Indium-mediated reformatsky-type reaction of β-aminovinyl chlorodifluoromethyl ketones with heteroaryl aldehydes

Article abstract of DOI:10.1055/s-2002-35618

Indium can efficiently mediate the Reformatsky-type reaction between some β-aminovinyl chlorodifluoromethyl ketones and a series of heteroaryl aldehydes, to afford the corresponding difluoromethylene compounds in good to high yields.

Full text of DOI:10.1055/s-2002-35618

SPECIAL TOPIC
2601
Indium-Mediated Reformatsky-Type Reaction of -Aminovinyl
Chlorodifluoromethyl Ketones with Heteroaryl Aldehydes
I
ndium-Mediate
d
Refo
a
rmatsky-Ty
u
pe Reactionrice Médebielle,*a Osamu Onomura,a Robert Keirouz,a Etsuji Okada,b Hirokazu Yano,b Terukazu Terauchib
a
Université Claude Bernard-Lyon 1 (UCBL), Laboratoire Synthèse, Electrosynthèse et Réactivité des Composés Organiques Fluorés
(SERCOF), UMR CNRS-UCBL 5622, Bâtiment E. Chevreul, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72431323; E-mail: medebiel@univ-lyon1.fr
b
Department of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501,
Japan
Received 23 October 2002
Abstract: Indium can efficiently mediate the Reformatsky-type re-
action between some -aminovinyl chlorodifluoromethyl ketones
and a series of heteroaryl aldehydes, to afford the corresponding di-
fluoromethylene compounds in good to high yields.
Key words: indium, Reformatsky, fluorine -aminovinyl ketones,
nucleophilic additions
There is still interest in new approaches for the synthesis
of new gem-difluoromethylene compounds because of
their synthetic and biological importance.1 For some
years, we have been interested in the search of new meth-
Scheme 1
odologies to prepare fluorinated organic molecules;2 It is noteworthy that Uneyama et al.9 recently presented an
among the recent studies developed in our laboratories, elegant electron-transfer based methodology to prepare
we have shown that a series of aromatic and heterocyclic-
the difluorinated analog of Danishefsky’s diene starting
CF2X (X: Br, Cl) substrates could be successfully en- from 4-butoxy-1,1,1-trifluorobut-3-en-2-one; this ap-
gaged in anionic3 and radical coupling reactions.4 Some of proach was applied to the synthesis of gem-difluorometh-
the compounds were found to exhibit some interesting bi- ylene dihydropyrone (and dihydropyridone) derivatives
ological activities such as anti-HIV-1 agents.5
via hetero Diels–Alder reaction (Scheme 2).
In a project devoted to the synthesis of new therapeutic
agents, we needed a mild and quick approach for the syn-
thesis of functionalized difluoromethylene -aminovinyl
ketones, as useful starting materials for further chemical
elaboration. Mostly trifluoromethylated -aminovinyl ke-
tones are known, and are frequently used as building
blocks for heterocyclic synthesis;6,7 however, as far as we
know, the reactivity of the C–Cl bond of the chlorodiflu-
oromethylated aminovinyl ketones has been rarely inves-
tigated. Lang et al.8 reported a Reformatsky reaction of 4-
butoxy-1-chloro-1,1-difluorobut-3-en-2-one and benzal-
dehyde with activated zinc in DMF (70 °C, 2 h); the final
product, a gem-difluoromethylene dihydropyrone was
isolated in 46% yield and resulted from a spontaneous cy-
clization. However in the same solvent, with less vigorous
conditions (40 °C, 16 h) a vinylogous amide and benzal-
dehyde gave a simple addition product in 60% yield
(Scheme 1).
Mg (8 equiv)
Me3SiCl (8 equiv)
BuO
BuO
F
DMF
CF3
50°C/3 min
Me3SiO
F
O
85%
O
O
F
R'CHO/ZnBr2
CH2Cl2
R'= Ph (64%)
p-MeOC6H4 (53%)
p-ClC6H4 (50%)
F
cat. CF3CO2H/CCl4
R'
Scheme 2
This paper describes our recent investigations in the
chemical and electrochemical activation of the C–Cl bond
of a series of chlorodifluoromethylated -aminovinyl ke-
tones in order to prepare, under very mild conditions, new
–CF2CHOH– derivatives for our target-oriented program
(Equation 1).
R3
Activation of the
C-Cl bond
R2
R4
New functionalized
-CF2CHOH- derivatives
N
R1
Chemical
Electrochemical
CF2Cl
Inductions
O
Synthesis 2002, No. 17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2601,2608,ftx,en;C05502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Equation 1

2602
M. Médebielle et al.
SPECIAL TOPIC
Starting materials of general structure 1, were prepared in
good yields in two steps, chlorodifluoroacetylation of
commercially available butyl vinyl ether [chlorodifluoro-
acetic anhydride (CDFAA)/pyridine in anhyd CH2Cl2],
followed by an O–N exchange reaction of the resulting
Scheme 5
crude
4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one,
with the corresponding aromatic amine in refluxing
CH3CN. Compounds 1a–d were obtained as Z isomers as
determined by 1H NMR (Scheme 3).
Since we have already developed some useful carbon-car-
bon bond forming reactions between aromatic and hetero-
cyclic chlorodifluoromethylated ketones and unsaturated
compounds, by utilizing tetrakis(dimethylamino)ethylene
(TDAE)3 as a synthetic electron-transfer reagent or elec-
trochemical reduction, we intended to apply these elec-
tron-transfer induced approaches to the coupling reaction
between 2a and benzaldehyde. Careful examination, by
cyclic voltammetry, of the reduction potential of starting
materials 1a–d, 2a–d, 3a, 4a and 5a, 5b shown that these
compounds were reduced at relatively low potentials
close to –1.25 to –1.60 V vs SCE (first peaks potentials
measured in DMF/NBu4PF6 0.1 M), with 5b being the
most difficult to reduce. These reduction steps correspond
to the cleavage of the C–Cl bond and to the formation of
the corresponding reduction product –COCF2H– (by com-
parison with authentic samples). As substrate 2a is a good
electron-acceptor, we thought of using the TDAE as a
mild and efficient organic reductant for the in situ gener-
ation and trapping of corresponding , -difluoroacetyl
anion with benzaldehyde. However, TDAE did not afford
any coupling product 6a with benzaldehyde, but gave the
corresponding Boc-protected anthranilonitrile through a
plausible retro-Michael addition (Scheme 6).10
Scheme 3
Protection of the free NH of substrates 1 was achieved
with (Boc)2O in good to excellent yields; benzylation and
tosylation of substrate 1a gave the corresponding protect-
ed substrates 3a and 4a in 82% and 97% isolated yields
(Scheme 4).
Scheme 6
Electrochemical activation of substrates 2a, 2b, 3a, and
4a using an undivided cell (carbon felt cathode/aluminum
anode)11 at controlled potential electrolysis corresponding
to the first peak potential measured by cyclic voltammetry
(–1.25 V vs SCE for 2a, –1.43 V vs SCE for 2b, –1.26 V
vs SCE for 3a, –1.60 V vs SCE for 3b) surprisingly didn’t
afford coupling product with benzaldehyde, and most of
unreacted starting materials with some minor amount of
reduction products were recovered, with a consumption of
electricity close to 2F/mol. However substrate 2d gave
Scheme 4
To introduce further functionality at the olefinic site of
starting materials 1, bromination of compounds 1a and 1b
was carried out. The corresponding mono-brominated
materials 5a and 5b were obtained in good yields with 1.2
equivalent of NBS in anhydrous dichloromethane
(Scheme 5).
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Indium-Mediated Reformatsky-Type Reaction
2603
under the same conditions (electrolysis potential of –1.42 recent14 and most of the work reported in the literature is
V vs SCE corresponding to the first peak potential; 2F/ related to allylation reactions of fluorinated compounds or
mol) coupling product 6d in 62% yield (Scheme 7).11
indium-mediated cross-coupling reactions of a gem-diflu-
oropropargyl starting material that generates a stable dif-
luoroallenyl indium species.
We first examined the possibility of reducing the C–Cl
bond of starting material 2a into the corresponding reduc-
tion product 9a; as observed by Welch et al.,12 we found
that THF containing 80% water by volume resulted in
clean reduction of 2a, after 24 h of vigorous stirring
(Scheme 9). In DMF containing water or anhydrous
DMF, starting material was recovered.
Scheme 7
Scheme 9
The Reformatsky reaction of halogenodifluoromethyl ke-
tones with carbonyl compounds mediated by zinc1 is one
of the well-known synthetic methodologies to obtain the
corresponding carbon-carbon bond coupling products.
This result may indicate that indium has the characteris-
tics as a suitable reagent for SET (single electron transfer)
processes.
Using the conditions described by Lang et al.8 with benz- We therefore examined the coupling reaction of 2a with
aldehyde as electrophile, starting material 2d gave the benzaldehyde and found that the corresponding alcohol
corresponding coupling product 6d and its deprotected 6a could be obtained in 82% yield after silica gel chroma-
form 8d in the ratio of 3:2 (combined yield 76%). Howev- tography. Similarly protected compounds 3a and 4a gave
er with starting material 2a, coupling product 6a was only the corresponding alcohols 7a and 7b in 86% and 66%
obtained in 20% yield (Scheme 8). In addition we found it yields, respectively. The Boc protected alcohol 6b, with
difficult to get reproducible results, which may came from an o-CO2Me substituent, was only obtained in 26% yield,
the purity of zinc as well as its mode of activation.
because of the low solubility of starting material 2b (73%
recovered) in water. The reaction seems to be independent
of substituents on the aromatic ring, as starting materials
2c and 2d, with methyl substituents at the ortho or para
position afforded corresponding alcohols adducts 6c and
6d in 82% and 67% isolated yields. All the protected alco-
hols were obtained as E isomers (Scheme 10).
Scheme 8
In order to find an alternative and general approach for the
formation of coupling products from the -aminovinyl
chlorodifluoromethyl ketones, we became aware of a re-
cent publication by Welch et al.12 who described the effi-
cient coupling reactions of heteroaryl chlorodifluoro-
methylated ketones, mediated by indium, with various
aldehydes. Indium closely resembles zinc in several as-
pects, and its first ionization potential (5.8 eV) is the low-
est relative to other metal elements near it in the periodic
table.13 Its synthetic use in organo-fluorine chemistry is
Scheme 10
More practically we also found that the unprotected free
NH starting materials 1a–d as well as 5a, 5b could also re-
act successfully with benzaldehyde and other heteroalde-
hydes such as 2-furaldehyde, 3,4-dimethoxybenz-
aldehyde and p-dimethylamino trans-cinnamaldehyde to
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

2604
M. Médebielle et al.
SPECIAL TOPIC
1a–d; General Procedure
give the corresponding alcohols 8 in 54–84% yields
(Scheme 11). So far the reaction failed with other alde-
hydes such as 2- and 4-pyridine carboxaldehydes proba-
bly due to competitive binding of nitrogen atoms at the
indium center, 5-nitrofurfuraldehyde because of competi-
tive reduction of the nitro group into the corresponding
amino group and p-trifluoromethylbenzaldehyde because
of pinacol coupling product formation.
To a stirred soln of butyl vinyl ether (2.0 g, 20 mmol) and pyridine
(1.58 g, 20 mmol) in anhyd CH2Cl2 (20 mL) was added dropwise
chlorodifluoroacetic anhydride (4.86 g, 20 mmol) with cooling
(0 °C). When the addition was finished, the soln was stirred at 0 °C
for 30 min and slowly warmed-up to r.t. and stirred at this tempera-
ture for 18 h. The yellowish solution was quenched with H2O (20
mL), the organic phase separated and washed with an aq soln of 1
N HCl (20 mL) and dried over MgSO4. Evaporation of the solvent
left a viscous yellow oil, 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-
one (4.03 g, 19 mmol, 95%), which was used for the next step.
To a stirred soln of 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one
(3.54 g, 16.6 mmol) in CH3CN (20 mL) was added the appropriate
substituted aniline (18.2 mmol) and the solution heated at reflux for
1 h (TLC monitoring). The solvent was removed under reduced
pressure and the residue purified by recrystallization or flash chro-
matography to give pure compounds.
1a
Yield: 91%; recrystallized (petroleum ether–EtOAc, 1:2); pale yel-
low needles; mp 113–114 °C .
1H NMR (300 MHz, CDCl3): = 5.81 (d, J = 7.7 Hz, 1 H), 7.23 (dd,
J = 7.6, 1.0 Hz, 1 H), 7.25–7.27 (m, 1 H), 7.31 (d, J = 8.1 Hz, 1 H),
7.60–7.73 (m, 3 H), 11.88 (br d, J = 10.2 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –66.18 (s, 2 F)
HRMS (CI): m/z calcd for C11H8ClF2N2O: 257.0293 (MH+); found:
257.0298.
Scheme 11
1b
In conclusion, we have demonstrated that indium was an
efficient reagent for the coupling reactions of -aminovi-
nyl chlorodifluoromethylated ketones with a series of het-
eroaryl aldehydes. Although the mechanism of the
reaction still remains to be elucidated, indium species (In,
In+ and/or In2+) may act as an electron-transfer reagent to
generate a reactive difluorinated enolate. This mild ap-
proach seems to be applicable to whatever substituent and
its position on the aromatic ring; this is in sharp contrast
with the electrochemical approach, which only worked
with a substituent at the para position of the aromatic ring.
We have still not yet clarified why the electrochemical ap-
proach did not work with substrates 6a,b and 7a,b. Is it a
steric, or an electronic effect? We are currently working
on the electrochemical coupling reaction of 2c so as to
compare it with the electrochemical/indium activation of
protected 2a–d. From a synthetic point of view we are
currently extending the indium methodology to other sub-
strates and electrophiles. The compounds described in this
report are now utilized for further chemical elaboration to
achieve the synthesis of a series of novel gem-difluoro-
methylene heterocycles of biological importance; these
results will be presented in our forthcoming papers.
Yield: 88%; recrystallized (petroleum ether–EtOAc, 1:10); yellow
crystals; mp 83–84 °C.
1H NMR (300 MHz, CDCl3): = 4.03 (s, 3 H), 5.71 (d, J = 7.9 Hz,
1 H), 7.17 (td, J = 7.6, 1.0 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.57
(td, J = 7.9, 1.6 Hz, 1 H), 7.70 (dd, J = 13.0, 8.1 Hz, 1 H), 8.10 (dd,
J = 7.9, 1.6 Hz, 1 H), 13.20 (br d, J = 11.3Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –65.73 (s, 2 F).
HRMS (CI): m/z calcd for C12H11ClF2NO3: 290.0395 (MH+); found:
290.0390.
1c
Yield: 95%; recrystallized (petroleum ether–EtOAc, 1:10); brown
crystals; mp 45–46 °C.
1H NMR (300 MHz, CDCl3): = 2.40 (s, 3 H), 5.70 (d, J = 7.3Hz,
1 H), 7.09–7.29 (m, 4 H), 7.69–7.75 (dd, J = 12.8, 7.3 Hz, 1 H),
11.87 (br s, 1 H).
19F NMR (282 MHz, CDCl3): = –65.13 (s, 2 F).
HRMS (CI): m/z calcd for C11H11ClF2NO: 246.0497 (MH+); found:
246.0498.
1d
Yield: 85%; flash chromatography (petroleum ether–EtOAc, 1:10);
yellow crystals; mp 70–71 °C.
1H NMR (300 MHz, CDCl3): = 2.35 (s, 3 H), 5.62 (d, J = 7.5 Hz,
1 H), 7.03 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.3 Hz, 2 H), 7.63 (dd,
J = 13.2, 7.5 Hz, 1 H), 11.72 (br d, J = 7.9 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –65.28 (s, 2 F).
HRMS (CI): m/z calcd for C11H11ClF2NO: 246.0497 (MH+); found:
Solvents were distilled before use. Reagents were obtained com-
mercially and used without further purification except for 3,4-
dimethoxybenzaldehyde, which was recrystallized from petroleum
1
ether (bp 45–60 °C). H and 19F NMR spectra were recorded in
CDCl3 at 300 MHz and 282 MHz, respectively. Chemical shifts are
given in ppm relative to TMS (1H) or CFCl3 (19F) as internal refer-
ences. Coupling constants are given in hertz. Flash chromatography
was performed on Merck Silica gel 60M (0.04–0.063 mm). Melting
points (uncorrected) were determined in capillary tubes on a Büchi
apparatus.
246.0497.
2a–d; General Procedure
To a stirred soln of 1a–d (4 mmol) in toluene (15 mL) containing
NaHCO3 (0.60 g, 7.2 mmol) was added (Boc)2O (1.40 g, 6.4 mmol)
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Indium-Mediated Reformatsky-Type Reaction
2605
and the soln heated at reflux until the starting material had been
completely consumed (1a, 18 h; 1b, 72 h; 1c, 18 h; 1d, 24 h). The
solvent was removed under reduced pressure and the residue puri-
fied by recrystallization or flash chromatography to give pure com-
pounds 2a–d.
3 H), 7.48 (br s, 1 H), 7.62 (td, J = 7.8, 1.6 Hz, 1 H), 7.77 (br s, 1
H), 8.05 and 8.19 (2 br s, 1 H).
19F NMR (282MHz, CDCl3): = –66.48 and –66.29 (2 s, 2 F).
HRMS (CI): m/z calcd for C18H14ClF2N2O: 347.0763 (MH+); found:
347.0771.
2a
4a
Yield: 90%; recrystallized (petroleum ether–Et2O, 1:1); pale yellow
needles; mp 78–79 °C.
To a stirred soln of 1a (1.28 g, 5 mmol) and TsCl (1.05 g, 5.5 mmol)
in toluene (10 mL) was added K2CO3 (0.83 g, 6 mmol) and the mix-
ture heated at 70 °C for 72 h until 1a had been completely con-
sumed. The soln was quenched with water, extracted with EtOAc
(2 15 mL), the combined organic phases washed with water
(4 15 mL) and dried over Na2SO4. Filtration and evaporation of
the solvent under reduced pressure left a brown oil (2.51 g) as crude
product, which was purified by flash chromatography (petroleum
ether–EtOAc, 2:1) 4a (2.0 g, 4.86 mmol, 97%); yellow crystals; mp
103–105 °C.
1H NMR (300 MHz, CDCl3): = 2.47 (s, 3 H), 5.09 (d, J = 13.6 Hz,
1 H), 7.31 (d, J = 7.9 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 2 H), 7.60 (d,
J = 8.5 Hz, 2 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.76 (d, J = 7.5 Hz, 2 H),
8.66 (d, J = 13.6 Hz, 1 H).
1H NMR (300 MHz, CDCl3): = 1.50 (s, 9 H), 5.20(d, J = 14.0 Hz,
1 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.77 (d,
J = 7.7 Hz, 1 H), 7.84 (t, J = 7.7 Hz, 1 H), 8.74 (d, J = 14.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = 67.39 (s, 2 F).
HRMS (CI): m/z calcd for C16H16ClF2N2O3: 357.0818 (MH+);
found: 357.0817.
2b
Yield: 75%; flash chromatography (petroleum ether–EtOAc, 10:1);
pale yellow crystals; mp 62–63 °C.
1H NMR (300 MHz, CDCl3): = 1.43 (s, 9 H), 3.84 (s, 3 H), 5.13
(d, J = 13.7 Hz, 1 H), 7.22 (dd, J = 7.8, 0.8 Hz, 1 H), 7.56 (td,
J = 7.5, 1.1 Hz, 1 H), 7.68 (td, J = 7.7, 1.6 Hz, 1 H), 8.15 (dd,
J = 7.9, 1.5 Hz, 1 H), 8.76 (d, J = 13.7 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –64.60 (s, 2 F).
HRMS (CI): m/z calcd for C18H14ClF2N2O3S: 411.0382 (MH+);
19F NMR (282 MHz, CDCl3): = –67.00 (s, 2 F).
found: 411.0384.
HRMS (CI): m/z calcd for C17H19ClF2NO5: 390.0920 (MH+), found
390.0917.
5a, 5b; General Procedure
To a stirred soln of 1a or 1b (3 mmol) in CH2Cl2 (15 mL) was added
N-bromosuccinimide (0.65 g, 3.6 mmol) and the mixture stirred at
r.t. until the starting material had been completely consumed. The
solution was quenched with an aq soln of Na2S2O3 (15 mL), the or-
ganic layer separated and washed with water (3 15 mL) and dried
over Na2SO4. Filtration and evaporation of the solvent under re-
duced pressure left a yellow solid (1.05 g) as crude product, which
was recrystallized to give pure product.
2c
Yield: 96%; flash chromatography (petroleum ether–EtOAc, 25:1);
oil.
1H NMR (300 MHz, CDCl3): = 1.46 (s, 9 H), 2.12 (s, 3 H), 5.15
(dd, J = 13.5, 1.1 Hz, 1 H), 7.05 (d, J = 7.1 Hz, 1 H), 7.32–7.37 (m,
3 H), 8.76 (d, J = 13.6 Hz, 1 H).
19F NMR (282MHz, CDCl3): = –67.13 (s, 2 F).
HRMS (CI): m/z calcd for C16H18ClF2NO3: 346.1022 (MH+); found:
5a
Yield: 87%; recrystallized (petroleum ether–EtOAc, 4:1); pale yel-
low crystals; mp 117–118 °C.
346.1020.
1H NMR (300 MHz, CDCl3): = 7.28 (t, J = 7.5 Hz, 2 H), 7.64–7.72
(m, 2 H), 7.98 (br d, J = 12.8 Hz, 1 H), 8.42 (d, J = 12.8 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –57.67 (s, 2 F).
2d
Yield: 81%; flash chromatography (petroleum ether–EtOAc, 25:1);
pale yellow solid; mp 80–81 °C.
1H NMR (300 MHz, CDCl3): = 1.49 (s, 9 H), 2.43 (s, 3 H), 5.32
(d, J = 13.8 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 2 H), 7.30 (d, J = 8.1 Hz,
2 H), 8.77 (d, J = 13.7 Hz, 1 H).
HRMS (CI): m/z calcd for C11H7BrClF2N2O: 334.9398 (MH+);
found: 334.9397.
19F NMR (282 MHz, CDCl3): = –67.12 (s, 2 F).
5b
Yield 80%; recrystallized (petroleum ether–EtOAc, 10:1); pale yel-
low crystals; mp 84–85 °C.
1H NMR (300 MHz, CDCl3): = 4.00 (s, 3 H), 7.19 (t, J = 7.6 Hz,
1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.62 (td, J = 7.9 Hz, 1 H), 8.11 (dd,
J = 8.0, 1.4 Hz, 1 H), 8.58 (d, J = 13.2 Hz, 1 H), 11.41 (br d,
J = 12.5 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –56.95 (s, 2 F).
HRMS (CI): m/z calcd for C12H10BrClF2NO3: 367.9501 (MH+);
HRMS (CI): m/z calcd for C16H19ClF2NO3: 346.1022 (MH+), found.
346.1023.
3a
To a stirred soln of 1a (0.72 g, 2.8 mmol) in DMF (5 mL) was added
60% NaH (0.13 g, 3.37 mmol) with cooling (0 °C). The solution
was further stirred at 0 °C for 30 min and then benzyl bromide (0.40
g, 3.37 mmol) was added dropwise. After complete addition, the so-
lution was warmed up to r.t. and stirred at this temperature for 18 h.
Solution was quenched with ice-water, extracted with EtOAc
(2 15 mL), the combined organic phases washed with water
(4 15 mL) and dried over Na2SO4. Filtration and evaporation of
the solvent under reduced pressure left a red-wine oil (1.40 g) as
crude product, which crystallized on standing to gave 3a as a mix-
ture of 2 rotamers (0.80 g, 2.3 mmol, 82%); colorless pellets; mp
97–98 °C.
found: 367.9502.
Electrolysis Coupling Reactions; General Procedure
The reaction was conducted in an undivided cylindrical Pyrex cell,
fitted with a carbon felt cathode (S = 15 cm2) and an aluminium rod
as anode under nitrogen. Starting material (0.5 mmol) was added to
a soln of anhyd DMF (40 mL) containing Et4NBF4 (0.26 g, 1.12
mmol). The electrolysis was performed under a constant current
(I = 0.01–0.018 A) until 2F/mol of electricity had passed. The solu-
tion was hydrolyzed with a sat. aq soln of NaCl (60 mL) and the or-
1H NMR (300 MHz, CDCl3): = 5.02 (br s, 2 H), 4.90 and 5.83 (2
br s, 1 H), 7.08 (br s, 1 H), 7.19–7.25 (m, 2 H), 7.32 and 7.34 (2 s,
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

2606
M. Médebielle et al.
SPECIAL TOPIC
ganic portion was extracted with EtOAc (3 60 mL). The
combined organic layers were washed with a sat. aq. soln of NaCl
(3 60 mL), water (3 60 mL) and dried over anhyd Na2SO4. Fil-
tration and evaporation of the solvent under reduced pressure left a
residue, which was purified by flash chromatography (petroleum
ether–EtOAc) to give the pure product.
7a
Yield: 86%; pale yellow crystals; mp 128–129 °C.
1H NMR (300 MHz, CDCl3): = 3.89 (br s, 1 H), 4.86 (br s, 2 H),
5.10 and 5.83 (2 br s, 1 H), 5.16 (dd, J = 17.6, 7.4 Hz, 1 H), 6.90–
7.45 (m, 12 H), 7.52 (td, J = 8.1, 1.3 Hz, 1 H), 7.67 (d, J = 7.5 Hz,
1 H), 8.06 (br s, 1 H).
19F NMR (282 MHz, CDCl3): = –121.63 (d, J = 268.4 Hz, 1 F),
–113.07 (d, J = 265.0 Hz, 1 F).
HRMS (CI): m/z calcd for C25H21F2N2O2: 419.1571 (MH+); found:
Indium Coupling Reactions; General Procedure
Under a nitrogen atmosphere, indium powder (1.2 mmol, 100 mesh)
was added to a suspension of starting material (1 mmol) and alde-
hyde (1 mmol) in THF (1 mL) and H2O (4 mL), and the mixture was
vigorously stirred. After 24 h, the reaction was quenched with a soln
of sat. aq NH4Cl (20 mL). The organic portion was extracted with
EtOAc (3 20 mL). The combined organic layers were dried over
anhyd Na2SO4. Filtration and evaporation of the solvent under re-
duced pressure left a residue, which was purified by flash chroma-
tography (petroleum ether–EtOAc) to give the pure product.
419.1572.
7b
Yield: 66%; recrystallized (Et2O); white crystals; mp 73–74 °C.
1H NMR (300 MHz, CDCl3): = 2.48 (s, 3 H), 2.93 (br s, 1 H), 5.09
(d, J = 13.7 Hz, 1 H), 5.12 (br dd, J = 16.0, 6.0 Hz, 1 H), 7.18 (br t,
J = 1.1 Hz, 1 H), 7.28–7.41 (m, 7 H), 7.61 (d, J = 8.3 Hz, 2 H),
7.63–7.75 (m, 3 H), 8.55 (d, J = 13.7 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –122.64 and –122.51 (2 dd,
J = 268.4, 16.1 Hz, 1 F), –113.39 and –113.03 (2 dd, J = 267.3, 5.7
Hz, 1 F).
6a
Yield: 82%; oil.
1H NMR (300 MHz, CDCl3): = 1.48 (s, 9 H), 2.91 (s, 1 H), 5.05–
5.21 (m, 2 H), 7.13–7.38 (m, 7 H), 7.55 (td, J = 7.7, 1.1 Hz, 1 H),
7.70 (t, J = 7.3 Hz, 1 H), 7.89 (d, J = 7.5 Hz, 1 H), 8.61 (d, J = 14.0
Hz, 1 H).
HRMS (CI): m/z calcd for C25H21F2N2O4S: 483.1190 (MH+), found:
483.1189.
19F NMR (282MHz, CDCl3): = –121.95 (dd, J = 269.2, 14.9 Hz,
1 F), –114.15 and –113.57 (2 dd, J = 270.7, 6.9 Hz, 1 F)
HRMS (CI): m/z calcd for C23H23F2N2O4: 429.1626 (MH+); found:
8a1
Yield: 80%; recrystallized (petroleum ether–EtOAc, 2:1); pale yel-
low crystals; mp 152–153 °C.
429.1624.
1H NMR (300 MHz, CDCl3): = 3.08 (d, J = 4.7 Hz, 1 H), 5.31
(ddd, J = 17.8, 6.3, 4.7 Hz, 1 H), 5.83 (dd, J = 7.9, 1.1 Hz, 1 H), 7.20
(t, J = 7.6 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.35–7.42 (m, 3 H),
7.45–7.51 (m, 2 H), 7.52 (dd, J = 12.0 and 4.1 Hz, 1 H), 7.59 (d,
J = 9.2 Hz, 1 H), 7.65 (dd, J = 7.7, 1.3 Hz, 1 H), 12.15 (br d,
J = 11.7 Hz, 1 H).
19F NMR (282MHz, CDCl3): = –122.58 (dd, J = 269.6, 17.8 Hz,
1 F), –111.96 (dd, J = 269.6, 6.3 Hz, 1 F).
HRMS (CI): m/z calcd for C18H15F2N2O2: 329.1101 (MH+); found:
6b
Yield: 26%; oil.
1H NMR (300 MHz, CDCl3): = 1.42 (s, 9 H), 2.99 (br d, J = 17.7
Hz, 1 H), 3.82 (2 s, 3 H), 5.06–5.14 (m, 2 H), 7.09 (t, J = 4.7 Hz, 1
H), 7.30–7.40 (m, 5 H), 7.50 (t, J = 7.7 Hz, 1 H), 7.56–7.65 (m, 1
H), 8.11 (d, J = 7.7 Hz, 1 H), 8.67 (d, J = 13.7 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –122.14 and –121.70 (2 dd,
J = 271.9, 15.2Hz, 1 F), –112.56 (d, J = 269.6 Hz, 1 F).
329.1110.
HRMS (CI): m/z calcd for C23H23F2N2O6: 462. 1728 (MH+); found:
462.1730.
8a2
Yield 84%; white solid; mp 113–114 °C.
6c
1H NMR (300 MHz, CDCl3): = 3.13 (s, 1 H), 5.33 (dd, J = 15.8,
7.1 Hz, 1 H), 5.90 (dd, J = 7.9, 2.1 Hz, 1 H), 6.40–6.44 (m, 1 H),
6.49 (d, J = 3.2 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.30 (d, J = 8.4
Hz, 1 H), 7.44–7.46 (m, 1 H), 7.55–7.69 (m, 3 H), 12.13 (br d,
J = 12.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –121.40 (dd, J = 270.7, 16.6 Hz,
1 F), –112.32 (dd, J = 269.6, 7.5 Hz, 1 F).
Yield 82%; oil.
1H NMR (300 MHz, CDCl3): = 1.44 (s, 9 H), 2.01 and 2.04 (2 s,
3 H), 3.12 (d, J = 4.4 Hz, 1 H), 5.07–5.20 (m, 1 H), 5.13 (d, J = 13.8
Hz, 1 H), 6.94 (t, J = 7.7 Hz, 1 H), 7.21–7.40 (m, 8 H), 8.63 (d,
J = 13.7 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –121.61 and –121.44 (2 dd,
J = 270.7, 16.1 Hz, 1 F), –113.52 and –113.33 (2d, J = 270.7 Hz, 1
HRMS (CI): m/z calcd for C16H13F2N2O3: 319.0894 (MH+); found:
319.0895.
F).
HRMS (CI): m/z calcd for C23H26F2NO4: 418.1830 (MH+); found:
418.1829.
8a3
Yield: 71%; yellow solid; mp 157–158 °C.
6d
1H NMR (300 MHz, CDCl3): = 3.03 (br s, 1 H), 3.88 (s, 3 H), 3.89
(s, 3 H), 5.25 (dd, J = 16.4, 7.8 Hz, 1 H), 5.82 (d, J = 7.5 Hz, 1 H),
6.86 (d, J = 8.1 Hz, 1 H), 6.98–7.03 (m, 2 H), 7.20 (t, J = 7.6 Hz, 1
H), 7.28 (d, J = 8.0 Hz, 1 H), 7.48–7.68 (m, 3 H), 12.16 (br d,
J = 12.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –122.06 (dd, J = 266.1, 16.6 Hz,
1 F), –113.24 (dd, J = 266.1, 6.9 Hz, 1 F).
Yield: 67%; oil.
1H NMR (300 MHz, CDCl3): = 1.46 (s, 9 H), 2.39 (s, 3 H), 3.05
(br s, 1 H), 5.15 (ddd, J = 16.6, 7.2, 3.2 Hz, 1 H), 5.32 (d, J = 13.7
Hz, 1 H), 6.94 (d, J = 8.3 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.33–
7.43 (m, 5 H), 8.65 (d, J = 13.7 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –121.99 (dd, J = 271.9, 16.0 Hz,
1 F), –112.96 (dd, J = 271.9, 6.9 Hz, 1 F).
HRMS (CI): m/z calcd for C20H19F2N2O4: 389.1313 (MH+); found:
389.1313.
HRMS (CI): m/z calcd for C23H26F2NO4: 418.1830 (MH+); found:
418.1825.
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Indium-Mediated Reformatsky-Type Reaction
2607
8a4
Acknowledgment
Yield: 55%; brown solid; mp 150–152 °C.
M. M would like to thank the CNRS for support of this work throu-
gh a research grant (Aide aux Jeunes Equipes-Appel d’offres 2000).
O. O is grateful to the CNRS for an associate position. At Kobe Uni-
versity this research was supported in part by the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Grant-in-Aid for
JSPS Fellows.
1H NMR (300MHz, CDCl3): = 2.90 (br s, 1 H), 2.96 (s, 6 H), 4.76–
4.86 (m, 1 H), 5.93 (d, J = 7.1 Hz, 1 H), 6.05 (dd, J = 15.9, 7.0 Hz,
1 H), 6.65–6.75 (m, 3 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.26–7.35 (m, 3
H), 7.55–7.67 (m, 3 H), 12.10 (br d, J = 12.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –121.75 (dd, J = 265.6, 14.3 Hz,
1 F), –113.92 (dd, J = 265.0, 8.0 Hz, 1 F).
HRMS (CI): m/z calcd for C22H22F2N3O2: 398.1680 (MH+); found:
398.1683.
References
(1) Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619.
(2) Médebielle, M.; Keyrouz, R.; Langlois, B.; Billard, T.;
Dolbier, W. R. Jr.; Burkholder, C.; Ait-Mohand, S.; Okada,
E.; Ashida, T. In Electron Transfer Reactions in Organic
Synthesis; Vanelle, P., Ed.; Research Signpost: Trivandrum,
2002, 89.
(3) (a) Billard, T.; Langlois, B. R.; Médebielle, M. Tetrahedron
Lett. 2001, 42, 3463. (b) Médebielle, M.; Keirouz, R.;
Okada, E.; Ashida, T. Synlett 2001, 821. (c) Burkholder, C.;
Dolbier, W. R. Jr.; Médebielle, M.; Ait-Mohand, S.
Tetrahedron Lett. 2001, 42, 3459. (d) Dolbier, W. R. Jr.;
Médebielle, M.; Ait-Mohand, S. Tetrahedron Lett. 2001, 42,
4811. (e) Burkholder, C.; Dolbier, W. R. Jr.; Médebielle, M.
J. Org. Chem. 1998, 63, 5385.
8a5
Yield: 54%; oil.
1H NMR (300 MHz, CDCl3): = 3.44 (br s, 1 H), 5.32 (dd, J = 18.5,
4.7 Hz, 1 H), 7.13 (d, J = 8.3 Hz, 2 H), 7.22 (td, J = 7.7, 0.8 Hz, 1
H), 7.34–7.52 (m, 5 H), 7.56–7.66 (m, 2 H), 7.92 (br d, J = 12.8 Hz,
1 H), 8.37 (d, J = 13.0 Hz, 1 H).
19F NMR (282MHz, CDCl3): = –113.36 (dd, J = 278.8, 18.4 Hz,
1 F), –101.26 (dd, J = 278.8, 5.7 Hz, 1 F).
HRMS (CI): m/z calcd for C18H14BrF2N2O2: 407.0207 (MH+);
found: 407.0204.
8b1
(4) (a) Tommasino, J.-B.; Brondex, A.; Médebielle, M.;
Thomalla, M.; Langlois, B. R.; Billard, T. Synlett 2002,
1697. (b) Hapiot, P.; Médebielle, M. J. Fluorine Chem.
2001, 107, 285. (c) Fujii, S.; Kato, K.; Médebielle, M.
Tetrahedron 2000, 56, 2655. (d) Burkholder, C.; Dolbier,
W. R.; Médebielle, M. J. Fluorine Chem. 2000, 102, 369.
(e) Médebielle, M. Tetrahedron Lett. 1995, 36, 2071.
(5) Burkholder, C.; Dolbier, W. R. Jr.; Médebielle, M. J.
Fluorine Chem. 2000, 102, 369.
Yield: 86%; yellow crystals; mp 151–152 °C.
1H NMR (300 MHz, CDCl3): = 1.40 (t, J = 7.0 Hz, 3 H), 3.61 (s,
1 H), 4.19 (q, J = 7.1 Hz, 2 H), 5.30 (dd, J = 17.4, 4.1 Hz, 1 H), 5.35
(s, 1 H), 7.20–7.30 (m, 1 H), 7.33–7.41 (m, 3 H), 7.48–7.51 (m, 2
H), 7.56–7.59 (m, 2 H), 7.67 (d, J = 7.7 Hz, 1 H), 12.71 (s, 1 H).
19F NMR (282 MHz, CDCl3): = –121.60 (dd, J = 261.5, 16.1 Hz,
1 F), –111.93 (dd, J = 262.7, 6.9 Hz, 1 F).
HRMS (CI): m/z calcd for C19H18F2NO4: 373.1364 (MH+); found:
373.1361.
(6) For a review see: Nenajdenko, V. G.; Sanin, A. V.;
Balenkova, E. S. Russ. Chem. Rev. (Engl. Trans.) 1999, 68,
437.
8b2
(7) Selected references: (a) Bonacorso, H. G.; Duarte, S. H. G.;
Zanatta, N.; Martins, M. A. Synthesis 2002, 1037.
(b) Kruchok, I. S.; Gerus, I. I.; Kukhar, V. P. Synthesis 2002,
71. (c) Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E.
S. Tetrahedron 2001, 57, 201. (d) Baraznenok, I. L.;
Nenajdenko, V. G.; Balenkova, E. S. Eur. J. Org. Chem.
1999, 937. (e) Okada, E.; Kinomura, T.; Higashiyama, Y.
Heterocycles 1998, 48, 2347. (f) Okada, E.; Kinomura, T.;
Higashiyama, Y.; Takeuchi, H.; Hojo, M. Heterocycles
1997, 46, 129. (g) Okada, E.; Kinomura, T.; Takeuchi, H.;
Hojo, M. Heterocycles 1997, 44, 349. (h) Okada, E.;
Masuda, R.; Hojo, M.; Inoue, R. Synthesis 1992, 533.
(i) Hojo, M.; Masuda, R.; Okada, E.; Mochizuki, Y.
Synthesis 1992, 455. (j) Okada, E.; Masuda, R.; Hojo, M.;
Yoshida, R. Heterocycles 1992, 34, 1435. (k) Okada, E.;
Masuda, R.; Hojo, M. Heterocycles 1992, 34, 1927.
(l) Okada, E.; Masuda, R.; Hojo, M. Heterocycles 1992, 34,
791. (m) Hojo, M.; Masuda, R.; Okada, E.; Yamamoto, H.;
Morimoto, K.; Okada, K. Synthesis 1990, 195. (n) Hojo,
M.; Masuda, R.; Okada, E. Chem. Lett. 1990, 2095.
(o) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1989,
30, 6173. (p) Hojo, M.; Masuda, R.; Okada, E. Synthesis
1986, 1013.
Yield: 76%; white solid; mp 160–162 °C.
1H NMR (300MHz, CDCl3): = 3.49 (d, J = 3.8 Hz, 1 H), 3.99 (s,
3 H), 5.36 (dt, J = 20.0 and 4.1 Hz, 1 H), 7.12 (td, J = 7.5, 0.8 Hz, 2
H), 7.33–7.48 (m, 4 H), 7.49–7.57 (m, 3 H), 8.08 (dd, J = 7.9,1.3
Hz, 1 H), 8.56 (d, J = 13.2 Hz, 1 H), 11.33 (br d, J = 13.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –113.23 (dd, J = 282.8, 20.0 Hz,
1 F), –100.00 (dd, J = 282.8 and 4.0 Hz, 1 F).
HRMS (CI): m/z calcd for C19H17BrF2NO4: 440.0309 (MH+);
found: 440.0316.
8d
Yield: yellow solid; mp 157–158 °C.
1H NMR (300 MHz, CDCl3): = 2.34 (s, 3 H), 3.38 (d, J = 4.7 Hz,
1 H), 5.15 (ddd, J = 16.1, 7.3, 4.7 Hz, 1 H), 5.62 (d, J = 7.5 Hz, 1
H), 7.01 (d, J = 8.3 Hz, 2 H), 7.18 (d, J = 8.3 Hz, 2 H), 7.32–7.40
(m, 3 H), 7.45–7.55 (m, 3 H), 11.92 (br d, J = 12.0 Hz, 1 H).
19F NMR (282 MHz, CDCl3): = –121.54 (dd, J = 265.0, 16.1 Hz,
1 F), –112.94 (dd, J = 263.9, 7.5 Hz, 1 F).
HRMS (CI): m/z calcd for C18H18F2NO2: 318.1306 (MH+); found:
318.1309.
(8) Lang, R. W.; Schaub, B. Tetrahedron Lett. 1988, 29, 2943.
(9) Amii, H.; Kobayashi, T.; Terasawa, H.; Uneyama, K. Org.
Lett. 2001, 3, 3103.
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York

2608
M. Médebielle et al.
SPECIAL TOPIC
(10) It is known that TDAE and their cyclic analogues could act
as electron-donors and good nucleophiles. See: (a) Wiberg,
N. Angew. Chem. 1968, 20, 869. (b) Lemal, D. M. In The
Chemistry of the Amino Group, Chap. 12; Patai, S., Ed.;
Wiley Interscience: New York, 1968, 701–748.
(12) Chung, W. J.; Higashiya, H.; Welch, J. T. J. Fluorine Chem.
2001, 112, 343.
(13) Reviews: (a) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
(b) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149.
(14) (a) Chung, W. J.; Higashiya, S.; Welch, J. T. Tetrahedron
Lett. 2002, 43, 5801. (b) Lan, Y.; Hammond, G. B. Org.
Lett. 2002, 4, 2437. (c) Shen, Q.; Hammond, G. B. Org.
Lett. 2001, 3, 2213. (d) Wang, Z.; Hammond, G. B. J. Org.
Chem. 2000, 65, 6547. (e) Kirihara, M.; Takuwa, T.;
Takizawa, S.; Momose, T.; Nemoto, H. Tetrahedron 2000,
56, 8275. (f) Percy, J. M.; Pintat, S. Chem. Commun. 2000,
607. (g) Loh, T.-P.; Li, X.-R. Tetrahedron 1999, 55, 5611.
(h) Loh, T.-P.; Li, X.-R. Eur. J. Org. Chem. 1999, 1893.
(i) Loh, T.-P.; Zhou, J.-R.; Li, X.-R. Tetrahedron Lett. 1999,
40, 9333. (j) Loh, T.-P.; Li, X.-R. Tetrahedron Lett. 1997,
38, 869.
(c) Wanzlick, H.-W.; Kleiner, H.-J. Chem. Ber. 1963, 96,
3024.
(11) (a) Chaussard, J.; Folest, J.-C.; Nédélec, J.; Périchon, J.;
Sibille, S.; Troupel, M. Synthesis 1990, 369. (b) We still
need to check if the coupling reactions of 2a, 2b, 3a, and 4a
with benzaldehyde could be achieved using another soluble
anode such as Mg. Indeed for some reported examples in the
literature choice of the sacrificial anode play a crucial role;
see for example: Rajaonah, M.; Rock, M. H.; Bégué, J.-P.;
Bonnet-Delpon, D.; Condon, S.; Nédélec, J.-Y. Tetrahedron
Lett. 1998, 39, 3137.
Synthesis 2002, No. 17, 2601–2608 ISSN 0039-7881 © Thieme Stuttgart · New York