Fluorinated butanolides and butenolides - Part 9. Synthesis of 2-(trifluoromethyl)butan-4-olides by Wittig reaction using methyl 3,3,3-trifluoropyruvate

Article abstract of DOI:10.1016/S0022-1139(01)00543-7

2-(Trifluoromethyl)butan-4-olides 13 and 14 were prepared by a three-step synthesis starting from a Wittig reagent and methyl 3,3,3-trifluoropyruvate (1) as a building block. The Wittig reaction of (2-oxoalkyl)triphenylphosphonium bromides with pyruvate 1 gave intermediate 4-oxobutenoates 8 and 9, which were stepwise selectively reduced with zinc borohydride firstly at the double bond and subsequently at the oxo group to afford unstable 4-hydroxy-2-trifluoromethylalkanoates 11 and 12, which cyclised spontaneously to the end butenolides 13 and 14.

Full text of DOI:10.1016/S0022-1139(01)00543-7

Journal of Fluorine Chemistry 113 (2002) 177–183
Fluorinated butanolides and butenolides
Part 9. Synthesis of 2-(trifluoromethyl)butan-4-olides by
Wittig reaction using methyl 3,3,3-trifluoropyruvate$
,$$
*
Ji rˇ ´ı Pale cˇ ek, Jaroslav Kv ´ı cˇ ala, Old ˇr ich Paleta
Department of Organic Chemistry, Prague Institute of Chemical Technology, Technick a´ 5, 16628 Prague 6, Czech Republic
Received 14 August 2001; accepted 19 September 2001
Abstract
2
-(Trifluoromethyl)butan-4-olides 13 and 14 were prepared by a three-step synthesis starting from a Wittig reagent and methyl 3,3,
-trifluoropyruvate (1) as a building block. The Wittig reaction of (2-oxoalkyl)triphenylphosphonium bromides with pyruvate 1 gave
3
intermediate 4-oxobutenoates 8 and 9, which were stepwise selectively reduced with zinc borohydride firstly at the double bond and
subsequently at the oxo group to afford unstable 4-hydroxy-2-trifluoromethylalkanoates 11 and 12, which cyclised spontaneously to the end
butenolides 13 and 14. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Methyl 3,3,3-trifluoropyruvate; Wittig reaction; 4-Oxo-2-(trifluoromethyl)alk-2-enoates; Zinc borohydride; Selective borohydride reduction;
2-(Trifluoromethyl)butan-4-olides; 2,3-Dibromo-2-trifluoromethyl-butanoate; Photo-a,b-didehalogenation
1
. Introduction
2. Results and discussion
Contemporary interest in the chemistry of trifluoromethy-
2.1. Wittig reaction
lated butanolides and butenolides together with synthetic
approaches and areas of potential applications have been
summarised in our preceding paper [1]. Among them, the
synthesis of 4-methyl-2-trifluoromethylbutan-4-olide as a
dopant for ferroelectric liquid crystals [2] and 4-phenyl-2-
trifluoromethylbutan-4-olide for ring-opening polymerisa-
tion studies [3] have been reported. In the meantime, a novel
synthetic approach using palladium-catalysed cyclocarbo-
nylation has been published [4].
Applications of the Wittig reaction and its modifications
have been so far applied in the synthesis of fluorinated but-2-
en-4-olides [5–7], but not in a synthesis of fluorinated
butanolides. In this paper, we present the application of
the Wittig reaction with methyl 3,3,3-trifluoropyruvate in
the synthesis of 4-substituted 2-(trifluoromethyl)butan-4-
olides.
The key synthetic step has been the reaction of a
suitable Wittig reagent with methyl 3,3,3-trifluoropyruvate
(1, Scheme 1). We have found only one reference on this
reaction in the literature [8], viz. the reaction of (ethoxy-
carbonylmethylene)triphenylphosphorane that afforded pre-
dominantly (60% relative intensity) the more strained
maleate structure. To get knowledge on the stereoselectivity
of the Wittig reactions with 1, we carried out the reaction with
two phosphonium salts (2 and 3) prepared from alkyl bro-
mides with different chain length (Scheme 1, Table 1). The
Wittig reagents were prepared according to the literature
[9–12]. As shown in Table 1, the stereoselectivity was low for
both alkyls (products 6 and 7) favouring the more strained
(E)-isomers 6a and 7a. The isomer excess for 7a with propyl
at the double bond product was lower relatively to (E)-but-
2-enoate 6a with a less bulky methyl at the double bond.
In contrast, much more positive results from the point of
view of the synthesis of the target compounds 13 and 14
were obtained in the Wittig reaction of oxophosphonium
salts 4 and 5, which were prepared from chloroacetone
or a-bromoacetophenone (phenacyl bromide) (Scheme 1,
Table 1) according to the literature [13,14]: the (E)-isomers
$
Presented at the 16th International Symposium on Fluorine Chem-
istry, Durham, 16–21 July 2000, UK (Poster 1P-120).
$$
Part 8, [1].
*
Corresponding author. Fax: þ42-2-2431-1082.
E-mail address: oldrich.paleta@vscht.cz (O. Paleta).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 1 ) 0 0 5 4 3 - 7

178
J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
Scheme 1. Reaction of methyl 3,3,3-trifluoropyruvate (1) with Wittig
reagents 2–5.
8
a and 9a with a convenient cis-configuration of the ester
and g-keto groups prevailed in the resulting 8 and 9.
Elucidation of the (E)- and (Z)-configurations was done
on the basis of NMR spectra according to the data reported
Scheme 2. Selective hydride reduction of 4-oxo-2-alkenoates 8–9;
spontaneous cyclisation to butanolides 13–14.
for trifluoromethylated a,b-unsaturated esters [1,15,16]. In
sodium borohydride in the preceding paper [1]. However,
when this method was applied to oxoalkenoates 8 and 9 a
complex mixture of compounds was obtained. Therefore, we
employed the milder zinc borohydride [17] in diethyl ether.
The reduction of oxoalkenoates 8 and 9 proceeded in two
distinct steps: in the first step the double bond was reduced
in 9 when the reaction was carried out at 0 8C (Scheme 2,
1
H NMR, the coupling of =CH and CF groups in (E)-
3
isomers 6a–9a was observed as a quadruplet. This coupling
was not observed for any (Z)-isomer 6b–9b. In 19F NMR, the
coupling between =CH and CF groups has a coupling
3
constant of ca. 1.5 Hz, which was observed in the spectra
of (E)-isomers 8a and 9a. In addition, (E)-isomers 6a–9a
display characteristic chemical shifts of ca. À65 ppm, while
the signals of (Z)-isomers 6b–9b appear at ca. À60 ppm.
Table 2). The reduction could easily be followed by 19
NMR as the signals of the trifluoromethyl groups in
-trifluoromethylbutenoate 9 and 2-trifluoromethylbutanoate
F
2
2
.2. Selective hydride reduction
10 display rather different chemical shifts: the signals of
the CF groups in alkanoates appear in the range from À70
3
For the selective reduction of the oxo group in 2-hydroxy-
-oxo-2-trifluoromethylalkanoates, we successfully applied
to À80 ppm [1], while signals in 2-trifluoromethylalk-2-
enoates are shifted downfield to ca. À60 ppm.
4
Table 1
Results of reactions of Wittig reagents with methyl 3,3,3-trifluoropyruvate: yields and configuration of isomers
Phosphonium reagent
(E)-products
(E):(Z) (%)
Yield (%)
68.8
a
2
6a
55:45
3
4
7a
8a
43:57
92:8
69.7
71.9
5
9a
84:16
78.4
a
The 6a–9a products with (E)-configuration; 6b–9b isomeric products with (Z)-configuration.

J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
179
Table 2
Results of zinc borohydride reductions of a,b-unsaturated g-ketoesters
Starting compound
Conditions
Product
Diastereoisomers
% relative intensity)
Yield
(%)
(
8
Et
Et
2
O rt
13
60:40
90
51
9
9
2
O 0 8C
10
14
Et
2
O rt
53:47
85
The reduction of 8 at room temperature afforded directly
lactone 13, as the intermediate g-hydroxyalkanoate 11
cyclised spontaneously in the reaction mixture (Scheme 2).
On the other hand, the reduction of 9 gave g-hydroxyalk-
anoate 12, which was stable in the reaction mixture (checked
by 19F NMR), but completely cyclised during purification on
a silica gel column to 4-phenyl-4-trifluoromethylbutan-4-
olide (14, Scheme 2). The lactones 13 and 14, which are
mixtures of diastereoisomers (Table 2), were not separated
in this work to the individual configurational stereoisomers
because the methodologies for the separation have recently
been reported [2,3].
bromoalkanoates 17 and 18 are accessible by a selective
photoreduction of dibromoalkanoates 15 and 16 [18–20],
which are in turn easily prepared by the reaction of alkeno-
ates 8 and 9 with bromine according to [21,22] (Scheme 3).
Photoreductions of dibromoalkanoates 15 and 16 were
performed in a photoreactor with 2-propanol as hydrogen
donor and acetone as a photosensitiser and the reaction was
followed by TLC to check the complete conversion of the
starting dibromoalkanes. However, instead of the expected
bromoalkanoates 17 and 18, a photo-a,b-didehalogenation
occurred to afford surprisingly the starting alkenoates 8
and 9.
2
2
.3. Attempts to prepare substituted 3-bromo-
-trifluoromethylbutan-4-olides
3. Experimental
3-Bromo-4-oxo-2-trifluoromethylalkanoates 17 and 18
could be potential intermediates in the synthesis of buteno-
lides 19 and 20 (Scheme 3). In a retrosynthetic view,
3.1. General experimental procedures
Temperature data were not corrected. Distillations of high
boiling compounds were carried out on a Vacuubrand RC5
high vacuum oil pump. Column chromatography (d ¼
2
:5 cm): CC1, column 20 cm; CC2, column 30 cm; CC3,
column 50 cm. GC analyses were performed on a Micromat
HRGC 412 (GCa, Nordion Analytical; FID, 25 m glass
capillary column, SE-30) and Chrom 5 (GCb, Laboratorn´ı
pr ´ı stroje, Prague; FID, 380 ꢀ 0:3 cm packed column, SE-
301 on Chromaton N-AW-DMCS (Lachema, Brno), nitro-
gen) instruments. NMR spectra were recorded on a Bruker
00 AM (FT, 19F at 376.6 MHz, 31P at 202.46 MHz), Varian
4
Gemini 300 HC (FT, H at 300.07 MHz, 13C at 75.46 MHz)
1
instruments: TMS, CFCl and H PO as the internal stan-
3
3
4
dards, chemical shifts in ppm (s: singlet, d: doublet, t: triplet,
q: quadruplet, m: multiplet), coupling constants J in Hz,
solvent CDCl . MS spectra were scanned on a Hewlett-
3
Packard MSD 5971A instrument (1989, EI 70 eV).
Chemicals used were as follows: methyl 3,3,3-trifluoro-
pyruvate (1) was prepared from hexafluoropropene-1,2-oxide
Scheme 3. Attempt to prepare b-bromobutanolide.

180
J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
according to our procedure [23,24]; silica gel (60–100 mm,
Merck), ethyl bromide (distilled, bp 37–40 8C), butyl
bromide (distilled, bp100–104 8C), a-bromoacetophenone
3.2.4. (2-Oxo-2-phenylethyl)triphenylphosphonium
bromide (5)
A mixture of a-bromacetophenone (10 g, 50.2 mmol),
triphenylphosphine (13.2 g, 50.2 mmol) and toluene
(100 ml) was refluxed for 48 h. Yield of 5: 21.6 g
(93.2%), mp 279–281 8C (literature [13]: mp 279–280 8C,
(
(
Aldrich), (2-oxopropyl)triphenylphosphonium chloride
4) (Aldrich), triphenylphoshine (Aldrich), butyllithium in
hexane (Aldrich), zinc borohydride (prepared from sodium
borohydride and zinc chloride, [15]), diethyl ether (distilled
1
literature [14]: mp 280–281 8C). H NMR (300.07 MHz,
2
over Na), hexane (distilled over CaCl , bp 69 8C), methylene
CDCl ): d 6.41 (d, 2H, CH , J ¼ 12:1 Hz); 7.49 (t, 2H,
2
3
2
HP
chloride (distilled, bp 42 8C), tetrahydrofuran (dried by
sodium benzophenone ketyl and distilled prior to use),
acetone (Lachema, Brno), toluene (distilled, bp 111 8C),
2-propanol UV pure (Lachema, Brno), 1,1,2-trichloro-1,2,2-
trifluoroethane (CFC-113, Spolek pro chemickou a hutn´ı
Ph); 7.64 (m, 7H, Ph); 7.74 (m, 3H, Ph); 7.95 (m, 6H, Ph);
3
1
8.38 (d, 2H, Ph) ppm. C NMR (75.46 MHz, CDCl ): d
3
1
38.76 (d, CH , JCP ¼ 61:3 Hz); 128.91 (Ph); 129.91 (Ph);
2
3
134.73 (Ph); 135.15 (d, Ph, JCP ¼ 5:7 Hz); 118.87 (d, Ph,
1
2
JCP ¼ 89:3 Hz); 130.06 (d, Ph, JCP ¼ 13:1 Hz); 134 (d,
´
v y´ robu, Ust ´ı nad Labem).
3
4
Ph, JCP ¼ 10:9 Hz); 134.64 (d, Ph, JCP ¼ 2:3 Hz) ppm.
1
3 3
3
P NMR (202.46 MHz, CDCl ): d 22.57 (s, PPh ) ppm.
3
3
.2. Phosphonium salts (compounds 2, 3 and 5)
3
.3. The Wittig reaction
.2.1. General procedure
The reactions were carried out in a round bottomed
3.3.1. General procedure
flask equipped with a reflux condenser with drying tube
CaCl ). The reaction mixture was refluxed on an oil
The reactions were carried out in a round bottomed
flask (250 ml, magnetic spinbar) under a dry atmosphere.
The dry flask was charged with phosphonium salt (2–5),
THF (100 ml) was then added dropwise and the mixture
was stirred for 30 min, then cooled to ca. À70 8C (dry ice–
ethanol) and a solution of butyllithium was added drop-
wise. The mixture was allowed to warm to rt over 2 h and
stirred for additional 1 h. The dark-red mixture was again
cooled to ca. À70 8C and pyruvate 1 was added dropwise.
(
2
bath while stirring (magnetic spinbar). The complete
conversion of triphenylphosphine was checked by 31P
NMR, solvent and/or reactant were removed on a rotary
evaporator and the residue was crystallised in a hexane:-
diethyl ether (10:1) mixture to give pure phosphonium
salts 2, 3, 5.
1
9
3
.2.2. Ethyl(triphenyl)phosphonium bromide (2)
A mixture of ethyl bromide (74.9 g, 687 mmol) and
The complete conversion of 1 was checked by F NMR.
The mixture was then warmed to rt, filtered through a short
column (CC2, silica gel 30 g, CH Cl ) to remove triphe-
triphenylphosphine (15 g, 57.2 mmol) was refluxed for
4
2
2
8 h. Yield of 2: 20.8 g (98%), mp 204–206 8C (literature
nylphosphine oxide and salts. Pure compounds 6–9 were
obtained by distillation in vacuum on a short-pass micro-
apparatus.
[
9]: mp 203–205 8C, literature [10]: mp 205–206 8C).
1
H NMR (300.07 MHz, CDCl ): d 1.37 (dt, 3H, CH ,
3
3
3JHH ¼ 7:2 Hz, J ¼ 20:3 Hz); 3.83 (dq, 2H, CH , J
3
3
¼
HP
2
HH
2
7
1
:2 Hz, J ¼ 12:6 Hz); 7.62–7.89 (m, 15H, PPh ) ppm.
3.3.2. Methyl 2-(trifluoromethyl)but-2-enoate (6)
HP
3
2
3
C NMR (75.46 MHz, CDCl ): d 6.29 (d, CH , J
¼
Phosphonium salt 2 (2.42 g, 6.51 mmol), THF (50 ml),
butyllithium (2.7 ml, 6.51 mmol) and pyruvate 1 (1.02 g,
6.51 mmol) were reacted according to Section 3.3.1. The
yield of 6: 0.57 g (69%), bp 40–49 8C/2 mmHg, as a mixture
3
3
CP
5
1
:1 Hz); 16.55 (d, CH2, 1JCP ¼ 51 Hz); 117.34 (d, Ph,
2
JCP ¼ 85:9 Hz); 130.02 (d, Ph, JCP ¼ 12:6 Hz); 133.04
3
31
(
(
d, Ph, JCP ¼ 10:3 Hz); 134.6 (s, Ph) ppm. P NMR
202.46 MHz, CDCl ): d 26.83 (s, PPh ) ppm.
of isomers E and Z (55:45).
1
3
3
The 6a, (E)-isomer: H NMR (300.07 MHz, CDCl ): d
3
3
3
.2.3. Butyl(triphenyl)phosphonium bromide (3)
A mixture of butyl bromide (10 g, 73 mmol), triphenyl-
1.95 (d, 3H, CH , J ¼ 6:6 Hz); 3.91 (s, 3H, COOCH );
3
HH
3
1
19
7.46 (m, H, CH) ppm. F NMR (376.6 MHz, CDCl ): d
3
1
3
phosphine (19.2 g, 73 mmol) and toluene (100 ml) was
refluxed for 48 h. Yield of 3: 27.9 g (95.6%), mp 240–
À64.66 (s, CF ) ppm. C NMR (75.46 MHz, CDCl3):
3
d 14.18 (CH ); 53.31 (COOCH ); 121.28 (q, CF ,
3
3
3
1
2
42 8C (literature [11]: mp 244–245 8C, literature [12]:
JCF ¼ 287:9 Hz); 128.64 (s, CH); 164.88 (COOCH )
3
1
mp 239–241 8C). H NMR (300.07 MHz, CDCl ): d 0.91
ppm (the signal of C–CF was not observed in the spec-
3
3
3
(
2
t, 3H, CH , JHH ¼ 6:6 Hz); 1.64 (m, 4H, (CH ) ); 3.88 (m,
trum).
3
2 2
13
1
H, CH ); 7.65–7.92 (m, 15H, PPh ) ppm. C NMR
2
The 6b, (Z)-isomer: H NMR (300.07 MHz, CDCl ): d
3
3
3
(
75.46 MHz, CDCl ): d 13.4 (CH ); 22.31 (d, CH ,
2.17 (d, 3H, CH , J ¼ 2:2 Hz); 3.94 (s, 3H, COOCH );
3
3
2
3
HH
3
1
2
19
JCP ¼ 49:8 Hz); 23.37 (d, CH , J ¼ 16 Hz); 24.24 (d,
7.64 (m, 1H, CH) ppm. F NMR (376.6 MHz, CDCl ): d
2
CP
3
3
1
13
CH , J ¼ 4 Hz); 117.89 (d, Ph, J ¼ 85:9 Hz); 130.22
À59.31 (s, CF ) ppm. C NMR (75.46 MHz, CDCl3):
2
CP
CP
3
3
(
1
d, Ph, 2JCP ¼ 12:6 Hz); 133.27 (d, Ph, J ¼ 10:9 Hz);
owing to low intensity, NMR signals were not observed.
Anal. calcd. for C H F O : C, 42.9; H, 4.2. Found: C, 43.0;
H, 4.0%.
CP
4
31
34.75 (d, Ph, JCP ¼ 2:9 Hz) ppm. P NMR (202.46 MHz,
3 3
6
7 3 2
CDCl ): d 24.98 (s, PPh ) ppm.

J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
181
3
.3.3. Methyl 2-(trifluoromethyl)hex-2-enoate (7)
Phosphonium salt 3 (3.62 g, 9.05 mmol), THF (50 ml),
7.49–7.91 (m, 5H, Ph) ppm. 19F NMR (376.6 MHz, CDCl3):
d À65.59 (d, CF , 4JHF ¼ 1:2 Hz) ppm. 13C NMR
3
butyllithium (3.7 ml, 9.05 mmol) and pyruvate 1 (1.41 g,
.05 mmol) were reacted according to Section 3.3.1. The
(75.46 MHz, CDCl ): d 52.82 (COOCH ); 75.20 (q, C–
3
3
2
1
9
CF , JCF ¼ 29:8 Hz); 120.97 (q, CF , JCF ¼ 274:3 Hz);
3
3
yield of 7: 1.24 g (69.7%), bp 45–58 8C/2 mmHg, a mixture
of isomers E and Z (43:57).
128.56, 129.01, 134.38, 134.96 (Ph); 141.23 (q, CH,
3
JCF ¼ 5:2 Hz); 161.14 (COOCH ); 190.56 (C=O) ppm.
3
1
1
The 7a, (E)-isomer: H NMR (300.07 MHz, CDCl ): d
The 9b, (Z)-isomer: H NMR (300.07 MHz, CDCl ): d
3
3
3
0
.97 (t, 3H, CH , J ¼ 7:6 Hz); 1.55 (m, 2H, CH ); 2.58
3.94 (s, 3H, COOCH ); 7.81 (s, 1H, CH); 7.49–7.91 (m, 5H,
3
HH
2
3
(
m, 2H, CH ); 3.83 (s, 3H, COOCH ); 6.84 (tq, 1H, CH,
2
Ph) ppm. 19F NMR (376.6 MHz, CDCl ): d À60.92 (s, CF )
3
3
3
3
JHH ¼ 7:7 Hz, J ¼ 1:1 Hz) ppm. 19F NMR (376.6 MHz,
4
ppm. 13C NMR (75.46 MHz, CDCl ): d 53.19 (COOCH );
HF
CDCl ): d À65.11 (s, CF ) ppm. 13C NMR (75.46 MHz,
3
3
1
123.19 (q, CF , JCF ¼ 286:9 Hz); 128.12, 128.79, 134.73,
3
3
3
3
CDCl ): d 13.57 (CH ); 21.71 (CH ); 30.51 (CH ); 51.94
135.02 (Ph); 145.05 (q, CH, JCF ¼ 2:9 Hz); 161.59
3
3
2
2
1
(
COOCH ); 122.50 (q, CF , JCF ¼ 274:2 Hz); 123.45 (q,
(COOCH ); 191.02 (C=O) ppm (the signal of C–CF was
3
3
3
3
2
3
C–CF , JCF ¼ 34:3 Hz); 150.93 (q, CH, JCF ¼ 5:2 Hz);
not observed in the spectrum). Anal. calcd. for C H F O :
12 9 3 3
3
1
63.41 (COOCH ) ppm.
3
C, 55.8; H, 3.5. Found: C, 55.5; H, 3.7%.
1
The 7b, (Z)-isomer: H NMR (300.07 MHz, CDCl ): d
3
3
0
.97 (t, 3H, CH , J ¼ 7:6 Hz); 1.55 (m, 2H, CH ); 2.46
3.4. Selective one-step reduction of 9 with Zn(BH4)2;
methyl 4-oxo-4-phenyl-2-(trifluoromethyl)butanoate (10)
3
HH
2
3
(
m, 2H, CH ); 3.81 (s, 3H, COOCH ); 7.22 (t, 1H, CH, J
2 3
HH
1
9
¼
7:7 Hz) ppm. F NMR (376.6 MHz, CDCl ): d À59.81
13
3 3 3
3
(
s, CF ) ppm. C NMR (75.46 MHz, CDCl ): d 13.54 (CH );
A round bottomed flask (50 ml, 2 magnetic spinbars) was
charged at 0 8C with butenoate 9 (0.1 g, 0.39 mmol),
2
1.85 (CH ); 30.97 (CH ); 52.34 (COOCH ); 122.07 (q, CF ,
2 2 3 3
3
1
JCF ¼ 272:6 Hz); 123.48 (q, C–CF ); 153.83 (q, CH, JCF ¼
Zn(BH ) (0.11 g, 1.16 mmol) and diethyl ether (10 ml),
the mixture was stirred at 0 8C and after 30 min methanol
(1 ml) was added. The reaction was followed by TLC
3
4 2
2
C, 49.0; H, 5.7. Found: C, 48.9; H, 5.9%.
:3 Hz); 162.8 (COOCH ) ppm. Anal. calcd. for C H F O :
8 11 3 2
3
(CH Cl ) until the conversion of 9 was complete. The
2 2
3
.3.4. Methyl 4-oxo-2-(trifluoromethyl)pent-2-enoate (8)
Phosphonium salt 4 (5.13 g, 14.5 mmol), THF (50 ml),
butyllithium (6 ml, 14.5 mmol) and pyruvate 1 (2.26 g,
4.5 mmol) were reacted according to the Section 3.3.1.
mixture was then chromatographed on a short column
(CC1, silica gel 10 g, diethyl ether). The solvent was
removed in vacuum, raw 10 was purified by CC2 (silica
gel 30 g, CH Cl ), and crystallised from hexane. The yield
1
2
2
The yield of 8: 2.04 g (71.9%), bp 67–75 8C/2 mmHg,
mixture of isomers E and Z (92:8).
of 10: 0.05 g (51%), mp 75–80 8C.
1
H NMR (300.07 MHz, CDCl ): d 3.29 (dt, 1H, CH ,
3
2
1
2
2
3
The 8a, (E)-isomer: H NMR (300.07 MHz, CDCl ): d
JHH ¼ 17:3 Hz, JHH ¼ 2:4 Hz); 3.75 (dt, 1H, CH ,
3
2
3
2
.39 (s, CH ); 3.85 (s, 3H, COOCH ); 6.96 (q, 1H, CH,
19
JHH ¼ 17:3 Hz, JHH ¼ 10:9 Hz); 3.75 (s, 3H, COOCH );
3
3
3
4
3
3
JHF ¼ 1:1 Hz) ppm. F NMR (376.6 MHz, CDCl ): d
3.83 (dtq, 1H, CH, JHH ¼ 2:4 Hz, JHH ¼ 10:8 Hz,
19
3
4
13
3
À65.68 (d, CF , J ¼ 1:3 Hz) ppm. C NMR (75.46
JHH ¼ 8:2 Hz); 7.41–7.92 (m, 5H, Ph) ppm. F NMR
3
HF
3
MHz, CDCl ): d 29.21 (CH ); 52.67 (COOCH ); 120.81 (q,
(376.6 MHz, CDCl ): d À68.17 (d, CF , JHF ¼ 7:9 Hz)
3
3
3
3
3
1
2
13
CF , JCF ¼ 273:7 Hz); 127.22 (q, C–CF , JCF ¼ 32:7 Hz);
ppm. C NMR (75.46 MHz, CDCl ): d 35.16 (CH );
3
3
3
2
3
3
1
41.37 (q, CH, JCF ¼ 4:6 Hz); 161.34 (COOCH ); 197.65
45.51 (q, CH, JCF ¼ 28:1 Hz); 53.11 (COOCH ); 124.73
3
3
1
(
C=O) ppm.
The 8b, (Z)-isomer: H NMR (300.07 MHz, CDCl ): d
(q, CF , JCF ¼ 280 Hz); 128.13, 128.78, 133.86, 135.64
3
1
(Ph); 167.31 (COOCH ); 192.62 (C=O) ppm. Anal. calcd.
3
3
2
.39 (s, CH ); 3.88 (s, 3H, COOCH ); 7.39 (s, 1H, CH) ppm.
3
for C H F O : C, 55.4; H, 4.3. Found: C, 55.3; H, 4.6%.
12 11 3 3
3
1
9
F NMR (376.6 MHz, CDCl ): d À60.83 (s, CF ) ppm. 13C
3
3
3
NMR (75.46 MHz, CDCl ): d 146.05 (q, CH,
2
were not assigned. Anal. calcd. for C H F O : C, 42.9; H,
J
:9 Hz) ppm; owing to low intensity, the other NMR signals
¼
3.5. Selective two-step reduction of 8 and 10
with Zn(BH ) ; butanolides 13 and 14
3
CF
4
2
7
7 3 3
3
.6. Found: C, 42.6; H, 3.7%.
3.5.1. General procedure
A round bottomed flask (100 ml, 2 magnetic spinbars)
was charged with butenoates 8 and 10, Zn(BH ) and diethyl
ether (50 ml). The reactions were carried out at rt and
followed by 19F NMR.
3
2
.3.5. Methyl 4-oxo-4-phenyl-2-(trifluoromethyl)but-
-enoate (9)
Phosphonium salt 5 (3.84 g, 8.33 mmol), THF (50 ml),
4
2
butyllithium (3.5 ml, 8.33 mmol) and pyruvate 1 (1.3 g,
.33 mmol) were reacted according to Section 3.3.1. The
8
3.5.2. 2-(Trifluoromethyl)pentan-4-olide (13)
yield of 9: 2.15 g (78.4%), bp 85–99 8C/2 mmHg, as a
mixture of isomers E and Z (84:16).
A mixture of pentenoate 8 (0.47 g, 2.42 mmol), Zn(BH4)2
(0.5 g, 5.28 mmol) and diethyl ether was reacted for 8 h.
The reaction mixture, which did not contain any pentanoate
11 (checked by 19F NMR), was then chromatographed on
1
The 9a, (E)-isomer: H NMR (300.07 MHz, CDCl ): d
3
4
3
.69 (s, 3H, COOCH ); 7.46 (q, 1H, CH, JHF ¼ 1:7 Hz);
3

182
J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
a short column (CC1, silica gel 10 g, diethyl ether), the
solvent was removed in vacuum and the raw butanolide 13
was purified by CC3 (silica gel 50 g, CH Cl ). The yield of
3.5.4. Methyl 4-hydroxy-4-phenyl-
2-(trifluoromethyl)butanoate (12)
1
9
F NMR (376.6 MHz, CDCl ): diastereoisomer A: d
2
2
3
3
liquid 13: 0.33 g (80%) diastereoisomer ratio 60:40.
1
À68.75 (d, CF , JHF ¼ 9:2 Hz); diastereoisomer B: d
3
3
H NMR (300.07 MHz, CDCl ): diastereoisomer A: d
À70.32 (d, CF , JHF ¼ 10:2 Hz) ppm. MS (Mr ¼ 262),
3
3
3
2
þ
1
.48 (d, 3H, CH , JHH ¼ 6 Hz); 2.02 (dt, 1H, CH , JHH ¼
m/z (% relative intensity): EI: 231/10 (M À 31), 230/92,
3
2
3
1
CH); 4.63 (qdt, 1H, CH,
4:3 Hz, JHH ¼ 6 Hz); 2.67 (m, 1H, CH ); 3.50 (m, 1H,
229/21, 147/9, 124/16, 117/55, 115/26, 107/100, 105/77, 96/
56, 95/23, 77/52, 69/12, 51/39.
2
3
3
J
¼ 6:2 Hz,
J
¼ 10 Hz,
HH
HH
3JHH ¼ 6 Hz); diastereoisomer B: d 1.43 (d, 3H, CH ,
3
3JHF ¼ 6:6 Hz); 2.18 (m, 1H, CH ); 2.62 (m, 1H, CH );
3.6. Bromo derivatives
2
2
3
3
3
.44 (m, 1H, CH); 4.81 (qdt, 1H, CH, JHH ¼ 6:6 Hz,
3
JHH ¼ 6:3 Hz, JHH ¼ 7:3 Hz) ppm.
3.6.1. Addition of bromine to 4-oxoalkenoates 8 and 9;
compounds 15 and 16
1
9
F NMR (376.6 MHz, CDCl ): diastereoisomer A: d
3
3
À69.23 (d, CF , JHF ¼ 8:6 Hz); diastereoisomer B: d
3
3
À69.02 (d, CF , JHF ¼ 9:3 Hz) ppm.
3.6.1.1. General procedure. A round bottomed flask (25 ml,
magnetic spinbar) was charged with alkenoate 8 or 9 and
CFC-113 (5 ml). The flask was immersed in a dry-ice cooled
bath and a solution of bromine in CFC-113 was added
dropwise while stirring. The progress of the reaction was
followed by 19F NMR. When the conversion of alkenoate
was complete, solventandvolatile components were removed
on a rotary evaporator.
3
1
3
C NMR (75.46 MHz, CDCl ): diastereoisomer A: d
3
2
2
3
1
(
1
0.7 (CH ); 31.32 (CH ); 46.02 (q, CH–CF , JCF
1
¼
3
2
3
0:7 Hz), 75.13 (CH); 123.8 (q, CF , J ¼ 277:1 Hz);
3
CF
69.11 (C=O); diastereoisomer B: d 20.71 (CH ); 30.34
3
2
CH ); 45.94 (q, CH–CF , JCF ¼ 30 Hz), 75.29 (CH);
2
3
24.03 (q, CF3, 1JCF ¼ 279:03 Hz; 169.20 (C=O) ppm.
MS (Mr ¼ 168), m/z (% relative intensity): EI: 169/1
þ
þ
þ
(
1
5
M þ 1), 168/1.5 (M ), 167/3 (M À 1), 153/30, 147/7,
33/38, 124/91, 105/71, 104/17, 96/63, 95/41, 77/88, 69/26,
5/100, 43/48.
3.6.1.2. Methyl 2,3-dibromo-4-oxo-2-(trifluoromethyl)-
pentanoate (15). A mixture of pentenoate 8 (0.107 g,
0.55 mmol), bromine (0.1 g, 0.6 mmol) in CFC-113 was
reacted for 2 h. The yield of liquid 15: 0.18 g (94.8%),
3
.5.3. 4-Phenyl-2-(trifluoromethyl)butan-4-olide (14)
A flask (100 ml) was charged with butenoate 9 (0.76 g,
.96 mmol), Zn(BH4)2 (0.52 g, 5.48 mmol) and diethyl
diastereoisomer ratio 71:29.
1
2
H NMR (300.07 MHz, CDCl ): diastereoisomer A: d
3
ether (50 ml) and the mixture reacted for 9 h. In the
mixture, hydroxybutanoate 12 (diastereoisomer ratio
2.49 (s, 3H, CH ), 3.92 (s, 3H, COOCH ); 5.07 (s, 1H, CH);
3
3
diastereoisomer B: d 2.46 (s, 3H, CH
), 3.93 (s, 3H,
COOCH ); 5.21 (s, 1H, CH) ppm. F NMR (376.6 MHz,
3
3
19
19
5
5:45) was observed ( F NMR and GC–MS) that cyclised
spontaneously to butanolide 14.The mixture was treated
as in Section 3.5.2 and pure 14 was obtained by crystal-
lisation from hexane. The yield of 14: 0.58 g (85.3%), mp
CDCl ): diastereoisomer A: d À66.87 (s, CF ); diastereoi-
3
3
1
3
somer B: d À68.75 (s, CF ) ppm. C NMR (75.46 MHz,
3
CDCl ):diastereoisomer A:d 27.75(CH ), 49.92(COOCH );
3
3
3
1
7
7
8–83 8C, diastereoisomer ratio 53:47 (literature [3]: mp
54.97 (CH); 121.85 (q, CF3, JCF ¼ 284:8 Hz); 162.07
6–88 8C).
(COOCH ); 196.17 (C=O); diastereoisomer B: d 27.61
3
1
H NMR (300.07 MHz, CDCl ): diastereoisomer A: d
(CH ), 51.37 (COOCH ); 55.02 (CH); 122.12 (q, CF ,
1
3
3
3
3
2
3
2
.38 (dt, 1H, CH , JHH ¼ 23:1 Hz, JHH ¼ 12:6 Hz); 2.92
JCF ¼ 284:2 Hz); 163.49 (COOCH
3
); 189.75 (C=O)
ppm. MS (Mr ¼ 356), m/z (% relative intensity): EI: 327/
2
(
m, 1H, CH ); 3.65 (m, 1H, CH); 5.46 (dt, 1H, CH,
2
3
JHH ¼ 6 Hz, 3JHH ¼ 10:4 Hz); 7.28–7.56 (m, 5H, Ph);
þ
6 (M À 29), 325/14, 323/7, 277/19, 275/20, 261/5, 259/8,
diastereoisomer B: d 2.55 (m, 1H, CH ); 2.92 (dt, 1H,
245/4, 243/4, 235/11, 233/14, 215/35, 213/33, 203/59, 201/
54.
2
2
3
CH , J ¼ 14:3 Hz, J ¼ 7:7 Hz) 3.47 (m, 1H, CH),
2
HH
HH
3
5
ppm.
.67 (t, 1H, CH, JHH ¼ 7:1 Hz); 7.29–7.47 (m, 5H, Ph)
3.6.1.3. Methyl 2,3-dibromo-4-phenyl-4-oxo-2-(trifluo-
romethyl)butanoate (16). A mixture of pentenoate 9
(0.124 g, 0.48 mmol), bromine (0.09 g, 0.53 mmol) in
CFC-113 was reacted for 2 h. The yield of liquid 16:
0.205 g (98%), diastereoisomer ratio 78:22.
1
9
F NMR (376.6 MHz, CDCl ): diastereoisomer A: d
3
3
À68.72 (d, CF , JHF ¼ 9:2 Hz); diastereoisomer B:
3
3
13
d À69.05 (d, CF , JHF ¼ 8:4 Hz) ppm.
C NMR
75.46 MHz, CDCl ): diastereoisomer A: d 31.98 (CH );
3
(
3
2
2
1H NMR (300.07 MHz, CDCl
4
5.06 (q, CH–CF , J ¼ 30:9 Hz); 79.24 (CH); 123.71 (q,
3
): diastereoisomer A: d
3.80 (s, 3H, COOCH ); 5.93 (s, 1H, CH); 7.47–7.99 (m, 5H,
3
CF
CF3, 1JCF ¼ 277:7 Hz); 125.47, 128.72, 128.79, 137.99
3
(
Ph); 169 (C=O); diastereoisomer B: d 31.09 (CH ),
Ph); diastereoisomer B: d 3.96 (s, 3H, COOCH
1H, CH); 7.47–7.99 (m, 5H, Ph) ppm.
); 5.92 (s,
3
2
2
4
4.32 (q, CH–CF , JCF ¼ 29:8 Hz); 79.08 (CH); 124.05
3
1
19F NMR (376.6 MHz, CDCl
(
(
q, CF , JCF ¼ 278:3 Hz); 124.94, 128.52, 128.93, 137.27
3
): diastereoisomer A: d
) ppm.
): diastereoisomer A: d 45.29
3
Ph); 169.20 (C=O) ppm. Anal. calcd. for C H F O : C,
1
À68.85 (s, CF
3
); diastereoisomer B: d À66.66 (s, CF
3
1 9 3 2
1
3
5
7.4; H, 3.9. Found: C, 57.3; H, 4.3%.
C NMR (75.46 MHz, CDCl
3

J. Pale cˇ ek et al. / Journal of Fluorine Chemistry 113 (2002) 177–183
183
2
(
1
1
COOCH ); 54.87 (CH); 62.6 (q, C–CF , J ¼ 28:8 Hz);
Acknowledgements
3
3
CF
1
22.34 (q, CF , J ¼ 284:4 Hz); 128.72, 128.84, 133.14,
3
CF
The research was supported by the Institute of Chemical
Technology, Prague, and the grant of the Ministry of Educa-
tion of the Czech Republic (Project LB98233). The authors
heartily thank Dr. B. Dolensk y´ for helpful discussions.
34.19 (Ph); 163.56 (COOCH ); 189.42 (C=O); diastereoi-
3
somer B: d 42.13 (COOCH ); 54.72 (CH); 61.38 (q, C–CF ,
3
3
2
1
JCF ¼ 29 Hz); 122.2 (q, CF , JCF ¼ 284:2 Hz); 128.72,
3
1
28.94, 133.13, 134.43 (Ph); 162.02 (COOCH ); 188.38
3
(
C=O) ppm. MS (Mr ¼ 418), m/z (% relative intensity): EI:
þ
3
1
1
09/38 (M À 109), 307/40, 261/13, 259/27, 258/89, 239/
3, 229/27, 228/14, 227/39, 209/21, 199/38, 183/29, 181/51,
79/42, 169/13, 153/15, 151/41.
References
[
[
[
[
1] O. Paleta, J. Pale cˇ ek, B. Dolensk y´ , J. Fluorine Chem. 111 (2001)
75–184.
1
2] S. Watanabe, Y. Sakai, M. Takeda, T. Kitazume, T. Yamazaki, J.
Fluorine Chem. 67 (1994) 149–152.
3.6.2. Photodehalogenations of dibromo derivatives 15
and 16; alkenoates 8 and 9
3] N. Reineke, N.A. Zaidi, M. Mitra, D. O’Hagan, A.S. Batsanov, J.A.K.
Howard, D.Y. Naumov, J. Chem. Soc., Perkin Trans. 2 (1996) 147–150.
4] F.-L. Qing, Z.-X. Jiang, in: Proceedings of the 13th European
Symposium on Fluorine Chemistry, Bordeaux, France, 15–20 July
3
.6.2.1. General procedure. Apparatus: the reactions were
carried out in a round-shaped two-necked (with septa) quartz
cell of volume ca. 20 ml (diameter 5 cm, thickness 1 cm,
plane-parallel sites) irradiated externally by a medium
pressure UV lamp (Tesla, RVK 250W), placed in a
reflecting-metal cylindrical housing, with a round window
2
001, Paper A14.
[5] T. Taguchi, S. Saito, T. Kanai, K. Kawada, Y. Kobayashi, M. Okada,
K. Ohta, Chem. Pharm. Bull. 33 (1985) 4026–4029.
[
[
6] T.B. Patrick, M.V. Lanahan, C. Yang, J.K. Walker, C.L. Hutchinson,
B.E. Neal, J. Org. Chem. 59 (1994) 1210–1212.
7] J. Kv ´ı cˇ ala, R. Vlas a´ kov a´ , J. Plocar, O. Paleta, A. Pelter, Collect.
Czech. Chem. Commun. 65 (2000) 773–778.
(
diameter 5 cm).
Reaction: the reaction mixture, which consisted of
[8] V.A. Soloshonok, J.L. Yagupolskii, B.P. Kukchar, Zh. Org. Khim. 25
1989) 2523–2527.
9] G. Wittig, D. Wittenberg, Justus Liebigs Ann. Chem. 606 (1957) 1–16.
(
dibromoalkanoate (15 or 16), propan-2-ol and acetone
was deaerated for 1 h at ca. À70 8C (dry ice–ethanol) with
a stream of argon (inlet–outlet by needles through septa)
then allowed to warm to rt and irradiated for ca. 3 h. The
progress of the dehalogenation was followed by TLC
[
[
[
10] W.M. Golebiewski, A. Cieniecka-Roslonkiewicz, A. Szybinska,
Pharmazie 54 (1999) 26–30.
11] L. Horner, A. Mentrup, Justus Liebigs Ann. Chem. 646 (1961) 65–77.
[12] A. Hercouet, M. Le Corre, Phosphorus Sulfur 29 (1987) 111–114.
[13] F. Ramirez, D. Dershowitz, J. Org. Chem. 22 (1957) 41–43.
(
CH Cl ) until the conversion of the starting compound
2 2
[
[
[
[
14] J.K. Stille, K.S.Y. Lau, J. Am. Chem. Soc. 98 (1976) 5841–5849.
15] T. Allmendinger, R.W. Lang, Tetrahedron Lett. 32 (1991) 339–340.
16] J. Leroy, J. Fluorine Chem. 53 (1991) 61–70.
was complete. Volatile components were then removed on
a rotary evaporator.
17] S. Narasimhan, R. Balakumar, Aldrichim. Acta 31 (1) (1998) 19–26.
3
.6.2.2. Methyl 4-oxo-2-(trifluoromethyl)pent-2-enoate (8).
A mixture of dibrompentanoate 15 (0.18 g, 0.52 mmol),
[18] V.P. Sˇ endrik, O. Paleta, V. D eˇ dek, Collect. Czech. Chem. Commun.
41 (1976) 874–879.
19] O. Paleta, R. Je zˇ ek, V. D eˇ dek, Collect. Czech. Chem. Commun. 48
1983) 766–771.
[
propan-2-ol (11.9 g, 197 mmol) and acetone (1.05 g,
18.1 mmol) afforded 8 in a yield of 0.08 g (81.7%) as a
mixture of E and Z isomers (52:48).
(
[
20] O. Paleta, V. Dad a´ k, V. D eˇ dek, J. Fluorine Chem. 39 (1988) 397–414.
21] O. Paleta, A. Po sˇ ta, Z. Novotn a´ , Collect. Czech. Chem. Commun. 33
[
(
1968) 2970–2982.
[22] J.V. Zeifman, L.T. Lantseva, A.A. Kadyrov, E.M. Rokhlin, Izv. Akad.
3
2
0
.6.2.3. Methyl 4-phenyl-4-oxo-2-(trifluoromethyl)but-
-enoate (9). A mixture of dibromobutanoate 16 (0.2 g,
.47 mmol), 2-propanol (10.9 g, 183 mmol) and acetone
Nauk. SSSR Ser. Khim. 5 (1984) 1116–1122.
23] B. Dolensk y´ , Ph.D. Thesis, Prague Institute of Chemical Technology,
999.
[
1
24] B. Dolensk y´ , J. Kv ´ı cala, J. Pale cˇ ek, O. Paleta, J. Fluorine Chem.,
(
(
0.99 g, 17.7 mmol) afforded 9 in the yield of 0.1 g
85.2%) as a mixture of isomers E and Z (66:34).
[
submitted for publication.