) 2.
4.2.4. 12-(Fluoromethoxy)dodecyl benzoate (2d) Colorless oil; IR (KBr): 2929, 2856, 1717, 1467, 1389, 1176, 951 cm−1; 1H NMR (500 MHz, CDCl3) δ: 8.05–8.03 (2H, m), 7.56–7.53 (1H, m), 7.45–7.42 (2H, m), 5.26 (2H, d, J = 56.7 Hz), 4.31 (2H, t, J = 6.9 Hz), 3.71 (2H, td, J = 6.9, 1.8 Hz), 1.79–1.73 (2H, m), 1.65–1.59 (2H, m), 1.46–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 166.7, 132.8, 130.5, 129.5, 128.3, 103.8 (d, J = 211.1 Hz), 70.8, 65.1, 29.53, 29.49, 29.3, 29.2, 28.7, 26.0, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.8 Hz); HRMS (MALDI-TOF): Anal. for C20H31O3FNa [M + Na]+ Calcd.: 361.2149, Found: 361.2147. 4.2.5. 1-Bromo-12-(fluoromethoxy)dodecane (2e) Colorless oil; IR (KBr): 2928, 2854, 1466, 1175, 951 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.27 (2H, d, J = 56.7 Hz), 3.71 (2H, td, J = 6.9, 1.7 Hz), 3.40 (2H, t, J = 6.9 Hz), 1.88–1.82 (2H, m), 1.65–1.59 (2H, m), 1.44–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 103.8 (d, J = 211.0 Hz), 70.9, 34.1, 32.8, 29.54, 29.49, 29.40, 29.3, 28.7, 28.1, 25.9; 19F NMR (282 MHz, CDCl3) δ: −149.25 (t, J = 56.7 Hz).
4.2.1. 1-Benzyloxy-12-(fluoromethoxy)dodecane (2a) Colorless oil; IR (KBr): 2925, 2855, 1496, 1454, 1174, 944 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 7.35–7.27 (5H, m), 5.27 (2H, d, J = 56.7 Hz), 4.51 (2H, s), 3.72 (2H, td, J = 6.9, 1.7 Hz), 3.47 (2H, t, J = 6.9 Hz), 1.64–1.59 (4H, m), 1.37–1.27 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 138.7, 128.3, 127.6, 127.4, 103.8 (d, J = 211.1 Hz), 86.2, 72.8, 70.9, 70.5, 29.7, 29.54, 29.50, 29.45, 29.3, 26.2, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.7 Hz); HRMS (MALDI-TOF): Anal. for C20H33O2FNa [M + Na]+ Calcd.: 347.2357, Found: 347.2355.
4.2.6. 1-(Fluoromethoxy)decane (2f) Colorless oil; 1H NMR (300 MHz, CDCl3) δ: 5.27 (2H, d, J = 56.7 Hz), 3.71 (2H, td, J = 6.9, 1.7 Hz), 1.67–1.58 (2H, m), 1.37–1.22 (14H, m), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 103.8 (d, J = 211.0 Hz), 70.9, 31.9, 29.6, 29.5, 29.33, 29.31, 25.9, 22.7, 14.1. Spectroscopic data for 2f were consistent with those previously reported for this compound.
4.2.2. 1-(Fluoromethoxy)-12-(triphenylmethyloxy)dodecane (2b) Colorless oil; IR (KBr): 2903, 1598, 1490, 1390, 913 cm−1; 1H NMR (300 MHz, CDCl3) δ: 7.46–7.19 (15H, m), 5.26 (2H, d, J = 56.7 Hz), 3.70 (2H, td, J = 6.5, 2.0 Hz), 3.04 (2H, t, J = 6.5 Hz), 1.66–1.57 (4H, m), 1.39–1.22 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 144.5, 128.7, 127.6, 126.8, 103.8 (d, J = 211.0 Hz), 70.9, 63.6, 30.0, 29.6, 29.5, 29.3, 26.2, 25.9; 19F NMR (376 MHz, CDCl3) δ: −154.14 (t, J = 57.8 Hz); HRMS (MALDI-TOF): Anal. for C32H41O2FNa [M + Na]+ Calcd.: 499.2983, Found: 499.2985.
4.2.7. 1-(Fluoromethoxy)undec-10-ene (2 g) Colorless oil; IR (KBr): 2928, 1466, 1175, 951 cm−1; 1H NMR (400 MHz, CD3OD) δ: 5.81 (1H, ddt, J = 17.4, 10.5, 6.8 Hz), 5.24 (2H, d, J = 56.8 Hz), 5.01–4.89 (2H, m), 3.70 (2H, dt, J = 6.8, 1.8 Hz), 2.08–2.02 (2H, m), 1.64–1.57 (2H, m), 1.42–1.29 (14H, m); 13C NMR (125 MHz, CDCl3) δ: 139.2, 114.1, 103.8 (d, J = 211.0 Hz), 70.9, 33.8, 29.54, 29.46, 29.37, 29.29, 29.1, 28.9, 25.9; 19F NMR (282 MHz, CDCl3) δ: −145.12 (t, J = 60.9 Hz).
4.2.3. 12-(Fluoromethoxy)dodecyl acetate (2c) Colorless oil; IR (KBr): 2926, 2854, 1739, 1464, 1389, 1175, 952 cm−1; 1H NMR (300 MHz, CDCl3) δ: 5.27 (2H, d, J = 57.0 Hz), 4.04 (2H, t, J = 6.9 Hz), 3.71 (2H, td, J = 6.9, 2.0 Hz), 2.04 (3H, s), 1.67–1.56 (4H, m), 1.37–1.21 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 171.3, 103.8 (d, J = 211.0 Hz), 70.9, 64.6, 29.7, 29.6, 29.5, 29.3, 29.2, 28.6, 25.9, 21.0; 19F NMR (376 MHz, CDCl3) δ: −154.15 (t,
4.2.8. 2-(Fluoromethoxy)decane (2 h) Colorless oil; IR (KBr): 2926, 2856, 1466, 1376, 1107, 983 cm−1; 1 H NMR (400 MHz, CD3OD) δ: 5.28 (2H, ddd, J = 57.3, 18.5, 2.7 Hz), 4
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7.57–7.54 (1H, m), 7.45–7.42 (2H, m), 5.05 (2H, d, J = 1.1 Hz), 4.31 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.9 Hz), 1.79–1.73 (2H, m), 1.62–1.56 (2H, m), 1.46–1.41 (2H, m), 1.38–1.25 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 166.7, 132.8, 130.5 (q, J = 305.2 Hz), 130.48, 129.5, 128.3, 72.2, 69.5, 65.1, 29.5, 29.28, 29.25, 29.0, 28.7, 26.02, 25.95; 19F NMR (376 MHz, CDCl3) δ: −43.86; HRMS (DART): Anal. for C21H32O3F3S+1 [M + H]+ Calcd.: 421.2019, Found: 421.2023.
3.80–3.72 (1H, m), 1.60–1.23 (14H, m), 1.20–1.19 (3H, d, J = 6.0 Hz), 0.92–0.89 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 102.7 (d, J = 211.1 Hz), 36.9, 31.9, 29.6, 29.5, 29.3, 25.3, 22.7, 20.6, 14.1; 19F NMR (282 MHz, CDCl3) δ: −149.96 (t, J = 60.9 Hz); HRMS (MALDITOF): Anal. for C11H23OFNa [M + Na]+ Calcd.: 213.1625, Found: 213.1620. 4.2.9. 2-(Fluoromethoxy)-2-methyldecane (2i) Colorless oil; IR (KBr): 2927, 2856, 1468, 1378, 1111, 911 cm−1; 1 H NMR (300 MHz, CDCl3) δ: 5.36 (2H, d, J = 57.7 Hz), 1.68–1.43 (2H, m), 1.27–1.21 (20H, m), 0.88 (3H, t, J = 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ: 98.4 (d, J = 209.5 Hz), 41.7, 31.9, 30.1, 29.6, 29.3, 26.2, 23.9, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ: −144.82 (d, J = 57.8 Hz).
4.3.5. 1-Bromo-12-(trifluoromethylthiomethoxy)dodecane (3e) Colorless oil; IR (KBr): 2926, 2855, 1466, 1133, 1084 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.05 (2H, s), 3.56 (2H, t, J = 6.9 Hz), 3.40 (2H, t, J = 6.9 Hz), 1.88–1.82 (2H, m), 1.64–1.56 (2H, m), 1.45–1.39 (2H, m), 1.37–1.27 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 130.5 (d, J = 305.2 Hz), 72.2, 70.9, 69.6, 34.0, 32.8, 29.47–29.40 (3C), 29.3, 29.0, 28.7, 28.2, 26.0; 19F NMR (376 MHz, CDCl3) δ: −39.07; HRMS (DART): Anal. for C14H30NOF3SBr+1 [M + NH4]+ Calcd.: 396.1178, Found: 396.1189.
4.3. General procedure for the synthesis of trifluoromethylthiomethyl ether (ROCH2SCF3) 3 (Table 4) TMSOTf (36.0 μL, 0.20 mmol, 2.0 equiv.) was added dropwise to a solution of MOM ether 1 (0.10 mmol, 1.0 equiv.) and 2,2′-bipyridyl (156.2 mg, 1.00 mmol, 10.0 equiv.) in CH3CN (1.0 mL) at 0 °C under N2, and the mixture was stirred at the same temperature. The disappearance of 1 was confirmed by TLC after 0.5 h, and then CuSCF3 (32.9 mg, 0.20 mmol, 2.0 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C. The polar component disappeared after 1 h, and then the reaction mixture was quenched with saturated NH4Cl (aq) solution, stirred for 20 min at 0 °C, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash SiO2 column chromatography to give corresponding trifluoromethylthiomethyl ether (ROCH2SCF3) 3.
4.3.6. 1-(Trifluoromethylthiomethoxy)decane (3f) Colorless oil; IR (KBr): 2925, 2857, 1468, 1134, 1085 cm−1; 1H NMR (300 MHz, CDCl3) δ: 5.05 (2H, q, J = 1.1 Hz), 3.56 (2H, t, J = 6.5 Hz), 1.64–1.55 (2H, m), 1.37–1.22 (14H, m), 0.88 (3H, t, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.5 (d, J = 305.2 Hz), 72.2 (d, J = 2.4 Hz), 69.6, 31.9, 29.5, 29.3, 29.0, 26.0, 22.7, 14.1; 19F NMR (282 MHz, CDCl3) δ: −43.86; HRMS (DART): Anal. for C12H27NOF3S+1 [M + NH4]+ Calcd.: 290.1760, Found: 290.1764. 4.3.7. 1-(Trifluoromethylthiomethoxy)undec-10-ene (3 g) Colorless oil; IR (KBr): 2928, 2857, 1133, 1084, 910, 756 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.81 (1H, ddt, J = 17.2, 10.3, 6.9 Hz), 5.05 (2H, s), 5.01–4.91 (2H, m), 3.56 (2H, t, J = 6.9 Hz), 2.06–2.02 (2H, m), 1.62–1.56 (2H, m), 1.40–1.26 (14H, m); 13C NMR (125 MHz, CDCl3) δ: 139.2, 130.5 (d, J = 305.2 Hz), 129.3, 114.1, 72.2 (q, J = 2.4 Hz), 69.5, 33.8, 29.5, 29.4, 29.3, 29.1, 29.0, 28.9, 26.0; 19F NMR (376 MHz, CDCl3) δ: −43.87; HRMS (DART): Anal. for C13H24OF3S+1 [M + H]+ Calcd.: 285.1495, Found: 285.1496.
4.3.1. 1-Benzyloxy-12-(trifluoromethylthiomethoxy)dodecane (3a) Colorless oil; IR (KBr): 2924, 2855, 1454, 1316, 1127, 1082 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 7.35–7.28 (5H, m), 5.04 (2H, s), 4.51 (2H, s), 3.56 (2H, t, J = 6.6 Hz), 3.46 (2H, t, J = 6.6 Hz), 1.64–1.57 (4H, m), 1.42–1.20 (16H, m); 13C NMR (125 MHz, CDCl3) δ: 138.7, 130.5 (d, J = 305.2), 128.3, 127.6, 127.4, 72.8, 72.2, 70.5, 69.5, 29.7, 29.6–29.5 (5C), 29.3, 29.0, 26.2, 26.0; 19F NMR (376 MHz, CDCl3) δ: −43.88; HRMS (DART): Anal. for C21H37NO2F3S+1 [M + NH4]+ Calcd.: 424.2492, Found: 424.2499.
4.3.8. 2-(Trifluoromethylthiomethoxy)decane (3 h) Colorless oil; IR (KBr): 2927, 2857, 1468, 1378, 1130, 1072, 756, 658 cm−1; 1H NMR (500 MHz, CDCl3) δ: 5.12 (A in ABq, 1H, J = 12.0 Hz),5.00 (B in ABq, 1H, J = 12.0 Hz), 3.77–3.70 (1H, m), 1.56–1.53 (2H, m), 1.44–1.21 (14H, m), 1.16 (3H, d, J = 6.3 Hz), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.6 (q, J = 305.2 Hz), 74.2, 69.6 (q, J = 2.4 Hz), 36.1, 31.9, 29.6, 29.5, 29.2, 25.2, 22.6, 19.0, 14.1; 19F NMR (376 MHz, CDCl3) δ: −43.90; HRMS (DART): Anal. for C12H27NOF3S+1 [M + NH4]+ Calcd.: 290.1760, Found: 290.1752.
4.3.2. 1-(Trifluoromethylthiomethoxy)-12-(triphenylmethyloxy)dodecane (3b) Colorless oil; IR (KBr): 3059, 2930, 2856, 1133, 1084 cm−1; 1H NMR (500 MHz, CDCl3) δ: 7.68–7.66 (6H, m), 7.53–7.43 (9H, m), 5.26 (1H, s), 3.78 (2H, t, J = 6.3 Hz), 3.26 (2H, t, J = 6.3 Hz), 1.87–1.79 (4H, m), 1.60–1.42 (16H, m); 13C NMR (100 MHz, CDCl3) δ: 144.5, 130.5 (d, J = 306.1 Hz), 128.7, 127.6, 126.8, 86.2, 72.2 (q, J = 1.9 Hz) 69.5, 63.7, 30.0, 29.55–29.50 (5C), 29.3, 29.0, 26.2, 26.0; 19 F NMR (376 MHz, CDCl3) δ: −43.89; HRMS (DART): Anal. for C33H41O2F3S+1 [M]+ Calcd.: 558.2774, Found: 558.2749.
4.3.9. 2-(Trifluoromethylthiomethoxy)-2-methyldecane (3i) Colorless oil; IR (KBr): 2925, 2855, 1467, 1370, 1132, 1068 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 4.94 (2H, s), 1.49–1.46 (2H, m), 1.34–1.25 (14H, m), 1.21 (6H, s), 0.88 (3H, t, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ: 130.7 (d, J = 305.2 Hz), 78.5, 64.0, 40.8, 31.9, 30.0, 29.5, 29.3, 25.3, 23.7, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ: −44.33; HRMS (DART): Anal. for C13H29NOF3S+1 [M + NH4]+ Calcd.: 304.1917, Found: 304.1911.
4.3.3. 12-(Trifluoromethylthiomethoxy)dodecyl acetate (3c) Colorless oil; IR (KBr): 2931, 2857, 1739, 1241, 1133, 1085 cm−1; 1 H NMR (500 MHz, CDCl3) δ: 5.05 (2H, s), 4.05 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.9 Hz), 2.04 (3H, s), 1.64–1.56 (4H, m), 1.37–1.21 (16H, m); 13C NMR (100 MHz, CDCl3) δ: 171.3, 130.5 (q, J = 310.3 Hz), 72.2 (q, J = 1.9 Hz), 69.5, 64.6, 29.49–29.46 (4C), 29.27–29.22 (2C), 29.0, 28.6, 25.94, 25.87, 21.0; 19F NMR (376 MHz, CDCl3) δ: −43.89; HRMS (DART): Anal. for C16H30O3F3S+1 [M + H]+ Calcd.: 359.1862, Found: 359.1858.
Acknowledgments This work was financially supported by JSPS KAKENHI grant number JP15H04632 and the Platform for Drug Discovery, Informatics, and Structural Life Science. We are also grateful to JEOL Ltd. for the measurement of MS spectra.
4.3.4. 12-(Trifluoromethylthiomethoxy)dodecyl benzoate (3d) Colorless oil; IR (KBr): 2927, 2856, 1718, 1452, 1316, 1131, 1083 cm−1; 1H NMR (500 MHz, CDCl3) δ: 8.06–8.04 (2H, m), 5
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