Preparation of δ-fluorinated homoallylic alcohol derivatives via regioselective hydride reduction of allylic alcohol derivatives

Article abstract of DOI:10.1016/S0022-1139(02)00150-1

δ-Fluoro and δ,δ-difluorohomoallylic alcohol derivatives can be efficiently prepared by LiAlH₄ reduction of the δ,δ-difluoroallylic alcohols and the γ-chlorodifluoromethylallylic alcohols, respectively, through regioselective SN2′ reaction, in

Full text of DOI:10.1016/S0022-1139(02)00150-1

Journal of Fluorine Chemistry 117 (2002) 143–148
Preparation of d-fluorinated homoallylic alcohol derivatives via
regioselective hydride reduction of allylic alcohol derivatives
Yuko Nakamuraa, Midori Okadaa, Hiroaki Horikawaa, Takeo Taguchib,*
aTokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
bSchool of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 20 April 2002; received in revised form 18 May 2002; accepted 20 May 2002
Dedicated to Professor Lev M. Yagupolskii on the occasion of his 80th birthday.
Abstract
d-Fluoro and d,d-difluorohomoallylic alcohol derivatives can be efficiently prepared by LiAlH4 reduction of the d,d-difluoroallylic alcohols
and the g-chlorodifluoromethylallylic alcohols, respectively, through regioselective SN20 reaction, in which the free hydroxyl group is
essential for the reaction to proceed.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluorohomoallyl alcohol; Difluorohomoallyl alcohol; Trimethylaluminum; Lithiumaluminum hydride
1. Introduction
fluoroalkene depsipeptide or peptide isosteres [8,9], since
fluoroolefin is recognized to be an ideal nonhydrolizable
steric and electronic mimic for an amide bond [8,15]. For the
synthesis of compound 2, hydride reduction of d,d-difluoro-
allylic alcohols 11 was conducted under a variety of reaction
conditions. Results are summarized in Table 1. As shown in
entries 2 and 3, with the e-hydroxylated substrate E-1a, on
using aluminum hydride reagent such as LiAlH4 or DIBAL,
SN20 hydride reduction proceeded to give 2a in moderate
yield (47 and 42%, respectively) along with the formation of
unidentified by-products. The stereoselectivity of the olefin
part of 2a was also moderate in Z-preferential manner, thus
Z=E ¼ 2:0 for LiAlH4 and 3.5 for DIBAL, respectively. We
found that the addition of trimethylaluminum (2.5 eq.)
resulted in clean reaction to increase in the chemical yield
(87%) and the Z-selectivity (Z=E ¼ 5:0) as shown in entry 1.
In comparison with the E isomer E-1a, reactivity of the
corresponding Z isomer Z-1a was found to be lower result-
ing in a requirement of a long reaction time to consume the
starting material and the Z-selectivity of the product 2a
was also lowered (entry 1 versus entry 4 and entry 2 versus
entry 5, respectively). Similarly with the substrate E-1b
(entry 6 versus entries 7, 8) and E-1c (entry 9 versus entry
10), the use of Me3Al as an additive afforded better results
with respect to the product yield and the Z-selectivity.
It is well known that the introduction of fluorine atom into
organic molecules brings about the strong modification of
their chemical, physical and biological properties. Therefore,
fluoro organic compounds attract considerable attention par-
ticularly in the field of medicinal chemistry and material
science [1–5]. Fluorinated olefins are an important class of
compounds as can be applied to enzyme inhibitors [6,7], bio-
isosteres of carboxamides [8,9] and building blocks [10,11],
and development of new methods for the synthesis of fluor-
oolefins has been extensively investigated [12–14]. In this
paper, we report the synthesis of d-fluorohomoallylic alcohol
derivatives 2 and d,d-difluorohomoallylic alcohol derivatives
5 or 8 by LiAlH4 reduction of the difluoroallylic alcohols 1
and the chlorodifluoromethylenoates 3 or enones 7, respec-
tively, in which the free hydroxyl group to form an alkoxyalu-
minum intermediate is essential for the reaction to proceed.
2. Results and discussion
d-Fluorohomoallylic alcohol derivative (e.g. 2aꢀ2c) hav-
ing another hydroxyl group at e-position or an amino group
at this position should be a useful synthetic intermediate for
* Corresponding author. Tel.: þ81-426-76-3257; fax: þ81-426-76-3257.
E-mail address: taguchi@ps.toyaku.ac.jp (T. Taguchi).
1 d,d-Difluoroallylic alcohol derivatives 1 were prepared by DIBAL
reduction of the corresponding g,g-difluoroenoates, see ref. [9].
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 5 0 - 1

144
Y. Nakamura et al. / Journal of Fluorine Chemistry 117 (2002) 143–148
Table 1
Preparation of d-fluorohomoallylic alcohol derivatives
Entry
1
R
Reagent/additive
Time (h)
2
Yield (%)
Z/E ratio
1
2
E-1a
Ph
LiAlH4/Me3Al
LiAlH4
8
5
2a
87
47
42
76
65
90
71
46
84
77
89
79
5.0
2.0
3.5
3.6
1.5
4.4
2.0
3.3
4.3
2.2
2.1
1.1
3
DIBAL
2.5
22
20
4
4
Z-1a
E-1b
Ph
LiAlH4/Me3Al
LiAlH4
2a
2b
5
6
PhCH2CH2
LiAlH4/Me3Al
LiAlH4
7
6
8
DIBAL
LiAlH4/Me3Al
LiAlH4
6
9
E-1c
Z-1c
PhCH2
PhCH2
5
2c
2c
10
11
12
6
LiAlH4/Me3Al
LiAlH4
23
23
Moreover, a similar effect of the olefin geometry of the
starting substrate on the reactivity and the Z-selectivity of
the product was also observed as can be seen in the reaction
of E-1c and Z-1c (entries 9, 10 versus entries 11, 12).
To see the effect of free hydroxyl groups in the substrate
1a on the reactivity and stereoselectivity in the hydride
reduction, we examined the reaction of the primary hydroxyl
group protected substrate 1d and the e-hydroxyl group
deleted substrate 1e (Scheme 1). Selective silylation of
the primary hydroxyl group of the diol 1a with tert-butyl-
diphenylsilyl chloride (1.2 eq.) and imidazole in DMF gave
1d. Under the similar reaction conditions employed for 1a
(LiAlH4/Me3Al or LiAlH4 alone in THF, rt, 5 h) no reaction
occurred and most of the starting material 1d was recovered.
Thus, the free allylic alcohol moiety is likely to be essential
for the reaction to proceed. This was further supported by the
following results. With the allylic alcohol lacking e-hydro-
xyl group 1e, both LiAlH4/Me3Al and LiAlH4 provided the
SN20 hydride reduction product 2e in 90 and 45% yield,
respectively (Scheme 1). In the LiAlH4 reduction of 1e,
reaction proceeded more slowly than that in the presence of
Me3Al and an appreciable amount of 1e (43%) was recov-
ered. In both cases reaction proceeded almost non-stereo-
seletively (Z=E ¼ 1:2 ꢀ 1:4), while Z/E ratio in the reaction
of 1a was up to 5:1 (Table 1, entry 1).
From these results and on the basis of the relatively strong
fluorine–aluminum coordination [9,16–18], we assume that
(1) the formation of an alkoxyaluminum form A or B by the
reaction of the aluminum hydride reagent with the primary
hydroxyl group is the first step, then the hydride transfer
efficiently occurs intramolecularly to give the d-fluoroho-
moallyl alcohol derivatives 2aꢀ2c or 2e, since no reaction
occurred with the O-silyl-protected substrate 1d. (2) The
role of Me3Al as an additive to increase in chemical yield
possibly caused by the coordination of a fluorine atom to
aluminum to facilitate the substitution reaction. Further-
more, (3) in the case of e-hydroxylated substrate 1aꢀ1c,
the formation of the five membered complex form A, in
which trans stereochemistry of the substituent R and allylic
alcohol part should be predominant due to the steric reason,
would not only facilitate the reaction rate but also enhance
the Z-selectivity of the product (see Fig. 1).
Next, we examined the hydride reduction of b-chlorodi-
fluoromethyl or b-trifluoromethylenoates 3 to obtain d,d-
difluorohomoallylic alcohol derivatives 5. As shown in
Table 2, with the chlorodifluoromethyl derivative 3a, 3b,
Fig. 1. Schematic roles of the hydroxyl groups on the reactivity and
selectivity.
Scheme 1. Effect of the hydroxyl group.

Y. Nakamura et al. / Journal of Fluorine Chemistry 117 (2002) 143–148
145
Table 2
Hydride reduction of enoates 3
Entry
3
R
X
Reagent
Solvent
Temperature
Time (h)
4
Yield (%)
5
Yield (%)
1
2
3
4
5
6
3a
Ph
Cl
DIBAL
DIBAL
LiAlH4
LiAlH4
DIBAL
LiAlH4
Et2O
THF
Et2O
THF
Et2O
Et2O
rt
1
4a
100
–
5a
–
100
73
68
–
60 8C
rt
1.5
20
–
3a0
3b
Ph
F
rt
20
–
PhCH2CH2
Cl
ꢁ78 8C
0.5
1.5
4b
96
–
5b
rt
87
Scheme 2.
while DIBAL reduction at low temperature is suitable to
reduce the ester group to the alcohol form 4a, 4b in excellent
yield (entries 1, 5), LiAlH4 reduction at room temperature
provided the difluorohomoallyl alcohol derivative 5a, 5b in
good yield (entries 3 and 6). Trifluoromethyl derivative 3a0
and 3c were also used in LiAlH4 reduction leading to d,d-
difluorohomoallylic alcohol derivative 5a (68%, entry 4) and
5c (71%, Scheme 2), respectively. In the case of 3c, further
reduction of the difluoride 5c to monofluorinated product 6
competitively proceeded [19] (Scheme 2).
formation of an alkoxyaluminum intermediate similar to B
should be essential for the reaction to proceed, since the
hydroxyl-protected substrate 4b0 did not react with LiAlH4
at all, while the allyl alcohol 4b gave the difluorohomoallyl
alcohol 5b in a high yield (92%) under the similar reaction
conditions (Scheme 3).
Examples of hydride reduction of b-chlorodifuoromethy-
lenone 7a, 7b or b-trifluoromethylenone 7c are shown in
Scheme 4. LiAlH4 reduction of these substrates provided
terminally difluorinated secondary homoallylic alcohol deri-
vatives 8aꢀ8c in good yields. It should be noted that a
moderate diastereoselectivity was observed in the reaction
of a-substituted substrate 7c to give a mixture of diaster-
eomers 8c in a ratio of 5:1.
As in the cases of hydride reduction of d,d-difluoroallyl
alcohol 1 mentioned earlier, the free hydroxyl group for the
Similar reductive elimination of a fluoride in the hydride
reduction of b,b-bis(trifluoromethyl)acrylate or enones were
reported, in which strong electron-withdrawing nature of
geminal trifluoromethyl groups makes the double bond very
electrophilic [20,21].
In conclusion, d-fluoro- and d,d-difluorohomoallylic
alcohol derivatives can be efficiently prepared by LiAlH4
reduction of d,d-difluoroallylic alcohols and the g-chlorodi-
fluoromethylallylic alcohols formed from the corresponding
enoates or enones, respectively, in which the free hydroxyl
group to form the alkoxyaluminum intermediate is essential
for the reaction to proceed.
Scheme 3.
3. Experimental details
General: 1H- and 13C-NMR spectra were taken on a
Brucker AM400 or a Varian Gemini-300 spectrometer,
and chemical shifts were reported in parts per million
(ppm) using CHCl3 (7.26 ppm) in CDCl3 for 1H-NMR,
Scheme 4. Hydride reduction of enones 7.

146
Y. Nakamura et al. / Journal of Fluorine Chemistry 117 (2002) 143–148
and CDCl3 (77.01 ppm) for 13C-NMR as an internal stan-
dard, respectively. 19F-NMR spectra were taken on a
Brucker AM400 spectrometer, and chemical shifts were
reported in parts per million (ppm) using benzotrifluoride
as a standard. Infrared spectra (IR) were recorded on a
Perkin-Elmer FTIR-1710 infrared spectrophotometer. Mass
spectra (MS) were obtained on a Hitachi M-80 or VG Auto
spec. Medium pressure liquid chromatography (MPLC) was
performed using prepacked column (silica gel, 50 mm) with
UV detector.
J ¼ 249 Hz), ꢁ48.46 (1F, dt, J ¼ 249, 12 Hz). IR (CHCl3):
3620, 3460, 2924, 1732, 1682 cmꢁ1. MS (EI) m/z; 228 (Mþ),
210 (Mþ–H2O), 190, 121. HRMS. Calcd. for C12H14O2F2
(Mþ): 228.0962. Found: 228.0954.
3.2. Typical procedure for hydride reduction of 1
in the presence of Me3Al
A mixture of E-1a (180 mg, 0.85 mmol), LiAlH4 (129 mg,
3.4 mmol) and trimethylaluminum (1 M hexane solution,
1.7 ml, 1.7 mmol) in THF (6 ml) was stirred at room tem-
perature for 8 h. After the reaction mixture was quenched by
the addition of 5% HCl followed by the extractive workup
(AcOEt), the residue was purified by silica gel column
chromatography (hexane: AcOEt ¼ 2:3) to give an unsepar-
able Z, E mixture (Z=E ¼ 5) of 2a (145 mg, 87%).
3.1. Preparation of (E)-4,4-difluoro-5-substituted-2-
pentene-1,5-diol E-1
Under an argon atmosphere, a mixture of ethyl (E)-4,4-
difluoro-5-hydroxy-5-substituted-2-pentenoate [9] (5 mmol)
and DIBAL (1 M hexane solution, 15 mmol) in THF was
stirred at room temperature for 3 h. The reaction mixture
was quenched by the addition of 5% HCl and extracted with
Et2O. The organic extract was dried over MgSO4, then
concentrated under vacuum. The residue was purified by
silica gel column chromatography to give E-1.
(E)- and (Z)-2-Fluoro-1-phenyl-2-pentene-1,5-diol (2a):
colorless oil. 1H-NMR (400 MHz, CDCl3) d; 2.25–2.36 (2H,
m), 3.05 (1H, brs), 3.58 (2H, t, J ¼ 6:2 Hz), 4.18 (0.83H,
brs), 4.45 (0.17H, brs), 4.95 (0.83H, dt, J ¼ 36:9, 7.6 Hz),
5.15 (0.83H, d, J ¼ 13:1 Hz), 5.20 (0.17H, ddd, J ¼ 21:1,
8.9, 8.0 Hz), 5.53 (0.17H, d, J ¼ 24:7 Hz), 7.25–7.48 (5H,
m). 13C-NMR (100.6 MHz, CDCl3) d; 26.8 (d, J ¼ 3:4 Hz),
61.5, 72.5 (d, J ¼ 31:8 Hz), 103.7 (d, J ¼ 13:2 Hz), 126.6,
128.1, 128.4, 139.4, 161.6 (d, J ¼ 258:5 Hz) for (Z)-2a; d;
27.8 (d, J ¼ 8:3 Hz), 61.2, 68.6 (d, J ¼ 28:8 Hz), 105.1 (d,
J ¼ 21:2 Hz), 126.2, 127.9, 128.1, 139.2, 160.1 (d,
J ¼ 250:7 Hz) for (E)-2a. 19F-NMR (376.5 MHz, CDCl3)
d; ꢁ54.09 (0.17F, dd, J ¼ 24, 21 Hz), ꢁ57.72 (0.83F, dd,
J ¼ 37, 13 Hz). IR (neat): 3000–3700, 3031, 2954, 2884,
(E)-4,4-Difluoro-5-phenyl-2-pentene-1,5-diol
(E-1a):
1
98% yield. Colorless oil. H-NMR (400 MHz, CDCl3) d;
2.66 (1H, brs), 3.62 (1H, brs), 4.10 (2H, brs), 4.84 (1H, t,
J ¼ 9:6 Hz), 5.73–5.85 (1H, m), 6.07–6.17 (1H, m), 7.26–
7.43 (5H, m). 13C-NMR (100.6 MHz, CDCl3) d; 61.6, 75.8
(t, J ¼ 30:5 Hz), 119.7 (t, J ¼ 244:3 Hz), 121.5 (t,
J ¼ 25:4 Hz), 127.7, 128.2, 128.7, 136.2 (d, J ¼ 2:7 Hz),
136.6 (t, J ¼ 8:2 Hz). 19F-NMR (376.5 MHz, CDCl3) d;
ꢁ41.61 (1F, d, J ¼ 247 Hz), ꢁ45.09 (1F, dt, J ¼ 247,
1705 cmꢁ1
.
11 Hz). IR (neat): 3622, 3150–3600, 2902, 1683 cmꢁ1
.
(E)- and (Z)-4-Fluoro-7-phenyl-3-heptene-1,5-diol (2b):
(E)-2b: colorless crystals; mp 38–39 8C. 1H-NMR
(400 MHz, CDCl3) d; 2.02–2.12 (2H, m), 2.21–2.27 (2H,
m), 2.74 (2H, t, J ¼ 7:9 Hz), 3.57–3.61 (1H, m), 3.70–3.73
(1H, m), 4.46 (1H, dt, J ¼ 26:0, 7.1 Hz), 5.21 (1H, dt,
J ¼ 21:3, 8.7 Hz), 7.22–7.35 (5H, m). 13C-NMR
(100.6 MHz, CDCl3) d; 27.8 (d, J ¼ 8:8 Hz), 31.6, 34.3,
61.2 (d, J ¼ 2:2 Hz), 65.9 (d, J ¼ 28:7 Hz), 105.0 (d,
MS (EI) m/z; 196 (Mþ–H2O), 177, 107. HRMS. Calcd.
for C11H10OF2 (Mþ–H2O): 196.0700. Found: 196.0712.
(E)-4,4-Difluoro-7-phenyl-2-heptene-1,5-diol
(E-1b):
1
91% yield. Colorless oil. H-NMR (400 MHz, CDCl3) d;
1.70–1.84 (1H, m), 1.90–2.04 (1H, m), 2.60–2.74 (1H, m),
2.84–2.96 (1H, m), 3.45 (1H, s), 3.69 (1H, s), 3.74 (1H, m),
4.20 (2H, s), 5.80–5.96 (1H, m), 6.18–6.30 (1H, m), 7.21–
7.32 (5H, m). 13C-NMR (100.6 MHz, CDCl3) d; 31.5, 61.5,
72.7 (t, J ¼ 30:2 Hz), 120.5 (t, J ¼ 243:3 Hz), 121.6 (t,
J ¼ 25:6 Hz), 126.0, 128.4, 136.1 (t, J ¼ 8:4 Hz), 141.1.
19F-NMR (376.5 MHz, CDCl3) d; ꢁ42.42 (1F, d,
J ¼ 248 Hz), ꢁ47.98 (1F, d, J ¼ 248 Hz). IR (CHCl3):
3622, 2932, 2866, 1683 cmꢁ1. MS (EI) m/z; 242 (Mþ),
224 (Mþ–H2O), 206, 117. HRMS. Calcd. for C13H16O2F2
(Mþ): 242.1118. Found: 242.1104.
J ¼ 21:5 Hz),
125.9,
128.4,
141.3,
161.2
(d,
J ¼ 254:8 Hz). 19F-NMR (376.5 MHz, CDCl3) d; ꢁ57.52
(1F, dd, J ¼ 26, 21 Hz). IR (CHCl3): 3622, 3436, 2962,
2884, 1698 cmꢁ1. MS (EI) m/z; 224 (Mþ), 206 (Mþ–H2O),
188, 105. HRMS. Calcd. for C13H17O2F (Mþ): 224.1213.
Found: 224.1227. (Z)-2b: colorless oil. 1H-NMR (400 MHz,
CDCl3) d; 1.98–2.06 (2H, m), 2.33–2.43 (2H, m), 2.71–2.82
(2H, m), 3.64–3.71 (2H, m), 4.12 (1H, dt, J ¼ 16:5, 6.7 Hz),
4.91 (1H, dt, J ¼ 37:5, 7.5 Hz), 7.22–7.35 (5H, m). 13C-
NMR (100.6 MHz, CDCl3) d; 26.8 (d, J ¼ 3:8 Hz), 31.5,
35.1, 61.6, 69.8 (d, J ¼ 30:2 Hz), 103.0 (d, J ¼ 13:5 Hz),
125.9, 128.4, 128.4, 141.4, 161.1 (d, J ¼ 259:0 Hz). 19F-
NMR (376.5 MHz, CDCl3) d; ꢁ61.06 (1F, dd, J ¼ 38,
17 Hz). IR (CHCl3): 3620, 3416, 3024, 3004, 2960, 2884,
1710 cmꢁ1. MS (EI) m/z; 225 (Mþ þ 1), 224 (Mþ), 206
(Mþ–H2O), 188. HRMS. Calcd. for C13H17O2F (Mþ):
224.1213. Found: 224.1215.
(E)-4,4-Difluoro-6-phenyl-2-hexene-1,5-diol (E-1c): 97%
1
yield. Colorless oil. H-NMR (400 MHz, CDCl3) d; 2.58
(1H, brs), 2.69 (1H, dd, J ¼ 14:2, 10.4 Hz), 2.90 (1H, d,
J ¼ 8:0 Hz), 3.03 (1H, dd, J ¼ 14:2, 2.4 Hz), 3.98 (1H, m),
4.23 (1H, s), 5.92–5.96 (1H, m), 6.29–6.34 (1H, m), 7.24–
7.36 (5H, m). 13C-NMR (100.6 MHz, CDCl3) d; 36.4, 61.7,
74.6 (t, J ¼ 30:3 Hz), 120.2 (t, J ¼ 243:5 Hz), 121.6 (t,
J ¼ 25:4 Hz), 126.7, 128.5, 129.4, 136.3 (t, J ¼ 8:4 Hz),
137.3. 19F-NMR (376.5 MHz, CDCl3) d; ꢁ42.38 (1F, d,

Y. Nakamura et al. / Journal of Fluorine Chemistry 117 (2002) 143–148
147
(E)- and (Z)-4-Fluoro-6-phenyl-3-hexene-1,5-diol (2c): a
Z/E mixture (Z=E ¼ 2). Colorless oil. 1H-NMR (400 MHz,
CDCl3) d; 1.85–1.95 (0.27H, m), 1.99–2.11 (0.27H, m),
2.18–2.37 (1.46H, m), 2.85–3.05 (2H, m), 3.27–3.35 (0.27H,
m), 3.35–3.44 (0.27H, m), 3.53 (1.46H, ddd, J ¼ 23:2, 10.8,
6.4 Hz), 4.27 (0.73H, dt, J ¼ 16:2, 6.9 Hz), 4.61 (0.27H, dt,
J ¼ 26:1, 7.3 Hz), 4.76 (0.73H, dt, J ¼ 37:6, 7.6 Hz), 5.07
(0.27H, ddd, J ¼ 21:4, 9.2, 7.5 Hz), 7.21–7.32 (5H, m). 13C-
NMR (100.6 MHz, CDCl3) d; 26.6 (d, J ¼ 8:6 Hz), 27.6 (d,
J ¼ 8:6 Hz), 39.4, 40.1, 60.9, 61.3, 67.8 (d, J ¼ 28:1 Hz),
71.7 (d, J ¼ 30:3 Hz), 103.3 (d, J ¼ 13:0 Hz), 105.2 (d,
J ¼ 21:2 Hz), 126.4, 128.2, 129.3, 137.1, 137.2, 159.7 (d,
J ¼ 253:5 Hz), 160.1 (d, J ¼ 258:7 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢁ58.15 (0.27F, ddd, J ¼ 26, 21,
10 Hz), ꢁ61.05 (0.73F, dd, J ¼ 37, 16 Hz). IR (CHCl3):
3616, 3412, 3036, 2932, 2884, 1708 cmꢁ1. MS (EI) m/z; 210
(Mþ), 193, 190, 173. HRMS. Calcd. for C12H15O2F (Mþ):
210.1056. Found: 210.1045.
141.0, 150.2 (t, J ¼ 22:7 Hz), 164.6. 19F-NMR (376.5 MHz,
CDCl3) d; 7.01 (2F, s). IR (CHCl3): 2992, 2876, 1726,
1660 cmꢁ1. MS (EI) m/z; 289 (Mþ þ 1), 243, 179, 159.
Anal. Calcd. for C14H15O2ClF2: C, 58.24; H, 5.24. Found: C,
57.95; H, 5.16.
4-Chloro-4,4-difluoro-3-phenyl-2-buten-1-ol (4a): color-
less oil. 1H-NMR (400 MHz, CDCl3) d; 1.56 (1H, brs), 4.08
(2H, brs), 6.51 (1H, tt, J ¼ 6:3, 1.3 Hz), 7.25–7.29 (2H, m),
7.39–7.43 (3H, m). 13C-NMR (100.6 MHz, CDCl3) d; 59.5,
125.8 (t, J ¼ 291 Hz), 128.5, 129.0, 129.8, 131.9, 132.8 (t,
J ¼ 6:4 Hz), 137.4 (t, J ¼ 23:8 Hz). 19F-NMR (376.5 MHz,
CDCl3) d; þ10.25 (2F, s). IR (neat): 3632, 2940, 1674 cmꢁ1
.
MS (EI) m/z; 220 (Mþ(37Cl)), 218 (Mþ(35Cl)), 182. Anal.
Calcd. for C10H9OClF2: C, 54.93; H, 4.15. Found: C, 55.33;
H, 4.47.
3-Chlorodifluoromethyl-5-phenyl-2-penten-1-ol
(4b):
colorless oil. 1H-NMR (400 MHz, CDCl3) d; 1.31 (1H,
s), 2.63 (2H, t, J ¼ 7:6 Hz), 2.87 (2H, t, J ¼ 7:6 Hz),
3.94 (2H, dt, J ¼ 6:5, 1.9 Hz), 6.25 (1H, tt, J ¼ 6:5,
1.3 Hz), 7.23–7.38 (5H, m). 13C-NMR (100.6 MHz, CDCl3)
d; 28.7, 35.0, 58.4, 126.4, 127.2 (t, J ¼ 291:4 Hz), 128.5,
128.8, 132.2 (t, J ¼ 7:3 Hz), 134.4 (t, J ¼ 22:1 Hz), 140.6.
19F-NMR (376.5 MHz, CDCl3) d; þ10.38 (2F, s). IR
(CHCl3): 3632, 3032, 2956, 2876, 1606 cmꢁ1. MS (EI)
m/z; 192 (Mþ–F, Cl), 174, 161, 91. Anal. Calcd. for
C12H13OClF2: C, 58.43; H, 5.31. Found: C, 58.45; H, 5.46.
4,4-Difluoro-3-phenyl-3-buten-1-ol (5a): colorless oil.
1H-NMR (400 MHz, CDCl3) d; 1.88 (1H, brs), 2.63 (2H,
tt, J ¼ 6:8, 2.3 Hz), 3.61 (2H, t, J ¼ 6:8 Hz), 7.20–7.39 (5H,
m). 13C-NMR (100.6 MHz, CDCl3) d; 31.2, 60.3, 89.3 (dd,
J ¼ 21:6, 14.5 Hz), 127.4, 128.2 (t, J ¼ 2:8 Hz), 128.5,
133.2 (t, J ¼ 3:6 Hz), 154.3 (dd, J ¼ 290:0, 287.7 Hz).
19F-NMR (376.5 MHz, CDCl3) d; ꢁ27.05 (1F, d,
J ¼ 41 Hz), ꢁ27.92 (1F, d, J ¼ 41 Hz). IR (neat): 3632,
2960, 2875, 1734 cmꢁ1. MS (EI) m/z; 184 (Mþ), 166. Anal.
Calcd. for C10H10OF2: C, 65.21; H, 5.47. Found: C, 65.23;
H, 5.51.
(E)- and (Z)-4-Fluoro-5-phenyl-3-penten-1-ol (2e): (E)-
2e: colorless oil. 1H-NMR (400 MHz, CDCl3) d; 1.48 (1H,
brd), 2.30–2.37 (2H, m), 3.60 (2H, d, J ¼ 23:5 Hz), 3.67
(2H, t, J ¼ 6:4 Hz), 5.17 (1H, dt, J ¼ 20:9, 8.1 Hz), 7.22–
7.28 (3H, m), 7.28–7.34 (2H, m). 13C-NMR (100.6 MHz,
CDCl3) d; 29.3 (d, J ¼ 8:7 Hz), 34.4 (d, J ¼ 28:8 Hz), 62.3,
102.9 (d, J ¼ 22:7 Hz), 126.8, 128.4, 128.6, 136.5, 160.1 (d,
J ¼ 249:6 Hz). 19F-NMR (376.5 MHz, CDCl3) d; ꢁ36.10
(1F, td, J ¼ 23, 22 Hz). IR (neat): 3125–3686, 3030, 2952,
1707 cmꢁ1. (Z)-2e: colorless oil. 1H-NMR (400 MHz,
CDCl3) d; 1.48 (1H, brd), 2.30–2.39 (2H, m), 3.49 (2H,
d, J ¼ 16:8 Hz), 3.64 (2H, t, J ¼ 6:5 Hz), 4.63 (1H, dt,
J ¼ 37:0, 7.5 Hz), 7.23–7.28 (3H, m), 7.29–7.35 (2H, m).
13C-NMR (100.6 MHz, CDCl3) d; 27.4 (d, J ¼ 3:9 Hz), 38.6
(d, J ¼ 28:9 Hz), 62.1, 102.7 (d, J ¼ 15:0 Hz), 126.8, 128.5,
128.8, 136.4, 160.1 (d, J ¼ 256:0 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢁ43.60 (1F, dt, J ¼ 37, 17 Hz).
IR (neat): 3136–3662, 3030, 2949, 1701 cmꢁ1
.
3.3. Physical data of enoates 3, enones 7 and their
reduction products 4, 5, 8, 9
4,4-Difluoro-3-phenethyl-3-buten-1-ol (5b): colorless oil.
1H-NMR (400 MHz, CDCl3) d; 1.63 (1H, s), 2.26 (2H, tt,
J ¼ 6:7, 2.1 Hz), 2.34 (2H, tt, J ¼ 7:9, 2.1 Hz), 2.75 (2H, t,
J ¼ 7:9 Hz), 3.69 (2H, t, J ¼ 6:7 Hz), 7.19–7.23 (3H, m),
7.26–7.32 (2H,m). 13C-NMR (100.6 MHz, CDCl3) d; 28.5
(d, J ¼ 1:7 Hz), 30.0, 34.0, 60.5, 86.7 (t, J ¼ 17:5 Hz),
126.2, 128.3, 128.4, 141.1, 154.4 (t, J ¼ 285:2 Hz), 19F-
NMR (376.5 MHz, CDCl3) d; ꢁ31.49 (1F, d, J ¼ 53 Hz),
ꢁ30.23 (1F, d, J ¼ 53 Hz). IR (CHCl3): 3635, 3045, 2975,
2950, 1750 cmꢁ1. MS (EI) m/z; 194 (Mþ–H2O), 174, 91.
Anal. Calcd. for C12H14OF2: C, 67.91; H, 6.65. Found: C,
67.68; H, 6.87.
5-Chloro-5,5-difluoro-4-phenyl-3-penten-2-one (7a): col-
orless oil. 1H-NMR (400 MHz, CDCl3) d; 1.86 (3H, s), 6.67
(1H, s), 7.29–7.36 (2H, m), 7.38–7.49 (3H, m). 13C-NMR
(100.6 MHz, CDCl3) d; 30.5, 125.4 (t, J ¼ 292:3 Hz), 128.6,
129.6, 129.8, 130.5 (t, J ¼ 5:8 Hz), 131.3, 144.0 (t,
J ¼ 24:7 Hz), 199.1. 19F-NMR (376.5 MHz, CDCl3) d;
ꢁ8.06 (2F, s). IR (neat): 3300–3400, 3010, 1710,
Ethyl 4-chloro-4,4-difluoro-3-phenyl-2-butenoate (3a):
1
colorless oil. H-NMR (400 MHz, CDCl3) d; 1.05 (3H, t,
J ¼ 7:1 Hz), 4.03 (2H, q, J ¼ 7:1 Hz), 6.58 (1H, t,
J ¼ 1:1 Hz), 7.28–7.47 (5H, m). 13C-NMR (100.6 MHz,
CDCl3) d; 13.6, 61.0, 122.7 (t, J ¼ 6:6 Hz), 125.2 (t,
J ¼ 292:2 Hz), 128.0, 129.1, 131.5, 147.2 (t,
J ¼ 24:5 Hz), 164.2. 19F-NMR (376.5 MHz, CDCl3) d;
þ7.71 (2F, s). IR (neat): 3024, 2990, 1726 cmꢁ1. MS (EI)
m/z; 260 (Mþ þ 1), 215, 159. HRMS. Calcd. for
C12H11O2F2Cl (Mþ): 260.0416. Found: 260.0420.
Ethyl 3-chlorodifluoromethyl-5-phenyl-2-pentenoate (3b):
1
colorless oil. H-NMR (400 MHz, CDCl3) d; 1.30 (3H, t,
J ¼ 7:1 Hz), 2.86–2.92 (2H, m), 4.23 (2H, q, J ¼ 7:1 Hz),
6.32 (1H, s), 7.17–7.21 (1H, m), 7.26–7.29 (4H, m). 13C-
NMR (100.6 MHz, CDCl3) d; 14.1, 29.8, 35.4, 60.9, 120.7
(t, J ¼ 7:5 Hz), 126.3, 126.5 (t, J ¼ 292:5 Hz), 128.3, 128.5,

148
Y. Nakamura et al. / Journal of Fluorine Chemistry 117 (2002) 143–148
1683 cmꢁ1. MS (EI) m/z; 229 (Mþ), 159, 155. Calcd. for
C11H9OF2Cl: C, 57.28; H, 3.93. Found: C, 57.40; H, 3.94.
Me), 166. Calcd. for C11H12OF2: C, 66.66; H, 6.10. Found:
C, 66.52; H, 6.19.
4,4,4-Trifluoro-2-methyl-1-phenyl-2-buten-1-ol (9c): col-
4-Chlorodifluoromethyl-6-phenyl-3-hexen-2-one
(7b):
colorless oil. 1H-NMR (400 MHz, CDCl3) d; 2.33 (3H,
s), 2.79–2.92 (4H, m), 6.58 (1H, s), 7.15–7.24 (1H, m),
7.25–7.32 (4H, m). 13C-NMR (100.6 MHz, CDCl3) d; 29.9,
32.1, 35.2, 125.3 (t, J ¼ 6:6 Hz), 126.2, 126.4 (t,
J ¼ 292:6 Hz), 128.5, 128.6, 140.9, 147.7 (t,
J ¼ 22:6 Hz), 197.7. 19F-NMR (376.5 MHz, CDCl3) d;
þ6.44 (2F, s). IR (CHCl3): 3024, 2956, 2872, 1702,
1634 cmꢁ1. MS (EI) m/z; 259 (Mþ þ 1), 241, 222, 202,
91. Anal. Calcd. for C13H15OClF2: C, 60.36; H, 5.07. Found:
C, 60.08; H, 5.09.
orless oil. H-NMR (400 MHz, CDCl3) d; 1.73 (3H, m).
1
2.21 (1H, brd, J ¼ 3:0 Hz), 5.05 (1H, s). 6.10 (1H, qm, J ¼
8:5 Hz),7.26–7.45(5H,m).13C-NMR(100.6 MHz,CDCl3)d;
14.51, 77.52, 114.17 (q, J ¼ 33:8 Hz), 124.01 (q, J ¼ 270:9
Hz), 126.95, 128.62, 128.88, 140.25, 150.93 (q, J ¼ 5:3 Hz).
19F-NMR (376.5 MHz, CDCl3) d; þ5.54 (3F, dm,
J ¼ 8:5 Hz). IR (neat): 3120–3680, 3033, 2875, 1683 cmꢁ1
.
References
5,5-Difluoro-4-phenyl-4-penten-2-ol (8a): colorless oil.
1H-NMR (400 MHz, CDCl3) d; 1.17 (3H, d, J ¼ 6:2 Hz),
1.71 (1H, brs), 2.48 (1H, ddt, J ¼ 14:3, 5.6, 2.8 Hz), 2.58
(1H, ddt, J ¼ 14:3, 7.5, 2.1 Hz), 3.77 (1H, m), 7.23–7.36
(5H, m). 13C-NMR (100.6 MHz, CDCl3) d; 22.9, 37.4, 66.1,
89.8 (dd, J ¼ 20:6, 15.4 Hz), 127.4, 128.3 (t, J ¼ 2:7 Hz),
128.5, 133.4 (m), 154.4 (dd, J ¼ 290:3, 288.4 Hz). 19F-
NMR (376.5 MHz, CDCl3) d; ꢁ30.61 (1F, d, 45 Hz),
ꢁ30.79 (1F, d, J ¼ 45 Hz). IR (neat): 3696, 3624, 2980,
1734 cmꢁ1. MS (EI) m/z; 178 (Mþ). Anal. Calcd. for
C11H12OF2: C, 66.66; H, 6.10. Found: C, 66.65; H, 6.03.
5,5-Difluoro-4-phenethyl-4-penten-2-ol (8b): colorless
oil. 1H-NMR (400 MHz, CDCl3) d; 1.22 (3H, d, J ¼ 6,
2 Hz), 1.68 (1H, s), 2.03–2.12 (1H, m), 2.13–2.22 (1H, m),
2.27–2.41 (2H, m), 2.74 (2H, t, J ¼ 8:0 Hz), 3.92 (1H, dq,
J ¼ 19:2, 6.1 Hz), 7.19–7.32 (5H, m). 13C-NMR
(100.6 MHz, CDCl3) d; 23.1, 28.6 (d, J ¼ 1:6 Hz), 33.9,
36.0 (d, J ¼ 2:0 Hz), 66.1, 86.0 (t, J ¼ 17:2 Hz), 126.1,
128.3, 128.4, 141.0, 154.5 (t, J ¼ 285:2 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢁ33.68 (1F, d, J ¼ 57:4 Hz),
ꢁ34.55 (1F, d, J ¼ 57:4 Hz). IR (CHCl3): 3693, 3628,
2936, 2868, 1750 cmꢁ1. MS (EI) m/z; 226 (Mþ), 209,
182. HRMS. Calcd. for C13H14F2 (Mþ–H2O): 208.1064.
Found: 208.1040.
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ture of diastereomers (ratio, 5:1). Colorless oil. H-NMR
(400 MHz, CDCl3) d; 0.96 (2.49H, d, J ¼ 6:9 Hz), 1.27
(0.51H, d, J ¼ 6:8 Hz), 2.04 (1H, brs), 2.65–2.80 (1H, m),
4.06 (0.17H, ddd, J ¼ 25:5, 10.0, 2.8 Hz), 4.18 (0.83H, ddd,
J ¼ 25:5, 10.0, 2.8 Hz), 4.40 (0.83H, d, J ¼ 6:7 Hz), 4.55
(0.17H, d, J ¼ 6:0 Hz), 7.25–7.38 (5H, m). 13C-NMR
(100.6 MHz, CDCl3) d; 17.5, 36.4 (d, J ¼ 4:0 Hz), 78.1,
80.1 (t, J ¼ 20:5 Hz), 126.5, 127.8, 128.3, 142.3, 156.6 (t,
J ¼ 287 Hz) for major isomer; 16.1, 35.7 (d, J ¼ 4:1 Hz),
77.8, 80.4 (t, J ¼ 20:4 Hz), 126.4, 127.7, 128.2, 142.2, 156.0
(t, J ¼ 287 Hz) for minor isomer. 19F-NMR (376.5 MHz,
CDCl3) d; ꢁ24.52 (0.83F, d, J ¼ 45 Hz), ꢁ25.48 (0.17F, d,
J ¼ 45 Hz), ꢁ26.77 (1F, dd, J ¼ 25:5, 45 Hz). IR (neat):
3622, 2980, 2938, 2878, 1749 cmꢁ1. MS (EI) m/z; 183 (Mþ–
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