Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4643–4646
Synthesis, resolution and racemisation studies of new
tridentate ligands for asymmetric catalysis
Brian A. Sweetman, Helge Muller-Bunzꢀ and Patrick J. Guiry*
¨
Centre for Synthesis and Chemical Biology, Conway Institute for Biomedical and Biomolecular Research,
Department of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
Received 21 March 2005; revised 19 April 2005; accepted 27 April 2005
Available online 23 May 2005
Abstract—A method for the high-yielding preparation of two tridentate, isoquinoline-derived ligands, involving successive Suzuki
cross-coupling reactions, is described. The first ligand could be resolved via molecular complexation with N-benzylcinchonidinium
chloride, while the second was resolved by chromatographic separation of its epimeric camphorsulfonates. The barrier to rotation
about the central biaryl axis was evaluated via racemisation studies, and the absolute configuration assigned by X-ray
crystallography.
Ó 2005 Elsevier Ltd. All rights reserved.
The preparation of enantiomerically pure compounds is
an important and challenging area of contemporary syn-
thetic organic chemistry.1,2 Asymmetric synthesis using
metal catalysts is one approach to such compounds.3–5
Recently, a number of tridentate ligands have been dis-
closed which have proven to form excellent catalysts for
a range of asymmetric processes.6–8 We have recently re-
ported a series of bidentate ligands, Quinazolinaps 1,
which give excellent enantioselectivities in a number of
catalytic reactions.9 We therefore initiated a research
program into the design, synthesis and resolution of a
series of ligands related to the previously reported tri-
dentate ligands and our Quinazolinaps. Ligands 2 and
3 (Fig. 1) were identified as potential candidates for a
wide range of asymmetric transformations, including
Ti(IV)-catalysed asymmetric aldol reactions and diethyl-
zinc addition to aldehydes.
required boronic acid under analogous conditions, pro-
duced 7 and 8 in poor to moderate yields and only when
it was performed under forcing conditions (110 °C in
DMF). Recently, Buchwald and co-workers1 XPhos 9
has emerged as an excellent ligand for the Suzuki
cross-coupling of aryl chlorides and tosylates.11 By heat-
ing biaryl 6 with Pd(OAc)2, XPhos and K3PO4 in THF
with the requisite boronic acid at 80 °C for 18 h, the
required aryl methyl ethers 7 and 8 were isolated in
excellent yields (85% and 95%, respectively). Double
demethylation with 48% HBr provided the desired tri-
dentate ligands 2 and 3 in good overall yield (Scheme 1).
A number of examples for the resolution of racemic
compounds via derivatisation to their diastereomers,
which may then be separated by either crystallisation
or chromatography, have been reported.12,13 Recently
Ding et al. reported the optical resolution of Kocovskyꢁs
NOBIN, a binaphthyl aminoalcohol, by molecular com-
plexation with N-benzylcinchonidinium chloride 10.14,15
The synthesis of ligands 2 and 3 began with Suzuki
cross-coupling of 1,3-dichloroisoquinoline 4 and 2-
methoxynaphth-1-ylboronic acid 5 to yield biaryl 6.
Compound 4 has previously been shown to react selec-
tively at the 1-position under the standard Suzuki condi-
tions employing Pd(PPh3)4.10 Reacting 6 with the
We envisaged that our structurally related compounds
might be suitable candidates for resolution by this meth-
od. To our delight, ligand 2 could be resolved by
employing a modified procedure. Stirring racemic ligand
2 with 0.5 equiv of N-benzylcinchonidinium chloride 10
in acetone for 18 h produced a white precipitate, (R)-
(+)-2Æ10 (Scheme 2). This precipitate was filtered off,
washed with acetone and then stirred in a HCl (3 M)/
EtOAc biphasic mixture until all the precipitate had dis-
solved. The organic layer was then separated, washed
Keywords: Atropisomerism; Biaryls; Suzuki cross-coupling; Resolu-
tion; Racemisation.
*
Corresponding author. Tel.: +353 1 716 2309; fax: +353 1 716
ꢀ Single-crystal X-ray analysis.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.139