Cyclodehydration of fluorinated diols using the mitsunobu reaction: Highly efficient synthesis of trifluoromethylated cyclic ethers

Article abstract of DOI:10.1055/s-0029-1218753

Synthesis of trifluoromethylated cyclic ethers has been achieved via the Mitsunobu cyclodehydration of fluorinated diols with high efficacy. The methodology is found to be widely applicable to the synthesis of cyclic ethers with varying ring size (3-7) fr

Full text of DOI:10.1055/s-0029-1218753

SPECIAL TOPIC
1891
Cyclodehydration of Fluorinated Diols Using the Mitsunobu Reaction:
Highly Efficient Synthesis of Trifluoromethylated Cyclic Ethers
Synthesis of
T
riflu
.
oromethylate
K
d Cyclic
E
thers . Surya Prakash,* Clement Do, Fang Wang, Thomas Mathew, George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661,
USA
E-mail: gprakash@usc.edu
Received 5 March 2010
ity caused by the harsh reaction conditions involved. On
Abstract: Synthesis of trifluoromethylated cyclic ethers has been
the other hand, the Mitsunobu reaction is known to permit
achieved via the Mitsunobu cyclodehydration of fluorinated diols
the formation of C–C, C–O, C–N, and C–S bonds with
with high efficacy. The methodology is found to be widely applica-
primary or secondary alcohols under mild conditions.17 In
ble to the synthesis of cyclic ethers with varying ring size (3–7)
from fluorinated diols of differing acidities and steric demands. Cy- particular, Falck and co-workers have achieved the inter-
clic ethers with considerable ring strain can be achieved in moderate
molecular condensation of polyfluorinated alcohols to the
corresponding ethers under the Mitsunobu conditions.18
yields by this protocol. The methodology is suitable for both prima-
ry and secondary alcohols as well as benzylic and aliphatic alcohols
Although the preparation of fluorinated cyclic ethers via
as electrophiles to afford the corresponding products in moderate to
the Mitsunobu reaction has been mentioned in the patent
good yields.
literature,19,20 the synthetic and mechanistic aspects of this
Key words: cyclic ethers, Mitsunobu reaction, trifluoromethyla-
methodology have not been studied in detail.
tion, stereoselectivity, inversion of configuration
Many fluoroorganics have unique physical properties
suitable for their application as pharmaceuticals, agro-
chemicals, and organic materials.21 It is well known that
Fluorinated ethers emerge as highly promising substitutes
the presence of fluorine can result in substantial changes
for chlorofluorohydrocarbons (CFCs) owing to their ex-
in the biological properties of an organic compound.21,22
cellent solvent properties, zero ozone-depleting potential,
and low toxicity.1 They have been widely used as deter-
gents, solvents, lubricants, heat transfer media, etc.2 Aro-
matic fluoromethylated ethers are known to have
significant applications in the pharmaceutical and agricul-
tural arenas.3 Albeit the methods known for the synthesis
of these compounds using reagents such as SF44 or CCl4/
HF,5 simple and convenient protocols are rare. Develop-
ments during this decade in this area include synthesis of
trifluoromethyl ethers via xanthates utilizing BrF3,6 trap-
ping of CF3OH as useful ether derivatives,7 alkylation of
fluorinated alkoxides generated from the corresponding
fluorinated acyl halides,8 electrophilic fluoromethylation
of alcohols,9 and trifluoromethoxylation using trifluoro-
methyl triflate.10 Fluorinated cyclic ethers have received a
lot of attention in synthetic organic chemistry due to their
wide variety of applications such as blood substitutes, var-
ious effective drug candidates11 and anesthetics.12 Despite
their unique bioactivity and high demand, the synthesis of
fluorinated cyclic ethers is still not extensively investigat-
ed.13 There have been a few synthetic methods for the
preparation of fluorinated cyclic ethers, including alkox-
ide alkylations (Williamson ether synthesis),14 intramo-
lecular cyclization of fluoromethylated alkenols,15 and the
cyclization of the corresponding fluorinated alcohols me-
diated by strong acids.16 Quite often, these synthetic
routes can lead to undesired by-products and low selectiv-
Incorporation of fluorine in drug molecules can affect
their physicochemical properties, such as bond strength,
liophilicity, bioavailability, conformation, electrostatic
potential, dipole moment, pKa, etc.; pharmacokinetic
properties, such as tissue distribution; rate of metabolism;
or pharmacological consequences, such as pharmacody-
namics and toxicology. In many instances, fluorine is in-
troduced as fluoromethyl groups (CF3, CF2H, CH2F, etc.)
and effective reagents and methods have been developed
during the last two decades. Nucleophilic trifluoromethy-
lation using Ruppert–Prakash reagent23 and electrophilic
trifluoromethylation using Umemoto’s reagent24 are two
key methods widely used for the introduction of a trifluo-
romethyl group into organic substrates. Antidepressant
behavior of various basic derivatives of phthalans and
chromans has been studied followed by investigations of
pharmacological consequence of phthalan ring oxygen in
the development of conformationally defined adrenergic
agents.14,25 Since the incorporation of a CF3 group into
drug candidates often improves their binding selectivity,
lipophilicity, and metabolic stability,26 similar approach
in the case of cyclic ethers such as oxiranes, phthalans,
and their homologues are highly warranted. Therefore, we
have focused on the development of a simple and efficient
protocol for the synthesis of fluorinated cyclic ethers.
Herein, we would like to disclose the synthesis of trifluo-
romethylated cyclic ethers via the Mitsunobu cyclodehy-
dration of fluorinated diols with high efficiency and
excellent stereoselectivity (Scheme 1).
SYNTHESIS 2010, No. 11, pp 1891–1898
x
x.
x
x
.
2
0
1
0
Advanced online publication: 23.04.2010
DOI: 10.1055/s-0029-1218753; Art ID: C00610SS
© Georg Thieme Verlag Stuttgart · New York
Owing to mild reaction conditions, high stereospecificity,
and versatility, the Mitsunobu reaction27 has been widely

1892
G. K. S. Prakash et al.
SPECIAL TOPIC
n
OH
O
n
Bu3P, TMAD
O
N
NMe2
TMAD =
OH
benzene
r.t., 12 h
Me2N
N
R2
O
R1
R1 R2
n = 1, 2, 3
1
2
R1 = R2 = CF3
R1 = CF3, R2 = H
R1 = CF3, R2 = Me
Scheme 1 Synthesis of trifluoromethylated cyclic ethers via the Mitsunobu cyclodehydration
used in organic synthesis. Significant progress has been (DEAD) at room temperature, products were formed in
made in recent years in the reagent modification and in the 37–39% yield range (Table 1, entries 1–3). Although a
application of the Mitsunobu reaction28 in many useful moderate yield was observed by increasing the tempera-
synthetic protocols. A useful strategy involving the ture to 100 °C (Table 1, entry 13), the yield could not be
Mitsunobu reaction for the cyclodehydration of fluorinat- further improved even after multiple attempts with modi-
ed diols under mild conditions in the absence of acids was fication of reaction parameters including the addition se-
our main goal.
quence of reagents, changing the quantity and proportion
of substrates and the reagents as well as the reaction
media.
Initial attempts to synthesize the fluorinated cyclic ethers
under the usual Mitsunobu conditions resulted in products
with low yield (Table 1, entry 1). In order to enhance the Based on the studies reported by Falck,18 we employed the
efficacy of the reaction, various modifications of the reac- 1,1¢-(azodicarbonyl)dipiperidine (ADDP)/tributylphos-
tion parameters have been carried out. With the generally phine (TBP) system, which has been shown to be superior
used azodicarboxylate reagents such as diisopropyl azodi- to the traditional DEAD/TPP and DIAD/TPP systems for
carboxylate (DIAD) and diethyl azodicarboxylate less acidic nucleophiles (pKa ~ 11–12).29 Although the
combination of ADDP with trimethylphosphine (TMP)
gave only 32% yield (Table 1, entry 5), we were delighted
to find that the ADDP/TBP system led to an increase in
yield to 75% when the reaction was carried out in anhy-
drous benzene (Table 1, entries 6–9). Therefore, it is rea-
sonable to conclude that the relatively low acidity of the
substrates suppresses the rate of the reaction and higher
acidity results in higher yields.
Table 1 Optimization of the Mitsunobu Cyclodehydration Reaction
reagents
solvent
OH
OH
O
CF3
CF3
1d
2d
Entry
Azodicarbonyl
reagent
Phosphine
reagent
Solvent
Yield
(%)a
Both N,N,N¢,N¢-tetramethylazodicarboxamides (TMAD)
and cyanomethylene-tributylphosphorane (CMBP) are
known to mediate the Mitsunobu reaction with nucleo-
philes having pKa values higher than 13.19 We observed
that both the TMAD/TBP and CMBP systems were sig-
nificantly better than the ADDP/TBP or the traditional
DIAD/DEAD/TPP systems. While it has been shown that
CMBP is a much more reactive reagent toward less acidic
substrates in comparison with TMAD/TBP,30 we have
discovered that the TMAD/TBP system afforded a con-
siderably better yield than the CMBP system suggesting
that additional factors other than the pKa values of the nu-
cleophiles influence the yields (Table 1, entries 10 and
13). Due to the low stability and the difficulty in practical
application of CMBP, the TMAD/TBP system has been
preferentially utilized for further optimization. The opti-
mal conditions were eventually found to employ 2.0
equivalents of TBP and 2.3 equivalents of TMAD using
benzene as the solvent (Table 1, entry 10). This reaction
conditions not only achieve quantitative conversion of the
diol (monitored by 19F NMR spectroscopy) but also allow
for the easy separation of the product from the by-prod-
ucts.
1
2
DEAD
DIAD
DIAD
DEAD
ADDP
ADDP
ADDP
ADDP
ADDP
TMAD
TMAD
TMAD
–
TPP
CH2Cl2
CH2Cl2
CH2Cl2
benzene
benzene
benzene
THF
37
39
0
TPP
3
TBP
TPP
4
61b
32
75
69
71
47b
89
55
55c
69d
5
TMP
TBP
TBP
TBP
TBP
TBP
TPP
6
7
8
Et2O
9
CH2Cl2
benzene
benzene
THF
10
11
12
13
TMP
CMBP
benzene
a All reactions were performed in accordance with the general proce-
dure in the experimental section, unless stated otherwise.
b 19F NMR conversion.
After optimizing the reaction conditions, we have investi-
gated the scope of this protocol to various substrates with
c Reaction carried out at 60 °C.
d Reaction carried out at 100 °C.
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Trifluoromethylated Cyclic Ethers
1893
different acidities and steric demands. The methodology Table 2 The Mitsunobu Cyclodehydration of Fluorinated Diols
is found to be widely applicable to the synthesis of cyclic
Entry Diol 1
Cyclic ether 2
Yield (%)a
ethers with three- to seven-membered ring size (Table 2).
It is worth mentioning that the cyclic ethers with consid-
erable ring strain can also be achieved in moderate yields
by this protocol (Table 2, entries a–c). For relatively larg-
er ring systems, the yields are independent of the ring size.
The methodology is suitable for both primary and second-
ary alcohols as well as benzylic and aliphatic alcohols as
electrophiles to afford the corresponding products in mod-
erate to good yields. Reactions involving secondary alco-
hols as electrophiles (Table 2, entries a–c) result in lower
yields than the primary alcohol counterparts, primarily
due to steric reasons. Also, the steric nature of the nucleo-
philic hydroxy groups significantly affects the reaction
yields. As the steric bulkiness increases, the yield decreas-
es (Table 2, entries b–f and h–j). However, the ‘unexpect-
ed’ high yield observed in the case of substrate in entry k
can be attributed to the anisotropic steric effect of the phe-
nyl group. A series of trifluoromethyl- and bis(trifluoro-
methyl)-substituted cyclic ethers were prepared in
moderate to high yields. A diol bearing the difluorometh-
ylphenylsulfone functionality can also undergo the cyclo-
dehydration reaction to generate the corresponding
product in almost quantitative yield (Table 2, entry g).
HO
OH
Ph
O
H
CF3
Ph
a
68b
H
Ph
Ph
CF3
OH OH
CF3
O
O
b
c
60c
56
Ph
Ph
CF3
CF3
Ph
Ph
CF3
CF3
OH OH
CF3
OH
OH
O
d
e
f
89
66
40
99
CF3
CF3
OH
OH
O
F3C
F3C
F3C
OH
OH
O
CF3
CF3
F3C
OH
OH
O
The present methodology has shown excellent stereose-
lectivity. This has been investigated by studying the cy-
clodehydration of the diastereoisomerically pure
trifluoromethylaryl substituted diol 1a (Scheme 2). The
g
CF2SO2Ph
CF2SO2Ph
OH
1
relative configuration of 1a has been determined by H
h
i
78
67
O
OH
1
NOESY and H-19F HOESY spectral studies. The pres-
1
ence of a strong H-1H NOE between the two hydroxy
CF3
CF3
OH
groups but undetectable 1H-1H NOE between the two phe-
nyl groups suggests the gauche conformation of the OH
groups and the anti position of the two phenyl rings. The
1H-19F HOESY further confirms the result derived from
O
O
OH
F3C
F3C
1
1
the H-1H NOE due to the strong H-19F interaction be-
tween the F in CF3 group and the proton in Ph¢ group
(Figure 1). In fact, we found that Mitsunobu cyclodehydra-
tion reaction of 1a afforded the corresponding oxirane in
moderate yield (68%) with quantitative inversion of con-
figuration (100% dr) as anticipated (Table 2, entries a–c).
OH
OH
j
38
90
80
F3C CF3
F3C CF3
OH
OH
k
l
O
1H NOESY
1H-19F HOESY
CF3
Ph CF3
Ph
NOE
OH
OH
OH OH
OH
Ph
H
OH
Ph'
Ph
H
OH
Ph'
H
Ph'
Ph
CF3
OH
CF3
O
CF3
no NOE
weak NOE
the Ph groups are in
trans position
F3C
F3C
1a
1a
1a
a Isolated yields.
Figure 1 The NMR analysis of 3,3,3-trifluoro-1,2-diphenylpro-
pane-1,2-diol (1a)
b Determined by 2D NMR experiments.
c Isolated yield of an inseparable mixture of diastereoisomers. Deter-
mined by 19F NMR analysis of the crude mixture.
Beside the development of the synthetic route into a prac-
tically useful methodology, we have also investigated the
mechanistic aspects of the reaction. As reported by Ver-
daguer et al.,31 the use of TBP under the Mitsunobu cyclo-
dehydration can lead to an inversion of configuration of
the diols, whereas the application of TPP results in the re-
tention of relative configuration. Although the similar in-
version result was observed in the TBP-mediated
cyclodehydration of 1a, the reported retention of configu-
ration was not found when TPP was used. Differing from
Verdaguer’s findings, this result evidently suggests that
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

1894
G. K. S. Prakash et al.
SPECIAL TOPIC
Ph
O–
Ph
O–
CF3
Ph
O
inversion
H
H
CF3
Ph
+
H
P+
O
CF3
O
P+
Ph
Ph
4a
4b
2a
A
B
P
HO
OH
Ph
O
O
H
H
Ph
CF3
Ph
CF3
Ph
–O
–O
+
1a
3
+
CF3
Ph
Ph
CF3
O
H
CF3
Ph
H
Ph
H
Ph
+
– Ph3P=O
Ph
4c
retention
4d
inversion
2a
+
inversion
retention
O
H
Ph
Ph
CF3
O–
CF3
O–
CF3
+
+
2a'
H
Ph
Ph
H
+
Ph
Ph
4e
retention
4f
inversion
Scheme 2 Proposed reaction pathway
the diastereoselectivity in the Mitsunobu cyclodehydra- synthesis of a series of fluorinated cyclic ethers of varying
tion reaction of fluorinated diol is independent of the ster- ring size (n = 3–7) in moderate to high yields as well as in
ic demands and electronegativity of the phosphines. high diastereoselectivity.
Consequently, the traditional Mitsunobu mechanism in-
volving the formation of the pentacoordinate phosphorane
Unless otherwise mentioned, all the chemicals were purchased from
commercial sources. TMAD,33 trifluoroacetaldehyde,34 and 3-(2-
bromophenyl)propan-1-ol35,36 were prepared according to known
procedures. The DriSolv® solvents were purchased from EMDTM
and used without further purification. Products were separated and
purified by column chromatography (silica gel, 60–200 mesh from
silicycle). 1H, 13C, 19F, and 2D spectra including COSY and NOESY
were recorded on 400 MHz Varian NMR spectrometer. The HOESY
spectra were recorded on 500 MHz Bruker NMR spectrometer.
1H NMR chemical shifts were determined relative to tetramethylsi-
lane (TMS) at d = 0.0 or to residual solvent peak (at d = 7.26 for
CDCl3 and d = 3.31 for CD3OD). 13C NMR shifts were determined
relative to TMS at d = 0.00 or to the residual solvent peak (at
d =77.16 for CDCl3 and d = 49.00 for CD3OD). 19F NMR chemical
shifts were determined relative to internal standard CFCl3 at
d = 0.00. Mass spectra were recorded on a high resolution mass
spectrometer in the EI, FAB, or ESI mode.
3 evolved from MBH (Morris–Brunn–Huisgen) betaine
intermediates can be proposed to rationalize the observa-
tions (Scheme 2, A and B). It is apparent that a high dia-
stereoselectivity can be accomplished in pathway A no
matter whether 4a or 4b is formed.31 According to
Richard,32 the transition states involving the intermediates
4c and 4d are expected to be unfavorable due to their ther-
modynamic instability and kinetic stability. In other
words, the intermediates 4e and 4f can play a significant
role in the diastereoselectivity of the reaction. If the reac-
tion follows the pathway B at any appreciable rate, a mix-
ture with lower diastereoisomeric purity is likely to be
formed. Since quantitative inversion of configuration was
observed in the product, the pathway A is obviously pre-
ferred. More electron-deficient and steric demanding TPP
was found to have no effect on the stereospecificity sug-
gesting that the Mitsunobu cyclodehydration reaction
may be phosphine independent. However, further investi-
gation is still needed.
cis-3,3,3-Trifluoro-1,2-diphenylpopane-1,2-diol (1a)
cis-3,3,3-Trifluoro-1,2-diphenylpropane-1,2-diol (1a) was pre-
pared according to the known procedure (Scheme 3).37 Addition of
TMSCF3 (1.2 equiv) to benzil (1 equiv) gave the corresponding
monosilyl-protected ether intermediate, which on hydrolysis using
TBAF produced the diphenyl keto alcohol in 83% yield; Rf = 0.73
(10:1 mixture of hexane and EtOAc).38 The corresponding fluori-
nated diol 1a was obtained by reduction of the diphenyl keto alcohol
with NaBH4; yield: 86%; Rf = 0.43 (4:1 mixture of hexane and
EtOAc).
In summary, a highly efficient Mitsunobu protocol for the
stereoselective cyclodehydration of fluorinated diols to
fluorinated cyclic ethers has been developed. This meth-
odology has been found to be widely applicable for the
O
HO CF3
HO
OH
Ph
TMSO CF3
TBAF, H2O
NaBH4
TMSCF3
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
CF3
O
O
O
1a
Scheme 3
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Trifluoromethylated Cyclic Ethers
1895
OH
OTIPS
OTIPS
OH
OH
OH
TBAF, H2O
TIPSCl
n-BuLi
F3C
imidazole
I
I
O
F3C
F3C
1e
1 M HCl
Scheme 4
Fluorinated Diols 1d–f and 1h–l (Table 2, Entries d–f, h–l);
1,1,1-Trifluoro-2-[2-(hydroxymethyl)phenyl]propan-2-ol (1e);
Typical Procedure
(1) TMSCF3 or PhSO2CF2H
(2) TBAF
OTIPS
H
OH
R
Triisopropylsilyl-protected alcohol was prepared following a re-
ported procedure (Scheme 4).39 To a stirred solution of 2-iodoben-
zyl alcohol (1.84 g, 7.85 mmol) in THF (22 mL) was added
imidazole (1.6 g, 22.55 mmol) and the mixture was stirred for 15
min. Triisopropylsilyl chloride (TIPSCl, 1.84 g, 10.21 mmol) was
then added to the solution and allowed to stir for another 12 h at r.t.
The reaction mixture was quenched with H2O (30 mL) and extract-
ed with CH2Cl2 (3 × 15 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure. The crude (2-iodobenzyloxy)triisopropyl-
silane obtained was dried and directly used in the next step. To a
stirred solution of (2-iodobenzyloxy)triisopropylsilane (1.40 g, 3.59
mmol) in anhyd Et2O (23.5 mL) was added a solution of 1.7 M t-
BuLi in pentane (4.22 mL, 7.18 mmol) dropwise at –78 °C under ar-
gon. After stirring the mixture for 10 min 1,1,1-trifluoroacetone
(0.804 g, 7.18 mmol) was added. When the mixture turned pale yel-
low, it was warmed to r.t. and was quenched with aq 1 M HCl (40
mL). The mixture was extracted with Et2O (3 × 15 mL), dried
(MgSO4), filtered, and evaporated under reduced pressure. The
crude product was purified by flash chromatography to obtain 1,1,1-
trifluoro-2-[2-(triisopropylsilyloxymethyl)phenyl)propan-2-ol.
1,1,1-Trifluoro-2-(2-[(triisopropylsilyloxymethyl)phenyl]propan-
2-ol (771 mg, 2.05 mmol) was suspended in THF (4 mL) and cooled
to 0 °C. A 1.0 M solution of TBAF in THF (2.67 mL, 2.67 mmol,
1.3 equiv) was added, the mixture was stirred for 1 h, and then the
THF was removed by vacuum evaporation. The residual oil was im-
mediately purified by chromatography on silica gel (1:1 mixture of
hexane and EtOAc as eluent) to give the corresponding diol in 62%
yield.
O
OH
1g: R = CF3, 1h: PhSO2CF2
Scheme 6
Mitsunobu Cyclodehydration Reaction; 1-(Trifluoromethyl)-
1,3-dihydroisobenzofuran (2d) ; Typical Procedure
To a stirred solution of the fluorinated diol 1d (49.4 mg, 0.24 mmol)
in anhyd benzene (2.5 mL) was added Bu4P (0.12 mL, 0.48 mmol)
followed by TMAD (95 mg, 0.55 mmol) at r.t. The reaction mixture
was then flushed with argon, sealed, and allowed to stir for 12 h at
the same temperature. The crude mixture was then purified by flash
column chromatography (silica gel 60–230 mesh, 10:1 mixture of
pentane and CH2Cl2 as eluent) to give the cyclic ether 2d (40 mg,
89%) as a colorless liquid.
(1R,2R)- and (1S, 2S)-3,3,3-Trifluoro-1,2-diphenylpropane-1,2-
diol (1a)
1H NMR: d = 7.71–7.66 (m, 2 H), 7.49–7.40 (m, 3 H), 7.40–7.31 (m,
5 H), 5.34 (d, J = 3.6 Hz, 1 H), 3.05 (s, 1 H), 2.14 (d, J = 3.7 Hz, 1
H).
13C NMR: d = 137.06, 135.26, 129.04, 128.96, 128.54, 128.33,
127.86, 126.53, 124.67 (q, 1JC,F = 286.3 Hz), 79.53 (q, 2JC,F = 26.8
Hz), 75.93.
19F NMR: d = –73.96.
HRMS (EI): m/z [M – H2O]+ calcd for C15H11F3O: 264.0762; found:
264.0762.
4,4,4-Trifluoro-1-phenylbutane-1,3-diol (1b)
Compounds 1b and 1c; General Procedure
1H NMR: d = 7.43–7.28 (m, 10 H), 5.11 (dd, J = 2.8, 8.8 Hz, 1 H),
4.99 (dd, J = 3.5, 9.7 Hz, 1 H), 4.36–4.16 (m, 2 H), 4.05 (br s, 1 H),
3.48 (br s, 1 H), 2.79 (br s, 1 H), 2.46 (br s, 1 H), 2.20–1.96 (m, 4 H).
4,4,4-Trifluoro-3-hydroxy-1-phenylbutan-1-one was prepared ac-
cording to the literature procedure (Scheme 5).40 The subsequent al-
dol product or the commercially available 4,4,4-trifluoro-3-
hydroxy-3-(trifluoromethyl)butyrophenone was subjected to
reduction41 using NaBH4 to give the corresponding diol.
13C NMR: d = 143.09, 142.84, 128.85, 128.77, 128.45, 128.09,
1
125.65, 125.46, 125.17 (q, JC,F = 287.1 Hz), 124.47 (q,
1JC,F = 280.9 Hz), 74.12, 70.69, 70.63 (q, 2JC,F = 31.6 Hz), 67.88 (q,
2JC,F = 31.3 Hz), 37.64, 37.47.
O
OH
OH OH
NaBH4
19F NMR: d = –79.89 (d, J = 7.0 Hz, 3 F), –80.84 (d, J = 6.5 Hz, 3
F).
R
CF3
R
CF3
Ph
Ph
1b: R = H, 1c: R = CF3
4,4,4-Trifluoro-1-phenyl-3-(trifluoromethyl)butane-1,3-diol
(1c)
Scheme 5
1H NMR: d = 7.50–7.38 (m, 5 H), 6.38 (s, 1 H), 5.31 (d, J = 11.6 Hz,
1 H), 2.88 (s, 1 H), 2.41 (dddd, J = 1.9, 3.9, 11.6, 15.5 Hz, 1 H), 2.24
(d, J = 15.3 Hz, 1 H).
Compounds 1g and 1h; General Procedure
2-(Triisopropylsilyloxymethyl)benzaldehyde was prepared from o-
xylene glycol following the known procedure (Scheme 6).38 The al-
13C NMR: d = 141.99, 129.02, 125.42, 123.46 (q, 1JC,F = 287.9 Hz),
23
1
2
dehyde could either undergo trifluoromethylation with TMSCF3
122.59 (q, JC,F = 287.2 Hz), 76.44 (sept, JC,F = 29.4 Hz), 71.87,
or difluoromethylation with difluoromethyl phenyl sulfone42 to give
the corresponding protected fluorinated alcohols. Removal of the
protecting groups with TBAF gave the desired fluorinated diols.
36.25.
19F NMR: d = –75.88 (q, J = 10.0 Hz, 3 F), –79.82 (q, J = 9.8 Hz, 3
F).
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

1896
G. K. S. Prakash et al.
SPECIAL TOPIC
2,2,2-Trifluoro-1-[2-(hydroxymethyl)phenyl]ethanol (1d)
1H NMR: d = 7.63–7.57 (m, 1 H), 7.44–7.34 (m, 3 H), 5.43 (q,
J = 7.1 Hz, 1 H), 4.84–4.76 (m, 2 H), 3.80 (br s, 1 H), 2.21 (br s, 1
H).
13C NMR: d = 139.79, 133.15, 130.38, 130.27, 128.16, 126.73,
1
2
123.13 (q, JC,F = 288.6 Hz), 79.92 (quint, JC,F = 29.3 Hz), 64.08,
35.44.
19F NMR: d = –74.81.
13C NMR: d = 138.49, 133.32, 129.95, 129.71, 128.92, 128.82,
124.63 (q, 1JC,F = 282.6 Hz), 70.41 (q, 2JC,F = 32.2 Hz), 64.09.
2,2,2-Trifluoro-1-[2-(2-hydroxyethyl)phenyl]-1-phenylethanol
(1k)
19F NMR: d = –77.37 (d, J = 5.6 Hz, 3 F).
1H NMR: d = 7.76 (d, J = 8.0 Hz, 1 H), 7.47–7.40 (m, 3 H), 7.40–
7.26 (m, 5 H), 5.87 (br s, 1 H), 4.00–3.63 (m, 2 H), 2.97–2.86 (m, 1
H), 2.46–2.35 (m, 1 H), 1.96 (br s, 1 H).
1,1,1-Trifluoro-2-[2-(hydroxymethyl)phenyl]propan-2-ol (1e)
1H NMR (CD3OD): d = 7.52–7.49 (m, 1 H), 7.39–7.35 (m, 1 H),
7.29 (dt, J = 1.5, 7.5 Hz, 1 H), 7.25–7.20 (m, 1 H), 4.97 (d, J = 13.6
Hz, 1 H), 4.77 (d, J = 13.6 Hz, 1 H).
13C NMR (CD3OD): d = 142.29, 137.89, 130.86, 129.58, 129.37, (q,
3J = 1.7 Hz), 128.13, 127.71 (q, 1J = 285.9 Hz), 77.94 (q, 2J = 28.6
Hz), 64.77, 25.10 (q, 3J = 1.3 Hz).
13C NMR: d = 140.72, 138.88, 138.81, 132.21, 129.13, 128.17,
3
127.80, 127.77, 127.42 (q, JC,F = 3.8 Hz), 126.02, 125.19 (q,
1JC,F = 286.5 Hz), 79.85 (q, 2JC,F = 27.2 Hz), 64.11, 34.84.
19F NMR: d = –74.53.
3-[2-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl]propan-1-
ol (1l)
19F NMR: d = –81.61.
1H NMR: d = 7.36–7.30 (m, 1 H), 7.27–7.18 (m, 2 H), 7.18–7.12 (m,
1 H), 5.21 (s, 1 H), 3.60–3.51 (m, 1 H), 3.50–3.45 (m, 1 H), 3.45–
3.33 (m, 1 H), 3.12 (s, 1 H), 2.87–2.78 (m, 1 H), 1.93–1.81 (m, 2 H),
1.77 (s, 3 H).
1,1,1,3,3,3-Hexafluoro-2-[2-(hydroxymethyl)phenyl]propan-2-
ol (1f)
1H NMR: d = 7.81–7.74 (m, 1 H), 7.66 (br s, 1 H), 7.49–7.41 (m, 2
H), 7.39–7.32 (m, 2 H), 4.95 (s, 1 H), 2.79 (br s, 1 H).
19F NMR: d = –80.09.
13C NMR d = 138.16, 132.67, 130.27, 130.11, 129.28 (hept, 3J = 3.4
1
Hz), 129.22, 122.88 (q, JC,F = 288.9 Hz), 104.99, 79.75 (hept,
(2S,3R)-2,3-Diphenyl-2-(trifluoromethyl)oxirane (2a)43
1H NMR: d = 7.32–7.20 (m, 5 H), 7.19–7.10 (m, 3 H), 7.02–6.96 (m,
2 H), 4.61 (s, 1 H).
2J = 29.4 Hz), 66.67.
19F NMR: d = –75.46.
13C NMR: d = 131.96, 129.28, 129.21, 128.50, 128.12, 128.08,
127.93, 126.70, 123.11 (q, 1JC,F = 279.5 Hz), 64.58 (q, 2JC,F = 35.7
Hz), 60.43.
19F NMR: d = –74.98.
2,2-Difluoro-1-[2-(hydroxymethyl)phenyl]-2-(phenylsulfo-
nyl)ethanol (1g)
1H NMR: d = 8.01 (d, 7.5 Hz, 2 H), 7.80–7.74 (m, 1 H), 7.66–7.58
(m, 3 H), 7.40–7.32 (m, 3 H), 6.02 (dd, J = 2.4, 22.1 Hz, 1 H), 4.76
(s, 2 H), 3.93 (br s, 1 H), 2.18 (br s, 1 H).
2-Phenyl-4-(trifluoromethyl)oxetane (2b)
13C NMR: d = 138.90, 135.59, 132.56, 132.45, 130.70, 129.67,
1H NMR: d = 7.31–7.48 (m, 10 H), 5.87 (t, J = 7.54 Hz, 1 H), 5.80
(t, J = 7.7 Hz, 1 H), 4.98–5.08 (m, 1 H), 4.85–4.96 (m, 1 H), 3.04–
3.14 (m, 2 H), 2.75–2.91 (m, 2 H).
1
129.52, 129.34, 129.26, 128.45, 120.64 (dd, JC,F = 289.0 Hz,
2
2
1JC,F = 299.5 Hz), 67.97 (dd, JC,F = 19.2 Hz, JC,F = 26.5 Hz),
63.55.
13C NMR: d = 141.53, 140.76, 128.72, 128.60, 128.57, 128.53,
125.54, 125.25, 124.93 (q, 1JC,F = 280.2 Hz), 123.77 (q, 1JC,F = 279
Hz), 81.90, 79.89, 74.14 (q, 2JC,F = 35.2 Hz), 72.72 (q, 2JC,F = 36.1
Hz), 30.15, 30.08.
19F NMR: d = –104.25 (dd, J = 2.0, 238.0 Hz, 1 F), –118.41 (dd,
J = 22.1, 238.0 Hz, 1 F).
2,2,2-Trifluoro-1-[2-(2-hydroxyethyl)phenyl]ethanol (1h)
1H NMR: d = 7.54 (d, J = 7.6 Hz, 1 H), 7.28–7.16 (m, 3 H), 5.32 (q,
J = 7.0 Hz, 1 H), 3.66 (t, J = 7.3 Hz, 2 H), 2.92 (td, J = 7.3, 14.6 Hz,
1 H), 2.79 (td, J = 7.9, 22.6 Hz, 1 H).
19F NMR: d = –80.3, –81.80.
HRMS (EI): m/z calcd for C10H9F3O: 202.0605; found: 202.0599.
3
13C NMR: d = 137.28, 133.95, 129.85, 128.52, 127.64 (q, J = 1.3
4-Phenyl-2,2-bis(trifluoromethyl)oxetane (2c)
1H NMR: d = 7.44–7.34 (m, 5 H), 5.92 (t, J = 7.68 Hz, 1 H), 3.23–
3.19 (m, 1 H), 3.12–3.04 (m, 1 H).
Hz), 126.14, 125.14 (q, 1JC,F = 282 Hz), 67.73 (q, 2JC,F = 31.2 Hz),
62.43, 35.30.
19F NMR: d = –74.89 (dd, J = 2.5, 6.6 Hz, 3 F).
13C NMR: d = 138.94, 129.08, 128.81, 125.40, 123.02 (q,
1JC,F = 284.6 Hz), 121.65 (q, 1JC,F = 283.0 Hz), 80.17, 78.57 (quint,
2JC,F = 33.3 Hz), 31.21.
19F NMR d = –78.68 (q, J = 8.9 Hz, 3 F), –79.53 (q, J = 8.9 Hz, 3 F).
1,1,1-Trifluoro-2-[2-(2-hydroxyethyl)phenyl]propan-2-ol (1i)
1H NMR: d = 7.41 (d, J = 7.9 Hz, 1 H), 7.35–7.30 (m, 1 H), 7.26–
7.21 (m, 2 H), 5.49 (br s, 1 H), 4.03 (td, J = 4.6, 9.4 Hz, 1 H), 3.86
(dt, J = 3.5, 9.6 Hz, 1 H), 3.70 (ddd, J = 4.7, 9.7, 14.2 Hz, 1 H), 2.96
(td, J = 4.2, 13.9 Hz, 1 H), 2.13 (br s, 1 H), 1.82–1.80 (m, 3 H).
HRMS (EI): m/z calcd for C11H8F6O: 270.0479; found: 270.0482.
1-(Trifluoromethyl)-1,3-dihydroisobenzofuran (2d)
1H NMR: d = 7.44–7.38 (m, 2 H), 7.38–7.32 (m, 1 H), 7.32–7.27 (m,
1 H), 5.48 (dq, J = 2.8, 6.5 Hz, 1 H), 5.33–5.27 (m, 1 H), 5.20 (d,
J = 12.2 Hz, 1 H).
13C NMR: d = 138.88, 137.94, 132.33, 128.97, 128.29, 126.39,
1
125.93 (q, JC,F = 285.9 Hz), 77.20 (q, J = 9.7 Hz), 64.34, 35.83,
26.12.
19F NMR: d = –80.31.
3
13C NMR: d = 140.02, 132.62 (q, JC,F = 1.4 Hz), 129.47, 127.89,
1
3
124.19 (q, JC,F = 282.4 Hz), 122.93 (q, JC,F = 1.1 Hz), 121.17,
1,1,1,3,3,3-Hexafluoro-2-[2-(2-hydroxyethyl)phenyl]propan-2-
ol (1j)
81.33 (q, 2JC,F = 33.1 Hz), 74.68.
19F NMR: d = –78.99 (d, J = 6.5 Hz, 3 F).
1H NMR: d = 7.68 (d, J = 8.2 Hz, 1 H), 7.43 (dt, J = 1.3, 7.5 Hz, 1
H), 7.34–7.27 (m, 2 H), 4.01 (t, J = 5.6 Hz, 2 H), 3.36 (t, J = 5.6 Hz,
2 H), 2.22 (br s, 1 H).
HRMS (EI): m/z calcd for C9H7F3O: 180.0449; found: 188.0455.
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Trifluoromethylated Cyclic Ethers
1897
1-Methyl-1-(trifluoromethyl)-1,3-dihydroisobenzofuran (2e)
1H NMR: d = 7.43–7.29 (m, 3 H), 7.29–7.23 (m, 1 H), 5.20 (q,
J = 12.2 Hz, 2 H), 5.20 (q, J = 1.1 Hz, 3 H).
13C NMR: d = 139.91, 137.44, 129.27, 127.85, 125.57 (q,
1JC,F = 286.0 Hz), 122.60, 121.08, 86.55 (q, 2JC,F = 29.9 Hz), 73.72,
20.95.
Hz, 1 H), 3.12 (ddd, J = 5.8, 10.2, 16.1 Hz, 1 H), 2.67 (dt,
J = 3.6, 16.4 Hz, 1 H).
13C NMR: d = 137.59, 135.13, 131.30, 129.62, 128.88, 128.65,
128.27, 127.90 (q, 3JC,F = 3.4 Hz), 125.99, 125.22 (q, 1JC,F = 286.2
Hz), 80.96 (q, 2JC,F = 27.9 Hz), 60.93, 28.58.
19F NMR: d = –73.71.
19F NMR: d = –81.58.
HRMS (EI): m/z calcd for C16H13F3O: 278.0918; found: 278.0916.
HRMS (EI): m/z calcd for C10H9F3O: 202.0605; found: 202.0619.
1-Methyl-1-(trifluoromethyl)-1,3,4,5-tetrahydrobenzo[c]ox-
epine (2l)
1,1-Bis(trifluoromethyl)-1,3-dihydroisobenzofuran (2f)
1H NMR: d = 7.57–7.50 (m, 2 H), 7.46–7.40 (m, 1 H), 7.37–7.32 (m,
1 H), 5.37 (s, 2 H).
1H NMR: d = 7.30–7.22 (m, 3 H), 7.17–7.12 (m, 1 H), 3.94–3.85 (m,
1 H), 3.68–3.57 (m, 1 H), 3.47–3.35 (m, 1 H), 2.69–2.59 (m, 1 H),
2.18–2.05 (m, 1 H), 1.83–1.67 (m, 4 H).
13C NMR: d = 140.56, 131.08, 129.55, 128.50, 123.80, 121.32,
122.33 (q, 1JC,F = 287.5 Hz), 87.70 (quint, 2JC,F = 31.7 Hz), 76.02.
13C NMR: d = 139.88, 135.48, 130.88, 129.08, 128.73, 126.82,
125.68 (q, 1JC,F = 285.6 Hz), 83.86 (q, 2JC,F = 27.8 Hz), 61.29, 30.33
(q, 3JC,F = 1.2 Hz), 27.80, 21.60.
19F NMR: d = –79.30.
19F NMR: d = –76.75.
HRMS (EI): m/z calcd for C10H6F6O: 256.0323; found: 256.0309.
1-[Difluoro(phenylsulfonyl)methyl]-1,3-dihydroisobenzofuran
(2g)
HRMS (EI): m/z calcd for C12H13F3O: 230.0918; found: 230.0915.
1H NMR: d = 8.02 (d, J = 7.6 Hz, 2 H), 7.78–7.71 (m, 1 H), 7.63–
7.57 (m, 2 H), 7.43–7.36 (m, 2 H), 7.35–7.25 (m, 2 H), 6.01–5.90
(m, 1 H), 5.22–5.11 (m, 2 H).
Acknowledgment
Support of our work by Loker Hydrocarbon Research Institute is
gratefully acknowledged.
13C NMR: d = 140.39, 135.29, 133.70, 132.52, 130.75, 129.50,
1
129.17, 127.84, 123.47, 121.16, 120.65 (dd, JC,F = 289.6, 297.1
Hz), 80.61 (dd, 2JC,F = 22.5, 28.5 Hz), 74.86.
References
19F NMR: d = –107.97 (d, J = 242.8 Hz, 1 F), –117.20 (dd,
J = 20.8, 240.8 Hz, 1 F).
(1) (a) Zurer, P. S. Chem. Eng. News 1993, (Nov. 15), 12.
(b) Lamanna, W. M.; Flynn, R. M.; Vitcak, D. R.; Qiu,
Z.-M. PCT Int. Appl., WO 9947480, 1999; Chem. Abstr.
1999, 131, 230275.
(2) (a) Takata, N.; Mochizuki, T.; Fujimoto, E.; Sekiya, A.
Japanese Patent 10045651, 1998; Chem. Abstr. 1998, 128,
192366. (b) Dams, R. J.; Qiu, Z.-M.; Smolders, R. L.;
Coppens, D. M.; Nagase, M. PCT Int. Appl., WO 9916809,
1999; Chem. Abstr. 1999, 130, 282529.
1-(Trifluoromethyl)isochroman (2h)
1H NMR: d = 7.34–7.16 (m, 4 H), 5.12 (q, J = 7.3 Hz, 1 H), 4.28–
4.16 (m, 1 H), 3.94–3.83 (m, 1 H), 2.99–2.77 (m, 2 H).
13C NMR: d = 135.23, 128.96, 128.32, 127.61, 126.71 (q, 3JC,F = 2.4
Hz), 126.51, 124.58 (q, 1JC,F = 283.9 Hz), 73.13 (q, 2JC,F = 30.3 Hz),
63.00, 28.47.
19F NMR: d = –75.28 (d, J = 7.3 Hz, 3 F).
(3) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555. (b) Becker, A. Inventory of Industrial Fluoro-
Biochemicals; Eyrolles: Paris, 1996.
HRMS (EI): m/z calcd for C10H9F3O: 202.0605; found: 202.0616.
(4) Dmowski, W.; Kaminski, M. J. Fluorine Chem. 1983, 23,
207.
(5) (a) Feiring, A. F. J. Org. Chem. 1979, 44, 2907.
(b) Langlois, B.; Desbois, M. Ann. Chim. (Paris) 1984, 9,
729. (c) Salom, J.; Mauger, C.; Brunet, S.; Schanen, V.
J. Fluorine Chem. 2004, 125, 1947.
(6) Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S.
J. Fluorine Chem. 1999, 97, 75.
(7) Christe, K. O.; Hegge, J.; Hoge, B.; Haiges, R. Angew.
1-Methyl-1-(trifluoromethyl)isochroman (2i)
1H NMR: d = 7.38–7.31 (m, 1 H), 7.30–7.21 (m, 2 H), 7.19–7.13 (m,
1 H), 4.20–4.11 (m, 1 H), 3.98–3.88 (m, 1 H), 2.87 (tdd, J = 5.2,
11.2, 16.1 Hz, 2 H), 1.67 (q, J = 1.0 Hz, 3 H).
13C NMR: d = 134.87, 132.81, 128.97, 127.97, 126.64, 126.58 (q,
1
2
3JC,F = 2.4 Hz), 125.89 (q, JC,F = 287.2 Hz), 76.25 (q, JC,F = 27.7
Hz), 61.47, 29.07, 23.27.
19F NMR: d = –77.71.
Chem. Int. Ed. 2007, 46, 6155.
(8) Prakash, G. K. S.; Hu, J.; Olah, G. A. ARKIVOC 2003, (iii),
104.
HRMS (EI): m/z calcd for C11H11F3O: 216.0762; found: 216.0777.
1,1-Bis(trifluoromethyl)isochroman (2j)
1H NMR: d = 7.66–7.60 (m, 1 H), 7.41 (dt, J = 1.3, 7.5 Hz, 1 H),
7.36–7.29 (m, 1 H), 7.27–7.22 (m, 1 H), 4.17 (t, J = 5.5 Hz, 2 H),
2.93 (t, J = 5.5 Hz, 2 H).
(9) (a) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.;
Niedermann, K.; Togni, A. Angew. Chem. Int. Ed. 2009, 48,
4332. (b) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org.
Chem. 2007, 72, 6905. (c) Prakash, G. K. S.; Ledneczki, I.;
Chacko, S.; Olah, G. A. Org. Lett. 2008, 10, 557.
(d) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A.
Org. Lett. 2007, 9, 1863. (e) For a recent review, see:
Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R.
J. Fluorine Chem. 2010, 131, 140.
3
13C NMR: d = 136.32, 129.78, 129.34, 127.23 (quint, JC,F = 2.8
1
Hz), 127.13, 123.80, 122.77 (q, JC,F = 288.6 Hz), 77.22 (quint,
2JC,F = 29.3 Hz), 63.27, 28.56.
19F NMR: d = –78.68 (q, J = 8.9 Hz, 3 F), –79.53 (q, J = 8.9 Hz, 3
F).
(10) Marrec, O.; Billard, T.; Vors, J.-P.; Pazenok, S.; Langlois, B.
R. J. Fluorine Chem. 2010, 131, 200.
HRMS (EI): m/z calcd for C11H8F6O: 270.0479; found: 270.0481.
(11) Satake, K. PCT Int. Appl. WO 9925714, 1999; Chem. Abstr.
1999, 131, 5190.
1-Phenyl-1-(trifluoromethyl)isochroman (2k)
1H NMR: d = 7.57–7.46 (m, 3 H), 7.39–7.25 (m, 5 H), 7.24–7.19 (m,
1 H), 4.09 (ddd, J = 3.3, 5.7, 11.1 Hz, 1 H), 3.76 (dt, J = 3.9, 10.8
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York

1898
G. K. S. Prakash et al.
SPECIAL TOPIC
(26) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
(12) Eger, E. I.; Leman, D.; Laster, M. J.; Liao, M.; Jankowska,
K.; Raghavanpillai, A.; Popov, A. V.; Gan, Y.; Lou, Y.
Anesth. Analg. 2007, 104, 1090.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: New York, 1993.
(b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Chem. Soc. Rev. 2008, 37, 320. (d) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359.
(13) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,
827.
(14) Shishido, Y.; Wakabayashi, H.; Koike, H.; Ueno, N.; Nukui,
S.; Yamagishi, T.; Murata, Y.; Naganeo, F.; Mizutani, M.;
Shimada, K.; Fujiwara, Y.; Sakakibara, A.; Suga, O.;
Kusano, R.; Ueda, S.; Kanai, Y.; Tsuchiya, M.; Satake, K.
Bioorg. Med. Chem. 2008, 16, 7193.
(15) Becker, H.-D. J. Org. Chem. 1970, 35, 2099.
(16) Parham, W. E.; Sayed, Y. A. Synthesis 1976, 116.
(17) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar,
K. V. P. P. Chem. Rev. 2009, 109, 2551.
(18) Falck, J. R.; Yu, J.; Cho, H.-S. Tetrahedron Lett. 1994, 35,
5997.
(19) Obach, R. S.; Scully, D. A. PCT Int. Appl. WO 0071538,
2000; Chem. Abstr. 2001, 134, 17405.
(27) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
React. 1992, 42, 335. (c) Mitsunobu, O.; Eguchi, M. Bull.
Chem. Soc. Jpn. 1971, 44, 3427. (d) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127. (e) Mcnulty, J.; Capretta,
A.; Laritchev, V.; Dyck, J.; Robertson, A. J. Angew. Chem.
Int. Ed. 2003, 42, 4051.
(28) (a) Dembinski, R. Eur. J. Org. Chem. 2004, 2763. (b) Ito,
S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053.
(c) Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10,
3130. (d) But, T. Y. S.; Toy, P. T. J. Am. Chem. Soc. 2006,
128, 9636.
(20) Caron, S.; Vazquez, E. Eur. Pat. Appl. EP 1095939A2, 2001;
Chem. Abstr. 2001, 134, 326407.
(29) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett.
1994, 3, 539.
(21) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, 2004. (c) Smart, R.
E.; Banks, B. E.; Tatlow, J. C. Organofluorine Chemistry:
Principles and Commercial Applications; Plenum: New
York, 1994.
(30) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.;
Yamamoto, H.; Ito, S. Tetrahedron Lett. 1996, 37, 2463.
(31) Garcia-Delgado, N.; Riera, A.; Verdaguer, X. Org. Lett.
2007, 9, 635.
(32) Richard, J. P.; Amyes, T. L.; Bei, L.; Stubblefield, V. J. Am.
Chem. Soc. 1990, 112, 9513.
(22) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Biomedical
Frontiers of Fluorine Chemistry, ACS Symposium Series
639; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.;
American Chemical Society: Washington DC, 1996.
(c) Banks, R. E. Organofluorine Chemicals and their
Industrial Applications; Ellis Harwood: New York, 1979.
(d) Peters, R. Carbon-Fluorine Compounds Chemistry,
Biochemistry and Biological Activities, A Ciba Foundation
Symposium; Elsevier: Amsterdam, 1972. (e) Walsh, C. T.
Annu. Rev. Biochem. 1984, 53, 493.
(23) Prakash, G. K. S.; Yudin, A. Chem. Rev. 1997, 97, 757.
(24) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(25) (a) Petersen, P. V.; Lassen, N.; Nørgaard, J.; Huld, T. US
Patent 3467675, 1969; Chem. Abstr. 1967, 66, 37770.
(b) DeBernardis, J. F.; Arendsen, D. L.; Kyncl, J. J.;
Kerman, D. J. J. Med. Chem. 1987, 30, 178.
(33) Smissman, E. E.; Makriyannis, A. J. Org. Chem. 1973, 38,
1652.
(34) Landge, S. M.; Borkin, D. A.; Török, B. Tetrahedron Lett.
2007, 48, 6372.
(35) Marshall, L. J.; Roydhouse, M. D.; Slawin, A. M. Z.;
Walton, J. C. J. Org. Chem. 2007, 72, 898.
(36) Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L.-H. J. Med. Chem.
2000, 43, 1050.
(37) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am.
Chem. Soc. 1989, 111, 393.
(38) Blagg, B. S. J.; Poulter, C. D. J. Org. Chem. 1999, 64, 1508.
(39) Brewer, A. R. E.; Drake, A. F.; Gibson, S. E.; Rendell, J. T.
Tetrahedron 2008, 64, 6615.
(40) Zhang, F.; Peng, Y.; Liao, S.; Gong, Y. Tetrahedron 2007,
63, 4636.
(41) Paleta, O.; Palecek, J.; Dolensky, B. J. Fluorine Chem. 2001,
111, 175.
(c) Dem’yanovich, V. M.; Shishkina, I. N.; Kuznetsova, A.
A.; Potekhin, K. A.; Chesnova, A. V. Russ. J. Org. Chem.
2006, 42, 986.
(42) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org.
Chem. 2005, 2218.
(43) Kawashima, T.; Ohno, F.; Okazaki, R.; Ikeda, H.; Inagaki, S.
J. Am. Chem. Soc. 1996, 118, 12455.
Synthesis 2010, No. 11, 1891–1898 © Thieme Stuttgart · New York