Indium-mediated reduction of β-aminovinyl chloro-difluoromethylated ketones in the presence of heteroaryl aldehydes. A mild entry to novel difluoromethylene enaminone derivatives

Article abstract of DOI:10.1016/j.jfluchem.2007.06.001

The synthesis of new β-aminovinyl chloro-difluoromethylated ketones 1 and 2 is presented. In some of them the activation of the C-Cl bond was achieved, under mild conditions, using indium powder. The corresponding difluoro-enolates were trapped with a ser

Full text of DOI:10.1016/j.jfluchem.2007.06.001

Journal of Fluorine Chemistry 128 (2007) 1286–1299
www.elsevier.com/locate/fluor
Indium-mediated reduction of b-aminovinyl chloro-difluoromethylated
ketones in the presence of heteroaryl aldehydes
A mild entry to novel difluoromethylene enaminone derivatives
a
a,
a
*
´
Fabrice Fenain , Maurice Medebielle , Mathias Rocher ,
Osamu Onomura a,b, Etsuji Okada c, Dai Shibata d
a
´ ´ ´
Universite Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS),
ˆ
Equipe SERCOF, UMR 5246 CNRS-UCBL-INSA-CPE, Batiment Chevreul, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b Nagasaki University, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki City, Japan
c Department of Chemical Science and Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
d Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Received 30 April 2007; received in revised form 30 May 2007; accepted 3 June 2007
Available online 7 June 2007
Dedicated to Professor Kenji Uneyama with friendship and deepest recognition on the occasion of his receipt of the 2007 ACS Award for
Creative Work in Fluorine Chemistry.
Abstract
The synthesis of new b-aminovinyl chloro-difluoromethylated ketones 1 and 2 is presented. In some of them the activation of the C–Cl bond
was achieved, under mild conditions, using indium powder. The corresponding difluoro-enolates were trapped with a series of aromatic and
heterocyclic aldehydes, to furnish the corresponding difluoromethylene aldol products 3 and 4, in moderate to good yields. The present synthetic
methodology provides a convenient approach for the preparation of novel difluoromethylene functionalized enaminone derivatives.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Indium; Enaminones; Nucleophilic addition; Electron transfer
1. Introduction
difluoromethylene derivatives [3]. Trifluoromethylated b-
aminovinyl ketones are known and have been frequently used
as valuable building blocks, to prepare various trifluoromethy-
lated aromatics and heterocycles [4]. Some chloro-difluor-
omethylated analogs were also prepared in these studies, but the
synthetic potential that could be derived from the chemose-
lective activation of the C–Cl bond, has been rarely investigated
[5]. As part of a research program directed to the synthesis
of novel fluorinated heterocycles with potential biological
applications, we presented the indium activation of some
aromatic chloro-difluoromethylated enaminones in the pre-
sence of a series of heteroaryl aldehydes [6]. Indium closely
resembles zinc in several aspects and its first ionization
potential (5.8 eV) is the lowest relative to other metal elements
near in the periodic table [7]. Its synthetic use in organo-
fluorine chemistry is recent [8] and most of the work reported in
the literature is related to allylation reactions of fluorinated
compounds or indium-mediated cross-coupling reactions of a
Difluoromethylene derivatives are an important class of
compounds because of their synthetic and biological impor-
tance [1]. One of the most common ways to prepare complex
molecules bearing a CF2 moiety is based on the ‘‘building
block’’ approach, i.e., starting from a difluoromethylene-
containing starting material [2]. For some years we have been
interested to develop new synthetic approaches to prepare
fluorinated organic molecules, especially those having a CF2
moiety. Among the recent studies developed in our laboratories,
we have shown that a series of halogeno-difluoromethyl
aromatics and heterocycles could be successfully engaged in
anionic and radical coupling reactions giving access to novel
* Corresponding author. Tel.: +33 4 72 43 19 89; fax: +33 4 72 43 13 23.
´
E-mail address: medebiel@univ-lyon1.fr (M. Medebielle).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.06.001

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1287
Scheme 1.
Scheme 2.
gem-difluoropropargyl starting material that generate a stable
difluoroallenyl indium species.
The aromatic substrates 1d,e [6] and 1f [9] were also obtained
in very good yields under refluxing conditions for 1 h (TLC
monitoring). The substrate 1g was obtained in a modest 50%
isolated yield after silica gel chromatography by means of using
p-toluenesulfonamide (1.1 equiv.) in the presence of NaH
(1.1 equiv.) in anhydrous DMF (ꢀ30 8C to room temperature
over 3 h). Substrate 1h was prepared by adding tryptamine to
crude 1-chloro-4,4-diethoxy-1,1-difluorobuten-3-en-2-one [10]
and was obtained in a 30% isolated yield (not optimized,
Scheme 3). The free NH substrates 1a–g were obtained as Z
This paper is an extension of our previous report [6], that
describes indium as a potential synthetic electron transfer
reagent, to promote C–C coupling reactions with some new b-
aminovinyl chloro-difluoromethylated ketones and a series of
heteroaryl aldehydes (Scheme 1). The coupling adducts are
envisaged as potential building blocks to prepare new
fluorinated aromatics and heterocycles.
1
2. Results and discussion
isomers (and E isomer for 1h), as determined by H NMR
(small coupling constant of the olefinic protons of 6–8 Hz and a
deshielded peak of the amino proton dH > 10.0 ppm) due to
hydrogen bonding between NH and C O. Compounds 1a–b
were obtained as yellowish liquids and are pure enough to be
used for the next steps, whereas 1c (yellowish liquid) was
purified by silica gel chromatography. 1d–g were obtained as
solids and were recrystallized from the crude product.
Tryptamine derivative 1h precipitated during the reaction
and was recovered as a white solid after a simple filtration.
Starting materials of general structure 2a–c were obtained
by adding secondary amines R1R2NH to the crude (E)-1-
chloro-4-ethoxy-1,1-difluoro-but-3-en-2-one in anhydrous
acetonitrile using the same conditions for the synthesis of 1
(Scheme 4). N-Allylbenzylamine was prepared as described in
Starting materials of the general structure 1 were prepared in
good yields in two steps: chloro-difluoroacetylation of
commercially available ethyl vinyl ether [chloro-difluoroacetic
anhydride (CDFAA)/pyridine in anhydrous dichloromethane],
followed by O–N exchange reaction of the resulting crude (E)-
1-chloro-4-ethoxy-1,1-difluoro-but-3-en-2-one, with the corre-
sponding amines (slight excess) in anhydrous acetonitrile
(Scheme 2). The allylic, propargylic and benzylic substrates
1a–c were obtained in moderate to good yields (60–95%)
through the dropwise addition of the amines to a cooled (0 8C)
anhydrous acetonitrile solution containing the crude (E)-1-
chloro-4-ethoxy-1,1-difluoro-but-3-en-2-one, followed by war-
ming the reaction mixture to room temperature for one hour.
Scheme 3.

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F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
Scheme 6.
As indium might be considered as a possible reductant, we
therefore examined the possibility to activate the C–Cl bond of
some of these enaminones, using indium in anhydrous THF
containing water [6]. The coupling reaction with a series of
aromatic and heterocyclic aldehydes was then achieved at room
temperature in THF/H2O (1/4) [6] and the results are presented
in Table 1. This combination of solvents was found to be the
best medium for these indium-mediated reactions, usually at
room temperature. Running the reactions at an elevated
temperature (80 8C) did shorten the reaction time but did
increase as well the yield of the reduction product 5. In addition
several new fluorinated impurities were detected by 19F NMR.
Replacing THF/H2O by EtOH/H2O gave similar results, at least
at room temperature. The reaction was best monitored by 19F
NMR (and TLC when possible) until all the starting material
was consumed or when the crude NMR spectrum remained
unchanged for a couple of hours.
Scheme 4.
[11], but the other secondary amines (N,N-diallylamine and N-
methylallylamine) were commercially available.
Protection of the free NH of substrates 1 was achieved with
Boc2O and tosyl chloride (TsCl) in moderate to excellent yields
(Scheme 5). The introduction of the Boc moiety into 1a, was
achieved with Boc2O and pyridine as the base and solvent, to
furnish the corresponding enaminone 2d in a 95% isolated
yield. The reaction conditions (Boc2O/NaHCO3/Toluene/D)
used to make derivatives 2g,h [6] did not give satisfactory
yields with 1a. Enaminone derivatives with a tosyl protecting
group 2e,f were obtained in moderate yields using anhydrous
potassium carbonate and tosyl chloride in toluene at 70 8C. A
minor impurity was often observed during these tosylation
reactions, identified as the bis-enaminone derivatives 2i and 2j
(Scheme 6).
Substrate 1a was chosen as a model and was engaged in
coupling reactions with three aromatic aldehydes: benzalde-
hyde, 2-bromo benzaldehyde and p-trifluoromethyl benzalde-
hyde. With benzaldehyde and an excess of indium (2.3 equiv.,
entry 1) the alcohol adduct 3aa was obtained in a 40% isolated
yield (60% by 19F NMR), after three hours of vigorous stirring.
Ratio of alcohol/reduction product was close to 2:1; we found
that 1.0 equiv. of indium gave a similar yield of 3aa, although
after a longer reaction time period (24 h) and a similar quantity
of reduction product 5. Other aldehydes gave similar yields of
adducts 3ab (entry 2) and 3ac (entry 3) with good conversions
(80–100%). Surprisingly the coupling reaction with p-
trifluoromethyl benzaldedhyde (entry 3) worked relatively
well with no appreciable formation of the pinacol, in contrast to
the coupling reactions of 1d or 1e with the same aldehyde,
where the pinacol was the only product [6].
It is worth to mention that, while attempting to improve the
yield of 2f using NaH and TsCl in anhydrous DMF, the
enaminone derivative 2j was obtained as the major product in a
48% isolated yield, along desired 2f in 19% isolated yield
(Scheme 7). Probably, part of the anion generated by the
deprotonation of the free NH with NaH gave rise a Michael
addition with 2f giving, after an N-N exchange reaction,
1
product 2j as a E,E isomer, as determined by H NMR.
Examination by cyclic voltammetry of the reduction
potential of substrates 1 and 2 showed that these compounds
were reduced at potentials between ꢀ1.25 and ꢀ1.95 V versus
SCE (first peak potentials measured in DMF/NBu4PF6 0.1 M);
the free NH enaminones 1a–c and 2a–c are the most difficult to
reduce, while the enaminones 1d–g (and 2g,h) were the easiest
compounds to be reduced in the series. These data indicate that
these enaminones might be good candidates for useful single
coupling reactions using suitable electron transfer reagents.
The coupling reaction of propargylic substrate 1b with
benzaldehyde (entry 4) gave a complex mixture as judged by
19F NMR analysis of the crude reaction, despite the starting
material being apparently consumed; no desired alcohol 3ba
Scheme 5.

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1289
Table 1
Indium coupling reactions of b-aminovinyl chloro-difluoromethylated ketones 1–2 with heteroaryl aldehydesa
Entry
1
1 or 2
Aldehyde
In (equiv.)
Time (h)
Conversion
Ratio (3 or 4):5
Yieldb
1a
2.3
1.0
3
100
97
2:1
2:1
3aa; 40 (60)
3aa; 45 (45)
24
2
3
1a
1a
1.0
1.0
24
48
80
90
1:1
3ab;50(60)
3ac; 60
15:1
4
5
6
1b
1d
1e
1.0
1.5
1.0
18
17
36
c
nd
3bac
100
9:1
8:1
3db; 90
3eb; 78
98
7
8
1e
1e
1.3
1.0
48
24
95
30
5:3
5:2
3ed;34
3ee;(11)
9
1f
1.2
2.0
24
27
95
2.5:1
50:1
3fa; 59
10
1g
100
3ga; (36)d

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F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
Table 1 (Continued )
Entry
11
1 or 2
Aldehyde
In (equiv.)
3.0
Time (h)
430
Conversion
50
Ratio (3 or 4):5
Yieldb
1h
3:2
3ha; (14)
12
13
14
15
16
17
18
19
2a
2b
2c
2d
2d
2e
2e
2e
1.0
1.2
1.0
1.0
1.0
2.3
1.0
1.0
4
100
100
100
100
92
3:2
3:2
2: 1
1:0
1:0
1:0
1:0
30:1
4aa; 30
4ba; 56
4ca; 55
4da; 60
4db; 53
4ea; 70
4eb;(74)
4ec; 30
15
4
18
48
24
24
48
100
100
100
20
21
2e
2e
1.0
1.0
24
48
75
15:1
50:1
4ed; 24 (82)
4ee; 41
100
a
Substrate 1 or 2 (1 mmol) was first dissolved in freshly distilled THF (1 mL) followed by the addition of the aldehyde (1–2 mmol). The mixture was stirred gently
and then H2O (4 mL) was added dropwise. Indium was finally added at once and the whole mixture was vigorously stirred and monitored by 19F NMR (and TLC) for
the indicated time. Mixture was then filtrated over Celite1 and the filter cake washed with EtOAc and H2O. Extraction and purification by recrystallization or silica
gel chromatography gave the desired alcohol adduct.
b
Isolated yields (in parentheses, 19F NMR yield).
c
Complex reaction mixture.
d
Alcohol adduct was unstable during silica gel chromatography purification.

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1291
Scheme 8.
coupling products of the general structure 3 and 4 usually show
a relatively large DJF–H for the two geminal fluorines which
indicates an intramolecular hydrogen bonding between the
C O and the OH [12]. For compounds 3 they may adopt a
‘‘pincer’’ type structure owing to the two hydrogen bonds
(NHꢂ ꢂ ꢂO C, OHꢂ ꢂ ꢂO C). Therefore adducts 3 and 4 may be
possibly drawn as in Scheme 8.
Some of the isolated yields reported in Table 1 are
sometimes modest, and this is mainly due to difficulties to
remove efficiently some gel formation obtained during the
work-up procedure. Usually the 19F NMR yields (when
available) before the work-up, are relatively good. Also for
some of the reactions presented in this paper (entries 1, 8, 10
and 11), we did observe that the balance material was not good.
Optimization of the reaction conditions and of the work-up
procedure is actively pursued in our laboratory. For one alcohol
adduct (3fa), it was shown that this molecule may exist as a
mixture of Z and E isomers in DMSO, because of a favourable
solvent–solute hydrogen bonding. It may be a general trend for
all the enaminones 1, 2, 3 and 4 synthesized in this work.
Scheme 7.
could be isolated. Other free NH enaminones 1d (entry 5), 1e
(entries 6 and 7), 1f (entry 9) gave usually good yields of
alcohols, with good conversions with the exception of reaction
of 1e with 3,4-dimethoxyphenyl benzaldehyde (entry 8) and 1h
with benzaldehyde (entry 11). Alcohol adduct 3ga (entry 10),
resulting from the coupling reaction of 1g and benzaldehyde
needed 2 equiv. of indium but was too unstable to be isolated by
silica gel chromatography. In addition 19F NMR analysis of the
crude reaction mixture revealed that for some reactions (with
1a, 1g and 1h) a substantial loss of mass balance was observed.
The reaction between 1h and benzaldehyde was found to take
place very slowly, even with an excess of indium (3 equiv.) and
with a modest conversion; the tryptamine derived adduct 3ha
was obtained in only 14% (19F NMR yield). In general in the
free NH enaminone series, the substrates having an aryl moiety
(1d–f) gave usually better yields of the corresponding alcohol
adducts.
3. Conclusions
In this study we demonstrated that indium is an effective
reagent to promote the coupling reactions of a series of new b-
aminovinyl chloro-difluoromethyl ketones with a series of
aromatic and heterocyclic aldehydes. Although the mechanism
of this reaction still remains to be elucidated, indium species is
likely to act as an electron-transfer reagent generating a reactive
difluoro-enolate. What we already know is that the coupling
reactions using indium are greatly accelerated in the presence
of the aldehyde; for example mixing substrate 1a (as a model
substrate) and 2.2 equiv. of indium at room temperature for 24 h
gave little conversion to the corresponding reduction product 5,
while the same reaction with benzaldehyde was completed after
only 3 h. We propose that a six-membered Zimmerman–Traxler
transition state model might be involved in these coupling
reactions to give the desired alcohol after hydrolysis
(Scheme 9). InCl3 might be formed after the possible two-
electron reduction of the C–Cl bond that can eventually act also
as a Lewis acid activator of the aldehyde.
The coupling reactions with disubstituted enaminones 2
gave also moderate to good yields of adducts, with usually good
conversions and within a comparable reaction time period. For
substrate 2e 19F NMR analysis of the crude reaction mixture
indicated the presence of a new fluorinated product (ꢁ2–5%)
besides the formation of alcohol adducts (4ea, 4eb, 4ec, 4ed
and 4ee; entries 17–21) and reduction product 5. This impurity
was identified as the cross aldol product of type 6 by ESI-MS
[m/z = 1282.8 (2M + Na)+, 653.1 (M + Na)+, 630.9 (MH+)]; this
impurity was only observed with the substrate 2e.
A series of new compounds were prepared under mild
conditions and these new difluoromethylene enaminones are
currently utilized as useful building blocks to prepare libraries
of new functionalized cyclic and heterocyclic structures. We
made significant progress in this area and the results will be
presented in our forthcoming papers. Recently some new b-
aminovinyl chloro-difluoromethylated ketones were prepared
and will be soon engaged in these coupling reactions. Finally
All the coupling reactions gave as by-product the
corresponding reduced enaminone 5 which can be separated
by silica gel chromatography, with the exception of the
reactions using 2d benzaldehyde and 2-bromo benzalde-
hyde (entries 15 and 16) and reaction using 2e and benzalde-
hyde (entry 17), which gave no hydrogenolysis product. The

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F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
Scheme 9.
other electrophiles than heteroaryl aldehydes, especially
ketones, enones, a-keto esters, potentially useful to prepare
more complex structures, will be soon tested in our laboratory.
4.2. General procedure for the synthesis of 1a–b and 2a–c
4.2.1. (E)-1-Chloro-4-ethoxy-1,1-difluoro-but-3-en-2-one
4. Experimental
4.1. General comments
To a stirred solution of ethyl vinyl ether (3.8 mL, 40 mmol)
and pyridine (3.6 mL, 44 mmol) in anhydrous dichloromethane
(10 mL), was added dropwise an anhydrous dichloromethane
solution (20 mL) containing chloro-difluoroacetic anhydride (7
mL, 40 mmol) with cooling (ꢀ10 8C). When the addition was
finished (30 min), the reaction mixturewas slowly warmed-up to
room temperature and stirred at this temperature for 18 h. The
solution was quenched with H2O (20 mL) and extracted with
dichloromethane (2 mL ꢃ 20 mL). Thecombinedorganiclayers
were washed with an aqueous solution of 1N HCl (2 mL ꢃ
20 mL) and water (2 mL ꢃ 20 mL) and dried over MgSO4.
Evaporation of the solvent left a yellowish oil (7.02 g, 36 mmol,
90%) as crude product. 13C NMR (CDCl3): d 181.1 (t, J = 28.8,
C-2), 168.1 (C-4), 120.4 (t, J = 304.9, C-1), 96.7 (C-3), 69.0 (C-
5), 14.4 (C-6). 1H NMR (CDCl3): d 7.85 (1H, d, J = 12.2, H-4),
5.82 (1H, d, J = 12.2, H-3), 4.07 (2H, q, J = 7.0, H-5), 1.35 (3H, t,
J = 7.0, H-6). 19F NMR (CDCl3): d ꢀ67.78.
Solvents were distilled before use. Reagents were obtained
commercially and used without further purification except for
3,4-dimethoxybenzaldehyde which was recrystallized from
petroleum ether (bp 45–60 8C) and benzylamine which was
distilled. N-Allylbenzylamine was prepared as described in
[11]. Compounds 1d–e were already described in [6] and 1c and
1
1f were already described in [9]. H, 19F and 13C NMR were
recorded with a Bruker Avance 300 spectrometer (in CDCl3 or
DMSO-d6) at 300, 282 and 75 MHz, respectively. Chemical
shifts are given in ppm relative to residual peak of solvent
(dH = 7.26 ppm for CHCl3, dH = 2.50 ppm for Me2SO,
dC = 77.0 ppm for CDCl3 and dC = 39.52 ppm for Me2SO-d6)
or CFCl3 (19F). Coupling constants are given in Hertz. Silica gel
chromatography was performed on Macherey–Nagel Silica gel
60 M (0.04–0.063 mm). Solvents for chromatography and
work-up are: ethyl acetate (EA), diethyl ether (ether), and
petroleum ether (PE). Mass spectra were recorded using a
FINIGAN MAT 95 [EI, CI (CH4 or NH3) and ESI]. Melting
points (uncorrected) were determined in capillary tubes on a
Buchi apparatus.
To a stirred solution of (E)-1-chloro-4-ethoxy-1,1-difluoro-
but-3-en-2-one (1.81 g, 9.8 mmol) in anhydrous acetonitrile
(30 mL) was added dropwise the appropriate amine (10.8
mmol) at 0 8C. The solution solution turned red or pink and was

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1293
stirred at room temperature (1a–c, 2a–c) or heated at reflux for
4.2.5. (E)-4-(Allyl-methyl-amino)-1-chloro-1,1-difluoro-
but-3-en-2-one, 2b
1 h (1d–f). The solvent was removed under reduced pressure
and the residue was pure enough (1a–b, 2a, 2c) for the next
steps, purified by silica gel chromatography (1c, 2b) or
recrystallized (1d–f).
4.2.2. (Z)-4-Allylamino-1-chloro-1,1-difluoro-but-3-en-2-
one, 1a
Yield: 87%, silica gel chromatography (PE/EA, 4/1), orange
oil. 13C NMR (CDCl3): d 178.8 (t, J = 26.7, C-2), 156.5 and
156.2 (C-4), 131.3 and 128.6 (C-6), 121.6 (t, J = 305.6, C-1),
119.6 and 118.7 (C-7), 86.2 and 86.0 (C-3), 60.7 and 52.7 (C-5),
43.3 and 35.4 (C-8) 1H NMR (CDCl3): d 7.74 (1H, d, J = 12.4,
H-4), 5.60 (1H, m, H-6), 5.19–5.04 (3H, m, H-3, H-7a and H-
7b), 3.82 (2H, d, J = 5.8, H-5), 2.77 (3H, s, H-8). 19F NMR
(CDCl3): d ꢀ65.46.
Yield: 99%, red-orange oil. 13C NMR (CDCl3): d 179.6 (t,
J = 27.4, C-2), 158.2 (C-4), 132.8 (C-6), 121.2 (t, J = 303.8, C-
1), 117.9(C-7),85.7(C-3), 51.4(C-5). 1H NMR(CDCl3):d10.08
(1H, br s, NH), 7.11 (1H, dd, J = 13.6, 7.2, H-4), 5.87–5.73 (1H,
m, H-6), 5.37 (1H, d, J = 7.2, H-3), 5.28 (1H, br d, J = 6.2, H-7a),
5.24 (1H, br s, H-7b), 3.94 (2H, br t, J = 5.8, H-5). 19F NMR
(CDCl3): d ꢀ64.92. MS (EI): 195 (Mꢄ+), 160 ([M ꢀ Cl]ꢄ+), 110
4.2.6. (E)-4-(Allyl-benzyl-amino)-1-chloro-1,1-difluoro-
but-3-en-2-one, 2c (2 rotamers)
+
([M ꢀ CF2Cl]ꢄ+), 82 ([M ꢀ COCF2Cl]ꢄ+), 41 (C3H5 ). HRMS
(EI): m/z calcd for C7H8ClF2NO 195.0262; found: 195.0262.
4.2.3. (Z)-1-Chloro-1,1-difluoro-4-prop-2-ynylamino-but-
3-en-2-one, 1b
Yield: 61%, pinkish oil (crude product). 13C NMR (CDCl3):
d 179.5 and 179.4 (t, J = 27.0, C-2), 156.5 and 156.2 (C-4),
134.5 and 133.9 (C-9), 131.4 and 129.0 (C-6), 129.1 and 128.3
(C-11), 128.5 and 127.8 (C-10), 127.3 (C-12), 120.3 and 119.0
(C-7), 115.5 (t, J = 305.6, C-1), 87.0 and 86.8 (C-3), 60.1 and
51.7 (C-8), 58.4 and 50.5 (C-5). 1H NMR (CDCl3): d 8.07 and
8.03 (1H, 2 d, J = 12.6 and J = 12.6, H-4), 7.44–7.31 (3H, m, H-
11 and H-12), 7.25–7.14 (2H, m, H-10), 5.85–5.61 (1H, 2 m, H-
6), 5.52 and 5.42 (1H, 2 d, J = 12.4 and J = 12.4, H-3), 5.33 and
5.28 (1H, dd, J = 10.1, 1.1, H-7a), 5.24 and 5.17 (1H, dd,
J = 17.0, 1.1, H-7b), 4.50 and 4.45 (2H, s br, H-8), 3.91 and 3.77
(2H, 2 br d, J = 6.2 and J = 5.6, H-5). 19F NMR (CDCl3): d
ꢀ65.60 (br s). MS (EI): 285 (Mꢄ+), 250 ([M ꢀ Cl]ꢄ+), 244
([M ꢀ C3H5]ꢄ+), 200 ([M ꢀ CF2Cl]ꢄ+), 194 ([M ꢀ C7H7]ꢄ+),
172 ([M ꢀ COCF2Cl]ꢄ+), 91 (C7H7ꢄ+). HRMS (EI): m/z calcd
for C8H10ClF2NO: 285.0732; found: 285.0725.
Yield: 89%, yellowish oil. 13C NMR (CDCl3): d 180.0 (t,
J = 27.4, C-2), 157.1 (C-4), 121.1 (t, J = 303.8, C-1), 86.5 (C-
1
3), 76.7 (C-6), 75.4 (C-7), 37.9 (C-5). H NMR (CDCl3): d
10.12 (1H, br s, NH), 7.36 (1H, dd, J = 13.2, 7.3, H-4), 5.46
(1H, d, J = 7.35, H-3), 4.17 (2H, dd, J = 4.5, 2.5, H-5), 2, 50
(1H, d, J = 2.6, H-7). 19F NMR (CDCl3): d ꢀ65.17. MS (EI):
193 (Mꢄ+), 158 ([M ꢀ Cl]ꢄ+), 108 ([M ꢀ CF2Cl]ꢄ+), 80
([M ꢀ COCF2Cl]ꢄ+). HRMS (EI): m/z calcd for C7H6ClF2NO
193.0106; found: 193.0105.
4.2.4. (E)-1-Chloro-4-diallylamino-1,1-difluoro-but-3-en-
2-one, 2a
4.3. (Z)-N-(4-Chloro-4,4-difluoro-3-oxo-but-1-enyl)-4-
methyl-benzenesulfonamide, 1g
Yield: 80%, silica gel chromatography (PE/EA, 4/1), orange
liquid. 13C NMR (CDCl3): d 179.1 (t, J = 26.9, C-2), 155.8 (C-
4), 131.5 and 129.1 (C-6 and C-60), 121.5 (t, J = 305.6, C-1),
119.9 and 118.6 (C-7 and C-70), 86.7 (C-3), 58.6 and 50.6 (C-5
1.1 g (6.5 mmol) of p-toluenesulfonamide was dissolved in
10 mL of anhydrous DMF under nitrogen. The solution was
cooled to ꢀ30 8C and 0.26 g (6.5 mmol) of NaH (60%
dispersion in oil) was added portion wise and the reaction
mixture stirred during 30 min. A solution of 1.0 g (5.4 mmol) of
(E)-1-chloro-4-ethoxy-1,1-difluoro-but-3-en-2-one in 10 mL of
anhydrous DMF was then added dropwise and the reaction
1
and C-50) H NMR (CDCl3): d 7.89 (1H, d, J = 12.4, H-4),
5.90–5.64 (2H, m, H-6), 5.42–5.15 (5H, m, H-3 and H-7a and
H-7b), 3.93 and 3.85 (4H, 2 d br, J = 6.0 and J = 5.5, H-5). 19
NMR (CDCl3): d ꢀ65.58.
F

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F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
mixture was slowly warmed-up to room temperature under
stirring. After 3 h, the DMF solution was hydrolysed with
20 mL of water, extracted with ethyl acetate (4 mL ꢃ 20 mL)
and the combined organic layers washed with water (4 mL
ꢃ 10 mL) and brine (2 mL ꢃ 10 mL). The solvent was rem-
oved under reduced pressure and the crude product purified by
silica gel chromatography. Yield: 50%, silica gel chromato-
graphy (PE/EA, 2/1), yellow solid. 1H NMR (CDCl3): d 10.93
(1H, br s, NH), 7.77 (2H, d, J = 8.5, H-6), 7.45 (1H, d, J = 8.5,
H-4), 7.36 (2H, d, J = 8.1, H-7), 5.74 (1H, d, J = 8.3, H-3), 2.45
(3H, s, H-12). 19F NMR (CDCl3): d ꢀ67.48. MS (CI): 310
(MHꢄ+), 224 ([M ꢀ CF2Cl]ꢄ+), 155, 91.
13C NMR (DMSO-d6): d 174.7 (t, J = 29.1, C-2), 169.4 (C-4),
136.4 (C-13), 127.0 (C-8), 123.2 (C-14), 122.3 (t, J = 303.8, C-
1), 121.1 (C-10), 118.4 (C-11), 118.3 (C-9), 111.5 (C-12), 110.7
(C-7), 70.5 (t, J = 2.2, C-3), 65.8 (C-15), 40.8 (C-5), 25.1 (C-6),
14.0 (C-16). 1H NMR (CDCl3): d 10.43 (1H, br s, NH), 8.16
(1H, br s, NH), 7.57 (1H, d, J = 7.9, H-9), 7.37 (1H, d, J = 7.9,
H-12), 7.23–7.18 (1H, m, H-9), 7.15–7.10 (2H, m, H-10 and H-
14), 5.03 (1H, s, H-3), 4.05 (2H, q, J = 7.0, H-15), 3.65 (2H, td,
J = 6.9, 5.9, H-5), 3.05 (2H, t, J = 6.9, H-6), 1.30 (3H, t, J = 7.0,
H-16). 19F NMR (CDCl3): d ꢀ63.99. MS (EI): 342 (Mꢄ+), 307
([M ꢀ Cl]ꢄ+), 257 ([M ꢀ CF2Cl]ꢄ+), 212 ([M ꢀ C9H8N]ꢄ+),
184 ([C6H7ClF2O2]ꢄ+), 130 ([C9H8N]ꢄ+). HRMS (EI): m/z
calcd for C16H17ClF2N2O2: 342.0947; found: 342.0946.
4.4. 1-Chloro-4-ethoxy-1,1-difluoro-4-[2-(1H-indol-3-yl)-
ethylamino]-but-3-en-2-one, 1h
4.5. 1-Chloro-1,1-difluoro-4-[(4-chloro-4,4-difluoro-3-oxo-
but-1-enyl)-prop-2-2-ynyl-amino]-but-3-en-2-one, 2j
4.4.1. 1-Chloro-4,4-diethoxy-1,1-difluoro-but-3-en-2-one
1.8 mL (10 mmol) of 1,1,1-triethoxy-ethane and 1.6 mL
(20 mmol) of pyridine were added under nitrogen to 10 mL of
anhydrous dichloromethane. The solution was cooled to
ꢀ30 8C and a 10 mL anhydrous dichloromethane solution
containing 3.5 mL (20 mmol) of chloro-difluoroacetic anhy-
dride was added dropwise over 1.5 h under stirring. The
reaction mixture was allowed to warm slowly to room
temperature and stirred overnight. The solution was hydrolysed
with 50 mL of a saturated aqueous solution of Na2CO3 and
extracted with dichloromethane (2 mL ꢃ 50 mL). The com-
bined organic layers were washed with a saturated aqueous
solution of Na2CO3 (1 mL ꢃ 20 mL) and water (2 mL ꢃ 20
mL) and then dried over MgSO4. The solvent was removed
under reduced pressure to give a crude product used without
further purification. Yield: 75%, orange liquid. 1H NMR
(CDCl3): d 4.89 (1H, s, H-3), 4.32 (2H, q, J = 7.1, H-7), 4.12
(2H, q, J = 7.0, H-5), 1.40 (3H, t, J = 7.1, H-8), 1.36 (3H, t,
J = 7.0, H-6). 19F NMR (CDCl3): d ꢀ65.70.
Under nitrogen 0.118 g (3.1 mmol) of NaH (60% dispersion
in oil) was added portion wise to an anhydrous cooled (ꢀ30 8C)
DMF (15 mL) solution containing 0.59 g (3.1 mmol) of 1b. The
initial orange solution became gradually dark and then after
30 min of stirring at this temperature, 0.65 g (3.4 mmol) of
tosyl chloride dissolved in 15 mL of anhydrous DMF was
added dropwise. After the addition was finished, the clear
solution was slowly warmed-up to room temperature overnight.
Solution was quenched with water (20 mL) and extracted with
ethyl acetate (4 mL ꢃ 10 mL), the combined organic phases
washed with brine (4 mL ꢃ 10 mL) and water (2 mL ꢃ 10
mL). After drying over MgSO4, the solvent was removed under
reduced to yield a brown oil as crude product which was
purified by silica gel chromatography. Yield: 48%, silica gel
chromatography (EA/PE, 9/1 ! EA), pale yellow solid, mp:
78 8C. 1H NMR (CDCl3): d 7.83 (2H, d, J = 13.57, H-3), 6.05
(2H, d, J = 13.57, H-4), 4.36 (2H, d, J = 2.4, H-5), 2.48 (1H, t,
J = 2.4, H-7). 19F NMR (CDCl3): d ꢀ67.82.
4.4.2. 1-Chloro-4-ethoxy-1,1-difluoro-4-[2-(1H-indol-3-
yl)-ethylamino]-but-3-en-2-one, 1h
4.6. General procedure to prepare 3 and 4
Substrate 1 or 2 (1 mmol) was first dissolved in freshly
distilled THF (1 ml) followed by the addition of the aldehyde (1–
2 mmol). The mixture was stirred gently and then H2O (4 ml)
was added dropwise. Indium (100 mesh) was finally added at
onceandthewholemixturewasvigorouslystirred and monitored
by 19F NMR (and TLC) for the indicated time in Table 1. Mixture
was then filtrated over Celite1 and the filter cake washed with
ethyl acetate and water. The organic phase was separated and the
aqueous phase extracted with ethyl acetate (2 mL ꢃ 25 mL), the
combined organic layers washed with water (2 mL ꢃ 25 mL)
and dried over MgSO4. The solvent was removed under reduced
pressure, and the crude product purified either by recrystalliza-
tion or silica gel chromatography.
0.69 g (3.0 mmol) of 1-chloro-4,4-diethoxy-1,1-difluoro-
but-3-en-2-one was dissolved in 10 mL of anhydrous acetoni-
trile under nitrogen. 0.48 g (3.0 mmol) of tryptamine was then
added portion wise at 0 8C over 5 min under stirring. The
solution turned pink and was allowed to warm to room
temperature and stirred for 1 h. A white solid precipitated and
was filtrated and dried. Yield: 30%, white solid, mp: 190 8C.

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1295
4.6.1. (Z)-1-Allylamino-4,4-difluoro-5-hydroxy-5-phenyl-
pent-1-en-3-one, 3aa
4), 140.0 (C-9), 132.9 (C-6), 130.7 (q, J = 32.4, C-12), 128.4
(C-10), 125.1 (q, J = 3.8, C-11), 124.1 (q, J = 272.1, C-13),
118.4 (C-7), 114.4 (dd, J = 260.7, 255.8, C-1), 89.0 (dd, J = 2.2,
1
1.6, C-3), 73.4 (dd, J = 28.8, 24.9, C-8), 51.6 (C-5). H NMR
(CDCl3): d 10.28 (1H, br s, NH), 7.66–7.55 (4H, m, H10 and H-
11), 7.03 (1H, dd, J = 13.4, 7.2, H-4), 5.88 (1H, m, H-6), 5.40
(1H, dt, J = 7.2, 1.3, H-7a), 5.32–5.18 (3H, m, H-3, H-7b and H-
8), 4.00 (1H, d, J = 4.2, OH), 3.93 (2H, tm, J = 5.75, H-5). 19
F
Yield: 45%, silica gel chromatography (PE/EA, 9/1),
yellowish oil. 13C NMR (CDCl3): d 179.6 (dd, J = 27.9, 26.3,
C-2), 157.3 (C-4), 136.0 (C-9), 133.1 (C-6), 128.5 (C-10), 128.1
(C-11), 128.0(C-12), 118.0(C-7), 114.9(dd, J = 259.6, 254.7, C-
1), 89.1 (C-3), 73.8 (dd, J = 28.6, 24.7, C-8), 51.4 (C-5). 1H NMR
(CDCl3):d10.23(1H, brs, NH), 7.44(2H, m, H-11), 7.33(3H, m,
H-10 andH-12), 6.94 (1H, dd, J = 13.4, 7.2, H-4), 5.90–5.77(1H,
m, H-6), 5.36 (1H, d, J = 7.2, H-3), 5.27–5.19 (2H, m, H-7a and
H-7b), 5.16 (1H, dd, J = 16.6, 7.6, H-8), 4.26 (1H, br s, OH), 3.85
(2H, t, J = 5.65, H-5). 19F NMR (CDCl3): d ꢀ112.7 (1F, dd,
J = 262.2, 7.6), ꢀ121.3 (1F, dd, J = 262.2, 16.6). MS (EI): 267
(Mꢄ+), 247 ([M ꢀ HF]ꢄ+), 226 ([M ꢀ C3H5]ꢄ+), 110 (C6H8
NOꢄ+), 107 (C7H7Oꢄ+), 82 (C5H8Nꢄ+), 41 (C3H5ꢄ+). HRMS (EI):
m/z calcd for C14H15F2NO2: 267.1071, found: 267.1069.
NMR (CDCl3): d ꢀ63.1 (3F, s), ꢀ111.9 (1F, dd, J = 268.5, 5.7),
ꢀ120.6 (1F, dd, J = 268.5, 16.6). MS (EI): 335 (Mꢄ+), 315
(Mꢄ+ ꢀ HF), 360 (Mꢄ+ ꢀ Br), 175 (C8H6F3Oꢄ+), 145
(C7H4F3ꢄ+), 110 (Mꢄ+ ꢀ C9H6F5O), 41 (C3H5ꢄ+). HRMS
(EI): m/z calcd for C15H14F5NO2: 335.0945, found: 335.0943.
4.6.4. 2-[5-(2-Bromophenyl)-4,4-difluoro-5-hydroxy-3-
oxopent-1-enylamino]benzonitrile, 3db
4.6.2. (Z)-1-Allylamino-5-(2-bromo-phenyl)-4,4-difluoro-
5-hydroxy-pent-1-en-3-one, 3ab
Yield: 90%, ochre powder, mp: 143 8C (CH2Cl2/pentane).
1H NMR (DMSO-d6): d 12.05 (1H, br d, J = 12.33, NH, isomer
Z), 10.55 (1H, br s, NH, isomer E), 8.26–8.05 (1H, m, H-4, both
isomers), 7.90–7.57 (5H, m, H-7, H-9, H-14, H-16 and H-17,
both isomers), 7.54–7.37 (1H, m, H-15, both isomers), 7.37–
7.20 (2H, m, H-6 and H-8, both isomers), 6.61 (1H, dd, J = 5.9,
1.2, OH, Z or E), 6.53 (1H, br d, J = 5.8, OH, Z or E), 6.30 (1H,
d, J = 13.1, H-3, isomer E), 5.84 (1H, dd, J = 7.8, 2.6, H-3,
isomer Z), 5.69–5.48 (1H, m, H-12, both isomers). 19F NMR
(CDCl3): d ꢀ110.3 (1F, dd, J = 276.5, 3.4), ꢀ123.8 (1F, dd,
J = 276.5, 19.0).
Yield: 50%, yellow solid, mp: 84 8C (CH2Cl2/pentane). 13
C
NMR (CDCl3): d 187.5 (t, J = 27.7, C-2), 157.6 (C-4), 135.5 (C-
9), 133.0 (C-6), 132.7 (C-13), 130.3 (C-10), 130.2 (C-12), 127.5
(C-11), 124.4(C-14), 118.4(C-7), 114.5(dd, J = 261.0, 256.6, C-
1), 88.9 (t, J = 1.9, C-3), 73.8 (dd, J = 29.6, 23.6, C-8), 51.7 (C-
1
4.6.5. (Z)-2-[5-(2-Bromo-phenyl)-4,4-difluoro-5-hydroxy-
3-oxo-pent-1-enylamino]-benzoic acid methyl ester, 3eb
5). H NMR (CDCl3): d 10.32 (1H, br s, NH), 7.69 (1H, dm,
J = 7.9, H-10), 7.56 (1H, dd, J = 7.9, 1.1, H-13), 7.36 (1H, m, H-
11), 7.19 (1H, m, H-12), 6.94 (1H, dd, J = 13.6, 7.2, H-4), 5.88
(1H, m, H-6), 5.74 (1H, dd, J = 18.5, 3.8, H-8), 5.46 (1H, d,
J = 7.2, H-3), 5.36–5.19 (3H, m, H-7a, H-7b and OH), 3.85 (2H,
t, J = 5.65, H-5). 19F NMR (CDCl3): d ꢀ111.1 (1F, dd, J = 267.5,
2.9), ꢀ122.4 (1F, dd, J = 267.3, 18.4). MS (EI): 345 (Mꢄ+), 325
(Mꢄ+ ꢀ HF), 266 (Mꢄ+ ꢀ Br), 246 (Mꢄ+ ꢀ Br-HF), 185
(C7H6BrO+), 110 (C6H8NOꢄ+), 41 (C3H5 ). HRMS (CI): m/z
+
Yield: 78%, yellow powder, mp: 126 8C (CHCl3). 13C NMR
(DMSO-d6): d 187.2 (dd, J = 30.1, 24.1, C-2), 166.4 (C-11),
146.1 (C-4), 141.3 (C-5), 137.0 (C-19), 134.8 (C-18), 132.2 (C-
15), 131.5 (C-9), 130.7 (C-8), 130.3 (C-7), 127.6 (C-17), 123.5
(C-14), 123.2 (C-16), 116.2 (J = 264.3, 251.1, C-1), 115.7 (C-
10), 115.6 (C-6), 93.4 (C-3), 69.7 (dd, J = 30.8, 21.8, C-13),
calcd for C14H14BrF2NO2 (MH+): 346.0176, found: 346.0254.
4.6.3. 1-Allylamino-4,4-difluoro-5-hydroxy-5-(4-
trifluoromethyl-phenyl)-pent-1-en-3-one, 3ac
1
52.5 (C-12). H NMR (CDCl3): d 13.21 (1H, br d, J = 13.0,
NH), 8.09 (1H, dd, J = 7.9, 1.5, H-9), 7.72 (1H, dm, J = 7.7, H-
7), 7.67–7.49 (3H, m, H-4, H-15 and H-18), 7.41–7.30 (2H, m,
H-6 and H-17), 7.24–7.11 (2H, m, H-8 and H-16), 5.95–5.77
(2H, m, H-3 and H-13), 4.03 (3H, s, H-12), 3.66 (1H, br d,
J = 3.4, OH). 19F NMR (CDCl3): d ꢀ109.9 (1F, dd, J = 268.5,
Yield: 60%, yellow pellets, mp: 77 8C (CH2Cl2/pentane).
13C NMR (CDCl3): d 187.1 (dd, J = 28.0, 26.3, C-2), 157.6 (C-

1296
F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
3.4), ꢀ124.9 (1F, dd, J = 268.5, 20.1). 19F NMR (DMSO-d6): d
ꢀ107.5 (1F, d, J = 254.7), ꢀ126.9 (1F, dd, J = 254.7, 21.3). MS
(EI): 439 (Mꢄ+), 419 (Mꢄ+ ꢀ HF), 360 (Mꢄ+ ꢀ Br), 284
(Mꢄ+ ꢀ C6H4Br), 204 (Mꢄ+ ꢀ C8H6BrF2O), 185 (C7H6BrOꢄ+).
+). HRMS (EI): m/z calcd for C19H16BrF2NO4: 439.0231,
found: 439.0230.
186.6 (dd, J = 28.1, 25.1, C-2, Z or E), 148.3 (C-4, Z or E),
146.1 (C-4, Z or E), 139.6 (C-5, Z or E), 138.7 (C-5, Z or E),
137.8 (C-10), 129.7 (C-6), 128.3 (C-11), 128.0 (C-12), 128.0
(C-13), 127.3 (C-8), 118.9 (C-7, Z or E), 117.9 (C-7, Z or E),
117.0 (dd, J = 261.2, 252.6, C-1), 96.1 (C-3, Z or E), 92.4 (C-
1
3, Z or E), 71.9 (dd, J = 28.6, 23.7, C-9). H NMR (CDCl3):
11.85 (1H, d, J = 12.3, NH), 7.60–7.27 (9H, m, H-4, H-7, H-
11, H-12, H-13 and OH), 7.11-6.96 (2H, m, H-6), 5.66 (1H, d,
J = 7.6, H-3), 5.23 (1H, dd, J = 15.9, 7.5, H-9) d 19F NMR
(CDCl3): d ꢀ113.9 (1F, dd, J = 257.0, 8.0), ꢀ122.8 (1F, dd,
J = 257.0, 16.1). MS (ESI): 696.9 (2M + Na)+, 360.0
(M + Na)+, 338.0 (MH)+, 180.2 ([M ꢀ C8H7F2O]+). HRMS
(EI): m/z calcd for C17H14ClF2NO2 337.0681, Found
337.06801.
4.6.6. (Z)-Methyl 2-(4,4-difluoro-5-furan-2-yl-5-hydroxy-3-
oxo-pent-1-enylamino)-benzoate, 3ed
4.6.9. (Z)-N-(4,4-Difluoro-5-hydroxy-3-oxo-5-phenyl-pent-
1-enyl)-4-methyl-benzenesulfonamide, 3ga
Yield: 34%, silica gel chromatography (PE/EA, 4/1),
orange powder, mp: 111 8C. 13C NMR (CDCl3): d 188.5
(dd, J = 28.6, 26.3, C-2), 167.2 (C-11), 149.5 (C-14), 145.6 (C-
4), 143.4 (C-17), 141.8 (C-5), 134.8 (C-7), 132.5 (C-9), 123.7
(C-8), 117.1 (C-10), 115.0 (C-6), 114.7 (dd, J = 261.3, 256.3,
C-1), 110.8 (C-16), 110.1 (C-15), 93.6 (C-3), 68.2 (dd,
J = 29.7, 25.3, C-13), 53.0 (C-12). 1H NMR (CDCl3): d 13.21
(1H, br d, J = 12.8, NH), 8.05 (1H, dd, J = 7.9, 1.5, H-9), 7.60–
7.50 (2H, m, H-4 and H-7), 7.41 (1H, m, H-17), 7.30 (1H, d,
J = 8.3, H-6), 7.12 (1H, m, H-8), 6.48 (1H, d, J = 3.0, H-15),
6.35 (1H, dd, J = 3.3, 1.8, H-16), 5.80 (1H, dd, J = 8.0, 1.5, H-
Yield (19F NMR): 36%. Unstable over silica gel. 19F NMR
(CDCl3): d ꢀ114.0 (1F, dd, J = 261, 7.5), ꢀ123.7 (1F, dd,
J = 262, 17.5).
4.6.10. 1-Ethoxy-4,4-difluoro-5-hydroxy-1-[2-(1H-indol-3-
yl)-ethylamino]-5-phenyl-pent-1-en-3-one, 3ha
3), 5.37 (1H, dd, J = 16.4, 6.8, H-13), 3.99 (3H, s, H-12). 19
F
NMR (CDCl3): d ꢀ113.0 (1F, dd, J = 263.9, 8.0), ꢀ122.2 (1F,
dd, J = 263.9, 17.2). MS (ESI): 724.9 (2M + Na)+, 374.1
(M + Na)+, 352.0 (MH)+, 204.0 ([M ꢀ C6H5F2O2]+), 172.1.
HRMS (EI): calcd for C17H15F2NO5 351.0918, found:
351.0917.
4.6.7. (Z)-Methyl-2-[5-(3,4-dimethoxyphenyl)-4,4-difluoro-
5-hydroxy-3-oxopent-1-enylamino]-benzoate, 3ee
Yield (19F NMR): 14%. 19F NMR (CDCl3): d ꢀ111.5 (1F, d,
J = 258.1), ꢀ123.7 (1F, dd, J = 258.1, 16.7).
4.6.11. (E)-1-Diallylamino-4,4-difluoro-5-hydroxy-5-
phenyl-pent-1-en-3-one, 4aa
Yield (19F NMR): 11%. 19F NMR (CDCl3): d ꢀ112.4 (1F,
dd, J = 266.1, 6.6), ꢀ122.6 (1F, dd, J = 266.1, 16.8).
4.6.8. 1-(4-Chloro-phenylamino)-4,4-difluoro-5-hydroxy-5-
phenyl-pent-1-en-3-one, 3fa
Yield: 30%, silica gel chromatography (PE/ EA, 9:1),
yellowish oil. 13C NMR (CDCl3): d 187.3 (dd, J = 27.7, 26.1, C-
2), 155.4 (C-4), 136.1 (C-9), 131.8 and 128.4 (C-6 and C-60),
128.4 (C-10), 128.1 (C-11), 128.0 (C-12), 120.1 and 118.9 (C-7
and C-70), 115.3 (dd, J = 261.8, 255.8, C-1), 90.1 (br s, C-3),
73.6 (dd, J = 28.5, 24.7, C-8), 58.6 and 50.7 (C-5 and C-50). 1H
NMR (CDCl3): d 7.81 (1H, d, J = 12.4, H-4), 7.48–7.45 (2H, m,
H-11), 7.37–7.29 (3H, m, H-10 and H-12), 5.80–5.56 (2H, m,
H-6 and H-60), 5.40 (1H, d, J = 12.4, H-3), 5.30–5.05 (5H, m,
Yield: 59%, yellow powder, mp: 156 8C (EA/pentane). 13
NMR (DMSO-d6): d 188.1 (dd, J = 28.3, 25.5, C-2, Z or E),
C

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1297
H-7 and H-70 and H-8), 4.33 (1H, br s, OH), 3.83 and 3.73 (4H,
2 br d J = 6.0 and J = 5.3, H-5 and H-50). 19F NMR (CDCl3): d
ꢀ112.0 (1F, d, J = 265.0), ꢀ121.5 (1F, dd, J = 266.2, 11.5). MS
(EI): 307 (Mꢄ+), 287 ([M ꢀ HF]ꢄ+), 200 (C10H12F2NOꢄ+), 150
(C9H12NOꢄ+), 122 (C8H12Nꢄ+), 96 (C6H10Nꢄ+), 41 (C3H5ꢄ+).
HRMS (EI): m/z calcd for C17H19F2NO2: 307.1384, found:
307.1383.
4.48 (1H, br s, OH), 4.38 and 4.31 (2H, br s and d, J = 2.6, H-
13), 3.78 and 3.64 (2H, 2 br d, J = 6.2 and J = 5.6, H-5). 19F
NMR (CDCl3): d ꢀ112.4 and ꢀ112.7 (1F, 2 br d, J = 265.0 and
J = 260.4), ꢀ121.5 and ꢀ121.8 (1F, 2 br d, J = 260.4 and
J = 265.0).
4.6.14. (E)-Allyl-(4,4-difluoro-5-hydroxy-3-oxo-5-phenyl-
pent-1-enyl)-carbamic acid tert-butyl ester, 4da
4.6.12. (E)-1-(Allyl-methyl-amino)-4,4-difluoro-5-hydroxy-
5-phenyl-pent-1-en-3-one, 4ba (2 rotamers)
Yield: 60%, silica gel chromatography (PE/EA, 9/1),
yellowish oil. 13C NMR (CDCl3): d 189.4 (dd, J = 29.1,
26.9, C-2), 151.5 (C-13), 145.9 (C-4), 135.4 (C-9), 130.2 (C-6),
128.6 (C-10), 128.1 (C-11), 127.9 (C-12), 117.4 (C-7) 115.5
(dd, J = 261.8, 255.8, C-1), 99.6 (C-3), 84.3 (C-14), 73.1 (dd,
J = 28.0, 24.2, C-8), 46.9 (C-5), 27.8 (C-15). 1H NMR (CDCl3):
d 8.37 (1H, d, J = 13.9, H-4), 7.45–7.36 (2H, m, H-11), 7.35–
7.26 (3H, m, H-10 and H-12), 5.73 (1H, d, J = 13.9, H-3), 5.61
(1H, m, H-6), 5.24–5.07 (2H, m, H-7a and H-8), 5.02 (1H, d,
J = 17.3, H-7b), 4.16–3.79 (3H, m, H-5 and OH), 1.48 (9H, s,
H-15). 19F NMR (CDCl3): d ꢀ113.8 (1F, dd, J = 262, 8.0),
ꢀ122.6 (1F, dd, J = 262, 16.1). MS (EI): 367 (Mꢄ+), 352
([M ꢀ CH3]ꢄ+), 326 ([M ꢀ C3H5]ꢄ+), 311 (M+-isobutene), 210
Yield: 56%, silica gel chromatography (PE/EA, 2/1),
yellow-orange oil. 13C NMR (CDCl3): d 200.2 and 186.9 (2
dd, J = 27.9, 26.3, C-2), 156.1 and 155.8 (C-4), 135.9 and
135.0 (C-9), 128.9 (C-10), 128.3 (C-11), 127.9 (C-12), 119.7
and 118.9 (C-7), 114.8 (dd, J = 261.8, 254.6, C-1), 88.6 (C-
3), 73.6 and 72.8 (2 dd, J = 28.8, 24.1 and J = 28.8, 24.7, C-
8), 60.8 and 52.7 (C-5), 43.8 and 36.0 (C-13). 1H NMR
(CDCl3): d 8.21–8.04 (1H, dm, J = 12.2, H-4), 7.51–7.39
(2H, m, H-11), 7.38–7.27 (3H, m, H-10 and H-12), 5.84–
5.55 (1H, m, H-6), 5.45 (1H, d, J = 12.1, H-3), 5.35–5.08
(3H, m, H-7 and H-8), 3.91 and 3.78 (2H, 2 br d, J = 6.2
and J = 5.6, H-5), 3.15 and 2.85 (3H, 2 s, H-13). 19F
NMR (CDCl3): d ꢀ110.4 and ꢀ110.7 (1F, 2 br d, J = 263.9
and J = 262.7), ꢀ122.1 and ꢀ122.4 (1F, 2 dd, J = 262.7, ꢄ1+8,
and J = 263.9, 16). MS (EI): 281 (Mꢄ+), 261 ([M ꢀ HF] ),
326 ([M ꢀ C3H5]ꢄ+), 124 (C7H10NOꢄ+), 41 (C3H5ꢄ+).
HRMS (EI): m/z calcd for C15H17F2NO2 281.1227, found:
281.1223.
+
+
([Mꢄ+-isobutene-PhCHOHCF2), 57 (C4H9 ), 41 (C3H5 ).
HRMS (EI): m/z calcd for C19H23F2NO4: 367.1595, found:
367.1598.
4.6.15. (E)-Allyl-[5-(2-bromo-phenyl)-4,4-difluoro-5-
hydroxy-3-oxo-pent-1-enyl]-carbamic acid tert-butyl ester,
4db
4.6.13. (E)-1-(Allyl-benzyl-amino)-4,4-difluoro-5-hydroxy-
5-phenyl-pent-1-en-3-one, 4ca (2 rotamers)
Yield: 53%, silica gel chromatography (PE/EA = 4/1),
yellowish oil. 13C NMR (CDCl3): d 189.1 (dd, J = 29.9,
27.7, C-2), 151.5 (C-15), 146.6 (C-4), 135.0 (C-9), 132.6 (C-
13), 130.4 (C-10), 130.3 (C-12), 130.3 (C-6), 127.6 (C-11),
124.3 (C-14), 117.7 (C-7), 115.1 (dd, J = 263.8, 257.8, C-1),
99.3 (C-3), 84.6 (C-16), 71.4 (dd, J = 29.1, 23.0, C-8), 47.2 (C-
5), 28.0 (C-17). 1H NMR (CDCl3): d 8.48 (1H, d, J = 13.8, H-
4), 7.67 (1H, dt, J = 7.7, 1.6, H-10), 7.55 (1H, dd, J = 7.9, 1.1,
H-13), 7.35 (1H, td, J = 7.6, 1.1, H-12), 7.20 (1H, m, H-12),
5.84 (1H, d, J = 13.9, H-3), 5.80–5.62 (2H, m, H-6 and H-8),
5.19 (1H, dm, J = 10.4, H-7a), 5.11 (1H, dm, J = 17.3, H-7b),
4.18 (2H, dm, J = 5.1, H-5), 3.52 (1H, d, J = 4.5, OH), 1.52 (9H,
s, H-17). 19F NMR (CDCl3): d ꢀ111.3 (1F, d, J = 277.6),
ꢀ123.7 (1F, dd, J = 262, 18.4).
Yield: 55%, silica gel chromatography (PE/ EA, 9/1),
yellowish oil. 13C NMR (CDCl3): d 187.3 (m, C-2), 155.9 and
155.6 (C-4), 136.2 and 134.2 (C-14), 134.8 (C-9), 131.6 and
129.2 (C-6), 129.0 (C-16), 128.5 (C-15), 128.3 (C-10), 128.0
(C-11), 127.9 (C-12), 127.4 (C-17), 120.2 and 118.9 (C-7),
115.5 (dd, J = 261.8, 256.3, C-1), 90.1 (br s, C-3), 73.4 (m, C-
8), 59.8 and 51.3 (C-13), 58.0 and 50.2 (C-5). 1H NMR
(CDCl3): d 8.01 and 7.94 (1H, 2 d, J = 12.4 and J = 12.4, H-4),
7.49 (2H, m, H-11), 7.40–7.27 (6H, m, H-10, H-12, H-16 and
H-17), 7.20–7.13 and 7.12–7.05 (2H, 2 m, H-15), 5.79–5.43
(2H, m, H-6 and H-3), 5.30–5.01 (3H, m, H-7 and H-8), 4.76–

1298
F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
4.6.16. (E)-N-Allyl-N-(4,4-difluoro-5-hydroxy-3-oxo-5-
phenyl-pent-1-enyl)-4-methyl-benzene-sulfonamide, 4ea
J = 272.1, C-18), 119.5 (C-7), 114.7 (dd, J = 262.9, 256.9, C-1),
99.5 (C-3), 72.7 (dd, J = 28.0, 24.7, C-13), 48.8 (C-5), 21.8 (C-
12). 1H NMR (CDCl3): d 8.37 (1H, d, J = 13.7, H-4), 7.71 (2H,
d, J = 8.1, H-9), 7.65–7.50 (4H, m, H-15 and H-16), 7.36 (2H,
d, J = 8.1, H-10), 5.66 (1H, d, J = 13.7, H-3), 5.57–5.33 (1H, m,
H-6), 5.33–5.18 (1H, m, H-13), 5.18–4.98 (2H, m, H-7a and H-
7b), 4.10–4.00 (2H, m, H-5), 3.43 (1H, br d, J = 4.3, OH), 2.43
(3H, s, H-12). 19F NMR (CDCl3): d ꢀ62.7 (3F, s), ꢀ112.2 (1F,
dd, J = 275.4, 6.7), ꢀ121.8 (1F, dd, J = 275.4, 16.6).
Yield: 70%, silica gel chromatography (PE/EA, 2/1), pale
yellow crystals, mp: 50 8C. 13C NMR (CDCl3): d 188.9 (dd,
J = 30.2, 27.4, C-2), 145.7 (C-11), 145.0 (C-4), 135.1 (C-14),
134.6 (C-8), 130.5 (C-10), 129.2 (C-6), 128.9 (C-17), 128.3 (C-
15), 128.0 (C-16), 127.6 (C-9), 119.4 (C-7), 115.3 (dd,
J = 261.8, 256.3, C-1), 100.0 (C-3), 73.3 (dd, J = 28.3, 24.4, C-
13), 48.7 (C-5), 21.7 (C-12). 1H NMR (CDCl3): d 8.33 (1H, d,
J = 13.7, H-4), 7.69 (2H, d, J = 8.3, H-9), 7.43–7.40 (2H, m, H-
16), 7.37–7.29 (5H, m, H-10 and H-15 and H-17), 5.67 (1H, d,
J = 13.6, H-3), 5.51–5.38 (1H, m, H-6), 5.16 (1H, dd, J = 16.4,
7.7, H-13), 5.12 (1H, dd, J = 9.6, 0.7, H-7a), 5.05 (1H, dd,
J = 17.1, 0.7, H-7b), 4.11–3.97 (2H, m, H-5), 3.37 (1H, br s,
OH), 2.44 (3H, s, H-12). 19F NMR (CDCl3): d ꢀ113.7 (1F, dd,
J = 266.2, 7.4), ꢀ121.3 (1F, dd, J = 266.2, 17.2). MS (EI): 421
(Mꢄ+), 401 ([M ꢀ HF]ꢄ+), 264 (C13H14NO3Sꢄ+), 155 (C7H7O2
Sꢄ+), 91 (C7H7ꢄ+). HRMS (EI): m/z calcd for C21H21F2NO4S:
421.1159, found: 421.1158.
4.6.19. (E)-N-Allyl-N-(4,4-difluoro-5-furan-2-yl-5-
hydroxy-3-oxo-pent-1-enyl)-4-methyl-benzene-sulfonamide,
4ed
Yield: 24%, silica gel chromatography (PE/EA: 4/1),
yellowish oil. 13C NMR (CDCl3): d : 188.0 (dd, J = 29.5,
27.2, C-2), 148.5 (dd, J = 2.5, 1.5, C-14), 145.5 (C-11), 145.1
(C-4), 143.0 (C-17), 134.4 (C-8), 130.2 (C-10), 129.1 (C-6),
127.4 (C-9), 119.2 (C-7), 114.4 (dd, J = 261.8, 257.5, C-1),
110.5 (C-16), 109.8 (C-15), 99.3 (C-3), 67.7 (dd, J = 29.1, 25.8,
C-13), 48.6 (C-5), 21.5 (C-12). 1H NMR (CDCl3): d 8.37 (1H,
d, J = 13.7, H-4), 7.71 (2H, d, J = 8.1, H-9), 7.47–7.28 (3H, m,
H-10 and H-17), 6.44 (1H, d, J = 3.3, H-15), 6.35 (1H, dd,
J = 3.3, 1.8, H-16), 5.79 (1H, d, J = 13.7, H-3), 5.62–5.39 (1H,
m, H-6), 5.30–5.02 (3H, m, H-7a, H-7b and H-13), 4.15–4.05
(2H, m, H-5), 3.24 (1H, br s, OH), 2.44 (3H, s, H-12). 19F NMR
(CDCl3): d ꢀ113.1 (1F, dd, J = 270.0, 7.8), ꢀ120.9 (1F, dd,
J = 270.0, 15.2).
4.6.17. (E)-N-Allyl-N-[5-(2-bromo-phenyl)-4,4-difluoro-5-
hydroxy-3-oxo-pent-1-enyl]-4-methyl-benzene-
sulfonamide, 4eb
4.6.20. (E)-N-Allyl-N-[5-(3,4-dimethoxy-phenyl)-4,4-
difluoro-5-hydroxy-3-oxo-pent-1-enyl]-4-methyl-
benzenesulfonamide, 4ee
Yield (19F NMR): 74%. Unstable over silica gel. 19F NMR
(CDCl3): d ꢀ112.0 (1F, dd, J = 270.5, 4.8), ꢀ123.9 (1F, dd,
J = 270.5, 17.9).
4.6.18. (E)-N-Allyl-N-[4,4-difluoro-5-hydroxy-3-oxo-5-(4-
trifluoromethyl-phenyl)-pent-1-enyl]-4-methyl-
benzenesulfonamide, 4ec
Yield: 41%, silica gel chromatography (PE/ EA = 3/1),
yellowish oil. 13C NMR (CDCl3): d 188.8 (dd, J = 29.6, 27.4, C-
2), 149.1 (C-17), 148.5 (C-16), 145.4 (C-11), 144.6 (C-4), 134.4
(C-8), 130.2 (C-10), 128.9 (C-6), 127.4 (C-14), 127.3 (C-9),
120.4 (C-19), 119.1 (C-7), 115.2 (dd, J = 261.1, 255.8, C-1),
110.6 (C-18), 110.5 (C-15), 99.8 (C-3), 72.8 (dd, J = 27.9, 24.4,
1
Yield: 30%, silica gel chromatography (PE/EA: 3/1),
colourless oil. 13C NMR (CDCl3): d 188.6 (dd, J = 30.0,
27.6, C-2), 145.8 (C-11), 145.7 (C-4), 139.1 (C-14), 134.6 (C-
8), 131.0 (q, J = 32.4, C-17), 130.5 (C-10), 129.2 (C-6), 128.4
(C-15), 127.7 (C-9), 125.2 (q, J = 3.8, C-16), 124.1 (q,
C-13), 55.7 (C-21), 55.6 (C-20), 48.4 (C-5), 21.5 (C-12). H
NMR (CDCl3): d 8.32 (1H, d, J = 13.7, H-4), 7.69 (2H, d,
J = 8.4, H-9), 7.34 (2H, d, J = 8.1, H-10), 7.00–6.76 (3H, m, H-
15, H-18 and H-19), 5.67 (1H, d, J = 13.7, H-3), 5.57–5.33 (1H,
m, H-6), 5.20–4.96 (3H, m, H-7a, H-7b and H-13), 4.10–4.00

F. Fenain et al. / Journal of Fluorine Chemistry 128 (2007) 1286–1299
1299
(f) E. Okada, R. Masuda, M. Hojo, Heterocycles 34 (1992) 791;
(2H, m, H-5), 3.84 (6H, s, H-20 and H-21), 3.16 (1H, br d,
J = 4.3, OH), 2.43 (3H, s, H-12). 19F NMR (CDCl3): d ꢀ113.6
(1F, dd, J = 266.2, 8.0), ꢀ121.7 (1F, dd, J = 266.2, 15.8).
(g) E. Okada, R. Masuda, M. Hojo, R. Yoshida, Heterocycles 34 (1992)
1435;
(h) E. Okada, T. Kinomura, H. Takeuchi, M. Hojo, Heterocycles 44
(1997) 349;
(i) E. Okada, T. Kinomura, Y. Higashiyama, H. Takeuchi, M. Hojo,
Heterocycles 46 (1997) 129;
Acknowledgments
(j) E. Okada, T. Kinomura, Y. Higashiyama, Heterocycles 48 (1998)
2347;
MM would like to thank the CNRS for financial support. OO
is grateful to the CNRS for an associate position. FF is
supported by a PhD fellowship from the French Ministry of
Education, Research and Technology (MENRT). Denis Bouchu
(k) I.L. Baraznenok, V.G. Nenajdenko, E.S. Balenkova, Eur. J. Org.
Chem. 937 (1999);
(l) H.G. Bonacorso, S.H.G. Duarte, N. Zanatta, M.A. Martins, Synthesis
(2002) 1037;
´
from the Centre de Spectroscopie de Masse of Universite Lyon
(m) H.G. Bonarcorso, I.S. Lopes, A.D. Wastowski, N. Zanatta, M.A.P.
Martins, J. Fluorine. Chem. 120 (2003) 29;
(n) H.G. Bonacorso, C.A. Cechinel, M.R. Oliveira, M.B. Costa, M.A.P.
Martins, N. Zanatta, A.F.C. Flores, J. Heterocyclic. Chem. 42 (2005)
1055;
1 is sincerely thanked for recording the mass spectra. Thierry
Billard is thanked for help and advice with the NMR. We would
like to acknowledge P. Sautet and L. Bonneviot of the
´
Laboratoire de Chimie de l’Ecole Normale Superieure de Lyon
¨
(o) I.I. Gerus, N.A. Tolmachova, S.I. Vdovenko, R. Frohlich, G. Haufe,
for having arranged a laboratory’s space for FF due to a
temporary relocation. At Kobe University this research was
supported in part by the Ministry of Education, Culture, Sports,
Science and Technology, Grant-in-Aid for JSPS Fellows.
Synthesis (2005) 1269;
(p) N. Zanatta, J.M.F.M. Schneider, P.H. Schneider, A.D. Wouters, H.G.
Bonacorso, M.A.P. Martins, L.A. Wessjohann, J. Org. Chem. 71 (2006)
6996.
[5] R.W. Lang, B. Schaub, Tetrahedron Lett. 29 (1988) 2943.
´
[6] M. Medebielle, O. Onomura, R. Keirouz, E. Okada, H. Yano, T. Terauchi,
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