Ring-opening of 1-CF3-substituted epoxy ethers with carboxylic, thiocarboxylic, and phosphinic acids in basic medium and in hexafluoro-2-propanol

Article abstract of DOI:10.1002/1099-0690(200210)2002:20<3402::AID-EJOC3402>3.0.CO;2-M

Ring-opening of 1-CF₃-substituted epoxy ethers with carboxylic acids was achieved in Et₃N as solvent, and α-CF₃-substituted acyloins and corresponding esters were obtained in good yields. In hexafluoro-2-propanol (HFIP) as solvent, the carboxylic acids acted as nucleophiles, and a-carbonyloxy trifluoromethyl ketones were isolated in good yields. After reduction, CF₃-substituted glycols were obtained as monoesters on one or the other hydroxy group. This reaction also allowed the preparation of α-carbonylsulfanyl- and α-phosphoryloxy trifluoromethyl ketones and corresponding alcohols. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:20<3402::AID-EJOC3402>3.0.CO;2-M

FULL PAPER
Ring-Opening of 1-CF3-Substituted Epoxy Ethers with Carboxylic,
Thiocarboxylic, and Phosphinic Acids in Basic Medium and in
Hexafluoro-2-propanol
[a]
[a]
`
´ ´[a]
Jernej Iskra, Daniele Bonnet-Delpon,* and Jean-Pierre Begue
Dedicated to L. M. Yagupolskii on the occasion of his 80th birthday
Keywords: Epoxy ethers / Fluorine / Hydrogen bonds / Trifluoromethyl ketones / Ring opening
Ring-opening of 1-CF3-substituted epoxy ethers with carb-
oxylic acids was achieved in Et3N as solvent, and α-CF3-sub-
ters on one or the other hydroxy group. This reaction also
allowed the preparation of α-carbonylsulfanyl- and α-phos-
stituted acyloins and corresponding esters were obtained in phoryloxy trifluoromethyl ketones and corresponding alco-
good yields. In hexafluoro-2-propanol (HFIP) as solvent, the
carboxylic acids acted as nucleophiles, and α-carbonyloxy
trifluoromethyl ketones were isolated in good yields. After
reduction, CF3-substituted glycols were obtained as monoes-
hols.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
ane ring opening of 1-CF3-substituted epoxy ethers with
carboxylic acids had not been studied, although it could
provide a good route to α-hydroxy TFMKs in protected
form, thus solving the problem of their stability.
Trifluoromethyl ketones (TFMKs) are a biologically in-
teresting class of compounds, as they are potent inhibitors
of variety of hydrolytic enzymes.[1] This activity is associ-
ated with their tendency to form hydrates that mimic the
tetrahedral intermediates formed during hydrolysis of esters
and amides.[2] The α-substituted TFMKs most widely
studied as enzyme inhibitors are α-peptidyl derivatives[2,3]
and, to a lesser extent, α-alkylthio trifluoromethyl ke-
tones.[4]
While α-hydroxy ketones (or acyloins) are useful building
blocks, the corresponding trifluoromethyl ketones have
been less commonly reported, probably due to their instab-
ility.[5,6] It was recently shown that the parent compounds,
α-trifluoromethyl acyloins (α-acyl trifluoromethyl alcohols),
induce apoptosis of human cancer cells,[7] which makes
them a potent bioactive class of compounds.
Some years ago we reported a synthesis of 1-CF3-substi-
tuted epoxy ethers by Wittig olefination of ethyl trifluo-
roacetate and subsequent epoxidation by MCPBA.[8] Nu-
cleophilic oxirane ring opening of these epoxy ethers offers
a general method for the synthesis of various α-func-
tionalized CF3-substituted ketones, and alcohols by further
reduction. In this way, β-CF3-substituted β-hydroxy amines
and sulfides could readily be synthesized.[9] Previously, oxir-
Results and Discussion
Ring-Opening with RCOOH
a) In Et3N: The nucleophilicity of carboxylic acids can
be enhanced by converting them into carboxylates.
Enantioselective ring opening of oxiranes with benzoic acid
and salen catalyst could be improved, as reported by
Jacobsen, by performing the reactions in iPr2NEt as solv-
ent.[10]
Treatment of 1-CF3-substituted 2-phenylepoxy ether 1
(PhEE) with 1.2 equivalent of benzoic acid (2a) and
iPr2NEt as solvent at 50 °C was stopped after 7 hours, at
which point there was no more conversion of starting mat-
erial. Compound 1 had largely been converted (89%), but
no formation of the expected trifluoromethyl ketone was
observed. Instead, 80% of the α-trifluoromethyl acyloin es-
ter 3a and 20% of product 4a (Scheme 1) was formed. The
[a]
´
BIOCIS UPRES-A 8076 CNRS, Faculte de Pharmacie,
´
Universite Paris-Sud,
´
ˆ
Rue J. B. Clement, Chatenay-Malabry, 92296 Cedex, France
Fax: (internat.) ϩ 33-1/46835740
E-mail: daniele.bonnet-delpon@cep.u-psud.fr
Scheme 1
3402
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1020Ϫ3402 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3402Ϫ3410

Ring-Opening of 1-CF3-substituted Epoxy Ethers
FULL PAPER
same results were obtained in Et3N. Similarly, 1-CF3-substi- phatic acids 2aϪf in Et3N as solvent, providing acyloin es-
tuted 2-hexylepoxy ether 6 (HexEE) and 1-CF3-substituted ters 3 as major products that could be isolated in 51Ϫ74%
2-(2-phenylethyl)epoxy ether 9 (PhenEE), when treated with yields. When PhEE was treated with trifluoroacetic acid, α-
acid 2a, produced mixtures of α-CF3-substituted acyloin es- CF3-substituted acyloin trifluoroacetate 3f was formed as
ter 7a/10a and α-benzoyloxy-α-ethoxy ketone 8a/11a, re- the only product. Hydrolysis occurred during the workup
spectively.
procedure, however, and only α-trifluoromethyl acyloin 3g
Both compounds 3a and 4a could be formed from the was isolated (Scheme 4). The high selectivity of the reaction
same intermediate A, the result of nucleophile ring opening with TFA could be explained by its stronger acidity, which
with CβϪO cleavage. Intermediate A could provide either B could promote the departure of the ethoxy group, while the
or C (Scheme 2), which could in turn further rearrange into haloform-type elimination of the CF3 group should be dis-
3a and 4a, respectively, through their enol forms favored with the weaker conjugate base.
(Scheme 3).
Table 1. Ring-opening of PhEE 1 with carboxylic acids in Et3N
Epoxy ether
RЈ (RЈ-COOH)
Time[a] [h]
3[b] [%]
PhEE (1)
Ph (2a)
6
8
5
7
13
16
56
57
67
51
3,4-diMeOC6H3(2b)
4-NO2-C6H4 (2c)
CH3 (2d)
C7H15 (2e)
CF3 (2f)
74
58[c]
[a] Stirring in Et3N at 50 °C. [b] Isolated yield after column chroma-
tography. [c] α-CF3-substituted acyloin 3g was isolated in 58% yield.
Scheme 2
Scheme 3
Scheme 4
In order to verify this hypothesis, the reaction was per-
formed at lower temperature (4 °C) and monitored by GC
(Figure 1). Under these conditions, 3a was accompanied by
another product, which was further determined to be B and
named 5a (vide infra). Once isolated, 5a was placed in
iPr2NEt and was rapidly and quantitatively converted at
room temperature into 3a. The intermediate C could not
be detected.
In conclusion, the ring opening of 1-CF3-substituted
epoxy ethers with different carboxylic acids under basic
conditions occurred at the β-carbon atom, through a nucle-
ophilic pathway, whatever the substituent on the β-carbon
atom. The rearrangement, promoted by the presence of
base, provided new α-trifluoromethyl acyloins.
b) In Hexafluoropropan-2-ol (HFIP): In order to avoid
the base-promoted rearrangement of the ketone 5a, the ring
opening reaction of 1-CF3-substituted epoxy ethers with
carboxylic acids in the absence of amine was investigated.
There were evident questions: are carboxylic acids nucleo-
philic enough to allow the nucleophile ring opening
(Scheme 5, path a) or/and would their acidity (pKa
PhCOOH ϭ 4.2) favor the formation of the α-CF3-substi-
tuted alkoxy carbocation (path b) as already observed with
Lewis acids?[11]
The reaction was then extended to other acids (Table 1).
PhEE 1 was able to react with various aromatic and ali-
Figure 1. Reaction of PhEE 1a in PhCOOH/iPr2NEt at 4° C
Eur. J. Org. Chem. 2002, 3402Ϫ3410
Scheme 5
3403

´
´
J. Iskra, D. Bonnet-Delpon, J.-P. Begue
FULL PAPER
Actually, PhEE 1 reacted slowly with PhCOOH in
Alkyl-substituted 1-CF3-substituted epoxy ethers 6 and 9
CH3CN or nitromethane, giving only 20% conversion after were much less reactive, and conversions were limited. The
24 hours at reflux, with the formation of a complex mixture reaction with 6 provided the acyloin ester 13a, which was
of compounds.
isolated in a 50% yield (Table 2). In the case of substrate 9,
We have recently found that hexafluoro-2-propanol the acyloin ester 14a was also a major reaction product;
(HFIP) can activate oxirane ring opening with neutral nu- however, it was accompanied by the cis-tetralol 15
cleophiles, with no need to generate the corresponding an- (Scheme 7). This latter product results from CαϪO ring
ionic species.[12] The use of HFIP as solvent had further opening of 1-CF3-substituted epoxy ether by internal nucle-
been applied to 1-CF3-substituted epoxy ethers, which re- ophile (phenyl group) and had previously been obtained
acted with aromatic amines to afford α-amino trifluorome- from treatment of PhenEE with Lewis acids.[11]
thyl ketones as primary products.[13] We thus investigated
the ring opening of 1-CF3-substituted epoxy ethers with
carboxylic acids in HFIP.
PhEE 1 was allowed to react with 1.2 equiv. of PhCOOH
in HFIP at reflux. The reaction was stopped after 24 hours,
and 88% of α-benzoyloxy TFMK 5a was obtained as a mix-
ture of ketone and hydrate forms in a variable ratio (see
Scheme 7
Exp. Section), together with a small amount of the acyloin
ether 12 (12%) (Scheme 6).
From all these results we can conclude that HFIP activ-
ates the oxirane ring in comparison to CH3CN. Further-
more, under both sets of conditions (basic with Et3N, and
in HFIP), the main process is the cleavage of CβϪO, what-
ever the nature of the substituent at C-β (except for the
formation of tetralol 15). Nevertheless, the substituent on
C-β has a great influence on the rate of reaction. In order
to quantify this effect, we measured the rate constants of
the reaction in Et3N/CH3CN and in HFIP (Figure 2): un-
Scheme 6
der basic conditions the phenyl derivative 1 was the most
reactive, the hexyl analogue 6 and the 2-phenylethyl 9 being
2.4 times and 1.8 times less reactive, respectively. The differ-
Similar reactivity was observed on treatment of PhEE 1
with various carboxylic acids (Table 2). The CF3-substi-
tuted acyloin ester 5c of the less nucleophilic 4-nitrobenzoic
ence in the reactivities of the epoxy ethers was more pro-
acid was isolated in good yield. Besides aromatic carboxylic
nounced in HFIP: alkyl 1-CF3-substituted epoxy ethers
acids, aliphatic acids (acetic and heptanoic acids) could also
be used as nucleophiles.
were 9 times (6) and 13 times (9) less reactive than the
phenyl-substituted one (1).
Table 2. Ring-opening of 1-CF3-substituted epoxy ethers (1, 6, 9)
with carboxylic acids in HFIP
Epoxy
ether
RЈ (RЈ-COOH)
Time[a] Conv.[b] 5[b]
12[b] 15[b]
[%]
PhEE (1)
Ph (2a)
3,4-diMeOC6H3 (2b) 25 h
4-NO2-C6H4 (2c)
CH3 (2d)
C7H15 (2e)
24 h
92
88
100
93
95
77
66
88 (62) 12
78 (65) 22
81 (77) 19
67 (53) 33
75 (68) 25
100 (50) 13a
70 (32) 14a
24 h
31 h
31 h
8 d
HexEE (6) Ph (2a)
PhenEE (9) Ph (2a)
8 d
30
[a] Stirring in HFIP at 60 °C. [b] Conversion and relative ratios were
Figure 2. The effect of the structure of 1-CF3-substituted epoxy
ethers on their rate of reaction with PhCOOH in HFIP and in
Et3N/CH3CN
1
calculated from H and 19F NMR spectra from the disappearance
of starting compound; isolated yield in parenthesis.
The reactions between carboxylic acids and 1-CF3-substi-
This marked phenyl substituent effect on the rate of reac-
tuted epoxy ethers in HFIP without addition of base were tion in HFIP suggests a strong development of positive
slower than those with carboxylates. However, HFIP has a charge on carbon atoms. This activation is not due to the
strong activating effect relative to other solvents. All prod- acidity of HFIP, since its pKa (9.3) is higher than that of
ucts arose from CβϪO cleavage. Compounds 12 result from PhCOOH (pKa ϭ 4.2), but more probably due to the polar-
the acid-catalyzed rearrangement of 1, with migration of ization of the oxirane ring by its strong hydrogen bond-
the ethoxy group. In HFIP, TFMKs 5 could be isolated donor ability (α ϭ 2.96 for HFIP, 0.19 for CH3CN, and 1.12
without further rearrangement into α-CF3-substituted acy- for AcOH)[14] and its strong ionizing power (Y ϭ 3.82).[15]
loin esters 3.
Surprisingly, unlike in reactions with Lewis acids, the nucle-
3404
Eur. J. Org. Chem. 2002, 3402Ϫ3410

Ring-Opening of 1-CF3-substituted Epoxy Ethers
FULL PAPER
Table 3. Reduction of CF3-substituted acyloin derivatives with NaBH4
[a]
Reducing agent was slowly added to the solution of ketone at low temperature and, if necessary, the temperature was allowed slowly
to rise to that indicated. conversion and relative ratios were determined from H and 19F NMR spectra.
[b]
1
ophile preferentially attacks at the Cβ atom, even with al- fully controlled. This rearrangement is facilitated by basic
kyl-substituted epoxy ethers 6, 9.
reaction conditions, as has been established in a separate
experiment in Et3N.
Reduction of Acyloin Esters
With α-CF3-substituted acyloin 3g, its benzoyl ester 3a,
and its trifluoromethyl acyloin ester 5a to hand, reduction
offered the potential to provide CF3-substituted glycols
monoprotected on either hydroxy group. Since we had used
HFIP for the ring opening reaction of 1-CF3-substituted
epoxy ethers, reduction in HFIP as solvent was also invest-
igated and compared to reductions in ethanol. The results
are presented in Table 3.
α-Benzoyloxy TFMK 5a was reduced with NaBH4 in
EtOH at Ϫ78 °C and the reaction was complete within one
hour. Besides the β-benzoyloxy CF3-substituted alcohol 16
(anti/syn ϭ 60:40, as determined by NMR spectroscopic
data for the corresponding cyclic carbonate, Scheme 8),
27% of glycol 18 was formed. Conversely, reduction in
HFIP at 0 °C selectively gave the glycol monoester 16 (anti/
syn ϭ 45:55). The lack of stereoselectivity might have been
due to the presence of two competitive repulsive substitu-
ents (OCOPh and Ph) but could also have been because of
the presence of the ketone in the hydrate form, which has
previously been reported to modify the stereoselectivity of
TFMK reduction.[16]
The α-CF3 acyloin 3g was also quantitatively reduced in
EtOH in one hour at Ϫ78 °C to CF3-substituted glycol 18
in a 77:23 anti/syn ratio. The reaction in HFIP was very
selective, only the anti isomer of 18 being formed. Selectiv-
ity in favor of the anti product could be explained either by
the fact that CF3 is much bigger than OH or by a possible
hydrogen bond between hydroxyl and carbonyl group.
However, the complete selectivity in HFIP could not be ex-
plained.
The use of HFIP as a solvent for reduction with NaBH4
offers two main advantages: milder reaction conditions
could be employed and the ester function was not hy-
drolyzed.
Extension to Other Acids
The ring opening reactions of 1-CF3-substituted epoxy
ethers were extended to thiobenzoic and phosphinic acids.
There are only a few reported examples of trifluoromethyl
ketones and alcohols substituted with thioester and phos-
phate functions, and no general synthetic route to these
compounds is available.[17,18]
In a first experiment, for purposes of comparison, PhEE
1 and thiobenzoic acid were mixed in Et3N. After 1 hour
of stirring at room temperature, an intractable mixture was
obtained. The reaction was then performed in HFIP and
without addition of amine. It was complete after 24 hours
at reflux, α-benzoylsulfanyl CF3-substituted ketone 20 be-
Scheme 8
Reduction of the α-trifluoromethyl acyloin derivative 3a ing formed as the sole product, as determined by NMR
gave α-benzoyloxy-α-CF3-substituted alcohol 17 in an anti/ and IR spectroscopy (Scheme 9). TFMK derivative 20 was
syn ratio of 71:29 in EtOH and of 45:55 in HFIP. After further reduced with NaBH4 in HFIP at 0 °C and, within
prolonged reaction times, 17 was converted into 16 by one hour, the corresponding alcohol 21 was formed and
benzoyl transfer, and so the reaction time had to be care- isolated in 58% overall yield. Surprisingly, the reduction was
Eur. J. Org. Chem. 2002, 3402Ϫ3410
3405

´
´
J. Iskra, D. Bonnet-Delpon, J.-P. Begue
FULL PAPER
diastereoselective and the anti diastereoisomer 21 was ob- namely, α-carbonyloxy CF3-substituted ketones and the
tained. Its structure was determined after hydrolysis and corresponding glycols as monoesters on one or the other
cyclization by phosgene to the 1,3-oxathiolan-2-one 22, and hydroxy group Ϫ are now available. Oxirane ring opening
HOEMSY NMR experiments showed a correlation be- with thiobenzoic acid and phosphinic acid offers a route
tween the CF3 group and the phenyl protons, indicating to new classes of α-substituted trifluoromethyl ketones and
their cis orientation. In an NMR experiment with the minor corresponding alcohols. The use of β-carbonylsulfanyl alco-
product, a correlation of CF3 and Hβ was observed (trans hols as precursors of trifluoromethyl-substituted thiols and
structure).
episulfides is under investigation.
Experimental Section
General Remarks: 1H, 13C, 19F, and 31P NMR spectra were re-
corded on 200 and 400 MHz multinuclear spectrometers in CDCl3
1
solutions with TMS (for H and 13C), CFCl3 (for 19F), and H3PO4
(for 31P) as external standards. GC analysis were performed on a
capillary column (SE-30, 10 M). Silica gel (60A) was used for col-
umn chromatography and silica 60 F254 plates for preparative
TLC.
Scheme 9
1-CF3-substituted epoxy ethers 1, 6 and 9 were synthesized by
known procedures.[8] Et3N, iPr2NEt, TFA, NaBH4, carboxylic ac-
ids, thiobenzoic acid, diphenylphosphinic acid, and HFIP were ob-
tained from commercial sources and were used as received.
The two β-alkyl-α-CF3-substituted epoxy ethers 6 and 9
exhibited lower reactivities and their reactions produced
mixtures of unstable compounds, accompanied in the case
of 9 by tetralol 15.
Diphenylphosphinic acid also acted as nucleophile, and
PhEE 1 was converted in 6 hours at reflux in HFIP
(Scheme 10). α-Diphenylphosphoryloxy CF3-substituted
ketone 23 was obtained as the only product, and was isol-
ated in its hydrate form in 75% yield. HexEE 6 and PhenEE
9 reacted similarly, CF3-substituted ketone derivatives 25
and 27 (hydrate forms) being isolated in 53% and 57%
yields, respectively. Here the reduction of these hydrates
again gave alcohols 24, 26, and 28 without stereoselectivity.
Ring-opening of 1-CF3-substituted Epoxy Ethers with RCOOH and
Et3N. Typical Procedure: Compound 1 (0.5 mmol) was added to a
mixture of 2a (0.6 mmol) and Et3N (0.6 mmol), and the mixture
was stirred at 50 °C. The reaction was monitored by GC analysis.
After 6 hours, the reaction mixture was dissolved in CH2Cl2 (20
mL) and washed with HCl (0.5 ) and then twice with a saturated
solution of NaHCO3. It was dried over MgSO4 and solvent was
evaporated under reduced pressure. The crude reaction mixture was
1
analyzed by H and 19F NMR spectroscopy and the product was
purified by column chromatography (SiO2, CH2Cl2/petroleum
ether, 1:1)
1-Benzoyl-2,2,2-trifluoroethyl Benzoate (3a): 86 mg, 56%; white
1
crystals, m.p. 92Ϫ93 °C (m.p.[6c] 87Ϫ88 °C). H NMR (200 MHz,
3
CDCl3, 27 °C): δ ϭ 6.55 (q, JH,F ϭ 7 Hz, 1 H), 7.4Ϫ7.6 (m, 2 H),
7.6Ϫ7.7 (m, 1 H), 8.0Ϫ8.2 (m, 2 H) ppm. 13C NMR: δ ϭ 71.4 (q,
2JC,F ϭ 32 Hz, CCF3), 122.0 (q, 1JC,F ϭ 282 Hz, CF3), 128.7, 129.0,
130.3, 134.3, 134.6, 134.7, 164.7, 188.4 ppm. 19F NMR: δ ϭ Ϫ71.5
3
(d, JF,H
ϭ
7 Hz) ppm. IR (neat): ν˜
ϭ
1743, 1695
cmϪ1.C16H11F3O3: calcd. C 62.34, H 3.60; found C 62.23, H 3.58.
Scheme 10
1-Ethoxy-2-oxo-2-phenylethyl Benzoate (4a): 17 mg, 12%; oil. 1H
3
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 1.2 (t, JH,H ϭ 7 Hz, 3 H),
4.25 (q, 3JH,H ϭ 7 Hz, 2 H), 6.5 (s, 1 H), 7.4Ϫ7.6 (m, 6 H), 8.0Ϫ8.2
(m, 4 H) ppm. 13C NMR: δ ϭ 14.0, 62.5, 75.0, 128.6, 128.8, 129.3,
130.2, 133.8, 134.2, 165.2, 189.8 ppm. IR (neat): ν˜ ϭ 1726, 1694,
Conclusion
1233, 1108 cmϪ1
.
In conclusion, 1-CF3-substituted epoxy ethers were able
to react with carboxylic acids if Et3N was used to generate
carboxylates; the reaction did not stop at first stage, how-
ever, but the ring opening products underwent rearrange-
ments to afford α-CF3-substituted acyloin esters. If HFIP
was used as solvent for oxirane ring opening reactions,
carboxylic acids could be used directly as nucleophiles and
α-substituted CF3-substituted ketones could be isolated in
good yields. No base was required for this reaction, and the
activating effect of HFIP did not affect the regioselectivity
1-Benzoyl-2,2,2-trifluoroethyl 3,4-Dimethoxybenzoate (3b): 105 mg,
1
57%; white crystals, m.p. 119 °C. H NMR (200 MHz, CDCl3, 27
3
°C): δ ϭ 3.9 (2s, 6 H), 6.5 (q, JH,F ϭ 7 Hz, 1 H), 6.88 (d, J ϭ
9.0 Hz, 1 H), 7.4Ϫ7.65 (m, 4 H), 7.75 (dd, J ϭ 9 and 2 Hz, 1 H),
8.0 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 55.9, 56.0, 71.1 (q,
1
2JC,F ϭ 32 Hz, CCF3), 110.4, 112.3, 119.9, 122.0 (q, JC,F
ϭ
282 Hz, CF3), 124.7, 128.8, 134.4, 134.6, 148.8, 154.1, 164.3, 188.5
3
ppm. 19F NMR: δ ϭ Ϫ71.6 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ
1729, 1701 cmϪ1. C18H15F3O5 (368.3): calcd. C 58.70, H 4.11;
of nucleophile ring opening. Valuable new synthons Ϫ found C 58.50, H 4.01.
3406
Eur. J. Org. Chem. 2002, 3402Ϫ3410

Ring-Opening of 1-CF3-substituted Epoxy Ethers
FULL PAPER
(1-Benzoyl-2,2,2-trifluoroethyl 4-Nitrobenzoate (3c): 118 mg, 67%;
ucts were isolated by column chromatography (SiO2, CH2Cl2 :ethyl
acetate ϭ 9 :1) and 5 was obtained as a mixture of ketone and
white crystals, m.p. 93Ϫ94 °C. 1H NMR (200 MHz, CDCl3, 27 °C):
3
δ ϭ 6.55 (q, JH,F ϭ 7 Hz, 1 H), 7.45Ϫ7.7 (m, 3 H), 8.0 (d, J ϭ hydrate forms. The ketone form could be isolated as a pure com-
2
7.0 Hz, 2 H), 8.3 (m, 4 H) ppm. 13C NMR: δ ϭ 71.8 (q, JC,F
ϭ
pound by distillation, but quickly reverts to equilibrium with its
1
32 Hz, CCF3), 121.5 (q, JC,F ϭ 281 Hz, CF3), 123.7, 128.8, 129.0, hydrate form. The hydrate could be isolated by crystallization. The
131.3, 133.0, 134.3, 134.7, 151.1, 162.8, 187.5 ppm. 19F NMR: δ ϭ
structures of 5, 13, and 14 were confirmed by their rearrangement
into 3, 7, and 10 in the presence of Et3N. (room temp., 2 h).
Ϫ71.3 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ 1741, 1697 cmϪ1
.
3
C16H10F3O5N (353.2507): calcd. C 54.40, H 2.85, N 3.97; found C
54.20, H 2.76, N 3.85.
(3,3,3-Trifluoro-2-oxo-1-phenylpropyl Benzoate (5a): 108 mg, 62%;
Ketone Form: 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 6.6 (s, 1
H), 7.3Ϫ7.7 (m, 8 H), 8.1 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR:
δ ϭ 76.8, 115.5 (q, 1JC,F ϭ 293 Hz, CF3), 128.4, 128.6, 128.8, 129.4,
130.0, 134.0, 165.8, 185.7 (q, 2JC,F ϭ 34 Hz, CϭO) ppm. 19F NMR:
δ ϭ Ϫ75.2 (s) ppm. IR (neat): ν˜ ϭ 1773, 1721 cmϪ1. Hydrate Form:
1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 3.3 (OH), 3.5 (OH), 6.3
(s, 1 H), 7.3Ϫ7.7 (m, 8 H), 8.1 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C
1-Benzoyl-2,2,2-trifluoroethyl Acetate (3d): 63 mg, 51%; oil. 1H
3
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 2.2 (s, 3 H), 6.3 (q, JH,F
ϭ
7 Hz, 1 H), 7.4Ϫ7.7 (m, 3 H), 7.95 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C
2
1
NMR: δ ϭ 20.0, 71.0 (q, JC,F ϭ 32 Hz, CCF3), 121.7 (q, JC,F
282 Hz, CF3), 128.8, 134.5, 135.0, 168.9, 188.4 ppm. 19F NMR:
δ ϭ Ϫ71.75 (d, 3JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ 1759, 1703 cmϪ1
ϭ
.
2
1
C11H9F3O3 (246.1831): calcd. C 53.67, H 3.68; found C 53.53, H
3.76.
NMR: δ ϭ 75.0, 93.4 (q, JC,F ϭ 31 Hz, CCF3), 122.0 (q, JC,F
ϭ
282 Hz, CF3), 165.2 ppm. 19F NMR: δ ϭ Ϫ82.25 (s) ppm. IR
(neat): ν˜ ϭ 3512, 1701 cmϪ1. C16H11F3O3·H2O (326.2687): calcd.
C 58.90, H 4.02; found C 58.75, H 3.99.
1
1-Benzoyl-2,2,2-trifluoroethyl Octanoate (3e): 122 mg, 74%; oil. H
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.90 (m, 3 H), 1.1Ϫ1.4 (m,
3
3
3-Ethoxy-1,1,1-trifluoro-3-phenylacetone (12):[19] 9 mg, 8%. 1H
10 H), 2.5 (t, JH,H ϭ 7 Hz, 2 H), 6.3 (q, JH,F ϭ 7 Hz, 1 H),
7.4Ϫ7.7 (m, 3 H), 7.95 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ
14.0, 22.6, 24.6, 28.8, 31.6, 33.4, 41.4, 70.8 (q, JC,F ϭ 32 Hz,
3
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 1.2 (t, JH,H ϭ 7 Hz, 3 H),
2
3
3.5 (q, JH,H ϭ 7 Hz, 2 H), 5.2, (s, 1 H), 7.4 (m, 5 H) ppm. 19F
1
NMR: δ ϭ Ϫ75.3 (s) ppm. IR: ν˜ ϭ 1768, 1151 cmϪ1
.
CCF3), 121.8 (q, JC,F ϭ 282 Hz, CF3), 128.9, 134.4, 134.7, 171.8,
188.5 ppm. 19F NMR: δ ϭ Ϫ71.75 (d, JF,H ϭ 7 Hz) ppm. IR
3
(neat): ν˜ ϭ 1755, 1704 cmϪ1. C17H21F3O3 (330.3439): calcd. C
3,3,3-Trifluoro-2-oxo-1-phenylpropyl 3,4-Dimethoxybenzoate (5b):
1
121 mg, 65%. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 3.9 (2s, 6
61.81, H 6.41; found C 61.91, H 6.54.
H), 6.25 (s, 1 H), 6.5 (s, 1 H), 6.9 (d, J ϭ 9.0 Hz, 1 H), 7.3Ϫ7.6
(m, 6 H), 7.7 (dd, J ϭ 9 and 2 Hz, 1 H) ppm. 13C NMR: δ ϭ 56.0,
3,3,3-Trifluoro-2-hydroxy-1-phenylpropan-1-one (3g): 59 mg, 58%;
1
m.p. 83Ϫ85 °C (m.p.[6c] 80Ϫ81 °C). H NMR (200 MHz, CDCl3,
1
76.5, 110.5, 112.4, 115.4 (q, JC,F ϭ 293 Hz, CF3), 120.7, 124.4,
3
3
2
27 °C): δ ϭ 4.35 (d, JH,H ϭ 8 Hz, OH), 5.45 (qd, JH,F ϭ 7 and
3JH,H ϭ 8 Hz, 1 H), 7.4Ϫ7.75 (m, 3 H), 8.0 (d, J ϭ 8.0 Hz, 2 H)
128.7, 129.4, 130.3, 148.9, 154.0, 165.4, 186.0 (q, JC,F ϭ 35 Hz,
CϭO) ppm. 19F NMR: δ ϭ Ϫ75.3 (s), Ϫ82.15 (s) ppm. IR (neat):
ν˜ ϭ 1773, 1715 cmϪ1. C18H17F3O6·H2O (404.3351): calcd. C 55.96,
H 4.44; found C 56.66, H 4.21.
ppm. 13C NMR: δ ϭ 71.0 (q, JC,F ϭ 32 Hz, CCF3), 122.3 (q,
2
1JC,F ϭ 284 Hz, CF3), 129.0, 129.4, 133.4, 135.2, 193.2 ppm. 19F
3
NMR: δ ϭ Ϫ74.2 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ 3370,
1682 cmϪ1. C9H7F3O2 (204.1463): calcd. C 52.95, H 3.42; found C
53.41, H 3.22.
3,3,3-Trifluoro-2-oxo-1-phenylpropyl 4-Nitrobenzoate (5c): 139 mg,
1
77%. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 6.25 (s, 1 H), 6.60
(s, 1 H), 7.3Ϫ7.6 (m, 5 H), 8.3 (m, 4 H), 13C NMR: δ ϭ 77.7, 118.3
2-Oxo-1-(trifluoromethyl)octyl Benzoate (7): 71 mg, 45%; oil. 1H
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.9 (m, 3 H), 1.3 (m, 6 H),
1
(q, JC,F ϭ 293 Hz, CF3), 123.7, 128.6, 128.9, 129.4, 129.6, 129.7,
2
131.1, 132.7, 133.7, 151.1, 163.2, 185.4 (q, JC,F ϭ 35 Hz, CϭO)
3
ppm. 19F NMR: δ ϭ Ϫ75.1 (s), Ϫ82.2 (s) ppm. IR (neat): ν˜ ϭ
1774, 1733 cmϪ1. C16H10F3O5N (353.2507): calcd. C 54.40, H 2.85,
N 3.97; found C 53.99, H 2.84, N 3.73.
1.6 (m, 2 H), 2.65 (m, 2 H), 5.7 (q, JH,F ϭ 7 Hz, 1 H), 7.4Ϫ7.7
(m, 3 H), 8.1 (d, J ϭ 8.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 13.9, 22.4,
2
22.8, 28.5, 31.5, 40.0, 74.7 (q, JC,F ϭ 32 Hz, CCF3), 121.8 (q,
1JC,F ϭ 281 Hz, CF3), 127.8, 128.7, 128.8, 130.2, 134.3, 164.6, 198.7
3,3,3-Trifluoro-2-oxo-1-phenylpropyl Acetate (5d): 68 mg, 53%. 1H
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 2.2 (s, 3 H), 6.1 (s, 1 H), 6.3
(s, 1 H), 7.4Ϫ7.7 (m, 5 H) ppm. 13C NMR: δ ϭ 42.0, 76.3, 115.3
3
ppm. 19F NMR: δ ϭ Ϫ72.1 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ
1733 cmϪ1. C16H19F3O3 (316.3171): calcd. C 60.75, H 6.05; found
C 60.61, H 6.12.
1
(q, JC,F ϭ 293 Hz, CF3), 128.5, 128.7, 129.3, 130.4, 171.0, (CϭO
non observed) ppm. 19F NMR: δ ϭ Ϫ75.35 (s), Ϫ82.64 (s) ppm. IR
(neat): ν˜ ϭ 1755, 1703 cmϪ1. C11H9F3O3·1/3H2O: calcd. C 52.49, H
3.86; found C 52.39, H 3.83.
2-Oxo-4-phenyl-1-(trifluoromethyl)butyl Benzoate (10): 109 mg,
1
65%; m.p. 66Ϫ67 °C. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 3.0
3
(m, 4 H), 5.7 (q, JH,F ϭ 7 Hz, 1 H), 7.1Ϫ7.4 (m, 5 H), 7.4Ϫ7.7
(m, 3 H), 8.1 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 28.9, 41.7,
2
1
3,3,3-Trifluoro-2-oxo-1-phenylpropyl Octanoate (5e): 115 mg, 68%.
74.7 (q, JC,F ϭ 32 Hz, CCF3), 121.7 (q, JC,F ϭ 282 Hz, CF3),
3
1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.9 (t, JH,H ϭ 7 Hz, 3
126.4, 127.7, 128.3, 128.6, 128.8, 130.3, 134.4, 140.0, 164.6, 197.8
3
ppm. 19F NMR: δ ϭ Ϫ72.0 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ
H), 1.3 (m, 6 H), 1.65 (m, 2 H), 2.45 (m, 2 H), 6.1 (s, 1 H), 6.3 (s,
1 H), 7.4 (m, 5 H) ppm. 13C NMR: δ ϭ 14.0, 22.5, 24.7, 28.9, 31.6,
1732, 1728 cmϪ1. C18H15F3O3 (336.3075): calcd. C 64.29, H 4.50;
found C 64.38, H 4.59.
1
33.6, 115.3 (q, JC,F ϭ 293 Hz, CCF3), 128.8, 129.2, 130.0, 130.3,
2
170.0, 185.9 (q, JC,F ϭ 35 Hz, CϭO) ppm. 19F NMR: δ ϭ Ϫ75.4
Ring-opening of 1-CF3-substituted Epoxy Ethers with RCOOH in
(s), Ϫ82.5 (s) ppm. IR (neat): ν˜ ϭ 1755, 1704 cmϪ1. C17H21F3O3
HFIP. Typical Procedure: Compounds
1 (0.5 mmol) and 2a
(330.3439): calcd. C 61.81, H 6.41; found C 61.60, H 6.46.
(0.6 mmol) were dissolved in HFIP (5 mL) and the mixture was
stirred under reflux for 24 hours. Solvent was evaporated (or dis-
tilled). CH2Cl2 (20 mL) was added, and the solution was washed
twice with a saturated solution of NaHCO3. After evaporation of
solvent, the crude reaction product was analyzed by NMR. Prod-
1-(2,2,2-Trifluoroacetyl)heptyl Benzoate (13): 81 mg, 50%. 1H
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.9 (m, 3 H), 1.1Ϫ1.6 (m, 8
H), 2.0 (m, 2 H), 5.35 (dd, JH,H ϭ 9 and 4 Hz, 1 H), 5.6 (dd, J ϭ
6 and 5 Hz, 1 H), 7.3Ϫ7.6 (m, 3 H), 8.05 (d, J ϭ 7.0 Hz, 2 H) ppm.
3
Eur. J. Org. Chem. 2002, 3402Ϫ3410
3407

´
´
J. Iskra, D. Bonnet-Delpon, J.-P. Begue
FULL PAPER
13C NMR: δ ϭ 14.0, 22.5, 25.1, 28.7, 30.0, 31.4, 74.4, 115.4 (q, H), 5.8 (qd, JH,F ϭ 7 and JH,H ϭ 5 Hz, 1 H, 2-H), 7.2Ϫ7.7 (m,
3
3
1JC,F ϭ 292 Hz, CF3), 128.6, 129.9, 133.8, 165.7, 187.7 (q, JC,F
ϭ
8 H), 8.1 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 71.4, 72.2 (q,
2
34 Hz, CϭO) ppm. 19F NMR: δ ϭ Ϫ76.2 (s), Ϫ81.95 (s) ppm. IR
(neat): ν˜ ϭ 1773, 1726 cmϪ1. C16H19F3O3: calcd. C 60.75, H 6.05;
found C 60.60, H 6.10.
2JC,F ϭ 30 Hz, CCF3), 123.1, (q, JC,F ϭ 282 Hz, CF3), 126.5,
1
128.5, 128.7, 128.8, 130.0, 133.9, 138.2, 164.7 ppm. 19F NMR: δ ϭ
3
Ϫ73.0 (d, JF,H ϭ 7.0 Hz) ppm.
3,3,3-Trifluoro-2-oxo-1-(2-phenylethyl)propyl Benzoate (14): 55 mg,
32%. 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 2.35 (m, 2 H), 2.90
(m, 2 H), 5.40 (dd, JH,H ϭ 9 and 3 Hz, 1 H), 5.55 (t, JH,H
Reduction of 3g in EtOH afforded after, workup and separation by
prep. TLC (CH2Cl2/EtOAc, 4:1):
3
3
ϭ
3,3,3-Trifluoro-1-phenylpropane-1,2-diol (18). anti-18: 60 mg, 58%,
6 Hz, 1 H), 7.1Ϫ7.4 (m, 5 H), 7.4Ϫ7.6 (m, 3 H), 8.0 (d, J ϭ 7.0 Hz,
1
3
1
2 H) ppm. 13C NMR: δ ϭ 31.4, 31.6, 73.8, 115.4 (q, JC,F
ϭ
oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 4.1 (dq, JH,H ϭ 6.3
3
3
and JH,F ϭ 7 Hz, 1 H, 2-H), 4.85 (d, JH,H ϭ 6.3 Hz, 1 H), 7.3
293 Hz, CF3), 126.4, 128.4, 128.7, 128.8, 130.0, 133.9, 139.5, 165.6,
(m, 5 H) ppm. 13C NMR: δ ϭ 72.7, 73.3 (q, 2JC,F ϭ 29 Hz, CCF3),
2
188.0 (q, JC,F ϭ 34 Hz, CCF3) ppm. 19F NMR: δ ϭ Ϫ76.05 (s),
124.5 (q, 1JC,F ϭ 281 Hz, CF3), 127.1, 128.7, 128.9, 138.4 ppm. 19
F
Ϫ81.85 (s) ppm. IR (neat): ν˜ ϭ 1773, 1724 cmϪ1. C18H15F3O3:
3
NMR: δ ϭ Ϫ75.05 (d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ 3391,
3265 cmϪ1. C9H9F3O2: calcd. C 52.43, H 4.40; found C 52.60, H
4.50.
calcd. C 64.29, H 4.50; found C 64.15, H 4.52.
1-Ethoxy-1-(trifluoromethyl)-2-cis-tetralol (15):[11] 19F NMR: δ ϭ
Ϫ74.4 (s) ppm.
1
syn-18: 15 mg, 15%; oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ
Reduction of CF3-Substituted Acyloin Derivatives with NaBH4. Typ-
ical Procedure: NaBH4 (1.0 mmol) was slowly added to a cooled
mixture of CF3-substituted acyloin (3a, 3g, 5a, 0.5 mmol) in alco-
hol (EtOH or HFIP, 5 mL) and the mixture was stirred. The reac-
tion was monitored by GC analysis. Excess reducing agent was de-
composed by addition of 1.0  HCl solution, and the mixture was
extracted twice with methylene chloride (10 mL). The organic frac-
tions were combined, washed with a saturated solution of NaHCO3
and with water, and dried over MgSO4, and the solvent was evapor-
ated under reduced pressure. The crude reaction mixture was ana-
lyzed by 1H and 19F NMR spectroscopy. The structures of the
products were determined after separation by preparative TLC
(CH2Cl2), while their configurations were determined first by hy-
drolysis of pure diastereoisomer to glycol 18, followed by cycliza-
tion with COCl2 to afford the 1,3-dioxolan-2-one 19.
3
3
3
4.0 (dq, JH,H ϭ 3 and JH,F ϭ 7 Hz, 1 H, 2-H), 4.95 (d, JH,H
ϭ
3.0 Hz, 1 H, 3-H), 7.3 (m, 5 H) ppm. 13C NMR: δ ϭ 70.7, 73.6 (q,
2JC,F ϭ 29 Hz, CCF3), 124.3 (q, 1JC,F ϭ 281 Hz, CF3), 126.4, 128.6,
128.7, 138.1 ppm. 19F NMR: δ ϭ Ϫ77.05 (d, JF,H ϭ 7 Hz) ppm.
3
Hydrolysis of Glycol Monoesters 16, 17: A diastereoisomer of glycol
monoester 16 or 17 (0.5 mmol) was added to a solution of NaOH
(40 mg) in water (0.15 mL) and the mixture was stirred at 90 °C
for 5 min. The solution was diluted with water, neutralized with
1  HCl, and extracted twice with CH2Cl2 (10 mL). The combined
organic fractions were dried over MgSO4, solvent was evaporated,
and a clean diastereoisomer of glycol 18 was obtained.
Cyclization of Glycol 18: Compound 18 (0.5 mmol) and Et3N
(126 mg) were dissolved in toluene (4 mL). The solution was cooled
to 0 °C, 20% COCl2 (1.5 mL) in toluene was added, and the mix-
ture was stirred for an additional 30 min. The reaction was stopped
by addition of MeOH (2 mL) and CH2Cl2 (20mL), and the solution
was washed twice with a saturated solution of NaHCO3 and with
water. After removal of solvent, clean cyclized product was ob-
tained.
Reduction of 5a in HFIP afforded after workup and separation:
3,3,3-Trifluoro-2-hydroxy-1-phenylpropyl Benzoate (16). anti-16:
1
57 mg, 37%; oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 2.9 (d,
3JH,H ϭ 7 Hz, OH), 4.45 [m, 1 H, 2-H), 6.2 (d, 3JH,H ϭ 6 Hz, 1 H,
3-H), 7.3Ϫ7.7 (m, 8 H), 8.05 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR:
δ ϭ 72.3 (q, 2JC,F ϭ 30 Hz, CCF3), 73.9, 126.9, 127.7, 128.5, 128.8,
4-Phenyl-5-(trifluoromethyl)-1,3-dioxolan-2-one (19). cis-19: 1H
129.2, 129.4, 129.8, 133.5, 135.3, 166.2 ppm. 19F NMR: δ ϭ Ϫ75.5
3
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 5.0 (qd, JH,F ϭ 6.3 and
3
(d, JF,H ϭ 7 Hz) ppm. IR (neat): ν˜ ϭ 3446, 1708 cmϪ1
.
3
3JH,H ϭ 7.9 Hz, 1 H, 5-H), 5.9 (d, JH,H ϭ 7.9 Hz, 1 H, 4-H),
syn-16: 67 mg, 43%; white crystals, m.p. 98Ϫ99 °C. 1H NMR
2
7.0Ϫ7.4 (m, 5 H) ppm. 13C NMR: δ ϭ 75.8 (q, JC,F ϭ 32 Hz,
3
1
(200 MHz, CDCl3, 27 °C): δ ϭ 2.82 (d, JH,H ϭ 9 Hz, OH), 4.33
CCF3), 78.2, 121.7 (q, JC,F ϭ 283 Hz, CF3), 126.5, 129.0, 129.1,
[m, 1 H, 2-H), 6.35 (d, 3JH,H ϭ 3 Hz, 1 H, 3-H), 7.3Ϫ7.7 (m, 8 H),
8.1 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 72.7, 73.3 (q, 2JC,F ϭ
130.3, 134.8, 162.6 ppm. 19F NMR: δ ϭ Ϫ73.4 (d, 3JF,H ϭ 6.3 Hz)
ppm. IR (neat): ν
˜ ϭ 1799 cmϪ1. trans-19: 1H NMR (200 MHz,
1
3
3
30 Hz, CCF3), 123.4 (q, JC,F ϭ 283 Hz, CF3), 126.9, 128.6, 128.8,
CDCl3, 27 °C): δ ϭ 4.75 (qd, JH,F ϭ 5.6 and JH,H ϭ 4.8 Hz, 1
129.0, 129.3, 129.9, 133.6, 135.9, 165.2 ppm. 19F NMR: δ ϭ Ϫ76.4
3
H, 5-H), 5.65 (d, JH,H ϭ 4.8 Hz, 1 H, 4-H), 7.3Ϫ7.6 (m, 5 H)
3
(d, JF,H ϭ 5.9 Hz) ppm. IR (neat): ν˜ ϭ 3425, 1690 cmϪ1
.
ppm. 19F NMR: δ ϭ Ϫ79.3 (d, JF,H ϭ 5.6 Hz) ppm.
3
C16H13F3O3: calcd. C 61.94, H 4.22; found C 61.90, H 4.29.
Ring-opening of PhEE 1 with Thiobenzoic Acid in HFIP: Com-
pound 1 (0.5 mmol) and PhCOSH (0.6 mmol) were dissolved in
HFIP (5 mL) and the solution was stirred under reflux for 24
hours. Solvent was evaporated, CH2Cl2 (20 mL) was added, and
the solution was washed twice with a saturated solution of
NaHCO3. After evaporation of solvent, the crude reaction product
was analyzed by NMR spectroscopy.
Reduction of 3a in EtOH afforded, after workup and separation:
2,2,2-Trifluoro-1-[hydroxy(phenyl)methyl]ethyl Benzoate (17). anti-
1
17: 98 mg, 63%; oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 2.8
3
3
(s, OH), 5.2 (d, JH,H ϭ 7 Hz, 1 H, 3-H), 5.8 (qd, JH,F ϭ 6.9 and
3JH,H ϭ 7 Hz, 1 H, 2-H), 7.2Ϫ7.5 (m, 8 H), 7.9 (d, J ϭ 7.0 Hz, 2
H) ppm. 13C NMR: δ ϭ 71.9, 72.2 (q, 2JC,F ϭ 30 Hz, CCF3), 123.5
1
(q, JC,F ϭ 283 Hz, CF3), 127.1, 128.3, 128.5, 128.9, 129.9, 133.8,
(3,3,3-Trifluoro-2-oxo-1-phenylpropyl) Benzenecarbothioate (20): 1H
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 6.0 (s), 7.3Ϫ7.8 (m, 8 H),
8.0 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR: δ ϭ 52.5, 115.9 (q, 1JC,F ϭ
294 Hz, CF3), 127.5, 128.8, 129.2, 129.5, 134.2, 135.2, 186.7 (q,
3JC,F ϭ 35 Hz, CϭO), 190.2 ppm. 19F NMR: δ ϭ Ϫ75.4 (s) ppm.
138.3, 164.5 ppm. 19F NMR: δ ϭ Ϫ72.85 (d, 3JF,H ϭ 6.9 Hz) ppm.
IR (neat): ν˜ ϭ 3478, 1724 cmϪ1. C16H13F3O3: calcd. C 61.94, H
4.22; found C 61.76, H 4.23.
1
syn-17: 30 mg, 19%; oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ
3
3
2.4 (d, JH,H ϭ 4 Hz, OH), 5.2 (dd, JH,H ϭ 4 and 5 Hz, 1 H, 3-
IR (neat): ν˜ ϭ 1765, 1661 cmϪ1
.
3408
Eur. J. Org. Chem. 2002, 3402Ϫ3410

Ring-Opening of 1-CF3-substituted Epoxy Ethers
FULL PAPER
TFMK 20 was reduced in HFIP as described above, and alcohol
21 was obtained.
1-(Trifluoroacetyl)heptyl Diphenylphosphinate (25): 114 mg, 53%.
1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.8 (m, 3 H), 0.9Ϫ1.4
(m, 8 H), 1.9 (m, 2 H), 4.4 (m, 1 H), 7.3Ϫ7.7 (m, 6 H), 7.7Ϫ8.0
(m, 4 H) ppm. 13C NMR: δ ϭ 13.9, 22.2, 22.5, 25.9, 28.4, 31.4,
anti-(3,3,3-Trifluoro-2-hydroxy-1-phenylpropyl) Benzenecarbothio-
ate (21): 95 mg, 58%; white crystals, m.p. 80Ϫ81 °C. 1H NMR
2
2
1
80.2 (d, JC,P ϭ 7 Hz), 92.9 (q, JC,F ϭ 31 Hz), 123.0 (q, JC,F
ϭ
3
(200 MHz, CDCl3, 27 °C): δ ϭ 4.6 (m, 1 H, 2-H), 5.2 (d, JH,H
ϭ
288 Hz), 127.8, 128.3, 128.6, 130.4, 130.9, 131.4, 131.6, 132.2,
132.4, 132.6, 132.8 ppm. 19F NMR: δ ϭ Ϫ80.6 (s) ppm. 31P NMR:
δ ϭ 90.3 (d, 3JP,H ϭ 8.1 Hz) ppm. IR (neat): ν˜ ϭ 1439, 1180, 1132,
3.3 Hz, 1 H), 7.3Ϫ7.7 (m, 8 H), 8.0 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C
2
1
NMR: δ ϭ 47.4, 73.2 (q, JC,F ϭ 30 Hz, CCF3), 123.9 (q, JC,F
ϭ
284 Hz, CF3), 127.3, 128.4, 128.5, 128.6, 129.4, 133.9, 135.0, 136.1,
976, 906 cmϪ1
.
3
190.1 ppm. 19F NMR: δ ϭ Ϫ75.35 (d, JF,H ϭ 6.9 Hz) ppm. IR
(neat): ν˜ ϭ 3468, 1661, 905 cmϪ1. C16H13F3O2S: calcd. C 58.89, H
1-(2,2,2-Trifluoro-1-hydroxyethyl)heptyl Diphenylphosphinate (26):
1
4.02; found C 59.02 H 4.03.
69 mg, 63%; oil. H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 0.8, (m,
3 H), 1.0Ϫ1.4 (m, 8 H), 1.8 (m, 2 H), 4.1 (m, 1 H), 4.4 (m, 1 H),
4.5 (m, 1 H), 5.8 (br. s, OH), 6.2 (d, 3JH,H ϭ 6.5 Hz, OH), 7.4Ϫ7.7
(m, 6 H), 7.7Ϫ7.9 (m, 4 H) ppm. 13C NMR: δ ϭ 13.8, 22.3, 25.6,
Alcohol 21 was first hydrolyzed, and then cyclized under the same
reaction conditions as used for the benzoyloxy derivatives 16 and
17. The structure of the 1,3-oxathiolan-2-one was determined by
HOEMSY NMR experiments.
2
2
28.5, 31.4, 71.6 (q, JC,F ϭ 29 Hz, CCF3), 77.3 (d, JC,P ϭ 6 Hz),
78.3 (d, 2JC,P ϭ 7 Hz), 124.4 (q, 1JC,F ϭ 284 Hz, CF3), 128.4, 128.6,
131.3, 131.5, 131.7, 131.9, 132.5 ppm. 19F NMR: δ ϭ Ϫ73.1 (d,
4-Phenyl-5-(trifluoromethyl)-1,3-oxathiolan-2-one (22). cis-22: 1H
3
3
3JF,H ϭ 6.6 Hz), Ϫ75.0 (d, JF,H ϭ 6.9 Hz) ppm. 31P NMR: δ ϭ
NMR (200 MHz, CDCl3, 27 °C): δ ϭ 5.1 (qd, JH,F ϭ 6.0 and
3
3
86.0 (d, JP,H ϭ 10 Hz), 87.3 (m) ppm. IR (neat): ν˜ ϭ 3256, 1168,
3JH,H ϭ 6.6 Hz, 1 H, 5-H), 5.2 (d, JH,H ϭ 6.6 Hz, 1 H, 4-H),
1130, 1110, 1013, 981, 941 cmϪ1. C21H26F3O3P: calcd. C 60.87, H
6.32; found C 60.67, H 6.51.
7.4Ϫ7.6 (m, 5 H) ppm. 13C NMR: δ ϭ 51.6, 78.6 (q, 2JC,F ϭ 33 Hz,
1
CCF3), 121.4 (q, JC,F ϭ 281 Hz, CF3), 127.3, 128.7, 128.8, 129.6,
3
132.4, 169.4 ppm. 19F NMR: δ ϭ Ϫ71.5 (d, JF,H ϭ 6.0 Hz) ppm.
3,3,3-Trifluoro-2-oxo-1-(2-phenylethyl)propyl Diphenylphosphinate
IR (neat): ν˜ ϭ 1728 cmϪ1
.
(27): 128 mg, 57%. 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ
trans-22: 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 4.9 (qd, 3JH,F ϭ
2.0Ϫ2.3 (m, 4 H), 4.4 (m, 1 H), 7.0Ϫ7.3 (m, 5 H), 7.4Ϫ7.7 (m, 6
2
H), 7.7Ϫ8.0 (m, 4 H) ppm. 13C NMR: δ ϭ 32.1, 79.8 (d, JC,P
ϭ
3
3
5.7 and JH,H ϭ 5.4 Hz, 1 H, 5-H), 5.15 (d, JH,H ϭ 5.4 Hz, 1 H,
2
1
4-H), 7.4Ϫ7.6 (m, 5 H) ppm. 19F NMR: δ ϭ Ϫ77.6 (d, JF,H
ϭ
3
7 Hz), 93.0 (q, JC,F ϭ 31 Hz), 123.1 (q, JC,F ϭ 288 Hz), 125.9,
127.8, 128.0, 128.3, 128.5, 128.7, 128.8, 131.0, 131.6, 131.8, 132.2,
5.7 Hz) ppm.
132.5, 132.8, 133.1, 140.6 ppm. 19F NMR: δ ϭ Ϫ80.7 (s) ppm. 31
P
NMR: δ ϭ 90.5 (d, 3JP,H ϭ 9 Hz) ppm. IR (neat): ν˜ ϭ 1439, 1180,
1132, 969, 906 cmϪ1
Ring Opening of 1-CF3-Substituted Epoxy Ethers with Diphenylpho-
sphinic Acid in HFIP: Compound 1 (or 6 or 9, 0.5 mmol) and
Ph2POOH (0.6 mmol) was dissolved in HFIP (5 mL), and the mix-
ture was stirred under reflux for 6 hours. Solvent was evaporated,
CH2Cl2 (20 mL) was added, and the solution was washed twice
with a saturated solution of NaHCO3. After evaporation of solv-
ent, the crude reaction product was analyzed by NMR spectro-
scopy and, after column chromatography (SiO2, CH2Cl2/EtOAc,
9:1), the pure hydrate form was obtained (Scheme 10). After reduc-
tion by NaBH4 (2 equiv.) in HFIP at 0 °C for 1 hour, the alcohol
was obtained and isolated by column chromatography (SiO2,
CH2Cl2/EtOAc, 9:1) (Scheme 10).
.
3,3,3-Trifluoro-2-hydroxy-1-(2-phenylethyl)propyl
Diphenylphos-
phinate (28): 68 mg, 55%. 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ
2.2 (m, 2 H), 2.6 (m, 2 H), 4.05 (m, 1 H), 4.1 (m, 1 H), 4.4 (m, 1
3
H), 4.5 (m, 1 H), 5.7 (br. s, OH), 6.1 (d, JH,H ϭ 10 Hz, OH), 6.85
(m, 2 H), 7.05Ϫ7.25 (m, 3 H), 7.3Ϫ7.65 (m, 6 H), 7.7Ϫ7.85 (m, 4
2
H) ppm. 13C NMR: δ ϭ 31.3, 33.0, 71.5 (q, JC,F ϭ 30 Hz), 71.6
2
2
2
(q, JC,F ϭ 30 Hz), 76.9 (d, JC,P ϭ 7 Hz), 77.9 (d, JC,P ϭ 7 Hz),
1
124.4 (q, JC,F ϭ 284 Hz, CF3); 126.1, 128.0, 128.4, 128.7, 130.4,
131.3, 131.6, 131.7, 131.9, 132.6, 140.3 ppm. 19F NMR: δ ϭ Ϫ72.9
(d, 3JF,H ϭ 6.9 Hz), Ϫ74.9 (d, 3JF,H ϭ 6.6 Hz) ppm. 31P NMR: δ ϭ
86.4 (m), 87.8 (m) ppm. IR (neat): ν˜ ϭ 3240, 1168, 1131, 1111,
1020, 981, 907. C23H22F3O3P: calcd. C 63.60, H 5.10; found C
63.69, H 5.13.
3,3,3-Trifluoro-2-oxo-1-phenylpropyl Diphenylphosphinate (23):
156 mg, 74%. 1H NMR (200 MHz, CDCl3, 27 °C): δ ϭ 5.3 (d,
3JH,P ϭ 11 Hz, 1 H), 7.2Ϫ7.6 (m, 13 H), 7.8 (m, 2 H) ppm. 13C
2
2
NMR: δ ϭ 79.9 (d, JC,P ϭ 7 Hz), 93.5 (q, JC,F ϭ 32 Hz), 122.5
1
Kinetic Experiments. In HFIP: Acid 2a (0.6 mmol) and dodecane
(20 mg, internal standard) were dissolved in HFIP (5 mL) and the
mixture was heated on an oil bath at 60 °C. The reaction was
started by addition of CF3-substituted epoxy ether (0.5 mmol) and
reaction progress was monitored by removal of aliquots (50 µL)
that were quenched with a saturated solution of NaHCO3, ex-
tracted with CH2Cl2, and analyzed by GC (SE-30, 75 °C, 5 min,
20 °C/min). First-order rate constants for consumption of starting
compound were calculated by the least squares method from the
equation ln c ؍ ln c0 ϩ k1t.
(q, JC,F ϭ 289 Hz), 127.9, 128.2, 128.5, 128.7, 129.0, 131.1, 131.3,
132.1, 132.3, 132.8, 133.0, 134.1 ppm. 19F NMR: δ ϭ Ϫ80.8 (s)
ppm. 31P NMR: δ ϭ 92.0 (d, JP,H ϭ 12 Hz) ppm. IR (neat): ν˜ ϭ
3
1186, 1132, 1022, 986 cmϪ1
.
3,3,3-Trifluoro-2-hydroxy-1-phenylpropyl Diphenylphosphinate (24):
102 mg, 70%; white crystals, m.p. 107Ϫ110 °C. 1H NMR
(200 MHz, CDCl3, 27 °C): δ ϭ 4.3 (m, 1 H, 2-H), 5.25 (dd, 3JH,P ϭ
3
10 and 3JH,H ϭ 7 Hz, 1 H, 3-H), 5.45 (dd, JH,P ϭ 10 and 3JH,H ϭ
3
2 Hz, 1 H, 3-H), 5.75 (br. s, OH), 5.95 (d, JH,H ϭ 10 Hz, OH),
2
7.1Ϫ7.9 (m, 15 H) ppm. 13C NMR: δ ϭ 73.7 (q, JC,F ϭ 29 Hz),
2
2
1
78.0 (d, JC,P ϭ 5.5 Hz), 78.3 (d, JC,P ϭ 6 Hz), 123.6 (q, JC,F
ϭ
In Et3N: Acid 2a (0.6 mmol), Et3N (0.6 mmol), and dodecane
(20 mg) were dissolved in CH3CN (5mL) and the mixture was
1
284 Hz), 124.1 (q, JC,F ϭ 284 Hz), 126.4, 127.5, 128.3, 128.4,
128.7, 129.1, 131.1, 131.3, 131.9, 132.1, 132.6, 132.7, 135.3 ppm. stirred for 20 min at 70 °C. After that, the 1-CF3-substituted epoxy
3
3
19F NMR: δ ϭ Ϫ72.7 (d, JF,H ϭ 6.6 Hz), Ϫ74.4 (d, JF,H
ϭ
ether (0.5 mmol) was added and the mixture was stirred at 70 °C.
Reaction progress was monitored by removal of aliquots (50 µL)
6.9 Hz) ppm. 31P NMR: δ ϭ 88.5 (m) ppm. IR (neat): ν˜ ϭ 3236,
1203, 1169, 1129, 1111, 991, 907 cmϪ1. C21H18F3O3P: calcd. C that were quenched by a saturated solution of NaHCO3, extracted
62.07, H 4.46; found C 61.53, H 4.47.
with CH2Cl2, and analyzed by GC as above.
Eur. J. Org. Chem. 2002, 3402Ϫ3410
3409

´
´
J. Iskra, D. Bonnet-Delpon, J.-P. Begue
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Acknowledgments
This research was supported by a European Community Human
Potential program Marie Curie Fellowship (J.I.) under contract
number HPMF-CT-1999Ϫ00097. We thank the European Union
(COST-program ЈFluorous MediumЈ D12/98/0012, Research Train-
ing Network ЈFluorous PhaseЈ HPRN CT 2000Ϫ00002). Central
Glass is acknowledged for a kind gift of HFIP. We are thankful to
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[O02151]
3410
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