Optical resolution of 5-alkyl-δ-valerolactones and synthesis of optically active 5-fluoroalkanols

Article abstract of DOI:10.1080/10242430210707

Optical resolutions of 5-alkyl-δ-valerolactones were carried out by derivatization to the diastereomeric amides, in which (R)-(+)-1-(1-naphthyl)ethylamine or (S)-(-)-1-phenylethylamine were used as resolving agents. Optically active 5-fluoroalkanols, useful intermediates for fluorinated ferroelectric liquid crystals, were derived from the resolved lactones in four steps without racemization.

Full text of DOI:10.1080/10242430210707

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Optical Resolution of 5-Alkyl-δ-Valerolactones and
Synthesis of Optically Active 5-Fluoroalkanols
Asep Riswoko a , Yoshio Aoki a , Takuji Hirose a & Hiroyuki Nohira a
a Department of Applied Chemistry, Faculty of Engineering , Saitama University , Urawa,
Japan
Published online: 17 Sep 2010.
To cite this article: Asep Riswoko , Yoshio Aoki , Takuji Hirose & Hiroyuki Nohira (2002) Optical Resolution of 5-Alkyl-δ-
Valerolactones and Synthesis of Optically Active 5-Fluoroalkanols, Enantiomer: A Journal of Sterochemistry, 7:1, 33-39, DOI:
10.1080/10242430210707
To link to this article: http://dx.doi.org/10.1080/10242430210707
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Enantiomer, Vol. 7, pp.33–39
c
Copyright 2002 Taylor & Francis
1024-2430/02 $12.00 + .00
Optical Resolution of
5-Alkyl- -Valerolactones and Synthesis
of Optically Active 5-Fluoroalkanols
Asep Riswoko,
Yoshio Aoki,
Takuji Hirose,
ABSTRACT Optical resolutions of 5-alkyl- -valerolactones were car-
ried out by derivatization to the diastereomeric amides, in which (R)-(+)-
1-(1-naphthyl)ethylamine or (S)-( )-1-phenylethylamine were used as re-
solving agents. Optically active 5-fluoroalkanols, useful intermediates for
fluorinated ferroelectric liquid crystals, were derived from the resolved
lactones in four steps without racemization.
and Hiroyuki Nohira
Department of Applied Chemistry,
Faculty of Engineering,
Saitama University,
Urawa, Japan
KEYWORDS optically active 5-alkyl- -valerolactones, optically active 5-fluoro-
alkanols, optical resolution
INTRODUCTION
Optically active fluorinated compounds are interesting organic mate-
rials and have often been used for pharmacological studies [1]. In these
days they also collect interest in liquid crystal studies since they can be
important intermediates of ferroelectric liquid crystals applicable for flat
panel display [2,3]. We have been working on fluorinated ferroelectric
liquid crystals in order to achieve short response time and have found
that the optically active 5-fluorodecanol derivatives showed the shortest
response time [4,5].
In the previous paper, we have reported a 9-step synthetic method
of 5-fluoroalkanols starting from optically active 1,2-epoxyalkanes [5].
However, this method has limitation that only (S)-( )-5-fluoroalkanols
are available as (R)-(+)-epoxyalkanes are commercially available. We
made a new synthetic strategy for both enantiomers of 5-fluoroalkanols
starting from optically active -valerolactones in order to develop
more convenient and practical method. Previously optically active
-valerolactones have been produced by extracting natural resources [6],
by asymmetric synthesis [7], or by fermenting bakers’ yeast [8]. How-
ever, these methods gave only one enantiomer of the optically active
-valerolactones and/or gave them in low yields, so that further investiga-
tions were required for our purpose. We have previously reported a conve-
nient resolution of 5-pentyl- -valerolactone ( -decalactone) by means of
Received December 1, 2000;
in final form March 5, 2001.
Address correspondence to Asep
Riswoko, Department of Applied
Chemistry, Faculty of Engineering,
Saitama University, 255
Shimo-ohkubo, Urawa, Saitama
338-8570, Japan. E-mail: asep@
apc.saitama-u.ac.jp
33

(Table 1). The choice of an appropriate solvent de-
pended on the length of the alkyl group. The longer
the alkyl groups, the lower polarity of the solvents
was chosen. By three or four times of recrystalliza-
tion, high diastereomeric purity of each diastereomer
was obtained (>90% d.e.). Each diastereomer was
hydrolyzed under acidic conditions, and the prod-
uct was cyclized without racemization to afford the
optically active 5-alkyl- -valerolactones 1 -n in high
yield and optical purity. The absolute configurations
of the lactones were determined by comparison
CHART 1 Resolving agents examined.
diastereomeric amide formation method [9]. Here
we report a further investigation to obtain a series
of optically active 5-alkyl- -valerolactones that were
different in the alkyl chain length by diastereomeric
amide formation method and their conversion to
optically active 5-fluoroalkanols in four steps.
with
a natural product of (S )-( )-5-hexyl- -
valerolactone [6], and the others [7,8] (see Experi-
mental section).
Synthesis of Optically Active
5-fluoroalkanols 8 -n
RESULTS AND DISCUSSION
Schemes 2 and 3 show the synthetic procedures of
the 5-fluoroalkanols 8( )-n using the 5-alkyl- -
valerolactones 1( )-n as starting materials. As shown
in Scheme 2, at first ring opening reaction of the
lactone 1-1 was carried out in good yield.
However, the fluorination of the product, methyl
5-chlorohexanoate (3), with AgF gave methyl
5-fluorohexanoate (4) in 10% yield. As a result, the
over all yield of this synthetic procedure was very
low (<5%), and another route was investigated.
A key strategy for the new synthetic route was
regio-selective protection of 1,5-alkanediol, 5 -n, ob-
tained by reducing the optically active lactones
1 -n. After protection of a primary hydroxyl group of
5 -n, the secondary hydroxyl group should be sub-
stituted with fluorine. Benzoylation of the primary
Optical Resolution of
5-alkyl- -valerolactones 1-n
The optical resolutions of the racemic 5-alkyl- -
valerolactones 1-n were carried out by the diastere-
omeric amide derivatization method. The diastere-
omeric amides 2-n were obtained by reaction of the
lactones 1-n with optically active amines as resolv-
ing agents. Three resolving agents were applied to
the procedure (Chart 1), and optically active 1-(1-
naphthyl)ethylamine (NEA) and/or 1-phenylethyl
amine (PEA) gave good results. That is, both diastere-
omers were easily separated by recrystallization from
proper solvents (Scheme 1).
The amides 2-n were recrystallized from pure or
mixed solvents to separate each of the diastereomers
SCHEME 1 Optical resolution of 5-alkyl- -valerolactones 1-n.
34
A. RISWOKO ET AL.

TABLE 1 Fractional crystallizations of the diastereomeric amides 2-n
Recrystallized
amide
Recryst.
times
4
Amine
Solvent
Yield/ %1 o.p./ % d.e.2 E/ % 3 m.p./ C [ ]D/
(R,R)-(+)-2 -1
(R,R)-(+)-2 -2
(R,R)-(+)-2 -3
(S,S)-( )-2 -4
(R)-(+)-NEA EtOH/AcOEt = 1/5
(R)-(+)-NEA AcOEt
4
4
4
3
3
18
36
39
14
36
97
92
94
97
99
17
33
37
13
35
133–134
127–130
124–126
97–98
+40
+31
+30
79
(R)-(+)-NEA AcOEt
(S)-( )-PEA Hexane/AcOEt = 1/1
(S,S)-( )-2 -5 5 (S)-( )-PEA Hexane/AcOEt = 1/1
105–107
77
1
Calculated based on half the amount of racemate.
2
Determined by HPLC analysis (Wakosil 5SIL; Ø 4.6 mm 250 mm; eluent, 70% (v/v) AcOEt in hexane; flow rate, 1.0 ml/min; detection wavelength,
254 nm).
3
4
5
Yield o.p./100.
(c 1.0, MeOH).
Ref. [9].
SCHEME 2 Synthesis of 5-fluorohexanol (8-1).
SCHEME 3 Synthesis of optically active 5-fluoroalkanols 8 -n.
RESOLUTION OF 5-ALKYL- -VALEROLACTONE
35

alcohol was carried out in two ways: by the use
of diethyl azodicarboxylate (DEAD) and triphenyl
phosphine [10] or by the use of benzoylchloride
and 1,4-diazabicyclo[2.2.2]octane (DABCO). It was
found that the latter method gave the monoben-
zoylated diols 6 -n in higher yield, and its purifi-
cation was easier than the former, Scheme 3. The
fluorinated compounds 7 -n were synthesized by
fluorination of 6 -n with a nucleophilic agent, di-
ethylaminosulfur trifluoride (DAST), under mild
conditions. The fluorination proceeded as SN2 re-
action with inversion of the absolute configuration
[11]. Finally, the optically active 7 -n were hydro-
lyzed under weakly basic conditions and gave the
optically active 5-fluoroalkanols 8 -n in good yield.
No racemization occurred in this synthetic route,
which was confirmed by determination of optical
purity of the intermediate (5-fluoroalkyl benzoate
7 -n) using HPLC equipped with a chiral column
(Daicel CHIRALCEL OB-H; Ø4.6 mm 250 mm;
5% (v/v) 2-PrOH in Hexane; flowrate, 0.5 ml/min;
detection wavelength, 254 nm).
diastereomerically pure amide [0.28 g, 1.0 mmol,
14% (calculated based on half the amount of race-
mate); [ ]2D4–78 (c 1.0, MeOH); m.p. 97–98 C; 97%
d.e.]. Diastereomeric excess of the amide was deter-
mined by HPLC analysis (Wakosil 5SIL; Ø4.6 mm
250 mm; eluent, 70% (v/v) AcOEt in hexane; flow
rate, 1.0 ml/min; detection wavelength, 254 nm).
The absolute configuration was determined from
its derivatization product, (S )-( )-5-butyl- -valerol-
actone (1 -4). 1H NMR (CDCl3): 0.89–0.94 (t, 3H,
CH3), 1.43–1.48 (m, 10H, CH2), 1.66–1.68 (d, 3H,
CH3), 1.82–1.85 (m, 1H, CHO), 2.30–2.59 (m, 2H,
CH2), 2.63 (m, 1H, OH), 3.55 (m, 1H, CHN), 5.90–
5.94 (m, 1H, NH), 7.43–8.09 (m, 5H, Ar); IR (neat,
cm 1) 3286 (OH), 2931–2870 (CH3, CH2), 1645
(C O); Elemental anal. calcd for C17H27NO2: C,
73.60; H, 9.81; N, 5.05. Found: C, 73.84; H, 9.97:
N, 5.05.
(R,R)-(+)-N-(1-(1-naphthyl)ethyl)-
5-hydroxyhexanamide (2 -1)
Diastereomerically pure amide: [ ]2D4 + 40 (c1.0,
MeOH); m.p. 133–134 C; 97% d.e.; 1H NMR
(CDCl3): 1.11–1.17 (d, 3H, CH3), 1.36–1.80 (m,
4H, CH2), 1.61–1.65 (d, 3H, CH3), 2.14–2.24 (m,
2H, CH2), 3.76 (m, 1H, CHN), 5.91–5.98 (m, 1H,
NH), 7.40–8.11 (m, 7H, Ar); IR (neat, cm 1) 3302
(OH), 1633 (C O); Elemental anal. calcd for
C18H23NO2: C, 75.75; H, 8.12; N, 4.91. Found: C,
75.84; H, 8.18; N, 4.89.
CONCLUSION
The optical resolutions of the racemic 5-alkyl- -
lactones were carried through diastereomeric amides
derivatization method. The method gave the opti-
cally active lactones in high optical purity, which
were used as starting materials to prepare the opti-
cally active 5-fluoroalkanols.
EXPERIMENTAL
(R,R)-(+)-N-(1-(1-naphthyl)ethyl)-
5-hydroxyheptanamide (2 -2)
The structures of the intermediates and products
1
were confirmed by H NMR, 13C NMR and 19F
Diastereomerically pure amide: [ ]2D4 + 31 (c1.0,
MeOH); m.p. 127–130 C; 92% d.e. 1H NMR
(CDCl3): 0.85–0.91 (t, 3H, CH3), 1.36–1.43 (m, 6H,
CH2), 1.66–1.69 (d, 3H, CH3), 1.72–1.75 (m, 1H,
CHO), 2.15–2.19 (m, 2H, CH2), 3.46 (m, 1H, CHN),
5.92 (m, 1H, NH), 7.41–8.09 (m, 7H, Ar); IR
(neat, cm 1) 3296 (OH), 1636 (C O).
NMR spectroscopy (Bruker ARX400 and AM400),
and infrared (IR) spectroscopy (Perkin-Elmer
FT1640).
(S,S)-( )-N-(1-Phenylethyl)-
5-hydroxynonanamide (2 -4)
A typical synthetic procedure of diastereomeric
amide is as follows: a mixture of 5-butyl- -valerol-
actone (2.81 g,18 mmol), (S)-( )-1-phenylethylamine
(2.18 g, 18 mmol) in dry benzene (4 ml) was stirred at
120 C for 3 hours. The solvent was evaporated off to
obtain crystalline amide. Four times recrystallization
from mixed solvent (AcOEt: Hexane = 1:1) gave
(R,R)-(+)-N-(1-(1-naphthyl)ethyl)-
5-hydroxyoctanamide (2 -3)
Diastereomerically pure amide: [ ]2D4 + 30 (c1.0,
MeOH); m.p. 124–126 C; 94% d.e. 1H NMR
(CDCl3): 0.89–0.94 (t, 3H, CH3), 1.43–1.48 (m, 8H,
CH2), 1.66–1.68 (d, 3H, CH3), 1.82–1.85 (m, 1H,
36
A. RISWOKO ET AL.

CHO), 2.30–2.59 (m, 2H, CH2), 2.63 (m, 1H, OH),
3.55 (m, 1H, CHN), 5.90–5.94 (m, 1H, NH), 7.43–
8.09 (m, 7H, Ar); IR (neat, cm 1) 3297 (OH), 1639
(C O); Elemental anal. calcd for C20H27NO2:
C, 76.64; H, 8.68; N, 4.47. Found: C, 76.45; H, 8.85;
N, 4.28.
As reference, optical rotation of (S)-( )-5-ethyl- -
valerolactone prepared by asymmetric synthesis:
[ ]2D3 48 (c1.6, THF) [7].
(R)-(+)-5-Propyl- -valerolactone(1 -3): [ ]2D7+48
1
(c1.0, MeOH); 98% e.e.; H NMR (CDCl3): 0.84–
0.92 (t, 3H, CH3), 1.44–1.81 (m, 4H, CH2), 2.41
1
(m, 2H, CH2), 4.21 (m, 1H, CH); IR (neat, cm
)
2957, 2872 (CH3, CH2), 1734 (C O). As reference,
optical rotation of (R)-(+)-5-propyl- -valerolactone
prepared by fermenting baker’s yeast: [ ]2D0 + 66
(c1.7, THF) [8].
(S)-( )-5-Butyl- -valerolactone
(1 -4)
A typical synthetic procedure of lactonization is
as follows: to a solution of amide 2 -4 (440 mg,
1.59 mmol) in 99% EtOH (10 ml), 6M hydrochloric
acid (0.5 ml) was added. The mixture was stirred at
90 C for five hours and was extracted with Et2O. The
mixture of the crude product and 2M NaOH (3.0 ml)
was stirred at 95 C for two hours, and 2M hydrochlo-
ric acid (5 ml) was added to the mixture. The mixture
was extracted with Et2O to yield a crude of 5-hydroxy
acid. A solution of the acid, p-toluenesulfonic acid
( 0.5 mg), and dry benzene was stirred at 85 C for
two hours and was extracted with Et2O. The ex-
tract was washed with 5% Na2CO3 aqueous solution
and was dried over Na2SO4. The crude product was
distilled and gave the lactone (230 mg, 1.47 mmol,
92.5%). [ ]2D6 35 (c1.0, MeOH); 97% e.e. Enan-
tiomeric excess of the lactone was determined
by HPLC analysis (Chiralcel OB-H; Ø4.6 mm
250 mm; eluent, 5% (v/v) 2-PrOH in hexane; flow
rate, 0.5 ml/min; detection wavelength, 220 nm). 1H
NMR (CDCl3): 0.88–0.91 (t, 3H, CH3), 1.30–1.92
(m, 10H, CH2), 2.42–2.56 (dm, 2H, CH2), 4.23–
4.29 (m, 1H, CH); IR (neat, cm 1) 2955, 2871 (CH3,
CH2), 1740 (C O). As reference, optical rotation of
(R)-(+)-5-butyl- -valerolactone prepared by ferment-
ing baker’s yeast: [ ]2D0 + 63 (c2.2, THF) [8].
(S)-(+)-5-Hydroxynonanol (5 -4): A typical prepa-
ration procedure of optically active alcohol is as fol-
lows: to a suspended solution of LiAlH4 (0.87 g,
23 mmol), a solution of (S)-( )-5-butyl- -valerol-
actone (2.3 g, 15 mmol) in dry THF (10 ml) was
slowly added. The mixture was stirred for six hours
at room temperature under N2 atmosphere. Satu-
rated Na2SO4 solution and 3M hydrochloric acid
was added. The organic layer was extracted with Et2O
and dried over anhydrous MgSO4. The condensed
crude product was distilled (135–150 C, 30 mmHg)
to yield a colorless liquid (2.26 g, 14.1 mmol, 94%).
[ ]2D4+0.5 (c1.0, MeOH); 1H NMR (CDCl3): 0.89–
0.92 (t, 3H, CH3), 1.29–1.61 (m, 12H, CH2), 2.63
(m, 1H, OH), 3.58–3.59 (m, 1H, CHO), 3.61–3.64
(t, 2H, CH2O); 13C NMR (CDCl3): 13.9 (CH3),
21.7, 22.7, 27.8, 32.4, 36.8, 37.2 (CH2), 62.3 (CH2OH),
71.6 (CHOH); IR (neat, cm 1) 3355 (OH), 2932–
2862 (CH3, CH2).
(R)-( )-5-Hydroxyhexanol(5 -1): [ ]2D4 6.3 (c1.0,
1
MeOH); H NMR (CDCl3): 1.83–1.86 (m, 1H,
CHO), 3.76 (q, 2H, CH2O); 13C NMR (CDCl3):
62.2 (CH2OH), 67.8 (CHOH); IR (neat, cm 1) 3345
(OH).
(S)-(+)-5-Hydroxyheptanol (5 -2): [ ]2D4 + 2.1
1
(R)-(+)-5-Methyl- -valerolactone (1 -1): [ ]D27
+
(c1.0, MeOH); H NMR (CDCl3): 2.52 (m, 1H,
1
OH), 3.53–3.54 (m, 1H, CHO), 3.62–3.65 (t, 2H,
CH2O); 13C NMR (CDCl3): 62.4 (CH2OH), 73.0
(CHOH); IR (neat, cm 1) 3357 (OH).
15 (c1.0, MeOH); 97% e.e.; H NMR (CDCl3):
1.31–1.34 (d, 3H, CH3), 1.75–1.91 (m, 4H, CH2),
2.46 (t, 2H, CH2), 4.35–4.43 (m, 1H, CH); 13C NMR
(CDCl3): 18.4 (CH3), 21.6, 29.1, 29.5 (CH2), 76.4
(CH), 170.8 (C O); IR (neat, cm 1) 2977 (CH3),
1736 (C O). As reference, optical rotation of (S)-
( )-5-methyl- -valerolactone prepared by asymmet-
ric synthesis: [ ]2D2 46 (c2.0, EtOH) [7].
(R)-( )-5-Hydroxyoctanol (5 -3): [ ]D26
1.0
1
(c1.0, MeOH); H NMR (CDCl3): 3.55–3.57 (m,
1H, CHO), 3.60–3.62 (t, 2H, CH2O); 13C NMR
(CDCl3): 62.5 (CH2OH), 71.5 (CHOH); IR (neat,
cm 1): 3372 (OH).
(S)-( )-5-Ethyl- -valerolactone (1 -2): [ ]D25 14
(c1.0, MeOH); 92% e.e.; 1H NMR (CDCl3):
0.82–0.91 (t, 3H, CH3), 1.38–1.63 (m, 6H, CH2),
2.30–2.41 (m, 2H, CH2), 4.01–4.12 (m, 1H, CH); IR
(neat, cm 1) 2939, 2877 (CH3, CH2), 1732 (C O).
(S)-(+)-5-Hydroxynonyl benzoate (6 -4): A typical
benzoylation is as follows: to a stirred solution of (S)-
(+)-5-hydroxynonanol (5 -4) (100 mg, 0.63 mmol)
and benzoyl chloride (88 mg, 0.62 mmol) in
dry CH2Cl2 (2 ml), 1,4-diazabicyclo[2.2.2]octane
RESOLUTION OF 5-ALKYL- -VALEROLACTONE
37

(DABCO) (213 mg, 1.9 mmol) was added slowly.
The solution was then stirred at room temperature
for 3 hours under N2 atmosphere. Dilute HCl solu-
tion was added. The organic layer was extracted with
CH2Cl2. The extract was washed with distilled water
and dried over anhydrous Na2SO4. The condensed
mixture was purified by thin layer chromatography
(AcOEt:Hexane = 1:5) to yield a light yellow liq-
uid (126 mg, 0.48 mmol, 77%). [ ]2D7 + 3.2 (c1.1,
MeOH); 1H NMR (CDCl3): 0.88–0.92 (t, 3H, CH3),
1.31–1.81 (m, 12H, CH2), 3.62 (m, 1H, CHO), 4.32–
4.35 (t, 2H, CH2O), 7.41–8.05 (m, 5H, Ar); 13C
NMR (CDCl3): 14.0 (CH3), 22.2, 22.7, 27.8, 28.8,
36.9, 37.2 (CH2), 64.9 (CH2OBzl), 71.7 (CHOH),
128.3–132.8 (Ar), 166.7 (C O); IR (neat, cm 1) 3411
(OH), 2932–2861 (CH3, CH2), 1720 (C O).
CH2Cl2. The extract was washed with distilled water
and dried over anhydrous Na2SO4. The solvent was
evaporated off, and remaining mixture was purified
by thin layer chromatography (AcOEt:Hexane = 1:7)
to yield a light yellow liquid (81 mg, 0.30 mmol,
54%). [ ]2D6 0.7 (c 0.8, MeOH); 95% e.e. (deter-
mined by Chiralcel OB-H; Ø4.6 mm
250 mm;
eluent, 5% (v/v) 2-PrOH in hexane; flow rate,
1
0.5 ml/min; detection wavelength, 254 nm); H
NMR (CDCl3): 0.88–0.92 (t, 3H, CH3), 1.31–1.82
(m, 12H, CH2), 4.32–4.35 (t, 2H, CH2O), 4.40–
4.57 (dm, 1H, CHF, JH-F = 49.45 Hz), 7.42–8.05
(m, 5H, Ar); 13C NMR (CDCl3): 13.9 (CH3), 21.8,
22.5, 27.2, 28.6, 34.7, 34.9 (CH2), 64.8 (CH2OBzl),
93.4–95.1 (d, CHF, J = 166.8 Hz), 128.3–132.8 (Ar),
166.6 (C O); 19F NMR (CDCl3): 181.2
181.0
(R)-( )-5-Hydroxyhexyl benzoate (6 -1): [ ]D27
(m, CHF); IR (neat, cm 1) 3063 (Ar), 2954–2870
(CH3, CH2), 1720 (C O).
1
0.7 (c0.9, MeOH); H NMR (CDCl3): 1.19–1.21
(d, 3H, CH3), 1.49–1.78 (m, 6H, CH2), 3.81 (m,
1H, CHO), 4.11–4.34 (t, 2H, CH2O), 7.41–8.05 (m,
5H, Ar); 13C NMR (CDCl3): 22.1 (CH3), 23.4, 28.6,
38.7 (CH2), 64.8 (CH2OBzl), 67.7 (CHOH), 128.3–
132.7 (Ar), 166.6 (C O); IR (neat, cm 1) 3400 (OH),
2962–2866 (CH3, CH2), 1720 (C O).
(S)-(+)-5-Fluorohexyl benzoate (7 -1): [ ]2D6 +2.7
(c 1.0, MeOH); 96% e.e.; 1H NMR (CDCl3): 1.22–
1.24 (d, 3H, CH3), 1.27–1.78 (m, 6H, CH2), 4.03
(t, 2H, CH2O), 4.40–4.58 (dm, 1H, CHF, JH-F
49.5 Hz), 7.40–8.03 (m, 5H, Ar); 19F NMR (CDCl3):
182.2
181.9 (m, CHF); IR (neat, cm 1) 3063
=
(S)-(+)-5-Hydroxyheptyl benzoate (6 -2): [ ]D27
+
(Ar), 2944–2870 (CH3, CH2), 1720 (C O).
1.5 (c1.0, MeOH); H NMR (CDCl3): 0.89–0.93
(t, 3H, CH3), 1.32–1.83 (m, 8H, CH2), 3.61 (m, 1H,
CHO), 4.31 (t, 2H, CH2O), 7.40–8.05 (m, 5H, Ar);
13C NMR (CDCl3): 13.4 (CH3), 22.2, 26.7, 36.2,
39.2 (CH2), 64.9 (CH2OBzl), 69.7 (CHOH), 128.3–
132.8 (Ar), 166.7 (C O); IR (neat, cm 1) 3349 (OH),
2936–2873 (CH3, CH2), 1719 (C O).
(R)-( )-5-Fluoroheptylbenzoate(7 -2): [ ]2D6 5.3
1
1
(c0.9, MeOH); 90% e.e.; H NMR (CDCl3): 0.95–
0.99 (t, 3H, CH3), 1.50–1.85 (m, 8H, CH2), 4.32
(t, 2H, CH2O), 4.32–4.49 (dm, 1H, CHF, JH-F
=
49.5 Hz), 7.42–8.05 (m, 5H, Ar); 13C NMR
(CDCl3): 9.3 (CH3), 21.8, 27.9, 28.6, 34.4 (CH2),
64.8 (CH2OBzl), 94.5–96.2 (d, CHF, J = 170.0 Hz),
128.3–132.8 (Ar), 166.6 (C O); 19F NMR (CDCl3):
(R)-( )-5-Hydroxyoctyl benzoate (6 -3): [ ]D25
1
2.6 (c1.1, MeOH); H NMR (CDCl3): 0.90–0.94
182.5
182.2 (m, CHF); IR (neat, cm 1) 3063
(t, 3H, CH3), 1.33–1.81 (m, 10H, CH2), 3.62 (m,
1H, CHO), 4.31–4.34 (t, 2H, CH2O), 7.41–8.05 (m,
5H, Ar); 13C NMR (CDCl3): 14.1 (CH3), 18.7, 22.1,
28.7, 36.8, 39.6 (CH2), 64.9 (CH2OBzl), 71.5
(CHOH), 128.3–132.8 (Ar), 166.7 (C O); IR (neat,
cm 1): 3427 (OH), 2956–2871 (CH3, CH2), 1720
(C O).
(R)-( )-5-Fluorononyl benzoate (7 -4): A typical
fluorination is as follows: a solution of diethylamino
sulfurtrifluoride (DAST) (320 mg, 2.0 mmol) in 5 ml
of dry CH2Cl2 was added to a stirred solution of (S)-
(+)-5-hydroxynonyl benzoate (6 -4) (150 mg,
0.6 mmol) in dry CH2Cl2 (3 ml) at 78 C under N2
atmosphere. The mixture was stirred for 30 minutes
at the same temperature. Saturated Na2SO4 solution
was added, and the organic layer was extracted with
(Ar), 2940–2871 (CH3, CH2), 1720 (C O).
(S)-(+)-5-Fluorooctyl benzoate (7 -3): [ ]D24 + 0.9
(c 0.95, MeOH); 92% e.e.; 1H NMR (CDCl3): 0.92–
0.95 (t, 3H, CH3), 1.48–1.82 (m, 10H, CH2), 4.32–
4.35 (t, 2H, CH2O), 4.41–4.58 (dm, 1H, CHF, JH-F
=
49.5 Hz), 7.41–8.05 (m, 5H, Ar); 13C NMR (CDCl3):
13.8 (CH3), 18.2, 21.7, 28.5, 34.8, 37.3 (CH2),
64.7 (CH2OBzl), 93.0–94.7 (d, CHF, J = 170.0 Hz),
128.3–132.8 (Ar), 166.5 (C O); 19F NMR (CDCl3):
181.7
181.4 (m, CHF); IR (neat, cm 1) 3063
(Ar), 2940–2871 (CH3, CH2), 1720 (C O).
(R)-(+)-5-Fluorononanol (8 -4): A typical proce-
dure to obtain optically active 5-fluoroalkanol is as
follows: to a stirred solution of (R)-( )-5-fluorononyl
benzoate (5 -4) (75 mg, 0.3 mmol) in MeOH (2 ml),
1M KOH (1 ml) was added. The mixture was stirred
38
A. RISWOKO ET AL.

(S)-( )-5-Fluorooctanol (8 -3): [ ]2D7 1.8 (c 2.2,
Et2O); 1H NMR (CDCl3): 0.92–0.95 (t, 3H, CH3),
1.33–1.71 (m, 10H, CH2), 3.63–3.66 (t, 2H, CH2O),
4.39–4.57 (dm, 1H, CHF, JH-F = 50 Hz); 13C NMR
(CDCl3): 13.8 (CH3), 18.3, 21.3, 32.4, 34.9, 37.3
(CH2), 62.6 (CH2OH), 93.3–94.9 (d, CHF,
J = 166.9 Hz); 19F NMR (CDCl3): 180.9 (dm,
CHF). Elementary analysis of this compound was
determined as its derivative, 2-(p-(5-fluorooctyloxy)
phenyl)-5-decyloxypyrimidine [12]: 1H NMR
(CDCl3): 0.87–0.96 (dt, 6H, CH3), 1.27–1.84 (m,
26H, CH2), 4.02–4.09 (dt, 4H, CH2O), 4.44–4.58
(dm, 1H, CHF, J = 49.5 Hz), 6.95–6.97 (d, 2H, Ar,
J = 8.8 Hz), 8.25–8.27 (d, 2H, Ar, J = 8.8 Hz),
8.41 (s, 2H, Ar); 13C NMR (CDCl3): 13.9, 14.1
(CH3), 18.3–31.8 (CH2), 67.7, 68.9 (CH2O), 93.2–
94.9 (d, CHF, J = 166.9 Hz), 114.4–160.5 (Ar); El-
emental analysis calculated for C28H43FN2O2: C,
73.32; H, 9.45; N, 6.11. Found: C, 73.34; H, 9.59;
N, 6.09.
at room temperature for overnight. The mixture was
extracted with Et2O, and washed with a 5 wt%
Na2CO3 solution. The extract was dried over an-
hydrous MgSO4. The solvent was evaporated off to
yield a colorless liquid (38 mg, 0.23 mmol, 84%).
[ ]2D7 + 0.2 (c 1.8, Et2O); 1H NMR (CDCl3): 0.89–
0.93 (t, 3H, CH3), 1.32–1.62 (m, 12H, CH2), 3.64–
3.67 (t, 2H, CH2O), 4.40–4.54 (dm, 1H, CHF,
JH-F = 49 Hz); 13C NMR (CDCl3): 13.9 (CH3), 21.4,
22.5, 27.2, 32.5, 34.7, 34.9 (CH2), 62.7
(CH2OH), 93.6–95.2 (d, CHF, J = 166.9 Hz); 19F
NMR (CDCl3): 181.1
180.7 (m, CHF). Ele-
mentary analysis of this compound was determined
as its derivative, 2-p-decyloxyphenyl-5-(5-fluoro-
nonyloxy)pyrimidine [12]: 1H NMR (CDCl3):
0.80–0.87 (dt, 6H, CH3), 1.21–1.76 (m, 28H, CH2),
3.93–4.04 (dt, 4H, CH2O), 4.37–4.50 (dm, 1H, CHF,
J = 49.6 Hz), 6.88–6.92 (d, 2H, Ar, J = 9.9 Hz),
8.19–8.21 (d, 2H, Ar, J = 8.8 Hz), 8.35 (s, 2H, Ar);
13C NMR (CDCl3): 13.9, 14.1 (CH3), 21.6–34.9
(CH2), 68.1, 68.6 (CH2O), 93.4–95.0 (d, CHF, J =
167.5 Hz), 114.4–160.78 (Ar); Elemental analysis
calculated for C29H45FN2O2: C, 73.69; H, 9.60; N,
5.93. Found: C, 73.79; H, 9.75; N, 5.91.
As reference, we have reported a synthesis of (S)-
( )-5-fluorodecanol from (R)-(+)-1,2-epoxyheptane
[5]: [ ]2D4 1.2 (c 2.0, Et2O); H NMR (CDCl3):
1
0.90 (t, 3H, CH3), 1.24–1.68 (m, 14H, CH2), 1.89
(s, 1H, OH), 3.64 (t, 2H, CH2O), 4.38–4.56 (dm,
1H, CHF, JH-F = 49 Hz); 13C NMR (CDCl3): 13.9
(CH3), 21.4, 22.5, 24.7, 31.6, 32.5, 34.8, 35.1 (CH2),
62.6 (CH2OH), 94.4 (d, CHF, J = 166.9 Hz); 19F
NMR (CDCl3): 180.9 (dm, CHF).
(S)-(+)-5-Fluorohexanol (8 -1): [ ]2D5 + 15.8
1
(c 1.0, MeOH); H NMR (CDCl3): 1.27 (d, 3H,
CH3), 1.35–1.88 (m, 6H, CH2), 3.66 (t, 2H, CH2O),
4.50–4.81 (dm, 1H, CHF, JH-F = 62 Hz); 13C NMR
(CDCl3): 21.2 (CH3), 21.4, 32.4, 36.6 (CH2), 62.7
(CH2OH), 90.9 (d, CHF, J = 164.2 Hz).
(R)-( )-5-Fluoroheptanol (8 -2): [ ]D25
6.7
REFERENCES
(c 0.7, MeOH); 1H NMR (CDCl3): 0.95–0.99 (t, 3H,
[1] J. T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic
Chemistry, p.109, John Wiley & Sons, New York, 1991.
[2] Canon Co., Stylish FLCD Product Catalog, 1997.
[3] P. J. Collings and M. Hird, Introduction to Liquid Crystals,
p.111, Taylor & Francis, London, 1997.
[4] S. Nakamura and H. Nohira, Mol. Cryst. Liq. Cryst. 1990,
185, 199.
[5] Y. Nagashima, T. Ichihashi, N. Koji, M. Iwamoto, Y. Aoki,
and H. Nohira, Liq. Cryst. 1997, 23, 537.
[6] R. Kuhn and K. Kum, Chem. Ber. 1962, 95,
2009.
[7] K. Soai, S. Yokoyama, T. Hayasaka, and K. Ebihara, Chem.
Lett. 1988, 843.
[8] M. Utaka, H. Watabu, and A. Takeda, J. Org. Chem. 1987,
52, 4363.
[9] H. Nohira, K. Mizuguchi, T. Murata, Y. Yazaki,
M. Kanazawa, Y. Aoki, and M. Nohira, Heterocycles
2000, 52, 1359.
[10] O. Mitsunobu, J. Kimura, K. Iizumi, and N. Yanagida, Bull.
Chem. Soc. Jpn. 1976, 49, 510.
CH3), 1.43–1.67 (m, 8H, CH2), 3.64–3.67 (t, 2H,
CH2O), 4.33–4.49 (dm, 1H, CHF, JH-F
=
48 Hz); 13C NMR (CDCl3): 9.3 (CH3), 21.4, 28.1,
32.5, 34.5 (CH2), 62.7 (CH2OH), 94.7–96.3 (d,
CHF, J = 166.9 Hz); 19F NMR (CDCl3):
182.3
181.9 (m, CHF). Elementary analysis of
this compound was determined as its derivative, 2-
(p-decyloxyphenyl)-5-(5-fluoroheptyloxy)pyrimidine
1
[12]: H NMR (CDCl3): 0.86–1.00 (dt, 6H, CH3),
1.27–1.87 (m, 24H, CH2), 3.93–4.10 (dt, 4H, CH2O),
4.38–4.51 (dm, 1H, CHF, J = 49.6 Hz), 6.95–6.98
(d, 2H, Ar, J = 8.8 Hz), 8.25–8.27 (d, 2H, Ar, J =
8.8 Hz), 8.41 (s, 2H, Ar); 13C NMR (CDCl3): 14.1
(2CH3), 21.4–34.4 (CH2), 68.1, 68.6 (CH2O), 94.5–
96.2 (d, CHF, J = 167.6 Hz), 114.4–160.7 (Ar); El-
emental analysis calculated for C27H41FN2O2: C,
72.94; H, 9.29; N, 6.30. Found: C, 72.62; H, 9.40;
N, 6.21.
[11] M. Hudlicky, Org. React. 1988, 35, 513.
[12] R. Asep, Y. Aoki, T. Hirose, and H. Nohira, Mol. Cryst. Liq.
Cryst. 2000, 346, 51.
RESOLUTION OF 5-ALKYL- -VALEROLACTONE
39