Magnetic nanoparticle-supported organocatalysis

1 Introduction

Catalysis is an important green chemistry tool to increase reaction efficiency, save energy, and reduce chemical waste. Compared to transition metal catalysis and biocatalysis, organocatalysis has unique features such as being toxic heavy metal-free, with novel activation mechanism, relatively low cost, reduced sensitivity to moisture and oxygen, good structural amenability, and good availability from nature sources [1–3]. However, high catalyst loading (up to 20%) is commonly requires for organocatalysis, which makes the catalyst recovery highly desirable. In addition to solids (polymers or silica gel) [4], ionic liquids [5], and fluorous tags [6], magnetic nanoparticles (MNPs) have recently emerged as a new supporting material for catalyst recovery [7, 8]. MNPs have been successfully used to immobilize transition metals, organic ligands, organocatalysts, and biocatalysts through absorption or formation of covalent bonds [9–19]. As a consequence of small size, big surface area and great pore volume, MNP-supported catalysis is quasi-homogeneous and has favorable reaction kinetics. The catalyst can be easily separated by applying an external magnetic field. The liquid phase containing the product is decanted for purification. The magnetic-field-held catalyst is washed with an appropriate solvent and then dried for reuse. Catalyst leaching is usually lower than in other material-supported catalysis. There are several excellent review articles [8–11] with detailed information on the preparation, characterization, tuning, and attachment of MNPs. Discussions on the chemical and physical properties of MNPs are beyond the scope of this short review. This article only focuses on the preparation of Fe₃O₄ MNP-supported organocatalyts and their synthetic applications.

2 Synthesis and application of Fe₃O₄ nanoparticle-immobilized organocatalysts

In contrast to transition metals, which could be non-covalently grated on the MNPs, organocatalysts are attached to Fe₃O₄ by covalent bonds such as –SiOR, –OR, and –SR. The typical loading of organocatalyst on MNP-support is around 0.1–1.0 mmol/g [8–11]. In 2007, the Connon group reported the first example of MNP-supported organocatalysis by the treatment of Fe₃O₄ particles with sodium silicate to form SiO₂-coated Fe₃O₄ particles. The coated-MNP catalyst was then used for the synthesis of 4-N,N-dialkylaminopyridine (DMAP)-type organocatalyst cat-1 (Scheme 1) [19]. This catalyst was used for acetylation of 1-phenylethanol, peracetylation of D-glucose, and formal oxidation of alkyne (Scheme 2). The results showed that cat-1 has good activity and recyclability. At 5 mol% catalyst loading, 1-phenylethanol can be acylated in 94–98% yields. No physical or chemical degradation of the catalyst was observed after 14 consecutive catalyst cycles. It is noteworthy that SiO₂-coated MNPs could reduce catalyst aggregation and facilitate surface functionalization.

Scheme 1

Preparation of DMAP catalyst cat-1.

Scheme 2

Acetylation and related reactions promoted by cat-1.

Silylation reaction is a good way to anchor organocatalysts. Cheng and coworkers used this method to synthesize supported bifunctional amino catalyst cat-2 (Scheme 3) [20]. It could be used to catalyze aldol reaction of aldehydes with acetone or cyclohexanone (Scheme 4). Acidic additives such as TFA or TfOH were used to improve the yield. Stronger acid TfOH gave slightly better enantioselectivity than TFA for the aldol reaction of acetone. But for the reaction of cyclohexanone, the TFA was more effective to afford the product in high yield and stereoselectivity.

Scheme 3

Preparation of chiral amine catalyst cat-2.

Scheme 4

The aldol reaction promoted by cat-2.

The Cheng group also prepared MNP-immobilized quinucidine catalyst cat-3 by direct silylation (Scheme 5) [21]. This catalyst was used to promote the Morita-Baylis-Hillman reactions of a wide range of Michael donors with aldehydes (Scheme 6). The yields are 80–99% under the neat condition. The cat-4 could be reused seven times without significant loss of activity.

Scheme 5

Synthesis of quinuclidine cat-3.

Scheme 6

MBH reaction promoted by cat-3.

The Connon group also reported the preparation of cat-4 via the reaction of Fe₃O₄-supported N-methyl dopamine hydrochloride with (S)-α,α-diphenylprolinolcatalyst (Scheme 7) [22]. This catalyst promoted acylative kinetic resolution of racemic mono-protected cis-diol (Scheme 8). It was found that 5 mol% catalyst loading could resolve cis-diol with a selectivity factor of 10.1 and allowed the generation of resolved alcohol with 99% ee (72% conversion), which is comparable to that obtained with the corresponding homogeneous catalyst of 97% ee (69% conversion) [23].

Scheme 7

Preparation of dopamine-l-prolinol catalyst cat-4.

Scheme 8

Kinetic resolution of mono-protected cis-diol catalyzed by cat-4.

The Pericas group synthesized MNP-attached prolinol catalyst cat-5 via click chemistry through an azide linker (Scheme 9) [24]. It has been utilized for highly selective asymmetric Michael reactions of propanal with nitroolefins (Scheme 10). After the third run, a significant decrease in catalytic activity was observed although the enantioselectivity was maintained. This is probably caused by catalyst leaching or decomposition.

Scheme 9

Preparation of (S)-α,α-diphenylprolinol catalyst cat-5.

Scheme 10

Michael addition catalyzed by cat-5.

Well-known bifunctional organocatalysts such as the cinchona alkaloid/thiourea system have been developed for a broad range of asymmetric reactions [25–28]. The Connon group reported the synthesis of Fe₃O₄-supported bifunctional catalyst cat-6 through a thiol linker (Scheme 11) [29]. The asymmetric Michael addition of dimethyl malonate with (E)-β-nitrostyrene could be promoted with cat-6 (Scheme 12). It was found that cat-6 is less enantioselective than unsupported bifunctional catalyst probably caused by the “ageing effect”, which was previously observed by the Takemoto group in the study of a homogeneous PEG-immobilized thiourea catalyst [30].

Scheme 11

Preparation of bifunctional urea catalyst cat-6.

Scheme 12

Asymmetric Michael addition catalyzed by cat-6.

Since cat-6 was found lacking of recyclability, the synthesis of sulfonamide derivative cat-7 was conducted by following a literature procedure reported for making polystyrene-supported sulfonamide catalyst [31]. The sulfonamide group is less basic and more stable than the urea group, so Fe₃O₄-supported bifunctional sulfonamide cat-7 has a better recyclability than cat-6 (Scheme 13) [29]. In addition, since the C₆F₅ substituent has suitable acidity and is less hindered, it is good for the improvement of catalyst reactivity. Modified bifunctional catalyst cat-7 was used by the Connon group to promote the asymmetric ring-opening reaction of meso succinic-anhydrides (Scheme 14). This catalyst has a high recyclability and was used for twenty consecutive cycles without significant decrease in catalyst activity and enantioselectivity.

Scheme 13

Synthesis of bifunctional sulfonamide catalyst cat-7.

Scheme 14

Asymmetric ring-opening promoted by cat-7.

The Gawande and Branco groups recently immobilized amino acids and peptides such as L-cysteine and glutathione on Fe₃O₄ MNPs through the reaction of the thiol group to form cat-8 and cat-9 (Schemes 15 and 16) [32, 33]. The Fe₃O₄-supported glutathione cat-9 could be further treated with CuCl₂ solution under a basic condition to generate Cu-coordinated particles [34]. Copper (II) ion is coordinated with the free primary amine and carbonyl groups of the glutathione scaffold in 3:1 ratio.

Scheme 15

Synthesis of L-cysteine catalyst cat-8.

Scheme 16

Synthesis of glutathione catalyst cat-9.

Catalyst cat-8 was utilized for the asymmetric Mannich reaction in the synthesis of β-amino carbonyl compounds (Scheme 17) [32]. The reaction of aniline, benzaldehyde, and cyclohexanone was carried out with or without a solvent. Highly reactive cat-8 was also used to promote the Hantzsch reaction for the preparation of hydroquinolines, a scaffold that has significant interest in medicinal chemistry due to its biological and pharmacological properties (Scheme 18). The reaction yield was good, but the syn:anti selectivity was poor. The magnetic catalyst could be easily recovered via simple magnetic decantation. When R=R¹=H of the substrates, the yield can also be 90% after nine consecutive instances of catalyst recovery. The multicomponent reaction between 3,4-diphenoxy benzaldehyde, ammonium acetate, ethyl acetoacetate, and 5,5-dimethyl cyclohexane-1,3-dione under mild conditions provided hydroquinolines with a yield of 88%. No enantioselectivity information was reported in the paper.

Scheme 17

Synthesis of β-amino carbonyl compounds promoted by cat-8.

Scheme 18

The Hantzsch reaction promoted by cat-8.

The Varma group employed cat-9 for the Paal-Knorr [33], aza-Michael [35] and Suzuki coupling reactions [36] (Scheme 19). The Paal-Knorr reaction of amines with tetrahydro-2,5-dimethoxyfuran was performed under microwave heating [33, 35]. The traditional Paal–Knorr reactions involve prolonged heating with strong acids in toxic solvents for dehydration. This work uses microwave heating to reduce the reaction time and water as a solvent. For the reaction of benzylamine, the catalyst could be directly recovered more than five times without significant loss of activity. This catalyst was also used for the aza-Michael reaction in the synthesis of pyrazoles [35] and Suzuki coupling reactions [36]. These reactions were conducted in an aqueous phase to eliminate the use of organic solvents.

Scheme 19

Reactions catalyzed by cat-9.

3 Summary

The synthesis of Fe₃O₄ MNP-supported organocatalysts and their applications for the Paal-Knorr, aza-Michael, Mannich, Hantzsch, aldol, Suzuki coupling, and other reactions are highlighted in this article. MNP-supported organocatalysts is a relatively new field with very limited numbers of publications. It has shown promising results on catalysts reactivity, selectivity, and recyclability. There is no doubt that it will be quickly developed to become a powerful green catalysis technology for enantioselective synthesis. We also expect that some potential challenges related to catalyst functional group compatibility, catalyst stability, and commercialization will be explored and addressed.