Electrochemical generation of tetraethylammonium N-acetoacetyloxazolidin-2-one enolates: An easy access to α-alkylated acetoacetic derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00464-1

A new electrochemical method for the mild generation of naked β-dicarbonyl derivative enolates is disclosed. The electrolysis, under galvanostatic control, of a solution of N-acetoacetyloxazolidin-2-ones/acetonitrile/tetraethylammonium perchlorate allowed

Full text of DOI:10.1016/S0040-4039(02)00464-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2881–2884
Electrochemical generation of tetraethylammonium
N-acetoacetyloxazolidin-2-one enolates: an easy access to
a-alkylated acetoacetic derivatives
Laura Palombi,a,* Marta Feroci,b Monica Orsini,a Leucio Rossia and Achille Inesia,*
aDip. di Chimica, Ingegneria Chimica e Materiali, Universita` degli Studi, I-67040 Monteluco di Roio, L’Aquila, Italy
bDip. di Ingegneria Chimica, Materiali, Materie Prime e Metallurgia, Universita` ‘La Sapienza’, Via Castro Laurenziano 7,
I-00161 Roma, Italy
Received 19 February 2002; revised 5 March 2002; accepted 7 March 2002
Abstract—A new electrochemical method for the mild generation of naked b-dicarbonyl derivative enolates is disclosed. The
electrolysis, under galvanostatic control, of a solution of N-acetoacetyloxazolidin-2-ones/acetonitrile/tetraethylammonium per-
chlorate allowed the selective a-monoalkylation of the 1,3-dicarbonyl residue with a variety of alkyl halides, in very good yields
and short reaction times. More interestingly, no by-products arising from either the electroreduction of the carbonyl functional-
ities or from nucleophilic cyanomethyl anion attack were detected. © 2002 Elsevier Science Ltd. All rights reserved.
In the field of the CꢀC bond-forming reactions, the
a-alkylation of 1,3-dicarbonyl derivatives is one of the
most used synthetic strategies. To this purpose, a con-
siderable number of procedures have been reported in
the literature, including the classical base-induced1 and
the metal-catalyzed alkylations.2 The demand for such a
variety of methods arises from the difficulty to have
efficient, mild and selective procedures to circumvent
the concurrent formation of side products (double alkyl-
ation, O-alkylation, b-diketone cleavage, etc.)3 and,
more recently, to also have low cost and environmen-
tally safe methodologies.
Shono and co-workers5 for example, obtained very good
results in the C-monoalkylation of 1,3-diketones and
b-keto sulfones with alkyl halides by means of an
electrogenerated base (2-pyrrolidone anion having tetra-
ethylammonium as counterion) (Scheme 1). In that
paper, the key role of tetraalkylammonium counterion
as well as the advantage of the electroreductive method
with respect to the chemical one were ascertained.
On the other hand, in our recent reports on the electro-
chemical-induced reactions of chiral nitrogen nucleo-
philes with acylating agents6 and nitroalkenes,7 we
demonstrated the electrogeneration of N-anions by elec-
trolysis under galvanostatic conditions in a system con-
stituted by the substrate (chiral oxazolidin-2-one), the
solvent (acetonitrile or propionitrile) and the supporting
electrolyte (tetraethylammonium perchlorate (TEAP)).
The addition of extra pro-bases was thus avoided.
In this regard, the exploitation of electrochemistry as a
tool to generate bases and reactive species allowed us to
set up new convenient procedures, with features of
simplicity, cheapness and selectivity, very attractive
from a synthetic standpoint.4
Scheme 1.
* Corresponding authors. Tel.: +39-0862-434216; fax: +39-0862-434203; e-mail: palombi@ing.univaq.it; inesi@ing.univaq.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00464-1

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L. Palombi et al. / Tetrahedron Letters 43 (2002) 2881–2884
In connection with the above investigations, we tested
the deprotonating ability of this electrochemical system
on suitable methylene-active compounds.
solution13), we have carried out a control experiment by
adding the substrate 1a to the pre-electrolysed solution
of CH3CN/TEAP (Scheme 3).
The following addition of BnBr led to the alkylation
product with comparable yield selectivity and reaction
time obtained herein before (i.e. Table 1, entry 6).
In particular, it seemed intriguing to accomplish the
electrogeneration of synthetically interesting N-aceto-
acetyloxazolidin-2-one enolates in order to examine
their reactivity with alkyl halides. Especially, the expec-
tation of a stereoselective CꢀC bond formation by using
an optically active oxazolidin-2-one moiety as chiral
inductor stimulated our interest.
Although it has been reported that cyanomethyl anion
adds to carbonyl compounds,14 quite interesting, in our
case, the cyanomethylation products arising from the
attack to the b-dicarbonyl derivative was not obtained.
It must be noted that, besides allowing access to vari-
ous classes of enantiomerically pure a-alkylated aceto-
acetic derivatives by simple removal of the Evans’
chiral auxiliary,8 the a-adducts of compounds 1 are
interesting as useful intermediates for the synthesis of
enantiopure amino acids and substituted heterocyclic
systems (such as oxazoles, isoxazoles and pyrazoles)
incorporating the oxazolidin-2-one ring.9
Finally, to check whether this electrochemical method
enabled a stereoselective alkylation process, the investi-
gation was extended to enantiomerically pure N-aceto-
acetyloxazolidin-2-ones 1b–f.
As reported in Table 2, alkylation reaction again took
place with very satisfactory yields, affording a mixture
of the two expected diastereoisomers. Although the
diastereoisomeric ratios were generally low, notewor-
thy, the chiral oxazolidin-2-ones behaved like efficient
resolving agents, allowing the access to both the enan-
In order to verify the efficiency of the electrochemical
deprotonation an acetonitrile/TEAP10 solution contain-
ing the model compound 1a11 was electrolysed at 0°C
under galvanostatic control (I=25 mA cm−2) in a
divided cell equipped with a platinum cathode and
anode. At the end of the electrolysis, the alkylating
agent was added to the cathodic solution and the
reaction was prolonged until TLC disappearance of the
starting material (Scheme 2).
tiomerically
pure
epimers
after
silica
gel
chromatography.
In summary, we have demonstrated a new and mild
electrochemical methodology to carry out the selective
a-monoalkylation of N-acetoacetyl derivatives, avoid-
ing either the use of chemical bases and probases or
polluting metal reagents. Further investigations devoted
to improve the stereoselectivity of the process are in
progress.
While the complete consumption of the starting mate-
rial took 1.2 F per mol, we always observed a total
chemoselectivity so that the a-adduct was the only
1
product detectable by H NMR analysis on the crude
mixture.
Table 1. Electrochemical activation and alkylation of
N-acetoacetiloxazolidin-2-one 1a
As shown by the data reported in Table 1, the method-
ology could be generalized to the selective C-monoalkyl-
ation with various primary, benzylic and allylic halides.
The reaction usually proceeded with high efficiency, as
supported by H NMR analysis on the crude products,
while slightly lower yields were occasionally observed
Entry F (Mol) RX
Time (h) Yielda (%)
1
2
3
4
5
6
8
9
1.0
1.1
1.2
1.3
1.2
1.2
1.2
1.2
MeI
MeI
MeI
MeI
EtI
BnBr
2
2
2
2
18
2
50
70
76
76
1
after standard purification procedures.
87 (\95)b
83 (\95)b
82
Since under the electrolysis conditions (CH3CN/TEAP,
galvanostatic control) two different reaction pathways
could be proposed (direct cathodic cleavage of CꢀH
bond12 and indirect deprotonation of the methylene
active compound by the electrogenerated base
cyanomethyl anion which may form in the cathodic
H2CꢁCHCH2Br
CH3CHꢁCHCH2Cl 18
4
69
a Yields were calculated on the starting material and refer to isolated
products.
b 1H NMR yields.
Scheme 2.

L. Palombi et al. / Tetrahedron Letters 43 (2002) 2881–2884
2883
Scheme 3.
Table 2. Electrochemical activation and alkylation of N-acetoacetyloxazolidin-2-ones 1b–f
Acknowledgements
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The authors wish to thank Mr. Antonio Ficara for
technical assistance and MURST (Cofin 2000) for
financial support.

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