Copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent

Article abstract of DOI:10.1016/j.jfluchem.2017.07.018

The catalytic allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent, which can be readily prepared via iodine-zinc exchange reaction of difluoroiodomethane with diethylzinc, was achieved by employing copper salt as a catalyst.

Full text of DOI:10.1016/j.jfluchem.2017.07.018

Accepted Manuscript
Title: Copper-catalyzed allylic difluoromethylation of allyl
carbonates with (difluoromethyl)zinc reagent
Authors: Kohsuke Aikawa, Koki Ishii, Yu Endo, Koichi
Mikami
PII:
S0022-1139(17)30288-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.018
FLUOR 9026
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FLUOR
Received date:
Revised date:
Accepted date:
28-6-2017
27-7-2017
27-7-2017
Please cite this article as: Kohsuke Aikawa, Koki Ishii, Yu Endo,
Koichi Mikami, Copper-catalyzed allylic difluoromethylation of allyl
carbonates
with
(difluoromethyl)zinc
reagent,
Journal
of
Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.018
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Journal
of
Fluorine
Chemistry
journal homepage: www.elsevier.com
Copper-catalyzed allylic difluoromethylation of allyl carbonates with
difluoromethyl)zinc reagent
(
Kohsuke Aikawa, Koki Ishii, Yu Endo, Koichi Mikami*
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
*
Corresponding author. Tel.: (+81)3-5734-2142; fax: (+81)3-5734-2776; e-mail: mikami.k.ab@m.titech.ac.jp
Graphical abstract
Highlights




The catalytic allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent in the presence of copper catalyst was achieved.
(Difluoromethyl)zinc reagent can be readily prepared via iodine-zinc exchange reaction of difluoroiodomethane with diethylzinc.
The catalytic reaction proceeded with not only good-to-high yields but also complete regioselectivity.
The catalytic reaction was found to be stereospecific, and hence chiral allylic difluoromethylated compound can be obtained by treatment of chiral
substrates.
ARTICLE INFO
Article history:Received, Received in revised form Accepted Available online
ABSTRACT
The catalytic allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent, which can be readily prepared via iodine-zinc exchange reaction
of difluoroiodomethane with diethylzinc, was achieved by employing copper salt as a catalyst. The difluoromethylation proceeded with not only good-to-high
yields but also complete regioselectivity. Furthermore, the reaction was demonstrated to be stereospecific, and hence chiral allylic difluoromethylated compound
can be obtained by treatment of chiral substrates which are synthesized through catalytic asymmetric hydrogenation of ,-unsaturated carbonyl compounds
2
017 Elsevier Ltd. All rights reserved
Keywords:organofluorine chemistry bioisosteric effect difluoromethyl group difluoromethylation allylic substitution
1
. Introduction
Huge successes of fluorine-containing drugs continue to stimulate research on fluorine in medicinal chemistry directed toward drug
discovery [1]. Therefore, various fluorinated functional groups are of great interest in the field of pharmaceuticals and agrichemicals [1-
2
2
]. Particularly, difluoromethyl (CF H) group as a lipophilic hydrogen-bonding donor has attracted quite recent attention, due to
bioisosteric nature of alcohols [3]. As a conventional synthetic method, it is widely known that difluoromethylated compounds can be
prepared by deoxofluorination of aldehydes by treatment of N,N-diethylaminosulfur trifluoride (DAST) or its derivatives [4]. However,
there is a possibility that the reaction undergoes explosive decomposition upon heating in large scale operation. Therefore, the direct
introduction of difluoromethyl group via carbon-carbon bond forming reaction has recently been desired instead of functional group
transformation [3e]. As practical and reliable cross-coupling reactions, in particular, the development of transition metal-catalyzed
direct difluoromethylations with (difluoromethyl)metal reagents (MCF
In fact, the first catalytic aromatic difluoromethylation with (difluoromethyl)silicone reagent (TMSCF
palladium/silver catalyst system has been described by Shen group in 2014 [5-6]. Quite recently, Vicic group has succeeded in the
nickel-catalyzed aromatic difluoromethylation with Zn(CF H) (dmpu) as a (difluoromethyl)zinc reagent [7] (Scheme 1a). At the same
time, our group has independently disclosed the copper- and palladium-catalyzed aromatic difluoromethylations by employment of
Zn(CF H) (dmpu) and Zn(CF H) (tmeda) reagents, respectively [8] (Scheme 1a). On the other hand, the direct difluoromethylation on
sp carbon with (difluoromethyl)metal reagents has so far been limited. As a sole single report, Burton group clarified that Zn(CF H)X
or Cd(CF H)X underwent the allylic difluoromethylation of allyl halides without a catalyst, but a mixture of regioisomer was obtained
9] (Scheme 1b). Furthermore, CuCF H prepared in situ via transmetalation from Cd(CF H)X was also found to facilitate the same
2
H) is essential in the field of synthetic organofluorine chemistry.
2
H) as the cooperative dual
2
2
2
2
2
2
2
2
3
2
2
[
2
2
reaction to give only liner product [9]. However, there is no report on the copper-catalyzed allylic difluoromethylation [10]. Herein, we
describe the first copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent which possesses the
complete regioselectivity and stereospecificity [11] (Scheme 1c).

2
. Results and discussion
Initially, the catalytic difluoromethylation of cinnamyl chloride 1a with Zn(CF
examined in the presence of 10 mol% copper iodide (Table 1). The reaction in DMF at -20 °C proceeded to give the products 2a and
a’ as regioisomers in 81% and 19% yields, which can be obtained via substitution in the - and -positions, respectively (entry 1). It
was confirmed that no reaction without copper salt occurred at -20 °C (entry 2). With the aim of enhancing -regioselectivity, the effect
of counteranion and ligand was investigated (entries 3-11). Although employment of CuBr(SMe ), CuCl, CuOTf(toluene)1/2, CuTC, and
2 2 2
H) (dmpu) [8] as a difluoromethyl source was
2
2
CuCN instead of CuI led to increase -regioselectivity, the reaction in the presence of CuOAc was found to enhance -regioselectivity
to furnish the products 2a and 2a’ in 31% and 33% yields, respectively (entries 3-7 vs. 8). Moreover, the addition of ligand to copper
catalyst did not sufficiently produce a desired effect on -regioselectivity, but the branch product 2a’ (40% and 47% yields) was
obtained preferentially by treatment of NHC liagnds (L2-3), compared to phosphoramidate (L1) (entries 9-11).
Encouraged by the efficient reactivity on the sp3 carbon, we next attempted to develop the -regioselective allylic
difluoromethylation depending on the leaving group (Table 2). Fortunately, substrates 3a and 4a bearing phosphate ester and carbonate
as leaving groups also underwent the reaction to give single regioisomer 2a in about 60% yields, in spite of decreasing of the reactivity
(entries 1 vs. 2-3). No reaction of 4a without CuI proceeded at room temperature, and even at 40 °C (entries 4 and 9). The introduction
of acetate as a leaving group extremely decreased the reactivity to give almost no product (entry 5). Furthermore, the use of DMPU
instead of DMF and higher reaction temperature (40 °C) led to the best yield (90%) with shorter reaction time (24 h) (entry 8).
To extend the scope of substrates, the difluoromethylation of various allyl carbonates (4) was further examined under the optimized
reaction conditions in hand (Table 3). Significantly, benzyl group instead of methyl group in 4b exhibited the good
result (2c: 80% yield), while 3.4 equivalents of zinc reagent was necessary. Allyl carbonates (4d-f) bearing aromatic ring with chlorine
in the ortho, meta, para-positions gave the excellent results without deleterious steric and electric effects (2d-f: 94-97% yields).
Electron-withdrawing and -donating substituents in the para-position of the aromatic ring also underwent the desired reaction to
provide the corresponding products in good-to-excellent yields (2g-k: 71-99% yields). Moreover, substrates (4l-m) with backbone such
as pyridine and naphthyl groups gave good yields (2l-m: 74-79% yields). Importantly, the transformation of alphatic substrate (4n) with
cyclohexyl group took place without deteriorating effect on the regioselectivity to afford 2n as an only regioisomer in 84% yield. It is
supposed that the complete regioselectivity originates from steric difference between cyclohexyl and methyl substituents.
To get insight of regioselectivity on the reaction, 4a’ and 4b’ which possess the leaving group in benzyl position were employed
under the same reaction conditions, and consequently 2a and 2b were obtained as single regioisomers in 97% yields, respectively
(Scheme 2, Eq. 1). It was clarified that the reductive elimination of copper(III) species in the benzyl position cannot be caused under the
same reaction conditions, because allyl carbonate 4o did not undergo the reaction at all (Scheme 2, Eq. 2). Significantly, the allylic
difluoromethylation was also found to proceed via the stereospecific manner. Treatment of optically active substrate (R)-4b (91% ee)
thus led to the allylic difluoromethylated product (S)-4b (90% ee) in 87% yield through the total inversion of stereochemistry (Scheme
2
, Eq. 3).
After hydrogenation of 2b by treatment of Pd/C to provide alkylated product 10 (Scheme 3b), the absolute configuration at the
created carbon center of 2b were determined to be the S in comparison with the optical rotation of (R)-10 obtained by the synthetic
method in the previous report [12] (Scheme 3a). According to the previous report, the catalytic asymmetric hydrogenation of 6 in the
presence of [RuCl (p-cymene)] and (R)-MeO-BIPHEP followed by reduction of the carboxylic acid (R)-7 by LiAlH provided the
2 2 4
corresponding alcohol (R)-8 [12]. Deoxofluorination of aldehyde (R)-9, which was obtained by treatment of DMP to (R)-8, with DAST
led to difluoromethylated product (R)-10 in a 70% ee.
Based on the above-mentioned results, the proposed catalytic cycle is visualized in Scheme 4 [10]. At first, transmetalation of the
-
difluoromethyl group from Zn(CF
2
H)
2
(dmpu)
2
to copper salt triggers the catalytic reaction to generate the cuprate [Cu(CF
2
H)X] [8].
Oxidative addition of allyl carbonate (R)-4b to cuprate leads to the formation of -allyl copper(III) species which occurs with inversion
of configuration. It is proposed that zinc(II) cation as a Lewis acid facilitates oxidative addition via coordination to carbonate moiety.
Finally, reductive elimination of copper(III) complex closes the catalytic cycle to afford the allylic difluoromethylated product (S)-2b
with not only complete regioselectivity but also total inversion of configuration from the chiral substrate (R)-4b.
3
. Conclusions
We have succeeded in the first copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent to
give the corresponding allylic difluoromethylated products in good-to-excellent yields. The reaction took place with complete
regioselectivity and stereospecificity to afford chiral difluoromethyl product by employing chiral allyl carbonate, which can be readily
prepared through catalytic asymmetric hydrogenation of ,-unsaturated carbonyl compounds. Development of catalytic
enantioselective allylic difluoromethylation is actively in progress in our laboratory.
4
. Experimental

4
.1. General
1
13
19
1
H, C, and F NMR spectra were measured with a Bruker AV300M (300 MHz) spectrometer. H NMR spectra were calibrated using
1
3
the singlet (δ = 7.26 ppm) for CDCl
central line of the triplet (δ = 77.0 ppm) for CDCl
using the singlet (δ = -63.24 ppm) for BTF (benzotrifluoride), used as an internal standard
3
, and chemical shifts are expressed in parts per million
, and chemical shifts are expressed in parts per million. F NMR data were calibrated
and chemical shifts are expressed in parts per
.
C NMR spectra were calibrated using the
1
9
3
,
million. Important NMR spectroscopic data are tabulated in the following order: multiplicity (s: singlet, d: doublet, t: triplet, q: quartet,
m: multiplet) and coupling constant [J (Hz)]. Mass spectra were measured with a JEOL JMS-T100CS (Accu-TOF) spectrometer. IR
spectra were measured with a JASCO FTIR-4200 spectrometer. Optical rotations were measured with a JASCO P-1020. High
performance liquid chromatography (HPLC) was conducted with JASCO PU-980, LG-980-02, DG-980-50, MD-2010, and CO-966
instrument equipped with model UV-975 spectrometers as an ultra violet light. Peak areas were calculated by JASCO chrom NAV
(
Windows 7) as an automatic integrator. DAICEL CHIRALPAK AD-3 and DAICEL CHIRALCEL OD-3 were used as chiral columns.
Column chromatography was carried out on KANTO Silica Gel 60N (spherical, neutral). Dichloromethane (dehydrate), THF
dehydrate), DMF(dehydrate), EtOH (dehydrate), and MeOH (dehydrate) were purchased from Kanto Chemical Co., Inc.. Copper salts
(
and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU, dehydrate) were purchased from Aldrich. Ethyl chloroformate and 1a
were purchased form TCI. Substrates 3a [13], 4a [14], 4a’ [14], 4b’ [15], 4c [16], 4o [17], and 5a [18] were synthesized employing
published procedure. Zn(CF H) (dmpu) was prepared employing published procedure [8a].
2 2 2
4
.2. General procedure for synthesis of allyl carbonate (4)
General Procedure A: The corresponding allyl alcohol (5 mmol) was dissolved in CH
2
2
Cl (15 mL) and pyridine (1.2 mL, 15 mmol)
under argon atmosphere. After the solution was cooled to 0 °C, ethyl chloroformate (0.95 mL, 10 mmol) was added dropwise. The
reaction mixture was stirred at room temperature for 24 h and quenched with water (15 mL). The organic layer was separated and the
aqueous phase was extracted with CH
2 2 2 4
Cl (15 mL × 2). The combined organic phases were dried over Na SO . After filtration and
evaporation of the solvent, the crude product was purified by silica-gel column chromatography to give the allyl carbonate 4.
4
.2.1. (R,E)-ethyl (4-phenylbut-3-en-2-yl) carbonate [(R)-4b]
The titled compound was synthesized from (R,E)-4-phenylbut-3-en-2-ol according to General Procedure A. The yield of the compound
1
9
(
90% yield) was determined by F NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column
chromatography (Hexane/EtOAc = 7/1, 1% Et N) gave the desired product (30.9 mg, 85% yield) as a colorless oil. The product was
3
1
1
known compound as (S)-isomer and H NMR data were in good accordance with the previous data [19]. H NMR (300 MHz, CDCl
3
) δ
1
1
9
.31 (t, 3H, J = 7.1 Hz), 1.47 (d, 3H, J = 6.5 Hz), 4.20 (q, 2H, J = 7.2 Hz), 5.32-5.42 (m, 1H), 6.20 (dd, 1H, J = 15.9, 7.0 Hz), 6.65 (d,
2
3
H, J = 16.0 Hz), 7.22-7.40 (m, 5H); [α]
D
+73.4 (c 1.25, CHCl
3
), 91% ee; HPLC (column, CHIRALPAK AD-3, Hexane/2-Propanol =
of minor (S)-isomer 9.4 min.
8/2, flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) t
R
of major (R)-isomer 7.9 min, t
R
4
.2.2.(E)-4-(2-chlorophenyl)but-3-en-2-yl ethyl carbonate (4d)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (939.5 mg, 86% yield) as a yellow oil. H NMR (300 MHz, CDCl
3
) δ 1.32 (t,
3
1
1
H, J = 7.1 Hz), 1.49 (d, 3H, J = 6.5 Hz), 4.21 (q, 2H, J = 7.1 Hz), 5.36-5.45 (m, 1H), 6.20 (dd, 1H, J = 16.0, 6.8 Hz), 7.03 (d, 1H, J =
1
3
5.9 Hz), 7.25-7.12 (m, 2H), 7.33-7.37 (m, 1H), 7.50-7.53 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 14.2, 20.3, 63.7, 74.5, 126.8, 126.9,
+
28.0, 128.9, 129.7, 131.1, 133.3, 134.3, 154.4; HRMS (ESI-TOF) calcd for C13 15ClNaO Na [M+Na] : 277.0607, found: 277.0617;
H
3
-
1
FT-IR (neat, cm ) 752, 1036, 1257, 13721471, 1591, 1743, 2935, 2983, 3063.
4
.2.3.(E)-4-(3-chlorophenyl)but-3-en-2-yl ethyl carbonate (4e)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(
Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (913.1 mg, 87% yield) as a pale yellow oil. H NMR (300 MHz, CDCl
.32 (t, 3H, J = 7.1 Hz), 1.47 (d, 3H, J = 6.5 Hz), 4.20 (q, 2H, J = 7.1 Hz), 5.31-5.40 (m, 1H), 6.21 (dd, 1H, J = 15.6, 6.8 Hz), 6.58 (d,
H, J = 15.9 Hz), 7.21-7.25 (m, 3H), 7.37 (s, 1H); 13C NMR (75 MHz, CDCl
) δ 14.2, 20.3, 63.7, 74.4, 124.8, 126.5, 127.8, 129.7,
29.8, 130.5, 134.4, 133.1, 154.4; HRMS (ESI-TOF) calcd for C13 15ClNaO Na [M+Na] : 277.0607, found: 277.0604; FT-IR (neat,
3
) δ
1
1
1
3
+
H
3
-
1
cm ) 789, 846, 1037, 1258, 1372, 1567, 1742, 2931, 2983.
4
.2.4.(E)-4-(4-chlorophenyl)but-3-en-2-yl ethyl carbonate (4f)
The titled compound was synthesized according to General Procedure A. urification by silica-gel column chromatography
1
(
3 3
Hexane/EtOAc = 7/1, 1% Et N) gave the desired product (760.5 mg, 88% yield) as a pale yellow oil. H NMR (300 MHz, CDCl ) δ
1
1
1
1
.31 (t, 3H, J = 7.1 Hz), 1.46 (d, 3H, J = 6.5 Hz), 4.20 (q, 2H, J = 7.1 Hz), 5.30-5.38 (m, 1H), 6.17 (dd, 1H, J = 16.0, 6.9 Hz), 6.60 (d,
H, J = 16.0 Hz), 7.27-7.30 (m, 4H); 13C NMR (75 MHz, CDCl
) δ 14.2, 20.3, 63.7, 74.6, 127.8, 128.7, 128.9, 130.7, 133.5, 134.7,
Na [M+Na] : 277.0607, found: 277.0614; FT-IR (neat, cm ) 829, 1091, 1258, 1372,
3
+
-1
54.4; HRMS (ESI-TOF) calcd for C13
492, 1593, 1742, 2935, 2983.
H
15ClNaO
3
4
.2.5.(E)-4-(4-bromophenyl)but-3-en-2-yl ethyl carbonate (4g)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(
1
1
Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (686.9 mg, 88% yield) as a pale yellow oil. H NMR (300 MHz, CDCl
.31 (t, 3H, J = 7.1 Hz), 1.46 (d, 3H, J = 6.5 Hz), 4.20 (q, 2H, J = 7.2 Hz), 5.30-5.37 (m, 1H), 6.19 (dd, 1H, J = 16.0, 6.9 Hz), 6.58 (d,
H, J = 16.0 Hz), 7.23-7.26 (m, 2H), 7.42-7.45 (m, 2H); 13C NMR (75 MHz, CDCl
) δ 14.3, 20.3, 63.7, 74.5, 121.7, 128.1, 129.0,
3
) δ
3
+
-
1
4
30.7, 131.6, 135.1, 154.4; HRMS (ESI-TOF) calcd for C14H19BrO Na [M+MeOH+Na] : 353.0364, found: 353.0355; FT-IR (neat, cm
1
)
733, 1037, 1257, 1372, 1487, 1588, 1741, 2871, 2934, 2982.

4
.2.6. (E)-ethyl (4-(4-(trifluoromethyl)phenyl)but-3-en-2-yl) carbonate (4h)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (406.2 mg, 74% yield) as a yellow oil. H NMR (300 MHz, CDCl
3
) δ 1.32 (t,
3
1
H, J = 7.1 Hz), 1.48 (d, 3H, J = 6.5 Hz), 4.21 (q, 2H, J = 7.2 Hz), 5.34-5.43 (m, 1H), 6.29 (dd, 1H, J = 16.0, 6.7 Hz), 6.67 (d, 1H, J =
1
3
3
6.0 Hz), 7.47 (d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 8.2 Hz); C NMR (75 MHz, CDCl ) δ 14.0, 20.1, 63.8, 74.3, 124.1 (q, JC-F = 270.0
1
9
Hz), 125.4 (q, JC-F = 3.7 Hz), 126.7, 129.6 (q, JC-F = 32.3 Hz), 130.3, 130.9, 139.7, 154.4; F NMR (282 MHz, CDCl ) δ -62.7 (s, 3F);
HRMS (ESI-TOF) calcd for C14H F O Na [M+Na] : 311.0871, found: 311.0885; FT-IR (neat, cm ) 833, 1124, 1165, 1259, 1325,
15 3 3
3
+
-1
1
373, 1616, 1742, 2937, 2985.
4
.2.7. (E)-ethyl (4-(p-tolyl)but-3-en-2-yl) carbonate (4i)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3 3
N) gave the desired product (428 mg, 79% yield) as a pale yellow oil. H NMR (300 MHz, CDCl ) δ 1.31
(
6
1
t, 3H, J = 7.1 Hz), 1.46 (d, 3H, J = 6.4 Hz), 2.33 (s, 3H), 4.19 (q, 2H, J = 7.1 Hz), 5.31-5.40 (m, 1H), 6.15 (dd, 1H, J = 15.9, 7.1 Hz),
1
3
.62 (d, 1H, J = 15.9 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.2 Hz); C NMR (75 MHz, CDCl
3
) δ 14.3, 20.5, 21.2, 63.7, 75.1,
+
26.6, 127.1, 129.3, 132.2, 133.5, 137.8, 154.5; HRMS (ESI-TOF) calcd for C14H O Na [M+Na] : 257.1154, found: 257.1160; FT-IR
18 3
-
1
(neat, cm ) 800, 1036, 1256, 1372, 1514, 1741, 2872, 2933, 2982.
4
.2.8. (E)-ethyl (4-(4-methoxyphenyl)but-3-en-2-yl) carbonate (4j)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (441 mg, 63% yield) as a yellow oil. H NMR (300 MHz, CDCl
3
) δ 1.31 (t,
3
1
1
H, J = 7.2 Hz), 1.46 (d, 3H, J = 6.5 Hz), 3.81 (s, 3H), 4.19 (q, 2H, J = 7.1 Hz), 5.35 (m, 1H), 6.06 (dd, 1H, J = 15.9, 7.2 Hz), 6.60 (d,
1
3
H, J = 15.9 Hz), 6.85 (dt, 2H, J = 9.6, 2.7 Hz), 7.32 (d, 2H, J = 8.7 Hz); C NMR (75 MHz, CDCl
3
) δ 14.2, 20.5, 55.1, 63.6, 75.2,
+
14.0, 125.9, 127.9, 128.9, 131.8, 154.5, 159.6; HRMS (ESI-TOF) calcd for C14H O Na [M+Na] : 273.1103, found: 273.1104; FT-IR
18 4
-
1
(neat, cm ) 834, 1035, 1252, 1512, 1607, 1740, 2837, 2935, 2982.
4
.2.9. (E)-4-(benzo[d][1,3]dioxol-5-yl)but-3-en-2-yl ethyl carbonate (4k)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(
3
(
1
Hexane/EtOAc = 5/1, 1% Et
H, J = 7.1 Hz), 1.45 (d, 3H, J = 6.5 Hz), 4.19 (q, 2H, J = 7.1 Hz), 5.29-5.38 (m, 1H), 5.95 (s, 2H), 6.02 (dd, 1H, J = 15.9, 7.1 Hz), 6.56
d, 1H, J = 15.8 Hz), 6.75 (d, 1H, J = 8.0 Hz), 6.82 (dd, 1H, J = 8.0, 1.6 Hz), 6.92 (d, 1H, J = 1.5 Hz); 13C NMR (75 MHz, CDCl
) δ
4.2, 20.4, 63.7, 75.0, 101.1, 105.7, 108.2, 121.5, 126.3, 130.6, 131.9, 147.6, 148.0, 154.5; HRMS (ESI-TOF) calcd for C14 Na
3 3
N) gave the desired product (366.6 mg, 53% yield) as a yellow oil. H NMR (300 MHz, CDCl ) δ 1.31 (t,
3
16 5
H O
+
-1
[
M+Na] : 287.0895, found: 287.0887; FT-IR (neat, cm ) 801, 1037, 1251, 1504, 1606, 1739, 2779, 2899, 2982.
4
.2.10. (E)-ethyl (4-(pyridin-3-yl)but-3-en-2-yl) carbonate (4l)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(
Hexane/EtOAc = 2/1, 2% Et
3
N) gave the desired product (558.1 mg, 62% yield) as a brown oil. H NMR (300 MHz, CDCl
H, J = 7.1 Hz), 1.48 (d, 3H, J = 6.5 Hz), 4.21 (q, 2H, J = 7.1 Hz), 5.30-5.43 (m, 1H), 6.29 (dd, 1H, J = 16.1, 6.6 Hz), 6.64 (d, 1H, J =
6.1 Hz), 7.27-7.31 (m, 1H), 7.73-7.76 (m, 1H), 8.48-8.50 (m, 1H), 8.61-8.62 (m, 1H); 13C NMR (75 MHz, CDCl
) δ 13.9, 20.0, 63.5,
3
) δ 1.32 (t,
3
1
7
2
3
+
3
4.0, 123.1, 128.0, 130.3, 131.5, 1323.6, 148.3, 148.7, 154.1; HRMS (ESI-TOF) calcd for C12H16NO [M+H] : 222.1130, found:
-
1
22.1140; FT-IR (neat, cm ) 708, 791, 1037, 1257, 1372, 1479, 1569, 1741, 2935, 2983.
4
.2.11. (E)-ethyl (4-(naphthalen-1-yl)but-3-en-2-yl) carbonate (4m)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (722.4 mg, 76% yield) as a yellow oil. H NMR (300 MHz, CDCl
3
) δ 1.33 (t,
3
5
1
H, J = 7.1 Hz), 1.55 (d, 3H, J = 6.5 Hz), 4.23 (q, 2H, J = 7.1 Hz), 5.45-5.54 (m, 1H), 6.23 (dd, 1H, J = 15.7, 6.9 Hz), 7.39-7.60 (m,
1
3
H), 7.78-7.86 (m, 2H), 8.08-8.11 (m, 1H); C NMR (75 MHz, CDCl
28.4, 128.6, 129.4, 131.3, 131.6, 133.7, 134.0, 154.7; HRMS (ESI-TOF) calcd for C17
3
) δ 14.3, 20.5, 63.7, 75.0, 123.8, 124.0, 125.6, 125.9, 126.2,
+
18 3
H O Na [M+Na] : 293.1154, found: 293.1155;
-
1
FT-IR (neat, cm ) 734, 792, 1038, 1151, 1257, 1371, 1446, 1590, 1740, 2934, 2981, 3059.
4
.2.12. (E)-4-cyclohexylbut-3-en-2-yl ethyl carbonate (4n)
The titled compound was synthesized according to General Procedure A. Purification by silica-gel column chromatography
1
(Hexane/EtOAc = 7/1, 1% Et
3
N) gave the desired product (436.7 mg, 84% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 0.98-
1
6
.35 (m, 10H), 1.58-1.72 (m, 6H), 1.93 (br, 1H), 4.17 (q, 2H, J = 7.1 Hz), 5.10-5.18 (m, 1H), 5.38-5.46 (m, 1H), 5.69 (dd, 1H, J = 15.6,
1
3
3
.5 Hz); C NMR (75 MHz, CDCl ) δ 14.0, 20.2, 25.8, 25.9, 32.4, 40.0, 63.1, 75.8, 126.5, 139.1, 154.2; HRMS (ESI-TOF) calcd for
+
-1
13 22 3
C H O Na [M+Na] : 249.1467, found: 249.1471; FT-IR (neat, cm ) 790, 846, 1036, 1256, 1371, 1449, 1742, 2852, 2925, 2982.
4
.3. General procedure for catalytic allylic difluoromethylation of allyl carbonate (Table 3)
General Procedure B: To a test tube equipped with a magnetic stir bar were added the corresponding allyl carbonate 4 (0.2 mmol), CuI
3.8 mg, 0.02 mmol, 10 mol%), and Zn(CF H) (dmpu) (0.17-0.18 M in DMPU, 1.9-2.1 mL, 0.34 mmol) [8a] at room temperature
under argon atmosphere. The reaction mixture was stirred at 40 °C for 24 h and quenched with 1M HCl aq. (10 mL). The mixture was
extracted with pentane (10 mL × 3) and the combined organic phases were dried over Na SO . After filtration and evaporation of the
(
2
2
2
2
4
1
9
solvent, the yield was determined by F NMR analysis using benzotrifluoride as an internal standard. The crude product was purified
by silica-gel column chromatography to give the difluoromethylated product 2.
4
.3.1. (E)-(4,4-difluorobut-1-en-1-yl)benzene (2a)

The titled compound was synthesized according to General Procedure B. The yield of the compound (95% yield) was determined by 19
F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
desired product (24.2 mg, 72% yield) as a colorless oil. The product was known compound and NMR data were in good accordance
1
with the previous data [9]. H NMR (300 MHz, CDCl
1
3
) δ 2.69-2.84 (m, 2H), 5.87 (tt, 1H, JH-F = 56.7, J = 4.5 Hz), 6.14 (dt, 1H, J =
1
9
19
5.7, 7.3 Hz), 6.57 (d, 1H, J = 15.9 Hz), 7.23-7.40 (m, 5H); F NMR (282 MHz, CDCl
3
) δ -115.6 (dt, 2F, J = 57.6, 17.5 Hz). 2a’: F
NMR (282 MHz, DMF) δ -122.2 (ddd, 1F, JF-F = 275.1, JF-H = 54.8, 13.8 Hz), -120.7 (ddd, 1F, JF-F = 275.6, JF-H = 55.4, 13.8 Hz).
4
.3.2. (S,E)-(4,4-difluoro-3-methylbut-1-en-1-yl)benzene [(S)-2b] (Scheme 2, Eq. 3)
The titled compound was synthesized according to General Procedure B. The yield of the compound (90% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (Pentane/ Et O = 20/1)
) δ 1.26 (d, 3H, J = 7.0 Hz), 2.71-2.91 (m,
H), 5.73 (td, 1H, JH-F = 56.8, J = 3.9 Hz), 6.16 (dd, 1H, J = 16.0, 7.8 Hz), 6.56 (d, 1H, J = 16.0 Hz), 7.25-7.43 (m, 5H); 13C NMR (75
2
1
gave the desired product (30.9 mg, 85% yield) as a colorless oil. H NMR (300 MHz, CDCl
1
3
3
MHz, CDCl ) δ 12.9 (t, JC-F = 4.5 Hz), 41.4 (t, JC-F = 20.2 Hz), 118.1 (t, JC-F = 242.3 Hz), 126.3 (t, JC-F = 5.3 Hz), 126.3, 127.7, 128.6,
1
9
1
5
3
32.9, 136.8; F NMR (282 MHz, CDCl ) δ -123.2 (ddd, 1F, JF-F = 276.2, JF-H = 56.3, 15.0 Hz), -121.2 (ddd, 1F, JF-F = 275.5, JF-H =
-
1
21
5.3, 13.8 Hz); FT-IR (neat, cm ) 693, 748, 967, 1067, 1125, 326, 1461, 2854, 2925; [α]
D
+0.63 (c 0.58, CHCl
3
), 90% ee; HPLC
(column, CHIRALCEL OD-3, Hexane/2-Propanol = 96/4, flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) t
R
of minor (R)-isomer
6
R
.2 min, t of major (S)-isomer 6.7 min.
4
.3.3.(E)-(3-(difluoromethyl)but-1-ene-1,4-diyl)dibenzene (2c)
The titled compound was synthesized according to General Procedure B (use of 3.4 equiv of zinc reagent). The yield of the compound
1
9
(
80% yield) was determined by F NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column
1
3
chromatography (pentane only) gave the desired product (41.3 mg, 80% yield) as a colorless oil. H NMR (300 MHz, CDCl ) δ 2.80-
.10 (m, 3H), 5.79 (td, 1H, JH-F = 56.4, J = 3.0 Hz), 6.10 (dd, 1H, J = 15.9, 8.4 Hz), 6.40 (d, 1H, J = 15.9 Hz), 7.20-7.33 (m, 10H); C
1
3
3
3
NMR (75 MHz, CDCl ) δ 34.8 (t, JC-F = 4.1 Hz), 48.9 (t, JC-F = 19.5 Hz), 117.1 (t, JC-F = 243.9 Hz), 124.1 (t, JC-F = 4.5 Hz), 126.4,
26.5, 127.7, 128.5, 128.6, 129.3, 134.7, 136.7, 138.2; 1 F NMR (282 MHz, CDCl
9
) δ -123.7 (ddd, 1F, JF-F = 278.6, JF-H = 56.5, 15.2
1
3
-
1
Hz), -122.4 (ddd, 1F, JF-F = 277.7, JF-H = 56.9, 13.6 Hz); FT-IR (neat, cm ) 695, 745, 966, 1049, 1129, 1381, 1454, 1603, 2857, 2933,
2
964, 3028.
4
.3.4. (E)-1-chloro-2-(4,4-difluoro-3-methylbut-1-en-1-yl)benzene (2d)
The titled compound was synthesized according to General Procedure B. The yield of the compound (94% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (37.6 mg, 87% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.26 (d, 3H, J = 7.0 Hz), 2.77-2.93 (m, 1H), 5.73
(
td, 1H, JH-F = 56.7, J = 3.8 Hz), 6.13 (dd, 1H, J = 16.0, 7.8 Hz), 6.93 (d, 1H, J = 15.9 Hz), 7.16-7.25 (m, 2H), 7.36 (dd, 1H, J = 7.3, 1.4
1
3
Hz), 7.53 (dd, 1H, J = 7.4, 2.1 Hz); C NMR (75 MHz, CDCl
Hz), 126.8, 126.9, 128.7, 129.1 (t, JC-F = 5.3 Hz), 129.2, 129.7, 133.0, 134.9; F NMR (282 MHz, CDCl
2
2
3
) δ 12.8 (t, JC-F = 4.9 Hz), 41.5 (t, JC-F = 20.2 Hz), 117.9 (t, JC-F = 242.2
1
9
3
) δ -123.1 (ddd, 1F, JF-F =
-
1
76.5, JF-H = 56.4, 15.0 Hz), -121.5 (ddd, 1F, JF-F = 278.4, JF-H = 55.3, 15.4 Hz); FT-IR (neat, cm ) 751, 995, 1054, 1120, 1390, 1471,
885, 2977, 3063.
4
.3.5. (E)-1-chloro-3-(4,4-difluoro-3-methylbut-1-en-1-yl)benzene (2e)
The titled compound was synthesized according to General Procedure B. The yield of the compound (96% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (36.9 mg, 85% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.23 (d, 3H, J = 7.0 Hz), 2.68-2.89 (m, 1H), 5.71
(
(
td, 1H, JH-F = 56.7, JH-F = 3.9 Hz), 6.15 (dd, 1H, J = 16.0, 7.8 Hz), 6.48 (d, 1H, J = 16.0 Hz), 7.19-7.28 (m, 3H), 7.37 (s, 1H); 13C NMR
75 MHz, CDCl ) δ 12.9 (t, JC-F = 4.9 Hz), 41.3 (t, JC-F = 20.2 Hz), 117.9 (t, JC-F = 242.2 Hz), 124.6, 126.3, 127.7, 127.9 (t, JC-F = 4.9
Hz), 129.8, 131.7, 134.6, 138.6; F NMR (282 MHz, CDCl
277.4, JF-H 57.3, 14.0 Hz); FT-IR (neat, cm ) 684, 779, 966, 1059, 1125, 1390, 1595, 2885, 2977, 3029.
3
1
9
3
) δ -122.9 (ddd, 1F, JF-F = 276.5, JF-H = 56.2, 14.8 Hz), -121.5 (ddd, 1F, JF-F
-
1
=
4
.3.6. (E)-1-chloro-4-(4,4-difluoro-3-methylbut-1-en-1-yl)benzene (2f)
1
9
The titled compound was synthesized according to General Procedure B. The yield of the compound (97% yield) was determined by F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (34.3 mg, 79% yield) as a colorless oil. H NMR (300 MHz, CDCl
(
3
) δ 1.22 (d, 3H, J = 7.0 Hz), 2.67-2.88 (m, 1H), 5.70
td, 1H, JH-F = 56.7, J = 3.9 Hz), 6.11 (dd, 1H, J = 16.0, 7.8 Hz), 6.48 (dd, 1H, J = 16.0, 0.8 Hz), 7.29 (br, 4H); 13C NMR (75 MHz,
3
CDCl ) δ 12.9 (t, JC-F = 4.5 Hz), 41.3 (t, JC-F = 20.2 Hz), 117.9 (t, JC-F = 242.2 Hz), 127.0 (t, JC-F = 5.3 Hz), 127.5, 128.7, 131.7, 133.3,
1
9
1
35.2; F NMR (282 MHz, CDCl
3
) δ -122.9 (ddd, 1F, JF-F = 276.5, JF-H = 56.6, 15.1 Hz), -121.5 (ddd, 1F, JF-F = 276.7, JF-H = 56.6, 14.3
-
1
Hz); FT-IR (neat, cm ) 701, 806, 968, 1057, 1390, 1492, 2855, 2962, 3032.
4
.3.7. (E)-1-bromo-4-(4,4-difluoro-3-methylbut-1-en-1-yl)benzene (2g)
The titled compound was synthesized according to General Procedure B. The yield of the compound (>99% yield) was determined by
1
9
F NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave
1
the desired product (40.6 mg, 78% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.24 (d, 3H, J = 7.0 Hz), 2.69-2.89 (m, 1H),
5
.72 (td, 1H, JH-F = 56.8, J = 3.9 Hz), 6.14 (dd, 1H, J = 16.0, 7.8 Hz), 6.49 (d, 1H, J = 16.0 Hz), 7.24-7.28 (m, 2H), 7.44-7.48 (m, 2H);
1
3
3
C NMR (75 MHz, CDCl ) δ 12.9 (t, JC-F = 4.5 Hz), 41.4 (t, JC-F = 20.2 Hz), 117.9 (t, JC-F = 242.2 Hz), 121.5, 127.1 (t, JC-F = 5.3 Hz),
1
9
1
2
3
27.9, 131.7, 131.8, 135.7; F NMR (282 MHz, CDCl ) δ -122.9 (ddd, 1F, JF-F = 276.1, JF-H = 56.3, 15.2 Hz), -121.5 (ddd, 1F, JF-F =
-
1
75.8, JF-H = 55.5, 13.8 Hz); FT-IR (neat, cm ) 804, 994, 1072, 1124, 1390, 1487, 1588, 2976, 3030.
4
.3.8. (E)-1-(4,4-difluoro-3-methylbut-1-en-1-yl)-4-(trifluoromethyl)benzene (2h)

The titled compound was synthesized according to General Procedure B. The yield of the compound (78% yield) was determined by 19
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
F
1
desired product (39.6 mg, 79% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.25 (d, 3H, J = 7.0 Hz), 2.71-2.92 (m, 1H), 5.72
(
td, 1H, JH-F = 56.7, J = 3.8 Hz), 6.24 (dd, 1H, J = 16.1, 7.7 Hz), 6.57 (d, 1H, J = 16.0 Hz), 7.47 (d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 8.3
1
3
Hz); C NMR (75 MHz, CDCl
25.5 (q, JC-F = 3.7 Hz), 126.5, 129.0 (t, JC-F = 5.3 Hz), 129.5 (q, JC-F = 32.2 Hz), 131.7, 140.2; F NMR (282 MHz, CDCl
ddd, 1F, JF-F = 275.9, JF-H = 44.6, 17.2 Hz), -121.6 (ddd, 1F, JF-F = 269.0, JF-H = 48.7, 14.1 Hz), -62.5 (s, 3F); FT-IR (neat, cm ) 818,
3
) δ 12.8 (t, JC-F = 4.5 Hz), 41.4 (t, JC-F = 20.2 Hz), 117.8 (t, JC-F = 242.6 Hz), 124.2 (q, JC-F = 270.0 Hz),
1
9
1
(
3
) δ -122.6
-
1
1
067, 1125, 1326, 1462, 1617, 2889, 2981, 3044.
4
.3.9. (E)-1-(4,4-difluoro-3-methylbut-1-en-1-yl)-4-methylbenzene (2i)
The titled compound was synthesized according to General Procedure B. The yield of the compound (73% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (26.8 mg, 68% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.22 (d, 3H, J = 7.0 Hz), 2.35 (s, 3H), 2.69-2.85
(
m, 1H), 5.70 (td, 1H, JH-F = 56.8, J = 3.9 Hz), 6.07 (dd, 1H, J = 16.0, 7.8 Hz), 6.50 (d, 1H, J = 16.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 7.28
1
3
(
(
d, 2H, J = 8.1 Hz); C NMR (75 MHz, CDCl
3
) δ 12.9 (t, JC-F = 4.9 Hz), 21.2, 41.4 (t, JC-F = 19.9 Hz), 118.1 (t, JC-F = 242.2 Hz), 125.3
) δ -123.4 (ddd, 1F, JF-F = 275.5, JF-H = 57.2, 16.0 Hz), -
t, JC-F = 4.9 Hz), 126.2, 129.3, 132.7, 134.0, 137.5; 19F NMR (282 MHz, CDCl
3
-
1
1
21.1 (ddd, 1F, JF-F = 275.5, JF-F = 59.1, 13.6 Hz); FT-IR (neat, cm ) 799, 995, 1058, 1126, 1389, 1515, 2856, 2925, 2972.
4
.3.10. (E)-1-(4,4-difluoro-3-methylbut-1-en-1-yl)-4-methoxybenzene (2j)
1
9
The titled compound was synthesized according to General Procedure B. The yield of the compound (71% yield) was determined by
F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (30.1 mg, 71% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.21 (d, 3H, J = 5.0 Hz), 2.65-2.85 (m, 1H), 3.81
(
(
J
s, 3H), 5.69 (td, 1H, JH-F = 56.9, J = 3.9 Hz), 5.98 (dd, 1H, J = 16.0, 7.8 Hz), 6.47 (d, 1H, J = 16.0 Hz), 6.84-6.88 (m, 2H), 7.29-7.34
1
3
m, 2H); C NMR (75 MHz, CDCl
C-F = 4.9 Hz), 127.5, 129.6, 132.3, 159.3; F NMR (282 MHz, CDCl
2
ddd, 1F, JF-F = 275.4, JF-H = 55.1, 13.6 Hz); HRMS (APCI-TOF) calcd for C12H15OF [M+H] : 213.1091, found: 213.1100; FT-IR
3
) δ 12.9 (t, JC-F = 4.9 Hz), 41.4 (t, JC-F = 20.2 Hz), 55.3, 114.0, 118.2 (t, JC-F = 242.3 Hz), 124.1 (t,
1
9
3
) δ -123.3 (ddd, 1F, JF-F = 275.5, JF-H = 57.2, 15.7 Hz), -121.1
+
(
(
-
1
neat, cm ) 814, 993, 1037, 1176, 1253, 1513, 1607, 2838, 2971.
4
.3.11. (E)-5-(4,4-difluoro-3-methylbut-1-en-1-yl)benzo[d][1,3]dioxole (2k)
The titled compound was synthesized according to General Procedure B. The yield of the compound (90% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane/Et O = 20/1)
) δ 1.21 (d, 3H, J = 7.0 Hz), 2.64-2.84 (m,
H), 5.68 (td, 1H, JH-F = 56.8, J = 3.9 Hz), 5.94 (dd, 1H, J = 15.9, 7.9 Hz), 5.95 (s, 2H), 6.44 (d, 1H, J = 15.9 Hz), 6.75 (d, 1H, J = 8.0
2
1
gave the desired product (42.9 mg, 95% yield) as a colorless oil. H NMR (300 MHz, CDCl
1
Hz), 6.80 (dd, 1H, J = 8.0, 1.5 Hz), 6.92 (d, 1H, J = 1.6 Hz); C NMR (75 MHz, CDCl
Hz), 101.1, 105.6, 108.3, 118.0 (t, JC-F = 244.6 Hz), 121.0, 124.5 (t, JC-F = 5.3 Hz), 131.3, 132.4, 147.3, 148.1; F NMR (282 MHz,
CDCl ) δ -123.2 (ddd, 1F, JF-F = 276.0, JF-H = 57.3, 16.2 Hz), -121.2 (ddd, 1F, JF-F = 276.0, JF-H = 59.4, 13.5 Hz); HRMS (APCI-TOF)
calcd for C12
3
13
3
) δ 12.9 (t, JC-F = 4.5 Hz), 41.3 (t, JC-F = 20.2
1
9
3
+
-1
13 2 2
H F O [M+H] : 227.0884, found: 227.0894; FT-IR (neat, cm ) 800, 1040, 1251, 1357, 1446, 1492, 1606, 2780, 2902,
2
976.
4
.3.12. (E)-3-(4,4-difluoro-3-methylbut-1-en-1-yl)pyridine (2l) The titled compound was synthesized according to General Procedure
1
9
B. The yield of the compound (74% yield) was determined by F NMR analysis using benzotrifluoride as an internal standard.
Purification by silica-gel column chromatography (pentane/Et O = 2/1, 1% Et N) gave the desired product (26.7 mg, 73% yield) as a
) δ 1.23 (d, 3H, J = 7.2 Hz), 2.73-2.88 (m, 1H), 5.71 (td, 1H, JH-F = 56.6, J = 3.8 Hz), 6.20 (dd,
2
3
1
colorless oil. H NMR (300 MHz, CDCl
3
1
3
1
H, J = 16.1, 7.7 Hz), 6.52 (d, 1H, J = 16.1 Hz), 7.26 (s, 1H), 7.71 (d, 1H, J = 7.8 Hz), 8.49 (br, 1H), 8.60 (br, 1H); C NMR (75 MHz,
3
CDCl ) δ 12.9 (t, JC-F = 4.9 Hz), 41.4 (t, JC-F = 20.2 Hz), 117.7 (t, JC-F = 242.2 Hz), 123.6, 128.8 (t, JC-F = 5.3 Hz), 129.4, 132.5, 132.9,
1
9
1
5
1
3
48.1, 148.5; F NMR (282 MHz, CDCl ) δ -122.7 (ddd, 1F, JF-F = 276.6, JF-H = 56.3, 14.7 Hz), -121.7 (ddd, 1F, JF-F = 277.7, JF-H =
+
-1
7.2, 15.1 Hz); HRMS (ESI-TOF) calcd for C10
462, 1570, 2853, 2924.
2
H12NF [M+H] : 184.0938, found: 184.0947; FT-IR (neat, cm ) 709, 793, 1060, 1377,
4
.3.13. (E)-1-(4,4-difluoro-3-methylbut-1-en-1-yl)naphthalene (2m)
The titled compound was synthesized according to General Procedure B. The yield of the compound (79% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (38.1 mg, 82% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.33 (d, 3H, J = 7.0 Hz), 2.83-3.03 (m, 1H), 5.79
(
8
1
td, 1H, JH-F = 56.8, J = 4.0 Hz), 6.16 (dd, 1H, J = 15.7, 7.8 Hz), 7.30 (d, 1H, J = 15.9 Hz), 7.43-7.61 (m, 4H), 7.79-7.89 (m, 2H), 8.09-
1
3
.12 (m, 1H); C NMR (75 MHz, CDCl
25.6, 125.8, 126.1, 128.1, 128.6, 129.7 (t, JC-F = 4.9 Hz), 130.3, 131.1, 133.6, 134.7; F NMR (282 MHz, CDCl
3
) δ 13.1 (t, JC-F = 12.4 Hz), 41.7 (t, JC-F = 20.2 Hz), 118.1 (t, JC-F = 242.2 Hz), 123.7, 124.0,
1
9
3
) δ -123.0 (ddd, 1F,
-
1
J
F-F = 275.8, JF-H = 57.0, 15.6 Hz), -121.2 (ddd, 1F, JF-F = 276.7, JF-H = 56.7, 14.0 Hz); FT-IR (neat, cm ) 775, 795, 969, 993, 1056,
1
392, 1460, 1509, 1591, 2977, 3047, 3061.
4
.3.14. (E)-(4,4-difluoro-3-methylbut-1-en-1-yl)cyclohexane (2n)
The titled compound was synthesized according to General Procedure B. The yield of the compound (84% yield) was determined by 19F
NMR analysis using benzotrifluoride as an internal standard. Purification by silica-gel column chromatography (pentane only) gave the
1
desired product (32.3 mg, 86% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) δ 1.00-1.34 (m, 5H), 1.10 (d, 3H, J = 6.5 Hz), 1.62-
1
.72 (m, 5H), 1.90-1.99 (m, 1H), 2.42-2.62 (m, 1H), 5.29 (ddd, 1H, J = 15.6, 7.6, 1.2 Hz), 5.54 (dd, 1H, J = 15.9, 6.6 Hz), 5.57 (td, 1H,
1
3
3
JH-F = 57.1, J = 4.0 Hz); C NMR (75 MHz, CDCl ) δ 12.9 (t, JC-F = 4.9 Hz), 26.0, 26.1, 32.9, 40.7, 40.9 (t, JC-F = 20.2 Hz), 118.5 (t, JC-

= 241.9 Hz), 124.0 (t, JC-F = 5.3 Hz), 140.0; 19F NMR (282 MHz, CDCl
) δ -124.1 (ddd, 1F, JF-F = 274.8, JF-H = 56.8, 16.7 Hz), -121.0
ddd, 1F, JF-F = 274.1, JF-H = 57.1, 12.9 Hz); FT-IR (neat, cm ) 968, 995, 1057, 1123, 1365, 1390, 1450, 2853, 2926.
F
3
-
1
(
4
4
.4. Determination of absolute configuration of 2b (Scheme 3)
.4.1. Synthetic procedure of (R)-2-methyl-4-phenylbutan-1-ol [(R)-8] [12]
2 2
To a test tube equipped with a magnetic stir bar were added [RuCl (p-cymene)] (11 mg, 0.018 mmol, 0.6 mol%) and (R)-MeO-
BIPHEP (21 mg, 0.036 mmol, 1.2 mol%) in methanol (1 mL) at room temperature under argon atmosphere. The solution was stirred at
room temperature for 3 h. To a stainless steel autoclave equipped with a magnetic stir bar were added 2-phenethylacrylic acid 6 (500
mg, 2.84 mmol) and triethylamine (363 μL, 2.84 mmol) in methanol (9 mL) and then the solution of ruthenium complex was added at
room temperature under argon atmosphere. It was pressurized with H
solvent was evapolated and the residue was dissolved in CH Cl (20 mL). The suspension was treated by 10% Na
aqueous phase was at pH = 11 and washed with Et O. The aqueous phase was acidified until pH = 1 and extracted with CH
3), and the combined organic phases were dried with anhydrous MgSO . After filtration and concentration under vacuum, (R)-2-
methyl-4-phenylbutyric acid (R)-7 (435 mg, 86% yield) was obtained as a colourless liquid. The product was known compound and the
2
(ca. 50 atm) and stirred at room temperature for 48 h. The
CO aq. until the
Cl (15 mL
2
2
2
3
2
2
2
×
4
1
3
following data were in good accordance with the previous data [12,20]. H NMR (300 MHz, CDCl ) δ 1.24 (d, 3H, J = 7.0 Hz), 1.69-
2
2
1
.81 (m, 1H), 1.99-2.09 (m, 1H), 2.48-2.55 (m, 1H), 2.65-2.73 (m, 2H), 7.17-7.21 (m, 3H), 7.28-7.31 (m, 2H); [α]
D
-18.7 (c 1.50,
2
5
CHCl
3
), (R)-isomer in ref 12: [α]
D
-28.0 (neat), 96% ee.
To a suspention of LiAlH
4
(185 mg, 4.88 mmol) in THF (2 mL) was added (R)-7 (435 mg, 2.44 mmol) in THF (3 mL) at 0 °C. The
resulting mixture was refluxed for 2 h. To a mixture, in order of water (0.18 mL), 15% NaOH aq. (0.18 mL), and water (0.4 mL) were
added. After the mixture was stirred for several minutes, the precipitation was generated. The reaction mixture was filtered through a
pad of celite with the aid of Et
2
O. After concentration under vacuum, the crude product was purified by silica-gel column
chromatography to give the product (R)-8 as a colourless liquid. The product was known compound and the following data were in
1
3
good accordance with the previous data [12,21]. H NMR (300 MHz, CDCl ) δ 0.99 (d, 3H, J = 6.6 Hz), 1.28-1.40 (br s, 1H), 1.40-1.52
2
2
(
1
m, 1H), 1.64-1.83 (m, 2H), 2.55-2.76 (m, 2H), 3.44-3.57 (m, 2H), 7.15-7.30 (m, 5H); [α]
D
3
+10.4 (c 2.47, CHCl ), (R)-isomer in ref
2
5
2: [α]
D
3
+19.1 (c 5.0, CHCl ), 96% ee.
4
.4.2. Synthetic procedure of (R)-2-methyl-4-phenylbutanal [(R)-9]
To a test tube equipped with a magnetic stir bar were added alcohol (R)-8 (164 mg, 1.0 mmol), Dess-Martin periodinane (636 mg, 1.5
mmol), and dry CH Cl (3 mL) at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature for
.5 h and then quenched with sat. NaHCO aq. (3 mL) and sat. Na SO aq. (3 mL). The organic layer was separated and the aqueous
phase was extracted with CH Cl (10 mL × 2). The combined organic phases were dried over Na SO . After filtration and evaporation
of the solvent, the crude product was purified by silica-gel column chromatography (Hexane/EtOAc = 15/1) to give chiral aldehyde (R)-
2
2
2
3
2
3
2
2
2
4
1
9
(105 mg, 65% yield). The product was known compound as racemate and H NMR data were in good accordance with the previous
1
data [22]. H NMR (300 MHz, CDCl
3
) δ 1.16 (d, 3H, J = 7.0 Hz), 1.62-1.74 (m, 1H), 2.01-2.13 (m, 1H), 2.32-2.44 (m, 1H), 2.64-2.71
(m, 2H), 7.18-7.23 (m, 3H), 7.28-7.33 (m, 2H), 9.63 (d, 1H, J = 1.8 Hz).
4
.4.3. Synthetic procedure of (R)-(4,4-difluoro-3-methylbutyl)benzene [(R)-10] (Scheme 3a)
To a test tube equipped with a magnetic stir bar was added aldehyde (R)-9 (105 mg, 0.65 mmol) in CH
temperature under argon atmosphere. After the solution was cooled to 0 °C, N,N-diethylaminosulfur trifluoride (94 μL, 0.72 mmol) was
added dropwise. The reaction mixture was stirred at room temperature for 24 h and then quenched with sat. NaHCO aq. (10 mL). The
organic layer was separated and the aqueous phase was extracted with CH Cl (10 mL × 3) and the combined organic phases were dried
over Na SO . After filtration and evaporation of the solvent, the crude product was purified by silica-gel column chromatography
pentane only) to give difluorinated product (R)-10 (35.4 mg, 30% yield) as pale yellow oil. H NMR (300 MHz, CDCl
J = 6.7 Hz), 1.49-1.60 (m, 1H), 1.84-2.00 (m, 2H), 2.57-2.67 (m, 1H), 2.71-2.80 (m, 1H), 5.64 (td, 1H, JH-F = 56.9, J = 3.7 Hz), 7.17-
2 2
Cl (1.5 mL) at room
3
2
2
2
4
1
(
3
) δ 1.06 (d, 3H,
1
9
7
F
.22 (m, 3H), 7.27-7.32 (m, 2H); F NMR (282 MHz, CDCl
3
) δ -124.2 (ddd, 1F, JF-F = 277.0, JF-H = 57.2, 16.0 Hz), -122.5 (ddd, 1F, JF-
2
1
= 275.8, JF-H = 55.7, 13.6 Hz); [α]
D
+8.2 (c 1.79, CHCl ), 70% ee.
3
4
.4.4. Synthetic procedure of (S)-(4,4-difluoro-3-methylbutyl)benzene [(S)-10] (Scheme 3b)
To a test tube equipped with a rubber septum and a magnetic stir bar were added the difluoromethylated product (S)-2b (36.4 mg, 0.2
mmol, 90% ee), palladium (10% on carbon, wetted with ca. 55% water) (33 mg, 0.02 mmol, 10 mol%), and ethanol (1 mL) at room
temperature under argon atmosphere. Then H
2
balloon was attached to the test tube and the suspension was stirred at room temperature
for 2.5 h. The resulting mixture was directly passed through short silica-gel column (pentane only) to isolate the reducted product (S)-10
1
(
2
3
29.4 mg, 94% yield) as pale yellow oil. H NMR (300 MHz, CDCl ) δ 1.06 (d, 3H, J = 6.7 Hz), 1.50-1.62 (m, 1H), 1.84-2.00 (m, 2H),
1
3
.57-2.67 (m, 1H), 2.71-2.81 (m, 1H), 5.64 (td, 1H, JH-F = 56.9, J = 3.6 Hz), 7.18-7.23 (m, 3H), 7.28-7.33 (m, 2H); C NMR (75 MHz,
3
CDCl ) δ 12.3 (t, JC-F = 5.6 Hz), 31.4 (t, JC-F = 4.5 Hz), 32.8, 36.7 (t, JC-F = 19.5 Hz), 119.2 (t, JC-F = 240.4 Hz), 126.0, 128.3, 128.5,
1
9
1
3
41.6; F NMR (282 MHz, CDCl ) δ -124.2 (ddd, 1F, JF-F = 276.7, JF-H = 56.7, 16.4 Hz), -122.5 (ddd, 1F, JF-F = 277.1, JF-H = 57.8, 13.5
-
1
21
Hz); FT-IR (neat, cm ) 699, 747, 990, 1057, 1396, 1455, 1496, 1604, 2865, 2945, 3029; [α]
column, CHIRALCEL OD-3, Hexane/2-Propanol = 99/1, flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) t
.1 min, t of major (S)-isomer 10.5 min.
D
-8.4 (c 2.90, CHCl
3
), 80% ee; HPLC
(
9
R
of minor (R)-isomer
R
Acknowledgments
This research was supported by JST ACT-C Grant Number JPMJCR12Z7 and JSPS KAKENHI Grant Number 26620078.

References and notes
1
.
(a) K. Müller, C. Faeh, F. Diederich, Science 317 (2007) 1881-1886;
(b) W. K. Hagmann, J. Med. Chem. 51 (2008) 4359-4369;
(c) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432-2506.
2
.
(a) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 111 (2011) 455-529;
(
(
(
b) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 111 (2011) 4475-4521;
c) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52 (2013) 8214-8264;
d) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications (2nd, completely revised and enlarged ed.), Wiley-VCH, Weinheim,
Germany, 2013.
3
4
.
.
(a) J. Hu, W. Zhang, F. Wang, Chem. Commun. (2009) 7465-7478;
(
(
(
(
b) B. Chen, D. Vicic, Top. Organomet. Chem. 52 (2014) 113-142;
c) C. Ni, J. Hu, Synthesis 46 (2014) 842-863;
d) M.-C. Belhomme, T. Besset, T. Poisson, X. Pannecoucke, Chem. Eur. J. 21 (2015) 12836-12865;
e) J. Rong, C. Ni, J. Hu, Asian J. Org. Chem. 6 (2017) 139-152.
(a) R. P. Singh, J. M. Shreeve, Synthesis (2002) 2561-2578;
b) N. Al-Maharik, D. O’Hagan, Aldrichimica Acta 44 (2011) 65-75.
(
5
6
.
.
Y. Gu, X.-B. Leng, Q. Shen, Nat. Commun. 5 (2014) 5405-5411.
Other reports of catalytic direct difluoromethylation with (difluoromethyl)metal reagents, see:
(
(
(
a) D. Chang, Y. Gu, Q. Shen, Chem. Eur. J. 21 (2015) 6074-6078;
b) J. R. Bour, S. K. Kariofillis, M. S. Sanford, Organometallics 36 (2017) 1220-1223;
c) C. Lu, Y. Gu J. Wu, Y. Gu, Q. Shen, Chem. Sci. (2017) DOI: 10.1039/c7sc00691h;
7
8
.
.
L. Xu, D. A. Vicic, J. Am. Chem. Soc. 138 (2016) 2536-2539.
(a) H. Serizawa, K. Ishii, K. Mikami, K. Aikawa, Org. Lett. 18 (2016) 3686-3689;
(b) K. Aikawa, H. Serizawa, K. Ishii, K. Mikami, Org. Lett. 18 (2016) 3690-3693.
9
1
.
D. J. Burton, G. A. Hartgraves, J. Fluorine Chem. 128 (2007) 1198-1215.
0. For reviews of copper-catalyzed allylic substitution, see:
(a) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez, Chem. Rev. 108 (2008) 2796-2823;
(b) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 108 (2008) 2824-2852;
(c) J. F. Teichert, B. L. Feringa, Angew. Chem. Int. Ed. 49 (2010) 2486-2528.
1
1. Copper-catalyzed allylic substitution for introduction of functionalized difluoromethyl (-CF
2
R) groups, see:
(
(
(
a) A. A. Zemtsov, N. S. Kondratyev, V. V. Levin, M. I. Struchkova, A. D. Dilman, J. Org. Chem. 79 (2014) 818-822;
b) M. D. Kosobokov, V. V. Levin, A. A. Zemtsov, M. I. Struchkova, A. A. Korlyukov, D. E. Arkhipov, A. D. Dilman, Org. Lett. 16 (2014) 1438-1441;
c) V. V. Levin, A. A. Zemtsov, M. I. Struchkova, A. D. Dilman, J. Fluorine Chem. 171 (2015) 97-101.
1
1
1
1
1
1
1
1
2
2
2. A. Scrivanti, S. Bovo, A. Ciappa, U. Matteoli, Tetrahedron Lett. 47 (2006) 9261-9265.
3. L. B. Delvos, D. J. Vyas, M. Oestreich, Angew. Chem. Int. Ed. 52 (2013) 4650-4653.
4. G. Cravotto, G. B. Giovenzana, M. Sisti, G. Palmisano, Tetrahedron 54 (1998) 1639-1646.
5. C. Li, J. Xing, P. Huynh, P. Jiang, Y. J. Zhang, Org. Lett. 14 (2012) 390-393.
6. J. Zhao, J. Ye, Y. J. Zhang, Adv. Synth. Catal. 355 (2013) 491-498.
7. T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H. Miura, K. Yanagi, J. Am. Chem. Soc. 111 (1989) 6301-6311.
8. P. A. Procopiou, S. P. Baugh, S. S. Flack, G. G. Inglis, J. Org. Chem. 63 (1998) 2342-2347.
9. U. Kazmaier, F. L. Zumpe, Eur. J. Org. Chem. (2001) 4067-4076.
0. Z. Wang, L. Zhu, F. Yin, Z. Su, Z. Li, C. Li, J. Am. Chem. Soc. 134 (2012) 4258-4263.
1. D. S. G. Henriques, K. Zimmer, S. Klare, A. Meyer, E. Rojo-Wiechel, M. Bauer, R. Sure, S. Grimme, O. Schiemann, R. A. Flowers II, A. Gansäuer, Angew.
Chem. Int. Ed. 55 (2016) 7671-7675.
2
2. R. W. Hoffmann, E. Haeberlin, T. Rohde, Synthesis (2002) 207-212.

Scheme 1. Catalytic or non-catalytic direct difluoromethylations with (difluoromethyl)zinc reagents
Scheme 2. Copper-catalyzed regioselective and stereospecific allylic difluoromethyations
Scheme 3. Determination of absolute configuration of product 2b

Table 1. Catalytic allylic difluoromethylation of cinnamyl chloride

Table 2. Catalytic allylic difluoromethylation with -regioselectivity

a
Table 3. Scope of allyl carbonates as substrates