Synthesis of new trifluoromethylated furans, dihydrofurans and butenolides starting from γ-ketothioesters and diisopropylamine

Article abstract of DOI:10.1055/s-2006-926352

γ-Ketothioesters were easily transformed into furans, dihydrofurans or butenolides by simple treatment with diisopropylamine in diethyl ether. The substitution pattern of the starting material has a great influence on the outcome of the reaction. Possible

Full text of DOI:10.1055/s-2006-926352

1050
PAPER
Synthesis of New Trifluoromethylated Furans, Dihydrofurans and Butenolides
Starting from g-Ketothioesters and Diisopropylamine
New
T
riflu
e
oromethyl
a
ate
d
Furans
n
,
D
ihydrofur
-
ans and
P
a
Laboratoire Sciences et Méthodes Séparatives (SMS), EA 3233, Université de Rouen, IRCOF, 76821 Mont-Saint-Aignan Cedex, France
Laboratoire Réactions Sélectives et Applications, UMR CNRS 6519, Université de Reims, Faculté des Sciences B.P. 1039,
51687 Reims Cedex 2, France
Laboratoire de Chimie Physique et de Cristallographie, Université Catholique de Louvain, 1 Place Louis Pasteur,
1348 Louvain-la-Neuve, Belgium
b
c
Fax +33(2)35522422; E-mail: jean-philippe.bouillon@univ-rouen.fr
Received 26 September 2005; revised 12 October 2005
O
Abstract: g-Ketothioesters were easily transformed into furans, di-
hydrofurans or butenolides by simple treatment with diisopropyl-
amine in diethyl ether. The substitution pattern of the starting
material has a great influence on the outcome of the reaction. Pos-
sible mechanisms for the formation of the heterocycles were pro-
posed. The structures of all new compounds were ascribed using
usual NMR data (19F, 1H, 13C NMR), X-ray diffraction analysis and
1H–1H NOE experiments.
Y
Me
CF3
X
(i)
X = O, Y = NHR' : 5
X = NR', Y = SEt : 6
Ref. 8
RF
O
RF
SEt
SEt
SEt
RF = C2F5
Ref. 9
F
O
Key words: fluorine, heterocycle, furan, dihydrofuran, butenolide
F3C
SEt
R
RF = CF3 : 1
RF = C2F5 : 2
1) (ii)
2) (i)
RF = CF3, R = Me: 3
H
R
RF = C2F5, R = Me, Ph: 4
O
N
The increasing interest in trifluoromethylated
heterocycles1,2 and the need of new fluorinated scaffolds
for parallel synthesis prompted us to investigate the appli-
cations of perfluoroketene dithioacetals 1, 2 and g-ke-
tothioesters 3, 4 towards the synthesis of a large variety of
heterocycles. Perfluoroketene dithioacetals 1, 2 are versa-
tile building blocks owing to the easy nucleophilic substi-
tution of the vinylic fluoride and to the masked carboxylic
function.3,4 We have reported the convenient conversion
of compounds 1, 2 into the corresponding g-ketothioesters
3, 4 (Scheme 1).5,6 The thioester 3 was shown to be an ex-
cellent precursor for the preparation of trifluoromethyl g-
lactones,5 g-lactams,6 pyridazin-3-ones7 and pyridazines.7
The higher homologues 4 offered further developments,
since an additional HF elimination easily occurred under
basic conditions. Indeed, when 4 (R = Me) was treated
with primary amines (which are basic as well as nucleo-
philic reagents), trifluoromethylated furans 5 and pyrroles
6 were obtained in good yields (Scheme 1).8 More recent-
ly, g-ketothioesters 4 (R = Me, Ph) were used in a one-pot
synthesis to prepare new a,b-unsaturated g-lactams 7
(Scheme 1).9
HO
R1
7
Scheme 1 Reagents and conditions: (i) R1NH2, Et2O, r.t., 24 h; (ii)
i-Pr2NH, Et2O, r.t. or reflux, 22–24 h.
The present paper reports on the full investigation of this
new transformation, especially the influence of substitu-
ents of the starting material on the outcome of the reac-
tion.
The new g-ketothioesters 16–19 were obtained according
to the following two-step procedure: nucleophilic
substitution5 of the vinylic fluoride of perfluoroketene
dithioacetal 10 or 11 (prepared from heptafluorobutanal
hydrate)3 by potassium enolates of ketones, followed by
acid hydrolysis6 of intermediates 12–15 (Scheme 3,
Table 1). This methodology allows us to introduce struc-
tural diversity at the initial step (using various aromatic
thiols) as well as at the vinylic substitution step (both ali-
phatic and aromatic enolates worked well).
As previously reported,8 the reaction of g-ketothioester 4
(R = Me) with non-nucleophilic diisopropylamine led to
the furan thioester 8 in moderate yield (Scheme 2). Sur-
prisingly, when the same reaction was done with the aro-
matic g-ketothioester analogue (Scheme 2, R1 = Ph), the
new heterocyclic compound 9 was isolated as a mixture
(53:47) of stereoisomers, instead of the expected furan.
Only a few analogues of arylsulfanyl perfluoroketene
dithioacetals 10, 11 were reported in the literature.10
The g-ketothioesters 16–19 were then reacted with diiso-
propylamine. We used our reported procedure8 using two
equivalents of diisopropylamine in diethyl ether at room
temperature overnight. The reactions led to different types
of compounds, in moderate to good yields (Scheme 4,
Table 2), depending on the substitution pattern of the
starting material.
SYNTHESIS 2006, No. 6, pp 1050–1056
x
x
.
x
x
.2
0
0
6
The first experiment carried out on the g-ketothioester 4
(R = Me) bearing an ethylsulfanyl group gave the furan 8
Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926352; Art ID: Z17905SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Trifluoromethylated Furans, Dihydrofurans and Butenolides
1051
O
fluoroalkyl substituent (RF) has no significant influence
on the outcome of the reaction.
SEt
CF3
Most of the syntheses of 2-(trifluoromethyl)furans de-
scribed in the literature are based on direct fluorination,11
trifluoromethylation methodology,12 or building-block
strategies.8,13 Fluorinated or non-fluorinated dihydrofuran
derivatives such as 21–23 have not yet been reported.
Me
O
R1 = Et
(i)
C2F5
O
8
52%
SR1
O
R1 = Ph
Me
CF3
In order to determine the effect of the thioester moiety, the
phenylsulfanyl thioester 16 was reacted with diisoprop-
ylamine using the same conditions. Instead of furan or its
tautomer, the butenolide 9 was obtained as a mixture
(53:47) of stereoisomers (Table 2, entry 3). The reaction
was also extended to p-ClC6H4 substituted derivative 19
which gave the new unsaturated g-lactone 24 as a mixture
(71:29) of stereoisomers. Therefore, this unexpected be-
havior of arylsulfanyl g-ketothioesters seemed to be gen-
eral. The stereoisomers of 9 and 24 were separated by
silica gel column chromatography, major stereoisomers
being identified with the letter a.
O
O
SPh
9
51% (53/47)
Scheme 2 Reagents and conditions: (i) i-Pr2NH, Et2O, r.t., 14 h.
SR1
SR1
C2F5
F
1) (i)
C3F7CHO⋅H2O
2) (ii)
R1 = Ph:
10 (59%)
11 (61%)
R1 = pClC6H4:
SR1
SR1
O
C2F5
C2F5
RFCF2
R2
O
O
O
(iii)
(iv)
R2
R2
R2
SR1
O
CF3
SEt
SR1
SR1
(i)
O
H
+
+
O
R3
Me
RF
O
R3
RF
O
O
O
SR1
R4
R4
12–15
16–19
8,20
21–23
9,24
Scheme 3 Reagents and conditions: (i) R1SH, TiCl4, CH2Cl2; (ii) aq
KOH, Bu4NBr, CH2Cl2; (iii) R2CH2COR3, KH, THF, 0 °C; (iv) TFA,
H2O, D.
Scheme 4 Reagents and conditions: (i) i-Pr2NH, Et2O, 25 °C, 14 h.
It is worth noting that spontaneous isomerization of com-
pound 9 or 24 occurred in solution, even at room temper-
ature. For example, a CDCl3 solution of stereoisomers of
9 ranged from 14:86 to 51:49 after one night at room tem-
perature. Moreover, this isomerization process was fa-
vored when the solution was heated to 50 °C leading to a
thermodynamic ratio of 85:15 after 24 hours.
and its tautomeric methylene form 21 (Scheme 4, Table 2,
entry 1).8 These two trifluoromethylated heterocycles
were easily separated by silica gel column chromatogra-
phy. Similar behavior was also observed for a higher per-
fluoroalkyl chain analogue [Scheme 4, RF = (CF2)2H]
leading to a mixture of furan 20 and dihydrofuran 22
(Table 2, entry 2).9 Although we have not studied this is-
sue further, we assume that the reaction occurs under ther-
To the best of our knowledge, compounds 9 and 24 are the
first examples of such unsaturated arylsulfanyl trifluo-
romethyl butenolides. There is only one paper reporting
on the synthesis of a non-fluorinated analogue which was
prepared from Wittig reaction of cyclic anhydride.14
+
modynamic control owing to the acido-basic (i-Pr2NH2 /
i-Pr2NH) medium. As a consequence, the fully conjugated
methylene derivatives 21 and 22 would have a resonance
energy only slightly lower than those of the corresponding
furans 8 and 20, respectively. It is worth noting that per-
An important problem was the confirmation of the struc-
ture and the stereochemistry of the new butenolides 9 and
Table 1 Preparation of Ketene Dithioacetals 12–15 and g-Ketothioesters 16–19
Entry
Starting
material
R1
R2
R3
Ketene
dithioacetal (%)
g-Ketothioester (%)
1
2
3
4
10
10
10
11
Ph
H
Me
Ph
Et
12 (79)
13 (80)a
14 (66)
15 (83)
16 (75)
17 (91)
18 (63)b
19 (62)
Ph
H
Ph
Me
H
p-ClC6H4
Me
a Compound 13 was accompanied by small amount of undetermined fluorinated product.
b Compound 18 was obtained as a mixture (72:28) of diastereoisomers, undetermined configuration.
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York

1052
J.-P. Bouillon et al.
PAPER
Table 2 Reactions of g-Ketothioesters with Diisopropylamine
Entry
RF
R1
R2
H
R4
H
Furan (%)
Dihydrofuran (%) Butenolide (%)
1
2
3
4
5
CF3
Et
8 (52)
21 (16)
22 (7)
–
–
–
(CF2)2H
CF3
Et
H
H
20 (51)
Ph
H
H
–
–
–
9 (51)a
CF3
p-ClC6H4
H
H
–
24 (72)b
CF3
Ph
Me
Me
23 (46)c
–
a Mixture of stereoisomers (53:47).
b Mixture of stereoisomers (71:29).
c Mixture of stereoisomers (67:33).
24. We performed two types of experiments: X-ray dif- In order to study the influence of the substituents R2 and
fraction analysis on 9a and 1H–1H NOE study on 24a.
R4 of g-ketothioesters (Scheme 4), the compound 18 was
reacted with diisopropylamine in the standard conditions.
Surprisingly, butenolide was not obtained, but the dihy-
drofuran 23 was isolated in a moderate yield as a mixture
(67:33) of stereoisomers (Table 2, entry 5).
After slow evaporation of a dichloromethane solution of
the major stereomer 9a, we obtained crystals that were
suitable for X-ray diffraction analysis. The perspective
view of 9a is given in Figure 1. The X-ray clearly showed
a cis relationship between the phenylsulfanyl group and Heterocycle 23 showed similar spectroscopic data as its
the lactone moiety.
analogue 21: two doublets at –67.8 ppm and –68.6 ppm
(3JF,H = 8.8 Hz) for the trifluoromethyl group (19F NMR),
a quartet at 5.54 ppm (3JH,H = 7.5 Hz) for the olefinic pro-
ton (1H NMR), and a singlet at 168.3 ppm which is char-
acteristic of the a,b-unsaturated thioester carbonyl (13C
NMR). The configuration of the major stereoisomer 23a
was ascribed using NOE experiments. Irradiation of the
methyl substituent at d = 2.18 ppm induced a 7% NOE on
the olefinic proton which proved their close relationship
and confirmed the Z configuration (Figure 2).
Figure 1 View and atom labeling of 9a15
Then, to assess the scope and limitations of our methodol-
ogy, the reaction was extended to 4-phenyl substituted g-
ketothioester 17. As expected, the reaction of 17 with two
equivalents of diisopropylamine afforded the new furan
25 in moderate yield (Scheme 5). This heterocycle was
quite unstable and was spontaneously transformed, in
CDCl3 solution, into an unidentified trifluoromethyl com-
pound, which itself quickly decomposed into a very com-
plex mixture.
1
The comparison of 19F, H or 13C NMR spectra of com-
pounds 9 and 24 gave no useful evidence to ascribe the
stereochemistry of the butenolide 24. Therefore we re-
corded 1H–1H NOE spectra of the major stereoisomer 24a.
Irradiation of the olefinic proton Ha at d = 6.21 ppm in-
duced a 13% NOE on the olefinic proton Hb and a 4%
NOE on the aromatic proton Hc, respectively (Figure 2).
This observation confirmed the close relationship be-
tween the protons Ha and Hb, which was in good agree-
ment with the cis configuration between the (p-
chlorophenyl)sulfanyl group and the lactone moiety.
Moreover, irradiation of the methylenic protons Hd at d =
3.24 ppm induced a 4% NOE on the olefinic proton Hb
(Figure 2).
In order to explain the present results (Schemes 4 and 5),
we had to examine the possible mechanisms for the cy-
clization reaction of g-ketothioesters with diisopropyl-
amine. The reaction pathways leading to the furan and
butenolide derivatives have a common first step: the easy
elimination of HF. Then, deprotonation by diisopropyl-
amine, giving an enolate which undergoes an intramolec-
ular Michael addition–fluoride elimination sequence,
4% NOE
Hb
Hd
Hd
O
CF3
13% NOE
Ha
CH3
7% NOE
S
4% NOE
Hc
O
H
O
H
O
S
CF3
O
C2F5
O
CH3
i-Pr2NH, Et2O,
SPh
CF3
23a
SPh
24a
Cl
25 °C, 14 h
O
Ph
O
Ph
Figure 2 Selected 1H–1H NOE for compounds 23a and 24a
25
17
43%
Scheme 5
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York

PAPER
New Trifluoromethylated Furans, Dihydrofurans and Butenolides
1053
leads to the furans 8, 20 and dihydrofurans 21–23.8 The
formation of the new butenolides 9 and 24 may be ex-
plained by the mechanism depicted in Scheme 6, where
the HF elimination is followed by a 1,3-proton shift lead-
ing to the intermediate 27. Such a process was already ob-
served during the treatment of g-carboethoxythioester
analogue with triethylamine affording ethyl 3-ethylsulfa-
F
H
C2F5
F
O
F3C
H
O
O
F3C
(i)
[1,3]
(i)
SR1
SR1
SR1
– HF
O
O
O
Me
Me
Me
16,19
26
27
R1 = Ph, p-ClC6H4
nyl-4-fluoro-5,5,5-trifluoropent-2-enoate.16
A
second
F
H
F
O
H
deprotonation with diisopropylamine gives the enolate 28
which may substitute the arylsulfanyl group (Scheme 6).
Then the highly conjugated g-lactone 29 reacts as a
Michael acceptor with the resulting thiol giving, after HF
elimination and a 1,5-proton migration sequence, the de-
sired butenolides 9, 24.
O
CF3
O
F3C
F3C
O
– HF
[1,5]
SR1
–
O
O +
SR1
H2Ni-Pr2
R1SH
29
9,24
28
Scheme 6 Reagents and conditions: (i) i-Pr2NH, Et2O, 25 °C, 14 h.
In conclusion, this work extends the field of synthetic ap-
plications of perfluoroketene dithioacetals. The synthons
10 and 11 were easily converted into the corresponding g-
ketothioesters 16–19 which behave as useful building
blocks for the synthesis of new heterocycles such as
furans 8 and 20, dihydro derivatives 21–23 as well as
butenolides 9 and 24. The selectivity depends on the sul-
fur substituent: ethylsulfanyl substitution favored the for-
mation of furan derivatives whereas butenolides were
obtained exclusively from aryl g-ketothioester. The struc-
tures of compounds 9, 23, 24 were confirmed by X-ray
diffraction analysis (for 9a) and by homonuclear NOE ex-
periments (for 23a and 24a). g-Lactones 9, 24 exhibit
highly conjugated ester function which could be an inter-
esting precursor for the synthesis of a new type of a,b-un-
saturated lactams; this new aspect is under investigation.
dures. For spectroscopic data of ketene dithioacetals 10–15 and g-
ketothioesters 16–19 see Table 3.
Reaction of g-Ketothioesters with Diisopropylamine; General
Procedure (Scheme 4, Table 2)
Diisopropylamine (0.33 mL, 2.44 mmol, 2.0 equiv) was added to a
solution of g-keto thioester 16–19 (1.22 mmol, 1.0 equiv) in Et2O (6
mL). A white solid precipitated immediately. The mixture was
stirred for 14 h at r.t., then diluted with Et2O (10 mL) and washed
with brine (10 mL). The aqueous phase was extracted with Et2O (4
× 10 mL). The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. The residue was chromato-
graphed on silica gel with PE–EtOAc (96:4 for 9, 24, and 98:2 for
23, 25] to give the heterocycles 9, 23–25 (Tables 2 and 4).
For information on instruments used, see ref.17 Compounds 10, 113,
12–155 and 16–196,8 were prepared according to reported proce-
Table 3 Spectroscopic Data of Ketene Dithioacetals 10–15 and g-Keto Thioesters 16–19
Com- Solventb IR
GC/MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
pda
(cm–1)
10d
PE
3062, 1603, 380 [M+],
1583, 1279, 261, 227,
–83.9 (m, 3 F),
–100.1 (m, 1 F),
–112.6 (m, 2 F)
7.0–7.1 (m, 4 H), 7.1–7.3 109.1 (m, CF2), 118.4 (qtd, 1JC,F
(m, 6 H)
287.5 Hz, 2JC,F = 37.1 Hz, 3JC,F = 3.2
=
1215
152, 127
Hz, CF3), 127.3 (dm, 2JC,F = 20.1 Hz,
Cq), 127.9 (s, CH), 128.7 (s, 2 × CH),
128.8 (s, 3 × CH), 129.2 (d, 4JC,F = 3.2
Hz, Cq), 131.0 (s, 2 × CH), 131.3 (s,
Cq), 134.3 (s, 2 × CH), 144.5 (dt,
1JC,F = 267.6 Hz, 2JC,F = 26.6 Hz, CF)
11
PE
1605, 1573, 450 [M +
1476, 1391 1], 448,
305, 261,
–83.9 (m, 3 F), –98.6 6.92 (d, 3JH,H = 8.5 Hz,
108.4 (tq, 1JC,F = 260.1 Hz, 2JC,F = 39.4
(m, 1 F), –112.6 (m, 2 H), 6.96 (d, 3JH,H = 8.5 Hz, CF2), 118.3 (qt, 1JC,F = 287.6 Hz,
2 F)
Hz, 2 H), 7.12 (d, 3JH,H
8.5 Hz, 2 H), 7.15 (d,
3JH,H = 8.5 Hz, 2 H)
=
2JC,F = 38.7 Hz, CF3), 126.1 (d, 2JC,F
=
186, 161,
107
20.4 Hz, Cq), 127.4 (d, 4JC,F = 2.7 Hz,
Cq), 129.0 (s, 2 × CH), 129.2 (s, 2 ×
CH), 129.5 (m, Cq), 132.1 (s, 2 × CH),
134.5 (s, Cq), 135.5 (s, 2 × CH), 135.6
(s, Cq), 145.1 (dt, 1JC,F = 269.7 Hz,
2JC,F = 26.9 Hz, CF)
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York

1054
J.-P. Bouillon et al.
PAPER
Table 3 Spectroscopic Data of Ketene Dithioacetals 10–15 and g-Keto Thioesters 16–19 (continued)
Com- Solventb IR
GC/MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
pda
(cm–1)
12e
PE–
EtOAc
(98:2)
3053, 2928, 418 [M+],
1716, 1581, 375, 360,
–83.2 (t, 3JF,F = 3.6
2.28 (s, 3 H), 3.90 (m,
29.4 (s, CH3), 46.7 (t, 3JC,F = 2.5 Hz,
Hz, 3 F), –107.3 (m, 2 H), 6.97 (d, 3JH,H = 7.6 CH2), 113.2 (tq, 1JC,F = 257.0 Hz,
1556
308, 297,
123
2 F)
Hz, 2 H), 7.07 (m, 2 H),
7.1–7.3 (m, 6 H)
2JC,F = 39.2 Hz, CF2), 119.2 (qt, 1JC,F
=
288.0 Hz, 2JC,F = 39.5 Hz, CF3), 126.2
(t, 2JC,F = 21.5 Hz, Cq), 127.5 (s, CH),
128.2 (s, CH), 128.4 (s, 2 × CH), 128.5
(s, 2 × CH), 131.2 (s, 2 × Cq), 131.7 (s,
2 × CH), 132.8 (s, 2 × CH), 147.7 (m,
Cq), 202.1 (s, CO)
13f
PE–
EtOAc
(98:2)
3058, 2930, 480 [M+],
1690, 1560, 375, 297,
–83.1 (t, 3JF,F = 3.6
4.56 (s, 2 H), 7.06 (d,
42.5 (m, CH2), 105–125 (m, CF2 +
3
Hz, 3 F), –107.5 (m, JH,H = 8.0 Hz, 2 H), 7.17– CF3), 126.5 (t, 2JC,F = 22.0 Hz, Cq),
1439
110, 105, 77 2 F)
7.26 (m, 2 H), 7.28–7.36 127.5 (s, CH), 128.2 (s, 3 × CH), 128.5
(m, 6 H), 7.59 (d, 3JH,H
=
(s, 4 × CH), 128.7 (s, 2 × CH), 131.4
(s, Cq), 131.7 (s, 2 × CH), 132.9 (s, 2 ×
7.7 Hz, 2 H), 7.69 (m,
1 H), 8.10 (d, 3JH,H = 7.7 CH), 133.0 (s, Cq), 133.5 (s, CH),
Hz, 2 H)
136.0 (s, Cq), 147.8 (s, Cq), 193.9 (s,
CO)
14
PE–
EtOAc
(98:2)
3050, 2981, 446 [M+],
1716, 1543, 389, 279,
–81.7 (m, 3 F), –99 0.99 (t, 3JH,H = 7.1 Hz, 3
7.8 (s, CH3), 15.2 (s, CH3), 33.0 (s,
to –102 (m, 1 F),
–107.1 (dm, 2JF,F
263.9 Hz, 1 F)
H), 1.48 (d, 3JH,H = 6.9
CH2), 50.5 (s, CH), 114.1 (tq, 1JC,F
=
1476
160, 137,
109
=
Hz, 3 H), 2.4–2.7 (m,
270.9 Hz, 2JC,F = 39.5 Hz, CF2), 119.1
2 H), 3.73 (q, 3JH,H = 6.9 (qt, 1JC,F = 288.3 Hz, 2JC,F = 39.5 Hz,
Hz, 1 H), 6.8–6.9 (m,
4 H), 7.0–7.2 (m, 6 H)
CF3), 127.8 (s, CH), 128.1 (s, CH),
128.4 (s, 2 × CH), 128.5 (s, 2 × CH),
131.2 (s, 2 × Cq), 132.0 (s, 2 × CH),
132.4 (s, 2 × CH), 133.0 (t, 2JC,F = 18.8
Hz, Cq), 147.0 (m, Cq), 207.8 (s, CO)
15g
PE–
EtOAc
(98:2)
3082, 2914, 486 [M+],
1726, 1572, 331, 189,
–83.3 (t, 3JF,F = 3.6
2.18 (s, 3 H), 3.79 (s,
29.5 (s, CH3), 46.6 (t, 3JC,F = 4.3 Hz,
Hz, 3 F), –107.4 (m, 2 H), 6.83 (d, 3JH,H = 8.5 CH2), 113.0 (tq, 1JC,F = 257.9 Hz,
1476
157, 143,
108, 43
2 F)
Hz, 2 H), 6.91 (d, 3JH,H
=
2JC,F = 39.0 Hz, CF2), 119.0 (qt, 1JC,F
288.0 Hz, 2JC,F = 39.5 Hz, CF3), 127.3
=
8.5 Hz, 2 H), 7.10 (d,
3JH,H = 8.5 Hz, 2 H), 7.11 (t, 2JC,F = 21.5 Hz, Cq), 128.8 (s, 2 ×
(d, 3JH,H = 8.5 Hz, 2 H)
CH), 128.9 (s, 2 × CH), 129.5 (s, Cq),
131.2 (s, Cq), 132.8 (s, 2 × CH), 134.0
(s, Cq), 134.1 (s, 2 × CH), 134.8 (s, Cq),
146.5 (m, Cq), 201.7 (s, CO)
16
PE–Et2O 3064, 2933, 344 [M + 1 –82.4 (m, 3 F),
2.23 (s, 3 H), 2.93 (dd,
29.3 (s, CH3), 39.5 (s, CH2), 48.9 (t,
(98:2)
1724, 1703, + NH3], 327 –115.0 (dd, 2JF,F
=
=
2JH,H = 18.4 Hz, 3JH,H
=
2JC,F = 21.0 Hz, CH), 113.3 (tq, 1JC,F
=
1479
[M + 1],
193, 109,
94, 78h
273.8 Hz, 3JF,H
=
3.2 Hz, 1 H), 3.33 (dd,
259.5 Hz, 2JC,F = 38.2 Hz, CF2), 118.6
(qt, 1JC,F = 286.9 Hz, 2JC,F = 36.0 Hz,
CF3), 126.3 (s, Cq), 129.3 (s, 2 × CH),
129.9 (s, CH), 134.3 (s, 2 × CH), 191.5
(s, COS), 202.9 (s, CO)
14.4 Hz, 1 F),
2JH,H = 18.4 Hz, 3JH,H
10.2 Hz, 1 H), 4.05 (m,
1 H), 7.4 (m, 5 H)
=
–116.4 (dd, 2JF,F
273.8 Hz, 3JF,H
=
14.4 Hz, 1 F)
17
PE–Et2O 3063, 2931, 389 [M +
(98:2) 1691, 1598, 1], 279,
–82.3 (m, 3 F),
3.43 (dd, 2JH,H = 18.2 Hz, 35.5 (s, CH2), 49.3 (t, 2JC,F = 20.7 Hz,
3JH,H = 2.8 Hz, 1 H), 3.95 CH), 110.0–125.0 (m, CF3 + CF2),
–114.7 (dd, 2JF,F
=
=
1582
259, 109,
105
274.1 Hz, 3JF,H
14.6 Hz, 1 F),
–116.4 (dd, 2JF,F
=
(dd, 2JH,H = 18.2 Hz,
126.4 (s, Cq), 128.2 (s, 2 × CH), 128.8
(s, 2 × CH), 129.3 (s, 2 × CH), 129.9
3JH,H = 10.3 Hz, 1 H),
4.29 (m, 1 H), 7.4–7.7 (m, (s, CH), 134.0 (s, CH), 134.4 (s, 2 ×
274.1 Hz, 3JF,H
=
8 H), 8.00 (dm, 3JH,H = 7.7 CH), 135.4 (s, Cq), 191.8 (m, COS),
14.6 Hz, 1 F)
Hz, 2 H)
194.7 (s, CO)
18ai
PE–Et2O 2982, 2936, 355 [M +
(98:2) 1712, 1479, 1], 245,
–82.9 (m, 3 F),
1.02 (t, 3JH,H = 7.2 Hz,
7.6 (s, CH3), 15.1 (s, CH3), 34.8 (s,
–110.9 (dd, 2JF,F
=
3 H), 1.17 (d, 3JH,H = 7.1 CH2), 41.9 (s, CH), 53.9 (t, 2JC,F = 19.1
1461
225, 177,
109
272.9 Hz, 3JF,H = 4.5 Hz, 3 H), 2.3–2.7 (m,
Hz, CH), 105.0–115.0 (m, CF2), 118.5
Hz, 1 F), –120.6 (dd, 2 H), 3.24 (m, 1 H), 4.01 (qt, 1JC,F = 286.9 Hz, 2JC,F = 36.3 Hz,
2JF,F = 272.9 Hz, (ddd, 3JH,F = 22.2 Hz, J = CF3), 126.2 (s, Cq), 129.5 (s, 2 × CH),
3JF,H = 22.4 Hz, 1 F) 9.2, 5.7 Hz, 1 H), 7.1–7.5 130.2 (s, CH), 134.2 (s, 2 × CH), 190.5
(m, 5 H) (s, COS), 209.9 (s, CO)
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York

PAPER
New Trifluoromethylated Furans, Dihydrofurans and Butenolides
1055
Table 3 Spectroscopic Data of Ketene Dithioacetals 10–15 and g-Keto Thioesters 16–19 (continued)
Com- Solventb IR
GC/MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
pda
(cm–1)
18bi
355 [M +
1], 245,
225, 177,
110, 91
–82.4 (m, 3 F),
0.97 (d, 3JH,H = 7.2 Hz,
34.6 (s, CH2), 44.9 (s, CH), 55.4 (t,
–107.8 (dd, 2JF,F
=
3 H), 1.25 (d, 3JH,H = 7.1 2JC,F = 19.9 Hz, CH), 110.0–125.0 (m,
278.2 Hz, 3JF,H = 8.1 Hz, 3 H), 2.3–2.7 (m,
CF2 + CF3), 126.3 (s, Cq), 129.4 (s, 2 ×
Hz, 1 F), –115.8 (dd, 2 H), 3.37 (m, 1 H), 3.83 CH), 130.0 (s, CH), 134.3 (s, 2 × CH),
2JF,F = 278.2 Hz, (dm, 3JH,F = 20.0 Hz, 1 H), 190.4 (s, COS), 210.6 (s, CO)j
3JF,H = 19.9 Hz, 1 F) 7.1–7.5 (m, 5 H)
19
PE–Et2O 2929, 1725, 361 [M+],
–82.4 (m, 3 F),
2.20 (s, 3 H), 2.94 (dd,
2JH,H = 18.5 Hz, 3JH,H
29.5 (s, CH3), 39.7 (s, CH2), 49.1 (t,
(98:2)
1705, 1478 217, 197,
–114.9 (dd, 2JF,F
=
=
=
2JC,F = 21.0 Hz, CH), 113.3 (tq, 1JC,F
=
169, 144,
108
274.7 Hz, 3JF,H
14.4 Hz, 1 F),
–116.3 (dd, 2JF,F
=
2.9 Hz, 1 H), 3.32 (dd,
259.5 Hz, 2JC,F = 38.2 Hz, CF2), 118.6
(qt, 1JC,F = 286.9 Hz, 2JC,F = 36.0 Hz,
CF3), 124.8 (s, Cq), 129.6 (s, 2 × CH),
2JH,H = 18.5 Hz, 3JH,H
=
10.4 Hz, 1 H), 4.01 (m,
274.4 Hz, 3JF,H
=
1 H), 7.34 (d, 3JH,H = 8.5 135.6 (s, 2 × CH), 136.5 (s, Cq), 191.3
13.5 Hz, 1 F)
Hz, 2 H), 7.40 (d, 3JH,H
=
(s, COS), 203.0 (s, CO)
8.5 Hz, 2 H)
a All compounds are oils except 12, 13 and 15. Satisfactory microanalyses or HRMS obtained.
b Solvent used for chromatographic separation (PE = petroleum ether).
c NMR solvent: CDCl3.
d Bp 108–112 °C/0.05 mbar.
e Mp 92–93 °C.
f Mp 120–121 °C.
g Mp 111–112 °C.
h Chemical ionization (NH3).
i Mixture (72:28) of diastereoisomers (major: 18a, minor: 18b). IR spectrum was recorded on the mixture.
j Selected data.
X-ray Crystal Structure Determination of Compound 9a (Fig-
ure 1)
finement with a common isotropic temperature factor. The final R
values are R = 0.047 for 1773 observed reflections and wR2 = 0.121.
The data have been deposit with the Cambridge Crystallographic
Data Centre (Nr CCDC276673). Selected bond lengths (Å): O(1)–
C(2) = 1.390(3), C(2)–O(14) = 1.199(3), C(2)–C(3) = 1.461(3),
C(3)–C(4) = 1.340(3), C(4)–C(5) = 1.430(3), O(1)–C(5) = 1.387(3),
C(5)–C(6) = 1.334(3), C(6)–S(7) = 1.728(3).
C13H9F3O2S, Mr = 286.26, monoclinic, P21/c (Nr 14), a = 8.534(2),
b = 6.058(2), c = 24.590(7) Å, b = 99.35(2)°, V = 1254.4(6) Å3, Z =
4, Dx = 1.52 gcm–3. A total of 7409 reflections were collected using
a MAR345 image plate detector and Mo Ka radiation (l = 0.71069
Å), 2020 independent reflections (Rint = 0.065), 2Qmax = 49°. The
structure was solved by direct methods with SHELXS-9718 and re-
fined by least square using F2 values and anisotropic thermal param-
eters for non-hydrogen atoms with SHELXL-97.18 The H atoms
were located by Fourier-difference synthesis and included in the re-
Table 4 Spectroscopic Data of Compounds 9, 23–25
Com- Sol-
IR
GC/MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
pda
9ad
ventb
(cm–1)
PE–
3060, 2924, 286 [M+],
–65.7 (t,
3JF,H = 10.3
Hz)
3.25 (q, 3JH,F = 10.3 Hz,
30.0 (q, 2JC,F = 32.2 Hz, CH2), 115.8 (s, CH),
EtOAc 1767, 1621, 189, 164,
(96:4)
2 H), 6.32 (s, 1 H), 7.30 (s, 120.2 (q, 3JC,F = 2.7 Hz, Cq), 124.9 (q, 1JC,F
=
1607, 1577 121
1 H), 7.3–7.4 (m, 3 H),
7.4–7.5 (m, 2 H)
276.7 Hz, CF3), 128.4 (s, CH), 129.6 (s, 2 ×
CH), 130.6 (s, 2 × CH), 133.0 (s, Cq), 138.7 (s,
CH), 144.9 (s, Cq), 168.6 (s, CO2)
9bd
3074, 2924, 286 [M+],
1744, 1604, 189, 164,
–65.5 (t,
3JF,H = 10.2
Hz)
3.28 (q, 3JH,F = 10.2 Hz,
2 H), 6.63 (s, 1 H), 7.3–
7.5 (m, 5 H), 7.76 (s, 1 H) 277.3 Hz, CF3), 127.8 (s, CH), 129.4 (s, 2 ×
CH), 129.5 (s, 2 × CH), 133.3 (s, Cq), 136.5 (s,
30.2 (q, 2JC,F = 32.2 Hz, CH2), 112.5 (s, CH),
123.2 (t, 3JC,F = 3.2 Hz, Cq), 124.8 (q, 1JC,F
=
1479
121, 110
CH), 148.6 (s, Cq), 168.7 (s, CO2)
23a
PE–
EtOAc 1675, 1650, 294, 205,
(98:2) 1441
2925, 2854, 314 [M+],
–67.8 (d,
1.99 (d, 3JH,H = 7.5 Hz,
3 H), 2.18 (s, 3 H), 4.66
(q, 3JH,F = 8.8 Hz, 1 H),
5.54 (q, 3JH,H = 7.5 Hz,
1 H), 7.2–7.4 (m, 3 H),
7.5–7.6 (m, 2 H)
10.9 (q, nJC,F = 2.0 Hz, CH3), 11.9 (s, CH3),
46.9 (q, 2JC,F = 32.2 Hz, CH), 110.2 (s, CH),
120.2 (s, Cq), 125.3 (q, 1JC,F = 279.9 Hz, CF3),
129.0 (s, CH), 129.4 (s, 2 × CH), 132.3 (s, Cq),
133.4 (s, 2 × CH), 150.2 (s, Cq), 151.7 (s, Cq),
168.3 (s, COS)
3JF,H = 8.8
141, 110, 55 Hz)
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York

1056
J.-P. Bouillon et al.
PAPER
Table 4 Spectroscopic Data of Compounds 9, 23–25 (continued)
Com- Sol-
IR
GC/MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
pda
ventb
(cm–1)
23be
–68.6 (d,
3JH,F = 8.8
Hz)
2.11 (s, 3 H), 4.38 (q, 3JH,F 113.0 (s, CH)
= 8.8 Hz, 1 H)
24a
PE–
3056, 2924, 320 [M+],
–65.7 (t,
3JF,H = 10.4
Hz)
3.24 (q, 3JH,F = 10.4 Hz,
30.0 (q, 2JC,F = 32.3 Hz, CH2), 114.6 (s, CH),
EtOAc 1733, 1613, 164, 155,
(96:4)
2 H), 6.21 (s, 1 H), 7.30 (s, 120.7 (q, 3JC,F = 4.0 Hz, Cq), 124.4 (q, 1JC,F
=
1596
136, 108,
75, 69
1 H), 7.36 (d, 3JH,H = 8.6
277.2 Hz, CF3), 129.7 (s, 2 × CH), 131.6 (s,
Cq), 131.9 (s, 2 × CH), 134.7 (s, Cq), 138.7 (s,
CH), 145.3 (s, Cq), 168.5 (s, CO2)
Hz, 2 H), 7.42 (d, 3JH,H
=
8.6 Hz, 2H)
24be
25
320 [M+],
164, 155,
88, 75, 69,
45
–65.4 (t,
3JF,H = 10.4
Hz)
3.28 (q, 3JH,F = 10.2 Hz,
2 H), 6.55 (s, 1 H)
111.4 (s, CH), 129.6 (s, 2 × CH), 130.6 (s, 2 ×
CH), 136.5 (s, CH)
PE–
EtOAc 1798, 1610, 279, 239,
(98:2) 1562 105, 77
3055, 2924, 348 [M+],
–57.6 (s)
6.65 (s, 1 H), 7.3–7.5 (m, 101.1 (q, 4JC,F = 3.8 Hz, CH), 122.4 (q, 1JC,F
8 H), 7.6–7.8 (m, 2 H) 277.2 Hz, CF3), 125.8 (s, 2 × CH), 127.0 (s,
=
Cq), 128.8 (s, CH), 129.0 (s, 2 × CH), 129.2 (s,
2 × CH), 130.5 (m, Cq), 131.5 (s, CH), 131.6
(s, Cq), 132.4 (s, 2 × CH), 132.5 (q, 2JC,F = 32.7
Hz, Cq), 157.0 (q, 4JC,F = 1.6 Hz, Cq), 164.3 (s,
COS)
a Oil. Satisfactory microanalyses or HRMS obtained. The compounds 9, 23, 24 were obtained as a mixture of stereoisomers (major stereo-
isomers are recognized by the letter a).
b Solvent used for chromatographic separation (PE = petroleum ether).
c NMR solvent: CDCl3.
d The stereoisomers of compound 9 were completely separated on silica gel chromatography. Compound 9a (CH2Cl2): mp 127–129 °C;
9b (CH2Cl2): mp 135–136 °C.
e Selected data.
(8) Bouillon, J.-P.; Hénin, B.; Huot, J.-F.; Portella, C. Eur. J.
Acknowledgment
Org. Chem. 2002, 1556.
We thank H. Baillia and S. Lanthony for NOE experiments and
(9) Bouillon, J.-P.; Tinant, B.; Nuzillard, J.-M.; Portella, C.
microanalyses. The authors also thank E. Sauvi for her help in the
synthesis of compound 9.
Synthesis 2004, 711.
(10) (a) Purrington, S. T.; Samaha, N. F. J. Fluorine Chem. 1989,
43, 229. (b) Purrington, S. T.; Sheu, K. W. Tetrahedron Lett.
1992, 33, 3289. (c) Markovskii, L. N.; Slyusarenko, E. I.;
Timoshenko, V. M.; Kaminskaya, E. I.; Kirilenko, A. G.;
References
Shermolovich, Y. G. Zh. Org. Khim. 1992, 28, 14; Chem.
Abstr. 1992, 117, 150502. (d) Purrington, S. T.; Sheu, K. W.
J. Fluorine Chem. 1993, 65, 165.
(1) (a) Biomedicinal Aspects of Fluorine Compounds; Filler, R.;
Kobayashi, Y., Eds.; Elsevier: New York, 1982. (b) Welch,
J. T. Tetrahedron 1987, 43, 3123. (c) Fluorine in
Bioorganic Chemistry; Welch, J. T.; Eswarakrishnan, S.,
Eds.; John Wiley & Sons: New York, 1991.
(2) (a) Hewitt, C. D.; Silvester, M. J. Aldrichimica Acta 1988,
21, 3. (b) Differding, E.; Frick, W.; Lang, R. W.; Martin, P.;
Schmit, C.; Veenstra, S.; Greuter, H. Bull. Soc. Chim. Belg.
1990, 99, 647. (c) Silvester, M. J. Aldrichimica Acta 1991,
24, 31. (d) Burger, K.; Wucherpfennig, U.; Brunner, E. Adv.
Heterocycl. Chem. 1994, 60, 1. (e) Silvester, M. J.
Aldrichimica Acta 1995, 28, 45.
(3) Muzard, M.; Portella, C. J. Org. Chem. 1993, 58, 29.
(4) Portella, C.; Bouillon, J.-P. Perfluoroketene Dithioacetals:
Versatile Building Blocks toward Trifluoromethyl
Heterocycles in Fluorine-Containing Synthons, ACS
Symposium Series 911; Soloshonok, V. A., Ed.; Oxford
University Press/American Chemical Society: Washington
D.C., 2005, Chap. 12, 232.
(5) Huot, J.-F.; Muzard, M.; Portella, C. Synlett 1995, 247.
(6) Hénin, B.; Huot, J.-F.; Portella, C. J. Fluorine Chem. 2001,
107, 281.
(11) Nishida, M.; Fujü, S.; Aoki, T.; Hayakawa, Y.; Muramatsu,
H.; Morita, T. J. Fluorine Chem. 1990, 46, 445.
(12) Naumann, D.; Kischkewitz, J. J. Fluorine Chem. 1990, 46,
265.
(13) (a) Begue, J.-P.; Bonnet-Delpon, D.; Dogbeavou, R.;
Ourevitch, M. J. Chem. Soc., Perkin Trans. 1 1993, 2787.
(b) Linderman, R. J.; Jamois, E. A.; Tennyson, S. D. J. Org.
Chem. 1994, 59, 957. (c) Smith, J. O.; Mandal, B. K.; Filler,
R.; Beery, J. W. J. Fluorine Chem. 1997, 81, 123.
(14) Babidge, P. J.; Massy-Westropp, R. A. Aust. J. Chem. 1981,
34, 1745.
(15) Spek, A. PLATON: Molecular Geometry Program;
University of Utrecht: The Netherlands, 1998.
(16) Brulé, C. PhD Dissertation; Université de Reims
Champagne Ardenne: France, 2004.
(17) Bouillon, J.-P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-
Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187.
(18) Sheldrick, G. M. SHELXS-97 and SHELXL-97: Program for
the Solution and Refinement of Crystal Structures;
University of Göttingen: Germany, 1997.
(7) Brulé, C.; Bouillon, J.-P.; Nicolaï, E.; Portella, C. Synthesis
2003, 436.
Synthesis 2006, No. 6, 1050–1056 © Thieme Stuttgart · New York