Synthesis of ortho-perfluoroalkyl phenones from hemifluorinated enones as key building blocks

Article abstract of DOI:10.1016/j.tet.2006.07.004

The title compounds are prepared by cycloaddition of perfluoroalkenyl ketones and 1,3-dienes, with a subsequent aromatization by basic dehydrofluorination. The perfluoroalkenyl ketones were prepared by the reaction of perfluoroorganometallic reagents with

Full text of DOI:10.1016/j.tet.2006.07.004

Tetrahedron 62 (2006) 9049–9053
Synthesis of ortho-perfluoroalkyl phenones from
hemifluorinated enones as key building blocks
a
a,*
b
a,*
Fr ꢀe d ꢀe ric Chanteau, Richard Plantier-Royon, G €u nter Haufe and Charles Portella
a
Laboratoire Re´actions Se´lectives et Applications, Associe´ au CNRS (UMR 6519), Universite´ de Reims,
Faculte´ des Sciences, BP 1039, F-51687 Reims Cedex 2, France
Organisch-Chemisches Institut, Westf a€ lische Wilhelms-Universit a€ t M u€ nster, Corrensstr. 40, D-48149 M u€ nster, Germany
b
Received 29 May 2006; revised 26 June 2006; accepted 1 July 2006
Available online 21 July 2006
Abstract—The title compounds are prepared by cycloaddition of perfluoroalkenyl ketones and 1,3-dienes, with a subsequent aromatization
by basic dehydrofluorination. The perfluoroalkenyl ketones were prepared by the reaction of perfluoroorganometallic reagents with acyl-
silanes. The transformation may be performed more efficiently in a simplified process without purification of the intermediate cycloadducts.
The overall methodology is an interesting entry to ortho-perfluoroalkyl phenones with the possibility to vary the substitution at the acyl and on
the ring moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
NHCH3
CF3
O
O
N
CF3
N
H
3
O
In recent years, the synthesis of fluorinated organic com-
pounds has become an important field in organic chemistry
due to the unique properties of the fluorine atom able to sig-
nificantly modify their physico-chemical and biological
F3C
CF
HO
Flutolanil 40 (fungicide)
HN
Fluoxetine (anti-depressant)
1
properties. Substitution of a hydrogen atom by a fluorine
Mefloquine (anti-malarial)
or introduction of a trifluoromethyl group may improve the
pharmacodynamic and the pharmacokinetic profiles of a bio-
active molecule by concomitant alteration of its electronic,
steric, lipophilic, or metabolic characteristics. In particular,
considerable efforts have been devoted to the introduction
Figure 1. Some selected trifluoromethyl aromatic compounds with bio-
logical activities.
2
effects of the vicinal perfluoroalkyl and acyl groups.
Recently, the application of vinyl fluorides in cycloadditions
has been reviewed. The polyfluorinated dienophiles used in
of a trifluoromethyl group into organic molecules.
7
Among these fluorinated molecules, fluorinated aromatics
and especially trifluoromethylated ones have been exten-
sively developed in the pharmaceutical and agrochemical
this work were of variable structure (aromatic, aliphatic,
carbohydrate-derived) and were prepared by our general
method starting from acylsilanes and perfluoroorganometal-
3
fields. Structures of some examples of such molecules are
presented in Figure 1.
8
lic reagents. This methodology was carried out with various
dienes such as cyclopentadienes or buta-1,3-dienes and gave
access to polyfluorinated norbornenes and cyclohexenes.
5
Aromatics bearing a longer F-alkyl chain have also been
extensively studied for their applications as amphiphilic
molecules or as fluorous catalysts in asymmetric catalysis.
The polyfluorinated cycloalkenes thus obtained are original
compounds, which deserved to be considered as elaborated
intermediates for further transformations. In particular, one
could expect an easy aromatization under basic conditions
owing to the vicinal difluoro pattern present in their struc-
tures. Thus, hemifluorinated enones should be building
blocks of choice toward ortho-perfluoroalkyl phenones.
4
We have recently reported an exploratory study of the [4+2]
cycloaddition reactions with hemifluorinated enones. These
5
6
substrates, in contrast to simple fluorovinylic derivatives,
behave as excellent dienophiles in normal electron-demand
Diels–Alder reactions, due to the additive withdrawing
We report here the synthesis of polysubstituted ortho-per-
fluoroalkyl phenones in a simple two-step process: a [4+2]
cycloaddition between a diene and a hemifluorinated enone
followed by a double HF elimination under basic conditions
as shown in the following retrosynthetic scheme (Scheme 1).
Keywords: Organofluorine compounds; Aromatics; Enones; Diels–Alder
reactions; Fluorinated phenones.
*
Corresponding authors. Tel.: +33 326913234; fax: +33 326913166;
e-mail: charles.portella@univ-reims.fr
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.004

9050
F. Chanteau et al. / Tetrahedron 62 (2006) 9049–9053
O
F
7.38 ppm
O
O
C2F5
C H
R
22.6 ppm
F
3J
R
R
F
8
17
R'
R'
R'
+
H3
RF
RF
RF
F
C2F5
C8H17
H6
O
3
205.1 ppm
2
2.3 ppm
3
J
J
Scheme 1.
7.06 ppm
O
6b
6′b
2
. Results and discussion
Figure 2. Determination of the structures of the aromatic regioisomers.
As previously reported, the cyclohexenes were prepared in
64–77% isolated yields by heating for several days the
dienes 1 and 2 and the enones 3 and 4 in toluene at 150 C
phenones 6 in 66–82% isolated yields (Table 2). Compounds
5 and 5 were converted into the corresponding phenones 6
0
and 6 with a similar regioisomeric ratio.
ꢀ
in a sealed tube (Table 1). The reaction with isoprene
0
5
gave a mixture of isomers in the ratio 60/40. The poor regio-
selectivity observed could be attributed to a weak polariza-
tion of the enone due to the presence of an electron
withdrawing group at each carbon of the double bond (CO
group and F-alkyl chain). The regioisomers were not sepa-
rated and the assignment of their structure was deduced
from the subsequent aromatic derivatives.
Although the compounds were not separated, the determina-
tion of the structure of the two regioisomers 6b and 6 b was
0
performed using a H– C HMBC NMR sequence. The two
1
13
singlets corresponding to H-3 for the regioisomer 6b and
H-6 for the regioisomer 6 b were attributed according to
0
long-distance coupling constants J between these two
3
hydrogen atoms, the carbonyl group, and the methyl group
as shown in Figure 2.
Treatment of these cycloadducts by potassium hydroxide
in methanol induced the double elimination of hydrogen
fluoride and led to the expected ortho-perfluoroalkylated
0
The same result was obtained with the regioisomers 6a and 6 a.
9
Interestingly, synthesis of the aromatic compounds can be
readily achieved in a ‘one-pot’ sequence without isolation
of the intermediate cycloadducts. After completion of the
Diels–Alder reaction (GC monitoring), toluene was evapo-
rated and the crude mixture dissolved in methanol with sub-
sequent addition of potassium hydroxide. This process
allowed a significant improvement of the yields (91–95%)
of the fluorinated aromatics (Table 3).
Table 1. Diels–Alder reactions of buta-1,3-dienes and hemifluorinated
enones
O
F
R1
R1
R1
R
C2F5
F
F
toluene, 4 days
150 °C
C2F5
F
+
+
F
O
C F
2 5
R2
R2
R2
R
F
R
O
(
5 equiv)
–2
5a–d
5′a–b
1
3–4
Table 3. ‘One-pot’ synthesis of the ortho-perfluoroalkyl phenones
a
Entry Diene R
1
2
0
b
Product Ratio 5/5 Yield (%)
(
1) Toluene, 150 °C,
R
Enone R
C2F5
F
F
C2F5
R
4
days
+
Me H
H Me
Me H
5a
0
1
2
1
1
3
4
Ph
62/38
51/49
64
65
O
(2) KOH, 2 equiv,
5 a
5b
MeOH, ∆
R
O
C
8
H
17
0
H
Me
5 b
5c
2
3–4
6c–d
3
4
2
2
Me Me 3
Me Me 4
Ph
C
—
—
76
77
8
H
17 5d
Entry
Enone
R
Product
Yield (%)
a
ꢀ
Reaction conditions: 5.0 equiv of diene, toluene 10 mL at 150 C (oil
bath) in a sealed tube.
Determined by F NMR.
1
2
3
4
Ph
C
6c
6d
91
95
b
19
8
H
17
Table 2. Synthesis of the ortho-perfluoroalkyl phenones
O
F
O
F
R1
R2
R1
R2
R
R1
R2
R1
C2F5
C2F5
KOH, 2 equiv
R
F
+
+
F
C2F5
MeOH, ∆
R
R2
R
C2F5
O
O
5a–d
5′a–b
6a–d
6′a–b
1
2
R
0
b
Entry
Cycloadduct
R
R
Product
Ratio 6/6
Yield (%)
5
5
5
5
5c
5d
a
a
Me
H
Me
H
Me
Me
H
Me
H
Me
Me
Me
6a
0
a
a
1
2
Ph
62/38
51/49
66
75
0
6 a
6b
b
C
8
H
H
17
17
0
0
b
6 b
6c
3
4
Ph
—
—
75
82
C
8
6d
a
Obtained as a mixture of non-separated regioisomers.
Determined by F NMR.
b
19

F. Chanteau et al. / Tetrahedron 62 (2006) 9049–9053
9051
3
. Conclusion
(t, 2H, J¼7.6 Hz, H-arom. meta), 7.49 (t, 1H, J¼7.6 Hz,
H-arom. para), 7.89 (d, 2H, J¼7.6 Hz, H-arom. ortho);
1
3
Hemifluorinated enones proved to be good dienophiles for
4+2] cycloaddition reactions with buta-1,3-dienes. Basic
C NMR (62.9 MHz, CDCl ): d 22.6 (CH ), 34.7 (C-2),
3 3
[
35.0 (C-5), 115.8 (C-4), 128.2–129.8 (CH-arom.), 129.9
(C-3), 133.1 (C -arom.), 192.8 (CO); F NMR (235.4 MHz,
1
9
treatment of the cycloadducts leads to the formation of
ortho-(perfluoroethyl)phenones with good yields. These
fluorinated aromatic compounds were also synthesized
without isolation of the intermediate cyclohexene deriva-
tives. Although it is limited to a few examples exhibiting
the feasibility of the transformation, this paper discloses
a potentially versatile methodology allowing to introduce
structural diversity at the acyl moiety (structure of the start-
ing acylsilane) and at the aryl substitution pattern (structure
of the diene and length of the perfluoroalkyl chain).
q
CDCl ): d ꢁ79.8 (d, 3F, J¼13.3 Hz, CF ), ꢁ117.1 (ddd,
3
3
2
1F, J ¼284.2 Hz, J¼17.1, 11.4 Hz, CF ), ꢁ119.1 (dd,
F,F
2
2
1F, JF,F¼284.2 Hz, J¼19.1 Hz, CF ), ꢁ166.2 (dt, 1F,
2
J¼38.2, 19.1 Hz, F-6), ꢁ171.9 (m, 1F, F-1).
4.2.1.2. 1-(1,6-Difluoro-3-methyl-6-pentafluoroethyl-
cyclohex-3-enyl)-phenone 5 a.
0
CDCl ): d 1.70 (s, 3H, CH ), 2.71–2.90 (m, 2H, H-5 ,
1
H
NMR (250 MHz,
0
H-2 ), 5.33 (br s, 1H, H-4); C NMR (62.9 MHz, CDCl3):
3
3
13
0
d 22.3 (CH ), 33.8 (C-2), 33.9 (C-5), 114.1 (C-4), 128.2–
3
1
29.8 (CH-arom.), 129.7 (C-3), 133.1 (C -arom.), 192.9
q
1
9
4. Experimental
(CO); F NMR (235.4 MHz, CDCl ): d ꢁ79.9 (d, 3F,
3
2
J¼13.3 Hz, CF ), ꢁ117.1 (ddd, 1F, J ¼284.2 Hz, J¼
3
F,F
2
4
.1. General methods
19.1, 11.4 Hz, CF ), ꢁ119.2 (dd, 1F, J ¼284.2 Hz, J¼
2
F,F
1
9.1 Hz, CF ), ꢁ165.0 (dt, 1F, J¼38.2, 19.1 Hz, F-6),
2
All air- and moisture-sensitive reactions were carried out
under an argon atmosphere. Diethyl ether was distilled
over Na/benzophenone before use. All reported NMR spec-
tra were recorded with a Bruker AC 250. Chemical shifts are
ꢁ173.4 (m, 1F, F-1).
0
4.2.2. Mixture of non-separated regioisomers 5b/5 b
ꢁ1
(62/38). Orange oil. Yield: 64%. IR (film) nmax cm
2928, 2857, 1732 (CO), 1445, 1205; EIMS m/z (%): 390
(M , 18), 370, 350, 280, 272, 230 (100). Anal. Calcd for
C H F O: C, 56.38; H, 6.45. Found: C, 56.46; H, 6.60.
:
reported as d values relative to CHCl peak defined at
3
1
13
+
d¼7.27 ( H NMR) or d¼77.0 ( C NMR). IR spectra were
recorded using NaCl film or KBr pellets on an Avatar 320
FT-IR (Nicolet) spectrometer. Mass spectra (MS) were ob-
tained on a Thermoquest Trace GC 2000 Series instrument.
Elementary analyses were taken on a Perkin–Elmer CHN
1
8 25 7
4.2.2.1.
(1,6-Difluoro-4-methyl-6-pentafluoroethyl-
1
cyclohex-3-enyl)-nonan-1-one 5b. H NMR (250 MHz,
CDCl ): d 0.88 (t, 3H, J¼6.9 Hz, CH ), 1.23–1.33 (m,
2
400 elementary analysis instrument. Analytical TLC was
3
3
performed on Merck 60 PF254 silica gel pre-coated plates.
Preparative flash silica gel chromatography was performed
using Merck Kieselgel 60 (40–63 mm). Petroleum ether
10H, CH ), 1.60 (m, 2H, CH ), 1.77 (s, 3H, CH ), 2.10–
2 2 3
0
1H, H-3); C NMR (62.9 MHz, CDCl ): d 14.0 (CH ),
0
2.98 (m, 6H, CH CO, H-2, H-2 , H-5, H-5 ), 5.39 (br s,
2
1
3
3
3
ꢀ
refers to the fraction with bp 40–65 C.
22.3 (CH ), 22.6 (CH ), 22.9 (CH ), 28.9 (CH ), 29.1
3 2 2 2
(CH ), 29.3 (CH ), 32.0 (CH ), 34.8 (C-2), 35.2 (C-5),
38.3 (CH CO), 114.3 (C-4), 130.5 (C-3), 204.2 (CO);
2 2 2
1
9
All commercially available chemicals were used as received
unless otherwise noted. Hemifluorinated enones 3 and 4
were obtained as previously described.
F
2
NMR (235.4 MHz, CDCl ): d ꢁ79.7 (d, 3F, J¼11.4 Hz,
3
8
2
CF ), ꢁ118.5 (dm, 1F, J ¼284.2 Hz, CF ), ꢁ120.3 (dd,
3
F,F
2
2
1
F, J ¼284.2 Hz, J¼21.0 Hz, CF ), ꢁ170.5 (dt, 1F, J¼
F,F
2
4
5
.2. General procedure for the synthesis of cycloadducts
0
38.2, 19.1 Hz, F-6), ꢁ174.1 (dt, 1F, J¼26.6, 13.3 Hz, F-1).
.2.2.2. (1,6-Difluoro-3-methyl-6-pentafluoroethyl-
and 5
4
cyclohex-3-enyl)-nonan-1-one 5 b. H NMR (250 MHz,
0
CDCl ): d 1.74 (s, 3H, CH ), 5.34 (br s, 1H, H-4);
1
A solution of the dienes 1 and 2 (5 mmol) and the hemifluori-
nated enones 3 and 4 (1 mmol) was warmed in toluene
1
3
C
3
3
ꢀ
(
15 mL) in an oil bath at 150 C in a sealed tube. After com-
NMR (62.9 MHz, CDCl ): d 31.8 (CH ), 34.9 (C-2), 35.1
3 2
pletion of the reaction (4 days), the reaction mixture was
cooled to room temperature and toluene was evaporated.
The crude mixture was purified by flash chromatography
over silica gel (petroleum ether/EtOAc 99:1) to afford pure
cycloadducts.
(C-5), 38.4 (CH CO), 116.0 (C-4), 129.9 (C-3), 204.4
2
1
9
(CO); F NMR (235.4 MHz, CDCl ): d ꢁ79.8 (d, 3F,
3
2
J¼13.3 Hz, CF ), ꢁ118.5 (d, 1F, J ¼284.2 Hz, CF ),
3
F,F
2
2
ꢁ120.5 (dd, 1F, J ¼284.2 Hz, J¼22.9 Hz, CF ), ꢁ169.3
F,F
2
(dt, 1F, J¼38.2, 19.1 Hz, F-6), ꢁ175.6 (dt, 1F, J¼26.6,
3.3 Hz, F-1).
1
0
4
.2.1. Mixture of non-separated regioisomers 5a/5 a
ꢁ
1
(
59/41). Orange oil. Yield: 65%. IR (film) nmax cm
:
925, 2858, 1698 (CO), 1579, 1448, 1383; EIMS m/z (%):
54 (M , 1), 334 (Mꢁ20), 295, 257, 237, 215, 137, 105
4.2.3. (1,6-Difluoro-3,4-dimethyl-6-pentafluoroethyl-
cyclohex-3-enyl)-phenone 5c. Yellow oil. Yield: 76%. IR
2
3
+
ꢁ1
(film) nmax cm : 2922, 2865, 1688 (CO), 1598, 1579,
1448, 1421, 1387, 1203, 748, 691; H NMR (250 MHz,
1
(
C, 54.33; H, 3.82.
100). Anal. Calcd for C H F O: C, 54.25; H, 3.70. Found:
1
6 13 7
CDCl ): d 1.71 (s, 3H, CH ), 1.74 (s, 3H, CH ), 2.42–2.57
3
3
3
0 0
(
m, 2H, H-5, H-2), 2.77–3.17 (m, 2H, H-5 , H-2 ), 7.44
4.2.1.1. 1-(1,6-Difluoro-4-methyl-6-pentafluoroethyl-
cyclohex-3-enyl)-phenone 5a.
(t, 2H, J¼7.6 Hz, H-arom. meta), 7.56 (t, 1H, J¼7.6 Hz,
1
H
NMR (250 MHz,
CDCl ): d 1.74 (s, 3H, CH ), 2.36–2.61 (m, 2H, H-5, H-2),
H-arom. para), 7.96 (d, 2H, J¼7.6 Hz, H-arom. ortho);
1
3
C NMR (62.9 MHz, CDCl ): d 18.1 (CH ), 18.3 (CH ),
3 3 3
3
3
0
0
2
3
2
.90–3.10 (m, 2H, H-5 , H-2 ), 5.37 (br s, 1H, H-3), 7.37
33.0 (dd, J ¼21.7 Hz, JC,F¼2.4 Hz, C-2 or C-5), 38.6
C,F

9052
F. Chanteau et al. / Tetrahedron 62 (2006) 9049–9053
2
3
0
(
dd, J ¼21.7 Hz, J ¼2.4 Hz, C-2 or C-5), 93.6 (dm,
4.3.1. Mixture of non-separated regioisomers 6a/6 a
:
C,F
C,F
1
1
2
ꢁ1
JC,F¼196.3 Hz, C-6), 97.2 (dd, J ¼196.4 Hz, J
C,F
¼
(61/39). Yellow oil. Yield: 75%. IR (film) nmax cm
2969, 1681 (CO), 1597, 1450, 1332, 1212, 1082, 998.
C,F
1
2
2.9 Hz, C-1), 117.6 (C-4), 118.4 (tq,
J
C,F
¼288.3 Hz,
2
JC,F¼34.5 Hz, CF ), 119.3 (C-3), 126.3–127.9 (CH-
3
2
0
none 6a. H NMR (250 MHz, CDCl ): d 2.40 (s, 3H,
0
arom.), 133.7 (C -arom.), 195.6 (d, J ¼27.3 Hz, CO);
4.3.1.1. (4 -Methyl-2 -pentafluoroethyl)phenyl-phe-
q
C,F
1
9
1
F NMR (235.4 MHz, CDCl ): d ꢁ79.9 (d, 3F, J¼13.3 Hz,
3
3
2
0
CF ), ꢁ117.3 (ddd, 1F, J ¼284.2 Hz, J¼11.4, 7.6 Hz,
CH ), 7.15 (d, 1H, J¼7.9 Hz, H-6 ), 7.32–7.40 (m, 3H,
3
F,F
3
2
0
0
CF ), ꢁ119.5 (dd, 1F, J ¼284.2 Hz, J¼17.2 Hz, CF ),
H-arom. meta, H-3 , H-5 ), 7.48 (t, 1H, J¼7.6 Hz, H-arom.
2
F,F
2
1
3
ꢁ
165.2 (dt, 1F, J¼38.1, 19.1 Hz, F-6), ꢁ172.2 (ddtt,1F,
para), 7.65 (d, 2H, J¼7.6 Hz, H-arom. ortho); C NMR
+
2
J¼38.1, 13.3, 5.7 Hz, F-1); EIMS m/z (%): 368 (M , 2),
48 (Mꢁ20, 100), 328, 295, 271, 251, 229. Anal. Calcd for
C H F O: C, 55.44; H, 4.11. Found: C, 55.59; H, 4.12.
(62.9 MHz, CDCl ): d 21.0 (CH ), 124.0 (t, J ¼30.0 Hz,
3
0
3
C,F
0
0
3
C-2 ), 126.6 (C-6 ), 128.4–130.1 (C-3 , CH-arom.), 132.0
(C-5 ), 133.2 (C -arom.), 139.7 (C-4 ), 139.9 (C-1 ), 195.9
0
0
0
1
7
15
7
q
1
9
(
CO); F NMR (235.4 MHz, CDCl ): d ꢁ83.8 (s, 3F,
3
4
.2.4. 1-(1,6-Difluoro-3,4-dimethyl-6-pentafluoroethyl-
cyclohex-3-enyl)-nonan-1-one 5d. Yellow oil. Yield:
7%. IR (film) n cm : 2927, 2858, 1733 (CO), 1460,
421, 1221; H NMR (250 MHz, CDCl ): d 0.89 (t, 3H,
CF ), ꢁ107.7 (s, 2F, CF ).
3 2
ꢁ
1
0 0
none 6 a. H NMR (250 MHz, CDCl ): d 2.43 (s, 3H,
7
1
4.3.1.2. (5 -Methyl-2 -pentafluoroethyl)phenyl-phe-
max
1
0
CH ), 7.07 (s, 1H, H-6 ), 7.32–7.40 (m, 3H, H-arom. meta,
1
3
3
0
J¼6.9 Hz, CH ), 1.23–1.35 (m, 10H, CH ), 1.61 (quint.,
3
2
3
0
0
2
(
5
(
H, CH ), 1.68 (s, 3H, CH ), 1.71 (s, 3H, CH ), 2.12–2.50
3
H-3 , H-4 ), 7.48 (t, 1H, J¼7.6 Hz, H-arom. para), 7.65 (d,
2
3
0
13
m, 2H, H-2, H-5), 2.59–2.99 (m, 4H, CH CO, H-2 , H-
2
2H, J¼7.6 Hz, H-arom. ortho); C NMR (62.9 MHz,
0
13
2
0
); C NMR (62.9 MHz, CDCl ): d 14.0 (CH ), 18.1
3
CDCl ): d 21.2 (CH ), 121.7 (t, JC,F¼30.0 Hz, C-2 ),
0 0
q
3
3
3
CH ), 18.3 (CH ), 22.6 (CH ), 22.8 (CH ), 22.9 (CH ),
3
8.9 (CH ), 29.1 (CH ), 29.3 (CH ), 31.8 (CH ), 34.6 (dm,
2
126.9 (C-6 ), 128.4–130.1 (C-3 , CH-arom.), 133.3 (C -
3
2
2
2
0
0
0
2
arom.), 135.7 (C-4 ), 144.0 (C-1 ), 144.2 (C-5 ), 196.1
(CO); F NMR (235.4 MHz, CDCl ): d ꢁ84.0 (s, 3F,
2
2
2
2
2
3
19
JC,F¼21.7 Hz, C-5), 38.4 (dd, JC,F¼21.7 Hz, JC,F
¼
3
3
2
1
(
ꢁ
.0 Hz, C-2), 38.5 (d, J ¼3.2 Hz, CH CO), 119.2 (C-4),
CF ), ꢁ107.7 (s, 2F, CF ).
C,F
2
3
2
2
19
21.0 (C-3), 206.6 (d,
J
¼29.3 Hz, CO); F NMR
C,F
0
235.4 MHz, CDCl ): d ꢁ79.8 (d, 3F, J¼11.4 Hz, CF ),
4.3.2. Mixture of non-separated regioisomers 6b/6 b
3
3
2
3
ꢁ1
118.6 (ddd, 1F,
J
¼284.2 Hz,
J
¼11.4, 5.7 Hz,
(60/40). Yellow oil. Yield: 66%. IR (film) nmax cm
2958, 2928, 2857, 1713 (CO), 1612, 1572, 1459, 1333,
:
F,F
F,F
2
CF ), ꢁ120.4 (dd, 1F, J ¼284.2 Hz, J¼22.9 Hz, CF ),
2
F,F
2
+
ꢁ
169.5 (dt, 1F, J¼40.0, 19.0 Hz, F-6), ꢁ174.4 (dt, 1F,
1205, 1086, 857; EIMS m/z (%): 350 (M , 8), 330, 302,
252, 237 (100), 219, 164, 159.
+
J¼40.0, 13.3 Hz, F-1); EIMS m/z (%): 404 (M , 4), 384,
3
H, 6.73. Found: C, 56.58; H, 6.81.
64, 314, 286, 229. Anal. Calcd for C H F O: C, 56.43;
19 27 7
0 0
1-(4 -Methyl-6 -pentafluoroethyl)phenyl-
nonan-1-one 6b. H NMR (250 MHz, CDCl ): d 0.88 (t,
4.3.2.1.
1
3
4
ortho-perfluoroalkyl phenones 6 and 6
.3. General procedure for the synthesis of
0
3H, J¼6.9 Hz, CH ), 1.23–1.33 (m, 10H, CH ), 1.68 (quint.,
3
2
2H, J¼6.9 Hz, CH ), 2.43 (s, 3H, CH ), 2.76 (t, 2H, J¼
0
2
2
3
6
.9 Hz, CH ), 7.17 (d, 1H, J¼8.3 Hz, H-6 ), 7.38 (s, 1H,
0
0
13
Method A: to a solution of the fluorinated cycloadduct 5 or
the mixture of cycloadducts 5–5 (1 mmol) in methanol
H-3 ), 7.39 (d, 1H, J¼8.3 Hz, H-5 ); C NMR (62.9 MHz,
0
5 mL) was added potassium hydroxide (2 mmol). The solu-
CDCl ): d 14.0 (CH ), 22.6 (CH ), 23.5 (CH ), 23.6
3
3
2
3
(
(CH ), 29.0 (CH ), 29.1 (CH ), 29.3 (CH ), 31.8 (CH ),
2
2
2
2
2
2
0
129.8 (C-3 ), 132.4 (C-5 ), 139.6 (C-4 ), 139.8 (C-1 ),
0
tion was refluxed for 24 h. After completion of the reaction,
the reaction mixture was cooled to room temperature and
methanol was evaporated. The crude mixture was dissolved
in diethyl ether (50 mL) and extracted twice with a saturated
NaCl solution. The organic layer was then dried over MgSO4
and the organic solvent was evaporated. The crude mixture
was purified by flash chromatography over silica gel (petro-
leum ether/EtOAc 99:1) to afford pure aromatic compounds.
44.0 (CH ), 124.5 (t, J ¼29.0 Hz, C-2 ), 126.5 (C-6 ),
2
C,F
0
0
0
0
1
9
205.1 (CO); F NMR (235.4 MHz, CDCl ): d ꢁ83.6 (s,
3
3F, CF ), ꢁ107.8 (s, 2F, CF ).
3
2
0 0
nonan-1-one 6 b. H NMR (250 MHz, CDCl ): d 0.88 (t,
4.3.2.2.
1-(4 -Methyl-2 -pentafluoroethyl)phenyl-
0
1
3
3H, J¼6.9 Hz, CH ), 1.23–1.33 (m, 10H, CH ), 1.68 (quint.,
3
2
2
H, J¼6.9 Hz, CH ), 2.42 (s, 3H, CH ), 2.78 (t, 2H,
0
2
2
3
Method B: to a solution of the dienes 1 and 2 (5 mmol) and
the hemifluorinated enones 3 and 4 (1 mmol) in toluene
J¼6.9 Hz, CH ), 7.06 (s, 1H, H-6 ), 7.31 (d, 1H, J¼
0
0
13
8.0 Hz, H-4 ), 7.47 (d, 1H, J¼8.0 Hz, H-3 ); C NMR
ꢀ
(
15 mL) in an oil bath at 150 C in a sealed tube. After com-
(62.9 MHz, CDCl ): d 14.0 (CH ), 22.6 (CH ), 23.4 (CH ),
3
3
2
3
pletion of the reaction (4 days), the reaction mixture was
cooled to room temperature and toluene was evaporated.
The crude residue was dissolved in methanol and potassium
hydroxide (2 mmol) was added. After completion of the re-
action (24 h), the reaction mixture was cooled to room tem-
perature and methanol was evaporated. The crude mixture
was dissolved in diethyl ether (50 mL) and extracted twice
with brine. The organic layer was then dried over MgSO4
and the organic solvent was evaporated. The crude mixture
was purified by flash chromatography over silica gel (petro-
leum ether/EtOAc 99:1) to afford pure aromatic compounds.
23.6 (CH ), 29.0 (CH ), 29.1 (CH ), 29.3 (CH ), 31.9
2 2 2 2
2
0
(CH ), 44.2 (CH ), 121.4 (t, J ¼30.0 Hz, C-2 ), 126.8
2
2
C,F
0
0
0
0
(C-6 ), 128.6 (C-3 ), 142.6 (C-1 ), 142.9 (C-5 ), 205.3
1
9
(CO); F NMR (235.4 MHz, CDCl ): d ꢁ83.9 (s, 3F,
3
CF ), ꢁ107.8 (s, 2F, CF ).
3
2
0
none 6c. Yellow oil. Yields: 75% (Method A), 95% (Method
0
0
4.3.3. 1-(4 ,5 -Dimethyl-2 -pentafluoroethyl)phenyl-phe-
ꢁ
1
B). IR (film) nmax cm : 2920, 2865, 1685 (CO), 1598, 1575,
1442, 1420, 1387, 1203, 748, 691; H NMR (250 MHz,
1
CDCl ): d 2.25 (s, 3H, CH ), 2.31 (s, 3H, CH ), 7.00 (s,
3
3
3

F. Chanteau et al. / Tetrahedron 62 (2006) 9049–9053
9053
0
0
1
H, H-3 ), 7.35 (t, 3H, J¼7.4 Hz, H-arom. meta, H-6 ), 7.49
2004, 5, 614–621; (g) Biffinger, J. C.; Kim, H. W.; DiMagno,
S. G. ChemBioChem 2004, 5, 622–627; (h) B €o hm, H.-J.;
Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; M €u ller, K.;
Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643;
(i) Rosen, T. C.; Yoshida, S.; Kirk, K. L.; Haufe, G.
ChemBioChem 2004, 5, 1033–1043; (j) Dolbier, W. R.
J. Fluorine Chem. 2005, 126, 157–163.
(t, 1H, J¼7.4 Hz, H-arom. para), 7.67 (d, 2H, J¼7.4 Hz,
H-arom. ortho); C NMR (62.9 MHz, CDCl ): d 19.6
CH ), 19.7 (CH ), 127.3 (C-3), 128.4 (CH-arom.), 129.0
3 3
(CH-arom.), 129.4 (C-6), 130.1 (CH-arom.), 133.5 (CH-
arom.), 136.8 (C -arom.), 138.4 (C-4 or C-5), 140.8 (C-4 or
1
3
3
(
q
1
9
C-5), 196.0 (CO); F NMR (235.4 MHz, CDCl ): d ꢁ83.9
3
+
(
s, 3F, CF ), ꢁ107.6 (s, 2F, CF ); EIMS m/z (%): 328 (M ,
2. (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
6555–6666; (b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997,
97, 757–786; (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
3
2
31), 309, 251, 201, 173, 133, 105 (100). Anal. Calcd for
C H F O: C, 62.20; H, 3.99. Found: C, 62.47; H, 4.21.
1
7 13 5
5
6, 7613–7632; (d) Prakash, G. K. S.; Mandal, M. J. Fluorine
0
0
nonan-1-one 6d. Yellow oil. Yields: 82% (Method A),
0
4
.3.4. 1-(4 ,5 -Dimethyl-2 -pentafluoroethyl)phenyl-
Chem. 2001, 112, 123–131; (e) Langlois, B. R.; Billard, T.
Synthesis 2003, 185–194; (f) Joubert, J.; Roussel, S.;
Christophe, C.; Billard, T.; Langlois, B. R.; Vidal, T. Angew.
Chem., Int. Ed. 2003, 42, 3241–3244; (g) Langlois, B. R.;
Billard, T.; Roussel, S. J. Fluorine Chem. 2005, 126, 173–179;
(h) Leuger, J.; Blond, G.; Fr €o hlich, R.; Billard, T.; Haufe, G.;
Langlois, B. R. J. Org. Chem. 2006, 71, 2735–2739.
1
9
3
2
1% (Method B). H NMR (250 MHz, CDCl ): d 0.88 (t,
3
H, J¼6.9 Hz, CH ), 1.23–1.35 (m, 10H, CH ), 1.68 (quint.,
3
2
H, J¼7.2 Hz, CH ), 2.32 (br s, 6H, 2CH ), 2.75 (t, 2H,
2
3
1
3
J¼7.4 Hz, CH ), 7.01 (s, 1H, H-3), 7.32 (s, 1H, H-6);
C
NMR (62.9 MHz, CDCl ): d 14.0 (CH ), 19.5 (CH ), 19.6
2
3
3
3
(
2
CH ), 22.6 (CH ), 23.6 (CH ), 29.0 (CH ), 29.1 (CH ),
3
9.3 (CH ), 31.8 (CH ), 44.8 (CH ), 127.5 (C-3), 129.0
2 2 2
3. (a) Welch, J. T.; Ewarakrishnan, S. E. Fluorine in Bioorganic
Chemistry; Wiley: New York, NY, 1991; (b) Filler, R.;
Kobayashi, Y.; Yagulpolskii, L. M. Organofluorine Compounds
in Medicinal Chemistry and Biomedical Applications; Elsevier:
Amsterdam, 1993; (c) Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Organofluorine Chemistry: Principles and Commercial Appli-
cations; Plenum: New York, NY, 1994; (d) Kukhar, V. P.;
Soloshonok, V. A. Fluorine-containing Aminoacids: Synthesis
and Properties; Wiley: Chichester, UK, 1995; (e) Becker, A.
Inventory of Industrial Fluoro-Biochemicals; Eyrolles: Paris,
2
2
2
2
(
C-6), 138.2 (C-4 or C-5), 141.1 (C-4 or C-5), 205.3 (CO);
F NMR (235.4 MHz, CDCl ): d ꢁ83.8 (s, 3F, CF ),
1
9
3
3
+
ꢁ
107.6 (s, 2F, CF ); EIMS m/z (%): 364 (M , 8), 349,
2
308, 279, 251 (100), 237, 223, 177. Anal. Calcd for
C H F O: C, 62.63; H, 6.91. Found: C, 62.94; H, 6.99.
1
9 25 5
Acknowledgements
1
996; (f) Jeschke, P. ChemBioChem 2004, 5, 570–589.
The authors are grateful to the ‘Minist ꢁe re de l’Education
Nationale, de l’Enseignement Sup ꢀe rieur et de la Recherche’
4. Gladysz, J. A.; Curran, D. P.; Horvath, I. T. Handbook of
Fluorous Chemistry; Wiley-VCH: Weinheim, 2004.
(
‘
M.E.N.E.S.R.) for a PhD fellowship (F.C.) and to the
Deutsche Forschungsgemeinschaft’ (Graduate College 71)
5. Chanteau, F.; Essers, M.; Plantier-Royon, R.; Haufe, G.;
Portella, C. Tetrahedron Lett. 2002, 43, 1677–1680.
6. (a) Ernet, T.; Haufe, G. Tetrahedron Lett. 1996, 37, 7251–7252;
for a short-term stipend (F.C.).
(
b) Ernet, T.; Maulitz, A. H.; W €u rthwein, E.-U.; Haufe, G.
J. Chem. Soc., Perkin Trans. 1 2001, 1929–1938.
7. Haufe, G. Fluorine-containing Synthons; Soloshonok, V. A., Ed.;
ACS Symposium Series 911; American Chemical Society:
Washington, DC, 2005; pp 155–172.
8. (a) Portella, C.; Dondy, B. Tetrahedron Lett. 1991, 32, 83–86; (b)
Dondy, B.; Portella, C. J. Org. Chem. 1993, 58, 6671–6674; (c)
Bouillon, J.-P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-
Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187–192; (d)
Chanteau, F.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-
Royon, R.; Portella, C. Eur. J. Org. Chem. 2004, 1444–1454.
9. Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998, 54,
5939–5948.
References and notes
1
. (a) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series
39; American Chemical Society: Washington, DC, 1996; (b)
Hiyama, T. Organofluorine Compounds: Chemistry and
Properties; Springer: Berlin, 2000; (c) Smart, B. E.
J. Fluorine Chem. 2001, 109, 3–11; (d) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004; (e)
Chambers, R. D. Fluorine in Organic Chemistry; Blackwell/
CRC: Boca Raton, FL, 2004; (f) Dunitz, J. D. ChemBioChem
6