Comparative study of the ring opening of 1-CF3-epoxy ethers mediated by Br?nsted acids and hexafluoro-2-propanol

Article abstract of DOI:10.1016/j.jfluchem.2004.12.008

In order to evaluate more deeply the nature of the activation of oxirane ring opening reactions by HFIP, ring opening of both CF₃-epoxy ethers 1a (R = Ph) and 1b (R = CH₂CH₂Ph) with HFIP alone, and with hard (MeOH) or soft (PhSH) nucleophiles in HFIP, were investigated and compared to reactions performed with Br?nsted acids. Nucleophilic ring opening reactions in HFIP were facilitated with PhSH and only α-substituted trifluoromethyl ketone 5 was isolated (nucleophilic ring opening), while with MeOH, both processes, nucleophile and electrophile-assisted ring opening were in competition. In the Br?nsted acid-catalysed ring opening of 1-CF₃-epoxy ethers 1 in HFIP, only the acid-catalysed ring opening process occurred with an inversed regioselectivity.

Full text of DOI:10.1016/j.jfluchem.2004.12.008

Journal of Fluorine Chemistry 126 (2005) 551–556
www.elsevier.com/locate/fluor
Comparative study of the ring opening of 1-CF3-epoxy
¨
ethers mediated by Bronsted acids and hexafluoro-2-propanol
1
Jernej Iskra , Daniele Bonnet-Delpon , Jean-Pierre Begue
*
`
´ ´
´ ´ ´ ˆ
BIOCIS UPRES-A 8076 CNRS, Faculte de Pharmacie, Universite Paris-Sud, rue J.B. Clement, Chatenay-Malabry 92296 Cedex, France
Received 15 December 2004; accepted 18 December 2004
Available online 26 January 2005
Dedicated to Prof. Richard D. Chambers on the occasion of his 70th birthday.
Abstract
In order to evaluate more deeply the nature of the activation of oxirane ring opening reactions by HFIP, ring opening of both CF3-epoxy
ethers 1a (R = Ph) and 1b (R = CH2CH2Ph) with HFIP alone, and with hard (MeOH) or soft (PhSH) nucleophiles in HFIP, were investigated
¨
and compared to reactions performed with Bronsted acids. Nucleophilic ring opening reactions in HFIP were facilitated with PhSH and only
a-substituted trifluoromethyl ketone 5 was isolated (nucleophilic ring opening), while with MeOH, both processes, nucleophile and
¨
electrophile-assisted ring opening were in competition. In the Bronsted acid-catalysed ring opening of 1-CF3-epoxy ethers 1 in HFIP, only the
acid-catalysed ring opening process occurred with an inversed regioselectivity.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Fluorinated alcohols; Hexafluoro-2-propanol; Trifluoromethyl-epoxy ethers; Trifluoromethyl ketones; Oxirane ring-opening; Hydrogen bonds;
¨
Bronsted acid
1. Introduction
the Lewis acid [5]. For instance, in the reaction of 2-phenyl-
a-CF3-epoxy ether (PhEE, 1a) with EtAlCl2, cleavage
occurs through the Cb–O bond because of the stabilization of
the positive charge on the benzylic position, while with the
2-phenylethyl derivative (REE, 1b) cleavage occurs through
the Ca–O bond since the alkoxy carbenium ion is the most
stable despite of the electron-withdrawing effect of CF3
group (Scheme 1) [5].
a-CF3-epoxy ethers are valuable building blocks for the
synthesis of various a-substituted trifluoromethyl ketones
(TFMKs), which can be powerful inhibitors of a variety of
hydrolytic enzymes [1]. a-Amino and a-thio TFMKs can be
synthesised by nucleophilic ring opening reactions of 1-CF3-
epoxy ethers with amines [2] or metal amides [3], and with
thiolates, respectively [4]. In all cases nucleophiles are
introduced at the b-carbon atom of the oxirane ring
(nucleophilic ring opening). Conversely, the regioselectivity
of oxirane ring opening of 1-CF3-epoxy ethers with Lewis
acids (electrophile assisted ring opening) has been found to
depend strongly on the structure of the oxirane ring and on
Fluoro alcohols such as hexafluoroisopropanol (HFIP)
and trifluoroethanol (TFE) are solvents with peculiar
properties [6] and consequently they are often used in
studies of peptide and protein structure [7], solvolysis [8]
and for their effect on reaction transformations [9], notably
the activation of hydrogen peroxide for oxidation, epoxida-
tion and the Baeyer-Villiger rearrangement [10].
Recently we found that HFIP can activate oxirane ring
opening [11], and this has been applied to a-CF3-epoxy
ethers which could easily react with aromatic amines and
even with carboxylic acids without any base catalysis
[12,13]. Interestingly, in these reactions, despite the
* Corresponding author. Tel.: +33 1 46835739; fax: +33 1 46835740.
E-mail address: daniele.bonnet-delpon@cep.u-psud.fr (D. Bonnet-
Delpon).
1
Present address: Laboratory of Organic and Bioorganic Chemistry,
‘‘Jozef Stefan’’ Institute, Jamova 39, 1000 Ljubljana, Slovenia.
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.12.008

552
J. Iskra et al. / Journal of Fluorine Chemistry 126 (2005) 551–556
Scheme 3.
Scheme 1.
electrophile-type assistance by HFIP, regioselectivity was
not dependent on the b-substituent and was the same as the
nucleophilic processes (Cb–O bond cleavage).
to be the tetralol 3 already obtained by the ring opening of 1b
in the presence of TiCl4 (Scheme 3) [5].
The purpose of this study was to evaluate more deeply the
nature of the activation of oxirane ring opening reactions by
HFIP, and our studies are reported in this paper. Therefore,
we took both CF3-epoxy ethers (1a, 1b), and have
investigated their reactions with hard (MeOH) and soft
(PhSH) nucleophiles and compared the activating effect of
2.2. Nucleophilic oxirane ring opening in HFIP
NextweevaluatedtheeffectofHFIPontheringopeningof
CF3-epoxy ethers in the presence of external nucleophiles. It
has been already observed that HFIP activates oxirane ring
opening reactions with aromatic amines while more
nucleophilic aliphatic amines were deactivated [11]. As
HFIP is a strong hydrogen bond donor, this interaction could
be the reason for deactivation of nucleophiles. Therefore we
investigated the ring opening of 1 with methanol as a hard
nucleophile and with PhSH as a soft one and a less strong
hydrogen bond acceptor [14,15]. In a control experiment, the
reaction of phenyl substituted CF3-epoxy ether 1a was
conducted with MeOH as a solvent. Reflux was required
for the reaction to occur, and after 6 h a-methoxy TFMK 4a
was quantitatively formed, resulting from the expected
nucleophilic process of oxirane ring opening (Scheme 4).
When the reaction was performed with 2 equiv. of MeOH in
HFIP, 61% conversion occurred after 24 h at reflux and an
approximately 1:1 mixture of 4a and the rearranged product 2
was obtained. In HFIP, the electrophilic process of
rearrangement competed with the nucleophilic ring opening
process. Conversely, PhEE 1a reacted with PhSH in HFIP
only through nucleophilic ring opening pathway and after 2 h
at reflux gave the ketone 5a in 95% yield with no traces of
formation of 2. In a control experiment conducted in THF,
thiophenol did not react with 1a at reflux temperature. This
process constitutes an excellent alternative to ring opening
with thiolates [4b], useful for substrates and products
sensitive to a basic medium. This would be of particular
interest for reactions performed with the non-racemic epoxy
ether 1 where products easily undergo racemisation under
basic conditions [16].
¨
HFIP to that of Bronsted acids.
2. Results
2.1. Acid catalysed rearrangement of epoxy ethers
We first investigated the activating effect of HFIP
(pKa = 9.3) on the possible acidic rearrangement of the
epoxy ethers 1 in the absence of any other external
nucleophile. After 2 days under reflux in HFIP, 59% of
PhEE 1a was consumed and a-ethoxy trifluoromethyl ketone
2 was isolated in 40% yield (Scheme 2). Conversely, REE 1b
was stable in HFIP and completely recovered even after 7
days of reflux. The acid-catalysed oxirane ring opening was
+
then investigated with a Bronsted acid (H BF4À) in various
¨
solvents. In a non-polar solvent (CH2Cl2), oxirane 1 led to the
formation of a complex reaction mixture and in isopropanol
no reaction took place. In HFIP the quantitative conversion of
1a into compound 2 occurred after 1 h at room temperature
(Scheme 2). It is worth noting that only one drop of 50%
ethereal solution of HBF4 in 5 mL of HFIP was required for
this complete acidic rearrangement. No incorporation of
HFIP was observed, although HFIPhas been reported to actas
a nucleophile with styrene oxide [10g].
Under the same conditions REE 1b was also completely
converted to a sole product, which has been proved by NMR
Scheme 2.
Scheme 4.

J. Iskra et al. / Journal of Fluorine Chemistry 126 (2005) 551–556
553
Scheme 6.
Scheme 5.
The same investigation was performed with the b-alkyl
substituted CF3-epoxy ether 1b (REE). Reaction of 1b in
MeOH was slower than for 1a and 24 h at reflux were needed
for a complete conversion to a-methoxy TFMK 4b (Scheme
5). Reaction of REE with 2 equiv. of MeOH in HFIP was very
slow with 10% conversion into a mixture of compounds after
48 h of reflux. Similarly to PhEE 1a, when REE 1b reacted
withPhSH inHFIPthenucleophilicringopeningpathwaywas
complete in 6 h of reflux, and provided quantitatively 5b
(95%) (Scheme 5). Here again, as expected, no product
resulting from the rearrangement of 1b into 3 was detected.
Neither did cycloalkylationbythe thiophenylsubstituentof5b
occur, while the corresponding b-phenylamino-trifluoro-
methyl ketones readily cyclized in HFIP [12].
The most striking result of these experiments is the
complete inversion of regioselectivity when the oxirane ring
opening, performed in HFIP, is catalyzed with one drop of
¨
Bronsted acid.
3. Discussion and conclusion
Hexafluoroisopropanol, when used as solvent, is able to
promote oxirane ring opening of CF3-substituted epoxy
¨
ethers, but in a different way to Lewis and Bronsted acids
used as catalysts. Acidic rearrangement is not an easy
process in HFIP and it occurs only with the more reactive
phenyl-substituted epoxy ether 1a, after a long reaction time
at reflux. The consequence is that this process does not often
compete with nucleophilic ring opening.
2.3. Acid-catalysed nucleophilic oxirane ring
opening in HFIP
Oxirane ring opening with nucleophiles in HFIP showed
two distinct patterns. With a hard nucleophile and good
hydrogen bond acceptor (MeOH), the presence of HFIP
disfavoured the ring opening by the nucleophile, compared
to reactions performed in MeOH alone (Schemes 4 and 5),
and compared to reactions performed in MeOH in the
Finally, we compared the activating effect of HFIP alone,
¨
and that of a Bronsted acid (HBF4) in ring opening reactions.
For this we chose 1b as model substrate since only this
epoxy ether can exhibit different regioselectivity depending
on whether an electrophilic (Lewis acid) or nucleophilic
process occurs.
¨
presence of the Bronsted acid, HBF4 (Scheme 6). MeOH is
deactivated by the strong hydrogen bond donation ability of
HFIP and can react only with the more reactive epoxy ether
1a, the acidic rearrangement into ketone 2 being a
competitive process. With a soft nucleophile and weaker
hydrogen bond acceptor (PhSH), HFIP activated the ring
opening compared to reaction performed in THF. Remark-
ably, despite of this activation, regioselectivity is the same as
in purely nucleophilic processes, with the exclusive
formation of a-substituted trifluoromethyl ketones 5a and
5b resulting from the addition of the nucleophile to C–b.
Conversely, oxirane ring opening of the epoxy ether 1b in
the presence of Lewis acid (Scheme 1), or in the presence of
HBF4 (Scheme 6) resulted only in a C–a bond cleavage by
either external nucleophile or internal one (phenyl group). In
summary, hard nucleophiles and good hydrogen bond
acceptors (alcohols, aliphatic amines) are not suitable for
oxirane ring opening in HFIP, while softer nucleophiles and
weaker hydrogen bond acceptors (thiols, aromatic amines,
carboxylic acids) are not deactivated, and nucleophilic ring
opening of oxiranes are facilitated by HFIP keeping the
regioselectivity at the less hindered C-atom. With thiols, this
constitutes clean access to a-thio trifluoromethyl ketones
HBF4-catalyzed ring opening of 1b was first investigated
in MeOH (one drop of 50% ethereal solution of HBF4 in
5 mL of MeOH). The complete conversion required 48 h at
room temperature instead of 24 h of reflux as in MeOH
alone. The sole product formed was 6b, resulting from a
Ca–O cleavage. It was isolated as a single diastereoisomer,
whose configuration could not be determined (Scheme 6).
When MeOH was used as the nucleophile (2 equiv.) in a
HBF4-catalyzed reaction in HFIP, the reaction was much
faster (2 h at room temperature) and provided a mixture of 3
(42%) and 6b (58%) but as a mixture of both diastereoi-
somers. When the same experiment was performed with
PhSH as the nucleophile in HFIP in the presence of HBF4,
the reaction was complete after 1 h at 0 8C and tetralol 3 and
disulphide 8 were isolated in 60% and 10% yield,
respectively. Disulphide 8 was not formed from PhSH
under the reaction conditions. Therefore the disulphide
could be the result of a previous addition of PhSH at the Ca-
atom of the epoxy ether, leading to 7b, which could undergo
a cycloalkylation leading to the tetralol 3, since PhSÀ is a
good leaving group, especially under acid conditions.

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J. Iskra et al. / Journal of Fluorine Chemistry 126 (2005) 551–556
with the following advantages: no effluent, and neutral
conditions compatible with substrates sensitive to basic
conditions, and in particular racemisation of chiral
compounds.
3-Ethoxy-1,1,1-trifluoro-3-phenyl-2-propanone (2) [19]:
197 mg (85%); ketone form: 19F NMR d À75.3 (s); 1H NMR
d 1.2 (t, J = 7 Hz, 3H), 3.5 (q, J = 7 Hz, 2H), 5.2 (s, 1H), 7.4
(m, 5H); hydrate form: 19F NMR d À82.7 (s); 1H NMR d 1.2
(t, J = 7 Hz, 3 H), 3.5 (q, J = 7 Hz, 2H), 4.6 (s, 1H), 7.4
(m, 5H).
Besides this insight into the role of HFIP in the ring
opening reactions of oxiranes, interesting results were
¨
obtained concerning the activation of Bronsted acid by
HFIP. Its high ionising power and strong ability to solvate
anionic species allows generation of a proton from HBF4 in
only a weakly solvated state [17]. The consequence is that
one drop of 50% ethereal solution of HBF4 in 5 mL of HFIP
is sufficient to markedly increase the rates of epoxy ether
ring opening reactions. Under these conditions, without a
nucleophile, the acidic rearrangement of 1a and 1b occurred
very smoothly in HFIP in 1h at room temperature and
provided quantitatively the rearranged ketone 2 and the
tetralol 3, respectively (Schemes 2 and 3). HFIP is also able
4.2. Acid catalysed ring opening of 1b in HFIP
To a solution of 1 mmol of 1b (260 mg) in 5 mL of HFIP
one drop of a 50% solution of HBF4 in Et2O was added and
stirred at room temperature for 1 h. The solvent was poured
into 20 mL of CH2Cl2 and the solution washed twice with a
saturated solution of NaHCO3 and dried over Na2SO4. After
evaporating the solvent, 3 was obtained as sole reaction
product, and was purified by column chromatography (SiO2,
CH2Cl2:Et2O = 9:1).
¨
to strongly activate Bronsted acid catalysed ring opening
1-Ethoxy-1-(trifluoromethyl)-2-cis-tetralol
(3)
[5]:
with nucleophiles. Reaction of MeOH with REE 1b in HFIP/
H+ was complete in 2 h, while the same reaction performed
in MeOH/H+ required 48 h to proceed quantitatively
(Scheme 6). Furthermore, the addition of only one drop
of HBF4 in HFIP is sufficient to markedly modify the
process of ring opening with a nucleophile: while in HFIP
alone, the epoxy ether 1b did not react with MeOH, it could
react in the presence of H+ through an electrophile-assisted
pathway with a Ca–O cleavage leading to a 1:1 mixture of
diastereoisomers, clearly indicating the formation of a
carbenium ion (Scheme 6).
221 mg (85%); oil, 19F NMR d À74.6 (s); 1H NMR d
1.25 (t, J = 7 Hz, 3H), 1.9 (m, 1H), 2.2 (m, 1H), 2.7 (m, 1H),
2.75 (br, s, OH), 2.95 (m, 1H), 3.5 (m, 1H), 3.7 (m, 1H), 4.4
(dd, J = 9, 3 Hz, 1H), 7.2 (m, 3H), 7.7 (m, 1H).
4.3. Nucleophilic ring opening of 1a in MeOH
A solution of 1 mmol of 1a (232 mg) in MeOH (5 mL)
was stirred at reflux temperature for 6 h. The solvent was
evaporated and a-methoxy TFMK 4a obtained as the sole
reaction product, isolated by column chromatography (SiO2,
CH2Cl2:Et2O = 9:1) as a mixture of ketone and a small
amount of its hydrate form.
4. Experimental
1,1,1-Trifluoro-3-methoxy-3-phenyl-2-propanone (4a)
[19]: 207 mg (95%); ketone form: 19F NMR d À75.6 (s);
1H NMR d 3.3 (s, 3H), 5.1 (s, 1H), 7.3 (m, 5H); hydrate form:
19F NMR d À82.7 (s); 1H NMR d 3.2 (s, 3H), 4.4 (s, 1H), 7.3
(m, 5H).
1H, 13C and 19F NMR spectra were recorded on a
200 MHz multinuclear spectrometer in CDCl3 solutions
with TMS (for 1H and 13C) and CFCl3 (for 19F) as external
standards. GC analysis was performed on a capillary column
(SE-30, 10 M). Silicagel 60A was used for column
chromatography and silica 60 F254 plates for preparative
TLC.
4.4. Nucleophilic ring opening of 1b in MeOH
A solution of 1 mmol of 1b (260 mg) in MeOH (5 mL)
was stirred at reflux temperature for 24 h. The solvent was
evaporated and a-methoxy TFMK 4b obtained as the sole
reaction product, purified by column chromatography (SiO2,
CH2Cl2:Et2O = 9:1) and isolated as a mixture of ketone and
hydrate forms. The pure hydrate form was obtained by
crystallization (hexane) in a 15% yield.
1-CF3-epoxy ethers 1a and 1b were synthesised by
known procedures [18]. Fifty percent solutions of HBF4 in
Et2O, MeOH, PhSH and HFIP were obtained from
commercial sources and used as received.
4.1. Acid catalyzed ring opening of 1a in HFIP
1,1,1-Trifluoro-3-methoxy-5-phenyl-2-pentanone (4b):
1
To a solution of 1 mmol of 1a (232 mg) in 5 mL of HFIP
one drop of a 50% solution of HBF4 in Et2O was added and
stirred at room temperature for 1 h. The solvent was poured
into 20 mL of CH2Cl2 and the solution washed twice with
a saturated solution of NaHCO3 and dried over Na2SO4.
After evaporation of the solvent, 2 was obtained as sole
reaction product, isolated by column chromatography
(SiO2, CH2Cl2:Et2O = 9:1) as a mixture of ketone and
small amount of its hydrate form.
215 mg (88%); ketone form: 19F NMR d À76.7 (s); H
NMR d 2.3 (m, 2H), 3.0 (m, 2H), 3.8 (s, 3H), 4.3 (dd, J = 8,
5 Hz, 1 H), 7.4 (m, 5 H); 13C NMR d 30.9, 32.7, 60.4, 81.7,
122.9 (q, J = 289 Hz), 126.3, 128.3, 128.4, 128.5, 140.1 and
141.3, 181.8 (q, J = 33 Hz, C=O); IR (neat) 1766,
1147 cmÀ1; hydrate form: 19F NMR d À83.2 (s); 1H
NMR d 2.3 (m, 2H), 3.0 (m, 2 H), 3.65 (s, 3 H), 3.75 (dd,
J = 9, 3.5 Hz, 1H), 7.4 (m, 5 H); 13C NMR d 30.9, 32.7, 58.5,
80.2, 94.0 (q, 31 Hz, CCF3-H), 115.4 (q, J = 294 Hz), 126.3,

J. Iskra et al. / Journal of Fluorine Chemistry 126 (2005) 551–556
555
128.3, 128.4, 128.5, 140.1 and 141.3, IR (neat) 3450,
1147 cmÀ1; Anal. Calcd for C12H13F3O2 Â H2O: C, 54.6; H,
5.7. Found: C, 54.5; H, 5.8.
1,1,1-Trifluoro-3-phenyl-3-phenylthio-2-propanone (5a):
243 mg (82%); oil; 19F NMR d À75.9 (s); 1H NMR d 5.2 (s,
1H), 7.1–7.4 (m, 10H) [4b].
4.5. Acid catalyzed ring opening of 1b in MeOH
4.8. Nucleophilic ring opening of 1b with PhSH
in HFIP
To a solution of 1 mmol of 1b (260 mg) in 5 mL of
MeOH one drop of a 50% solution of HBF4 in Et2O was
added and stirred at room temperature for 48 h. The solvent
was poured into 20 mL of CH2Cl2 and the solution washed
twice with a saturated solution of NaHCO3 and dried over
Na2SO4. After evaporating the solvent, 6b was obtained as
the sole reaction product, and purified by column
chromatography (SiO2, CH2Cl2:Et2O = 9:1).
A solution of 260 mg of 1b (1 mmol) and 165 mg of
PhSH (1.5 mmol) in HFIP (5 mL) was stirred at reflux for
6 h. The reaction mixture was diluted with 20 mL of CH2Cl2
and washed twice with a saturated solution of NaHCO3 and
dried over Na2SO4. After evaporating the solvent, 5b was
obtained as the sole reaction product, and was purified by
column chromatography (SiO2, CH2Cl2).
2-Ethoxy-1,1,1-trifluoro-2-methoxy-5-phenyl-3-pentanol
(6b): 245 mg (84%); oil; 19F NMR d À73.5 (s); 1H NMR d
1.3 (t, J = 7 Hz, 3H), 2.0 (m, 2H), 2.75 (m, 1H), 3.05 (m,
1H), 3.5 (s, 3H), 3.65 (q, J = 7 Hz, 2H), 3.9 (d, J = 10 Hz,
1H), 7.3 (m, 5H); 13C NMR d 15.0, 32.4, 32.6, 50.7, 58.8,
71.7, 98.7 (q, J = 28 Hz), 123.0 (q, J = 293 Hz), 125.9,
1,1,1-Trifluoro-5-phenyl-3-phenylthio-2-propanone (5b):
308 mg (95%); oil; 19F NMR d À74.9 (s); 1H NMR d 2.1 (m,
2H), 2.75 (t, J = 8 Hz, 2H), 3.85 (t, J = 7 Hz, 1H), 7.1–7.5
(m, 10H) [4b].
4.9. Acid catalysed ring opening of 1b with PhSH
in HFIP
128.3, 128.5, 141.6; IR (neat) 3575, 1175, 1144, 1069 cmÀ1
.
Anal. Calcd for C14H19F3O3: C, 57.5; H, 6.6. Found: C, 57.4;
H, 6.8.
A solution of 260 mg of 1b (1 mmol) and 165 mg of
PhSH (1.5 mmol) in HFIP (5 mL) was cooled to 0 8C, one
drop of a 50% solution of HBF4 in Et2O was added and
stirred at 0 8C for 1 h. The reaction mixture was diluted with
20 mL of CH2Cl2 and washed twice with a saturated solution
of NaHCO3 and dried over Na2SO4. After evaporating the
solvent, the crude reaction mixture was separated by column
chromatography (SiO2, CH2Cl2).
4.6. Acid catalyzed ring opening of 1b in
MeOH/HFIP
To a solution of 1 mmol of 1b (260 mg) and 20 mmol of
MeOH (640 mg) in 5 mL of HFIP one drop of a 50%
solution of HBF4 in Et2O was added and stirred at room
temperature for 2 h. The solvent was poured into 20 mL of
CH2Cl2 and the solution washed twice with a saturated
solution of NaHCO3 and dried over Na2SO4. After
evaporating the solvent, products 3 and 6b (1:1 mixture
of diastereoisomers) were separated by column chromato-
graphy (SiO2, CH2Cl2:Et2O = 20:1).
1-Ethoxy-1-(trifluoromethyl)-2-cis-tetralol (3): 156 mg
(60%); diphenylsulphide (8): 22 mg.
Acknowledgements
1-Ethoxy-1-(trifluoromethyl)-2-cis-tetralol
(3)
[5]:
This research was supported by a Marie Curie Fellowship
(J.I.) of the European Community programme Human
Potential under contract number HPMF-CT-1999-00097.
We thank the European Union (COST-programme ‘Fluorous
Medium’ D12/98/0012, Research Training Network
‘Fluorous Phase’ HPRN CT 2000-00002). The Central
Glass Company is acknowledged for a kind gift of HFIP.
114 mg (39%); 2-ethoxy-1,1,1-trifluoro-2-methoxy-5-phe-
nyl-3-pentanol (6b): 120 mg (45%); oil; 19F NMR d À73.5
1
(s) and À73.6 (s); H NMR d 1.3 (t, J = 7 Hz, 3H), 2.0 (m,
2H), 2.75 (m, 1H), 3.05 (m, 1H), 3.4 and 3.5 (s, 3H), 3.65 (m,
2H), 3.85 (m, 1H), 7.3 (m, 5H); 13C NMR d 15.0, 32.4, 32.6,
50.7 and 50.8, 58.8 and 58.9, 71.7 and 71.8, 98.7 (q,
J = 28 Hz), 123.0 (q, J = 293 Hz), 125.9, 126.2, 128.3,
128.4, 128.5, 141.6.
` ´
We are grateful to Michele Ourevitch for NMR experiments
`
and Imene Chebbi for experimental work.
4.7. Nucleophilic ring opening of 1a with PhSH
in HFIP
References
´
´
[1] J.P. Begue, D. Bonnet-Delpon, Tetrahedron 47 (1991) 3207–3258;
N.P. Peet, J.P. Burkhart, M.R. Angelastro, E.L. Giroux, S. Mehdi, P.
Bey, M. Kolb, B. Neises, D. Schirlin, J. Med. Chem. 33 (1990) 394–
407;
A solution of 232 mg of 1a (1 mmol) and 165 mg of
PhSH (1.5 mmol) in HFIP (5 mL) was stirred at reflux for
2 h. The reaction mixture was diluted with 20 mL of CH2Cl2
and washed twice with a saturated solution of NaHCO3 and
dried over Na2SO4. After evaporation of the solvent, 5a was
obtained as the sole reaction product, and was purified by
column chromatography (SiO2, CH2Cl2).
M.F. Parisi, R.H. Abeles, Biochemistry 31 (1992) 9429–9435;
D.V. Patel, K. Rielly-Gauvin, D.E. Ryono, C.A. Free, S.A. Smith,
E.W. Petrillo, J. Med. Chem. 36 (1993) 2431–2447;
P. Warner, R.C. Green, B. Gomes, A.M. Strimper, J. Med. Chem. 37
(1994) 3090–3099;

556
J. Iskra et al. / Journal of Fluorine Chemistry 126 (2005) 551–556
´ ´
(b) J. Iskra, D. Bonnet-Delpon, J.P. Begue, Tetrahedron Lett. 43
D.L. Boger, H. Sato, A.E. Lerner, B.J. Austin, J.E. Patterson,
M.P. Patricelli, B.F. Cravatt, Bioorg. Med. Chem. Lett. 9 (1999)
265–270.
(2002) 1001–1003;
´ ´
(c) J. Legros, B. Crousse, D. Bonnet-Delpon, J.-P. Begue, Eur. J. Org.
´ ´
[2] J.P. Begue, D. Bonnet-Delpon, H. Sdassi, Tetrahedron Lett. 33 (1992)
Chem. (2002) 3290–3293;
´ ´
(d) K.S. Ravikumar, Y.M. Zhang, J.P. Begue, D. Bonnet-Delpon, Ew.
1879–1882.
´ ´
[3] A. Abouabdellah, J.P. Begue, D. Bonnet-Delpon, A. Kornilov, I.
J. Org. Chem. (1998) 2937–2940;
Rodrigues, C. Richard, J. Org. Chem. 63 (1998) 6529–6534.
´ ´
[4] (a) J.P. Begue, D. Bonnet-Delpon, A. Kornilov, N. Fischer-Durand, J.
(e) S. Kobayashi, H. Tanaka, H. Amii, K. Uneyama, Tetrahedron 59
(2003) 1547–1552;
Fluorine Chem. 80 (1996) 13–16;
´ ´
(b) J.P. Begue, D. Bonnet-Delpon, A. Kornilov, Synthesis (1996) 529–
(f) A. Berkessel, M.R.M. Andreae, H. Schmickler, J. Lex, Angew.
Chem. Int. Ed. 41 (2002) 4481–4484;
532.
´ ´
[5] J.P. Begue, F. Benayoud, D. Bonnet-Delpon, J. Org. Chem. 60 (1995)
(g) K. Neimann, R. Neumann, Org. Lett. 2 (2000) 2861–2863;
(h) G.-J. ten Brink, J.M. Vis, I.W.C.E. Arends, R.A. Sheldon, Tetra-
hedron 58 (2002) 3977–3983;
5029–5036.
[6] L. Eberson, M.P. Hartshorn, O. Persson, F. Radner, Chem. Commun.
(1996) 2105–2112.
(i) G.-J. ten Brink, J.M. Vis, I.W.C.E. Arends, R.A. Sheldon, J. Org.
Chem. 66 (2001) 2429.
´ ´
[11] V. Kesavan, D. Bonnet-Delpon, J.P. Begue, Tetrahedron Lett. 41
[7] I. Sirangelo, P. Dal Piaz, C. Malmo, M. Casillo, L. Birolo, P. Pucci, G.
Marino, G. Irace, Biochemistry 42 (2003) 312–319;
L.A. Munishkina, C. Phelan, V.N. Uversky, A.L. Fink, Biochemistry
42 (2003) 2720–2730;
(2000) 2895–2898;
´ ´
U. Das, B. Crousse, V. Kesavan, D. Bonnet-Delpon, J.P. Begue, J. Org.
Chem. 65 (2000) 6749–6751.
´ ´
[12] I. Rodrigues, D. Bonnet-Delpon, J.P. Begue, J. Org. Chem. 66 (2001)
M. Fioroni, M.D. Diaz, S. Berger, J. Am. Chem. Soc. 124 (2002)
7737–7744, and references cited therein.
2098–2103.
´ ´
[13] J. Iskra, D. Bonnet-Delpon, J.P. Begue, Eur. J. Org. Chem. (2002)
[8] D.N. Kevill, M.J. D’Souza, J. Phys. Org. Chem. 15 (2002) 881–888;
J.P. Richard, M.M. Toteva, T.L. Amyes, Org. Lett. 3 (2001) 2225–
2228;
3402–3410.
[14] M.H. Abraham, P.L. Grellier, D.V. Prior, J.J. Morris, P.J. Taylor, J.
Chem. Soc., Perkin Trans. 2 (1990) 521–529.
K.-T. Liu, H.-I. Chen, J. Chem. Soc., Perkin Trans. 2 (2000)
893–898;
[15] C. Laurence, M. Berthelot, J.-Y. Le Questel, M.J. El Ghomari, J.
Chem. Soc., Perkin Trans. 2 (1995) 2075–2079.
F.L. Schadt, T.V. Bentley, P.V.R. Schleyer, J. Am. Chem. Soc. 98
(1976) 7667–7674.
´
´
[16] A. Abouabdellah, J.P. Begue, D. Bonnet-Delpon, A. Kornilov, I.
Rodrigues, C. Richard, J. Org. Chem. 63 (1998) 6529–6534.
[17] D. Farcasiu, A. Ghenciu, G. Marino, R.V. Kastrup, J. Mol. Cat. A 126
(1997) 141–150.
[9] R. Ben-Daniel, S.P. de Visser, S. Shaik, R. Neumann, J. Am. Chem.
Soc. 125 (2003) 12116–12117;
U. Habusha, E. Rozental, S. Hoz, J. Am. Chem. Soc. 124 (2002)
15006–15011;
´ ´ ´
[18] J.P. Begue, D. Bonnet-Delpon, D. Mesureur, G. Nee, S.-W. Wu, J. Org.
R. Takita, T. Ohshima, M. Shibasaki, Tetrahedron Lett. 43 (2002)
4661–4665;
Chem. 57 (1992) 3807–3814;
´ ´
J.P. Begue, D. Bonnet-Delpon, A. Kornilov, Org. Synth. 75 (1998)
T.G. Levitskaia, B.A. Moyer, P.V. Bonnesen, A.P. Marchand, K.
Krishnudu, Z. Chen, Z. Huang, H.G. Kruger, A.S. McKim, J. Am.
Chem. Soc. 123 (2001) 12099–12100;
153–159;
´ ´
F. Benayoud, J.P. Begue, D. Bonnet-Delpon, N. Fischer-Durand, H.
Sdassi, Synthesis (1993) 1083–1085.
H. Abe, H. Amii, K. Uneyama, Org. Lett. 3 (2001) 313–315.
´ ´
[10] (a) J.P. Begue, D. Bonnet-Delpon, B. Crousse, Synlett (2004)
[19] V.S. Karavan, V.G. Tribulovich, V.A. Nikiforov, Zh. Org. Khim. 28
(1992) 1455–1459.
18–29;