BOX structures with additional coordination sites: Potential ligands for bifunctional catalysis

Article abstract of DOI:10.1002/ejoc.201300279

The synthesis of four new bis(oxazoline) (BOX) derivatives bearing two additional coordination sites at the 4,4′-positions is presented. As these BOX scaffolds contain an unsubstituted methylene bridge, they should be capable of forming neutral metal comp

Full text of DOI:10.1002/ejoc.201300279

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SHORT COMMUNICATION
Bifunctional Catalysis
S. M. Seifermann, T. Muller,*
S. Bräse* ........................................... 1–5
BOX Structures with Additional Coordi-
nation Sites: Potential Ligands for Bifunc-
tional Catalysis
The efficient synthesis of bis(oxazoline)
(BOX) derivatives bearing two additional
coordination sites at the 4,4Ј-positions is
presented. As these BOX scaffolds contain
an unsubstituted methylene bridge, they
should be capable of forming neutral metal
complexes. Thus, these molecules are very
interesting ligands for bifunctional cataly-
sis.
Keywords: Asymmetric catalysis / Bifunc-
tional catalysis / Ligand design / N ligands /
Neutral metal complexes
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S. M. Seifermann, T. Muller, S. Bräse
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300279
BOX Structures with Additional Coordination Sites: Potential Ligands for
Bifunctional Catalysis
Stefan M. Seifermann,[a] Thierry Muller,*[a] and Stefan Bräse*[a,b]
Keywords: Asymmetric catalysis / Bifunctional catalysis / Ligand design / N ligands / Neutral metal complexes
The synthesis of four new bis(oxazoline) (BOX) derivatives
bearing two additional coordination sites at the 4,4Ј-positions
interesting ligands for bifunctional catalysis. In addition, one
BOX scaffold bearing two azide moieties was successfully
is presented. As these BOX scaffolds contain an unsubsti- employed in copper-free 1,3-dipolar cycloaddition reactions.
tuted methylene bridge, they should be capable of forming
neutral metal complexes. Thus, these molecules are very
The resulting products have yet again high ligand potential.
groups, generally results in high ee values during catalysis.[3]
The substituents of the methylene bridge, connecting the
two oxazoline moieties, also constitute an important trigger
for reaction optimization. Sterically demanding R2 groups
reduce the angle between the oxazoline units, which gen-
erally enhances the enantioselectivity of these cationic
BOX–metal complexes.[2b,2c,3a] An unsubstituted methylene
bridge (R2 = H) most often results in neutral metal com-
plexes owing to the α-CH acidity of the BOX scaffold.[4]
For some time now, bifunctional ligands capable of
simultaneously undergoing two binding actions have come
into the focus of catalysis. These ligands are often inspired
by the mode of action of natural enzymes. The basic idea
is that additional interactions with the substrate may lead to
enhanced reactivity and better selectivity. Structure BOX-II
is the most representative form of a bifunctional bis(oxaz-
oline) ligand (Figure 1).[5]
Introduction
To be an efficient ligand in metal-catalyzed asymmetric
syntheses, the molecular scaffold in question needs to meet
a number of requirements. Amongst others, their ste-
reogenic centers should be in close proximity to the coordi-
nation site(s) and should be connected through a rigid skel-
eton so that they can strongly direct the stereochemical
course of the metal-catalyzed reactions. C2-symmetric chiral
bis(oxazoline)s (BOX) fulfil these criteria. They belong to
the most effective and widespread chiral inductors (Fig-
ure 1).[1]
Several groups have explored BOX-II-type ligands in ca-
talysis. Aggarwal showed that catalytic asymmetric sulfur
ylide mediated carbonyl epoxidation is feasible in high
yields with high ee values by using BOX-II bearing a sulfide
at the 4-position (X = S).[6] Reiser demonstrated that a hy-
droxymethylene side chain (X = O, R4 = H) is necessary
for enantioselective addition of organozinc compounds to
aldehydes and to cyclic enones in good yields[7] and that an
α-amino acid methylene chain is best for asymmetric cyclo-
propanation of furans.[8] Pinel and Djakovitch tested BOX-
Figure 1. Structures of classical BOX-I and bifunctional BOX-II
ligands.
Classical BOX-I (R1 = alkyl or aryl, R2 = H or alkyl)
mostly act as bidentate ligands that complex metal ions ex-
clusively through their nitrogen atoms. The close proximity
of the two stereogenic centers to the coordination sites,[2] in
combination with adequate steric hindrance of the R1
[a] Institute of Organic Chemistry and Center for Functional
Nanostructures (CFN), Karlsruhe Institute of Technology I diacids (R1 = CO2H) and several BOX-II structures with
(KIT),
free or silylated hydroxymethylene side chains in asymmet-
Campus South, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
ric RhI-, IrI-, and RuII-induced reductions.[9] Moberg at-
Fax: +49-72160848581
E-mail: braese@kit.edu
thierry.muller@kit.edu
tached two crown ethers through an ester moiety and tested
the resulting BOX-II ligand in Pd-catalyzed allylic alkyl-
ations.[10] Further studies by Svensson and Moberg on
BOX-II scaffolds with free or methylated hydroxymethylene
side chains showed drastic changes in enantioselective ef-
fects depending on whether hydroxy or O-alkylated BOX-
Homepage: http://www.ioc.kit.edu/braese/english/index.php
[b] Institute of Toxicology and Genetics, KIT, Campus North,
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-
Leopoldshafen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300279
2
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BOX Structures with Additional Coordination Sites
II was used.[11] Rowlands used aminomethylene BOX-II in
catalytic addition for reactions of diethylzinc to benzalde-
hyde.[12]
The large majority of the employed BOX-II ligands in
bifunctional catalysis bear two methyl groups (R2 = Me)
on the methylene bridge and are generally prepared from
hydroxymethylene BOX-II (X = O, R2 = Me, R4 = H) by
dimesitylation and subsequent nucleophilic substitution re-
actions. This reaction sequence is, however, often problem-
atic with the more base-sensitive unsubstituted BOX-II
o(R2 = H) scaffold. Consequently, there are only few exam- Scheme 1. Synthesis of common dibromo precursor 2.
ples of these types of ligands.[6,10] Herein we present general
access to BOX-II ligands bearing an unsubstituted methyl-
With common precursor 2 in hand, we tested a series of
ene bridge (R2 = H) as well as subsequent functionalization
SN2 reactions with common nucleophiles to generate inter-
reactions of some of these compounds.
esting BOX-II structures (Table 1).
Diazide 4a as well as dicyano BOX-II 4b were readily
obtained in excellent yields (Table 1, entries 1 and 2). As all
Results and Discussion
classical ester syntheses starting from diol 1 failed (results
For an ongoing research project we were interested in not shown), we were pleased to find that diesters 4c and 4d
BOX-II ligands bearing an unsubstituted methylene bridge could be obtained in excellent yields by separately treating
(Figure 1; R2 = H, R3 = Ph). In our hands, dimesitylation dibromide 2 with the rather weak nucleophiles potassium
of 2,2Ј-methylenebis(5-phenyl-4,5-dihydrooxazole-4,2-diyl)- acetate and sodium benzoate (Table 1, entries 3 and 4). Al-
dimethanol (1) and subsequent reaction with NaN3 – or though several attempts were made to synthesize dialkyne
other nucleophiles – only resulted in degradation products 4e (Table 1, entries 5–7), only trace amounts of 4e could be
(results not shown). As all optimization attempts failed, we detected by mass spectrometry. The same was true for
turned towards the synthesis of corresponding dibromo methyl ether 4f (Table 1, entry 8). Efforts to prepare diiso-
BOX-II 2.
To our surprise, the latter could be obtained in good of the starting material (Table 1, entries 9 and 10).
yield through an Appel reaction and isolated as a pure Starting from dibromo 2, four new BOX-II structures
ocyanate 4g and dithiol 4h only resulted in decomposition
product that was reasonably stable (Scheme 1). Diiodo 4a–d were obtained in excellent yields and represent poten-
BOX-II 3 could also be prepared by adapting the reaction tially interesting ligands for bifunctional catalysis. To fur-
conditions (Scheme 1), as verified by analysis of the crude ther enlarge the spectrum, we decided to explore click
1
reaction mixture by H NMR spectroscopy (see the Sup- chemistry through Huisgen 1,3-dipolar cycloadditions on
porting Information). We were, however, unable to obtain diazido BOX-II 4a. Such reactions are unknown on the
BOX-II 3 as a pure product. All attempts to remove tri- BOX motive but have already been performed on the pyr-
phenylphosphane oxide by column chromatography failed. idine bis(oxazoline) (PyBOX) scaffold.[13] The use of cop-
All recrystallization efforts were also in vain, as 3 readily per-promoted reactions for BOX compounds is always chal-
decomposed upon heating.
lenging, as the latter are very efficient chelating agents for
Table 1. Reaction conditions for the conversion of dibromo BOX-II 2.
Entry
Reaction conditions[a]
R
Compound
Yield [%]
1
2
3
4
5
6
7
8
9
10
NaN3, DMF, 12 h
NaCN, DMSO, 12 h
KOAc, DMSO, 12 h
NaOBz, DMSO, 12 h
N3
CN
OAc
OBz
alkyne
alkyne
alkyne
OMe
NCO
SH
4a
4b
4c
4d
4e
4e
4e
4f
88
97
quant.
86
Na acetylide, DMSO, 12 h[b]
TMS-acetylene, BuLi, THF, –78 °C to r.t.
Li acetylide·H2NCH2NH2, THF, r.t.
NaOMe, DMSO, 18 h
–
[c]
[c]
–
[c]
–
[c]
–
[d]
NaOCN, DMSO, 12 h
NaSH, DMSO, 18 h
4g
4h
–
[d]
–
[a] All reactions were performed at 50 °C in dry solvents unless stated otherwise. [b] 50 °C and r.t. [c] Product was detected by ESI-TOF-
MS. [d] Only degradation products were detected.
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S. M. Seifermann, T. Muller, S. Bräse
SHORT COMMUNICATION
these metal ions. This can result in problems during the ogether with their additional coordination sites at the 4-
reaction or the workup, which was what we found. All per- position, makes them very interesting ligands for bifunc-
formed click reactions with copper seemed to work, but we tional catalysis, especially for metal ions in high oxidation
were unable to obtain the copper-free BOX-II products (re- states. We are currently exploring the potential of some of
sults not shown). We thus turned to copper-free variants of the synthesized BOX-II structures in asymmetric catalytic
this reaction.[14]
reactions.
We were pleased to notice that sodium acetylide reacted
quantitatively with diazide 4a at room temperature in 18 h
(Scheme 2). On the basis of these results, we also expected
a strained dithiacyclooctyne to react at ambient tempera-
ture, but we needed to slightly heat the reaction mixture to
drive it to completion (Scheme 2).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra of all key intermediates and final
products.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG), Excellence Cluster Center for Functional Nanostructures
(CFN), project number C1.6. Tobias Hagendorn is thanked for do-
nation of dithiacyclooctyne.
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Conclusions
We have presented straightforward access to four new
BOX-II structures. Most probably because of their base-
sensitive methylene bridge, these structures have, up to now,
not yet been prepared. It is, however, the latter that allows
them to build formally neutral metal complexes. This, to-
4
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BOX Structures with Additional Coordination Sites
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Received: February 24, 2013
Published Online: ᭿
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