A click strategy for the immobilization of macmillan organocatalysts onto polymers and magnetic nanoparticles

Article abstract of DOI:10.1021/ol301515d

A chemically modified, first generation MacMillan imidazolidin-4-one has been anchored onto 1% DVB Merrifield resin and Fe₃O₄ (5.3 ± 1.4 nm) magnetic nanoparticles through copper-catalyzed alkyne azide cycloaddition (CuAAC) reactions. The resulting immobilized catalysts have been successfully used in the asymmetric Friedel-Crafts alkylation of N-substituted pyrroles with α,β-unsaturated aldehydes. The PS-supported catalyst (B) showed higher catalytic activity and enantioselectivity, while the MNP-supported one (A) showed higher recyclability and could be used in a sequential process with intermediate magnetic decantation.

Full text of DOI:10.1021/ol301515d

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3668–3671
A Click Strategy for the Immobilization of
MacMillan Organocatalysts onto Polymers
and Magnetic Nanoparticles
†
Paola Riente, Jagjit Yadav, and Miquel A. Pericas*
†
,†,‡
ꢀ
Institute of Chemical Research of Catalonia, Av. Paısos Catalans, 16, 43007 Tarragona,
´
¨
Spain, and Departament de Quımica Organica, Universitat de Barcelona, c/Martı I
´
Franques 1-11, 08080 Barcelona, Spain
ꢀ
ꢁ
mapericas@iciq.es
Received June 1, 2012
ABSTRACT
A chemically modified, first generation MacMillan imidazolidin-4-one has been anchored onto 1% DVB Merrifield resin and Fe3O4 (5.3 ( 1.4 nm)
magnetic nanoparticles through copper-catalyzed alkyne azide cycloaddition (CuAAC) reactions. The resulting immobilized catalysts have been
successfully used in the asymmetric FriedelÀCrafts alkylation of N-substituted pyrroles with R,β-unsaturated aldehydes. The PS-supported
catalyst (B) showed higher catalytic activity and enantioselectivity, while the MNP-supported one (A) showed higher recyclability and could be
used in a sequential process with intermediate magnetic decantation.
Organocatalysis has become one of the most active
research areas in asymmetric organic synthesis.1 However,
its practical applications are often limited by factors such
as high catalyst cost, the requirement of high catalyst
loadings, and difficulties in catalyst recovery and reuse.
To avoid these limitations, the immobilization of organo-
catalysts onto solid supports2 such as polymers,3 mesopor-
ous materials,4 or magnetic nanoparticles5 leading to
asymmetric catalysis under heterogeneous conditions has
emerged as a promising strategy.
The enantiopure imidazolidin-4-one derived from phe-
nylalanine N-butylamide and acetone (the first generation
MacMillan catalyst) is one of the most versatile organo-
catalysts and has been used with success in a large variety
of enantioselective reactions, such as the DielsÀAlder
reaction,6 1,3-dipolar cycloadditions,7 and FriedelÀCrafts
† Institute of Chemical Research of Catalonia.
‡ Universitat de Barcelona.
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Biomol. Chem. 2009, 7, 2669.
r
10.1021/ol301515d
Published on Web 07/03/2012
2012 American Chemical Society

alkylation8 among others.9 The heterogenization of this
species has also received considerable attention, and ex-
amples of the covalent inmobilization of the MacMillan
catalyst on different solid organic (JandaJel,10 polystyrene,11
liquid crystals12) and inorganic13 materials have been re-
ported in the literature. These immobilized species have
almost exclusively been applied in DielsÀAlder reactions,
while its possible use in asymmetric FriedelÀCrafts (FÀC)
alkylation reactions14 has remained almost completely
unexplored.15
MacMillan catalyst onto slightly cross-linked (1% DVB)
Merrifield resin and superparamagnetic Fe3O4 nanoparti-
cles using CuAAC reactions and the use of the resulting
species as recyclable catalysts for the enantioselective FÀC
alkylation of N-substituted pyrroles with R,β-unsaturated
aldehydes via iminium intermediates.
In recent years we have successfully used the copper-
catalyzed alkyne azide cycloaddition (CuAAC) reaction16
as a tool for the covalent immobilization of catalytic
ligands17 and organocatalysts onto polystyrene resins
(PS)18 and magnetic nanoparticles (MNPs)19 and have
shown that the 1,2,3-triazole linkers exert highly beneficial
effects on the performance of supported organocatalysts in
both enamine and iminium mediated processes.18
Scheme 1. Immobilization of the First Generation MacMillan
Catalyst through CuAAC Reactions
Figure 1. Micrographs and size distribution of MNPs analyzed
by TEM. (a) MNPs (1), (b) MNPs supported imidazolidinone
(A), and (c) size distribution of the MNPs.
The target catalysts A and B were easily prepared by the
procedures outlined in Scheme 1. The Fe3O4 MNPs 1 used
as support were prepared by thermal decomposition of
iron(III) acetylacetonate inthe presenceofoleic acid, oleyl-
amine, and 1,2-dodecanediol as surfactants20 and showed
a narrow size distribution (5.3 ( 1.4 nm). Grafting with
3-(azidopropyltrimethoxy)silane (2) afforded the azide
functionalized MNPs (3),19 and incorporation of the
propargyloxy-substituted imidazolidinone L through a
As a continuation of these efforts, we report in this
communication the immobilization of the first generation
(8) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 1172. (c) Gordillo, R.; Carter, J.; Houk, K. N. Adv. Synth.
Catal. 2004, 346, 1175. (d) King, H. D.; Meng, Z.; Denhart, D.; Mattson,
R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437.
(e) Liu, C.-F; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org.
Lett. 2007, 9, 1847. (f) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.;
(16) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004.
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(17) (a) Bastero, A.; Font, D.; Pericas, M. A. J. Org. Chem. 2007,
72, 2460. (b) Popa, D.; Marcos, R.; Sayalero, S.; Vidal-Ferran, A.;
€
Brase, S. J. Am. Chem. Soc. 2009, 131, 2086.
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Pericas, M. A. Adv. Synth. Catal. 2009, 351, 1539. (c) de la Fuente, V.;
(9) For a recent example dealing with R-alkylation of aldehydes, see:
Gualandi, A.; Emer, E.; Capdevila, M. G.; Cozzi, G. Angew. Chem., Int.
Ed. 2011, 50, 7842.
ꢁ
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Marcos, R.; Cambeiro, X. C.; Castillon, S.; Claver, C.; Pericas, M. A.
€
Adv. Synth. Catal. 2011, 353, 3255. (d) Ozkal, E.; Ozc-ubukc-u, S.; Jimeno,
C.; Pericas, M. A. Catal. Sci. Technol. 2012, 2, 195.
ꢀ
€ €
(10) Selkala, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P. Adv.
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(18) (a) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653.
Synth. Catal. 2002, 344, 941.
(11) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Campisciano,
V.; Noto, R. Catal. Commun. 2011, 16, 75.
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2005, 17, 4889.
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2006, 348, 2027. (b) Shi, J. Y.; Wang, C. A.; Li, Z. J.; Wang, Q.; Zhang,
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(15) For the catalytic FriedelÀCrafts alkylation of N-methylpyrrole
with trans-cinnamaldehyde, see ref 13a.
Org. Lett., Vol. 14, No. 14, 2012
3669

CuAAc reaction led to catalyst A (Scheme 1, top). Trans-
mission electron microscopy (TEM) (Figure 1) showed
that the size of the MNPs remained practically unchanged
over the whole synthetic sequence, and no agglomeration
phenomena could be observed.
Table 1. FriedelÀCrafts Alkylation of N-Substituted Pyrroles
with R,β-Unsaturated Aldehydesa
Following a similar approach, commercially available
Merrifield resin (1% DVB, f = 1.3 mmol gÀ1) was con-
3
vertedtoazidomethylpolystyrene,17a and organocatalyst L
was immobilized through a CuAAC reaction to afford
catalyst B (Scheme 1, bottom). The functionalization level
of both catalysts was determined by elemental analysis of
nitrogen as 0.34 mmol gÀ1 (A) and 0.91 mmol gÀ1 (B).
3
3
The use of functional materials A and B in the FriedelÀ
Crafts alkylation of N-substituted pyrroles with R,β-
unsaturated aldehydes was next studied. The reaction
between trans-cinnamaldehyde and N-methylpyrrole (see
Supporting Information (SI) for details) was used for the
optimization of reaction conditions. Working in THFÀ
H2O, catalyst B gave the best results at 0 °C. The perfor-
mance of catalyst A, in turn, was rather independent
from the reaction temperature, and reactions mediated by
this species could be conveniently carried out at rt. The
results obtained in the FÀC alkylation of N-methyl and
N-benzylpyrrole with a representative family of enals have
been summarized in Table 1.
As it can be seen, the polystyrene-based catalyst B leads
in all the studied cases to higher yields and enantioselec-
tivities in shorter reaction times than the nanoparticle-
based catalyst A. However, as we will see later, this last
catalyst offers important practical advantages derived
from its ready separation by magnetic decantation.
When the influence of the R,β-unsaturated aldehyde
alkylating agent on the performance of the reaction is
analyzed, some trends can be clearly observed: (a) Both
β-alkyl and β-aryl substituted enals are appropriate sub-
strates for the reaction; (b) among β-aryl substituted enals,
those bearing electron-withdrawing groups lead to the
highest yields and enantioselectivities; and (c) other things
being equal, more sterically congested substrates lead to
higher enantioselectivity.
When supported catalysts A and B are compared with
the homogeneous, first generation MacMillan catalyst
(N-methyl),8a important practical advantages of the hetero-
geneized species become evident; thus, while the homo-
geneous catalyst requires reaction temperatures from À60
to À30 °C, A and B can be used at rt or 0 °C, respectively,
with much shorter reaction times. Most notably, the
enantioselectivities depicted by the homogeneous MacMillan
catalyst (91% mean ee)8a and B (89.5% mean ee) are
essentially identical in spite of the differences in reaction
temperature.
The major practical advantage offered by heterogenized
catalysts in comparison with their homogeneous counter-
parts is its easy separation from the reaction medium for
recycling and reuse. While polystyrene resins can be readily
separated by filtration, superparamagnetic Fe3O4 nano-
particles can be easily and quantitatively recovered by
magnetic decantation. In the present instance, we studied
the possibility of recycling and reusing catalysts A and B in
a N-Substituted pyrrole (1.25 mmol), aldehyde (0.25 mmol), catalyst
(10 mol %), TFA 0.5 M (10 mol %), H2O (0.054 mL), THF (0.350 mL).
b Isolated yield. c By chiral GLC.
the reaction of N-methylpyrrole with trans-cinnamalde-
hyde (Figure 2). After each cycle, the catalysts were treated
with equimolar amounts of 0.5 M TFA solution in order to
reactivate the catalyst. We were pleased to observe that
both catalysts A and B could be reused for six consecutives
runs (24 h reaction time for B and 48 h reaction time for A).
For catalyst A, the initial activity is retained until the fifth
cycle, while, for catalyst B, a decrease in yield was observed
after the third run. Very interestingly, enantioselectivity
remains essentially unchanged for both catalysts over the
six reaction cycles. Leaching of the functional monomers
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Org. Lett., Vol. 14, No. 14, 2012

catalyst could be redispersed in THF and reused in the
FÀC alkylation without an appreciable decrease in its
performance.
Scheme 2. Use of Catalyst A in a Sequential Process with
Intermediate Magnetic Decantation
Figure 2. Recycling and reuse of catalyst A or B.
In conclusion, we have reported for the first time the
immobilization of the first generation MacMillan catalyst
onto a polystyrene resin and Fe3O4 magnetic nanoparticles
using a CuAAC strategy. The resulting functional materi-
als have been successfully used as catalysts in the FriedelÀ
Crafts alkylation of N-substituted pyrroles with R,β-
unsaturated aldehydes. The best results were obtained with
the PS-supported imidazolidinone, but the catalyst sup-
ported onto MNPs showed more stability in the recycling
tests and, thanks to its facile separation from the reaction
medium through magnetic decantation, could be used in
sequential processes without isolation of the intermediate
FÀC adduct.
during the recycling can be almost completely excluded, since
elemental analysis after six cycles indicated a functionaliza-
tion almost identical to the initial ones (f = 0.27 gmmolÀ1 for
A and f = 0.86 gmmolÀ1 for B). In addition, any significant
agglomeration phenomenon in A during the recycling could
be excluded by TEM after the sixth run (see SI). According to
these observations, the decrease of activity in catalyst B
during recycling can be probably attributted to partial
structural collapse of its rather fragile gel structure with
repeated use, making part of the catalytic sites unavailable
to reagents. This phenomenon would not affect the more
robust nanoparticles A.
The magnetic nature of catalyst A offers practical ad-
vantages for its application to complex sequences. We have
represented in Scheme 2 two such examples, where the
alkylation of N-methylpyrrole with (E)-3-(2-nitrophenyl)-
propenal mediated by A is performed, the catalyst is
concentrated at the walls of the reaction flask by applica-
tion of a magnet once the FÀC reaction is complete, and
the adduct is further transformed by selective reduction
withNaBH4 (83% overallyield, 91% ee).21 Inaddition, the
Acknowledgment. This work was supported by MINE-
CO (Grants CTQ2008-00947/BQU and NSF Quımica
1026553), DEC (Grant 2009SGR623), and the ICIQ founda-
tion. P.R. and J.Y. thank MINECO for Torres Quevedo and
postdoctoral contracts, respectively. We also thank ICIQ
Chromatography Support Unit for chiral GLC analysis.
Supporting Information Available. Experimental de-
tails, spectroscopic data of FÀC adducts, NMR spectra,
and GC chromatograms. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Ee was determined by GLC at the level of the intermediate
aldehyde (50À170 °C/1 °C minÀ1, 1.5 mL/min): R isomer tr = 156.96 min
and S isomer tr = 161.24 min.
The authors declare no competing financial interest.
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