Difluoromethylation reactions of ethyl pyruvate with the TDAE - A mild approach to the synthesis of 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric ethyl esters derivatives

Article abstract of DOI:10.1055/s-2002-33517

New 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric ethyl esters derivatives are easily obtained in moderate to good yields from the tetrakis(dimethylamino)ethylene (TDAE) mediated reduction of a series of RCF₂X (X = Cl or Br) starting materials in the presence of ethyl pyruvate.

Full text of DOI:10.1055/s-2002-33517

LETTER
1541
Difluoromethylation Reactions of Ethyl Pyruvate with the TDAE – A Mild
Approach to the Synthesis of 3,3-Difluoro-2-hydroxy-2-methyl-4-oxo-butyric
Ethyl Esters Derivatives
D
ifluoromethylationR
a
eactions of
u
Ethyl Pyruv
r
a
te
w
ith
i
the TD
c
A
E
e Médebielle,*a Katsuya Kato,b William R. Dolbier Jr. c
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, F-69622 Villeurbanne Cedex, France
Fax +33(4)72431323; E-mail: medebiel@univ-lyon1.fr
b
c
AIST Chubu, National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami,
Moriyama-ku, Nagoya 463-8560, Japan
University of Florida, Department of Chemistry, Gainesville, FL 32611, USA
Received 1 July 2002
compounds with a difluoromethylene moiety are un-
known.
Abstract: New
3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric
ethyl esters derivatives are easily obtained in moderate to good
yields from the tetrakis(dimethylamino)ethylene (TDAE) mediated
reduction of a series of RCF2X (X = Cl or Br) starting materials in
the presence of ethyl pyruvate.
Therefore a series of halogeno-difluoromethylated sub-
strates 1–7 (Figure 1) chosen as good electron-acceptors
(peak potentials measured at a glassy carbon electrode in
anhydrous DMF are in the range of –1.15 to –1.65 V vs
SCE), were engaged in coupling reactions with ethyl
pyruvate, in the presence of TDAE, using anhydrous
DMF as solvent (Scheme 1).
Key words: electron transfer, fluorine, tetrakis(dimethylami-
no)ethylene, ethyl pyruvate, nucleophilic additions
There continues to be an interest in the synthesis of fluor-
inated compounds because of the unique properties of
such molecules.1 For some years, we have been interested
in the search of new methodologies to the synthesis of flu-
orine containing molecules;2 among the recent studies de-
veloped in our laboratories, we have shown that the
tetrakis(dimethylamino)ethylene (TDAE) reagent, a pow-
erful electron-donor, was able to generate remarkably sta-
bilized RCF2 and CF3 anions, in anhydrous DMF and
other solvents.3 Pawelke earlier demonstrated that the
combination of CF3I and TDAE could be used to prepare
CF3TMS from TMSCl.4 A stepwise electron-transfer
mechanism is presumed to take place. A series of electro-
philes were found to react successfully with these anions,
such as heteroaryl aldehydes and ketones, heteroaryl thio-
cyanates and acyl chlorides.
NMe2
N
R
PhCOCF2Cl
N
1
COCF2Cl
COCF2Cl
R= H; 3
R= Ph; 4
2
N
Ph
N
CF2Br
BrCF2CO2Et 7
CF2Br
O
N
O
6
5
Figure 1
In a project devoted to the synthesis of new CF2 contain-
ing molecules for biological evaluation, we sought to ob-
tain a series of 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-
butyric ethyl esters derivatives by the reaction of halo-
geno-difluoromethylated substrates with TDAE in the
presence of ethyl pyruvate.
TDAE
CH3COCO2Et
OH
Me2N
Me2N
NMe2
NMe2
TDAE:
RCF2
X
RCF2
CO2Et
anhyd DMF
-20 °C to r.t.
CH3
1–7
8–14
Scheme 1
3,3,3-Trifluoro-2-hydroxy-2-methyl propionic acid ethyl
ester derivatives (and the corresponding Mosher’s acid)
have been prepared from the condensation of CF3Br in the
presence of the Zn in pyridine5 or by the reaction of the
Ruppert’s reagent (CF3TMS) with -keto ester deriva-
tives.6 However to the best of our knowledge, related
In a typical experiment, 1.25 equivalents of TDAE (nec-
essary for complete reaction of the starting ketone)
was added dropwise to one equivalent of ketone 1 and
three equivalents of ethyl pyruvate in anhydrous DMF at
–20 °C, with the reaction being almost complete after
two hours (TLC monitoring). After the usual work-up, a
19F NMR spectrum of the crude product mixture revealed
the presence of the desired alcohol 8, which was charac-
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1541,1543,ftx,en;D12202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
terized by an AB system ( = –103.3 and –111.9 ppm/
F
CFCl3 with JF-F = 288 Hz). Two other fluorinated prod-

1542
LETTER
ucts were also observed, the reduction product
PhCOCF2H ( = –125.7 ppm/CFCl3; doublet with
F
TDAE 1.25 eq.
CH3COCO2Et 3 eq.
CH3
CO2Et
2JH-F = 54.2 Hz) and a small amount of a product charac-
terized by a singlet at F = –63.1 ppm. Using PhCF3 as in-
ternal standard, the yield of the desired alcohol adduct was
estimated to be 72%, plus 18% of PhCOCF2H. The alco-
hol adduct was isolated as a viscous, yellowish oil in 61%
yield after purification by silica gel chromatography.7 The
other, minor product (a colourless viscous oil; 8%) was
found to be PhCOCF2COCOCH3, which resulted from the
nucleophilic attack of the difluoracetyl anion at the ester
function. The other chlorodifluoracetylated ketones, 2–4,
were found to react in a similar fashion, with the alcohols
adducts 9–11 being obtained in moderate to good yields
(Scheme 2). In these cases, the two by-products detected
by fluorine NMR of the crude reaction mixture were the
RCOCF2COCOCH3 and RCOCF2H compounds.
RCF2X
RCF2
anhyd DMF
-20 °C to r.t.
OH
8-14
1-7
F
CH3
CO2Et
F
CH3
CO2Et
F
F
Me2N
OH
OH
O
O
9; 54%
8; 61%
F
CH3
CO2Et
R
F
F
F
CH3
CO2Et
N
OH
OH
O
N
O
N
12; 68%
R= H; 10; 43%
R= Ph; 11; 58%
The bromodifluoromethyl heterocycles 5,6 could also be
used effectively in this coupling reaction. Fluorine NMR
yields of alcohol adducts 12 and 13 were estimated to be
75% and 78% respectively and the reactions were usually
complete in less than 2 hours. In contrast to the chlorodi-
fluoroacetylated ketones substrates, none of the
RCF2COCOCH3 by-products were obtained. The reaction
with ethyl bromodifluoroacetate 7 was slower (comple-
tion after 8 hours), and the yield of desired alcohol 14 was
rather low (25%), with the major product being
HCF2CO2Et. This difference in reactivity may be attribut-
ed to the higher reduction potential of this substrate (peak
potential was measured to be –1.65 V vs SCE at a glassy
carbon electrode in anhydrous DMF). Increasing the
amount of TDAE (from 1.25 to 2 equiv) resulted in almost
quantitative yield formation of HCF2CO2Et.
F
CH3
CO2Et
F
CH3
CO2Et
F
F
O
OH
EtO
OH
N
N
O
13; 65%
14; 25%
Scheme 2
F
OMe
N
OMe
BuLi
F3C
N
NBn
F
H
Recent investigations have shown that the reaction can be
also extended to methyl benzoyl formate PhCOCO2CH3
with similar yields being obtained (Figure 2).
NBn
Ph OH
PhCOCO2CH3
TfOSiMe3
MeO
CO2Me
F
F
O
F
Ph
F
85%
CO2CH3
F
Ph
F
OH
Scheme 3
CO2CH3
O
N
OH
O
None of the yields have been optimised, and they should
be able to be improved.
16; 65%
15; 54%
Figure 2
In conclusion, we have demonstrated, that under very
mild conditions, new 3,3-difluoro-2-hydroxy-2-methyl-4-
While our work was in progress, dehydrofluorination of a oxo-butyric ethyl ester derivatives could be obtained in
methylated hemiaminal of trifluoroacetaldehyde, and sub- reasonable yields using tetrakis(dimethylamino)ethylene
sequent in-situ addition of the resulting ketene hemiami- (TDAE) as an efficient electron transfer reagent. The
nal towards methyl benzoyl formate (and other compounds synthesized in this work are potentially useful
electrophiles),8 was found to be an alternative methodolo- for biological applications. Further chemical elaboration
gy to prepare similar derivatives (Scheme 3).
of these derivatives is currently under investigation as
well as enzymatic resolution of the racemates.
Synlett 2002, No. 9, 1541–1543 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Difluoromethylation Reactions of Ethyl Pyruvate with the TDAE
1543
(7) A typical procedure for the reaction between 1,
Acknowledgement
CH3COCO2Et and TDAE is as follows:
M. M. would like to thank the CNRS for support of this research
through a research grant [‘Aide aux Jeunes Equipes-Appel d’Offres
2000’] and the Direction des Relations Internationales (DRI) of the
CNRS.
Into a three-necked flask equipped with a calcium chloride
drying tube, and a nitrogen inlet was added, under nitrogen,
5 mL of anhyd DMF and then 1 (0.50 g, 2.62 mmol)
followed by ethyl pyruvate (0.91 g, 7.9 mmol, 0.87 mL). The
solution was cooled down to –20 °C, stirred and maintained
at this temperature for 30 min and then was added dropwise
(via a syringe) the TDAE (0.63 g, 3.15 mmol). A red color
immediately developed with the formation of a white fine
precipitate. The solution was vigorously stirred at –20 °C for
1 h and then warmed up to r.t. for one hour (orange-red
color). After this time TLC analysis [Hexane/EtOAc
(60:40)] clearly showed that 1 was totally consumed. The
orange-red turbid solution was filtered (to remove the
octamethyloxamidinium dichloride) and hydrolyzed with 30
mL of an aq NaCl solution. The aq solution was extracted
with CH2Cl2 (3 30 mL), the combined organic solutions
washed with brine (3 30 mL), H2O (3 30 mL) and dried
over MgSO4. Evaporation of the solvent left an orange
viscous liquid as crude product. Purification by silica gel
chromatography [Hexane/EtOAc (60:40)] gave 0.43 g (1.58
mmol, 61%) of 8 as a yellowish viscous oil.
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3,3-Difluoro-2-hydroxy-2-methyl-4-oxo-4-phenyl-
butyric Acid Ethyl Ester: 1H NMR (CDCl3): = 1.31 (3 H,
t, -CH3CH2), 1.66 (3 H, s, -CH3), 4.32 (2 H, m, -CH2), 7.4–
7.7 (4 H, m), 8.10 (1 H, d, J = 7.2 Hz). 19F NMR (CDCl3/
CFCl3): = –103.3 (1 F, d, J = 288 Hz), –119.2 (1 F, d,
J = 288 Hz). GC/MS: M+ = 272, M+ – CO2Et: 199, 156
(PhCOCF2), 105 (PhCO), 77 (Ph). HRMS: Calcd for
C13H14F2O4: 272.0860. Found: 272.0845.
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Synlett 2002, No. 9, 1541–1543 ISSN 0936-5214 © Thieme Stuttgart · New York