Selective mono-fluorination of diols via a cyclic acetal of N,N-diethyl-4-methoxybenzamide

Article abstract of DOI:10.1016/j.jfluchem.2007.04.020

Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et₃N-3HF. The reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and anot

Full text of DOI:10.1016/j.jfluchem.2007.04.020

Journal of Fluorine Chemistry 128 (2007) 1121–1125
www.elsevier.com/locate/fluor
Selective mono-fluorination of diols via a cyclic acetal
of N,N-diethyl-4-methoxybenzamide
*
Mitsuhiro Suwada, Tsuyoshi Fukuhara, Shoji Hara
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 16 March 2007; received in revised form 8 April 2007; accepted 15 April 2007
Available online 19 April 2007
Abstract
Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et3N-3HF. The
reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and another one was acylated.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Mono-fluorination of diol; Benzamide acetal; Triethylamine trishydrogen fluoride
1. Introduction
conditions. Among them, 1d gave the best result and 2-
fluoroethyl 4-methoxybenzoate (2d) was obtained in 80% yield
(Table 1). From the cyclic acetals of DMF and DMA, the
corresponding fluorination products could not be obtained under
the same conditions.
Recently, we succeeded in the selective mono-fluorination
of 1,2- and 1,3-diols using N,N-diethyl-a,a-difluoro-4-methyl-
benzylamine (DFMBA), and a cyclic acetal of the benzamide
was expected to be formed as an intermediate from DFMBA
and the diol [1]. In this paper, we prepared the cyclic amide
acetals from amide diethyl acetals and diols, and converted
them to the mono-fluorination products by Et3N-3HF.
The cyclic acetal intermediate 1d is isolable by distillation
after the transacetalization, and from the isolated 1d, 2d could
be obtained in 83% yield by the reaction with Et3N-3HF at
140 8C for 30 min. These results showed that the reaction
proceeds through the cyclic acetal intermediate 1 as expected.
The reaction from 1 to 2 must be proceeding as follows:
Elimination of diethylamine from 1 took place to give a
dioxolenium intermediate [3], and subsequent fluoride attack,
generated from DFMBA or Et3N-3HF, on the dioxolenium
intermediate gave the fluoroethyl benzoate 2 (Scheme 1).
In order to optimize the reaction conditions, the fluorination
reaction of 1d was carried out under various conditions. Lower
temperature (120 8C) or shorter reaction time (10 min) caused
the decrease of the yield. On the other hand, higher temperature
(160 8C) or longer reaction time (1 h) could not improve the
result. We also applied various fluoride sources such as KF,
TBAF, Et3N-2HF, and Et3N-4HF, but the results could not be
improved. The present method was applied to the reaction with
various 1,2- and 1,3-diols (Table 2). From cis-1,2-cyclohex-
anediol, trans-2-fluorocyclohexyl 4-methoxybenzoate (3)
was obtained in 75% yield (Entry 1). The reaction proceeded
with inversion of the stereochemistry. On the other hand, from
trans-1,2-cyclohexanediol, trans-2-fluorocyclohexanol was
obtained in low yield and the expected methoxybenzoyl ester
2. Result and discussion
The cyclic acetal of N,N-diethyl-3-methylbenzamide (1a),
which is an expected intermediate in the reaction of ethylene
glycolwithDFMBA[1], waspreparedbytransacetalizationfrom
N,N-diethyl-3-methylbenzamide diethyl acetal and ethylene
glycol [2], and was applied to the fluorination without isolation.
Whenthereaction of1awithEt3N-3HFwascarriedoutat140 8C
for 30 min, 2-fluoroethyl 3-methylbenzoate (2a), which is the
same product as in the reaction of ethylene glycol with DFMBA
[1], was obtained in 66% yield. Similarly, the cyclic acetal of
N,N-diethylbenzamide (1b), N,N-diethyl-4-chlorobenzamide
(1c), and N,N-diethyl-4-methoxybenzamide (1d) were prepared
from the corresponding bezamide diethyl acetal and ethylene
glycol, and used for the fluorination reaction under the same
* Corresponding author. Fax: +81 11 706 6556.
E-mail address: hara@org-mc.eng.hokudai.ac.jp (S. Hara).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.04.020

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M. Suwada et al. / Journal of Fluorine Chemistry 128 (2007) 1121–1125
Table 1
Fluorination of ethylene glycol using benzamide diethyl acetalsa
1 (X)
Product 2 (X)
Yield (%)b
1a (3-Me)
1b (H)
1c (4-CI)
1d (4-MeO)
2a (3-Me)
2b (H)
2c (4-CI)
2d (4-MeO)
66
54
57
80
a
Transacetalization was carried out using 1.1 eq of acetal under reduced pressure at 50 8C for 1 h. Fluorination was carried out at 140 8C for 30 min using 2 eq of
Et3N-3HF.
b
Isolated yield based on ethylene glycol.
of cis-2-fluorocyclohexanol was not formed. In this case, the
formation of the cyclic acetal is slow due to the steric effect and
a cyclohexene oxide must be initially formed by the reaction of
the trans-cyclohexanediol with amide acetal [4]. The
subsequent ring opening fluorination of the epoxide by
Et3N-3HF provided trans-2-fluorocyclohexanol [5]. In the
reaction with 1,2-dodecanediol, the fluorination took place
non-regioselectively to give a mixture of 1- and 2-fluorinated
products (4a:4b = 71:29) (Entry 2). In the reaction of cis-1,2-
cyclododecandiol, the resulting trans-2-fluorocyclododecyl 4-
methoxybenzoate was subjected to the transesterification
reaction without isolation [6] and trans-2-fluorocyclododeca-
nol (5) was obtained in 56% overall yield from cyclodode-
candiol (Entry 3). As the reaction proceeds stereoselectively,
the optically active fluorohydrin derivatives could be
selectively prepared from optically active diols without losing
their original enantiomeric purity. For instance, when (R,R)-
hydrobenzoin was subjected to the reaction, (1R,2S)-2-fluoro-
1,2-diphenylethyl 4-methoxybenzoate (7) was obtained in
77% yield (>95%de) (Entry 5). Its absolute stereochemistry
was determined by comparison of its optical rotation with the
product from DFMBA after converting to the 3-methylbenzoic
acid ester (Scheme 2). Similarly, from (R,R)-2,3-butanediol,
(2R,3S)-3-fluoro-2-butyl 4-methoxybenzoate (6) was obtained
in 79 % yield (>95%de) (Entry 4).
The reaction of 1,3-diols is sluggish and higher temperature
(160 8C) was required to complete the reaction (Entries 6 and
7). Recently, we found that the reaction of b-amino alcohols
with DFMBA also proceeds through the similar cyclic
intermediate to give fluoroalkylamides [7]. The reaction of
N-phenyl-2-aminoethanol and N-phenyl-1-amino-2-octanol
with the benzamide diethyl acetal and Et3N-3HF proceeded
as in the case of DFMBA and N-acylated 2-fluoroethylamine
(10) and 2-fluorooctylamine (11) were obtained, respectively
(Entries 8 and 9).
3. Experimental
3.1. General methods
The melting points were measured with a Yanagimoto micro
melting-point apparatus and uncorrected. The IR spectra were
recorded using a JASCO FT/IR-410. The 1H NMR (400 MHz)
spectra, 19F NMR (376 MHz) spectra and 13C NMR (100 MHz)
spectra were recorded in CDCl3 on a JEOL JNM-A400II FT
NMR and the chemical shift, d, are referred to TMS (1H, 13C) and
CFCl3 (19F), respectively. The 1H NMR (270 MHz) spectra and
13C NMR (68 MHz) spectra were recorded on a JEOL JNM-
A270II FT NMR. The EI-high-resolution mass spectra were
measuredonaJEOLJMS-700TZ. Opticalrotationwasmeasured
with a Horiba High Sensitive Polarimeter. cis-1,2-Cyclohex-
anediol, 1,2-dodecanediol, (R,R)-2,3-butanediol, 1,3-propane-
diol, 2,2-dimethyl-1,3-propanediol, N-phenyl-2-ethanolamine
Scheme 1.
Scheme 2.

M. Suwada et al. / Journal of Fluorine Chemistry 128 (2007) 1121–1125
1123
Table 2
3.2. Preparation of N,N-diethyl-4-methoxybenzamide
diethyl acetal
Fluorination of diols and amino alcohol using p-methoxybenzamide diethyl
acetal and Et3N-3HFa
Entry
1
Substrate
Product
Yield (%)b
To a 300 ml three-necked glass flask equipped with
mechanical stirrer, a reflux condenser, and a dropping funnel
were introduced N,N-diethyl-4-methoxybenzamide (20.73 g,
100 mmol) and CH2Cl2 (50 ml) under N2 atmosphere. After
addition of oxalyl chloride (12.95 g, 102 mmol) from the
dropping funnel at room temperature, the reaction mixture was
stirred under reflux for 90 min. The mixture was cooled to
ꢀ40 8C, and a dry ethanol (27.64 g, 600 mmol) and Et3N
(20.60 g, 204 mmol) were added successively. Then, the
temperature was allowed to rise up to room temperature and
CH2Cl2 was carefully removed under reduced pressure. After
the addition of hexane (100 ml), the precipitate was removed by
filtration under N2 atmosphere. The filtrate was concentrated
under reduced pressure and the residue was distilled to give
N,N-diethyl-4-methoxybenzamide diethyl acetal (14.08 g,
50 mmol) in 50% yield (bp 94 8C/0.42 mmHg). As it is
moisture sensitive, it was kept and used as 1 M CH2Cl2 solution
under N2. IR: (neat) n 2972, 1609, 1509, 1244, 1083 cmꢀ1. 1H
NMR (270 MHz) d 0.97 (t, J = 7.1 Hz, 6H), 1.17 (t, J = 7.1 Hz,
6H), 2.60 (q, J = 7.1 Hz, 4H), 3.25–3.37 (m, 2H), 3.45–3.56 (m,
2H), 3.80 (s, 3H), 6.83 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz,
2H). 13C NMR (68 MHz) d 15.05 (2C), 16.05 (2C), 42.37 (2C),
55.14, 56.37 (2C), 109.02, 112.59 (2C), 128.37 (2C), 132.71,
158.67. HRMS (EI): calc. for C16H27NO3: 281.1991, found:
281.1990.
75
2
83
3
56c
4
5
79 (>95)
77 (>95)
6
7
60d
66d
3.2.1. N,N-Diethyl 4-methoxybenzamide ethylene acetal
(1d)
bp 85 8C/0.28 mmHg. IR (neat): 2968, 1509, 1246 cmꢀ1. 1H
NMR (270 MHz) d 0.98 (t, J = 7.16, 6H), 2.71 (q, J = 7.11, 4H),
3.73–3.78 (m, 2H), 3.82 (s, 3H), 4.01–4.06 (m, 2H), 6.84–6.89
(m, 2H), 7.45–7.48 (m, 2H). 13C NMR d 14.18 (2C), 40.34 (2C),
55.20, 63.85 (2C), 113.07 (2C), 119.75, 128.31 (2C), 133.13,
159.38. HRMS (EI): calc. for C14H20NO3 (M+-H): 250.1443,
found: 250.1447.
8
72e
9
72e
a
lf otherwise not mentioned, the reaction was carried out at 140 8C for
30 min. Ar = p-MeOC6H4.
b
lsolated yield based on diol or amino alcohol used and in paretheses,
3.3. Fluorination of diols
diasteromeric excess.
c
1,2-Dichloroethane was used as solvent and the product was converted to
3.3.1. 2-Fluoroethyl 4-methoxybenzoate (2d)
fluorohydrin before isolation.
d
The reaction was carried out at 160 8C for 30 min.
A mixture of ethylene glycol (62 mg, 1 mmol) and a CH2Cl2
solution of N,N-diethyl-4-methoxybenzamide diethyl acetal
(1.2 ml of 1 M solution, 1.2 mmol) in a 30 ml-Teflon FEP tube
was stirred at 50 8C under reduced pressure for 1 h to remove
the generate ethanol and complete the transacetalization. To the
crude 1d, Et3N-3HF (322 mg, 2 mmol) was added and the
mixture was stirred at 140 8C for 30 min. The reaction mixture
was cooled to room temperature and aq. NaHCO3 (6 ml) was
added. The product was extracted with ether, dried over
MgSO4, and concentrated under reduced pressure. Purification
by column chromatography (silica gel/hexane-ether) gave 2d
(158 mg, 0.8 mmol) in 80% yield. IR: (neat) n 2959, 1715,
e
The reaction was carried out at 100 8C for 30 min.
N,N-diethylbenzamide,
N,N-diethyl-4-methyoxybenzamide,
N,N-diethyl-3-methylbenzamide, and N,N-diethyl-4-chloroben-
zamide were purchased from Tokyo Chemical Industry Co., Ltd.
cis-1,2-Cyclododecanediol was separated by column chromato-
graphy from a mixture of the stereoisomers obtained from Tokyo
Chemical Industry Co., Ltd. (R,R)-Hydrobenzoin (99%ee) was
obtained from Aldrich. Et3N-3HF was prepared according to the
literature [8]. Dichlorotetrabutyldistannoxane was prepared
according to the literature [9]. A 30 ml-Teflon FEP centrifuge
tube with screw cup was obtained from Flon Industry and used as
a reaction vessel in fluorination reaction.
1
1607, 1511, 1258, 1169 cmꢀ1. H NMR (400 MHz) d 3.87 (s,
3H), 4.59 (dt, J = 28.8, J = 4.2 Hz, 2H), 4.68 (dt, J = 47.4,
J = 4.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz,

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M. Suwada et al. / Journal of Fluorine Chemistry 128 (2007) 1121–1125
2H). 13C NMR (100 MHz) d 55.42, 63.54 (d, J = 19.9 Hz),
81.55 (d, J = 170.4 Hz), 113.64 (2C), 122.03 (2C), 131.79,
163.55, 166.08. 19F NMR (376 MHz) d ꢀ225.01 (tt, J = 47.6,
J = 28.7 Hz, 1F). HRMS (EI): calc. for C10H11FO3: 198.0686,
found: 198.0692.
3.3.7. 2-Fluoro-1-dodecyl 4-methoxybenzoate (4b)
White solid. mp 36 8C. IR: (KBr) n 2926, 1718, 1607,
1
1257 cmꢀ1. H NMR (400 MHz) d 0.88 (t, J = 6.8 Hz, 3H),
1.26–1.84 (m, 18H), 3.87 (s, 3H), 4.29–4.50 (m, 2H), 4.79
(dm, J = 49.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 8.03 (d,
J = 8.8 Hz, 2H). 13C NMR (100 MHz) d 14.10, 22.67, 24.81
(d, J = 4.3 Hz), 29.31, 29.35, 29.42, 29.51, 29.57, 31.46 (d,
J = 20.6 Hz), 31.88, 55.43, 66.01 (d, J = 22.3 Hz), 91.58 (d,
J = 172.1 Hz), 113.64 (2C), 122.16, 131.77 (2C), 163.52,
166.06. 19F NMR (376 MHz) d ꢀ187.52–ꢀ187.13 (m, 1F).
HRMS (EI): calc. for C20H31FO3: 338.2257, found:
338.2262.
3.3.2. 2-Fluoroethyl 3-methylbenzoate (2a)
IR: (neat) n 2958, 1725, 1596, 1276 cmꢀ1 1H NMR
.
(400 MHz) d 2.40 (s, 3H), 4.52–4.80 (m, 4H) 7.31–7.38 (m,
2H), 7.87 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H). 13C NMR
(100 MHz) d 21.12, 63.70 (d, J = 20.7 Hz), 81.39 (d, J =
171.0 Hz), 126.80, 128.23, 129.50, 130.15, 133.91, 138.14,
166.43. 19F NMR (376 MHz) d ꢀ225.03 (tt, J = 47.6, J =
28.7 Hz, 1F). HRMS (EI): calc. for C10H11FO2: 182.0743,
found: 182.0743.
3.3.8. trans-2-Fluorocyclododecanol (5)
A CH2Cl2 solution of N,N-diethyl-4-methoxybenzamide
diethyl acetal (1.2 ml of 1 M solution, 1.2 mmol) and cis-1,2-
cyclododecanediol (200 mg, 1 mmol) were introduced into a
30 ml-Teflon FEP tube, and a volatile part was removed under
reduced pressure. Then 1 ml of 1,2-dichloroethane was added
and the reaction mixture was stirred at 50 8C for 1 h under
reduced pressure. To the reaction mixture, Et3N-3HF
(325 mg, 2.1 mmol) was added and the mixture was
stirred at 140 8C for 30 min. The reaction mixture was
cooled to room temperature and aq. NaHCO3 (6 ml) was
added. The product was extracted with ether, dried over
MgSO4, and concentrated under reduced pressure. The crude
product, butanol (10 ml), and dichlorotetrabutyldistannoxane
(0.534 mg, 1 mmol), and toluene (5 ml) were introduced into
a 25-ml glass flask equipped with a reflux condenser and the
mixture was stirred under reflux. The transesterification
reaction was monitored by GC and the disappearance of the 2-
fluorocyclododecyl 4-methoxybenzoate was confirmed after
160 h. After removal of the volatile part under reduced
pressure, 2-fluorocyclododecanol (112 mg, 0.56 mmol) was
isolated by column chromatography (silica gel/hexane-ether)
in 56% overall yield from the diol. White solid. mp 65 8C. IR:
(KBr) n 3366, 2933, 1470, 1022 cmꢀ1. 1H NMR (400 MHz) d
1.26–1.95 (m, 20H), 2.21 (t, J = 3.3 Hz, 1H), 3.84–3.96 (m,
1H), 4.56 (dm, J = 49.5 Hz, 1H). 13C NMR (100 MHz) d
20.35 (d, J = 3.3 Hz), 20.57, 22.55, 22.59, 23.72, 23.76,
23.98, 24.01, 27.83 (d, J = 21.7 Hz), 28.73 (d, J = 5.6 Hz),
70.44 (d, J = 18.4 Hz), 95.31 (d, J = 166.1 Hz). 19F NMR
(376 MHz) d ꢀ194.02–ꢀ194.32 (m, 1F). HRMS (EI): calc.
for C12H23FO: 202.1733, found: 202.1726.
3.3.3. 2-Fluoroethyl benzoate (2b)
1
IR: (neat) n 2958, 1724, 1276 cmꢀ1. H NMR d 4.53–4.81
(m, 4H), 7.26–7.48 (m, 2H), 7.56–7.60 (m, 1H), 8.07–8.10 (m,
2H). 13C NMR (100 MHz) d 63.83 (d, J = 19.9 Hz), 81.43 (d,
J = 170.9 Hz), 128.42 (2C), 129.66, 129.75 (2C), 133.24,
166.37. 19F NMR (376 MHz) d ꢀ225.09 (tt, J = 47.6, J =
28.6 Hz, 1F). HRMS (EI): calc. for C9H9FO2: 168.0586, found:
168.0589.
3.3.4. 2-Fluoroethyl 4-chlorobenzoate (2c)
IR: (neat) n 2958, 1725, 1596, 1276 cmꢀ1 1H NMR
.
(400 MHz) d 4.52–4.80 (m, 4H), 7.42–7.45 (m, 2H), 8.00–8.03
(m, 2H). 13C NMR (100 MHz) d 64.03 (d, J = 19.8 Hz), 81.31
(d, J = 170.9 Hz), 128.06, 128.78 (2C), 131.13 (2C), 139.72,
165.49. 19F NMR (376 MHz) d ꢀ225.13 (tt, J = 47.6, J =
28.7 Hz, 1F). HRMS (EI): calc. for C9H8ClFO2: 202.0197,
found: 202.0181.
3.3.5. trans-2-Fluorocyclohexyl 4-methoxybenzoate (3)
IR: (neat) n 2994, 1713, 1607, 1259, 1103 cmꢀ1. 1H NMR
(400 MHz) d 1.34–1.81 (m, 6H), 2.12–2.20 (m, 2H), 3.86 (s,
3H), 4.59 (dm, J = 50.3 Hz, 1H), 5.05–5.13 (m, 1H), 6.91–
6.94 (m, 2H), 8.00–8.03 (m, 2H). 13C NMR (100 MHz) d
22.76 (d, J = 9.5 Hz), 22.99, 29.38 (d, J = 6.1 Hz), 30.40 (d,
J = 18.3 Hz), 55.43, 74.03 (d, J = 19.5 Hz), 91.93 (d,
J = 178.5 Hz), 113.55 (2C), 122.73, 131.70 (2C), 163.37,
165.62. 19F NMR (376 MHz) d ꢀ182.11 (brd, J = 45.2 Hz,
1F). HRMS (EI): calc. for C14H17FO3: 252.1162, found:
252.1162.
3.3.9. (2R,3S)-3-Fluoro-2-butyl 4-methoxybenzoate (6)
3.3.6. 1-Fluoro-2-dodecyl 4-methoxybenzoate (4a)
IR: (neat) n 2926, 1714, 1607, 1257 cmꢀ1 1H NMR
.
IR: (neat) n 2988, 1713, 1258, 1168, 1101 cmꢀ1. 1H NMR
(400 MHz) d 1.35–1.44 (m, 6H), 3.86 (s, 3H), 4.78 (dm,
J = 48.3 Hz, 1H), 5.16 (dm, J = 18.3 Hz, 1H), 6.92 (d,
J = 9.0 Hz, 2H), 8.01 (d, J = 9.1 Hz, 2H). 13C NMR
(100 MHz) d 14.14 (d, J = 6.3 Hz), 16.40 (d, J = 22.8 Hz),
55.24, 71.94 (d, J = 22.4 Hz), 90.83 (d, J = 172.3 Hz), 113.49
(2C), 122.50, 131.55 (2C), 163.37, 165.37. 19F NMR
(376 MHz) d ꢀ186.64 to ꢀ187.01 (m, 1F). (2R,3R)-isomer,
ꢀ186.64 to ꢀ186.03 (m, 1F). HRMS (EI): calc. for
(400 MHz) d 0.87 (t, J = 6.9 Hz, 3H), 1.24–1.43 (m, 16H),
1.67–1.83 (m, 2H), 3.36 (s, 3H), 4.56 (dm, J = 45.0 Hz, 2H),
5.26 (dm, J = 19.2 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 8.02 (d,
J = 8.9 Hz, 2H). 13C NMR (100 MHz) d 14.10, 22.66, 25.19,
29.29, 29.40 (2C), 29.50, 29.55, 29.71 (d, J = 5.5 Hz), 31.87,
55.43, 72.56 (d, J = 19.2 Hz), 83.77 (d, J = 173.9 Hz), 113.59
(2C), 122.47, 131.74 (2C), 163.45, 165.83. 19F NMR
(376 MHz) d ꢀ231.25 (dt, J = 22.6, J = 47.7 Hz, 1F). HRMS
(EI): calc. for C20H31FO3: 338.2257, found: 338.2256.
22:4
C12H15FO3: 226.1005, found: 226.1008. ½aꢁD ¼ ꢀ10:0
(c = 1.00, MeOH).

M. Suwada et al. / Journal of Fluorine Chemistry 128 (2007) 1121–1125
1125
3.3.10. (1R,2S)-2-Fluoro-1,2-diphenylethyl 4-
methoxybenzoate (7)
J = 47.0, J = 25.7 Hz, 1F). HRMS (EI): calc. for C11H13FO3:
212.0849, found: 212.0841.
White solid. mp 100 8C. IR: (KBr) n 1709, 1258, 706 cmꢀ1
.
1H NMR (400 MHz) d 3.87 (s, 3H), 5.85 (dd, J = 46.3,
J = 4.1 Hz, 1H), 6.26 (dd, J = 18.1, J = 4.2 Hz, 1H), 6.93 (d,
J = 8.9 Hz, 2H), 7.18–7.32 (m, 10H), 8.02 (d, J = 8.9 Hz, 2H).
13C NMR (100 MHz) d 55.36, 77.35 (d, J = 25.4 Hz), 94.44 (d,
J = 181.1 Hz), 113.65 (2C), 122.09, 126.37, 126.44, 127.75
(2C), 127.99 (2C), 128.04 (2C), 128.41, 128.61, 131.76 (2C),
134.97 (d, J = 2.9 Hz), 135.59 (d, J = 20.6 Hz), 163.57, 164.90.
19F NMR (376 MHz) d ꢀ188.91 (dd, J = 46.3, J = 18.3 Hz, 1F).
HRMS (EI): calc. for C22H19FO3: 350.1318, found: 350.1316.
3.3.12. 3-Fluoro-2,2-dimethylpropyl 4-methoxybenzoate
(9)
IR: (neat) n 2968, 1714, 1607, 1258 cmꢀ1 1H NMR
.
(400 MHz) d 1.05 (d, J = 1.8 Hz, 6H), 3.84 (s, 3H), 4.14 (d,
J = 1.1 Hz, 2H), 4.27 (d, J = 47.9 Hz, 2H), 6.92 (d, J = 9.0 Hz,
2H), 7.99 (d, J = 8.9 Hz, 2H). 13C NMR (100 MHz) d 20.63 (d,
J = 5.0 Hz, 2C), 35.87 (d, J = 17.4 Hz), 55.26, 68.56 (d, J =
4.1 Hz), 88.10, 113.54 (2C), 122.44, 131.42 (2C), 163.32,
165.92. 19F NMR (376 MHz) d ꢀ226.89 (t, J = 47.6 Hz, 1F).
HRMS (EI): calc. for C13H17FO3: 240.1162, found: 240.1160.
20:4
½aꢁD ¼ þ96:0 (c = 1.00, MeOH).
3.3.10.1. (1R,2S)-2-Fluoro-1,2-diphenylethanol. Butanol
(13 ml), 7 (298 mg, 0.85 mmol), dichlorotetrabutyldistannox-
ane (578 mg, 1.1 mmol), and toluene (5 ml) were introduced
into a 25-ml glass flask equipped with a reflux condenser, and
the mixture was stirred under reflux for 90 h. After removal of
the volatile part under reduced pressure, (1R,2S)-2-fluoro-1,2-
diphenylethanol (330 mg, 0.65 mmol) was isolated by column
chromatography (silica gel/hexane-ether). White solid. mp
98 8C (lit. [10] 99 8C). IR: (KBr) 3578, 3033, 2880, 1452, 1050,
965, 706 cmꢀ1. 1H NMR (400 MHz) d 2.10 (d, J = 3.9 Hz, 1H),
4.98–5.03 (m, 1H), 5.52 (dd, J = 45.8, J = 5.56 Hz, 1H), 7.22–
7.35 (m, 10H). 13C NMR (100 MHz) d 76.31 (d, J = 27.2 Hz),
96.21 (J = 177.8 Hz), 126.78 (d, J = 7.2 Hz), 126.98 (2C),
127.00 (2C), 128.19 (2C), 128.25 (2C), 128.79 (d, J = 1.7 Hz),
3.3.13. N-(2-Fluoroethyl)-N-phenyl 4-methoxybenzamide
(10)
1
IR: (neat) n 2959, 2839, 1642, 1606, 1254 cmꢀ1. H NMR
(400 MHz) d 3.74 (s, 3H), 4.19 (dt, J = 25.6, J = 4.9 Hz, 2H),
4.75 (dt, J = 47.5, J = 4.9 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H),
7.09–7.29 (m, 7H). 13C NMR (100 MHz) d 51.58 (d, J =
21.4 Hz), 55.10, 81.43 (d, J = 169.0 Hz), 112.91 (2C), 126.48,
127.47 (2C), 127.58, 129.14 (2C), 130.90 (2C), 144.46, 160.67,
170.12. 19F NMR (376 MHz) d ꢀ222.81–ꢀ222.43 (m, 1F).
HRMS (EI): calc. for C16H16FNO2: 273.1165, found:
273.1159.
3.3.14. N-(2-Fluorooctyl)-N-phenyl 4-methoxybenzamide
(11)
135.95 (d, J = 19.9 Hz), 138.82 (d, J = 3.1 Hz). 19F NMR
White solid. mp 47 8C. IR: (KBr) n 2931, 2857, 1644, 1606,
22:1
1
1254 cmꢀ1. H NMR (400 MHz) d 0.88 (t, J = 6.8 Hz, 3H),
(376 MHz) d ꢀ183.83 (dd, J = 45.8, J = 12.2 Hz, 1F). ½aꢁD
¼
þ19:7 (c = 1.00, MeOH).
1.29–1.72 (m, 10H), 3.70 (s, 3H), 3.71–3.78 (m, 1H), 4.30 (ddd,
J = 33.7, J = 14.4, J = 2.1 Hz, 1H), 4.95 (dm, J = 51.0 Hz, 1H),
6.64 (d, J = 8.9 Hz, 2H), 7.09–7.29 (m, 7H). 13C NMR
(100 MHz) d 13.93, 22.40, 24.69 (d, J = 3.0 Hz), 28.92, 31.52,
32.85 (d, J = 19.9 Hz), 54.99, 55.48 (d, J = 21.4 Hz), 92.13 (d,
J = 170.5 Hz), 112.83 (2C), 126.26, 127.42 (2C), 127.72,
128.97 (2C), 130.82 (2C), 144.80, 160.56, 170.09. 19F NMR
(376 MHz) d ꢀ184.97–ꢀ184.58 (m, 1F). HRMS (EI): calc. for
C22H28NO2F: 357.2104, found: 357.2103.
3.3.10.2. (1R,2S)-2-Fluoro-1,2-diphenylethyl 3-methylben-
zoate. To a CH2Cl2 solution (3 ml) of 2-fluoro-1,2-dipheny-
lethanol (66 mg, 0.3 mmol) in a 30 ml-Teflon FEP tube was
added DFMBA (70 mg, 0.33 mmol) at 0 8C, and the mixture
was stirred at room temperature for 1 h. To the reaction mixture,
2 ml of water was added and the separated aqueous layer was
extracted with ether three times. Organic layer was dried over
MgSO4 and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel/hexane-
ether) to give 2-fluoro-1,3-diphenylethyl 3-methylbenzoate
References
24
(87 mg, 0.26 mmol). ½aꢁD ¼ þ60:7 (c = 1.00, MeOH) {lit [1]
[1] A. Yoneda, T. Fukuhara, S. Hara, Chem. Commun. (2005) 3589–3590.
[2] R.A. McClelland, S. Gedge, J. Bohonek, J. Org. Chem. 46 (1982) 886–
891.
21
½aꢁD ¼ þ61:3 (c = 1.02, MeOH)}
[3] R.A. McClelland, M. Ahmad, J. Org. Chem. 44 (1979) 1855–1860.
[4] R.F. Abdulla, R.S. Brinkmeyer, Tetrahedron 35 (1979) 1675–1735.
[5] T. Inagaki, T. Fukuhara, S. Hara, Synthesis (2003) 1157–1159.
[6] J. Otera, N. Dan-oh, H. Nozaki, J. Org. Chem. 56 (1991) 5307–5311.
[7] T. Nomoto, T. Fukuhara, S. Hara, Synlett (2006) 1744–1746.
[8] S. Ayuba, N. Yoneda, T. Fukuhara, S. Hara, Bull. Chem. Soc. Jpn. 75
(2002) 1597–1603.
3.3.11. 3-Fluoro-1-propyl 4-methoxybenzoate (8)
1
IR: (neat) n 2970, 1710, 1607, 1511, 1257, 1103 cmꢀ1. H
NMR (400 MHz) d 2.16 (dm, J = 25.7 Hz, 2H), 3.87 (s, 3H),
4.43 (t, J = 6.2 Hz, 2H), 4.62 (dt, J = 46.9, J = 5.9 Hz, 2H), 6.92
(d, J = 9.0 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H). 13C NMR
(100 MHz) d 29.81 (d, J = 19.8 Hz), 55.26, 60.44 (d, J =
5.7 Hz), 80.61 (d, J = 165.2 Hz), 113.50 (2C), 122.37, 131.45
(2C), 163.31, 166.03. 19F NMR (376 MHz) d ꢀ222.57 (tt,
[9] D.L. Tierney, P.J. Moehs, D.L. Hasha, J. Organometal. Chem. 620 (2001)
211–226.
[10] S. Rozen, O. Lerman, J. Org. Chem. 45 (1980) 672–678.