New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol

Article abstract of DOI:10.1016/j.jfluchem.2004.12.006

The reaction of β-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of trifluoroacetyl acetaldehyde, such as β-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivati

Full text of DOI:10.1016/j.jfluchem.2004.12.006

Journal of Fluorine Chemistry 126 (2005) 543–550
www.elsevier.com/locate/fluor
New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol
a
Ivan S. Kondratov , Igor I. Gerus , Aleksey D. Kacharov , Marina G. Gorbunova ,
a,
a
a
*
a
Valery P. Kukhar , Roland Frohlich
b
¨
aInstitute of Bioorganic Chemistry and Petrochemistry of National Ukrainian Academy of Science, Murmanska 1, Kiev 02094, Ukraine
b
¨ ¨ ¨
Organisch-Chemisches Institut der Universitat Munster, Corrensstraße 40, D-48149 Munster, Germany
Received 7 December 2004; accepted 13 December 2004
Available online 18 January 2005
Dedicated to Prof. Richard D. Chambers on the occasion of his 70th birthday.
Abstract
The reaction of b-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of
trifluoroacetyl acetaldehyde, such as b-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivatives synthesized
contain chiral auxiliaries. Reduction of the compounds 1, 3, 4 under various reaction conditions leads to the trifluoroaldol derivatives 6, 7, 9,
10 containing a protected aldehyde group. The compounds obtained are useful building blocks in fluoroorganic synthesis.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Fluorinated b-alkoxyvinyl ketones; Fluorinated b-keto acetals; O-nucleophiles; Chiral auxiliary; Reduction
1. Introduction
trifluoromethyl ketones (Fig. 1) [7,8], which are prepared
easily by trifluoroacetylation of corresponding alkylvinyl
ethers [9,10]. This route to the b-alkoxyvinyl trifluoromethyl
ketones becomes more complicated when it is necessary to
use non-commercial alkyl vinyl ethers, for example with
chiral alkoxy group such as a-phenylethoxy. In this case it
was demonstrated only once for the asymmetric synthesis of
trifluoromethyl containing deoxysugars (Scheme 1) [11].
Substitution of an ethoxy group in b-ethoxyvinyl
trifluoromethyl ketone 1 with any alkoxy group looks very
attractive and useful for the synthesis of various b-
alkoxyvinyl trifluoromethyl ketones. Earlier substitution
of the methoxy group in b-methoxy-b-methylvinyl trifluoro-
methyl ketone with some alkoxygroups in b-methoxy-b-
methylvinyl trifluoromethyl ketone (a derivative of trifluor-
acetyl acetone) by heating in CCl4 with dry SiO2 was
described [12]. However, the reactivity of b-methoxy-b-
methylvinyl trifluoromethyl ketone is lower than that of the
enone 1 [13]. For example, we have observed previously,
that the latter reacts with methanol at room temperature in
contrast to its nonfluorinated analogue and b-methoxy-b-
methylvinyl trifluoromethyl ketone [14].
The exchange of a methyl group by a trifluoromethyl
group is a possible strategy for the design of new
biologically active compounds [1,2]. Along with a number
of methods based on trifluoromethylation reagents suitable
for direct introducing of the trifluoromethyl group into
certain position of the molecules, methods, based on the
use of available CF3-containning reactive compounds as
building blocks, are actual too [3,4].
Typical examples of such building blocks are fluorinated
1,3-dicarbonyl compounds [5,6]. Fluorine containing b-
diketones and b-ketoesters are used widely in synthetic
practice and one can expect that fluorinated b-ketoaldehydes
can be beneficial in fluoroorganic synthesis. However,
fluorinated b-ketoaldehydes are mostly unknown. Trifluoro-
acetyl acetaldehyde building blocks attract the most attention
due to their availability and, the diversity of trifluoromethyl
compounds, which can be synthesized using them [7].
Among various known derivatives of trifluoroacetyl
acetaldehyde the most popular are available b-alkoxyvinyl
This article describes reactions of b-ethoxyvinyl tri-
fluoromethyl ketone 1 with O-nucleophiles as a convenient
* Corresponding author. Tel.: +380 445 732 598; fax: +380 445 732 552.
E-mail address: igerus@hotmail.com (I.I. Gerus).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.12.006

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I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
Fig. 1. Trifluoroacetyl acetaldehyde, b-alkoxyvinyl trifluoromethyl keton-
es.
Scheme 3. Reaction of enone 1 with diols.
catalysts allowed us to isolate acetal 2a in moderate yield.
Some of the mixed keto acetals 2 (R = Me, Et, allyl,
propargyl) were obtained earlier as hydrates by the reaction
of enone 1 with an alcohol in water solution in presence of
sodium azide [15]. Acidic catalysts (p-toluenesulfonic acid
and its pyridinium salt) also accelerate addition of the
alkoxy group to enone 1 but under these conditions the
intermediate acetals 2 are unstable and enones 3 were
obtained as the main products. Thus, for the preparation of
the majority of alkoxyenones 3 the typical reaction
conditions are p-toluenesulfonic acid as a catalyst with
the azeotropic removal of ethanol in solvents such as
benzene or toluene. Only in the case of the reaction between
enone 1 with a-phenylethanol an acidic catalyst cannot be
used because of the formation of styrene.
Scheme 1. Asymmetric synthesis of trifluoromethyl containing deoxysu-
gars.
method for the synthesis of trifluoroacetyl acetaldehyde
derivatives.
The reaction with alcohols is of particular interest as a
simple, one step method for obtaining enones 3 with chiral
auxiliaries. We have synthesized enones 3 with the menthyl
(h), bornyl (i) and a-phenylethyl (g) chiral alkoxy groups.
The synthesis of the last compound, 3g, seems to be more
convenient than that described [11], because the chiral
alcohol was involved at the last step. All of the enones 3
obtained are colourless liquids with specific smell as starting
enone 1. The structures of the compounds were proved by
NMR spectra, and we have found that C=C double bond has
the E-configuration (3JHH ꢀ 12 Hz).
2. Results and discussion
Enone 1 reacts easily with various alcohols and new
corresponding b-alkoxyvinyl trifluoromethyl ketones 3 are
obtained in good to high yields (Scheme 2). The reaction is
similar to trans-esterification because enone 1 is a vinylog of
ethyl trifluoroacetate. The first step is Michael addition of
alcohols to the C=C double bond of enone 1 with the
formation of the corresponding mixed keto acetals 2, which
eliminate ethanol easily with the formation of products 3.
The formation of intermediate keto acetals 2 can be observed
1
by H and 19F NMR spectra of the reaction mixtures, but
Enone 1 reacts with various diols with heating both neat
and in toluene solution, with catalytic quantity of p-
toluenesulfonic acid and simultaneous removal of ethanol.
Corresponding cyclic keto acetals 4 were obtained in high
yields (Scheme 3).
after vacuum distillation only products 3 were obtained.
The reaction conditions depend on the nature of the
alcohol ROH. Thus, at room temperature, enone 1 reacts
with ethanol slowly (about 10 days in a 10% solution). More
hindered alcohols such as i-propanol and t-butanol react too
slowly and the reaction was carried out with heating. We also
used various catalysts to accelerate the reaction. Basic
catalysts (K2CO3, KOH) work well for the fast addition of an
alkoxy group to C=C double bond of the enone 1 but in
addition they provoke further side condensation of the
intermediate acetals 2 as a result of interaction between the
carbonyl and methylene groups. However, only basic
Similarly to the reaction of enone 1 with alcohols, the
interaction with diols also involves Michael addition of one
hydroxy group of the diol to the C=C double bond of enone 1
in the first step. The following intramolecular nucleophilic
substitution of the ethoxy group by the second hydroxy
group of the diol gives cyclic keto acetals 4 as the result of
their higher stability in comparison with acyclic acetals 2.
Compounds 4 are trifluoroacetyl acetaldehyde derivatives
with protected aldehyde groups and may be new building
blocks for fluoroorganic synthesis. The chiral keto acetal 4b
was synthesized when diethyl L-tartrate was used as a diol.
Keto acetals 4a–c react easily with water and corre-
sponding hydrates 5a–c were obtained as crystalline and
quite stable compounds in high yields (Scheme 4).
We can explain the stability of the hydrates 5 by
an influence of the electron withdrawing trifluoromethyl
Scheme 2. Reaction of enone 1 with alcohols.

I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
545
Table 1
The percentage of hydrate form 5b in equilibrium:
Solvent
=2?
CH3CN
CHCl3
PhCH3
CCl4
Percentage of hydrate 5b (%)
100
88
Scheme 4. Formation of hydrates 5.
80
71.5
58.5
group and formation of the intramolecular hydrogen
bond between the hydroxy group and the oxygen atom of
the acetal cycle. The explanation of the stabilisation of
ketone hydrates by a heteroatom at the b-position to
carbonyl group was previously described for b-N,N-
dialkylamino trifluoromethyl ketones [16]. The X-ray
analysis data of the compound 5c confirmed our assumption
that intramolecular hydrogen bond is formed (Fig. 2). The
main geometric parameters of the H-bonds: intramolecular
hydroxyl-groups involved in hydrogen bond formation (at
OH 3430 cmꢂ1) and no band due to COCF3-group, whereas
n
in CHCl3 solution additional bands of free water (at nOH
3670 cmꢂ1) and the carbonyl group of the COCF3-fragment
(at nC=O 1770 cmꢂ1) were observed.
To demonstrate the possibilities of the synthetic use of
compounds 3 and 4 we have studied reduction of their free
carbonyl group and the diastereoselectivity of the reaction
was evaluated for the chiral compounds 3h–i and 4b.
We have found that reduction of enone 1 with sodium
borohydride leads to the formation of a mixture of products
(Scheme 5). The structures of the products determined by
NMR spectroscopy depend on the nature of a solvent. When
the reduction was carried out in ethanol solution, the mixture
of alcohol 6 (the carbonyl group reduction product) and
hydroxy acetal 7 (product of ethanol addition to the C=C
double bond followed by the reduction of the intermediate
keto acetal) was formed. Use of aprotic solvents such as
ether, dioxane or dichloromethane for this reaction gives the
mixture of the products 6 and 8 (product of total reduction).
Alcohols 9a,b were obtained as sole products when
reducing agent DIBAL-H was used for the reduction of
chiral enones 3h,i; unfortunately, yields and diastereoselec-
tivity were low (Scheme 6). The ratio between the
diastereomers was observed by 19F NMR spectra due to
the difference in the chemical shifts of the signals of CF3-
groups of the diastereomeric alcohols. In the 1H NMR
spectra of the diastereomers 9a signals of the protons of the
C=CH–O fragment also have different chemical shifts but
other signals overlapped. Low diastereoselectivity can be
explained by the long distance between the chiral alkoxy
fragment and the reacting carbonyl group. Compounds 9 and
˚
O(81) ꢁ ꢁ ꢁ O(2) 2.696 A, O(81)H(O81)O(2) 1428; intermo-
**
**
**
˚
lecular O(82 ) ꢁ ꢁ ꢁ O(6) 2.753 A, O(82 )H(O82 )O(6)
1698.
We have found that hydrates 5a–c partially dissociate in
solutions to give ketones 4a–c and water. The equilibrium
was observed by 1H and 19F NMR spectra: in CDCl3 solution
hydrates 5 are present as a mixture of the compounds 4 and 5
in about 1:4 ratio and the signal of water protons at
ꢀ1.7 ppm is present. The easiest way to control the
equilibrium between 4 and 5 is the observation by 19F
NMR spectra because signals of CF3-group of the ketones 4
are observed at ꢂ80.2 ppm whereas the signals of hydrates 5
are strongly shifted ꢀ8 ppm to higher field (up to ꢂ88 ppm).
This methodology allowed us to determine the ratio formed
of hydrate 5b to ketone 4b when dissolving 5b in various
solvents. The degree of dissociation depends on the polarity
of the solvents; the percentage of hydrate 5b decreases
with the decrease of the solvent polarity (Table 1). This
tendency was detected also by IR spectroscopy. IR spectra of
hydrates 5 in KBr plates contained a broadened band due to
Fig. 2. An ORTEP view of keto acetal hydrate 5c.
Scheme 5. The reduction of enone 1 with NaBH4.

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I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
4. Experimental
4.1. General
1H and 19F NMR spectra were recorded on a Varian VXR
instrument (300 and 282.2 MHz) in CDCl3 solutions using
TMS and CCl3F as internal standards, respectively. IR
spectra were recorded on ‘‘Specord M-80’’. A data set for X-
ray analysis was collected with a Nonius KappaCCD
diffractometer, equipped with a rotating anode generator
Nonius FR591. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN [17],
structure solution SHELXS-97 [18], structure refinement
Scheme 6. The reduction of enones 3h,i with DIBAL-H.
¨
¨
SHELXL-97 (G.M. Sheldrick, Universitat Gottingen, 1997),
graphics SCHAKAL (E. Keller, 1997). The conversion of
reactions was monitored by GLC-chromatography on a
‘‘Chrom-5’’ instrument (FID, thermostat temperature: 100–
250 8C, gas-carrier-nitrogen (20–30 ml minꢂ1), steel col-
umn 3 mm ꢃ 2400 mm, stationary phase SE-30 (5%))
or by TLC-plates (silica gel 60 F254, Merck). Column
chromatography was carried out on silica gel 60 (Merck no.
109385, particle size 0.040-0.063). Starting materials were
commercially available (Aldrich, Fluka, Merck). All
solvents and liquid reagents were distilled before using.
Starting enone 1 was prepared according to the literature
procedure [9].
Scheme 7. The reduction of keto acetals 4a,b with NaBH4.
6 have an E-configuration of C=C double bond (3JHH = 12–
13 Hz).
In contrast to the formation of mixtures of products
and low yields for the reduction of enones 1 and 3,
reduction of keto acetals 4a,b by sodium borohydride in
ether gives corresponding hydroxy acetals 10a,b in high
yields (Scheme 7). For the chiral keto acetal 4b poor
diastereoselectivity of the reduction was observed by 19F
NMR spectroscopy in a similar manner as for the
compounds 9.
4.2. 4,4-Diethoxy-1,1,1-trifluoro-2-butanone (2a)
Compounds 9 and 10 are derivatives of trifluoroaldol with
a protected aldehyde group and potential building blocks for
the synthesis of trifluoromethyl containing compounds. Easy
determination of the diastereomeric ratio of alcohols 9 or 10
by 19F NMR spectroscopy makes these compounds
attractive for the investigation of diastereoselective reduc-
tion by the chiral reducing reagents or in the presence of
chiral catalysts
The mixture of enone 1 (5.8 g, 35 mmol), ethanol
(4.7 g, 102 mmol) and catalytic amount of KOH (0.2 g)
was stirred for 24 h at 20 8C. The product was distilled
in vacuum and corresponding compound 2a (6.1 g, 81%)
1
was obtained. b.p. 50–51 8C (12 Torr). H NMR dH 1.13 t
(6H, 2CH3, JHH = 6.8 Hz), 3.0
d
(2H, CO–CH2,
HH = 5.0 Hz), 3.55 m (4H, 2OCH2), 4.95 t (1H, CHO2,
J
J
HH = 5.0 Hz). 19F NMR: dF ꢂ80.00 s (EF3). Anal. Calcd.
for C8H13F3O3: C, 44.86; H, 6.06. Found: C, 44.75; H,
6.30%. Spectroscopic data are corresponded to literature
data [15].
4.3. (E)-1,1,1-Trifluoro-4-isopropoxy-3-buten-2-one (3b)
Enone 1 (4.2 g, 25 mmol) was refluxed in excess of
isopropyl alcohol (6 g, 100 mmol). The conversion was
monitored by GLC. After about 5 h the equilibrium
between 1 and 3 was reached and the product was distilled
in vacuum and corresponding compound 3b (2.2 g, 48%
as mixture with 18% of starting enone 1) was obtained.
b.p. 53–54 8C (12 Torr). H NMR: dH 1.37 d (6H, 2CH3,
JHH = 6.2 Hz), 4.41 sept (1H, CH, JHH = 6.2 Hz), 6.00 d
(1H, C=CH–C, JHH = 11.9 Hz), 7.89 d (1H, C=CH–O,
3. Conclusions
The reaction of b-ethoxyvinyl trifluoromethyl ketone 1
with various O-nucleophiles makes it possible to
synthesize new derivatives of trifluoroacetyl acetaldehyde.
Several derivatives contain chiral auxiliaries and can be
used in asymmetric synthesis. Reduction of the trifluor-
oacetyl acetaldehyde derivatives leads to the synthetic
equivalents of trifluoroaldol. The compounds synthesized
are potentially useful building blocks for fluoroorganic
synthesis.
1
J
HH = 11.9 Hz); 19F NMR: dF ꢂ78.60 s (EF3). Anal.
Calcd. for C7H9F3O2: C, 46.16; H, 4.98. Found: C, 45.67;
H, 4.88%.

I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
547
4.4. (E)-Trifluoro-4-(tert-butoxy)-3-buten-2-one (3c)
19F NMR: dF ꢂ78.23 s (EF3). Anal. Calcd. for C11H9F3O2:
C, 57.40; H, 3.94. Found: C, 57.73; H, 3.81.
3c was obtained in conditions as described above for
enone 3b (Section 4.3) from 4.2 g (25 mmol) of enone 1 in
7.4 g (100 mmol) of tert-butyl alcohol. Yield: 2.0 g (41% as
mixture with 15% of starting enone 1). b.p. 58–62 8C
4.8. (E)-1,1,1-Trifluoro-4-(1-phenylethoxy)-3-buten-2-one
(3g)
1
(12 Torr). H NMR: dH 1.43 s (9H, 3CH3), 5.96 d (1H,
(1=, E=CH–?,
3g was obtained in conditions as described above
for enone 3d (Section 4.5) from 1.2 g (7 mmol) of enone
1 and 0.73 g (6 mmol) of 1-phenylethanol in 10 ml of
toluene. Yield: 0.92 g (60.7%). b.p. 74–76 8C (0.1 Torr). 1H
NMR: dH 1.68 d (3H, CH3, JHH = 6.4 Hz), 5.21 q (1H, CHO,
JHH = 6.4 Hz), 5.95 d (1=, E=E=–E, JHH = 12.1 Hz), 7.38
m (5=, E6=5), 7.88 d (1=, E=CH–?, JHH = 12.1 Hz). 19F
NMR: dF ꢂ77.7 s (EF3).). Anal. Calcd. for C12H11F3O2: C,
59.02; H, 4.54. Found: C, 59.34; H, 4.43%. Spectroscopic
data corresponded to literature data [11].
C–CH=C,
J
J
HH = 11.5 Hz), 8.06
d
HH = 11.5 Hz). 19F NMR: dF ꢂ78.62 s (CF3). Anal. Calcd.
for C8H11F3O2: C, 48.98; H, 5.65. Found: C, 48.38; H,
5.49%.
4.5. (E)-1,1,1-Trifluoro-4-(isopentyloxy)-3-buten-2-one
(3d)
The mixture of enone 1 (3 g, 18 mmol), 4 g (45 mmol) of
3-methyl-1-butanol, 10 ml of benzene and catalytic amount
of p-toluenesulfonic acid (10 mg) was refluxed with
simultaneous distillation of ethanol/benzene azeotrope.
The conversion was monitored by GLC and, if it was
necessary, additional portion of benzene was added until
enone 1 disappeared by GLC. After about 2 h benzene was
removed and the residue was distilled in vacuum and 2.55 g
(68.0%) of corresponding compound 3d was obtained. b.p.
98–100 8C (20 Torr). 1H NMR: dH 0.95 d (6H, 2CH3,
4.9. (E)-1,1,1-Trifluoro-4-[((1R, 2S, 5R)-2-isopropyl-5-
methylcyclohexyl)oxy]-3-buten-2-one (3h)
3h was obtained in conditions as described above for
enone 3d (Section 4.5) from 4.2 g (25 mmol) of enone 1,
3.9 g (25 mmol) of (ꢂ)-menthol and 10 mg of p-toluene-
sulfonic acid in 15 ml of toluene. Yield: 6.21 g (90.1%). b.p.
24
D
1
J
HH = 6.5 Hz), 1.65 dt (2=, C–E=2–C, JHH = 6.7, 6.8 Hz),
138–140 8E (11 Torr). ½aŠ ¼ ꢂ73:75 (F = 4, CHCl3). H
1.74 t sept (1=, E=, JHH = 6.5, 6.8 Hz), 4.06 t (2=, E=2?,
NMR: dH 0.76–1.22 m (12=, protons of menthol skeleton),
1.40–1.53 m (2=, protons of menthol skeleton), 1.72 m
(2=, protons of menthol skeleton), 2.00 m (2=, protons
of menthol skeleton), 3.91 dt (1=, E=? of menthol
skeleton, JHH = 10.6, 4.6 Hz), 5.92 d (1=, E–E==E,
J
HH = 6.7 Hz), 5.86 d (1=, E–E==E, JHH = 12.2 Hz), 7.90 d
(1=, E=CH–?, JHH = 12.2 Hz). 19F NMR: dF ꢂ78.25 s
(CF3). Anal. Calcd. for C9H13F3O2: C, 51.43; H, 6.23.
Found: C, 51.95; H, 6.34%.
J
HH = 12.0 Hz), 7.91 d (1=, E=CH–?, JHH = 12.0 Hz).
19F NMR: dF ꢂ78.18 s (EF3). IR (E=El3, cmꢂ1): n 3030,
2960, 2925, 2875, 1700, 1600, 1260, 1190, 1145, 1050, 970.
Anal. Calcd. for C14H21F3O2: C, 60.42; H, 7.61. Found: C,
60.89; H, 7.70%.
4.6. (E)-1,1,1-Trifluoro-4-(2-methylbutoxy)-3-buten-2-one
(3e)
3e was obtained in conditions as described above for
enone 3d (Section 4.5) from 3 g (18 mmol) of enone 1, 4 g
(45 mmol) of 2-methylbutanol and 10 mg of p-toluenesul-
fonic acid. Yield: 2.41 g (64.3%). b.p. 97–98 8C (18 Torr).
1H NMR: dH 0.94 m (6H, 2CH3), 1.48 m (2H, C–CH2–C),
1.84 m (1H, C–CH–C), 3.82 dd (1H, Ha of CH2O, JHH = 6.6,
9.8 Hz), 3.90 dd (1H, Hb of CH2O, JHH = 5.8, 9.8 Hz), 5.86 d
(1=, E–E==E, JHH = 12.2 Hz), 7.91 d (1=, E=CH–?,
4.10. (E)-1,1,1-Trifluoro-4-[(endo-(1S)-1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-yl)oxy]-3-buten-2-one (3i)
3i was obtained in conditions as described above for
enone 3d (Section 4.5) from 4.2 g (25 mmol) of enone 1,
3.85 g (25 mmol) of (ꢂ)-borneol and 10 mg of p-toluene-
sulfonic acid in 15 ml of toluene. Yield: 5.5 g (79.7%). b.p.
J
HH = 12.2 Hz). 19F NMR: dF ꢂ78.27 s (EF3). Anal. Calcd.
24
D
1
for C9H13F3O2: C, 51.43; H, 6.23. Found: C, 51.81; H,
6.27%.
139–140 8E (11 Torr). ½aŠ ¼ ꢂ46; 67 (F = 3, CHCl3). H
NMR: dH 0.9 m (9=, 3E=3), 1.09–1.42 m (3=, protons
of borneol skeleton), 1.69–2.00 m (3=, protons of borneol
skeleton), 2.38 m (1=, proton of borneol skeleton), 4.31
ddd (1=, E=? of borneol sceleton, JHH = 10.0, 2.9,
1.9 Hz), 5.84 d (1=, E–E==E, JHH = 12.2 Hz), 7.90 d
(1=, E=CH–?, JHH = 12.2 Hz). 19F NMR: dF ꢂ78.37 s
(EF3). IR (E=El3, cmꢂ1): n 3025, 2955, 2870, 1705, 1600,
1580, 1250, 1195, 1150, 1070, 1035, 1015. Anal. Calcd.
for C14H19F3O2: C, 60.86; H, 6.93. Found: C, 61.04; H,
7.01%.
4.7. (E)-4-(Benzyloxy)-1,1,1-trifluoro-3-buten-2-one (3f)
3f was obtained in conditions as described above for
enone 3d (Section 4.5) from 1.2 g (7 mmol) of enone 1 and
0.64 g (6 mmol) of benzyl alcohol in 10 ml of toluene.
Yield: 1.07 g (78.6%). b.p. 125–127 8C (11 Torr). 1H NMR:
dH 5.08 s (2H, CH2), 6.00 d (1H, C–CH=C, JHH = 12.3 Hz),
7.42 m (5H, E6=5), 8.01 d (1=, O–CH=C, JHH = 12.3 Hz).

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I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
4.11. 3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoroacetone (4a)
NMR: dF ꢂ87.49 s (CF3). IR (E=El3, cmꢂ1): n 3585, 3455,
3030, 2995, 2900, 1770, 1275, 1185, 1130, 1105, 945. Anal.
Calcd. for C6H9F3O4: C, 35.65; H, 4.49. Found: C, 35.33; H,
4.57%.
4a was obtained in conditions as described above for
enone 3d (Section 4.5) from 4 g (24 mmol) of enone 1 and
1.55 g (25 mmol) of ethylene glycol in 10 ml of benzene.
1
Yield 2.7 g (61.6%). b.p. 50–52 8C (13 Torr). H NMR: dH
4.15. Diethyl (4R, 5R)-2-(3,3,3-trifluoro-2,2-
dihydroxypropyl)-1,3-dioxolane-4,5-dicarboxylate (5b)
3.09 d (2=, E=2–C=O, JHH = 4.8 Hz), 3.85–4.10 m (4=,
E=2E=2), 5.37 t (1=, E=?2, JHH = 4.8 Hz). 19F NMR: dF
ꢂ79.99 s (EF3). Anal. Calcd. for C6H7F3O3: C, 39.14; H,
3.83. Found: C, 39.47; H, 3.87%.
5b was obtained in conditions as described above for
hydrate 5a (Section 4.14) from 0.5 g (1.6 mmol) of acetal
4b. Yield: 0.41 g (77.4%). m.p. 53–55 8E (with decomposi-
24
D
4.12. Diethyl (4R, 5R)-2-(3,3,3-trifluoro-2-oxopropyl)-1,3-
dioxolane-4,5-dicarboxylate (4b)
tion). ½aŠ ¼ ꢂ5:56 (F = 2.7, H2O). NMR data described
are only for gem-diol 5b (see Section 2): 1H NMR: dH 1.29–
1.38 m (6=, 2E=3), 2.19 dd (1=, Ha of CF3COE=2–C,
J = 14.3, 7.3 Hz), 2.46 dd (1=, Hb of CF3COE=2–C,
JHH = 14.3, 3.4 Hz), 4.00 s (1=, ?=), 4.23–4.38 m (4=,
The mixture of enone 1 (4.8 g, 28.5 mmol), diethyl L-
tartrate (6 g, 28.5 mmol) and catalytic amount of p-
toluenesulfonic acid (10 mg) was heated at 100–150 8C
and ethanol was distilled. The conversion was controlled by
GLC. After about 2 h the residue was distilled in vacuum and
5.5 g (61%) of compound 4b was obtained. b.p. 125–127 8E
2E=2?), 4.84
HH = 2.8 Hz), 4.90 d (1=, proton of E=E=-fragment,
d (1=, proton of E=E=-fragment,
J
JHH = 2.8 Hz), 5.12 s (1H, OH), 5.82 m (1=, E=?2); 19F
NMR: dF ꢂ87.85 s (CF3). IR (E=El3, cmꢂ1): n 3692, 3577,
3495, 3018, 2986, 2941, 1748, 1373, 1274, 1191, 1146,
1095, 1024, 946, 859; (KBr, cmꢂ1): n 3515, 3460, 3005,
2990, 1762, 1747, 1478, 1384, 1304, 1247, 1188, 1176,
1132, 1108, 1003, 948, 852. Anal. Calcd. for C12H17F3O8:
C, 41.63; H, 4.95. Found: C, 41.42; H, 5.06%.
1
(0.1 Torr). H NMR: dH 1.29–1.38 m (6=, 2E=3), 3.26 dd
(1=, Ha of CF3COE=2–C, JHH = 18.0, 4.0 Hz), 3.36 dd (1=,
Hb of CF3COE=2–C, JHH = 18.0, 5.0 Hz), 4.23–4.38 m (4=,
2E=2?), 4.77
d (1=, proton of E=E=-fragment,
J
HH = 2.8 Hz), 4.83 d (1=, proton of E=E=-fragment,
J
HH = 2.8 Hz), 5.82 m (1=, E=?2). 19F NMR: dF ꢂ80.22 s
(EF3). Anal. Calc. for C12H15F3O7: C, 43.91; H, 4.61.
Found: C, 43.45; H, 4.63%.
4.16. 3-(1,3-Dioxan-2-yl)-1,1,1-trifluoromethyl-2,2-
propanediol (5c)
4.13. 3-(1,3-Dioxan-2-yl)-1,1,1-trifluoroacetone (4c)
5c was obtained in conditions as described above for
hydrate 5a (Section 4.14) from 0.5 g (2.53 mmol) of acetal
4c. Yield: 0.44 g (80.8% yield). m.p. 45–47 8E (with
decomposition). Described NMR data are only for gem-diol
5c (see Section 2): 1H NMR: dH 1.44 m (1=, =a of fragment
E–E=2–E), 2.14 m (1=, =b of fragment E–E=2–E), 2.14 d
(2=, EF3COCH2–C, JHH = 5.2 Hz), 3.86 ddd (2=, =a of
E=2?-fragments of acetal cycle, JHH = 12.1, 10.9, 2.3 Hz),
4.18 ddd (2=, =b of E=2?-fragments of acetal cycle,
4c was obtained in conditions as described above for
enone 3d (Section 4.5) from 4 g (24 mmol) of enone 1 and
1.88 g (25 mmol) of 1,3-propanediol in 10 ml of benzene.
Yield: 3.1 g (65.8%). b.p. 50–52 8C (13 Torr). 1H NMR: dH
1.37 m (1=, =a of fragment E–E=2–E), 2.11 m (1=, =b of
fragment E–E=2–E), 3.02
d
(2=, EF3COCH2–C,
JHH = 5.2 Hz), 3.81 ddd (2=, =a of E=2?-fragments of
acetal cycle, JHH = 12.2, 11.0, 2.4 Hz), 4.11 ddd (2=, =b of
E=2?-fragments of acetal cycle, JHH = 12.2, 5.2, 1.2 Hz),
5.07 t (1=, E=?2, JHH = 5.2 Hz). 19F NMR: dF ꢂ80.26 s
(CF3). Anal. Calcd. for C7H9F3O3: C, 42.43; H, 4.58. Found:
C, 42.68; H, 4.66%.
JHH = 10.8, 5.2, 1.2 Hz), 4.78 s (2H, 2OH), 5.12 t (1=,
E=?2, JHH = 5.2 Hz), 19F NMR: dF ꢂ87.77 s (EF3). IR
(E=El3, cmꢂ1): n 3674, 3580, 3018, 2984, 2962, 2929,
2869, 1768, 1603, 1432, 1380, 1287, 1238, 1184, 1164,
1140, 1113, 1076, 1021, 928; (KBr, cmꢂ1): n 3432, 2979,
2952, 2886, 2178, 1468, 1441, 1284, 1240, 1166, 1108,
1072, 1009, 969, 824. Anal. Calc. for C7H11F3O4: C, 38.90;
H, 5.13. Found: C, 38.59; H, 5.21%.
4.14. 3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoromethyl-2,2-
propanediol (5a)
X-ray crystal structure analysis for 5c: formula
C7H11F3O4, M = 216.16, colourless crystal 0.20 mm ꢃ
The mixture of 0.5 g (2.7 mmol) of acetal 4a and water
(5 ml) was heated for 15 min at 80–90 8E and was left for 2 h
at room temperature. Crystals obtained were filtered and
crystallised from a mixture of hexane/CCl4 giving 0.35 g
(64.8%) of compound 5a as colourless crystals. m.p. 45–
47 8E (with decomposition). NMR data described are only
for gem-diol 5a (see Section 2): 1H NMR: dH 2.19 d (2=, C–
E=2–C, JHH = 5.0 Hz), 3.87–4.15 m (4=, 2E=2?), 4.64 s
(2H, 2OH), 5.26–5.46 t (1=, E=?2, JHH = 5.0 Hz); 19F
0.20 mm ꢃ 0.15 mm, a = 10.470(1), b = 9.187(1), c =
3
V = 1835.3(3) A ,
˚
˚
19.080(1) A,
r ,
calc = 1.565 g cmꢂ3
m = 1.62 cmꢂ1, no absorption correction (0.968 ꢄ T ꢄ
0.976), Z = 8, orthorhombic, space group Pbca (No. 61),
˚
l = 0.71073 A, T = 198 K, v and w scans, 4057 reflections
collected (ꢅh, ꢅk, ꢅl), [sin u/l] = 0.66 Aꢂ1, 2183 inde-
˚
pendent (Rint = 0.018) and 1702 observed reflections
[I ꢆ 2s(I)], 129 refined parameters, R = 0.036, wR2 ¼

I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
549
0:106, maximum residual electron density 0.24 electro-
4.18. (E)-1,1,1-Trifluoro-4-[((1R, 2S, 5R)-2-isopropyl-5-
methylcyclohexyl)oxy]-3-buten-2-ol (9a)
ꢂ3
˚
ns A (ꢂ0.23), hydrogen atoms calculated and refined.
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication CCDC-252154. Copies of the data can be
obtained free of charge on application to The Director,
CCDC, 12 Union Road, CambridgeCB21EZ, UK [fax: +44
1223 336 033, e-mail: deposit@ccdc.cam.ac.uk].
Two milliliters of 1 M DIBAL-H solution in toluene was
addeddropwisetoastirredsolutionof0.556 g(2 mmol)enone
3h in 5 ml of CH2Cl2 at ꢂ78 8E via the syringe. Then the
mixture was warmed to room temperature and stirred for 2 h.
To the stirred mixture 1 ml of methanol was added and after
5 min 1 ml of water was added also. After aluminium
hydroxide precipitation, 1 g of MgSO4 was added and the
mixture was stirred for 30 min. The precipitate was filtered,
washed with CH2Cl2 (2 ꢃ 10 ml) and the solvent was
removed in vacuum. Product 9a was isolated and purified
by column chromatography (eluent: CH2Cl2; Rf = 0.6). Yield:
4.17. Reduction of enone 1 with sodium borohydride
4.17.1. Reduction in ethanol
The solution of enone 1 (0.45 g, 2.7 mmol) in 5 ml of
ethanol was added to a stirred suspension of NaBH4
(0.051 g, 1.35 mmol) in 5 ml of ethanol at 0 8E. The reaction
was stirred for 2 h at room temperature. Then 10 ml of water
were added and mixture was stirred for 15 min. The solution
was extracted with diethyl ether (3 ꢃ 10 ml), combined
ether portion were dried under MgSO4. Ether was removed
in vacuum and 0.35 g of mixture of compounds 6 and 7 as
colourless liquid (in 1:1 ratio) was obtained.
1
0.055 g (10%, de ꢀ 0%). H NMR: dH 0.72–1.10 m (12=,
protons of menthol skeleton, ?=), 1.29–1.48 m (2H, protons
of menthol skeleton), 1.58–1.73 m (2H, protons of menthol
skeleton),1.98–2.12m(3H,protonsofmentholskeleton, OH),
3.52–3.63 m (1=, E=? of menthol skeleton), 4.32 m (1=,
EF3E=O), 4.92 dd (1=, E–CH=C, JHH = 12.4, 8.5 Hz), 6.56 d
(0.5=, C=E=–O, JHH = 12.4 Hz), 6.57 d (0.5=, C=E=–O,
J
HH = 12.4 Hz). Last two signals belong to different
diastereomers. 19F NMR: dF ꢂ80.30 d (0.5EF3, JHF = 6.6 Hz),
4.17.1.1. (E)-4-Ethoxy-1,1,1-trifluoro-3-buten-2-ol (6). 1H
NMR: dH 1.31 t (3H, CH3, JHH = 7.0 Hz), 2.36 s (1H, OH),
3.82 q (2H, CH2O, JHH = 7.0 Hz), 4.33 dq (1H, CF3CHO,
ꢂ80.31 d (0.5EF3, JHF = 6.6 Hz). Anal. Calcd. for
C14H23F3O2: C, 59.98; H, 8.27. Found: C, 60.25; H, 8.39%.
J
J
HH = 8.6 Hz, JHF = 6.5 Hz), 4.82 dd (1H, C–CH=C,
HH = 8.6, 12.7 Hz), 6.67 d (1H, C=CH–O, 12.7 Hz). 19F
4.19. (E)-1,1,1-Trifluoro-4-[(endo-(1S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl)oxy]-3-buten-2-ol (9b)
NMR: dF ꢂ80.34 d (CF3, JHF = 6.5 Hz).
9b was obtained in conditions as described above for
alcohol 9a (Section 4.17) from 0.553 g (2.0 mmol) of enone
3i and was purified by column chromatography (eluent:
4.17.1.2. 4,4-Diethoxy-1,1,1-trifluoro-2-butanol
(7). 1H
NMR: dH 1.16 t (6H, CH3, JHH = 5 Hz), 1.91 m (2H,
O=C–CH2), 3.55 m (4H, 2CH2O), 4.1 m (2H, CHCF3 and
OH), 4.71 t (1H, CHO2, JHH = 5 Hz). 19F NMR: dF ꢂ80.39 d
(CF3, JHF = 6.1 Hz).
1
CH2Cl2. Rf = 0.54). Yield: 0.075 g (13.5%, de ꢀ 34%). H
NMR: dH 0.79–0.94 m (9=, 3CH3), 1.07 m (1H, proton of
borneol skeleton), 1.63–1.81 m (2H, protons of borneol
skeleton), 1.89–2.07 (2H, proton of borneol skeleton, OH),
2.19–2.31 (2H, protons of borneol skeleton), 4.01–4.09 m
(1=, E=? of borneol skeleton), 4.32 m (1=, E=(EF3)O),
4.76 dd (1=, E–CH=C, JHH = 12.6, 9.0 Hz), 6.62 d (1=, E–
C=E=O, JHH = 12.6 Hz). 19F NMR: dF ꢂ80.22 d (0.33EF3,
4.17.2. Reduction in diethyl ether
The solution of enone 1 (0.45 g, 2.7 mmol) in 5 ml
of diethyl ether was added to a stirred suspension of
NaBH4 (0.051 g, 1.35 mmol) in 5 ml of diethyl ether at 0 8E.
The reaction mixture was stirred for 12 h at room
temperature. Then 10 ml of water were added and mixture
was stirred for 15 min. Ether layer was separated, and
water layer was extracted with diethyl ether (3 ꢃ 5 ml).
Combined ether portions were dried under MgSO4, ether
was removed in vacuum and 0.38 g of mixture of compounds
6 and 8 (in 2:1 ratio) as colourless liquid was obtained.
Similar results were obtained in dichloromethane and
dioxane.
J
J
HF = 6.6 Hz, minor diastereomer), ꢂ80.32 d (0.67EF3,
HF = 6.6 Hz, major diastereomer). Anal. Calcd. for
C14H21F3O2: C, 60.42; H, 7.61. Found: C, 60.53; H, 7.73%.
4.20. 3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoropropan-2-ol
(10a)
10a was obtained in conditions as described above for the
reduction of enone 1 in diethyl ether (Section 4.16) from 0.5 g
1
(2.7 mmol) of acetal 4a. Yield: 0.45 g (89%). H NMR: dH
4.17.2.1. 4-Ethoxy-1,1,1-trifluoro-2-butanol (8). 1H NMR:
dH 1.21 t (3H, CH3, JHH = 7.0 Hz), 1.91–2.23 m (2H, C–
CH2–C), 3.54 q (2H, CH2O of ethoxy group, JHH = 7.0 Hz),
3.60–4.03 m (3H, OH, CH2O of CH2CH2O-fragment), 4.24
m (1H, CF3CHO). 19F NMR: dF ꢂ80.34 d (CF3,
1.96–2.17 m (2=, E–E=2–E), 3.12 s (1=, ?=), 3.87–4.11 m
(4=, ?E=2E=2?), 4.30 m (1=, EF3CHO), 5.14 t (1=, E=?2,
J
HH = 4.2 Hz). 19F NMR: dF ꢂ80.52 d (EF3, JHF = 8.5 Hz). IR
(E=El3, cmꢂ1): n 3605, 3496, 2976, 2896, 1401, 1272, 1212,
1176, 1136, 1067, 1034, 944, 856, 824. Anal. Calcd. for
C6H9F3O3: C, 38.72; H, 4.87. Found: C, 38.78; H, 4.99%.
J
HF = 6.5 Hz).

550
I.S. Kondratov et al. / Journal of Fluorine Chemistry 126 (2005) 543–550
[2] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine
Compounds in Medicinal Chemistry and Biochemical Applications,
Elsevier, Amsterdam, 1993.
4.21. Diethyl (4R, 5R)-2-(3,3,3-trifluoro-2-hydroxypropyl)-
1,3-dioxolane-4,5-dicarboxylate (10b)
[3] K. Uneyama, J. Fluorine Chem. 97 (1999) 11–25.
[4] S.Z. Zhu, Y.L. Wang, W.M. Peng, L.P. Song, G.F. Jin, Curr. Org.
Chem. 6 (2002) 1057–1096.
10b was obtained in conditions as described above for the
reduction of enone 1 in diethyl ether (Section 4.16) from 0.84 g
(2.7 mmol) of acetal 4b. Product was purified by column
chromatography (eluent: ethyl acetate/hexane 1/1; Rf = 0.75).
Yield:0.59 g(69.6%yield, de ꢀ 15%). 1HNMR:dH 1.27–1.39
m (6=, 2E=3), 2.08–2.28 m (2=, C–E=2–C), 3.47 s (1=, ?=),
4.19–4.46 m (5=, 2E=2?, EF3CHO), 4.72–4.83 m (2=, E=–
E=), 5.57 m (1=, E=O2). 19F NMR: dF ꢂ80.12 d (0.43EF3,
[5] B.A. Donohue, E.L. Michelotti, J.C. Reader, V. Reader, M. Stirling,
C.M. Tice, J. Comb. Chem. 4 (2002) 23–32.
[6] A.B. Denisova, V.Y. Sosnovskih, W. Dehaen, S. Toppet, L. Van
Meervelt, V.A. Bakulev, J. Fluorine Chem. 115 (2002) 183–192.
[7] I.I. Gerus, M.G. Gorbunova, V.P. Kukhar, J. Fluorine Chem. 69 (1994)
195–198.
[8] V.G. Nenaidenko, A.V. Sanin, E.S. Balenkova, Russ. Chem. Rev. 68
(1999) 483–505.
J
HF = 7 Hz, minor diastereomer), ꢂ80.65 d (0.57EF3,
[9] M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, S. Matsuo, Chem. Lett. 5
(1976) 499–502.
J
HF = 7 Hz, major diastereomer). IR (E=El3, cmꢂ1): n
3470, 3030, 2990, 2950, 2910, 1750, 1270, 1225, 1210,
1175, 1140, 1110, 1075, 1015. Anal. Calcd. for C12H17F3O7:C,
43.64; H, 5.19. Found: C, 43.87; H, 5.23%.
[10] M. Hojo, R. Masuda, S. Sakaguchi, M. Takagawa, Synthesis (1986)
1016–1017.
[11] C.M. Hayman, L.R. Hanton, D.S. Larsen, J.M. Guthrie, Aust. J. Chem.
52 (1999) 921–927.
[12] Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, T. Kobuchi, T. Nishi-
gaki, Synthesis (1986) 340–342.
Acknowledgement
[13] S.I. Vdovenko, I.I. Gerus, J. Wojcik, J. Phys. Org. Chem. 14 (2001)
533–542.
[14] S.I. Vdovenko, I.I. Gerus, M.G. Gorbunova, J. Fluorine Chem. 82
(1997) 167–169.
We thank Dr. S.I. Vdovenko (Kiev) for IR-spectra.
[15] N. Zanatta, L.S. da Rosa, E. Loro, H.G. Bonacorso, M.A.P. Martins, J.
Fluorine Chem. 107 (2001) 149–154.
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