Gold-catalyzed electrophilic activation of 1,1-difluoroallenes: α- and γ-selective addition of heteroatom nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2020.109452

Transition metal-catalyzed nucleophilic addition of heteroatom nucleophiles to 1,1-difluoroallenes has been demonstrated here for the first time. Treatment of 1,1-difluoroallenes with O-nucleophiles, such as phenols, carboxylic acids, and sulfonic acids, facilitated unprecedented α-selective addition in the presence of AuCl₃ or AuCl(PPh₃)/AgSbF₆ catalysts which afforded 1,1-difluoroallyl alcohol derivatives. In contrast, amides and thiols underwent γ-selective addition to 1,1-difluoroallenes on their nitrogen or sulfur centers to provide 3,3-difluoroallyl amine and thiol derivatives.

Full text of DOI:10.1016/j.jfluchem.2020.109452

Journal Pre-proof
Gold-catalyzed electrophilic activation of 1,1-difluoroallenes: ␣- and
␥-selective addition of heteroatom nucleophiles
Kohei Fuchibe, Masashi Abe, Mizore Sasaki, Junji Ichikawa
PII:
S0022-1139(20)30003-8
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109452
FLUOR 109452
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
13 November 2019
13 December 2019
15 December 2019
Please cite this article as: { doi: https://doi.org/
This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.
© 2019 Published by Elsevier.

1
Gold-Catalyzed Electrophilic Activation of 1,1-Difluoroallenes: - and -Selective addition of
Heteroatom Nucleophiles
Kohei Fuchibe,a Masashi Abe,a Mizore Sasaki,a and Junji Ichikawaa*
a Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki
305-8571, Japan
Graphical abstract
Highlights

Catalytic addition of heteroatom nucleophiles to 1,1-difluoroallenes was studied.> O-nucleophiles underwent -
selective addition in the presence of Au catalysts.> Phenols, carboxylic acids, and sulfonic acids afforded 1,1-
difluoroallyl alcohol derivatives.> N- and S-nucleophiles underwent -selective addition in the presence of Au
catalysts.> Amides and thiols afforded 3,3-difluoroallyl amine and thiol derivatives.

2
Dedicated to Professor Norio Shibata with recognition on the occasion of his being awarded the 2019
ACS Award for Creative Work in Fluorine Chemistry.
ABSTRACT: Transition metal-catalyzed nucleophilic addition of heteroatom nucleophiles to 1,1-
difluoroallenes has been demonstrated here for the first time. Treatment of 1,1-difluoroallenes with O-
nucleophiles, such as phenols, carboxylic acids, and sulfonic acids, facilitated unprecedented -selective
addition in the presence of AuCl3 or AuCl(PPh3)/AgSbF6 catalysts which afforded 1,1-difluoroallyl
alcohol derivatives. In contrast, amides and thiols underwent -selective addition to 1,1-difluoroallenes
on their nitrogen or sulfur centers to provide 3,3-difluoroallyl amine and thiol derivatives.
KEYWORDS: Addition, carbocations, difluoroalkenes, difluoroallenes, gold

3
1. Introduction
1,1-Difluoroallenes, having cumulative double bonds and two vinylic fluorines, are fascinating
building blocks for the synthesis of both cyclic and acyclic compounds with one or two fluorine
substituents [1]. In the early stages of study, their cycloaddition reactions were extensively studied by
Dolbier Jr. [2], who reported regioselective [2 + 4] [3] and [2 + 3] [4] cycloaddition (on their non-
fluorinated double bond) and [2 + 2] cycloaddition (mainly on their fluorinated double bond) [5]. Over
the past decade, hydrometallation of 1,1-difluorinated allenes has emerged to provide synthetically
promising (2,2-difluorovinyl)metals and [1-(difluoromethyl)vinyl]metals, through the reaction on their
non-fluorinated and fluorinated double bonds, respectively [6].
As well as cycloaddition and hydrometallation, mentioned above, reactions of 1,1-difluoroallenes
with nucleophiles are of potential use. However, reports on these reactions have been limited only to the
following four examples: Thiolates underwent regioselective addition on the position  to the fluorine
substituents to produce 3,3-difluoroallyl sulfides (Scheme 1, Eq 1) [7]. Hammond reported two types of
nucleophilic substitution reactions, involving 1,1-difluoroallenes, that proceeded via attacks of carbon
and heteroatom nucleophiles on the  carbons, followed by elimination of either an allenylic bromine
(Eq 3) [8] or an allenylic fluorine substituent (Eq 4) [9]. Our group previously reported the three-
component coupling of monosubstituted 1,1-difluoroallenes with organocoppers and electrophiles on the
 and  positions (Eq 2) [10]. Thus, the electrophilicity of 1,1-difluoroallenes is only moderate, requiring
reactive nucleophiles. This defect could be rectified by a catalytic system; however, use of this solution
has never been reported.

4
Scheme 1. Reactions of 1,1-difluoroallenes with nucleophiles.
Recently, we reported an intramolecular Friedel–Crafts-type cyclization of 1,1-difluoroallenes,
promoted by an InBr3 catalyst [11]. Treatment of 1,1-difluoroallenes with InBr3 generated fluorine-
stabilized and charge-localized allylic cations (electrophilic activation) [11b]. Thus, we noted that
catalytically activated 1,1-difluoroallenes underwent cyclization with arene nucleophiles exclusively at
the  carbon to afford pinpoint-fluorinated polycyclic aromatic hydrocarbons.
Encouraged by these results, we envisaged that -selective addition of heteroatom nucleophiles, to
1,1-difluoroallenes, would be effected via electrophilic activation by metal catalysts. Herein, we disclose
unprecedented, gold-catalyzed, regioselective-addition of oxygen nucleophiles (phenols, carboxylic
acids, and sulfonic acids, Scheme 2). Amides and thiols, in contrast, underwent -selective addition to
1,1-difluoroallenes.

5
Scheme 2. Electrophilic activation of 1,1-difluoroallenes for addition of heteroatom nucleophiles.
2. Results and discussion
2.1. Preparation of 1,1-difluoroallenes
The required 1,1-difluoroallenes 1 were prepared by the difluorovinylidenation of aldehydes or
ketones (Scheme 3) [12]. Thus, aldehydes or ketones were treated with (2,2-difluoro-1-iodovinyl)lithium,
generated from commercially available 1,1,1-trifluoro-2-iodoethane and 2 equiv of LDA, followed by
acetic anhydride (for aldehydes) or isopropenyl acetate/TsOH (for ketones). The formed 3,3-difluoro-2-
iodoallyl acetates were then reduced with zinc metal to produce the desired 1,1-difluoroallenes through
elimination of Zn(OAc)I.
Scheme 3. Preparation of 1,1-difluoroallenes 1.

6
2.2. -Selective addition of oxygen nucleophiles
Using monosubstituted 1,1-difluoroallene 1a as a model substrate, the addition of phenol was
examined (Table 1). Difluoroallene 1a was treated with phenol (1.2 equiv) in the presence of metal
catalysts (and additives). When AuCl and AgSbF6 were employed, as a catalyst system in the presence
of molecular sieves 4A (MS 4A), the desired addition product 2a was obtained in a 62% yield, as a
single E isomer. Starting difluoroallene 1a was recovered in 26% (Entry 1). Formation of 2a indicated
that the addition took place regioselectively, at the position  to the fluorine substituents. The reaction
did not proceed in the absence of the gold complex, and the starting difluoroallene 1a was recovered
quantitatively (Entry 2). Even when the silver salt, AgSbF6, was not used, 2a was obtained in a similar
yield (65%), where the mass balance was poor (Entry 3). Whereas an Au(III) complex produced 2a in
higher yields with AgPF6 (71% yield, Entry 5), AgNTf2 (72% yield, Entry 6), and AgBF4 (73% yield,
Entry 7) [13], the use of AuCl3 alone gave the highest yield of 2a, which was isolated in a yield of 80%
(Entry 9, Catalyst A).[14]
Ligated Au complex also exhibited catalytic activity. When 1a was treated with phenol, in the
presence of catalytic amounts of AuCl(PPh3)/AgSbF6 and MS 4A, the addition product 2a was obtained
in a 54% yield (Entry 10, Catalyst B). When the reaction was performed in the absence of MS 4A,
phenyl ester 2a’ was obtained in a 34% yield (Entry 11), suggesting that MS 4A was necessary to
prevent undesired hydrolysis of the product 2a. InBr3, which was effective for the previous Friedel–
Crafts-type cyclization, gave poor results for the reaction with phenol, where starting 1a was not
recovered (Entry 12). PtCl2 showed catalytic activity while being moderate (a 54% yield of 2a, 1 day,
Entry 13).

7
Table 1.
Optimization in Addition of Oxygen Nucleophiles to 1,1-Difluoroallenes.
Entry
Metal Catalyst, mol%
AuCl, 4
AgX / mol%
AgSbF6, 5
AgSbF6, 11
–
MS 4A a t / h
2a / % b,c
1a / % (Recovery) b
1
2
3
4
5
6
7
8
+
+
+
+
+
+
+
+
+
+
–
3
62
26
99
4
–
overnight
trace
AuCl, 4
3
65
AuCl3, 3
AuCl3, 3
AuCl3, 3
AuCl3, 3
AuCl3, 3
AuCl3, 4
AgSbF6, 9
AgPF6, 9
AgNTf2, 9
AgBF4, 9
AgOTf, 9
–
9
64
15
9
9
71
9
72
5
9
73
7
9
52
21
–
9 d
15 min
78 (80)
10 e AuCl(PPh3), 3
AgSbF6, 3
AgSbF6, 5
–
3
54
trace
trace
–
11
12
13
AuCl(PPh3), 4
InBr3, 4
3
34 f
–
+
+
3
PtCl2, 4
–
1 day
54
–
R = CH2CH2Ph. a +: MS 4A 400 mg/1a 1 mmol; –: without MS 4A. b 19F NMR yield based on an internal standard
(CF3)2Cp-Tol2. c Isolated yield in parentheses. d Catalyst A. e Catalyst B. f Yield of 2a’.
The scope of the Au-catalyzed, -selective addition was next examined. We found that: (i) the
addition was applied to not only monosubstituted difluoroallenes but also disubstituted difluoroallenes
and (ii) Catalyst A was effective for less acidic oxygen nucleophiles while Catalyst B was effective for
more acidic oxygen nucleophiles (Table 2). As well as 1a, monosubstituted 1b, bearing a
dimethylmethylene moiety, underwent the addition with phenol [pKa (in DMSO) = 18.0] to afford the
corresponding product 2b in a 64% yield (E only, Catalyst A, Entry 2). The product 2b was
accompanied by fluoronaphthalene 5, whose formation was due to our previous cyclization/migration
sequence [11b] via the allylic cations. Disubstituted 1c underwent the addition with phenol yielding the

8
corresponding fluorinated allyl ether 2c in a 77% yield (E / Z = 77:23, Catalyst A, Entry 3). Acetic acid
[pKa (in DMSO) = 12.6], using Catalyst A, reacted with 1a to produce acetate 2d in an 85% yield (E
only), whereas a 62% yield of 2d was obtained with Catalyst B (Entry 4). Benzoic acid [pKa (in DMSO)
= 11.1] produced the corresponding benzoate 2e in high yields (E only) with both Catalyst A (a 93%
yield) and Catalyst B (a 96% yield, Entry 5). Trifluoroacetic acid [pKa (in DMSO) = 3.5] produced the
corresponding 2f in a 61% yield (E / Z = 84:16) with Catalyst A and a 94% yield (E only) with Catalyst
B (Entry 6). Finally, methanesulfonic acid [pKa (in DMSO) = 1.6], the most acidic among the examined
O-nucleophiles underwent the -selective addition to 1a leading to sulfonate 2g in a 92% yield (E only)
with Catalyst B, albeit giving a 74% yield (E / Z = 77:23, a 70% isolated yield) with Catalyst A (Entry 7).
Thus, the borderline of pKa was 11, and the -addition products were obtained from the less acidic
(pKa> 11) and the more acidic (pKa < 11) oxygen nucleophiles with Catalyst A and Catalyst B,
respectively. It is noteworthy that, throughout the studies in Table 2, substitution products 3 and
regioisomeric products (-addition products) 4 were not isolated. The gold catalyst facilitated the first -
selective addition of heteroatom nucleophiles to 1,1-difluoroallenes.

9
Table 2.
-Selective Addition of Oxygen Nucleophiles to 1,1-Difluoroallenes.
2 / %,a E / Z ratio
pKa (ROH)
in DMSO
Entry
1
ROH
Product
Catalyst A b
Catalyst B b
54 d
1
2
3
4
5
6
7
1a
1b
1c
1a
1a
1a
1a
PhOH
18.0 [15]
18.0 [15]
18.0 [15]
12.6 [16]
11.1 [16]
3.5 [17]
2a
2b
2c
2d
2e
2f
78 (80) c E only
E only
E only
PhOH
64 e
E only
PhOH
77
77:23
MeCO2H
PhCO2H
CF3CO2H
CH3SO3H
85 (74) E only
62
93
61
E only
96 (73) E only
84:16
94
92
E only
E only
1.6 [18]
2g
74 (70) 77:23
a 19F NMR yield based on an internal standard PhCF3. b Isolated yield in parentheses. c Table 1, Entry 9. d Table 1, Entry 10.
e Fluoronaphthalene 5 was obtained in 21% yield.
2.3. -Selective addition of nitrogen and sulfur nucleophiles
Under the gold-catalyzed conditions, -selective addition of nitrogen and sulfur nucleophiles was
observed. When 1,1-difluoroallene 1a was subjected to benzamide in the presence of AuCl3 (Catalyst A),
the addition proceeded regioselectively at the position  to the fluorine substituents to afford N-(3,3-
difluoroallyl)amide 6 albeit in a yield of 30%, where the amide reacted with 1a on its nitrogen center

10
regioselectively (Scheme 4, Eq 5) [19]. Performing the reaction with Catalyst B [AuCl(PPh3)/AgSbF6]
increased the yield of 6 to 81%. Benzenethiol also underwent the -addition to afford the corresponding
3,3-difluoroallyl thioether 7 in a 72% yield (Eq 6). In these cases, regioisomers (-addition products)
were not observed by 19F NMR spectroscopy.
Scheme 4. -Selective addition of nitrogen and sulfur nucleophiles to 1,1-difluoroallenes (R =
CH2CH2Ph).
2.4. Reaction mechanism
A plausible mechanism for the -addition is shown in Scheme 5. Coordination of 1,1-
difluoroallenes 1 to AuCl3 (Catalyst A) or (Ph3P)Au+ (Catalyst B) generates aurated difluoroallylic
cations 8, which allow the addition of oxygen nucleophiles onto the CF2 carbon. Subsequent proton
transfer eventually causes the regioselective formation of 1,1-difluoroallyl ethers and esters 2.

11
Scheme 5. Plausible mechanism.
Theoretical calculation of model systems 8’A (Catalyst A) and 8’B (Catalyst B) in Z- and E- forms
was performed to examine the structure of key difluoroallylic cations 8 [Figure 1, DFT, B3LYP/6-
31G*(C,H,O),LANL2DZ(Au)]. The optimized structures and their relative energies indicate that all the
CF2 () carbons possess positive charges (electrostatic charges, +0.75, +0.83, +0.71, and +0.82 for Z-
8’A, E-8’A, Z-8’B, and E-8’B, respectively), which is due to the -cation stabilizing effect of fluorine
substituents (Figure 2) [20].
Figure 1. Optimized structures and electrostatic charges of the key difluoroallylic cations (note that Z-
and E-8’A adopt a square planar geometry around Au).

12
Figure 2. -Cation stabilizing effect of fluorine.
The observed  selectivity might be attributed to the hardness of the O-nucleophiles, whose
selectivity is governed by the positive charges. In contrast, N- and S-nucleophiles undergo additions onto
not the -carbons but the -carbons of the 1,1-difluoroallenes.
The theoretical calculation also indicates that Z-8’A and Z-8’B are more stable than E-8’A and E-
8’B, by 2–3 kcal/mol, respectively. The instability of the E isomers is ascribed to steric repulsion
between CH3 and CF2 groups that causes the twisted double bonds [Me–C=C–CF2 dihedral angles: E-
8’A (20.6°); E-8’B (22.3°), H–C=C–CF2 dihedral angles: Z-8’A (0.1°) and Z-8’B (0.2°)]. The
diastereoselectivity (E selectivity) can be explained by the favored generation of more stable Z allylic
cations, whereas attempts to observe the key cationic intermediates by 19F NMR spectroscopy were
fruitless.
3. Conclusion
Treatment of 1,1-difluoroallenes with phenols, carboxylic acids, or sulfonic acids in the presence of
AuCl3 or (Ph3P)AuCl/AgSbF6 catalysts facilitated -selective addition to produce 1,1-difluoroallyl
alcohol derivatives. These products were predominantly obtained in E forms. In contrast, amides or
thiols underwent -selective addition to 1,1-difluoroallenes on their nitrogen or sulfur centers to give
3,3-difluoroallyl amine or thiol derivatives. This is the first report on the transition metal-catalyzed
nucleophilic addition of heteroatom nucleophiles to 1,1-difluoroallenes.

13
4. Experimental
4.1. General information
IR spectra were recorded on Horiba FT-300S spectrometer. NMR spectra were recorded on Bruker
Avance 500 or Jeol JNM ECS-400 spectrometers in CDCl3, at 500 or 400 MHz (1H NMR), at 126 or
100 MHz (13C NMR), and at 470 or 372 MHz (19F NMR). Chemical shift values were given in ppm
relative to internal Me4Si (for 1H NMR: δ = 0.00), CDCl3 (for 13C NMR: δ= 77.0), and C6F6 (for 19F
NMR: δ = 0.0) [21]. Mass spectra were taken with a JMS-T100GCV spectrometer (EI, 70 eV).
Elemental analyses were performed with a YANAKO MT-3 CHN Corder apparatus. Preparation and
spectral data of 1,1-difluoroallenes 1a–c were described in the previous publication [12].
Trifluoroacetate 2f was unstable under chromatographic purification and the spectral data were collected
using a sample of an extracted reaction mixture containing 2f (94 wt%).
4.2. Regioselective addition of oxygen nucleophiles to difluoroallenes
4.2.1. -Selective addition of phenol with AuCl3 (Catalyst A)
A 1,2-dichloroethane solution (3 mL) of 1,1-difluoroallene 1a (213 mg, 1.18 mmol) was added to a 1,2-
dichloroethane suspension (7 mL) of AuCl3 (15.3 mg, 50.4 µmol), phenol (150 mg, 1.42 mmol), and
molecular sieves 4A (400 mg) at room temperature. The mixture was heated at 70 °C for 1 h and then
filtered through celite using dichloromethane as an eluent. Phosphate buffer (pH = 7) was added and
organic materials were extracted with dichloromethane three times. The combined extracts were washed
with brine, and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the
residue was purified by column chromatography on silica gel (deactivated with 5 wt% H2O, Hexane–
EtOAc 50:1) to give 1,1-difluoroallyl ether 2a (258 mg, 80%) as a colorless liquid.

14
4.2.2. -Selective addition of benzoic acid with AuCl(PPh3)/AgSgF6 (Catalyst B)
A 1,2-dichloroethane solution (1.5 mL) of 1,1-difluoroallene 1a (37 mg, 0.21 mmol) was added to a 1,2-
dichloroethane suspension (0.5 mL) of AuCl(PPh3) (3 mg, 6 µmol), AgSbF6 (3 mg, 8 µmol), benzoic
acid (29 mg, 0.24 mmol), and molecular sieves 4A (80 mg) at room temperature. The mixture was
heated at 70 °C for 3 h and then filtered through celite using dichloromethane as an eluent. Phosphate
buffer (pH = 7) was added and organic materials were extracted with dichloromethane three times. The
combined extracts were washed with brine, and dried over anhydrous Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by column chromatography on silica gel
(deactivated with 10 wt% H2O, Hexane–EtOAc 20:1) to give 1,1-difluoroallyl ester 2e (46 mg, 73%) as
a colorless liquid.
4.2.3. -Selective addition of benzenethiol with AuCl(PPh3)/AgSgF6 (Catalyst B)
A 1,2-dichloroethane solution (3 mL) of 1,1-difluoroallene 1a (205 mg, 1.14 mmol) was added to a 1,2-
dichloroethane solution (7 mL) of AuCl(PPh3) (15 mg, 31 µmol), AgSbF6 (13 mg, 36 µmol), and
benzenethiol (140 µL, 1.37 mmol) at room temperature. The mixture was heated at 70 °C for 2 h.
Phosphate buffer (pH = 7) was added and organic materials were extracted with dichloromethane three
times. The combined extracts were washed with brine, and dried over anhydrous Na2SO4. After removal
of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel
(Hexane–EtOAc 50:1) to give 3,3-difluoroallyl thioether 7 (238 mg, 72%) as a colorless liquid.
4.3. Spectral data of products
4.3.1. (E)-1,1-Difluoro-1-phenoxy-5-phenylpent-2-ene (2a)
1H NMR (500 MHz, CDCl3): δ 2.43–2.50 (m, 2H), 2.76 (t, J = 8.0 Hz, 2H), 5.74 (dtt, J = 16.0, 2.0 Hz,
JHF = 6.0 Hz, 1H), 6.43 (dtt, J = 16.0, 6.8 Hz, JHF = 2.0 Hz, 1H), 7.16–7.23 (m, 6H), 7.27–7.35 (m, 4H);

15
13C NMR (126 MHz, CDCl3): δ 33.3, 34.6, 121.0 (t, JCF = 259 Hz), 121.6, 121.8, 122.1, 122.2 (t, JCF
=
33 Hz), 128.4, 128.5, 129.3, 137.8 (t, JCF = 6 Hz), 140.9, 150.5; 19F NMR (470 MHz, CDCl3): δ 95.4 (d,
JFH = 6 Hz); IR (neat): ν~ 1491, 1323, 1122, 914, 744 cm–1; HRMS (70 eV, EI): m/z calcd. for C17H16F2O
([M]+): 274.1169; found: 274.1166.
4.3.2. (E)-1,1-Difluoro-4-methyl-4-phenyl-1-phenoxypent-2-ene (2b)
1H NMR (500 MHz, CDCl3): δ 1.45 (s, 6H), 5.69 (dt, J = 15.9 Hz, JHF = 6.8 Hz, 1H), 6.54 (dt, J = 15.9
Hz, JHF = 2.1 Hz, 1H), 7.19–7.27 (m, 6H), 7.30–7.36 (m, 4H); 13C NMR (126 MHz, CDCl3): δ 28.0,
40.3, 115.2 (t, JCF = 270 Hz), 118.7 (t, JCF = 33 Hz), 122.0, 125.4, 126.0, 126.3, 128.3, 129.3, 146.7,
147.4 (t, JCF = 6 Hz), 150.5; 19F NMR (470 MHz, CDCl3): δ 97.2 (d, JFH = 7 Hz); IR (neat): ν~ 1496,
1313, 1120, 771, 700 cm–1; HRMS (70 eV, EI): m/z calcd. for C18H18F2O ([M]+): 288.1326; found:
288.1323.
4.3.3. (E)-1,1-Difluoro-3-methyl-1-phenoxy-5-phenylpent-2-ene (2c)
1H NMR (500 MHz, CDCl3): δ 1.98 (td, JHF = 3.4 Hz, J = 1.4 Hz, 3H), 2.38 (td, J = 8.2, 1.4 Hz, 2H),
2.76 (t, J = 8.2 Hz, 2H), 5.55 (ttq, JHF = 9.0 Hz, J = 1.4, 1.4 Hz, 1H), 7.16–7.22 (m, 6H), 7.27–7.35 (m,
4H); 13C NMR (126 MHz, CDCl3): δ 17.9, 33.9, 41.4, 118.0 (t, JCF = 33 Hz), 121.6, 121.8 (t, JCF = 260
Hz), 125.2, 126.1, 128.3, 128.4, 129.3, 141.2, 148.4 (t, JCF = 5 Hz), 150.6; 19F NMR (470 MHz, CDCl3):
δ 102.9 (d, JFH = 9 Hz); IR (neat): ν~ 1493, 1265, 1107, 1032, 700 cm–1; HRMS (70 eV, EI): m/z calcd.
for C18H18F2O ([M]+): 288.1326; found: 288.1325.
4.3.4. (E)-1,1-Difluoro-5-phenylpent-2-en-1-yl acetate (2d)
1H NMR (500 MHz, CDCl3): δ 2.12 (s, 3H), 2.41–2.49 (m, 2H), 2.74 (t, J = 7.8 Hz, 2H), 5.81 (dtt, J =
15.8, 1.5 Hz, JHF = 8.8 Hz, 1H), 6.34 (dtt, J = 15.8, 6.8 Hz, JHF = 2.0 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H),
7.20 (t, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.6, 7.6 Hz, 2H); 13C NMR (126 MHz, CDCl3): δ 21.3, 33.3, 34.5,

16
120.3 (t, JCF = 262 Hz), 121.3 (t, JCF = 31 Hz), 126.1, 128.36, 128.44, 138.3 (t, JCF = 7 Hz), 140.7,
165.6; 19F NMR (470 MHz, CDCl3): δ 92.0 (dd, JFH = 9, 2 Hz); IR (neat): ν~ 1784, 1259, 1039, 746, 698
cm–1; HRMS (70 eV, EI): m/z calcd. for C13H12F2O ([M–H2O]+): 222.0856; found: 222.0850.
4.3.5. (E)-1,1-Difluoro-5-phenylpent-2-en-1-yl benzoate (2e)
1H NMR (500 MHz, CDCl3): δ 2.44–2.51 (m, 2H), 2.76 (t, J = 7.8 Hz, 2H), 5.96 (dtt, J = 15.8, 1.6 Hz,
JHF = 8.7 Hz, 1H), 6.42 (dtt, J = 15.8, 6.8 Hz, JHF = 2.0 Hz, 1H), 7.15–7.20 (m, 3H), 7.26 (dd, J = 7.1,
7.1 Hz, 2H), 7.47 (dd, J = 7.6, 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 8.02–8.06 (m, 2H); 13C NMR (126
MHz, CDCl3): δ 33.3, 34.5, 121.0 (t, JCF = 263 Hz), 121.5 (t, JCF = 31 Hz), 126.1, 128.38, 128.42, 128.5,
128.6, 130.1, 134.1, 138.5 (t, JCF = 7 Hz), 140.7, 161.4 (t, JCF = 3 Hz); 19F NMR (470 MHz, CDCl3): δ
92.7 (dd, JFH = 9, 2 Hz); IR (neat): ν~ 1755, 1452, 1254, 1039, 696 cm–1; HRMS (70 eV, EI): m/z calcd.
for C18H16F2O2 ([M]+): 302.1118; found: 302.1108.
4.3.6. (E)-1,1-Difluoro-5-phenylpent-2-en-1-yl trifluoroacetate (2f)
1H NMR (400 MHz, CDCl3): δ 2.46–2.53 (m, 2H), 2.77 (t, J = 7.6 Hz, 2H), 5.76 (dtt, J = 15.8, 1.6 Hz,
JHF = 9.2 Hz, 1H), 6.48 (dt, J = 15.8, 6.8 Hz, JHF = 2.0 Hz, 1H), 7.15–7.31 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 32.3, 34.2, 113.7 (q, JCF = 285 Hz), 119.0 (t, JCF = 29 Hz), 121.3 (t, JCF = 269 Hz), 126.3,
128.3, 128.5, 140.2, 141.3 (t, JCF = 7 Hz), 152.0 (qt, JCF = 45, 3 Hz); 19F NMR (470 MHz, CDCl3): δ
87.5 (s, 3F), 93.0 (dd, JFH = 9, 2 Hz); IR (neat): ν~ 1817, 1234, 1182, 1142, 1030, 700 cm–1; HRMS (70
eV, EI): m/z calcd. for C13H11F5O2 ([M]+): 294.0679; found: 294.0674.
4.3.7. (E)-1,1-Difluoro-5-phenylpent-2-en-1-yl methanesulfonate (2g)
1H NMR (500 MHz, CDCl3): δ 2.45–2.52 (m, 2H), 2.76 (t, J = 7.8 Hz, 2H), 3.20 (s, 3H), 5.71 (dtt, J =
15.7, 1.6 Hz, JHF = 8.2 Hz, 1H), 6.44 (dtt, J = 15.7, 6.8 Hz, JHF = 2.1 Hz, 1H), 7.15–7.24 (m, 3H), 7.30
(dd, J = 7.6, 7.6 Hz, 2H); 13C NMR (126 MHz, CDCl3): δ 33.2, 34.2, 41.1, 120.2 (t, JCF = 30 Hz), 121.0

17
(t, JCF = 270 Hz), 126.3, 128.3, 128.5, 140.0 (t, JCF = 7 Hz), 140.4; 19F NMR (470 MHz, CDCl3): δ 96.3
(d, JFH = 8 Hz); IR (neat): ν~ 1379, 1196, 1030, 957, 698 cm–1; HRMS (70 eV, EI): m/z calcd. for
C12H14F2O3S ([M]+): 276.0632; found: 276.0630.
4.3.8. 1-Fluoro-3,4-dimethylnaphthalene (5)
1H NMR (500 MHz, CDCl3): δ 2.47 (s, 3H), 2.55 (s, 3H), 6.99 (d, JHF = 11.3 Hz, 1H), 7.47 (dd, J = 8.1,
7.0 Hz, 1H), 7.54 (dd, J = 8.6, 7.0 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H); 13C NMR
(126 MHz, CDCl3): δ 20.8, 29.7, 112.2 (d, JCF = 19 Hz), 120.8 (d, JCF = 6 Hz), 122.3 (d, JCF = 15 Hz),
123.7 (d, JCF = 3 Hz), 124.7, 126.6, 126.8 (d, JCF = 4 Hz), 133.2 (d, JCF = 8 Hz), 133.9 (d, JCF = 5 Hz),
156.7 (d, JCF = 248 Hz); 19F NMR (470 MHz, CDCl3): δ 35.0 (d, JFH = 11 Hz); IR (neat): ν~ = 2926,
1604, 1387, 1074, 756 cm–1; HRMS (70 eV, EI): m/z calcd. for C12H11F ([M]+): 174.0845; found:
174.0837.
4.3.9. N-(1,1-difluoro-5-phenylpent-1-en-3-yl)benzamide (6)
1H NMR (500 MHz, CDCl3): δ 1.91–2.00 (m, 1H), 2.05–2.14 (m, 1H), 2.65–2.76 (m, 2H), 4.37 (ddd, J
= 8.0, 2.2 Hz, JHF = 24.6 Hz, 1H), 4.81 (tdd, J = 8.0, 8.0, 8.0 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 7.16–
7.22 (m, 3H), 7.28 (dd, J = 7.8, 7.8 Hz, 2H), 7.39 (dd, J = 7.7, 7.7 Hz, 2H), 7.48 (dd, J = 7.5, 7.5 Hz,
1H), 7.67 (d, J = 7.3 Hz, 2H); 13C NMR (126 MHz, CDCl3): δ 32.2, 36.9, 44.7 (d, JCF = 7 Hz), 80.2 (dd,
JCF = 22, 19 Hz), 126.1, 126.8, 128.3, 128.5, 128.6, 131.6, 134.2, 140.9, 156.9 (dd, JCF = 292, 289 Hz),
166.6; 19F NMR (470 MHz, CDCl3): δ 75.6 (d, J = 38 Hz, 1F), 77.0 (dd, J = 38 Hz, JFH = 25 Hz, 1F); IR
(neat): ν~ = 3298, 1745, 1635, 912, 742 cm–1; HRMS (70 eV, EI): m/z calcd. for C18H17F2NO ([M]+):
301.1278; found: 301.1270.
4.3.10. 1,1-Difluoro-5-phenyl-3-(phenylsulfanyl)pent-1-ene (7)

18
1H NMR (500 MHz, CDCl3): δ 1.87 (dddd, J = 18.0, 8.4, 5.9, 5.9 Hz, 1H), 2.02–2.10 (m, 1H), 2.70 (ddd,
J = 14.0, 9.2, 6.8 Hz, 1H), 2.78 (ddd, J = 14.0, 9.4, 5.9 Hz, 1H), 3.76–3.83 (m, 1H), 4.21 (ddd, JHF
=
24.1 Hz, J = 10.8, 2.0 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 6.8 Hz, 1H), 7.25–7.31 (m, 5H),
7.36–7.39 (m, 2H); 13C NMR (126 MHz, CDCl3): δ 33.3, 36.6, 42.3 (d, JCF = 6 Hz), 81.3 (dd, JCF = 23,
19 Hz), 126.1, 127.7, 128.4, 128.5, 128.9, 133.3, 133.4, 140.8, 157.0 (dd, JCF = 290, 290 Hz); 19F NMR
(470 MHz, CDCl3): δ 73.7 (dd, J = 40 Hz, JFH = 24 Hz, 1F), 74.5 (d, J = 40 Hz, 1F); IR (neat): ν~ = 1734,
1176, 908, 737, 688 cm–1; HRMS (70 eV, EI): m/z calcd. for C17H16F2S ([M]+): 290.0941; found:
290.0938.
Acknowledgements
This research is supported by JSPS KAKENHI Grant Numbers JP18H04234 and JP19H02707. TOSOH
FINECHEM COOPERATION is acknowledged for the generous gift of CF3CH2I.

19
References
[1] K. Fuchibe, J. Ichikawa, in Science of Synthesis: Knowledge Updates 2014/2, Georg Thieme Verlag KG, Stuttgart, 2014,
pp. 217–231.
[2] (a) W. R. Dolbier, Jr., C. R. Burkholder, G. E. Wicks, G. J. Palenik, M. Gawron, J. Am. Chem. Soc. 107 (1985) 7183–
7184;
(b) W. R. Dolbier, Jr., Acc. Chem. Res. 24 (1991) 63–69.
[3] W. R. Dolbier, Jr., C. R. Burkholder, C. A. Piedrahita, J. Fluorine Chem. 20 (1982) 637–647.
[4] (a) W. R. Dolbier, Jr., C. R. Burkholder, W. R. Winchester, J. Org. Chem. 49 (1984) 1518–1522;
(b) W. R. Dolbier, Jr., C. R. Burkholder, Israel J. Chem. 26 (1985) 115–119;
(c) W. R. Dolbier, Jr., G. E. Wicks, C. R. Burkholder, J. Org. Chem. 57 (1987) 2196–2201.
[5] (a) W. R. Dolbier Jr., G. E. Wicks, J. Am. Chem. Soc. 107 (1985) 3626–3631;
(b) for a metal-catalyzed formal [2+2] cycloaddition, see: Q. Shen, G. B. Hammond, J. Am. Chem. Soc. 124 (2002)
6534–6535.
[6] (a) M. F. Kühnel, D. Lentz, J. Chem. Soc., Dalton Trans. 2009 (2009) 4747–4755;
(b) see also: M. F. Kuehnel, T. Schloeder, S. Riedel, B. Nieto-Ortega, F. J. Ramirez, J. T. Lopez Navarrete, J. Casado, D.
Lentz, Angew. Chem. Int. Ed. 51 (2012) 2218–2220.
[7] Y.-Y. Xu, F.-Q. Jin, W.-Y. Huang, J. Fluorine Chem. 70 (1995) 5–6.
[8] B. Xu, G. B. Hammond, Angew. Chem. Int. Ed. 44 (2005) 7404–7407.
[9] M. Mae, J. A. Hong, B. Xu, G. B. Hammond, Org. Lett. 8 (2006) 479–482.
[10] (a) K. Fuchibe, M. Ueda, M. Yokota, J. Ichikawa, Chem. Lett. 41 (2012) 1619–1621;
(b) for addition of O- and N-nucleopohiles to tetrafluoroallene, see: J.-C. Xiao, Q.-Y. Chen, J. Fluorine Chem. 123
(2003) 189–195.
[11] (a) K. Fuchibe, Y. Mayumi, N. Zhao, S. Watanabe, M. Yokota, J. Ichikawa, Angew. Chem. Int. Ed. 52 (2013) 7825–
7828;
(b) K. Fuchibe, Y. Mayumi, M. Yokota, H. Aihara, J. Ichikawa, Bull. Chem. Soc. Jpn. 87 (2014) 942–949;
(c) K. Fuchibe, K. Shigeno, N. Zhao, H. Aihara, R. Akisaka, T. Morikawa, T. Fujita, K. Yamakawa, T. Shimada, J.
Ichikawa, J. Fluorine Chem. 203 (2017) 173–184;
(d) K. Fuchibe, H. Imaoka, J. Ichikawa, Chem. Asian J. 12 (2017) 2359–2363;
(e) K. Fuchibe, T. Fujita, J. Ichikawa, J. Synth. Org. Chem., Jpn. 76 (2018) 938–953.
[12] (a) K. Oh, K. Fuchibe, J. Ichikawa, Synthesis (2011) 881–886;
(b) K. Oh, K. Fuchibe, M. Yokota, J. Ichikawa, Synthesis 44 (2012) 857–861;
(c) K. Fuchibe, M. Abe, K. Oh, J. Ichikawa, Org. Synth. 93 (2016) 352–366;
(d) see also: M. Yokota, K. Fuchibe, M. Ueda, Y. Mayumi, J. Ichikawa, Org. Lett. 11 (2009) 3994–3997.
[13] The effect of the silver salts cannot be attributed to the stabilities of the counteranions because the yields of 2a showed
no correlation with the acidities of the corresponding HX compounds. Calculated gas phase acidities in kcal/mol:
[HSbF6] 256; [HPF6] 277; [HNTf2] 287; [HBF4] 288; [HOTf] 293 (I. A. Koppel, P. Burk, I. Koppel, I. Leito, T. Sonoda,
M. Mashima, J. Am. Chem. Soc. 122 (2000) 5114–5124; I. Leito, E. Raamat, A. Kütt, J. Saame, K. Kipper, I. A. Koppel,

20
I. Koppel, M. Zhang, M. Mashima, L. M. Yagupolskii, R. Y. Garlyauskayte, A. A. Filatov, J. Phys. Chem. A 113 (2009)
8421–8424). See also: A. Zhdanko, M. E. Maier, ACS Catal. 5 (2015) 5994–6004.
[14] Although limited, 1,1-difluoroallyl alcohol derivatives were synthesized by an SN2’-type reaction of 3,3-difluoroallyl
acetates with oxygen nucleophiles, or difluorination of thioesters:
(a) P. R. O. Montellano, W. A. Vinson, J. Am. Chem. Soc. 101 (1979) 2222–2224;
(b) W. A. Vinson, K. S. Prickett, B. Spahic, P. R. O. Montellano, J. Org. Chem. 48 (1983) 4661–4668;
(c) W. H. Bunnelle, B. R. McKinnis, B. A. Narayanan, J. Org. Chem. 55 (1990) 768–770.
Recently, an SN2-type reaction of (trifluoromethyl)alkenes was reported for the synthesis of 1,1-difluoroallyl alcohol
derivatives:
(d) H. Zeng, C. Zhu, H. Jiang, Org. Lett. 21 (2019) 1130.
[15] F. G. Bordwell, R. J. McCallum, W. N. Olmstead, J. Org. Chem. 49 (1984) 1424–1427.
[16] I. M. Kolthoff, M. K. Chantooni, S. Bhowmik, J. Am. Chem. Soc. 90 (1968) 23–28.
[17] F. G. Bordwell, Acc. Chem. Res. 21 (1988) 456–463.
[18] C. McCallum, A. D. Pethybridge, Electrochem. Acta 20 (1975) 815–818.
[19] Theoretical calculation (DFT, B3LYP/6-31G*) indicated that the -addition product on the O atom of benzamide,
imidate, is less stable than the -additioin product on the N atom of benzamide, amide 6, by 3.9 kcal/mol. We therefore
cannot exclude the possibility, where 6 was formed through [3,3]-sigmatropic rearrangement of the imidate. In addition,
aniline underwent the -selective addition to 1,1-difluoroallene 1a, albeit in 5% yield (46% recovery of 1a).
[20] It is noteworthy that we recently reported -selectivity in arylation of 1-trifluoromethyl-1-alkenes which proceeded via
difluoroallylic cations. The -selectivity was ascribed to the avoidance of -attack due to (a) the destabilization of the
arenium intermediates by the electron-withdrawing inductive effect of fluorines and/or (b) the steric hinderance of the
CF2 group compared to the CH2 group. See: K. Fuchibe, H. Hatta, K. Oh, R. Oki, J. Ichikawa, Angew. Chem. Int. Ed. 56
(2017) 5890–5893.
[21] C6F6 exhibits a 19F NMR signal at –162.9 ppm vs. CFCl3.