2016 Volume 64 Issue 7 Pages 737-753
The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C–H bonds are described. The catalytic oxidation of C–H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C–H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF3)-substituted sp3-carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-hydroxy precatalysts containing such a CF3 moiety, and investigated their utility in the aerobic oxidation of benzylic C–H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF3 and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C–H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.
The catalytic oxidation of C–H bonds is a valuable transformation in organic chemistry that leads to medicinally attractive oxygenated functional molecules in a small number of synthetic steps.1–3) In the context of green chemistry, the use of molecular oxygen (O2) for this conversion has recently attracted much attention, as it minimizes both the use of potentially hazardous oxidants and the generation of byproducts. However, C–H oxidations using O2 are challenging, as the formation of reactive oxygen species from triplet O2 is kinetically unfavorable. Therefore, bespoke initiators/catalysts that activate C–H bonds and/or O2 are required, in order to perform aerobic C–H oxidations efficiently.3,4)
Electron-deficient N-oxyl radicals, which are generated from the oxidation of N-hydroxy compounds, have been used to homolytically cleave the inert C(sp3)–H bonds of alkanes. The phthalimidoyl N-oxyl (PINO) radical, derived from N-hydroxyphthalimide (1), is a representative example that has been applied to various aerobic or non-aerobic C–H oxidations.5–7) However, 1 suffers from serious limitations in such reactions, e.g. poor solubility in common organic solvents and rapid autodecomposition.8,9)
Introducing substituents at the aromatic ring of 1 has been reported to enhance its solubility and stability (Fig. 1). Thus, the group of Ishii was able to develop a lipophilic derivative of 1 (A), which is soluble in alkanes,10) as well as derivatives B and C, which contain long fluorinated alkyl chains and are thus soluble in trifluorotoluene.11) The group of Einhorn synthesized tetraphenyl- (D)12) and silyl-substituted13) (E) analogues with enhanced stability, and the group of Xu reported the synthesis of tetrahalogenated derivatives of 1, whereby tetrachloro analogue F showed the best catalytic performance.14) Nevertheless, the backbone of 1 remains characterized by its inherent planarity and its limited number of modification sites, which restrict a further improvement of the catalytic performance and the introduction of additional functional groups.
Herein, we report an unprecedented approach towards nonplanar, electron-deficient N-oxyl radicals, containing an additional tunable site, which provides these compounds with enhanced solubility, stability, and structural diversity. We furthermore explored the utility of these compounds in the catalytic oxidation, etherification, and acetoamidation of benzylic C(sp3)–H bonds.
The high bond dissociation energy (BDE) of the NO–H bond in 1 (88.1 kcal/mol in t-BuOH), which is sufficient for cleaving benzylic, tertiary, and even secondary C(sp3)–H bonds, is due to the presence of two carbonyl groups adjacent to the N-OH moiety. These electron-withdrawing groups destabilize the resulting oxyl radical by rendering the delocalization of the nitrogen-lone pair inefficient therein.15)
Due to the structural simplicity of 1, modifiable sites are limited, except for those of the aromatic ring. To overcome this limitation, we envisaged that the transformation of one carbonyl group into an sp3 carbon should provide a feasible route to an additional tunable site in close proximity to the N-hydroxy moiety, which would simultaneously afford a nonplanar structure. This strategy should allow access to unprecedented structural tuning in order to improve catalytic performance, even though the elimination of a carbonyl group should lower the BDE.
The substitution of the carbonyl group at the R5 position in 1 with the lipophilic and electron-withdrawing trifluoromethyl (CF3) group should not only counterbalance such a decreased BDE, but also enhance the solubility of the resulting derivative.16) Simultaneous modifications of the aromatic substituents (R1–R4) should further improve these properties (Fig. 2).
N-Hydroxy precatalysts 5, 6, and 9 were synthesized from 1 in five steps (Chart 1). Initially, 1 was converted into intermediate 2 in three steps, following our previously reported procedure.16) Then, the chloro group of 2 was substituted with methoxy, 2,2,2-trifluoroethoxy, or acetophenone moieties under silver-mediated SN1 conditions, using the corresponding alcohols or a silyl enol ether (7). The ensuing removal of the protecting benzyl group under hydrogenolysis conditions afforded N-hydroxy precatalysts 5, 6, and 9.
We also synthesized N-oxyl radical precursors containing a CF3 group at position 7 of the aromatic ring (20 and 21; Chart 2). For this purpose, commercially available 3-nitrophthalic anhydride (10) was reacted with H2NOBn·HCl to afford 11, whose nitro group was reduced with iron powder to yield amine 12. Subsequently, 12 was converted into iodide 13 by a Sandmeyer reaction, and an ensuing Ruppert–Prakash trifluoromethylation17) afforded the 7- and 4-iodo isomers 14a (46%) and b (36%), which were separated after trituration with Et2O and column chromatography.18) Treatment of alcohol 14a with methanesulfonyl chloride (MsCl) furnished chloride 15, whose chloro group was removed by reaction with methanol or 2,2,2-trifluoroethanol (TFE) to afford ethers 16 and 17, respectively. The iodo group of these compounds was substituted with a CF3 group using (Ph3P)3CuCF3,19) and deprotection eventually afforded CF3-substituted N-hydroxy precatalysts 20 and 21.
Acetophenone-substituted 7-trifluoromethyl analogue 28 was prepared following a similar synthetic route, starting from 22.20) As the removal of the benzyl group was unsuccessful in this case, the p-methoxybenzyl (PMB) group was selected as a protecting group for the N-hydroxy moiety (Chart 3). The PMB group could be removed successfully in the last step under trifluoroacetic acid (TFA)/C6Me5H conditions16,21) to afford 28.
Next, we tackled the synthesis of tetrafluoro analogues 34 and 35, starting from 29, i.e., the 4,5,6,7-tetrafluoro derivative of 122) as shown in Chart 4. As expected, protection of the N-hydroxy moiety in 29 as a PMBether, followed by nucleophilic trifluoromethylation successfully furnished alcohol 31. However, our general protocol (Chart 1), consisting of chlorination (Et3N–MsCl) followed by silver-mediated SN1 substitution,16) did not afford 32 or 33 from 30, most likely on account of the low reactivity of the chlorinated intermediate towards the silver salt. As an alternative, we chose to carry out a one-pot mesylation-substitution reaction. After 31 was mesylated using Ms2O–Et3N at −78°C, methanol or TFE was added to the mixture, which was then warmed to room temperature. This protocol successfully furnished ethers 32 and 33, and their PMB groups could be removed with TFA–C6Me5H to afford 4,5,6,7-tetrafluoro N-hydroxy precatalysts 34 and 35. Unfortunately, an acetophenone-substituted analogue could not be synthesized, presumably due to the low reactivity of the silyl enol ether towards the mesylated or chlorinated intermediates.
As a part of our ongoing research program directed towards N-oxyl radical-catalyzed aerobic oxidations,23–25) we applied the newly synthesized N-hydroxy precatalysts to the aerobic oxidation of benzylic C–H bonds. The results obtained are summarized in Table 1.
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|---|---|---|---|---|---|
| Entry | Catalyst | Yield (%)a) | Entry | Catalyst | Yield (%)a) |
| 1b) |  | 92 | 6 |  | 66 |
| 2 |  | 23 | 7 |  | 28 |
| 3 |  | 45 | 8 |  | 46 |
| 4 |  | 39 | 9 |  | 71 |
| 5 |  | 46 | |||
a) 1H-NMR yield. b) The reaction time was 12 h.
The oxygenation of the benzylic C–H bonds in 36a was investigated using 5 mol% of the N-hydroxy precatalyst, 1 mol% of Co(OAc)2, and 1 mol% of Mn(OAc)3·2H2O in CH3CN under an atmosphere of O2 (1 atm) at 60°C. When 1 was used as a control catalyst, ketone 37a was obtained in 92% yield after 12 h (entry 1). Precatalyst 5, containing a CF3 and a methoxy substituent instead of a carbonyl group, afforded 37a in lower yield (23%, entry 2). We found that substituting the methoxy group with more electron-deficient 2,2,2-trifluoroethoxy (6) or acetophenone (9) moieties led to improved yields of 45% and 39%, respectively (entries 3, 4). 7-Trifluoromethyl- and 4,5,6,7-tetrafluoro-substituted precatalysts 20 and 34 also afforded improved yields (entries 2 vs. 5, 8), probably on account of their increased electron-withdrawing properties. Whereas the combination of the 7-trifluoromethyl and the acetophenone moieties in 28 proved to be mismatched (entries 4 vs. 7), the combination of a 7-trifluoromethyl substitution pattern with a 2,2,2-trifluoroethoxy group (21) displayed an additive effect, resulting in the formation of ketone 37a in 66% yield (entries 3, 5 vs. 6). The best performance (71% yield, entry 9) was obtained with N-hydroxy precatalyst 35, which contained a 4,5,6,7-tetrafluoro-substituted aromatic ring and a 2,2,2-trifluoroethoxy group.
Subsequently, we examined the scope and limitations of the oxidation of benzylic C–H bonds using precatalyst 35 (Table 2). When 3-phenylpropyl benzoate (36b) was used as the substrate, the corresponding ketone 37b was obtained in 78% yield. p-Substituted alkylarenes, bearing either electron-donating or withdrawing substituents such as OMe (36c), CF3 (36d), or F (36e), all reacted under these conditions to afford ketones 37c–e in moderate to high yields (42–69%). The high functional group tolerance of the present system is evident from the successful transformation of a variety of alkylbenzenes that bear different functional groups, e.g. a carboxylic acid (36f), a methyl ester (36g), a carboxamide (36h), an alkylbromide (36i), a nitrile (36j), or a methyl imidate (36k), into the corresponding ketones 37f–k in a chemoselective manner (39–80% yield). Interestingly, tetralin (36l), xanthene (36m), or isochromane (36n) were oxidized more readily than alkylarenes, furnishing the corresponding ketones 37l–n in 41–78% yield even at room temperature.
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a) Percentage values in parentheses refer to isolated yields.
During our investigations on the utility of N-hydroxy precatalyst 35, we discovered novel conditions for the intermolecular benzylic etherification and a Ritter-type reaction that uses NBS as the oxidant (Chart 5). We were thus able to synthesize 2,2,2-trifluoroethylethers, whose preparation via the classical Williamson ether procedure is limited by their low nucleophilicity. The conventional synthetic method for the generation of benzylic 2,2,2-trifluoroethylethers involves the nucleophilic attack of TFE to the corresponding benzylic cation, which is generated from a prefunctionalized benzylic compound.26–28) To the best of our knowledge, the direct transformation of a benzylic sp3 C–H bond into a C–OCH2CF3 moiety has not been reported so far. For that purpose, 36b was treated with a catalytic amount of 35 to mediate this 2,2,2-trifluoroetherification, which afforded 38 in modest yield (54%).29)
a) Percentage values refer to 1H-NMR yields using 2,4,6-trioxane as an internal standard. Percentage values in parentheses refer to isolated yields.
Ritter-type aminations of benzylic sp3 C–H bonds usually require harsh conditions, i.e. heating and/or the presence of a strong oxidant such as N-fluoro-N′-(chloromethyl)triethylenediamine pentafluoro phosphate (F-TEDA-PF6) or ceric ammonium nitrate.30–33) We found that 36b could be successfully aminated under mild conditions in CH3CN to afford 2,2,2-trifluoroethylether 39 in 49% yield using 35. These reactions may proceed via a carbocation intermediate generated by a two-electron oxidation process.33)
We have developed a synthetic procedure to prepare highly tunable, nonplanar, and electron-deficient N-oxyl radical species that can be used for the catalytic aerobic oxidation of benzylic C–H bonds. This method is based on the introduction of a CF3-substituted sp3-carbon as an additional functionalization site in close proximity to the N-hydroxy moiety of 1. Subsequently, modulation of the catalyst activity was accomplished by changing the substituents at both the aromatic ring and at the α-position with respect to the CF3 group. In general, the introduction of more electron-withdrawing groups led to a significant improvement of the catalyst activity, which is in good agreement with previously reported results.34) Although the best precatalyst performance still remains inferior to that of 1 itself, these investigations provide fundamental information on the design of novel N-oxyl radical catalysts and effective radical directing activators.16) Further studies on the functionalization of these compounds that may eventually lead to more active and selective catalysts are ongoing in our laboratory and results will be reported elsewhere in due course.
NMR spectra were recorded on JEOL JNM-LA500, JEOL ECX500 (500 MHz for 1H-NMR and 125 MHz for 13C-NMR), and JEOL ECS400 (400 MHz for 1H-NMR, 100 MHz for 13C-NMR, and 368 MHz for 19F-NMR) spectrometer. Chemical shifts were reported downfield from tetramethylsilane (TMS) (δ=0 ppm) for 1H-NMR. For 13C-NMR, chemical shifts were reported in the scale relative to the solvent used as an internal reference. For 19F-NMR, chemical shifts were reported downfield from hexafluorobenzene (δ=−164.9 ppm). IR spectra were recorded on a JASCO FT/IR 410 Fourier transform IR spectrophotometer. Electrospray ionization (ESI)-MS spectra were measured on a Waters ZQ4000 spectrometer (for low resolution (LR)-MS), and a JEOL JMS-T100LC AccuTOF spectrometer (for high resolution (HR)-MS). Column chromatographies were performed with silica gel Merck 60 (230–400 mesh ASTM). All reactions other than substrates synthesis were carried out in dry solvents (purchased from Aldrich, Kanto Chemical Co., Inc. or Wako Pure Chemical Industries, Ltd.). Other reagents of which preparation is not described in this manuscript were purchased from Aldrich, Tokyo Chemical Industry Co., Ltd. (TCI), Kanto Chemical Co., Inc., and Wako Pure Chemical Industries, Ltd., and used without further purification. NMR yield was calculated by 1H-NMR of crude product using an internal standard (1,3,5-trioxane).
Preparation of N-Hydroxy PrecatalystsFull spectroscopic data were described for new compounds. Compound 2,16) 22,20) and 2922) were prepared following the reported procedures.
General Procedure for Etherification (Procedure A)
To a suspension of silver trifluoromethanesulfonate (AgOTf) (2.18 g, 8.50 mmol) in toluene (5 mL), chloride 2 (1.71 g, 5.00 mmol) in toluene (5 mL) and MeOH (243 µL, 6.00 mmol) were added at 0°C. The reaction mixture was stirred for 1 h at 0°C, and for 3 h at room temperature (rt). Brine was added to the mixture, and the suspension was filtered over Celite. The filtered organic layer was separated, washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=9 : 1→4 : 1) to afford methylether 3 (1.60 g, 95%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.89 (d, J=7.2 Hz, 1H), 7.51–7.72 (m 5H), 7.32–7.42 (m, 3H), 5.30 (d, J=9.9 Hz, 1H), 5.13 (d, J=9.9 Hz, 1H), 2.99 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 165.56, 134.55, 134.47, 133.52, 131.75, 130.10, 129.45 (2C), 128.86, 128.41 (2C), 124.28, 124.19, 122.07 (q, J=285.6 Hz), 91.37 (q, J=32.9 Hz), 79.09, 51.28; 19F-NMR (368 MHz, CDCl3) δ: −77.92 (s, 3F); IR (KBr, cm−1) ν: 3586, 3443, 2939, 1742, 1654, 1559, 1541, 1185, 671; LR-MS (ESI): m/z 360 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H14F3NO3Na [M+Na]+ 360.0818. Found 360.0831.
General Procedure for Hydrogenolysis of Benzyl Ether (Procedure B)
A suspension of benzylether 3 (1.48 g, 4.39 mmol) and 10 wt% Pd/C (319 mg, 0.300 mmol) in EtOH (12.0 mL) was stirred for 2 h under H2 atmosphere (1 atm, balloon). The mixture was purged with Ar and filtered over Celite. The filtrate was evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=2 : 1→1 : 1) to afford 5 (1.02 g, 94%). White powder; 1H-NMR (500 MHz, CDCl3) δ: 7.82 (d, J=7.6 Hz, 1H), 7.57–7.70 (m, 3H), 3.13 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 165.92, 134.58, 131.69, 130.06, 124.16, 124.05, 121.88 (q, J=286.2 Hz), 91.40 (q, J=33.1 Hz), 51.58; 19F-NMR (368 MHz, CDCl3) δ: −78.41 (s, 3F); IR (KBr, cm−1) ν: 3136, 2952, 2887, 1711, 1471, 1315, 1195, 1124, 1086, 1007, 878, 731; LR-MS (ESI): m/z 270 [M+Na]+; HR-MS (ESI): m/z Calcd for C10H8F3NO3Na [M+Na]+ 270.0348. Found 270.0341.
According to the procedure A in which 2,2,2-trifluoroenthanol was used as the alcohol instead, chloride 2 (1.71 g, 5.00 mmol) was converted into ether 4 (1.57 g, 78%). Colorless oil; 1H-NMR (500 MHz, CDCl3) δ: 7.92 (d, J=7.5 Hz, 1H), 7.74 (dd, J=7.4, 7.4 Hz, 1H), 7.69 (dd, J=7.4, 7.4 Hz, 1H), 7.60 (d, J=6.9 Hz, 1H), 7.54 (d, J=7.4 Hz, 2H), 7.35–7.44 (m, 3H), 5.30 (d, J=9.8 Hz, 1H), 5.16 (d, J=9.8 Hz, 1H), 3.40–3.50 (m, 1H), 3.19–3.29 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 165.63, 134.37, 134.23 (2C), 133.53, 132.54 (2C), 129.78, 129.42, 129.07, 128.56, 124.62, 124.58, 122.72 (q, J=277.1 Hz), 121.57 (q, J=286.7 Hz), 91.0 (q, J=33.6 Hz), 79.31, 61.3 (q, J=36.0 Hz); 19F-NMR (368 MHz, CDCl3) δ: −74.02 (s, 3F), −77.52 (s, 3F); IR (neat, cm−1) ν: 3433, 2917, 2848, 1750, 1470, 1293, 1190, 984, 766, 635; LR-MS (ESI): m/z 428 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H13F6NO3Na [M+Na]+ 428.0692. Found 428.0690.
According to the procedure B, benzyl ether 4 (1.45 g, 3.58 mmol) was converted into 6 (1.07 g, 95%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 7.71–7.90 (m, 4H), 3.97–4.10 (m, 1H), 3.64–3.78 (m, 1H); 13C-NMR (125 MHz, acetone-d6) δ: 164.68, 134.69, 134.11, 133.45, 131.47, 125.54, 124.73, 124.43 (q, J=277.1 Hz), 122.59 (q, J=285.5 Hz), 91.49 (q, J=33.6 Hz), 61.95 (q, J=36.0 Hz); 19F-NMR (368 MHz, acetone-d6) δ: −74.80 (s, 3F), −78.38 (s, 3F); IR (KBr, cm−1) ν: 3426, 3137, 2942, 1719, 1616, 1508, 1473, 1427, 1378, 1305, 1172, 1125, 1087, 1038, 993, 968, 882, 766; LR-MS (ESI): m/z 338 [M+Na]+; HR-MS (ESI): m/z Calcd for C11H7F6NO3Na [M+Na]+ 338.0222. Found 338.0223.
To a suspension of AgOTf (437 mg, 1.70 mmol) in toluene (1.0 mL), chloride 2 (342 mg, 1.00 mmol), Et3N (279 µL, 2.00 mmol) and [(1-phenyl-1-ethenyl)oxy]trimethylsilane (7) (385 mg, 2.00 mmol) in toluene (1.0 mL) were added at 0°C. The reaction mixture was stirred for 1 h at 0°C, and for 35 h at rt. Brine was added to the mixture and the suspension was filtered over Celite. The organic layer was separated, washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=9 : 1→4 : 1) to afford 8 (264 mg, 62%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.90–7.96 (m, 1H), 7.72 (dd, J=7.2, 1.3 Hz, 2H), 7.71–7.59 (m 6H), 7.27–7.37 (m, 5H), 5.43 (d, J=9.9 Hz, 1H), 5.05 (d, J=9.9 Hz, 1H), 4.00 (d, J=17.5 Hz, 1H), 3.74 (d, J=17.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ: 195.56, 168.49, 137.90, 136.05, 134.61, 133.46, 132.91, 130.56, 130.12, 129.43 (2C), 128.65, 128.45 (2C), 128.30 (2C), 127.80, 124.58 (q, J=284.7 Hz), 124.15 (2C), 122.31, 79.20, 67.20 (q, J=29.1 Hz), 34.31; 19F-NMR (368 MHz, CDCl3) δ: −76.46 (s, 3F); IR (KBr, cm−1) ν: 3450, 3061, 3035, 2968, 2926, 1733, 1698, 1594, 1469, 1374, 1275, 1185, 991, 751; LR-MS (ESI): m/z 448 [M+Na]+; HR-MS (ESI): m/z Calcd for C24H18F3NO3Na [M+Na]+ 448.1131. Found 448.1140.
According to the procedure B, benzyl ether 8 (740 mg, 1.74 mmol) was converted into 9 (530 mg, 91%). Colorless oil; 1H-NMR (500 MHz, CDCl3) δ: 7.77 (d, J=7.4 Hz, 2H), 7.70 (d, J=7.5 Hz, 1H), 7.42–7.55 (m, 4H), 7.38 (dd, J=7.5, 7.5 Hz, 2H), 4.02–4.21 (m, 1H), 3.75–3.93 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 193.39, 168.14, 137.61, 136.23, 133.71, 132.66, 130.41, 130.07 (2C), 128.62 (2C), 128.01, 124.14, 124.13 (q, J=285.5 Hz), 122.41, 67.98 (q, J=34.8 Hz), 34.21; 19F-NMR (368 MHz, CDCl3) δ: −76.68 (s, 3F); IR (KBr, cm−1) ν: 3422, 2926, 1696, 1643, 1278, 1185, 754; LR-MS (ESI): m/z 358 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H12F3NO3Na [M+Na]+ 358.0661. Found 358.0677.
A suspension of 3-nitrophthalic anhydride 10 (1.00 g, 5.18 mmol) and H2NOBn·HCl (827 mg, 5.18 mmol) in xylene (19 mL) was heated to reflux for 3 h with Dean–Stark apparatus. The mixture was evaporated under reduced pressure. The residue was triturated with EtOH to afford 11 (1.39 g, 90%). Pale yellow powder; 1H-NMR (500 MHz, DMSO-d6) δ: 8.30 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.06 (dd, J=8.0, 8.0 Hz, 1H), 7.50–7.55 (m, 2H), 7.38–7.45 (m, 3H), 5.17 (s, 2H); 13C-NMR (125 MHz, DMSO-d6) δ: 161.17, 158.81, 144.11, 136.42, 134.02, 130.53, 129.66 (2C), 129.18, 128.69, 128.52 (2C), 127.03, 120.62, 79.48; IR (KBr, cm−1) ν: 3449, 3109, 3048, 2952, 2896, 1793, 1732, 1545, 1350, 1144, 1005, 865, 699; LR-MS (ESI): m/z 321 [M+Na]+; HR-MS (ESI): m/z Calcd for C15H11N2O5Na [M+Na]+ 321.0482. Found 321.0497.
A suspension of 11 (34.0 g, 0.114 mol), Fe powder (63.7 g, 1.14 mol), and NH4Cl (3.66 g, 0.0684 mol) in H2O (380 mL) was heated to reflux for 2 h. The mixture was diluted with H2O and CH2Cl2, and filtered over Celite. The organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with Et2O to afford amine 12 (15.4 g, 51%). Yellow powder; 1H-NMR (400 MHz, DMSO-d6) δ: 7.32–7.57 (m, 6H), 6.89–7.04 (m, 2H), 6.50 (br s, 2H), 5.11 (s, 2H); 13C-NMR (125 MHz, DMSO-d6) δ: 164.58, 163.36, 146.56, 135.43, 134.32, 129.56 (2C), 128.98 (2C), 128.41 (2C), 122.14, 111.05, 105.05, 79.07; IR (KBr, cm−1) ν: 3479, 3336, 3032, 1759, 1715, 1630, 1481, 1385, 1181, 1026, 903, 730; LR-MS (ESI): m/z 291 [M+Na]+; HR-MS (ESI): m/z Calcd for C15H12N2O3Na [M+Na]+ 291.0740. Found 291.0732.
To a suspension of amine 12 (15.4 g, 57.4 mmol) and 3 N HCl aq. (165 mL) in CH3CN (674 mL), NaNO2 (4.75 g, 68.9 mmol) in H2O (57.4 mmol) was added dropwise at 0°C, and the mixture was stirred for 0.5 h at the same temperature. To the mixture, KI (14.3 g, 86.1 mmol) in H2O (57.4 mL) was added at 0°C, and the mixture was stirred for 1 h at the same temperature. To the mixture, CH2Cl2 was added, and the phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with 20% Na2S2O3 aq., H2O, and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with n-hexane–EtOAc=2 : 1 to afford iodide 13 (16.1 g, 74%). white powder; 1H-NMR (400 MHz, CDCl3) δ: 8.09 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.2 Hz, 2H), 7.49–7.54 (m, 2H), 7.32–7.42 (m, 3H), 5.19 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ: 162.34, 161.39, 145.55, 134.94, 133.44, 130.82, 129.80 (2C), 129.53, 129.33, 128.52 (2C), 123.21, 88.76, 79.94; IR (KBr, cm−1) ν: 3501, 3079, 3033, 1790, 1742, 1455, 1391, 1146, 984, 876, 718; LR-MS (ESI): m/z 402 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H11F3INO3Na [M+Na]+ 401.9598. Found 401.9590.
To a solution of phthalimide 13 (16.0 g, 42.2 mmol) and CsF (8.34 g, 54.9 mmol) in N,N-dimethylformamide (DMF) (422 mL), trimethyl(trifluoromethyl)silane3 (TMSCF3) (8.13 mL, 54.9 mmol) was added dropwise at 0°C. The mixture was stirred for 0.5 h at 0°C, then for 12 h at rt. To the mixture, H2O was added at 0°C, and the whole was extracted with EtOAc for 3 times. The combined organic layer was washed with 1 N HCl aq., H2O for 3 times, and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with Et2O to afford alcohol 14a (6.54 g, 35%). The mother liquor was evaporated under reduced pressure, and the residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=9 : 1→1 : 1) to afford alcohol 14a (2.11 g, 11%) and 14b (6.86 g, 36%). Compound 14a: White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.16 (dd, J=7.6, 0.9 Hz, 1H), 7.81 (dd, J=7.6, 0.9 Hz, 1H), 7.51–7.60 (m, 3H), 7.35–7.46 (m, 3H), 5.31 (d, J=9.4 Hz, 2H), 5.19 (d, J=9.4 Hz, 2H); 13C-NMR (100 MHz, acetone-d6) δ: 163.88, 143.81, 141.61, 135.89, 135.52, 130.22 (2C), 129.57 (2C), 129.19 (2C), 124.96 (q, J=1.9 Hz), 123.57 (q, J=286.6 Hz), 89.65, 86.33 (q, J=33.8 Hz), 80.52; 19F-NMR (368 MHz, acetone-d6) δ: −79.43 (s, 3F); IR (KBr, cm−1) ν: 3254, 3031, 1717, 1460, 1376, 1198, 989, 946, 794, 714; LR-MS (ESI): m/z 472 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H11F3INO3Na [M+Na]+ 471.9628. Found 471.9618. Compound 14b: white powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.25 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.34–7.49 (m 4H), 5.29 (d, J=9.9 Hz, 1H), 5.22 (d, J=9.9 Hz); 13C-NMR (100 MHz, acetone-d6) δ: 162.90, 146.79, 139.73, 136.00, 133.77, 132.91, 130.10 (2C), 129.49, 129.12 (2C), 124.14, 123.93 (q, J=290.3 Hz), 90.14 (q, J=32.9 Hz), 90.10, 80.84; 19F-NMR (368 MHz, acetone-d6) δ: −75.41 (s, 3F); IR (KBr, cm−1) ν: 3169, 2956, 2885, 1702, 1574, 1461, 1372, 1251, 1191, 1092, 870, 760, 700; LR-MS (ESI): m/z 472 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H11F3INO3Na [M+Na]+ 471.9628. Found 471.9624.
To a suspension of alcohol 14a (8.64 g, 19.2 mmol) in CH2Cl2 (192 mL), Et3N (4.26 mL, 28.8 mmol) and MsCl (2.23 mL, 30.7 mmol) were added at 0°C, and the mixture was stirred for 0.5 h at 0°C, then for 13 h at rt. To the mixture, Et3N (798 µL, 5.76 mmol) and MsCl (446 µL, 5.76 mmol) were added at rt, and the mixture was stirred for 1 h at rt. To the mixture, H2O was added and the phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=19 : 1→9 : 1) to afford chloride 15 (8.46 g, 94%). white powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.28 (dd, J=9.3, 0.9 Hz, 1H), 7.93 (dd, J=7.7, 0.9 Hz, 1H), 7.67 (dd, J=7.6, 7.6 Hz, 1H), 7.57–7.62 (m, 2H), 7.41–7.49 (m, 3H), 5.42 (d, J=9.4 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H); 13C-NMR (100 MHz, acetone-d6) δ: 163.85, 144.63, 140.68, 136.46, 135.07, 130.46 (2C), 129.93, 129.33 (2C), 128.34, 125.13 (q, J=1.9 Hz), 122.46 (q, J=283.8 Hz), 90.85, 80.48, 79.00 (q, J=36.6 Hz); 19F-NMR (368 MHz, acetone-d6) δ: −76.34 (s, 3F); IR (KBr, cm−1) ν: 3484, 3069, 3033, 2960, 2897, 1752, 1456, 1264, 1171, 977, 903, 713; LR-MS (ESI): m/z 490 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H10ClF3INO2Na [M+Na]+ 489.9289. Found 489.9300.
According to the procedure A, the chloride 15 (4.09 g, 8.75 mmol) was converted into ether 16 (2.09 g, 52%). white powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.23 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.56–7.63 (m, 3H), 7.35–7.46 (m, 3H), 5.29 (d, J=10.0 Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 3.13 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 164.68, 144.40, 137.53, 135.84, 135.68, 131.27, 130.16 (2C), 129.65, 129.24 (2C), 125.44, 122.93 (q, J=285.6 Hz), 90.82 (q, J=32.9 Hz), 90.32, 79.88, 51.83; 19F-NMR (368 MHz, acetone-d6) δ: −78.29 (s, 3F); IR (KBr, cm−1) ν: 3466, 3077, 3029, 2965, 2898, 1742, 1456, 1276, 1187, 986, 869, 724, 697; LR-MS (ESI): m/z 486 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3INO3Na [M+Na]+ 485.9784. Found 485.9781.
The mixture of iodide 16 (100 mg, 0.216 mmol), (PPh3)3CuCF3 (218 mg, 0.237 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (4,4′-dtbpy) (63.6 mg, 0.237 mmol) in toluene (2.2 mL) was stirred for 20 h at 80°C. To the mixture, (PPh3)3CuCF3 (39.7 mg, 0.0432 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (11.6 mg, 0.0432 mmol) were added and the mixture was stirred for 4 h at 80°C. The mixture was diluted with EtOAc, washed with H2O, 28% NH3 aq., H2O and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=19 : 1→9 : 1) to afford trifluoromehylated compound 18 (41.7 mg, 48%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.94 (dd, J=4.3 Hz, 1H), 7.81 (d, J=4.3 Hz, 2H), 7.54 (d, J=5.9 Hz, 2H), 7.32–7.44 (m, 3H), 5.32 (d, J=9.7 Hz, 1H), 5.13 (d, J=9.7 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ: 162.44, 137.00, 134.30, 133.52, 129.63 (2C), 129.23 (q, J=4.8 Hz), 129.04 (2C), 128.53, 127.74, 127.83, (q, J=28.8 Hz), 127.81, 122.00 (q, J=274.8 Hz), 121.86 (q, J=286.7 Hz), 97.78 (q, J=36.0 Hz), 79.20, 51.49; 19F-NMR (368 MHz, CDCl3) δ: −60.96 (s, 3F), −77.67 (s, 3F); IR (KBr, cm−1) ν: 3584, 3388, 2918, 2847, 1755, 1604, 1325, 1173, 989, 760, 641; LR-MS (ESI): m/z 428 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H13F6NO3Na [M+Na]+ 428.0692. Found 428.0701.
According to the procedure B, the benzyl ether 18 (38.0 mg, 0.0938 mmol) was converted into 20 (29.4 mg, 99%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.76–7.92 (m, 3H), 3.17 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 162.91, 137.07, 133.36, 129.11, 127.78 (q, J=36.0 Hz), 127.61, 127.56, 121.89 (q, J=273.5 Hz), 121.55 (q, J=286.7 Hz), 90.60 (q, J=33.6 Hz), 51.65; 19F-NMR (368 MHz, CDCl3) δ: −60.86 (s, 3F), −78.04 (s, 3F); IR (KBr, cm−1) ν: 3426, 3178, 2954, 1734, 1610, 1509, 1329, 1195, 1135, 1016, 983, 878, 812, 704; LR-MS (ESI): m/z 338 [M+Na]+; HR-MS (ESI): m/z Calcd for C11H7F6NO3Na [M+Na]+ 338.0222. Found 338.0226.
According to the procedure A in which 2,2,2-trifluoroenthanol was used as the alcohol instead, the chloride 15 (0.935 g, 2.00 mmol) was converted into ether 17 (1.04 g, 98%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.27 (dd, J=7.6, 0.9 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.64 (dd, J=7.6, 7.6 Hz, 1H), 7.63 (dd, J=7.6, 1.8 Hz, 2H), 7.37–7.48 (m, 3H), 5.26–5.33 (m, 2H), 4.00–4.11 (m, 1H), 3.82–3.94 (m, 1H); 13C-NMR (100 MHz, acetone-d6) δ: 164.82, 145.00, 136.40, 136.08, 135.67, 131.28, 130.14, 129.77, 129.34, 125.76 (q, J=1.9 Hz), 124.36 (q, J=276.3 Hz), 122.50 (q, J=286.6 Hz), 90.86, 90.59 (q, J=32.9 Hz), 80.23, 62.20 (q, J=35.7 Hz); 19F-NMR (368 MHz, acetone-d6) δ: −74.61 (s, 3F), −77.85 (s, 3F); IR (KBr, cm−1) ν: 3482, 3034, 2941, 2873, 1754, 1584, 1463, 1283, 1190, 1002, 953, 874, 798, 727; LR-MS (ESI): m/z 554 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H12F6INO3Na [M+Na]+ 553.9658. Found 553.9634.
According to the procedure described for the preparation of the trifluoromehyl compound 18 from iodide 16, the iodide 17 (444 mg, 0.837 mmol) was converted into trifluoromethyl compound 19 (346 mg, 87%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.98 (d, J=4.5 Hz, 1H), 7.86 (d, J=4.5 Hz, 1H), 7.52 (d, J=5.4 Hz, 2H), 7.37–7.41 (m, 3H), 5.32 (d, J=9.9 Hz, 1H), 5.16 (d, J=9.9 Hz, 1H), 3.40–3.52 (m, 1H), 3.13–3.24 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 162.45, 136.03, 134.25, 134.15, 129.98 (q, J=6.0 Hz), 129.56 (2C), 129.23 (2C), 128.65 (2C), 128.3 (q, J=34.8 Hz), 128.04, 122.59 (q, J=277.1 Hz), 121.85 (q, J=274.7 Hz), 121.38 (q, J=286.7 Hz), 90.18 (q, J=34.8 Hz), 79.40, 61.51 (q, J=36.0 Hz); 19F-NMR (368 MHz, CDCl3) δ: −61.05 (s, 3F), −74.06 (s, 3F), −77.24 (s, 3F); IR (KBr, cm−1) ν: 3512, 3439, 3043, 2967, 2898, 1770, 1611, 1330, 1182, 980, 873, 820, 693; LR-MS (ESI): m/z 496 [M+Na]+; HR-MS (ESI): m/z Calcd for C19H12F9NO3Na [M+Na]+ 496.0566. Found 496.0546.
According to the procedure B, the benzyl ether 19 (300 mg, 0.634 mmol) was converted into 21 (233 mg, 95%). White powder; 1H-NMR (500 MHz, CDCl3) δ: 7.94 (d, J=8.0 Hz, 1H), 7.83–7.91 (m, 2H), 4.01–4.12 (m, 1H), 3.31–3.38 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 163.18, 136.15, 134.12, 129.82 (q, J=6.0 Hz), 128.07 (q, J=36.0 Hz), 127.96, 127.15, 122.71 (q, J=277.1 Hz), 121.73 (q, J=273.5 Hz), 121.10 (q, J=286.7 Hz), 90.13 (q, J=33.6 Hz), 61.86 (q, J=37.2 Hz); 19F-NMR (368 MHz, CDCl3) δ: −61.14 (s, 3F), −74.33 (s, 3F), −77.55 (s, 3F); IR (KBr, cm−1) ν: 3419, 3207, 2968, 1724, 1332, 1296, 1178, 984, 885, 811, 689; LR-MS (ESI): m/z 406 [M+Na]+; HR-MS (ESI): m/z Calcd for C12H6F9NO3Na [M+Na]+ 406.0096. Found 406.0103.
To a solution of alcohol 14b (1.00 g, 2.23 mmol) in CH2Cl2 (22 mL), MsCl (259 µL, 3.35 mmol) and Et3N (495 µL, 3.57 mmol) were added dropwise at 0°C, and the mixture was stirred for 1 h at 0°C, then for 24 h at rt. To the mixture, MsCl (173 µL, 2.23 mmol) and Et3N (340 µL, 2.45 mmol) were added at rt and stirred for 3 h at the same temperature. To the mixture, LiCl (189 mg, 4.46 mmol) was added, and stirred for 12 h at rt. To the mixture, MeOH (5.0 mL) was added, stirred for 12 h at rt, then H2O was added. The phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with H2O, and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=19 : 1→9 : 1) to afford chloride 40a (630 mg, 59%) and ether 40b (335 mg, 32%). Chloride 40a: White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.44 (dd, J=8.1, 1.4 Hz, 1H), 7.99 (dd, J=8.1, 0.9 Hz, 1H), 7.53–7.63 (m, 3H), 7.40–7.48 (m, 3H), 5.42 (d, J=9.4 Hz, 1H), 5.35 (d, J=9.4 Hz, 1H); 13C-NMR (100 MHz, acetone-d6) δ: 162.90, 146.79, 139.73, 136.00, 133.77, 132.92, 130.10 (2C), 129.49, 129.12 (2C), 124.14, 123.93 (q, J=290.1 Hz), 90.14 (q, J=32.9 Hz), 90.10, 80.84; 19F-NMR (368 MHz, CDCl3) δ: −72.02 (s, 3F); IR (KBr, cm−1) ν: 3462, 3065, 2930, 2878, 1752, 1454, 1173, 1000, 915, 720; LR-MS (ESI): m/z 490 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H10ClF3INO2Na [M+Na]+ 489.9289. Found 489.9283. Ether 40b: Colorless oil; 1H-NMR (400 MHz, CDCl3) δ: 8.12 (dd, J=7.6, 0.9 Hz, 1H), 7.88 (dd, J=7.6, 0.9 Hz, 1H), 7.53 (dd, J=7.2, 1.3 Hz, 2H), 7.32–7.42 (m, 2H), 7.30 (dd, J=7.6, 7.6 Hz, 1H), 5.25 (d, J=10.3 Hz, 1H), 5.19 (d, J=10.3 Hz, 1H), 3.15 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 164.17, 145.94, 136.28, 134.73, 133.15, 132.84, 129.19 (2C), 128.87, 128.46 (2C), 124.12, 122.12 (q, J=289.4 Hz), 93.80 (q, J=32.9 Hz), 89.95, 78.97, 51.54; 19F-NMR (368 MHz, CDCl3) δ: −73.41 (s, 3F); IR (neat, cm−1) ν: 3433, 1748, 1640, 1457, 1186, 1122, 1000, 733; LR-MS (ESI): m/z 486 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3INO3Na [M+Na]+ 485.9784. Found 485.9791.
The mixture of iodide 40b (330 mg, 0.712 mmol), trimethylboroxine (0.299 mL, 2.14 mmol), Pd(OAc)2 (16.0 mg, 0.0712 mmol), PPh3 (37.3 mg, 0.142 mmol), and K2CO3 (197 mg, 1.42 mmol) in dioxane (7.1 mL) and H2O (0.71 mL) was heated to reflux for 18 h. The mixture was diluted with H2O and extracted with EtOAc twice. The combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=19 : 1→9 : 1) to afford compound 41 (217 mg, 87%). Colorless oil; 1H-NMR (400 MHz, CDCl3) δ: 7.72 (d, J=7.2 Hz, 1H), 7.30–7.56 (m, 7H), 5.26 (d, J=10.3 Hz, 1H), 5.18 (d, J=10.3 Hz, 1H), 3.05 (s, 3H), 2.46 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 165.83, 136.41, 136.30, 134.95, 131.56, 131.52, 130.86, 129.26, 128.79, 128.44, 122.55 (q, J=287.9 Hz), 121.97, 93.59 (q, J=32.4 Hz), 78.92, 51.05, 17.80 (q, J=3.6 Hz); 19F-NMR (368 MHz, CDCl3) δ: −75.41 (s, 3F); IR (neat, cm−1) ν: 3426, 2916, 1746, 1637, 1282, 1193, 1114, 1020, 735; LR-MS (ESI): m/z 374 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H16F3NO3Na [M+Na]+ 374.0974. Found 374.0978.
To a solution of 4-iodo-NHPI (22) (5.03 g, 17.4 mmol) in DMF (35 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.60 mL, 19.1 mmol) and PMBCl (2.80 mL, 19.1 mmol) were added at 0°C and the mixture was stirred for 2 h at the same temperature. H2O was added to the mixture and the resulted suspension was filtered. The collected precipitate was triturated with iPr2O to afford ether 23 (6.88 g, 97%). Brown powder; 1H-NMR (500 MHz, acetone-d6) δ: 8.24 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.58 (dd, J=7.5, 7.5 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 5.15 (s, 2H), 3.80 (s, 3H); 13C-NMR (125 MHz, acetone-d6) δ: 163.02, 162.14, 161.40, 146.40, 136.18, 132.37 (2C), 132.15, 130.83, 127.23, 123.76, 114.62 (2C), 88.94, 80.05, 55.54; IR (KBr, cm−1) ν: 3444, 3078, 2961, 2933, 2837, 1789, 1739, 1611, 1515, 1390, 1252, 1144, 982, 876, 814, 717; LR-MS (ESI): m/z 432 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H12INO4Na [N+Na]+ 431.9703. Found 431.9722.
According to the procedure described for the preparation of the alcohol 14a and b from phthalimide 13, the phthalimide 23 (6.60 g, 16.1 mmol) was converted into alcohol 24a (1.77 g, 23%) and 24b (1.74 g, 23%). Alcohol 24a: White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.15 (dd, J=8.1, 0.9 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.54 (dd, J=8.1, 8.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 5.24 (d, J=9.0 Hz, 1H), 5.12 (d, J=9.0 Hz, 1H), 3.81 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 163.87, 161.15, 143.81, 141.61, 135.49, 132.03 (2C), 130.30, 127.88, 124.94, 123.57 (q, J=286.6 Hz), 114.53 (2C), 89.64, 86.25 (q, J=32.9 Hz), 80.22, 55.53; 19F-NMR (368 MHz, CDCl3) δ: −79.34 (s, 3F); IR (KBr, cm−1) ν: 3420, 3186, 2956, 2836, 1717, 1697, 1613, 1517, 1254, 1194, 1092, 976, 827, 708; LR-MS (ESI): m/z 502 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3INO4Na [M+Na]+ 501.9734. Found 501.9740. Alcohol 24b: White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.24 (dd, J=8.1, 0.9 Hz, 1H), 7.84 (dd, J=7.6, 1.4 Hz, 1H), 7.41–7.88 (m 3H), 6.95 (d, J=9.0 Hz, 2H), 5.21 (d, J=9.9 Hz, 1H), 5.13 (d, J=9.9 Hz, 1H), 3.81 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 162.87, 161.05, 146.72, 139.74, 133.74, 133.00, 131.93 (2C), 127.96, 124.11, 123.92 (q, J=290.4 Hz), 114.46 (2C), 90.09, 90.07 (q, J=32.9 Hz), 80.56, 55.48; 19F-NMR (368 MHz, acetone-d6) δ: −75.38 (s, 3F); IR (KBr, cm−1) ν: 3181, 2960, 2836, 1702, 1612, 1516, 1254, 1196, 1131, 983, 833, 756; LR-MS (ESI): m/z 502 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3INO4Na [M+Na]+ 501.9734. Found 501.9732.
According to the procedure described for the preparation of the chloride 15 from alcohol 14a, the alcohol 24a (1.72 g, 3.59 mmol) was converted into chloride 25 (1.55 g, 87%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.27 (dd, J=8.1, 0.9 Hz, 1H), 7.92 (d, J=7.6 Hz), 7.66 (dd, J=7.6, 7.6 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 5.34 (d, J=9.0 Hz, 1H), 5.19 (d, J=9.0 Hz, 1H), 3.83 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 163.78, 161.36, 144.58, 140.68, 136.38, 132.28, 128.40, 127.03, 125.11 (q, J=1.9 Hz), 122.45 (q, J=283.8 Hz), 114.65, 90.79, 80.18, 78.85 (q, J=35.7 Hz), 55.54; 19F-NMR (368 MHz, acetone-d6) δ: −76.31 (s, 3F); IR (KBr, cm−1) ν: 3422, 2959, 2834, 1742, 1515, 1459, 1249, 974, 706; LR-MS (ESI): m/z 520 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H12ClF3INO3Na [M+Na]+ 520.9395. Found 519.9382.
According to the procedure described for the preparation of the phenylketone 8 from chloride 2, the chloride 25 (498 mg, 1.00 mmol) was converted into acetophenone 26 (464 mg, 80%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.09 (d, J=7.6 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.76 (d, J=7.6 Hz, 1H), 7.56 (dd, J=7.6, 7.6 Hz, 1H), 7.34–7.46 (m, 5H), 6.86 (d, J=8.5 Hz, 2H), 5.27 (d, J=9.4 Hz, 1H), 5.03 (d, J=9.4 Hz, 1H), 4.24 (s, 1H), 4.23 (s, 1H), 3.73 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 193.71, 167.72, 161.04, 142.37, 142.15, 137.05, 134.86, 134.33, 134.95, 131.95 (2C), 129.39 (2C), 128.73 (2C), 127.99 (q, J=217.1 Hz), 127.80, 123.77, 114.51 (2C), 90.18, 79.49, 66.83 (q, J=29.1 Hz), 55.44, 35.03; 19F-NMR (368 MHz, acetone-d6) δ: −76.93 (s, 3F); IR (KBr, cm−1) ν: 3436, 3066, 2998, 2955, 2836, 1730, 1695, 1611, 1517, 1259, 1195, 1156, 1002, 822, 688; LR-MS (ESI): m/z 604 [M+Na]+; HR-MS (ESI): m/z Calcd for C25H19F3INO4Na [M+Na]+ 604.0203. Found 604.0228.
According to the procedure described for the preparation of the trifluoromethylated compound 18 from iodide 16, the iodide 26 (440 mg, 0.757 mmol) was converted into trifluoromethylated compound 27 (141 mg, 36%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 8.05 (d, J=7.2 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.86–7.95 (m, 3H), 7.57 (dd, J=7.4, 7.4 Hz, 1H), 7.38–7.61 (m, 4H), 6.86 (d, J=8.5 Hz, 2H), 5.27 (d, J=9.4 Hz, 1H), 5.04 (d, J=9.4 Hz, 1H), 3.74 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 193.78, 165.85, 161.08, 141.87, 136.95, 134.40, 134.20, 131.98 (2C), 129.40 (2C), 129.25, 128.74 (2C), 128.32 (q, J=5.6 Hz), 127.88, 127.66, 127.27, 125.51 (q, J=284.7 Hz), 123.11 (q, J=272.5 Hz), 114.53 (2C), 79.52, 67.85 (q, J=29.1 Hz), 55.43, 34.97; 19F-NMR (368 MHz, acetone-d6) δ: −60.90 (s, 3F), −76.96 (s, 3F); IR (KBr, cm−1) ν: 3442, 2957, 1742, 1693, 1612, 1518, 1323, 1255, 1193, 1140, 1006, 812, 867; LR-MS (ESI): m/z 546 [M+Na]+; HR-MS (ESI): m/z Calcd for C26H19F6NO4Na [M+Na]+ 546.1110. Found 546.1097.
To a solution of PMBether 27 (52.3 mg, 0.100 mmol) and pentamethyl benzene (44.4 mg, 0.300 mmol) in CH2Cl2 (2.0 mL), TFA (1.0 mL) was added at 0°C, and the mixture was stirred for 0.5 h at 0°C, then for 2 h at rt. The mixture was neutralized with sat. NaHCO3 aq. at 0°C, then the phases were separated. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=4 : 1→2 : 1) to afford 28 (36.8 mg, 91%). Pale yellow powder; 1H-NMR (400 MHz, acetone-d6) δ: 7.81–8.09 (m, 5H), 7.39–7.66 (m, 3H), 4.20–4.39 (m, 2H); 13C-NMR (100 MHz, acetone-d6) δ: 193.90, 164.41, 141.69, 137.19, 134.40, 133.50, 129.94, 129.48 (2C), 128.79 (2C), 128.06 (q, J=5.6 Hz), 127.73, 127.43, 125.44 (q, J=284.7 Hz), 123.74 (q, J=273.4 Hz), 67.93 (q, J=28.2 Hz), 34.68; 19F-NMR (368 MHz, acetone-d6) δ: −60.74 (3F), −77.48 (3F); IR (KBr, cm−1) ν: 3422, 3187, 2926, 1720, 1691, 1598, 1327, 1279, 1172, 814, 688; LR-MS (ESI): m/z 426 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H11F6NO3Na [M+Na]+ 426.0535. Found 426.0531.
To a solution of phthalimide 29 (1.51 g, 6.42 mmol), 4-methoxylbenzylalcohol (1.06 g, 7.70 mmol) and PPh3 (2.02 g, 7.70 mmol) in tetrahydrofuran (THF) (13 mL), diisopropyl azodicarboxylate in toluene (4.05 mL, 7.70 mmol) was added at 0°C, and the reaction mixture was stirred for 1 h at 0°C and for 12 h at rt. The reaction mixture was evaporated under reduced pressure. The residue was triturated with EtOAc to afford benzylether 30 (1.40 g, 61%). Pale yellow powder; 1H-NMR (400 MHz, acetone-d6) δ: 7.47 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 5.13 (s, 2H), 3.81 (s, 3H); 13C-NMR (125 MHz, DMSO-d6) δ: 160.04, 158.19 (2C), 143.09–145.45 (m, 2C), 141.49–143.79 (m, 2C), 131.63 (2C), 125.80, 113.92 (2C), 111.11 (d, J=8.4 Hz, 2C), 79.33, 55.19; 19F-NMR (368 MHz, acetone-d6) δ: −139.54 (s, 2F), −146.37 (s, 2F); IR (KBr, cm−1) ν: 3513, 3039, 2984, 2850, 1736, 1610, 1499, 1406, 1254, 1154, 942, 860, 733; LR-MS (ESI): m/z 378 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H9F4NO4Na [M+Na]+ 378.0360. Found 378.0345.
According to the procedure described for the preparation of alcohol 14a and b from phthalimide 13, the phthalimide 30 (1.29 g, 3.63 mmol) was converted into alcohol 31 (1.43 g, 93%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 7.46 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 5.22 (d, J=9.4 Hz, 1H), 5.12 (d, J=9.4 Hz, 1H), 3.81 (s, 3H); 13C-NMR (125 MHz, acetone-d6) δ: 161.32, 159.48, 145.46 (ddd, J=259.1, 15.6, 15.6 Hz), 144.65 (dd, J=260.3, 12.0 Hz), 144.62 (dd, J=260.3, 12.0 Hz), 143.97 (ddd, J=257.9, 13.2, 13.2 Hz), 132.17 (2C), 127.47, 123.13 (q, J=286.7 Hz), 120.29 (d, J=13.2 Hz), 114.60 (2C), 113.67 (d, J=12.0 Hz), 87.65 (q, J=34.8 Hz), 80.75, 55.54; 19F-NMR (368 MHz, acetone-d6) δ: −79.03 (s, 3F), −139.73 (s, 1F), −142.66 (s, 1F), −148.13 (s, 1F), −150.75 (s, 1F); IR (KBr, cm−1) ν: 3255, 3010, 2970, 2943, 2843, 1560, 1613, 1519, 1254, 1181, 978, 904, 823, 730; LR-MS (ESI): m/z 448 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H10F7NO4Na [M+Na]+ 448.0390. Found 448.0368.
To a solution of Ms2O (110 mg, 0.635 mmol) in CH2Cl2 (1.0 mL), a solution of alcohol 31 (180 mg, 0.423 mmol) and Et3N (94 µL, 0.677 mmol) in CH2Cl2 (1.0 mL) was added at −78°C, and the mixture was stirred for 0.5 h at the same temperature. To the mixture, MeOH (2.0 mL) was added, and the mixture was stirred for 0.5 h at −78°C, then for 18 h at rt. H2O was added to the mixture and the whole was extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=9 : 1) to afford ether 32 (100 mg, 54%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.43 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 5.18 (d, J=9.9 Hz, 1H), 5.05 (d, J=9.9 Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 160.35, 159.91, 144.58 (dddd, J=264.0, 14.1, 14.1, 1.9 Hz), 144.13 (ddd, J=266.9, 12.2, 1.9 Hz), 141.82–144.94 (m, 2C), 131.28 (2C), 126.18, 121.29 (q, J=286.6 Hz), 115.81 (dd, J=13.2, 2.8 Hz), 113.89 (2C), 113.48 (q, J=12.2, 2.8 Hz), 91.40 (q, J=35.7 Hz), 79.21, 55.26, 52.16; 19F-NMR (368 MHz, CDCl3) δ: −77.21 (3F), −136.30 (1F), −137.66 (1F), −143.80 (1F), 146.03 (1F); IR (KBr, cm−1) ν: 3503, 2959, 2846, 1766, 1613, 1505, 1391, 1206, 1029, 914, 733; LR-MS (ESI): m/z 462 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H12F7NO4Na [M+Na]+ 462.0547. Found 462.0558.
According to the procedure described for the preparation of N-oxyl 28 from PMBether 27, PMBether 32 (30.0 mg, 0.0591 mmol) was converted into 34 (1.3 mg, 6%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 3.31 (s, 3H); 13C-NMR (100 MHz, acetone-d6) δ: 159.39, 142.83–146.66 (m, 4C), 122.64 (q, J=287.5 Hz), 116.57 (d, J=11.3 Hz), 114.91 (d, J=10.3 Hz), 91.71 (q, J=32.0 Hz), 52.52; 19F-NMR (368 MHz, acetone-d6) δ: −78.04 (s, 3F), −139.84 (s, 1F), −142.44 (s, 1F), −148.50 (s, 1F), −150.57 (s, 1F); IR (KBr, cm−1) ν: 3434, 2935, 1735, 1508, 1198, 1109, 918, 803, 731; LR-MS (ESI): m/z 318 [M−H]−; HR-MS (ESI): m/z Calcd for C10H3F7NO3 [M−H]− 318.0007. Found 318.0021.
According to the procedure described for the preparation of ether 32 from alcohol 31 in which 2,2,2-trifluoroenthanol was used as the alcohol instead, alcohol 31 (1.00 g, 2.35 mmol) was converted into ether 33 (0.593 g, 50%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 7.47 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 5.20 (s, 2H), 4.17–4.30 (m, 1H), 4.05–4.17 (m, 1H), 3.82 (s, 3H); 13C-NMR (100 MHz, DMSO-d6) δ: 160.04, 159.39, 141.90–146.29 (m, 4C), 131.16 (2C), 128.59 (d, J=195.4 Hz), 125.93, 123.38 (q, J=279.2 Hz), 120.93 (q, J=286.6 Hz), 114.04 (2C), 113.20 (ddd, J=78.0, 12.2, 2.8 Hz), 90.24 (q, J=34.8 Hz), 79.36, 61.87 (q, J=35.7 Hz), 55.18; 19F-NMR (368 MHz, acetone-d6) δ: −74.48 (s, 3F), −77.29 (s, 3F), −137.71 (s, 1F), −140.71 (s, 1F), −145.83 (s, 1F), −149.04 (s, 1F); IR (KBr, cm−1) ν: 3435, 2967, 2851, 1750, 1615, 1516, 1290, 1175, 1032, 997, 917, 731; LR-MS (ESI): m/z 530 [M+Na]+; HR-MS (ESI): m/z Calcd for C19H11F10NO4Na [M+Na]+ 530.0421. Found 530.0434.
According to the procedure with that described for the preparation of 28 from PMBether 27, PMBether 33 (53.0 mg, 0.104 mmol) was converted into 35 (26.8 mg, 67%). White powder; 1H-NMR (400 MHz, acetone-d6) δ: 4.17–4.29 (m, 1H), 4.00–4.11 (m, 1H); 13C-NMR (100 MHz, acetone-d6) δ: 159.46, 145.78 (ddd, J=259.3, 13.9, 13.9 Hz), 143.23–146.48 (m, 3C), 124.29 (q, J=275.3 Hz), 122.29 (q, J=284.8 Hz), 115.64 (d, J=11.2 Hz), 114.82 (q, J=12.2 Hz), 91.09 (q, J=34.8 Hz), 62.76 (q, J=36.6 Hz); 19F-NMR (368 MHz, acetone-d6) δ: −74.77 (s, 3F), −77.64 (s, 3F), −138.55 (s, 1F), −141.89 (s, 1F), −147.54 (s, 1F), −149.86 (s, 1F); IR (KBr, cm−1) ν: 3425, 3126, 2926, 1722, 1519, 1502, 1410, 1297, 1173, 927, 807, 733; LR-MS (ESI): m/z 386 [M−H]−; HR-MS (ESI): m/z Calcd for C11H2F10NO3 [M−H]– 385.9880. Found 385.9882.
Preparation of Substrates for Aerobic Benzylic C–H OxidationFull spectroscopic data were described for new compounds. Compound 36a,35) b,36) g,37) h,38) j,39) and k40) were prepared following the reported procedures.
General Procedure for Benzoate from Alcohol (Procedure C)
To a solution of 3-(4-methoxyphenyl)-1-propanol 42c (1.66 g, 10.0 mmol) in CH2Cl2 (20 mL), BzCl (1.39 mL, 12.0 mol) and pyridine (1.93 mL, 24.0 mmmol) were added at 0°C. The reaction mixture was stirred for 1 h at the same temperature, and for 2 h at rt. The mixture was cooled to 0°C, and sat. NaHCO3 aq. was added. The phases were separated. The organic layer was washed with H2O, 1 N HCl aq., H2O, and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=19 : 1→9 : 1) to afford benzoate 36c (1.69 g, 63%). Colorless oil ; 1H-NMR (500 MHz, CDCl3) δ: 8.02 (d, J=7.5 Hz, 2H), 7.55 (dd, J=7.5, 7.5 Hz, 1H), 7.43 (dd, J=7.5, 7.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 4.31 (t, J=7.5 Hz, 2H), 3.77 (s, 3H), 2.72 (t, J=7.5 Hz, 2H), 2.05 (tt, J=7.5, 7.5 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 166.36, 157.74, 132.99, 132.69, 130.21, 129.36 (2C), 129.15 (2C), 128.16 (2C), 113.69 (2C), 64.06, 54.99, 31.18, 30.32; IR (neat, cm−1) ν: 3434, 1716, 1637, 1513, 1274, 1116, 711; LR-MS (ESI): m/z 293 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H18O3Na [M+Na]+ 293.1148. Found 293.1147.
According to the procedure C, 3-(4-fluorophenyl)-1-propanol 42d (1.34 g, 8.89 mmol) was converted into benzoate 36d (1.97 g, 86%). Colorless oil; 1H-NMR (500 MHz, CDCl3) δ: 8.01 (dd, J=7.5. 1.2 Hz, 2H), 7.55 (dd, J=7.5, 7.5 Hz, 1H), 7.43 (dd, J=7.5, 7.5 Hz, 2H), 7.15 (dd, J=8.6, 5.3 Hz, 2H), 6.96 (dd, J=10.9, 10.9 Hz, 2H), 4.32 (t, J=6.9 Hz, 2H), 2.75 (t, J=8.1 Hz, 2H), 2.06 (tt, J=7.5, 6.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 166.33, 161.19 (d, J=243.4 Hz), 136.63 (d, J=14.3 Hz), 132.76, 129.86 (d, J=55.4 Hz), 129.51 (d, J=28.2 Hz), 128.20, 115.12, 114.91, 63.90, 31.31, 30.21; 19F-NMR (368 MHz, CDCl3) δ: −117.79 (s, 1F); IR (neat, cm−1) ν: 3421, 1717, 1644, 1509, 1274, 1221, 1116, 711; LR-MS (ESI): m/z 281 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H15FO2Na [M+Na]+ 281.0948. Found 281.0960.
According to the procedure C, 3-(4-trifluoromethylphenyl)-1-propanol 42e (1.59 g, 7.79 mmol) was converted into benzoate 36e (1.99 g, 83%). Colorless oil; 1H-NMR (500 MHz, CDCl3) δ: 7.98 (d, J=8.1 Hz, 2H), 7.51–7.58 (m, 3H), 7.43 (dd, J=7.5, 7.5 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.33 (t, J=6.3 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.11 (tt, J=6.9, 6.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 166.28, 145.26, 132.78, 130.04, 129.32 (2C), 128.58 (2C), 128.18, 128.17 (q, J=32.0 Hz, 2C), 125.17 (q, J=3.8 Hz, 2C), 124.21 (q, J=271.6 Hz), 63.83, 32.05, 29.75; 19F-NMR (368 MHz, CDCl3) δ: −62.69 (s, 3F); IR (neat, cm−1) ν: 3431, 1643, 1327, 1274, 1118, 1067, 708; LR-MS (ESI): m/z 331 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H15F3O2Na [M+Na]+ 331.0916. Found 331.0908.
Aerobic Benzylic C–H Oxidation, Etherification, and AcetamidationFull spectroscopic data were described for new compounds. Compound 37b,41) f,42) g,43) h,44) i,45) j,46) l,47) m,48) and n49) are known compounds.
General Procedure for the Oxidation of Benzylic C–H (Procedure D)
To a solution of benzoate 36a (72.1 mg, 0.300 mmol) in 35 (5.8 mg, 0.015 mmol), TFE (0.15 mL), Co(OAc)2 (0.53 mg, 0.00300 mmol) and Mn(OAc)3·H2O (0.80 mg, 0.00300 mmol) were added. The reaction mixture was stirred for 48 h at 60°C under O2 atmosphere. The mixture was evaporated under reduced pressure, and the residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=9 : 1) to afford ketone 37a (59.8 mg, 75%). White powder; 1H-NMR (500 MHz, CDCl3) δ: 8.08 (d, J=8.6 Hz, 2H), 7.98 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.6 Hz, 2H), 7.58 (dd, J=7.4, 7.4 Hz, 1H), 7.48 (dd, J=8.0 Hz, 2H), 4.80 (t, J=6.3 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ: 196.80, 165.31, 136.49, 134.47 (q, J=32.4 Hz, 2C), 133.55, 133.20, 130.01 (2C), 128.76, 128.10 (2C), 125.37 (q, J=4.8 Hz, 2C), 123.58 (q, J=273.5 Hz), 60.77, 37.33; 19F-NMR (368 MHz, CDCl3) δ: −63.46 (s, 3F); IR (KBr, cm−1) ν: 3431, 3072, 2979, 1719, 1683, 1324, 1269, 1169, 1100, 1064, 958, 866, 741; LR-MS (ESI): m/z 345 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3O3Na [M+Na]+ 345.0709. Found 345.0707.
According to the procedure D, benzoate 36c (81.1 mg, 0.300 mmol) was converted into ketone 37c (36.0 mg, 42%). Colorless oil; 1H-NMR (500 MHz, CDCl3) δ: 7.93–7.99 (m, 4H), 7.52 (dd, J=7.5, 7.5 Hz, 1H), 7.39 (dd, J=7.4, 7.4 Hz, 2H), 6.93 (d, J=9.2 Hz, 2H), 4.74 (t, J=6.3 Hz, 2H), 3.85 (s, 3H), 3.38 (t, J=6.3 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 195.60, 166.55, 163.71, 132.94 (2C), 130.41, 130.02, 129.74, 129.58 (2C), 128.29 (2C), 113.81 (2C), 60.51, 55.47, 37.16; IR (neat, cm−1) ν: 3433, 1637, 1508, 1458, 1275, 1174, 1110, 669; LR-MS (ESI): m/z 307 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H16O4Na [M+Na]+ 307.0941. Found 307.0929.
According to the procedure D, benzoate 36d (92.5 mg, 0.300 mmol) was converted into ketone 37d (42.6 mg, 44%). White powder; 1H-NMR (500 MHz, CDCl3) δ: 8.08 (d, J=8.0 Hz, 2H), 7.96 (d, J=6.9 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.53 (dd, J=7.5 Hz, 1H), 7.39 (dd, J=7.5, 7.5 Hz, 2H), 4.77 (t, J=6.3 Hz, 2H), 3.47 (t, J=6.3 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ: 196.16, 166.49, 139.16, 134.71 (q, J=32.4 Hz, 2C), 133.11, 129.82, 129.58, 128.46 (2C), 128.36 (2C), 125.81 (q, J=3.6 Hz, 2C), 123.49 (q, J=272.3 Hz), 59.96, 37.85; 19F-NMR (368 MHz, CDCl3) δ: −63.49 (s, 3F); IR (neat, cm−1) ν: 3412, 3078, 2957, 1716, 1685, 1414, 1322, 1273, 1123, 1065, 857, 710; LR-MS (ESI): m/z 345 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3O3Na [M+Na]+ 345.0709. Found 345.0705.
According to the procedure D, benzoate 36e (77.5 mg, 0.300 mmol) was converted into ketone 37e (56.7 mg, 69%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.95–8.04 (m, 4H), 7.53 (dd, J=7.2, 7.2 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz, 2H), 7.13 (dd, J=8.5 Hz, 2H), 4.75 (t, J=6.7 Hz, 2H), 3.41 (t, J=6.7 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 195.43, 166.45, 165.87 (d, J=254.7 Hz), 132.99, 130.73 (d, J=9.4 Hz, 2C), 129.89, 129.53 (2C), 128.29 (2C), 115.78 (d, J=21.6 Hz, 2C), 60.17, 37.39; 19F-NMR (368 MHz, CDCl3) δ: −104.88 (s, 1F); IR (neat, cm−1) ν: 3415, 3072, 2955, 1717, 1677, 1598, 1507, 1332, 1274, 1215, 1120, 976, 850, 713; LR-MS (ESI): m/z 295 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H13FO3Na [M+Na]+ 295.0741. Found 295.0731.
According to the procedure D, benzoate 36k (17.1 mg, 0.0894 mmol) was converted into ketone 37k (14.3 mg, 78%). White powder; 1H-NMR (400 MHz, CDCl3) δ: 7.94 (dd, J=9.9, 1.8 Hz, 2H), 7.53 (dd, J=9.0, 9.0 Hz, 1H), 7.44 (dd, J=7.6 Hz, 2H), 3.66 (s, 3H), 3.03 (t, J=7.2 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.05 (tt, J=7.2, 7.2 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 199.39, 173.72, 136.76, 133.07, 128.58 (2C), 128.00 (2C), 51.57, 37.41, 33.09, 19.29; IR (KBr, cm−1) ν: 3433, 1636, 1563, 1507, 1265, 1101, 664; LR-MS (ESI): m/z 228 [M+Na]+; HR-MS (ESI): m/z Calcd for C12H15NO2Na [M+Na]+ 228.0995. Found 228.1002.
To a solution of benzoate 36b (72.1 mg, 0.300 mmol) in 35 (5.8 mg, 0.015 mmol), TFE (3.0 mL), NBS (106.8 mg, 2.0 eq) was added. The reaction mixture was stirred for 20 h at rt. To the mixture, 10% Na2S2O3 aq. was added, and the whole was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with flash column chromatography (SiO2, n-hexane–EtOAc=97 : 3→4 : 1) to afford ether 38 (37.3 mg, 37%). Colorless oil; 1H-NMR (400 MHz, CDCl3) δ: 7.94 (d, J=7.2 Hz, 2H), 7.49 (dd, J=7.6, 7.6 Hz, 1H), 7.22–7.40 (m, 7H), 4.55 (dd, J=8.5, 5.4 Hz, 1H), 4.36–4.45 (m, 1H), 4.24–4.34 (m, 1H), 3.50–3.71 (m, 2H), 2.20–2.31 (m, 1H), 2.01–2.12 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ: 166.41, 139.74, 132.95, 130.17, 129.52 (2C), 128.88 (2C), 128.51, 128.35 (2C), 126.61 (2C), 123.99 (q, J=278.1 Hz), 80.49, 65.88 (q, J=33.8 Hz), 61.45, 37.19; 19F-NMR (368 MHz, CDCl3) δ: −74.33 (s, 3F); IR (neat, cm−1) ν: 3427, 1723, 1634, 1446, 1274, 1117, 1071, 798; LR-MS (ESI): m/z 361 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H17F3O3Na [M+Na]+ 361.1022. Found 361.1019.
To a solution of benzoate 36b (72.1 mg, 0.300 mmol) 35 (5.8 mg, 0.015 mmol) in CH3CN (3.0 mL), NBS (106.8 mg, 2.0 eq) was added. The reaction mixture was stirred for 24 h at rt. To the mixture, 10% Na2S2O3 aq. was added, and the whole was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with preparative TLC (SiO2, n-hexane–EtOAc=4 : 1) to afford ether 39 (38.9 mg, 44%). White powder; 1H-NMR (500 MHz, CDCl3) δ: 7.96 (d, J=8.6 Hz, 2H), 7.54 (dd, J=8.1, 8.1 Hz, 1H), 7.38–7.44 (m, 2H), 7.22–7.35 (m, 5H), 5.97 (br s, 1H), 5.19 (td, J=8.0, 8.0 Hz, 1H), 4.29 (t, J=6.3 Hz, 2H), 2.18–2.36 (m, 2H), 1.96 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.29, 166.45, 141.13, 133.02, 129.53 (2C), 128.88 (2C), 128.37 (2C), 128.25, 127.70, 126.51 (2C), 61.99, 51.05, 34.86, 23.41; IR (KBr, cm−1) ν: 3277, 3075, 1718, 1653, 1558, 1271, 1115, 714; LR-MS (ESI): m/z 320 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H19NO3Na [M+Na]+ 320.1257. Found 320.1254.
The authors declare no conflict of interest.
