Facile synthesis of aromatic unsymmetrical fluorine-containing acyloins through the reductive trifluoroacetylation of benzaldehyde and transposition of the carbonyl group

Article abstract of DOI:10.1016/j.tet.2014.02.016

The reductive coupling reaction between benzaldehyde and ethyl trifluoroacetate in the presence of magnesium and chlorotrimethylsilane in N-methyl-2-pyrrolidinone gave the acetal of the corresponding coupling compound in good yields. The yield of the coup

Full text of DOI:10.1016/j.tet.2014.02.016

Tetrahedron 70 (2014) 2081e2087
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Facile synthesis of aromatic unsymmetrical fluorine-containing
acyloins through the reductive trifluoroacetylation of benzaldehyde
and transposition of the carbonyl group
*
Hirofumi Maekawa , Masashi Kudo, Yutaro Nishiyama, Kazuyuki Shimizu,
Mitsuhiro Abe
Department of Materials Science and Technology, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka 940-2188, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 January 2014
Received in revised form 8 February 2014
Accepted 8 February 2014
Available online 14 February 2014
The reductive coupling reaction between benzaldehyde and ethyl trifluoroacetate in the presence of
magnesium and chlorotrimethylsilane in N-methyl-2-pyrrolidinone gave the acetal of the corresponding
coupling compound in good yields. The yield of the coupling product largely depended on the benzal-
dehyde concentration in the solution and it was essential to avoid the formation of pinacol type com-
pounds in order to obtain the coupling product in high yields. The subsequent desilylation of the acetal
using tetrabutylammonium fluoride easily yielded an acyloin compound as the sole product after the
transposition of the carbonyl group through ketoeenol tautomerism.
Keywords:
Benzaldehyde
Trifluoroacetylation
Transposition
Magnesium
Ó 2014 Elsevier Ltd. All rights reserved.
Umpolung
1. Introduction
trifluoroacetylation occurs at the para-position of the benzene ring
of branched alkyl phenyl ketones under similar reaction
Fluorine-containing organic compounds have been the focus of
attention in recent years because of the unique properties and
physical characteristics. In particular, there has been a striking in-
crease in applications of fluorinated compounds in pharmaceutical
drugs because of the discovery of their bioactivities.1,2 However,
introducing fluorine atoms into organic compounds frequently
involves a difficult process or requires severe reaction conditions.
The typical synthetic routes for fluorinated compounds are mono-
fluorination3e8 and trifluoromethylation,9e11 which have been seen
as attractive methods and studied for a long time. However,
trifluoroacetylation12e22 is less used to synthesize fluorinated
compounds except in FriedeleCrafts type acylation reactions,12e15
probably because of the electrophilic acylating agent moiety.
We have already reported the magnesium-promoted tri-
fluoroacetylation of benzophenone and acetophenone in the
presence of chlorotrimethylsilane (TMSCl) to give the correspond-
ing compounds that are trifluoroacetylated at the carbonyl group,
which were then deacetalized.23 We have also found that
conditions.24
In this study presented here, the reductive trifluoroacetylation
of aromatic aldehydes was performed in the presence of chloro-
trimethylsilane to give high yield of acetals of the corresponding
compounds that were trifluoroacetylated at the carbonyl group
under optimized reaction conditions. Desilylation of the acetals
using tetrabutylammonium fluoride in tetrahydrofuran gave acy-
loin compounds as the single products through transposition of the
carbonyl group. (Scheme 1).
Scheme 1.
2. Results and discussion
The solvent effect is quite important to the reaction and aprotic
polar solvents such as N,N-dimethylformamide (DMF), N-methyl-2-
* Corresponding author. Tel.: þ81 258 47 9320; fax: þ81 258 47 9300; e-mail
address: maekawa@vos.nagaokaut.ac.jp (H. Maekawa).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.016

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H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
pyrrolidinone (NMP), and N,N-dimethylacetamide (DMAc) are re-
quired to synthesize trifluoroacetylated compound (2a), while us-
ing acetonitrile or tetrahydrofuran (THF) gave no coupling
compound as shown in Scheme 2 and Table 1. However, pinacols,
which were undesirable by-products were the major products in
most of the cases.
trifluoroacetylated compounds as a mixture of diastereomers in
good to excellent yields. (Scheme 3, Table 3) The reaction was also
applicable to naphthylaldehyde and heteroaromatic aldehydes, but
gave poorer yields. (Table 3, entries 10e12) Aromatic aldehydes
with a methyl group or a methoxy group were transformed into the
coupling compounds in low yields because of the electron-
donating and destabilizing effects to the aldehyde moiety on the
corresponding electron-negative anion radical intermediate.
Scheme 2.
Scheme 3.
Table 1
Solvent effect on the coupling reaction between benzaldehyde and ethyl
trifluoroacetate
Table 3
Entry
Solvent
Yieldb (%)
Mg-promoted coupling reaction of benzaldehydes with ethyl trifluoroacetate
2a
3a
Entry
Ar
Diastereomers
Ratio (dr)
Isolated yield (%)
1
2
3
4
5
6
DMF
18
15
27
42
d
d
64
66
63
38
Trace
Trace
2
DMAc
NMP
NMPa
THF
1
2
3
4
5
6
7
8
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
1:0.67
1:0.67
1:0.82
1:0.82
1:0.82
1:0.50
1:0.80
1:1
73
50
66
71
84
88
84
47
68
55
30
60
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
4-FC6H4
CH3CN
Mg (2 equiv mol), CF3CO2Et (11 equiv mol), TMSCl (4 equiv mol), solvent (30 mL),
25 ꢁC, benzaldehyde (1a) in the solvent (20 mL) was added dropwise. at 120 mL hꢀ1
.
a
Using a drop rate of 20 mL hꢀ1
Determined by gas chromatography.
.
b
9
2-FC6H4
1:1
10
11
12
1-Naphthyl
2-Thienyl
3-Pyridyl
2j
2k
2l
1:0.75
1:0.90
1:0.16
The dropping rate of benzaldehyde in NMP (Table 1, entries 3
and 4) and the reaction temperature (Table 2, entries 4, 8, and 9)
were the most important factors that affected the yield of the
coupling compound 2a. Performing the reaction at ꢀ15 ꢁC dra-
matically improved the yield and 2a was obtained in 73% yield
under the optimized reaction conditions (Table 2, entry 9).
The reducing agent, magnesium that was commercially avail-
able and for use as a Grignard reagent, was used without pre-
treatment and using only 2 equiv of magnesium gave the best
results.
Mg (2 equiv mol), CF3CO2Et (11 equiv mol), TMSCl (4 equiv mol), NMP (10 mL),
ꢀ15 ꢁC, aromatic aldehyde (1) in NMP (40 mL) was added dropwise at 20 mL hꢀ1
.
The transformation of acetals 2 into the corresponding carbonyl
compounds was investigated under acidic conditions using sulfuric
acid, p-toluenesulfuric acid or hydrochloric acid, but the starting
material was recovered quantitatively. Hydrolysis in trifluoroacetic
acid also failed to form the complex mixture. Elimination of the
trimethylsilyl group with tetrabutylammonium fluoride in THF was
the best method for synthesizing the aromatic unsymmetrical
acyloins 4. (Scheme 4).
Various benzaldehyde derivatives were prepared by using this
coupling reaction, giving the acetals of the corresponding
Table 2
Effects of important factors on the coupling reaction between benzaldehyde and
ethyl trifluoroacetate
Entry
CF3CO2Et
(equiv mol)
TMSCl
(equiv mol)
Temperature
(ꢁC)
Yieldb (%)
2a
3a
1
2
9
11
11
11
11
11
13
11
11
4
3
4
4
5
6
4
4
4
25
25
25
25
25
25
25
0
35
33
42
49
36
30
39
39
36
38
44
41
35
43
17
8
3
4a
5
Scheme 4.
6
7
8a
9a
49
ꢀ15
70 (73)c
The structure of 4 does not correspond with the one expected
from the hydrolysis of the acetal, and it was identified by NMR
analysis. After the elimination of trimethylsilyl groups and elimi-
nation of the ethoxy group, the carbonyl group will initially remain
Mg (2 equiv mol), NMP (30 mL), benzaldehyde (1a) in NMP (20 mL) was added
dropwise at 20 mL hꢀ1
.
a
Benzaldehyde (1a) in NMP (40 mL) was added to the reagents in NMP (10 mL)
dropwise at 20 mL hꢀ1
.
b
at the
b-position of the aromatic ring, forming the trifluoroacetyl
Determined by gas chromatography.
Isolated yield.
c
group. The trifluoroacetyl group may be unstable because the

H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
2083
carbonyl carbon atom is attached to both the trifluoromethyl group
and the oxygen atom, giving an electron-withdrawing effect.
Therefore, the transposition of the carbonyl group occurred after
ketoeenol tautomerism, giving the more stable compound 4 as the
sole product.
The results are summarized in Table 4 and it can be seen that
acyloins 4 were obtained in moderate to good yields. In most of the
cases, the electronic effect of the substituent on the aromatic ring
did not influence the product yield. Each compound with a sub-
stituent at the ortho-position afforded a complex mixture including
the desired product 4, but the reason for this behavior is not clear.
(Table 4, entries 6 and 9). Compound 4c was obtained after acidic
treatment, probably because of the formation of a hydrated or
a dimeric structure.
Table 4
Desilylation of 2 and the synthesis of aromatic unsymmetrical acyloins
Entry
Ar
Yielda (%)
4
1
2
3
4
5
6
7
8
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
71 (67)b
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
4-FC6H4
65
63c
69 (63)b
63
Complex mixture
56
57
9
2-FC6H4
Complex mixture
10
11
12
1-Naphthyl
2-Thienyl
3-Pyridyl
4j
4k
4l
40b
67b
90b
Scheme 5.
Compound 2 (2 mmol), n-Bu4NF (0.5 equiv mol), THF (20 mL), 0e5 ꢁC, nitrogen
atmosphere.
a
dimerization reaction rate depends on the concentration of 6a, and
6a may be reduced by magnesium through a second electron
transfer when 6a is present at a low concentration. Anion species
7a reacts with ethyl trifluoroacetate, then is trimethylsilylated to
give 2a as the main product.
A proposed reaction mechanism for the formation of aromatic
unsymmetrical acyloins is shown in Scheme 6. Compound 9a will
be initially generated after the removal of two trimethylsilyl groups
by tetrabutylammonium fluoride. Enolization and protonation
through the usual workup may give compound 10a.
The tautomerism between 10a and 11a will be unfavorable with
no stabilizing effect, while formation of tautomer 4a may be more
favorable because the carbonyl group is conjugated with the aro-
matic ring and the electron-deficient carbonyl carbon atom is not
directly attached to the trifluoromethyl group that gives the
electron-withdrawing effect. Therefore, acyloin 4a may be exclu-
sively yielded after protonation.
Determined by gas chromatography.
isolated yield.
The product was obtained after reflux in a mixture of 6 N hydrochloric acid and
b
c
THF.
The reduction potential of the starting materials was measured
by cyclic voltammetry to elucidate the reaction mechanism for the
coupling reaction between ethyl trifluoroacetate and 1.
Chlorotrimethylsilane did not show a significant reduction peak,
whereas each of the aromatic aldehydes 1 showed a reduction peak
between ꢀ1.80 and ꢀ2.16 V versus Ag/AgCl.25 (Table 5) However,
ethyl trifluoroacetate showed a more negative reduction peak of
ꢀ2.47
V
versus Ag/AgCl.26 Therefore, the reductive tri-
fluoroacetylation may be initiated by a single electron transfer from
magnesium to aromatic aldehyde 1. A plausible reaction mecha-
nism for the trifluoroacetylation of 1a is proposed in Scheme 5.
Table 5
Our previous study on the acylation of aromatic aldehydes in-
cluding acetylation and propionylation allowed the direct and se-
lective formation of acyloins, the analogues of 11a.27 It is
noteworthy that the strong electron-withdrawing effect given by
the trifluoromethyl group causes the carbonyl group to migrate to
the neighboring position, and no product without migration can be
detected.
Reduction potentials of aromatic aldehydes
Entry
Compound
Reduction potential
V vs Ag/AgCl
1
2
3
4
5
6
7
C6H5CHO
4-MeOC6H4CHO
2-FC6H4CHO
1-Naphthylaldehyde
2-Thienylaldehyde
3-Pyridylaldehyde
CF3CO2Et
1a
1c
1h
1j
1k
1l
ꢀ1.90
ꢀ1.80
ꢀ2.16
ꢀ1.83
ꢀ1.98
ꢀ1.86
ꢀ2.47
3. Conclusions
The magnesium-promoted coupling reactions between aro-
matic aldehydes and ethyl trifluoroacetate gave the acetals of the
trifluoroacetylated compounds in good to excellent yields. Desily-
lation of the coupling products using tetrabutylammonium fluo-
ride, followed by the usual quenching afforded aromatic
unsymmetrical acyloins with the carbonyl group transposed. This
procedure is a novel way of synthesizing aromatic fluorine-
Working electrode: Pt, counter electrode: Pt, reference electrode: Ag/AgCl. solvent:
NMP, supporting electrolyte: Bu4NClO4, scan rate: 200 mV sꢀ1
.
An anion radical species 5a may be formed by the transfer of
a single electron from magnesium metal to 1a and silylation
with chlorotrimethylsilane will give a radical species 6a. The

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H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
chromatography (TLC) analysis, Merck pre-coated plates (silica gel
60 F254, Art 5715, 0.25 mm) were used. Aromatic aldehydes 1 were
commercially available and were used after simple distillation.
Analytical data of pinacol derivative 3a have been already
reported.28
4.2. Typical procedure for coupling reaction of aromatic al-
dehyde (1) and ethyl trifluoroacetate
A mixture of TMSCl (2.2 g, 20 mmol), ethyl trifluoroacetate
(7.8 g, 55 mmol), magnesium turnings (0.25 g, 10 mmol) for
Grignard reagent with no pre-treatment, and dry NMP (10 mL)
was placed in 100 mL-four-necked flask and after activation of
magnesium for 30 min at room temperature, a solution of benz-
aldehyde (5 mmol) in dry NMP (40 mL) was added dropwise over
2 h at ꢀ15 ꢁC and stirring was continued until 1a was completely
consumed. Then the reaction mixture was poured into a saturated
sodium hydrogen carbonate solution (200 mL) and stirring was
continued for 30 min at room temperature. Then the reaction
mixture was extracted with ethyl ether twice. The combined or-
ganic layers were washed with water and brine, dried over an-
hydrous magnesium sulfate, and evaporated under reduced
pressure. The residue was purified by column chromatography to
give 2a.
4.2.1. 2-Ethoxy-1,1,1-trifluoro-2,3-bistrimethylsiloxy-3-phenylpropane
(2a). Isolated yield 73% (diastereomeric mixture¼1:0.67), colorless
oil.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.11 (5.4H, s), 0.00 (5.4H,
Scheme 6.
s), 0.02 (3.6H, s), 0.12 (3.6H, s), 1.00 (1.8H, t, J¼6.9 Hz), 1.20 (1.2H, t,
J¼6.9 Hz), 3.37e3.41 (0.4H, m), 3.53e3.57 (0.4H, m), 3.89e3.94
(0.6H, m), 4.18e4.22 (0.6H, m), 4.92 (0.6H, s), 4.94 (0.4H, s),
7.28e7.34 (3H, m), 7.39e7.42 (2H, m). 19F NMR (376 MHz, CDCl3)
containing unsymmetrical acyloins from aromatic aldehydes in
only two steps.
d
(ppm): ꢀ76.38, ꢀ76.80. IR (neat): 3034, 2960,1455,1253, 759, 701
(cmꢀ1). MS (EI): m/z 394 [Mþ]. Anal. Calcd for C17H29F3O3Si2: C,
51.75, H, 7.41. Found: C, 51.95, H, 7.12.
4. Experimental section
4.1. General
4.2.2. 2-Ethoxy-1,1,1-trifluoro-3-(4-methylphenyl)-2,3-bistrimethylsilo
xypropane (2b). Isolated yield 50% (diastereomeric mixture¼1:0.67),
colorless oil.
All reactions were carried out under nitrogen atmosphere un-
less otherwise noted.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.09 (3.6H, s), 0.00 (3.6H,
s), 0.01 (5.4H, s), 0.13 (5.4H, s), 1.01 (1.8H, t, J¼6.9 Hz), 1.20 (1.2H, t,
J¼6.9 Hz), 2.33 (1.2H, s), 2.36 (1.8H, s), 3.37e3.42 (0.6H, m),
3.53e3.57 (0.6H, m), 3.86e3.92 (0.4H, m), 4.12e4.20 (0.4H, m), 4.88
(0.6H, s), 4.91 (0.4H, s), 7.10e7.13 (2H, m), 7.27e7.30 (2H, m). 19F
1H NMR and 13C NMR were measured on a JEOL JNM AL-400
(400 MHz), or a JEOL JNM EX-400 (400 MHz) spectrometer. Pro-
ton chemical shifts are expressed in parts per million (ppm)
downfield from internal standard (tetramethylsilane, 0.00 ppm),
and coupling constants are reported in hertz (Hz). Carbon chemical
shifts are referenced to the carbon signal of the solvent at
77.00 ppm (CDCl3). Fluorine chemical shifts were referenced to the
external fluorine signal of trifluoroacetic acid at ꢀ76.50 ppm.
Splitting patterns are indicated as follows: br, broad; s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet. Infrared (IR) spectra
were recorded on a JASCO 470Plus FTIR spectrometer. Mass spectra
and high-resolution mass spectra were recorded on a JEOL JMS-
600H spectrometer. Melting point (mp) determinations were per-
formed by using a Yanaco MP-J3 instrument and are uncorrected.
Elemental analyses were measured on Yanaco CHN coder MT-6.
Cyclic voltammograms were measured by ALS model 600. Cyclic
voltammetry was carried out with a three-electrode system using
a platinum working electrode, a platinum counter electrode, and
Ag/AgCl as a reference electrode with sweeping rate of 200 mV sꢀ1
in 1% tetrabutylammonium perchlorate/NMP. GC yield was calcu-
lated from GC analysis using n-hexadecane as an internal standard.
NMP, DMF, and DMAc were distilled under reduced pressure
after drying over calcium hydride. Acetonitrile was distilled over
calcium hydride. THF was distilled over sodium. For thin-layer
NMR (376 MHz, CDCl3)
d
(ppm): ꢀ76.36, ꢀ76.74. IR (neat): 3098,
2960, 1514, 1253, 840 (cmꢀ1). Anal. Calcd for C18H31F3O3Si2: C,
52.91, H, 7.65. Found: C, 53.11, H, 7.43.
4.2.3. 2-Ethoxy-1,1,1-trifluoro-3-(4-methoxyphenyl)-2,3-bistrimethyl
siloxypropane (2c). Isolated yield 66% (diastereomeric mixture¼
1:0.82), colorless oil.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.07 (4.9H, s), ꢀ0.01 (4.9H,
s), 0.02 (4.1H, s), 0.13 (4.1H, s), 1.00 (1.6H, t, J¼6.9 Hz), 1.20 (1.4H, t,
J¼6.9 Hz), 3.37e3.41 (0.55H, m), 3.52e3.56 (0.55H, m), 3.82 (3H, s),
3.87e3.91 (0.45H, m), 4.12e4.16 (0.45H, m), 4.86 (0.55H, s), 4.89
(0.45H, s), 6.82e6.87 (2H, m), 7.30e7.33 (2H, m). 19F NMR
(376 MHz, CDCl3)
d
(ppm): ꢀ76.32, ꢀ76.77. IR (neat): 3030, 2959,
1513,1251,1038, 844 (cmꢀ1). Anal. Calcd for C18H31F3O4Si2: C, 50.92,
H, 7.36. Found: C, 51.26, H, 7.17.
4.2.4. 3-(4-Chlorophenyl)-2-ethoxy-1,1,1-trifluoro-2,3-bistrimethylsilo
xypropane (2d). Isolated yield 71% (diastereomeric mixture¼1:0.82),
colorless oil.
1H NMR (400 MHz, CDCl3)
s), 0.02 (4.1H, s), 0.12 (4.1H, s), 0.99 (1.6H, t, J¼6.9 Hz), 1.19 (1.4H, t,
d
(ppm): ꢀ0.08 (4.9H, s), 0.00 (4.9H,

H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
2085
J¼6.9 Hz), 3.36e3.40 (0.55H, m), 3.51e3.55 (0.55H, m), 3.89e3.91
(0.45H, m), 4.12e4.16 (0.45H, m), 4.88 (0.55H, s), 4.91 (0.45H, s),
4.2.10. 2-Ethoxy-1,1,1-trifluoro-3-(1-naphthyl)-2,3-bistrimethylsilo
xypropane (2j). Isolated yield 55% (diastereomeric mixture¼
7.30e7.36 (4H, m). 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ76.01,
1:0.75), colorless oil.
ꢀ76.58. IR (neat): 3053, 2961, 1490, 1093, 844 (cmꢀ1). Anal. Calcd
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.53 (3.9H, s), ꢀ0.02
for C17H28ClF3O3Si2: C, 47.59, H, 6.58. Found: C, 47.73, H, 6.38.
(10.2H, s), 0.24 (3.9H, s), 0.48 (1.3H, t, J¼6.9 Hz), 1.27 (1.7H, t,
J¼6.9 Hz), 2.94e2.96 (0.43H, m), 3.28e3.32(0.43H, m), 4.08e4.10
(0.57H, m), 4.49e4.52 (0.57H, m), 4.88 (0.57H, s), 4.91 (0.43H, s),
7.47e7.53 (3H, m), 7.80e7.87 (3H, m), 8.10e8.20 (1H, m). 19F NMR
4.2.5. 3-(3-Chlorophenyl)-2-ethoxy-1,1,1-trifluoro-2,3-bistrimethylsilo
xypropane (2e). Isolated yield¼84% (diastereomeric mixture¼
1:0.82), colorless oil.
(376 MHz, CDCl3)
d
(ppm): ꢀ76.48, ꢀ77.59. IR (neat): 3052, 2960,
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.09 (4.9H, s), 0.01 (4.9H,
1512, 1253, 843 (cmꢀ1). Anal. Calcd for C21H31F3O3Si2: C, 56.73, H,
7.03. Found: C, 57.00, H, 7.06.
s), 0.03 (4.1H, s), 0.13 (4.1H, s), 0.99 (1.6H, t, J¼6.9 Hz), 1.19 (1.4H, t,
J¼6.9 Hz), 3.38e3.40 (0.55H, m), 3.51e3.55 (0.55H, m), 3.89e3.91
(0.45H, m), 4.13e4.17 (0.45H, m), 4.88 (0.55H, s), 4.90 (0.45H, s),
4.2.11. 2-Ethoxy-1,1,1-trifluoro-3-(2-thienyl)-2,3-bistrimethylsiloxy
propane (2k). Isolated yield 30% (diastereomeric mixture¼
1:0.90), colorless oil.
7.23e7.29 (3H, m), 7.41 (1H, s). 19F NMR (376 MHz, CDCl3)
d (ppm):
ꢀ76.21, ꢀ76.76. IR (neat): 3072, 2960, 1577, 1105, 839 (cmꢀ1). Anal.
Calcd for C17H28ClF3O3Si2: C, 47.59, H, 6.58. Found: C, 47.54, H,
6.28.
1H NMR (400 MHz, CDCl3)
d (ppm): 0.00 (4.3H, s), 0.03 (4.3H, s),
0.06 (4.7H, s), 0.18 (4.7H, s), 1.07 (1.6H, t, J¼6.9 Hz), 1.25 (1.4H, t,
J¼6.9 Hz), 3.47e3.64 (1.06H, m), 3.88e3.96 (0.47H, m), 4.10e4.17
(0.47H, m), 5.18 (0.53H, s), 5.22 (0.47H, s), 6.96 (0.47H, d, J¼4.9 Hz),
6.97 (0.53H, d, J¼4.9 Hz), 7.02e7.03 (1H, m), 7.28 (0.53H, d,
J¼4.9 Hz), 7.31 (0.47H, d, J¼4.9 Hz). 19F NMR (376 MHz, CDCl3)
4.2.6. 3-(2-Chlorophenyl)-2-ethoxy-1,1,1-trifluoro-2,3-bistrimethylsilo
xypropane (2f). Isolated yield 88% (diastereomeric mixture¼1:0.50),
colorless oil.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.14 (3H, s), ꢀ0.01 (9H, s),
d
(ppm): ꢀ76.31, ꢀ76.92. IR (neat): 3074, 2960, 1436, 1322, 760
0.15 (6H, s), 0.93 (2H, t, J¼6.9 Hz), 1.26 (1H, t, J¼6.9 Hz), 3.37e3.41
(0.67H, m), 3.55e3.58 (0.67H, m), 3.95e3.98 (0.33H, m),
4.25e4.29 (0.33H, m), 5.51 (0.67H, s), 5.60 (0.33H, s), 7.23e7.31
(cmꢀ1). Anal. Calcd for C15H27F3O3SSi2: C, 44.97, H, 6.79. Found: C,
45.24, H, 6.45.
(3H, m), 7.62e7.66 (1H, m). 19F NMR (376 MHz, CDCl3)
d
(ppm):
4.2.12. 2-Ethoxy-1,1,1-trifluoro-3-(3-pyridyl)-2,3-bistrimethylsiloxy
propane (2l). Isolated yield¼60% (diastereomeric mixture¼1:0.16),
colorless oil.
ꢀ76.53, ꢀ76.87. IR (neat): 3072, 2960, 1574, 1037, 758 (cmꢀ1).
Anal. Calcd for C17H28ClF3O3Si2: C, 47.59, H, 6.58. Found: C, 47.31,
H, 6.31.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.13 (7.8H, s), ꢀ0.02 (7.8H,
s), 0.00 (1.2H, s), 0.11 (1.2H, s), 0.95 (0.4H, t, J¼6.9 Hz), 1.17 (2.6H, t,
J¼6.9 Hz), 3.33e3.41 (0.14H, m), 3.48e3.56 (0.14H, m), 3.84e3.91
(0.86H, m), 4.09e4.17 (0.86H, m), 4.91 (0.14H, s), 4.93 (0.86H, s),
7.22e7.27 (1H, m), 7.69e7.74 (1H, m), 8.50e8.58 (2H, m). 19F NMR
4.2.7. 3-(4-Bromophenyl)-2-ethoxy-1,1,1-trifluoro-2,3-bistrimethylsilo
xypropane (2g). Isolated yield 84% (diastereomeric mixture¼1:0.8),
colorless oil.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.09 (5.0H, s), 0.00 (5.0H,
(376 MHz, CDCl3)
d
(ppm): ꢀ75.93, ꢀ76.54. IR (neat): 3039, 2961,
s), 0.01 (4.0H, s), 0.13 (4.0H, s), 0.98 (1.33H, t, J¼6.9 Hz), 1.18 (1.67H,
t, J¼6.9 Hz), 3.33e3.41 (0.44H, m), 3.48e3.56 (0.44H, m), 3.84e3.91
(0.56H, m), 4.08e4.15 (0.56H, m), 4.85 (0.44H, s), 4.88 (0.56H, s),
7.26e7.29 (2H, m), 7.41e7.45 (2H, m). 19F NMR (376 MHz, CDCl3)
1580, 1254, 844 (cmꢀ1). Anal. Calcd for C16H28F3NO3Si2: C, 48.58, H,
7.13, N, 3.54. Found: C, 48.54, H, 6.84, N, 3.49.
4.3. Typical procedure for desilylation of acetal 2
d
(ppm): ꢀ76.10, ꢀ76.67. IR (neat): 3093, 2959, 1592, 1252, 1049,
844 (cmꢀ1). Anal. Calcd for C17H28BrF3O3Si2: C, 43.12, H, 5.96.
Found: C, 43.32, H, 5.64.
To a solution of 2a (2 mmol) in dry THF (20 mL) is added
dropwise 1 M tetrabutylammonium fluoride (1 mL, 1 mmol) at
0e5 ꢁC and the reaction mixture was stirred until 2a disappeared
by TLC. Then 10 mL of water was added at 5 ꢁC and stirring was
continued for 30 min. The reaction mixture was extracted with
ethyl acetate three times. Usual workup and subsequent silica gel
column chromatography gave 3,3,3-trifluoro-2-hydroxy-1-
phenylpropan-1-one (4a) in 71% yield. In case of formation of 4c,
silica gel column chromatography was performed after the crude
material was refluxed in a mixture of 6 N hydrochloric acid (10 mL)
and THF (10 mL) for 5 h.
4.2.8. 2-Ethoxy-1,1,1-trifluoro-3-(4-fluorophenyl)-2,3-bistrimethylsilo
xypropane (2h). Isolated yield 47% (diastereomeric mixture¼1:1),
colorless oil.
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.09 (4.5H, s), ꢀ0.01 (4.5H,
s), 0.01 (4.5H, s), 0.13 (4.5H, s), 0.98 (1.5H, t, J¼6.9 Hz), 1.19 (1.5H, t,
J¼6.9 Hz), 3.34e3.41 (0.5H, m), 3.49e3.56 (0.5H, m), 3.85e3.92
(0.5H, m), 4.10e4.18 (0.5H, m), 4.88 (0.5H, s), 4.91 (0.5H, s),
6.97e7.03 (2H, m), 7.34e7.39 (2H, m). 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ76.14, ꢀ76.69, ꢀ115.54 (m), ꢀ115.92 (m). IR (neat): 3042,
2961, 1509, 1253, 1225, 844 (cmꢀ1). Anal. Calcd for C17H28F4O3Si2: C,
49.49, H, 6.84. Found: C, 49.69, H, 6.62.
4.3.1. 3,3,3-Trifluoro-2-hydroxy-1-phenylpropan-1-one
(4a). GC
yield 71%, white solid.29
1H NMR (400 MHz, CDCl3)
d
(ppm): 4.32 (1H, d, J¼8.2 Hz),
4.2.9. 2-Ethoxy-1,1,1-trifluoro-3-(2-fluorophenyl)-2,3-bistrimethylsilo
xypropane (2i). Isolated yield 68% (diastereomeric mixture¼1:1),
colorless oil.
5.41e5.46 (1H, m), 7.55 (2H, t, J¼7.6 Hz), 7.71 (1H, t, J¼7.6 Hz), 7.99
(2H, d, J¼7.6 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm): 70.94 (q,
1
2JCF¼31.5 Hz), 122.31 (q, JCF¼284.7 Hz), 129.00, 129.44, 133.34,
1H NMR (400 MHz, CDCl3)
d
(ppm): ꢀ0.85 (4.5H, s), ꢀ0.09 (4.5H,
135.26, 193.07. 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ73.83 (d, 3F,
s), 0.00 (4.5H, s), 0.07 (4.5H, s), 1.00 (1.5H, t, J¼6.9 Hz), 1.22 (1.5H, t,
J¼6.9 Hz), 3.48e3.56 (0.5H, m), 3.61e3.68 (0.5H, m), 3.85e3.93
(0.5H, m), 4.10e4.18 (0.5H, m), 5.38 (0.5H, s), 5.41 (0.5H, s),
6.96e7.01 (1H, m), 7.10e7.15 (1H, m), 7.23e7.29 (1H, m), 7.56e7.62
J¼6.1 Hz). IR (KBr): 3345, 3078, 1685, 1597, 1401, 1323, 1224, 1169,
1126, 976, 853 (cmꢀ1). LRMS (EI) m/z 203 [Mþꢀ1].
4.3.2. 3,3,3-Trifluoro-2-hydroxy-1-(4-methylphenyl)-propan-1-one
(4b). GC yield 65%, white solid.29
(1H, m). 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ76.35, ꢀ76.60,
ꢀ117.96 (m), ꢀ118.65 (m). IR (neat): 3044, 2961, 1490, 1180, 843
(cmꢀ1). Anal. Calcd for C17H28F4O3Si2: C, 49.49, H, 6.84. Found: C,
49.51, H, 6.59.
1H NMR (400 MHz, CDCl3)
d (ppm): 2.47 (3H, s), 4.31 (1H, d,
J¼8.3 Hz), 5.38e5.42 (1H, m), 7.35 (2H, d, J¼7.8 Hz), 7.89 (2H, d,
J¼7.8 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm): 21.88, 70.75 (q,

2086
H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
1
2JCF¼31.4 Hz), 122.37 (q, JCF¼284.5 Hz), 129.62, 129.70, 130.78,
J¼8.3 Hz), 8.56 (1H, d, J¼8.8 Hz). 13C NMR (100 MHz, CDCl3)
146.78, 192.37. 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ76.00 (d, 3F,
d
(ppm): 72.50 (q, 2JCF¼30.6 Hz), 122.37 (q, 1JCF¼284.7 Hz), 123.79,
J¼6.1 Hz). IR (KBr): 3443, 3050, 1680, 1605, 1570, 1403, 1317, 1187,
125.05, 127.21, 128.72, 129.10, 129.99, 130.28, 131.21, 133.90, 135.21,
1122, 971, 862 (cmꢀ1). LRMS (EI) m/z 218 [Mþ].
195.12. 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ73.65 (d, 3F, J¼6.1 Hz).
IR (KBr): 3477, 3064, 2942, 1684, 1508, 1238, 864, 783 (cmꢀ1). LRMS
(EI) m/z 254 [Mþ]. HRMS (EI) calcd for: C13H9O2F3, 254.0555; found:
254.0535.
4.3.3. 3,3,3-Trifluoro-2-hydroxy-1-(4-methoxyphenyl)-propan-1-one
(4c). GC yield 63%, colorless oil.29
1H NMR (400 MHz, CDCl3)
d (ppm): 3.91 (3H, s), 4.31 (1H, br s),
5.36 (1H, q, J¼6.8 Hz), 7.00 (2H, d, J¼8.6 Hz), 7.98 (2H, d, J¼8.6 Hz).
4.3.9. 3,3,3-Trifluoro-2-hydroxy-1-thiophen-2-yl-propan-1-one
(4k). Isolated yield 67%, white solid.29
13C NMR (100 MHz, CDCl3)
d
(ppm): 55.65, 70.32 (q, 2J CF¼31.5 Hz),
114.26, 122.46 (q, 1JCF¼284.2 Hz), 126.11, 132.06, 165.23, 190.77. 19
F
1H NMR (400 MHz, CDCl3)
d (ppm): 4.20 (1H, br s), 5.22 (1H, q,
NMR (376 MHz, CDCl3)
d
(ppm): ꢀ74.88 (d, 3F, J¼6.8 Hz). IR (neat):
J¼6.8 Hz), 7.26 (t, 1H, J¼3.9 Hz), 7.88 (d, 1H, J¼3.9 Hz), 7.89 (d, 1H,
3437, 3079, 2940, 1678, 1605, 1572, 1515, 1248, 1180, 1132, 975, 869
J¼3.9 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm): 71.20 (q,
(cmꢀ1). LRMS (EI) m/z 234 [Mþ].
2JCF¼31.4 Hz), 122.23 (q, JCF¼283.9 Hz), 128.85, 135.46, 137.45,
1
139.54, 184.59. 19F NMR (376 MHz, CDCl3)
3F, J¼6.8 Hz). IR (KBr): 3353, 3120, 3107, 2953, 1837, 1655,
1519, 1415, 1325, 1245, 1125, 873, 813 (cmꢀ1). LRMS (EI) m/z 210
[Mþ].
d
(ppm): ꢀ74.69 (d,
4.3.4. 1-(4-Chlorophenyl)-3,3,3-trifluoro-2-hydroxypropan-1-one
(4d). GC yield 69%, white solid of mp 62.0e63.5 ꢁC.
1H NMR (400 MHz, CDCl3)
d
(ppm): 4.30 (1H, d, J¼6.8 Hz),
5.38e5.41 (1H, m), 7.53 (2H, d, J¼8.3 Hz), 7.93 (2H, d, J¼8.3 Hz). 13
C
NMR (100 MHz, CDCl3)
d
(ppm): 71.00 (q, 2JCF¼31.4 Hz), 122.20 (q,
4.3.10. 3,3,3-Trifluoro-2-hydroxy-1-(3-pyridyl)-propan-1-one
(4l). Isolated yield 90%, white solid of mp 115.8e117.0 ꢁC.
1JCF¼284.7 Hz), 129.41, 130.74, 131.60, 142.09, 191.97. 19F NMR
(376 MHz, CDCl3)
d
(ppm): ꢀ73.81 (d, 3F, J¼7.5 Hz). IR (KBr): 3445,
1H NMR (400 MHz, CDCl3)
d (ppm): 4.24 (1H, br s), 5.41 (1H, q,
3044, 2983, 1687, 1591, 1492, 1400, 1315, 1219, 1127, 972, 860
(cmꢀ1). LRMS (EI) m/z 238 [Mþ]. HRMS (EI) calcd for: C9H6O2F3Cl,
238.0008; found: 238.0034.
J¼6.4 Hz), 7.53 (1H, dd, J¼4.9, 8.0 Hz), 8.28 (1H, dt, J¼1.9, 8.0 Hz),
8.92 (1H, dd, J¼1.9, 4.9 Hz), 9.21 (1H, d, J¼1.9 Hz). 13C NMR
2
(100 MHz, CDCl3)
d
(ppm): 71.70 (q, JCF¼31.4 Hz), 122.18 (q,
1JCF¼284.7 Hz), 123.99, 129.33, 136.80, 150.21, 154.91, 192.34. 19F
4.3.5. 1-(3-Chlorolophenyl)-3,3,3-trifluoro-2-hydroxypropan-1-one
(4e). GC yield 63%, white solid of mp 60.5e61.2 ꢁC.
NMR (376 MHz, CDCl3)
d
(ppm): ꢀ74.33 (d, 3F, J¼6.4 Hz). IR (KBr):
3391, 3038, 2834, 2683, 1706, 1598, 1391, 1278, 1136, 1050, 849
(cmꢀ1). LRMS (EI) m/z 205 [Mþ]. Anal. Calcd for C8H6F3NO2: C,
46.84, H, 2.95, N, 6.83. Found: C, 46.85, H, 3.12, N, 7.03.
1H NMR (400 MHz, CDCl3)
d (ppm): 4.24 (br, 1H, s), 5.37e5.42
(1H, m), 7.50 (1H, t, J¼7.8 Hz), 7.68 (1H, d, J¼7.8 Hz), 7.85 (1H,
d, J¼7.8 Hz), 7.97 (1H, s). 13C NMR (100 MHz, CDCl3)
d (ppm):
2
71.20 (q, JCF¼31.4 Hz), 122.15 (q, 1JCF¼284.7 Hz), 127.50, 129.28,
130.27, 134.83, 135.15, 135.48, 192.24. 19F NMR (376 MHz, CDCl3)
Acknowledgements
d
(ppm): ꢀ73.91 (d, 3F, J¼7.5 Hz). IR (KBr): 3438, 3187, 3076,
2960, 1715, 1595, 1576, 1480, 1079, 998 (cmꢀ1). LRMS (EI) m/z 238
[Mþ]. HRMS (EI) calcd for: C9H6O2F3Cl, 238.0008; found:
238.0020.
This work was supported in part by JSPS KAKENHI Grant
Number 22605003.
4.3.6. 1-(4-Bromophenyl)-3,3,3-trifluoro-2-hydroxypropan-1-one
(4g). GC yield 56%, white solid of mp 67.3e68.8 ꢁC.
References and notes
1H NMR (400 MHz, CDCl3)
d
(ppm): 4.20 (1H, d, J¼8.3 Hz), 5.37
ꢀ
ꢀ
1. Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992e1012.
2. Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303e319.
3. Moilliet, J. S. J. Fluorine Chem. 2001, 109, 13e17.
(1H, qd, J¼6.3 Hz, J¼8.3 Hz), 7.71 (2H, d, J¼8.5 Hz), 7.85 (2H, d,
J¼8.5 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm): 71.18 (q,
4. Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomioka, K. J.
Am. Chem. Soc. 1990, 112, 8563e8575.
2JCF¼31.4 Hz), 126.42 (q, JCF¼283.9 Hz), 130.74, 131.00, 132.02,
1
132.44, 192.20. 19F NMR (376 MHz, CDCl3)
d
(ppm): ꢀ74.39 (d, 3F,
5. Hayashi, M.; Hashimoto, S.; Noyori, R. Chem. Lett. 1984, 1747e1750.
6. Yoshida, Y.; Kimura, Y. Chem. Lett. 1988, 1355e1358.
7. Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561e2578.
8. Barrio, J. R.; Namavari, M.; Phelps, M. E.; Satyamurthy, N. J. Am. Chem. Soc. 1996,
118, 10408e10411.
9. Itoh, Y.; Mikami, K. J. Fluorine Chem. 2006, 127, 539e544.
10. Mizuta, S.; Shibata, N.; Hibino, M.; Nagano, S.; Nakamura, S.; Toru, T. Tetrahe-
dron 2007, 63, 8521e8528.
J¼6.3Hz). IR (KBr): 3449, 3073, 2980, 1688, 1587, 1488, 1397, 1315,
1219, 1127, 972, 860 (cmꢀ1). LRMS (EI) m/z 282 [Mþ]. HRMS (EI)
calcd for: C9H6O2F3Br, 281.9503; found: 281.9485.
4.3.7. 1-(4-Fluorophenyl)-3,3,3-trifluoro-2-hydroxypropan-1-one
(4h). GC yield 57%, white solid of mp 94.8e96.3 ꢁC.
11. Kawai, H.; Kusuda, A.; Mizuta, S.; Nakamura, S.; Funahashi, Y.; Masuda, H.;
Shibata, N. J. Fluorine Chem. 2009, 130, 762e765.
12. Keumi, T.; Shimada, M.; Takahashi, M.; Kitajima, H. Chem. Lett. 1990,
783e786.
13. Zhu, L.; Miao, Z.; Sheng, C.; Yao, J.; Zhuang, C.; Zhang, W. J. Fluorine Chem. 2010,
131, 800e804.
1H NMR (400 MHz, CDCl3)
d (ppm): 4.23 (1H, br s), 5.39 (1H, q,
J¼6.8 Hz), 7.24 (2H, dd, J¼5.2 Hz, J¼13.4 Hz), 8.04 (2H, dd,
J¼5.2 Hz, J¼8.8 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm) : 71.09 (q,
3
2JCF¼31.4 Hz), 116.40 (d, JCF¼22.3 Hz), 122.26 (q, 1JCF¼284.7 Hz),
14. Kiselyov, A. S.; Harvey, R. G. Tetrahedron Lett. 1995, 36, 4005e4008.
15. Ruiz, J.; Astruc, D.; Gilbert, L. Tetrahedron Lett. 1996, 37, 4511e4514.
16. Creary, X. J. Org. Chem. 1987, 52, 5026e5030.
4
2
129.76 (d, JCF¼2.5 Hz), 132.34 (d, JCF¼9.9 Hz), 167.03 (d,
1JCF¼259.0 Hz), 191.42. 19F NMR (376 MHz, CDCl3)
(ppm): ꢀ74.49
d
ꢀ
17. Salazar, J.; Lopez, S. E.; Rebollo, O. J. Fluorine Chem. 2003, 124, 111e113.
(d, 3F, J¼6.8 Hz), ꢀ101.02 (m, 1F). IR (KBr): 3444, 3085, 2930,
1686, 1600, 1512, 1406, 1249, 1127, 976, 866 (cmꢀ1). LRMS (EI) m/z
222 [Mþ]. HRMS (EI) calcd for: C9H6O2F4, 222.0304; found:
222.0330.
ꢀ
ꢀ
18. Lopez, S. E.; Perez, Y.; Restrepo, J.; Salazar, J.; Charris, J. J. Fluorine Chem. 2007,
128, 566e569.
19. Prashad, M.; Hu, B.; Har, D.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2000, 41,
9957e9961.
20. Ohtaka, J.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 2009, 50, 1681e1683.
21. Pelaez, W. J.; Burgos Paci, M. A.; Arguello, G. A. Tetrahedron Lett. 2009, 50,
1934e1938.
22. Kim, J.; Jang, D. O. Tetrahedron Lett. 2010, 51, 683e685.
23. Maekawa, H.; Ozaki, T.; Nishiguchi, I. Tetrahedron Lett. 2010, 51, 796e799.
24. Maekawa, H.; Ozaki, T.; Zulkeflee, D.; Murakami, T.; Kihara, S.; Nishiguchi, I.
Synlett 2012, 401e404.
4.3.8. 3,3,3-Trifluoro-2-hydroxy-1-naphtharen-1-yl-propan-1-one
(4j). Isolated yield 40%, white solid of mp 83.5e85.0 ꢁC.
1H NMR (400 MHz, CDCl3)
5.53e5.56 (1H, m), 7.56e7.71 (3H, m), 7.90 (2H, m), 8.14 (1H, d,
d
(ppm): 4.50 (1H, d, J¼5.8 Hz),

H. Maekawa et al. / Tetrahedron 70 (2014) 2081e2087
2087
25. Aliphatic aldehydes are not easily reduced by magnesium metal under the
same reaction conditions because of their much more negative reduction
potential.
26. Application of ethyl perfluoropropionate instead of ethyl trifluoroacetate gave
a complex result probably because of the more positive reduction potential of
the perfluoropropionyl group, while ethyl difluoroacetate with the lower
electrophilicity did not react benzaldehyde.23
27. Nishiguchi, I.; Sakai, M.; Maekawa, H.; Ohno, T.; Yamamoto, Y.; Ishino, Y. Tet-
rahedron Lett. 2002, 43, 635e637.
28. So, J.-H.; Park, M.-K.; Boudjouk, P. J. Org. Chem. 1988, 53, 5871e5875.
29. Singh, R. P.; Leitch, J. M.; Twamley, B.; Shreeve, J. M. J. Org. Chem. 2001, 66,
1436e1440.