The immobilisation of chiral organocatalysts on magnetic nanoparticles: the support particle cannot always be considered inert

Abstract

A systematic study concerning the immobilisation onto magnetic nanoparticles of three useful classes of chiral organocatalyst which rely on a confluence of weak, easily perturbed van der Waals and hydrogen bonding interactions to promote enantioselective reactions has been undertaken for the first time. The catalysts were evaluated in three different synthetically useful reaction classes: the kinetic resolution of sec-alcohols, the conjugate addition of dimethyl malonate to a nitroolefin and the desymmetrisation of meso anhydrides. A chiral bifunctional 4-N,N-dialkylaminopyridine derivative could be readily immobilised; the resulting heterogeneous catalyst is highly active and is capable of promoting the kinetic resolution of sec-alcohols with synthetically useful selectivity under process-scale friendly conditions and has been demonstrated to be reusable in a minimum of 32 consecutive cycles. The immobilisation of a cinchona alkaloid-derived urea-substituted catalyst proved considerably less successful in terms of both catalyst stability and product levels of enantiomeric excess. An immobilised cinchona alkaloid-derived sulfonamide catalyst was also prepared, with mixed results: the catalyst exhibits outstanding recyclability on a par with that associated with the successful N,N-dialkylaminopyridine analogue, however product enantiomeric excess is consistently lower than that obtained using the corresponding homogeneous catalyst. While no physical deterioration of the heterogeneous catalysts was detected on analysis after multiple recycles, in the cases of both the conjugate addition to nitroolefins and the desymmetrisation of meso anhydrides, significant levels of background catalysis by the nanoparticles in the absence of the organocatalyst was detected, which explains in part the poor performance of the immobilised organocatalysts in these reactions from a stereoselectivity standpoint. It seems clear that the immobilisation of sensitive chiral organocatalysts onto magnetite nanoparticles does not always result in heterogeneous catalysts with acceptable activity and selectivity profiles, and that consequently the applicability of the strategy must be ascertained (until more data is available) on a case-by-case basis.

In situ preparation of a multifunctional chiral hybrid organic–inorganic catalyst for asymmetric multicomponent reactions

“…The generality of the method was also verified by using poliaromatic aldehydes (entry 14), as well as heteroaromatic substrates, such as furfural (entries 15 and 16). The enantioselectivity achieved in all cases is 35 similar, oscillating slightly between 85:15 and 93:7 enantiomeric ratio. Aliphatic aldehydes (entries 17 and 18) probed more challenging, though acceptable yields are achieved after 48 h reaction time forming the desired product in modest enantiomeric ratio (72:28 to 76:24).…”

“…Therefore, we have used here a soft synthetic method 38 that involves a sol-gel procedure catalyzed by very small amounts of NH4F, in absence 30 of structural directing agents, at low temperature and at neutral pH, to obtain the hybrid organic-inorganic mesoporous material (see ESI for details). The presence of the organic component in the silica framework was confirmed by elemental and thermogravimetrical analysis 35 and by NMR spectroscopy. The content of C and N in the solid measured by elemental analysis (Table S1 in the ESI) is an evident probe of the incorporation of the bifunctional catalyst in the material, as the latter was prepared in the absence of structural directing agents.…”

“…Silane precursor 3 exhibits only one peak at - 45.6 ppm, while in the solid, the signal corresponding to silicon atoms bonded to carbon units are shifted to -57 and -67 ppm ( Figure S4 in the ESI) showing the effective attachment of organic linkers by covalent interaction between surface silanol groups and terminal 80 alkoxide units of organosilane. We were concerned however, by the presence of a peak at 105 ppm in 13 C CPMAS NMR spectrum of the solid material that was not observed for the organosilane precursor 3 (Figure 2), and On the other hand, carbamate hydrolysis was observed for derivative 3 at some extent when running the 1 H NMR spectrum in MeOH-d4 after 24 hours, and also when a catalytic amount of NH4F was added to the NMR tube equating the reaction 35 conditions followed for the preparation of the solid although in the absence of tetramethylorthosilicate. With these results together with the observation of the peak at 105 ppm in 13 C CPMAS NMR, we could conclude that the hybrid solid presents the structure depicted in Figure 1, with part of the cinchone-based 40 units covalently attached to the surface and some of them strongly adsorbed to the silaceous surface.…”

“…14 The extraordinary pace of 35 innovation and progress in asymmetric homogeneous catalysis contrasts profoundly with asymmetric heterogeneous procedures. A commonly used strategy in asymmetric heterogeneous catalysis involves the heterogeneization of a successful homogeneous catalyst by covalent linkage to an inorganic oxide support or 40 organic polymer.…”

“…[31][32][33] The unique ability of this organocatalyst to engage in general-base plus hydrogen bonding catalyzed stereoselective transformations makes it an interesting candidate for heterogeneization. [34][35] With this in mind, we synthesized first the trialkoxysilylated 10 urea-based cinchona alkaloid derivative 3 (Scheme 1). The known primary amine 5, prepared from quinine in two steps, [36][37] was reacted with 3,5-bis(trifluoromethyl)phenyl isocyanate in THF at room temperature to form the urea derivative 6 in 84% yield.…”