Tetrahedron Letters 48 (2007) 6434–6436
New stabilising groups for lateral lithiation
of ortho-cresol derivatives
James A. Wilkinson,* Eun-Ang Raiber and Sylvie Ducki
Centre for Molecular Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford,
Salford M5 4WT, UK
Received 1 June 2007; revised 2 July 2007; accepted 11 July 2007
Available online 17 July 2007
Abstract—1-(2-Methoxyethoxy)-2-methylbenzene and 1-(2-dimethylaminoethoxy)-2-methylbenzene have been lithiated using sec-
BuLi under a variety of conditions and the laterally lithiated species trapped with electrophiles.
Ó 2007 Elsevier Ltd. All rights reserved.
The methoxyethoxy substituent has been reported as
being an effective stabiliser for ortho-lithiation.1 In our
previous work on compound 1 it gave very efficient
lateral lithiation.2 We were intrigued to know whether
the stabilisation of laterally lithiated species by this
group and the related dimethylaminoethoxy group was
general.
trations of all reagents low was important with the for-
mation of ortho-cresol (as well as ortho-methylation
product 5b) accompanying product formation above
0.05 M in 2. Use of tert-butyl methyl ether as a solvent
led to increased methylation at the ortho-position.
Use of TMEDA as an additive, common in the prepara-
tion of organolithium compounds, shifted the reaction
from lateral to ortho-lithiation products completely,
again accompanied by some of the deprotected com-
pound 6. Allylation gave a clean reaction at the lateral
position but with only 25% conversion to product. This
could be improved to 50% by the addition of tetrabutyl-
ammonium iodide. Silylation with TMSCl was also
clean and gave somewhat better conversion to product.
Generation of the lithio species over longer time periods
and/or at higher temperatures in diethyl ether and
TBME tended to result in lower conversion to 4 and
more recovered starting material, suggesting that the
lithio species may be quenched by the solvent in these
cases. The wide variations in product distribution with
solvent, concentration and electrophile suggest that
the degree of aggregation is the most important factor
in these systems. The complete change of regioselectivi-
tiy when TMEDA was added would seem to confirm
this.
Here we report lithiations of compounds 2 and 3.3 The
two outcomes felt to be most probable: lateral and
ortho-lithiation, are shown (Fig. 1). In the literature,
2-methoxytoluene has been deprotonated with n-BuLi/
KO-t-Bu leading to lateral deprotonation products
including products arising from migration of the methyl
from oxygen to carbon, while the methoxymethyl ana-
logue of 3 gives exclusive ortho-lithiation when treated
with sec-BuLi.4
The results of reactions of 2 are shown in Table 1. Deu-
teration could be carried out cleanly and with good
conversion (72:26 product to starting material) in
diethyl ether by generating the lithio species at À30 °C
for 2 h using 1.3 equiv of sec-BuLi before quenching
with D2O. Only a small amount of the ortho-deuterated
product 5a was observed.5 Generating the lithio species
at À78 °C for 2 h led to isolation of starting material
only. Methylation could be carried out cleanly with
76% conversion to compound 4b. Keeping the concen-
Removal of the methoxyethyl group was carried out on
compounds 4b and 4c using aluminium triiodide in tol-
uene giving the known compounds 7 and 8 in 62% and
65% yields, respectively (Scheme 1).6
Keywords: Lateral lithiation; Alkylation; Cresol.
*
A similar range of electrophiles was investigated with
Corresponding author. Tel.: +44 161 295 4046; fax: +44 161 295
compound 3 (Table 2). More than 2 equiv of sec-BuLi
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.070