Fluorinated hydrazones. Part 1: Reductive coupling reactions of chlorodifluoroacetylated dialkylhydrazones using tetrakis(dimethylamino) ethylene (TDAE)

Article abstract of DOI:10.1016/j.tetlet.2003.09.020

A series of new α-diketone derived gem-difluorinated mono-hydrazone derivatives are easily obtained in moderate to good yields from the tetrakis(dimethylamino)ethylene-mediated reductive coupling reactions of chlorodifluoroacetylated dialkylhydrazones with aromatic aldehydes, ethyl pyruvate and an N-tosyl aldimine.

Full text of DOI:10.1016/j.tetlet.2003.09.020

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7871–7873
Fluorinated hydrazones. Part 1: Reductive coupling reactions of
chlorodifluoroacetylated dialkylhydrazones using
tetrakis(dimethylamino)ethylene (TDAE)
Maurice Me´debielle,a,* Katsuya Katob and William R. Dolbier, Jr.c
aUniversite´ Claude Bernard-Lyon 1, Laboratoire SERCOF (UMR CNRS 5622), Baˆtiment E. Chevreul,
43, Bd du 11 novembre 1918, F-69622 Villeurbanne, France
bAIST Chubu, National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami,
Moriyama-ku, Nagoya 463-8560, Japan
cUniversity of Florida, Department of Chemistry, Gainesville, FL 32611-7200, USA
Received 24 July 2003; revised 28 August 2003; accepted 4 September 2003
Abstract—A series of new a-diketone derived gem-difluorinated mono-hydrazone derivatives are easily obtained in moderate to
good yields from the tetrakis(dimethylamino)ethylene-mediated reductive coupling reactions of chlorodifluoroacetylated dialkyl-
hydrazones with aromatic aldehydes, ethyl pyruvate and an N-tosyl aldimine.
© 2003 Elsevier Ltd. All rights reserved.
In order to prepare new fluorine-containing molecules
having potential biological applications, we have
recently reported a number of radical and anionic
methodologies that can be used to prepare new fluori-
nated organic molecules.1 Among such procedures
developed in our laboratories, we have shown that
aromatic and heterocyclic-CF2X (X: Br, Cl), as well as
trifluoromethyl iodide, can be used in conjunction with
the electron-transfer agent, tetrakis-(dimethylamino)-
ethylene (TDAE), to generate the respective, surpris-
ingly stable anions,2 which can be used in various
nucleophilic substitution reactions. Hydrazones consti-
tute an important class of compounds due to the rich
chemistry of the hydrazono group, because of which,
they have attracted a great deal of attention in recent
years.3 Synthetic applications of fluorinated hydrazones
have been relatively less explored. Kamitori et al.4 have
shown that the dimethylhydrazone of aromatic and
aliphatic aldehydes as well as formaldehyde dialkyl-
hydrazones can be acylated with trifluoroacetic anhy-
dride (TFAA) at the azomethine carbon. Some of the
corresponding trifluoroacylated compounds have been
used for the synthesis of a series of trifluoromethylated
heterocycles.5 Lassaletta et al.6 similarly presented the
1,2-addition of formaldehyde N,N-dialkylhydrazones to
fluoral (CF3CHO) and an asymmetric version using
chiral hydrazones. The same group also reported an
enantioselective approach of a-hydroxy-a-trifluoro-
methyl hydrazones through the addition of chiral
hydrazones to trifluoromethyl ketones.7 Recently tri-
fluoroacetaldehyde hydrazones have been proposed for
the synthesis of CF3-containing heterocycles8 and for
the asymmetric synthesis of a-trifluoromethyl-substi-
tuted primary amines.9 Finally Okano et al. achieved
the synthesis of optically active trifluoromethylated
indolizidine derivatives via a stereoselective radical
cyclization involving a trifluoroacetone SAMP-hydra-
zone as starting material.10
Scheme 1.
Keywords: hydrazones; tetrakis(dimethylamino)ethylene; electron
transfer; fluorine and compounds.
* Corresponding author. Fax: +33 (0)
4 72 43 13 23; e-mail:
medebiel@univ-lyon1.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.020

7872
M. Me´debielle et al. / Tetrahedron Letters 44 (2003) 7871–7873
Within a project devoted to the synthesis of new build-
ing blocks and therapeutic agents, a mild and rapid
approach for the synthesis of functionalized
difluoromethylene aromatic and heterocyclic dialkylhy-
drazones was sought, in order to provide novel starting
materials for chemical elaboration. We report here the
synthesis of chlorodifluoroacetylated dialkylhydrazones
1, 211 and a new elaboration of our TDAE methodol-
ogy to generate the corresponding difluoroacetyl
anions, which undergo nucleophilic additions to het-
eroaryl aldehydes 3, 4, ethyl pyruvate 5 and N-tosyl
−1.50 V/SCE for 2]. The corresponding carbinol 7 was
obtained in 57% isolated yield after silica gel chro-
matography. Reaction with hydrazone 2 was more
efficient and needed only 8 h stirring at room tempera-
ture for complete conversion affording addition
product 9 in 68% isolated yield (Scheme 2).12
The TDAE-mediated reductive coupling studies were
extended to the use of ethyl pyruvate 5 as the elec-
trophile. We obtained the corresponding hydroxy ester
derivatives 10 and 11 in 42% and 53% isolated yields,
respectively. Required reaction times were found to be
longer than those needed for the heteroaldehydes
(−20°C /1 h and 24 h at room temperature, Scheme 3).
aldimine
6
to give the corresponding new
difluoromethylene derivatives 7–13 (Schemes 1–3).
As a model substrate, chlorodifluoroacetylated hydra-
zone 1 was treated with 3 equivalents of benzaldehyde
3 in the presence of TDAE (1 equiv.) in anhydrous
DMF at −20°C; TLC and fluorine NMR analysis
showed that the reaction was slower compared to the
reaction involving aromatic-COCF2Cl derivatives. Usu-
ally, stirring at −20°C for 1 h followed by 18 h at room
temperature was necessary for a complete conversion of
the starting material. This is attributed to the fact that
these hydrazones, because of their relatively electron-
rich character, are probably poorer electron-acceptors
than the chlorodifluoroacetylated ketones2d or the bro-
modifluoromethylated heterocycles2e [as judged by their
reduction potentials measured by cyclic voltammetry in
DMF/NBu4PF6 0.1 M; glassy carbon electrode, Ep1
(first peak potential)=−1.66 V/SCE for 1 and Ep1=
Recently Prakash et al.13 reported that TMSCF3 and
tetra-n-butylammonium
triphenyldifluorosilicate
(TBAT) could be used for the efficient nucleophilic
trifluoromethylation of N-tosylaldimines. Such readily
available aldimines, prepared in good yields following a
recent procedure described by Chemla et al.,14 were also
found to be good electrophiles in the reaction with the
carbanions derived from hydrazones 1 and 2. The
corresponding sulfonaldimines 12 and 13 were obtained
in good yields (12: 65%; 13: 62%) after stirring at −20°C
for 1 h, and then at room temperature for 18 h (Scheme
4). These molecules are potentially useful for the syn-
thesis of novel COCF2-containing amines.
In all the reactions presented here, the remaining bal-
ance of material was found to be the corresponding
COCF2H hydrazones 14 and 15.
In conclusion, we have shown that, in conjunction with
the
electron-transfer
agent,
TDAE,
chloro-
difluoroacetylated dialkylhydrazones are good sources
of difluoroketoenolate carbanions that have been
shown to undergo nucleophilic addition reactions with
a series of electrophiles. The yields were mostly good,
but have not yet been optimized. All the products are
new and potentially useful for chemical elaboration.
Work is in progress in this direction as well as toward
Scheme 2.
Scheme 3.
Scheme 4.

M. Me´debielle et al. / Tetrahedron Letters 44 (2003) 7871–7873
7873
the extension of this chemistry to other chlorodi-
fluoroacetylated hydrazones.
6. Fernandez, R.; Martin-Zamora, E.; Pareja, C.; Alcarazo,
M.; Martin, J.; Lassaletta, J. M. Synlett 2001, 1158–1160.
7. Pareja, C.; Martin-Zamora, E.; Fernandez, R.; Las-
saletta, J. M. J. Org. Chem. 1999, 64, 8846–8854.
8. Kamitori, Y. Tetrahedron Lett. 2000, 41, 9267–9270.
9. (a) Funabiki, K.; Nagamori, M.; Matsui, M.; Enders, D.
Synlett 2002, 2585–2588; (b) Enders, D.; Funabiki, K.
Org. Lett. 2001, 3, 1575–1577.
10. Okano, T.; Fumoto, M.; Kusukawa, T.; Fujita, M. Org.
Lett. 2002, 4, 1571–1573.
11. Hydrazones 1 (yellow solid; mp 75°C) and 2 (orange
viscous oil) were prepared in 62% and 71% isolated
yields, by chlorodifluoroacetylation of the corresponding
Acknowledgements
M.M. gratefully acknowledges the CNRS for the sup-
port of this work through a research grant (‘Aide aux
Jeunes Equipes-Appel d’Offres 2000’) and the Direction
des Relations Internationales (DRI) of the CNRS. We
also thank Franc¸ois Paquet and Nidhal Selmi for some
preliminary experiments.
hydrazones
using
chlorodifluoroacetic
anhydride
(CDFAA/2 equiv.) and 2,6-lutidine (2 equiv.) in anhy-
drous dichloromethane (0°C/1 h and room temperature
for 3 h) following the procedure described in Ref. 4a for
the trifluoroacetylated analogs.
References
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12. A typical reaction: Hydrazone 1 (0.30 g, 1.15 mmol) and
3-benzaldehyde 3 (0.37 g, 3.45 mmol, 3 equiv.) were
mixed in anhydrous DMF (5 ml) under nitrogen. The
solution was cooled to −20°C and maintained at this
temperature for 30 min and was then added dropwise (via
a syringe) to TDAE (0.23 g, 0.27 ml, 1.15 mmol). A red
color immediately developed with the formation of a fine
white precipitate. The solution was vigorously stirred at
−20°C for 1 h and then warmed up to room temperature
for 18 h. After this time TLC analysis (CH2Cl2/EtOAc,
7/3) clearly showed that 1 had been totally consumed.
The orange–red turbid solution was filtered (to remove
the octamethyloxamidinium dichloride) and hydrolyzed
with 25 ml of brine. The aqueous solution was extracted
with CH2Cl2 (3×50 mL), the combined organic layers
washed with brine (3×50 ml), H2O (3×50 mL) and then
dried over MgSO4. Evaporation of the solvent left an
orange viscous liquid as the crude product. Purification
by silica gel chromatography (CH2Cl2/EtOAc, 8/2) gave
0. 215 g (0.65 mmol; 57%) of a yellowish viscous oil of 7.
1-(Dimethyl-hydrazono)-3,3-difluoro-
1
4-hydroxy-1,4-diphenyl-butan-2-one. H NMR (300 MHz/
CDCl3): lH 2.48 (6H, s, CH3), 5.21 (1H, brs, OH),
5.42–5.60 (1H, dd, J=16.5, 6.9 Hz, -CHOH), 7.20–7.68
(3H, m, H-arom), 7.61–7.78 (5H, m, H-arom), 8.01–8.06
(2H, m, H-arom). 19F NMR (282 MHz/CDCl3/CFCl3):
lF −106.92 (1F, dd, J=266, 6.8 Hz), −113.52 (1F, dd,
J=266, 16.4 Hz). HRMS (CI): calcd for C18H18F2N2O2:
332. 1336 (MH+); found 332. 1348.
13. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001,
77–78.
14. Chemla, F.; Hebbe, V.; Normant, J.-F. Synlett 2000,
75–77.