1,4-Additions of electron-rich heterocycles onto β-perfluoroalkyl enones

Article abstract of DOI:10.1016/j.jfluchem.2011.04.004

β-(Trifluoromethyl) enones, easily obtained in few steps from commercially available methyl hemiketal of trifluoroacetaldehyde, react with electron-rich O- and N-containing heterocycles (furans and benzofurans, pyrroles and indoles, hydroxycoumarins), thr

Full text of DOI:10.1016/j.jfluchem.2011.04.004

Journal of Fluorine Chemistry 132 (2011) 799–803
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
1,4-Additions of electron-rich heterocycles onto
b
-perfluoroalkyl enones
b
a,
Julia Leuger b, Gaelle Blond c,1, Thierry Billard a, , Gu¨nter Haufe , Bernard R. Langlois
*
*
a Universite´ de Lyon, Universite´ Lyon 1, CNRS ICBMS (UMR CNRS 5246) – Laboratoire SURCOOF, 43 Bd du 11 novembre 1918, Bat Raulin, F-69622 Villeurbanne, France
b Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Correnstrasse 40, D-48149 Mu¨nster, Germany
c Universite´ de Strasbourg, Faculte´ de Pharmacie, Laboratoire d’innovation the´rapeutique, UMR CNRS 7200, 74 route du Rhin, F-67401 Illkirch, France
A R T I C L E I N F O
A B S T R A C T
-(Trifluoromethyl) enones, easily obtained in few steps from commercially available methyl hemiketal
Article history:
b
Received 2 March 2011
Received in revised form 7 April 2011
Accepted 11 April 2011
Available online 16 April 2011
of trifluoroacetaldehyde, react with electron-rich O- and N-containing heterocycles (furans and
benzofurans, pyrroles and indoles, hydroxycoumarins), through a 1,4 addition, to give heterocycles
bearing a functionalized side-chain.
behave in the same way.
b
-(chlorodifluoromethyl)enones and
b-(pentafluoroethyl)enones
ß 2011 Elsevier B.V. All rights reserved.
In honor of Alain Tressaud, with
congratulations.
Keywords:
b
b
-(Trifluoromethyl)enones
-(Perfluoroalkyl)enones
Heterocycles
Furans
Benzofurans
Pyrroles
Indoles
Hydroxycoumarins
Side-chain perfluoroalkylated heterocycles
Perfluoroalkyl Warfarin analogs
1,4-Addition
1. Introduction
such as acetophenone, did not deliver any
carbinol but a -(trifluoromethyl)- -piperazinoketone [5]. These
compounds, which exhibit a limited stability, can be treated in
acidic medium (TFA) to provide stable -(trifluoromethyl) enones
3. As it was suspected that, during this reaction, an iminium
intermediate was trapped by the enolic form of the ketone, it
appeared that 3 was more conveniently prepared in one pot from 2
after treatment with a Lewis acid (such as BF3ÁEt2O) then with
trifluoroacetic acid [5] (Scheme 2). It can be noticed that the
occurrence of such an iminium intermediate has been amply
demonstrated by trapping with various nucleophiles, such as
alcohols, amines, azidosilanes, silyl hydrides, allyl silanes (which
a-(trifluoromethyl)-
b
b
Several years ago, we described the preparation, from
commercially available methyl hemiketal of trifluoroacetaldehyde
(fluoral), of stable and environmentally friendly hemiaminals of
fluoral, especially the one derived from N-benzylpiperazine 1.
Under basic conditions, this hemiaminal constitutes as an efficient
nucleophilic trifluoromethylating agent towards non-enolizable
carbonylated substrates or disulfides and diselenides. Moreover,
under fluoride activation, its O-silylated derivative 2 behaves in the
same way [1–4] (Scheme 1). Analogs of reagents 1 and 2, in which
the CF3 group was replaced by CF2Cl or CF3CF2, were obtained in
the same way from the corresponding aldehyde hydrates and
reacted similarly.
b
led to
-CF3 allylamines) or electron-rich aromatics [6,7].
Obviously, such -(fluoroalkyl) enones look as very valuable
a-CF3 homoallylamines), vinyl trifluoroborates (which led to
a
Surprisingly, we observed that, in the presence of a catalytic
amount of t-BuOK, the reaction of the 1 with enolizable ketones,
b
building-blocks for the synthesis of numerous fluoroalkylated
compounds and we already reported on their use in Diels–Alder
reactions (which allowed us to produce fluoroalkylated norbor-
nenes, acylcyclohexenes and acylcyclohexenones) [8] or Michael
* Corresponding authors.
additions leading to (trifluoromethyl)cyclohexenones [9] and D1
-
E-mail address: billard@univ-lyon1.fr (T. Billard).
1
(trifluoromethyl)pyrrolines [10].
Present address.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.04.004

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J. Leuger et al. / Journal of Fluorine Chemistry 132 (2011) 799–803
O
O
1 / t-BuOK
O
THF / r.t.
OR
CF3
Ph
CF2Cl
Ph
CF2CF3
Ph
O
CF3
R1
R2
R = H; TMS
R1
R2
3aA
3bA
3cA
O
2 / CsF
O
O
O
DME / 60 °C
O
O
CF2Cl
CF2CF3
CF3
1 or 2
same cond.
RS-SR
RS-CF3
3cB
3aB
3bB
Scheme 1. Preparation and use of fluoral hemiaminals 1 and 2.
Scheme 3. Substrates used in this study.
Now, we wish to present our results about the reaction of
(fluoroalkyl)enones with electron-rich heterocycles.
b
-
-
temperature. As expected also, N-benzylindole reacted regioselec-
tively at the 3-position. In contrast, benzofuran appeared less
reactive than furan or N-containing substrates; consequently,
heating up to 50 8C was necessary to get good yields.
Unprotected indole was also used as substrate against 3aA. In
this case, no adduct was obtained with BF3ÁEt2O as catalyst. It could
be suspected that some intermolecular interactions could occur
between the rather acidic hydrogen of the indole nucleus and the
fluorine atoms of the adduct. Thus, elimination of HF cannot be
ruled out, all the more so since such an elimination would be
favored by a hard Lewis acid such as BF3ÁEt2O. Nevertheless, a
softer Lewis acid, such as Cu(OTf)2, delivered the adduct but in a
poor yield (Scheme 7).
2. Results and discussion
The reactivity with electron-rich heterocycles of the
(fluoroalkyl) enones described in Scheme 3 have been studied.
b
Following our previous results from Diels–Alder reactions of
these enones with cyclopentadiene, we thought that furan would
react in the same way and provide bicyclic Diels–Alder adducts.
However, no bicyclic adduct was obtained from 3aA–3cA, even at
150 8C. When catalytic amounts of a Lewis acid were added to
activate the reaction, the enone became more electrophilic and
thus allowed furan to act as a nucleophile rather than a diene.
Consequently, it underwent a 1,4-addition on 3aA which delivered
4-Hydroxycoumarin is also an electron-rich heterocycle which
easily reacts with electrophiles under various conditions. For
example, when opposed to benzylideneacetone, it provides
a
b
-(trifluoromethyl)-b-(2-furyl) ketone 4aA (Scheme 4).
Warfarin (CoumadinTM
) which is a well-known and potent
Catalysis of this 1,4-addition by several Lewis acids was also
anticoagulant [12]. This condensation has been achieved in an
enantioselective way by Jorgensen, by using a chiral organocatalyst
[13] (Scheme 8).
examined and it appeared that Cu(OTf)2 and In(OTf)3 were as
efficient as BF3ÁEt2O, whereas Zn(OTf)2, La(OTf)3 and Yb(OTf)3 did
not catalyzed the reaction (Scheme 5). The same alpha-regios-
electivity was observed whatever the catalyst.
It can be also noticed that, when two equivalents of 3aA and
TiCl4 were used, a double condensation of 3aA with furan was
observed (Scheme 6).
By analogy with a recent Jorgensen’s work, dealing with the
enantioselective addition of indole onto benzylidene methyl
pyruvate, catalyzed by chiral Cu(OTf)2/(S)-tBu-BOX [11], we
examined the behavior of this Cu(II) complex and its indium
congener, in the reaction of furan with 3aA. Unfortunately, no
condensation occurred in both cases, probably because Cu(II) or
In(III), liganded in such a way, are not electrophilic enough to
chelate the carbonyl moiety of 3aA.
We then studied the BF3ÁEt2O catalyzed addition of 3aA–3cA on
other electron-rich heterocycles, namely benzofuran, N-methyl-
pyrrole and N-benzylindole, under conditions similar to those used
for furan (Fig. 1). As expected, N-containing heterocycles usually
reacted faster and delivered better yields than furan at room
Because of the analogy of such a structure with those we
obtained from 3aA, we started studying the addition of 4-
hydroxycoumarin with enones 3aA–3cA and 3aB–3cB, in order
to get fluorinated analogs of Warfarin. As we were firstly interested
in the racemic series, we did not use Jorgensen’s conditions but,
more simply, the reaction was carried out in basic medium
(Scheme 9). As depicted in Fig. 2, good to excellent yields are
generally obtained.
In conclusion, after several contributions from our laboratory
and from others [14], this work demonstrates again that
b-
perfluoroalkylated enones are very powerful tools and very
valuable building-blocks for the synthesis of various fluorinated
products, and especially heterocyclic ones, which could find highly
interesting applications in the design of bioactive molecules. There
is no doubt that several other properties of these building-blocks
have to be exploited. For our part, we are currently studying a
stereoselective version of the condensations reported in this paper.
O
Rf
O
TMSO
Rf
1) BF3.Et2O / 50 °C
CH2Cl2
R1
N
R2
+
N
N Bn
R1
R2
NBn
a: Rf = CF3
b: Rf = CF2Cl
c: Rf = CF2CF3
2a-c
2) TFA
0 °C
50 °C
O
R1
Rf
R2
3a-c
(30-95%)
Scheme 2. Preparation of
b-(fluoroalkyl) enones 3a–3c.

J. Leuger et al. / Journal of Fluorine Chemistry 132 (2011) 799–803
801
O
CF2X
4aA: 90 %
4bA:67 %
4cA: 76 %
O
O
O
BF3.Et2O (0.1 eq)
CH2Cl2 / r.t.
+
Ph
CF2X
Ph
3a-cA
X = F (a), Cl (b), CF3 (c)
4a-cA
Scheme 4. 1,4-Addition of furan onto 3aA.
L.A. = BF3.Et2O (90 %)
L.A. = TiCl4 (70 %)
O
CF3
O
O
O
L.A. (0.1 eq)
CH2Cl2 / r.t.
L.A. = SnCl4 (70 %)
+
Ph
CF3
Ph
L.A. = Cu(OTf)2 (89 %)
L.A. = In(OTf)3 (> 99 %)
3aA
4aA
Scheme 5. 1,4-Addition of furan onto 3aA with various Lewis acids.
O
CF3
3.1. General procedure for the Lewis acid-catalyzed addition of
different heterocycles onto -fluoroalkylated enones 3
O
O
O
TiCl4 (0.1 eq.)
CH2Cl2 / r.t.
O
O
b
+
+
Ph
CF3
Ph
70 %
The Lewis acid (0.075 mmol, 0.1 eq.) was added to a solution of 3
(0.75 mmol, 1 equiv.) in CH2Cl2 (0.5 mL). After the reaction mixture
has been stirred for 0.5 h at room temperature, the heteroaromatic
compound (0.75 mmol, 1.0 equiv.) was added. The resulting
solution was stirred at room temperature (or at 50 8C in the case
of benzofuran) until no (or only traces) starting material was
detected by 19F NMR (ca. 16 h) then water was added. The reaction
mixture was diluted with CH2Cl2 and treated with a 6% aqueous
solution of NaHCO3. After decantation, the aqueous phase was
extracted with CH2Cl2, the combined organic phases were washed
twice with a 6% aqueous solution of NaHCO3, dried over Na2SO4 and
evaporated under vacuum. The crude residue was purified by flash
column chromatography on silica gel to afford the pure adduct.
3aA (1 eq.)
O
F3C
CF3
TiCl4 (2 eq.)
CH2Cl2 / r.t.
O
O
Ph
CF3
Ph
Ph
3aA (2 eq.)
43 %
Scheme 6. Double vs. single condensation of 3aA with furan.
3. Experimental
Dichloromethane was dried over molecular sieves. Other
reagents were used as purchased.
1H, 13C (CPD and DEPT 135) and 19F NMR spectra were generally
recorded in CDCl3 at, respectively, 300, 75 and 282 MHz, otherwise
specified. The signal’s attribution of 1H and 13C NMR spectra may
have required 2D NMR experiments (COSY, HSQC, HMBC, NOESY,
and HOESY). Chemical shifts are given in ppm relative to TMS (1H
3.2. 4,4,4-Trifluoro-3-(2-furyl)-1-phenylbutan-1-one (4aA)
Orange oil. Yield: 90%. 1H NMR:
d 7.96 (m, 2H), 7.58 (m, 1H),
7.47 (m, 2H), 7.34 (dd, J = 2 Hz, 1H), 6,34 (bd, J = 3 Hz, 1H), 6.32 (dd,
J = 3, 2 Hz, 1H), 4.42 (ddq, J = 9, 9, 4 Hz, 1H), 3.77 (dd, J = 17, 9 Hz,
and 13C) or CFCl3 19F) as internal references. Coupling constants
(
are given in Hertz. The following abbreviations have been used to
describe NMR spectra: ‘‘s’’ singlet, ‘‘bs’’ broad singlet, ‘‘d’’ doublet,
‘‘bd’’ broad doublet, ‘‘t’’ triplet, ‘‘q’’ quadruplet, and ‘‘m’’ multiplet.
Flash chromatography was performed on silica gel 60 M (40–
60 (m). Melting points (uncorrected) were determined in capillary
tubes on a Bu¨chi apparatus.
H
N
O
CF3
Cu(OTf)2 (0.1 eq.)
CH2Cl2 / r.t.
O
+
Ph
CF3
Ph
N
H
3aA
32 %
Scheme 7. Addition of 3aA upon unprotected indole.
Cl
F3C
CF3
CF2
CF2
O
O
O
H
O
O
O
Ph
Ph
N
OH Ph
*
O
OH
O
CO2H (0.1 eq.)
Ph
Ph
Ph
O
N
H
+
Ph
5aA (50 °C, 60 %)
5bA (50 °C, 75 %)
5cA (50 °C, 65 %)
r.t.
O
O
O
Cl
F3C
Warfarin
Me
N
Me
N
Me
N
CF2
CF2
CF3
O
O
Ph
O
Ph
Scheme 8. Enantioselective synthesis of Warfarin (CoumalinTM).
Ph
6aA (r.t., 84 %)
6bA (r.t., 87 %)
6cA (r.t., 81 %)
OH Rf
O
OH
O
O
Cl
F3C
DBU (1 eq.)
CH2Cl2 / r.t.
Ar
+
CF3
O
CF2
O
CF2
O
Ar
Rf
O
O
O
3
8
Ph
Ph
Ph
N
N
N
Rf = CF3, CF2Cl, CF2CF3
Ar = Ph, 2-furyl
Bn
7aA (r.t., 85 %)
Bn
7bA (r.t., 87 %)
Bn
7cA (r.t., 91 %)
Scheme 9. Condensation of enones 3 with 4-hydroxycoumarin.
Fig. 1. Addition of benzofuran, N-methylpyrrole and N-benzylindole onto 3aA–3cA.

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J. Leuger et al. / Journal of Fluorine Chemistry 132 (2011) 799–803
F3C
Cl
CF2
O
OH CF3
O
OH
O
OH CF2
O
Ph
Ph
Ph
O
O
O
O
O
8aA (83 %)
8bA (35 %)
8cA (93 %)
F3C
Cl
CF2
OH CF2
O
OH CF3
O
OH
O
O
O
O
O
O
O
O
O
O
8aB (74 %)
8bB (89 %)
8cB (71 %)
Fig. 2. Condensation of 4-hydroxycoumarin with various fluorinated enones 3.
1H), 3.46 (dd, J = 17, 4 Hz, 1H). 13C NMR:
d
194.9, 147.4, 142.4,
J = 10, 10, 3 Hz, 1H), 3.84 (dd, J = 18, 10 Hz, 1H), 3.51 (dd, J = 18,
3 Hz, 1H). 13C NMR:
195.2, 155.3, 151.4 (t, J = 3 Hz), 136.5, 134.2,
1
136.1, 133.5, 128.7, 128.0, 125.9 (q, JC–F = 278 Hz), 110.5, 109.3,
d
2
39.0 (q, JC–F = 29 Hz), 35.9. 19F NMR:
d
À70.8 (d, J = 9 Hz).
129.8 (t, J = 296 Hz), 129.2, 128.6, 128.4, 125.0, 123.5, 121.6, 111.8,
107.5, 46.5 (t, J = 25 Hz), 37.5. 19F NMR:
3 Hz), À54.89 (ddd, J = 163, 10, 3 Hz).
d
À54.18 (ddd, J = 163, 10,
3.3. 4-Chloro-4,4-difluoro-3-(2-furyl)-1-phenylbutan-1-one (4bA)
Colorless oil. Yield: 67%. 1H NMR:
d
8.00 (m 2H), 7.62 (m, 1H),
3.8. 4,4,5,5-Pentafluoro-3-(2-benzofuryl)-1-phenylpentan-1-one
7.51 (m, 2H), 7.39 (dd, J = 2, 1 Hz, 1H), 6.38 (m, 2H), 4.58 (tdd, J = 10,
10, 3 Hz, 1H), 3.88 (dd, J = 18, 10 Hz, 1H), 3.58 (dd, J = 18, 3 Hz, 1H).
(5cA)
13C NMR:
d
195.5, 148.56 (dd, J = 4, 3 Hz), 143.1, 136.6, 134.1, 129.9
White solid. Mp: 46–63 8C. Yield: 65%. 1H NMR:
d 7.82 (m, 2H),
(t, J = 295 Hz), 129.2, 128.5, 111.1, 110.3, 45.8 (t, J = 25 Hz), 37.5 (t,
7.40 (m, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 6.64 (s, 1H), 4.53 (dddd,
J = 1.7 Hz). 19F NMR:
J = 162.0, 10 Hz, 1F).
d
À54.7 (dd, J = 162, 10 Hz, 1F), À55.48 (dd,
J = 21, 10, 10, 3 Hz, 1H), 3.80 (dd, J = 18, 10 Hz, 1H), 3.51 (dd, J = 18,
3 Hz, 1H). 13C NMR:
d 195.1, 155.5, 150.34 (d, J = 7, 2 Hz), 136.4,
134.2, 129.2, 128.6, 128.3, 125.1, 123. 5, 121.6, 119.5 (qt, J = 286,
36 Hz), 114.0 (tq, J = 259, 37 Hz), 111.8, 107.6, 37.8 (dd, J = 24,
3.4. 4,4,5,5-Pentafluoro-3-(2-furyl)-1-phenylpentan-1-one (4cA)
21 Hz), 35.8. 19F NMR:
d
À82.6 (s, 3F), À115.1 (dd, J = 270, 10 Hz,
White solid. Mp: 87–89 8C. Yield: 76%. 1H NMR:
7.49 (m, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.23 (m, 2H), 4.38 (m, 1H),
3.71 (dd, J = 18, 10 Hz, 1H), 3.44 (dd, J = 18, 4 Hz, 1H). 13C NMR:
d
7.87 (m, 2H),
1F), À119.3 (dd, J = 270, 21 Hz, 1F).
d
3.9. 4,4,4-Trifluoro-3-(N-methyl-2-pyrrolyl)-1-phenylbutan-1-one
195.4, 147.4 (dd, J = 7, 2 Hz), 143.3, 136.5, 134.1, 129.2, 128.5,
119.4 (qt, J = 285, 36 Hz), 113.95 (tq, J = 257, 36 Hz), 111, 110.4,
(6aA)
37.25 (dd, J = 24, 21 Hz), 35.8. 19F NMR:
d
À82.8 (s, 3F), À115.4 (dd,
Yield: 84%. 1H NMR:
d 7.97 (m, 2H), 7.62 (m, 1H), 7.49 (m, 2H),
6.62 (m, 1H), 6.16 (m, 1H), 6.09 (m, 1H), 4.36 (qdd, J = 9, 10, 3 Hz,
1H), 3.78 (dd, J = 18, 10 Hz, 4H), 3.55 (dd, J = 18, 3 Hz, 1H). 13C NMR:
J = 269, 10 Hz, 1F), À120.3 (dd, J = 269, 21 Hz, 1F).
3.5. 2,5-bis-[2-(1,1,1-Trifluoro-4-oxo-4-phenylbutyl)]furan (mixture
of diastereomers)
d
196.0, 136.7, 134.0, 129.1, 128.5, 127.0 (q, J = 279 Hz), 126.4 (q,
J = 2 Hz), 123.4, 107.9, 107.5, 39.3 (q, J = 2 Hz), 36.6 (q, J = 29 Hz),
34.4. 19F NMR:
À71.1 (d, J = 9 Hz).
d
Orange oil. 1H NMR:
d 7.88 (m, 4H), 7.57 (m, 2H), 7.45 (m, 4H),
6.30 (bs, 2H), 4.36 (qdd, 2H, J = 9, 9, 4 Hz), 3.70 (dd, 1H, J = 9, 18 Hz),
3.72 (dd, 1H, J = 9, 18 Hz), 3.39 (dd, 1H, J = 4, 18 Hz), 3.36 (dd, 1H,
3.10. 4-Chloro-4,4-difluoro-3-(N-methyl-2-pyrrolyl)-1-
phenylbutan-1-one (6bA)
J = 4, 18 Hz). 13C NMR:
d
194.5, 147.4, 135.8, 133.2, 128.4, 127.7,
125.2 (q, J = 280 Hz, CF3), 110.1, 38.8 (q, J = 29 Hz), 38.8 (q, J = 31 Hz),
35.5, 35.3. 19F NMR:
À70.68 (d, J = 9 Hz), À70.72 (d, J = 9 Hz).
Yellow solid. Mp: 59–63 8C. Yield: 87%. 1H NMR:
d 7.82 (m, 2H),
7.45 (m, 1H), 7.33 (m, 2H), 6.47 (m, 1H), 6.04 (m, 1H), 5.95 (m, 1H),
d
4.33 (dddd, J = 11, 12, 10, 3 Hz, 1H), 3.69 (dd, J = 18, 10 Hz, 1H), 3.66
3.6. 4,4,4-Trifluoro-3-(2-benzofuryl)-1-phenylbutan-1-one (5aA)
(s, 3H), 3.47 (dd, J = 18, 3 Hz, 1H). 13C NMR:
d
196.1, 136.7, 134.0,
131.1 (t, J = 295 Hz), 129.2, 128.5, 127.2 (t, J = 2 Hz), 123.4, 108.2,
107.5, 43.22 (t, J = 25 Hz), 40.6, 34.5. 19F NMR:
Yield: 60%. 1H NMR:
6.83 (s, 1H), 4.65 (qdd, J = 9, 10, 4 Hz, 1H), 3.97 (dd, J = 18, 10 Hz,
1H), 3.63 (dd, J = 18, 4 Hz, 1H). 13C NMR:
195.1, 155.3, 150.8 (q,
d
8.02 (m, 2H), 7.59 (m, 5H), 7.28 (m, 2H),
d
À55.1 (ddd,
J = 161, 11, 2 Hz, 1F), À55.9 (ddd, J = 161, 12, 3 Hz, 1F).
d
J = 2 Hz), 136.4, 134.2, 129.2, 128.6, 128.4, 126.2 (q, J = 280 Hz),
125.0, 123.4, 121.6, 111.8, 107.1, 40.0 (q, J = 29 Hz), 36.4 (q,
3.11. 4,4,5,5-Pentafluoro-3-(N-methyl-2-pyrrolyl)-1-phenylpentan-
1-one (6cA)
J = 1 Hz). 19F NMR:
d
À69.9 (d, J = 9 Hz).
White solid. Mp: 87–89 8C. Yield: 81 1H NMR:
d 7.81 (m, 2H),
3.7. 4-Chloro-4,4-difluoro-3-(2-benzofuryl)-1-phenylbutan-1-one
7.45 (m, 1H), 7.34 (m, 2H), 6.45 (m, 1H), 6.03 (m, 1H), 5.94 (m, 1H),
(5bA)
4.26 (m, 1H), 3.66 (dd, J = 18, 10 Hz, 1H), 3.65 (s, 3H), 3.45 (dd,
J = 18, 3 Hz, 1H). 13C NMR:
d
196.2, 136.7, 134.0, 129.1, 128.5, 125.9
(dd, J = 6, 1 Hz), 123.2, 119.7 (qt, J = 289, 38 Hz), 114.7 (tq, J = 260,
36 Hz), 108.6, 107.7, 39.2, 34.3 (dd, J = 23, 22 Hz), 34.2. 19F NMR:
White solid. Mp: 49–55 8C. Yield: 75%. 1H NMR:
7.41 (m, 2H), 7.31 (m, 3H), 7.09 (m, 2H), 6.66 (s, 1H), 4.57 (tdd,
d 7.83 (m, 2H),
d

J. Leuger et al. / Journal of Fluorine Chemistry 132 (2011) 799–803
803
À82.5 (s, 3F), À116.2 (dd, J = 268, 12 Hz), À120.1 (dd, J = 268,
131.60 (t, J = 297 Hz), 129.1, 128.3, 124.4, 124.2 (bs), 116.7, 115.9,
99.0 (bs), 42.5 (bs), 35.8 (bs). 19F NMR (DMSO d6):
À51.8 (bs).
20 Hz).
d
3.12. 4,4,4-Trifluoro-3-(N-benzyl-3-indolyl)-1-phenylbutan-1-one
3.18. 3-[3-(1,1,1,2,2-Pentafluoro-5-oxo-5-phenylpentyl)]-4-
(7aA)
hydroxycoumarin (8cA)
Yield: 85%. 1H NMR:
7.48 (m, 2H), 7.28 (m, 7H), 7.10 (m, 2H), 5.29 (s, 2H), 4.71 (m, 1H),
3.76 (m, 2H). 13C NMR:
196.3, 137.5, 137.00, 136.96, 133.9, 129.2,
d
7.97 (m, 2H), 7.85 (m, 1H), 7.60 (m, 1H),
Yellow solid. Mp: 83–90 8C. Yield: 93%. 1H NMR:
7.94 (m, 1H), 7.84 (m, 2H), 7.44 (m, 4H), 7.17 (m, 2H), 4.51 (bm, 1H),
4.33 (dt, J = 19, 10 Hz, 1H), 3.52 (dd, J = 19, 2 Hz, 1H). 13C NMR:
d 9.40 (bs, 1H),
d
d
129.1, 128.5, 128.1, 128.0, 127.9 (q, J = 280 Hz), 127.8, 127.1, 122.7,
120.4, 120.0, 110.5, 109.3 (q, J = 2 Hz), 50.5, 38.9, 37.3 (q, J = 29 Hz).
199.9, 164.8, 162.8, 153.4, 135.8, 134.9, 133.3, 129.3, 129.0, 124.6,
124.5, 119.74 (qt, J = 277, 32 Hz), 117.0, 116.1, 115.6 (tq, J = 264,
19F NMR:
d
À70.4 (d, J = 10 Hz).
37 Hz), 99.9, 36.0, 33.8 (dd, J = 24, 22 Hz). 19F NMR:
À111.3 (dd, J = 268, 16 Hz, 1F), À116.5 (dd, J = 268, 16 Hz, 1F).
d
À83.9 (s, 3F),
3.13. 4-Chloro-4,4-difluoro-3-(N-benzyl-3-indolyl)-1-phenylbutan-
1-one (7bA)
3.19. 3-{2-[1,1,1-Trifluoro-4-oxo-4-(2-furyl)butyl]}-4-
hydroxycoumarin (8aB)
White solid. Mp: 127–129 8C. Yield: 87%. 1H NMR:
2H), 7.69 (m, 1H), 7.43 (m, 1H), 7.30 (m, 2H), 7.09 (m, 7H), 6.89 (m,
2H), 5.13 (s, 2H), 4.67 (dddd, J = 12, 11 8, 5 Hz, 1H), 3.65 (m, 2H). 13
NMR: 196.3, 137. 6, 137.0, 136.9, 133.8, 132.0 (t, J = 304 Hz),
129.2, 129.1, 128.5, 128.2, 128.12, 128.06, 127.0, 122.7, 120.5,
120.1, 110.4, 110.3 (t, J = 3 Hz), 50.5, 44.0 (t, J = 24 Hz), 39.9. 19F
d 7.80 (m,
Pale yellow solid. Mp: 145–146 8C. Yield: 74%. 1H NMR (DMSO
C
d6):
d
12.10 (bs, 1H), 8.07 (m, 1H), 7.97 (m, 1H), 7.60 (m, 1H), 7.46
(m, 1H), 7.33 (m, 2H), 6.69 (m, 1H), 4.79 (bs, 1H), 4.13 (dd, J = 17,
9 Hz, 1H), 3.56 (bd, J = 17 Hz, 1H). 13C NMR (DMSO d6):
185.2,
d
d
164.5 (bs), 161.5 (bs), 152.6, 151.7, 148.3, 133.2, 127.59 (q,
NMR:
d
À54.3 (dd, J = 160, 11 Hz), À55.08 (dd, J = 160, 12 Hz).
J = 281 Hz), 124.3, 124.1, 118.9, 116.7, 115.8, 112.9, 98.2 (bs), 35.35
(bs), 34.66 (bs). 19F NMR (DMSO d6):
d
À67.83 (d, J = 10 Hz).
3.14. 4,4,5,5-Pentafluoro-3-(N-benzyl-3-indolyl)-1-phenylpentan-1-
one (7cA)
3.20. 3-{2-[1-Chloro-1,1-difluoro-4-oxo-4-(2-furyl)butyl]}-4-
hydroxycoumarin (8bB)
White solid. Mp: 105–113 8C. Yield: 91%. 1H NMR:
2H), 7.78 (m, 1H), 7.59 (m, 1H), 7.45 (m, 2H), 7.25 (m, 7H), 7.01 (m,
2H), 5.31 (m, 2H), 4.74 (m, 1H), 3.78 (m, 2H). 19F NMR:
d 7.94 (m,
Yellow solid. Mp: 141–142 8C. Yield: 89%. 1H NMR (DMSO d6):
11.84 (bs, 1H), 8.03 (m, 2H), 7.63 (m, 1H), 7.44 (m, 1H), 7.36 (m,
2H), 6.70 (m, 1H), 4.89 (bs, 1H), 4.19 (bs, 1H), 3.43 (bs, 1H). 13C
NMR (DMSO d6):
d 185.2, 165.0 (bs), 161.0 (bs), 152.8 (bs), 151.8,
d
d
À81.85 (s,
3F), À114.28 (dd, J = 266, 10 Hz, 1F), À120.04 (dd, J = 266, 25 Hz,
1F).
148.3, 133.2, 131.4 (t, J = 297 Hz), 124.3, 124.2 (bs), 119.0, 116.7,
3.15. General procedure for the base-catalyzed addition of 4-
115.9, 113.0, 98.9 (bs), 41.8 (bs), 35.4 (bs). 19F NMR (DMSO d6):
d
hydroxycoumarin onto
b
-fluoroalkylated enones 3
À52.0 (bs).
A solution of 3 (1.0 mmol, 1.0 equiv.) in dry CH2Cl2 (0.5 mL) was
added to a suspension of 4-hydroxycoumarin (162 mg, 1.0 mmol,
1.0 equiv.) in dry CH2Cl2 (0.5 mL). Then, DBU (0.15 mL, 1.0 mmol,
1.0 equiv.) was added. The resulting solution was stirred at room
temperature until no (or only traces) starting material was
detected by 19F NMR (16–20 h). The reaction mixture was diluted
with CH2Cl2 and treated with a 2 N aqueous solution of HCl. After
decantation, the aqueous phase was extracted with CH2Cl2, the
combined organic phases were washed twice with a 2 N aqueous
solution of HCl, dried over Na2SO4 and evaporated under vacuum.
The crude residue was purified by recrystallisation from CH2Cl2/
acetone/pentane to afford pure adduct 8.
3.21. 3-{3-[1,1,1,2,2-Pentafluoro-5-oxo-5-(2-furyl)pentyl]}-4-
hydroxycoumarin (8cB)
Yellow solid. Mp: 60–65 8C. Yield: 71%. 1H NMR (DMSO d6):
12.1 (bs, 1H), 8.1 (m, 1H), 7.74 (m, 1H), 7.52 (m, 1H), 7.25 (m, 4H),
d
6.56 (m, 1H), 4.85 (m, 1H), 4.12 (dd, J = 18, 9 Hz, 1H), 3.32 (dd,
J = 18, 4 Hz, 1H). 13C NMR (DMSO d6):
d 185.0, 164.5, 161.3, 152.9,
151.8, 147.5, 132.7, 124.2, 123.9, 119.3 (qt, J = 288, 39 Hz), 118.36,
117.1 (tq, J = 240, 38 Hz), 116.5, 115.5, 112.6, 98.0 (bs), 34.0 (bs),
32,6 (t, J = 23 Hz). 19F NMR (DMSO d6):
(dd, J = 267, 14 Hz, 1F), À116.73 (dd, J = 267, 19 Hz, 1F).
d
À82.94 (s, 3F), À112.76
References
3.16. 3-[2-(1,1,1-Trifluoro-4-oxo-4-phenylbutyl)]-4-
hydroxycoumarin (8aA)
[1] T. Billard, S. Bruns, B.R. Langlois, Opt. Lett. 2 (2000) 2101–2103.
[2] T. Billard, B.R. Langlois, G. Blond, Tetrahedron Lett. 41 (2000) 8777–8780.
[3] T. Billard, B.R. Langlois, G. Blond, Eur. J. Org. Chem. (2001) 1467–1471.
[4] G. Blond, T. Billard, B.R. Langlois, Tetrahedron Lett. 42 (2001) 2473–2475.
[5] G. Blond, T. Billard, B.R. Langlois, J. Org. Chem. 66 (2001) 4826–4830.
[6] T. Billard, B.R. Langlois, J. Org. Chem. 67 (2002) 997–1000.
[7] T. Billard, S. Gille, A. Ferry, A. Barthe´le´my, C. Christophe, B.R. Langlois, J. Fluorine
Chem. 126 (2005) 189–196.
[8] J. Leuger, G. Blond, R. Fro¨hlich, T. Billard, G. Haufe, B.R. Langlois, J. Org. Chem. 71
(2006) 2735–2739.
[9] C. Christophe, T. Billard, B.R. Langlois, Eur. J. Org. Chem. (2005) 3745–3748.
[10] O. Marrec, C. Christophe, T. Billard, B. Langlois, J.P. Vors, S. Pazenok, Adv. Synth.
Catal. 352 (2010) 2825–2830.
[11] K.B. Jensen, J. Thorhauge, R.G. Hazell, K.A. Jorgensen, Angew. Chem. Int. Ed. 40
(2001) 160–163.
[12] S.C. Sweetman (Ed.), Martindale, the Complete Drug Reference, 36th ed., Phar-
maceutical Press, London, 2009, p. 1425.
[13] N. Halland, T. Hansen, K.A. Jorgensen, Angew. Chem. Int. Ed. 42 (2003) 4955–
4957.
[14] T. Billard, Chem. Eur. J. 12 (2006) 974–979 (Concept article).
Yield: 83%. 1H NMR (DMSO d6):
7.97 (m, 2H), 7.64 (m, 2H), 7.52 (m, 2H), 7.38 (m, 2H), 4.81 (bs, 1H),
4.38 (dd, J = 18, 9 Hz, 1H), 3.66 (bd, J = 18, 1H). 13C NMR (DMSO d6):
d 12.11 (bs, 1H), 8.06 (m, 1H),
d
196.8, 164.6 (bs), 161.2 (bs), 152.8, 136.4, 133.8, 133.2, 129.1,
128.3, 127.8 (d, J = 278 Hz), 124.4, 124.09, 116.7, 116.0, 98.3 (bs),
35.8 (bs), 35.0 (bs). 19F NMR (DMSO d6):
À67.7 (d, J = 10 Hz).
d
3.17. 3-[2-(1-Chloro-1,1-difluoro-4-oxo-4-phenylbutyl)]-4-
hydroxycoumarin (8bA)
Yellow solid. Mp: 123–127 8C. Yield: 35%. 1H NMR (DMSO d6):
d
12.12 (bs, 1H), 8.09 (m, 1H), 7.96 (m, 2H), 7.64 (m, 2H), 7.52 (m, 2H),
7.35 (m, 2H), 4.94 (bs, 1H), 4.46 (bs, 1H), 3.68 (bs, 1H). 13C NMR
(DMSO d6):
d
196.8, 165.1 (bs), 161.2 (bs), 152.8, 136.5, 133.8, 133.2,