Electrochemically induced free-radical tandem cyclisation of chlorodifluoromethylated ketones: Application to the synthesis of gem-difluorinated heterocycles

Article abstract of DOI:10.1016/S0022-1139(00)00372-9

The synthesis of a series of chlorodifluoromethylated ketones 1-6 is presented and the cyclic voltammetry of the reductive cleavage of these ketones was investigated, in N,N-dimethylformamide (DMF), at an inert electrode. Indirect electrochemical reduction (by means of an electrogenerated anion radical) in acetonitrile (CH₃CN) or in N,N-dimethylformamide (DMF), of the naphthalene-derived chlorodifluoroacetylated compounds 1 and 2 in the presence of the olefinic substrates 7-10, yields new gem-difluoro heterocyclic compounds 11-16 after intramolecular cyclisation of a γ,γ-difluoroalkyl radical. Aromatic nucleophilic substitution of α,α-difluoroketones 12 and 13, in anhydrous dimethylsulfoxide, with several tetramethylammonium salts of imidazole as nucleophiles, proceeds under mild conditions to give the corresponding nitrogen-nitrogen exchanged products 17-23 in moderate to good yields.

Full text of DOI:10.1016/S0022-1139(00)00372-9

Journal of Fluorine Chemistry 107 (2001) 285±300
Electrochemically induced free-radical tandem cyclisation of
chlorodi¯uoromethylated ketones
Application to the synthesis of gem-di¯uorinated heterocycles
*
Â
Philippe Hapiot, Maurice Medebielle
 Â
UMR CNRS 7591, Laboratoire d'Electrochimie Moleculaire, Universite Paris 7 Denis Diderot, Case courrier 7107,
2 place Jussieu, F-75251 Paris Cedex 05, France
Received 3 April 2000; accepted 18 May 2000
Abstract
The synthesis of a series of chlorodi¯uoromethylated ketones 1±6 is presented and the cyclic voltammetry of the reductive cleavage of
these ketones was investigated, in N,N-dimethylformamide (DMF), at an inert electrode. Indirect electrochemical reduction (by means of an
electrogenerated anion radical) in acetonitrile (CH3CN) or in N,N-dimethylformamide (DMF), of the naphthalene-derived
chlorodi¯uoroacetylated compounds 1 and 2 in the presence of the ole®nic substrates 7±10, yields new gem-di¯uoro heterocyclic
compounds 11±16 after intramolecular cyclisation of a g,g-di¯uoroalkyl radical. Aromatic nucleophilic substitution of a,a-di¯uoroketones
12 and 13, in anhydrous dimethylsulfoxide, with several tetramethylammonium salts of imidazole as nucleophiles, proceeds under mild
conditions to give the corresponding nitrogen±nitrogen exchanged products 17±23 in moderate to good yields. # 2001 Elsevier Science
B.V. All rights reserved.
Keywords: Free-radical cyclisation; Electrochemistry; a,a-Di¯uoroketones; gem-Di¯uorinated compounds
1. Introduction
free-radical di¯uoromethylene radicals including carbon±
carbon bond formation via intramolecular cyclisation of a-
¯uorinated carbon radicals [4±9], as well as nucleophilic
di¯uoromethylene synthons [10]. Chlorodi¯uoromethylated
ketones have been known for a long time [11±14] and have
been used in various synthetic applications [3] (the Refor-
matstky and related reactions being the most common of all
the synthetic studies). Such halodi¯uoromethylated sub-
strates are potentially useful to build new di¯uorinated
materials as it is anticipated that the carbon±halogen bond
should be quite reactive in single electron transfer (SET)
reactions, both chemically and electrochemically. There are
a few reports on the use of these substrates in SET reactions
and free-radical cyclisations [15±18], but to the best of our
knowledge, their use in electrochemical free-radical cycli-
sation reactions has not been reported in the literature
[19].
As part of our ongoing effort in the synthesis of new
¯uorinated compounds with potential biological and syn-
thetic applications [20±26], we wish to present herein a
novel and practical method for the synthesis of a,a-di¯uor-
oketones 11±16 involving free-radical electrochemical
addition of chlorodi¯uoroacetylated compounds 1 and 2
in the presence of ole®nic substrates 7±10 followed by
An increasing interest has been paid for several years to
the chemistry of various ¯uorine-containing heterocycles
due to their unique physical properties, speci®c chemical
reactivity, and their remarkable potential biological activity
[1]. Important efforts have been made toward the synthesis
of compounds containing a di¯uoromethylene group adja-
cent to a carbonyl group [2], because a,a-di¯uoroketones
have been successfully used as inhibitors of hydrolytic
enzymes, and greatly enhanced biological activity has been
reported compared with their non¯uorinated analogues [3].
Methods for the preparation of gem-di¯uorocyclic
compounds are very limited and have some limitations
[2]. Very recently, highly desirable new methodologies
for the synthesis of interesting gem-di¯uoromethylene
compounds have been published. Among the numerous
approaches and systems developed, we can cite the
* Corresponding author. Tel.: ‡33-144-27-56-65;
fax: ‡33-144-27-76-25.
Â
E-mail address: mauricem@paris7.jussieu.fr (M. Medebielle).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 7 2 - 9

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
286
Scheme 1.
intramolecular cyclisation of the resulting g,g-di¯uoroalkyl
radical (Scheme 1).
2-methyl-5-nitroimidazole to yield new heterocyclic a,a-
di¯uoroketones 17±23 (Scheme 2).
The a,a-di¯uoroketones 12 and 13, prepared by our
electrochemical approach, were found to undergo various
nitrogen±nitrogen exchange reactions with imidazole
nucleophiles such as imidazole, benzimidazole, imidazole
2-carboxaldehyde, 2-(40-methoxyphenyl)imidazole and
The structure of compounds is shown in Charts 1 (starting
materials), 2 (cyclised products) and 3 (exchanged pro-
ducts). The reduction products (RCOCF2H) of the starting
ketones RCOCF2Cl will be numbered 1A, 2A and 2B, 3A,
4A, 5A and 6A.

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
287

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
288
Scheme 2.
2. Results and discussion
formaldehyde sulfoxylate (Rongalite) as the reductant
[30,31] (Scheme 5), in re¯uxing absolute EtOH. The reac-
tions are usually complete in 3 h (as checked by TLC).
2.1. Synthesis of the chlorodifluoromethylated ketones 1±6
The chlorodi¯uoromethylated ketones 1±3 were prepared
by chlorodi¯uoroacetylation, with chlorodi¯uoroacetic
anhydride, in anhydrous chloroform (or dichloromethane)
of the corresponding electron-rich substrates (N,N-
dimethyl-1-naphthylamine and butylvinylether) in the pre-
sence of pyridine as a base. The methodology has been
previously presented for similar tri¯uoroacetylation reac-
tions [27,28]. The reactions can be easily monitored by TLC
and are preferably run at 08C (under nitrogen atmosphere)
during the addition of the electron-rich substrate/pyridine
(1:1 mol equivalent) solution to the anhydride (1 M equiva-
lent), and then slowly warmed-up to room temperature and
maintained at this temperature until complete consumption
of the ole®nic substrate. The ketone 2 was prepared similarly
using 2.5 mol equivalents of the anhydride and pyridine. The
ketones 4±6 were prepared by nucleophilic displacement of
the ±OC4H9 group in ketone 3 with the appropriate amines
[29], in re¯uxing acetonitrile and the reactions are usually
completed in few minutes. Ketone 3 was isolated as the trans
product as was shown by the large magnitude of the coupling
2.2. Electrochemical behaviour of the ketones
Cyclic voltammetry of compound 1, the 2-chloro-1-
(4-dimethylamino-naphthalen-1-yl)-2,2-di¯uoro-ethanone,
shows two successive reduction waves; the ®rst is irrever-
sible (up to 1000 V/s), corresponding to the uptake of two
electrons (as compared with the one-electron reversible
oxidation wave of ferrocene) and located at 1.16 V versus
SCE (peak potential Ep at 0.2 V/s on a glassy carbon
electrode; Fig. 1, peak (a)). This reduction step corresponds
to the cleavage of the C±Cl bond and to the formation of the
(4-dimethylamino-naphthalen-1-yl-)-1-di¯uoroacetyl (1A)
as the reduction product. The other wave, partially rever-
sible, located at a more negative potential (Ep ˆ 1:51 V
versus SCE at 0.2 V/s on a glassy carbon electrode; Fig. 1,
peak (b)) is attributed to the reduction of this compound, as
was shown by comparison with an authentic sample. Addi-
tional reduction steps are observed at more negative poten-
tials and may correspond to the reduction of the C=O bond
into the corresponding alcohol (RCHOHCF2H) or dimer-
isation of the anion radical into the corresponding pinacol
[32], or pinacolate as observed for the electrochemical
reduction of acetophenone [33].
The other ketones 3±6 also present two reduction steps in
the same electrochemical medium, usually with reduction
potentials ranging from 1.28 to 1.57 V versus SCE (peak
potentials Ep at 0.2 V/s on a glassy carbon electrode). The
cyclic voltamogramm of ketone 2 is very similar to ketone 1
(despite the presence of the two C±Cl bonds) with a ®rst two-
electron reduction, located at a more positive potential, close
to 0.97 V versus SCE (peak potential at 0.2 V/s). A second
reduction step is located at 1.36 V versus SCE. From the
constant JHa
isolated as cis products (JHa
ˆ 12:2 Hz whereas the ketones 4±6 were
Hb
Hb
ˆ 7:67 Hz) due to the
hydrogen bonding between NHc and C=O. Yields of the
chlorodi¯uoromethylated ketones are generally good and
most of the products were isolated as coloured crystals (1, 2
and 6) or viscous oils (3±5) (Schemes 3 and 4). All the
ketones are stable compounds except for ketones 3±5 for
which storage in the refrigerator is needed to avoid decom-
position.
The reduction products (RCOCF2H, 1A±6A) could be
prepared in good yields, under milder conditions, by reduc-
tive dechlorination using commercially available sodium

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289
Scheme 3.
Scheme 4.

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
290
Scheme 5.
cyclic voltammetry it is dif®cult to predict which C±Cl bond
is ®rst reduced. Therefore, different electrolyses were con-
ducted, at different potentials, in order to have more infor-
mation on the reduction process of ketone 2. If the
electrolysis was maintained at a constant potential corre-
sponding roughly to the foot of the reduction wave
(E ꢀ 0:75 V versus SCE in DMF ‡ 0:1 M Et4NBF4),
the reduction of the C±Cl bond occurs predominantly at
position 4, and the major product identi®ed by ¯uorine NMR
(65% yield), after 2.1F/mol was 2A. Additional products
were the bis-COCF2H 2B (15% yield) and unreacted starting
material. A constant potential electrolysis in the same
electrolytic medium, at a more negative potential, close
to 1.25 V versus SCE gave after 2.3F/mol, a major com-
pound identi®ed as the bis-COCF2H reduction product 2B
(62%) from its ¯uorine NMR spectrum. If the electrolysis
was run at a constant potential corresponding to the second
reduction step observed in cyclic voltammetry, a complex
mixture of ¯uorinated products including 2A, 2B with some
alcohols was observed by ¯uorine NMR. From these experi-
ments we can assume that the reduction of the two C±Cl
bonds occur at very close potentials, the C±Cl bond of the ±
COCF2Cl moiety at position 4 being slightly easier to
reduce.
From a mechanistic point of view, we have examined
more carefully the ®rst electrochemical reduction of ketone
1. A linear variation of the peak potential with the scan rate
was obtained and a slope of 55 mV/log v was measured for
scan rates between 1 and 100 V/s. For lower scan rates
(0:1 < v < 1 V/s) a slope of 47 mV/log v was obtained.
These results are in agreement with an electrochemical
chemical electrochemical (ECE) mechanism [34]
(Scheme 6) under mixed kinetic control by the initial
electron transfer step generating the anion radical and the
following cleavage step (stepwise mechanism).
Comparison of these experimental results with simulated
curves [34], allows an estimation of the rate constant of the
cleavage of the C±Cl bond in the anion radical, in the range
1
of 108±109 M 1 s (assuming the same standard hetero-
geneous electron transfer rate constant ks as 4-bromoaceto-
phenone 0.5 cm 1 s 1; [35]). The cyclic voltammetry of
ketone 2 is comparable to ketone 1 where a slope of 35 mV/
log v was obtained. For the other ketones 3±6, examination
Fig. 1. Cyclic voltammetry of ketone 1 in DMF ‡ 0:01 M Et4NBF4.
C ˆ 3:13 mM. Scan rate: 0.2 V/s. T ˆ 228C. Glassy carbon electrode.
Scheme 6.

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
291
of the ®rst reduction step reveals a value of the transfer
coef®cient a close to 0.5, derived from the value of the peak
width Ep=2 Ep ‰Ep ˆ peak potential; Ep=2 ˆ half-peak
potential: a ˆ RT=Fꢁ1:85=Ep=2 Ep†] showing a similar
stepwise mechanism [36]. A more detailed mechanistic
study of a series of chlorodi¯uoromethylated ketones is
currently under way.
Quantum mechanical calculations were performed on
ketone 1 using semi-empirical AM1 and density functional
B3LYP methods. A minimum of energy was found in the
optimisation of the geometry for the anion radical which
con®rms the electrochemical results that the anion radical is
indeed a reaction intermediate in the reduction process. Spin
density calculations show that the unpaired electron is
localised in all the aromatic system which can explain its
chemical stability. On the contrary, for the radical produced
after the cleavage of the C±Cl bond, the unpaired electron is
clearly localised on the ±C(O)±CF2 functionality (0.63 on
the C, 0.29 on O; Fig. 2). For ketone 2, spin densities
calculation for the anion radical, shows that almost similar
densities of the unpaired electron are present on both
carbonyl groups, which does not allow prediction of which
of the C±Cl bond will cleave ®rst.
2.3. Cyclisation reactions
Then the question was posed: could we generate a stable
and reactive di¯uoroacetyl electrophilic radical electroche-
mically, and trap it with ole®nic rich substrates? Upon
addition of the ole®nic substrate 7 (2,3-dihydrofuran) to
the DMF (or CH3CN) solution of 1, no change in the
voltamogramm was observed, even if large excess of the
ole®n was used. Such behaviour indicates either that the
major pathway of the a,a-di¯uoroalkyl radical is a further
reduction to the hydrogenolysis product or that the a,a-
di¯uoroalkyl addition onto the ole®nic substrate is too slow
to be observed during the time of the cyclic voltammetric
experiments. Another possibility could be that the overall
electron stoichiometry of the radical addition or the cyclisa-
tion process, remains close to 2F/mol. To test this possibility,
we carried out the constant potential electrolysis (E ˆ
1:30 V versus SCE on a carbon felt cathode) of ketone
1 in the presence of 10 mol equivalents of 7, in anhydrous
CH3CN ‡ 0:1 M Et4NBF4; the major product observed by
¯uorine NMR (82% yield), was the reduction product 1A.
No radical addition product was observed. Evidently the
reduction of the a,a-di¯uoroalkyl is the major pathway upon
direct electrochemical reduction, probably due its low
reduction potential. Therefore single electron transfer induc-
tion by electrochemically generated nitrobenzene anion
radical (E0 ˆ 1:10 V versus SCE) for the redox catalysed
reduction [37] of substrates 1, 3±7 and by the 4-nitropyr-
idine-N-oxide (E0 ˆ 0:70 V versus SCE) for the redox
catalysed reduction of substrate 2, was then employed so as
to operate under less reducing conditions. As a typical
experiment we carried out a preparative-scale electrolysis
Fig. 2. AM1 optimised conformations and spin densities (calculated at
B3LYP/6-31GÃ level) of the anion radical (a) and of the radical (b)
produced after cleavage of C±Cl bond of 1. Spin densities are drawn for an
isodensity of 0.004 a.u.
of the substrate 1 in the presence of large excess of the
ole®nic acceptor 7 at a potential behind the nitrobenzene
(E ˆ 1:30 V versus SCE). Using a two-compartment cell
with carbon felt as cathode and anode materials, a glass frit
as separator, we found that the starting material was con-
sumed after 2.2F/mol (as checked by TLC or HPLC) and
that two major compounds were produced along with some
minor by-products. The major compounds were separated
by silica gel chromatography and were identi®ed as 1A
(28%) and as the 5-dimethylamino-11,11-di¯uoro-1, 2,
11,11a-tetrahydro-3aH-phenanthro[1,2-b]furan-10-one 11
(60%). The structure of compound 11 was con®rmed by

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292
Table 1
its proton NMR spectrum where the proton at position 4 (see
structure in Chart) on the naphthalene ring, appeared as a
singlet demonstrating the absence of proton±proton cou-
pling due to the intramolecular cyclisation. A resonance
centred at d 5.3 ppm appeared as a doublet and was
Synthesis of the cyclised a,a-difluoroketones
Substratea
Olefinic acceptor
Product (%)b
1c
2,3-Dihydrofuran 7
n-Butylvinylether 8
1-Vinylimidazole 9
3,4-Dihydropyran 10
11 (60)
15 (50)d
16 (30)e
14 (45)
2
assigned to H3a with a J close to 7.15 Hz suggesting a
cis conformation. The ¯uorine NMR of compound 11 shows
clearly two pairs of doublets of doublets (centred at d 99.9
and 111.4 ppm/CFCl3) demonstrating that the ¯uorines
2f
2,3-Dihydrofuran 7
12 (32)g
13 (28)h
are non-equivalent, with F±F and F±H coupling (JF
3
ˆ
a
3
Csub ˆ 3:53  10 3 mol ‡ Colefin 35:3  10 mol in anhydrous
F
272 Hz, JF ˆ 12:5 and 11.5 Hz). It is dif®cult from the
H
DMF ‡ 0:1 M Et4NBF4.
b Isolated yield; 2.2F/mol of starting substrate.
NMR to distinguish between the two possible conformers.
The other possible structure (with the same molecular peak
at 317) could have been the seven-membered ring cyclised
product 110. This structure was ruled out since we should
have observed in its proton NMR spectrum, the H-3 as a
doublet. The simple addition product 1100 was also ruled out
since we did obtain a molecular peak of 317 instead of 319 as
con®rmed by GC/MS as well by microanalysis (Scheme 7).
The new gem-di¯uorinated cyclised compounds 11±16
were obtained similarly in moderate yields after separation
by silica gel column chromatography (Table 1).
c PhNO2 (C ˆ 0:75  10 mol) was used as redox mediator; electro-
3
lysis potential E ˆ 1:30 V versus SCE.
d Obtained as a cis/trans mixture.
e Fluorine NMR yield.
f 4-Nitro pyridine-N-oxide (C ˆ 0:75  10 mol) was used as redox
3
mediator; electrolysis potential E ˆ 0:70 V versus SCE.
g After 1.7F/mol.
h After 3.4F/mol.
Cyclised product 12 was obtained in 32% isolated yield
from the redox catalysed cyclisation of ketone 2 after the
consumption of 1.7F/mol, at a constant potential close to
0.70 V versus SCE, and compound 13 was obtained in
28% isolated yield after the consumption of 3.2F/mol at a
more negative potential close to 1.0 V versus SCE, or
more conveniently from the reductive dechlorination of 12
with Rongalite (in absolute EtOH for 5 h). Compound 12
can be also synthesised (52%) by direct chlorodi¯uoroace-
tylation of 11 in re¯uxing 1,2-dichloroethane (3 h, no pyr-
idine). We should note that the electrochemical synthesis of
12 and 13 gave also other ¯uorinated products, usually
reduction products in appreciable amounts. Compounds
15 and 16 were obtained as mixture of isomers. Due to
overlapping signals in 1H NMR we are not able to determine
the ratio of isomers. AM1 optimised geometry calculation
suggested that for 15, the trans isomer is more stable by
2.5 kcal/mol. Similar semi-empirical calculations show that
the more stable structures for the cyclised product 11, among
the four possible geometries, were the conformations with
H3a and H11a being either axial±axial or equatorial±
equatorial (Fig. 3).
Scheme 7.

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293
Reaction of ketone 3 (electrolysis was run at 08C) with 7
gave at least three ¯uorinated products where 3A was the
major component; other products were characterised by
complicated AB systems and doublet of doublets (cyclised
products: 5-exo and/or 6-endo) in the ¯uorine spectrum of
the crude product. GC/MS could not distinguish between the
different possible products since they have the same mole-
cular weight. Work is under progress to ®nd the conditions to
obtain the desired cyclised products.
Fig. 3. AM1-optimised geometry of the cyclised product 11.
The products which represent the remaining balance
material were usually the hydrogenolysis compounds from
hydrogen atom transfer to the a,a-di¯uoroalkyl or from
further reduction and protonation. For all the cyclised
products, the reduction of the C=O occurs at more negative
potentials than the ®rst reduction step of the starting ketones
1 and 2, close to 1.45 V versus SCE as checked by cyclic
voltammetry. For cyclised product 12, the reductive clea-
vage of the C±Cl bond seems to occur at 1.38 V versus
SCE therefore opening the possibility of further chemical
and electrochemical transformations at this site.
Attempts to obtain cyclised products with ketones 3±6
and 2,3-dihydrofuran 7 have been thus far less successful;
for example the redox catalysed reduction of ketone 3 in the
presence of large excess of 7, in DMF or CH3CN as solvent,
resulted in the formation of the corresponding reduction
product 4A as major component (65%) along with some
simple addition product X (20%), characterised by its AB
pattern in the ¯uorine spectrum.
The rather low yield obtained in the reaction of substrate 1
and vinyl imidazole 9 may be related to some partial
polymerisation of the ole®nic substrate and/or steric hin-
drance of the imidazole heterocycle unit. The yield of the
product was 30% (isomeric mixture) by ¯uorine NMR;
attempts to purify the product by silica gel chromatography
resulted in signi®cant loss of product.

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
294
Scheme 8.
The mechanism of formation of the cyclised products
The N,N-dimethylamino group of the heterocyclic a,a-
di¯uoroketones 12 and 13 was successfully displaced by
the dried tetramethylammonium salt of imidazole
([NuNMe4/‰substrateŠ ˆ 3) in anhydrous DMSO, at 508C
for 10 h, to give the exchanged products 17 (65%) and 18
(55%). Imidazole-2-carboxaldehyde and 2-methyl-5-nitroi-
midazole anions, less reactive nucleophiles, gave exchanged
products in moderate yields with increasing the concentra-
tion of the nucleophiles ([NuNMe4/‰substrateŠ ˆ 10). 2-(40-
Methoxyphenyl)imidazole, despite the increasing electron
density on the imidazole ring, reacts poorly as compared to
the imidazole anion. This unsatisfactory result may be
explained by a repulsive effect between the chloro or
di¯uoroacetyl group and the methoxyphenyl ring. The pro-
ducts which represent the remaining balance material were
the unreacted starting material (major compound) and other
yet unidenti®ed products (as observed by HPLC and 19F
NMR of the raw solution). The nucleophilic substitution
reaction was found to be regiospeci®c as the ±N(1) isomer
was isolated as the sole product. Formation of the substituted
products was monitored by HPLC and the yields are mod-
erate to good. The structures of compounds 17±23 obtained
after column chromatography, were con®rmed by their
spectroscopic and analytical data (Table 2).
involves the intramolecular cyclisation of the g,g-di¯uor-
oalkyl radical obtained after the addition of the a,a-di¯uor-
oalkyl radical on the double-bond. The observed
consumption of electricity (as measured by cyclic voltam-
metry and coulometry) is close to 2F/mol. This can be due
either to the further reduction of the cyclised radical in
solution by the anion radical of the catalyst or to an hydrogen
atom abstraction from the solvent [38] to give the ®nal
product after rearomatisation (Scheme 8). A dismutation of
the `cyclised radical' cannot explain the consumption of
electricity (2F/mol) since it should have been close to 1F/
mol.
2.4. Aromatic N±N exchanged reactions
N, N-dimethyl-2, 4-bis(tri¯uoroacetyl)-1-naphthylamine
was found to undergo various nitrogen±nitrogen, nitrogen±
sulfur and nitrogen±oxygen exchange reactions to give
interesting tri¯uoromethylated heterocycles [39]. We have
found that the heterocyclic a,a-di¯uoroketones 12 and 13
could also undergo N±N exchange reactions with several
tetramethylammonium salts of imidazoles to give the
exchanged products 17±23 in moderate to good yields.

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295
Table 2
376.498 Hz) used CCl3F as internal standard. Melting points
are uncorrected.
Synthesis of the 5-imidazol-1-yl a,a-difluoroketones
Substratea
Nucleophileb
Product (%)c
All calculations were carried out with the Gaussian 94
package [43]. Geometries of the anions radical and radical
were calculated by full optimisation of the conformations
using semi-empirical method AM1 [44]. Spin densities were
calculated using the B3LYP density functional theory [45]
with a 6-31GÃ basis set [46] on the previously optimised
AM1 conformations.
12
Imidazole
17 (65)
19 (71)
16 (32)
22 (45)
23 (40)
Benzimidazole
2-(40-Methoxphenyl) imidazole
Imidazole-2-carboxaldehyded
2-Methyl-5-nitro imidazoled
13
Imidazole
18 (55)
20 (48)
Benzimidazole
a Csub ˆ 1:58  10 3 mol ‡ CNuNMe ˆ 4:74  10 3 mol in anhydrous
4.1. 2-Chloro-1-(4-dimethylamino-naphthalen-1-yl)-2,2-
difluoro-ethanone (1)
4
DMSO at 508C for 10 h.
b Used as the tetramethylammonium salt.
c Isolated yield.
A representative procedure for the synthesis of the 2-
chloro-1-(4-dimethylamino-naphthalen-1-yl)-2,2-di¯uoro-
ethanone (1) is described. Into a three-necked ¯ask equipped
with a dropping funnel, a re¯ux condenser (with a silica gel
drying tube) and a nitrogen inlet, were added under nitrogen
at 08C, 25 ml of anhydrous CHCl3 followed by
(ClCF2CO)2O (14.1 g, 58 mmol) via a syringe. The solution
was stirred and maintained at this temperature for 30 min
and then was added dropwise a solution containing the N,N-
dimethyl-1-naphthylamine (10 g, 58.4 mmol) and pyridine
(4.7 g, 59.4 mmol). When the addition was ®nished, the
solution was stirred at 08C for 30 min and warmed-up slowly
to room temperature over 3 h. After this time, TLC analysis
indicated that the N,N-dimethyl-1-naphthylamine was
totally consumed. The yellow solution was diluted with
CHCl3, washed with 1N HCl aqueous solution (4Â) and
dried over MgSO4. Evaporation of the solvent left a viscous
orange oil which was recrystallised (two crops) from cold
absolute EtOH to give 1 (75%): mp 748C (yellow crystals).
1H NMR (CDCl3): dH 3.11 (6H, s, NMe2), 6.91 (1H, d, H-2,
J ˆ 8:42 Hz), 7.52±7.66 (2H, m, H-6 and H-7), 8.16±8.28
(2H, m, H-3 and H-8), 9.01 (1H, dd, H-5, J ˆ 7:69,
0.65 Hz). 19F NMR (CDCl3/CFCl3): dF 58.03 (2F, s).
d Csub ˆ 1:58  10 3 mol ‡ CNuNMe ˆ 15:8  10 3 mol in anhydrous
4
DMSO at 508C for 10 h.
3. Conclusions
These results represent the ®rst example of a free-radical
electrochemical intramolecular synthesis of some interest-
ing gem-di¯uoro heterocyclic compounds that could be
dif®cult to obtain from other types of reactions. None of
the yields has been optimised and room for improvement
certainly exists. The N±N exchange reaction is a facile and
convenient synthetic method to obtain ¯uorine-containing
naphthalene-fused heterocycles which are dif®culty acces-
sible by other methods. This reaction is now being extended
to bifunctional nucleophiles and other nitrogen nucleo-
philes. Work is under progress to ®nd the best conditions
to obtain the bicyclic gem-di¯uorinated products with
ketones 3±6 as starting materials. The successful cyclisation
reaction with the naphthalene ketones 1 and 2, will be
extended to more sophisticated starting chlorodi¯uoro-
methylated ketones. Evaluation of the biological activities
of all the compounds will be done in a due course.
‡
‡
GC/MS: M ˆ 283, M
CF2Cl ˆ 198. Anal. Calcd. for
4. Experimental
C14H12ClF2NO: C 59.27%, H 4.26%, N 4.94%. Found C
59.10%, H 4.43%, N 4.76%.
The electrochemical equipment has been described in
[40]. All the ole®nic acceptors are from commercial origins.
Benzimidazole, imidazole, 2-methyl-5-nitro imidazole were
purchased from Aldrich. Rongalite was purchased from
Fluka. Imidazole-2-carboxaldehyde was prepared as in
[41] and 2-(40-methoxyphenyl)imidazole was prepared as
in [42]. Anhydrous DMF, CH3CN (Fluka Puriss dried over
molecular sieve) and DMSO (Gold label from Aldrich) were
used as received. Silica gel (MN Kieselgel 60, 70±230 mesh,
Macherey±Nagel) was employed for column chromatogra-
phy. Analytical TLC was performed with 0.25 mm coated
commercial plates (Macherey±Nagel, Polygram SIL G/
UV254). All the reactions with air-sensitive compounds were
carried out under nitrogen atmosphere.
4.2. 2-Chloro-1-[3-(chloro-difluoro-acetyl)-(4-dimethyl-
amino-naphthalen-1-yl)-2,2-difluoro-ethanone (2)
1
Mp 848C (orange crystals). H NMR (CDCl3): dH 3.16
(6H, s, NMe2), 7.58±7.62 (1H, m, H-7), 7.73±7.77 (1H, m,
H-6), 8.22±8.24 (1H, dd, H-8, J ˆ 7:71, 0.88 Hz), 8.64 (1H,
s, H-3), 8.9 (1H, d, H-5, J ˆ 8:55 Hz). 19F NMR (CDCl3/
‡
CFCl3): dF 60.17 (2F, s), 59.18 (2F, s). GC/MS: M
ˆ
‡
395, M CF2Cl ˆ 310. Anal. Calcd. for C16H11ClF4NO2:
C 48.51%, H 2.80%, N 3.54%. Found C 48.38%, H 2.63%, N
3.76%.
4.3. 4-Butoxy-1-chloro-1,1-difluoro-but-3-en-2-one (3)
NMR spectra (400 MHz Bruker spectrometer) were taken
in DMSO-d6 and CDCl3 using TMS as the internal standard
Yellowish oil. 1H NMR (CDCl3): dH 0.92 (3H, m, CH3),
1.47 (2H, m, CH2), 1.69 (2H, m, CH2), 4.02 (2H, t, CH2,
1
for H (250.133 and 400.132 Hz). 19F NMR (235.323 and

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
296
J ˆ 6:49 Hz), 5.85 (1H, d, Ha, J ˆ 12:21 Hz), ), 7.87 (1H, d,
Hb, J ˆ 12:22 Hz). 19F NMR (CDCl3/CFCl3): dF 71.65
4.7. 4-Dimethylamino-naphthalen-1-yl-1-difluoroacetyl
(1A)
‡
‡
(2F, s). GC/MS: M ˆ 213, M
CF2Cl ˆ 127. Anal.
Calcd. for C8H11ClF2O2: C 45.19%, H 5.21%. Found C
45.28%, H 5.43%.
A representative procedure for the synthesis of the 4-
dimethylamino-naphthalen-1-yl-1-di¯uoroacetyl (1A) is
described. Into a three-necked ¯ask equipped with a re¯ux
condenser (with a silica gel drying tube) and a nitrogen inlet,
were added under nitrogen, 25 ml of absolute EtOH fol-
lowed by 1 (0.5 g, 1.76 mmol). The solution was stirred until
complete dissolution and then Rongalite (0.32 g,
2.12 mmol) was added. The whole mixture was then heated
at re¯ux until complete consumption of starting material
(2 h). The solution was ®ltered, and evaporated to dryness.
The crude product was ®ltered through a short column of
silica gel eluting with hexane/EtOAc (70:30) and recrystal-
lised from hexane to give 1A (68%); mp ˆ 70±728C (yellow
4.4. 1-Chloro-4-(4-chloro-phenylamino)-1,1-difluoro-but-
3-en-2-one (4)
A representative procedure for the synthesis of the 1-
chloro-4-(4-chloro-phenylamino)-1,1-di¯uoro-but-3-en-2-
one (4) is described. Into a three-necked ¯ask equipped with
a re¯ux condenser (with a silica gel drying tube) and a
nitrogen inlet, were added under nitrogen 15 ml of an
anhydrous CH3CN solution containing 3 (2.1 g, 9.85 mmol).
The solution was stirred at room temperature for 30 min and
then were added 1.2 g (10 mmol) of 4-chloroaniline. When
the addition was ®nished, the solution was heated to re¯ux
for 30 min. After this time, TLC indicated that the amine
was totally consumed. Evaporation of the solvent left a
viscous orange oil which was recrystallised (two crops)
from hexane to give 4 (58%): mp 848C (yellowish needles).
1H NMR (CDCl3): dH 5.68 (1H, d, Ha, J ˆ 7:62 Hz), 7.03±
7.09 (2H, m, H-arom), 7.32±7.37 (2H, m, H-arom), 7.61
1
powder). H NMR (CDCl3): dH 3.07 (6H, s, ±NMe2), 6.44
(1H, t, ±CF2H, 2JH ˆ 57 Hz), 6.92 (1H, d, H-2,
F
J ˆ 8:36 Hz), 7.50±7.68 (2H, m, H-6 and H-7), 8.13±8.20
(2H, m, H-3 and H-8), 9.2 (1H, d, H-5, J ˆ 8:38 Hz). 19F
2
NMR (CDCl3/CFCl3): dF 119.31 (2F, d, JH ˆ 54 Hz).
F
‡
‡
GC/MS: M ˆ 249, M
CF2H ˆ 198. Anal. Calcd. for
C14H13F2NO: C 67.46%, H 5.22%, N 5.62%. Found C
67.68%, H 5.43%, N 5.87%.
(1H, dd, Hb, J ˆ 13:0, 7.62 Hz), 11.62 (1H, br s, Hc). 19F
4.8. 1-[3-(2,2-Difluoro-acetyl)-4-dimethylamino-
naphthalen-1-yl]2,2-difluoro-ethanone (2B)
‡
NMR (CDCl3/CFCl3): dF 65.75 (2F, s). GC/MS: M
ˆ
‡
265, M CF2Cl ˆ 180. Anal. Calcd. for C10H7Cl2F2NO:
C 45.14%, H 2.65%, N 5.26%. Found C 45.10%, H 2.53%, N
5.46%.
1
Yellowish viscous oil. H NMR (CDCl3): dH 3.12 (6H,
s, ±NMe ), 6.44 (1H, t, ±CF H, 2JH ˆ 57 Hz), 6.58 (1H, t,
F
2
2
2
±CF H, JH ˆ 52 Hz), 7.68±8.01 (2H, m, H-6 and H-7),
F
2
4.5. 1-Chloro-1,1-difluoro-4-[(furan-2-ylmethyl)-amino]-
but-3-en-2-one (5)
8.22±8.24 (1H, dd, H-8, J ˆ 7:71, 0.88 Hz), 8.64 (1H, s, H-
3), 8.9 (1H, d, H-5, J ˆ 8:55 Hz). 19F NMR (CDCl3/CFCl3):
dF
119.31 (2F, d, 2JH ˆ 57 Hz),
123.2 (2F, d,
CF2H ˆ 276.
F
‡
The product was puri®ed by silica gel chromatography
1
2JH ˆ 52 Hz). GC/MS: M ˆ 327, M
‡
F
(Et2O/hexane, 60:40) and obtained as a yellowish oil. H
Anal. Calcd. for C16H13F4NO2: C 58.72%, H 4.00%, N
4.28%. Found C 58.68%, H 4.33%, N 4.53%.
NMR (CDCl3): dH 4.46 (2H, d, J ˆ 5:75 Hz), 5.39 (1H, d,
Ha, J ˆ 7:27 Hz), 6.27±6.34 (2H, m, H-furan), 7.17 (1H, dd,
Hb, J ˆ 13:4, 7.3 Hz), 7.36 (1H, d, H-furan, J ˆ 1:0 Hz),
10.16 (1H, br s, Hc). 19F NMR (CDCl3/CFCl3): dF 68.81
4.9. 4-Butoxy-1,1-difluoro-but-3-en-2-one (3A)
‡
‡
(2F, s). GC/MS: M ˆ 235, M
CF2Cl ˆ 150. Anal.
The product was obtained as a yellowish oil after pur-
i®cation by silica gel chromatography (hexane/EtOAc,
80:20). 1H NMR (CDCl3): dH 0.96 (3H, m, CH3), 1.34
(2H, m, CH2), 1.66 (2H, m, CH2), 4.02 (2H, t, CH2,
J ˆ 6:49 Hz), 5.85 (1H, d, Ha, J ˆ 12:21 Hz), ), 6.68
Calcd. for C9H8ClF2NO2: C 45.88%, H 3.42%, N 5.94%.
Found C 45.62%, H 3.52%, N 6.03%.
4.6. 4-Benzylamino-1-chloro-1,1-difluoro-but-3-en-2-one
(6)
(2H, t, ±CF2H, 2JH ˆ 51 Hz), 7.87 (1H, d, Hb,
F
J ˆ 12:22 Hz). 19F NMR (CDCl3/CFCl3): dF 122.2 (2F,
‡
‡
t, 2JH ˆ 51 Hz). GC/MS: M ˆ 178, M
CF2H ˆ 127
The product was puri®ed by silica gel chromatography
1
F
(hexane/EtOAc, 70:30) and obtained as a yellowish oil. H
Anal. Calcd. for C8H12F2O2: C 53.93%, H 6.79%. Found C
54.04%, H 6.43%.
NMR (CDCl3): dH 4.71 (2H, br s, CH2), 5.58 (1H, d, Ha,
J ˆ 7:54 Hz), 7.17 (1H, dd, Hb, J ˆ 13:2, 7.1 Hz), 7.37±
7.58 (5H, m, arom-H), 10.26 (1H, br s, Hc). 19F NMR
4.10. 4-(4-Chloro-phenylamino)-1,1-difluoro-but-3-en-2-
one (4A)
‡
(CDCl3/CFCl3): dF 68.32 (2F, s). GC/MS: M ˆ 245,
‡
M
CF2Cl ˆ 160. Anal. Calcd. for C11H10ClF2NO: C
53.78%, H 4.10%, N 5.70%. Found C 53.82%, H 4.32%,
N 5.53%.
The product was obtained as a yellowish viscous oil after
puri®cation by silica gel chromatography (hexane/EtOAc,

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
297
80:20). 1H NMR (CDCl3): dH 5.45 (1H, d, Ha, J ˆ 7:62 Hz),
6.05 (1H, t, ±CF H, 2JH ˆ 56 Hz), 7.03±7.09 (2H, m, H-
the 4-dimethylamino-naphthalen-1-yl-1-di¯uoroacetyl 1A
(0.24 g, 0.98 mmol, 28%) and then 11 in 60% yield:
F
2
1
arom), 7.32±7.37 (2H, m, H-arom), 7.61 (1H, dd, Hb,
J ˆ 13:0, 7.62 Hz), 11.42 (1H, br s, Hc). 19F NMR
mp ˆ 108 1108C (greenish powder). H NMR (CDCl3):
0
0
dH 2.06±2.13 (1H, m, H1 or H1 ), 2.28±2.35 (1H, m, H1 or
(CDCl3/CFCl3): dF 125.2 (2F, t, 2JH ˆ 57 Hz). GC/
H1), 3.08 (6H, s, ±NMe2), 3.41±3.44 (1H, m, H11a), 3.85±
0
4.00 (2H, m, H2 and H2 ), 5.32±5.35 (1H, d, H3a,
F
‡
‡
MS: M ˆ 231, M
CF2Cl ˆ 180. Anal. Calcd. for
C10H8ClF2NO: C 51.85%, H 3.48%, N 6.05%. Found C
51.68%, H 3.53%, N 6.26%.
JH
H-7 and H-8), 8.11±8.15 (1H, d, H-6), 9.29±9.34 (1H, d,
ˆ 7 Hz), 7.05 (1H, s, H-4), 7.49±7.69 (2H, m,
H11a
3a
H-9). 19F NMR (CDCl3/CFCl3): dF 99.22 (1F, dd,
4.11. 1,1-Difluoro-4-[(furan-2-yl-methyl)-amino]-but-3-
en-2-one (5A)
JF ˆ 272 Hz, 3JF
ˆ 12:5 Hz),
111.40 (1F, dd,
ˆ 11:5 Hz). MS (CI/NH3): M‡
F
H11a
JF ˆ 272 Hz, 3JF
F
H11a
‡
‡
H ˆ 318, M ‡ NH4 ˆ 335. Anal. Calcd. for C18H17-
F2NO2: C 68.13%, H 5.40%, N 4.41%. Found C 68.32%,
H 5.32%, N 4.73%.
The product was puri®ed by silica gel chromatography
1
(Et2O/hexane, 60:40) and obtained as a yellowish oil. H
NMR (CDCl3): dH 4.26 (2H, d, J ˆ 5:75 Hz), 5.29 (1H, d,
Ha, J ˆ 7:27 Hz), 6.15 (1H, t, ±CF2H, 2JH ˆ 52 Hz),
4.14. 4-(2-Chloro-2,2-difluoro-acetyl)-5-dimethylamino-
11,11-difluoro-1,2,11,11a-tetrahydro-3aH-phenanthro[1,2-
b]furan-10-one (12)
F
6.57±6.84 (2H, m, H-furan), 7.37 (1H, dd, Hb, J ˆ 13:4,
7.3 Hz), 7.56 (1H, d, H-furan, J ˆ 1:0 Hz), 10.26 (1H, br s,
Hc). 19F NMR (CDCl3/CFCl3): dF
124.5 (2F, t,
CF2Cl ˆ 150.
‡
‡
1
2JH ˆ 53 Hz). GC/MS: M ˆ 201, M
Mp ˆ 1278C (yellowish powder). H NMR (CDCl3): dH
F
0
2.06±2.13 (1H, m, H1 or H1 ), 2.28±2.35 (1H, m, H1 or H1),
0
Anal. Calcd. for C9H9F2NO2: C 53.73%, H 4.51%, N 6.96%.
Found C 53.62%, H 4.52%, N 6.93%.
3.08 (6H, s, ±NMe2), 3.41±3.44 (1H, m, H11a), 3.85±4.00
0
(2H, m, H2 and H2 ), 5.32±5.35 (1H, d, H3a, JH3a-H11a
7:2 Hz), 7.42±7.58 (2H, m, H-7 and H-8), 8.22±8.26 (1H, d,
ˆ
4.12. 4-Benzylamino-1,1-difluoro-but-3-en-2-one (6A)
H-6), 9.32±9.37 (1H, d, H-9). 19F NMR (CDCl3/CFCl3): dF
3
The product was puri®ed by silica gel chromatography
1
61.4 (s, 2F), 99.22 (1F, dd, JF ˆ 272 Hz, JF
ˆ
F
H11a
(hexane/EtOAc, 70:30) and obtained as a yellowish oil. H
NMR (CDCl3): dH 4.71 (2H, CH2, br s), 5.78 (1H, d, Ha,
12:5 Hz), 111.40 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ
F
H11a
‡
‡
11:5 Hz). MS (CI/NH3): M ‡ H ˆ 430, M ‡ NH4
ˆ 447. Anal. Calcd. for C20H16F4NO3: C 55.89%, H
3.75%, N 3.26%. Found C 55.72%, H 3.82%, N 3.43%.
2
J ˆ 7:54 Hz), ), 6.15 (1H, t, ±CF2H, JH ˆ 52 Hz), 7.37
F
(1H, dd, Hb, J ˆ 13:2, 7.1 Hz), 7.67±7.98 (5H, m, arom-H),
10.16 (1H, br s, Hc). 19F NMR (CDCl3/CFCl3): dF 126.5
‡
‡
(2F, t, 2JH ˆ 55 Hz). GC/MS: M ˆ 211, M
CF2Cl ˆ
4.15. 4-(2,2-Difluoro-acetyl)-5-dimethylamino-11,11-
difluoro-1,2,11,11a-tetrahydro-3aH-phenanthro[1,2-
b]furan-10-one (13)
F
160. Anal. Calcd. for C11H11F2NO: C 62.55%, H 5.25%, N
6.63%. Found C 62.62%, H 5.32%, N 6.73%.
1
4.13. 5-Dimethylamino-11,11-difluoro-1,2,11,11a-
tetrahydro-3aH-phenanthro[1,2-b]furan-10-one (11)
Mp ˆ 1198C (yellowish powder). H NMR (CDCl3): dH
0
2.06±2.13 (1H, m, H1 or H1 ), 2.28±2.35 (1H, m, H1 or H1),
0
3.08 (6H, s, ±NMe2), 3.41±3.44 (1H, m, H11a), 3.85±4.00
0
(2H, m, H2 and H2 ), 5.32±5.35 (1H, d, H3a,
A representative procedure for the synthesis of the
cyclised product 5-dimethylamino-11,11-di¯uoro-1,2,11,
11a-tetrahydro-3aH-phenanthro[1,2-b]furan-10-one (11) is
described. A solution of nitrobenzene (0.15 g, 1.2 mmol), 2-
chloro-1-(4-dimethylamino-naphthalen-1-yl)-2,2-di¯uoro-
ethanone 1 (1 g, 3.53 mmol), 2,3-dihydrofuran 7 (2.5 g,
35.3 mmol) and NEt4BF4 (2.17 g, 10 mmol) in DMF
(80 ml) was reduced at 1.30 V versus SCE in a cylindrical
Pyrex cell with carbon felt (15 cm2) as cathode, separated
from the anolyte compartment (carbon felt anode 10 cm2)
with a glass frit (porosity 4), until almost all the starting
material was consumed (as checked by TLC; 2.2F/mol). The
red solution was evaporated to dryness and the crude product
was extracted with CHCl3 (3Â); the combined organic
extracts were washed with brine (3Â), water (3Â), dried
over MgSO4 and ®ltered. Evaporation of the solvent
left an orange-red viscous solid as crude product. Silica
gel chromatography using EtOAc/hexane (50/50) gave ®rst
JH
7.42±7.58 (2H, m, H-7 and H-8), 8.22±8.26 (1H, d, H-6),
ˆ 7 Hz), 6.58 (1H, t, ±CF2H, 2HH ˆ 54 Hz),
H11a
F
3a
9.32±9.37 (1H, d, H-9). 19F NMR (CDCl3/CFCl3): dF
99.22 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ 12:5 Hz),
F
H11a
111.40 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ 11:5 Hz),
F
H11a
‡
2
122.4 (2F, d, JH ˆ 54 Hz). MS (CI/NH3): M ‡ H ˆ
F
‡
396, M ‡ NH4 ˆ 413. Anal. Calcd. for C20H17F4NO3: C
60.76%, H 4.33%, N 3.54%. Found C 60.72%, H 4.42%, N
3.43%.
4.16. 6-Dimethylamino-12,12-difluoro-2,3,12,12a-
tetrahydro-1H-4aH-4-oxa-chrysen-11-one (14)
1
Mp ˆ 1058C (yellowish powder). H NMR (CDCl3): dH
0
1.56±2.13 (4H, m, H1 and H1 and H2 and H2 ), 3.08 (6H, s, ±
0
NMe2), 3.41±3.44 (1H, m, H12a), 3.85±4.00 (2H, m, H3 and
ˆ 7 Hz), 7.12 (1H, s,
0
H3 ), 5.32±5.35 (1H, d, H4a, JH
H12a
4a

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P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
298
H-5), 7.42±7.58 (2H, m, H-8 and H-9), 8.22±8.26 (1H, d, H-
7), 9.32±9.37 (1H, d, H-10). 19F NMR (CDCl3/CFCl3): dF
and dried over MgSO4. Filtration and evaporation of the
solvent under reduced pressure gave a yellow solid as crude
product which was puri®ed by silica gel chromatography
(hexane/EtOAc 70:30); evaporation of the appropriate frac-
tions and recrystallisation from CHCl3/hexane gave 0.35 g
(1.03 mmol, 65%) of the 4-(2-chloro-2,2-di¯uoro-acetyl)-
11, 11-di¯uoro-5-imidazolyl-1-yl-1, 2, 11, 11a-tetrahydro-
3aH-phenanthro[1,2-b]furan-10-one (17); mp ˆ 122±
1248C (yellowish powder). 1H NMR (DMSO-d6): dH
101.22 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ 12:5 Hz),
F
H12a
3
114.40 (1F, dd, JF ˆ 272 Hz, JF
ˆ 11:5 Hz). MS
F
H12a
‡
‡
(CI/NH3): M ‡ H ˆ 332, M ‡ NH4 ˆ 349. Anal. Calcd.
for C19H19F2NO2: C 68.87%, H 5.78%, N 4.23%. Found C
68.72%, H 5.82%, N 4.13%.
4.17. 1-Butoxy-9-dimethylamino-3,3-difluoro-2,3-dihydro-
1H-phenanthren-4-one (15)
0
0
2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38 (1H, m, H1 or
H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (2H, m, H2 and
Viscous yellowish oil. 1H NMR (CDCl3): dH 0.92 (3H, m,
CH3), 1.47 (2H, m, CH2), 1.69 (2H, m, CH2), 2.28±2.35 (1H,
H2 ), 5.32±5.35 (1H, d, H3a, JH3a-H11a ˆ 6:87 Hz Hz), 7.28
0
(1H, s, H-200), 7.49±7.69 (2H, m, H-7 and H-8), 7.72 (1H, s,
H-400 or H-500), 8.11±8.15 (1H, d, H-6), 9.29±9.34 (d, 1H, H-
0
m, H2 and H2 ), 2.85 (6H, s, ±NMe2), 3.47 (2H, t, CH2,
J ˆ 6:49 Hz), 3.85±4.00 (1H, m, H1 and H1 ), 7.05 (1H, s, H-
9). 19F NMR (DMSO-d6/CFCl3): dF 56.7 (2F, s), 101.2
0
3
10), 7.49±7.69 (2H, m, H-6 and H-7), 8.11±8.15 (1H, d, H-
8), 9.29±9.34 (1H, d, H-5). 19F NMR (CDCl3/CFCl3): dF
(1F, dd, JF ˆ 272 Hz, JF
ˆ 13:5 Hz), 112.40 (1F,
F
H11a
dd, JF ˆ 272 Hz, 3JF
ˆ 12:5 Hz) Mass (CI/CH4):
F
H11a
3
‡
99.22 (1F, ddd, JF ˆ 272 Hz, JF ˆ 23:2, 11.5 Hz),
m=e ˆ 341 (M ‡ H ). Anal. Calcd. for C21H13ClF4N2O3:
C 55.71%, H 2.89%, N 6.19%. Found C 55.42%, H 2.72%, N
6.33%.
F
H
3
102.4 (1F, ddd, JF ˆ 272 Hz, JF ˆ 23:2; 11:5 Hz).
F
H
‡
‡
MS (CI/NH3): M ‡ H ˆ 348, M ‡ NH4 ˆ 365. Anal.
Calcd. for C20H23F2NO2: C 69.15%, H 6.67%, N 4.03%.
Found C 69.42%, H 6.72%, N 4.33%.
4.20. 4-(2,2-Difluoro-acetyl)-11,11-difluoro-5-imidazol-1-
yl-1,2,11,11a-tetrahydro-3aH-phenanthro[1,2-b]furan-10-
one (18)
4.18. 9-Dimethylamino-3,3-difluoro-1-imidazol-1-yl-2,3-
dihydro-1H-phenanthren-4-one (16)
The compound can be prepared as described for the
synthesis of 17 or by reductive dechlorination of 17 with
Rongalite (1.5 equivalents) in re¯uxing absolute EtOH (3 h);
Viscous yellowish oil. 1H NMR (CDCl3): dH 2.85 (6H, s,
0
±NMe2), 2.28±2.45 (1H, m, H2 and H2 ), 3.85±4.00 (1H, m,
00
1
0
H1 and H1 ), 7.15 (1H, s, H-10), 7.22 (2H, m, H-4 and H-
mp ˆ 101±1048C (yellowish powder). H NMR (DMSO-
500), 7.49±7.69 (2H, m, H-6 and H-7), 8.11±8.15 (2H, m, H-8
d6): dH 2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38 (1H, m, H1
or H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (2H, m, H2 and
0
0
and H-200), 9.29±9.34 (1H, d, H-5). 19F NMR (CDCl3/
CFCl3): dFdF 101.2 (1F, ddd, JF ˆ 272 Hz, 3JF
ˆ
ˆ
H2 ), 5.32±5.35 (1H, d, H3a, JH
2
ˆ 6:87 Hz), 6.51 (1H,
0
F
H
H
H11a
3a
3
25:2; 12:5 Hz), 103.5 (1F, ddd, JF ˆ 272 Hz, JF
t, ±CF H, JF ˆ 58 Hz), 7.28 (1H, s, H-200), 7.49±7.69
F
F
2
‡
22:3; 11:5 Hz). MS (CI/NH3): M ‡ H ˆ 342, M‡
(2H, m, H-7 and H-8), 7.72 (1H, s, H-400 or H-500), 8.11±8.15
‡
NH4 ˆ 359. Anal. Calcd. for C19H17F2N3O: C 66.85%,
(1H, d, H-6), 9.29±9.34 (d, 1H, H-9). 19F NMR (DMSO-d6/
H 5.02%, N 12.31%. Found C 66.61%, H 5.42%, N 12.54%.
CFCl3): dF 101.2 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ
ˆ
F
H11a
H11a
13:5 Hz), 112.40 (1F, dd, JF ˆ 272 Hz, 3JF
F
2
4.19. 4-(2-Chloro-2,2-difluoro-acetyl)-11,11-difluoro-5-
imidazolyl-1-yl-1,2,11,11a-tetrahydro-3aH-
phenanthro[1,2-b]furan-10-one (17)
12:5 Hz), 122.4 (2F, d, JH ˆ 58 Hz). Mass (CI/CH ):
F
4
‡
m=e ˆ 419 (M ‡ H ). Anal. Calcd. for C21H14F4N2O3: C
60.29%, H 3.37%, N 6.70%. Found C 60.42%, H 3.52%, N
6.83%.
A typical procedure for the reaction between a,a-di¯uor-
oketone 12 and the anion of imidazole is as follows: into a
three-necked ¯ask equipped with a re¯ux condenser, a
dropping funnel and a nitrogen inlet were added 0.5 g
(1.58 mmol) of the a,a-di¯uoroketone 12 in 20 ml of anhy-
drous DMSO. The solution was stirred vigorously until
complete dissolution. Then a 20 ml DMSO solution of
0.66 g (4.73 mmol) of the tetramethylammonium salt of
imidazole (carefully dried under high vacuum) was added
dropwise over 20 min. When the addition was complete, the
solution was heated at 508C for 10 h when the yield of the
exchanged product remains constant (as checked by HPLC).
The solution was diluted with brine (100 ml) and extracted
with EtOAc (3 Â 100 ml); the combined organic solutions
were washed with brine (2 Â 100 ml), water (2 Â 100 ml)
4.21. 5-Benzoimidazol-1-yl-4-(2-chloro-2,2-difluoro-
acetyl)-11,11-difluoro-1,2,11,11a-tetrahydro-3aH-
phenanthro[1,2-b]furan-10-one (19)
1
Mp ˆ 1418C (off-white powder). H NMR (DMSO-d6):
0
0
dH 2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38 (1H, m, H1 or
H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (2H, m, H2 and
0
H2 ), 5.32±5.35 (1H, d, H3a, JH
ˆ 6:87 Hz), 7.28 (2H,
H11a
3a
m, H-500 and H-600), 7.49±7.69 (2H, m, H-7 and H-8), 7.72±
7.88 (3H, m, H-400 and H-700 and H-6), 8.11 (1H, s, H-200),
9.29±9.34 (d, 1H, H-9). 19F NMR (DMSO-d6/CFCl3): dF
3
61.2 (2F, s), 101.2 (1F, dd, JF ˆ 272 Hz, JF
ˆ
F
H11a
13:5 Hz), 112.40 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ
F
H11a
‡
12:5 Hz). Mass (CI/CH4): m=e ˆ 503 (M ‡ H ). Anal.

Â
P. Hapiot, M. Medebielle / Journal of Fluorine Chemistry 107 (2001) 285±300
299
Calcd. for C25H15ClF4N2O3: C 59.71%, H 3.01%, N 5.57%.
Found C 59.62%, H 3.22%, N 5.63%.
54.96%, H 2.73%, N 5.83%. Found C 55.02%, H 2.72%,
N 5.63%.
4.22. 5-Benzoimimidazol-1-yl-4-(2,2-difluoro-acetyl)-
11,11-difluoro-1,2,11,11a-tetrahydro-3aH-phenanthro[1,2-
b]furan-10-one (20)
4.25. 4-(2-Chloro-2,2-difluoro-acetyl)-11,11-difluoro-5-(2-
methyl-5-nitro-imidazol-1-yl)-1,2,11,11a-tetrahydro-3aH-
phenanthro[1,2-b]furan-10-one (23)
1
The compound can be prepared as described for the
synthesis of 17 or by reductive dechlorination of 19 with
Rongalite (1.5 equivalents) in re¯uxing absolute EtOH
(4.5 h); mp ˆ 1328C (off-white powder). 1H NMR
At mp ˆ 1528C (yellowish powder). H NMR (CDCl3):
0
0
dH 2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38 (1H, m, H1 or
H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (2H, m, H2 and
0
H2 ), 5.32±5.35 (1H, d, H3a, JH
ˆ 6:87 Hz), 7.49±7.69
H11a
3a
0
(DMSO-d6): dH 2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38
(2H, m, H-7 and H-8), 7.72 (1H, s, H-400), 8.11±8.15 (1H, d,
0
(1H, m, H1 or H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (2H,
0
H-6), 9.29±9.34 (d, 1H, H-9). 19F NMR (CDCl3/CFCl3): dF
3
m, H2 and H2 ), 5.32±5.35 (1H, d, H3a, JH
ˆ 6:87 Hz),
56.7 (2F, s), 101.2 (1F, dd, JF ˆ 272 Hz, JF
ˆ
H11a
F
H11a
3a
6.51 (1H, t, ±CF H, 2JH ˆ 58 Hz), 7.28 (2H, m, H-500 and
13:5 Hz), 112.40 (1F, dd, JF ˆ 272 Hz, 3JF
ˆ
F
F
H11a
2
‡
H-600), 7.49±7.69 (2H, m, H-7 and H-8), 7.72±7.88 (3H, m,
H-400 and H-700 and H-6), 8.11 (1H, s, H-200), 9.29±9.34 (d,
1H, H-9). 19F NMR (DMSO-d6/CFCl3): dF 101.2 (1F, dd,
12:5 Hz) Mass (CI/CH4): m=e ˆ 512 (M ‡ H ). Anal.
Calcd. for C22H14ClF4N3O5: C 51.63%, H 2.76%, N
6.93%. Found C 51.42%, H 2.72%, N 6.73%.
JF ˆ 272 Hz, 3JF
ˆ 13:5 Hz),
112.40 (1F, dd,
2
F
H11a
3
JF ˆ 272 Hz, JF
ˆ 12:5 Hz), 122.4 (2F, d, JH
F
H11a
F
‡
ˆ 58 Hz). Mass (CI/CH4): m=e ˆ 469 (M ‡ H ). Anal.
Calcd. for C25H16F4N2O3: C 64.10%, H 3.44%, N 5.98%.
Found C 64.32%, H 3.62%, N 5.83%.
Acknowledgements
We thank Marie-Noelle Rager (ENSCP, Paris) for the 1H
and 19F NMR spectra and David Clainquart (Universite Paris
Â
7) for the mass spectra. Professor Jean Pinson (Universite
Â
4.23. 4-(2-Chloro-2,2-difluoro-acetyl)-11,11-difluoro-5-
[2-(4-methoxy-phenyl)-imidazol-1-yl]-1,2,11,11a-
tetrahydro-3aH-phenanthro[1,2-b]furan-10-one (21)
Paris 7) is sincerely thanked for his continued interest, as
well as Professor William R. Dolbier Jr. (University of
Florida, USA). We are also grateful to Professor Etsuji
Okada (Kobe University, Japan) for valuable discussions.
Mp ˆ 122±1248C (yellowish powder). 1H NMR (DMSO-
0
0
d6): dH 2.03±2.12 (1H, m, H1 or H1 ), 2.30±2.38 (1H, m, H1
or H1), 3.46±3.48 (1H, m, H11a), 3.85±4.00 (5H, m, H2 and
0
H2 and ±OCH3), 5.32±5.35 (1H, d, H3a, JH
ˆ
H11a
3a
References
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400 and H-500), 8.11±8.15 (1H, d, H-6), 9.29±9.34 (d, 1H, H-
9). 19F NMR (DMSO-d6/CFCl3): dF 56.7 (2F, s), 101.2
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ˆ 13:5 Hz),
112.40 (1F, dd,
ˆ 12:5 Hz) Mass (CI/CH4): m=e
F
H11a
JF ˆ 272 Hz, 3JF
F
H11a
‡
ˆ 481 (M ‡ H ). Anal. Calcd. for C22H13ClF4N2O4: C

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