A new entry to the construction of a quaternary carbon center having a fluorine atom - SN2′ reaction of γ-fluoroallylic alcohol derivatives with various cyanocuprates

Article abstract of DOI:10.1039/c2ob25718a

Treatment of γ-fluoroallylic phosphate with various lower-ordered cyanocuprates derived from Grignard reagents, organolithium, and organozincs gave the corresponding S_N2′ products having a fluorine atom at a quaternary carbon center in excellent yields. This system could be successfully extended to the chiral version, enantiomerically pure fluorine-containing materials also being obtained in high yield.

Full text of DOI:10.1039/c2ob25718a

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 8154
www.rsc.org/obc
PAPER
A new entry to the construction of a quaternary carbon center having a
fluorine atom – SN2′ reaction of γ-fluoroallylic alcohol derivatives with
various cyanocuprates†
Tsutomu Konno,* Atsushi Ikemoto and Takashi Ishihara
Received 12th April 2012, Accepted 21st August 2012
DOI: 10.1039/c2ob25718a
Treatment of γ-fluoroallylic phosphate with various lower-ordered cyanocuprates derived from Grignard
reagents, organolithium, and organozincs gave the corresponding SN2′ products having a fluorine atom at
a quaternary carbon center in excellent yields. This system could be successfully extended to the chiral
version, enantiomerically pure fluorine-containing materials also being obtained in high yield.
Introduction
Results and discussion
It has been well recognized that the substitution of hydrogen
with fluorine can bring about a profound effect on the biological
activity, metabolism, solubility, hydrophobicity, and bulk proper-
ties of organic substances.1 Consequently, fluorine-containing
materials are extremely important as pharmaceuticals, imaging
agents, fine chemicals, materials, and so on.
Among such fluorinated molecules, the compounds having a
fluorine atom at a quaternary carbon center 1 (Fig. 1) have
recently been attracting much attention, due to their unique
properties,2 and convenient synthetic methods for the preparation
of such molecules have been reported in the laboratories of
Togni,3 Shibata,4 Cahard,5 Sodeoka,6 Kim,7 Nakamura,8
Barbas III,9 Jørgensen,10 Jun–An–Ma,11 Shibatomi,12 Maruoka,13
and so on.14 Herein is described a new entry to 1 via the highly
regioselective SN2′ reaction of the γ-fluoroallylic phosphate
2 with lower-ordered organocuprates.15 In addition, we wish to
disclose a highly stereoselective SN2′ reaction of the chiral
γ-fluoroallylic phosphate, which enables us to afford an enantio-
merically pure fluorine-containing substance.
The starting γ-fluoroallylic phosphates could be easily prepared
as follows (Schemes 1 and 2). Thus, treatment of (Z)-β-fluoro-
α,β-unsaturated esters 3a–c, which could be prepared according
to the literature,16 with an excess amount of DIBAL-H, followed
by the usual phosphorylation,17 gave the corresponding phos-
phates 2a–c. On the other hand, α-silyloxyacetaldehyde 5d18
underwent a sequential Horner–Wadsworth–Emmons reaction
and the acid hydrolysis to afford the corresponding allylic
alcohol 4d. Then the phosphorylation of 4d provided the desired
γ-fluoroallylic phosphate 2d as a diastereomeric mixture.
With the substrates in hand, we first investigated SN2′ reaction
using γ-fluoroallylic phosphate 2a as described in Table 1.
Thus, treatment of 2a with 1.1 equiv. of lower-ordered cyano-
cuprate, prepared from 1.1 equiv. each of CuCN and n-BuMgBr,
in THF at −78 °C for 0.5 h did not give any desired product at
all (entry 1). The reaction at −40 °C, on the other hand, took
place to afford the γ-product γ-1a in 45% yield, together with
Fig. 1 Intended program.
Department of Chemistry and Materials Technology, Kyoto Institute of
Technology, Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan.
E-mail: konno@chem.kit.ac.jp
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25718a
Scheme 1 Preparation of the substrates 2a–c.
8154 | Org. Biomol. Chem., 2012, 10, 8154–8163
This journal is © The Royal Society of Chemistry 2012

View Online
Scheme 3 Reaction using various γ-fluoroallylic phosphates.
to give the corresponding adducts γ-1b–d in high yields. In all
cases, the corresponding α-adducts were not detected at all.
Next, our attention was directed toward the SN2′ reaction with
various organometallics, by using the substrate 2d. The results
are collected in Table 2.
Scheme 2 Preparation of the substrate 2d.
As shown in entries 1–5, various primary Grignard reagents,
such as MeMgBr, n-BuMgBr, 3-phenylpropylMgBr, 1,3-di-
oxolane-2-ethylMgBr, and 5-pentenylMgBr, were found to be
good reagents for the present reaction, the desired SN2′
products γ-1 being exclusively obtained in high to excellent
yields. On the other hand, BnMgCl is somewhat less reactive,
the desired product being afforded in only 55% yield, together
with 6% of the reduction product 6 (entry 6). In the case
of allylMgCl, 6 was also obtained in 31% yield, and no
γ-product was detected at all (entry 7). The reaction of secon-
dary alkyl Grignard reagents, such as i-PrMgBr and c-HexMgBr,
took place smoothly to give the SN2′ products in good
yields, though a slight decrease of the regioselectivity was
observed and a small amount of the starting allylic phosphate
remained unreacted (entries 8 and 9). Surprisingly, the use of a
tertiary alkyl Grignard reagent, such as t-BuMgBr, caused a sig-
nificant change in the regioselectivity, the α-product being
obtained exclusively (entry 10). As described in entry 11,
PhMgBr could not be applied for the SN2′ reaction, only
reduction product 6 was afforded. Additionally, the increase of
the amount of PhMgBr did not lead to a satisfactory result
(entry 12).
Table 1 Investigation of the reaction conditions
Cu(I) X/
Entry equiv.
Y/
equiv. °C
Temp./ Yielda/% of Ratioa
Recoverya/
% of 2a
γ-1 + α-1
(γ:α)
1
2
3b
4
5
6
7
8
9
CuCN/1.1 1.1
CuCN/1.1 1.1
CuCN/1.1 1.1
CuCN/1.1 1.1
CuCN/2.2 2.2
CuCN/0.2 2.2
−78
−40
−40
0
−40
−40
−40
−40
−40
0
45
58
—
100
55
39
71
0
40
0
100 : 0
100 : 0
100 : 0
97 : 3
19 : 81
0 : 100
0 : 100
0 : 100
27
100 (50)c
43
CuI/2.2
4.4
4.4
2.2
27
27
29
CuBr/2.2
CuBr/0.2
0
0
a Determined by 19F NMR. The value in parentheses is of isolated yield.
b Carried out for 4 h. c The product was partially decomposed in silica
gel column chromatography.
We also examined the SN2′ reaction using organolithium and
organozinc reagents. As shown in entry 13, the reaction of
cyanocuprate derived from MeLi and CuCN proceeded slug-
gishly, the desired SN2′ product being obtained in only 32%
yield. The use of n-BuLi led to an exclusive formation of the
SN2′ product in 80% yield (entry 14), however, PhLi was found
to be less reactive, similar to PhMgBr, no desired product being
afforded at all (entry 15). As described in entries 16 and 17, the
reaction with Et2Zn or (i-Pr)2Zn in the presence of CuCN as
well as LiCl took place smoothly to give the corresponding SN2′
products in good to high yields, whereas the use of Ph2Zn did
not bring about a fruitful result (entry 18).
Finally, we attempted the SN2′ reaction using the chiral allylic
substrate (Scheme 4). Thus, optically pure α-silyloxypropanal
7,19 prepared readily from commercially available S-(−)-methyl
lactate in two steps, was subjected to the Horner–Wadsworth–
Emmons reaction, followed by a silica gel column separation of
the isomeric mixture, giving the corresponding (E)-α,β-unsatu-
rated ester 8 in 77% yield. Deprotection and the subsequent
phosphorylation gave the enantiomerically pure substrate 9 in
53% yield. Then treatment of 9 with 2.2 equiv. of (n-C9H19)Cu-
(CN)MgBr in THF at −40 °C for 0.5 h afforded the corres-
ponding SN2′ adduct 10 in 91% yield.
55% recovery of the starting material (entry 2). In this case, γ-1a
was obtained exclusively and no α-1a was detected at all. As
shown in entries 3 and 4, the prolonged reaction time or higher
temperature did not lead to satisfactory results. The use of
2.2 equiv. of cyanocuprate caused a significant improvement of
the yield, γ-1a being afforded in 97% yield, along with a small
amount of the α-product (3%) as shown in entry 5. In this case,
the product was found to be somewhat unstable for silica gel, the
product being obtained in only 50% isolated yield. Unfortu-
nately, the copper-catalyzed attempt led to a decrease of the yield
as well as the preferential formation of the α-product (entry 6).
As described in entries 7 and 8, other copper salts, such as
CuI and CuBr, brought about a significant change in the regio-
selectivity, the α-product being obtained exclusively, though the
yield was only 27%. CuBr-catalyzed reaction also gave α-1a
exclusively, and no γ-1a was detected at all (entry 9).
With the optimized reaction conditions, we next examined the
reaction using various γ-fluoroallylic phosphates 2b–d as sum-
marized in Scheme 3.
Various substrates having cyclohexyl, n-C8H17, or ethoxy-
carbonyl groups could participate in the SN2′ reaction very well
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8154–8163 | 8155

View Online
Table 2 SN2′ Reaction using various organometallics
Entry
R-Met or R2Zn
Temp./°C
Yielda/% of γ-1 + α-1
Ratioa (γ:α)
Recoverya/% of 2d
1
2
MeMgBr
n-BuMgBr
−40
−40
85
86 (78)
( 1e)
( 1d)
100 : 0
100 : 0
0
4
3
4
−40
98 (97)
98 (92)
( 1f)
100 : 0
100 : 0
0
2
−40
( 1g)
( 1h)
5
−40
97 (93)
100 : 0
0
6b
7c
BnMgCl
−40
−40
55 (53)
0
( 1i)
100 : 0
0
0
—
—
8
9
i-PrMgBr
c-HexMgBr
t-BuMgBr
PhMgBr
PhMgBr
MeLi
n-BuLi
PhLi
Et2Zn
−40
−40
−40
−40
−40
−20
−20
−20
0
67 (53)
88 (78)
84d (78)
0
0
32
80 (78)
0
76 (68)
57 (55)
0
( 1j)
( 1k)
( 1l)
—
94 : 6
93 : 7
0 : 100
—
11
7
0
0
0
0
0
0
0
0
0
10
11e
12f,g
13
—
—
( 1e)
( 1d)
—
( 1m)
( 1j)
—
100 : 0
100 : 0
—
100 : 0
100 : 0
—
14
15
16h
17h
18h
i-Pr2Zn
Ph2Zn
0
0
a Determined by 19F NMR. Values in parentheses are of isolated yields. b The reduction product 6 was obtained in 6% yield. c The reduction product 6
was obtained in 31% yield. d E/Z = 74/26. e The reduction product 6 was obtained in 67% yield. f 4.4 equiv. of PhMgBr was used. g The reduction
product 6 was obtained in 46% yield. h 4.4 equiv. of LiCl was used as an additive.
Scheme 4 Synthesis of an enantiomerically pure compound having a fluorine atom at an asymmetric quaternary carbon center.
The stereochemical assignment of 10 was made as follows.
The ozonolysis of 10 produced crude α-fluoroaldehyde, which
was immediately reduced with an excess amount of NaBH4 to
give the corresponding alcohol. MOM protection and the sub-
sequent reduction gave the known compound 11.20 The compari-
son of the observed optical rotation of 11 with its literature value
8156 | Org. Biomol. Chem., 2012, 10, 8154–8163
This journal is © The Royal Society of Chemistry 2012

View Online
made it possible to determine the absolute configuration of 10 as
R. Additionally, 11 was treated with (S)-MTPA and DCC in the
presence of a catalytic amount of DMAP to give the correspond-
ing MTPA ester 12, whose diastereomeric excess was deter-
mined by 19F NMR. It was found that the ester 12 had >99%
diastereomeric excess. Accordingly, these results strongly
suggest that the SN2′ reaction proceeded in a complete anti selec-
tive fashion.
copper intermediate Int-B, then leading to an exclusive for-
mation of the α-product via reductive elimination at the less hin-
dered α-carbon (Path B).
On the other hand, it has been well known that the transfer
ability of aryl groups is much lower than alkyl groups.22 Thus,
the reductive elimination of Int-A, B or C may proceed much
more slowly, while the oxidative addition of the substrates to
Cu(I) may take place smoothly. Consequently, decomposition or
protonation (Path C) of Int-A, B, C, instead of reductive elimin-
ation, may proceed predominantly.
Mechanism
Based on the results of the stereochemical assignment, the pro-
posed mechanism for the present SN2′ reaction is outlined in
Scheme 5. Thus, when copper reagents coordinate on the double
bond of allylphosphate, oxidative addition of the phosphate to
Cu(I) takes place to form the intermediate Int-A. In this case, a
copper d orbital may interact with π* at the γ carbon as well as
σ* at the backside of the α carbon, resulting in the high anti
stereoselectivity.21
An exclusive formation of the SN2′ product in the case of
primary alkyl organometallic reagents is probably because the
primary alkyl group is less hindered and has the highly potent
transfer ability as a ligand (Path A). Though the secondary alkyl
group is bulkier than the primary alkyl group, the rate of the
alkyl transfer may be still fast, resulting in a high γ-regioselectiv-
ity. However, the sterically bulkiest tertiary alkyl group rendered
Int-A much more congested and less stable, which may isomer-
ise easily to form σ-allyl copper intermediate Int-C via π-allyl
Conclusions
In summary, we have demonstrated the SN2′ reaction of γ-fluoro-
allylic phosphates with various organocuprates. The reaction
proceeded in a highly regioselective manner to give the corre-
sponding γ-adducts in high yields. This system could be also
applied for the chiral substrate, affording the desired compound
having a fluorine atom at an asymmetric quaternary carbon
center in an optically pure form.
Experimental
General methods
Infrared spectra (IR) were determined in a liquid film on a NaCl
plate with a JASCO FT/IR-4100 type A spectrometer. H and
1
13C NMR spectra were measured with a JEOL JNM-AL 400
NMR spectrometer in a chloroform-d (CDCl3) solution with tet-
ramethylsilane (Me4Si) as an internal reference. A JEOL
JNM-AL 400 NMR spectrometer was used for determining the
yield of the products with hexafluorobenzene (C6F6). 19F NMR
(376.05 MHz) spectra were measured with a JEOL JNM-AL 400
NMR spectrometer in a chloroform-d (CDCl3) solution with tri-
chlorofluoromethane (CFCl3) as an internal standard. High-resolu-
tion mass spectra (HRMS) were taken on a JEOL JMS-700MS
spectrometer by electron impact (EI), chemical ionization (CI),
and fast atom bombardment (FAB) methods.
All chemicals were of reagent grade and, if necessary, were
purified in the usual manner prior to use. Thin-layer chromato-
graphy (TLC) was done with Merck silica gel 60 F254 plates, and
column chromatography was carried out using Wako gel C-200
as an adsorbent.
General procedure for the preparation of γ-fluoroallylic alcohol
β-Fluoro-α,β-unsaturated ester (3.42 mmol) in CH2Cl2 (6.84 mL,
0.5 M) was placed in a three-necked flask under an argon atmo-
sphere. To the mixture was added a solution of diisobutylalumi-
num hydride in n-hexane (0.98 M, 8.72 mL, 8.55 mmol) at
0 °C. After stirring for 30 min at 0 °C, a solution of 10% HCl
was added. The resulting mixture was extracted with CH2Cl2,
and the organic layers were dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting mixture was purified by
silica gel column chromatography.
Scheme 5 A plausible reaction mechanism.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8154–8163 | 8157

View Online
(Z)-3-Fluoro-3-phenyl-2-propen-1-ol (4a)
column chromatography to afford the corresponding γ-fluoro-
allylic alcohol (87 mg, 0.59 mmol, 80%).
Yield: 98%; 1H NMR (CDCl3) δ 1.47 (1H, br s), 4.46 (2H, br s),
5.67 (1H, dt, J = 36.77, 6.79 Hz), 7.34–7.41 (3H, m), 7.52–7.55
(2H, m) ppm; 13C NMR (CDCl3) δ 56.01 (d, J = 7.43 Hz),
104.75 (d, J = 14.96 Hz), 124.36 (d, J = 7.43 Hz), 128.48 (d,
J = 2.41 Hz), 129.26, 131.69 (d, J = 28.92 Hz), 158.01 (d, J =
250.50 Hz) ppm; 19F NMR (CDCl3) δ −117.71 (1F, d, J = 36.77
Hz) ppm; IR (neat) 3339, 2885, 1679, 1496, 1449, 1282, 1101,
1036, 1015 cm−1; HRMS (FAB) calcd for C9H9FO (M+)
152.0637, found 152.0641.
Ethyl 2-fluoro-4-hydroxy-2-butenoate (4d)
Combined yield: 59% (E/Z = 84/16).
E isomer. 1H NMR (CDCl3) δ 1.36 (3H, t, J = 6.99 Hz), 1.64
(1H, m), 4.29 (2H, q, J = 6.99 Hz), 6.27 (1H, dt, J = 19.98,
6.39 Hz) ppm; 19F NMR (CDCl3) δ −121.22 (1F, d, J =
19.98 Hz) ppm.
Z isomer. 1H NMR (CDCl3) δ 1.33 (3H, t, J = 6.99 Hz), 2.55
(1H, br s), 4.33 (2H, q, J = 6.99 Hz), 6.16 (1H, dt, J = 32.77,
6.39 Hz) ppm; 19F NMR (CDCl3) δ −126.73 (1F, d, J =
32.77 Hz) ppm.
(Z)-3-Cyclohexyl-3-fluoro-2-propen-1-ol (4b)
1
Yield: 83%; H NMR (CDCl3) δ 1.15–1.31 (6H, m), 1.67–1.70
(1H, m), 1.76–1.87 (4H, m), 2.04–2.13 (1H, m), 4.20–4.23 (2H,
m), 4.80 (1H, dt, J = 35.35, 6.39 Hz) ppm; 13C NMR (CDCl3)
δ 25.71, 25.88, 29.63 (d, J = 2.51 Hz), 40.30 (d, J = 24.80 Hz),
55.64 (d, J = 8.23 Hz), 102.36 (d, J = 14.06 Hz), 165.88 (d, J =
259.53 Hz) ppm; 19F NMR (CDCl3) δ −109.95 (1F, dd, J =
35.35, 14.67 Hz) ppm; IR (neat) 3330, 2930, 2856, 1702, 1451,
1313, 1284, 1161, 1014 cm−1; HRMS (FAB) calcd for C9H15FO
(M+) 158.1107, found 158.1114.
General procedure for the preparation of allylic phosphates
Allylic alcohol (1.09 mmol) in CH2Cl2 (2.2 mL) was placed in a
three-necked flask under an argon atmosphere where at 0 °C was
added DMAP (4 mg, 0.033 mmol), diethyl chlorophosphate
(0.19 mL, 1.31 mmol) followed by addition of triethylamine
(0.18 mL, 1.31 mmol). The reaction mixture was allowed to
warm to room temperature and stirred overnight. The solution
was quenched with water and after separation of the two layers,
the aqueous solution was washed with CH2Cl2 twice and the
combined organic layers were washed with brine, dried
(Na2SO4) and concentrated in vacuo. The resulting mixture was
purified by silica gel column chromatography.
(Z)-3-Fluoro-2-undecen-1-ol (4c)
Yield: 93%; 1H NMR (CDCl3) δ 0.88 (3H, t, J = 6.19 Hz),
1.27–1.29 (11H, m), 1.46–1.53 (2H, m), 2.17 (2H, dt, J = 17.58,
8.09 Hz), 4.22 (2H, br s), 4.83(1H, dt, J = 36.63, 7.19 Hz) ppm;
13C NMR (CDCl3) δ 14.03, 22.61, 25.91, 25.92, 28.90, 29.18
(d, J = 11.55 Hz), 31.79, 31.84 (d, J = 26.41 Hz), 55.62 (d, J =
8.23 Hz), 104.44 (d, J = 14.06 Hz), 162.13 (d, J = 258.73 Hz)
ppm; 19F NMR (CDCl3) δ −105.31 (1F, dt, J = 36.63, 17.58 Hz)
ppm; IR (neat) 3324, 2927, 2856, 1707, 1466, 1432, 1378,
1310, 1242, 1158, 1112, 1082, 1010 cm−1; HRMS (FAB) calcd
for C9H15FO (M+) 158.1107, found 158.1114.
(Z)-Diethyl 3-fluoro-3-phenyl-2-propenyl phosphate (2a)
1
Yield: quant.; H NMR (CDCl3) δ 1.35 (6H, dt, J = 1.20, 7.19
Hz), 4.13 (2H, q, J = 7.19 Hz), 4.14 (4H, dq, J = 7.19, 7.19 Hz),
5.67 (1H, dt, J = 34.77, 7.59 Hz), 7.37–7.39 (3H, m), 7.54–7.57
(2H, m) ppm; 13C NMR (CDCl3) δ 16.04 (d, J = 7.43 Hz),
60.40 (dd, J = 8.33, 5.82 Hz), 63.78 (d, J = 5.72 Hz), 100.59
(dd, J = 14.86, 6.63 Hz), 124.56 (d, J = 7.43 Hz), 128.52,
129.71, 131.09 (d, J = 34.24 Hz), 159.34 (d, J = 254.51 Hz)
ppm; 19F NMR (CDCl3) δ −115.02 (1F, d, J = 34.77 Hz) ppm;
31P NMR (CDCl3) δ −1.41 (1P, s) ppm; IR (neat) 3062, 2984,
2910, 1683, 1496, 1448, 1392, 1268, 1035 cm−1; HRMS (FAB)
calcd for C13H18FNaO4P (M + Na) 311.0824, found 311.0835.
Synthetic procedure for the preparation of γ-hydroxy-
α-fluoroesters
To a suspension of sodium hydride (60% in oil, 0.06 g,
1.5 mmol) in THF (4 mL) at 0 °C was added triethyl 2-fluoro-
2-phosphonoacetate (0.31 mL, 1.5 mmol). After stirring for
30 min at 0 °C, a solution of α-(tert-butyldimethylsilyloxy)acet-
aldehyde (0.17 g, 1.0 mmol) in THF (1 mL) was added. After
stirring the resulting solution for 30 min at 0 °C, the solution
was quenched with an aqueous saturated NH4Cl solution and
extracted with ethyl acetate. The organic layers were dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting
mixture was purified by silica gel column chromatography to
give the corresponding adduct (0.19 g, 0.74 mol, 74%).
To a solution of the adduct (0.19 g, 0.74 mmol) in THF
(7 mL) at room temperature was added TsOH·H2O (28 mg,
0.15 mmol) in water (0.5 mL). After stirring overnight at room
temperature, the solution was quenched with an aqueous satu-
rated NaHCO3 solution and extracted with ethyl acetate. The
organic layers were dried over anhydrous Na2SO4, and concen-
trated in vacuo. The resulting mixture was purified by silica gel
(Z)-Diethyl 3-cyclohexyl-3-fluoro-2-propenyl phosphate (2b)
Yield: 98%; 1H NMR (CDCl3) δ 1.15–1.36 (11H, m), 1.67–1.90
(5H, m), 2.04–2.12 (1H, m), 4.11 (4H, dq, J = 7.29, 7.29 Hz),
4.59–4.64 (2H, m), 4.80 (1H, dt, J = 35.57, 7.19 Hz) ppm;
13C NMR (CDCl3) δ 16.03 (d, J = 6.62 Hz), 25.76, 25.58, 29.41
(d, J = 2.41 Hz), 40.24 (d, J = 23.90 Hz), 60.25 (dd, J = 9.94,
5.82 Hz), 63.61 (d, J = 5.72 Hz), 98.60 (dd, J = 13.15, 6.53 Hz),
167.28 (d, J = 263.65 Hz) ppm; 19F NMR (CDCl3) δ −106.95
(1F, dd, J = 35.57, 14.67 Hz) ppm; 31P NMR (CDCl3) δ −1.48
(1P, s) ppm; IR (neat) 2983, 2932, 2857, 1703, 1451, 1392,
1273, 1168, 1030 cm−1; HRMS (FAB) calcd for C13H25FO4P
(M + H) 295.1474, found 295.1481.
8158 | Org. Biomol. Chem., 2012, 10, 8154–8163
This journal is © The Royal Society of Chemistry 2012

View Online
(Z)-Diethyl 3-fluoro-2-undecenyl phosphate (2c)
diethyl ether. The combined organic layers were dried over anhy-
drous Na2SO4, concentrated in vacuo. The residue was purified
by silica gel column chromatography.
1
Yield: quant.; H NMR (CDCl3) δ 0.88 (3H, t, J = 6.59 Hz),
1.27–1.36 (16H, m), 1.46–1.54 (2H, m), 2.18 (2H, dt, J = 17.58,
7.99 Hz), 4.07–4.15 (4H, m), 4.61 (2H, dd, J = 7.79, 7.79 Hz),
4.86 (1H, dt, J = 35.17, 7.79 Hz) ppm; 13C NMR (CDCl3)
δ 14.00, 16.05 (d, J = 6.63 Hz), 22.57, 25.70, 25.71, 28.81,
29.13 (d, J = 9.93 Hz), 31.75, 31.78 (d, J = 26.51 Hz), 60.16
(dd, J = 9.04, 5.72 Hz), 63.64 (d, J = 5.72 Hz), 100.62 (dd, J =
13.15, 6.58 Hz), 163.67 (d, J = 262.85 Hz) ppm; 19F NMR
(CDCl3) δ −102.25 (1F, dt, J = 35.17, 17.58 Hz) ppm; 31P NMR
(CDCl3) δ −1.40 (1P, s) ppm; IR (neat) 2929, 2857, 1709, 1467,
1392, 1277, 1166, 1098, 1034 cm−1; HRMS (FAB) calcd for
C15H30FO4P (M+) 324.1866, found 324.1875.
General procedure for the reaction of γ-fluoroallylic phosphate
with cuprate derived from organozinc reagents
To a suspension of CuCN–2LiCl (0.059 g, 0.66 mmol) in anhy-
drous THF (2 mL) was added dropwise a hexane solution of
Et2Zn (1.6 M, 0.41 mL, 0.66 mmol) at −78 °C under an argon
atmosphere. After stirring for 10 min, the mixture was warmed
to 0 °C, then stirred for 10 min. The reaction mixture was again
cooled to 0 °C, and to this mixture was added dropwise a solu-
tion of γ-fluoroallylic phosphate (0.3 mmol) in anhydrous THF
(2 mL). After 24 h, the reaction was quenched with an aqueous
saturated NH4Cl solution and the whole was extracted with
diethyl ether. The combined organic layers were dried over anhy-
drous Na2SO4, concentrated in vacuo. The residue was purified
by silica gel column chromatography.
Ethyl 4-[(diethoxyphosphinyl)oxy]-2-fluoro-2-butenoate (2d)
Combined yield: 95% (E/Z = 80/20).
E isomer. 1H NMR (CDCl3) δ 1.36 (9H, dt, J = 3.60,
7.19 Hz), 4.14 (4H, dq, J = 7.19, 7.19 Hz), 4.33 (2H, q, J =
7.19 Hz), 5.04 (2H, ddd, J = 8.79, 5.99, 2.80 Hz), 6.08 (1H, dt,
J = 17.98, 5.99 Hz) ppm; 19F NMR (CDCl3) δ −120.27 (1F, d,
J = 17.98 Hz) ppm.
3-Fluoro-3-phenyl-1-heptene ( 1a)
Yield: 50%; 1H NMR (CDCl3) δ 0.87 (3H, t, J = 7.59 Hz),
1.20–1.41 (4H, m), 1.96–2.05 (2H, m), 5.19 (1H, d, J =
11.19 Hz), 5.32 (1H, dt, J = 17.18, 1.60 Hz), 6.11 (1H, ddd, J =
17.18, 17.18, 11.19 Hz), 7.26–7.31 (1H, m), 7.34–7.36 (4H, m)
ppm; 13C NMR (CDCl3) δ 13.92, 22.80 (d, J = 0.80 Hz), 25.34
(d, J = 3.31 Hz), 39.78 (d, J = 24.00 Hz), 98.06 (d, J =
176.00 Hz), 113.96 (d, J = 11.55 Hz), 124.69 (d, J = 9.04 Hz),
127.25 (d, J = 11.71 Hz), 128.21 (d, J = 1.71 Hz), 140.30 (d,
J = 23.09 Hz), 142.67 (d, J = 23.19 Hz) ppm; 19F NMR
(CDCl3) δ −158.10 (1F, dt, J = 17.18, 21.81 Hz) ppm; IR (neat)
3062, 3030, 2958, 2872, 1603, 1495, 1448, 1409, 1380, 1226,
1102, 1071 cm−1; HRMS (FAB) calcd for C13H17F (M+)
192.1314, found 192.1315.
Z isomer. 1H NMR (CDCl3) δ 1.34 (9H, dt, J = 3.60,
7.19 Hz), 4.14 (4H, dq, J = 7.19, 7.19 Hz), 4.31 (2H, q, J =
6.79 Hz), 4.78 (2H, ddd, J = 8.79, 6.79, 2.40 Hz), 6.28 (1H, dt,
J = 31.57, 6.79 Hz) ppm; 19F NMR (CDCl3) δ −123.81 (1F, d,
J = 31.57 Hz) ppm.
General procedure for the reaction of γ-fluoroallylic phosphate
with various cuprates derived from Grignard reagent
To a suspension of CuCN (0.059 g, 0.66 mmol) in anhydrous
THF (2 mL) was added dropwise a THF solution of Grignard
reagent (0.66 mmol, prepared from RBr and magnesium) at
−78 °C under an argon atmosphere. After stirring for 10 min,
the mixture was warmed to −10 °C, then stirred for 10 min. The
reaction mixture was again cooled to −40 °C, and to this mixture
was added dropwise a solution of γ-fluoroallylic phosphate
(0.3 mmol) in anhydrous THF (2 mL). After 30 min, the reaction
was quenched with an aqueous saturated NH4Cl solution and the
whole was extracted with diethyl ether. The combined organic
layers were dried over anhydrous Na2SO4, concentrated
in vacuo. The residue was purified by silica gel column
chromatography.
3-Cyclohexyl-3-fluoro-1-heptene ( 1b)
Yield: 85%; 1H NMR (CDCl3) δ 0.90 (3H, t, J = 7.19 Hz),
0.99–1.34 (9H, m), 1.52–1.83 (8H, m), 5.15 (1H, ddd, J =
11.19, 2.00, 2.00 Hz), 5.22 (1H, dd, J = 16.99, 2.00 Hz), 5.72
(1H, ddd, J = 22.10, 16.99, 11.19 Hz) ppm; 13C NMR (CDCl3)
δ 14.03, 23.05, 25.11 (d, J = 4.12 Hz), 26.24, 26.39, 26.51
(d, J = 5.82 Hz), 35.89 (d, J = 23.09 Hz), 45.57 (d, J =
22.29 Hz), 100.07 (d, J = 176.90 Hz), 113.82 (d, J = 12.35 Hz),
138.21 (d, J = 22.29 Hz) ppm; 19F NMR (CDCl3) δ −166.41
(1F, ddt, J = 29.33, 22.10, 14.67 Hz) ppm; IR (neat) 2931, 2855,
1451, 1411, 1379, 1141 cm−1; HRMS (FAB) calcd for C13H23F
(M+) 198.1784, found 198.1787.
General procedure for the reaction of γ-fluoroallylic phosphate
with cuprate derived from organolithium reagents
To a suspension of CuCN (0.059 g, 0.66 mmol) in anhydrous
THF (2 mL) was added dropwise a hexane solution of organo-
lithium (0.66 mmol) at −78 °C under an argon atmosphere.
After stirring for 10 min, the mixture was warmed to −20 °C,
then stirred for 15 min. Then, a solution of γ-fluoroallylic phos-
phate (0.3 mmol) in anhydrous THF (2 mL) was dropwise
added. After 30 min, the reaction was quenched with an aqueous
saturated NH4Cl solution and the whole was extracted with
3-Butyl-3-fluoro-1-undecene ( 1c)
1
Yield: 89%; H NMR (CDCl3) δ 0.88 (3H, t, J = 6.79 Hz), 0.89
(3H, t, J = 6.79 Hz), 1.26–1.33 (16H, m), 1.54–1.70 (4H, m),
5.13 (1H, ddd, J = 11.19, 1.60, 1.60 Hz), 5.23 (1H, dd, J =
17.58, 1.60 Hz), 5.75 (1H, ddd, J = 20.38, 17.58, 11.19 Hz)
ppm; 13C NMR (CDCl3) δ 14.00, 14.09, 22.67, 22.99, 23.23
(d, J = 4.12 Hz), 25.41 (d, J = 5.02 Hz), 29.28, 29.51, 29.63,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8154–8163 | 8159

View Online
Ethyl 2-ethenyl-2-fluoro-7-octenote ( 1h)
31.89, 38.50 (d, J = 23.19 Hz), 38.78 (d, J = 23.09 Hz), 98.22
(d, J = 173.59 Hz), 113.88 (d, J = 12.45 Hz), 139.75 (d, J =
22.29 Hz) ppm; 19F NMR (CDCl3) δ −159.49 to −159.68 (1F,
m) ppm; IR (neat) 3095, 2928, 2857, 1647, 1467, 1412, 1379,
1340, 1260, 1132, 1075 cm−1; HRMS (FAB) calcd for C15H29F
(M+) 228.2253, found 228.2248.
1
Yield: 93%; H NMR (CDCl3) δ 1.26–1.65 (7H, m), 1.77–2.08
(4H, m), 4.25 (2H, q, J = 6.79 Hz), 4.93–5.02 (2H, m),
5.26–5.29 (1H, m), 5.48 (1H, d, J = 17.18 Hz), 5.78 (1H, m),
5.97 (1H, m) ppm; 13C NMR (CDCl3) δ 14.09, 22.33 (d, J =
2.51 Hz), 28.55, 33.38, 37.24 (d, J = 23.19 Hz), 61.70, 95.98
(d, J = 190.06 Hz), 114.58, 115.93 (d, J = 11.55 Hz), 134.99
(d, J = 21.49 Hz), 138.41, 170.17 (d, J = 26.41 Hz) ppm; 19F
NMR (CDCl3) δ −169.59 (1F, dt, J = 26.70, 19.18 Hz) ppm; IR
(neat) 3076, 2932, 2858, 1761, 1736, 1641, 1463, 1409, 1370,
1253, 1185, 1027 cm−1; HRMS (FAB) calcd for C12H19FO2
(M+) 214.1369, found 214.1362.
Ethyl 2-ethenyl-2-fluoro-3-hexanoate ( 1d)
1
Yield: 78% (in both cases of n-BuMgBr and n-BuLi); H NMR
(CDCl3) δ 0.90 (3H, t, J = 6.99 Hz), 1.22–1.48 (7H, m),
1.77–2.06 (2H, m), 4.25 (2H, q, J = 7.19 Hz), 5.25–5.28 (1H,
m), 5.47 (1H, d, J = 17.58 Hz), 5.97 (1H, ddd, J = 19.98, 17.58,
10.99 Hz) ppm; 13C NMR (CDCl3) δ 13.81, 14.11, 22.47, 24.97
(d, J = 2.51 Hz), 37.17 (d, J = 22.29 Hz), 61.69, 96.06 (d, J =
190.06 Hz), 115.86 (d, J = 11.55 Hz), 134.59 (d, J = 21.49 Hz),
170.26 (d, J = 26.51 Hz) ppm; 19F NMR (CDCl3) δ −169.56
(1F, dt, J = 19.98, 27.08 Hz) ppm; IR (neat) 2960, 2873, 1762,
1737, 1467, 1408, 1370, 1274, 1206, 1136, 1035 cm−1; HRMS
(FAB) calcd for C10H17FO2 (M+) 188.1213, found 188.1219.
Ethyl 2-benzyl-2-fluoro-3-butenoate ( 1i)
1
Yield: 53%; H NMR (CDCl3) δ 1.19 (3H, t, J = 7.39 Hz), 3.14
(1H, dd, J = 19.98, 14.79 Hz), 3.29 (1H, dd, J = 28.77, 14.79
Hz), 4.11–4.19 (2H, m), 5.27–5.30 (1H, m), 5.47 (1H, d, J =
17.18 Hz), 6.06 (1H, ddd, J = 19.18, 17.18, 10.79 Hz),
7.21–7.31 (5H, m) ppm; 13C NMR (CDCl3) δ 13.95, 43.76
(d, J = 22.39 Hz), 61.74, 95.85 (d, J = 194.27 Hz), 116.53
(d, J = 10.74 Hz), 127.14, 128.12, 130.31 (d, J = 1.71 Hz),
134.04, 134.68 (d, J = 21.49 Hz), 169.43 (d, J = 21.49 Hz) ppm;
19F NMR (CDCl3) δ −167.13 (1F, ddd, J = 28.77, 19.98,
19.18 Hz) ppm; IR (neat) 3032, 2983, 1760, 1735, 1605, 1496,
1455, 1408, 1370, 1275, 1195, 1084, 1046, 1000 cm−1; HRMS
(FAB) calcd for C13H16FO2 (M + H) 223.1134, found 223.1134.
Ethyl 2-fluoro-2-methyl-3-butenoate ( 1e)
This product was inseparable from impurities, therefore only the
peak that could be assigned was described.
1H NMR (CDCl3) δ 4.25 (2H, q, J = 6.79 Hz), 5.28 (1H, d,
J = 10.79 Hz), 5.49 (1H, d, J = 17.58 Hz), 6.03 (1H, ddd, J =
17.58, 17.58, 10.79 Hz) ppm; 19F NMR (CDCl3) δ −157.25 (1F,
dq, J = 17.58, 17.58 Hz) ppm; HRMS (FAB) calcd for
C7H12FO2 (M + H) 147.0821, found 147.0819.
Ethyl 2-fluoro-2-(1-methylethyl)-3-butenoate ( 1j)
Yield: 53% (in the case of i-PrMgBr), 55% (in the case of
(i-Pr)2Zn); 1H NMR (CDCl3) δ 0.96 (6H, dd, J = 13.59,
6.79 Hz), 1.31 (3H, t, J = 7.19 Hz), 2.21 (1H, dsept, J = 26.78,
6.79 Hz), 4.25 (2H, q, J = 7.19 Hz), 5.28–5.31 (1H, m), 5.47
(1H, d, J = 17.88 Hz), 5.93 (1H, ddd, J = 21.58, 17.88,
10.99 Hz) ppm; 13C NMR (CDCl3) δ 14.11, 15.43 (d, J = 4.12
Hz), 16.44 (d, J = 4.12 Hz), 34.45 (d, J = 22.29 Hz), 61.55,
98.37 (d, J = 195.08 Hz), 116.16 (d, J = 11.55 Hz), 134.40 (d,
J = 21.48 Hz), 170.22 (d, J = 26.51 Hz) ppm; 19F NMR
(CDCl3) δ −184.22 (1F, dd, J = 26.78, 21.58 Hz) ppm; IR (neat)
2977, 1762, 1737, 1469, 1391, 1371, 1255, 1200, 1135,
1039 cm−1; HRMS (FAB) calcd for C9H15FO2 (M+) 174.1056,
found 174.1061.
Ethyl 2-ethenyl-2-fluoro-5-phenylpentanoate ( 1f)
Yield: 97%; 1H NMR (CDCl3) δ 1.29 (3H, t, J = 7.19 Hz),
1.57–2.11 (4H, m), 2.64 (2H, t, J = 7.59 Hz), 4.24 (2H, q, J =
7.19 Hz), 5.27 (1H, m), 5.47 (1H, d, J = 16.79 Hz), 5.88–6.01
(1H, m), 7.16–7.30 (5H, m) ppm; 13C NMR (CDCl3) δ 14.02,
24.53 (d, J = 2.41 Hz), 35.33, 36.77 (d, J = 23.09 Hz), 61.69,
95.87 (d, J = 190.86 Hz), 116.01 (d, J = 11.55 Hz), 134.80 (d,
J = 21.49 Hz), 170.01 (d, J = 26.51 Hz) ppm; 19F NMR
(CDCl3) δ −169.54 (1F, dt, J = 19.98, 21.93 Hz) ppm; IR (neat)
3584, 3062, 3026, 2937, 2867, 1758, 1735, 1603, 1496, 1454,
1408, 1369, 1263, 1180, 1091, 1024 cm−1; HRMS (FAB) calcd
for C15H20FO2 (M + H) 251.1447, found 251.1468.
Ethyl 2-ethenyl-5,5-(ethylenedioxy)-2-fluoro-pentanoate ( 1g)
Ethyl 2-cyclohexyl-2-fluoro-3-butenoate ( 1k)
1
Yield: 92%; 1H NMR (CDCl3) δ 1.31 (3H, t, J = 7.19 Hz),
1.60–2.22 (4H, m), 3.82–3.98 (4H, m), 4.25 (2H, q, J = 7.19
Hz), 4.90 (1H, t, J = 4.40 Hz), 5.29–5.32 (1H, m), 5.50 (1H, d,
J = 17.58 Hz), 5.96 (1H, ddd, J = 19.58, 17.58, 10.79 Hz) ppm;
13C NMR (CDCl3) δ 14.04, 27.25 (d, J = 2.41 Hz), 31.22 (d, J =
22.29 Hz), 61.78, 64.88 (2C), 95.39 (d, J = 190.96 Hz), 103.42,
116.40 (d, J = 10.74 Hz), 134.48 (d, J = 21.49 Hz), 169.81 (d,
J = 25.60 Hz) ppm; 19F NMR (CDCl3) δ −169.80 (1F, dt, J =
19.58, 21.81 Hz) ppm; IR (neat) 2980, 2886, 1758, 1736, 1643,
1446, 1410, 1370, 1257, 1195, 1142, 1026 cm−1; HRMS (FAB)
calcd for C11H18FO4 (M + H) 233.1189, found 233.1188.
Yield: 78%; H NMR (CDCl3) δ 1.02–1.37 (8H, m), 1.52–1.67
(2H, m), 1.77–1.93 (4H, m), 4.21–4.30 (2H, m), 5.27–5.30 (1H,
m), 5.45 (1H, d, J = 17.18 Hz), 5.91 (1H, ddd, J = 21.58, 17.18,
10.79 Hz) ppm; 13C NMR (CDCl3) δ 14.12, 25.37 (d, J =
2.51 Hz), 25.92, 26.06 (d, J = 3.31 Hz), 43.85 (d, J = 20.68 Hz),
61.51, 98.27 (d, J = 194.27 Hz), 116.01 (d, J = 11.55 Hz),
134.23 (d, J = 21.59 Hz), 170.16 (d, J = 26.41 Hz) ppm;
19F NMR (CDCl3) δ −181.17 (1F, dd, J = 24.44, 21.58 Hz)
ppm; IR (neat) 2933, 2856, 1761, 1735, 1451, 1267, 1235,
1198, 1168, 1098, 1056, 1036 cm−1; HRMS (FAB) calcd for
C12H19FO2 (M+) 214.1369, found 214.1376.
8160 | Org. Biomol. Chem., 2012, 10, 8154–8163
This journal is © The Royal Society of Chemistry 2012

View Online
Ethyl 2-fluoro-5,5-dimethyl-2-hexenoate (1l)
Combined yield: 78% (E/Z = 95/5).
Subsequently, the obtained alcohol in CH2Cl2 (5 mL) was
placed in a three-necked flask under an argon atmosphere where
at 0 °C was added DMAP (11 mg, 0.091 mmol), diethyl chloro-
phosphate (0.46 mL, 3.17 mmol) followed by addition of
triethylamine (0.44 mL, 3.20 mmol). The reaction mixture was
allowed to warm to room temperature and stirred overnight. The
solution was quenched with water and after separation of the two
layers, the aqueous solution was washed with CH2Cl2 twice and
the combined organic layers were washed with brine, dried
(Na2SO4) and concentrated in vacuo. The resulting mixture was
purified by silica gel column chromatography to give the corres-
ponding γ-fluoroallylic phosphate (0.54 g, 1.8 mmol, 53%
yield).
E isomer. 1H NMR (CDCl3) δ 0.93 (9H, s), 1.34 (3H, t, J =
7.39 Hz), 2.44 (2H, dd, J = 8.19, 1.60 Hz), 4.29 (2H, q, J =
7.39 Hz), 5.97 (1H, dt, J = 22.78, 8.19 Hz) ppm; 19F NMR
(CDCl3) δ −120.74 (1F, d, J = 22.78 Hz) ppm; HRMS (FAB)
calcd for C10H18FO2 (M + H) 189.1291, found 189.1298.
Z isomer. 1H NMR (CDCl3) δ 0.93 (9H, s), 1.34 (3H, t, J =
7.39 Hz), 2.13 (2H, dd, J = 8.19, 1.60 Hz), 4.16 (2H, q, J =
7.39 Hz), 6.17 (1H, dt, J = 33.17, 8.19 Hz) ppm; 19F NMR
(CDCl3) δ −130.88 (1F, d, J = 33.17 Hz) ppm; HRMS (FAB)
calcd for C10H18FO2 (M + H) 189.1291, found 189.1298.
(S)-(E)-Ethyl 4-[(diethoxyphosphinyl)oxy]-2-fluoro-2-pentenoate
(9)
Ethyl 2-ethyl-2-fluoro-3-butenate (1m)
1
[α]2D7 = +43.0 (c 1.05, CDCl3); H NMR (CDCl3) δ 1.30–1.38
1
Yield: 68%; H NMR (CDCl3) δ 0.96 (3H, t, J = 7.19 Hz), 1.31
(9H, m), 1.48 (3H, d, J = 5.99 Hz), 4.06–4.13 (4H, m), 4.33
(2H, q, J = 7.19 Hz), 5.85 (1H, m), 5.98 (1H, m) ppm; 13C
NMR (CDCl3) δ 13.93, 16.00 (dd, J = 16.57, 1.66 Hz), 22.09
(dd, J = 5.32, 2.91 Hz), 61.97, 63.70 (dd, J = 5.82, 1.61 Hz),
69.58 (dd, J = 8.28, 4.97 Hz), 123.11 (dd, J = 19.43, 5.37 Hz),
146.60 (d, J = 262.04 Hz), 159.99 (d, J = 34.64 Hz) ppm; 19F
NMR (CDCl3) δ −121.79 (1F, d, J = 19.18 Hz) ppm; 31P NMR
(CDCl3) δ −2.69 (1P, s) ppm; IR (neat) 3482, 2986, 2937, 2911,
1731, 1674, 1447, 1396, 1337, 1332, 1276, 1229, 1151, 1097,
1036 cm−1; HRMS (FAB) calcd for C11H21FO6P (M + H)
299.1060, found 299.1060.
(3H, t, J = 6.39 Hz), 1.82–2.11 (2H, m), 4.26 (2H, q, J =
7.19 Hz), 5.27–5.30 (1H, m), 5.49 (1H, d, J = 17.18 Hz), 5.97
(1H, ddd, J = 18.78, 17.18, 10.39 Hz) ppm; 13C NMR (CDCl3)
δ 7.16 (d, J = 4.12 Hz), 14.09, 30.62 (d, J = 23.09 Hz), 61.65,
96.28 (d, J = 190.16 Hz), 116.89 (d, J = 11.55 Hz), 134.82 (d,
J = 21.49 Hz), 170.16 (d, J = 26.41 Hz) ppm; 19F NMR
(CDCl3) δ −170.16 (1F, m) ppm; IR (neat) 2957, 2925, 2854,
1738, 1714, 1647, 1464, 1377, 1261, 1033 cm−1; HRMS (FAB)
calcd for C8H14FO2 (M + H) 161.0978, found 161.0970.
Ethyl 2-fluoro-3-butenoate (6)
This product was inseparable from impurities, therefore only the
peak that could be assigned was described.
SN2′ reaction of the chiral γ-fluoroallylic phosphate
1H NMR (CDCl3) δ 1.31 (3H, t, J = 7.19 Hz), 4.27 (2H, q,
J = 7.19 Hz), 5.29 (1H, ddd, J = 47.96, 5.60, 0.80 Hz), 5.42
(1H, d, J = 10.79 Hz), 5.57 (1H, dd, J = 17.58, 0.80 Hz), 5.99
(1H, dddd, J = 17.58, 16.79, 10.79, 5.60 Hz) ppm; 19F NMR
(CDCl3) δ −190.02 (1F, dd, J = 47.96, 16.79 Hz) ppm.
To a suspension of CuCN (0.059 g, 0.66 mmol) in anhydrous
THF (2 mL) was added dropwise
a THF solution of
n-C9H19MgBr (0.66 mmol, prepared from n-C9H19Br and mag-
nesium) at −78 °C under an argon atmosphere. After stirring for
10 min, the mixture was warmed to −10 °C, then stirred for
10 min. The reaction mixture was again cooled to −40 °C, and
to this mixture was added dropwise a solution of γ-fluoroallylic
phosphate (89 mg, 0.30 mmol) in anhydrous THF (2 mL). After
30 min, the reaction was quenched with an aqueous saturated
NH4Cl solution and the whole was extracted with diethyl ether.
The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo. The residue was purified by
silica gel column chromatography to give the corresponding
SN2′ adduct (74 mg, 0.27 mmol, 91% yield).
Preparation of the chiral γ-fluoroallylic phosphate 9
To a suspension of sodium hydride (60% in oil, 0.26 g,
6.8 mmol) in THF (22 mL) at 0 °C was added triethyl 2-fluoro-
2-phosphonoacetate (1.32 mL, 6.4 mmol). After stirring for
30 min at 0 °C, a solution of the chiral aldehyde 7 (0.81 g,
4.3 mmol) in THF (5 mL) was added. After stirring the resulting
solution for 30 min at 0 °C, the solution was quenched with an
aqueous saturated NH4Cl solution and extracted with ethyl
acetate. The organic layers were dried over anhydrous Na2SO4,
and concentrated in vacuo. The resulting mixture was purified by
silica gel column chromatography to give the corresponding
adduct (0.89 g, 3.4 mmol, 77% yield).
To a solution of this adduct in THF (40 mL) at room temp-
erature was added TsOH·H2O (0.13 g, 0.68 mmol) in water
(2 mL). After stirring overnight at room temperature, the solution
was quenched with an aqueous saturated NaHCO3 solution and
extracted with ethyl acetate. The organic layers were dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting
mixture was purified by silica gel column chromatography.
(R)-Ethyl-2-fluoro-2-(1-propenyl)-undecanoate (10)
1
[α]2D4 = +29.6 (c 1.15, CHCl3); H NMR (CDCl3) δ 0.88 (3H,
t, J = 6.79 Hz), 1.25–2.04 (22H, m), 4.21–4.28 (2H, m),
5.55–5.64 (1H, m), 5.88 (1H, dq, J = 14.39, 6.49 Hz) ppm;
13C NMR (CDCl3) δ 14.02, 14.09, 17.61, 22.60, 22.85, 22.89,
29.21, 29.30, 29.75 (d, J = 3.31 Hz), 31.80, 37.67 (d, J = 22.29
Hz), 61.47, 95.71 (d, J = 187.65 Hz), 127.44 (d, J = 10.74 Hz),
128.17 (d, J = 20.68 Hz), 170.70 (d, J = 26.41 Hz) ppm;
19F NMR (CDCl3) δ −164.68 (1F, dt, J = 33.49, 18.33 Hz) ppm;
IR (neat) 2926, 2855, 1762, 1738, 1406, 1370, 1259, 1136,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8154–8163 | 8161

View Online
1027 cm−1; HRMS (FAB) calcd for C16H30FO2 (M + H)
273.2230, found 273.2229.
22.68, 29.26, 26.45, 26.47, 30.00, 31.84, 32.59 (d, J =
21.28 Hz), 55.43, 64.70 (d, J = 25.60 Hz), 68.38 (d, J = 28.11
Hz), 96.78, 97.37 (d, J = 171.99 Hz) ppm; 19F NMR (CDCl3)
δ −170.69 (1F, tt, J = 36.60, 18.30 Hz) ppm.
Determination of the stereochemistry
The SN2′ product 10 (0.49 g, 1.81 mmol) dissolved in CH2Cl2
(5 mL) was cooled to −78 °C and then ozone gas was bubbled
into the solution. After the solution turned blue, argon gas was
bubbled into the reaction mixture at that temperature. Dimethyl
sulfide (0.20 mL, 2.72 mmol) was added to the mixture, which
was allowed to warm to room temperature for 1 h. To this solu-
tion was added water and after separation of the two layers,
the aqueous solution was washed with CH2Cl2 and the
combined organic layers were washed with brine, dried (MgSO4)
and concentrated under vacuum. The resulting mixture was
purified by flash chromatography to give the corresponding
α-fluoroaldehyde.
To a solution of the aldehyde in EtOH (15 mL) was added
NaBH4 (0.082 g, 2.17 mmol) at 0 °C. After stirring for 30 min
at 0 °C, aqueous 10% HCl solution was slowly added to the
reaction mixture and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to afford the
corresponding alcohol (0.41 g, 1.58 mmol).
To a solution of this alcohol in CH2Cl2 (15 mL) was added
DIPEA (1.30 mL, 7.5 mmol) and MOMCl (0.50 mL,
6.75 mmol) successively at room temperature. After the reaction
was completed, saturated aqueous NaCl solution was slowly
added to the reaction mixture and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chrom-
atography to afford the MOM ether (0.48 g, 1.56 mmol).
To a solution of this MOM ether in CH2Cl2 (3 mL) was added
a solution of diisobutylaluminum hydride in n-hexane (1.02 M,
6.14 mL, 6.24 mmol) at −78 °C. After stirring for 2 h at
−78 °C, MeOH was slowly added and then water was added to
the reaction mixture. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by flash chromatography to give the corresponding
aldehyde.
Notes and references
1 For review, see: (a) S. Purser, P. R. Moore, S. Swallow and
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330; (b) D. O’Hagan,
Chem. Soc. Rev., 2008, 37, 308–319; (c) K. Müller, C. Faeh and
F. Diederich, Science, 2007, 317, 1881–1886; (d) V. A. Soloshonok,
K. Mikami, T. Yamazaki, J. T. Welch and J. F. Honek, Current Fluoro-
organic Chemistry, American Chemical Society, Washington, DC, 2007;
(e) K. K. Laali, Advance in Organic Synthesis, Bentham Science Publi-
cations Ltd., Hilversum, 2006; (f) K. L. Kirk, J. Fluorine Chem., 2006,
127, 1013–1029; (g) J. P. Bégué and D. Bonnet-Delpon, J. Fluorine
Chem., 2006, 127, 992–1012; (h) C. Isanbor and D. O’Hagan, J. Fluorine
Chem., 2006, 127, 303–319; (i) D. O’Hagan and H. S. Rzepa, Chem.
Commun., 1997, 645–652.
2 (a) X. Xu, T. Henninger, D. Abbanat, K. Bush, B. Foleno, J. Hilliard and
M. Macielag, Bioorg. Med. Chem. Lett., 2005, 15, 883–887;
(b) C.-H. Liang, S. Yao, Y.-H. Chiu, P. Y. Leung, N. Robert, J. Seddon,
P. Sears, C.-K. Hwang, Y. Ichikawa and A. Romero, Bioorg. Med. Chem.
Lett., 2005, 15, 1307–1310; (c) H.-W. Man, L. G. Corral, D. I. Stirling
and G. W. Muller, Bioorg. Med. Chem. Lett., 2003, 13, 3415–3417;
(d) T. Fujiwara, K. Omata, K. Kabuto, C. Kabuto, T. Takahashi,
M. Segawa and Y. Takeuchi, Chem. Commun., 2001, 2694–2695;
(e) T. Takahashi, A. Fukushima, Y. Tanaka, Y. Takeuchi, K. Kabuto and
C. Kabuto, Chem. Commun., 2000, 787–788; (f) Y. Takeuchi,
T. Shiragami, K. Kimura, E. Suzuki and N. Shibata, Org. Lett., 1999, 1,
1571–1573; (g) Y. Takeuchi, M. Konishi, H. Hori, T. Takahashi,
T. Kometani and K. L. Kirk, Chem. Commun., 1998, 365–366.
3 (a) L. Hintermann and A. Togni, Angew. Chem., Int. Ed., 2000, 39,
4359–4362; (b) S. Piana, I. Devillers, A. Togni and U. Rothlisberger,
Angew. Chem., Int. Ed., 2002, 41, 979–982; (c) R. Frantz,
L. Hintermann, M. Perseghini, D. Broggini and A. Togni, Org. Lett.,
2003, 5, 1709–1712; (d) H. Ibrahim and A. Togni, Chem. Commun.,
2004, 1147–1155; (e) P. Y. Toullec, I. Devillers, R. Frantz and A. Togni,
Helv. Chim. Acta., 2004, 87, 2706–2711.
4 (a) N. Shibata, E. Suzuki and Y. Takeuchi, J. Am. Chem. Soc., 2000, 122,
10728–10729; (b) N. Shibata, E. Suzuki, T. Asahi and M. Shiro, J. Am.
Chem. Soc., 2001, 123, 7001–7009; (c) N. Shibata, J. Kohno, K. Takai,
T. Ishimaru, S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem., Int.
Ed., 2005, 44, 4204–4207; (d) D. S. Reddy, N. Shibata, J. Nagai,
S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem. Int., Ed., 2008,
47, 164–168; (e) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda,
S. Nakamura, T. Toru and M. Shiro, Angew. Chem., Int. Ed., 2008, 47,
4157–4161.
5 (a) D. Cahard, C. Audouard, J.-C. Plaquevent and N. Roques, Org. Lett.,
2000, 2, 3699–3701; (b) B. Mohar, J. Baudoux, J.-C. Plaquevent and
D. Cahard, Angew. Chem., Int. Ed., 2001, 40, 4214–4216; (c) B. Mohar,
J. Baudoux, J.-C. Plaquevent and D. Chard, Tetrahedron Lett., 2005, 46,
5029–5031.
6 (a) Y. Hamashima, K. Yagi, H. Takano, L. Tamás and M. Sodeoka,
J. Am. Chem. Soc., 2002, 124, 14530–14531; (b) Y. Hamashima,
T. Suzuki, H. Takano, Y. Shimura and M. Sodeoka, J. Am. Chem. Soc.,
2005, 127, 10164–10165; (c) T. Suzuki, T. Goto, Y. Hamashima and
M. Sodeoka, J. Org. Chem., 2007, 72, 246–250; (d) Y. Hamashima,
T. Suzuki, Y. Shimura, T. Shimizu, N. Umebayashi, T. Tamura,
N. Sasamoto and M. Sodeoka, Tetrahedron Lett., 2005, 46, 1447–1450;
(e) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, Y. Tsuchiya,
K.-I. Moriya, T. Goto and M. Sodeoka, Tetrahedron, 2006, 62,
7168–7179.
To a solution of this aldehyde in EtOH (15 mL) was added
NaBH4 (0.073 g, 1.93 mmol) at 0 °C. After stirring for 30 min
at 0 °C, saturated aqueous 10% HCl solution was slowly added
to the reaction mixture and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to give the
desired compound (0.27 g, 1.03 mmol, 57% yield).
7 (a) D. Y. Kim and E. J. Park, Org. Lett., 2002, 4, 545–547; (b) E. J. Park,
H. R. Kim, C. U. Joung and D. Y. Kim, Bull. Korean Chem. Soc., 2004,
25, 1451–1452.
8 M. Nakamura, A. Hajra, K. Endo and E. Nakamura, Angew. Chem., Int.
Ed., 2005, 44, 7248–7251.
9 D. D. Steiner, N. Mase and C. F. Barbas III, Angew. Chem., Int. Ed.,
2005, 44, 3706–3710.
10 (a) L. Bernard and K. A. Jørgensen, Chem. Commun., 2005, 1324–1326;
(b) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard and
K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039–6052.
(S)-2-Fluoro-2-methoxymethoxymethylundecan-1-ol (11)
Known compound: [α]2D4 = +6.4 (c 0.55, CHCl3); 1H NMR
(CDCl3) δ 0.88 (3H, t, J = 6.39 Hz), 1.10–1.45 (14H, m),
1.60–1.80 (2H, m), 2.0–2.1 (1H, m), 3.39 (3H, s), 3.62–3.80
(4H, m), 4.66 (2H, s) ppm; 13C NMR (CDCl3) δ 14.08, 22.64,
8162 | Org. Biomol. Chem., 2012, 10, 8154–8163
This journal is © The Royal Society of Chemistry 2012

View Online
11 J. Nie, H.-W. Zhu, H.-F. Cui, M.-Q. Hua and J.-A. Ma, Org. Lett., 2007,
9, 3053–3056.
4651–4654; (b) T. Yamazaki, H. Umetani and T. Kitazume, Isr. J. Chem.,
1999, 39, 193–205; (c) T. Yamazaki, H. Umetani and T. Kitazume, Tetra-
hedron Lett., 1997, 38, 6705–6708.
12 (a) K. Shibatomi, K. Futatsugi, F. Kobayashi, S. Iwasa and H. Yamanato,
J. Am. Chem. Soc., 2010, 132, 5625–5627; (b) K. Shibatomi and
H. Yamamoto, Angew. Chem., Int. Ed., 2008, 47, 5796–5798.
13 X. Wang, Q. Lan, S. Shirakawa and K. Maruoka, Chem. Commun., 2010,
46, 321–323.
14 For reviews, see: (a) J.-A. Ma and D. Cahard, Chem. Rev., 2004, 104,
6119–6146, and references cited therein. (b) M. Oestreich, Angew. Chem.,
Int. Ed., 2005, 44, 2324–2327; (c) P. M. Pihko, Angew. Chem., Int. Ed.,
2006, 45, 544–547; (d) G. K. S. Prakash and P. Beier, Angew. Chem., Int.
Ed., 2006, 45, 2172–2174; (e) C. Bobbio and V. Gouverneur, Org. Biomol.
Chem., 2006, 4, 2065–2075; (f) N. Shibata, T. Ishimaru, S. Nakamura and
T. Toru, J. Fluorine Chem., 2007, 128, 469–483; (g) V. A. Brunet and
D. O’Hagan, Angew. Chem., Int. Ed., 2008, 47, 1179–1182.
16 (a) P. Albert and J. Cousseau, J. Chem. Soc., Chem. Commun., 1985,
961–962; (b) M. Yoshida, A. Komada and S. Hara, Tetrahedron, 2006,
62, 8636–8645.
17 M. Kimura, T. Yamazaki, T. Kitazume and T. Kubota, Org. Lett., 2004,
25, 4651–4654.
18 I. Azumaya, D. Uchida, T. Kato, A. Yokoyama, A. Tanatani,
H. Takayanagi and T. Yokozawa, Angew. Chem., Int. Ed., 2004, 43,
1360–1363.
19 J. A. Marshall, M. M. Yanik, N. D. Adams, K. C. Ellis and
H. R. Chobanian, Org. Synth., 2005, 81, 157–170.
20 K. Okubo, S. Masauji and G. Kou, JP Patent, 2004-331649.
21 E. J. Corey and N. W. Boaz, Tetrahedron Lett., 1984, 25, 3063–3066.
22 (a) B. H. Lipshutz, R. S. Wilhelm, J. A. Kozlowski and D. Parker, J. Og.
Chem., 1984, 49, 3928–3938; (b) B. H. Lipshutz, R. S. Wilhelm and
J. A. Kozlowski, Tetrahedron, 1984, 40, 5005–5038.
15 The SN2′ reaction of γ-trifluoromethylated allylic alcohol derivatives with
various organocuprates has been reported. See: (a) M. Kimura,
T. Yamazaki, T. Kitazume and T. Kubota, Org. Lett., 2004, 25,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8154–8163 | 8163