Stereoselective Organocatalytic Synthesis of α,α-Difluoro-γ,γ-Disubstituted Butenals

Article abstract of DOI:10.1021/acs.joc.6b01334

A highly stereoselective reaction of α,α-difluoro-γ,γ-disubstituted butenals 2 bearing two different substituents at the γ position has been developed with an organocatalytic system of l-proline (30 mol %) and salicylic acid (60 mol %). This novel reactio

Full text of DOI:10.1021/acs.joc.6b01334

Article
pubs.acs.org/joc
Stereoselective Organocatalytic Synthesis of α,α-Difluoro-γ,γ-
Disubstituted Butenals
Satoru Arimitsu* and Makoto Nakasone
Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Senbaru 1, Nishihara, Nakagami, Okinawa
903-0123, Japan
S
* Supporting Information
ABSTRACT: A highly stereoselective reaction of α,α-
difluoro-γ,γ-disubstituted butenals 2 bearing two different
substituents at the γ position has been developed with an
organocatalytic system of L-proline (30 mol %) and salicylic
acid (60 mol %). This novel reaction demonstrated a wide
substrate scope and excellent E stereoselectivity in most cases.
The obtained difluorinated aldehyde 2a was applied as a useful synthetic precursor for constructing 3,3-disubstituted allylic
difluoride moieties.
protocol for the synthesis of allylic difluorides with high
efficiency and high reliability (Scheme 1).6
INTRODUCTION
■
The allylic motif has been found in many bioactive compounds
and medicines, and compounds with a fluorine atom at the α
position of an allylic moiety, allylic fluorides, have exhibited
excellent enhancement of the bioactivity of their parent
compounds, as shown in Figure 1.1 Furthermore, allyl fluorides
Scheme 1. Recent Examples of Transition Metal-Catalyzed
Reactions for the Synthesis of Allylic Difluorides
Among all possible substitutional patterns of allylic
difluorides, 3-monosubstituted allylic difluorides have been
more frequently reported than 3,3-disubstituted allylic
difluorides;7 to date, no general synthesis for 3,3-disubstituted
allylic difluorides with nonequivalent substituents (R1 ≠ R2)8
has been described (Figure 2) because of the inaccessibility of
vinylic compounds with highly controlled stereoconfigurations.
During the past several decades, organocatalysis has become
the norm for environmentally friendly stereoselective reactions.
Recently, electrophilic functionalization of dienamine inter-
mediates generated from γ-enolizable α,β-unsaturated alde-
Figure 1. Examples of bioactive allylic fluorides.
have served as versatile intermediates in the synthesis of a large
number of fluorinated compounds,2 motivating the develop-
ment of numerous synthesis methods with controlled regio-
and stereoselectivity for allylic fluorides.3
The importance of allylic difluorides has been validated by
the success of Tafluprost, a potent prostanoid FP receptor
agonist that has been commercialized for the treatment of
glaucoma.4 The most common method of synthesizing allylic
difluorides is the deoxygenative fluorination of allylic ketones
with diethylaminosulfur trifluoride (DAST) or its derivatives
used for manufacturing of Tafluprost and other medicinal
compounds.5 Recent extensive efforts focusing on the transition
metal-catalyzed reaction of vinylic coupling units with CF2-
containing reagents have led to the emergence of an alternative
Figure 2. Summary of structural features of allylic difluorides.
Received: June 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01334
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The Journal of Organic Chemistry
Article
Scheme 2. Our Strategy, Difluorination of Enolizable α,β-Unsaturated Aldehydes
hydes has gained attention as a new subject of organocatalysis.9
Table 1. Catalyst Screening
Dienamine intermediates are known to react with electrophiles
at the α or γ position;10 therefore, if this vinylogous principle
could be applied in an electrophilic fluorination, a wide variety
of allylic fluorides could be prepared.
Here, we report the first highly regio- and stereoselective
organocatalytic synthesis of α,α-difluoro-γ,γ-disubstituted bute-
nals; these compounds are useful synthetic intermediates for
many types of 3,3-disubstituted allylic difluorides.
The details of our synthetic strategy are depicted in Scheme
2. Although a dienamine intermediate possesses ambident
nucleophilicity at both α and γ positions, in the case of γ,γ-
disubstituted α,β-unsaturated aldehydes 1, the reaction at the γ
position can be suppressed because of steric hindrance;
therefore, the first fluorination can presumably be performed
at only the α position to produce the monofluorinated
aldehyde, mono-F INT, with the thermodynamically favored
stereochemistry on the vinylic moiety. Furthermore, the second
fluorination can occur smoothly to furnish allylic difluorides 2
because the presence of a fluorine at the α position will enhance
the reactivity toward the amino catalyst.11 Notably, stereo-
controlled prefunctionalization of starting material 1 is not
necessary for this strategy.
a
b
c
entry
amine catalyst
time (h)
E/Z of 2a
yield of 2a (%)
1
2
3
4
5
6
7
8
9
cat-1
cat-2
cat-3
cat-4
cat-5
cat-6
cat-7
cat-8
cat-9
8
8
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
28
32
23
5
d
24
24
6
24
d
45
50
68
80
6
3
d
24
41
a
RESULTS AND DISCUSSION
The reaction time was determined by monitoring consumption of the
■
b
starting material 1a by TLC. The stereoselectivity was determined by
The initial investigation commenced with the screening of the
amine catalyst. Thus, treatment of (E)-4-phenyl-2-enal 1a12 and
N-fluorobenzenesulfonimide (NFSI) with a catalytic amount of
an amine catalyst (30 mol %) in THF at room temperature
produced the corresponding α,α-difluorobutenal 2a with
excellent regio- and stereoselectivity; only α fluorination and
the E isomer were observed in all cases (Table 1). In general,
primary amine catalysts gave low yields because of the
formation of many nonfluorinated byproducts (entries 1−3).
By contrast, secondary amine catalysts gave cleaner reaction
profiles (entries 4−8); in particular, the use of L-proline
resulted in a good yield of the corresponding product 2a in just
3 h (entry 8). Interestingly, the presence of acidic functional
groups in secondary amines can play a critical role in smooth
reaction (entries 6−8), and the possibility of hydrogen bonding
between the dienamine intermediate and NFSI is indicated by a
comparison of catalyst efficacy for L-proline and pyrrolidine
(entries 8 and 9, respectively).13 It is important to mention that
all efforts to isolate 2a failed because of the volatile and unstable
nature of 2a; therefore, a reduction of 2a to corresponding
alcohol 3a was necessary for successful purification and
characterization.14
1H NMR of the reaction mixture after reduction to its alcohol 3a by
c
d
NaBH4. The yield of 2a was determined by 19F NMR. The starting
material 1a remained after 24 h.
(entries 4 and 5, respectively), whereas other solvents gave a
sluggish reaction (entries 1−3, 6, and 7) or a complex reaction
mixture (entry 8). Among all of the tested solvents, THF was
observed to be optimal, and the yield was dramatically
improved by lowering the concentration despite the longer
reaction time (entry 9). To shorten the reaction time, we next
surveyed the effect of Brønsted acid additives (entries 10−16).
When relatively stronger Brønsted acids were utilized, the E/Z
isomer ratio decreased (entries 10 and 11); however, benzoic
acid and its analogues allowed for a shorter reaction time, with
excellent E/Z ratios (entries 12−15), where salicylic acid was
observed to be the best additive.15 Finally, increasing the
amount of salicylic acid (60 mol %) dramatically accelerated the
reaction speed and produced target compound 2 with excellent
selectivity and yield (entry 16).
After determining the optimal conditions, we examined the
scope of the substrates with regard to γ-enolizable α,β-
unsaturated aldehydes 1 (Table 3). Aldehydes with para-
substituted aromatics on R1 possessing either electron-with-
drawing (entries 2−4) or electron-donating (entries 5 and 6)
functional groups gave only the E isomer (E/Z = >20/1) in
We next screened solvents and additives; the results are listed
in Table 2. The reactions were performed in various solvents,
and substantial solvent effects were observed. The use of cyclic
ethers such as 1,4-dioxane and THF resulted in good yields
B
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Table 2. Optimization of the Reaction
a
b
c
entry
solvent (conc, M)
additive (mol %)
time (h)
E/Z of 2a
yield of 2a (%)
1
toluene (1.0)
CH2Cl2 (1.0)
Et2O (1.0)
1,4-dioxane (1.0)
THF (1.0)
MeCN (1.0)
DMF (1.0)
i-PrOH (1.0)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
−
−
−
−
−
−
−
−
−
24
24
24
8
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
−
8
2
28
3
57
4
72
5
3
80
6
24
24
12
24
5
53
7
60
8
no reaction
9
>20/1
94
83
69
79
82
84
94
10
11
12
13
14
15
16
TFA (30)
11/1
p-TsOH (30)
24
15
15
15
15
3
18/1
PhCO2H (30)
>20/1
>20/1
>20/1
>20/1
>20/1
4-MeO-C6H4CO2H (30)
4-CF3-C6H4CO2H (30)
2-OH-C6H4CO2H (30)
2-OH-C6H4CO2H (60)
d
98 (79)
a
b
1
The reaction time was determined by monitoring consumption of the starting material 1a by TLC. The stereoselectivity was determined by H
c
d
NMR of the reaction mixture after reduction to its alcohol 3a by NaBH4. The yield of 2a was determined by 19F NMR. The value in parentheses is
the isolated yield of its alcohol 3a.
Table 3. Scope of Substrates
a
b
c
d
entry
R1
R2
time (h)
E/Z of 2
yield of 2 (%)
yield of 3 (%)
1
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
3
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
5/1
2a, 98
2b, 93
2c, 80
2d, 96
2e, 99
2f, 98
2g, 96
2h, 86
2i, 82
2j, 99
2k, 82
2l, 90
3a, 79
3b, 74
3c, 70
3d, 75
3e, 79
3f, 72
3g, 70
3h, 77
3i, 66
3j, 72
3k, 77
3l, 60
2
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
Ph
3
5
4
3
5
5
6
5
7
3
8
12
7
9
>20/1
>20/1
3/1
10
11
12
Ph
H
5
PhCH2
Me
H
5
n-Hex
5
1.8/1
a
b
1
The reaction time was determined by monitoring consumption of the starting material 1 by TLC. The stereochemistry was determined by H
c
d
NMR of the reaction mixture after reduction to its alcohol 3 by NaBH4. The yield of 2 was determined by 19F NMR. Isolated yield.
Scheme 3. Synthetic Application of 2a
C
DOI: 10.1021/acs.joc.6b01334
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General Procedure for γ-Enolizable α,β-Unsaturated Alde-
hydes 1.12 Step i: Wittig reaction. To a stirred solution of the branched
aldehyde17 (1.0 equiv) in anhydrous DCM (2.0 M) was added
methyl(triphenylphosphoranyliden)acetate (1.1 equiv) in one portion
at 0 °C. The reaction mixture was stirred at room temperature for 3
days until aldehyde was consumed. Then, the solvent was removed
under reduced pressure, and a hexane/Et2O mixture (1/1) was added
to the residue at 0 °C. The precipitated solid was removed by Celite
filtration and washed several times with a cold hexane/Et2O mixture
(1/1). The solvent of a filtrate was removed under reduced pressure.
The residue was purified by flash chromatography to afford the ester.
Step ii: Reduction by DIBAL-H. To a stirred solution of the obtained
ester (1.0 equiv) in anhydrous DCM (0.2 M) was added dropwise
DIBAL-H (2.5 equiv, 1.0 M in Hexane) under an argon atmosphere at
−78 °C. After being stirred for 2 h at −78 °C, the mixture was allowed
to warm to 0 °C, and the reaction was quenched by MeOH. After
addition of a saturated aqueous solution of potassium sodium tartrate
at room temperature and stirring for 1 h, the aqueous phase was
extracted with EtOAc. The combined organic phase was washed with
brine and dried over MgSO4. The solvent was removed under reduced
pressure after filtration. The residue was purified by flash
chromatography to afford the alcohol.
Step iii: Oxidation by IBX. To a stirred solution of the obtained
allylic alcohol (1.0 equiv) in anhydrous DMSO (0.2 M) was added a
solution of IBX (2.0 equiv) in DMSO (0.4 M), and the whole solution
was stirred for 30 min at room temperature. Then H2O was added to
the reaction mixture, and the resulting cloudy suspension was filtered
through Celite and washed with EtOAc. The filtrate was extracted with
EtOAc, and the combined organic phases were washed with brine and
dried over MgSO4. The solvent was removed under reduced pressure
after filtration. The residue was purified by flash chromatography to
afford α,β-unsaturated aldehyde 1.
good yields. The influence of the steric hindrance was apparent
in the case of ortho substitution on R1 and gave rise to a longer
reaction time with diminished E/Z selectivity (entry 8);
however, meta substitution on R1 still afforded an excellent
result (entry 7). The other substituents on R2, such as Et and H
instead of Me, also gave excellent selectivity and good yields as
long as a phenyl group was present on R1 (entries 9 and 10). By
contrast, the E selectivity was drastically decreased in the case
of aliphatic groups on R1 (entries 11 and 12). Although the
comprehensive reaction mechanism and the origin of excellent
regio- and stereoselectivity are still under investigation, it is
apparent that the steroisomers of dienamine intermediates with
an aliphatic group can be close in energy,16 and this could be
one of the reasons for poor E selectivity. Notably, in all cases,
the corresponding monofluorinated intermediates were not
observed under our optimal reaction conditions.
The obtained α,α-difluoro butenal 2a was demonstrated to
be a useful synthetic precursor for constructing various 3,3-
disubstituted allylic difluorides, including homoallylic alcohol
3a and amine 4a, carboxylic acid 5a, and 1,4-diene 6a, without
touching the excellent E/Z ratio of 2a (Scheme 3). The E
configuration of all products was determined by comparison of
the chemical shifts and coupling constants with those of 6a, for
which the stereochemistry was revealed by NOESY experi-
ments (see the Supporting Information).
CONCLUSION
■
In summary, we developed the first stereoselective organo-
catalytic synthesis of α,α-difluoro-γ,γ-disubstituted butenal
bearing two different substituents at the γ position, with high
E selectivity in most cases. Thus, the combination of L-proline
(30 mol %) and salicylic acid (60 mol %) in THF (0.1 M)
facilitated the smooth difluorination of γ-enolizable α,β-
unsaturated aldehyde 1 at room temperature and gave the
desired difluorinated aldehyde 2 with excellent E selectivity and
good yield as long as R1 was the aromatic group. Under these
optimal reaction conditions, monofluorinated aldehydes were
not observed. Investigations of the enantioselective synthesis of
α-monofluorinated butenals are continuing in our laboratory.
Difluorinated aldehyde 2a has been demonstrated to be a useful
synthetic unit for constructing 3,3-disubstituted allylic
difluorides maintaining the E configuration.
(2E)-4-Phenylpent-2-enal (1a).12 Purification by flash chromatog-
raphy (SiO2, 20/1 hexane/EtOAc) afforded 1a (1.30 g, 8.10 mmol,
81% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.47 (3H,
d, J = 7.0 Hz), 3.73 (1H, quint, J = 6.6 Hz), 6.11 (1H, ddd, J = 15.6,
7.8, 1.4 Hz), 6.96 (1H, dd, J = 15.6, 6.4 Hz), 7.18−7.35 (5H, m), 9.53
(1H, d, J = 7.8 Hz).
(2E)-4-(4-Fluorophenyl)pent-2-enal (1b). Purification by flash
chromatography (SiO2, 20/1 hexane/EtOAc) afforded 1b (0.46 g,
2.60 mmol, 87% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 1.46 (3H, d, J = 7.0 Hz), 3.73 (1H, quint, J = 6.8 Hz), 6.08 (1H, dd, J
= 15.6, 7.7 Hz), 6.91 (1H, dd, J = 15.6, 6.3 Hz), 7.00−7.04 (2H, m),
7.15−7.26 (2H, m), 9.54 (1H, d, J = 7.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 20.0, 41.7, 115.6 (d, J = 21.2 Hz), 128.7 (d, J = 7.9 Hz),
131.3, 138.3 (d, J = 3.3 Hz), 161.2, 161.8 (d, J = 245.4 Hz), 193.8; 19F
NMR (376 MHz, CDCl3) δ −115.6 (1F, m); HRMS (FAB) exact
mass calcd for [M + H]+ (C11H12FO) m/z 179.0872, found m/z
179.0863.
(2E)-4-(4-Chlorophenyl)pent-2-enal (1c). Purification by flash
chromatography (SiO2, 20/1 hexane/EtOAc) afforded 1c (0.36 g,
1.86 mmol, 62% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 1.45 (3H, d, J = 7.0 Hz), 3.72 (1H, quint, J = 6.8 Hz), 6.09 (1H, dd, J
= 15.6, 7.7 Hz), 6.91 (1H, dd, J = 15.6, 6.3 Hz), 7.13 (2H, J = 8.2 Hz),
7.30 (2H, J = 8.2 Hz), 9.53 (1H, d, J = 7.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 19.9, 41.8, 128.7, 129.0, 131.4, 132.8, 141.1, 160.7, 193.7;
HRMS (FAB) exact mass calcd for [M + H]+ (C11H12ClO) m/z
195.0577, found m/z 195.0575.
EXPERIMENTAL SECTION
■
General Information. All commercially available reagents were
used without further purification. All solvents were dried on MS 3A or
1
by the reported procedure. H NMR spectra were recorded using a
400 or 500 MHz NMR spectrometer. Data were reported as follows:
chemical shifts in parts per million from tetramethylsilane as an
internal standard in CDCl3, integration, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; dd, doublet doublet; m, multiplet; br,
broad), coupling constants (hertz), and assignment. 13C NMR spectra
were recorded using a 100 or 125 MHz NMR spectrometer with
complete proton decoupling. Chemical shifts are reported in parts per
million from the residual solvent as an internal standard. 19F NMR
spectra were recorded using a 376 or 470 MHz NMR spectrometer.
The 19F NMR yield in the mixture was obtained using
(trifluoromethoxy)benzene as an internal reference. High-resolution
mass spectroscopy (HRMS) was performed using an LTQ Orbitrap
ESI ion trap or FAB. For thin-layer chromatography (TLC) analysis,
TLC plates (silica gel 60 F254) were used. The products were purified
by flash column chromatography on silica gel 60 (spherical, neutral,
40−50 μm). trans-2-Decenal (1l) was purchased and used without
purification.
(2E)-4-(4-Bromophenyl)pent-2-enal (1d). Purification by flash
chromatography (SiO2, 40/1 hexane/EtOAc) afforded 1d (0.51 g,
1
2.14 mmol, 71% yield) as a pale yellow oil: H NMR (400 MHz,
CDCl3) δ 1.45 (3H, d, J = 7.0 Hz), 3.71 (1H, quint, J = 6.7 Hz), 6.09
(1H, dd, J = 15.6, 7.7 Hz), 6.91 (1H, dd, J = 15.6, 6.3 Hz), 7.07 (2H, d,
J = 8.28 Hz), 7.46 (2H, d, J = 8.3 Hz), 9.53 (1H, d, J = 7.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 19.8, 41.9, 120.9, 129.0, 131.5, 132.0,
141.6, 160.6, 193.7; HRMS (FAB) exact mass calcd for [M + H]+
(C11H12BrO) m/z 239.0072, found m/z 239.0081.
(2E)-4-(4-Methylphenyl)pent-2-enal (1e). Purification by flash
chromatography (SiO2, 40/1 hexane/EtOAc) afforded 1e (0.42 g,
2.42 mmol, 80% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3)
D
DOI: 10.1021/acs.joc.6b01334
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The Journal of Organic Chemistry
Article
δ 1.46 (3H, d, J = 7.0 Hz), 2.33 (3H, s), 3.70 (1H, quint, J = 6.8 Hz),
6.10 (1H, dd, J = 15.6, 7.7 Hz), 6.94 (1H, dd, J = 15.6, 6.4 Hz), 7.09
(2H, d, J = 7.0 Hz), 7.15 (2H, d, J = 7.9 Hz), 9.52 (1H, d, J = 7.8 Hz);
13C NMR (100 MHz, CDCl3) δ 19.9, 21.0, 42.1, 127.1, 129.5, 131.0,
136.7, 139.6, 162.0, 194.1; HRMS (FAB) exact mass calcd for [M +
H]+ (C12H14O) m/z 175.1123, found m/z 175.1113.
35 °C (note that some difluorinated aldehydes 2 were very volatile).
The resulting difluorinated aldehyde 2 was dissolved in a 3/2 CH2Cl2/
EtOH mixture (0.1 M), and NaBH4 (10 equiv) was added at 0 °C.
After 1 h, the reaction was quenched with saturated NH4Cl and the
mixture extracted EtOAc. The organic phase was dried over MgSO4
and concentrated, and the residue was subsequently purified by silica-
gel chromatography to afford the corresponding alcohols 3.
(2E)-4-(4-Methoxyphenyl)pent-2-enal (1f). Purification by flash
(3E)-2,2-Difluoro-4-phenylpent-3-en-1-ol (3a). Purification by
chromatography (SiO2, 20/1 hexane/EtOAc) afforded 1f (0.30 g, 1.57
1
flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3a as a
mmol, 66% yield) as a colorless oil: H NMR (400 MHz, CDCl3) δ
1
colorless oil (E/Z = >20/1, 15.2 mg, 0.077 mmol, 77% yield): H
1.44 (3H, d, J = 7.0 Hz), 3.69 (1H, quint, J = 6.8 Hz), 3.78 (3H, s),
6.08 (1H, dd, J = 15.6, 7.8 Hz), 6.87 (2H, d, J = 8.5 Hz), 6.93 (1H, dd,
J = 15.6, 7.8 Hz), 7.11 (2H, d, J = 8.5 Hz), 9.52 (1H, d, J = 7.8 Hz);
13C NMR (100 MHz, CDCl3) δ 19.9, 41.7, 55.2, 114.2, 128.2, 130.9,
134.7, 158.6, 162.1, 194.0; HRMS (FAB) exact mass calcd for [M +
H]+ (C12H15O2) m/z 191.1072, found m/z 191.1076.
NMR (400 MHz, CDCl3) δ 1.98 (1H, brs), 2.28 (3H, s), 3.89 (2H, t, J
= 13.1 Hz), 5.80 (1H, t, J = 14.3 Hz), 7.32−7.41 (5H, m); 19F NMR
(376 MHz, CDCl3) δ −101.14 (2F, q, J = 13.6 Hz); 13C NMR (100
MHz, CDCl3) δ 17.3 (t, J = 2.1 Hz), 65.5 (t, J = 31.4 Hz), 119.5 (t, J =
25.1 Hz), 120.3 (t, J = 239.0 Hz), 126.1, 128.4, 128.5, 142.2, 146.5 (t, J
= 5.7 Hz); HRMS (FAB) exact mass calcd for [M − H]+ (C11H11F2O)
requires m/z 197.0778, found m/z 197.0781.
(3E)-2,2-Difluoro-4-(4-fluorophenyl)pent-3-en-1-ol (3b). Purifica-
tion by flash chromatography (SiO2, 5/1 hexane/EtOAc) afforded 3b
as a colorless oil (E/Z = >20/1, 16.1 mg, 0.074 mmol, 74% yield): 1H
NMR (400 MHz, CDCl3) δ 2.14 (1H, brs), 2.26 (3H, s), 3.88 (2H, t, J
= 13.2 Hz), 5.78 (1H, t, J = 14.2 Hz), 7.03 (2H, t, J = 8.6 Hz), 7.38
(2H, dd, J = 8.4, 5.6 Hz); 19F NMR (376 MHz, CDCl3) δ −113.64
(1F, m), −101.28 (2F, m); 13C NMR (100 MHz, CDCl3) δ 17.5 (t, J
= 2.4 Hz), 65.4 (t, J = 31.6 Hz), 115.3 (t, J = 21.3 Hz), 119.4 (t, J =
24.6 Hz), 120.1 (t, J = 239.0 Hz), 127.8 (t, J = 8.3 Hz), 138.2 (d, J =
3.0 Hz), 145.4 (t, J = 5.5 Hz), 162.8 (d, J = 246.3 Hz); HRMS (FAB)
exact mass calcd for [M]+ (C11H11F3O) m/z 216.0762, found m/z
216.0772.
(3E)-4-(4-Chlorophenyl)-2,2-difluoropent-3-en-1-ol (3c). Purifica-
tion by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3c
as a pale yellow oil (E/Z = >20/1, 16.3 mg, 0.070 mmol, 70% yield):
1H NMR (400 MHz, CDCl3) δ 2.05 (1H, brs), 2.25 (3H, s), 3.89 (2H,
dt, J = 13.0, 3.7 Hz), 5.82 (1H, t, J = 14.2 Hz), 7.33−7.36 (4H, m); 19F
NMR (376 MHz, CDCl3) δ −101.38 (2F, q, J = 2.5, 13.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 17.4 (t, J = 2.2 Hz), 65.5 (t, J = 31.6 Hz),
119.9 (t, J = 25.0 Hz), 120.1 (t, J = 239.1 Hz), 127.4, 128.6, 134.4,
140.6, 145.3 (t, J = 5.5 Hz); HRMS (FAB) exact mass calcd for [M]+
(C11H11ClF2O) m/z 232.0466, found m/z 232.0466.
(3E)-4-(4-Bromophenyl)-2,2-difluoropent-3-en-1-ol (3d). Purifica-
tion by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3d
as a pale yellow oil (E/Z = >20/1, 20.9 mg, 0.075 mmol, 75% yield):
1H NMR (400 MHz, CDCl3) δ 2.14 (1H, brs), 2.25 (3H, s), 3.88 (2H,
t, J = 13.1 Hz), 5.82 (1H, t, J = 14.2 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.47
(2H, d, J = 8.4 Hz); 19F NMR (376 MHz, CDCl3) δ −101.39 (2F, dq,
J = 2.5, 13.6 Hz); 13C NMR (100 MHz, CDCl3) δ 17.4 (t, J = 2.3 Hz),
65.4 (t, J = 31.7 Hz), 119.9 (t, J = 25.1 Hz), 120.1 (t, J = 240.2 Hz),
122.5, 127.7, 131.6, 141.0, 145.3 (t, J = 5.5 Hz); HRMS (FAB) exact
mass calcd for [M]+ (C11H11BrF2O) m/z 275.9961, found m/z
275.9954.
(3E)-2,2-Difluoro-4-(4-methylphenyl)pent-3-en-1-ol (3e). Purifica-
tion by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3e
as a colorless oil (E/Z = >20/1, 16.7 mg, 0.078 mmol, 79% yield): 1H
NMR (400 MHz, CDCl3) δ 2.01 (1H, brs), 2.25 (3H, s), 2.35 (3H, s),
3.88 (2H, t, J = 12.9 Hz), 5.82 (1H, t, J = 14.3 Hz), 7.96 (2H, d, J = 7.2
Hz), 8.04 (2H, d, J = 7.3 Hz); 19F NMR (376 MHz, CDCl3) δ
−101.39 (2F, q, J = 14.1 Hz); 13C NMR (100 MHz, CDCl3) δ 17.4 (t,
J = 2.3 Hz), 21.1, 65.5 (t, J = 31.4 Hz), 118.6 (t, J = 24.9 Hz), 120.4 (t,
J = 238.8 Hz), 125.9, 129.1, 138.4, 139.2, 146.3 (t, J = 5.6 Hz); HRMS
(FAB) exact mass calcd for [M − H]+ (C12H13F2O) m/z 211.0935,
found m/z 211.0936.
(3E)-2,2-Difluoro-4-(4-methoxyphenyl)pent-3-en-1-ol (3f). Purifi-
cation by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded
3f as a colorless oil (E/Z = >20/1, 16.4 mg, 0.072 mmol, 72% yield):
1H NMR (400 MHz, CDCl3) δ 2.03 (1H, brs), 2.25 (3H, s), 3.81 (3H,
s), 3.88 (2H, t, J = 14.5 Hz), 5.77 (1H, t, J = 14.3 Hz), 6.87 (2H, d, J =
8.7 Hz), 7.36 (2H, d, J = 8.7 Hz); 19F NMR (376 MHz, CDCl3) δ
−100.85 (2F, q, J = 13.0 Hz); 13C NMR (100 MHz, CDCl3) δ 17.3 (t,
J = 2.1 Hz), 55.3, 65.5 (t, J = 31.6 Hz), 113.8, 117.7 (t, J = 25.0 Hz),
120.4 (t, J = 239.0 Hz), 127.2, 134.3, 145.7 (t, J = 5.6 Hz), 159.9;
(2E)-4-(3-Methoxyphenyl)pent-2-enal (1g). Purification by flash
chromatography (SiO2, 40/1 hexane/EtOAc) afforded 1g (0.17 g, 0.88
1
mmol, 88% yield) as a colorless oil: H NMR (400 MHz, CDCl3) δ
1.46 (3H, d, J = 7.0 Hz), 3.70 (1H, quint, J = 6.8 Hz), 3.79 (3H, s),
6.11 (1H, dd, J = 15.6, 7.8 Hz), 6.74 (1H, s), 6.79 (2H, d, J = 7.8 Hz),
6.94 (dd, 1H, J = 15.6, 6.4 Hz), 7.25 (1H, t, J = 7.8 Hz), 9.53 (1H, d, J
= 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 19.8, 42.5, 55.2, 112.0,
113.4, 119.6, 129.8, 131.2, 144.3, 159.9, 161.4, 193.9; HRMS (FAB)
exact mass calcd for [M]+ (C12H14O2) m/z 190.0994, found m/z
190.0989.
(2E)-4-(2-Methoxyphenyl)pent-2-enal (1h). Purification by flash
chromatography (SiO2, 40/1 hexane/EtOAc) afforded 1h (0.39 g, 2.07
1
mmol, 69% yield) as a colorless oil: H NMR (400 MHz, CDCl3) δ
1.43 (3H, d, J = 7.0 Hz), 3.82 (3H, s), 4.17 (1H, quint, J = 7.2 Hz),
6.10 (1H, dd, J = 15.6, 7.8 Hz), 6.87−7.02 (m, 3H), 7.11 (1H, d, J =
7.2 Hz), 7.23 (1H, t, J = 7.5 Hz), 9.52 (1H, d, J = 7.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 18.3, 35.5, 55.3, 110.7, 120.8, 127.4, 128.0,
130.9, 131.0, 156.7, 162.2, 194.3 (CHO); HRMS (FAB) exact mass
calcd for [M]+ (C12H14O2) m/z 190.0994, found m/z 190.0999.
(2E)-4-Phenylhex-2-enal (1i). Purification by flash chromatography
(SiO2, 40/1 hexane/EtOAc) afforded 1i (0.37 g, 2.11 mmol, 14% yield
1
for three steps) as a pale yellow oil: H NMR (400 MHz, CDCl3) δ
0.91 (3H, t, J = 7.4 Hz), 1.87 (2H, m), 3.43 (1H, q, J = 7.4 Hz), 6.10
(1H, dddd, J = 15.6, 7.8, 1.2 Hz), 6.93 (1H, dd, J = 7.5 Hz), 7.17−7.36
(5H, m), 9.52 (1H, d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ
12.0, 27.7, 50.6, 127.1, 127.8, 128.8, 131.6, 141.4, 160.9, 194.0; HRMS
(FAB) exact mass calcd for [M]+ (C12H14O) m/z 174.1045, found m/
z 174.1053.
(2E)-4-Phenylbut-2-enal (1j). Purification by flash chromatography
(SiO2, 20/1 hexane/EtOAc) afforded 1j (1.18 g, 8.10 mmol, 8% yield
for three steps) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.65
(2H, d, J = 6.7 Hz), 6.11 (1H, dd, J = 15.5, 7.9 Hz), 6.96 (1H, dt, J =
15.5, 6.7 Hz), 7.17−7.35 (5H, m), 9.53 (1H, d, J = 7.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 39.0, 127.0, 128.8, 128.9, 133.6, 137.0, 156.3,
193.7; HRMS (FAB) exact mass calcd for [M]+ (C10H10O) m/z
146.0732, found m/z 146.0741.
(2E)-4-Methyl-5-phenylpent-2-enal (1k). Purification by flash
chromatography (SiO2, 20/1 hexane/EtOAc) afforded 1k (68 mg,
0.39 mmol, 66% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 1.12 (3H, d, J = 6.2 Hz), 2.73 (3H, m), 6.05 (1H, dd, J = 15.7, 7.8
Hz), 6.79 (1H, dd, J = 15.7, 6.4 Hz), 7.13−7.31 (5H, m), 9.48 (1H, d,
J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 18.7, 38.6, 42.3, 126.4,
128.4, 129.1, 131.5, 139.1, 162.7, 194.1; HRMS (FAB) exact mass
calcd for [M + H]+ (C12H15O) m/z 175.1123, found m/z 175.1116.
General Procedure for α,α-Difluoro-γ,γ-Disubstituted Bute-
nals 2 and Reduction to the Corresponding Alcohols 3.
Aldehyde 1 (1.0 equiv) and NFSI (2.2 equiv) were added at room
temperature to a suspension of L-proline (30 mol %) and salicylic acid
(60 mol %) in THF (0.1 M), and the entire solution was stirred until
TLC showed that aldehyde 1 was totally consumed. After Me2S was
added to quench the reaction, the solution was stirred for 30 min. The
resulting mixture was mixed with saturated NaHCO3 and extracted
with Et2O. The combined organic phase was washed with brine and
dried over MgSO4. The organic solvents were filtered and
concentrated under moderately reduced pressure at 450 mbar and
E
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Article
HRMS (FAB) exact mass calcd for [M + H]+ (C12H15F2O2) requires
m/z 229.1040, found m/z 229.1040.
(t, J = 240.0 Hz), 126.4, 128.5, 128.9, 138.4, 146.9 (t, J = 5.2 Hz);
HRMS (FAB) exact mass calcd for [M + H]+ (C12H14F2O) m/z
212.1013, found m/z 212.1003.
(3E)-2,2-Difluoro-4-(3-methoxyphenyl)pent-3-en-1-ol (3g). Purifi-
cation by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded
3g as a colorless oil (E/Z = >20/1, 15.9 mg, 0.070 mmol, 70% yield):
1H NMR (400 MHz, CDCl3) δ 2.10 (1H, brs), 2.26 (3H, s), 3.82 (3H,
s), 3.88 (2H, t, J = 13.3 Hz), 5.82 (1H, t, J = 14.4 Hz), 6.87 (1H, d, J =
8.8 Hz), 6.92 (1H, s), 7.00 (1H, d, J = 7.9 Hz), 7.26 (1H, t, J = 8.0
Hz); 19F NMR (376 MHz, CDCl3) δ −101.41 (2F, q, J = 13.4 Hz);
13C NMR (100 MHz, CDCl3) δ 17.4 (t, J = 2.3 Hz), 55.2, 65.4 (t, J =
31.5 Hz), 112.0, 113.6, 118.5, 119.6 (t, J = 25.0 Hz), 120.2 (t, J = 240.3
Hz), 129.3, 143.7, 146.3 (t, J = 5.7 Hz), 159.6; HRMS (EI+) exact
mass calcd for [M + H]+ (C12H15F2O2) m/z 229.1040, found m/z
229.1037.
(3E)-2,2-Difluorodec-3-en-1-ol (3l). Purification by flash chroma-
tography (SiO2, 10/1 hexane/EtOAc) afforded 3l as a colorless oil (E/
Z = 1.8/1, 11.6 mg, 0.060 mmol, 60% yield) (as a mixture of E and Z
1
isomers): H NMR (400 MHz, CDCl3) δ 0.89 (8.4H, t, J = 7.0 Hz),
1.26−1.37 (17H, m), 1.39−1.44 (5H, m), 1.86 (2.8H, brs), 2.09−2.15
(4H, m), 2.24−2.30 (2H, m), 3.78 (5.6H, t, J = 12.8 Hz), 5.43−5.70
(2.8H, m), 5.83−5.90 (1H, m), 6.14−6.23 (1.8H, m); 19F NMR (376
MHz, CDCl3) δ −102.23 (Z isomer, 2F, q, J = 13.9 Hz), − 105.48 (E
isomer, 2F, dq, J = 2.7, 12.5 Hz); 13C NMR (100 MHz, CDCl3) δ
14.1, 22.55, 22.57, 28.3, 28.6, 28.8, 28.9, 29.1, 29.4, 29.7, 31.6, 32.0,
65.1 (t, J = 33.2 Hz), 65.4 (t, J = 33.2 Hz), 119.4 (t, J = 239.4 Hz),
120.3 (t, J = 240.0 Hz), 121.5 (t, J = 26.2 Hz), 122.1 (t, J = 25.1 Hz),
138.6 (t, J = 9.1 Hz), 140.9 (t, J = 6.0 Hz); HRMS (FAB) exact mass
calcd for [M]+ (C10H19F2O) m/z 193.1402, found m/z 193.1404.
General Procedure for the Reductive Amination of 2a. The
resulting difluorinated aldehyde 2a (1.0 equiv) and benzylamine (10
equiv) were mixed in DCM (0.2 M), and then to the solution were
added sodium triacetoxyborohydride (10 equiv) and AcOH (10
equiv). The mixture was stirred at room temperature under an argon
atmosphere for 15 h. The reaction was quenched with saturated
Na2CO3, and the product was extracted with EtOAc and dried over
MgSO4. The organic layer was filtered and concentrated in vacuo. The
residue was purified by a silica-gel chromatography (20/1 hexane/
EtOAc) that afforded 4a as a colorless oil (E/Z = >20/1, 18 mg, 0.063
mmol, 63% yield).
(3E)-2,2-Difluoro-4-(2-methoxyphenyl)pent-3-en-1-ol (3h). Purifi-
cation by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded
3h as a colorless oil (E/Z = 5/1, 17.6 mg, 0.077 mmol, 77% yield).
1
The assignments were made for a mixture of E and Z isomers: H
NMR (400 MHz, CDCl3) δ 2.07 (0.6H, s), 2.20 (3H, s), 3.44 (3H, t, J
= 12.4 Hz), 3.82 (3H, s), 3.83 (0.6H, s), 3.88 (2H, t, J = 13.4 Hz), 5.56
(1H, t, J = 14.4 Hz), 5.72 (1H, t, J = 12.0 Hz), 6.87−6.96 (2.4H, m),
7.07 (0.2H, d, J = 4.0 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.25−7.30 (1.2H,
m); 19F NMR (376 MHz, CDCl3) δ −97.50 (Z isomer, 2F, brs),
−101.90 (E isomer, 2F, q, J = 13.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 18.7 (t, J = 2.0 Hz), 26.2, 55.4, 55.5, 64.7 (t, J = 33.2 Hz), 65.4 (t, J =
31.2 Hz), 117.8 (t, J = 239.4 Hz), 120.2 (t, J = 241.4 Hz), 120.6, 120.7,
121.1 (t, J = 28.2 Hz), 121.3 (t, J = 25.2 Hz), 125.6, 127.3, 129.0,
129.05, 129.10, 129.3, 132.9 137.0, 145.1 (t, J = 10.1 Hz), 146.7 (t, J =
6.0 Hz), 155.3, 156.2; HRMS (EI+) exact mass calcd for [M + H]+
(C12H15F2O2) m/z 229.1040, found m/z 229.1039.
(3E)-2,2-Difluoro-4-phenylhex-3-en-1-ol (3i). Purification by flash
chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3i as a pale
yellow oil (E/Z = >20/1, 13.9 mg, 0.065 mmol, 66% yield): 1H NMR
(400 MHz, CDCl3) δ 0.99 (3H, t, J = 7.5 Hz), 2.01 (1H, brs), 2.73
(2H, q, J = 7.5 Hz), 3.88 (2H, dt, J = 13.2, 5.9 Hz), 5.67 (1H, t, J =
14.6 Hz), 7.26−7.38 (5H, m); 19F NMR (376 MHz, CDCl3) δ
−101.21 (2F, q, J = 13.7 Hz, CF2); 13C NMR (100 MHz, CDCl3) δ
13.5, 24.3 (t, J = 1.7 Hz), 65.7 (t, J = 31.4 Hz), 119.1 (t, J = 25.3 Hz),
120.2 (t, J = 239.2 Hz), 126.7, 128.3, 128.5, 141.9, 153.3 (t, J = 5.6
Hz); HRMS (EI+) exact mass calcd for [M]+ (C12H14F2O) m/z
212.1013, found m/z 212.1010.
(3E)-N-Benzyl-2,2-difluoro-4-phenylpent-3-en-1-amine (4a). 1H
NMR (400 MHz, CDCl3) δ 2.24 (1H, s), 3.11 (2H, t, J = 14.1 Hz),
3.92 (2H, s), 5.87 (1H, t, J = 13.7 Hz), 7.31−7.41 (10H, m); 19F NMR
(376 MHz, CDCl3) δ −95.22 (2F, q, J = 13.8 Hz); 13C NMR (100
MHz, CDCl3) δ 17.3 (t, J = 2.1 Hz), 53.5, 54.1 (t, J = 28.7 Hz), 121.3
(t, J = 25.1 Hz), 121.5 (t, J = 240.63 Hz), 126.0, 127.1, 128.0, 128.1,
128.3, 128.4, 139.8, 142.2, 144.9 (t, J = 5.65 Hz); HRMS (FAB) exact
mass calcd for [M]+ (C18H19F2N) m/z 287.1486, found m/z 287.1492.
General Procedure for Pinnick Reaction of 2a. Sodium
phosphate monobasic (8.0 equiv) was added at 0 °C to a solution
of difluorinated aldehyde 2a (1.0 equiv) in a 2/1 t-BuOH/H2O
mixture (0.05 M). The resulting suspension was treated with 2-methyl-
2-butene (30 equiv) and sodium chlorite (80%, 10 equiv) at 0 °C. The
reaction mixture was then warmed to room temperature and stirred for
3 h. After the reaction had reached completion, the reaction was
quenched with saturated NH4Cl; the product was subsequently
extracted with EtOAc and dried over MgSO4. The organic layer was
filtered and concentrated in vacuo. The residue was purified by silica-
gel chromatography (5/1 DCM/MeOH) to afford 5a as a colorless oil
(E/Z = >20/1, 15.1 mg, 0.072 mmol, 72% yield).
(3E)-2,2-Difluoro-4-phenylbut-3-en-1-ol (3j). Purification by flash
chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3j as a colorless
1
oil (E/Z = >20/1, 40 mg, 0.217 mmol, 72% yield): H NMR (400
MHz, CDCl3) δ 2.11 (1H, brs), 3.89 (2H, t, J = 12.7 Hz), 6.25 (1H,
dt, J = 16.3, 12.7 Hz), 7.01 (1H, d, J = 16.3 Hz), 7.25−7.45 (5H, m);
19F NMR (376 MHz, CDCl3) δ −106.00 (2F, q, J = 12.4 Hz); 13C
NMR (100 MHz, CDCl3) δ 65.2 (t, J = 32.6 Hz), 119.8 (t, J = 240.1
Hz), 120.4 (t, J = 25.2 Hz), 127.2, 128.8, 129.2, 134.6, 135.7 (t, J = 9.4
Hz); HRMS (FAB) exact mass calcd for [M]+ (C10H10F2O) m/z
184.0700, found m/z 184.0694.
1
(3E)-2,2-Difluoro-4-phenylpent-3-enoic acid (5a). H NMR (400
MHz, DMSO-d6) δ 2.19 (3H, s), 6.00 (1H, t, J = 13.8), 7.32−7.47
(5H, m); 19F NMR (376 MHz, DMSO-d6) δ −93.81 (2F, s); 13C
NMR (100 MHz, DMSO-d6) δ 17.2, 115.1 (t, J = 246.1 Hz), 122.8 (t,
J = 26.4 Hz), 126.2, 128.1, 128.9, 141.9, 143.3, 166.2 (t, J = 29.9 Hz);
HRMS (FAB) exact mass calcd for [M − H]− (C11H9F2O2) m/z
211.0571, found m/z 211.0572.
(3E)-2,2-Difluoro-4-methyl-5-phenylpent-3-en-1-ol (3k). Purifica-
tion by flash chromatography (SiO2, 10/1 hexane/EtOAc) afforded 3k
as a pale yellow oil (E/Z = 3/1, 49.0 mg, 0.231 mmol, 77% yield). The
1
assignments were made as a mixture of E and Z isomers: H NMR
(400 MHz, CDCl3) of the E isomer δ 1.70 (0.9H, s), 1.82 (3H, s),
1.86 (1H, brs), 3.37 (2H, s), 3.61 (0.6H, s), 3.79 (2.6H, dt, J = 13.2,
3.3 Hz), 5.38 (1H, t, J = 14.1 Hz), 5.51 (0.3H, t, J = 14.2 Hz), 7.16−
7.32 (6.5H, m); 1H NMR (400 MHz, CDCl3) of the Z isomer δ 1.70
(3H, s), 3.61 (2H, s), 3.79 (2H, dt, J = 3.3, 13.2 Hz, overlapping with
the E isomer), 5.51 (1H, t, J = 14.2 Hz), 7.16−7.32 (5H, m,
overlapping with the E isomer); 19F NMR (376 MHz, CDCl3) δ
−99.69 (Z isomer, 2F, q, J = 13.8 Hz), −101.41 (E isomer, 2F, dq, J =
2.3, 22.4 Hz); 13C NMR (100 MHz, CDCl3) of the E isomer δ 17.6 (t,
J = 2.1 Hz), 23.8, 39.0, 46.5, 65.4 (t, J = 31.5 Hz), 65.7 (t, J = 31.5 Hz),
119.0 (t, J = 25.4 Hz, overlapping with two isomers), 119.8 (t, J =
240.0 Hz), 120.1 (t, J = 239.0 Hz), 126.4, 126.6, 128.48, 128.54, 128.9,
129.0, 138.1, 138.4, 146.9 (t, J = 5.2 Hz), 147.5 (t, J = 5.7 Hz); 13C
NMR (100 MHz, CDCl3) of the Z isomer δ 23.8, 39.0, 65.7 (t, J =
31.5 Hz), 119.0 (t, J = 25.4 Hz, overlapping with the E isomer), 119.8
General Procedure for Horner−Wadsworth−Emmons Re-
action of 2a. A solution of diisopropylamine (2.52 equiv) in THF
(0.2 M) was carefully treated with n-BuLi (2.4 equiv) at 0 °C under an
argon atmosphere, and the resulting solution was stirred for 15 min at
0 °C. Triethyl phosphonoacetate (2.0 equiv) was added to a prepared
LDA solution at 0 °C. After 30 min, the reaction mixture was cooled to
−40 °C and difluorinated aldehyde 2a (1.0 equiv) was added to the
solution at this temperature. After the mixture had been stirred for 1 h
at −40 °C, the reaction was quenched with saturated NH4Cl; the
product was then extracted with EtOAc and dried over MgSO4. The
organic layer was filtered and concentrated in vacuo. The residue was
purified by silica-gel chromatography (40/1 hexane/Et2O) to afford 6a
as a colorless oil (E/Z = >20/1, 15.6 mg, 0.059 mmol, 60% yield).
Ethyl (2E,5E)-4,4-Difluoro-6-phenylhepta-2,5-dienoate (6a). 1H
NMR (400 MHz, CDCl3) δ 1.32 (3H, t, J = 7.1 Hz), 2.21−2.22 (3H,
F
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Article
m), 4.26 (2H, q, J = 7.1 Hz), 5.86 (1H, dt, J = 13.4, 1.2 Hz), 6.32 (1H,
dt, J = 15.7, 2.4 Hz), 6.95 (1H, dt, J = 15.7, 10.0 Hz), 7.32−7.42 (5H,
m); 19F NMR (376 MHz, CDCl3) δ −89.18 (2F, m); 13C NMR (100
MHz, CDCl3) δ 14.2, 17.5 (t, J = 1.5 Hz), 61.2, 118.0 (t, J = 235.9
Hz), 120.9 (t, J = 24.8 Hz), 124.5 (t, J = 8.0 Hz), 126.0, 128.50,
128.54, 139.4 (t, J = 30.7 Hz), 141.8, 145.9 (t, J = 7.2 Hz), 165.3;
HRMS (FAB) exact mass calcd for [M + H]+ (C15H17F2O2) m/z
267.1197, found m/z 267.1197.
116, 422. (c) Al-Maharik, N.; O’Hagan, D. Aldrichimica Acta 2011, 44,
65. (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(6) (a) Chen, Q.; Wang, C.; Zhou, J.; Wang, Y.; Xu, Z.; Wang, R. J.
Org. Chem. 2016, 81, 2639. (b) Li, G.; Wang, T.; Fei, F.; Su, Y.; Li, Y.;
Lan, Q.; Wang, X. Angew. Chem., Int. Ed. 2016, 55, 3491. (c) Ivanova,
M. V.; Bayle, A.; Besset, T.; Poisson, T.; Pannecoucke, X. Angew.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01334.
NMR spectra of compounds 1, 3, 4a, 5a, and 6a (PDF)
(7) (a) See ref 6. For other synthetic methods, see: (b) Omote, M.;
Miake, T.; Tarui, A.; Sato, K.; Kumadaki, I.; Ando, A. J. Fluorine Chem.
2013, 147, 1. (c) Munemori, D.; Narita, K.; Nokami, T.; Itoh, T. Org.
Lett. 2014, 16, 2638. (d) Patel, S. T.; Percy, J. M.; Wilkes, R. D. J. Org.
Chem. 1996, 61, 166.
(8) For a sporadic example, see: Ueki, H.; Chiba, T.; Yamazaki, T.;
Kitazume, T. J. Org. Chem. 2004, 69, 7616.
(9) For recent reviews, see: (a) Jiang, H.; Albrecht, Ł.; Jørgensen, K.
A. Chem. Sci. 2013, 4, 2287. (b) Jurberg, I. D.; Chatterjee, I.; Tannert,
R.; Melchiorre, P. Chem. Commun. 2013, 49, 4869. (c) Melchiorre, P.
Angew. Chem., Int. Ed. 2012, 51, 9748.
(10) See ref 9 and references cited therein.
(11) (a) Jones, J. H.; Appayee, C.; Brenner-Moyer, S. E. Eur. J. Org.
Chem. 2014, 2014, 5273. (b) Fadeyi, O. O.; Lindsley, C. W. Org. Lett.
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2009, 11, 943. (c) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.
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18296.
AUTHOR INFORMATION
Corresponding Author
*E-mail: arimitsu@sci.u-ryukyu.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors appreciate Dr. Michael C. Roy and Prof. Fujie
Tanaka at Okinawa Institute of Science and Technology
Graduate University for assistance with HRMS. Part of this
research was financially supported by JSPS, Grant-in-Aid for
Young Scientists (B), Grant 25810022.
(12) Starting material 1 was prepared according to a modified
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DOI: 10.1021/acs.joc.6b01334
J. Org. Chem. XXXX, XXX, XXX−XXX