Synthesis, resolution and racemisation studies of new tridentate ligands for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2005.04.139

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.

Full text of DOI:10.1016/j.tetlet.2005.04.139

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
2127; e-mail: patrick.guiry@ucd.ie
ꢀ 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

4644
B. A. Sweetman et al. / Tetrahedron Letters 46 (2005) 4643–4646
N
R
OH
OH
OH
OH
N
N
N
PPh2
1: R = H, Me, iPr, tBu, Ph, Bn
2
3
Figure 1.
N
OR
OR
3
Cl
N
b
1Cl
85%
7: R = Me
2: R = H
c
Cl
4
83%
N
a
OMe
79%
6
b
B(OH)2
OMe
N
OR
95%
OR
PCy2
iPr
iPr
5
8: R = Me
3: R = H
c
9
91%
iPr
Scheme 1. Reagents and conditions: (a) Pd(PPh3)4 (5 mol%), CsF, DME, 90 °C, 18 h; (b) 2-methoxyphenyl or 2-methoxynaphth-1-ylboronic acid,
Pd(OAc)2, XPhos, K3PO4, THF, 80 °C, 18 h; (c) 48% HBr, AcOH, 140 °C, 18 h.
with brine, dried over Na2SO4, filtered and evaporated
in vacuo to yield (R)-2 in 36% yield with 90% ee. The
mother liquor was worked up in a similar manner to
give the opposite enantiomer in 56% yield and 88% ee.
This resolution process could be repeated with the enan-
tioenriched (R)-2 and (S)-2 to yield each enantiomer in
O
99% and 98% ee, respectively. A single crystal of the
molecular complex (R)-(+)-2Æ10 was grown by slow dif-
N
O
O
fusion of pentane into an Et2O solution at room temper-
ature. X-ray crystal analysis revealed formation of an
intramolecular hydrogen bond between the phenol
hydrogen and the isoquinoline nitrogen of (R)-2 and
an intermolecular bond between the naphthol hydrogen
and the chloride anion (Fig. 2). Crystallographic data
for (R)-(+)-2Æ10 have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC 266371.
Cl
Unfortunately, ligand 3 could not be resolved using this
method as no precipitate formed when it was stirred in
acetone in the presence of N-benzylcinchonidinium chlo-
ride. Racemic 3 was therefore converted to its bis((1S)-
camphor-10-sulfonate) (Scheme 3) using the procedure
Figure 2.
of Chow et al.16 The epimers formed were separated
by column chromatography over silica using pentane–

B. A. Sweetman et al. / Tetrahedron Letters 46 (2005) 4643–4646
4645
H
N
HO
Cl
10
Ph
(0.5 eq)
N
OH
OH
OH
N
N
(R)-(+)-2 10
+
OH
Me2CO, 18 h
(S)-(-)-2
( )-2
Scheme 2.
OH
OH
OR*
OR*
N
N
R*Cl
Et3N, CH2Cl2,
0 °C to rt
epi-11
+
( )-3
11 (aR or aS)
R*
=
O
S
O
O
Scheme 3.
EtOAc (3:1) to yield four fractions, the yields and
diastereomeric excesses for which are shown in Table
1. The epimers were then converted to enantiomerically
enriched 3 by stirring in 50% w/v NaOH at 0 °C, fol-
lowed by acidic work-up and extraction into CH2Cl2.
determined.17 The racemisation of an individual enan-
tiomer was studied in benzene at a range of tempera-
tures, and the rotational energy barrier was calculated
to be ꢀ88 kJ/mol obtained from Arrhenius and Eyring
plots (Fig. 3).
Following the protocol of Cagle and Eyring, the rota-
tional energy barrier about the biaryl axis of 3 was
Extrapolation of both Arrhenius and Eyring plots indi-
cated that an enantiomerically pure sample of biaryl 3
would lose 1% of its optical purity after 37 h at room
temperature (20 °C), implying a racemisation half-life
of over 105 days. Due to the structural analogy between
2 and 3, it may be assumed that 2 displays a similar rac-
emisation rate.
Table 1.
Yield (%)
De (%)
1
2
3
4
17
24
14
21
98 (11)
79 (11)
In conclusion, a simple route to two new tridentate iso-
quinoline-containing ligands has been developed. Both
ligands were resolved and the absolute configuration
84 (epi-11)
95 (epi-11)
The Eyring plot for Racemisation
of Ligand 3 in PhH
T/K
107
kracem/s-1
007.5 (0.4)
041 (4)00
230 (3)0
860 (12)
Eyring functions
y = 10.330x - 13.186
20
313
328
348
363
∆H#/kJ mol-1
∆S#/ J mol-1K-1
∆G#/ kJ mol-1
-086 (10)
0-88 (29)
-112 (9)
R2 = 0.999
18
16
14
Arrhenius parameters
Ea/kJ mol-1
ln(A/s-1)
-089 (10)
-020 (4)
2.7
2.9
3.1
3.3
103/T (K-1)
Figure 3. Figures in parentheses are errors calculated for 95% confidence level.

4646
B. A. Sweetman et al. / Tetrahedron Letters 46 (2005) 4643–4646
5. Brunner, H.; Zettlmeier, W. Handbook for Enantioselective
Catalysis; Weinheim, 1993.
6. Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc.
1994, 116, 8837–8838.
7. Kwong, H.-L.; Lee, W.-S.; Lai, T.-S.; Wong, W.-T. Inorg.
Chem. Commun. 1999, 2, 66–69.
of 2 was assigned by X-ray crystallography. Racemisa-
tion studies were carried out to determine the barrier
to rotation about the central biaryl axis of 3. Both li-
gands are currently being investigated to assess their
suitability as ligands for asymmetric catalysis.
8. Kim, T.-J.; Lee, H.-Y.; Ryu, E.-S.; Park, D.-K.; Cho, C.
S.; Shim, S. C.; Jeong, J. H. J. Organomet. Chem. 2002,
649, 258–267.
Acknowledgements
9. Connolly, D. J.; Lacey, P. M.; McCarthy, M.; Saunders,
C. P.; Carroll, A.-M.; Goddard, R.; Guiry, P. J. J. Org.
Chem. 2004, 69, 6572–6589.
10. Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin
Trans. 1 1997, 927–934.
11. Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11818–11819.
12. Jacques, J.; Fouquey, C. Tetrahedron Lett. 1971, 4617–
4620.
Financial support for this work was provided by Enter-
prise Ireland and the Centre for Synthesis and Chemical
Biology (CSCB), which is funded under the Programme
for Research in Third-Level Institutions (PRTLI)
administered by the Higher Education Authority
(HEA).
13. Luo, Y.; Wang, F.; Zhu, G.; Zhang, Z. Tetrahedron:
Asymmetry 2004, 15, 17–19.
References and notes
14. Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.;
Okubo, Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734–1737.
15. Smrcina, M.; Polakova, J.; Vyskocil, S.; Kocovsky, P.
J. Org. Chem. 1993, 58, 4534–4538.
16. Chow, H.-F.; Wan, C.-W.; Ng, M.-K. J. Org. Chem. 1996,
61, 8712–8714.
1. Morrison, J. D. In Asymmetric Synthesis; Academic Press:
New York, 1983–1985; Vols. 1–5.
2. Nogradi, M. Stereoselective Synthesis; Weinheim, 1995.
3. Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wein-
heim, 2000.
4. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
17. Cagle, F. W.; Eyring, H. J. Am. Chem. Soc. 1951, 73,
5628–5630.