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Communication

Ionic, Core-Corona Polymer Microsphere-Immobilized MacMillan Catalyst for Asymmetric Diels-Alder Reaction

by
Md. Wali Ullah
and
Naoki Haraguchi
*
Department of Applied Chemistry and Life Science, Graduate School of Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
*
Author to whom correspondence should be addressed.
Catalysts 2019, 9(11), 960; https://doi.org/10.3390/catal9110960
Submission received: 11 October 2019 / Revised: 7 November 2019 / Accepted: 12 November 2019 / Published: 15 November 2019
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
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Abstract

:
The improvement of the catalytic activity of a heterogeneous chiral catalyst is one of the most critical issues, as are its recovery and reuse. The design of a heterogeneous chiral catalyst, including the immobilization method and the support polymer, is of significance for the catalytic activity in asymmetric reactions. An ionic, core-corona polymer microsphere-immobilized MacMillan catalyst (ICCC) was successfully synthesized by the neutralization reaction of sulfonic acid functionalized core-corona polymer microsphere (CCM–SO3H) with a chiral imidazolidinone precursor. We selected the core-corona polymer microsphere as the polymer support for the improvement of catalytic activity and recovery. The MacMillan catalyst was immobilized onto the pendant position of the corona with ionic bonding. ICCC exhibited excellent enantioselectivity up to 92% enantiomeric excess (ee) (exo) and >99% ee (endo) in the asymmetric Diels-Alder (DA) reaction of (E)-cinnamaldehyde and 1,3-cyclopentadiene. ICCC was quantitatively recovered by centrifugation because of the microsphere structure. The recovered ICCC was reused without significant loss of the enantioselectivity.

Graphical Abstract

1. Introduction

Chiral organocatalysis is one of the most attractive methods for the production of optically active medical and pharmaceutical products due to advantages such as being metal-free, exhibiting higher stability against moisture and oxygen, and facilitating experimental operation [1,2,3]. Among the chiral organocatalysts, chiral imidazolidinones and their salts, so-called MacMillan catalysts, have been applied to various asymmetric reactions via HOMO or LUMO activation mechanisms, such as the Diels-Alder (DA) reaction [4], 1,3-dipolar cycloaddition [5], Friedel-Crafts alkylation [6], indole alkylation [7], the α-halogenation of aldehydes [8,9], direct aldol reaction [10], intramolecular Michael reaction [11], and the epoxidation [12] of aldehydes. The MacMillan catalysts were also applied for the α-alkylation, α-allylation [13,14,15,16,17,18], α-benzylation [19], β-arylation [20], and β-alkylation [21] of aldehydes or ketones via the SOMO-activation mechanism [22].
Despite the efficiency of MacMillan organocatalysts in asymmetric reactions, relatively high catalyst loading (generally 5 to 20 mol %) is required to proceed with such asymmetrical reactions at reasonable reaction rates; besides, a burdensome purification method, such as column chromatography, is required to isolate a product and to separate the MacMillan catalyst from a reaction mixture. Therefore, a MacMillan catalyst is generally not reused.
The covalent immobilization of MacMillan catalyst onto a heterogeneous support represents an attractive approach to solving the issues, in regard to its sustainability. Covalently immobilized MacMillan catalysts have been developed and applied for catalytic, asymmetric reactions [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. However, conventional, polymer-immobilized MacMillan catalysts possess some drawbacks, such as elaborate multistep preparation, and the decrement of catalytic activity due to the modification of the MacMillan catalyst. Therefore, the design of a heterogeneous chiral catalyst, including the immobilization method and the support polymer, is essential for efficient asymmetric reactions.
For the immobilization of method, we developed an ionic immobilization method for chiral organocatalysts, such as MacMillan catalyst and cinchonidinium, via neutralization reaction or ion-exchange reaction with sulfonated polymers [39,40]. The ionic immobilization methodology has been applied for the synthesis of the main chain of chiral polymers, many of which were prepared by intermolecular reactions of chiral organocatalyst dimers with disulfonic acid derivatives [41,42,43,44,45,46].
Functionalized polymer microspheres have been widely used as industrial materials in various areas, such as coatings, electronics, biomedical engineering, and organic synthesis [47,48,49]. Interestingly, some polymer microspheres with achiral or chiral catalysts have been used as heterogeneous catalysts for organic reactions [50,51,52]. We first synthesized polymer microsphere-immobilized chiral 1,2-diamine ligands with uniform, core-shell, or core-corona structures, and these complexes with ruthenium were used as heterogeneous, polymeric chiral catalysts in the asymmetric transfer hydrogenation (ATH) of ketones [51]. Both the yield and enantiomeric excess (ee) of the product were greatly influenced by the introduction position of the chiral catalyst onto the polymer microsphere and the degree of crosslinking, along with the hydrophobicity of polymer microsphere. Recently, we successfully synthesized core-corona polymer microsphere-supported cinchonidinium salt and applied it as a heterogeneous polymeric catalyst for the asymmetric alkylation reaction of a glycine derivative [52].
In this communication, we describe the synthesis of an ionic, core-corona polymer microsphere-immobilized MacMillan catalyst (ICCC) by the neutralization reaction of the core-corona polymer microsphere having a sulfonic acid moiety (CCM–SO3H) with the precursor of the MacMillan catalyst. These catalysts were used as heterogeneous polymeric catalysts in a typical asymmetric DA reaction of (E)-cinnamaldehyde and 1,3-cyclopentadiene. The catalytic activity of ionic, core-corona polymer microsphere-immobilized MacMillan catalyst was compared with those of a model catalyst, linear-type catalyst, crosslinked gel-type catalyst, polymer microsphere catalyst, and covalently core-corona polymer microsphere-immobilized catalyst in detail.

2. Results and Discussion

2.1. Preparation of Core-Corona Polymer Microsphere Having Sulfonic Acid (CCM–SO3H)

The preparation of CCM–SO3H is illustrated in Scheme 1. Benzyl chloride-functionalized polymer microsphere having phenylsulfonate 1 was prepared by the precipitation polymerization of styrene (St), divinylbenzene (DVB), and 4-vinylbenzyl chloride (VBC) [53]. The molar ratio of St/DVB/VBC was set to 60/20/20. The number-averaged diameter (Dn) of the polymer microsphere was 1.14 μm. Because the polydispersity (U) was quite low (1.00), monodispersed polymer microsphere 1d20C was successfully obtained. 1d20C means polymer microsphere synthesized from 20 mol % of divinylbenzene and 4-vinylbenzyl chloride (Scheme 1). The chlorine content measured by the halogen titration method (1.67 mmol g−1) was in good agreement with that calculated (1.68 mmol g−1). In addition to the monodispersed benzyl chloride-functionalized polymer microsphere with 20 mol % DVB, a monodispersed, poorly-crosslinked, benzyl bromide-functionalized polymer microsphere 1d10B was successfully synthesized with a relatively higher yield (37%) by the precipitation polymerization of St, DVB, and a chemically cleavable divinyl crosslinker, followed by a transformation reaction [54]. From the FT-IR spectrum of 1d10B, a new stretching vibration of the C–Br bond was observed at 1227 cm−1 (Figure 1). These results indicate that both polymerization and transformation reaction successfully occurred. The Dn of 1d10B was 1.08 μm with narrow size distribution (U = 1.13).
The core-corona polymer microsphere functionalized with phenylsulfonate (CCM-SO3Ph) 2 was synthesized by the surface-initiated atom transfer radical polymerization (SI-ATRP) of styrene (70 mol %) and phenyl p-styrenesulfonate (S) (30 mol %) by using 1d20C or 1d10B as a macroinitiator [55]. In the polymerization, benzyl chloride (BnCl) was simultaneously added as a sacrificial initiator. By the SEC analysis of the resultant free polymer initiated with BnCl, both Mn and Mw/Mn of the grafted polymers onto the surface of 1 were estimated. In FT-IR of 2, two characteristic absorption peaks at 1376 and 1175 cm−1 were observed for the stretching vibration of the S = O bond of phenylsulfonate (Figure 1). The Mn of the corona was successfully controlled by changing the M/I, and the Mw/Mn values were relatively low (<1.3). The Mw/Mn was increased with the increase of the M/I. We found that the SI-ATRP with low M/I proceeded in a controlled manner, and a well-defined CCM-SO3Ph was obtained. Compared with Dn (1), Dn (2) was increased when the grafted polymers were formed only by the initiators on the surface. Dn (2) became higher when increasing M/I from 50 to 200. The polydispersity (U) was low enough (<1.3).
The CCM–SO3H 4 was prepared by the deprotection of phenylsulfonate moiety of 2, followed by treatment with H2SO4. For example, 4d10C represents the CCM–SO3H synthesized from 1d10C and SI-ATRP of styrene and p-styrenesulfonate with M/I = 50, and 4d10B-200 represents that from 1d10B with M/I = 200. The deprotection reaction was conducted with NaOH aqueous solution in a 50/10/1 THF/CH3OH/H2O mixed solvent at 50 °C for 24 h. The characterization is summarized in Table 1. The yield was quantitative (93%–97%), and the sulfur content was in the range between 1.0 and 1.6 mmol g−1. The absorption peaks at 1376 cm−1 disappeared after the deprotection of phenylsulfonate moiety of 2 from the FT-IR spectra of 3 and 4 (Figure 1). Sulfur contents determined by the titration method were close to those calculated. As a result, CCM–SO3H was successfully prepared by the precipitation polymerization, SI-ATRP, and the regeneration of the sulfonic acid.

2.2. Synthesis of Core-Corona Polymer, Microsphere-Immobilized Macmillan Catalyst (ICCC)

The ionic, core-corona polymer, microsphere-immobilized MacMillan catalyst (ICCC) 6 was synthesized by the neutralization reaction of the CCM–SO3H 4 with MacMillan catalyst precursor 5 (Scheme 2). For example, 6d20C was synthesized from 4d20C and 5. These results were summarized in Table 2. The degree of catalyst immobilization measured by the recovered catalyst was more than 60%. No side reaction was observed at all. The degree was slightly increased when low-crosslinked polymer microsphere 4d10B was used instead of that with 20 mol % of crosslinking 4d20C. The significant improvement was observed when the reaction was conducted in CH2Cl2/CH3OH mixed solvent (entry 7 versus 8) Interestingly, the degree by the core-corona polymer microsphere with longer corona (6d10B-200) was higher, possibly because the graft polymer chain was an extended chain rather than a random coil due to the higher Mn of the corona. The catalyst contents in 6 determined from the mass of the recovered catalyst were in the range of 0.53–1.1 mmol g−1. The characteristic strong absorption peak at 1721 cm−1 for C = O in the imidazolidinone moiety was observed from the FT-IR of 6 (Figure 1). The SEM images of ICCC are shown in Figure 2. Since the deprotection of phenylsulfonate of 2, the acidification of the sodium sulfonate of 3, and the ionic immobilization between 4 and 5 did not affect the particle diameter, the Dn (6) was unchanged. For example, the Dn values of 3d10B, 4d10B, and 6d10B were 1.90, 1.92, and 1.91 μm, respectively. The nitrogen content measured in 6d10B was comparable to that calculated. From these results, MacMillan catalyst precursor 5 was successfully immobilized onto the pendant position of CCM with ionic bonding by the neutralization reaction to afford ICCC 6.

2.3. The Effect of Solvent in an Asymmetric DA Reaction Catalyzed by ICCC 6

The asymmetric DA reaction of (E)-cinnamaldehyde 7 and 1,3-cyclopentadiene 8 catalyzed by ICCC 6 was carried out as a benchmark reaction (Scheme 3). The optimization of the reaction solvent was firstly investigated (Table 3). The reaction solvent in the asymmetric reaction using MacMillan catalyst significantly affected the catalytic reactivity, and did when using a homogeneous catalyst as well [40,45,56]. The reaction was performed with 10 mol % of catalyst 6 in a solvent at 25 °C for the comparison of the catalytic performance of 6 with those previously reported. The reaction time was determined by the consumption of 7 by TLC. Both the yield and enantiomeric excess (ee) were increased by increasing the polarity of the reaction solvent (entries 1–4). The catalyst 6d10B showed low reactivity with slightly low enantioselectivity (82% ee (exo)) when a highly polar solvent, such as H2O, was used as the solvent, which was probably due to poor dispersity of the polymer microsphere and the hydrophobic polymer chains (entry 4 versus 5). When dry MeOH was used, enantioselectivity was decreased (entry 4 versus 6), which indicated that a trace of H2O in the solvent assisted with increasing the ee value. There has been a report that the presence of H2O in the DA reaction catalyzed by the MacMillan catalyst enhances reactivity [56]. With the addition of H2O (in 95/5 THF/H2O or 95/5 CH3CN/H2O), both reactivity and enantioselectivity were improved (entry 1 versus 7 and entry 3 versus 8). When a 95/5 MeOH/H2O mixed solvent was used, the catalyst showed excellent reactivity and enantioselectivity (92% ee (exo), >99% ee (endo)) (entry 9). When the amount of H2O in the mixed solvent was increased to 25 vol%, the yield and ee were decreased due to the decrease of dispersity of the catalyst (entry 11). From these results, 95/5 MeOH/H2O mixed solvent was accepted as the optimized reaction solvent for the asymmetric DA reaction.

2.4. Comparison of the Catalytic Activeity of a Model and Polymeric Macmillan Catalyst in an Asymmetric DA Reaction

The catalytic activity of 6 was compared with that of the corresponding MacMillan catalyst and another polymeric MacMillan catalyst in the same reaction (Table 4 and Figure 3). The original MacMillan catalyst 5Cl exhibited excellent reactivity with 93% ee (exo) and 93% ee (endo) (entry 1). The enantioselectivity of MacMillan catalyst with p-toluenesulfonate 5OTs was somewhat lower (entry 2). The linear-type polymeric catalyst in which MacMillan catalyst is immobilized at the pendant 10 (Figures S7–S9) exhibited high enantioselectivity comparable to the low molecular weight counterpart (entry 3). By contrast, the enantioselectivity of the gel-type polymeric catalyst 11 was decreased, possibly due to the steric hindrance or the conformational restriction by polymer network (entry 4). Even though the reactivity was somewhat low, the polymer microsphere-immobilized MacMillan catalyst 12d20C exhibited high enantioselectivity (entry 5). The ICCC 6d20C exhibited higher reactivity and enantioselectivity than 12d20C (entry 6 versus entry 5). The enantioselectivity was comparable to the corresponding model and linear-type polymeric catalysts. The improvement of the yield was observed when low-crosslinked ICCC 6d10B was used due to the increase of the accessibility of substrates to the catalytic site (entry 7 versus entry 6) (Figures S19 and S20). The effect of corona length on the catalytic performance was also examined. Both the yield and enantiomeric excess were decreased when 6d10B-200 was used (entry 8). This result indicated that the increase of steric hindrance near the catalytic site significantly affected the catalytic performance. We also surveyed the effect of the immobilization method. The covalently core-corona polymer nanosphere-immobilized MacMillan catalyst 13 developed by Z. Fu group afforded endo-enriched 9 in 95/5 CH3CN/H2O, and the catalytic activity was lower than that of 6d10B (entry 9) [38]. These results clearly indicated that the combination of the core-corona structure and ionic immobilization was critical to increasing the catalytic activity. The asymmetric reaction between (E)-2-methoxycinnamaldehyde and 8 afforded the Diels-Alder adducts 14 (Figures S13–S15) with 99% yields with 91% ee (exo) and 88% ee (endo) (Figure 4, Figures S21 and S22). The stability of ionic bonding between phenylsulfonate and chiral imidazolidinonium was also checked. We carefully checked the reaction mixture after the reaction, and no leaching of MacMillan catalyst was observed by TLC and elemental analysis. Finally, the core-corona catalyst used in entry 7 was easily and quantitatively recovered by centrifugation and could be reused twice with maintaining the catalytic performance (entry 10 and 11).

3. Materials and Methods

3.1. General Methods

All solvents and reagents were purchased from Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries, Ltd., or Sigma-Aldrich at the highest available purity and used as is unless noted otherwise. Styrene, divinylbenzene, and 4-vinylbenzylchloride were washed with NaOH, and distilled from CaH2. 1,3-Cyclopentadine was obtained by the pyrolysis of dicyclopentadiene at 200 °C. Reactions were monitored by TLC using precoated silica gel aluminum plates (Merck 5554, 60F254, Merck & Co., Inc.). Column chromatography was performed with a silica gel (Wakogel C-200, 100–200 mesh, Wako Pure Chemical Industries, Ltd.) as a stationary phase. NMR spectra were recorded on JEOL JNM-ECS 400SS spectrometers (JEOL Ltd.) in CDCl3 or DMSO-d6 at 25 °C operating at 400 MHz (1H) and 100 MHz (13C). IR spectra were recorded with a JEOL JIR-7000 FT-IR spectrometer and are reported in reciprocal centimeters (cm−1). Size exclusion chromatography (SEC) was obtained with Tosoh instrument with HLC 8020 UV (254 nm) detection. DMF was used as a carrier solvent at a flow rate of 1.0 mL/min at 40 °C. Two polystyrene gel columns of bead size 10 μm (Shodex KF-806L, Showa Denko K. K.) were used. GC measurements were performed using a Shimadzu Capillary Gas Chromatograph GC-2014 equipped with a capillary column (Astec CHIRALDEX β-PH, 30 m × 0.25 mm). HPLC analyses were performed with a JASCO HPLC system composed of 3-line degasser DG-980-50, HPLC pump PU-2080, column oven CO-2065, equipped with a chiral column (CHIRALCEL OJ-H, Daicel) using hexane/2-propanol as eluent. A UV detector JASCO UV-2075 was used for the peak detection.

3.2. General Procedure for the Preparation of CCM–SO3H

To a glass vial (6 mL) with a magnetic stirring bar, CuBr (34 mg, 0.24 mmol), benzyl chloride-functionalized polymer microsphere (0.120 g, 0.200 mmol) and Ph2O (2 mL) were added. After the purging with Ar for 5 min, 2,2′-bipyridine (0.114 g, 0.730 mmol) was added to the mixture, and additional Ar purging for 5 min was performed. Next, styrene (0.872 g, 8.37 mmol, 70 mol %), p-phenyl styrenesulfonate (0.944 g, 3.63 mmol, 30 mol %), and benzyl chloride (5.6 mg, 0.044 mmol) were added to the mixture. The polymerization was conducted at 110 °C for 24 h. The solid was separated from the reaction mixture by centrifugation and washed with THF, methanol-glacial acetic acid mixed solvent (95/5, v/v), and Et2O three times. The white solid was dried at 40 °C under vacuum for 12 h.
To a round-bottom flask (25 mL) with a magnetic stirring bar, CCM-SO3Ph (0.334 g, 0.477 mmol of phenylsulfonate moiety), NaOH (0.059 g, 1.4 mmol), and 50/10/1 THF/MeOH/H2O mixed solvent (9.6 mL) were added. The mixture was stirred at 50 °C for 24 h. The solid was isolated by centrifugation and washed with CH3OH, H2O, and acetone three times. The white solid was dried at 40 °C under vacuum for 12 h.
To a round-bottom flask (50 mL) with a magnetic stirring bar, CCM-SO3Na (0.284 g, 0.440 mmol of the sodium sulfonate moiety) and THF (15 mL) were added. H2SO4 (0.47 mL, 8.8 mmol) was slowly added to the mixture at room temperature. The reaction was stirred at room temperature for 24 h. The solid was isolated by centrifugation and washed with H2O, CH3OH, and acetone three times. The white solid was dried at 40 °C under vacuum for 12 h.

3.3. General Procedure for the Preparation of ICCC

To a Schlenk tube with a magnetic stirring bar, CCM–SO3H (0.144 g, 0.118 mmol of sulfonic acid moiety) in THF (1.2 mL) and MacMillan catalyst precursor (54 mg, 0.25 mmol) in CH3OH (1.2 mL) were added at room temperature. The reaction mixture was vigorously stirred at room temperature for 48 h. The solid was separated from the mixture by centrifugation. After washing with CH3OH and acetone, the white solid was dried at 40 °C under vacuum for 12 h.

3.4. General Procedure for the Asymmetric DA Reaction

To a Schlenk tube equipped with a magnetic stirring bar, ionic, core-corona polymer microsphere-immobilized catalyst (0.050 mmol of catalyst), (E)-cinnamaldehyde (66 mg, 0.50 mmol), and CH3OH/H2O (95/5, v/v) mixed solvent (0.25 mL) were added. Afterwards, 1,3-cyclopentadiene (99 mg, 1.5 mmol) was added at room temperature, and the reaction mixture was stirred at 25 °C for 36 h. The catalyst was then isolated by centrifugation and washed with Et2O three times. The solution of products was concentrated by rotary evaporator until the solution was 1 mL. For the deprotection of acetal, 2/2/1 CH2Cl2/H2O/trifluoroacetic acid was then added to the solution and stirred at room temperature for 2 h. That was followed by adding saturated NaHCO3 aqueous solution. After the extraction with Et2O, the collected organic layer was washed with saturated NaCl and dried with anhydrous MgSO4. The removal of MgSO4 by filtration and the concentration by rotary evaporator and vacuum gave the crude. The leaching of MacMillan catalyst was checked by TLC and the elemental analysis for nitrogen content. The crude was purified by silica gel column chromatography (with 1/19 ethyl acetate/hexane) to give the Diels-Alder adducts as colorless liquids. The yield and exo/endo ratio were determined using 1H NMR spectrum through comparison of the 1H signals of aldehydes. The enantiomeric excess (ee) for exo and endo isomers was determined using GC through a comparison of the peak area ratio of isomers (Astec CHIRALDEX β-PH; injection temperature of 180 °C; detection temperature of 180 °C; the column temperature was increased from 150 °C to 180 °C with 1 °C/min; retention times: 35.1 min (exo(2R)), 35.7 min (exo(2S)), 36.6 min (endo(2R)), and 37.1 min (endo(2S))).
9: 1H NMR (400 MHz, CDCl3, δ = 7.26 (CHCl3)): δ = 9.92 (d, J = 2.1 Hz, 1H), 9.60 (d, J = 2.1 Hz, 1H), 7.31–7.16 (m, 10H), 6.42 (dd, J = 5.8, 2.4 Hz, 1H), 6.34 (dd, J = 5.5, 1.8 Hz, 1H), 6.17 (dd, J = 5.5, 2.8 Hz, 1H), 6.07 (dd, J = 5.5, 2.4 Hz, 1H), 3.73 (dd, J = 4.9, 1.5 Hz, 1H), 3.34–3.33 (m, 1H), 3.24–3.22 (m, 2H), 3.14–3.13 (m, 1H), 3.10 (d, J = 1.22 Hz, 1H), 3.08 (d, J = 1.22, 1H), 3.00–2.97 (m, 1H), 2.61–2.59 (m, 1H), 1.82–1.80 (m, 1H), 1.64–1.60 (m, 2H), 1.57–1.54 (m, 2H). 13C NMR (100 MHz, CDCl3, δ = 77.1 (CDCl3)): δ = 203.5, 202.8, 143.5, 142.6, 139.2, 136.5, 136.3, 133.8, 128.6, 128.1, 127.9, 127.3, 126.3, 126.2, 60.8, 59.4, 48.4, 48.4, 47.6, 47.1, 45.6, 45.5, 45.4, 45.2.

4. Conclusions

The core-corona polymer microsphere with sulfonic acid (CCM–SO3H) 4 was prepared by the surface-initiated ATRP (SI-ATRP) of styrene and phenyl p-styrenesulfonate with monodispersed benzyl halide-functionalized polymer microsphere 1 prepared via precipitation polymerization as a macroinitiator, followed by the regeneration of sulfonic acid. The ionic, core-corona polymer microsphere-immobilized chiral MacMillan catalyst (ICCC) 6 was successfully synthesized by the neutralization reaction between the CCM–SO3H 4 and MacMillan catalyst precursor 5. The solvent effect and the structural effect of the catalyst was evaluated in the asymmetric Diels-Alder (DA) reaction of (E)-cinnamaldehyde and 1,3-cyclopentadiene. We found that the increase of steric hindrance near the catalytic site by longer corona significantly decreased both the reactivity and enantioselectivity. The catalyst 6d10B gave the DA adducts with 99% yields and excellent ee values (92% ee for the exo isomer and >99% ee for the endo isomer). The catalytic activity of the ionic, core-corona polymer microsphere catalyst was comparable to that of the linear-type polymeric catalyst. We conclude that the design of polymeric chiral organocatalyst, including the immobilization method and the support polymer, is of significance for improving the catalytic activity. The effect of the monomer and the diameter of 6 are under investigation.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/9/11/960/s1: Synthesis and characterization of 10 and 12d20C. Figure S1: SEM image of 12d20C, Figure S2: FT-IR spectra of M-S, M-SNa, M-SH, and 12d20C, Figure S3: 1H NMR of sS30 in CDCl3, Figure S4: 13C NMR of sS30 in CDCl3, Figure S5: 1H NMR of sSNa30 in CDCl3, Figure S6: 13C NMR of sSNa30 in CDCl3, Figure S7: 1H NMR of 10 in DMSO-d6, Figure S8: 13C NMR of 10 in DMSO-d6, Figure S9: FT-IR spectra of sS30, sSNa30, sSH30 and 10, Procedure for check of MacMillan catalyst leaching, Procedure for asymmetric Diels-Alder reaction of (E)-2-methoxycinnamaldehyde with 1,3-cyclopentadiene, Figure S10: 1H NMR of crude 9 in CDCl3, Figure S11: 1H NMR of 9 after purification in CDCl3, Figure S12: 13C NMR of 9 after purification in CDCl3, Figure S13: 1H NMR of crude 14 in CDCl3, Figure S14: 1H NMR of 14 after purification in CDCl3, Figure S15: 13C NMR of 14 after purification in CDCl3, Figure S16: 1H NMR of 14 after reduction in CDCl3, Figure S17: 13C NMR of 14 after reduction in CDCl3, Figure S18: GC chromatogram of racemic 9. (a) Full chromatogram. (b) Expanded chromatogram, Figure S19: GC chromatogram of crude 9 (entry 7 in Table 4). (a) Full chromatogram. (b) Expanded chromatogram, Figure S20: GC chromatogram of 9 after purification (entry 7 in Table 4). (a) Full chromatogram. (b) Expanded chromatogram, Figure S21: HPLC chromatogram of crude 14 after reduction, Figure S22: HPLC chromatogram of 14 after reduction.

Author Contributions

Conceptualization, methodology, and supervision, N.H.; formal analysis and data curation, M.W.U.; writing—original draft preparation, M.W.U.; writing—review and editing, N.H. All authors read and approved the final manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors are grateful to Shinichi Itsuno at Toyohashi University of Technology for useful discussions.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Berkessel, A.; Groger, H. (Eds.) Wiley-VCH: Weinheim, Germany, 2005. [Google Scholar]
  2. Enantioselective Organocatalysis; Dalko, P.I. (Ed.) Wiley-VCH: Weinheim, Germany, 2007. [Google Scholar]
  3. Pellissier, H. Asymmetric organocatalysis. Tetrahedron 2007, 63, 9267–9331. [Google Scholar] [CrossRef]
  4. Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. New strategies for organic catalysis:  The first highly enantioselective organocatalytic Diels-Alder reaction. J. Am. Chem. Soc. 2000, 122, 4243–4244. [Google Scholar] [CrossRef]
  5. Jen, W.S.; Wiener, J.J.M.; MacMillan, D.W.C. New Strategies for Organic Catalysis:  The First Enantioselective Organocatalytic 1, 3-Dipolar Cycloaddition. J. Am. Chem. Soc. 2000, 122, 9874–9875. [Google Scholar] [CrossRef]
  6. Pares, N.A.; MacMillan, D.W.C. New strategies in organic catalysis:  The first enantioselective organocatalytic Friedel-Crafts alkylation. J. Am. Chem. Soc. 2001, 123, 4370–4371. [Google Scholar] [CrossRef] [PubMed]
  7. Austin, J.F.; MacMillan, D.W.C. Enantioselective organocatalytic indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis. J. Am. Chem. Soc. 2002, 124, 1172–1173. [Google Scholar] [CrossRef] [PubMed]
  8. Brochu, M.P.; Brown, S.P.; MacMillan, D.W.C. Direct and enantioselective organocatalytic α-chlorination of aldehydes. J. Am. Chem. Soc. 2004, 126, 4108–4109. [Google Scholar] [CrossRef]
  9. Beeson, T.D.; MacMillan, D.W.C. Enantioselective organocatalytic α-fluorination of aldehydes. J. Am. Chem. Soc. 2005, 127, 8826–8828. [Google Scholar] [CrossRef]
  10. Northrup, A.B.; MacMillan, D.W.C. The first direct and enantioselective cross-aldol reaction of aldehydes. J. Am. Chem. Soc. 2002, 124, 6798–6799. [Google Scholar] [CrossRef]
  11. Fonseca, M.T.H.; List, B. Catalytic asymmetric intramolecular Michael reaction of aldehydes. Angew. Chem. Int. Ed. 2004, 43, 3958–3960. [Google Scholar] [CrossRef]
  12. Lee, S.; MacMillan, D.W.C. Enantioselective organocatalytic epoxidation using hypervalent iodine reagents. Tetrahedron 2006, 62, 11413–11424. [Google Scholar] [CrossRef]
  13. Beeson, T.D.; Mastracchio, A.; Homg, J.B.; Ashton, K.; MacMillan, D.W.C. Enantioselective Organocatalysis Using SOMO Activation. Science 2007, 316, 582–585. [Google Scholar] [CrossRef]
  14. Nicewicz, D.A.; MacMillan, D.W.C. Merging photoredox catalysis with organocatalysis: The direct asymmetric alkylation of aldehydes. Science 2008, 322, 77–80. [Google Scholar] [CrossRef] [PubMed]
  15. Devery, J.J., III; Conrad, J.C.; MacMillan, D.W.C.; Flowers, R.A., II. Mechanistic Complexity in Organo-SOMO Activation. Angew. Chem. Int. Ed. 2010, 49, 6106–6110. [Google Scholar] [CrossRef] [PubMed]
  16. Mastracchio, A.; Warkentin, A.A.; Walji, A.M.; MacMillan, D.W.C. Direct and enantioselective α-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis. Proc. Natl. Acd. Sci. USA 2010, 107, 20648–20651. [Google Scholar] [CrossRef] [PubMed]
  17. Pham, P.V.; Ashton, K.; MacMillan, D.W.C. The intramolecular asymmetric allylation of aldehydes via organo-SOMO catalysis: A novel approach to ring construction. Chem. Sci. 2011, 2, 1470–1473. [Google Scholar] [CrossRef] [PubMed]
  18. Neumann, M.; Füldner, S.; König, B.; Zeitler, K. Metal-Free, Cooperative Asymmetric Organophotoredox Catalysis with Visible Light. Angew. Chem. Int. Ed. 2011, 50, 951–954. [Google Scholar] [CrossRef] [PubMed]
  19. Shih, H.W.; Vander Wal, M.N.; Grange, R.L.; MacMillan, D.W.C. Enantioselective α-Benzylation of Aldehydes via Photoredox Organocatalysis. J. Am. Chem. Soc. 2010, 132, 13600–13603. [Google Scholar] [CrossRef]
  20. Pirnot, M.T.; Rankic, D.A.; Martin, D.B.C.; MacMillan, D.W.C. Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes. Science 2013, 339, 1593–1596. [Google Scholar] [CrossRef]
  21. Terrett, J.A.; Clift, M.D.; MacMillan, D.W.C. Direct β-Alkylation of Aldehydes via Photoredox Organocatalysis. J. Am. Chem. Soc. 2014, 136, 6858–6861. [Google Scholar] [CrossRef]
  22. Prier, C.K.; Rankic, D.A.; MacMillan, D.W.C. Visible Light Photoredox Catalysis with Transition Metal Complexes. Chem. Rev. 2013, 113, 5322–5363. [Google Scholar] [CrossRef]
  23. Benaglia, M.; Celentano, G.; Cinquini, M.; Puglisi, A.; Cozzi, F. Poly (ethylene glycol)-supported chiral imidazolidin-4-one: An efficient organic catalyst for the enantioselective Diels-Alder cycloaddition. Adv. Synth. Catal. 2002, 344, 149–152. [Google Scholar] [CrossRef]
  24. Selkälä, S.A.; Tois, J.; Pihko, P.M.; Koskinen, A.M.P. Asymmetric organocatalytic Diels-Alder reactions on solid support. Adv. Synth. Catal. 2002, 344, 941–945. [Google Scholar] [CrossRef]
  25. Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Enantioselective 1, 3-dipolar cycloadditions of unsaturated aldehydes promoted by a poly (ethylene glycol)-supported organic catalyst. Eur. J. Org. Chem. 2004, 567–573. [Google Scholar] [CrossRef]
  26. Zhang, Y.G.; Zhao, L.; Lee, S.S.; Ying, J.Y. Enantioselective catalysis over chiral imidazolidin-4-one immobilized on siliceous and polymer-coated mesocellular foams. Adv. Synth. Catal. 2006, 348, 2027–2032. [Google Scholar] [CrossRef]
  27. Mason, B.P.; Bogdan, A.R.; Goswami, A.; McQuade, D.T. A general approach to creating soluble catalytic polymers heterogenized in microcapsules. Org. Lett. 2007, 9, 3449–3451. [Google Scholar] [CrossRef]
  28. Kristensen, T.E.; Vestli, K.; Jakobsen, M.G.; Hansen, F.K.; Hansen, T. A general approach for preparation of polymer-supported chiral organocatalysts via acrylic copolymerization. J. Org. Chem. 2010, 75, 1620–1629. [Google Scholar] [CrossRef]
  29. Guizzetti, S.; Benaglia, M.; Siegel, J.S. Poly (methylhydrosiloxane)-supported chiral imidazolinones: New versatile, highly efficient and recyclable organocatalysts for stereoselective Diels-Alder cycloaddition reactions. Chem. Commun. 2012, 48, 3188–3190. [Google Scholar] [CrossRef]
  30. Riente, P.; Yadav, J.; Pericàs, M.A. A click strategy for the immobilization of MacMillan organocatalysts onto polymers and magnetic nanoparticles. Org. Lett. 2012, 14, 3668–3671. [Google Scholar] [CrossRef]
  31. Moore, B.L.; Lu, A.; Longbottom, D.A.; O’Reilly, R.K. Immobilization of MacMillan catalyst via controlled radical polymerization: Catalytic activity and reuse. Polym. Chem. 2013, 4, 2304–2312. [Google Scholar] [CrossRef]
  32. Chiroli, V.; Benaglia, M.; Cozzi, F.; Puglisi, A.; Annuziata, R.; Cwlwntano, G. Continuous-flow stereoselective organocatalyzed Diels-Alder reactions in a chiral catalytic “Homemade” HPLC column. Org. Lett. 2013, 15, 3590–3593. [Google Scholar] [CrossRef]
  33. Wang, C.A.; Zhang, Y.; Shi, J.Y.; Wang, W. A self-supported polymeric MacMillan catalyst for homogeneous organocatalysis and heterogeneous recycling. Chem. Asian J. 2013, 8, 1110–1114. [Google Scholar] [CrossRef] [PubMed]
  34. Chiroli, V.; Benaglia, M.; Puglisi, A.; Porta, R.; Jumde, R.P.; Mandoli, A. A chiral organocatalytic polymer-based monolithic reactor. Green Chem. 2014, 16, 2798–2806. [Google Scholar] [CrossRef] [Green Version]
  35. Salvo, A.M.P.; Giacalone, F.; Nato, R.; Gruttadauria, M. Recyclable heterogeneous and low-loading homogeneous chiral imidazolidinone catalysts for α-alkylation of aldehydes. ChemPlusChem 2014, 79, 857–862. [Google Scholar] [CrossRef]
  36. Takata, L.M.S.; Iida, H.; Shimomura, K.; Hayashi, K.; Santos, A.A.D.; Yashima, E. Helical poly (phenylacetylene) bearing chiral and achiral imidazolidinone-based pendants that catalyze asymmetric reactions due to catalytically active achiral pendants assisted by macromolecular helicity. Macromol. Rapid Commun. 2015, 36, 2047–2054. [Google Scholar] [CrossRef]
  37. Ranjbar, S.; Riente, P.; Rodriguez-Escrich, C.; Yadav, J.; Ramineni, K.; Pericàs, M.A. Polystyrene or magnetic nanoparticles as support in enantioselective organocatalysis? A case study in Friedel-Crafts chemistry. Org. Lett. 2016, 18, 1602–1605. [Google Scholar] [CrossRef] [Green Version]
  38. Li, X.; Yang, B.; Zhang, S.; Jia, X.; Hu, Z. Facile synthesis of hairy microparticle-/nanoparticle-supported MacMillan and its application to Diels-Alder reaction in water. Colloid. Polym. Sci. 2017, 295, 573–582. [Google Scholar] [CrossRef]
  39. Arakawa, Y.; Haraguchi, N.; Itsuno, S. An immobilization method of chiral quaternary ammonium salts onto polymer supports. Angew. Chem. Int. Ed. 2008, 47, 8232–8235. [Google Scholar] [CrossRef]
  40. Haraguchi, N.; Takemura, Y.; Itsuno, S. Novel polymer-supported organocatalyst via ion exchange reaction: Facile immobilization of chiral imidazolidin-4-one and its application to Diels-Alder reaction. Tetrahedron Lett. 2010, 51, 1205–1208. [Google Scholar] [CrossRef]
  41. Itsuno, S.; Paul, D.K.; Salam, M.A.; Haraguchi, N. Main-chain ionic chiral polymers: Synthesis of optically active quaternary ammonium sulfonate polymers and their application in asymmetric catalysis. J. Am. Chem. Soc. 2010, 132, 2864–2865. [Google Scholar] [CrossRef]
  42. Haraguchi, N.; Kiyono, H.; Takemura, Y.; Itsuno, S. Design of main-chain polymers of chiral imidazolidinone for asymmetric organocatalysis application. Chem. Commun. 2012, 48, 4011–4013. [Google Scholar] [CrossRef] [PubMed]
  43. Itsuno, S.; Oonami, T.; Takenaka, N.; Haraguchi, N. Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units and Application as Catalyst in Asymmetric Diels–Alder Reaction. Adv. Synth. Catal. 2015, 357, 3995–4002. [Google Scholar] [CrossRef]
  44. Hassan, M.M.; Haraguchi, N.; Itsuno, S. Highly active polymeric organocatalyst: Chiral ionic polymers prepared from 10,11-didehydrogenated cinchonidinium salt. J. Polym. Sci. Part A Polym. Chem. 2016, 54, 621–627. [Google Scholar] [CrossRef]
  45. Haraguchi, N.; Nguyen, T.L.; Itsuno, S. Polyesters containing chiral imidazolidinone salts in polymer main chain: Heterogeneous organocatalysts for the asymmetric Diels-Alder reaction. CHEMCATCHEM 2017, 9, 3786–3794. [Google Scholar] [CrossRef]
  46. Haraguchi, N.; Takenaka, N.; Najwa, A.; Takahara, Y.; Kar Mun, M.; Itsuno, S. Synthesis of main-chain ionic polymers of chiral imidazolidinone organocatalysts and their application to asymmetric Diels-Alder reactions. Adv. Synth. Catal. 2018, 360, 112–123. [Google Scholar] [CrossRef]
  47. Xia, Y.; Gates, B.; Yin, Y.; Lu, Y. Monodispersed colloidal spheres: Old materials with new applications. Adv. Mater. 2000, 12, 693–713. [Google Scholar] [CrossRef]
  48. Wang, J.; Cormack, P.A.G.; Sherrington, D.C.; Khoshdel, E. Monodisperse, molecularly imprinted polymer microspheres prepared by precipitation polymerization for affinity separation applications. Angew. Chem. Int. Ed. 2003, 42, 5336–5338. [Google Scholar] [CrossRef]
  49. Barner, L. Synthesis of microspheres as versatile functional scaffolds for materials science applications. Adv. Mater. 2009, 21, 2547–2553. [Google Scholar] [CrossRef]
  50. Zhang, J.; Zhang, W.; Wang, Y.; Zhang, M. Palladium-iminodiacetic acid immobilized on pH-responsive polymeric microspheres: Efficient quasi-homogeneous catalyst for Suzuki and Heck reactions in aqueous solution. Adv. Synth. Catal. 2008, 350, 2065–2076. [Google Scholar] [CrossRef]
  51. Haraguchi, N.; Nishiyama, A.; Itsuno, S. Synthesis of polymer microspheres functionalized with chiral ligand by precipitation polymerization and their application to asymmetric transfer hydrogenation. J. Polym. Sci. Part A Polym. Chem. 2010, 48, 3340–3349. [Google Scholar] [CrossRef]
  52. Ullah, M.W.; Thao, N.T.P.; Sugimoto, T.; Haraguchi, N. Synthesis of core-corona polymer microsphere-supported cinchonidinium salt and its application to asymmetric synthesis. Mol. Catal. 2019, 473. [Google Scholar] [CrossRef]
  53. Li, W.-H.; Li, K.; Stöver, H.D.H. Monodisperse poly (chloromethylstyrene-co-divinylbenzene) microspheres by precipitation polymerization. J. Polym. Sci. Part A Polym. Chem. 1999, 37, 2295–2303. [Google Scholar] [CrossRef]
  54. Haraguchi, N.; Sugimoto, T.; Ullah, M.W. Synthesis of monodispersed polymer microsphere functionalized with benzyl bromides by chemical scission of cleavable crosslinker. 2019; under preparation. [Google Scholar]
  55. Ullah, M.W.; Haraguchi, N. Synthesis of well-defined hairy polymer microspheres by precipitation polymerization and surface-initiated atom transfer radical polymerization. J. Polym. Sci. Part A Polym. Chem. 2019, 57, 1296–1304. [Google Scholar] [CrossRef]
  56. Brazier, J.B.; Jones, K.M.; Platts, J.A.; Tomkinson, N.C.O. On the roles of protic solvents in imidazolidinone-catalyzed transformations. Angew. Chem. Int. Ed. 2011, 50, 1613–1616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Catalysts 09 00960 sch001 550
Scheme 1. Synthesis of corona polymer microsphere having a sulfonic acid moiety (CCM–SO3H) 4.
Scheme 1. Synthesis of corona polymer microsphere having a sulfonic acid moiety (CCM–SO3H) 4.
Catalysts 09 00960 sch001
Catalysts 09 00960 g001 550
Figure 1. FT-IR spectra. (a) 1d10B, (b) 2d10B, (c) 3d10B, (d) 4d10B, and (e) 6d10B.
Figure 1. FT-IR spectra. (a) 1d10B, (b) 2d10B, (c) 3d10B, (d) 4d10B, and (e) 6d10B.
Catalysts 09 00960 g001
Catalysts 09 00960 sch002 550
Scheme 2. Synthesis of ionic, core-corona polymer microsphere-immobilized MacMillan catalyst (ICCC) 6 by neutralization reaction.
Scheme 2. Synthesis of ionic, core-corona polymer microsphere-immobilized MacMillan catalyst (ICCC) 6 by neutralization reaction.
Catalysts 09 00960 sch002
Catalysts 09 00960 g002 550
Figure 2. SEM images. (a) 1d10B, (b) 2d10B, (c) 3d10B, (d) 4d10B, and (e) 6d10B.
Figure 2. SEM images. (a) 1d10B, (b) 2d10B, (c) 3d10B, (d) 4d10B, and (e) 6d10B.
Catalysts 09 00960 g002
Catalysts 09 00960 sch003 550
Scheme 3. Asymmetric Diels-Alder (DA) reaction catalyzed by ICCC 6.
Scheme 3. Asymmetric Diels-Alder (DA) reaction catalyzed by ICCC 6.
Catalysts 09 00960 sch003
Catalysts 09 00960 g003 550
Figure 3. Model and polymeric MacMillan catalysts.
Figure 3. Model and polymeric MacMillan catalysts.
Catalysts 09 00960 g003
Catalysts 09 00960 g004 550
Figure 4. DA adducts 14 from (E)-2-methoxycinnamaldehyde and 8 catalyzed by ICCC 6.
Figure 4. DA adducts 14 from (E)-2-methoxycinnamaldehyde and 8 catalyzed by ICCC 6.
Catalysts 09 00960 g004
Table
Table 1. Characterization of CCM–SO3H 4.
Table 1. Characterization of CCM–SO3H 4.
Entry4Dn (Core) (μm) aCoronaDn (Core-Corona) (μm) aU (4) aS Content (mmol g−1) c
MnbMw/Mnb
14d20C1.1476301.181.341.001.00
24d10B1.0811,0001.321.401.231.61
34d10B-2001.0830,4001.571.951.201.48
a Measured from SEM image. b Determined by SEC (polystyrene standards). c Determined by titration method.
Table
Table 2. Characterization of ICCC 6.
Table 2. Characterization of ICCC 6.
Entry6SolventDegree of Immobilization (%)Catalyst Content (mmol g−1)
16d20C1/1 THF/CH3OH610.533
26d10B1/1 THF/CH3OH670.581
36d10B1/1 CH2Cl2/CH3OH861.06
46d10B-2001/1 CH2Cl2/CH3OH981.10
Table
Table 3. Asymmetric DA reaction catalyzed by ICCC 6 a.
Table 3. Asymmetric DA reaction catalyzed by ICCC 6 a.
EntrySolventTime (h)9
Yield (%) bExo/Endobee (Exo) (%) cee (Endo) (%) c
1THF601851/495767
2CH2Cl2602550/506168
3CH3CN602952/486674
4MeOH389156/4488>99
5H2O609752/4882>99
6Dry MeOH389244/568594
795/5 THF/H2O608752/488597
895/5 CHCN/H2O609653/478192
995/5 MeOH/H2O389954/4692>99
1085/15 MeOH/H2O509956/449199
1175/25 MeOH/H2O629950/508998
a Reactions were conducted with 7 and 8 (3 equiv.) at 25 °C using 6d10B (10 mol %). b By 1H NMR spectroscopy. c By GC analysis (CHIRALDEX β-PH).
Table
Table 4. Catalyst comparison in the asymmetric DA reaction a.
Table 4. Catalyst comparison in the asymmetric DA reaction a.
EntryCatalystTime (h)9
Yield (%) bExo/Endobee (Exo) (%) cee (Endo) (%) c
15Cl89957/439393
25OTs249455/458892
310368960/409496
411249955/458483
512d20C449755/4590>99
66d20C369454/4692>99
76d10B3899 (97) d54/4692>99
86d10B-200606451/499195
9 e13217836/649288
10 f6d10B409954/4692>99
11 g6d10B439955/4591>99
a Reactions were conducted with 7 and 8 (3 equiv.) in 95/5 CH3OH/H2O at 25 °C using 10 mol % of catalyst. b By 1H NMR spectroscopy. c By GC analysis (CHIRALDEX β-PH). d By isolated yield. e In 95/5 CH3CN/H2O. f Recovered catalyst in entry 7 was used. g Recovered catalyst in entry 10 was used.

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Ullah, M.W.; Haraguchi, N. Ionic, Core-Corona Polymer Microsphere-Immobilized MacMillan Catalyst for Asymmetric Diels-Alder Reaction. Catalysts 2019, 9, 960. https://doi.org/10.3390/catal9110960

AMA Style

Ullah MW, Haraguchi N. Ionic, Core-Corona Polymer Microsphere-Immobilized MacMillan Catalyst for Asymmetric Diels-Alder Reaction. Catalysts. 2019; 9(11):960. https://doi.org/10.3390/catal9110960

Chicago/Turabian Style

Ullah, Md. Wali, and Naoki Haraguchi. 2019. "Ionic, Core-Corona Polymer Microsphere-Immobilized MacMillan Catalyst for Asymmetric Diels-Alder Reaction" Catalysts 9, no. 11: 960. https://doi.org/10.3390/catal9110960

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