Enantioselective Functionalization of Difluorocyclopropenes Catalyzed by Chiral Copper Complexes: Proposal for Chiral gem-Dimethyl and tert-Butyl Analogues

Article abstract of DOI:10.1021/acs.joc.0c00622

The highly enantioselective copper/chiral phosphine-catalyzed hydro-, bora-, and carbo-metalations of difluorocyclopropenes with PHMS [H-Si], H-BPin, (BPin)2, and (CH3)2Zn [Zn-Me] are shown to regiodivergently afford highly enantioenriched and functionalized difluorocyclopropanes. These examples can be viewed as the first successful syntheses of "chiral"gem-dimethyl and tert-butyl analogues.

Full text of DOI:10.1021/acs.joc.0c00622

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Article
Enantioselective Functionalization of Difluorocyclopropenes
Catalyzed by Chiral Copper Complexes: Proposal
for Chiral gem-Dimethyl and tert-Butyl Analogues
Keisuke Sekine, Aina Ushiyama, Yu Endo, and Koichi Mikami
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00622 • Publication Date (Web): 19 May 2020
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Page 1 of 10
The Journal of Organic Chemistry
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Enantioselective Functionalization of Difluorocyclopropenes Catalyzed
by Chiral Copper Complexes: Proposal for Chiral gem-Dimethyl and
tert-ButylAnalogues
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0
Keisuke Sekine, Aina Ushiyama, Yu Endo, and Koichi Mikami*
Department of Chemical Science and Engineering, School of Materials and Chemical Technology,
Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Supporting Information Placeholder
ABSTRACT: The highly enantioselective copper/chiral phosphine-catalyzed hydro-, bora-, and carbo-metalations of
difluorocyclopropenes with PHMS [H-Si], H-BPin, (BPin) and (CH ) Zn [Zn-Me] are shown to regiodivergently afford highly
2 3 2
enantioenriched and functionalized difluorocyclopropanes. These examples can be viewed as the first successful syntheses of “chiral”
gem-dimethyl and tert-butyl analogues.
INTRODUCTION
gem-Difluorocyclopropanes particularly in optically active
Scheme 1. Catalytic asymmetric synthesis of
form have attracted current attention in pharmaceutical and
difluorocyclopropane
1
Previous Work
material sciences, because gem-difluorocyclopropane groups
F
F
F
F
n-Bu3Sn-H (
t3 0m
1
o
. e2 q
.
)
F
1
2
)MeLi (
)MeCOOH (
1 . e5 q . )
have metabolic stability, lipophilicity, and bioisostere to
B
E
(
2
l
%
)
Ph
H
Sn
e
x
c
e
s
s
)
Ph
Ph
2
( 1 )
epoxides, based on their unique chemical and biological
Ph
Ph
Ph
OCOMe
3
Q
u
a
n
t
.
5
4 %
properties. Therefore, highly efficient synthetic methods for
This Work
difluorocyclopropanation of olefinic compounds have
intensively been developed (Figure 1). Difluorocyclopropene
analogues have been synthesized under a similar reaction
condition using acetylenic compounds and hence can in turn be
F
F
4
F
R1
F
F
L*Cu-H
Hydrocupration
El+
R1
F
R1
( 2
L*Cu
R2
El
R2
R2
H
H
employed
as
synthetic
intermediates
for
4
difluorocyclopronanes. However, synthetic transformation of
difluorocyclopropenes via hydro- or carbo-functionalization is
quite limited, due to their instability under various reaction
conditions. Recently, radical hydrostannylation reaction of
difluorocyclopropene was reported (Scheme 1, Eq. 1) but
subsequent treatment of the tin intermediates with
Scheme 2. “Chiral” gem-dimethyl and tert-butyl analogues
H
F
H
F
Me Me
F
F
H
H
*
* CH3-nFn
l i p o p h i l i c c y c l o p ro p a n edi f l u o ro - c y c l o p rodpi af nl eu o ro - c y c l o
gem- di m e t h y l( gem- di m e t h y l( c h i rg ae lm - di m e t h y l ( c h i rt ea r lt - b u t y l
5
a n a l o g u e )
a n a l o g u e )
a n a l o g u e )
methyllithium led only to cyclopropane ring opening products.
gem-dimethyl or tert-butyl analogues in close analogy to the
well-accepted gem-dimethyl or tert-butyl analogues however
in totally achiral form (Scheme 2).
Obviously, development of transition metal-catalyzed
hydrometalation reaction of difluorocyclopropenes affords
formidable endeavour particularly in an enantioselective
manner. Herein, we report the highly regio- and stereoselective
copper-catalyzed functionalization of difluorocyclopropenes
under mild reaction conditions even at ambient temperature
6
7
RESULTS AND DISCUSSION
The
enantioselective
hydrometalation
of
8
difluorocyclopropenes was first executed with rhodium,
(Scheme 1, Eq. 2). Enantio-enriched gem-difluorocyclopropane
9
10
nickel, and finally copper catalysts. However, rhodium and
nickel catalysts gave only ring opening products via M-F
elimination even with silyl, boryl, and aluminum hydrides. In
contrast, copper catalysis via copper hydrides easily prepared
from copper salts and metal hydrides including hydro-silane
and -borane afforded the desired hydrometalation product
products can thus be employed as chiral
Me3SiCF2Cl
CHClF2
FSO2CF2CO2H
BrCF2CO2Na
+
-
CF Br or CF I , Zn
CF3SnMe3
P
h
3
P
C
F
2
B
r
B
r
2
2
2
2
Me3SiCF2Br
1
9
6
0
1
9
7
0
1
9
8
0
1
9
9
0
2
0
0
0
2 0 1 0
ClCF2CO2Na
PhHgCF3
Hg(CF3)2
CF2Br2, Pb
Cd(CF3)2
BrCF2PO(OEt)2
Me3SiCF3
(Table 1); Hydrocupration of difluorocyclopropene 1a was
FSO2CF2CO2SiMe3
Bi(CF3)3
N
F
11
Zn(CF3)2
attempted initially with the Stryker reagent, [(Ph P) CuH]
3
3
6
N
F
(20 mol%) and 4 eq. of polymethyl-hydrosilane (PMHS) to give
Figure 1. History of difluorocyclopropa(e)nes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
7
1%
yield
of
the
desired
reduction
product,
gave, for example, quinolone derivative 2l in an excellent
yield of 80%.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
difluorocyclopropane 2a via retarding Cu−F elimination by
sterically demanding and electron-donating phosphine ligands
(entry 2). No reaction was confirmed to take place in the
absence of either copper pre-catalyst or (di-)phosphine ligands
Deuteration clarified the regioselectivity of Cu-C
intermediates in hydrocupration to produce deuterated 2a-D
along with the formation of Walphos-Cu-H species (Scheme 3).
MeOD gave solely the cis-diastereomeric product 2m-D
(Scheme 3) stabilized as the -benzylic copper species, while
the more sterically demanding DTBM-SEGPHOS-Cu-H
species gave the opposite regioisomer (Table 3).
(entry 1-3). When difluorocyclopropene 1a was treated with
Cu(OAc) (10 mol%) and (R)-MeO-BIPHEP (12 mol%) in
2
toluene at ambient temperature, the desired product 2a was
generated in 67% yield with 13% ee along with 1% recovery of
difluorocyclopropene 1a (entry 3). Extensive screening of
solvents clarified that toluene, THF, and dioxane are the best
solvent employed in term of high enantioselectivity. After
screening copper pre-catalysts, Cu(OAc)
best pre-catalysts in terms of enantioselectivity and chemical
yield. CuCl, CuTC, Cu(OTf) , and Cu[O(C=O)CF turned out
to be far inferior to Cu(OAc) and CuOt-Bu in view of not only
Table 2. Substrate scopea
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
and CuOt-Bu are the
C
u
T
(
O
A
c2 ·) H2 O
(
5m
o
o
l
%
)
P t- B u
2
P
P
h
h
Walphos ( 6m
l
%
)
P
P
h
h
F
F
P
t-
B
u2
O
O
O
O
F
P
MH
i-P rO
S
H
(
4
. e0 q
.
)
F
P
N
2
3
)
2
F e
A
r
(
2
. e0 q
.
)
A
r
o
l
u
e
n6e0,° C ,4 0 h
2
1
2
Walphos
Phosphoramidite
chemical yield but also enantioselectivity. Additional sec- and
prim-alcohols rather than tert-alcohol are critical to attain not
only higher chemical yield but also higher enantioselectivity
F
F
F
F
F
F
F
F
(entry 5, 8, and 9).
A significant improvement in
Me
O
enantioselectivity up to 86% ee along with 79% yield was
attained by changing chiral ligands from BIPHEP, BINAP, and
2a: 8 1 % ( 9 2 : 8 )
2b: 7 3 % ( 9 3 : 7 )
2c: 6 0 % *( 8 7 : 1 3 ) 2d: 8 8 % *( 9 1 : 9 )
F
F
F
F
F
F
F
F
(DTBM)SEGPHOS to Walphos ligands (entry 11), fine-tuned
by TADDOL-derived phosphoramidites and -BINAP,
H
8
C
l
E
t
O2 C
C
O
2 E
t
O 2 N
depending on the substrates specified (Supporting Information).
In combination of an elevated temperature with shortened
reaction time, high enantioselectivity was recorded along with
an increased yield (81%) (entry 12).
2e: 8 9 % ( 9 5 : 5 )
2f: 8 0 % ( 9 4 : 6 )
2g: 6 4 % ( 8 4 : 1 6 ) 2h: 6 2 % ( 5 6 : 4 4 )
b
6
9 % ( 7 1 : 2 9 )
F
F
F
F
F
F
F
F
Me
O
O
Me
N
Table 1. Optimization of reaction conditionsa
O
Me
2i: 3 1 % ( 8 2 : 1 8 ) 2j: 8 3 % *( 8 5 : 1 5 ) 2k: 6 7 % *( 9 0 : 1 0 ) 2l: 8 0 % ( 9 5 : 5 )
Cu(OAc)2·H2O (
n( d1 2m
Silane (
. e0 q
1 0m o l % )
o l % )
F
F
L
i
g
a
F
F
[
p
a I] s
re
o
l
a
ty ei de
sree fs e tr oe
l
d* sN.MR y
i
t
e
i
l id sn c
a
s
eo fs
i
l
o
a rn e em
a
o
i
ra
n
eadf
i (d i1 t0meo
t
ec rh ro
l
m
%
a
)i
t
n
o
s
g
t
ra p( hs ye eS :I )V.a l u eisn
4
.
)

a
n
t
h
e
n
a
n
o
mr aetri o[sb. P] h
s
p
h
m
e oa fdW
a
l
p
h
o rs . ,t 4. 0, h .
A
l
c
o
h (o 2l . e0 q
. )
Scheme 3. Regio- and cis-selectivity of deuteration in
Me
O
T
o
l
u
e
nr e. ,t T. i, m e(
h
)
Me O
1a
2a
hydrocupration
Entry
Ligand
Silane Alcohol Time (h) Yield (%) Ee (%)
F
Cu(OAc)2 ( 5m o l % )
W a l p h o(s6m o l % )
PMHS ( 4 . e0 q . )
F
F
(H)D
F
1
-
-
P
P
P
P
MH
MH
MH
MH
S
S
S
S
i-
i-
i-
P
P
P
rO
rO
rO
H
H
H
1
1
1
1
8
8
8
8
0
-
-
2 [ a ]
7
6
2
1
7
1
3
(R)
(R)
-
-
Me
Me
O
O
-
-
B
B
I
I
P
P
H
H
E
E
P
1 3
Me O
MeOD ( 2 . e0 q . )
Me O
4
P
-
-
1a
F
2a-D:62%, 55%(D)
T o l u e n6e0,° C ,4 0 h
5
6
(R)-SEGPHOS
PMHS
i-PrOH
18
73
22
(R)
(R)
(R)
(R)
-
-
-
-
S
S
S
S
E
E
E
E
G
G
G
G
P
P
P
P
S
H
H
H
H
E
O
O
O
O
G
S
E
E
P
P
t3 S
i
H
i-
i-
P
P
rO
rO
O
H
H
1
1
1
1
1
7
4
8
8
8
8
8
2
0
0
-
Cu(OAc)2 ( 1 0m o l % )
8 - B I N A (P 1 2m o l % )
PMHS ( 4 . e0 q . )
7
S
S
S
P
(
t
O3 S) i
H
6
7
5
7
7
8
0
6
2
0
9
1
1
1
1
7
6
2
H
F
F
(H)D
F
8
MH
MH
S
S
S
S
S
E
t
H
9
t-
i-
i-
i-
B
u
O
H
P h
P h
1
1
0
(R)
-
D
T
B
M-
H
O
SP MH
P
P
P
rO
rO
rO
H
H
H
4
MeOD ( 2 . e0 q . )
T o l u e nr e. ,t 1. 8, h
O A c
O A c
2m-D:68%, 62%(D)
1
W
W
a
a
l
l
p
p
h
h
o
o
s
s
P
P
MH
MH
8
8
6
5
1m
1
2[ b ]
[
[
a U] s
b R] e
i
a
n [g (
P
P3 )h C
u
e
H6 ]i
ra
n
s
t
e oa fdC
u
(
O
A
c2 )• H 2 O
Regioselectivity was found to be dependent primarily on
steric demand of ligands employed for copper complexes
c
t
i to en m
p
t
u6r e0 ｰ: C
O
P
t- B u2
O
O
P
P
A
r2
r
12
tB
P
t-
B
u2
(Table 3). Walphos-Cu-H species gave the -benzylic copper
Me
Me
Me
O
O
P
P h
u
O
u
2
A
2
O
S
i
P
P
h2
A
R
r =
Me
F
e
species (B) (entry 1), while the sterically demanding DTBM-
H
n
O
tB
A
)
r =
-
P
E
h
G
13
SEGPHOS-Cu-H species provided the opposite regioisomer
P MH S
(
R
)
-
Me
O
-
B
I
P
H
E
P (
R
S
P
H
O
S(
)
-
D
T
B
M-
S
E
G
P
H
O
S
W a l p h o s
(A) (entry 2). Further hydroboration with pinacol borane,
HBPin with DTBM-SEGPHOS-Cu complex also afforded the
hydroboration regioisomer (A) (entry 3). Boracupration was
then executed with bis(pinacolato)-diboron (BPin) , catalyzed
2
by DTBM-SEGPHOS-Cu complex to show the same
regiochemistry to give the borylated product in 82% ee with 91
3 2
: 9 regioisomeric ratio (entry 4). Significantly, (CH ) Zn
afforded carbometalation product of difluorocyclopropenes
with modified DTBM, namely bis(trifluoromethyl), BTFM-
Substrate generality was then scrutinized under the optimal
reaction conditions thus established (5 mol% of the Cu pre-
catalyst, Cu(OAc) , Walphos ligands (6 mol%) and ambient
2
reaction temperatures) (Table 2). Both electron-donating and -
withdrawing substituents in either para- or ortho-positions
showed good reactivity and enantioselectivity to give the
desired products (2e-k). Moderate enantioselectivity (71:29)
was fine-tuned by phosphoramidite ligand for para-nitro
substrate (1h). Methoxy substituent at meta-position did also
provide good yield (2j). Heterocyclic compounds such as 1l
Garphos-Cu
complex
exhibited
complete
(100%)
regioselectivity and 80 : 20 enantiomer ratio (60% ee) (entry 6).
Table 3. Regioselectivity depending on steric demand of
ACS Paragon Plus Environment

Page 3 of 10
ligands
The Journal of Organic Chemistry
EXPERIMENTAL SECTION
F
F
F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
F
LCu
F
F
Nu-El
Nu
General
LCu Cat.
A
r
CuL
A
r
Nu
1
13
19
31
H, C, F, and P NMR spectra were measured on a Bruker
H
H
Me
O
1
AV300M (300 MHz) spectrometer. Chemical shifts of H NMR
Entry
Nu
Ligand
A
0
B
combined yield (%)
1
2
3
4
5
6
H-Si
Walphos
:
:
:
:
:
100(85% ee)
81
65
32
53
18
were expressed in parts per million relative to the singlet (δ =
DTBM-SEGPHOS
DTBM-SEGPHOS
DTBM-SEGPHOS
Walphos'
54
46
0
13
7.26) for CHCl
3
. Chemical shifts of C NMR were expressed
H-BPin
100
in parts per million relative to the central line of the triplet (δ =
PinB-BPin
91(82% ee)
11
9
1
9
89
77.0) for CDCl . Chemical shifts of F NMR were expressed
3
(CH3)2-Zn
BTFM-Garphos
100(60% ee)
:
0
56
in parts per million relative to the singlet (δ= -63.24) for BTF
as an internal standard Important NMR data were tabulated in
.
following order: multiplicity (s: singlet, d: doublet, t: triplet, q:
quartet, sept: septet, m: multiplet, brs: broad singlet) and
coupling constant (J (Hz)).
O
Me
C
C
F
3
3
Me
Me
O
O
P
P
A
A
r2
r2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
r =
F
F
O
Me
B
T
M-
G
a
rp
h o s
The reaction mechanism of the present copper-catalyzed
functionalization poses a challenge to clarify particularly the
Analytical thin layer chromatography (TLC) was performed
on a glass plates pre-coated with silica-gel (Merck Kieselgel 60
10,14
regioselectivity (Figure 2);
Based on the experimental
F254, layer thickness 0.25 mm). Visualization was accomplished
results, the plausible catalytic reaction course can be visualized
for cis-addition (Scheme 3) of the catalytically active CuNu
species (i). The regioselectivity depends primarily on the steric
demand of ligands employed, and secondary on the steric and
electronic effects of the Cu-C intermediates (A and B).
Generally, copper hydride species has been reported to be in the
range of dimeric to hexameric, depending on the steric demand
by UV light (254 nm), anisaldehyde and KMnO . Column
4
chromatography was performed on KANTO Silica Gel 60N
(spherical, neutral).
Optical rotations were measured on JASCO P-1020.
Mass spectra were measured on JEOL JMS-T100CS (Accu-
TOF) spectrometer.
IR spectra were measured on JASCO FT/IR-4200
spectrometer.
High performance liquid chromatography (HPLC) was
conducted on JASCO PU-980, LG-980-02, DG-980-50, MD-
1
1,13
of ligands therewith.
The Walphos-copper species (B) is
stabilized at -benzylic position. In turn, the more sterically
1
3
demanding DTBM-SEGPHOS provides the less sterically
demanding and hence terminal organo-copper species (A). The
two initially formed cyclopropyl copper regioisomers (A and B)
are likely in equilibrium and eventually lead to regioselective
products (Figure 2).
2
010, and CO-966 instrument equipped with model UV-975
spectrometers as an ultra violet light. Peak areas were calculated
by JASCO chrom NAV (Windows 7) as an automatic integrator.
DAICEL CHIRALCEL OD-3, DAICEL CHIRALCEL OD-H,
DAICEL CHIRALCEL OJ-3, and DAICEL CHIRALCEL OJ-
H were used as chiral columns.
F
F
Dichloromethane
(dehydrate),
toluene
(dehydrate),
A r
tetrahydrofuran (dehydrate), diethyl ether (dehydrate), N,N-
dimethylformamide (dehydrate), 2-propanol (dehydrate),
ethanol (dehydrate), methanol (dehydrate) and acetonitrile
1
P
P
C u X 2 +
*
+
E l- N u
*
C u N u
P
- E l- X
P
(dehydrate) were purchased from Kanto Chemical Co., Inc.
(
i )
Triethylamine (dehydrate), copper(I) thiophene-2-carboxylate,
copper(I) iodide, copper(I) acetate were purchased from
Aldrich. Copper(I) trifluoromethanesulfonate was purchased
from TCI. Copper(II) acetate monohydrate and copper(I)
chloride were purchased from Wako Pure Chemical Industries.
F
F
F
F
F
A r
A r
C u
H
H
B
(
H ) E l
N u
P
N u
P
*
o r
8
(R)-BINOL, (S)-BINAP, (S)-H -BINAP (R)-tol-BINAP, (R)-
DM-BINAP, (R)-Cy-BINAP, (R)-SEGPHOS, (R)-DTBM-
SEGPHOS, (R)-MeO-BIPHEP were provided from Takasago
International Co. (R)-2-furyl-MeO-BIPHEP, (R)-DTBM-MeO-
BIPHEP, Walphos and Joshiphos ligands were provided from
Solvias AG. (R)-BTFM-Garphos was purchased from Strem
F
F
F
A r
N u
E l- N u
A r
N u
H
H
A
E l ( H )
C u
P
P
*
Figure 2. Proposed reaction course
3
Chemicals, Inc. (Trifluoromethyl)trimethylsilane (CF TMS)
was gifted from TOSOHF-TECH. All other reagents were
purchased from Sigma-Aldrich, Kanto Chemical, Tokyo
Chemical Industries, and Wako Pure Chemical Industries and
used without further purification. Phenylethyne 1d’ and p-
chlorophenylethyne 1e’ were purchased from TCI.
Highly enantio-enriched difluorocyclopropane products can
thus be employed as chiral gem-dimethyl or tert-butyl
6
analogues in close analogy to the well-accepted gem-dimethyl
7
or tert-butyl analogues of cyclopropanes but in totally achiral
form.
2
1
-Ethynyl-6-methoxynaphthalene 1a’, 2-ethynylnaphthylene
b’, 1-ethynylnaphthylene 1c’ were synthesized by Corey-
CONCLUSION
15
Fuchs alkyne synthesis . Ethyl (p-ethynyl)benzoate 1f’, ethyl
o-ethynyl)benzoate 1g’ (p-ethynyl)nitrobenzene 1h’, (p-
ethynyl)methoxybenzene 1i’, (m-ethynyl)methoxybenzene 1j’,
o-ethynyl)methoxybenzene 1k’, 3-ethynylquinolone 1l’ were
In conclusion, we have succeeded in the development of
highly enantioselective copper-catalyzed hydro-, bora-, and
carbo-cupration reactions of difluorocyclopropanes. This is a
new route to gem-difluorocyclopropyl analogues of chiral gem-
dimethyl and tert-butyl with all carbon quaternary centers.
(
(
16
synthesized by Sonogashira coupling reaction .
All experiments were carried out under argon atmosphere
unless otherwise noted.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 10
-
·
7
69, 748; HRMS (APCI-TOF) m/z: [M] Calcd for C13H F
8 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of ethyl 2-ethynylbenzoate (1f’)
To a solution of Pd(PPh Cl (28.1 mg, 0.04 mmol) and CuI
202.0594; Found 202.0595.
3
)
2
2
(15.2 mg, 0.08 mmol) in diethylamine (27 mL) were added
ethyl 2-iodobenzoate (1.24 mL, 8.0 mmol) and
trimethylsilylethyne (1.22 mL, 8.8 mmol) by Sonogashira
1-(3,3-difluorocycloprop-1-en-1-yl)naphthalene (1c)
This compound was prepared from 1-ethynylnaphthylene 1c’
and purified by silica-gel column chromatography
1
6
coupling reaction . The reaction mixture was stirred at room
temperature for 12 h. During the reaction a second liquid phase
(hexane/NEt
3
= 40/1) as a brown liquid (59% yield).
H NMR (300 MHz, CDCl ) δ 8.30 (d, 1H, J = 8.4 Hz), 8.02
(d, 1H, J = 8.2 Hz), 7.92 (t, 2H, J = 7.4 Hz), 7.71-7.55 (m, 4H);
1
3
formed. The solvent was removed in vacuo. Et
water (20 mL) were added and the aqueous phase was extracted
with Et O (20 mL). The combined organic phase was washed
with aqueous 4N HCl solution (20 mL) and water (20 mL).
After drying over anhydrous MgSO , filtered and concentrated
under reduced pressure to give ethyl 2-(2-
2
O (20 mL) and
13
C{H} NMR (75 MHz, CDCl
C-F = 11.9 Hz), 131.6 (s), 130.7 (s), 128.7 (s), 128.0 (s), 126.8
(s), 125.3 (s), 124.2 (s), 120.1 (s), 113.9 (t, JC-F = 12.2 Hz),
3
) δ 133.6 (s), 132.5 (s), 132.4 (t,
J
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
3
101.2 (t, JC-F = 268.5 Hz); F NMR (282 MHz, CDCl ) δ -104.5
(s, 2F); FT-IR (neat, cm ) 3126, 3057, 1705, 1508, 1341, 1299,
1238, 1216, 1186, 1020, 857, 843, 807, 777, 767, 593; HRMS
(APCI-TOF) m/z: [M] Calcd for C13
202.0591.
4
-1
trimethylsilylethynyl)benzoate. The compound was used for
next step without further purification.
To a solution of ethyl 2-(2-trimethylsilylethynyl)benzoate in
-·
8 2
H F 202.0594; Found
ethanol (24 mL) was added K
reaction mixture was stirred at room temperature for 2 h, water
20 mL) was added and the aqueous phase was extracted with
Et O (20 mL). The combined organic phase was washed with
saturated aqueous NaCl (20 mL). After drying over anhydrous
MgSO , filtered and solvent was removed. Resulting crude
2 3
CO (1.11 g, 8.0 mmol). The
1
-chloro-4-(3,3-difluorocycloprop-1-en-1-yl)benzene (1e)
This compound was prepared from p-chlorophenylethyne 1e’
and purified by silica-gel column chromatography
(
2
(
hexane/NEt
3
= 40/1) as a brown liquid (50% yield).
H NMR (300 MHz, CDCl ) δ 7.61-7.58 (m, 2H), 7.50-7.45 (m,
3H); C{H} NMR (75 MHz, CDCl ) δ 133.9 (s), 133.0 (t, JC-F
10.6 Hz), 131.3 (s), 129.5 (s), 121.8 (s), 114.1 (t, JC-F = 12.3
1
3
4
1
3
product was purified by silica-gel column chromatography
(hexane/EtOAc = 20/1) to give the ethyl 2-ethynylbenzoate
(460 mg, 33%) as a brown solid.
3
=
1
9
Hz), 101.3 (t, JC-F = 268.7 Hz); F NMR (282 MHz, CDCl
3
) δ
-106.6 (s, 2F); FT-IR (neat, cm ) 3134, 1721, 1593, 1486, 1310,
291, 1486, 1310, 1291, 1274, 1092, 1018, 838, 820, 777;
-1
1
3
H NMR (300 MHz, CDCl ) δ 7.94 (dd, 1H, J = 7.7, 1.4 Hz),
1
7
.62 (dd, 1H, J = 7.8, 1.4 Hz), 7.50-7.37 (m, 2H), 4.40 (q, 2H,
-·
1
3
9 5 2
HRMS (APCI-TOF) m/z: [M] Calcd for C H ClF 186.0048;
Found 186.0052.
J = 7.1 Hz), 3.38 (s, 1H), 1.40 (t, 3H, J = 7.1 Hz); C{H} NMR
75 MHz, CDCl ) δ 166.0 (s), 134.9 (s), 132.8 (s), 131.5 (s),
30.2 (s), 128.4 (s), 122.5 (s), 82.2 (s), 82.0 (s), 61.3 (s), 14.2
(
1
3
-1
Ethyl 4-(3,3-difluorocycloprop-1-en-1-yl)benzoate (1f)
This compound was prepared from ethyl 2-ethynylbenzoate 1f’
and purified by silica-gel column chromatography
(s); FT-IR (neat, cm ) 3287, 2982, 2939, 2904, 2107, 1725,
1
483, 1445, 1366, 1292, 1273, 1254, 1134, 1077, 758; HRMS
+
(APCI-TOF) m/z: [M+H] Calcd for C11
11 2
H O 175.0759; Found
(hexane/EtOAc/NEt
3
= 40/2/1) as a brown solid (40% yield).
H NMR (300 MHz, CDCl ) δ 8.15 (dd, 2H, J = 6.7, 1.7 Hz),
.72 (d, 2H, J = 8.3 Hz), 7.62 (t, 1H, J = 1.4 Hz), 4.41 (q, 2H, J
1
75.0755.
1
3
7
Typical
difluorocyclopropenes
Procedure:
Synthesis
of
gem-
1
3
4
f
= 7.1 Hz), 1.42 (t, 3H, J = 7.1 Hz); C{H} NMR (75 MHz,
CDCl ) δ 165.6 (s), 133.3 (t, JC-F = 10.7 Hz), 133.1 (s), 130.2
s), 129.9 (s), 127.1 (s), 116.1 (t, JC-F = 12.2 Hz), 101.1 (t, JC-F
Corresponding alkyne 1’ (8.0 mmol), TMSCF
3
(2.37 mL, 16
3
(
mmol), NaI (2.638 g, 17.6 mmol), and THF (24 mL) were
mixed into a pressure tube at room temperature. Then the
reaction mixture was heated in an oil bath at 110 °C for 2 h.
The reaction mixture was quenched by adding saturated
19
=
3
269.2 Hz), 61.5 (s), 14.3 (s); F NMR (282 MHz, CDCl ) δ
-1
-106.5 (s, 2F); FT-IR (neat, cm ) 3126, 2985, 1718, 1410, 1368,
1
311, 1277, 1233, 1176, 1110, 1021, 865, 818, 759, 694; HRMS
-·
(APCI-TOF) m/z: [M] Calcd for C12
224.0657.
10 2 2
H F O 224.0649; Found
Na
mL x3). The combined organic phase was dried over anhydrous
CO , filtered and concentrated under reduced pressure.
Resulting crude product was purified by silica-gel column
chromatography (hexane/EtOAc/NEt = 40/0/1 ~ 40/2/1) to
give the corresponding difluorocyclopropane 1 (the column
should be eluted previously with hexane/NEt (10/1)).
2 3 2
CO solution (20 mL), followed by extraction with Et O (30
K
2
3
Ethyl 2-(3,3-difluorocycloprop-1-en-1-yl)benzoate (1g)
This compound was prepared from ethyl (o-ethynyl)benzoate
3
1
g’ and purified by silica-gel column chromatography
hexane/EtOAc/NEt = 40/2/1) as a brown solid (40% yield).
H NMR (300 MHz, CDCl ) δ 8.07 (dd, 1H, J = 7.7, 1.4 Hz),
.75-7.72 (m, 1H), 7.67-7.54 (m, 3H), 4.44 (q, 2H, J = 7.1 Hz),
(
3
3
1
3
7
1
2
-(3,3-difluorocycloprop-1-en-1-yl)naphthalene (1b)
13
3
.42 (t, 3H, J = 7.1 Hz); C{H} NMR (75 MHz, CDCl ) δ 165.9
This compound was prepared from 2-ethynylnaphthylene 1b’
and purified by silica-gel column chromatography
(s), 132.6(s), 132.6 (t, JC-F = 10.2 Hz), 132.3 (s), 131.3 (s), 131.1
(s), 130.7 (s), 123.2 (s), 118.2 (t, JC-F = 11.4 Hz), 102.0 (t, JC-F
= 270.3 Hz), 61.7 (s), 14.2 (s); F NMR (282 MHz, CDCl ) δ
3
(
hexane/NEt
3
= 40/1) as a yellow solid (79% yield).
H NMR (300 MHz, CDCl ) δ 8.18 (s, 1H), 7.94-7.86 (m, 3H),
7.71 (dd, 1H, J = 8.4, 1.5 Hz), 7.76-7.53 (m, 3H); C{H} NMR
(75 MHz, CDCl ) δ 134.5 (s), 134.1 (t, JC-F = 10.6 Hz), 132.9
s), 131.2 (s), 129.0 (s), 128.7 (s), 128.1 (s), 127.9 (s), 127.0 (s),
1
9
1
3
-1
1
3
-105.5 (s, 2F); FT-IR (neat, cm ) 3131, 3071, 2983, 1724, 1596,
447, 1368, 1311, 1263, 1133, 1111, 1074, 1021, 812, 753;
1
3
-
·
HRMS (APCI-TOF) m/z: [M] Calcd for C12
Found 224.0640.
10 2 2
H F O 224.0649;
(
1
2
25.8 (s), 120.6 (s), 113.6 (t, JC-F = 12.3 Hz), 101.8 (t, JC-F
=
1
9
68.5 Hz); F NMR (282 MHz, CDCl
3
) δ -106.3 (s, 3F); FT-
-1
1-(3,3-difluorocycloprop-1-en-1-yl)-4-nitrobenzene (1h)
This compound was prepared from (p-ethynyl)nitrobenzene 1h’
and purified by silica-gel column chromatography
IR (neat, cm ) 3133, 3062, 1718, 1287, 1007, 831, 808, 783,
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
4
l
(
hexane/EtOAc/NEt
3
= 40/2/1) as a brown solid (20% yield).
) δ 8.35 (d, 2H, J = 8.8 Hz), 7.83
the literature.
1
1
1
H NMR (300 MHz, CDCl
(d, 2H, J = 8.7 Hz), 7.77 (t, 1H, J = 1.3 Hz); C{H} NMR (75
MHz, CDCl
1
3
H NMR (300 MHz, CDCl ) δ 8.10 (s, 1H), 7.82 (d, 2H, J = 8.7
Hz), 7.65 (dd, 1H, J = 8.4, 1.6 Hz), 7.46 (t, 1H, J = 1.8 Hz), 7.22
(dd, 1H, J = 8.9, 2.5 Hz), 7.16 (d, 1H, J = 2.4 Hz), 3.95 (s, 1H);
3
1
3
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
) δ 149.4 (s), 132.5 (t, JC-F = 11.1 Hz), 130.9 (s),
1
9
29.0 (s), 124.3 (s), 118.3 (t, JC-F = 12.2 Hz), 100.5 (t, JC-F
=
3
F NMR (282 MHz, CDCl ) δ -106.3 (s, 2F).
1
9
2
70.1 Hz); F NMR (282 MHz, CDCl
3
) δ -106.5 (s, 2F); FT-
-1
(3,3-difluorocycloprop-1-en-1-yl)benzene (1d)4l
This compound was prepared from phenylethyne 1d’ and
purified by silica-gel column chromatography (hexane/NEt =
3
IR (neat, cm ) 3115, 1717, 1601, 1520, 1347, 1319, 1305, 1286,
1
C
-·
022, 817, 745; HRMS (APCI-TOF) m/z: [M] Calcd for
197.0288; Found 197.0279.
9
H
5
F
2
N
1
O
2
4
0/1) as a brown liquid (61% yield). The following data are
4l
1
-(3,3-difluorocycloprop-1-en-1-yl)-3-methoxybenzene (1j)
This compound was prepared from (m-
ethynyl)methoxybenzene 1j’ and purified by silica-gel column
identical to those in the literature.
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H NMR (300 MHz, CDCl
) δ 7.68-7.65 (m, 2H), 7.51-7.46 (m,
) δ -106.5 (s, 2F).
3
1
9
4H); F NMR (282 MHz, CDCl
3
3
chromatography (hexane/EtOAc/NEt = 40/1/1) as a yellow
liquid (79% yield).
1-(3,3-difluorocycloprop-1-en-1-yl)-4-methoxybenzene
(1i)
This compound was prepared from (p-ethynyl)methoxybenzene
1i’ and purified by silica-gel column chromatography
(hexane/EtOAc/NEt
1
4g
H NMR (300 MHz, CDCl
3
) δ 7.46 (t, 1H, J = 1.7 Hz), 7.39 (t,
1
H, J = 7.9 Hz), 7.25 (d, 1H, J = 7.5 Hz), 7.15 (t, 1H, J = 1.9
1
3
Hz), 7.05 (ddd, 1H, J = 8.3, 2.6, 0.9 Hz), 3.85 (s, 3H); C{H}
NMR (75 MHz, CDCl ) δ 159.9 (s), 134.0 (t, JC-F = 10.5 Hz),
30.1 (s), 124.4 (s), 122.5 (s), 117.9 (s), 114.7 (s), 113.7 (t, JC-F
3
= 40/1/1) as a yellow liquid (65% yield).
3
4g
1
=
The following data are identical to those in the literature.
19
1
12.3 Hz), 101.7 (t, JC-F = 268.4 Hz), 55.4 (s); F NMR (282
H NMR (300 MHz, CDCl
1H, J = 1.9 Hz), 6.99 (d, 2H, J = 8.8 Hz), 3.87 (s, 3H); F NMR
(282 MHz, CDCl ) δ -106.4 (s, 2F).
3
) δ 7.60 (d, 2H, J = 8.8 Hz), 7.28 (t,
-1
19
3
MHz, CDCl ) δ -106.3 (s, 2F); FT-IR (neat, cm ) 3131, 2965,
2
944, 2840, 1720, 1598, 1582, 1484, 1304, 1273, 1212, 1181,
3
-·
1019, 808, 785, 686; HRMS (APCI-TOF) m/z: [M] Calcd for
182.0543; Found 182.0548.
(3,3-difluoro-2-phenylcycloprop-1-en-1-yl)methyl acetate
10 8 2 1
C H F O
4
l
(1m)
1
-(3,3-difluorocycloprop-1-en-1-yl)-2-methoxybenzene (1k)
This compound was prepared from (o-ethynyl)methoxybenzene
k’ and purified by silica-gel column chromatography
hexane/EtOAc/NEt = 40/1/1) as a yellow liquid (65% yield).
H NMR (300 MHz, CDCl ) δ 7.58 (dd, 1H, J = 7.5, 1.7 Hz),
.50-7.44 (m, 1H), 7.42 (t, 1H, J = 2.0 Hz), 7.03 (td, 1H, J =
This compound was prepared from 3-phenyl-2-propyl acetate
1
7
1m’ and purified by silica-gel column chromatography
(hexane/EtOAc/NEt = 40/1/1) as a yellow solid (88% yield).
The following data are identical to those in the literature.
1
3
4l
(
3
1
1
H NMR (300 MHz, CDCl
3H), 5.19 (t, 2H, J = 2.7 Hz), 2.22 (s, 3H); F NMR (282 MHz,
CDCl ) δ -108.0 (s, 2F).
3
) δ 7.65-7.62 (m, 2H), 7.49-7.47 (m,
3
19
7
7
13
.5, 0.7 Hz), 6.98 (d, 1H, J = 8.4 Hz), 3.93 (s, 3H); C{H}
) δ 159.3 (s), 133.4 (s), 131.9 (s), 130.0
(s), 120.6 (s), 113.7 (t, JC-F = 12.4 Hz), 112.4 (s), 111.1 (s),
3
NMR (75 MHz, CDCl
3
General
Difluorocyclopropene
Procedure A
To a mixture of Cu(OAc) ･ H O (1.0 mg, 0.005 mmol) and
2 2
Walphos (3.5 mg, 0.006 mmol) was added toluene (1.0 mL) at
room temperature in a test tube, and the solution was stirred for
Procedure
for
Hydrocupration
of
1
9
3
101.2 (t, JC-F = 267.8 Hz), 55.7 (s); F NMR (282 MHz, CDCl )
-1
δ -105.3 (s, 2F); FT-IR (neat, cm ) 3135, 2944, 2842, 1724,
598, 1489, 1466, 1306, 1273, 1164, 1023, 825, 784, 755, 729;
1
-·
HRMS (APCI-TOF) m/z: [M] Calcd for C10
Found 182.0551.
H
8
F
2
O
1
182.0543;
2
h. Difluorocyclopropene 1 (0.1 mmol), PMHS (26 μL, 0.4
3
-(3,3-difluorocycloprop-1-en-1-yl)quinolone (1l)
This compound was prepared from 3-ethynylquinolone 1l’ and
purified by silica-gel column chromatography
(hexane/EtOAc/NEt = 40/2/1) as a yellow solid (28% yield).
H NMR (300 MHz, CDCl ) δ 9.12 (d, 1H, J = 2.1 Hz), 8.44
d, 1H, J = 1.8 Hz), 8.16 (d, 1H, J = 8.5 Hz), 7.91 (d, 1H, J =
.2 Hz), 7.86-7.80 (m, 1H), 7.71 (t, 1H, J = 1.5 Hz), 7.67-7.61
mmol) and i-PrOH (15 μL, 0.2 mmol) were added to the
reaction mixture at room temperature. The solution was
warmed up to 60 °C in an oil bath and stirred for 40 h. The
solvent was removed under reduced pressure, and the yield of
3
1
19
3
crude product was determined by F NMR analysis using BTF
(
8
as an internal standard. The crude product was purified by
silica-gel column chromatography to give corresponding
difluorocyclopropane 2. Enantiomer ratio was determined by
chiral HPLC analysis.
1
3
(
1
(
m, 1H); C{H} NMR (75 MHz, CDCl
38.0 (s), 131.7 (t, JC-F = 11.0 Hz), 131.7 (s), 129.6 (s), 128.6
s), 127.8 (s), 127.2 (s), 116.7 (s), 115.6 (t, JC-F = 12.3 Hz),
3
) δ 149.9 (s), 148.9 (s),
Procedure B
1
9
1
00.8 (t, JC-F = 269.5 Hz); F NMR (282 MHz, CDCl
3
) δ -106.5
To a mixture of Cu(OAc) ･ H O (1.0 mg, 0.005 mmol) and
2
2
-1
(s, 2F); FT-IR (neat, cm ) 3140, 1720, 1570, 1495, 1286, 995,
phosphoramidite L (5.7 mg, 0.010 mmol) was added toluene
1.0 mL) at room temperature in a test tube, and the solution
was stirred for 2 h. Difluorocyclopropene 1 (0.1 mmol), PMHS
26 μL, 0.4 mmol) and i-PrOH (15 μL, 0.2 mmol) were added
9
82, 914, 802, 789, 771, 752, 583; HRMS (APCI-TOF) m/z:
(
-·
7 2 1
[M] Calcd for C12H F N 203.0547; Found 203.0553.
(
to the reaction mixture at room temperature. The solution was
stirred for at room temperature. The solvent was removed under
reduced pressure, and the yield of crude product was
2
-(3,3-difluorocycloprop-1-en-1-yl)-6-methoxynaphthalene
4
l
(1a)
19
determined by F NMR analysis using BTF as an internal
This compound was prepared from 2-ethynyl-6-
methoxynaphthalene 1a’ and purified by silica-gel column
chromatography (hexane/EtOAc/NEt
solid (74% yield). The following data are identical to those in
standard. The crude product was purified by silica-gel column
chromatography to give corresponding difluorocyclopropane 2.
Enantiomer ratio was determined by chiral HPLC analysis.
3
= 40/1/1) as a yellow
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
chromatography (pentane only) as a colorless liquid (7.6 mg,
49% yield). The following data are identical to those in the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2-(2,2-difluorocyclopropyl)-6-methoxynaphthalene (2a)
Procedure A
This compound was purified by silica-gel column
4
f 1
literature. H NMR (300 MHz, CDCl
2.85-2.74 (m, 1H), 1.92-1.80 (m, 1H), 1.72-1.64 (m, 1H);
NMR (282 MHz, CDCl ) δ -125.8 (dt, 1F, JF-F = 154.0 Hz, JF-H
= 12.9 Hz), -142.4 (dd, 1F, JF-F = 156.6 Hz, JF-H = 13.7 Hz).
3
) δ 7.42-7.26 (m, 5H),
1
9
F
chromatography (hexane/EtOAc = 20/1) as a white solid (18.7
3
1
mg, 81% yield). H NMR (300 MHz, CDCl
3
) δ 7.70 (dd, 2H,
2
1
J = 8.5, 2.6 Hz), 7.61 (s, 1H), 7.31 (dd, 1H, J = 8.5, 1.6 Hz),
[]D -26.0 (c 0.77, CHCl ), 82% ee. HPLC (column,
3
7
=
.17-7.12 (m, 2H), 3.92 (s, 3H), 2.89 (td, 1H, JH-F = 12.3 Hz, J
CHIRALCEL OJ-3, Hexane/2-Propanol = 99/1, flow rate 1.0
1
3
8.2 Hz), 1.93-1.81 (m, 1H), 1.77-1.68 (m, 1H); C{H} NMR
) δ 157.7 (s), 133.7 (s), 129.1 (s), 128.8 (s),
mL/min, 20 °C detection UV 230 nm) t of major isomer 7.1
R
(75 MHz, CDCl
3
min, t of minor isomer 7.5 min.
R
1
2
28.7 (s), 127.0 (s), 126.7 (s), 119.1 (s), 112.8 (dd, JC-F = 285.1,
85.1 Hz), 105.6 (s), 55.3 (s), 27.2 (t, JC-F = 11.4 Hz), 17.0 (t,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1-chloro-4-(2,2-difluorocyclopropyl)benzene (2e)20
Procedure A
1
9
J
J
C-F = 10.4 Hz); F NMR (282 MHz, CDCl
F-F = 153.4 Hz, JF-H = 12.8 Hz), -142.1 (d, 1F, JF-F = 151.6 Hz);
3
) δ -125.7 (dt, 1F,
This compound was purified by silica-gel column
chromatography (hexane only) as a colorless liquid (16.8 mg,
89% yield). The following data are identical to the literature
-1
FT-IR (neat, cm ) 2968, 1606, 1465, 1305, 1268, 1209, 1160,
032, 932, 904, 856, 818, 708; HRMS (APCI-TOF) m/z:
1
+
20 1
[M+H] Calcd for C14
H
13
F
2
O
1
235.0935; Found 235.0934.
data. H NMR (300 MHz, CDCl ) δ 7.30 (d, 2H, J = 8.5 Hz),
3
2
1
[]
D
-37.3 (c 1.00, CHCl
3
), 84% ee. HPLC (column,
7.16 (d, 2H, J = 8.6 Hz), 2.72 (td, 1H, JH-F = 12.2 Hz, J = 8.0
1
9
CHIRALCEL OJ-3, Hexane/2-Propanol = 90/10, flow rate 1.0
mL/min, 22 °C detection UV 230 nm) t of major isomer 29.3
min, t of minor isomer 48.3 min.
Hz), 1.90-1.78 (m, 1H), 1.64-1.53 (m, 1H); F NMR (282 MHz,
R
3
CDCl ) δ -126.1 (dt, 1F, JF-F = 154.3 Hz, JF-H = 12.7 Hz), -142.2
(d, 1F, JF-F = 152.1 Hz). []D21 -21.9 (c 0.46, CHCl ), 90% ee.
R
3
HPLC (column, CHIRALCEL OJ-3, Hexane/2-Propanol = 99/1,
2
-(2,2-difluorocyclopropyl)naphthalene (2b)4j
flow rate 1.0 mL/min, 20 °C detection UV 230 nm) t of major
R
Procedure A
isomer 7.6 min, t of minor isomer 7.1 min.
R
This compound was purified by silica-gel column
chromatography (hexane only) as a white solid (14.9 mg, 73%
yield). The following data are identical to those in the
Ethyl 4-(2,2-difluorocyclopropyl)benzoate (2f)
Procedure A
4
j 1
literature. H NMR (300 MHz, CDCl
7
3
) δ 7.85-7.80 (m, 3H),
.70 (s, 1H), 7.53-7.44 (m, 2H), 7.36 (dd, 1H, J = 8.5, 1.5 Hz),
.92 (td, 1H, JH-F = 12.3 Hz, J = 8.2 Hz), 1.96-1.84 (m, 1H),
This compound was purified by silica-gel column
chromatography (hexane/EtOAc = 20/1) as a colorless liquid
1
2
1
(18.1 mg, 80% yield). H NMR (300 MHz, CDCl ) δ 8.00 (d,
3
1
9
.82-1.71 (m, 1H); F NMR (282 MHz, CDCl
3
) δ -125.6 (dt,
2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.5 Hz), 4.37 (q, 2H, J = 7.1
Hz), 2.79 (td, 1H, JH-F = 12.1 Hz, J = 8.2 Hz), 1.95-1.83 (m,
1
F, JF-F = 153.8 Hz, JF-H = 12.7 Hz), -142.0 (dd, 1F, JF-F = 156.7
2
0
13
Hz, JF-H = 13.8 Hz). []
D
-32.8 (c 1.00, CHCl
3
), 86% ee. HPLC
1H), 1.74-1.63 (m, 1H), 1.39 (t, 3H, J = 7.1 Hz); C{H} NMR
(column, CHIRALCEL OD-3, Hexane/2-Propanol = 99/1, flow
(75 MHz, CDCl
3
) δ 166.3 (s), 138.9 (s), 129.7 (s), 129.5 (s),
rate 1.0 mL/min, 23 °C detection UV 230 nm) t
R
of major
127.9 (s), 112.2 (dd, JC-F = 285.2, 282.5 Hz), 61.0 (s), 27.3 (t,
19
isomer 7.4 min, t of minor isomer 6.6 min.
R
J
C-F = 11.5 Hz), 17.5 (t, JC-F = 10.5 Hz), 14.3 (s); F NMR (282
MHz, CDCl ) δ -125.6 (dt, 1F, JF-F = 154.8 Hz, JF-H = 12.8 Hz),
3
-
1-(2,2-difluorocyclopropyl)naphthalene (2c)
Procedure A
NMR yield (60%) was determined by using BTF as an internal
standard. This compound was purified by silica-gel column
-142.2 (dd, 1F, JF-F = 150.6 Hz, JF-H = 9.2 Hz); FT-IR (neat, cm
) 2978, 1718, 1614, 1468, 1277, 1234, 1186, 1107, 1041, 935,
755, 709; HRMS (APCI-TOF) m/z: [M+H] Calcd for
C H F O 227.0884; Found 227.0873. [] -16.4 (c 1.57,
CHCl ), 88% ee. HPLC (column, CHIRALCEL OJ-3,
1
+
2
1
12 13
2
2
D
chromatography (hexane only) as a colorless liquid (6.9 mg,
3
1
3
4% yield). H NMR (300 MHz, CDCl
3
) δ 8.13 (d, 1H, J = 8.3
Hexane/2-Propanol = 98/2, flow rate 1.0 mL/min, 20 °C
Hz), 7.89 (d, 1H, J = 8.5 Hz), 7.82 (d, 1H, J = 7.9 Hz), 7.63-
.51 (m, 2H), 7.48-7.39 (m, 2H), 3.14 (td, 1H, JH-F = 12.4 Hz, J
detection UV 230 nm) t of major isomer 14.3 min, t of minor
R
R
7
isomer 12.4 min.
13
=
(
8.3 Hz), 2.07-1.95 (m, 1H), 1.84-1.73 (m, 1H); C{H} NMR
75 MHz, CDCl ) δ 133.5 (s), 133.1 (s), 129.9 (s), 128.6 (s),
128.2 (s), 126.5 (s), 126.0 (s), 125.8 (d, JC-F = 3.5 Hz), 125.3
(s), 124.1 (s), 113.0 (dd, JC-F = 283.1, 281.5 Hz), 25.1 (t, JC-F
3
Ethyl 2-(2,2-difluorocyclopropyl)benzoate (2g)
Procedure A
This compound was purified by silica-gel column
=
1
9
11.3 Hz), 16.3 (t, JC-F = 10.7 Hz); F NMR (282 MHz, CDCl
3
)
chromatography (hexane/EtOAc = 20/1) as a colorless liquid
1
δ -126.6 (dt, 1F, JF-F = 152.0 Hz, JF-H = 12.6 Hz), -140.2 (dd, 1F,
(14.5 mg, 64% yield). H NMR (300 MHz, CDCl ) δ 7.99 (dd,
3
-
1
J
1
F-F = 152.4 Hz, JF-H = 8.8 Hz); FT-IR (neat, cm ) 3063, 3016,
472, 1371, 1304, 1241, 1209, 1095, 1022 954, 930, 800, 777;
1H, J = 7.7, 1.3 Hz), 7.52-7.47 (m, 1H), 7.39-7.30 (m, 2H),
4.46-4.36 (m, 2H), 3.27 (td, 1H, JH-F = 11.5 Hz, J = 8.6 Hz),
+
HRMS (APCI-TOF) m/z: [M+H] Calcd for C13
H
), 74%
11
F
2
1.90-1.78 (m, 1H), 1.64-1.53 (m, 1H), 1.41 (t, 3H, J = 7.1 Hz);
2
1
13
2
05.0837; Found 205.0829. []
ee. HPLC (column, CHIRALCEL OJ-3, Hexane/2-Propanol =
8/2, flow rate 1.0 mL/min, 20 °C detection UV 230 nm) t of
major isomer 6.6 min, t of minor isomer 7.7 min.
D
-19.9 (c 0.59, CHCl
3
3
C{H} NMR (75 MHz, CDCl ) δ 167.1 (s), 134.4 (s), 132.1
(s), 131.7 (s), 130.7 (s), 129.5 (d, JC-F = 3.0 Hz), 127.5 (s), 112.4
(dd, JC-F = 284.9 Hz, 280.0 Hz), 61.3 (s), 26.9 (t, JC-F = 11.2 Hz),
9
R
19
R
16.4 (t, JC-F = 10.6 Hz), 14.2 (s); F NMR (282 MHz, CDCl
3
)
δ -126.7 (td, 1F, JF-F = 154.1 Hz, JF-H = 12.4 Hz), -140.3 (dd, 1F,
(2,2-difluorocyclopropyl)benzene (2d)4f
Procedure A
NMR yield (88%) was determined by using BTF as an internal
standard. This compound was purified by silica-gel column
J
F-F = 150.1 Hz, JF-H = 11.9 Hz); FT-IR (neat, cm ) 2981, 2934,
1466, 1291, 1262, 1229, 1134, 1081, 1024, 725; HRMS (APCI-
-1
+
TOF) m/z: [M+H] Calcd for C12
H
13
F
2
O
2
227.0884; Found
227.0894. []D -0.67 (c 1.19, CHCl ), 68% ee. HPLC (column,
2
1
3
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
CHIRALCEL OD-3 and OD-H, Hexane/2-Propanol = 99/1,
flow rate 0.6 mL/min, 20 °C detection UV 220 nm) t of major
isomer 16.8 min, t of minor isomer 17.5 min.
NMR (300 MHz, CDCl
1H), 6.95-6.88 (m, 2H), 3.87 (s, 3H), 2.92-2.81 (m, 1H), 1.84-
1.72 (m, 1H), 1.62-1.52 (m, 1H); F NMR (282 MHz, CDCl )
3
δ -126.9 (dt, 1F, JF-F = 151.9 Hz, JF-H = 12.9 Hz), -142.1 (d, 1F,
JF-F = 150.0 Hz). []D21 -20.1 (c 0.58, CHCl ), 80% ee. HPLC
3
) δ 7.29-7.23 (m, 1H), 7.11-7.09 (m,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R
1
9
R
1
-(2,2-difluorocyclopropyl)-4-nitrobenzene (2h)18
Procedure B
3
(column, CHIRALCEL OJ-3, Hexane/2-Propanol = 98/2, flow
rate 1.0 mL/min, 20 °C detection UV 230 nm) t of major
This compound was purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) as a white solid (13.7
mg, 69% yield). The following data are identical to those in the
R
isomer 5.9 min, t of minor isomer 6.6 min.
R
1
8 1
literature. H NMR (300 MHz, CDCl
3
) δ 8.20 (dt, 2H, J = 9.3,
3-(2,2-difluorocyclopropyl)quinolone (2l)
Procedure A
2
.4 Hz), 7.38 (d, 2H, J = 8.8 Hz), 2.84 (td, 1H, JH-F = 12.1 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
J = 8.2 Hz), 2.04-1.91 (m, 1H), 1.78-1.67 (m, 1H); C{H}
NMR (75 MHz, CDCl ) δ 147.1 (s), 141.4 (s), 128.8 (s), 123.7
(s), 111.8 (dd, JC-F = 286.4, 282.0 Hz), 27.1 (t, JC-F = 11.7 Hz),
18.0 (t, JC-F = 10.5 Hz); 19F NMR (282 MHz, CDCl
) δ -125.5
dt, 1F, JF-F = 155.5 Hz, JF-H = 12.2 Hz), -141.9 (dd, 1F, JF-F
This compound was purified by silica-gel column
chromatography (hexane/EtOAc = 5/1) as a brown solid (16.5
3
1
mg, 80% yield). H NMR (300 MHz, CDCl ) δ 8.84 (s, 1H),
3
3
8.10 (d, 1H, J = 8.5 Hz), 7.96 (s, 1H), 7.79 (dd, 1H, J = 8.1, 1.1
Hz), 7.73-7.68 (m, 1H), 7.58-7.53 (m, 1H), 2.92 (td, 1H, JH-F
=
(
=
2
1
1
55.6 Hz, JF-H = 13.3 Hz). []
D
-6.16 (c 1.29, CHCl
3
), 42% ee.
12.1 Hz, J = 8.1 Hz), 2.05-1.93 (m, 1H), 1.82-1.71 (m, 1H);
1
3
HPLC (column, CHIRALCEL OJ-3, Hexane/2-Propanol = 99/1,
flow rate 1.0 mL/min, 20 °C detection UV 230 nm) t of major
isomer 30.3 min, t of minor isomer 28.1 min.
C{H} NMR (75 MHz, CDCl
C-F = 1.8 Hz), 129.4 (s), 129.3 (s), 127.6 (s), 127.5 (s), 127.0
(s), 126.9 (s), 112.1 (dd, JC-F = 285.9, 282.0 Hz), 24.9 (t, JC-F
3
) δ 151.0 (s), 147.3 (s), 134.2 (t,
R
J
R
=
3
)
1
9
1
1.7 Hz), 17.3 (t, JC-F = 10.6 Hz); F NMR (282 MHz, CDCl
1
-(2,2-difluorocyclopropyl)-4-methoxybenzene (2i)4f
δ -126.2 (dt, 1F, JF-F = 154.5 Hz, JF-H = 11.9 Hz), -141.5 (d, 1F,
-1
Procedure A
J
F-F = 155.1 Hz); FT-IR (neat, cm ) 3063, 3016, 1495, 1473,
This compound was purified by silica-gel column
chromatography (hexane/EtOAc = 20/1) as a colorless liquid
(5.6 mg, 31% yield). The following data are identical to those
1366, 1305, 1222, 1018, 955, 910, 787, 754; HRMS (APCI-
+
10 2 1
TOF) m/z: [M+H] Calcd for C12H F N 206.0788; Found
2
1
206.0781. []D -27.2 (c 1.25, CHCl ), 90% ee. HPLC (column,
3
4
f 1
in the literature. H NMR (300 MHz, CDCl
8.8 Hz), 6.87 (dt, 2H, J = 9.6, 2.9 Hz), 3.80 (s, 3H), 2.71 (td,
H, JH-F = 11.9 Hz, J = 8.1 Hz), 1.84-1.72 (m, 1H), 1.60-1.49
3
) δ 7.16 (d, 2H, J
CHIRALCEL OD-3, Hexane/2-Propanol = 98/2, flow rate 1.0
=
1
mL/min, 20 °C detection UV 230 nm) t of major isomer 33.7
R
min, t of minor isomer 37.4 min.
R
1
9
(
m, 1H); F NMR (282 MHz, CDCl
3
) δ -126.2 (dt, 1F, JF-F
=
(2,2-difluoro-3-phenylcyclopropyl)methyl acetate (2m)21
Procedure B
Use of H -BINAP as a ligand. The reaction mixture was
8
warmed up to 60 °C in an oil bath. This compound was purified
by silica-gel column chromatography (hexane/EtOAc = 20/1)
as a colorless liquid (16.7 mg, 74% yield). The following data
1
=
53.0 Hz, JF-H = 12.7 Hz), -142.4 (dd, 1F, JF-F = 150.3 Hz, JF-H
2
1
12.5 Hz). []
D
3
-20.5 (c 0.27, CHCl ), 64% ee. HPLC
(
column, CHIRALCEL OJ-3, Hexane/2-Propanol = 98/2, flow
rate 1.0 mL/min, 20 °C detection UV 230 nm) t of major
isomer 12.5 min, t of minor isomer 11.1 min.
R
R
2
1 1
1-(2,2-difluorocyclopropyl)-3-methoxybenzene (2j)
Procedure A
NMR yield (83%) was determined by using BTF as an internal
standard. This compound was purified by silica-gel column
are identical to those in the literature. H NMR (300 MHz,
CDCl ) δ 7.31 (br, 5H), 4.15-4.07 (m, 1H), 3.89-3.82 (m, 1H),
3.01 (t, 1H, JH-F = 12.9 Hz), 2.36-2.22 (m, 1H), 2.04 (s, 3H); F
NMR (282 MHz, CDCl ) δ -121.8 (dt, 1F, JF-F = 160.8, JF-H
3
1
9
3
=
2
1
chromatography (hexane/EtOAc = 20/1) as a colorless liquid.
13.4 Hz), -147.6 (d, 1F, JF-F = 162.1 Hz). []D -24.1 (c 1.43,
1
H NMR (300 MHz, CDCl
3
) δ 7.27-7.25 (m, 1H), 6.84-6.77 (m,
CHCl ). HPLC (column, CHIRALCEL OJ-3, Hexane/2-
3
3
1
H), 3.81 (s, 3H), 2.73 (td, 1H, JH-F = 13.1 Hz, J = 8.2 Hz), 1.87-
Propanol = 95/5, flow rate 1.0 mL/min, 20 °C detection UV 210
1
3
.75 (m, 1H), 1.67-1.59 (m, 1H); C{H} NMR (75 MHz,
) δ 159.7 (s), 135.2 (s), 129.4 (s), 120.4 (s), 114.0 (s),
12.5 (t, JC-F = 283.7 Hz), 112.5 (s), 55.2 (s), 27.2 (t, JC-F = 11.4
nm) t of major isomer 9.4 min, t of minor isomer 8.8 min,
R
R
CDCl
1
3
72% ee.
19
Hz), 17.0 (t, JC-F = 10.5 Hz); F NMR (282 MHz, CDCl
3
) δ -
2-(2,2-difluorocyclopropyl-1-d)-6-methoxynaphthalene
(2a-D)
Procedure A
125.7 (dt, 1F, JF-F = 153.6 Hz, JF-H = 12.6 Hz), -142.2 (dd, 1F,
-1
J
F-F = 151.4 Hz, JF-H = 8.4 Hz); FT-IR (neat, cm ) 2972, 2937,
1604, 1494, 1469, 1268, 1219, 1158, 1136, 1091, 1041, 905,
Use of Cu(OAc) as a catalyst and MeOD instead of i-PrOH.
2
+
8
C
CHCl
47, 778; HRMS (APCI-TOF) m/z: [M+H] Calcd for
NMR yield (62%, 55% D) was determined by using BTF as an
internal standard. This compound was purified by silica-gel
2
1
10
H
11
F
2
O
1
185.0778; Found 185.0780. []
), 70% ee. HPLC (column, CHIRALCEL OD-3,
Hexane/2-Propanol = 99/1, flow rate 0.8 mL/min, 20 °C
D
-23.4 (c 0.88,
3
column chromatography (hexane/EtOAc = 20/1) as a white
1
solid. H NMR (300 MHz, CDCl
3
) δ 7.70 (dd, 2H, J = 8.4, 2.5
detection UV 230 nm) t
R
of major isomer 12.6 min, t
R
of minor
Hz), 7.61 (s, 1H), 7.31 (dd, 1H, J = 8.4, 1.1 Hz), 7.17-7.12 (m,
1
9
isomer 13.2 min.
2H), 3.92 (s, 3H), 1.93-1.81 (m, 1H), 1.78-1.68 (m, 1H);
NMR (282 MHz, CDCl ) δ -126.0 (dd, 1F, JF-F = 154.0, JF-H
F
3
=
1
-(2,2-difluorocyclopropyl)-2-methoxybenzene (2k)20
Procedure A
12.2 Hz), -142.3 (dd, 1F, JF-F =151.9, JF-H = 10.5 Hz).
NMR yield (67%) was determined by using BTF as an internal
standard. This compound was purified by silica-gel column
chromatography (hexane/EtOAc = 20/1) as a colorless liquid.
2,2-difluoro-3-phenylcyclopropyl-3-d)methyl acetate (2m-
D)
Procedure B
2
0 1
The following data are identical to those in the literature.
H
2
Use of Cu(OAc) as a catalyst and MeOD instead of i-PrOH.
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NMR yield (68%, 62% D) was determined by using BTF as an
internal standard. This compound was purified by silica-gel
To a mixture of CuTC (1.0 mg, 0.005 mmol) and BTFM-
Garphos (7.1 mg, 0.006 mmol) was added CH Cl (1.0 mL) at
room temperature in a test tube, and the solution was stirred for
2 h. The solvent was removed under reduced pressure, and the
prepared catalyst was dissolved in THF (1.0 mL).
Difluorocyclopropene 1 (23.2 mg, 0.1 mmol) was added to the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
column chromatography (hexane/EtOAc = 20/1) as a colorless
1
liquid. H NMR (300 MHz, CDCl
3
) δ 7.31 (s, 5H), 4.15-4.07
(
m, 1H), 3.90-3.83 (m, 1H), 2.31-2.26 (m, 1H), 2.04 (s, 3H);
1
9
F NMR (282 MHz, CDCl
3
) δ -121.9 (dd, 1F, JF-F = 161.9, JF-
H
= 12.2 Hz), -147.8 (d, 1F, JF-F = 163.3 Hz).
2
solution. After the solution was cooled to 0 °C, ZnMe (1.0 M
in heptane, 150 μL, 0.15 mmol) was added in one portion. The
reaction mixture was stirred at the same temperature for 2 h.
The resulting mixture was quenched with 1N HCl (1 mL) at
Typical
Difluorocyclopropene
To a mixture of CuCl (1.0 mg, 0.01 mmol), ligand L (0.012
Procedure
C
:
Hydroboration
of
0 °C. Et
organic layer was separated and the aqueous layer was extracted
with Et O (10 mL) twice. The combined organic layer was dried
over anhydrous MgSO and evaporated under reduced pressure.
2
O (10 mL) and 1N HCl (10 mL) were added, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
2
mmol) and NaO Bu (5.9 mg, 6.0 mmol) was added Et O (1.0
mL) at room temperature in a test tube, and the solution was
stirred for 1 h. HBPin (17.3 μL, 0.12 mmol) were added to the
reaction mixture at room temperature, and the solution was
stirred for 10 min. Difluorocyclopropene 1a (0.1 mmol) were
added to the reaction mixture at room temperature. The solution
was warmed up to 60 °C in an oil bath and stirred for 48 h. The
solvent was removed under reduced pressure, and the yield of
2
4
1
9
The yield of crude product was determined by F NMR
analysis using BTF as an internal standard. The crude product
was purified by silica-gel column chromatography
(hexane/EtOAc = 30/1). Enantiomer ratio was determined by
chiral HPLC analysis.
1
9
crude product was determined by F NMR analysis using BTF
as an internal standard. The crude product was purified by
silica-gel column chromatography to give corresponding
difluorocyclopropane.
2-(2,2-difluoro-1-methylcyclopropyl)-6-
methoxynaphthalene (5a)
Procedure E
This compound was purified by silica-gel column
Typical
procedure
D
:
Boracupration
of
chromatography (hexane/EtOAc = 30/1) as a white solid (13.9
1
difluorocyclopropene
mg, 56% yield). H NMR (300 MHz, CDCl
3
) δ 7.74-7.69 (m,
To a mixture of CuCl (1.0 mg, 0.01 mmol), ligand L (0.01
3H), 7.40 (dd, 1H, J = 8.5, 1.8 Hz), 7.17-7.12 (m, 2H), 3.92 (s,
t
mmol) and NaO Bu (2.0 mg, 2.0 mmol) was added toluene (1.0
3H), 1.82-1.73 (m, 1H), 1.59-1.57 (m, 3H), 1.50-1.42 (m, 1H);
1
3
mL) at room temperature in a test tube, and the solution was
3
C{H} NMR (75 MHz, CDCl ) δ 157.7 (s), 134.2 (t, JC-F = 2.2
stirred for 30 min. Difluorocyclopropene 1a (0.1 mmol), B
2
Pin
2
Hz), 133.6 (s), 129.2 (s), 128.8 (s), 127.1 (s), 127.0 (d, JC-F
1.7 Hz), 126.8 (d, JC-F = 2.4 Hz), 119.0 (s), 114.8 (dd, JC-F
=
=
(30.5 mg, 0.12 mmol) and MeOH (8.4 μL, 0.2 mmol) were
added to the reaction mixture at room temperature, and the
solution was stirred for 24 h at room temperature. The solvent
was removed under reduced pressure, and the yield of crude
287.7, 285.4 Hz), 105.6 (s), 55.3 (s), 31.2 (t, JC-F = 10.2 Hz),
19
22.6 (t, JC-F = 9.9 Hz), 21.4 (dd, JC-F = 6.2, 1.7 Hz); F NMR
3
(282 MHz, CDCl ) δ -132.5 (dd, 1F, JF-F =150.0 Hz, JF-H = 12.9
19
product was determined by F NMR analysis using BTF as an
Hz), -137.3 (dd, 1F, JF-F =128.8 Hz, JF-H = 11.1 Hz); FT-IR (neat,
-1
internal standard. The crude product was purified by silica-gel
cm ) 2966, 2940, 1608, 1469, 1448, 1256, 1201, 1163, 1029,
+
column
chromatography
to
give
corresponding
1004, 852, 821, 677; HRMS (APCI-TOF) m/z: [M+H] Calcd
2
0
difluorocyclopropane.
for C H F O 249.1091; Found 249.1091. [] +24.2 (c 0.90,
15 15
2
1
D
CHCl
3
), 60% ee. HPLC (column, CHIRALCEL OJ-3,
Hexane/2-Propanol = 99/1, flow rate 1.0 mL/min, 20 °C
detection UV 230 nm) t of major isomer 25.7 min, t of minor
R R
isomer 30.0 min.
2
4
-(2,2-difluoro-1-(6-methoxynaphthalen-2-yl)cyclopropyl)-
,4,5,5-tetramethyl-1,3,2-dioxaborolane (3a)
Procedure D
This compound was purified by silica-gel column
chromatography (hexane/CH
1
2
1
Cl
2
= 2/1) as a white solid (mp
39-143℃, 19.1 mg, 53%). H NMR (300 MHz, CDCl ) ) δ
7.70 (s, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H, J = 8.4,
1.8 Hz), 7.14-7.11 (m, 2H), 3.91 (s, 3H), 2.12 (ddd, 1H, J H-F
10.9, 4.9 Hz, J = 6.3 Hz), 1.79 (ddd, 1H, J H-F = 11.9, 2.6 Hz, J
ASSOCIATED CONTENT
Supporting Information
3
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
=
1
1
=
6.7 Hz), 1.24 (s, 6H), 1.19 (s, 6H); B NMR (96 MHz,
1
3
3 3
CDCl ) δ 30.9 (brs.); C{H} NMR (75 MHz, CDCl ) δ 157.5
AUTHOR INFORMATION
Corresponding Author
(
s), 133.4 (s), 131.5 (s), 129.2 (s), 128.9 (s), 128.5 (d, J = 1.8
Hz), 127.3 (d, J = 2.8 Hz), 126.7 (s), 118.7 (s), 105.6 (s), 84.4
s), 77.2 (s), 55.3 (s), 24.7 (s), 24.4 (s), 20.7 (t, J = 9.9 Hz); 19
NMR (282 MHz, CDCl ) δ -125.1 (dd , J = 143.3, 9.5 Hz), -
31.9~-132.5 (m); HRMS (APCI+) m/z: [M+H] Calcd for
361.17866; Found 361.18214. HPLC (column,
CHIRALCEL AS-H and AD-3, Hexane/2-Propanol = 97/3,
flow rate 1.0 mL/min, 22 ℃ detection UV 230 nm) t of major
isomer 9.307 min, t of minor isomer 98.720 min, 82% ee.ꢀꢀ
(
F
*
E-mail for K. M.: mikami2329@icloud.com
3
+
1
ACKNOWLEDGMENT
This work was financially supported by a grant program
20 24 1 2 3
C H B F O
“
Advanced Catalytic Transformation program for Carbon
R
utilization (ACT-C)” from the Japan Science and Technology
Agency (JST). We are grateful to Profs. Kohsuke Aikawa and
Shigekazu Ito for their helpful discussions. We appreciate Solvias
AG for offering of Walphos. We appreciate Takasago International
Co. for offering of BINAP and SEGPHOS derivatives.
R
Typical Procedure E : Cu-catalyzed Methylation of
Difluorocyclopropene
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REFERENCES
The Journal of Organic Chemistry
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8) Review: (a) Chen, J.; Lu, Z. Asymmetric Hydrofunctionalization
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Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky,
S. J. New Efficient Synthesis of Resorcinylic Macrolides via
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(
9) Takimoto, M.; Nakamura, Y.; Kimura, K.; Mori, M. Ni-catalyzed
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Fritzemeier, R.; Westcott, S. A.; Santos, W. L.; Steel, P. G.
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Drug Design: A Case Study with Fluoroanisoles ChemMedChem
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(Ph
Tetrahedron Lett. 1988, 29, 3749-3752. The Stryker reagent has
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3 6
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12) Review: Dian, L.; Marek, I. Asymmetric Preparation of
Polysubstituted Cyclopropanes Based on Direct Functionalization
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(c) Birchall, J. M.; Cross, G. E.; Haszeldine, R. N.
Difluorocarbene Proc. Chem. Soc., London 1960, 81. (d) Tian,
F.; Kruger, V.; Bautista, O.; Duan, J. -X.; Li, A. -R.; Dolbier, W.
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Evaluating the Thermal Vinylcyclopropane Rearrangement
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P t-
B u2
(VCPR) as a Practical Method for the Synthesis of Difluorinated
P t-
B u2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cyclopentenes: Experimental and Computational Studies of
Rearrangement Stereospecificity. Chem. Eur. J. 2014, 20, 14305-
F
F
L 
L C u
A r
F
F
F
e
=
Walphos
Nu
Walphos
1
4314.
F

F
[ LC u -N u]
t-
B
u
O
O Me
A r
L 
=
DTBM-SEGPHOS
Nu
O
O
P
P
t-
t-
B
B
u
u
2
2
C u L
•
Up to >99% yield, 90% ee
• Nu = H, BPin, Me, Et
Regiochemical control depending on steric demand of ligands (L*)
A r
O
O
Me
t-
B
u
•
(R)-DTBM-SEGPHOS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment