Synthesis of a novel carboxy functionalized PyOX-ligand

Article abstract of DOI:10.1016/j.tetlet.2004.12.045

A short and convenient synthesis of a carboxy functionalized PyOX-core is presented. The carboxy functionality offers a wide variety of possibilities for further modification. In this paper, the core is functionalized with a mercapto tail.

Full text of DOI:10.1016/j.tetlet.2004.12.045

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 967–969
Synthesis of a novel carboxy functionalized PyOX-ligand
Markku J. Oila, Jan E. Tois and Ari M. P. Koskinen*
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
Received 29 October 2004;revised 29 November 2004;accepted 8 December 2004
Abstract—A short and convenient synthesis of a carboxy functionalized PyOX-core is presented. The carboxy functionality offers a
wide variety of possibilities for further modification. In this paper, the core is functionalized with a mercapto tail.
Ó 2004 Elsevier Ltd. All rights reserved.
In the late 1980s, non-C2-symmetric oxazoline ligands
and especially the 2-(20-pyridyl)oxazolines (PyOX) were
shown to be excellent ligands in asymmetric synthesis.
Chiral PyOX-ligands have been used in, e.g. hydrosilylation1
and Michael reactions.2 In the late 1990s, C1-symmetric
PyOX was also found to be an outstanding ligand in Pd-
catalyzed allylic alkylation reactions,3 being superior to
the C2-symmetric ligands (e.g. PyBOX) due to itÕs ability
to form two different palladium complexes.3a The metal
complex forming ability of the PyOX-core also confers
biological activity, e.g. as iron chelators.4
Amido alcohol 5 was constructed from L-phenylalaninol
4 and pyridine-2,5-dicarboxylic acid 1 as follows.
Exhaustive esterification of 1, followed by selective
hydrolysis of the more electrophilic9 ester at the 2-posi-
tion of the diester 2 gave the monoacid 3. The acid was
then converted to the corresponding acid chloride and
reacted with amino alcohol 4. In the case of 2-pyridyl
acids, the coupling is very selective using equimolar
amounts of amino alcohol and acid and no ester by-
products were observed after recrystallization. This
was, however, not the case when the corresponding benz-
oic acids were used.10(Scheme 1)
We present herein a new and convenient method to con-
struct PyOX-ligands substituted with functionalities
suitable for further conversion, e.g. to nanomaterials.
Our approach is based on amido alcohol formation,
mesylation and base-assisted cyclization. To our knowl-
edge, this general method has only been tried by
Meyers,5 using long reaction times. In our hands, the
cyclization in this one-pot protocol required very long
reaction times and prolonged heating to complete,
which led to dark coloured reaction mixtures, as also
observed by Wuts.6 PyOX-ligands have usually been
prepared by longer synthetic routes from 2-pyridyl nitr-
iles by heating with an amino alcohol in a solvent with a
metal salt catalyst like ZnCl2,7a CuCl27b or Cd(OAc)2.7c
Another common route to the PyOX-core involves imi-
date formation8 and further reaction with the desired
amino alcohol.
Cyclization of 5 was performed in two steps for three
reasons: ease of purification, reaction efficiency and ease
of reaction monitoring. The similar polarity of amido
alcohol 5 and oxazoline 7 makes monitoring on TLC
very difficult. The formation and disappearance of mes-
ylate 6, however, were easily followed by TLC. Mesyla-
tion of 5 proceeded very fast using DMAP as catalyst at
room temperature, total conversion was always reached
within 15 min. The mesylate 6 is stable to aqueous
extractions and silica and it was isolated by a simple
extraction and recrystallization. It was converted to
the PyOX-adduct 7 using DBU as the base.6 No by-
products were observed in this step, either. It has been
reported that base treatment could also yield two by-
products: the aziridinyl or the vinylic amide. The aziridi-
nyl amide was formed selectively, if Mitsunobu condi-
tions were used.11a The use of t-BuOK as the base has
been reported to yield the aziridinyl amide and the cor-
responding vinyl amide as products, but no oxazoline
formation.11b Stoichiometric amounts of base used in
the final hydrolysis facilitated the hydrolysis of 7 with-
out decomposition of the PyOX-core, yielding the key
intermediate 8.12(Scheme 2)
Keywords: PyOX-ligand;Cyclization;Mesylate;Amido alcohol;DBU;
Oxazoline.
*
Corresponding author. Tel.: +358 9 451 2526;fax: +358 9 451 2538;
e-mail: ari.koskinen@hut.fi
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.045

968
M. J. Oila et al. / Tetrahedron Letters 46 (2005) 967–969
O
O
O
i
ii
HO
O
O
OH
O
O
OH
N
N
N
O
O
O
O
1
2
3
iii, iv
H
N
3
N
O
HO
5
HO
NH2
4
Scheme 1. Reagents and conditions: (i) MeOH, H2SO4, reflux, 17.5 h, 91%;(ii) NaOH, MeOH, reflux, 2.5 h, 90%;(iii) SOCl 2, reflux, 3 h;(iv) 4, NEt3,
CH2Cl2, rt, 30 min, 64%.
O
O
MeO
MeO
H
N
i
H
N
N
N
O
O
5
6
HO
MsO
ii
O
O
MeO
HO
iii
O
N
O
N
N
N
8
7
Scheme 2. Reagents and conditions: (i) MsCl, NEt3, DMAP, CH2Cl2, rt, 3 min, 92%;(ii) DBU, THF, 50 °C, 8 h, 84%;(iii) NaOH, aq MeOH, reflux,
4 h, 71%.
O
O
TrS
HS
i
ii
O
O
8
O
O
N
N
N
N
9
10
Scheme 3. Reagents and conditions: (i) (a) DIC, CH2Cl2, DMF;(b) TrSCH 2CH2 OH, DMAP, CH2Cl2, rt, 22 h, 72%;(ii) TFA, Et 3SiH, CH2Cl2, rt,
10 min, 91%.
To prove the versatility of the carboxy functionality in 8,
a mercapto tail was attached to the acid. The tail, S-tri-
tylmercaptoethanol,13 was coupled with the acid using a
standard procedure (Scheme 3) to form the protected
mercapto ester 9. Deprotection of the thiol using TFA
with triethylsilane as scavenger yielded the target mole-
cule 10.14
This is of great interest for catalyst development and is
under investigation in our laboratory and results will
be presented in the near future.
Acknowledgements
Financial support from the Finnish National Techno-
logy Agency, TEKES, is gratefully acknowledged.
A novel key intermediate 8 for the preparation of
PyOX-ligands was prepared using a new and simple pro-
tocol. Reaction steps were optimized to be clean and
moderately to very fast. The first application of interme-
diate 8 is the mercapto ester 10, which has a mercapto
terminus for attachment to materials such as gold15a–c
or functionalized glass15c,d in various applications.16
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D
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D
1
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