Synthesis and application of phosphorus dendrimer immobilized azabis(oxazolines)

Article abstract of DOI:10.1021/ol071128p

Phosphorus dendrimer immobilized azabis(oxazoline) ligands can be efficiently synthesized up to the third generation with 48 ligand molecules being attached to the periphery using click chemistry. The so-assembled macromolecules were evaluated in copper(II)-catalyzed asymmetric benzoylations, showing good yields and enantioselectivlties. Moreover, the copper(II)-catalysts could be readily recovered and reused in several cycles. The globular structure of the dendritic ligands seems to prevent interference of the triazole moieties in the catalysis, contrasting MeOPEG or polystyrene bound ligands of the same type.

Full text of DOI:10.1021/ol071128p

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2895-2898
Synthesis and Application of
Phosphorus Dendrimer Immobilized
Azabis(oxazolines)
Anja Gissibl,†,‡ Cle´ment Padie´,†,‡ Markus Hager,†,‡ Florian Jaroschik,†,‡
Ramesh Rasappan,† Erick Cuevas-Yan˜ez,† Ce´dric-Olivier Turrin,‡
Anne-Marie Caminade,‡ Jean-Pierre Majoral,*,‡ and Oliver Reiser*,†
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
93053 Regensburg, Germany, and Laboratoire de Chimie de Coordination du CNRS,
205 route de Narbonne, 31077 Toulouse cedex 4, France
oliVer.reiser@chemie.uni-regensburg.de; majoral@lcc-toulouse.fr
Received May 15, 2007
ABSTRACT
Phosphorus dendrimer immobilized azabis(oxazoline) ligands can be efficiently synthesized up to the third generation with 48 ligand molecules
being attached to the periphery using click chemistry. The so-assembled macromolecules were evaluated in copper(II)-catalyzed asymmetric
benzoylations, showing good yields and enantioselectivities. Moreover, the copper(II)-catalysts could be readily recovered and reused in
several cycles. The globular structure of the dendritic ligands seems to prevent interference of the triazole moieties in the catalysis, contrasting
MeOPEG or polystyrene bound ligands of the same type.
Azasemicorrins1 and bis(oxazolines)1,2 have proven to be
privileged classes of chiral ligands, being able to form
complexes with a broad variety of metals that are able to
catalyze a great number of reactions with unparalleled
enantioselectivity. Owing to the success of bis(oxazoline)
ligands, more recently their immobilization on various
supports has been intensively studied.3 As a general trend it
is observed that bis(oxazolines) grafted on soluble supports
such as poly(ethylene glycole) behaved similarly to their non-
immobilized counterparts; however, an efficient recovery is
often problematic and requires large amounts of solvents
from which the catalysts can be precipitated. On the other
hand, immobilization of bis(oxazoline) ligands on hetero-
geneous supports such as polystyrenes allows efficient
recovery by simple filtration; however, selectivities and
especially yields are often drastically reduced. Azabis-
(oxazolines)4 have proved to be especially suitable ligands
for attachment onto supports owing to their strong binding
† Universita¨t Regensburg.
‡ Laboratoire de Chimie de Coordination du CNRS.
(1) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.
(2) (a) Lowenthal, R.; Abiko, A.; Masamune, S. Tetrahedron Lett. 1990,
31, 6005. (b) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J. Am. Chem. Soc. 1991, 113, 726. (c) Corey, E. J.; Imai, N.; Zhang, H. Y.
J. Am. Chem. Soc. 1991, 113, 728. For recent reviews see: (d) McManus,
H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151. (e) Desimoni, G.; Faita,
G.; Jorgensen, K. A. Chem. ReV. 2006, 106, 3561.
(4) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045. (b) Werner, H.;
Vicha, R.; Gissibl, A.; Reiser, O. J. Org. Chem. 2003, 68, 10166. (c) Gissibl,
A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325. (d) Werner, H.;
Herrerias, C. I.; Glos, M.; Gissibl, A.; Fraile, J. M.; Perez, I.; Mayoral, J.
A.; Reiser, O. AdV. Synth. Catal. 2006, 348, 125.
(3) Rechavi, D.; Lemaire, M. Chem. ReV. 2002, 102, 3467.
10.1021/ol071128p CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

to metals and therefore greatly reduced leaching when they
are used in repeating cycles in catalyses.5
Scheme 1. Synthesis of Azabis(oxazoline)-Containing
Dendrimers G1-G3•4
Dendrimers might offer an attractive alternative for the
immobilization of catalysts, combining homogeneity but also
ease of recovery owing to their solubility properties and,
moreover, offer the additional potential for continuous
processes through confining them by size exclusion in a
membrane reactor. However, the defined build-up of den-
drimers is often laborious and low yielding because of
purification problems.
We report here that phosphorus dendrimers, which can
be reliably constructed up to eight generations (1536 terminal
functional groups) with high purity6 are excellent cores for
dendrimer bound azabis(oxazoline) ligands.7 Moreover, we
demonstrate that the copper-catalyzed8 azide-alkyne cyclo-
addition9 (CuAAC) reaction can be used as a superior
immobilization strategy to ligate aza(bisoxazoline) ligands
onto such dendrimers.10
proved to be highly labile and therefore not suitable. A stable
linkage with a phenol moiety was achieved with the synthesis
of 4; however, the reaction between 1 and 2 was extremely
sensitive to the reaction temperature, resulting in little
conversion below 25 °C and substantial decomposition above
35 °C, which made the scale-up of this reaction difficult.
Nevertheless, 4 proved to be an excellent building block
for the ligation with G1-G3, giving rise to dendrimers with
12 (G1•4) (Figure 2), 24 (G2•4), and 48 (G3•4) azabis-
(oxazoline) ligands on the periphery.
We initially wanted to make use of the high reactivity of
P(S)Cl2 groups with phenols to attach dendrimers G1-G3
(Figure 1) to azabis(oxazoline) ligands being modified by a
Figure 1. Dendrimers generation G0-G3 with P(S)Cl2-end groups.
suitable phenolic linker (Scheme 1). Benzylation of the
central nitrogen of azabis(oxazoline) 1 generally works well;4
however, such a connection with a 4-hydroxybenzyl group
(5) (a) Fraile, J. M.; Garcia, J. I.; Harmer, M. A.; Herrerias, C. I.;
Mayoral, J. A.; Reiser, O.; Werner, H. J. Mater. Chem. 2002, 12, 3290. (b)
Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, A.; Reiser, O.;
Socue´llamos, A.; Werner, H. Chem.sEur. J. 2004, 10, 2997. (c) Fraile, J.
M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.; Reiser, O.; Vaultier, M.
Tetrahedron Lett. 2004, 45, 6765.
(6) (a) Caminade, A.-M.; Majoral, J.-P. Acc. Chem. Res. 2004, 37, 341.
(b) Launay, N.; Caminade, A.-M.; Majoral, J.-P. J. Organomet. Chem. 1997,
529, 51.
(7) Achiral dendritic bis(oxazoline)copper(II) catalysts have been re-
ported: Chow, H.-F.; Mak, C. C. J. Org. Chem. 1997, 62, 5116.
(8) (a) Tornøe, C. W.; Meldal, M. In American Peptide Symposium; Lebl,
M., Houghten, R. A., Eds.; American Peptide Society and Kluwer Academic
Publishers: San Diego, CA, 2001, p 263. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596. (d) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K.
B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192. (e) Kolb, H. C.;
Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128.
Figure 2. Formula of G1•4.
We recently demonstrated that the copper-catalyzed alkyne
azide cycloaddition (CuAAC) allows an effective ligation
of catalysts and reagents to organic supports.4c,11 Applying
this concept to P,S-dendrimers and having already azabis-
(oxazolines) with propargylic linkers in hand required the
(9) Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
2896
Org. Lett., Vol. 9, No. 15, 2007

synthesis of P,S-dendritic building blocks with a terminal
azide functionality (Scheme 2). This seemingly simple task
difficult. Nevertheless, the conversion of Ga3 could be judged
by the complete disappearance of the azide band at 2098
cm-1 in the IR spectrum.
To evaluate the new ligands for metal catalysis, we chose
the copper(II)-catalyzed asymmetric benzoylation of diols
(Table 1) pioneered by Matsumura and co-workers.13 From
Scheme 2. Ligation of P,S-Dendrimers and
Azabis(oxazolines) by the Copper-Catalyzed Azide-Alkyne
Cycloaddition
Table 1. Copper(II) Catalyzed Asymmetric Benzoylation of
Diols with Dendrimer Bound Azabis(oxazoline) Ligandsa
yieldb 7
selectivity 7
entry
substrate
ligand
cycle
%
%ee
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
1
3
G1•4
G1•4
G2•4
G2•4
G2•4
G3•4
Ga1•5
Ga1•5
Ga1•5
Ga2•5
Ga2•5
Ga2•5
Ga3•5
Ga3•5
Ga3•5
Ga1•5
Ga1•5
Ga1•5
Ga2•5
Ga2•5
Ga2•5
Ga3•5
Ga3•5
Ga3•5
1
1
1
1
1
2
3
1
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
45
35
34
34
41
32
36
40
31c
30c
34c
28c
32c
35c
30
70
80
78
76
80
73
54
73
73c
82c
85c
86c
80c
82c
33
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
was more problematic than anticipated, since, for example,
direct coupling of G1 with p-hydroxybenzyl azide or 3-azi-
dopropan-1-amine failed, most likely because of a cross
reactivity of the dichlorophosphine with the azide group.
Since the reaction of G0-G3 with p-hydroxybenzaldehyde
is well established as part of the dendrimer build-up, we
envisioned to use the formyl-containing derivatives6 Gf1-
Gf3 as the starting point for P,S-dendrimers with a terminal
azide functionality.
18
27
38
34
35c
43c
41c
36c
45c
41c
39
99c
99c
99c
99c
99c
95c
83
Indeed, Gf1-Gf3 could be converted with high yields to
the azides Ga1-Ga3 by reduction of the aldehyde to the
corresponding alcohol, followed by chlorination with thionyl
chloride and final chloride azide exchange. Ligation of Ga1-
Ga3 using 1.2 equiv of 5 for each azide group proceeded
with excellent efficiency in the presence of 5 mol % CuI12
to give Ga1•5-Ga3•5 by precipitation with pentane from
the reaction mixture. Ga3•5 turned out to be only scarcely
soluble in organic solvents, making its characterization
38
28
85
23
a Reagents and Conditions: 5 mol % CuCl2, 5 mol % ligand 1 or 3 or
10-3 to 10-2 mol % (5 mol % end groups) dendritic ligands, 1.0 equiv 6,
0.5 equiv PhCOCl, CH2Cl2, 3 h, 0 °C. b Isolated yield based on 6 (maximum
theoretical yield 50%). c Average of two runs.
the two different series of dendritic azabox ligands compared,
the copper complexes of the Gan•5 series proved to be
superior to the Gn.4 series with respect to recoverability: the
former could be precipitated much more easily from hexanes
than the latter, most likely because of the very polar triazole
moieties present. In fact, Ga3•5 was already difficult to apply
in the benzoylation reactions because of its low solubility
in organic solvents, making Ga1•5 and Ga2•5 the ligands of
(10) Synthesis of functional dendrimers using click chemistry: (a) Wu,
P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.;
Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem.,
Int. Ed. 2004, 43, 3928. (b) Wu, P.; Malkoch, M.; Hunt, J. N.; Vestberg,
R.; Kaltgrad, E.; Finn, M. G.; Fokin, V. V.; Sharpless, K. B.; Hawker, C.
J. Chem. Commun. 2005, 5775. (c) Kehat, T.; Portnoy, M. Chem. Commun.,
published online 2007, http://dx.doi.org./10.1039/b703016a).
(11) (a) Gheorghe, A.; Matsuno, A.; Reiser, O. AdV. Synth. Catal. 2006,
348, 1016. (b) Gheorghe, A.; Cuevas-Yanez, E.; Horn, J.; Bannwarth, W.;
Narsaiah, B.; Reiser, O. Synlett 2006, 2767.
(12) Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5,
1753.
(13) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am. Chem.
Soc. 2003, 125, 2052.
Org. Lett., Vol. 9, No. 15, 2007
2897

Quite strikingly, the dendritic catalysts could rival or even
exceed the parent metal-ligand complexes with respect to
selectivity (Figure 3). While with 9 high enantioselectivity
in the copper(II)-catalyzed benzoylation of 6b was achieved,
the triazole modified ligand 104c alone, bound to MEOPEG
114c or polystyrene 12, gave much inferior results. This can
be attributed to the ability of the achiral triazole moiety to
coordinate with copper,14 therefore competing with the chiral
oxazoline moieties for the metal. In contrast, both Ga1•5 and
Ga2•5 gave excellent selectivity, each being used in three
repetitive runs without a loss of performance (Table 1, entries
18-23). Obviously, the triazole moieties do not interfere with
the catalysis, which could be an indication that owing to the
globular structure of the dendrimers only the azabox end
groups are exposed enough to coordinate with copper and/
or to consequently perform the catalysis.
In conclusion, we have developed a facile method for the
synthesis of dendrimer bound azabis(oxazoline) ligands using
copper-catalyzed azide-alkyne cycloaddition. Depending on
the generation, the dendritic ligands seem to be promising
in metal-catalyzed processes, as was demonstrated for the
copper(II)-catalyzed benzoylation. A special advantage seems
to be the globular structure of the dendritic ligands which
prevents interference of the triazole moieties in the catalysis,
contrasting immobilized azabis(oxazolines) being attached
in an analogous fashion to linear polymers.
Acknowledgment. This work was supported by the
DAAD (Procope travel grants (C.P., A.G., M.H.) and
fellowships for R.R. and E.C.), the International Doktoran-
denkolleg NANOCAT (Elitenetzwerk Bayern), the Fonds der
Chemischen Industrie, and through generous chemical gifts
by Degussa Rexim, Degussa AG.
Supporting Information Available: Experimental pro-
1
cedures, spectroscopical data, and copies of H and 13C
Figure 3. Comparison of ligands for the benzoylation of 6b. For
reaction conditions see Table 1.
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL071128P
choice for the title transformation. Notably, the recovered
complexes could be reused without further addition of copper
salt, pointing again to the good binding affinity of azabox
ligands to metals that minimizes leaching in contrast to the
corresponding bis(oxazoline) ligands.5
(14) (a) Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Org. Lett. 2006,
8, 6099. (b) For a related observation on the addition of zincorganyls to
aldehydes see: Bastero, A.; Font, D.; Pericas, M. A. J. Org. Chem. 2007,
72, 2460.
2898
Org. Lett., Vol. 9, No. 15, 2007