Polymer-supported pyridine - Bis(oxazoline). Application to ytterbium-catalyzed silylcyanation of benzaldehyde

Article abstract of DOI:10.1021/ol0353363

(Matrix presented) Terminal acetylenes containing hydroxy and carboxylic acid groups were subjected to Sonogashira coupling with 4-bromo-2,8-bis[(R)-4- phenyloxazolin-2-yl]pyridine and the resulting pybox derivatives were immobilized on Tentagel resins. Y

Full text of DOI:10.1021/ol0353363

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3663-3665
Polymer-Supported
Pyridine Bis(oxazoline). Application to
−
Ytterbium-Catalyzed Silylcyanation of
Benzaldehyde
Stina Lundgren, Serghey Lutsenko, Christina Jo1nsson, and Christina Moberg*
Department of Chemistry, Organic Chemistry, Royal Institute of Technology,
SE-100 44 Stockholm, Sweden
kimo@kth.se
Received July 18, 2003
ABSTRACT
Terminal acetylenes containing hydroxy and carboxylic acid groups were subjected to Sonogashira coupling with 4-bromo-2,6-bis[(R)-4-
phenyloxazolin-2-yl]pyridine and the resulting pybox derivatives were immobilized on Tentagel resins. Ytterbium(III) chloride complexes of the
polymeric ligands catalyzed the addition of trimethylsilyl cyanide to benzaldehyde with 80−81% ee. The ligands were reused more than 30
times without any loss in selectivity or activity, and the metal complexes could be recovered and reused at least four times, although with
slightly decreasing activity.
Asymmetric catalysis constitutes a powerful method for the
preparation of chiral compounds in enantiomerically pure
form.1 The chiral ligands responsible for the transfer of
chirality to the substrates undergoing reaction often require
multistep synthetic procedures for their preparation. The
possibility of recovering and reusing the ligands is therefore
desirable and increases the usefulness of the catalytic
methods.2 This is the reason in recent years considerable
attention has been devoted to the development of procedures
to attach chiral ligands and catalysts to solid supports,
consisting of organic polymers3 or inorganic materials.4
It is particularly valuable to have access to methods
allowing the immobilization of ligands with a wide range
of catalytic applications. Bisoxazoline, box,5 and pyridine-
2,6-bisoxazoline, pybox,6 derivatives are examples of ligands
which are employed in a variety of metal-catalyzed processes
yielding highly enantioenriched products.
While several methods for the preparation of supported
box ligands have been reported,7 only a few examples of
the immobilization of pybox derivatives exist.8 Thus, a chiral
pybox with a vinyl group at the 4-position of the pyridine
ring, introduced via Stille coupling, was copolymerized with
styrene and divinylbenzene.9 Ruthenium complexes of the
(2) De Vos, D. E.; Vankelecom, I. F. J.; Jacobs, P. A. Chiral Catalyst
Immobilization and Recycling; Wiley-VCH: Weinheim, Germany, 2000.
(3) (a) Leadbeater, N. E.; Marco, M. Chem. ReV. 2002, 102, 3217-3274.
(b) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102,
3275-3300.
(4) Song, C. E.; Lee, S. Chem. ReV. 2002, 102, 3495-3524.
(5) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1-45.
(6) (a) Nishiyama, H. AdV. Catal. Proc. 1997, 2, 153-188. (b) Desimoni,
G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119-3154.
(7) Rechavi, D.; Lemaire, M. Chem. ReV. 2002, 102, 3467-3494.
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; John Wiley & Sons:
New York, 2000. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994. (c) Seyden-Penne, J. Chiral
Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley & Sons: New
York, 1995. (d) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe
Asymmetric Catalysis; Springer: Berlin, 1999; Vols. 1-3.
10.1021/ol0353363 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/12/2003

resulting insoluble polymer were used in enantioselective
cyclopropanations, with results somewhat inferior to those
obtained with use of the monomeric analogue. We have
previously attached 4-(3-hydroxyethyloxy)-2,6-bis[(R)-phen-
yloxazolin-2-yl]pyridine to silica surfaces via formation of
ester bonds.10 The 4-substituted pybox was prepared by
nucleophilic substitution of 4-chloro-2,6-bis[(R)-4-phenyl-
oxazolin-2-yl]pyridine with ethylene glycol in the presence
of base. Under the basic conditions used for the reaction,
some degradation of the oxazoline rings occurred, resulting
in variable yields of the product. We therefore desired a more
reliable process for the functionalization of the 4-position
of the pyridine ring with a substituent containing a suitable
functional group for subsequent attachment to a solid support.
Suzuki methodology was recently employed for the
coupling of a 4-chlorosubstituted pybox precursor to the
4-position of pyridine.11 The desired product was obtained
in high yield, provided that the palladium-catalyzed coupling
was performed prior to ring closure to the final oxazoline
compound. Our preliminary experiments aiming at the
introduction of aliphatic substituents via palladium-catalyzed
coupling with ω-functionalized alkylboronates were unsuc-
cessful, however. We therefore decided to attempt Sono-
gashira coupling,12 a Pd-Cu-catalyzed process that tolerates
a wide range of functional groups.13 We were pleased to find
that hydroxyalkynyl as well as carboxyalkynyl substituents
were conveniently introduced and that immobilization to
suitably functionalized cross-linked polymers could be
achieved via ester bond formation.
groups, 5-hexynoic acid and 3-butyne-1-ol, were connected
to the pyridine ring. The function of the alkyl chain,
consisting of three and two carbon atoms, respectively, is to
serve as a spacer between the ligand and the polymer. To
study whether an acetylene substituent in the 4-position of
the pyridine ring has an effect on the outcome of the
homogeneous catalytic reaction, ligand 7 was also prepared.
The Sonogashira couplings were accomplished in 2 h at 55
°C by using 3.4% Pd(OAc)2 and 1% CuI (Scheme 2). After
Scheme 2. Sonogashira Coupling
workup and purification, the desired compounds 5, 6, and 7
were obtained in high yields (75, 86%, and 74%, respec-
tively).
The functionalized pybox derivatives 5 and 6 were linked
via ester bond formation to resins containing carboxylic acid
and hydroxy groups, respectively. Thus, reaction of ligand
5 with TentaGel MB-OH resin and ligand 6 with TentaGel
HL-COOH resin in the presence of DCC and DMAP in
dichloromethane for 48 h at room temperature gave the
desired solid-supported ligands 8 and 9 in high yields (74%
and 84%, respectively, according to elemental analyses,
Scheme 3).
The synthesis of the 4-bromo-substituted phenyl-pybox
ligand 1, selected as a suitable derivative for further
functionalization, started from chelidamic acid (2), which
was transformed to 4-bromopyridine-2,6-dicarboxylic acid
dimethyl ester (3), in analogy to the procedure described for
the corresponding diethyl ester14 (Scheme 1).15 Reaction with
The polymer-bound pybox ligands were evaluated in
asymmetric metal-catalyzed silylcyanations of benzaldehyde
to form nonracemic cyanohydrins, which are important chiral
building blocks in organic synthesis.16 The first reported use
of pybox in metal-catalyzed addition of trimethylsilyl cyanide
(TMSCN) to aldehydes was with isopropyl-pybox and
AlCl3.17 This catalyst provided high yields of products but
only modest enantioselectivity in reactions with benzalde-
hyde. More efficient catalysts, consisting of pybox-lan-
Scheme 1. Synthesis of 4-Bromo-Substituted Phenyl-Pybox
(9) Cornejo, A.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Gil, M.
J.; Legarreta, G.; Luis, S. V.; Marti´ınez-Merino, V.; Mayoral, J. A. Org.
Lett. 2002, 4, 3927-3930.
(10) Andersson, H.; Jo¨nsson, C.; Moberg, C.; Stemme, G. Sens.
Actuators, B 2001, 79, 78-84.
(11) Jouaiti, A.; Hosseini, M. W.; Kyritsakas, N. Chem. Commun. 2002,
1898-1899.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46-49.
(13) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
(14) Takalo, H.; Kankare, J. Acta Chem. Scand. 1987, B41, 219-221.
(15) Pryor, K. E.; Shipps, G. W., Jr.; Skyler, D. A.; Rebek, J., Jr.
Tetrahedron 1998, 54, 4107-4124.
(R)-phenylglycinol generated diamide 4, which was trans-
formed into 1 in two steps.
To evaluate the efficiency of the Sonogashira coupling
two different 1-alkynes with different terminal functional
(16) (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (b) North,
M. Tetrahedron: Asymmetry 2003, 14, 147-176.
(8) Jo¨nsson, C.; Hallman, K.; Anderson, H.; Stemme, G.; Malkoch, M.;
Malmstro¨m, E.; Hult, A.; Moberg, C. Bioorg. Med. Chem. Lett. 2002, 12,
1857-1861.
(17) Iovel, I.; Popelis, Y.; Flesicher, M.; Lukevics, E. Tetrahedron:
Asymmetry 1997, 8, 1279-1285.
3664
Org. Lett., Vol. 5, No. 20, 2003

due to the presence of the acetylene function, as ligand 7
afforded the product with the same enantioselectivity as the
parent phenyl-pybox ligand (84% ee, 92% conversion).
The polymeric ligands could easily be recovered by
filtration, washing, and drying after the catalytic reaction and
reused over 30 times without any change in the reaction
outcome. There was no significant difference in the perfor-
mance of the two polymer-supported ligands.
Scheme 3. Preparation of Solid-Supported Ligands 8 and 9
Since it would be desirable to be able to recover not only
the chiral ligand but also the ligand with the coordinated
metal ion, we examined the possibility of recycling the
ytterbium-pybox complex. For this purpose, the catalytic
reactions were performed in vessels containing a filter,
enabling convenient filtering and washing procedures. The
results of the recovery of the metal-ligand complexes are
summarized in Table 1. After each reaction, the solvent was
Table 1. Recycling of the Polmeric Ytterbium Complexa
conversion [%]b
ligand 8 ligand 9
89 88
ee [%]b
reaction
time [h]
runa
ligand 8
ligand 9
thanide complexes, were reported later.18 The highest ee
reported for lanthanide-catalyzed addition of TMSCN to
benzaldehyde was achieved with a catalyst prepared from
phenyl-pybox and ytterbium trichloride.
1
2
3
4
0.5
0.5
0.5
0.5
81
80
81
81
80
81
81
81
84
75
66
89
82
72
The solid-supported pybox derivatives 8 and 9 were
assessed in the catalytic silylcyanation of benzaldehyde
(Scheme 4), using 10% YbCl3 and 20% ligand. The reactions
a All reactions were carried out in acetonitrile at room temperature with
1.2 equiv of TMSCN, 20 mol % of polymer-bound ligand, and 10 mol %
of YbCl3. b Determined by GC analysis, using a chiral column (Supelco
Gamma-DEX-120).
removed from the reaction vessel and new solutions of
reactants were added. No additional ytterbium trichloride was
added after the initial loading. The metal complex could be
recovered at least four times without any change in ee and
only a slight reduction in activity, the later probably being
due to decreasing metal loading.
Scheme 4. Asymmetric Ytterbium Catalyzed Silylcyanation of
Benzaldehyde
In summary, we have developed an efficient procedure
for the immobilization of chiral pybox derivatives, which
allows for variation of the length and nature of the spacer
connecting the ligand and the solid support as well as the
functional group used for the attachment to the solid support.
The polymeric ligands exhibit as high reactivity as their
homogeneous analogues, yielding products with only mar-
ginally lower enantioselectivity.
afforded the cyanohydrin with 88-89% conversion within
30 min, which is about the same as that observed for the
reaction with the corresponding homogeneous ligand.18
Somewhat lower enantioselectivity was observed, however.
For the homogeneous ligand an enantiomeric excess of 89%
was reported,18 although in our hands, the published proce-
dure resulted in only 84% ee, as compared to 81% and 80%
ee for 8 and 9, respectively.19 With a lower ligand-to-metal
ratio, 1.5:1, a lower ee (72%) was observed, in analogy to
the situation with homogeneous catalyst. The slightly lower
ee observed in reaction with the polymeric ligands was not
Acknowledgment. This work was supported by the
Swedish Foundation for Strategic Research (the Nanochem-
istry Program).
Supporting Information Available: Experimental pro-
cedures for the preparation of 7, 8, and 9, characterization
data, and description of catalytic studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Aspinall, H. C.; Greeves, N.; Smith, P. M. Tetrahedron Lett. 1999,
40, 1763-1766.
(19) A referee suggested that complexation of ytterbium to the polyether
chain of the polymeric backbone might result in a nonselective catalyst.
However, a mixture of unfunctionalized TentaGel HL-COOH and YbCl3
afforded merely 2% of the racemic product after 30 min.
OL0353363
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