Electrochemical, nickel-catalyzed Reformatsky reaction with methyl chlorodifluoroacetate

Article abstract of DOI:10.1016/0022-328X(91)86209-9

2,2-difluoro-3-hydroxyesters are readily obtained from methyl chlorodifluoroacetate and carbonyl compounds by electrolysis in a one-compartment cell with use of a sacrificial zinc anode and a nickel-complex catalyst.

Full text of DOI:10.1016/0022-328X(91)86209-9

211
Journal of Organometallic Chemistry, 401 (1991) 211-215
Elsevier Sequoia S.A., Lausanne
JOM 21211
Electrochemical, nickel-catalyzed Reformatsky reaction
with methyl chlorodifluoroacetate
Slah Mcharek, Soline Sibille, Jean-Yves Nrdrlec and Jacques Prrichon
Laboratoire d'Electrochimie, Catalyse et Synth~se Organique, UMR 28, CNRS, 2, Rue Henri Dunant,
94320 Thiais (France)
(Received June 15th, 1990)
Abstract
2,2-difluoro-3-hydroxyesters are readily obtained from methyl chlorodifluoroacetate and carbonyl
compounds by electrolysis in a one-compartment cell with use of a sacrificial zinc anode and a
nickel-complex catalyst.
I n t r o d u c t i o n
We recently described [1] an electrochemical Reformatsky reaction which ad-
vantageously uses a-chloroesters instead of the corresponding bromo-compounds to
give high yields of fl-hydroxyesters in coupling with various carbonyl compounds.
The main features of the process are the use of a sacrificial zinc anode in
a
one-compartment electrolysis cell and catalytic amounts of nickel-2,2'-bipyridine
complex, with DMF as the solvent. The catalytic cycle (Eq. 1-4) involves the
reduction of the Ni n complex to a zerovalent one, the oxidative addition of the
chloroester to Ni °, followed by a metal exchange between the organonickel(II)
species and Znn, and addition of the organozinc species to the carbonyl compound.
Ni !I + 2e ~ Ni °
(1)
(2)
(3)
Ni ° + RX --, RNiX
RNiX + ZnX 2 ---} RZnX + NiX 2
I
RZnX + ~C---O ---, R C O Z n X
(4)
I
The Reformatsky reaction using iodo-, bromo- or chloro-difluoroacetate has been
recently reported [2-4] and its synthetic utility in the field of fluoroorganic chem-
istry has been outlined. In the case of the less expensive chlorodifluoroacetate
however, the reaction requires relatively severe conditions ( D M F , 70 o C, 20 h), and
only applies to non-enolizable aldehydes. This prompted us to examine the suitabil-
ity of our method for the synthesis of 2,2-difluoro-3-hydroxyesters.
0022-328X/91/$03.50
© 1991 - Elsevier Sequoia S.A.

212
Results and discussion
As shown in Table 1, electrolyses performed in DMF containing a four-fold
excess of methyl chlorodifluoroacetate relative to the carbonyl compound gave high
yield of the fl-hydroxyester in the case of benzaldehyde, but much lower yields with
heptanal or various ketones. Unchanged ketone was mostly recovered, but not
heptanal. The main by-products were CHF2CO2Me and a Claisen condensation
product isolated in the hydrated form C1CF2C(OH)2CF2CO2CH3 (I). Near the end
of the electrolysis the latter was formed almost exclusively, and the ketone was no
longer consumed. In the absence of carbonyl compound, (I) was obtained in 75%
yield.
In the reaction of non fluorinated a-chloroesters, DMF can be replaced by a
90:10 CH2C12-DMF mixture, with essentially the same yield of fl-hydroxyesters
[1]. Interestingly, with chlorodifluoroacetate, the use of CH2C12-DMF as solvent
led to substantial improvements in the synthesis of 2,2-difluoro-3-hydroxyesters, in
respect of both the required amount of chlorodifluoroacetate (2-2.5 eq. relative to
the carbonyl) and the yield of the product (Table 2).
High yields were obtained in this way even with ketones and enolizable al-
dehydes. A lower yield in the case of 5-methylfurfural was due to the polymerization
of the substrate, but no conjugate addition was detected.
There are noteworthy differences between the reactions carried out in CH2C12-
DMF and those in DMF. The 19F NMR monitoring of the electrolysis indicated
that the major by-product was CHF2CO2Me, formed in the same amount as in
DMF, but that the formation of CICF2COCF2CO2CH3 was far less important. When
the electrolysis was performed in the absence of carbonyl compound, a singlet at
-115 ppm (CFC13), which was not detected in DMF was observed. It can be
assigned to an organometallic species which reacts rapidly with water or
acetophenone to give CHF2CO2Me or PhC(OH)(CH3)CF2CO2CH3, respectively,
and slightly more slowly (in 10-30 min) with an excess of methyl chlorodi-
fluoroacetate to give the Claisen condensation product (I). This organometallic
species, although not very stable could be kept in CH2C12-DMF solution during the
electrolysis at concentrations of up to 0.15 M (as judged by 19F NMR spectroscopy
with CF3SO3Li as internal standard), much higher than that of the nickel catalyst
(0.025 M). It must be an organozinc species, its NMR signal then being in
agreement with literature data [2,5].
Table 1
Electrosynthesis of 2,2-difluoro-3-hydroxyesters in DMF
Carbonyl compound
Product
Isolated yield
(~)
PhCHO
PhCHOHCF2CO2CH3 (II)
C6H13CHOHCF2CO2CH3 (Ill)
PhC(OH)(CH3)CF2CO2CH3 (IV)
OH
79
35
34
CrH13CHO
PhCOCH3
~ - - ~ - O
~)('CF2CO2CH3(V)
20

213
Table
2
Electrosynthesis of 2,2-difluoro-3-hydroxyesters in 90:10 CHzCI2-DMF
Carbonyl compound
Product
Isolated yield
(~)
PhC(OHXCH 3)CO2CH3 (IV)
Ph2C(OH)CF2CO2CH 3 (VI)
OH
72
54
PhCOCH3
PhCOPh
~ C
(V)
63
62
F2CO2CH3
OH
)(C
C>°
n-C3HTCOCH3
C2HsCOC2H5
PhCHO
(VII)
F2CO2CH3
n-C3H 7C(OH)(CH3)CF2CO2CH 3 (VIII)
(C2 Hs)2C(OH)CF2CO2CH 3 (IX)
PhCHOHCF2CO2CH 3 (IX)
77
64
70
CH3
~
CHOHCF2CO2CH3 (X)
45
56
C H 3 - ~ C H O
n-C6HI3CHO
n-C6H13CHOHCF2CO2CH3 (III)
This evidence for an organozinc intermediate strengthens the case for the
suggestion that nickel zinc exchange is the key-step in the catalytic cycle [1]:
C1NiCF2CO2CH 3 + ZnBr2 ---, C1ZnCF2CO2CH3 + NiBr2
In DMF the intermediate will react rapidly with the excess of chlorodifluoroacetate
to give the Claisen product (I) in high yield. In CH2C12 as solvent this side-reaction
will be slower, and the condensation with the carbonyl compound thus favoured.
In conclusion, this simple, easy to scale-up electrosynthetic process enables
preparation of reactive organometallic species under milder conditions and from
cheaper reagents than classical organometallic chemistry, and provides an efficient
synthesis of valuable 2,2-difluoro-3-hydroxyesters.
Experimental
General procedure for the electrolyses
A solution in 40 ml of the relevant solvent (DMF or 9 0 : 1 0 CH2C12-DMF) of
NiBrE-2,2'-bipyridine (1 mmol), ZnBr2 (5 mmol), the carbonyl compound (10
mmol), and an excess C1CF2CO2CH3 was introduced into an electrolysis cell fitted
with a zinc rod as the anode and a carbon fiber cathode (20 cm2 area). The solution
was kept under argon at room temperature and a constant current intensity (0.3 A)
applied. The electrolysis was stopped when the product concentration, as monitored
by GC, became constant. Acid hydrolysis, diethyl-ether extraction, and evaporation
of the extract, followed by preparative column chromatography (silica gel, 9 0 : 1 0
pentane-ether as eluant) gave the pure product. Yields are relative to the initial
carbonyl compound.

214
Products analysis
1H NMR (8, ppm from TMS) and 19F NMR (8, ppm from CFC13) spectra were
obtained from an AC200 Bruker spectrometer (CDCI3 solution). IR spectra were
recorded on a Perkin Elmer 577 spectrometer.
Methyl 4-chloro-3,3-dihydroxy-2,2,4,4-tetrafluorobutanoate (I). 1H NMR: 5.4 (s, 2
OH) 3.8 (s, 3H). 19F NMR: - 66.3 (t, J(FF) - 13.6 Hz), - 117.2 (t, J(FF) = 13.6
Hz). IR: 3440, 1760, 1445, 1330, 1160, 1065 cm -~. Found: C: 24.78; H: 2.31; CI:
13.97; F: 30.75. CsH~C1F404 calc.: C: 24.96; H: 2.10; CI: 14.70; F: 31.50%.
Methyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate (11). 1H NMR: 7.25 (s, 5H),
5.1 (dd, 1H), 3.75 (s, 3H), 3.1 (OH). 19F NMR: -112.8 (dd, J ( F F ) = 271Hz,
J(HF) = 7.4 Hz), -120.8 (dd, J ( F F ) = 271, J ( H F ) = 16.8 Hz). Found: C: 55.63;
H: 4.92; F: 17.4. Ca0Hl0FzO3 calc.: C: 55.56; H: 4.66; F: 17.58%.
Methyl 2,2-difluoro-3-hydroxynonanoate (111). 1H NMR: 4.0 (m, 1H), 3.9 (s, 3H),
2.75 (s, OH), 1.65-1.5 (m, 2H), 1.45-1.2 (m, 8H), 0.9 (t, 3H). 19F NMR: -114.1
(dd, 1F, J(FF) = 254, J(HF) = 6 Hz), - 125.5 (dd, 1F, J(FF) = 254, J(HF) --- 15.2
Hz). The alcohol III could not be obtained very pure. Acetylation (acetyl chloride,
pyridine in CH2C12) gave the acetate: n-C6H13CH(OCOCH3)CF2CO2CH 3. 1H
NMR: 5.35 (m, 1H), 3.85 (s, 3H), 2.1 (s, 3H) 1.7 (m, 2H), 1.3-1.25 (m, 8H), 0.9 (t,
3H). 19F NMR: - 114.1 (dd, 1F, J(FF) = 263, J(HF) = 8.4 Hz), - 118.4 (dd, 1F,
J(FF) = 263, J ( H F ) = 13.9 Hz). Found: C: 54.47; H: 7.52; F: 14.36. C~2H20F204
calc: C: 54.13; H: 7.57; F: 14.27%.
Methyl 2,2-difluoro-3-hydroxy-3-phenylbutanoate (IV). 1H NMR: 7.5 (m, 2H),
7.3 (m, 3H), 3.6 (s, 3H), 3.4 (OH), 1.8 (s, 3H). 19F NMR: -114.7 (s, 2F). IR: 3500,
1760, 1450, 1315, 1130, 1070, 1040 cm -~. Found: C: 57.19; H: 5.31; F: 15.5.
CllH12F203 calc: C: 57.39; H: 5.25; F: 16.5%.
Methyl 2,2-difluoro-2(1-hydroxycyclopentyl)-ethanoate (V). 1H NMR: 3.9 (s, 3H),
2.4 (OH), 2.2-1.8 (m, 8H). 19F NMR: -116 (s, 2F). IR: 3480, 2960, 1760, 1440,
1320, 1130, 1090 cm -1. Found: C: 49.60; H: 6.38; F: 18.66. CsH~2F/O3 calc: C:
49.48; H: 6.23, F: 19.57%.
Methyl 2,2-difluoro-3,3-diphenyl.3-hydroxypropanoate (I/1). lH NMR: 7.4 (m,
10H), 4.5 (OH), 3.7 (s, 3H). 19F NMR: -101.5 (s, 2F). VI could not be obtained
free from benzophenone.
Methyl 2,2-difluoro-2-(1-hydroxycyclohexyl)-ethanoate (I/'11). 1H NMR: 3.8 (s,
19
3H), 2.5 (OH), 1.8-1.4 (m, 10H). F NMR: -119.4 (s, 2F). IR: 3500, 2940, 1760,
1450, 1320, 1200, 1125 cm -1. Found: C: 51.92; H: 6.66; F: 16.75. C9HI4F203 calc:
C: 51.92; H: 6.78; F: 18.25%.
Methyl 2,2-difluoro-3-hydroxy-3-methylhexanoate (VIII). 1H NMR: 3.65 (s, 3H),
2.5 (OH), 1.5-1.2 (4H), 1.1 (m, 3H), 0.8 (t, 3H). 19F NMR: - 117 (s, 2F). IR: 3480,
2960, 1760, 1440, 1320, 1120, 1040 cm -~. Found: C: 48.82; H: 7.24; F: 19.26.
CsH14F203 calc: C: 48.98; H: 7.19; F: 19.37%.
Methyl 2,2-difluoro-3-ethyl-3-hydroxypentanoate (IX). ~H NMR: 3.9 (s, 3H), 2.3
(OH), 1.7 (m, 4H), 0.9 (m, 6H). 19F NMR: -114 (s, 2F). IR: 3500, 2980, 1760,
1450, 1310, 1200, 1120 cm -1. Found: C: 48.92; H: 7.27; F: 18.66. CsH14F203 calc:
C: 48.96; H: 7.19; F: 19.37%.
Methyl 2,2-difluoro-3-hydroxy-3-(2-O-methyifuryl))-propanoate (X). 1H NMR:
6.55 (d, 1H, J(HH) = 3.5 Hz), 6.2 (d, 1H, J(HH) = 3.5 Hz), 5.3 (m, 1H), 4.1 (s, 3H),
3.6 (OH), 2.5 (s, 3H). 19F NMR: -113.7 (dd, J ( F F ) = 268.8, J ( H F ) = 8.2Hz),
-119.6 (dd, J ( F F ) = 268.8, J ( F H ) = 16Hz). IR: 3460, 1760, 1560, 1445, 1310,

215
1220, 1080 cm -1. F o u n d : C: 48.04; H: 4.44; F: 16.04. C9HIoF204 calc: C: 49.1; H:
4.58; F: 17.26%.
Acknowledgements
The Soci6t6 Nationale des Poudres et Explosifs and Electricit6 de F r a n c e are
gratefully acknowledged for financial s u p p o r t of the work.
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