An efficient and versatile approach for the immobilization of carbene precursors via copper-catalyzed [3+ 2]-cycloaddition and their catalytic application

Article abstract of DOI:10.1002/adsc.200700174

Different classes of alkynyl-substituted heterazolium derivatives could be covalently immobilized on an azide-functionalized support via copper-catalyzed 1,3-dipolar cycloaddition, which efficiently yields a rigid and robust 1,2,3-triazole linkage. The catalytic performance of the corresponding nucleophilic carbenes (NHCs) was examined in intramolecular Stetter reactions (chroman-4-one products) and organocatalytic redox esterifications (α,β-unsaturated esters). The MeOPEG-im-mobilized organocatalysts are highly active, and show comparable diastereoselectivities to non-supported derivatives. Additionally, they allow simplified work-up procedures and also have proven to be recyclable.

Full text of DOI:10.1002/adsc.200700174

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DOI: 10.1002/adsc.200700174
An Efficient and Versatile Approach for the Immobilization of
Carbene Precursors via Copper-Catalyzed [3+2]-Cycloaddition
and their Catalytic Application
a,
a
Kirsten Zeitler * and Ina Mager
a
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, 93053 Regensburg, Germany
Fax : (+49)-941-943-4121; e-mail: kirsten.zeitler@chemie.uni-regensburg.de
Received: April 5, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
[
6]
Abstract: Different classes of alkynyl-substituted
heterazolium derivatives could be covalently immo-
bilized on an azide-functionalized support via
copper-catalyzed 1,3-dipolar cycloaddition, which
efficiently yields a rigid and robust 1,2,3-triazole
linkage. The catalytic performance of the corre-
sponding nucleophilic carbenes (NHCs) was exam-
ined in intramolecular Stetter reactions (chroman-
cycling, but can also be seen with regard to changes
in the catalystꢀs solubility properties or its stabiliza-
[
7]
tion. Therefore, immobilization has become an im-
portant tool for combinatorial library synthesis.
Only very few examples are known for the success-
ful use of immobilized organocatalytic carbenes,
such as a recently reported thiazolium-catalyzed intra-
molecular Stetter reaction in ionic liquids under mi-
[8]
[9]
[
10]
4-one products) and organocatalytic redox esterifi-
crowave irradiation or Barrettꢀs ROMPgel-support-
ed thiazolium iodide for intermolecular Stetter reac-
cations (a,b-unsaturated esters). The MeOPEG-im-
mobilized organocatalysts are highly active, and
show comparable diastereoselectivities to non-sup-
ported derivatives. Additionally, they allow simpli-
fied work-up procedures and also have proven to
be recyclable.
[
11]
tions. Usually, lower yields are obtained compared
to non-supported thiazolium salts and catalyst recy-
[
12]
cling generally seems to be problematic.
As part of our ongoing studies, we herein report a
highly versatile and efficient method for the immobili-
zation of several classes of heterazolium carbene pre-
cursors by a Cu-mediated cycloaddition approach.
Their catalytic application in two different organoca-
talytic umpolung reactions is documented.
Keywords: carbenes; catalyst immobilization; click
chemistry; organocatalysis; redox esterification;
Stetter reaction
In recent years, the copper-catalyzed azide-alkyne
[
13]
cycloaddition reaction (“CuAAC”), a mild and re-
gioselective version of a Huisgen-type 1,3-dipolar cy-
[
14]
cloaddition, has proven to be one of the most effi-
cient tools for the covalent assembly of highly func-
[
1]
Within the rapidly growing field of organocatalysis,
N-heterocyclic carbene (NHC)-catalyzed processes tionalized molecules or their ligation to various sup-
[
15]
have proven to be highly versatile not only consider- ports.
ing substrate variations, but also with regard to differ- Based on its favorable thermodynamics, high modu-
ent types of transformations, which depend on the larity, orthogonality to other functional groups and
nature of the applied catalyst and the properties of tolerance towards changing reaction conditions, this
the starting materials. The scope of these carbene cat- selective transformation of terminal alkynes with
[2]
alysts is impressively illustrated by synthetic applica- azides yielding a 1,2,3-triazole linkage presents an
[16]
tions ranging from “classic” umpolung reactions, almost ideal case of so-called “click reactions”. Ad-
transesterifications and cyanosilylation etc. to newer ditionally, it therefore fulfills many of the crucial re-
developments within the class of “extended” umpo- quirements for a mild catalyst immobilization method
[
3]
[17]
lung reactions, such as hetero-Diels–Alder reac- which include high linker stability,
especially to-
[4]
[5]
tions or oxy-Cope rearrangements.
A general approach for the immobilization of this lack of by-products for this atom economic
wards hydrolysis and temperature. Furthermore, the
[
18]
cou-
class of catalysts seems therefore to be highly desira- pling reaction turns it into an enviromentally highly
ble. Advantages of catalyst fixation not only lie in the attractive approach for the generation of immobilized
context of simplified product isolation and catalyst re- and recyclable catalysts. However, whereas this cyclo-
Adv. Synth. Catal. 2007, 349, 1851 – 1857
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1851

Kirsten Zeitler and Ina Mager
COMMUNICATIONS
Scheme 1. Synthesis of supported heterazolium precatalysts via “CuAAC”.
addition concept has been widely used not only in taining additional ascorbic acid proved to work best
synthesis, drug discovery and biochemistry, but also in in our hands. The MeOPEG-supported catalysts could
[
19]
material and polymer sciences, there appear to be be isolated by precipitation in almost quantitative
only few examples in the context of ligand or catalyst yields with catalyst loadings generally ranging from
1
linkages. Apart from its efficient use for the immobili- 80% to 100% as judged by H NMR. Figure 1 pro-
zation and property modulation of TEMPO deriva- vides an overview on the different types of heterazoli-
[20]
tives, the fixation of ligands to polymeric supports um precatalysts prepared by this method. Apart from
[
21]
has been reported,
but proven to be somewhat immobilized imidazolium, thiazolium and triazolium
problematic in terms of providing a potential further catalysts also some benzyl-substituted derivatives
[
22]
metal binding site.
Only recently, an insoluble, (Bn-5 and Bn-7) have been prepared to compare
CuAAC-immobilized hydroxyproline derived organo- their catalytic performance.
[
23]
catalyst was successfully employed for asymmetric
The intramolecular Stetter-type cyclization to form
substituted chroman-4-one derivatives 12, represent-
for ing a large class of natural products with diverse bio-
[24]
aldol reactions.
Due to the advantages of MeOPEG-resins
the characterization of the supported catalyst (simple logical activities, has become a benchmark to test
determination of loading by NMR, etc.), we turned catalyst efficiency.
our attention to the ligation of heterazolium ions onto application of the MeOPEG-supported heterazolium
these soluble polymeric supports. precatalysts with the salicylaldehyde-derived substrate
[
25]
[
30]
[
31]
Our initial experiments for the
The catalyst preparation works straight-forward in 11 concentrated on the evaluation of reaction param-
two steps starting from the different heterazoles 1 and eters, such as solvent, catalyst type, catalyst loading
MeOPEG-supported azide 3, which was conveniently and different bases (Table 1).
[
26]
synthesized as reported. An anchor for the triazole-
From these studies with our test substrate 11
linkage was provided by base-free propargylation to Hünigꢀs base (DIPEA) emerged as the most suitable
yield the desired heterazolium precursors 2 in quanti- base giving best conversions in chloroform as solvent
tative yield (Scheme 1). Several conditions for triazole for thiazolium catalyst 5 or 6 at room temperature.
formation were tested, indicating that water plays a
Gratifyingly, the supported catalyst 5 showed simi-
crucial role for the successful copper(I)-catalyzed cy- lar catalytic performance as compared to the benzyl-
[
27]
cloaddition of these cationic substrates.
Only the triazole derivative Bn-5 (entries 3 and 5). Further-
desired 1,4-substituted triazole regioisomer was more, the catalyst loading could be decreased to 10
formed during the copper(I)-mediated transforma- mol% without loss of activity. An attempt to apply
[
32]
tion. Performing the reaction in aprotic solvents, such Rovisꢀ conditions using supported triazolium salt 9
as CH Cl , THF or toluene, did not yield the desired (entry 8) and 10 only gave moderate yields, which is
2
2
immobilized catalysts. However, pure water could be probably due to different electronic properties of
used, but generally afforded lower catalyst loadings. these catalysts. Imidazolium catalyst 7 did not show
This case presents an example for the strong solvent any catalytic activity for this transformation (entry 7).
dependence of such usually insensitive “click” trans-
The use of stronger bases favors by-product forma-
[
28]
[33]
formations. Nolan similarly observed poor conver- tion such as 1-methylbenzoxepin-4-carboxylate 13,
sions in organic solvents and a strong acceleration in which stems from olefin isomerization and subsequent
water using NHC-containing Cu(I) complexes for the aldol-type cyclization. While performing the reaction
[
29]
1
,3-dipolar cycloaddition of azides and alkynes.
In order to avoid anion scrambling, the use of lyst, the product formation could be shifted from the
Cu(I) bromide in a water/t-butyl alcohol mixture con- Stetter product towards benzoxepin 13, which was ob-
using DBU as base, without any heterazolium cata-
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Immobilization of Carbene Precursors via Copper-Catalyzed [3+2]-Cycloaddition
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Figure 1. 1,2,3-Triazolo-linked heterazolium precatalysts (loading in%).
Table 1. Optimization of the conditions for the intramolecu-
lar Stetter reaction.
Scheme 2. Benzoxepin formation.
[a]
[b]
Entry
Catalyst
Base
Solvent
CH Cl
Yield [%]
[c]
1
2
3
4
5
6
7
8
9
5
5
5
5
DIPEA
DIPEA
DIPEA
DBU
DIPEA
DIPEA
DIPEA [
KHDMS
DIPEA
73
2
2
tained as the sole product in good yields under mild
conditions (Scheme 2).
THF
traces
81
<10%
84
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
[d]
Using our optimized conditions for the intramolec-
ular Stetter reaction, further experiments focussed on
exploring the scope of the transformation (Table 2).
Different aromatic substrates could be converted to
the corresponding products in good yields, irrespec-
tive of whether electron-donating or electron-with-
drawing substituents were present. Indicatively, the
mild reaction conditions may account for the success-
ful cyclization of nitro derivative 17, which was re-
Bn-5
6
7
9
82
–
40
30
e]
toluene
CHCl3
10
[
a]
All reactions were performed using 10 mol% of catalyst
at room temperature, 16 h.
Isolated yields.
Reaction does not go to completion. 14% of starting ma-
terial was reisolated.
Mainly by-product 13 is formed (see Scheme 2).
[
[
b]
c]
[
10]
ported to be problematic earlier. Additionally, the
formation of a quaternary center was smoothly
achieved in very good yields starting from methyl-
[
[
d]
e]
[34]
10 mol% KHDMS were used; reaction time 24 h.
substituted substrate 19 (entry 7).
Adv. Synth. Catal. 2007, 349, 1851 – 1857
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Kirsten Zeitler and Ina Mager
COMMUNICATIONS
Table 2. Intramolecular Stetter reactions with immobilized thiazolium catalyst.
[a]
[b]
Entry
1
Substrate
Product
Yield [%]
84
[c]
[d]
2
3
82; 81
84
4
5
43
86
6
7
89
86
[
[
[
[
a]
b]
c]
d]
All reactions were performed using 10 mol% catalyst in CHCl , room temperature, 16 h.
Isolated yields.
Yield after column chromatography.
Yield after catalyst precipitation and aqueous work-up.
3
An important advantage of the application of of silica and subsequent filtration, thereby providing a
MeOPEG-immobilized thiazolium catalysts is the beneficial simplification for combinatorial applica-
simplified product isolation. Instead of applying stan- tions.
dard column chromatography the desired, pure prod-
uct can be obtained following a minimal work-up bility of our catalyst. So far, only two examples of suc-
procedure in similar yields (entry 2). Removal of the cessful carbene organocatalyst recycling have been re-
In further experiments we investigated the recycla-
[35]
[
10,11]
catalyst after precipitation with Et O or i-PrOH by ported.
However, these approaches use higher
2
filtration is followed by a simple aqueous wash of the catalyst loadings and harsher conditions (15 mol%,
[
36]
remaining organic phase in order to remove base T=808C).
Taking advantage of NMR analysis of
traces. If catalyst reuse is not required, the product the polymer-bound catalyst, we could only detect
can be easily obtained after addition of small amounts intact thiazolium species when the reaction was per-
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Immobilization of Carbene Precursors via Copper-Catalyzed [3+2]-Cycloaddition
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formed in the presence of a cosolvent, such as EtOH, ample for the powerful concept of using these soluble
which unfortunately lowered the yield to 49% (not MeOPEG-linked catalysts, their application under
optimized). However, in a second cycle only a slight standard conditions yielded the desired a,b-unsaturat-
decrease in catalytic activity was observed, to afford ed esters in good yields without the need of optimiza-
the product in 36% yield.
tion. In fact, linkage to MeOPEG polymers turned
Following the successful application of MeOPEG- out to be beneficial for this transformation. In com-
supported thiazolium catalysts in intramolecular Stet- parison to the corresponding N-benzyltriazolo preca-
ter reactions, we decided to examine the catalytic ac- talyst Bn-7, the supported derivatives 7 and 8 general-
tivity of the corresponding immobilized imidazolium ly generated higher yields.
salts 7 and 8 in our recently developed diastereoselec-
tive redox esterification (Table 3). Presenting an ex- of the reaction was influenced by the steric hindrance
of the catalyst. Whereas the monomesityl-substituted
Similar to previous results the diastereoselectivity
[
37]
precatalyst 7 gave E/Z-ratios of 18:1 (entry 1b), the
monoisopropylimidazolium precatalyst 8 essentially
Table 3. Carbene-catalyzed redox esterification with immo-
provided selectivities of greater than 95:5 (entry 1c).
bilized imidazolium precatalysts.
Various aromatic propargylic aldehyde substrates
could be transformed to the corresponding esters, ir-
respective of the electronic nature of the aryl substitu-
ent (Table 3).
The attractive transformation proceeds under mild
[
a]
[b]
Entry Catalyst Product
Yield Ratio
conditions with low catalyst loadings, providing fur-
ther operational simplicity and practicability through
the immobilized catalyst. Simple removal of the cata-
lyst after its precipitation and subsequent aqueous
washing of the organic phase allows the direct isola-
tion of the trans-configurated unsaturated esters in
high yields and with diastereoselectivities, generally
greater than 10:1. After having developed an efficient
protocol for this transformation, we wondered wheth-
er the catalyst could be recycled and reused. NMR
spectroscopic analysis of the recovered catalyst prom-
ised conserved catalytic activity. Whereas the recycla-
bility of the thiazolium catalyst used for the Stetter
reaction was found to be strongly dependent on the
reaction conditions, in the case of the redox esterifica-
tion the immobilized imidazolium catalysts could be
recycled very efficiently. Within two further subse-
quent cycles the recycled imidazolium catalyst re-
[c]
E/Z
1a
1b
1c
Bn-7
7
8
63
77
83
11:1
18:1
>95:5
[
[
d]
e]
7
7
7
5
2
3
4
5
6
8
8
8
8
8
67
63
8:1
>95:5
5911:1
71
rd
mained highly productive (75% yield in 3 cycle)
with virtually no loss in diastereoselectivity (Table 3;
entry 1c).
14:1
8:1
In summary, we have developed a new and effi-
cient, atom-economic immobilization of various heter-
azolium salts, which could conveniently be prepared
via Cu-catalyzed [3+2]-cycloaddition. The high cata-
lytic activity of their corresponding carbene deriva-
tives, which is comparable to standard non-supported
catalysts, was demonstrated in both intramolecular
Stetter reactions and redox esterifications, represent-
ing examples of classic and extended umpolung reac-
tions, respectively. Furthermore, mild reaction condi-
tions, low catalyst loadings and simple removal of the
supported catalysts contribute to operational simplici-
ty and practicability. Additionally, the successful recy-
cling of different types of heterazolium catalysts
offers a highly attractive extension to previously ap-
plied carbene-catalyzed procedures.
72
7
8
28
>95:5
[
a]
All reactions were performed using 5 mol% catalyst in
toluene, 608C, 12 h.
b]
[
[
[
[
Isolated yields.
c]
d]
e]
1
As determined by H NMR.
nd
2
3
cycle.
cycle.
rd
Adv. Synth. Catal. 2007, 349, 1851 – 1857
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Kirsten Zeitler and Ina Mager
COMMUNICATIONS
Experimental Section
Supporting Information
General experimental conditions, preparation of catalysts
and characterization of compounds.
General Procedure for the Immobilization via Cu-
Catalyzed [3+2]-Cycloaddition
A round-bottom flask was charged with MeOPEG-azide
[
26]
3
(0.20 mmol) and 6 mL of a degassed 1:1 mixture of H O
2
and t-BuOH. To this solution was added the propargylated Acknowledgements
heterazolium salt 2 (1.2 equivs.). After the subsequent addi-
tion of ascorbic acid (0.2 equivs.) and CuBr (6 mol%) the
solution was allowed to stir at ambient temperature for 24 h
We thank the Fonds der Chemischen Industrie for a Liebig
fellowship (K. Zeitler), the Deutsche Bundesstiftung Umwelt
(DBU) for a graduate scholarship (I. Mager) and Prof.
Oliver Reiser for his encouragement and support.
(
typically). The mixture was extracted three times with
CH Cl ; the combined organic phases were washed with
2
2
water, brine and dried over MgSO . Concentration under
4
vacuum, followed by precipitation with Et O and subse-
2
quent filtration afforded the immobilized catalyst as a color-
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[
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General Procedure for the Redox Esterification with
MeOPEG-Imidazolium Precatalysts
To an oven-dried screw-capped, N -filled test tube was
2
added imidazolium precatalyst 8 (0.020 mmol, 5 mol%), and
suspended in 0.6 mL dry toluene. To this mixture was added
sequentially alkynal aldehyde (0.40 mmol, 1.0 equiv.) in
0.3 mL in dry toluene, alcohol (1.2 mmol, 3 equivs.) and fi-
nally DMAP (0.020 mmol, 5 mol%). After exchange of the
septum with a screw cap, the sealed tube was stirred at 608C
for 2 to 12 h (TLC control). The mixture was then cooled to
0
8C, the catalyst was precipitated upon addition of Et O
2
and filtered off (the so obtained catalyst can be reused in
further reaction cycles without need of purification). The re-
sulting solution was washed with 1.1M KHSO solution and
4
brine and dried over MgSO . Concentration under reduced
4
pressure afforded the pure unsaturated ester.
Alternatively, addition of small amounts of silica and sub-
sequent filtration yielded the product in similar purity, al-
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Adv. Synth. Catal. 2007, 349, 1851 – 1857

Immobilization of Carbene Precursors via Copper-Catalyzed [3+2]-Cycloaddition
COMMUNICATIONS
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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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