production scale.5 Therefore, it is not surprising that the
use of achiral catalysts under flow conditions recently has
been the subject of many studies.6
more appealing and immediately accessible to every syn-
thetic chemist, we decided to use as support commercially
available silica, without any modification or special func-
tionalization.14
However, much less is known of the use of chiral
supported catalysts under flow conditions.7 The past
decade has witnessed an incredibly intense activity focused
onto the use of different chiral organometallic catalysts
under flow conditions,8 but only a few examples of chiral
organocatalysts were investigated. After the pioneering
work by Lectka with polystyrene-immobilized cinchona
alkaloid derivatives,9 in the very past few years, Pericas
has reported the use of polymer-supported proline,10 and
prolinol derivatives11 under flow conditions, showing the
great potentialities of the methodology.
Scheme 1. Synthesis of the Silica-Supported Chiral Catalyst
In all of these works, packed-bed reactors, filled with a
resin-supported catalyst, were used. Nonhomogeneous pack-
ing of the reactor, with formation of stagnation zones and hot
spots, no control of fluid dynamics, and the problems related
to the resin swelling properties are the main drawbacks of
those systems. It is also worth mentioning that organocata-
lyzed reactions in flow are so far limited almost exclusively to
proline derivatives and substrate activation via enamine
intermediates.12
We decided to study the immobilization of chiral imidazo-
lidinones13 on silica gel, thus expanding the class of chiral
organocatalysts used in reactors under continuous-flow
conditions and overcoming the problems inherent to a
polymeric support. In the intent to make the approach even
A properly modified MacMillan-type catalyst was easily
prepared in three steps and a single purification; starting from
(S)-tyrosine methyl ester 1, imidazolidinone 3 was easily
obtained in 77% yield by N-butyl amide 2 formation, fol-
lowed by treatment with acetone (Scheme 1). Reaction with
allyl bromide allowed introducing the carbonÀcarbon double
bond, instrumental to catalyst immobilization.15 Platinum-
catalyzed hydrosilylation of 4 with trimethoxysilane led to the
enantiopure trialkoxysilane 5 in 99% yield, which was attac-
hed to silica particles by a standard grafting process to afford
the supported MacMillan-type catalyst SiO2-5.16
In the present preliminary study, two different types
of commercially available silica were used as supports
(particle sizes of 8 and 10 μm). Materials, of different
morphological properties, were purchased from different
companies. For Apex Prepsil Silica Media 8 μm (Grace
Davison - Discovery Sciences; asymmetry, 0.9; pore
(5) (a) Nieuwland, P. J.; Segers, R.; Koch, K.; van Hest, J. C. M.;
Rutjes, F. P. J. Org. Process Res. Dev. 2011, 15, 783. (b) For a recent
review on the combination of heterogeneous catalysis with microreactor
technology, see: Frost, C. G.; Mutton, L. Green Chem. 2010, 12, 1687.
(6) (a) Jas, G.; Kirschning, A. Chem.;Eur. J. 2003, 9, 5708. (b)
Ahmed-Omer, B.; Brabdt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5,
733. (c) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 1655. (d) Ceylan, S.;
Kirschning, A. Organic Synthesis with Mini Flow Reactors Using
Immobilized Catalysts. In Recoverable and Recyclable Catalysts;
Benaglia, M., Ed.; JohnWiley & Sons Ltd.: Chichester, U.K., 2009.
(7) (a) Review: Puglisi, A.; Benaglia, M.; Chiroli, V. Green Chem.
2013, 15, 1790–1813. (b) For a review on stereoselective reactions in
continuousflow, see: Geyer, K.; Gustafson, T.; Seeberger, P. H. Beilstein
J. Org. Chem. 2009, 5, 1.
˚
diameter, 120 A; mean particle size, 8.4 μm; surface area,
162 m2/g), a loading of 0.39 mmol/g was determined,
˚
whereas for Luna Silica 10 μm (pore diameter, 101 A;
mean particle size, 8.57 μm; surface area, 380 m2/g), the
loading was found to be 0.53 mmol/g.16
(8) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. Comprehensive
Asymmetric Catalysis. Supplement 1; Springer: New York, 2004.
(9) Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J. Am. Chem.
Soc. 2001, 123, 10853.
The DielsÀAlder cycloaddition between cyclopentadiene
and trans-cinnamaldehyde, carried out in the presence of
various salts of the supported imidazolidinones at different
temperatures, was used to evaluate the performance of the
catalysts.17 At first, the behavior of the catalytic HPLC
column filled with the tetrafluoroborate salt of the 8 μm
silica-supported imidazolidinone SiO2-5 was studied.18
ꢀ
(10) (a) Font, D.; Bastero, A.; Sayalero, S.; Jimeno, C.; Pericas, M. A.
Org. Lett. 2007, 9, 1943. (b) Font, D.; Bastero, A.; Sayalero, S.; Jimeno,
ꢀ
C.; Pericas, M. A. Org. Lett. 2008, 10, 337. (c) Alza, E.; Cambeiro, X. C.;
ꢀ
Jimeno, C.; Pericas, M. A. Org. Lett. 2007, 9, 3717.
(11) (a) Alza, E.; Sayalero, S.; Cambeiro, X. C.; Martin-Rapun, R.;
ꢀ
Miranda, P. O.; Pericas, M. A Synlett 2011, 464–468. (b) Fan, X.;
Sayalero, S.; Pericas, M. A. Adv. Synth. Catal. 2012, 354, 2971.
(12) (a) For a recent work where silica-supported 5-(pyrrolidin-2-yl)-
tetrazole was employed under continuous-flow conditions, see: Bortolini, O.;
Caciolli, L.; Cavazzini, A.; Costa, V.; Greco, R.; Massi, A.; Pasti, L. Green
Chem 2012, 14, 992. (b) For a very recent report on an extraordinarily
stable and long-lasting polymer-supported organocatalyst for Michael
addition, see: Arakawa, Y.; Wennemers, H. ChemSusChem2013, 6, 242–
245. (c) See also: Otvos, S. B.; Mandity, I. M.; Fulop, F. ChemSusChem
2012, 5, 266–269.
(15) For our previous works with immobilized MacMillan catalysts,
see: (a) Benaglia, M.; Celentano, G.; Cinquini, M.; Puglisi, A.; Cozzi, F.
Adv. Synth. Catal. 2002, 344, 149. (b) Benaglia, M.; Celentano, G.;
Cinquini, M.; Puglisi, A.; Cozzi, F. Eur. J. Org. Chem. 2004, 567. (c)
Guizzetti, S.; Benaglia, M.; Siegel, J. S. Chem. Commun. 2012, 48, 3188.
(16) See the Supporting Information for synthesis, analysis, and
characterization of the supported chiral catalyst.
(13) For a review, see: Lelais, G.; MacMillan, D. W. C. Aldrichimica
Acta 2006, 39, 79.
(17) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. The yield and dr were determined by NMR
and confirmed on isolated products; the ee was determined by HPLC. As
expected, 50:50 mixtures of endo and exo cycloadducts were obtained.
(18) For details on the preparation of the catalytic column, see the
Supporting Information.
(14) (a) For our previous work with silicate-supported catalysts, see:
Puglisi, A.; Annunziata, R.; Benaglia, M.; Cozzi, F.; Gervasini, A.;
Bertacche, V.; Sala, M. C. Adv. Synth. Catal. 2009, 351, 219. (b) For a
recent work on silica-supported imidazolidinone, see also: Shi, J. Y.;
Wang, C. A.; Li, Z. J.; Wang, Q.; Zhang, Y.; Wang, W. Chem.;Eur. J.
2011, 17, 6206.
B
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