Synthesis of gem-Difluoromethylene Containing Cycloalkenes via the Ring-Opening Reaction of gem-Difluorocyclopropanes and Subsequent RCM Reaction

Article abstract of DOI:10.1021/acs.joc.9b00415

The radical-type ring-opening reaction of gem-difluorocyclopropanes and subsequent regioselective monoepoxidation of the products were demonstrated. Introduction of a vinyl or allyl group to the epoxide produced the diene derivatives that were subjected to the ring closing metathesis reaction to furnish the gem-difluoromethylene containing cyclopentene, cycloheptene, and cyclooctene derivatives in good to excellent yields.

Full text of DOI:10.1021/acs.joc.9b00415

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Article
Synthesis of gem-Difluoromethylene Containing
Cycloalkenes via Ring-opening Reaction of gem-
Difluorocyclopropanes and Subsequent RCM Reaction
Yoshihiro Masuhara, Toshiki Tanaka, Hiroaki Takenaka, Shuichi Hayase, Toshiki Nokami, and Toshiyuki Itoh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00415 • Publication Date (Web): 01 Apr 2019
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The Journal of Organic Chemistry
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Synthesis of gem-Difluoromethylene Containing Cycloal-
kenes via Ring-opening Reaction of gem-Difluorocyclopro-
panes and Subsequent RCM Reaction
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Yoshihiro Masuhara,† Toshiki Tanaka,† Hiroaki Takenaka,† Shuichi Hayase,† Toshiki Nokami,†, ‡ Toshi-
yuki Itoh*,†, ‡
†Department of Chemistry and Biotechnology, ‡Center for Research on Green Sustainable Chemistry, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
KEYWORDS. Gem-difluorocyclopropane; Ring-opening allylation reaction; Ring-closing metathesis; Medium sized cyclo-
alkane; gem-Difluoromethylene.
Supporting information
ABSTRACT: The radical type ring-opening reaction of gem-difluoro-
cyclopropanes and subsequent regioselective mono-epoxidation of the
products were demonstrated. Introduction of a vinyl or allyl group to the
epoxide produced the diene derivatives that were subjected to the Ring
Closing Metathesis (RCM) reaction to furnish the gem-difluorometh-
ylene containing cyclopentene, cycloheptene, and cyclooctene deriva-
tives in good to excellent yields.
the formation of 2,2-difluoroketones via the ring-opening re-
action of siloxy-gem-difluorocyclopropane derivatives in
1. INTRODUCTION
the same year. Since then, siloxy-gem-difluorocyclopropane
has fascinated many researchers; Fuchibe and co-workers re-
ported the preparation of Nazarov reaction precursors
through the ring-opening reaction of siloxy-gem-difluorocy-
clopropane.13 Recently, Wangalso developed the ring-open-
ing diarylation of the same compound.14 Specklin15 reported
the stereoselective ring-opening reaction of gem-difluorocy-
clopropanes.15 The ring-opening methodology of gem-
difluorocyclopropanes is now recognized as a useful method
for the synthesis of fluorinated organic compounds.
The incorporation of a fluorine atom into an organic mole-
cule can alter the chemical reactivity of the resulting com-
pound due to the strong electron-withdrawing nature of the
fluorine with no significant modification of their molecular
sizes. Using this characterisitic of the gem-fluorinated com-
pounds, we can create a new molecule that exhibits unique
physical and biological properties.1,2,3 For example, Ahmeda
and co-workers recently succeeded in synthesizing a strong
musk-smelling compound which contains the gem-difluoro-
methylene moiety.3 Therefore, the development of an effi-
cient means to access gem-fluorinated compounds has
gained strong attention from the synthetic organic chemistry
community.1,2,4-9
We have synthesized gem-difluorocyclopropane derivatives
and revealed their unique physical and biological proper-
ties.2 We next accomplished the synthesis of various types
of gem-difluoromethylene compounds via the radical type
regioselective ring-opening allylation of gem-difluorocyclo-
propane derivatives.16 Furthermore, we recently found that
aerobic oxidation took place after the visible light-mediated
ring-opening reaction of gem-difluorocyclopropane in the
presence of an organic dye and amine to furnish 2,2-
difluoro-homoallylic alcohols in good yields.17 Since our
ring-opening products have two olefin moieties with differ-
ent reactivities, they are expected to become key intermedi-
ates for various types of cycloalkenes through the ring clos-
ing methathesis (RCM) reaction. The RCM reaction is now
The syntheses of gem-difluoromethylene compounds have
been generally achieved by the difluorination of carbonyl or
thiocarbonyl functional groups.5 Recently, great progress in
the synthesis of gem-difluoromethylene compounds has
been accomplished using various methodologies.6-9 Syn-
thetic strategies that use economical building blocks contain-
ing a gem-difluoromethylene moiety have also been recog-
nized as an attractive route to access gem-difluoromethylene
compounds.10 Among such methodologies, the strategy of
the ring-opening of gem-difluorocyclopropane derivatives is
very attractive; Amii11 and Gilman12 independently reported
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considered as one of the most powerful tools for preparing
Page 2 of 12
cyclic compounds.18,19 In fact, this methodology has been
applied for preparing gem-difluoromethylenes containing
cyclic compounds.20,21 Qing et al. first reported the use of
the RCM reaction for the synthesis of gem-difluorinated cy-
clic compounds, and they prepared analogues of massoialac-
tone20a and 7-epi-castanospermine.20b O’Hagan and co-
workers reported the synthesis of gem-difluoromethylene
groups containing macrocyclic compounds that exhibited an
olfactory property via the RCM reaction.3,19 Inspired by
these results, we planned the synthesis of five types of me-
dium-sized cyclic compounds, such as 3, 4, 5, 6, and 7 from
gem-difluorocyclopropanes 1 or 2 as the starting molecules
(Figure 1).
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Figure 2. Retrosynthetic analysis for synthesizing three types
of gem-difluorinated cycloalkenes, 3, 4, 5, and 6.
Figure 1. Synthetic plan for gem-difluorinated cycloalkenes 3,
4, 5, 6, and 7 using two types of gem-difluorocyclopropanes 1
and 2 as starting molecules through the RCM reaction.
2.1. PREPARATION OF TWO TYPES OF GEM-
DIFLUORINATED CYCLOPENTENES 3 AND 4.
As already mentioned, we prepared diene 8 through the re-
gioselective allylation of the gem-difluorocyclopropane de-
rivative 1 through a radical-type ring-opening reaction.16
The RCM reaction of the diene 8 smoothly took place using
10 mol% of the 1st generation Grubbs catalyst (Grubbs I) to
afford the desired cyclopentene 3 in 97% yield (Figure 3).
2. RESULTS AND DISCUSSION
Figure 2 shows the retrosynthetic analysis of the target cy-
cloalkenes using gem-difluorocyclopropane 1 as the starting
molecule. The benzyloxy moiety in the starting compounds
1 and 2 allows easy handling of the products due to increased
boiling point, though fluorinated small molecules are gener-
ally easily escaped during the purification process due to
their high volatility. We used different protecting groups,
such as allyl, methoxymethyl (MOM), and p-methoxybenzyl
groups, as the starting compounds considering a further syn-
thesizing process.2d,2e,2h We postulated that cyclopentene 3,
cycloheptene 5, and cyclooctane 6 might be derived from the
dienes 8, 12, and 13 via the RCM reaction, respectively. The
dienes 12 and 13 might be derived from the epoxide 10 that
could be produced by the regioselective oxidation of the
diene 8 that was prepared by the ring-opening allylation of
the gem-difluorocyclopropane 1.16 The cyclopentene 4
might be derived from the diene 9 and this compound might
be derived from the gem-difluorocyclopropane 2.
We next synthesized the cyclopentene 4 through the route
described in Figure 3; the gem-difluorocyclopropane 217 was
treated with 8 equiv. of allyltributylstannane and 10 mol%
of AIBN, then the mixture was heated at 80°C without any
solvent. The desired ring-opening reaction proceeded and
the diene 9 was obtained in 76% yield. Although the RCM
reaction of diene 9 proceeded using the Grubbs I catalyst,
the yield of the desired compound 4 was moderate (73%)
and it required the Stewart-Grubbs catalyst22 to obtain the
cyclopentene 4 in excellent yield (94 %) (Figure 3). It is pos-
tulated that the increase in the catalytic activity of the Stew-
art-Grubbs catalyst in the RCM reaction might occur from
the significantly more open steric environment around the
ruthenium center, which allows the catalytic site to accom-
modate larger organic fragments.22 Since the RCM reaction
of the diene 9 might proceed via a more sterically bulky in-
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termediate compared to that of the cyclization of 8, the Stew-
art-Grubbs catalyst thus gave a better result compared to the
Grubbs I catalyst.
using the Grubbs II catalyst25 successfully proceeded and the
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4
desired cycloheptene 5 was obtained in 91 % yield (Figure
4). Although the Grubbs I catalyst also gave the cyclohep-
tene 5, the yield was insufficient (35%) compared to that of
the Grubbs II-catalyzed reaction and the unreacted 12 was
recovered in 62% yield.
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Figure 3. Synthesis of cyclopentenes 3 and 4.
Figure 4. Synthesis of cycloheptene 5.
We next undertook the synthesis of the cyclooctane 6 start-
ing from the epoxide 10 (Figure 5). The epoxide 10 was re-
acted with the allyl Grignard reagent in the presence of 10
mol% of CuCN in THF at -40°C to afford the allylation
product 13 in 80% yield. Although the undesired SN2’-
reaction product 16 was also produced, the separation of 13
and 16 was easily accomplished by silica gel TLC. The RCM
reaction of 13 using the Grubbs II catalyst was successful
and the desired cyclooctane 6 was obtained in 84% yield.
We have thus accomplished the synthesis of four types of
compounds, i.e., 3, 4, 5, and 6.
2.2 PREPARATION OF CYCLOHEPTENE 5 AND
CYCLOOCTENE 6.
We next accomplished the synthesis of the cycloheptene 5
and cyclooctene 6 starting from the diene 8 as summarized
in Figures 4 and 5. Selective epoxidation of 8 was easily ac-
complished by the treatment of 8 with m-CPBA (1.3 equiv.)
and the desired oxirane 10 was selectively obtained in 72%
yield because the olefinic group adjacent to the gem-difluo-
romethylene moiety exhibited a poor reactivity towards the
oxidant compared to the other olefinic moiety.
The epoxide 10 was treated with the vinyl Grignard reagent
in the presence of copper(I) cyanide (CuCN) in THF at -
40°C to provide the vinylation product 12.23 Although the
unexpected by-product 15 was produced by the defluori-
nated SN2’ type vinylation,24 the separation of 12 and the by-
product 15 was easily accomplished by silica gel thin layer
chromatography (TLC), and the diene 12 was obtained in
68% yield. The RCM reaction under high dilution conditions
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Figure 5. Synthesis of cyclooctene 6.
2.3
ATTEMPT
TO
SYNTHESIZE
THE
CYCLOHEPTENE 7.
Figure 6. Unsuccessful results to produce the cycloheptene 7.
In order to synthesize the cycloheptene 7, the epoxide 11 was
reacted with the vinyl Grignard reagent. Different from the
reaction of the epoxide 10, the reaction of the epoxide 11
with vinyl MgBr successfully proceeded, and gave the de-
sired diene 14 in 82% yield. Although undesired SN2’-
reaction product 17 (15%) was also produced in the reaction,
the separation of 14 and the by-product 17 was easily accom-
plished by silica gel thin layer chromatography (TLC). How-
ever, we encountered a serious problem in the next RCM re-
action; no cyclized product 7 was obtained and only the
starting diene 14 and unidentified solids were obtained when
using the three types of Grubbs catalysts, i.e., Grubbs I and
II, and Stewart-Grubbs. Shu and co-workers reported such
an example of the RCM reaction under high reaction tem-
perature conditions; they conducted the RCM reaction at
110°C using the nitro-Hoveyda-Grubbs catalyst26 in a tolu-
ene solvent system.27 Bräse, Balova, and co-workers suc-
cessfully overcame the thermodynamic barrier in the RCM
reaction using this catalyst.28 Hence, we attempted the RCM
reaction of 14 using nitro-Hoveyda-Grubbs catalyst under
toluene or 1,1-dichloroethane reflux conditions. Unfortu-
nately, we again failed to synthesize the desired cyclohep-
tene 7 and only decomposition of the diene 14 was observed
even when the reaction was conducted under highly diluted
conditions using four types of Ru catalysts (Figure 6). Even
when the hydroxyl group was protected as the trimethylsilyl
ether, no desired cyclization product was again obtained.
To elucidate the reason why the RCM reaction was unsuc-
cessful for the diene 14, we conducted calculations and com-
pared the energy profile for two possible intermediates using
the B3LYP/6-311+G(d,p) calculations.29-31 We used the chi-
ral forms of (4R,6R)-6-((benzyloxy)methyl)-7,7-difluoro-
nona-1,8-dien-4-ol (12) and (S)-8-((benzyloxy)methyl)-7,7-
difluoronona-1,8-dien-4-ol (14) for the calculations to sim-
plify the reaction, though racemic compounds were em-
ployed in the present RCM reactions. The optimized struc-
tures for the precursor of the cycloheptene 5 should be A#
(Figures 7 and 8). On the other hand, the optimized precursor
of the cycloheptene 7 should be B# as shown in Figures 7
and 8. The calculations suggested that there might be a sig-
nificant difference between the two key intermediates A#
and B# (Figure 7). As already mentioned, the RCM reaction
of 12 easily took place and the desired cycloheptene 5 was
obtained in excellent yield as shown in Figure 4. Isomeriza-
tion from the A-transoid to the A-cisoid forms, which are
precursors of the key intermediate A#, easily proceeded be-
cause only a small energy barrier (3.2 KJ/mol) was esti-
mated; changing the A-cisoid form to cis-A# might more
easily occur because A# is 3.5 KJ/mol more stable than the
A-cisoid conformer (Figure 7). On the contrary, the calcula-
tions suggested that 57.2 KJ/mol might be needed to access
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B# from the B-cisoid intermediate, because the quaternary of cyclopentene 3 via the possible intermediate C# by the
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8
carbon would be formed (Figures 7 and 8). We postulated
that the difficulty to access B# from the B-cisoid form would
be solved by elevating the reaction temperature. However,
as already mentioned, we failed to obtain the desired cyclo-
alkene 7 after extensive studies using four types of the
Grubbs catalysts. On the other hand, we succeeded in syn-
thesizing two cyclopentane derivatives 3 and 4 via the RCM
reaction. To elucidate the reason why the RCM reaction was
successful for dienes 8 and 9, we investigated the energy
profile for two possible intermediates (C# and D#) using the
B3LYP/6-311+G(d,p) calculations (Figure 9).29-31 The cal-
culations suggested that the energy barrier in the synthesis
RCM reaction of 8 is very low; it needed only 3.5 KJ/mol.
Although conversion energy of the synthesis of cyclopen-
tene 4 through D# of the RCM reaction of diene 9 was higher
(45.0 KJ/mol) than that of diene 8, it is noteworthy that the
value was still lower than that needed for the synthesis of the
cycloheptene 5 (55.6 KJ/mol) (Figures 7 and 9). It is well
known that 7-membered cyclic compounds are conforma-
tionally more unstable than the 5-membered cyclic com-
pounds. Therefore, the energy barrier between the B-cisoid
and B# might be too high to produce the desired cyclization.
It was thus concluded that the diene 14 was unsuitable for
the Ru-catalyzed RCM reaction.
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126.6
B#
A-cisoid
86.1 B-transoid
78.0
74.5
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0
74.8
A-transoid
A#
55.0
69.4
B-cisoid
cat 1 + Product
55.0
21.0
18.9
Reactant A
Reactant B
0.0
cat 2 + Product
0.0
6
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5
Reaction path
Figure 7. Plausible Gibbs energy profile for the reaction pathways to access cycloheptenes 5 and 7 based on B3LYP/ Lanl2dz calculations
via cis-A#(––■––) and cis-B#(---□---). For ease of the calculations, we used model compounds in which the configuration of the 3-hydroxyl
groups was tentatively fixed as (3S) and the tri(cyclohexyl)phosphine group was simplified to the trimethylphosphine from tri(cyclo-
hexyl)phosphine.
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Page 6 of 12
odology was unsuccessful. Since the synthesized cycloal-
1
2
3
4
kenes have three important functional groups, i.e., the hy-
droxyl, olefinic, and gem-difluoromethylene groups, we ex-
pect that our compounds may become useful key intermedi-
ates for preparing fluorine-containing biologically-active or
functional compounds.
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A#
Figure 9. Plausible Gibbs energy profile for the reaction path-
ways to access cycloheptenes 3 and 4 based on B3LYP/
Lanl2dz calculations via cis-C# and cis-D.
B#
Figure 8. Optimized structure of the key intermediates A# and
B# by B3LYP/ Lanl2dz calculation.
EXPERIMENTAL SECTION
General Experimental Details. The 1H, 13C, and 19F NMR
spectra were recorded by a Bruker Avance III (600 MHz for
1H, 565 MHz for 19F, and 151 MHz for 13C). Chemical shifts
are expressed in ppm downfield from tetramethylsilane
(TMS) in CDCl3 as the internal reference. The high resolu-
tion mass spectra were recorded by a Thermo Fisher Scien-
tific EXACTIVE mass spectrometer. Quantum mechani-
cal calculations were carried out with Gaussian 1629 at
the Research Center for Computational Science (RCCS,
Okazaki, Japan). Geometry optimizations were performed
and followed by the vibrational analysis to ensure the ener-
getic stability of the optimized structures using the
3. CONCLUSION
We have accomplished the synthesis of four types of novel
gem-difluorinated cycloalkenes, i.e., (((2,2-difluorocyclo-
pent-3-en-1-yl)methoxy)methyl)benzene (3), (((5,5-difluo-
rocyclopent-1-en-1-yl)methoxy)methyl)benzene (4), 6-
((benzyloxy)methyl)-5,5-difluorocyclohept-3-enol (5), and
7-((benzyloxy)methyl)-6,6-difluorocyclooct-4-enol
(6)
starting from the gem-difluorocyclopropanes through four
straightforward sequences, i.e., (1) ring-opening allylation,
(2) chemoselective epoxidation, (3) vinylation or allylation
of the epoxide moiety, and finally, (4) the RCM reaction.
However, unfortunately, the synthesis of (benzyloxy)me-
thyl)-5,5-difluorocyclohept-3-enol (7) by the present meth-
B3LYP/LanL2dz level of theory.30,31
Synthesis of the starting gem-difluorocyclopropanes (1 and
2)
(((3-(bromomethyl)-2,2-difluorocyclopropyl)methoxy)me-
thyl)benzene (1).17
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(1) A solution of sodium chlorodifluoroacetate (84 g, 440 luted with water (ca. 100 mL) and extracted with ethyl ace-
1
mmol) in dry diglyme (100 mL) was dropwise added to a dry
diglyme (150 mL) solution of (E)-but-2-ene-1,4-diyl diace-
tate (15.1 g, 88 mmol) at 180°C for over 5 h under Ar. The
reaction mixture was stirred for 30 min at rt, then the reac-
tion was quenched by the addition of water (50 mL) and ex-
tracted with hexane (4×50 mL). The combined organic lay-
ers were washed with water (3×50 mL), dried over MgSO4
and concentrated to give a yellow liquid oil (24 g). To a
methanol (300 mL) solution of this oil (24 g) was added po-
tassium carbonate (24.8 g, 180 mmol) at rt and the mixture
was stirred for 12 h at rt, then the reaction was quenched by
the addition of water (50 mL) and evaporated to dryness. The
resulting residue was extracted with ethyl acetate (3×30 mL)
and the combined organic layers were dried over MgSO4,
evaporated and purified by silica gel (SiO2) column chroma-
tography (hexane/ethyl acetate=4/1) to give (3,3-difluorocy-
clopropane-1,2-diyl)dimethanol (CAS 1393563-23-9, 11.2
g, 81 mmol) in 92% yield.
tate (3 times). The combined organic layers were washed
with brine (2 times) and dried over MgSO4, then evaporation
and subsequent purification by silica gel flash chroma-
tograohy (hexane/ ethyl acetate = 17:3) afforded 2-meth-
ylenepropane-1,3-diyl diacetate (10.7 g, 62. 4 mmol) in 78
% yield. To a solution of 2-methylenepropane-1,3-diyl diac-
etate (10.4 g, 60 mmol) in dry diglyme (100 mL) was drop-
wise added a solution of sodium chlorodifluoroacetate (45.7
g, 300 mmol) in dry diglyme (50 mL) at 180°C over 3 h, then
the mixture was stirred at the same temperature for 1 h. The
reaction was quenched by the addition of water (50 mL),
then extracted with hexane (3×50 mL). The combined or-
ganic layers were washed with water (8×5 mL), dried over
MgSO4 and concentrated to give a yellow liquid oil (10.30
g). To a methanol (200 mL) solution of this oil (10.30 g) was
added potassium carbonate (K2CO3) (8.3 g, 60 mmol) at rt
and the mixture was stirred for 3 h at rt, then the reaction was
quenched by the addition of water (30 mL) and evaporated
to dryness. The resulting residue was extracted with ethyl
acetate (3×20 mL) and the combined organic layers were
dried over MgSO4, evaporated and purified by SiO2 column
chromatography (hexane/ethyl acetate=4/1) to give (2,2-
2
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(2) To a solution of NaH (0.90 g, 60%, 22.5 mmol) in DMF
(45 mL) was added a DMF (5 mL) solution of (3,3-difluoro-
cyclopropane-1,2-diyl)dimethanol (2.6 g, 18.8 mmol) at 0°C
and the mixture was stirred at the same temperature for 0.5
h, then benzyl bromide (2.9 mL, 20.7 mmol) was dropwise
added at 0°C. The resulting mixture was stirred at rt for 12
h, then the reaction was quenched by the addition of water,
and extracted 3 times with ethyl acetate. The combined or-
ganic layers were washed 3 times with water, dried over
MgSO4, then evaporated to dryness. The resulting residue
was purified by SiO2 flash column chromatography (hex-
ane/ethyl acetate = 20:1) to give (3-((benzyloxy)methyl)-
2,2-difluorocyclopropyl)methanol (18)2g (3.13 g, 13.7
mmol) in 73% yield.
difluorocyclopropane-1,1-diyl)dimethanol
(19)(CAS
228580-15-2) (7.73 g, 56 mmol) in 70% yield (3 steps).
(2) To a solution of NaH (0.90 g, 60%, 22.5 mmol) in DMF
(45 mL) was added a DMF (5 mL) solution of the diol 19
(2.6 g, 18.8 mmol) at 0°C and the mixture was stirred at the
same temperature for 0.5 h, then benzylbromide (2.9 mL,
20.7 mmol) was dropwise added at 0°C. The resulting mix-
ture was stirred at rt for 12 h, then the reaction was quenched
by the addition of water, and extracted 3 times with ethyl
acetate. The combined organic layers were washed 3 times
with water, dried over MgSO4, then evaporated to dryness.
The resulting residue was purified by SiO2 flash column
chromatography (hexane/ethyl acetate = 20:1) to give the
mono-benzyl ether, (1-((benzyloxy)methyl)-2,2-difluorocy-
clopropyl)methanol (20)(2.78 g, 12.2 mmol) in 65% yield:
1H NMR (CDCl3, 600 MHz) δ 7.29-7.38 (m, 5 H), 4.60 (d,
(3) To a dry CH2Cl2 (70 mL) solution of 18 (3.0 g, 13.1
mmol) was added pyridine (10.0 mL, 126 mmol), tri-
phenylphosphine (8.1 g, 31 mmol) and CBr4 (5.0 g, 15
mmol) at rt and the mixture was stirred for 30 min, then the
solvent was removed by evaporation. The residue was puri-
fied by SiO2 column chromatography (hexane/ethyl ace-
1
tate=9/1) to give 1 (2.82 g, 9.69 mmol) in 74% yield: H
1 H, J = 12.0 Hz), 4.55 (d, 1 H, J = 12.0 Hz), 3.77-3.83 (ｍ,
NMR (600 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 4.57(d, 1H,
J=11.9 Hz), 4.50 (d, 1H, J=11.9 Hz), 3.64-3.60 (m, 1H),
3.55-3.52 (m, 1H), 3.47-3.38 (m, 2H), 1.92-1.86 (m, 1H),
1.75 (sext, 1H, J=7.0 Hz); 13C NMR (151 MHz, CDCl3) δ
137.8, 128.5, 127.9, 127.7, 114.8 (t, JC-F = 287.9 Hz), 72.7,
2 H), 3.68 (, 2 H), 2.35 (brs, OH), 1.36-1.41 (m, 1H), 1.25-
1.29 (m, 1H);13C NMR (CDCl3, 151 MHz) δ 137.5, 128.5,
128.0, 127.7, 114.7 (t, J = 286 Hz), 73.3, 69.0 (d, JC-F= 6.2
Hz), 61.9 (d, JC-F = 6.4 Hz), 31.8,18.9; 19F NMR (CDCl3,
MHz) δ 24.92 (d, 1F, J =164 Hz), 23.00 (d, 1F, J = 158 Hz);
IR (neat) 3400, 2932, 2871, 1472, 1455, 1192, 1092, 1006,
901, 735, 697 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C12H14F2O2Na 251.0860; Found 251.0854.
65.6 (d, JC-F = 4.5 Hz), 30.0 (t, JC-F = 10.0 Hz), 28.9 (t, JC-F
=
10.8 Hz), 27.5 (d, JC-F = 5.5 Hz); 19F NMR (565 MHz,
CDCl3) δ 25.16 (dd, J=161.8 Hz, 13.0 Hz), 22.05 (dd,
J=161.8 Hz, 13.0 Hz). IR (neat) 3033, 2867, 1473, 1455,
1366, 1291, 1211, 1089, 1028, 980, 739, 698, 658 cm-1;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H13F2OBrNa
313.0016; Found 313.0010.
(3) To a dichloromethane (CH2Cl2)(12 mL) solution of 20
(3.78 g, 14.6 mmol) were added triethylamine (2.2 mL, 21.9
mmol) and methylsulfonyl chloride (2.5 g, 21.9 mmol) at
0°C, then the mixture was stirred at rt for 4 h. The reaction
mixture was quenched by addition of a saturated NaHCO3
aqueous solution, then extracted with CH2Cl2 (3 times). The
combined organic layers were evaporated to dryness and the
residue was diluted with acetone (73 mL). To this mixture
was added sodium iodide (NaI) powder (21.8 g, 146 mmol)
at rt and the mixture was stirred at 60°C for 6 h. After being
allowed cool to rt, the mixture was evaporated to dryness,
(((2,2-difluoro-1-(iodomethyl)cyclopropyl)methoxy)me-
thyl)benzene (2).17
(1) A mixture of 1,1-bis(chloromethyl)ethylene (CAS 1871-
57-4, 10.0 g, 80 mmol), triethylamine (33.5 mL, 240 mmol)
and acetic acid (11.4 mL, 200 mmol) was stirred at 70°C for
12 h. After being allowed to cool to rt, the mixture was di-
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The Journal of Organic Chemistry
Page 8 of 12
then washed with a saturated NaHSO4 aqueous solution (3
Synthesis of cyclopentenes (3 and 4).
(RS)-(((2,2-difluorocyclopent-3-en-1-
1
2
3
4
5
6
7
8
times), and purified by SiO2 flash column chromatography
(hexane/ethyl acetate = 9/1) to furnish 2 (3.78 g, 11.2 mmol)
in 77% yield (2 steps); 1H NMR (CDCl3, 600 MHz) δ 7.37-
7.30 (m, 5 H), 4.58 (d, 1 H, J = 12.0 Hz), 4.53 (d, 1 H, J =
12.0 Hz), 3.76 (ddd, 1 H, J = 10.8 Hz, 4.2 Hz, 1.2 Hz), 3.59
(dd, 1 H, J = 10.8 Hz, 1.8 Hz), 3.44 (dd, 1 H, J = 10.2 Hz,
0.6 Hz,), 3.33 (dd, 1 H, J = 1.8 Hz, 0.6 Hz), 1.34 (m, 1 H),
1.21 (m, 1 H);13C NMR (CDCl3, 151 MHz) δ 137.8, 128.6,
127.9, 127.8, 116.4 (dd, JC-F = 292.9 Hz, 4.7 Hz), 77.2 (t, JC-
F = 31.9 Hz), 68.3 (d, JC-F = 5.4 Hz), 32.6 (t, JC-F = 9.8 Hz),
22.8 (t, JC-F = 45.3 Hz), 5.8; 19F NMR (CDCl3, MHz) δ 29.91
(ddd, 1F, J = 158.2 Hz, 11.3 Hz, 11.3 Hz), 23.02 (ddd, 1F, J
= 158.2 Hz, 11.3 Hz, 11.3 Hz); IR (neat) 3031, 2863, 1455,
1375, 1212, 1093, 994, 901, 735, 696 cm-1; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C12H13F2OINa 360.9877;
Found 360.9870.
yl)methoxy)methyl)benzene (3). A CH2Cl2 (80 mL) solu-
tion of a mixture of the Grubbs (I) catalyst (16.7 mg, 0.020
mmol) and diene 8 (50.8 mg, 0.20 mmol) was stirred at re-
flux conditions under Ar for 24. After being allowed to cool
to rt, the mixture was evaporated to dryness and the residue
was purified by SiO2 TLC (hexane/ ethyl acetate = 4:1) to
afford the cyclopentane 3 (42.6 mg, 0.19 mmol) in 95%
1
9
yield: H NMR (CDCl3, 600 MHz) δ 7.36-7.31 (m, 5 H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6.31 (1H, dt, J= 6.0 Hz, 2.4 Hz), 5.84 (1H, dt, J= 4.5 Hz, 2.0
Hz), 4.57 (1H, d, J= 27.0 Hz), 4.55 (1H, d, J= 27 Hz), 3.77
(1H, dd, J= 9.6 Hz, 6.0 Hz), 3.46 (1H, dd, J= 9.0 Hz, 0.6
Hz), 2.75-2.68 (2H, m), 2.34-2.33 (1H, m); 13C NMR
(CDCl3, 151 MHz) δ 141.2, 141.1, 141.0, 138.2, 132.6 (t, JC-
F= 245 Hz), 128.5, 127.7, 127.4 (t, JC-F= 27.2 Hz), 73.3, 68.3,
44.4 (dd, JC-F= 22.7 Hz, 24.2 Hz), 34.3; 19F NMR (CDCl3,
565 MHz) δ76.43 (1F, d, J= 255 Hz), 63.78 (1F, d, J= 256
Hz) ; IR (neat) 3031, 2939, 2861, 1367, 1207, 1174, 1051,
1027, 740, 698 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C13H14F2ONa 247.0910; Found 247.0903.
Ring-opening allylation
(((2-Allyl-3,3-difluoropent-4-en-1-yl)oxy)methyl)benzene
(8).16 Into a solution of allyltributylstannane (129 μL, 0.4
mmol), AIBN (8.2 mg, 0.05 mmol) and 1 (58.2 mg, 0.2
mmol) in dry benzene (2.0 mL) was bubbled nitrogen gas for
10 min, then the mixture was stirred for 12 h at 80℃. After
allowing to cool to rt, the reaction mixture was concentrated
under reduced pressure, then diluted with ether and stirred
with an aq. solution of KF for 3 h at rt and filtered through a
glass sintered filter to remove the produced filtrate. The fil-
trate was washed with water, dried over anhydrous MgSO4,
concentrated and the residue was purified by SiO2 column
chromatography (hexane/ ethyl acetate=4/1) to give 8 (45.4
mg, 0.18 mmol) in 77% yield: bp130°C, 1.5 torr (Ku-
gelrohr); 1H NMR (600 MHz, CDCl3) δ 7.36-7.27 (m, 5H),
5.96 (m, 1H), 5.79 (m, 1H), 5.62 (dt, 1H, J = 17.3 Hz, 2.1
Hz), 5.41 (d, 1H, J = 11.0 Hz), 5.05 (dd, 2H, J = 24.0 Hz,
17.3 Hz), 4.47 (dd, 2H, J = 18.0 Hz, 12.0 Hz), 3.55 (ddd, 2H,
J = 18.0 Hz, 6.0 Hz, 4.4Hz), 2.39-2.37 (m, 1H), 2.27-2.20
(m, 1H); 13C NMR (151 MHz, CDCl3) δ 138.2, 135.7, 132.3
(((5,5-Difluorocyclopent-1-en-1-yl)methoxy)methyl)ben-
zene (4). By the same method using the Stewart-Grubbs cat-
alyst, the cyclopentene 4 (42.2 mg, 0.188 mmol) was ob-
tained in 94 % yield from the diene 9 (50.8 mg, 0.20 mmol):
1H NMR (CDCl3, 600 MHz) δ 7.38-7.29 (5H, m), 6.26-6.25
(1H, m), 4.57 (2H, s), 4.18 (2H, s), 2.50-2.46 (2H, m), 2.42-
2.35 (2H, m); 13C NMR (CDCl3, 151 MHz) δ 141.1, 137.8,
136.8, 128.4, 138.1, 137.4 (t, JC-F= 9.0 Hz), 137.0 (t, JC-F
=
25.7 Hz), 132.9 (t, JC-F = 243 Hz), 128.5, 127.8, 127.7, 72.8,
63.7, 34.2 (t, JC-F = 25.6 Hz), 27.4 (t, JC-F = 3.0 Hz); 19F NMR
(CDCl3, 565 MHz) δ 73.03-72.95 (2F, m); IR (neat) 3031,
2930, 2860, 1454, 1369, 1331, 1157, 1058, 935, 698 cm-1;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H14F2ONa
247.0910; Found 247.0904.
Chemo-selective epoxidation and subsequent vinylation or
allylation
(t, JC-F = 25.7 Hz), 128.4, 127.60, 127.58, 121.9 (t, JC-F
=
(RS)-2-((SR)-2-((benzyloxy)methyl)-3,3-difluoropent-4-en-
1-yl)oxirane (10). To m-CPBA (280 mg, 1.13 mmol, purity
70%) in a CH2Cl2 (7.0 mL) solution was added a CH2Cl2 (2.0
mL) solution of the diene 8 (220. mg, 0.87 mmol) at 0°C,
then the mixture was stirred at rt for 12 h. The mixture was
washed 3 times with a 1.0 M-NaOH aqueous solution, then
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, evaporated to dryness, then purified by
SiO2 flash column chromatography (hexane/ ethyl acetate=
9:1) to afford the epoxide 10 (170 mg, 0.63 mmol) in 72%
yield as an ca. 1:1 mixture of diastereomers: 1H NMR
(CDCl3, 600 MHz) δ 7.36-7.29 (5H, m), 5.99-5.95 (1H,m),
5.63 (1H, d, J = 17.4 Hz), 5.44 (1H, d, J = 11.4 Hz), 4.50
(2H, s), 3.71-3.57 (2H, m), 3.07-3.02 (1H, m), 2.77-2.75
(1H, m), 2.47-2.46 (1H, m), 2.40-2.36 (1H, m), 1.84-1.73
(2H, m); 13C NMR (CDCl3, 151 MHz) δ 138.0, 137.9, 131.9
(t, JC-F = 3.47 Hz), 131.8 (t, JC-F = 3.47 Hz), 128.5, 128.4,
238.4 Hz), 119.2 (t, JC-F = 9.7 Hz), 117.0, 73.2, 67.3 (t, JC-F
= 5.1 Hz), 46.1 (t, JC-F = 24.2 Hz), 30.3 (t, JC-F = 3.3 Hz);
19F NMR (565 MHz, CDCl3) δ 62.38 (dt, J = 245.1Hz, 9.7
Hz), 58.5 (dt, J=244.6 Hz, 14.0Hz); IR (neat) 3067, 3033,
2924, 2871, 1641, 1454, 1420, 1365, 1114, 1060, 698 cm-1;
HRMS (ESI-TOF) m/z: [M]+ Calcd for C15H18F2O
253.1404; Found 253.1362.
(((3,3-Difluoro-2-methylenehept-6-en-1-yl)oxy)me-
thyl)benzene (9). Using the same method, the diene 9 was
prepared in 76% yield from 2: 1H NMR (CDCl3, 600 MHz)
δ 7.36-7.31 (m, 5 H), 5.80 (1H, ddt, J = 19.8 Hz, 6.6 Hz, 3.6
Hz), 5.57 (1H, s), 5.52 (1H, s), 5.03 (1H, dd, J = 24.6 Hz,
1.8 Hz), 4.99 (1H, dd, J = 10.3 Hz, 1.8 Hz). 4.55 (2H, s),
4.10 (2H, s), 2.43-2.21 (2H, m), 2.11-2.06 (2H, m); 13C
NMR (CDCl3, 151 MHz) δ 141.1, 137.8, 136.8, 128.4,
127.8, 127.6, 122.1 (t, JC-F = 242 Hz), 117.1, 117.0, 116.9,
115.2, 72.5, 68.3, 68.2, 35.8 (t, JC-F = 26.4 Hz), 26.5 (t, JC-F
= 4.8 Hz) ; 19F NMR (CDCl3, 565 MHz) δ 62.70; IR (neat)
3067, 2933, 2862, 1643, 1453, 1364, 1173, 1071, 1028, 915,
734, 697cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C15H18F2ONa 275.1223; Found 275.1218.
127.8, 127.7, 127.6, 121.6 (t, JC-F = 242 Hz), 121.5 (t, JC-F
242 Hz), 119.79, 119.75, 119.73, 119.68, 119.66, 119.62,
73.3, 73.3, 67.8 (t, JC-F = 5.1 Hz), 63.4 (t, JC-F = 5.3 Hz),
=
50.9, 50.4, 47.9, 47.4, 44.5 (t, JC-F = 24.9 Hz), 43.9 (t, JC-F
=
F
25.0 Hz), 29.9 (t, JC-F = 3.0 Hz), 29.6 (t, JC-F = 3.3 Hz) ; 19
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The Journal of Organic Chemistry
NMR (CDCl3, 565 MHz) δ 63.21 (0.5 F, d, J = 248 Hz), F = 22.9 Hz), 103.9 (d, JC-F = 22.8 Hz), 73.3, 73.1, 71.4, 71.1,
1
2
3
4
5
6
7
8
62.13 (0.5F, d, J = 248 Hz), 58.02 (0.5 F, d, J = 249 Hz),
57.33 (0.5 F, d, J = 249 Hz); IR (neat) 3032, 2926, 2871,
1454, 1420, 1366, 1204, 1058, 987 cm-1; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C15H18F2O2Na 291.1173; Found
291.1163.
70.8, 68.8, 68.5, 68.4, 42.6, 41.83, 41.75, 40.6, 40.5, 39.9,
39.7, 36.4, 36.1, 35.7, 35.6, 29.3 (d, JC-F = 9.8 Hz), 27.83 (d,
JC-F= 3.6 Hz), 27.79 (d, JC-F = 4.3 Hz); 19F NMR (CDCl3,
565 MHz) δ 46.15 (dd, J = 22.6 Hz, 11.3 Hz), 45.20 (dd, J =
39.5 Hz, 22.6 Hz), 42.08 (dd, J = 39.5 Hz, 28.2 Hz); IR (neat)
3429, 3077, 2917, 2862, 1704, 1454, 1100, 914, 737 cm-1;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H25FO2Na
327.1737; Found 327.1728.
(4RS,6RS)-6-((benzyloxy)methyl)-7,7-difluoronona-1,8-
dien-4-ol (12). To a THF (2.0 mL) suspension of dry
Cu(I)CN (2.0 mg, 0.02 mmol) was added the epoxide 10
(53.9 mg, 0.20 mmol) under Ar and the mixture was cooled
to -40°C. To this mixture was dropwise added a vinyl MgBr-
THF solution (1.0 M, 0.4 mL) and stirred for 12 h at the same
temperature. The reaction was quenched by the addition of a
saturated NH4Cl aqueous solution and extracted 3 times with
ether. The combined organic layers were dried over MgSO4,
evaporated dryness, and purified by SiO2 TLC to give the
diene 12 (40.3 mg, 0.136 mmol) in 68% yield. Since 12 is a
mixture of diastereomers (ca. 1:1), the NMR spectra were
complicated: 1H NMR (CDCl3, 600 MHz) δ 7.36-7.29 (5H,
m), 5.62 (1H, dt, J = 17.4 Hz, 4.2 Hz), 5.44 (1H, dd, J = 10.8
Hz, 5.4 Hz), 5.13-5.11 (1H, m), 5.09 (1H, d, J = 1.2 Hz),
4.52 (2H, d (germinal coupling), J = 14.4 Hz), 3.81-3.70
(2H, m), 3.53-3.46 (1H, m), 2.52-2.46 (0.5H, m), 2.41-2.36
(0.5H, m), 2.36-2.33 (0.5 H, m), 2.28-2.17 (2H, m), 1.91
(0.5H, dt, J = 14.4 Hz, 3.6 Hz), 1.71 (0.5H, dt, J= 10.7 Hz,
3.6 Hz), 1.63 (0.5H, dt, J = 10.8 Hz, 3.6 Hz), 1.52-1.47 (1H,
m); 13C NMR (CDCl3, 151 MHz) δ 137.6, 137.3, 134.8,
132.0 (t, JC-F = 27.2 Hz), 131.6 (t, JC- F = 26.6 Hz), 128.6,
128.5, 128.0, 127.9, 127.84, 127.79, 121.9 (t, JC-F = 243 Hz),
121.7 (t, JC-F = 242 Hz), 120.0 (t, JC-F = 9.5 Hz), 119.7 (t, JC-
F = 9.5 Hz), 117.8, 117.7, 73.5, 73.5, 70.3, 69.6 (t, JC-F = 5.1
Hz), 68.2 (t, JC-F = 4.9 Hz), 67.7, 44.7 (t, JC-F = 24.2 Hz), 42.4
(t, JC-F = 24.3 Hz), 42.4, 42.2, 34.9, 33.9 ; 19F NMR (CDCl3,
565 MHz) δ 61.28 (0.5F, dt, J= 242 Hz, 16.9 Hz), 60.18
(0.5F, dt, J = 299 Hz, 11.3 Hz), 59.19 (0.5F, dt, J = 248 Hz,
11.3 Hz), 58.86 (0.5F, dt, J = 242 Hz, 16.9 Hz); IR (neat)
3423, 2933, 2865, 1454, 1366, 1174, 1073, 1029, 920, 738
cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C17H22F2O2Na 319.1486, found 319.1468.
9
Synthesis of cycloheptene (5) and cyclooctane (6)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1RS,6RS)-6-((benzyloxy)methyl)-5,5-difluorocyclohept-3-
enol (5). A CH2Cl2 (30 mL) solution of a mixture of the
Grubbs (II) catalyst (8.6 mg, 0.01 mmol) and the diene 12
(30.2 mg, 0.10 mmol) was stirred at reflux conditions under
Ar for 24. After being allowed to cool to rt, the mixture was
evaporated to dryness and the residue was purified by SiO2
TLC (hexane/ ethyl acetate = 3:2) to afford the cycloheptene
5 (24.4 mg, 0.091 mmol) in 91% yield (ca. 1:1 diastereomix-
1
ture): H NMR (CDCl3, 600 MHz) δ 7.36-7.27 (5H, m),
5.97-5.9 (1H, m), 5.84-5.74 (1H, m), 4.56 (1H, d, J = 12.0
Hz), 4.51 (1H, d, J = 12.0 Hz), 4.00 (0.5 H, dt, J = 12.0 Hz,
6.0 Hz), 3.88-3.84 (0.5 H, m), 3.82 (1H, dd, J = 9.6 Hz, 3.2
Hz), 3.79 (1H, dd, J = 9.6 Hz, 4.2 Hz), 3.5 (1H, OH, dt, J =
9.0 Hz, 6.6 Hz), 2.71-2.62 (0.5 H, m), 2.50-2.38 (2.5 H, m),
2.38-2.32 (0.5 H, m), 2.13-2.04 (0.5 H, m), 2.13-2.04 (1H,
m), 1.85 (0.5H, dt, J = 13.8 Hz, 9.6 Hz); 13C NMR (CDCl3,
151 MHz) δ 137.97, 137.93, 132.5 (t, JC-F = 13.6 Hz), 131.9
(dd, JC-F = 13.6 Hz, 9.1 Hz), 129.6 (dd, JC-F = 36.2 Hz, 27.2
Hz), 129.0 (t, JC-F = 31.7 Hz), 128.5, 127.86, 127.85, 127.83,
127.82, 122.0 (t, JC-F = 237 Hz), 121.9 (t, JC-F = 193 Hz),
73.5, 73.3, 68.5 (t, JC-F = 31.7 Hz), 65.9, 43.1 (t, JC-F = 24.2
Hz), 40.7 (t, JC-F = 22.7 Hz), 36.2, 36.2, 36.0, 34.4 (t, JC-F
=
4.5 Hz) ; 19F NMR (CDCl3, 565 MHz) δ 73.16 (0.5F, dd, J =
267 Hz, 10.2 Hz), 72.60 (0.5F, dt, J = 267 Hz, 13.0 Hz),
66.40 (0.5F, dd, J = 268 Hz, 122.6 Hz), 63.76 (0.5F, dd, J =
266 Hz, 22.6 Hz); IR (neat) 3395, 3032, 2931, 1497, 1454,
1370, 1207, 1100, 1055, 1001, 698 cm-1; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C15H18F2O2Na 291.1173; Found
291.1163.
During the course of the reaction, the defluorinated allylic
alkylation simultaneously took place to afford the mono-
fluorinated diene 15 (18.2 mg, 0.060 mmol) in 30 % yield:
(5RS,7RS)-7-((benzyloxy)methyl)-8,8-difluorodeca-1,9-
dien-5-ol (13). To a THF (2.0 mL) suspension of dry
Cu(I)CN (6.6 mg, 0.065 mmol) was added the epoxide 10
(175.0 mg, 0.65 mmol) under Ar and the mixture was cooled
to -40°C. To this mixture was dropwise added an allyl
MgBr-Et2O solution (0.7 M, 1.3 mL) and stirred for 12 h at
the same temperature. The reaction was quenched by the ad-
dition of a saturated NH4Cl aqueous solution and extracted
3 times with ether. The combined organic layers were dried
over MgSO4, evaporated to dryness, and underwent SiO2
TLC (hexane/ ethyl acetate= 4:1) to give the diene 13 (162
mg, 0.52 mmol) in 80% yield as an ca. 1:1 mixture of dia-
(4RS,6RS,ZE)-6-((benzyloxy)methyl)-7-fluoroundeca-
1,7,10-trien-4-ol (15)(ca. 1:1 mixture of E,Z and diastere-
1
omers): H NMR (CDCl3, 600 MHz) δ 7.36-7.25 (5H, m),
5.85-5.76 (2H, m), 5.13 (2H, g, J = 14.4 Hz), 5.05 (1H, dt, J
= 16.8 Hz, 3.6 Hz), 4.99 (1H, d, J = 10.2 Hz), 4.71 (0.5 H,
dt, J=38.4 Hz, 7.2 Hz), 4.69 (0.5 H, dt, J = 43.2 Hz, 7.8 Hz),
4.53 (2H, d (germinal coupling), J = 4.3 Hz), 3.79-3.71 (1H,
m), 3.60 (0.5 H, dd, J = 8.4 Hz, 6.0 Hz), 3.58 (0.5 H, dd, J =
11.4 Hz, 6.6 Hz), 3.01 (0.5 H, dd, J = 6.6 Hz, 4.8 Hz), 3.45
(0.5 H, dd, 7.2 Hz, 6.6 Hz), 2.84 (2H, dt, J = 7.8 Hz, 1.8 Hz),
2.76-2.68 (1H, m), 2.30-2.25 (1H, m), 2.21-2.17 (1H, m),
2.14-2.02 (1H, m), 1.72-1.67 (1H, m), 1.65-1.50 (1H, m);
13C NMR (CDCl3, 151 MHz) δ 160.7 (d, JC-F = 207 Hz),
160.3 (d, JC-F = 182 Hz), 159.1 (d, JC-F = 257 Hz), 138.1,
137.9, 136.4, 136.3, 134.7, 134.6, 128.5, 128.4, 127.8,
127.71, 127.69, 127.67, 127.6, 118.17, 118.14, 118.07,
115.2, 114.92, 114.88, 104.8 (d, JCF = 14.8 Hz), 104.6 (d, JC-
1
stereomers: H NMR (CDCl3, 600 MHz) δ 7.37-7.30 (5H,
m), 5.93-5.79 (2H, m), 5.63 (1H, d, J = 30.7 Hz), 5.45 (1H,
dd, J = 13.2 Hz, 6.0 Hz), 5.03 (1H, d, J = 17.4 Hz), 4.97 (1H,
dd, J = 9.6 Hz, 4.0 Hz), 4.73 (1H, brs, OH), 4.54 (2H, s),
3.77-3.73 (1.5H, m), 3.67-3.63 (0.5 H, m), 3.48 (1H, m),
2.52-2.44 (0.5 H, m), 2.40-2.33 (0.5 H, m), 2.23-2.09 (2H,
m), 1.93-1.89 (0.5 H, m), 1.73-1.68 (0.5 H, m), 1.61-1.46
(3H, m); 13C NMR (CDCl3, 151 MHz) δ 138.6, 138.5, 137.5,
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137.2, 132.1 (t, JC-F = 26.7 Hz), 131.6 (t, JC-F = 26.5 Hz), extracted 3 times with CH2Cl2. The combined organic layers
1
2
3
4
5
6
7
8
128.6, 128.5, 128.0, 127.9, 127.8, 121.8 (t, JC-F = 243 Hz),
121.7 (t, JC-F = 245 Hz), 120.1 (t, JC-F = 17.5 Hz), 119.7 (t,
JC-F = 9.5 Hz), 114.8, 114.6, 73.6, 70.6, 69.6 (t, JC-F = 5.1
Hz), 68.5 (t, JC-F = 5.0 Hz), 67.9, 44.8 (t, JC-F = 23.9 Hz), 42.5
(t, JC-F = 24.2 Hz), 37.1, 36.7, 34.7, 30.2, 30.0; 19F NMR
(CDCl3, 565 MHz) δ 461.16-59.91 (1F, m), 59.10-58.04 (1F,
m); IR (neat) 3424, 2929, 2864, 1640, 1454, 1420, 1365,
1204, 1059, 988, 699 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C18H24F2O2Na 333.1544; Found 333.2209.
were dried over Na2SO4, evaporated to dryness, then puri-
fied by SiO2 flash column chromatography (hexane/ ethyl
acetate= 9:1) to afford the epoxide 11 (164 mg, 0.61 mmol)
in 87% yield as an ca. 1:1 diastereo-mixture: 1H NMR
(CDCl3, 600 MHz) δ 7.36-7.29 (5H, m), 5.55 (2H, d, J =
27.6 Hz), 4.55 (2H, s), 4.10 (2H, s), 2.96-2.93 (1H, m), 2.75
(1H, t, J = 4.8 Hz), 2.47 (1H, dd, J = 5.4 Hz, 3.0 Hz), 2.20-
2.01 (1H, m), 1.82-1.76 (1H, m), 1.69-1.63 (1H, m); 13C
NMR (CDCl3, 151 MHz) δ 140.9 (t, JC-F = 24.7 Hz), 128.5,
127.8, 127.7, 121.9 (t, JC-F = 242 Hz), 117.3 (t, JC-F = 8.2 Hz),
72.5 (t, JC-F = 23.4 Hz), 68.2, 51.3, 47.1, 32.9 (t, JC-F = 26.7
Hz), 25.5; 19F NMR (CDCl3, 565 MHz) δ 62.58 (dddd, J =
379 Hz, 254 Hz, 17.0 Hz, 11.3 Hz); IR (neat) 2931, 2864,
1454,1175,1092, 1062, 944, 738, 639 cm-1; HRMS (ESI-
TOF) m/z: [M+NH4]+ Calcd for C15H18F2O2(NH4) 286.1619;
Found 286.1619.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5RS,7RS)-7-((benzyloxy)methyl)-8-fluorotrideca-1,8,12-
trien-5-ol (16). The mono-fluorinated diene 16 (28.3 mg,
0.085 mmol) was formed in 13 % yield (ca. 1:1 mixture of
E,Z and diastereomers): 1H NMR (CDCl3, 600 MHz) δ 7.37-
7.29 (5H, m),5.86-5.76 (2H, m), 5.06-4.96 (4H, m), 4.67 (0.5
H, t, J= 7.2 Hz), 4.61 (0.5 H, t, J = 7.2 Hz), 4.54 (2H, s),
3.69-6.67 (1H, m), 3.57 (1H, dd, J = 9.6 Hz, 6.6 Hz), 3.43
(1H, dd, J = 9.0 Hz, 6.6 Hz), 2.79-2.70 (1H, m), 2.23-2.08
(6H, m), 1.99 (1H, OH, d, J = 4.8 Hz), 1.66-1.62 (1H, m),
1.59-1.47 (3H, m) ; 13C NMR (CDCl3, 151 MHz) δ 158.9 (d,
JC-F = 256 Hz), 138.9,138.1,138.0, 128.4, 127.7, 127.7,
115.0, 114.8, 106.7 (d, JC-F = 15.2 Hz), 73.1, 71.6, 69.1, 40.7,
40.5, 37.2, 36.8, 33.6, 30.1, 22.9 (d, JC-F = 5.1 Hz); 19F NMR
(CDCl3, 565 MHz) δ 42.30; IR (neat) 3412, 3076, 2921,
2858, 1706, 1641, 1454, 1102, 913., 737, 698 cm-1; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C21H29FO2Na 355.2050;
Found 355.2042.
(RS)-8-((benzyloxy)methyl)-7,7-difluoronona-1,8-dien-4-
ol (14). To a THF (2.0 mL) suspension of dry Cu(I)CN (2.0
mg, 0.02 mmol) was added epoxide 11 (53.7 mg, 0.20 mmol)
under Ar and the mixture was cooled to -20°C. To this mix-
ture was dropwise added a vinyl MgBr-THF solution (1.0 M,
0.40 mL) and stirred for 12 h at the same temperature. The
reaction was quenched by the addition of a saturated NH4Cl
aqueous solution and extracted 3 times with ether. The com-
bined organic layers were dried over MgSO4, evaporated to
dryness, and purified by SiO2 TLC to give the diene 14 (48.6
mg, 0.164 mmol) in 82% yield: 1H NMR (CDCl3, 600 MHz)
δ 7.36-7.29 (5H, m), 5.90-5.57 (1H, m), 5.57 (2H, d, J = 31.8
Hz), 5.15-5.11 (2H, m), 4.55 (2H, s), 4.10 (2H, s), 3.65-3.63
(1H, m), 2.27-2.13 (3H, m), 1.67-1.58 (1H, m), 1.57-1.55
(1H, m); 13C NMR (CDCl3, 151 MHz) δ 141.0 (t, JC-F = 24.3
Hz), 137.8, 128.5, 127.8, 127.7, 122.4 (t, JC-F = 242 Hz),
118.4, 117.1 (t, JC-F = 8.0 Hz), 72.5, 69.8, 68.2 (t, JC-F = 3.0
(1RS,7RS)-7-((benzyloxy)methyl)-6,6-difluorocyclooct-4-
enol (6). A CH2Cl2 (40 mL) solution of a mixture of the
Grubbs (II) catalyst (8.7 mg, 0.01 mmol) and the diene 13
(31.2 mg, 0.10 mmol) was stirred at reflux conditions under
Ar for 24. After being allowed to cool to rt, the mixture was
evaporated to dryness and the residue was purified by SiO2
TLC (hexane/ ethyl acetate = 3:2) to afford the cyclooctene
6 (23.8 mg, 0.084 mmol) in 70% yield (ca. 2:3 cis/trans mix-
Hz), 42.0, 32.7 (t, JC-F = 27.2 Hz), 29.3 (t, JC-F = 3.0 Hz); 19
F
1
NMR (CDCl3, 565 MHz) δ 63.94-62.56 (2F, m); IR (neat)
3412, 3069, 2933, 2865,1641, 1453, 1365, 1173, 1064,
1027, 916, 735, 697 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C17H22F2O2Na 319.1486; Found 319.1483.
ture): H NMR (CDCl3, 600 MHz) δ 7.36-7.27 (5H, m),
5.96-5.90 (1H, m), 5.84-5.74 (1H, m), 4.567-4.49 (2H,
m),4.04-4.01 (0.4 H, m), 3.99-3.84 (0.6 H, m), 3.78 (1H, dd,
J = 9.0 Hz, 4.2 Hz), 3.51 (1H, t, J = 9.0 Hz), 2.70-2.60 (0.4
H, m), 2.52-2.32 (3H, m), 2.13-2.08 (1H, m), 1.88-1.83
(0.4H, m), 1.60-1.49 (0.6H, m); 13C NMR (CDCl3, 151
MHz) ; 138.0, 137.9, 132.3 (t, JC-F = 12.2 Hz), 131.8 (dd, JC-
F= 15.1 Hz, 10.6 Hz), 129.7 (dd, JC-F = 36.2 Hz, 27.5 Hz),
129.3 (t, JC-F = 31.7 Hz), 128.5, 128.4, 127.79, 127.75,
127.71, 127.69, 121.9 (t, JCF = 238 Hz), 121.8 (t, JC-F = 204
Hz), 73.4, 73.3, 71.3, 68.6 (dd, JC-F = 142 Hz, 7.4 Hz), 68.53,
68.49 (dd, JC-F = 135 Hz, 4.5 Hz), 66.1, 45.4 (t, JC-F = 24.0
Hz), 43.1 (t, JC-F = 22.3 Hz), 40.8 (t, JC-F = 23.4 Hz), 36.2 (t,
JC-F = 5.6 Hz), 36.1, 35.7, 34.6 (t, JC-F = 3.8 Hz), 22.49,
22.48;19F NMR (CDCl3, 565 MHz) δ 59.58 (t, J= 17.0 Hz);
IR (neat) 3396, 2932, 2868, 1454, 1370, 1158, 1100, 1055,
1001, 752 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C16H20F2O2Na 305.1329; Found 305.1307.
8-((benzyloxy)methyl)-7-fluoroundeca-1,7,10-trien-4-ol
(17). The mono-fluorinated diene 17 (9.13 mg, 0.030 mmol)
was also obtained in 15% yield as a by-product as an ca. 1:1
(E,Z) mixture. 1H NMR (CDCl3, 600 MHz) δ 7.37-7.28 (5H,
m), 5.85-5.71 (2H, m), 5.17-5.06 (4H, m), 4.49 (1H, s), 4.45
(1H, s), 4.11 (2H, d (geminal coupling), J = 3.0 Hz), 3.79
(1H, s, OH), 3.69-3.60 (1H, m), 2.97-2.80 (2H, m), 2.54-
2.35 (2H, m), 2.33-2.31 (1H, m), 2.26-2.23 (0.5 H, m), 2.18-
2.14 (1H, m), 1.78-1.71 (1H, m), 1.65-1.59 (1H, m), 1.59-
1.53 (1.5 H, m); 13C NMR (CDCl3, 151 MHz) δ 159.8 (d, JC-
F = 125 Hz), 158.2 (d, JC-F=123 Hz), 138.5, 137.9, 135.6 (d,
JC-F = 2.9 Hz), 135.5, 134.8, 134.4, 128.5, 128.4,
128.0,127.84, 127.81, 127.6, 118.5, 117.7, 115.8, 112.3 (d,
JC-F =16.1 Hz), 111.7 (d, JC- F= 12.9 Hz), 72.3, 71.9, 69.6,
69.0, 67.4 (d, JC-F =10.6 Hz), 64.5 (d, JC-F = 9.7 Hz), 42.1,
42.0, 33.3, 33.2, 31.8 (d, JCF = 5.1 Hz), 31.3 (d, JC-F = 7.2
Hz), 25.1, 24.9; 19F NMR (CDCl3, 565 MHz) δ 56.43 (t, J=
17.0 Hz), 54.18 (t, J = 22.6 Hz); IR (neat) 3418, 3077, 2917,
2862, 1704, 1640, 1454, 1100, 914, 737, 698 cm-1; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C19H25FO2Na
327.1638; Found 327.1730.
(RS)-2-(4-((benzyloxy)methyl)-3,3-difluoropent-4-en-1-
yl)oxirane (11). To m-CPBA (226mg, 1.10 mmol, purity
70%) in a CH2Cl2 (5.0 mL) solution was added a CH2Cl2 (2.0
mL) solution of the diene 9 (181 mg, 0.70 mmol) at 0°C,
then the mixture was stirred at rt for 12 h. The mixture was
washed 3 times with a 1.0 M-NaOH aqueous solution, then
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Nohira, H. Synthesis of Novel Liquid Crystals which Possess gem-
ASSOCIATED CONTENT
Difluorocyclopropane Moieties. Chem. Lett. 2003, 32, 494–495. (g)
Itoh, T.; Ishida, N.; Mitsukura, K.; Uneyama, K. Synthesis of novel bis-
and oligo-gem-difluorocyclopropanes. J. Fluorine Chem. 2001, 112,
63–68. (h) Itoh, T.; Mitsukura, K.; Ishida, N.; Uneyama, K. Synthesis
of Bis- and Oligo-gem-difluorocyclopropanes Using the Olefin Metath-
esis Reaction. Org. Lett. 2000, 2, 1431–1434.
1
2
3
4
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: XXXXX
1
The H, 13C, and 19F NMR spectra for all the new com-
5
6
7
8
(3) Ahmed, L.; Zhang, Y.; Block, E.; Buehl, M.; Corr, M. J.; Cor-
manich, R. A.; Gundala, S.; Matsunami, H.; O’Hagan, D.; Ozbil, M.;
Pan, Y.; Sekharan, S.; Ten, N.; Wang, M.; Yang, M.; Zhang, Q.; Zhang,
R.; Batista, V. S.; Zhuang, H. Molecular mechanism of activation of
human musk receptors OR5AN1 and OR1A1 by (R)-muscone and di-
verse other musk-smelling compounds. PNAS, 2018, 115, E3950–
E3958.
pounds, 3-6, and 9-17 (PDF) and the details of the MO cal-
culations reported in Figures 7, 8, and 9 (Tables S1, S2, S3,
S4, S5, S6, S7, and S8).
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AUTHOR INFORMATION
(4) Reviews see: (a) Zhu, Y.; Han, J.-L.; Wang, J.-D.; Shibata, N.;
Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Modern
Approaches for Asymmetric Construction of Carbon-Fluorine Quater-
nary Stereogenic Centers: Synthetic Challenges and Pharmaceutical
Needs. Chem. Rev. 2018, 118, 3887−3964. (b) Zhou, Y.; Wang, J.; Gu,
Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu,
H. Next Generation of Fluorine-Containing Pharmaceuticals, Com-
pounds Currently in Phase II–III Clinical Trials of Major Pharmaceuti-
cal Companies: New Structural Trends and Therapeutic Areas. Chem.
Rev. 2016, 116, 422−518. (c) Huang, Y.-Y.; Yang, X.; Chen, Z.; Ver-
poort, F.; Shibata, N. Catalytic Asymmetric Synthesis of Enantioen-
riched Heterocycles Bearing a C-CF3 Stereogenic Center. Chem. Eur.
J. 2015, 21, 8664−8684. (d) Wang, J.; Sanchez-Rosello, M.; Acena, J.
L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.;
Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing
Drugs Introduced to the Market in the Last Decade (2001–2011).
Chem. Rev. 2014, 114, 2432−2506. (e) D. Barnes-Seeman, J. Beck, C.
Springer, Fluorinated compounds in medicinal chemistry: recent appli-
cations, synthetic advances and matched-pair analyses. Curr. Top.
Med. Chem. 2014, 14, 855−864. (f) Landelle, G.; Panossian, A.;
Pazenok, S.; Vors, J-P.; Leroux, F. R. Recent advances in transition
metal-catalyzed Csp2-monofluoro-, difluoro-, perfluoromethylation
and trifluoromethylthiolation. Beilstein J. Org. Chem. 2013, 9, 2476-
2536. (g) Chen, P.; Liu, G. Recent Advances in Transition-Metal-Cat-
alyzed Trifluoromethylation and Related Transformations. Synthesis
2013, 2919-2939. (h) Y.-L. Liu, J.-S. Yu and J. Zhou. Catalytic Asym-
metric Construction of Stereogenic Carbon Centers that Feature a gem-
Difluoroalkyl Group. Asian J. Org. Chem. 2013, 2, 194−206. (i) Gior-
nal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J-P.; Leroux, F. R.
Synthesis of diversely fluorinated pyrazoles as novel active agrochem-
ical ingredients. J. Fluorine Chem. 2013, 152, 2-11.
(5) Fedorynski, M. Syntheses of gem-Dihalocyclopropanes and
Their Use in Organic Synthesis. Chem. Rev. 2003, 103, 1099–1132.
(6) Rong, Jian; Ni, Chuanfa; Hu, Jinbo, Metal‐Catalyzed Direct
Difluoromethylation Reactions. Asian J. Org. Chem. 2017, 6, 139–152.
(7) (a) A. D. Dilman, V. V. Levin, Difluorocarbene as a Building
Block for Consecutive Bond-Forming Reactions. Acc. Chem. Res.,
2018, 51, 1272−1280. (b) S. S. Ashirbaev, V. V. Levin, M. I.
Struchkov, A. D. Dilman, Copper-Catalyzed Coupling of Acyl Chlo-
rides with gem-Difluorinated Organozinc Reagents via Acyl Dithiocar-
bamates. J. Org. Chem. 2018, 83, 478−483. (d) M. D. Kosobokov, V.
V. Levin, M. I. Struchkova, A. D. Dilman, Nucleophilic Bromo- and
Iododifluoromethylation of Aldehydes. Org. Lett. 2014, 16,
3784−3787. (f) V. V. Levin, A. L. Trifnov, A. A. Zemtsov, M. I.
Struchkov, D. E. Aekhipov, A. D. Dilman, Difluoromethylene Phos-
phabetaine as an Equivalent of Difluoromethyl Carbanion. Org. Lett.
2014, 16, 6256−6259.
Corresponding Author
* Toshiyuki Itoh. E-mail: titoh@tottori-u.ac.jp
ORCID
*Toshiyuki Itoh: http://orcid.org/0000-0002-8056-6287
Toshiki Nokami: http://orcid.org/0000-0001-5447-4533
Author Contributions
YM, HT, and TM equally contributed for the synthetic
studies and SH contributed to the MO calculations. The
manuscript was prepared by TN and TI.
Funding Sources
The present study was partly supported by JSPS KAKENHI
KIBAN(A) Grant (No.26241030).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
All calculations with Gaussian16 were performed at the Re-
search Center for Computational Science (RCCS) in Oka-
zaki (Nagoya, Japan). The authors thank the RCCS for their
permission to access their computer resources.
REFERENCES
(1) Review see: Ed. Ojima, I. “Fluorine in Bioorganic and Medicinal
Chemistry”, Wiley-Blackwell, London, UK (2009).
(2) Review see: (a) Itoh, T. “gem-Difluorinatedcyclopropanes as key
building blocks for novel biologically active molecules” in “Fluorine
in Bioorganic and Medicinal Chemistry”, (Ed. Ojima, I), Wiley-Black-
well, London, UK, Chapter 12，pp. 313–355 (2009). Our examples
see: (b) Itoh, T.; Kanbara, M.; Nakajima, S; Sakuta, Y.; Hayase, S.;
Kawatsura, M.; Kato, T.; Miyazawa, K.; Uno, H. Chemo-enzymatic
Synthesis of Spiro Type gem-Difluorocyclopropane as Core Molecule
Candidate for Liquid Crystal Compounds. J. Fluorine Chem. 2009,
130, 1157–1163. (c) Itoh, T.; Kanbara, M.; Ohashi, M.; Hayase, S.; Ka-
watsura, M.; Kato, T.; Miyazawa, K.; Takagi, Y.; Uno, H. gem-Difluo-
rocyclopropane as Core Molecule Candidate for Liquid Crystal Com-
pounds. J. Fluorine Chem. 2007, 128, 1112–1120. (d) Ninomiya, K.;
Tanimoto, K.; Ishida, N.; Horii, D.; Sisido, M.; Itoh, T. Synthesis of
novel gem-difluorinatedcyclopropane hybrids: applications for DNA
cleavage agents switched by photo irradiation. J. Fluorine Chem. 2006,
127, 651–656. (e) Itoh, T.; Ishida, N.; Mitsukura, K.; Hayase, S.;
Ohashi, K. Synthesis of Optically Active gem-Difluorocyclopropanes
through a Chemo-Enzymatic Reaction Strategy. J. Fluorine Chem.
2004, 125, 775–783. (f) Itoh, T.; Ishida, N.; Ohashi, M.; Asep, R.;
(8) Fuchibe, K.; Takayama, R.; Aono, T.; Hu, L.; Hidano, T.; Sasa-
gawa, H.; Fujiwara, M.; Miyazaki, S.; Nadano, R.; Ichikawa, J. Regi-
oselective Syntheses of Fluorinated Cyclopentanone Derivatives: Ring
Construction Strategy Using Transition-Metal–Difluorocarbene Com-
plexes and Free Difluorocarbene. Synthesis, 2018, 50, 514–528.
(9) Y-L. Lai.; D-Z. Lin.; Huang, J-M. Copper-Catalyzed Decarbox-
ylative Difluoroalkylation and Perfluoroalkylation of α,β-Unsaturated
Carboxylic Acids. J. Org. Chem. 2017, 82, 597−305.
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(10) Song, X.; Xu, C.; Wang, M. Transformations based on ring-
(22) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R.
opening of gem-difluorocyclopropanes. Tetrahedron Lett. 2017, 58,
1806−1816.
H.; Schrodi, Y. Highly Efficient Ruthenium Catalysts for the For-
mation of Tetrasubstituted Olefins via Ring-Closing Metathesis. Org.
Lett. 2007, 9, 1589–1592.
(23) (a) Yamamoto, Y. Selective Synthesis by Use of Lewis Acids
in the Presence of Organocopper and Related Reagents. New Synthetic
Methods (61). Angew. Chem. Int. Ed. 1986, 25, 947-1038. (b) Lipshutz,
B. H.; Ellsworth, E. L.; Siahaan, T. The Role of BF3•Et2O in Reactions
of Lower Order (Gilman) Organocuprates. J. Am. Chem.
Soc. 1989, 111, 1351–1358.
(24) Watanabe, D.; Koura, M.; Saito, A.; Yanai, H.; Nakamura, Y.;
Okada, M.; Sato, A.; Taguchi, T. Copper mediated defluorinative al-
lylic alkylation of difluorohomoallyl alcohol derivatives directed to an
efficient synthetic method for (Z)-fluoroalkene dipeptide isosteres. J.
Fluorine Chem. 2011, 132, 327–338.
(25) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Synthesis and
Activity of a New Generation of Ruthenium-Based Olefin Metathesis
Catalysts Coordinated with 1,3-Dimesityl-4,5-dihydroimidazol-2-yli-
dene Ligands. Org. Lett. 1999, 1, 953–956.
1
2
3
4
5
6
7
8
(11) Kageshima, Y.; Suzuki, C.; Oshiro, K.; Amii, H. Highly Con-
trolled Ring-Opening of Siloxydifluorocyclopropanes: A Versatile
Route to Cyclic Fluoroketones. Synlett. 2015, 26, 63-66.
(12) O.V. Fedorov, M. D. Kosobokov, V. V. Levin, M. I.
Struchkova, A. D. Dilman, Halogenative Difluorohomologation of Ke-
tones. J. Org. Chem. 2015, 80, 5870−5876.
(13) Fuchibe, K.; Takayama, R.; Yokoyama, T.; Ichikawa, J. Regi-
oselective Synthesis of α‐Fluorinated Cyclopentenones by Organocat-
alytic Difluorocyclopropanation and Fluorine‐Directed and Fluorine‐
Activated Nazarov Cyclization. Chem. Eur. J. 2017, 23, 2831–2831.
(14) Song, X.; Xu, C.; Du, D.; Zhao, Z.; Zhu, D.; Wang, M. Ring-
Opening Diarylation of Siloxydifluorocyclopropanes by Ag(I) Cataly-
sis: Stereoselective Construction of 2-Fluoroallylic Scaffold. Org. Lett.
2017, 19, 6542–6545.
(15) Specklin, S.; Fenneteau, J.; Subramanian, P.; Cossy, J. Stere-
oselective Ring‐Opening of gem‐Difluorocyclopropanes: An Entry to
Stereo‐defined (E,E)‐ and (E,Z)‐Conjugated Fluorodienes. Chem. Eur.
J. 2018, 24, 332–336.
(16) Munemori, D.; Narita, K.; Nokami, T.; Itoh, T. Synthesis of
gem-Difluoromethylene Building Blocks through Regioselective Al-
lylation of gem-Difluorocyclopropanes. Org. Lett. 2014, 16,
2638−2641.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26) Michrowska, A.; Bujok, R.; Harutynyan, S.; Sashuk, V.; Dol-
gonos, G.; Grela, K. Nitro-Substituted Hoveyda−Grubbs Ruthenium
Carbenes:ꢀ Enhancement of Catalyst Activity through Electronic Acti-
vation. J. Am. Chem. Soc. 2004, 126, 9318–9325.
(27) Shu, C.; Zeng, X.; Hao, M-H.; Wei, X.; Yee, N. K.; Busacca,
C. A.; Han, Z.; Farina, V.; Senanayake, C. H. RCM Macrocyclization
Made Practical:ꢀ An Efficient Synthesis of HCV Protease Inhibitor
BILN 2061. Org. Lett. 2008, 10, 1303–1306.
(28) Danilkina, N. A.; Lyapunova, A. G.; Khlebnikov, A. F.;
Starova, G. L.; Bräse, S.; Balova, I. A. Ring-Closing Metathesis of
Co2(CO)6–Alkyne Complexes for the Synthesis of 11-Membered
Dienediynes: Overcoming Thermodynamic Barriers. J. Org. Chem.
2015, 80, 5546–5555.
(29) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Peters-
son, G. A.; Nakatsuji, H. et al., Gaussian 16, Revision B.01, Gaussian,
Inc., Wallingford CT, 2016. (b) Dennington, R.; Keith, T. A.; Millam,
J. M., GaussView, Version 6, Semichem Inc., Shawnee Mission, KS,
2016.
(30) (a) Becke, A. D. Density‐functional thermochemistry. III. The
role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correla-
tion-energy formula into a functional of the electron density. Phys. Rev.
B 1988, 37, 785–789.
(17) Takenaka, H.; Masuhara, Y.; Narita, K.; Nokami, T.; Itoh, T.
Synthesis of 2,2-difluoro-homoallylic alcohols via ring-opening of
gem-difluorocyclopropane and aerobic oxidation by photo-irradiation
in the presence of an organic pigment. Org. Biomol. Chem. 2018, 16,
6106−6114.
(18) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. A Series
of
Well‐Defined
Metathesis
Catalysts–Synthesis
of
[RuCl2(=CHR′)(PR3)2] and Its Reactions. Angew. Chem. Int. Ed. Engl.
1995, 34, 2039–2041.
(19) Recent reviews see: (a) Deraedt, C.; d’Halluin, M.; Astruc, D.
Metathesis Reactions: Recent Trends and Challenges. Eur. J. Inorg.
Chem. 2013, 4881-4908. (b) Li, H.; Seechurn, C.C.C.J.; Colacot, T. J.
Development of Preformed Pd Catalysts for Cross-Coupling Reactions,
Beyond the 2010 Nobel Prize. ACS Catalysis, 2012, 2, 1147–1164.
(20) (a) You, Z-W.; Wu, Y-Y.; Qing, F. L. Synthesis of gem-difluo-
romethylenated massoialactone by ring-closing metathesis. Tetrahe-
dron Lett. 2004, 45, 9479–9481. (b) Jian, X-Y.; Xu, X-H.; Qing, F-L.
Design and concise synthesis of gem-difluoromethylenated analogue of
7-epi-castanospermine. Chinese ChemLett. 2014, 25, 1115–1120.
(21) Skibi´nski, M.; Urbina-Blanco, C. A.; Slawin, A. M. Z.; Nolan,
S. P.; O’Hagan, D. Synthesis and structure of large difluoromethylene
containing alicycles by ring closing metathesis (RCM). Org. Biomol.
Chem. 2013, 11, 8209–8213.
(31) (a) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials
for molecular calculations. Potentials for the transition metal atoms Sc
to Hg. J. Chem. Phys. 1985, 82 270–283. (b) Wadt, W. R.; Hay, P. J.
Ab initio effective core potentials for molecular calculations. Potentials
for main group elements Na to Bi. J. Chem. Phys. 1985, 82, 284–298.
(c) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials for mo-
lecular calculations. Potentials for K to Au including the outermost core
orbitals. J. Chem. Phys. 1985, 82, 299–310.
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