158
E. M. Brun et al.
LETTER
The obtained results with these additives are summarised
in Table 2. Only tiglic acid (1) was used for dianion gen-
eration because it showed the least regioselectivity under
standard conditions.5 Considering only those cases where
an acceptable yield was attained and no starting acid was
recovered some conclusions can be extracted: DMI, that
can act as a lithium ion ligands or as a co-solvent that in-
crease the polarity, led to a higher a/g ratio. However, the
ratio did not improve with the amount of DMI, which in-
dicated that only a fixed amount of DMI molecules were
able to chelate lithium ions. These results allowed us to af-
firm that this compound had no effect as a co-solvent (Ta-
ble 2, entries 6 and 7). This is in agreement with the
hypothesis, stated above, that regioselectivity is a function
of the ion-pair structure of the lithium reagent. Addition of
DMI and the use of lower temperatures favoured the pres-
ence of solvent separated ion pairs (SIP) versus contact
ion pairs with an intact C-Li association.9a A similar effect
was observed with LiBr (Table 2, entries 8 to 10) a well
known additive for changing aggregation states of lithium
enolates.12 Consequently, contact ion pairs would favour
attack to the most accessible site whereas separate pairs
would react on the a-position. Entries 3 to 6 (Table 1)
clearly show that a temperature change, under standard
conditions, has no effect on the regioselectivity. So, the
combined effect of additives and temperature is which
controls the a-regioselectivity.
Acknowledgement
The present research has been financed by DGCYT (PB98-1430-
C02-01). One of us E.M.B. acknowledges a DGCYT grant.
References and Notes
(1) Thomson, C. M. Dianion Chemistry in Organic Synthesis;
CRS Press :Boca Raton (Florida), 1994; pp. 88. Aurell, M. J.;
Gil, S.; Martinez, P. V.; Parra, M.; Tortajada, A.; Mestres, R.
Synth. Commun. 1991, 21, 1833. Aurell, M. J.; Gaviña, P.; Gil,
S.; Mestres, R.; Parra, M.; Tortajada, A. Synth. Commun.
1993, 23, 2827. Brun, E. M.; Gil, S.; Mestres, R.; Parra, M.
Synthesis 2000, 273.
(2) Brun, E. M.; Casades, I.; Gil, S.; Mestres, R.; Parra, M.
Tetrahedron Lett. 1998, 39, 5443.
(3) Caine, D. Alkylation of Carbon; in Trost, B. M.; Fleming, I.
ed.; Comprehensive Organic Synthesis. Vol. 3; Oxford:
Pergamon Press, 1991; p 50.
(4) Katzenellenbogen, J. A.; Crumrine, A. L. J. Am. Chem. Soc.
1976, 98, 4925.
(5) Aurell, M. J.; Gil, S.; Mestres, R.; Parra, M.; Parra, L.
Tetrahedron 1998, 54, 4357. Brun, E. M.; Gil, S.; Mestres, R.;
Parra, M. Tetrahedron 1998, 54, 15305.
(6) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synthesis 2000,
1160.
(7) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopedhyay,
T.; Simon, M.; Seebach, D. Synthesis 1993, 1271. Olsher, U.;
Izatt, R. M.; Bradshaw, J. S.; Dalley, N. K. Chem. Rev. 1991,
137.
(8) General procedure for a-alkylation of carboxylic acids:
Diethylamine (5 mmol) in THF (1 mL) was added to a
solution of BuLi (5 mmol) in THF (1 mL) and stirred under Ar
atmosphere at -78 ºC (CO2/acetone bath). After half an hour
at 0 ºC, the corresponding carboxylic acid (2.25 mmol) in THF
(2 mL) was slowly added at -78 ºC. The solution was stirred
for 30 minutes at 0 ºC and cooled again at -78 ºC. DMI and the
corresponding halide (2.25 mmol) in THF (2 ml) was added
dropwise, and the solution stirred at -10 °C for 1 hour for the
primary bromide and 5 hours for the secondary halides.
General procedure for g-alkylation of carboxylic acids:
Diethylamine (5 mmol) in THF (1 mL) was added to a
solution of BuLi (5 mmol) in THF (1 mL) and the mixture was
stirred under Ar atmosphere at -78 ºC (CO2/acetone bath).
After half an hour at 0 ºC, the corresponding carboxylic acid
(2.25 mmol) in THF (2 mL) was slowly added at -78 ºC. The
solution was stirred for 30 minutes at 0 ºC. The amine and
THF were eliminated by strong Ar stream. Then, the mixture
was suspended in cyclohexane (2 mL) and cooled again at
-78 ºC. 12-Crown-4 and the corresponding halide (2.25
mmol) in cyclohexane (2 mL) was added dropwise, and the
solution stirred at room temperature for 1 hour for the primary
bromide and 5 hours for the secondary halides. Water (15 mL)
was added and the aqueous layer was extracted with (3 ¥ 15
mL) diethyl ether that was dried (MgSO4). Evaporation of
solvent, gave the amine as a reusable material. The aqueous
layer was acidified under ice-cooling by careful addition of
concd HCl, and then extracted with (3 ¥ 15 mL) ethyl acetate.
The organic layer was washed with water, aqueous NaCl, and
water, and dried (MgSO4). Evaporation of solvent, gave the
crude acid reaction mixture that was analysed by 1H NMR to
give the a/g ratio. Both a- and g-adducts could be easily
isolated by column chromatography from the crude mixture.
Compounds 3 to 6 are described in reference 5.
An important change in the selectivity of this alkylation of
unsaturated carboxylic acids dienediolates was experi-
mented on addition of 12-crown-4 ether. In this case a non
polar solvent was needed. g-Regioisomer was obtained in
70% ratio when 1 equivalent of crown ether and a second-
ary halide was used (Table 2, entries 14 and 17) and even
with primary halide a 63% yield was observed (entry 12:
comparing Table 1, entry 1). This effect can be associated
to a steric hindrance of the a position in close contact ion
pairs. By contrast, in more polar solvents the effect is lost
because the coordination between the crown-ether and the
lithium aggregate decrease.
Unfortunately, results with DDOMG and DDOTG are not
much better. Although a/g ratios are similar to those ob-
tained above, which confirms their capability to chelate
lithium (Table 2, entry 21), yields decrease probably be-
cause of the lower solubility of the aggregated complexes
(leaving 50% starting acid unreacted).
In conclusion, a/g regioselectivity in alkylation of diene-
diolates from unsaturated carboxylic acids may be con-
trolled on addition of specific lithium chelating
compounds that can modify the aggregation system what
direct the preferred position.
Synlett 2001, No. 1, 156–159 ISSN 0936-5214 © Thieme Stuttgart · New York
Brun
