Photoredox-Catalyzed Hydrodifluoroalkylation of Alkenes Using Difluorohaloalkyl Compounds and a Hantzsch Ester

Article abstract of DOI:10.1021/acs.joc.7b00609

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.

Full text of DOI:10.1021/acs.joc.7b00609

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Note
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
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2017
Downloaded from http://pubs.acs.org on May 5, 2017
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Photoredox Catalyzed Hydrodifluoroalkylation of Alkenes Using Difluorohaloalkyl
Compounds and a Hantzsch Ester
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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 599ꢀ8531, Japan
‡Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan
§Daikin Industries, Ltd. 1ꢀ1, NishiꢀHitotsuya, Settsu, Osaka 566ꢀ8585, Japan
ABSTRACT: Photoredoxꢀcatalyzed 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.
A continuous photo flow reaction was also successful.
EtO2C
CO2Et
H
photoredox catalyst
F
F
F
F
+
+
R'
R
X
N
R
R'
H
Radical addition reactions to alkenes represented by Kharaschꢀtype reactions1
and Gieseꢀtype reactions2 provide useful tools for CꢀC bond formation in organic
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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
Hanztsch ester was recently established as a good hydrogen source,4,5 and we recently
reported a Gieseꢀtype reaction of alkyl iodides with Hantzsch ester in a Pd/light
combined system (eq 1, Scheme 1).6
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In view of the increasing importance of fluorineꢀcontaining compounds in
pharmaceuticals, agrochemicals, and materials, developement 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 catalysts3,9 with wellꢀestablished CF3ꢀreagents such as Umemoto reagent,10
Langlois reagent,11 and Togni reagent,12, 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 photoredoxꢀcatalyzed protocol for
hydrodifluoroalkylation of alkenes and alkynes using difluorohaloalkyl compounds and
Hantzsch ester as a hydrogen source (eq 2, Scheme 1).
Scheme 1. Concept: Hydrodifluoroalkylation of Alkenes by Radical Addition and
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Reduction Using Hanztsch Ester
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We examined the reaction of bromodifluoromethylbenzene 1a and 1ꢀoctene 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 a 21% yield together with a 25% yield of the 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 2ꢀ4). In the case of facꢀIr(ppy)3, difluoromethylbenzene was
also obtained in 10% yield (Table 1, entry 3). Pd/light combined system was not effective
for the present hydrodifluoroalkylation (Table 1, entry 5).6 In the absence of photoredox
catalyst, the reaction proceeded but in low yield (Table 1, entry 6). Other hydrogen
sources, such as NaBH3CN and PMHS (polymethylhydrosiloxane:
Mn = 1700 ꢀ 3200),
gave inferior results (Table 1, entries 7 and 8). In the absence of Et3N, the selectivity
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was decreased to 87/13 (Table 1, entries 9 and 10).19
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Table 1. Optimized Reaction Conditionsa
a 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. b Determined by GC. c Et3N 1 equiv. d
Without Et3N. e DMF 5 mL.
Table 2 lists the results of the Ruꢀphotoredoxꢀcatalyzed hydrodifluoroalkylation
using difluorohaloalkyl compounds 1aꢀ1d and alkenes and alkynes 2aꢀ2m. The reaction
of 1a with acrylonitrile 2b and methyl acrylate 2c gave 3b and 3c as a sole product 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 electronꢀrich alkenes such as vinyl acetate 2e gave 3e in a
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modest yield (Table 2, entry 5). The reaction of ethyl 2ꢀbromoꢀ2,2ꢀdifluoroacetate 1b
with 2a gave 3f in a 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 7ꢀ9). Internal alkenes, 2i, 2j, and
2k, also participated in the reaction albeit in moderate yields (Table 2, entries 10ꢀ12).
Perfluoroꢀ1ꢀbromohexane 1c and perfluoroꢀ1ꢀiodohexane 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
1ꢀoctyne 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, entry 16). In these reactions considerable amounts of difluoromethylbenzene
was formed, which suggested that the addition reaction is competed by premature
quenching of phenyldifluoromethyl radical. The reaction of 1a and allyl ether 2n gave
3,4ꢀdisubstituted tetrahydrofuran 3o in a 59% yield (Table 2, entry 17). It is confirmed
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that the cis/trans ratio of 3o was nearly the same as that of a related radical
cyclization.20
Table 2. Hydrodifluoroalkylation of Alkenes and Alkynes Using a Photoredox Catalyst
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and Hanztsch Ester
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a 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. b Determined by GC. c 2a
(20 mmol). d Determined by 1HꢀNMR.
To verify the effect of photoirradiation, we investigated onꢀoff 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 Dꢀlabeled 3a and 3b (Scheme S1). A plausible
reaction mechanism is illustrated in Scheme 2, which is based on the related photoredox
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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 photoꢀexcited 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
resultant radical would abstract hydrogen at the 4ꢀposition of radical cation A to give
the products 3 and pyridine B. We assume that Et3N would facilitate deprotonation of A
to give B.
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Scheme 2. Proposed Reaction Mechanism
In order to explore a more photoꢀeffective 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 Lꢀ1: for details see SI), a residence time of 20 min sufficed to
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obtain 82 % yield of 3c.
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Scheme 3. Continuous Photo Flow Hydrodifluoroalkylation
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.
EXPERIMENTAL SECTION
General Information: Photoirradiation was carried out with a White LED Lump
(Panasonic, LDR5DꢀW). Thin layer chromatography (TLC) was performed on Merck
precoated plates (silica gel 60 F254, Art 5715, 0.25 mm) and were visualized by
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fluorescence
quenching
under
UV
light
or
by
staining
with
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pꢀanisaldeyde/AcOH/H2SO4/EtOH, or 12MoO3•H3PO4/EtOH. The products were
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purified by flash chromatography on silica gel (Kanto Chem. Co. Silica Gel 60N
(spherical, neutral, 40ꢀ50 mm)) and, if necessary, were further purified by recycling
preparative HPLC (Japan Analytical Industry Co. Ltd., LCꢀ918) equipped with GPC
columns (JAIGELꢀ1H + JAIGELꢀ2H columns) using CHCl3 as eluent. 1H NMR spectra
were recorded with a JEOL JMNꢀECS400 (400 MHz) or JEOL JMNꢀECA600 (600 MHz)
spectrometer and referenced to the solvent peak at 7.26 ppm. 13C NMR spectra were
recorded with a JEOL JMNꢀECS400 (100 MHz) or JEOL JMNꢀECA600 (150 MHz)
spectrometer and referenced to the solvent peak at 77.00 ppm. 19F NMR spectra were
recorded with a JEOL JMNꢀECS400 (376 MHz) or JEOL JMNꢀECA600 (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/IRꢀ4100 spectrometer and are reported as wavenumber (cmꢀ1).
Highꢀresolution mass spectra were recorded with a JEOL MS700 spectrometer or
Bruker ESIꢀQTOF (compactꢀNPC) or Shimadzu LCMSꢀITꢀTOF with JEOL DART as ion
source. Cyclic voltammetry was measured with BAS Electrochemical Analyzer ALS
Model 612B.
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Procedure for the synthesis of bromodifluoromethylbenzene 1a25: A magnetic stirring
bar, PhCF3 (146 g, 1.0 mol) were placed into a threeꢀnecked 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 to yellow initially and amberꢀlike.
After 1 h, the effervescence ceased and the mixture started to cool down. 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 then
was dried over Na2SO4. After the reaction mixture was filtered and evaporated, amber
color liquid was collected as crude product, which was distilled to give 15.6 g of product
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1
1a as a colorless liquid, bp 50 °C/19.1 Torr, 97% purity. HꢀNMR (CDCl3, 400 MHz) δ
7.60ꢀ7.63 (m, 2H), δ 7.43ꢀ7.51 (m, 3H); 13CꢀNMR (CDCl3, 100 MHz) δ 138.1 (t,
JFꢀC = 22.9
Hz), δ 131.2 δ 128.6, δ 124.3 (t, JFꢀC = 5.7 Hz), δ 118.4 (t, JFꢀC = 306.4 Hz); 19FꢀNMR
(CDCl3, 367 MHz) δ ꢀ43.35 (s, 2F).
26
Procedure for the synthesis of Hantzsch Ester
: 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 threeꢀnecked round
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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. 1HꢀNMR (CDCl3, 400
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MHz) δ 4.17 (q,
J = 7.0 Hz, 4H), δ 3.27 (s, 2H), δ 2.20 (s, 6H), δ 1.28 (t, J = 7.3 Hz, 6H);
13CꢀNMR (CDCl3, 100 MHz) δ 168.0, δ 144.8, δ 99.5, δ 59.6, δ 30.9, δ 24.8, δ 19.2, δ 14.5.
Typical procedure for the hydrodifluoroalkylation of bromodifluoromethylbenzene 1a to
give (1,1ꢀdifluorononyl)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), 1ꢀoctene 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 LED lump (5 W) with stirring for 12h. 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 then was dried over MgSO4. The reaction mixture was
filtered and concentrated in vacuo to give crude product. The crude product was purified
by column chromatography on silica gel (Hexane) to give 3a as colorless oil (151.6 mg,
63%).
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Typical procedure for the reaction of bromodifluoromethylbenzene 1a and methyl
acrylate 2c using flow photoreactor (Scheme 4): Photochemical reactions were carried
out using a flow photoreactor MiChS Lꢀ1 (Figure S1), which has a single lane channel (2
mm in width, 1 mm in depth, 3 m in length; total volume 6 mL) covered with quartz.
The photoreactor was irradiated by two white LED lumps (Panasonic, LDR5DꢀW). 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 gas tight
syringe, and was pumped into the photoreactor at a rate of 18 mL/h (residence time: 20
min) (Figure S2). 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%.
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Spectrum Data
1,1ꢀDifluorononylbenzene (3a)27 151.6 mg, 63%, Colorless oil; Rf = 0.93 (Hexane :
EtOAc = 10 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 7.44ꢀ7.48 (m, 2H), δ 7.40ꢀ7.43 (m, 3H), δ
2.03ꢀ2.19 (m, 2H), δ 1.41 (quint,
J = 7.8 Hz, 2H), δ 1.20ꢀ1.32 (m, 10H), δ 0.87 (t, J = 7.0
Hz, 3H); 13CꢀNMR (CDCl3, 100 MHz) δ 137.5 (t,
J
FꢀC = 27.0 Hz), δ 129.5, δ 128.3, δ 124.9
(t,
J
FꢀC = 6.3 Hz), δ 123.2 (t,
J
FꢀC = 246.8 Hz), δ 39.09 (t,
JFꢀC = 27.0 Hz), δ 31.79, δ 29.29, δ
29.25, δ 29.11, δ 22.61, δ 22.48 (t,
J
FꢀC = 3.9 Hz), δ 14.08; 19FꢀNMR (CDCl3, 367 MHz) δ
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ꢀ95.3 (s, 2F).
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4,4ꢀDifluoroꢀ4ꢀphenylbutanenitrile (3b)27 139.4 mg, 77%, Colorless oil; Rf = 0.16
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(Hexane : EtOAc = 20 : 1); HꢀNMR (CDCl3, 400 MHz) δ 7.47 (m, 5H), δ 2.45ꢀ2.60 (m,
4H); 13CꢀNMR (CDCl3, 100 MHz) δ 135.3 (t,
JFꢀC = 25.5 Hz), δ 130.4, δ 128.7, δ 124.6 (t,
J
FꢀC = 6.3 Hz), δ 121.0 (t,
JFꢀC = 241.5 Hz), δ 118.1, δ 35.0 (t, JFꢀC = 29.0 Hz), δ 11.1 (t, JFꢀC
= 4.8 Hz); 19FꢀNMR (CDCl3, 367 MHz) δ ꢀ98.15 (s, 2F).
Methyl 4,4ꢀdifluoroꢀ4ꢀphenylbutanoate (3c)15d 152.1 mg, 71%, Colorless oil; Rf = 0.36
(Hexane : EtOAc = 10 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 7.42ꢀ7.47 (m, 5H), δ 3.66 (s, 3H),
δ 2.45ꢀ2.55 (m, 4H); 13CꢀNMR (CDCl3, 100 MHz) δ 172.5, δ 136.5 (t,
JFꢀC = 53.0 Hz), δ
129.9, δ 128.5, δ 124.8 (t, JFꢀC = 12.5 Hz), δ 122.1 (t, JFꢀC = 240.6 Hz), δ 51.8, δ 34.3 (t, JFꢀC
= 56.8 Hz), δ 27.5 (t,
J
FꢀC = 8.7 Hz); 19FꢀNMR (CDCl3, 367 MHz) δ ꢀ97.0 (s, 2F).
.
Ethyl 4,4ꢀdifluoroꢀ3ꢀmethylꢀ4ꢀphenylbutanoate (3d)
Obtained as an inseparable
mixture with regioisomer (9/1) 145.4 mg, 60%, Colorless oil; Rf = 0.57 (Hexane : EtOAc =
10 : 1); 1HꢀNMR (CDCl3, 600 MHz) major product: δ 7.40ꢀ7.52 (m, 5H), δ 4.12 (t,
J
= 7.2
Hz, 2H), δ 2.84ꢀ2.74 (m, 1H), δ 2.67 (dd,
J = 4.2, 15.6 Hz, 1H), δ2.22 (dd, J = 9.6, 15.6 Hz,
1H), δ 1.25 (t,
5H), δ 4.08 (t,
1H), δ 1.13 (t,
J = 7.2 Hz, 3H), δ 1.01 (d, J = 7.2 Hz, 3H); minor product: δ 7.40ꢀ7.52 (m,
J
= 7.2 Hz 2H), δ 3.07ꢀ2.98 (m, 1H), δ 1.94ꢀ1.86 (m, 1H), δ 1.76ꢀ1.68 (m,
= 7.2 Hz 2H); 13CꢀNMR (CDCl3, 150 MHz)
J
= 7.2 Hz 2H), δ 0.92 (t, J
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major product: δ 171.9, δ 135.8 (t, JFꢀC = 26.6 Hz), δ 129.7, δ 128.3, δ 125.4 (t, JFꢀC = 5.7
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8
9
Hz), δ 123.6 (t,
14.1, δ 13.6 (t,
JFꢀC = 244.2 Hz), δ 60.5, δ 38.6 (t, JFꢀC = 26.6 Hz), δ 35.2 (t, JFꢀC = 2.9 Hz), δ
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J
FꢀC = 3.6 Hz); minor product: δ 169.6, δ 135.7 (t, JFꢀC = 26.6 Hz), δ 129.9, δ
128.2, δ 125.3 (t,
JFꢀC = 15.7 Hz), δ 120.8 (t, JFꢀC = 247.1 Hz), δ 60.8, δ 56.6 (t, JFꢀC = 27.3
Hz), δ 19.6 (t,
J
FꢀC = 3.0 Hz), δ 13.9, δ 11.7; 19FꢀNMR (CDCl3, 564 MHz) major product: δ
ꢀ100.4 (d, JFꢀC= 244.8 Hz, 1F), δ ꢀ106.2 (d, JFꢀC= 261.1 Hz, 1F); minor product: δ ꢀ99.1 (s,
1F), δ ꢀ105.3 (s, 1F); IR (neat) 2982 cmꢀ1, 2942 cmꢀ1, 1737 cmꢀ1, 1464 cmꢀ1, 1452 cmꢀ1,1375
cmꢀ1, 1308 cmꢀ1, 1265 cmꢀ1, 1182 cmꢀ1, 1055 cmꢀ1, 990 cmꢀ1, 765 cmꢀ1, 648 cmꢀ1; HRMS
(DART) m/z calcd for [M+NH4]+ ([C13H16F2O2+NH4]+) 260.1457, found 260.1443.
3,3ꢀDifluoroꢀ3ꢀphenylpropyl acetate (3e) 64.3 mg, 30%, Colorless oil; Rf = 0.57
(Hexane : EtOAc = 10 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 7.40ꢀ7.52 (m, 5H), δ 4.22 (t,
J=
6.7 Hz 2H), δ 2.46ꢀ2.59 (m, 2H) δ 1.94 (s, 3H); 13CꢀNMR (CDCl3, 100 MHz) δ 170.7, δ
136.6 (t,
J
FꢀC = 26.0 Hz), δ 129.9, δ 128.5, δ 124.8 (t,
JFꢀC = 6.3 Hz), δ 121.6 (t, JFꢀC = 242.8
Hz), δ 58.4 (t, JFꢀC = 5.3 Hz), δ 38.0 (t, J
FꢀC = 5.3 Hz), δ 20.7; 19FꢀNMR (CDCl3, 367 MHz) δ
ꢀ94.72 (s, 2F); IR (neat) 2970 cmꢀ1, 1746 cmꢀ1, 1454 cmꢀ1, 1369 cmꢀ1, 1238 cmꢀ1, 765 cmꢀ1,
699 cmꢀ1; HRMS (ESI) m/z calcd for [M+Na]+ ([C11H12F2O2+Na]+) 237.0698, found
237.0698.
Ethyl 2,2ꢀdifluorodecanoate (3f)28 141.8 mg, 60%, Colorless oil; Rf = 0.65 (Hexane :
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EtOAc = 10 : 1); HꢀNMR (CDCl3, 400 MHz) δ 4.32 (q,
J
= 7.2 Hz, 2H), δ 1.98ꢀ2.11 (m,
= 6.9 Hz, 3H); 13CꢀNMR
2H), δ 1.42ꢀ1.49 (m, 2H), δ 1.20ꢀ1.37 (m, 13H), δ 0.88 (t,
J
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(CDCl3, 100 MHz) δ 164.5 (t,
JFꢀC = 33.2 Hz), δ 116.4 (t, JFꢀC = 249.5 Hz), δ 62.7, δ 34.5 (t,
J
FꢀC = 23.1 Hz), δ 31.7, δ 29.2, δ 29.0, δ 22.6, δ 21.4, δ 21.4, δ 14.0, δ 14.0; 19FꢀNMR
(CDCl3, 367 MHz) δ ꢀ105.87 (s, 2F).
Ethyl 2,2ꢀdifluoroꢀ6ꢀphenylhexanoate (3g)18 141.0 mg, 55%, Colorless oil; Rf = 0.30
a
(Hexane : EtOAc = 10 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 7.25ꢀ7.29 (m, 2H), δ 7.15ꢀ7.20
(m, 3H), δ 4.30 (q,
J
= 7.2 Hz, 2H), δ 2.63 (t,
J
= 7.5 Hz, 2H), δ 2.00ꢀ2.10 (m, 2H), δ 1.68
(quint,
J = 7.8 Hz, 2H), δ 1.48ꢀ1.55 (m, 2H), δ 1.33 (t, J
= 7.3 Hz, 3H); 13CꢀNMR (CDCl3,
100 MHz) δ 164.3 (t,
J
FꢀC = 33.2 Hz), δ 141.8, δ 128.3, δ 125.8, δ 116.3 (t,
JFꢀC = 250.0 Hz),
δ 62.7, δ 35.5, δ 34.3 (t,
J
FꢀC= 23.1 Hz), δ 30.8, δ 21.1,δ 21.0, δ 14.0; 19FꢀNMR (CDCl3, 367
MHz) δ ꢀ105.7 (t,
Ethyl 8ꢀchloroꢀ2,2ꢀdifluorooctanoate (3h)29 133.5 mg, 55%, Colorless oil; Rf = 0.20
(Hexane : EtOAc = 30 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 4.32 (q,
J = 16.6 Hz, 2F).
J
= 7.6 Hz, 2H), δ 3.53 (t,
J
= 6.8 Hz, 2H), δ 2.06 (m, 2H), δ 1.77 (m, 2H), δ 1.46 (m, 6H), δ 1.35 (t,
13CꢀNMR (CDCl3, 100 MHz) δ 164.2 (t,
FꢀC = 23.1 Hz), δ 32.2, δ 28.2, δ 26.4, δ 21.2, δ 13.8; 19FꢀNMR (CDCl3, 367
J = 7.6 Hz, 3H);
J
FꢀC = 33.3 Hz), δ 116.2 (t, J FꢀC = 250 Hz), δ 62.7, δ
44.8, δ 34.2 (t,
J
MHz) δ ꢀ105.9 (s, 2F).
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Ethyl 2,2ꢀdifluoroꢀ12ꢀhydroxydodecanoate (3i)28 115.0 mg, 41%, Colorless oil; Rf = 0.16
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(Hexane : EtOAc = 5 : 1); 1HꢀNMR (CDCl3, 400 MHz) δ 4.32 (q,
J = 7.2 Hz, 2H), δ 3.64 (t,
10
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J
= 6.7 Hz, 2H), δ 1.99ꢀ2.09 (t, 2H), δ 1.20ꢀ1.60 (m, 21H); 13CꢀNMR (CDCl3, 100 MHz) δ
164.5 (t,
J
FꢀC = 33.3 Hz), δ 116.4 (t,
J
FꢀC= 250 Hz), δ 63.0, δ 62.7, δ 34.4 (t,
JFꢀC = 23.1 Hz),
δ 32.7, δ 29.5, δ 29.3, δ 29.3, δ 29.2, δ 29.0, δ 25.7,δ 21.4 (t,
J
FꢀC= 3.8 Hz),δ 14.0; 19FꢀNMR
(CDCl3, 367 MHz) δ ꢀ105.82 (t,
J = 17.3 Hz, 2F).
Ethyl 2ꢀcyclohexylꢀ2,2ꢀdifluoroacetate (3j)29 84.5 mg, 41%, Colorless oil; Rf = 0.30
1
(Hexane : EtOAc = 20 : 1); HꢀNMR (CDCl3, 400 MHz) δ 4.32 (q,
J = 7,4 Hz, 2H), δ
1.98ꢀ2.14 (m, 1H), δ 1.66ꢀ1.86 (m, 5H), δ 1.35 (t,
13CꢀNMR (CDCl3, 100 MHz) δ 164.4 (t,
J = 7.1 Hz, 3H), δ 1.14ꢀ1.31 (m, 5H);
J
FꢀC = 32.8 Hz), δ 117.3 (t, JFꢀC = 252 Hz), δ 62.50,
δ 42.21 (t,
ꢀ113.64 (d,
J
FꢀC = 21.6 Hz), δ 25.77, δ 25.28, 24.71, δ 14.00; 19FꢀNMR (CDCl3, 367 MHz) δ
= 14.4 Hz).
J
Ethyl 2,2ꢀdifluoroꢀ3ꢀpropylheptanoate (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); 1HꢀNMR (CDCl3, 600 MHz) δ 4.32 (t,
J = 6.6 Hz 2H), δ 2.15ꢀ2.01 (m, 1H), δ 1.57ꢀ1.25
(m, 13H), δ 0.94ꢀ0.86 (m, 6H); 13CꢀNMR (CDCl3, 150 MHz) δ 164.7 (t,
J
FꢀC = 33.0 Hz), δ
118.3 (t, JFꢀC = 251.3 Hz), δ 62.5, δ 42.2 (t, JFꢀC = 21.6 Hz), δ 29.8, δ 29.3, δ 27.3, δ 22.9, δ
20.4, δ 14.2, δ 14.0, δ 13.9; 19FꢀNMR (CDCl3, 564 MHz) δ ꢀ109.8 (s, 2F); IR (neat) 2961
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cmꢀ1, 2874 cmꢀ1, 1770 cmꢀ1, 1468 cmꢀ1, 1373 cmꢀ1, 1308 cmꢀ1, 1198 cmꢀ1, 1142 cmꢀ1, 1051
cmꢀ1, 858 cmꢀ1, 733 cmꢀ1; HRMS (DART) m/z calcd for [M+NH4]+ ([C12H22F2O2+NH4]+)
254.1926, found 254.1914.
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1,1,1,2,2,3,3,4,4,5,5,6,6ꢀTridecafluorotetradecane (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),
1HꢀNMR (CDCl3, 400 MHz) δ 1.98ꢀ2.10 (m, 2H), δ 1.60 (quin,
J = 7.7 Hz, 2H), δ 1.19ꢀ1.37
(m, 10H), δ 0.89 (t,
J
= 6.9 Hz, 3H); 13CꢀNMR (CDCl3, 100 MHz) δ 122.1ꢀ105.6 (m, CF2,
CF3), δ 31.85, δ 31.00 (t, JFꢀC = 22.2 Hz), δ 29.21 (t, JFꢀC = 6.7 Hz), δ 22.68, δ 20.15, δ
14.00; 19FꢀNMR (CDCl3, 367 MHz) δ ꢀ80.70 (s, 3F), δ ꢀ114.32 (s, 2F), δ ꢀ121.88 (s, 2F), δ
ꢀ122.80 (s, 2F), δ ꢀ123.50 (s, 2F), δ ꢀ126.07 (s, 2F).
(1,1ꢀDifluorononꢀ2ꢀenꢀ1ꢀyl)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); 1HꢀNMR (CDCl3, 400 MHz) δ 7.60ꢀ7.30 (m, 5H, E/Z
mixture), δ 5.95 (m, 0.41H,
E isomer), δ 5.80 (m, 1.58H, E/Z mixture), δ 2.20 (m, 2H), δ
1.40ꢀ1.20 (m, 8H), δ 0.90ꢀ0.80 (m, 2H); 13CꢀNMR (CDCl3, 100 MHz) δ 138.8 (t,
J
FꢀC = 6.7
Hz), δ 138.0 (t, JFꢀC = 27.9 Hz), δ 137.3 (t, JFꢀC = 8.7 Hz), δ 137.0 (t, JFꢀC = 27.9 Hz), δ
129.8, δ 129.7, δ 128.4, δ 128.3, δ 126.0 (t, JFꢀC = 29.4 Hz), δ 125.5 (t, JFꢀC = 5.8 Hz), δ
125.4ꢀ125.0 (m), δ 120.0 (t, JFꢀC = 237 Hz), δ 119.7 (t, JFꢀC = 237 Hz), δ 31.8, δ 31.6, δ 31.5,
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δ 29.1, δ 28.8, δ 28.8, δ 28.4, δ 28.3, 22.5, 14.0; 19FꢀNMR (CDCl3, 458 MHz) δ ꢀ84.53 (s, 2F,
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9
Z
isomer), δ ꢀ90.07 (s, 2F,
E isomer).
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(3,3ꢀDifluoropropꢀ1ꢀeneꢀ1,3ꢀdiyl)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
1
= 0.40 (Hexane : EtOAc = 10 : 1); HꢀNMR (CDCl3, 400 MHz) δ 7.20ꢀ7.60 (m, 10H, E/Z
mixture), δ 6.86 (dt,
J
= 1.8, 12.4 Hz, 0.85H,
Z
isomer), δ 6.86ꢀ6.80 (m, 1H,
E
isomer), δ
6.46 (dt,
J = 9.8, 16.1 Hz, 0.15H), δ 6.03 (dt, J = 12.9, 13.3 Hz, 0.85H, Z isomer).;
1HꢀNMR (CDCl3, 500 MHz); 13CꢀNMR (CDCl3, 100 MHz) δ 137.2 (t, JFꢀC = 27.5 Hz), δ
136.1 (t,
JFꢀC = 7.2 Hz), δ 134.9, δ 129.9, δ 129.1, δ 128.3, δ 128.0, δ 127.9, δ 126.0 (t, JFꢀC
= 30.3 Hz), δ 125.4 (t, JFꢀC = 5.3 Hz), δ 119.4 (t, JFꢀC = 239 Hz); 19FꢀNMR (CDCl3, 367
MHz) δ ꢀ82.66 (s, 2F,
Z isomer), δ ꢀ90.62 (s, 2F, E isomer).
3ꢀ(2,2ꢀDifluoroꢀ2ꢀphenylethyl)ꢀ4ꢀmethyltetrahydrofuran (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); 1HꢀNMR (CDCl3, 400 MHz) δ 7.42ꢀ7.48 (m, 5H),
δ 3.81ꢀ4.03 (m, 2H), δ 3.26ꢀ3.49 (m, 1.83H), δ 3.26ꢀ3.31 (m, 0.25H), δ 2.15ꢀ2.50 (m,
2.65H), δ 1.86ꢀ2.15 (m, 1.23H), δ 1.01 (d,
13CꢀNMR (CDCl3, 100 MHz) δ 137.3 (t,
J = 6.0 Hz, 0.58H), δ 0.94 (d, 6.9 Hz, 2.34H);
J
FꢀC = 26.5 Hz), δ 129.8, δ 128.5, δ 124.8 (t, JFꢀC =
6.3 Hz), δ 122.9 (t,
J
FꢀC = 242.8 Hz), δ 75.0, δ 74.3, δ 72.0, δ 71.5, δ 41.5 (t, JFꢀC = 13.5 Hz),
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δ 37.5 (t,
J
FꢀC = 27.9 Hz), δ 36.6, δ 36.0, δ 15.5, δ 13.5; 19FꢀNMR (CDCl3, 367 MHz) δ ꢀ93.0
7
8
9
ꢀ ꢀ94.1 (m, 1F), δ ꢀ96.1 ꢀ ꢀ96.7 (m, 1F); IR (neat) 3066 cmꢀ1, 3038 cmꢀ1, 2963 cmꢀ1, 2931
cmꢀ1, 2860 cmꢀ1, 1452 cmꢀ1, 1383 cmꢀ1, 1322 cmꢀ1, 1304 cmꢀ1, 1246 cmꢀ1, 1170 cmꢀ1, 1106
cmꢀ1, 1023 cmꢀ1, 986 cmꢀ1, 911 cmꢀ1, 771 cmꢀ1, 762 cmꢀ1, 735 cmꢀ1, 700 cmꢀ1, 625 cmꢀ1;
HRMS (ESI) m/z calcd for [M+Na]+ ([C13H16F2O+Na]+) 249.1061, found 249.1076.
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: ryu@c.s.osakafuꢀu.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by a GrantꢀinꢀAid for Scientific Research (A) (no. 26248031)
from the JSPS and Scientific Research on Innovative Areas 2707 Middle molecular
strategy (no. 15H05850) from the MEXT.
Supporting Information
Experimental procedures, mechanistic experiments, characterization for all new
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compounds, copies of NMR spectra, and CV of 1a provided.
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Reference
1
(a) Kharasch, M.; Jensen, E.; Urry, W. Science 1945, 102, 128. (b) Kharasch, M. S.;
Jensen, E. V.; Urry, W. H. J. Am. Chem. Soc. 1947, 69, 1100.
2
For Giese–type reactions, see: (a) Burke, S. D.; Fobare, W. F.; Armistead, D. M. J. Org.
Chem. 1982, 47, 3348. (b) Giese, B.; Dupuis, J. Angew. Chem., Int. Ed. Engl. 1983, 22, 622.
Also see a review: (c) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (d) Kawamoto, T.;
Ryu, I. Org. Biomol. Chem. 2014, 12, 9733.
3
For reviews, see: (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2010,
40, 102. (b) Reckenthäler, M.; Griesbeck, A. G. Adv. Synth. Catal. 2013, 355, 2727. (c) Prier,
C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
4
(a) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637. (b) Hantzsch, A. Justus Liebigs
Ann. Chem. 1882, 215, 1.
5
For the use of Hantzsch ester in photoredox catalyzed system, see: (a) Narayanam, J. M.
R.; Tucker, J.; Stephenson, C. R. J. Am. Chem. Soc. 2009, 131, 8756. (b) Chen, W.; Liu, Z.;
Tian, J.; Li, J.; Ma, J.; Cheng, X.; Li, G. J. Am. Chem. Soc. 2016, 138, 12312. (c) Park, G.; Yi,
S. Y.; Jung, J.; Cho, E. J.; You, Y. Chem. – Eur. J. 2016, 22, 17790. And references cited
therein' following a reference.
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In terms of the light efficiency, the Pd/light combined system was not as effective as
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