Photoredox-Catalyzed Hydrodifluoroalkylation of Alkenes Using

May 5, 2017 - Radical addition reactions to alkenes represented by Kharasch-type reactions(1) and Giese-type reactions(2) provide useful tools for Câ€...
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Photoredox-Catalyzed Hydrodifluoroalkylation of Alkenes Using Difluorohaloalkyl Compounds and a Hantzsch Ester Shuhei Sumino,† Misae Uno,† Takahide Fukuyama,† Ilhyong Ryu,*,†,‡ Makoto Matsuura,§ Akinori Yamamoto,§ and Yosuke Kishikawa§ †

Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan § Daikin Industries, Ltd., 1-1 Nishi-Hitotsuya, Settsu, Osaka 566-8585, Japan ‡

S Supporting Information *

ABSTRACT: Photoredox-catalyzed hydrodifluoroalkylation of alkenes proceeded smoothly in the presence of a Hantzsch ester as a hydrogen source under visible light irradiation. The reaction was also applicable to the hydrodifluoroalkylation of alkynes, and a continuous photo flow reaction was also successful.

R

difluoromethylbenzene was also obtained in 10% yield (Table 1, entry 3). The Pd/light combined system was not effective for the present hydrodifluoroalkylation (Table 1, entry 5).8 In the absence of photoredox catalyst, the reaction proceeded but in low yield (Table 1, entry 6). Other hydrogen sources, such as NaBH3CN and polymethylhydrosiloxane (PMHS, Mn = 1700− 3200), gave inferior results (Table 1, entries 7 and 8). In the absence of Et3N, the selectivity was decreased to 87:13 (Table 1, entries 9 and 10).19 Table 2 lists the results of the Ru-photoredox-catalyzed hydrodifluoroalkylation using difluorohaloalkyl compounds 1a−1d and alkenes and alkynes 2a−2m. The reaction of 1a with acrylonitrile 2b and methyl acrylate 2c gave 3b and 3c as sole products in 78 and 71% yields, respectively (Table 2, entries 2 and 3). The reaction of 1a with 2d also gave hydrodifluoroalkylation product in 60% yield (Table 2, entry 4). On the other hand, a similar reaction with electron-rich alkenes such as vinyl acetate 2e gave 3e in a modest yield (Table 2, entry 5). The reaction of ethyl 2-bromo-2,2difluoroacetate 1b with 2a gave 3f in 60% yield with 96% selectivity (Table 2, entry 6). Similarly, the reaction of 1b with Ph-, Cl-, and OH-substituted alkenes 2f, 2g, and 2h gave the corresponding products 3g, 3h, and 3i (Table 2, entries 7−9). Internal alkenes 2i, 2j, and 2k also participated in the reaction albeit in moderate yields (Table 2, entries 10−12). Perfluoro-1bromohexane 1c and perfluoro-1-iodohexane 1d reacted with 2a to give 3l in 50 and 56% yields, respectively (Table 2, entries 13 and 14). We then examined the hydrodifluoroalkylation of two terminal alkynes 2l and 2m. The reaction of 1a with 1octyne 2l gave 3m in a 33% yield as a 41:59 (E/Z) mixture (Table 2, entry 15). The reaction of 1a with phenylacetylene 2m gave 3n in a 35% yield as a 15:85 (E/Z) mixture (Table 2,

adical addition reactions to alkenes represented by Kharasch-type reactions1 and Giese-type reactions2 provide useful tools for C−C bond formation in organic synthesis. A variety of improved methods are currently available beyond the original stage, and recent notable progress has included the use of photoredox catalysis.3 A Hanztsch ester was recently established as a good hydrogen source,4,5 and we recently reported a Giese-type reaction of alkyl iodides with Hantzsch ester in a Pd/light combined system (eq 1, Scheme 1).6 In light of the increasing importance of fluorine-containing compounds in pharmaceuticals, agrochemicals, and materials, development of a practical method to introduce a fluorinated group into organic molecules is highly desirable,7 and radical reactions offer many opportunities.8 Recent progress includes a system that combines a photoredox catalyst3,9 with wellestablished CF3 reagents such as Umemoto reagent,10 Langlois reagent,11 and Togni reagent12 to name a few.13 Methods for the introduction of a difluoroalkyl unit into organic molecules using a photoredox catalyst have been a recent focus of researchers such as the Qing group,14 the Dolbier Group,15 the Akita Group,16 and so on.17,18 In this paper, we report a photoredox-catalyzed protocol for hydrodifluoroalkylation of alkenes and alkynes using difluorohaloalkyl compounds and Hantzsch ester as a hydrogen source (eq 2, Scheme 1). We examined the reaction of bromodifluoromethylbenzene 1a and 1-octene 2a as a model reaction under a variety of conditions (Table 1). When a DMF solution of 1a, 2a, Ru(bpy)3Cl2·6H2O, and Et3N was irradiated using a white LED lamp (5 W) through a Pyrex tube, 3a was obtained in 21% yield together with 25% yield of brominated product 4a (Table 1, entry 1). When Hantzsch ester was added as a hydrogen source, the reaction gave 3a in a 77% yield with high selectivity (3a/4a = 96:4) (Table 1, entry 2). Among the photoredox catalysts tested, Ru(bpy)3Cl2·6H2O was by far the best for this reaction (Table 1, entries 2−4). In the case of fac-Ir(ppy) 3 , © 2017 American Chemical Society

Received: March 14, 2017 Published: May 5, 2017 5469

DOI: 10.1021/acs.joc.7b00609 J. Org. Chem. 2017, 82, 5469−5474

Note

The Journal of Organic Chemistry Scheme 1. Concept: Hydrodifluoroalkylation of Alkenes by Radical Addition and Reduction Using Hanztsch Ester

Table 1. Optimized Reaction Conditionsa

a b

entry

cat.

H source

solvent

3a yield (%)b

ratio (3a:4a)b

1 2 3 4 5 6 7 8 9c 10d 11c,e 12c 13c

Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O fac-Ir(ppy)3 eosin Y Pd(PPh3)4 none Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O Ru(bpy)3Cl2·6H2O

none Hantzsch ester Hantzsch ester Hantzsch ester Hantzsch ester Hantzsch ester NaBH3CN PMHS Hantzsch ester Hantzsch ester Hantzsch ester Hantzsch ester Hantzsch ester

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF CH2Cl2 MeCN

21 77 53 20 37 32 16 17 67 63 74 60 70

46:56 96:4 93:7 91:9 93:7 92:8 64:36 59:41 95:5 87:13 96:4 90:10 83:17

Reaction conditions: 1a (1 mmol), 2a (5 equiv), catalyst (1 mol %), H-source (1.5 equiv), Et3N (2 equiv), solvent (10 mL), white LED 5 W, 12 h. Determined by GC. cEt3N (1 equiv). dWithout Et3N. eDMF (5 mL).

entry 16). In these reactions, considerable amounts of difluoromethylbenzene were formed, which suggested that the addition reaction is competed by premature quenching of the phenyldifluoromethyl radical. The reaction of 1a and allyl ether 2n gave 3,4-disubstituted tetrahydrofuran 3o in a 59% yield (Table 2, entry 17). It is confirmed that the cis/trans ratio of 3o was nearly the same as that of a related radical cyclization.20 To verify the effect of photoirradiation, we investigated on− off switching of the light in the present system (Figure S1). When the reaction did not proceed during the “OFF” periods but after irradiation was “ON”, the yield increased again. To identify the source of hydrogen in the products, we examined the reaction of 1a with 2a and 2b in the presence of D2O. The reaction did not give D-labeled 3a and 3b (Scheme S1). A plausible reaction mechanism is illustrated in Scheme 2, which is based on the related photoredox-catalyzed radical reaction,3,5,9,21 and the assumption that Hantzsch ester would contribute in both SET and hydrogen transfer processes. First, a SET process from a Hantzsch ester to a photoexcited Ru(II)* would take place to generate Ru(I) and radical cation A. Then, Ru(I) would cause SET to 1 to generate the radical anion,22

which generates a difluoroalkyl radical. Then, radical addition onto 2 takes place, and the resulting radical would abstract hydrogen at the 4-position of radical cation A to give the products 3 and pyridine B. We assume that Et3N would facilitate deprotonation of A to give B. To explore a more photoeffective protocol, we examined a continuous flow reaction (Scheme 3).23,24 When the reaction of 1a with 2c was carried out using a flow photoreactor (MiChS L-1; for details, see SI), a residence time of 20 min sufficed to obtain 82% yield of 3c. In summary, we have demonstrated that radical hydrodifluoroalkylation of alkenes and alkynes can be effectively achieved by using readily available difluorohaloalkyl compounds and a Hantzsch ester under photoredox catalysis of Ru(bpy)3Cl2. A continuous photo flow reaction proceeded with a significantly shortened reaction time.

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EXPERIMENTAL SECTION

General Information. Photoirradiation was carried out with a white LED Lump (Panasonic, LDR5D-W). Thin layer chromatography (TLC) was performed on Merck precoated plates (silica gel 60 F254, Art 5715, 0.25 mm), which were visualized by fluorescence 5470

DOI: 10.1021/acs.joc.7b00609 J. Org. Chem. 2017, 82, 5469−5474

Note

The Journal of Organic Chemistry Table 2. Hydrodifluoroalkylation of Alkenes and Alkynes Using a Photoredox Catalyst and Hanztsch Ester

Reaction conditions: 1 (1 mmol), 2 (5 equiv), Ru(bpy)3Cl2·6H2O (1 mol %), Hantzsch ester (1.5 equiv), Et3N (1 or 2 equiv), DMF (5 or 10 mL), white LED (5 W), 12 h. bDetermined by GC. cCompound 2a (20 mmol). dDetermined by 1H NMR. a

Scheme 2. Proposed Reaction Mechanism

Scheme 3. Continuous Photo Flow Hydrodifluoroalkylation

quenching under UV light or by staining with p-anisaldeyde/AcOH/ H2SO4/EtOH or 12MoO3·H3PO4/EtOH. The products were purified by flash chromatography on silica gel (Kanto Chem. Co. Silica Gel 60N (spherical, neutral, 40−50 mm)) and, if necessary, were further purified by recycling preparative HPLC (Japan Analytical Industry Co. Ltd., LC-918) equipped with GPC columns (JAIGEL-1H + JAIGEL2H columns) using CHCl3 as eluent. 1H NMR spectra were recorded with a JEOL JMN-ECS400 (400 MHz) or JEOL JMN-ECA600 (600 MHz) spectrometer and referenced to the solvent peak at 7.26 ppm. 13 C NMR spectra were recorded with a JEOL JMN-ECS400 (100 MHz) or JEOL JMN-ECA600 (150 MHz) spectrometer and referenced to the solvent peak at 77.00 ppm. 19F NMR spectra were recorded with a JEOL JMN-ECS400 (376 MHz) or JEOL JMN-

ECA600 (551 MHz) spectrometer. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet. Infrared spectra were recorded on a JASCO FT/ IR-4100 spectrometer and are reported as wavenumber (cm−1). Highresolution mass spectra were recorded with a JEOL MS700 spectrometer or Bruker ESI-QTOF (compact-NPC) or Shimadzu LCMS-IT-TOF with JEOL DART as ion source. Cyclic voltammetry was measured with a BAS Electrochemical Analyzer ALS Model 612B. Procedure for the Synthesis of Bromodifluoromethylbenzene 1a.25 A magnetic stirring bar and PhCF3 (146 g, 1.0 mol) were placed into a three-necked round-bottom flask equipped with a condenser and two septa under Ar. Then, BBr3 (25 g, 0.1 mol) was added slowly at room temperature. The reaction mixture became warm, and gaseous BF3 started bubbling out. The color of the mixture turned yellow initially and then amberlike. After 1 h, the effervescence 5471

DOI: 10.1021/acs.joc.7b00609 J. Org. Chem. 2017, 82, 5469−5474

Note

The Journal of Organic Chemistry

400 MHz) δ 7.42−7.47 (m, 5H), 3.66 (s, 3H), 2.45−2.55 (m, 4H); 13 C NMR (CDCl3, 100 MHz) δ 172.5, 136.5 (t, JF−C = 53.0 Hz), 129.9, 128.5, 124.8 (t, JF−C = 12.5 Hz), 122.1 (t, JF−C = 240.6 Hz), 51.8, 34.3 (t, JF−C = 56.8 Hz), 27.5 (t, JF−C = 8.7 Hz); 19F-NMR (CDCl3, 367 MHz) δ −97.0 (s, 2F). Ethyl 4,4-Difluoro-3-methyl-4-phenylbutanoate (3d). Obtained as an inseparable mixture with regioisomer (9:1), 145.4 mg, 60%, colorless oil; Rf = 0.57 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 600 MHz) major product δ 7.40−7.52 (m, 5H), 4.12 (t, J = 7.2 Hz, 2H), 2.84−2.74 (m, 1H), 2.67 (dd, J = 4.2, 15.6 Hz, 1H),2.22 (dd, J = 9.6, 15.6 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H); minor product δ 7.40−7.52 (m, 5H), 4.08 (t, J = 7.2 Hz 2H), 3.07− 2.98 (m, 1H), 1.94−1.86 (m, 1H), 1.76−1.68 (m, 1H), 1.13 (t, J = 7.2 Hz 2H), 0.92 (t, J = 7.2 Hz 2H); 13C NMR (CDCl3, 150 MHz) major product δ 171.9, 135.8 (t, JF−C = 26.6 Hz), 129.7, 128.3, 125.4 (t, JF−C = 5.7 Hz), 123.6 (t, JF−C = 244.2 Hz), 60.5, 38.6 (t, JF−C = 26.6 Hz), 35.2 (t, JF−C = 2.9 Hz), 14.1, 13.6 (t, JF−C = 3.6 Hz); minor product δ 169.6, 135.7 (t, JF−C = 26.6 Hz), 129.9, 128.2, 125.3 (t, JF−C = 15.7 Hz), 120.8 (t, JF−C = 247.1 Hz), 60.8, 56.6 (t, JF−C = 27.3 Hz), 19.6 (t, JF−C = 3.0 Hz), 13.9, 11.7; 19F-NMR (CDCl3, 564 MHz) major product δ −100.4 (d, JF−C = 244.8 Hz, 1F), −106.2 (d, JF−C = 261.1 Hz, 1F); minor product δ −99.1 (s, 1F), −105.3 (s, 1F); IR (neat) 2982, 2942, 1737, 1464, 1452,1375, 1308, 1265, 1182, 1055, 990, 765, 648 cm−1; HRMS (DART) m/z calcd for [M + NH4]+ ([C13H16F2O2 + NH4]+) 260.1457, found 260.1443. 3,3-Difluoro-3-phenylpropyl Acetate (3e). 64.3 mg, 30%, colorless oil; Rf = 0.57 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.40−7.52 (m, 5H), 4.22 (t, J = 6.7 Hz 2H), 2.46−2.59 (m, 2H) δ 1.94 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.7, 136.6 (t, JF−C = 26.0 Hz), 129.9, 128.5, 124.8 (t, JF−C = 6.3 Hz), 121.6 (t, JF−C = 242.8 Hz), 58.4 (t, JF−C = 5.3 Hz), 38.0 (t, JF−C = 5.3 Hz), 20.7; 19F-NMR (CDCl3, 367 MHz) δ −94.72 (s, 2F); IR (neat) 2970, 1746, 1454, 1369, 1238, 765, 699 cm−1; HRMS (ESI) m/z calcd for [M + Na]+ ([C11H12F2O2 + Na]+) 237.0698, found 237.0698. Ethyl 2,2-Difluorodecanoate (3f).28 141.8 mg, 60%, colorless oil; Rf = 0.65 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 4.32 (q, J = 7.2 Hz, 2H), 1.98−2.11 (m, 2H), 1.42−1.49 (m, 2H), 1.20− 1.37 (m, 13H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 164.5 (t, JF−C = 33.2 Hz), 116.4 (t, JF−C = 249.5 Hz), 62.7, 34.5 (t, JF−C = 23.1 Hz), 31.7, 29.2, 29.0, 22.6, 21.4, 21.4, 14.0, 14.0; 19F-NMR (CDCl3, 367 MHz) δ −105.87 (s, 2F). Ethyl 2,2-Difluoro-6-phenylhexanoate (3g).18a 141.0 mg, 55%, colorless oil; Rf = 0.30 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.25−7.29 (m, 2H), 7.15−7.20 (m, 3H), 4.30 (q, J = 7.2 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.00−2.10 (m, 2H), 1.68 (quint, J = 7.8 Hz, 2H), 1.48−1.55 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 164.3 (t, JF−C = 33.2 Hz), 141.8, 128.3, 125.8, 116.3 (t, JF−C = 250.0 Hz), 62.7, 35.5, 34.3 (t, J F−C = 23.1 Hz), 30.8, 21.1,δ 21.0, 14.0; 19F-NMR (CDCl3, 367 MHz) δ −105.7 (t, J = 16.6 Hz, 2F). Ethyl 8-Chloro-2,2-difluorooctanoate (3h).29 133.5 mg, 55%, colorless oil; Rf = 0.20 (hexane/EtOAc = 30:1); 1H NMR (CDCl3, 400 MHz) δ 4.32 (q, J = 7.6 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.06 (m, 2H), 1.77 (m, 2H), 1.46 (m, 6H), 1.35 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 164.2 (t, JF−C = 33.3 Hz), 116.2 (t, J F−C = 250 Hz), 62.7, 44.8, 34.2 (t, J F−C = 23.1 Hz), 32.2, 28.2, 26.4, 21.2, 13.8; 19F-NMR (CDCl3, 367 MHz) δ −105.9 (s, 2F). Ethyl 2,2-Difluoro-12-hydroxydodecanoate (3i).28 115.0 mg, 41%, colorless oil; Rf = 0.16 (hexane/EtOAc = 5:1); 1H NMR (CDCl3, 400 MHz) δ 4.32 (q, J = 7.2 Hz, 2H), 3.64 (t, J = 6.7 Hz, 2H), 1.99−2.09 (t, 2H), 1.20−1.60 (m, 21H); 13C NMR (CDCl3, 100 MHz) δ 164.5 (t, JF−C = 33.3 Hz), 116.4 (t, JF−C = 250 Hz), 63.0, 62.7, 34.4 (t, JF−C = 23.1 Hz), 32.7, 29.5, 29.3, 29.3, 29.2, 29.0, 25.7,δ 21.4 (t, JF−C = 3.8 Hz),δ 14.0; 19F-NMR (CDCl3, 367 MHz) δ −105.82 (t, J = 17.3 Hz, 2F). Ethyl 2-Cyclohexyl-2,2-difluoroacetate (3j).29 84.5 mg, 41%, colorless oil; Rf = 0.30 (hexane/EtOAc = 20:1); 1H NMR (CDCl3, 400 MHz) δ 4.32 (q, J = 7,4 Hz, 2H), 1.98−2.14 (m, 1H), 1.66−1.86 (m, 5H), 1.35 (t, J = 7.1 Hz, 3H), 1.14−1.31 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 164.4 (t, JF−C = 32.8 Hz), 117.3 (t, JF−C = 252

ceased, and the mixture started to cool. The mixture was refluxed for another 2 h followed by stirring at room temperature overnight. Then, the reaction mixture was poured into 100 mL of ice water and extracted with CH2Cl2 (50 mL × 3). The combined organic phase was washed with water (30 mL × 3) and was then dried over Na2SO4. After the reaction mixture was filtered and evaporated, amber-colored liquid was collected as crude product, which was distilled to give 15.6 g of product 1a as a colorless liquid; bp 50 °C, 19.1 Torr, 97% purity. 1H NMR (CDCl3, 400 MHz) δ 7.60−7.63 (m, 2H), 7.43−7.51 (m, 3H); 13 C NMR (CDCl3, 100 MHz) δ 138.1 (t, JF−C = 22.9 Hz), 131.2, 128.6, 124.3 (t, JF−C = 5.7 Hz), 118.4 (t, JF−C = 306.4 Hz); 19F-NMR (CDCl3, 367 MHz) δ −43.35 (s, 2F). Procedure for the Synthesis of Hantzsch Ester.26 A magnetic stirring bar, paraformaldehyde (1.5 g, 50 mmol), NH4OAc (7.7 g, 100 mmol), ethyl acetoacetate (25 mL, 200 mmol), and degassed H2O (100 mL) were placed into a three-necked round-bottom flask equipped with a condenser and two septa under Ar. The solution was refluxed with vigorous stirring for 2 h. The resulting mixture was cooled to room temperature, and then it was quickly filtered, washed with water (3×), and dried in vacuo to give Hantzsch ester (9.8 g, 87%) as a yellow fluffy solid. 1H NMR (CDCl3, 400 MHz) δ 4.17 (q, J = 7.0 Hz, 4H), 3.27 (s, 2H), 2.20 (s, 6H), 1.28 (t, J = 7.3 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 168.0, 144.8, 99.5, 59.6, 30.9, 24.8, 19.2, 14.5. Typical Procedure for the Hydrodifluoroalkylation of Bromodifluoromethylbenzene 1a to Give (1,1-Difluorononyl)benzene 3a (Table 2, Entry 1). A magnetic stirring bar, Ru(bpy)3Cl2·6H2O (7.5 mg, 0.01 mmol), Hantzsch ester (380 mg, 1.5 mmol), bromodifluoromethylbenzene 1a (207 mg, 1.0 mmol), 1octene 2a (0.78 mL, 5.0 mmol), Et3N (202 mg, 2.0 mmol), and DMF (10 mL) were placed in a φ10 mm Pyrex-sealed vial under Ar. The solution was irradiated by an LED lamp (5 W) with stirring for 12 h. After the reaction, the reaction mixture was poured into 40 mL of organic solvent (hexane/EtOAc = 30:1), and washed with H2O (20 mL × 3). The combined organic phase was washed with brine (30 mL) and was then dried over MgSO4. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (hexane) to give 3a as a colorless oil (151.6 mg, 63%). Typical Procedure for the Reaction of Bromodifluoromethylbenzene 1a and Methyl Acrylate 2c Using a Flow Photoreactor (Scheme 3). Photochemical reactions were carried out using a flow photoreactor MiChS L-1, which has a single lane channel (2 mm in width, 1 mm in depth, 3 m in length; 6 mL total volume) covered with quartz. The photoreactor was irradiated by two white LED lamps (Panasonic, LDR5D-W). A DMF solution (0.09 M, 15 mL) containing 1a (1.5 mmol), 2c (5 equiv), Ru(bpy)3Cl2·6H2O (1 mol %), Hantzsch ester (1.5 equiv), and Et3N (2 equiv) were placed in a gastight syringe and pumped into the photoreactor at a rate of 18 mL/h (20 min residence time) (Figure S3). The reaction mixture eluted from the outlet was discarded for the first 25 min, and the subsequent portion was collected for 28 min (8.4 mL). The yield of product 3c was determined by GC analysis to be 82%. Spectrum Data. 1,1-Difluorononylbenzene (3a).27 151.6 mg, 63%, colorless oil; Rf = 0.93 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.44−7.48 (m, 2H), 7.40−7.43 (m, 3H), 2.03− 2.19 (m, 2H), 1.41 (quint, J = 7.8 Hz, 2H), 1.20−1.32 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 137.5 (t, JF−C = 27.0 Hz), 129.5, 128.3, 124.9 (t, JF−C = 6.3 Hz), 123.2 (t, JF−C = 246.8 Hz), 39.09 (t, JF−C = 27.0 Hz), 31.79, 29.29, 29.25, 29.11, 22.61, 22.48 (t, JF−C = 3.9 Hz), 14.08; 19F-NMR (CDCl3, 367 MHz) δ −95.3 (s, 2F). 4,4-Difluoro-4-phenylbutanenitrile (3b).27 139.4 mg, 77%, colorless oil; Rf = 0.16 (hexane/EtOAc = 20:1); 1H NMR (CDCl3, 400 MHz) δ 7.47 (m, 5H), 2.45−2.60 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 135.3 (t, JF−C = 25.5 Hz), 130.4, 128.7, 124.6 (t, JF−C = 6.3 Hz), 121.0 (t, JF−C = 241.5 Hz), 118.1, 35.0 (t, JF−C = 29.0 Hz), 11.1 (t, JF−C = 4.8 Hz); 19F-NMR (CDCl3, 367 MHz) δ −98.15 (s, 2F). Methyl 4,4-Difluoro-4-phenylbutanoate (3c).15b 152.1 mg, 71%, colorless oil; Rf = 0.36 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 5472

DOI: 10.1021/acs.joc.7b00609 J. Org. Chem. 2017, 82, 5469−5474

The Journal of Organic Chemistry

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Hz), 62.50, 42.21 (t, JF−C = 21.6 Hz), 25.77, 25.28, 24.71, 14.00; 19FNMR (CDCl3, 367 MHz) δ −113.64 (d, J = 14.4 Hz). Ethyl 2,2-Difluoro-3-propylheptanoate (3k). 75.6 mg, 32% (from 2j, Table 2, entry 12), 90.5 mg, 40% (from 2k, Table 2, entry 13), colorless oil; Rf = 0.57 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 600 MHz) δ 4.32 (t, J = 6.6 Hz 2H), 2.15−2.01 (m, 1H), 1.57−1.25 (m, 13H), 0.94−0.86 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ 164.7 (t, JF−C = 33.0 Hz), 118.3 (t, JF−C = 251.3 Hz), 62.5, 42.2 (t, JF−C = 21.6 Hz), 29.8, 29.3, 27.3, 22.9, 20.4, 14.2, 14.0, 13.9; 19F-NMR (CDCl3, 564 MHz) δ −109.8 (s, 2F); IR (neat) 2961, 2874, 1770, 1468, 1373, 1308, 1198, 1142, 1051, 858, 733 cm−1; HRMS (DART) m/z calcd for [M + NH4]+ ([C12H22F2O2 + NH4]+) 254.1926, found 254.1914. 1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluorotetradecane (3l).30 216.2 mg, 50% (from 1c, Table 2, entry 13), 242.1 mg, 56% (from 1d, Table 2, entry 14), colorless oil; Rf = 0.93 (hexane); 1H NMR (CDCl3, 400 MHz) δ 1.98−2.10 (m, 2H), 1.60 (quin, J = 7.7 Hz, 2H), 1.19−1.37 (m, 10H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 122.1−105.6 (m, CF2, CF3), 31.85, 31.00 (t, JF−C = 22.2 Hz), 29.21 (t, JF−C = 6.7 Hz), 22.68, 20.15, 14.00; 19F-NMR (CDCl3, 367 MHz) δ −80.70 (s, 3F), −114.32 (s, 2F), −121.88 (s, 2F), −122.80 (s, 2F), −123.50 (s, 2F), −126.07 (s, 2F). (1,1-Difluoronon-2-en-1-yl)benzene (3m).31 Obtained as an inseparable mixture (E/Z = 41:59 determined by GC analysis of crude mixture), 78.6 mg, 33%, colorless oil; Rf = 0.80, 0.73 (hexane/ EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.60−7.30 (m, 5H, E/ Z mixture), 5.95 (m, 0.41H, E isomer), 5.80 (m, 1.58H, E/Z mixture), 2.20 (m, 2H), 1.40−1.20 (m, 8H), 0.90−0.80 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 138.8 (t, JF−C = 6.7 Hz), 138.0 (t, JF−C = 27.9 Hz), 137.3 (t, JF−C = 8.7 Hz), 137.0 (t, JF−C = 27.9 Hz), 129.8, 129.7, 128.4, 128.3, 126.0 (t, JF−C = 29.4 Hz), 125.5 (t, JF−C = 5.8 Hz), 125.4−125.0 (m), 120.0 (t, JF−C = 237 Hz), 119.7 (t, JF−C = 237 Hz), 31.8, 31.6, 31.5, 29.1, 28.8, 28.8, 28.4, 28.3, 22.5, 14.0; 19F-NMR (CDCl3, 458 MHz) δ −84.53 (s, 2F, Z isomer), −90.07 (s, 2F, E isomer). (3,3-Difluoroprop-1-ene-1,3-diyl)dibenzene (3n).32 Obtained as an inseparable mixture (E/Z = 15:85 determined by GC analysis of crude mixture), 80.6 mg, 35%, colorless oil; Rf = 0.40 (hexane/EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.20−7.60 (m, 10H, E/Z mixture), 6.86 (dt, J = 1.8, 12.4 Hz, 0.85H, Z isomer), 6.86−6.80 (m, 1H, E isomer), 6.46 (dt, J = 9.8, 16.1 Hz, 0.15H), 6.03 (dt, J = 12.9, 13.3 Hz, 0.85H, Z isomer); 13C NMR (CDCl3, 100 MHz) δ 137.2 (t, JF−C = 27.5 Hz), 136.1 (t, JF−C = 7.2 Hz), 134.9, 129.9, 129.1, 128.3, 128.0, 127.9, 126.0 (t, JF−C = 30.3 Hz), 125.4 (t, JF−C = 5.3 Hz), 119.4 (t, JF−C = 239 Hz); 19F-NMR (CDCl3, 367 MHz) δ −82.66 (s, 2F, Z isomer), −90.62 (s, 2F, E isomer). 3-(2,2-Difluoro-2-phenylethyl)-4-methyltetrahydrofuran (3o). Obtained as a cis/trans (81:19) mixture (determined by GC analysis of crude mixture), 133.5 mg, 59%, colorless oil; Rf = 0.27 (hexane/ EtOAc = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.42−7.48 (m, 5H), 3.81−4.03 (m, 2H), 3.26−3.49 (m, 1.83H), 3.26−3.31 (m, 0.25H), 2.15−2.50 (m, 2.65H), 1.86−2.15 (m, 1.23H), 1.01 (d, J = 6.0 Hz, 0.58H), 0.94 (d, 6.9 Hz, 2.34H); 13C NMR (CDCl3, 100 MHz) δ 137.3 (t, JF−C = 26.5 Hz), 129.8, 128.5, 124.8 (t, JF−C = 6.3 Hz), 122.9 (t, JF−C = 242.8 Hz), 75.0, 74.3, 72.0, 71.5, 41.5 (t, JF−C = 13.5 Hz), 37.5 (t, JF−C = 27.9 Hz), 36.6, 36.0, 15.5, 13.5; 19F-NMR (CDCl3, 367 MHz) δ −93.0 to −94.1 (m, 1F), −96.1 to −96.7 (m, 1F); IR (neat) 3066, 3038, 2963, 2931, 2860, 1452, 1383, 1322, 1304, 1246, 1170, 1106, 1023, 986, 911, 771, 762, 735, 700, 625 cm−1; HRMS (ESI) m/z calcd for [M + Na]+ ([C13H16F2O + Na]+) 249.1061, found 249.1076.

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Note

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shuhei Sumino: 0000-0002-7109-8995 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research (A) (no. 26248031) from the JSPS and Scientific Research on Innovative Areas 2707 Middle molecular strategy (no. 15H05850) from MEXT.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00609. Experimental procedures, mechanistic experiments, characterization for all new compounds, copies of NMR spectra, and CV of 1a (PDF) 5473

DOI: 10.1021/acs.joc.7b00609 J. Org. Chem. 2017, 82, 5469−5474

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