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Article

Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers for Asymmetric Catalysis Using Quaternization Polymerization

by
Naoki Haraguchi
*,
Parbhej Ahamed
,
Md. Masud Parvez
and
Shinichi Itsuno
Department of Environmental and Life Sciences, Graduate School of Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi, Aichi 441-8580, Japan
*
Author to whom correspondence should be addressed.
Molecules 2012, 17(6), 7569-7583; https://doi.org/10.3390/molecules17067569
Submission received: 27 April 2012 / Revised: 4 June 2012 / Accepted: 13 June 2012 / Published: 19 June 2012
(This article belongs to the Special Issue Asymmetric Catalysis)
Browse Figures
Versions Notes

Abstract

:
Main-chain chiral quaternary ammonium polymers were successfully synthesized by the quaternization polymerization of cinchonidine dimer with dihalides. The polymerization occurred smoothly under optimized conditions to give novel type of main-chain chiral quaternary ammonium polymers. The catalytic activity of the polymeric chiral organocatalysts was investigated on the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.

Graphical Abstract

1. Introduction

Cinchona alkaloids are among the most attractive chiral molecules because they represent readily available and inexpensive natural chiral amino alcohols with pseudo-enantiomer forms. Cinchona alkaloids and their derivatives have been widely applied as chiral organocatalysts for some asymmetric reactions [1,2,3]. Among them, the quaternary ammonium salts of cinchona alkaloids [1,2,3,4] are widely used for asymmetric reactions such as alkylations [5,6], aldol reactions [7,8,9], nitroaldol reactions [7], Mannich reactions [10], nitro-Mannich reactions [11], Darzens reactions [12], Strecker reactions [13], α-hydroxylations [14], α-fluorinations [15], Michael reactions [16,17], epoxidations [18,19], aziridations [20,21], and reductions [22,23].
From the viewpoint of the practical use of cinchona alkaloid quaternary ammonium salts, some issues exist. For example, compared with transition metal based catalysts, large amounts (1–20 mol%) of organocatalyst molecule are generally required to complete the reaction, and only a few active cinchona alkaloid quaternary ammonium salts are reported. Moreover, due to the amphiphilicity of the quaternary ammonium salt, the catalyst separation might be difficult in some cases. One potential solution to the last problem is the immobilization on the catalyst on a polymer [1,4,24,25,26,27]. Several examples of polymer-immobilized chiral quaternary ammonium salts have been developed and successfully used as catalysts for asymmetric synthesis [28,29,30,31,32,33,34,35,36,37,38,39]. In these polymeric catalyst examples the catalyst was immobilized on the side-chain of the support polymer.
In addition of these polymer-immobilized chiral quaternary ammonium salts, we have recently developed main-chain chiral polymers with chiral organocatalysts [40,41,42,43,44,45]. Some useful polymerization techniques such as etherification polymerization [40], ion exchange polymerization [41,42,43,44], and neutralization polymerization [45] were used for the synthesis of main-chain chiral polymers with chiral organocatalysts. Interestingly, some main-chain chiral polymers showed higher enantioselectivity than the corresponding monomeric catalysts.
In this article, some main-chain chiral quaternary ammonium polymers were synthesized by a quaternization polymerization of cinchonidine dimer with dihalides. The resulting main-chain chiral quaternary ammonium polymers were used as polymeric chiral organocatalysts for the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.

2. Results and Discussion

2.1. Synthesis of Thiolated Cinchonidine Quaternary Ammonium Dimers 5

We have firstly prepared some thiolated cinchonidine quaternary ammonium salt dimers as model compounds. The synthetic scheme followed is shown in Scheme 1. The thiolated cinchonidine quaternary ammonium dimers 5 were prepared in two steps from cinchonidine (1), thiols 2 and dihalides 4. The first thiol-ene click reaction of methyl-3-mercaptopropionate (2) and 1 was carried out in the presence of AIBN in CHCl3 at 70 °C for 24 h [46]. The reaction proceeded quantitatively and the thiolated cinchonidine 3 was obtained in 90% isolated yield.
Dimerization of cinchona alkaloids was versatile because of the presence of some functional groups such as hydroxyl groups, the quinuclidine framework amine and even double bonds in cinchona alkaloids. Cinchona alkaloids are generally dimerized by etherification with dihalide to afford chiral diamine derivatives. The other dimerization method is a quaternization of cinchona alkaloids with dihalides to give chiral quaternary ammonium dimers. We employed the quaternization reaction for the synthesis of chiral quaternary ammonium dimers. The quaternization reaction was carried out at 100 °C using 2.2 equivalents of 3 to 4. The reaction was complete within 6 h when the mixed solvent of ethanol/DMF/chloroform (5/6/2) was used. The isolated yields of 5a–d were 92–96%. We found that cinchonidine could be easily modified with thiol via thiol-ene click reaction and the thiolated cinchonidine could be dimerized with dihalides by the quaternization reaction.
Molecules 17 07569 g001 550
Scheme 1. Synthesis of cinchonidine quaternary ammonium dimers 5.
Scheme 1. Synthesis of cinchonidine quaternary ammonium dimers 5.
Molecules 17 07569 g001

2.2. Synthesis of Cinchonidine Dimers 7 Using Thiol-Ene Click Reaction

Another useful dimerization method we focused on here is the use of the double bond in cinchona alkaloids. Some useful coupling reactions such as thiol-ene click reaction [47,48,49,50] are available for the dimerization reaction. We tried to synthesize cinchonidine dimers 7a and 7b by the thiol-ene click reaction of 1 and dithiols 6, as illustrated in Scheme 2.
Molecules 17 07569 g002 550
Scheme 2. Synthesis of cinchonidine dimers 7.
Scheme 2. Synthesis of cinchonidine dimers 7.
Molecules 17 07569 g002
The thiol-ene click reaction of two equivalents of cinchonidine with dithiol was carried out in the presence of AIBN in CHCl3 at 70 °C. Compared with the reaction of 1 and 2 in the synthesis of monothiolated cinchonidine 3, the reaction with 6 was slow. In addition, we were faced with a problem in the purification of 7a and 7b by silica gel column chromatography. Large amounts of the product interacted with the stationary phase of column chromatography, which led to a decrease in the isolated yield of 7a and 7b.

2.3. Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers 8 Using Quaternization Polymerization

We next tried to synthesize main-chain chiral quaternary ammonium polymers 8 using the thiolinked cinchonidine dimers 7. The synthesis of 8 using quaternization polymerization is illustrated in Scheme 3. The procedure is quite simple. Compound 7 and equimolar dihalide 4 were reacted in DMSO at 90 °C. Neither initiator of the polymerization nor additives is necessary. In fact, the corresponding main-chain chiral quaternary ammonium polymers 8a–h were obtained in high yield. In all cases polymeric products were precipitated into diethyl ether, which could be easily isolated by filtration.
Molecules 17 07569 g003 550
Scheme 3. Synthesis of main-chain chiral quaternary ammonium polymers 8.
Scheme 3. Synthesis of main-chain chiral quaternary ammonium polymers 8.
Molecules 17 07569 g003
Mn values of these polymers can be measured by SEC. The measured values in the elemental analysis of 8 were somewhat different from the calculated ones, possibly because of the hydrophilicity of the quaternary ammonium moiety and the low degree of polymerization. In the 1H-NMR spectra of the polymers, proton signals assigned to the quinuclidine framework and the dihalide disappeared completely. On the other hand, some signals assigned to the quaternary ammonium salt were alternatively observed. These results clearly indicated that successive intermolecular quaternization reaction occurred without side reaction participation to afford main-chain chiral quaternary ammonium polymers 8. Due to the simplicity of the quaternization polymerization, various kinds of main-chain chiral quaternary ammonium polymers can be easily prepared by this method. In addition, this is the first successful report of the synthesis of main-chain polymers of cinchonidine quaternary ammonium salts using the double bond, in which the cinchonidine quaternary ammonium salts were incorporated uniformly into the main-chain of the polymer.

2.4. Asymmetric Benzylation of N-(Diphenylmethylidene)glycine tert-butyl Ester 9 Catalyzed by Main-Chain Chiral Quaternary Ammonium Polymers 8

Since these main-chain chiral quaternary ammonium polymers contain chiral quaternary ammonium structures in their repeating units, the polymers should have catalytic activity in some asymmetric transformations. In order to evaluate the catalytic activity of the new chiral ionic polymers, we chose the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester 9 as a typical asymmetric transformation using chiral quaternary ammonium salt. We designed and synthesized some main-chain chiral quaternary ammonium polymers based on various combinations of thiolinked cinchonidine dimers and dihalides to investigate the effect of the structure on the catalytic activity and the enantioselectivity.
At first, we have tested the asymmetric benzylation reaction with the chiral quaternary ammonium dimers 5a–d. The results of the asymmetric reaction are summarized in Table 1. The substrate 9 was allowed to react in an organic solvent with benzyl bromide in the presence of the chiral quaternary ammonium dimer 5 and aqueous potassium hydroxide. In all cases, the asymmetric reaction took place smoothly in the two phase system. For example, chiral quaternary ammonium dimer 5a catalyzed the benzylation to give the corresponding chiral (S)-phenylalanine derivative 10 in 97% yield with 84% ee (Table 1, entry 1). The structure of the spacer (R) between two chiral quaternary ammonium salts in the dimeric catalyst influences the enantioselectivity. When anthracenyl or naphthyl moieties were introduced as spacer, higher enantioselectivity (up to 90% ee) was observed (entries 2,3,4). In contrast, thiolated cinchonidine 3 and thiolinked cinchonidine dimers 7 did not show any catalytic activity at all. We thus confirmed that the chiral quaternary ammonium salt framework was essential to catalyze the asymmetric benzylation.
Table
Table 1. Asymmetric benzylation of glycine derivative using chiral quaternary ammonium dimer 5.
Table 1. Asymmetric benzylation of glycine derivative using chiral quaternary ammonium dimer 5.
EntryCatalystRTime (h)Yield (%) aee (%) b
15a Molecules 17 07569 i001 49784
25b Molecules 17 07569 i002 49290
35c Molecules 17 07569 i003 49188
45d Molecules 17 07569 i004 49290 Molecules 17 07569 i005
a Determined by 1H-NMR; b Determined by HPLC (CHIRALCEL OD-H column).
Encouraged by these results in the asymmetric benzylation using chiral quaternary ammonium dimers 5, main-chain chiral quaternary ammonium polymers 8a–h were used as polymeric chiral organocatalysts in the asymmetric benzylation reaction under similar conditions in order to investigate their catalytic activity. The reaction conditions are as same as those using the dimeric catalyst. These results were summarized in Table 2. Compounds 8a–h were not soluble, but were suspended in a mixed solvent of toluene/chloroform and aqueous potassium hydroxide. The benzylation reaction proceeded quantitatively without side reactions within 11 h. After the asymmetric benzylation reaction was complete, chiral product 10 was easily obtained by extracting the mixture with dichloromethane. Since these polymeric chiral catalysts were not soluble in the mixed solvent used in the reaction, these polymers could be easily separated from the reaction mixture. When 8a was used as a polymeric chiral organocatalyst, the reaction occurred smoothly to afford 10 in 88% yield with 86% ee (entry 1). Unfortunately, the enantiomeric excess of 10 decreased to 79% when 8b,c were used (entries 2 and 3). When 8d with an ether linkage was used instead of 8a with an alkyl one, both the yield and enantioselectivity increased slightly (cf. entry 1 vs. 4).
Table
Table 2. Asymmetric benzylation of 9 using main-chain chiral quaternary ammonium polymer 8.
Table 2. Asymmetric benzylation of 9 using main-chain chiral quaternary ammonium polymer 8.
EntryCatalystR1R2Time (h)Yield (%) aee (%) b
18a Molecules 17 07569 i006 Molecules 17 07569 i007 88886
28b Molecules 17 07569 i008 Molecules 17 07569 i009 88479
38c Molecules 17 07569 i010 Molecules 17 07569 i011 88679
48d Molecules 17 07569 i012 Molecules 17 07569 i013 118987
58e Molecules 17 07569 i014 Molecules 17 07569 i015 55371
68f Molecules 17 07569 i016 Molecules 17 07569 i017 87580
78g Molecules 17 07569 i018 Molecules 17 07569 i019 118088
88h Molecules 17 07569 i020 Molecules 17 07569 i021 88588 Molecules 17 07569 i022
a Determined by 1H-NMR; b Determined by HPLC (CHIRALCEL OD-H column).
Using the ether linkage as R1, the effect of R2 on the catalytic activity was also investigated. Enantioselectivity decreased significantly with the use of m-xylene-linked 8e (entry 4 vs. 5). In contrast, naphthyl-linked 8g,h showed higher enantioselectivity, which is comparable to the corresponding dimeric catalyst 5c (entries 7 and 8). These results clearly indicated that these main-chain chiral quaternary ammonium polymers 8 showed good catalytic activity in the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester (9) and the modification of the structure of R1 and R2 in 8 is of significant importance for the design of main-chain chiral quaternary ammonium polymers as polymeric chiral catalysts. The catalytic activity of 8 was comparable to that of the other main-chain chiral quaternary ammonium polymers that were prepared by a successive etherification of cinchonidine quaternary ammonium salt dimers with dihalides [40].

3. Experimental

3.1. General

All solvents and reagents were purchased from Sigma-Aldrich, Wako Pure Chemical Industries, Ltd., or Tokyo Chemical Industry Co., Ltd. at the highest available purity and used as is, unless noted otherwise. Reactions were monitored by thin-layer chromatography (TLC) using Merck precoated silica gel plates (Merck 5554, 60F254). Column chromatography was performed on a silica gel column (Wakogel C-200, 100–200 mesh). Melting points were recorded using a Yanaco micro melting apparatus and are uncorrected. 1H- (300 MHz) and 13C-NMR (75 MHz) spectra were measured on a Varian Mercury 300 spectrometer. Peaks were referenced to the (CH3)4Si) (TMS) peak at δ = 0 (1H) or the solvent peak [i.e., the CDCl3 one at δ = 77. 1 (13C) or the DMSO ones at δ = 2.5 (1H)/39.5 (13C)]. The J values are reported in Hertz. IR spectra were recorded with a JEOL JIR-7000 FT-IR spectrometer and are reported in reciprocal centimeters (cm−1). Elemental analyses were performed at the Microanalytical Center of Kyoto University. Size exclusion chromatography (SEC) was performed with a Tosoh instrument with HLC 8020 UV (254 nm) or refractive index 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 were used. A calibration curve was made to determine number-average molecular weight (Mn) and molecular weight distribution (Mw/Mn) values with polystyrene standards. HPLC analyses were performed with a JASCO HPLC system composed of a 3-line degasser DG-980, HPLC pump PV-980, column oven CO-965, equipped with a chiral column (CHIRALCEL OD-H or OD, Daicel) using hexane/2-propanol as eluent. A UV detector (JASCO UV-975 for the JASCO HPLC system) was used for the peak detection. Optical rotations were recorded with a JASCO DIP-149 digital polarimeter using a 10 cm thermostated microcell.

3.2. Preparation of Thiolated Chiral Quaternary Ammonium Salt Dimer 5

3.2.1. Preparation of Thiolated Cinchonidine 3

A mixture of cinchonidine (1, 3.53 g, 12.0 mmol), methyl-3-mercaptopropionate (2, 2.16 g, 18.0 mmol), and AIBN (0.039 g, 0.24 mmol) was stirred at 70 °C for 30 h. After the removal of the solvent under high vacuum, the residue was washed several times with hexane. The product 3 (4.48 g, 90% yield) was used for next reaction without further purification. m.p. 142 °C; [α]D25 = −52.50 (1.0, DMSO); 1H-NMR (CDCl3, TMS): δ = 1.38–1.55 (m, 4H), 1.63 (s, 1H), 1.74–1.80 (m, 3H), 2.31–2.38 (m, 3H), 2.43–2.56 (m, 2H), 2.67–2.73 (m, 2H), 2.98–3.06 (m, 2H), 3.40–3.51 (m, 1H), 5.63–5.73 (m, 1H), 7.34–7.40 (m, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.60–7.66 (m, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.05–8.08 (m, 1H), 8.79 (d, J = 4.8 Hz, 1H); 13C-NMR (CDCl3): δ = 20.97, 25.76, 27.10, 28.02, 30.19, 34.42, 34.60, 34.67, 43.28, 51.87, 58.22, 60.27, 71.52, 118.40, 123.05, 125.64, 126.71, 129.11, 130.09, 148.04, 150.02, 172.43; IR (KBr): ν = 1,585 (C=N), 1,220 (C-N), 1,130 (C-O), 750 (C-S); Elem. Anal. calc. for C23H30N2O3S: C 66.64, H 7.29, N 6.76; found C 66.50, H 7.27, N 6.62.

3.2.2. Preparation of Thiolated Chiral Quaternary Ammonium Salt Dimer 5

A mixture of 3 (0.456 g, 1.10 mmol) and 4 (0.50 mmol) in EtOH/DMF/CHCl3 = 5:6:2 mixed solvent (3 mL) was stirred at 100 °C for 6 h. After cooling the reaction mixture to room temperature, the mixture was dissolved in MeOH (2.5 mL) and poured into Et2O (20 mL). The mixture was stirred at room temperature for 1 h and filtered. The resulting solid was washed with Et2O several times to give the product 5.
Thiolated chiral quaternary ammonium salt dimer 5a: 96% yield. m.p. 189 °C; [α]D25 = −102.63 (1.0, DMSO); 1H-NMR (DMSO-d6): δ = 1.44 (br, 3H), 1.79 (br, 1H), 2.03 (br, 4H), 2.34–2.40 (m, 2H), 2.52–2.58 (m, 2H), 3.98 (d, J = 7.2 Hz, 2H), 4.32 (br, 2H), 5.02 (d, J = 11.4 Hz, 1H), 5.30 (d, J = 12.3 Hz, 1H), 6.65 (s, 1H), 7.04 (s, 1H), 7.88 (br, 3H), 7.96–8.00 (m, 2H), 8.21–8.24 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 9.14 (d, J = 4.2 Hz, 1H); 13C-NMR (DMSO-d6): δ = 20.50, 23.39, 24.36, 25.73, 28.00, 32.19, 32.33, 33.79, 61.02, 61.63, 63.92, 67.15, 120.20, 124.09, 124.30, 126.46, 128.10, 129.40, 130.86, 133.73, 143.53, 147.75, 149.31, 171.55; IR (KBr): ν = 1,730 (-COOR), 1,633 (C=N), 1,218 (C-N), 1,040 (C-O), 759 (C-S); Elem. Anal. calc. for C54H68Br2N4O6S2: C 59.33, H 6.27, N 5.13; found C 58.49, H 6.34, N 5.14.
Thiolated chiral quaternary ammonium salt dimer 5b: 92% yield. m.p. 166 °C; [α]D25 = −215.81 (1.0, DMSO); 1H-NMR (DMSO-d6): δ = 1.19 (br, 3H), 1.43–1.51 (m, 3H), 1.86–1.96 (br, 2H), 2.18–2.25 (br, 2H), 2.40–2.44 (br, 2H), 4.48–4.55 (br, 2H), 5.93–5.98 (br, 1H), 6.36–6.55 (br, 1H), 7.11 (br, 1H), 7.72–8.04 (m, 5H), 8.14 (br, 1H), 8.25–8.33 (m, 1H), 8.79–8.84 (m, 1H), 8.97 (d, J = 7.5 Hz, 1H), 9.06–9.12 (m, 1H), 9.20 (d, J = 3.9 Hz, 1H); 13C-NMR (DMSO-d6): δ = 17.03, 21.22, 22.46, 24.04, 24.72, 25.82, 28.10, 31.96, 32.35, 32.78, 33.72, 33.83, 51.09, 54.33, 59.01, 62.02, 65.02, 65.60, 67.06, 119.02, 120.61, 123.89,124.65, 125.73, 126.29, 128.16, 131.14, 131.53, 132.52, 143.63, 147.45, 150.48, 171.53; IR (KBr): ν = 1,730 (-COOR), 1,625 (C=N), 1,215 (C-N), 1,038 (C-O), 779 (C-S); Elem. Anal. calc. C62H72Cl2N4O6S2: C 67.43, H 6.57, N 5.07; found C 65.95, H 7.03, N 4.98.
Thiolated chiral quaternary ammonium salt dimer 5c: 93% yield. m.p. 192 °C; 1H-NMR (DMSO-d6): δ = 1.46 (br, 4H), 1.72 (br, 1H), 2.05 (br, 5H), 2.37–2.41 (m, 2H), 2.57 (d, J = 6.0 Hz, 2H), 4.01 (br, 1H), 4.38 (br, 1H), 5.12 (d, J = 12.9 Hz, 1H), 5.37 (d, J = 12.9 Hz, 1H), 6.63 (s, 1H), 6.79 (s, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 3.9 Hz, 2H), 7.94 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.8 Hz, 2H), 9.01 (d, J = 3.9 Hz, 1H); 13C-NMR (DMSO-d6): δ = 20.52, 23.53, 24.54, 25.74, 28.02, 32.00, 32.47, 33.85, 50.58, 51.12, 61.19, 62.32, 63.79, 67.40, 119.97, 123.64, 124.17, 126.24, 127.05, 128.03, 129.18, 129.53, 131.48, 131.85, 134.14, 145.14, 147.33, 149.89, 171.62; IR (KBr): ν = 1,730 (-COOR), 1,617 (C=N), 1,235 (C-N), 1,022 (C-O), 777 (C-S); Elem. Anal. calc. C58H70Br2N4O6S2: C 60.94, H 6.17, N 4.90; found C 59.81, H 6.29, N 4.91.
Thiolated chiral quaternary ammonium salt dimer 5d: 96% yield. m.p. 190 °C; 1H-NMR (DMSO-d6): δ = 1.41–1.46 (m, 4H), 1.74 (br, 1H), 1.97–2.03 (br, 4H), 2.18 (br, 1H), 2.32 (d, J = 6.3 Hz, 2H), 4.26 (br, 1H), 4.41 (br, 1H), 5.37 (d, J = 12.9 Hz, 1H), 5.81 (d, J = 12.0 Hz, 1H), 6.78 (s, 1H), 6.93 (d, J = 3.9 Hz, 1H), 7.79–7.90 (m, 4H), 8.13–8.16 (m, 2H), 8.44 (d, J = 8.4 Hz, 1H), 8.64 (br, 1H), 9.03 (d, J = 4.5 Hz, 1H); 13C-NMR (DMSO-d6): δ = 20.78, 23.16, 24.53, 25.84, 28.12, 32.39, 32.61, 33.84, 50.76, 51.14, 58.74, 61.49, 64.18, 67.43, 120.11, 123.90, 124.27, 125.13, 126.97, 127.25, 128.99, 129.56, 133.37, 133.64, 146.16, 146.69, 149.56, 171.60; IR (KBr): ν = 1,730 (-COOR), 1,632 (C=N), 1,235 (C-N), 1,062 (C-O), 758 (C-S); Elem. Anal. calc. C58H70 Br2N4O6S2: C 60.94, H 6.17, N 4.90; found C 59.77, H 6.18, N 4.96.

3.3. Preparation of Main-Chain Chiral Quaternary Ammonium Polymers 8

3.3.1. Preparation of Cinchonidine Dimer 7

A mixture of cinchonidine 1 (1.18 g, 4.00 mmol), dithiol (2.00 mmol), AIBN (6.4 mg, 0.04 mmol), and CHCl3 (6 mL) was stirred at 70 °C. During the reaction AIBN (0.04 mmol) was added three times successively. The residue after the removal of solvent under high vacuum was purified by column chromatography to give the product 7.
Cinchonidine dimer 7a: 40% yield. m.p. 116 °C; [α]D25 = −59.56 (1.0, DMSO); 1H-NMR (CDCl3, TMS): δ = 1.32–1.56 (m, 5H), 1.61–1.64 (m, 4H), 1.72–1.79 (m, 3H), 2.29–2.48 (m, 6H), 2.92–3.02 (m, 2H), 3.44–3.46 (m, 1H), 5.05 (s, 1H), 5.62 (s, 1H), 7.33–7.41 (m, 1H), 7.52–7.55 (m, 1H), 7.59–7.66 (m, 1H), 7.96–7.98 (m, 1H), 7.98–8.08 (m, 1H), 8.73–8.78 (m, 1H); 13C-NMR (CDCl3): δ = 20.54, 25.55, 27.84, 28.36, 29.87, 31.57, 34.57, 43.07, 49.81, 58.08, 60.08, 71.11, 118.27, 122.91, 125.46, 126.52, 128.94, 129.65, 147.65, 149.65, 150.40; IR (KBr): ν = 1,580 (C=N), 1,225 (C-N), 1,120 (C-O), 755 (C-S); Elem. Anal. calc. C42H54N4O2S2: C 70.95, H 7.65, N 7.88; found C 70.39, H 8.01, N 7.71.
Cinchonidine dimer 7b: 37% yield (for 70 h). m.p. 109 °C; [α]D25 = −52.57 (1.0, DMSO); 1H-NMR (CDCl3, TMS): δ = 1.37–1.49 (br, 4H), 1.58–1.76 (br, 5H), 2.30–2.42 (m, 4H), 2.54–2.58 (m, 2H), 2.91–3.02 (m, 2H), 3.46–3.52 (m, 4H), 5.35 (s, 1H), 5.65 (s, 1H), 7.35–7.40 (m, 1H), 7.54 (d, J = 4.2, 1H), 7.61–7.66 (m, 1H), 7.99–8.07 (m, 2H), 8.72 (d, J = 4.5, 1H); 13C-NMR (CDCl3): δ = 20.89, 25.64, 28.02, 30.63, 31.61, 34.61, 38.56, 43.23, 58.23, 60.24, 69.22, 70.76, 70.86, 71.40, 118.42, 123.04, 125.66, 126.74, 129.14, 129.98, 147.93, 149.90, 150.28; IR (KBr): ν = 1,590 (C=N), 1,235 (C-N), 1,100 (C-O), 760 (C-S); Elem. Anal. calc. C42H54N4O3S2: C 69.38, H 7.49, N 7.71; found C 69.02, H 7.70, N 7.61.

3.3.2. Preparation of Main-Chain Chiral Quaternary Ammonium Polymers 8

A mixture of cinchonidine dimer 7 (0.500 mmol), dihalide 4 (0.500 mmol) in DMSO (2 mL) was stirred at 90 °C for 10 h. The residue after the removal of solvent under high vacuum was dissolved in MeOH (5 mL) and poured into Et2O (120 mL). After the filtration of the mixture, the solid was washed with hexane and ethyl acetate, and was dried under high vacuum to give the polymer 8.
Main-chain chiral quaternary ammonium polymers 8a: 88% yield. [α]D25 = −117.1 (1.0, DMSO); Mn(SEC) = 3.1 kg/mol; Elem. Anal. calc. C50H62Br2N4O2S2: C 61.59, H 6.41, N 5.75; found C 61.56, H 6.42, N 5.75.
Main-chain chiral quaternary ammonium polymers 8b: 84% yield. Mn(SEC) = 2.8 kg/mol; Elem. Anal. calc. C70H64Cl2N4O2S2: C 70.64, H 6.75, N 5.68; found C 69.93, H 6.75, N 5.68.
Main-chain chiral quaternary ammonium polymers 8c: 93% yield. [α]D25 = −146.22 (1.0, DMSO); Mn(SEC) = 3.6 kg/mol; Elem. Anal. calc. C54H64Br2N4O2S2: C 63.27, H 6.29, N 5.47; found C 62.47, H 6.62, N 5.46.
Main-chain chiral quaternary ammonium polymers 8d: 96% yield. [α]D25 = −120.1 (1.0, DMSO); Mn(SEC) = 10.8 kg/mol; Elem. Anal. calc. C50H62Br2N4O3S2: C 60.60, H 6.31, N 5.65; found C 60.78, H 6.23, N 5.62.
Main-chain chiral quaternary ammonium polymers 8e: 96% yield. [α]D25 = −131.24 (1.0, DMSO); Mn(SEC) = 6.8 kg/mol; Elem. Anal. calc. C50H62Br2N4O3S2: C 60.60, H 6.31, N 5.65; found C 61.10, H 6.21, N 5.61.
Main-chain chiral quaternary ammonium polymers 8f: 67% yield. Mn(SEC) = 2.8 kg/mol; Elem. Anal. calc. C58H66Cl2N4O3S2: C 69.51, H 6.64, N 5.59; found C 70.54, H 6.54, N 5.53.
Main-chain chiral quaternary ammonium polymers 8g: 90% yield. [α]D25 = −135.48 (1.0, DMSO); Mn(SEC) = 3.7 kg/mol; Elem. Anal. calc. C54H64Br2N4O3S2: C 62.30, H 6.20, N 5.38; found C 62.43, H 6.22, N 5.48.
Main-chain chiral quaternary ammonium polymers 8h: 96% yield. [α]D25 = −139.7 (1.0, DMSO); Mn(SEC) = 4.3 kg/mol; Elem. Anal. calc. C54H64Br2N4O3S2: C 62.30, H 6.20, N 5.38; found C 62.23, H 6.22, N 5.39.

3.4. General Procedure for Asymmetric Benzylation of N-(Diphenylmethylidene)glycine tert-butyl Ester 9 Catalyzed by Main-Chain Chiral Quaternary Ammonium Polymers 8

Main-chain chiral quaternary ammonium polymer 8 (0.018 mmol) and N-(diphenyl-methylidene)glycine tert-butyl ester (9, 0.053 g, 0.180 mmol) were added into a mixed solvent of toluene (7 mL) and chloroform (3 mL). 50 wt% aqueous KOH solution (2.5 mL) was added to the above mixture. Benzyl bromide (0.037 g, 0.216 mmol) was then added dropwise at 0 °C to the mixture. The reaction mixture was stirred vigorously at 0 °C. The reaction was monitored by TLC. After completion of the reaction, 10 mL of saturated sodium chloride solution was added, and the mixture was subsequently filtered to recover 8, which was washed with water and dichloromethane several times. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were washed with brine and dried over MgSO4. Evaporation of solvents and purification of the residual oil by column chromatography on silica gel (diethyl ether:hexane = 1:10 as eluent) gave (S)-phenylalanine derivative 10. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralcel OD-H, hexane/2-propanol = 100:1, flow rate = 0.3 mL/min, retention time: R enantiomer = 27.6 min, S enantiomer = 47.9 min). The absolute configuration was determined by comparison of the HPLC retention time with the authentic sample independently synthesized by the reported procedure [6].

4. Conclusions

We have designed novel main-chain chiral quaternary ammonium salt polymers using thiol-ene click reaction followed by quaternization polymerization. The resulting main-chain chiral quaternary ammonium salt polymers have successfully been applied as polymeric chiral organocatalysts for the asymmetric benzylation of glycine derivatives. Thiolinked cinchonidine dimer could be synthesized by the thiol-ene click reaction of cinchonidine with dithiol. The quaternization polymerization with dihalide proceeded smoothly without side reactions to afford main-chain chiral quaternary ammonium salt polymers. We found that these main-chain chiral quaternary ammonium polymers showed good catalytic activity in the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester. Furthermore, the modification of the structure of R1 and R2 in 8 was significantly important for the design of main-chain chiral quaternary ammonium polymers as polymeric chiral catalysts. The effect of hydroxyl group functionalization and the reusability of the main-chain chiral quaternary ammonium salt polymers are now under investigation.

Acknowledgments

This work was partially supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” (No. 24105514) and by a Grant-in-Aid for Scientific Research on Innovative Areas “Molecular Activation Directed toward Straightforward Synthesis” (No. 2335003) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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  • Sample Availability: Samples of the compounds of are available from the authors.

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Haraguchi, N.; Ahamed, P.; Parvez, M.M.; Itsuno, S. Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers for Asymmetric Catalysis Using Quaternization Polymerization. Molecules 2012, 17, 7569-7583. https://doi.org/10.3390/molecules17067569

AMA Style

Haraguchi N, Ahamed P, Parvez MM, Itsuno S. Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers for Asymmetric Catalysis Using Quaternization Polymerization. Molecules. 2012; 17(6):7569-7583. https://doi.org/10.3390/molecules17067569

Chicago/Turabian Style

Haraguchi, Naoki, Parbhej Ahamed, Md. Masud Parvez, and Shinichi Itsuno. 2012. "Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers for Asymmetric Catalysis Using Quaternization Polymerization" Molecules 17, no. 6: 7569-7583. https://doi.org/10.3390/molecules17067569

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