Lithium- α-lithioacetate and β-lithiopropionate: Useful intermediates in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(00)00794-2

The reaction of chloroacetic acid and 3-chloropropionic acid with a base (LDA or Bu(n)Li, respectively) and then with an excess of lithium and a catalytic amount of 4,4'-di-tert-butylbiphenyl (DTBB, 5%) in the presence of different electrophiles [Bu'CHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe] in THF at -78°C leads, after hydrolysis with water, to the expected hydroxy acids, which in the second case are directly cyclised under acidic conditions to give the expected γ-lactones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00794-2

Tetrahedron Letters 41 (2000) 5335±5339
Lithium- a-lithioacetate and b-lithiopropionate: useful
intermediates in organic synthesis
Isidro M. Pastor and Miguel Yus*
Departamento de QuõÂmica Org a nica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Received 10 April 2000; accepted 12 May 2000
Abstract
n
The reaction of chloroacetic acid and 3-chloropropionic acid with a base (LDA or Bu Li, respectively)
0
and then with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB, 5%) in the
ꢀ
t
presence of di€erent electrophiles [Bu CHO, PhCHO, Et CO, (CH ) CO, PhCOMe] in THF at ^78 C
2
2 5
leads, after hydrolysis with water, to the expected hydroxy acids, which in the second case are directly
cyclised under acidic conditions to give the expected g-lactones. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: chlorine/lithium exchange; b-hydroxy acids; g-lactones; DTBB-catalysed lithiation.
1
Dianions derived from carboxylic acids (I, II) are interesting intermediates in synthetic organic
chemistry because they are able to transfer the carboxylic acid functionality in only one reaction
step by reaction with electrophiles. In the case of the a-derivatives, the so-called carboxylate
enolates (I), they have been prepared by double deprotonation using strong and hindered bases
2
(in order to minimise their nucleophilic character). However, to the best of our knowledge, from
the examples described in the literature the simplest acetic acid dianion is rare, its reaction with
3
4
5
n-butyl bromide, ethyl chloroformiate and some aromatic aldehydes being the only reactions
described so far: this fact is probably due to the low solubility of this dianion in common organic
6
7,8
solvents. Concerning b-enolates (II), also called carboxylate homoenolates, the corresponding
deprotonation works only if a stabilising group is present at the b-position or when it is at an
allylic or benzylic position. Other alternatives to the deprotonation reaction, which are useful
for normal carboxylates such as the simple propionate, are tin/lithium transmetallation and
bromine/lithium exchange. On the other hand, in the last few years we have been using an arene-
catalysed lithiation
precursors; (b) functionalised organolithium compounds from chlorinated materials,
phenyl ethers1 or thioethers, or heterocyclic compounds;19d,e and (c) polylithium synthons
9
10
11
12
13�16
for the generation of: (a) organolithium reagents from non-halogenated
18
17
19a
9b
19c
20
*
Corresponding author. Fax: +34 965 903549; e-mail: yus@ua.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00794-2

5
336
from polychlorinated precursors. In this paper we report the application of the arene-catalysed
lithiation to the generation of lithium a- and b-lithio carboxylates by chlorine/lithium exchange
and their reaction with electrophiles.
The reaction of chloroacetic acid (1) with lithium diisopropylamide (LDA, 1:2 molar ratio) in
ꢀ
THF at ^78 C for 30 min, followed by treatment of the resulting mixture with a green suspension
of an excess of lithium powder (1:10 molar ratio) and a catalytic amount of 4,4 -di-tert-butyl-
0
t
biphenyl (DTBB, 5 mol%) and the corresponding electrophile [Bu CHO, PhCHO, Et CO,
2
21
(
CH ) CO, PhCOMe] at the same temperature for 1 h led, after ®nal hydrolysis with water, to
2 5
the formation of the expected b-hydroxy acids 2a±e (Scheme 1 and Table 1). From a mechanistic
point of view, intermediate III (resulting from a double deprotonation of the acid 1 followed by
chlorine/lithium exchange) is probably involved in the process. The reaction has to be performed
ꢀ
1
2
t
Scheme 1. (i) 2 LDA, THF, ^78 C; (ii) Li, DTBB cat. (5 mol%), R R COˆBu CHO, PhCHO, Et
PhCOMe, ^78 C; (iii) H O, ^78 to 20 C
2 2 5
CO, (CH ) CO,
ꢀ
ꢀ
2
Table 1
Preparation of hydroxy acids 2

5
337
in the presence of the electrophile (Barbier-type conditions)21 in order to get the higher yields
Table 1, entry 2 and footnote d). As a comparison with the stoichiometric version of the lithiation,
(
22
when it was carried out using lithium-naphthalene under Barbier-type conditions and with
benzaldehyde as electrophile, only decomposition products were detected.
b-Hydroxy acids 2 are interesting starting materials for the formation of b-lactones by intra-
As an example of this transformation, compound 2c was treated with
molecular dehydration.2
3,24
ꢀ
benzenesulfonyl chloride (1:2 molar ratio) in dry pyridine at 0 C overnight yielding, after hydrolysis
with water at the same temperature, the expected 3,3-diethyl-b-propiolactone in 67% isolated yield.
In the second part of this study we lithiated in situ generated lithium 3-chloropropionate
(derived from compound 3a) under catalytic conditions (DTBB, 5% molar) and in the presence
of di€erent carbonyl compounds [Bu CHO, PhCHO, Et CO, (CH ) CO, PhCOMe] in THF at
t
2
2 5
ꢀ
^78 C to give, after hydrolysis with water and treatment of the crude reaction product with a
catalytic amount of p-toluenesulfonic acid (10% molar) under benzene re¯ux (Dean±Stark), the
expected g-butyrolactones 4aa±ae (Scheme 2 and Table 2, entries 1±5). The last treatment is
Table 2
Preparation of g-lactones 4

5
338
n
1
2
t
ꢀ
2 2 5
CO, (CH ) CO, PhCOMe, THF, ^78 C;
Scheme 2. (i) Bu Li, Li, DTBB (5 mol%), R R COˆBu CHO, PhCHO, Et
ꢀ
(
ii) H
2
O, ^78 to 20 C; (iii) p-TSA (10 mol%), PhH re¯ux
convenient in order to purify the mixture of the lactone 4 and the corresponding g-hydroxy acid
obtained at the end of the reaction. Intermediate IV probably takes part in the reaction shown in
Scheme 2. On the other hand, DTBB is shown to be a better electron transfer reagent than
naphthalene (Table 2, entry 2 and footnote e).
In order to see if the reaction could work better in the absence of hydrogen atoms at the
a-position in the starting 3-chloropropionic acid we applied the protocol shown in Scheme 2
to the corresponding a,a-dimethyl derivative 3b. As can be seen in Table 2 (entries 6±8), the yields of
isolated lactones are comparable in both cases, so we can conclude that there is no in¯uence
of the mentioned a-protons.
From the results described here we conclude that this methodology allows to accede to b-hydroxy
acids (easily transformed into the corresponding b-lactones) or directly to g-lactones. In both
cases this is a simple and new way for these types of compounds, which are important units in
many naturally occurring compounds.
Acknowledgements
This work was generously supported by the DGES (no. PB97-0133) from the Spanish Ministerio
de Educacion y Cultura (MEC). I.M.P. thanks the Generalitat Valenciana for a fellowship.
Â
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