A convenient generation of acetic acid dianion

Article abstract of DOI:10.1002/ejoc.200390195

The lithium enediolate of acetic acid can be generated efficiently, as a 0.5 M solution in THF, using lithium amides prepared from n-butyllithium in THF and either diethylamine or 1,3,3-trimethyl-6-azabicyclo-(3.2.1)-octane (AZA). Its reaction with carbon

Full text of DOI:10.1002/ejoc.200390195

SHORT COMMUNICATION
A Convenient Generation of Acetic Acid Dianion
Margarita Parra,*[a] Enrique Sotoca,[a] and Salvador Gil[a]
Keywords: Lithium amides / Aldol reactions / Nucleophilic addition / Carbanions / Carboxylic acids
The lithium enediolate of acetic acid can be generated effici-
ently, as a 0.5 solution in THF, using lithium amides pre- usually obtained when these amines are added in sub-stoi-
pared from n-butyllithium in THF and either diethylamine or chiometric amounts.
1,3,3-trimethyl-6-azabicyclo-(3.2.1)-octane (AZA). Its reac- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
hydroxy acids in good to moderate yields. Better yields are
M
tion with carbonyl compounds leads to the corresponding β-
Germany, 2003)
Introduction
acid[12] show that, despite the acetate anion stability (acetic
acid pKa ϭ 4.6) when compared with enolate anion (carbon
ionisation of acetic acid pKca ഠ 26.5), the intermediate mini-
mum on the enolate pathway makes the kinetically con-
trolled proton abstraction from carbon quite competitive
with respect to oxygen. This is confirmed in flowing after-
glow experiments,[15] where hydroxide reacts with
CD3CO2H; 60% of the proton abstraction occurs from the
carbon and 40% from the oxygen atom. Once acetic acid
Carboxylic acids are synthetically useful building blocks
because, after double deprotonation, they afford enediolates
that react with several electrophiles under appropriate con-
ditions.[1,2] Lithium dialkylamides are generally used as
bases to generate lithium dienediolates[1Ϫ3] due to their
strength and low nucleophilicity — especially when they are
derived from sterically hindered amines — and to their
solubility in non-polar solvents.[3,4] It is well known that, in
these solvents, lithium enolates generally exist as complex
ion-pair aggregate structures whose metal centre may be co-
ordinated to solvent molecules or other chelating ligands,
such as the amines resulting from deprotonation of the acid
by the lithium amide. The available data confirm the com-
plexity present in these aggregated reactive species, whose
reactivity and selectivity products can be influenced by
many different factors.[2,4Ϫ9]
The reactivity of acetic acid dianion appears to be a spe-
cial case as its generation in THF is slow and incomplete.
It is prone to equilibrate with other species in solution as
can be seen from its alkylation reaction, where the forma-
tion of the corresponding α-branched acids (secondary
product) competes with the formation of the expected
straight-chain homologues (primary product).[10]
enolate is formed, it is quite acidic (pKa ഠ 11.7;[11] 13.3[13]
)
and its second deprotonation can be quicker than ketonis-
ation. On the other hand, simulation data indicate that sol-
vent effects have a much greater contribution to the keto-
enol equilibrium of the acetate ion than acetic acid in
water.[14]
Despite this, to the best of our knowledge, synthetic pro-
cedures based on the simplest carboxylic acid dianion are
rare[16] and, according to the literature, this should be as-
cribed to the low solubility of acetic acid dianion in com-
mon organic solvents.[17]
As an alternative route, Yus et al.[18] start from chlo-
roacetic acid, which, on deprotonation with LDA followed
by treatment with an excess of lithium in the presence of a
catalytic amount of 4,4Ј-di-tert-butylbiphenyl (DTBB, 5%),
yields an equivalent of acetic acid dianion that, on reaction
with carbonyl compounds, leads, after hydrolysis and acidi-
fication, to the expected hydroxy acids in 46Ϫ65% yield.
Related theoretical studies have been described and, not
surprisingly, most of them concentrate on the enol, enolate
and enediolate of acetic acid.[11Ϫ14] Although, from a
thermodynamic point of view, dianions of carboxylic acids
are more basic (pKa ഠ 33.5) than the corresponding enol-
ates from amides (pKa ഠ 29) and esters (pKa ഠ 26),[11] from
a kinetic point of view, double deprotonation of carboxylic
acids is not as difficult as their pKa value would suggest.
Theoretical studies of proton abstraction from acetic
Results and Discussion
In the last years we have developed new conditions for
the generation of dianions of carboxylic acids,[9,19] which,
as we report here, can be applied to acetic acid in order to
improve its reaction with carbonyl compounds (Scheme 1).
A variety of conditions have been tested on a ketone and
both an aromatic and an aliphatic aldehyde. These results
are summarized in Table 1.
[a]
´
´
`
Departament de Quımica Organica, Universitat de Valencia,
Dr. Moliner 50, 46100 Burjassot, Spain
Fax: (internat.) ϩ34-963/543-152
E-mail: Margarita.Parra@uv.es
1386
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1386 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1386Ϫ1388

A Convenient Generation of Acetic Acid Dianion
SHORT COMMUNICATION
We have optimised a complete generation of dianions of
carboxylic acids by using an equimolar amount of nBuLi
combined with a sub-stoichiometric amount of amine[19]
(Scheme 2). The amount and nature of the amine can be
changed, but 0.6 equivalents of 1,3,3-trimethyl-6-azabicy-
clo-(3.2.1)-octane (AZA) has evolved as a standard in our
laboratory because it has proved to be of general use to
generate dianions efficiently, avoiding addition of nBuLi to
the acid or appearance of any self-condensation products.
These conditions, when applied to the generation of acetic
acid dianion, lead to a clear increase in the yield for the
addition to p-methoxybenzaldehyde (entry 5). Alternatively,
the amount of amine can be further reduced after genera-
tion of the dianion by total evaporation under vacuum and
dissolving the resulting semisolid lithium dianion in THF,
although lower yields are obtained (entries 9, 16).
Scheme 1. Methods for generation of the acetic acid dianion
Table 1. Conditions optimisation for generation of acetic acid di-
anion
Scheme 2. Generation of acetic acid dianion under catalytic con-
ditions
Highly aggregated states of the dianionic species could
also be responsible for the low yields. Addition of LiCl, a
disaggregating agent of enolates,[20] to the acetic acid di-
anion results in clearly worse yields. LiCl also enhances the
acidity of the amine and probably favours the protonation
of the dianion to the acetate ion. 1,3-Dimethylimidazolidin-
2-one (DMI) has also been described as a Li coordination
agent that does not favour protonation of dianions.[19,21]
Lower yields were obtained when two equivalents were ad-
ded to the acetic acid dianion (entries 8 and 18). Addition
of up to 18 equivalents of DMI, which should increase the
medium’s polarity, has no further effect. The latter obser-
vation, in agreement with that previously described,[8,15]
shows that DMI only acts as a Li coordinating agent of
dianions and has no effect as a co-solvent.
[a] Two equiv. of DMI were added to the enediolate before addition
[b]
of the carbonyl compound.
The amine was evaporated under
vacuum (0.5 Torr) for half an hour before addition of the carbonyl
compound
As can be deduced from Table 1, best results for alde-
There are two main problems for acetic acid dianion gen- hydes are obtained with a 1:1 ratio between acid and car-
eration. First of all, it is slow and incomplete, probably due bonyl compound, whereas for ketones an increase in yield
to the low solubility of some of the species involved. Sec- is obtained until a 1:3 ratio is reached, a higher ratio does
ondly, the deprotonation equilibrium by the lithium amide not increase the yield.
seems to be slightly displaced to the right, and many factors
After the optimisation test, we decided to apply these
can move the equilibrium towards the acetate ion by repro- conditions, namely B and E, to fix the scope and limitations
tonation of the dianion by the amine.
The first problem can be easily solved by generating the
of this method. The results are summarized in Table 2.
Surprisingly, carbonyl compounds prone to enolization
dianion in THF as the only solvent. This means that hexane give better results with an equimolar amount of amine (B
contained in the commercially available 1.6  nBuLi solu- conditions in Table 2). This can be explained by considering
tion must be evaporated and replaced by THF before the that, under conditions D or E, the addition is slower, al-
acetic acid dianion is generated. Under these conditions, a lowing secondary aldol reactions to compete. In a similar
0.5  yellow solution of acetic acid dianion can be obtained manner, benzaldehyde leads to low yields under both reac-
(compare any entries in Table 1 with entries 1 and 10).
tion conditions due to its Cannizzaro disproportionation.
Eur. J. Org. Chem. 2003, 1386Ϫ1388
1387

M. Parra, E. Sotoca, S. Gil
SHORT COMMUNICATION
Table 2. Reaction of acetic acid dianion with aldehydes and ketones
Experimental Section
General Remarks: All reagents were of commercial quality and sol-
vents were dried using standard procedures. All products obtained
have been already described in the literature.
General Procedure: As standard conditions, acetic acid (2.25 mmol)
and carbonyl compound (1 or 3 equivalents) were used. The base
was generated from n-butyllithium (5.0 mmol) and amine (number
of equivalents is stated in each case) in THF (2 mL). Acetic acid,
in THF (2 mL), was slowly added at Ϫ78 °C. The temperature was
allowed to rise to 0 °C and the mixture kept for half an hour to
ensure the enediolate generation. After slow addition of the car-
bonyl compound, in THF (2 mL), to the enediolate at Ϫ78 °C, the
solution was stirred at room temperature for 1 h. In the work up,
the acid layer was obtained by acidification to a pH of roughly 1,
with hydrochloric acid, leading to the isolation of crude products
with chromatographic purity.
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Received January 30, 2003
[O03055]
[17]
In conclusion, solutions of acetic acid dianion in pure
THF can be generated easily. Its direct use in the addition
to carbonyl compounds is possible, with the results de-
pending on the mode of generation and reaction conditions.
From those results it can be concluded that this method-
ology allows an easy access to β-hydroxy acids, which can
be easily transformed into the corresponding β-lactones.
These compounds, which are important units in many nat-
urally occurring compounds, are thus easily obtained in
yields similar to, or even better than, those described for
more complicated methodologies.[18,22]
[18]
[19]
[20]
[21]
[22]
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Eur. J. Org. Chem. 2003, 1386Ϫ1388