Enantioselective palladium-catalyzed addition of malonates to 3,3-difluoropropenes

Article abstract of DOI:10.1016/j.tet.2018.08.034

Monofluoroalkenes bearing a malonate unit at the β position can be synthesized by the enantioselective addition of diesters to 3,3-difluoropropenes. The difference in reactivity regarding the geometry and the substituents of the alkene of the 3,3-difluoropropenes, as well as the alkyl groups of the malonates, was studied and limitations were identified. The reaction was also performed with different 3,3-difluoropropenes. Further synthetic transformations of a newly functionalized monofluoroalkene were also accomplished.

Full text of DOI:10.1016/j.tet.2018.08.034

Accepted Manuscript
Enantioselective palladium-catalyzed addition of malonates to 3,3-difluoropropenes
Myriam Drouin, Jean-François Paquin
PII:
S0040-4020(18)31000-7
10.1016/j.tet.2018.08.034
TET 29754
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 July 2018
Revised Date: 14 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Drouin M, Paquin Jean-Franç, Enantioselective palladium-catalyzed addition
of malonates to 3,3-difluoropropenes, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.034.
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Enantioselective palladium-catalyzed addition of
malonates to 3,3-difluoropropenes
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Myriam Drouin and Jean-François Paquin
Département de chimie, 1045 avenue de la médecine, Université Laval, Québec, QC, G1V 0A6

1
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Tetrahedron
journal homepage: www.elsevier.com
Enantioselective palladium-catalyzed addition of malonates to 3,3-difluoropropenes
Myriam Drouin and Jean-François Paquin
a CCVC, PROTEO, Département de chimie, 1045 avenue de la Médecine, Université Laval, Québec, QC G1V 0A6, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Monofluoroalkenes bearing a malonate unit at the β position can be synthesized by the enantioselective
addition of diesters to 3,3-difluoropropenes. The difference in reactivity regarding the geometry and the
substituents of the alkene of the 3,3-difluoropropenes, as well as the alkyl groups of the malonates, was
studied and limitations were identified. The reaction was also performed with different 3,3-
difluoropropenes. Further synthetic transformations of a newly functionalized monofluoroalkene were
also accomplished.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Asymmetric synthesis
Palladium catalysis
Monofluoroalkene
3,3-Difluoropropene
Organofluorine chemistry
1. Introduction
The fluorine atom presents unique and interesting properties,1
which explains the importance of its incorporation in organic
molecules for applications in medicinal chemistry, agrochemistry
and material sciences.2,3,4 Of all the fluorinated motifs,
monofluoroalkenes are useful as non-hydrolyzable amide bonds
or enol ethers isosteres.5,6 Numerous synthetic strategies towards
monofluoroalkenes have been developed over the years.7 Our
group has been particularly interested in using 3,3-
difluoropropenes
as
starting
materials
to
access
monofluoroalkenes using catalyzed or metal-free process (Figure
1a).8,9,10 In this context, we recently reported the palladium-
catalyzed addition of dimethylmalonate and its derivatives to
different
3,3-difluoropropenes
(Figure
1b).11
Many
monofluoroalkenes bearing a malonate at the β position were
obtained in up to 78% yield. As a preliminary result, we also
disclosed that the reaction of trisubstituted alkene (E)-1 provided
the chiral monofluoroalkene 2 in 56% yield and 55% ee using
(R)-BINAP as the chiral ligand (Figure 1c), a rare example of
enantioselective reaction involving the activation of a C−F
bond.12 Herein, we report our progress based on this initial result
(Figure 1d). Specifically, optimization of the chiral ligand and a
study of the reactivity depending on the geometry of the alkene,
on its substituents and on the alkyl groups of the malonate was
performed, as well as the extension of the reaction on different
3,3-difluoropropenes. This study allowed the identification of
some limitations. Synthetic transformations were also
accomplished on a monofluoroalkene.
Fig. 1. Previous work, initial result and current work.
———
Corresponding author. Tel.: +1-418-656-2131 ext. 11430; fax: +1-418-656-7619; e-mail: jean-francois.paquin@chm.ulaval.ca

2
Tetrahedron
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2. Results and Discussion
(R,S)-JOSIPHOS (17% ee). Further screening revealed that (R)-
SEGPHOS (78% ee) was superior that its more hindered analogs:
(R)-DM-SEGPHOS (59% ee) and (R)-DTBM-SEGPHOS (29%
ee). While (S)-MeO-BIPHEP also gave interesting results (−74%
ee), it was decided to pursue the study with (R)-SEGPHOS.
The enantioselective palladium-catalyzed addition of
dimethylmalonate was first studied on 3,3-difluoropropene (E)-1
and the initial screening of chiral ligands is summarized in Table
1. As reported previously,11 (R)-BINAP provided the higher ee at
this point (55% ee),13 compared to (R)-DM-BINAP (<1% ee) and
Table 1
Initial screening of ligandsa,b
aIsolated yield of 2.
bThe ee's were determined by chiral HPLC.
cThe yield could not be determined. Numerous side products were present in the crude mixture and purification only provided a small pure sample for HPLC
analysis.
Table 2
Screening of solvents, bases and temperature.
Entry
1
2
3
4
5
6
7
8
Base
Solvent
Toluene
CH3CN
Et2O
x (mol%)
10
10
10
10
10
10
10
10
10
10
10
20
20
20
20
20
Temperature (°C)
Yield (%)a
ee (%)b
67
69
75
75
71
76
84
77
77
80
82
86
-
-
-
-
-
82
80
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
Et2Zn
KH
BSA (3 equiv.)
NaOMe
110
85
40
85
70
70
40
70
70
60
50
50
50
50
50
50
50
50
50
33
71
20
55
67
61
23
66
58
54
72
51
0
0
0
0
0
67
75
DCE
Dioxane
2-Me-THF
CH2Cl2
THF/CH2Cl2 (1:1)
THF/CH2Cl2 (1:3)
THF
THF
THF
THF
THF
9
10
11
12
13
14
15
16
17
18
19c
THF
THF
THF
THF
BSA (3 equiv.), KOAc (0.3 equiv.)
NaH
NaH
20
15
15
THF
aIsolated yield of 2.
bThe ee's were determined by chiral HPLC.
cMolecular sieves (4Å) were added to the reaction mixture.

3
Further optimization of the reaction conditions was then
undertaken (Table 2). A screening of solvents (Table 2, entries 1-
9) showed that when the reaction was run in toluene, Et2O or
CH2Cl2, low yields and similar enantiomeric excess were
observed compared to THF. Using of CH3CN, dioxane or 2-
methyl(tetrahydrofuran) provided similar results to THF.
Interestingly, performing the transformation in CH2Cl2 afforded 2
with a higher enantiomeric excess (Table 2, entry 7), however, in
low yield due to an incomplete conversion. A mixture of CH2Cl2
and THF was explored, but no improvement was observed (Table
2, entries 8-9). To counter the formation of unidentified side
products, lower temperatures (Table 2, entries 10-11) were tested,
and 50 °C was found to be the most efficient. It was noted that
using 20 mol% of (R)-SEGPHOS (Table 2, entry 12) provided a
small increase of the enantiomeric excess, but at the expense of
the yield due to purification issues. Other bases were screened
(Table 2, entries 13-17), but no formation of the final product
was observed. Finally, using 15 mol% of (R)-SEGPHOS and
adding 4Å molecular sieves in the reaction mixture provided a
good compromise between yield and enantioselectivity as 2 was
isolated in 75% yield with 80% ee (Table 2, entry 19).
effect of the alkene geometry on the reaction was studied (Table
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4). Higher yield and enantiomeric excess were observed starting
from (E)-1 (75%, 80% ee) compared to (Z)-1 (66%, 55% ee).14
Furthermore, when a 29:71 E/Z mixture of 1 was used, the
reactivity was found to be closer to that of (Z)-1 (68%, 58% ee).
The difference may be due to the nature of the diastereomeric π-
allyl complex formed.15 Indeed, in the case of the (E) isomer, the
most stable syn π-allyl complex is initially produced while with
the (Z) isomer, the less stable anti π-allyl complex would be
generated. The latter could isomerize via a σ-π-σ mechanism
producing a mixture of diastereomeric π-allyl complexes, with
different (and lower) enantioselectivity. Afterwards, the influence
of the alkene substituent was evaluated. The replacement of the
methyl group by an ethyl moiety resulted in a considerable
decrease in the yields for both (E)-3 (15%) and (Z)-3 (32%),
probably due to an increase in the steric hindrance. Interestingly,
the reaction showed a similar enantioselectivity with (E)-3 (77%
ee) compared to (E)-1, while it was superior for (Z)-3 (70% ee)
compared to (Z)-1. Finally, when a benzyl was present on the
alkene, less than 3% of the desired monofluoroalkene was
observed. Overall, this transformation seems, under the current
reaction conditions, limited to the use of methyl trisubstituted
alkenes.
In parallel, a few additional ligands structurally-related to
SEGPHOS were screened (Table 3) using the conditions reported
in entry 12 of Table 2. No reaction was observed at 50 °C when
using (R)-DIFLUORPHOS. However, at 70 °C, the product was
obtained in 45% yield and 30% ee. In the case of (R)-SYNPHOS,
Table 4
Influence of the alkene geometry and the alkene substituant.a,b
a
good yield was obtained (79%), but with lower
enantioselectivity (33% ee) compared to (R)-SEGPHOS. Finally,
(R)-C3-TunePhos gave the monofluoroalkene with a better yield,
but with a lower enantiomeric excess than with (R)-SEGPHOS
(70%, 62% ee). In the end, (R)-SEGPHOS provided the highest
enantioselectivity and the conditions used in entry 19 of Table 2
were used for the rest of the study.
Table 3
Additional ligand screening.a,b
aIsolated yield of 2, 5-6.
bThe ee’s were determined by chiral HPLC.
cCompound 1 was a 29:71 E/Z mixture.
The influence of the ester groups on the malonate was studied
and as such, dimethylmalonate, diethylmalonate and
diisopropylmalonate were subjected to the palladium-catalyzed
reaction on (E)-1 and (Z)-1 (Table 5). For the reaction on (E)-1,
the yields decreased from methyl (75%, 80% ee) to ethyl (66%,
81% ee) to isopropyl (52%, 83% ee), while the enantiomeric
excess stayed similar. A slightly different behavior was observed
with (Z)-1. The best results were obtained using
dimethylmalonate (66%, 55% ee), but diethylmalonate gave a
lower yield with a similar enantiomeric excess (41%, 55% ee)
and diisopropylmalonate gave a similar yield, but with a lower
enantiomeric excess (62%, 46% ee). Overall, the best result was
obtained when using dimethylmalonate on (E)-1. Unfortunately,
aIsolated yield of 2.
bThe ee’s were determined by chiral HPLC.
cReaction was conducted at 70 °C.
As the synthesis of the 3,3-difluoropropenes allowed, in some
cases (vide infra), the separation of the (E) and (Z) isomers, the

4
Tetrahedron
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di-tert-butylmalonate, dibenzylmalonate and α-substituted
malonates were unsuitable substrates for the transformation.
Table 5
Influence of the malonate alkyl groups.a,b
aIsolated yield of 2, 7-8.
bThe ee’s were determined by chiral HPLC.
We next explored the extension of this reaction to different
3,3-difluoropropene derivatives (Table 6). It should be noted that
in some cases, the separation of the (E) and (Z) alkenes was not
possible and thus, the catalytic reactions were performed on the
mixture. The presence of a methoxy group on the starting
material (i.e. 9) was well tolerated. Reaction on the E/Z mixture
gave 14 (69%, 58% ee), with similar yields and enantiomeric
excesses than the ones observed with the E/Z mixture of 1 (68%,
58% ee). The reaction also tolerated heteroatoms in the 6-
membered cyclic structure. In the case of the thiochromanone
derivative 10, the monofluoroalkene 15 was obtained with
moderate yield and high enantiomeric excess starting from (Z)
(46%, 91% ee), and good yield and enantiomeric excess starting
from (E) (78%, 87% ee). For the chromanone derivative 11, 16
was observed in 76% yield and 80% ee, although the reaction
was performed on a E/Z mixture of the 3,3-difluoropropene.
Unfortunately, starting from the indanone 12, the five-membered
cycle equivalent, almost racemic monofluoroalkene 17 was
obtained in moderate yields from either isomer. Finally, this
methodology can also be applied to the acyclic 3,3-
difluoropropene 13 to give the terminal monofluoroalkene 18,
but with low yield and enantiomeric excess (18%, 24% ee).
aIsolated yield of 2, 14-18.
bThe ee’s were determined by chiral HPLC.
cCompound 1 was a 29:71 E/Z mixture.
dCompound 9 was a 24:76 mixture.
eCompound 11 was a 43:57 mixture.
fReaction conditions of Table 1 were used ((R)-BINAP (10 mol%), THF, 70
°C).
gCompound 13 was a 18/82 mixture.
Finally, some transformations of
2 were explored to
demonstrate the versatility of the monofluoroalkenes obtained.
The diester can be reduced in the corresponding diol 19 in good
yield (85%, 80% ee) using LiAlH4. Also, the use of benzyl
bromide in presence of sodium hydride allowed the alkylation in
alpha of the diester to give 20 in moderated yield (48%, 82% ee).
This transformation represents an alternative to the addition of a
α-substituted malonate, an unsuccessful reaction under the
current conditions (vide supra). Finally, as shown previously,10,11
2 can be transformed into the corresponding monofluoroalkene
21 in a 2-step sequence (monodecarboalkoxylation/hydrolysis;
57%, 80% ee/83%, 85% ee). The monofluoroalkene containing a
carboxylic acid obtained here can be seen as a “beta-alanine”
isostere.
Table 6
Extension to other derivatives.a,b

5
quartet, p = pentet, sext = sextet, hept = heptuplet, m =
ACCEPTED MANUSCRIPT
multiplet, bs = broad signal. High-resolution mass spectra were
obtained on a LC/MS–TOF Agilent 6210 using electrospray
ionization (ESI) or atmospheric pressure photoionization (APPI).
Infrared spectra were recorded using a ABB MB 3000 FT-IR
spectrometer. Melting points were recorded on a Stanford
Research System OptiMelt capillary melting point apparatus and
are uncorrected. Optical rotations were measured on a Jasco DIP-
360 Polarimeter with a sodium lamp at ambient temperature.
Enantiomeric excesses were determined by HPLC analysis using
a Hewlett Packard 1200 Series and Daicel Corporation columns
(OJ-H, AD-H or IB)
4.1. General procedure
To a solution of NaH (2 equiv.) in THF (0.1 M, 1/3 of the total
amount) containing 4 Å MS (approx. 10 mg) was added dropwise
dimethylmalonate (2 equiv.) at rt and the resulting reaction
mixture was stirred for 15 min. The 3,3-difluoropropene (1
equiv.) was dissolved in THF (0.1 M, 1/3 of the total amount)
and added dropwise, followed by a solution of [Pd(allyl)Cl]2 (5
mol%) and (R)-SEGPHOS (15 mol%) in THF (0.1 M, 1/3 of the
total amount). The reaction mixture was then warmed to 50 °C
and stirred for 18 h. The reaction mixture was cool to room
temperature, quenched with H2O and extracted with Et2O (3×).
The combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated.
Dimethyl
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)ethyl)
malonate (2)
For the racemic synthesis of 2, see ref. 11. <1% ee (determined
by chiral HPLC, OJ-H, hexanes/2-propanol = 98:2, flow rate 1.1
mL min-1, tr,1 = 26.6 min, tr,2 = 29.9 min, wavelength = 254 nm;
Scheme 1. Synthetic transformation of 2.
3. Conclusion
or IB, hexanes/2-propanol = 95:5, flow rate 0.7 mL min-1, tr,1
=
6.9 min, tr,2 = 7.4 min, wavelength = 220 nm). For the
enantioselective synthesis starting from (Z)-1, the general
procedure was performed on a 0.155 mmol scale to give 2 (31
mg, 66%) as a yellow oil by flash chromatography (3%
The enantioselective palladium-catalyzed addition of
malonates to 3,3-difluoropropenes was developed as a novel
approach to enantioenriched functionalized monofluoroalkenes.
A study of the impact on the structure of the alkenes and the
malonates was performed and some limitations were found.
Further derivatization of the products was also possible. Overall,
the transformation reported herein represents a rare example of
enantioselective reactions involving the activation of a C−F bond.
Et2O/toluene). [α]21 = +11.2 (c 0.048, MeOH); 55% ee
D
(determined by chiral HPLC, IB, hexanes/2-propanol = 95:5,
flow rate 0.7 mL min-1, tr,minor = 7.0 min, tr,major = 7.6 min,
wavelength = 220 nm). For the enantioselective synthesis starting
from (E)-1, the general procedure was performed on a 0.155
mmol scale to give 2 (35 mg, 75%) as a yellow oil by flash
chromatography (3% Et2O/toluene). [α]21 = +15.7 (c 0.48,
4. Experimental section
D
MeOH); 80% ee (determined by chiral HPLC, IB, hexanes/2-
Materials and Methods
propanol = 95:5, flow rate 0.7 mL min-1, tr,minor = 6.9 min, tr,major
=
7.4 min, wavelength = 220 nm). For the enantioselective
synthesis starting from a mixture (E)/(Z) = 29:71 of 1, the general
procedure was performed on a 0.155 mmol scale to give 2 (32
mg, 68%) as a colourless oil by flash chromatography (3%
The following includes general experimental procedures, specific
details for representative reactions and isolation, and
spectroscopic information for the new compounds prepared. All
reactions were carried out under an argon atmosphere with dry
solvents. Et2O, THF, CH3CN, CH2Cl2 and toluene were purified
using a Vacuum Atmospheres Inc. Solvent Purification System.
All other commercially available compounds were used as
received. Thin-layer chromatography (TLC) analysis of reaction
mixtures was performed using Silicycle silica gel 60 Å F254
TLC plates, and visualized under UV (λ = 254 nm) or by staining
with potassium permanganate. Flash column chromatography
Et2O/toluene). [α]21 = +11.1 (c 0.48, MeOH); 58% ee
D
(determined by chiral HPLC, IB, hexanes/2-propanol = 95:5,
flow rate 0.7 mL min-1, tr,minor = 7.0 min, tr,major = 7.5 min,
wavelength = 220 nm).
Dimethyl
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)propyl)
malonate (5)
1
was carried out on Silicycle silica gel 60 Å, 230–400 mesh. H,
13C and 19F NMR spectra were recorded in CDCl3 at ambient
temperature using Agilent DD2 500 and Varian Inova 400
For the racemic synthesis of 5, the general procedure was
followed on a 0.24 mmol scale of (Z)-3 using rac-BINAP (10
mol%) as the ligand and stirring at 70 °C. The desired product 5
1
spectrometers. H and 13C chemical shifts are reported in ppm
downfield of tetramethylsilane (1H NMR) or residual CHCl3 (1H
and 13C NMR) as the internal standard. For 19F NMR, CFCl3 is
used as the external standard. Coupling constants (J) are
measured in hertz (Hz). Multiplicities are reported using the
following abbreviations: s = singlet, d = doublet, t = triplet, q =
(14 mg, 18%) was isolated as
a yellow oil by flash
chromatography (10% EtOAc/hexanes). IR (ATR, diamond) ν =
2955, 2839, 1755, 1738, 1670, 1435, 1225, 1148, 1097, 764 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.45 (1H, d, J = 7.9 Hz), 7.21 (1H,
m), 7.09 (2H, d, J = 4.4 Hz), 4.03 (1H, d, J = 11.3 Hz), 3.78 (3H,

6
Tetrahedron
s), 3.45 (3H, s), 2.94-2.82 (2H, m), 2.49 (2H, q, J = 7.6 Hz),
procedure was performed on a 0.155 mmol scale using
ACCEPTED MANUSCRIPT
1.78 (1H, m), 1.67 (1H, m), 0.88 (3H, t, J = 7.4 Hz); 19F NMR
(470 MHz, CDCl3) δ −96.0 (1F, s); 13C NMR (126 MHz, CDCl3)
δ 169.3, 168.5, 160.9 (d, JC-F = 270.0 Hz), 133.0, 127.3, 127.2,
126.7, 126.0 (d, JC-F = 2.0 Hz), 123.7 (d, JC-F = 6.2 Hz), 119.3,
55.8 (d, JC-F = 5.0 Hz), 52.6, 52.2, 38.8, 29.2 (d, JC-F = 6.4 Hz),
25.4 (d, JC-F = 25.0 Hz), 25.1, 12.2; HRMS-ESI calcd for
C18H22FO4 [M+H]+ 321.1497, found 321.1470; <1% ee
(determined by chiral HPLC, IB, hexanes/2-propanol = 98:2,
flow rate 0.8 mL min-1, tr,1 = 6.7 min, tr,2 = 7.1 min, wavelength =
254 nm). For the enantioselective synthesis starting from (Z)-3,
the general procedure was performed on a 0.144 mmol scale to
give 5 (16 mg, 32%) as a yellow oil by flash chromatography
diethylmalonate (2 equiv.) instead of dimethylmalonate to give 7
(21 mg, 41%) as a pink oil by flash chromatography (5%
Et2O/toluene). [α]21 = +20.2 (c 0.20, MeOH); 54% ee
D
(determined by chiral HPLC, IB, hexanes/2-propanol = 97:3,
flow rate 0.7 mL min-1, tr,minor = 6.6 min, tr,major = 7.3 min,
wavelength = 254 nm). For the enantioselective synthesis starting
from (E)-1, the general procedure was performed on a 0.155
mmol scale diethylmalonate (2 equiv.) instead of
dimethylmalonate to give 7 (33 mg, 66%) as a yellow oil by flash
chromatography (3% Et2O/toluene). [α]21 = +11.3 (c 0.20,
D
MeOH); 81% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 97:3, flow rate 0.7 mL min-1, tr,minor = 6.5 min, tr,major
=
(3% Et2O/toluene). [α]21 = +13.5 (c 0.72, MeOH); 70% ee
7.0 min, wavelength = 254 nm).
D
(determined by chiral HPLC, IB, hexanes/2-propanol = 98:2,
flow rate 0.8 mL min-1, tr,minor = 6.7 min, tr,major = 7.1 min,
wavelength = 254 nm). For the enantioselective synthesis starting
from (E)-3, the general procedure was performed on a 0.144
mmol scale to give 5 (7 mg, 15%) as a yellow oil by flash
chromatography (3% Et2O/toluene) followed by a second flash
Diisopropyl
malonate (8)
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)ethyl)
For the racemic synthesis of 8, the general procedure was
followed on a 0.18 mmol scale of (Z)-1 using rac-BINAP (10
mol%) as the ligand, diisopropylmalonate (2 equiv.) as the
nucleophile and stirring at 70 °C. The desired product 8 (41 mg,
63%) was isolated as a colorless oil by flash chromatography
(5/35/60 EtOAc/toluene/hexanes). IR (ATR, diamond) ν = 2980,
chromatography (3% Et2O/toluene).
= +10.7 (c 0.38,
MeOH); 77% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 98:2, flow rate 0.8 mL min-1, tr,minor = 6.3 min, tr,major
=
2837, 1747, 1728, 1672, 1452, 1225, 1182, 1099, 762 cm-1; H
1
6.8 min, wavelength = 254 nm).
NMR (500 MHz, CDCl3) δ 7.43 (1H, d, J = 7.8 Hz), 7.21 (1H,
m), 7.12-7.05 (2H, m), 5.11 (1H, hept, J = 6.4 Hz), 4.81 (1H,
hept, J = 6.2 Hz), 3.94 (1H, d, J = 11.3 Hz), 3.59 (1H, dt, J =
17.2, 6.6 Hz), 2.86 (2H, td, J = 8.1, 2.6 Hz), 2.55-2.37 (2H, m),
1.38-1.21 (12H, m), 1.04 (3H, d, J = 6.2 Hz), 0.86 (3H, d, J = 6.3
Hz); 19F NMR (470 MHz, CDCl3) δ −97.8 (1F, s); 13C NMR (126
MHz, CDCl3) δ 168.4, 167.7, 160.6 (d, JC-F = 269.3 Hz), 134.4
(d, JC-F = 8.6 Hz), 133.0, 127.3, 126.7, 126.0 (d, JC-F = 1.9 Hz),
123.2 (d, JC-F = 6.3 Hz), 116.5 (d, JC-F = 10.9 Hz), 68.9, 68.5, 57.1
(d, JC-F = 5.6 Hz), 31.6, 29.0 (d, JC-F = 6.7 Hz), 25.4 (d, JC-F = 24.9
Hz), 21.7, 21.6, 21.5, 21.0, 17.6 (d, JC-F = 2.7 Hz); HRMS-ESI
calcd for C21H28FO4 [M+H]+ 363.1966, found 363.1954; <1% ee
(determined by chiral HPLC, OJ-H, hexanes/2-propanol = 96:4,
flow rate 0.7 mL min-1, tr,1 = 5.8 min, tr,2 = 6.5 min, wavelength =
254 nm). For the enantioselective synthesis starting from (Z)-1,
the general procedure was performed on a 0.155 mmol scale
Dimethyl
phenylethyl)malonate (6)
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)-2-
For the racemic synthesis of 6, the general procedure was
followed on a 0.18 mmol scale of (Z)-4 using rac-BINAP (10
mol%) as the ligand and stirring at 70 °C. The desired product 6
(4 mg, 5%, not pure) was isolated as a yellow oil by flash
chromatography (3% Et2O/toluene). 1H NMR (500 MHz, CDCl3)
δ 7.53-7.46 (2H, m), 7.40-7.36 (2H, m), 7.32-7.28 (2H, m), 7.19-
7.16 (3H, m), 6.88 (1H, dt, J = 16.5, 1.6 Hz), 6.68 (1H, d, J =
16.4 Hz), 5.07 (1H, bs), 3.77 (6H, s), 3,42 (1H, bs), 2.88-2.81
(2H, m), 2.52-2.47 (2H, m); 19F NMR (470 MHz, CDCl3) δ −95.5
(1F, s). As the substrate was not suitable, the reaction using (R)-
SEGPHOS was not performed. Furthermore,
characterization was not performed as the final product was not
pure.
a
full
using
diisopropylmalonate
(2
equiv.)
instead
of
Diethyl
yl)ethyl)malonate (7)
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-
dimethylmalonate to give 8 (35 mg, 62%) as a yellow oil by flash
chromatography (3% Et2O/toluene). [α]21 = +5.3 (c 0.52,
D
MeOH); 46% ee (determined by chiral HPLC, AD-H, hexanes/2-
propanol = 97:3, flow rate 0.7 mL min-1, tr,minor = 10.6 min, tr,major
= 9.0 min, wavelength = 254 nm). For the enantioselective
synthesis starting from (E)-1, the general procedure was
performed on a 0.155 mmol scale using diisopropylmalonate (2
equiv.) instead of dimethylmalonate to give 8 (29 mg, 52%) as a
For the racemic synthesis of 7, the general procedure was
followed on a 0.183 mmol scale of (Z)-1 using rac-BINAP (10
mol%) as the ligand, diethylmalonate (2 equiv.) as the
nucleophile and stirring at 70 °C. The desired product 7 (48 mg,
78%) was isolated as a colorless oil by flash chromatography
(10% EtOAc/hexanes). IR (ATR, diamond) ν = 2980, 2897,
yellow oil by flash chromatography (3% Et2O/toluene). [α]21
=
D
1
1751, 1726, 1452, 1367, 1225, 1148, 1028, 762 cm-1; H NMR
+12.0 (c 0.52, MeOH); 83% ee (determined by chiral HPLC,
AD-H, hexanes/2-propanol = 97:3, flow rate 0.7 mL min-1, tr,minor
= 10.6 min, tr,major = 9.1 min, wavelength = 254 nm).
(500 MHz, CDCl3) δ 7.42 (1H, d, J = 8.5 Hz), 7.21 (1H, dt, J =
8.2, 4.2 Hz), 7.09 (2H, d, J = 4.0 Hz), 4.25 (2H, q, J = 7.2 Hz),
4.01 (1H, d, J = 11.4 Hz), 3.95 (2H, q, J = 7.21 Hz), 3.62 (1H,
dq, J = 13.5, 7.1 Hz), 2.94-2.81 (2H, m), 2.43-2.40 (2H, m), 1.36-
1.27 (6H, m), 0.96 (3H, t, J = 7.1 Hz); 19F NMR (470 MHz,
CDCl3) δ −97.8 (1F, s); 13C NMR (126 MHz, CDCl3) δ 168.8,
168.2, 160.7 (d, JC-F = 269.4 Hz), 134.2 (d, JC-F = 8.5 Hz), 133.0,
127.3, 126.7, 126.1 (d, JC-F = 1.9 Hz), 123.1 (d, JC-F = 6.3 Hz),
116.3 (d, JC-F = 10.6 Hz), 61.5, 61.1, 56.7 (d, JC-F = 5.6 Hz), 31.9,
29.0 (d, JC-F = 6.8 Hz), 25.4 (d, JC-F = 24.9 Hz), 15.6 (d, JC-F = 2.6
Hz), 14.1, 13.7; HRMS-ESI calcd for C19H27FNO4 [M+NH4]+
352.19487, found 352.19186; <1% ee (determined by chiral
HPLC, OJ-H, hexanes/2-propanol = 93:7, flow rate 0.7 mL min-1,
tr,1 = 8.3 min, tr,2 = 10.1 min, wavelength = 254 nm). For the
enantioselective synthesis starting from (Z)-1, the general
Dimethyl 2-(1-(2-fluoro-7-methoxy-3,4-dihydronaphthalen-1-yl)
ethyl)malonate (14)
For the racemic synthesis of 14, the general procedure was
followed on a 0.223 mmol scale of a mixture (E)/(Z) = 24:76 of 9
using rac-BINAP (10 mol%) as the ligand and stirring at 70 °C.
The desired product 14 (62 mg, 77%) was isolated as a colourless
oil by flash chromatography (10% EtOAc/hexanes). IR (ATR,
diamond) ν = 2953, 2837, 1755, 1736, 1670, 1433, 1227, 1144,
1
1043, 818 cm-1; H NMR (500 MHz, CDCl3) δ 7.03-6.97 (2H,
m), 6.63 (1H, dd, J = 8.2, 2.5 Hz), 4.05 (1H, d, J = 11.3 Hz), 3.81
(3H, s), 3.78 (3H, s), 3,56 (1H, m), 3.51 (3H, s), 2.83-2.76 (2H,

7
m), 2.51-2.38 (2H, m), 1.31 (3H, d, J = 7.0 Hz); 19F NMR (470
MHz, CDCl3) δ −97.1 (1F, s); 13C NMR (126 MHz, CDCl3) δ
168.3, 151.5 (d, JC-F = 271.5 Hz), 151.8, 128.1 (d, JC-F = 2.2
ACCEPTED MANUSCRIPT
Hz), 123.9 (d, JC-F = 6.3 Hz), 122.2, 121.8 (d, JC-F = 6.1 Hz),
116.0, 114.0 (d, JC-F = 7.9 Hz), 63.7, 63.4, 56.0 (d, JC-F = 4.6 Hz),
52.6 (d, JC-F = 30.1 Hz), 31.1, 17.3 (d, JC-F = 2.9 Hz); HRMS-ESI
calcd for C16H18FO5 [M+H]+ 309.1133, found 309.1163; <1% ee
(determined by chiral HPLC, IB, hexanes/2-propanol = 96:4,
flow rate 0.7 mL min-1, tr,1 = 7.8 min, tr,2 = 8.5 min, wavelength =
220 nm). For the enantioselective synthesis starting from a
mixture (E)/(Z) = 43:57 of 11, the general procedure was
performed on a 0.155 mmol scale to give 16 (26 mg, 76%) as a
colourless oil by flash chromatography (10% EtOAc/hexanes).
169.2, 168.5, 161.4 (d, JC-F = 269.8 Hz), 158.7, 135.4 (d, JC-F
9.0 Hz), 127.9, 125.2, 116.2 (d, JC-F = 11.0 Hz), 110.2 (d, JC-F
=
=
6.6 Hz), 110.1 (d, JC-F = 2.0 Hz), 56.2, 55.4, 52.6, 52.2, 32.2, 28.1
(d, JC-F = 6.7 Hz), 25.8 (d, JC-F = 24.6 Hz), 17.5 (d, JC-F = 2.8 Hz);
HRMS-ESI calcd for C18H22F5 [M+H]+ 338.1480, found
338.1506; <1% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 97:3, flow rate 0.7 mL min-1, tr,1 = 9.1 min, tr,2 = 9.7
min, wavelength = 254 nm). For the enantioselective synthesis
starting from a mixture (E)/(Z) = 24:76 of 9, the general
procedure was performed on a 0.132 mmol scale to give 14 (31
mg, 69%) as a colourless oil by flash chromatography (10%
[α]21 = +5.5 (c 0.24, MeOH); 80% ee (determined by chiral
D
HPLC, IB, hexanes/2-propanol = 96:4, flow rate 0.7 mL min-1,
EtOAc/hexanes). [α]21 = +6.3 (c 0.33, MeOH); 58% ee
tr,minor = 7.9 min, tr,major = 8.6 min, wavelength = 220 nm).
D
(determined by chiral HPLC, IB, hexanes/2-propanol = 97:2,
flow rate 0.7 mL min-1, tr,minor = 9.1 min, tr,major = 9.8 min,
wavelength = 254 nm).
Dimethyl 2-(1-(2-fluoro-1H-inden-3-yl)ethyl)malonate (17)
For the racemic synthesis of 17, the general procedure was
followed on a 0.278 mmol scale of (Z)-12 using rac-BINAP (10
mol%) as the ligand and stirring at 70 °C. The desired product 17
Dimethyl
2-(1-(3-fluoro-2H-thiochromen-4-yl)ethyl)malonate
(15)
(45 mg, 57%) was isolated as
a yellow oil by flash
For the racemic synthesis of 15, the general procedure was
followed on a 0.236 mmol scale of (Z)-10 using rac-BINAP (10
mol%) as the ligand and stirring at 70 °C. The desired product 15
chromatography (10% EtOAc/hexanes). IR (ATR, diamond) ν =
2955, 2843, 1790, 1736, 1437, 1271, 1155, 1009, 912, 764 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.34 (1H, dt, J = 7.4, 1.1 Hz), 7.29
(2H, d, J = 7.3 Hz), 7.15 (1H, td, J = 7.5, 1.2 Hz), 3.93 (1H, d, J
= 11.0 Hz), 3.79 (3H, s), 3.64 (1H, m), 2.88 (3H, m), 3.42 (2H,
m), 1.34 (3H d, J = 7.4 Hz); 19F NMR (470 MHz, CDCl3) δ
−122.0 (1F, s); 13C NMR (126 MHz, CDCl3) δ 168.8, 168.3,
163.2 (d, JC-F = 281.4 Hz), 141.9 (d, JC-F = 7.0 Hz), 134.8 (d, JC-F
= 8.1 Hz), 126.8, 124.4 (d, JC-F = 4.3 Hz), 123.7 (d, JC-F = 1.4 Hz),
(45 mg, 58%) was isolated as
a yellow oil by flash
chromatography (3% Et2O/toluene). IR (ATR, diamond) ν =
2955, 2847, 1751, 1738, 1664, 1435, 1263, 1198, 1148, 935 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.52 (1H, d, J = 7.9 Hz), 7.30 (1H,
dd, J = 7.7, 1.4 Hz), 7.20 (1H, m), 7.09 (1H, td, J = 7.5, 1.3 Hz),
4.05 (1H, d, J = 11.4 Hz), 3.78 (3H, s), 3.56 (1H, m), 3.54 (3H,
s), 3.50-3.31 (2H, m), 1.33 (3H, d, J = 6.7 Hz); 19F NMR (470
MHz, CDCl3) δ −94.3 (1F, t, J = 10.9 Hz); 13C NMR (126 MHz,
119.6 (d, JC-F = 8.1 Hz), 119.4 (d, JC-F = 6.7 Hz), 55.9 (d, JC-F
=
2.8 Hz), 52.6, 52.4, 35.1 (d, JC-F = 21.1 Hz), 29.8 (d, JC-F = 1.9
Hz), 16.9 (d, JC-F = 2.2 Hz); HRMS-ESI calcd for C16H18FO4
[M+H]+ 293.11836, found 293.12063; <1% ee (determined by
chiral HPLC, IB, hexanes/2-propanol = 99:1, flow rate 0.8 mL
min-1, tr,1 = 8.6 min, tr,2 = 9.2 min, wavelength = 220 nm). For the
enantioselective synthesis starting from (Z)-12, the general
procedure was performed on a 0.278 mmol scale using (R)-
BINAP (10 mol%) as the ligand and stirring at 70 °C. The
desired product 17 (38 mg, 47%) was isolated as a yellow oil by
CDCl3) δ 169.0, 168.4, 154.5 (d, JC-F = 275.7 Hz), 133.9 (d, JC-F
=
6.8 Hz), 129.7, 127.3, 126.8 (d, JC-F = 1.8 Hz), 126.3, 125.3 (d,
JC-F = 5.6 Hz), 118.1 (d, JC-F = 12.8 Hz), 56.2 (d, JC-F = 5.8 Hz),
52.6, 52.4, 34.2, 26.1 (d, JC-F = 31.4 Hz), 17.6 (d, JC-F = 3.2 Hz);
HRMS-ESI calcd for C16H18FO4S [M+H]+ 325.0904, found
325.0903; <1% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 96:4, flow rate 0.7 mL min-1, tr,1 = 8.3 min, tr,2 = 8.8
min, wavelength = 254 nm). For the enantioselective synthesis
starting from (Z)-10, the general procedure was performed on a
0.141 mmol scale to give 15 (21 mg, 46%) as a pinky oil by flash
flash chromatography (10% EtOAc/hexanes). [α]21 = +4.0 (c
D
0.28, MeOH); 3% ee (determined by chiral HPLC, IB,
hexanes/2-propanol = 99:1, flow rate 0.8 mL min-1, tr,minor = 8.5
min, tr,major = 9.1 min, wavelength = 220 nm). For the
enantioselective synthesis starting from (E)-12, the general
procedure was performed on a 0.278 mmol scale using (R)-
BINAP (10 mol%) as the ligand and stirring at 70 °C. The
desired product 17 (49 mg, 60%) was isolated as a yellow oil by
chromatography (3% Et2O/toluene). [α]21 = +26.2 (c 0.33,
D
MeOH); 91% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 96:4, flow rate 0.7 mL min-1, tr,minor = 8.3 min, tr,major
=
9.0 min, wavelength = 254 nm). For the enantioselective
synthesis starting from (E)-1, the general procedure was
performed on a 0.141 mmol scale to give 15 (38 mg, 78%) as a
colourless oil by flash chromatography (3% Et2O/toluene). [α]21
flash chromatography (10% EtOAc/hexanes). [α]21 = +2.8 (c
D
D
= +20.5 (c 0.33, MeOH); 87% ee (determined by chiral HPLC,
0.28, MeOH); 2% ee (determined by chiral HPLC, IB,
hexanes/2-propanol = 99:1, flow rate 0.8 mL min-1, tr,minor = 8.4
min, tr,major = 9.1 min, wavelength = 220 nm).
IB, hexanes/2-propanol = 96:4, flow rate 0.7 mL min-1, tr,minor
8.3 min, tr,major = 8.9 min, wavelength = 254 nm).
=
Dimethyl 2-(1-(3-fluoro-2H-chromen-4-yl)ethyl)malonate (16)
(Z)-dimethyl
2-(3-([1,1'-biphenyl]-4-yl)-4-fluorobut-3-en-2-
yl)malonate (18)
For the racemic synthesis of 16, the general procedure was
followed on a 0.204 mmol scale of a mixture (E)/(Z) = 43:57 of
11 using rac-BINAP (10 mol%) as the ligand and stirring at 70
°C. The desired product 16 (51 mg, 84%) was isolated as a
colorless oil by flash chromatography (10% EtOAc/hexanes). IR
(ATR, diamond) ν = 2955, 2845, 1755, 1736, 1690, 1487, 1252,
For the racemic synthesis of 18, the general procedure was
followed on a 0.205 mmol scale of a mixture (E)/(Z) = 18:82 of
13 using rac-BINAP (10 mol%) as the ligand and stirring at 70
°C. The major Z-isomer 18 (19 mg, 26%) was isolated as a
colorless oil by flash chromatography (3% Et2O/toluene). IR
(ATR, diamond) ν = 3030, 2953, 1755, 1736, 1666, 1489, 1435,
1
1189, 1144, 928 cm-1; H NMR (500 MHz, CDCl3) δ 7.40 (1H,
1
dd, J = 7.9, 1.6 Hz), 7.11 (1H, td, J = 7.7, 1.6 Hz), 6.99 (1H, t, J
= 7.6 Hz), 6.85 (1H, dd, J = 8.0, 1.3 Hz), 4.66 (4.66 (2H, d, J =
3.9 Hz), 3.99 (1H, d, J = 11.3 Hz), 3.79 (3H, s), 3.60 (1H, m),
3.55 (3H, s), 1.31 (3H, d, J = 6.8 Hz); 19F NMR (470 MHz,
CDCl3) δ −113.7 (1F, s); 13C NMR (126 MHz, CDCl3) δ 168.8,
1273, 1196, 1009 cm-1; H NMR (500 MHz, CDCl3) δ 7.62-7.58
(4H, m), 7.45 (2H, t, J = 7.7 Hz), 7.38-7.31 (3H, m), 3.73 (3H, s),
3.72 (3H, s), 3.49 (1H, d, J = 9.6 Hz), 3.33 (1H, m), 1.20 (3H, d,
J = 6.9 Hz); 19F NMR (470 MHz, CDCl3) δ −130.9 (1F, d, J =
83.2 Hz); 13C NMR (126 MHz, CDCl3) δ 168.5, 168.3, 146.2 (d,

8
Tetrahedron
ACCEPTED MANUSCRIPT
JC-F = 260.4 Hz), 140.6 (d, JC-F = 1.3 Hz), 132.5 (d, JC-F = 1.9
with brine (3×) to remove the DMF, and then dried over MgSO4
Hz), 129.54, 129.52, 128.8, 127.4, 127.1, 127.0, 124.9 (d, JC-F
4.8 Hz), 56.0 (d, JC-F = 2.9 Hz), 52.6, 52.5, 36.3 (d, JC-F = 5.6
=
and concentrated. Purification by flash chromatography (10%
EtOAc/hexanes) afforded the final product 20 (22 mg, 57%) as a
colourless oil. IR (ATR, diamond) ν = 3030, 2949, 2839, 1724,
Hz), 17.3 (d, JC-F
= 2.3 Hz); HRMS-ESI calcd for C21H22FO4
[M+H]+ 357.1497, found 357.1495; <1% ee (determined by
chiral HPLC, IB, hexanes/2-propanol = 95:5, flow rate 0.7 mL
min-1, tr,1 = 8.5 min, tr,2 = 9.0 min, wavelength = 254 nm). The
1668, 1433, 1259, 1178, 1090, 1034 cm-1; H NMR (500 MHz,
1
CDCl3) δ 7.38 (1H, m), 7.20 (1H, m), 7.15-7.09 (5H, m), 7.07-
7.01 (2H, m), 3.83 (1H, q, J = 6.8 Hz), 3.73 (3H, s), 3.44 (1H, d,
J = 13.7 Hz), 3.40 (3H, s), 3.07 (1H, td, J = 15.0, 6.7 Hz), 2.90-
2.73 (2H, m), 2.57 (1H, td, J = 15.7, 6.5 Hz), 2.42 (1H, s), 1.49
(3H, d, J = 7.2 Hz); 19F NMR (470 MHz, CDCl3) δ −92.1 (1F, d,
J = 13.9 Hz); 13C NMR (126 MHz, CDCl3) δ 171.2, 170.6, 161.9
(d, J = 270.8 Hz), 137.0, 135.5 (d, JC-F = 9.2 Hz), 133.3, 130.2,
127.7, 127.5, 126.8, 126.6, 126.0 (d, JC-F = 1.8 Hz), 123.0 (d, JC-F
= 6.2 Hz), 114.4 (d, JC-F = 11.7 Hz), 63.9, 51.9, 51.8, 41.0, 37.9,
stereochemistry of the alkene was proven by 1D H-1H-NOESY
1
and NOE experiments. For the enantioselective synthesis starting
from a mixture (E)/(Z) = 18:82 of 13, the general procedure was
performed on a 0.123 mmol scale to give the major isomer (Z)-18
(8 mg, 18%) as a colourless oil by flash chromatography (3%
Et2O/toluene). [α]21D = −1.3 (c 0.40, MeOH); 24% ee (determined
by chiral HPLC, IB, hexanes/2-propanol = 95:5, flow rate 0.7 mL
min-1, tr,minor = 9.1 min, tr,major = 8.6 min, wavelength = 254 nm).
29.1 (d, JC-F = 6.7 Hz), 25.8 (d, JC-F = 25.4 Hz), 16.1 (d, JC-F
=
5.5 Hz); HRMS-ESI calcd for C24H26FO4 [M+H]+ 397.1810,
found 397.1810; <1% ee (determined by chiral HPLC, IB,
hexanes/2-propanol = 96:4, flow rate 0.7 mL min-1, tmin = 6.1
min, tmaj = 6.5 min, wavelength = 254 nm). The reaction was also
performed using the same protocol on a 0.096 mmol scale of the
enantioenriched monofluoroalkene 2 (29 mg, 82% ee). The final
product 20 (18 mg, 48%) was isolated as a colourless oil by flash
4.2. Synthetic transformation of 2
4.2.1. ReductionE r r o r !
B o o k m a r k n o t d e f i n e d .
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)ethyl)propane-1,3-
diol2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)ethyl)propane-
1,3-diol (19)
chromatography (10% EtOAc/hexanes). [α]21 = −6.4 (c 0.98,
D
LiAlH4 (22 mg, 0.59 mmol, 6 equiv.) was added to THF (3.3 mL,
0.03 M) at −78 °C. Then, the racemic monofluoroalkene 2 (30
mg, 0.098 mmol, 1 equiv.) was added dropwise. The mixture was
stirred at −78 °C for 1 h, then allowed to warm to room
temperature overnight. The reaction was cooled to 0 °C, sat. aq.
Na2CO3 was added and the reaction was filtered using Et2O. The
organic layer was separated, dried over Na2SO4, filtered and
concentrated. Flash chromatography (5% MeOH/CH2Cl2)
afforded the final product 19 as a white solid (20 mg, 81%). mp =
79.6-83.8 °C; ; IR (ATR, diamond) ν = 3350, 2941, 2887, 1666,
1485, 1178, 1148, 1065, 762 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.38 (1H, d, J = 7.8 Hz), 7.19 (1H, td, J = 7.4, 1.9 Hz), 7.16-7.08
(2H, m), 4.06 (1H, dd, J = 10.9, 2.8 Hz), 3.90 (1H, dd, J = 10.9,
6.1 Hz), 3.83 (10.8, 3.3 Hz), 3.70 (1H, dd, J = 10.7, 5.9 Hz), 3.09
(1H, dq, J = 13.1, 6.4 Hz), 2.97-2.85 (2H, m), 2.54-2.45 (2H, m),
2.19 (1H, m), 1.34 (3H, d, J = 7.1 Hz); 19F NMR (470 MHz,
CDCl3) δ −98.5 (1F, s); 13C NMR (126 MHz, CDCl3) δ 159.9 (d,
MeOH); 83% ee (determined by chiral HPLC, IB, hexanes/2-
propanol = 96:4, flow rate 0.7 mL min-1, tmin = 6.1 min, tmaj = 6.5
min, wavelength = 254 nm).
B o o k m a r k n o t d e f i n e d .
4.2.3. DecarboxylationE r r o r !
Methyl 3-(2-fluoro-3,4-dihydronaphthalen-1-yl)butanoate (21a)
H2O (18 mg, 1.00 mmol, 2.4 equiv.) was weighted in a
microwave vial, and a solution of the racemic monofluoroalkene
2 (128 mg, 0.418 mmol, 1 equiv.) in DMF (4.2 mL, 0.1 M) was
next added. The mixture was stirred at 200 °C for 75 minutes
under microwave irradiation, and then brought back to ambient
temperature. Et2O and water were added, and the layers were
separated. The ethereal layer was washed with water (1x), brine
(1x), dried over Na2SO4, filtered and concentrated in vacuo. The
desired product (70 mg, 68%) was isolated as a colorless oil by
flash chromatography using 100% toluene. IR (ATR, diamond) ν
= 2949, 2839, 1736, 1672, 1435, 1223, 1148, 1082, 926 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.37 (1H, d, J = 7.8 Hz), 7.22 (1H,
m), 7.15-7.02 (2H, m), 3.66 (3H, s), 3.36 (1H, app. br. hex. J =
7.1 Hz), 2.91 (2H, td, J = 8.1, 2.7 Hz), 2.82-2.70 (2H, m), 2.49
(2H, td, J = 8.1, 6.4 Hz), 1.34 (3H, d, J = 6.6 Hz); 19F NMR (470
MHz, CDCl3) δ −99.6 (1F, s); 13C NMR (126 MHz, CDCl3) δ
173.4, 160.3 (d, JC-F = 268.4 Hz), 134.5 (d, JC-F = 8.5 Hz), 133.3,
127.5, 126.7, 125.9 (d, JC-F = 1.9 Hz), 122.8 (d, JC-F = 6.6 Hz),
117.8 (d, JC-F = 10.7 Hz), 51.5, 39.9 (d, JC-F = 5.2 Hz), 29.1 (d, JC-
F = 7.1 Hz), 28.6, 25.5 (d, JC-F = 25.3 Hz), 19.2 (d, JC-F = 3.7 Hz);
HRMS-ESI calcd for C15H18FO2 [M+H]+ 249.1285, found
249.1268; <1% ee (determined by chiral HPLC, IB, hexanes/2-
JC-F = 267.4 Hz), 133.5, 127.6, 126.73, 126.70, 126.1 (d, JC-F
=
1.8 Hz), 123.3 (d, JC-F = 6.3 Hz), 117.6 (d, JC-F = 11.3 Hz), 65.8,
64.6, 44.7 (d, JC-F = 3.4 Hz), 29.2 (d, JC-F = 6.8 Hz), 28.4, 25.4 (d,
JC-F = 25.7 Hz), 17.2 (d, JC-F = 3.3 Hz); HRMS-ESI calcd for
C15H20FO2 [M+H]+ 251.1442, found 251.1427; <1% ee
(determined by chiral HPLC, IB, hexanes/2-propanol = 90:10,
flow rate 0.7 mL min-1, tmin = 10.6 min, tmaj = 11.9 min,
wavelength = 220 nm). The reaction was also performed using
the same protocol on a 0.096 mmol scale of the enantioenriched
monofluoroalkene 2 (30 mg, 82% ee). The final product 19 (20
mg, 83%) was isolated as a white solid by flash chromatography
(5% MeOH/CH2Cl2). [α]21 = +21.3 (c 0.78, MeOH); 80% ee
D
propanol = 95:5, flow rate 0.7 mL min-1, tr,minor = 6.0 min, tr,major
=
(determined by chiral HPLC, IB, hexanes/2-propanol = 90:10,
flow rate 0.7 mL min-1, tmin = 10.6 min, tmaj = 11.9 min,
wavelength = 220 nm).
7.5 min, wavelength = 254 nm).The reaction was also performed
using the same protocol on a 0.234 mmol scale of the
enantioenriched monofluoroalkene 2 (72 mg, 79% ee). The final
product 21a (33 mg, 57%) was isolated as a colourless oil by
B o o k m a r k n o t d e f i n e d .
4.2.2. AlkylationE r r o r !
flash chromatography using 100% toluene. [α]21 = +12.9 (c
Dimethyl
2-benzyl-2-(1-(2-fluoro-3,4-dihydronaphthalen-1-
D
0.49, MeOH); 80% ee (determined by chiral HPLC, IB,
hexanes/2-propanol = 95:5, flow rate 0.7 mL min-1, tr,minor = 6.1
min, tr,major = 7.3 min, wavelength = 254 nm).
yl)ethyl)malonate (20)
NaH (60% in mineral oil, 4 mg, 0.108 mmol, 1.1 equiv.) was
added to DMF (0.98 mL, 0.1 M) at 0 °C, followed by the racemic
monofluoroalkene 2 (29 mg, 0.098 mmol, 1 equiv.) and the
mixture was stirred for 15 min. Benzyl bromide (14 ꢀL, 0.118
mmol, 1.2 equiv.) was added and the reaction was heated at 100
°C for 3 h. EtOAc was added, and the organic layer was washed
3-(2-fluoro-3,4-dihydronaphthalen-1-yl)butanoic acid (21)
To a solution of the racemic ester 21a (70 mg, 0.28 mmol) in
EtOH (1.2 mL, 0.24 M) was added aqueous NaOH (0.5 M, 1.1
mL, 0.57 mmol, 2 equiv.). The resulting mixture was stirred at

9
ambient temperature for 18 hours. HCl (3 M) was added, and the
ACCEPTED MANUSCRIPT
aqueous mixture was extracted with EtOAc (3x). The organic
layers were combined, washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The desired product 21 (63
mg, 95%) was isolated as a colorless oil by flash chromatography
using 3% MeOH/CH2Cl2. IR (ATR, diamond) ν = 3061, 2932,
5. For selected recent examples, see: (a) Chang, W.; Mosley, R. T.;
Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.;
Sofia, M. J. Bioorg. Med. Chem. Lett. 2012, 22, 2938–2942; (b)
Choi, W. J.; Chung, H.-J.; Chandra, G.; Alexander, V.; Zhao, L.
X.; Lee, H. W.; Nayak, A.; Majik, M. S.; Kim, H. O.; Kim, J.-H.;
Lee, Y. B.; Ahn, C. H.; Lee, S. K.; Joeng, L. S. J. Med. Chem.
2012, 55, 4521–4525; (c) Urban, J. J.; Tillman, B. G.; Cronin, W.
A. J. Phys. Chem. A 2006, 110, 11120–11129; (d) Malo-Forest,
B.; Landelle, G.; Roy, J.-A.; Lacroix, J.; Gaudreault, R. C.;
Paquin, J.-F. Bioorg. Med. Chem. Lett. 2013, 23, 1712–1715; (e)
Huleatt, P. B.; Khoo, M. L.; Chua, Y. Y.; Tan, T. W.; Liew, R. S.;
Balogh, B.; Deme, R.; Gölöncsér, F.; Magyar, K. Sheela, D. P.;
Ho, H. K.; Sperlágh, B.; Mátyus, P.; Chai, C. L. L. J. Med. Chem.
2015, 58, 1400–1419; (f ) Cheng, J.; Giguère, P. M.; Onajole, O.
K.; Lv, W.; Gaisin, A.; Gunosewoyo, H.; Schmerberg, C. M.;
Pogorelov, V. M.; Rodriguiz, R. M.; Vistoli, G.; Wetsel, W. C.;
Roth, B. L.; Kozikowski, A. P. J. Med. Chem. 2015, 58, 1992–
2002; (g) Hohlfeld, K.; Wegner, J. K.; Kesteleyn, B. Linclau, B.;
Unge, J. J. Med. Chem. 2015, 58, 4029–4038.
1
2625, 1701, 1663, 1414, 1294, 905, 760 cm-1; H NMR (500
MHz, CDCl3) δ 7.34 (1H, d, J = 7.8 Hz), 7.20 (1H, m), 3.33 (1H,
app. br. hex., J = 7.3 Hz), 2.89 (2H, td, J = 8.1, 2.6 Hz), 2.85-
2.72 (2H, m), 2.47 (2H, dt, J = 9.2, 6.9 Hz), 1.35 (3H, d, J = 7.0
Hz); 19F NMR (470 MHz, CDCl3) δ −99.5 (1F, s); 13C NMR (126
MHz, CDCl3) δ 179.4, 160.4 (d, JC-F = 268.5 Hz), 134.4 (d, JC-F
8.6 Hz), 133.3, 127.5, 126.7, 126.0 (d, JC-F = 1.9 Hz), 122.7 (d,
C-F = 6.3 Hz), 117.6 (d, JC-F = 10.9 Hz), 39.8 (d, JC-F = 5.4 Hz),
=
J
29.0 (d, JC-F = 6.8 Hz), 28.3, 25.5 (d, JC-F = 25.2 Hz), 19.2 (d, JC-F
= 3.3 Hz); HRMS-ESI calcd for C14H16FO2 [M+H]+ 235.1129,
found 235.1106; <1% ee (determined by chiral HPLC, AD-H,
hexanes/2-propanol = 98:2, flow rate 1.1 mL min-1, tr,minor = 14.3
min, tr,major = 16.6 min, wavelength = 254 nm). The reaction was
also performed using the same protocol on a 0.133 mmol scale of
the enantioenriched ester 21a (33 mg, 80% ee). The final product
21 (26 mg, 83%) was isolated as a colourless oil by flash
6. Drouin, M.; Paquin, J.-F Beilstein J. Org. Chem. 2017, 13, 2637–
2658.
7. For reviews on their synthesis, see: (a) Landelle, G.; Turcotte-
Savard, M.-O.; Bergeron; M.; Paquin, J.-F. Chem. Soc. Rev. 2011,
40, 2867–2908. (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem.
2011, 5939–5954. (c) Hara, S. Top. Curr. Chem. 2012, 327, 59–
86. (d) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Synthesis 2018, 50,
881–955.
8. (a) Pigeon, X.; Bergeron, M.; Barabé, F.; Dubé, P.; Frost, H. N.;
Paquin, J.-F. Angew. Chem. Int. Ed. 2010, 49, 1123–1127. (b)
Bergeron, M.; Johnson, T.; Paquin, J.-F. Angew. Chem. Int. Ed.
2011, 50, 11112–11116. (c) Bergeron, M.; Guyader, D.; Paquin,
J.-F. Org. Lett. 2012, 14, 5888–5891. (d) Hamel, J.-D.; Drouin,
M.; Paquin, J.-F. J. Fluorine Chem. 2015, 174, 81–87.
chromatography (3% MeOH/CH2Cl2). [α]21 = +6.9 (c 0.44,
D
MeOH); 85% ee (determined by chiral HPLC, AD-H, hexanes/2-
propanol = 98:2, flow rate 1.1 mL min-1, tr,minor = 17.2 min, tr,major
= 14.8 min, wavelength = 254 nm).
Acknowledgments
9. Accounts: (a) Paquin, J.-F. Synlett 2011, 289–293. (b) Drouin, M.;
Hamel, J.-D.; Paquin, J.-F. Synlett 2016, 821–830.
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the FRQNT
Centre in Green Chemistry and Catalysis (CCVC), the FRQNT
Network for Research on Protein Function, Engineering, and
Applications (PROTEO), and the Université Laval. M. D. thanks
NSERC for a Vanier Canada Graduate Scholarship.
10. For
a related strategy using gem-chlorofluoropropenes, see:
Hamel, J.-D.; Cloutier, M.; Paquin, J.-F. Org. Lett. 2016, 18,
1852–1855.
11. Drouin, M.; Tremblay, S.; Paquin, J.-F. Org. Biomol. Chem. 2017,
15, 2376–2384.
12. (a) Nishimine, T.; Fukushi, K.; Shibata, N.; Taira, H.; Tokunaga,
E.; Yamano, A.; Shiro M.; Shibata, N. Angew. Chem., Int. Ed.
2014, 53, 517–520; (b) Nishimine, T.; Taira, H.; Tokunaga, E.;
Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2016, 55, 359–363;
(c) Tanaka, J.; Suzuki, S.; Tokunaga, E.; Haufe G.; Shibata, N.
Angew. Chem., Int. Ed. 2016, 55, 9432–9436.
13. It has not been possible, so far, to determine the absolute
stereochemistry of any of the chiral products generated in this
study.
Supplementary Material
Electronic supplementary information (ESI) available: Full
experimental details for the synthesis of the 3,3-difluoropropenes
and 1H, 13C, and 19F NMR spectra for all the new compounds.
References and notes
14. In our previous communication, we reported that reaction of (Z)-1
provided racemic 2; however, it was later found that this result
was due to a faulty chiral column.
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