(L)-Prolinamide imidazolium hexafluorophosphate ionic liquid as an efficient reusable organocatalyst for direct asymmetric aldol reaction in solvent-free condition

Abstract

We have designed a new hydrophobic ionic liquid derived from bromoester of trans-4-hydroxy-(L)-prolinamide and N-methylimidazole. (L)-Prolinamide imidazolium hexafluorophosphate ionic liquid (2 mol%) found to be an excellent organocatalyst for direct asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone using acetic acid (2 mol%) as an additive at −15 °C in solvent-free condition, the aldol product was afforded in excellent yield with diastereomeric ratio (anti/syn; 97 : 3) and 94% ee of anti-aldol product. Ionic liquids can catalyze the direct aldol reaction between benzaldehyde derivatives and cycloalkanones and the best dr (anti/syn; 99.9/0.01) and 99% ee was obtained for aldol product of 2-trifluoromethyl benzaldehyde and cyclohexanone. (L)-Prolinamide imidazolium hexafluorophosphate ionic liquid was reused up to 6 continuous cycles without decrease in the conversion of the product with 92% ee and found to be superior than its counterpart trans-4-hydroxy-(L)-prolinamide. Continuous cycle experiments do not require isolation of the catalyst after each cycle. The results of reusability of the ionic liquid catalyst were found to be better than most of other reported reusable catalysts.

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Introduction

The aldol reaction is recognized as one of the most powerful carbon–carbon bond-forming reactions in modern organic synthesis. It provides an atom-economic approach to β-hydroxyl carbonyls, which make up a large family of chiral intermediates for the synthesis of biologically active substances and natural products.¹ Since the early reports in the 1970s that the L-proline catalysed intramolecular aldol reactions^2a,b later the pioneering work by List et al. in 2000.^2c,d After these reports numerous proline-derived organocatalysts such as proline analogues,³ acyclic amino acids,⁴ different types of prolinamides,^5–13 prolinethioamides,¹⁴ sulfonamides,¹⁵ chiral amines,¹⁶ organic salts¹⁷ were exploited as organocatalysts for direct asymmetric aldol reaction. The organocatalyst is usually used for direct asymmetric aldol reaction in a substantial quantity, in some cases up to 30 mol%, its recovery and reuse is vital for reduce the cost and to facilitate the separation of the product from the catalyst. Several research groups are attentive to develop a recoverable organocatalysts for direct asymmetric aldol reaction.¹⁸ Immobilization of modified proline derivatives are desirable due to their non-commercial viability and their high reactivity.

In our ongoing research on development of organocatalyst for asymmetric Diels–Alder reaction and direct asymmetric aldol reaction.¹⁹ We recently reported the trans-4-hydroxy-(L)-prolinamide (1) as organocatalyst for aldol reaction between aromatic aldehydes and cycloalkanes under solvent free conditions.²⁰ Herein, we wish to report synthesis of imidazolium ionic liquids from bromoester of trans-4-hydroxy-(L)-prolinamide and N-methylimidazole and their catalytic activity in direct asymmetric aldol reaction (Fig. 1).

Fig. 1 Prolinamide catalysts for direct asymmetric aldol reaction.

Results and discussion

Prolinamide imidazolium ionic liquids 2 and 3 were synthesized according to Scheme 1. First, trans-4-hydroxy-(S)-proline 4 was protected as N-boc protecting group in quantitative yield. N-Boc-trans-4-hydroxy-(S)-proline 5 was treated with (S)-1-phenylethylamine, in presence of triethylamine and ethylchloroformate, gave corresponding N-boc-prolinamide 6 in 81% yield. The esterification of compound 6 with 5-bromovaleric acid in the presence of DCC and DMAP in dichloromethane gave the product 7 in a 94% yield. The compound 8 was synthesised by the reaction of N-methyl imidazole and compound 7, which affords N-boc protected imidazolium bromide 8 in 97% yield. The bromide anion of the ionic liquid 8 was exchanged by KPF₆ to hexafluorophosphate anion in 86% yield. Deprotection of N-boc group in compounds 8 and 9 by TFA in dichloromethane at room temperature gave ionic liquid (IL) 2 and 3.

Scheme 1 Synthesis of ionic liquids (IL) 2 and 3.

In our initial investigation, the direct asymmetric aldol reaction between 4-nitrobenzaldehyde 10 and cyclohexanone using ionic liquid 3 (10 mol%) and acetic acid (10 mol%) as additives at room temperature gave >99% conversion and 29% enantiomeric excess (ee) of product anti 11 with poor diastereoselectivity (Table 1, entry 1). Decreasing of the reaction temperature to −15 °C, improved the diastereomeric ratio (dr; anti/syn; 94 : 6) and ee (96%) of the product anti-11 (Table 1, entry 2). We also varied the catalyst loading and even though at low catalyst loading (2 mol%) with additive acetic acid (2 mol%), product anti-11 was obtained in excellent yield with 94% ee and dr (anti/syn; 97 : 3) after 24 h (Table 1, entry 3 and 4). We also compared the catalytic result with organocatalyst 1 with ionic liquid 3 (IL 3) under identical conditions and the organocatalyst 1 was found to be more reactive but better ee for product anti-11 was observed with IL 3 (Table 1, entry 5). IL 2 gave the aldol product in poor yield (39%) with 76% ee of anti-11 (Table 1, entry 6).

Table 1 Optimization of reaction conditions for direct asymmetric aldol reaction^a

Entry	Organocatalyst	Catalyst loading (mol%)	Time (h)	Yield^b (%)	dr (anti : syn)^c	ee (%) (anti)^d
a Organocatalyst (2–10 mol%), CH3COOH (2–10 mol%), cyclohexanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at −15 °C for specified time.b Conversion was determined by HPLC using response factor for 4-nitrobenzaldehyde 10 and product 11.c Diastereomeric ratio (dr) (anti/syn) and enantiomeric excess (ee) were determined by HPLC using Chiralpak AD-H column.d The absolute configuration was determined by comparing the specific rotation of product anti-11 with literature values and found to be (1′S,2R).e Reaction carried out at room temperature.
1	3	10	6	>99	59 : 41	29^e
2	3	10	12	>99	94 : 6	96
3	3	5	12	>99	96 : 4	91
4	3	2	24	99	97 : 3	94
5	1	2	8	>99	93 : 7	92
6	2	2	24	39	85 : 15	76

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We also compared our organocatalyst IL 3 with other reusable organocatalysts reported in literature for the direct asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone are shown in ESI Table 1.† The results show that IL 3 was found to be better catalyst in terms of catalyst loading and turnover frequency than the most of the reported reusable catalysts.

We have investigated the asymmetric direct aldol reaction between substituted benzaldehydes and cyclohexanone catalyzed by IL 3 (2 mol%) and additive CH₃COOH (2 mol%) at −15 °C in solvent-free conditions. All the benzaldehyde derivatives gave the anti diastereomer as major product. Benzaldehyde afforded aldol product in a 60% yield with diastereomeric ratio of anti : syn (91/9) with 98% ee of anti diastereomer and bulkier naphthaldehyde improved the anti : syn ratio but ee was slightly decreased (Table 2, entry 1 and 2). Electron withdrawing group (EWG) such as nitro on benzaldehyde improved the reactivity and 2-nitrobenzaldehyde gave 97% ee (Table 2, entry 3). 4-Halogenated benzaldehydes were found to be less reactive with excellent ee and dr. The order of reactivity of 4-halogenated benzaldehydes (F < Cl < Br) was increasing when electronegativity of halogen is decreasing due to enhancement of electrophilicity of carbonyl carbon of halobenzaldehydes (Table 2, entries 5, 7, and 9). 2-Halobenzaldehydes gave the corresponding aldol products in 88–90% yields and 91–97% ee (Table 2, entries 4, 6, and 8). Electron donating group (EDG) like methoxy on benzaldehyde, found to be less reactive compared to derivatives of EWG. The EWG's enhance the electrophilicity of carbonyl carbons in aldehydes which facilitate the reaction, while EDG's lessen the electrophilicity of carbonyl carbons. 4-Methoxybenzaldehyde was found to be least active and afforded only 5% of the product but by increasing the catalyst loading was increased to 5 mol% and 25% yield of the product was obtained (Table 2, entries 11 and 12). In case of 2-(trifluoromethyl)benzaldehyde, exclusively afforded anti product in 99% ee (Table 2, entry 13).

Table 2 Aldol reaction of cyclohexanones with substituted benzaldehydes catalysed by IL 3^a

Entry	Ar	Time [h]	Yield^b (%)	dr (anti : syn)^c	ee (%) (anti)^d
a IL 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclohexanone (3 mmol) and substituted benzaldehyde (1 mmol) were stirred at −15 °C for specified time.b Isolated yield after purification by column chromatography.c Diastereomeric ratios (dr) were determined by ^1H-NMR of crude products.d Enantiomeric excess (ee) was determined by HPLC using Chiralpak AD-H and Chiralcel OD-H columns.e 5 mol% catalyst was used.
1	Phenyl	24	60	91 : 9	98
2	1-Naphthyl	48	25	98 : 2	93
3	2-NO2C6H4	17	87	96 : 4	97
4	2-FC6H4	18	88	97 : 3	91
5	4-FC6H4	24	49	98 : 2	93
6	2-ClC6H4	18	90	95 : 5	97
7	4-ClC6H4	26	74	98 : 2	97
8	2-BrC6H4	18	90	97 : 3	97
9	4-BrC6H4	26	84	97 : 3	98
10	2-OMeC6H4	40	23	99 : 1	91
11	4-OMeC6H4	48	5	63 : 37	ND
12	4-OMeC6H4	48	25	99.8 : 0.2	52^e
13	2-CF3C6H4	17	69	100 : 0	99
14	4-CF3C6H4	17	87	97 : 3	91

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We have also studied the direct asymmetric aldol reaction between 2- and 4-substituted benzaldehydes with cyclopetanone catalyzed by IL 3 (2 mol%) at −15 °C in solvent-free conditions (Table 3). The reactivity of benzaldehydes having EWG's was faster than the EDG's. In case of 4-substituted benzaldehydes anti aldol products were obtained as major diastereomers while syn diastereomers were obtained with 2-substituted benzaldehydes except 2-nitrobenzaldehyde (Table 3, entries 1–8). The better ee was obtained for anti diastereomers of the aldol products than syn diastereomers. The reactivity of 4-methoxy was found to be poor and but by increasing the catalyst loading to 5 mol% increased the yield (Table 3, entries 8 and 9).

Table 3 Aldol reaction of cyclopentanone with substituted benzaldehydes catalysed by IL 3^a

Entry	Ar	Time (h)	Yield^b (%)	dr (anti : syn)^c	ee (%) (anti/syn)^d
a IL 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclopentanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at −15 °C for specified time.b Isolated yield after purification by column chromatography.c Diastereomeric ratios were determined by ^1H-NMR of crude products.d The ee was determined by HPLC using Chiralpak AD-H, and Chiralcel OD-H columns.e Reaction carried out using 5 mol% of the catalyst.
1	2-NO2C6H4	30	71	55 : 45	99/28
2	4-NO2C6H4	30	66	50 : 50	66/40
3	2-FC6H4	40	76	43 : 57	81/26
4	4-FC6H4	40	69	72 : 28	82/20
5	2-ClC6H4	38	37	40 : 60	99/45
6	4-ClC6H4	38	72	54 : 46	84/26
7	2-OMeC6H4	48	33	21 : 79	97/33
8	4-OMeC6H4	48	7	72 : 28	70/20
9	4-OMeC6H4	44	64	44 : 56	81/8^e

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The reusability performance of the IL 3 (2 mol%) was carried out for the asymmetric aldol reaction of 4-nitrobenzaldehyde 10 (1 mmol) and cyclohexanone (3 mmol) using acetic acid (2 mol%) as additive at −15 °C (Table 4). The reaction was monitored on TLC and HPLC, after complete conversion of 4-nitrobenzaldehyde 10, 4-nitrobenzaldehyde 10 (1 mmol) and cyclohexanone (3 mmol) were added to the reaction mixture without any additive and catalyst. This procedure was repeated for 6 continuous cycles and afforded aldol products in overall >99% conversion of the product with anti/syn 96 : 4 with 92% ee of product 11-anti and total turnover number (TON) of the catalyst was found to be more than 346 (Table 4, entry 7 and Fig. 2). The advantages of continuous cycle for the reuse of the catalyst are: (i) IL 3 and catalytic product of the aldol reaction are polar so it's difficult to separate catalyst from the product by using the different solvents therefore use of continuous cycle is beneficial, (ii) it enhances economic viability of the process because it does not require separation of the catalyst after completion of each cycle which save the cost of the manpower and solvents and (iii) the product is stable during the reaction even though we are stirring the reaction up to 7 cycles. Similar strategy was used by List and co-workers in cyanosilylation of aldehydes.²⁰ We also compared the catalysis of IL 3 in low loading (0.4 mol%) in identical reaction conditions and afforded product in >99% yield and anti/syn 95 : 5 with 85% ee of product 11-anti after 4.5 days and these results are found to be poor in terms of ee than the continuous use of the IL 3. We also conducted the aldol reaction using catalyst 1 (2 mol%) under identical conditions to compare the reusability in continuous cycle. Catalyst 1 afforded the desired product anti-11 in 97% yield and 96% ee but reaction took 65 h for completion of a 4^th continuous cycle. The overall TON and TOF was found to be better for the catalyst 3 compared to the catalyst 1. The hydrophobic nature of the ionic liquid unit of the catalyst 3 maintains the catalytic activity at dilution of the catalyst concentration in continuous cycle.

Table 4 Reusability of IL 3 in continuous cycle for asymmetric aldol reaction^a

Cycle	Time (h)	Conversion^b (%)	dr (anti : syn)^c	ee (%) (anti)^c^,^d
a Catalyst 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclopentanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at −15 °C for specified time.b Conversion was determined by HPLC using response factor for 4-nitrobenzaldehyde 10 and product 11.c Diastereomeric ratio (dr) and enantiomeric excess (ee) were determined by HPLC using Chiralpak AD-H column.d The absolute configuration was determined by comparing optical rotation of product 11-anti with literature and found to be (1′S,2R).e Results in parenthesis are for catalyst 1 under identical reaction conditions.f Turn over frequency (TOF) for catalyst 3 = 2.22 h^−1 and for catalyst 1 = 1.34 h^−1; turn over number (TON) for catalyst 3 = 346 and for catalyst 1 = 194.5.
1	20 (8)^e	>99 (>99)	97 : 3 (93 : 7)	88 (92)
2	20 (24)	>99 (96)	91 : 9 (95 : 5)	88 (93)
3	20 (48)	>99 (96)	95 : 5 (96 : 4)	93 (96)
4	24 (65)^f	>99 (97)	96 : 4 (96 : 4)	92 (96)
5	24	>99	96 : 4	92
6	24	>99	96 : 4	92
7	24^f	>99	96 : 4	92

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Fig. 2 Reusability of IL 3 in continuous cycle.

Experimental section

General

Benzaldehyde derivatives, cyclohexanone and cyclopentanone were purchased from commercial source and used as such. Proton and carbon nuclear magnetic resonance spectra (¹H and ¹³C NMR, respectively) were recorded on 400 MHz (operating frequencies: ¹H, 400.13 MHz; ¹³C, 100.61 MHz) Jeol-FT-NMR spectrometers at ambient temperature. The chemical shifts (δ) for all compounds are listed in parts per million (ppm) downfield from tetramethylsilane using the NMR solvent as an internal reference. The reference values used for deuterated chloroform (CDCl₃) were 7.26 and 77.00 ppm for ¹H and ¹³C NMR spectra, respectively. HRMS analysis was carried out using QSTAR XL Pro system microTOF-Q-II. The reaction was monitored by thin layer chromatography was carried out using Merck Kieselgel 60 F254 silica gel plates. Compounds were purified by column chromatography separations were performed using silica gel 230–400 mesh. The enantiomeric excess was determined on Shimadzu LC-2010HT using Chiralcel OD-H, and Chiralpak AD-H columns. Infrared spectra were recorded on a Perkin-Elmer FT-IR spectrometer. Optical rotations were taken using Rudolph digipol polarimeter. (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5) and (2S,4R)-tert-butyl-4-hydroxy-2-((S)-1-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (6) were synthesised according to our earlier report.^19a All the unknown compounds were characterized by ¹H, ¹³C NMR and HRMS. Aldol products were characterized by ¹H-NMR and compared with our earlier report.^19a Copy of ¹H-NMR, ¹³C-NMR and HPLC chromatogram are given in ESI.†

(2S,4R)-tert-Butyl-2-((S)-1-phenylethylcarbamoyl)-4-(5-bromopentanoyloxy)pyrrolidine-1-carboxylate (7). 5-Bromovaleric acid (0.712 g, 3.94 mmol) was added to a solution of DCC (0.812 g, 3.94 mmol) and DMAP (0.0356 g, 0.292 mmol) in CH₂Cl₂ (24 mL) at 0 °C and compound 6 (1.02 g, 3.07 mmol) was added in 10 min. The reaction mixture was stirred at 0 °C for 1 h. The reaction progress was monitored by TLC. The combined organic washings were evaporated, the residue was purified by column chromatography on silica gel (eluent: EtOAc/hexane 8/2) to afford the ester 7 as colourless liquid. Yield 1.52 g (94%); [α]²⁵_D = −55.1 (c 1.2, CHCl₃); IR (KBr): 3297, 2975, 1735, 1698, 1405, 1163 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.19 (m, 5H), 5.20–5.17 (m, 1H), 5.09–4.96 (m, 1H), 4.27 (t, J = 7.63 Hz, 1H), 3.58–3.48 (m, 1H), 3.34 (t, J = 6.10 Hz, 2H), 2.48 (t, J = 6.87 Hz, 1H), 2.27 (t, J = 7.63 Hz, 2H), 1.86–1.68 (m, 6H), 1.42 (s, 9H), 1.33–1.20 (m, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.75, 170.21, 154.89, 142.70, 127.91 (2C), 126.38, 125.27 (2C), 80.07, 72.30, 68.79, 59.69, 57.74, 51.76, 48.21, 32.56, 32.46, 31.25, 27.66, 22.77 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₄BrN₂O₅: 497.1651; found: 497.1661.

(2S,4R)-tert-Butyl-2-((S)-1-phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine-1-carboxylate (1-methyl-1H-imidazol-3-ium)bromide (8). A mixture of ester 7 (3.04 g, 6.14 mmol) and 1-methyl-1H-imidazole (2.28 g, 27.8 mmol) was heated at 80 °C for 10 min, cooled to r.t. and washed thoroughly with Et₂O (5 × 40 mL). The residue was dissolved in MeOH (6 mL), then Et₂O (60 mL) was added to the solution. The separated oil was dried under reduced pressure for 1 h to afford bromide 8 as colourless liquid. Yield 3.44 g (97%); [α]²⁰_D = −69.6 (c 0.6, CHCl₃); IR (KBr): 3302, 2927, 1728, 1691, 1408, 1053, 842 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 10.33 (brs, 1H), 7.43 (s, 1H), 7.33–7.16 (m, 7H), 5.17–5.13 (m, 1H), 5.07–4.95 (m, 1H), 4.43 (t, J = 7.63 Hz, 2H), 4.38–4.28 (m, 1H), 4.01 (s, 3H), 3.70–3.49 (m, 2H), 2.53–2.33 (m, 4H), 1.93 (quin, J = 7.63 Hz, 2H), 1.62 (quin, J = 6.87 Hz, 2H), 140 (s, 9H), 1.35–1.31 (m, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.14, 170.92, 154.38, 143.57, 137.06, 128.33 (2C), 126.28, 125.95 (2C), 123.32, 122.23, 80.52, 72.50, 58.88, 52.07, 52.07, 49.35, 48.83, 36.43, 33.09, 29.29, 28.10, 22.17, 21.13 ppm. HRMS (ESI): m/z [M]⁺ calcd for C₂₇H₃₉N₄O₅⁺: 499.2915; found: 499.2916.

(2S,4R)-tert-Butyl-2-((S)-1-phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine-1-carboxylate (1-methyl-1H-imidazol-3-ium)hexafluorophosphate (9). A solution of KPF₆ (552 mg, 3 mmol) in water (3 mL) was added to a stirred solution of bromide 8 (1.73 g, 3.0 mmol) in water (9 mL). The precipitate was filtered off, washed with water (3 × 9 mL) and dried under reduced pressure (0.5 Torr) for 1 h to afford hexafluorophosphate 9 as colourless solid. Yield 1.66 g (86%); [α]²⁵_D = −39.7 (c 1.5, CHCl₃); IR (KBr): 3294, 2931, 1727, 1655, 1449, 1199, 841 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 8.44 (s, 1H), 7.26–7.15 (m, 8H), 5.17–5.12 (m, 1H), 5.02–4.91 (m, 1H), 4.33–4.24 (m, 1H), 4.05 (t, J = 7.63 Hz, 2H), 3.77 (s, 3H), 3.67–3.39 (m, 2H), 2.28–2.26 (m, 3H), 1.85–1.80 (m, 3H), 1.54 (t, J = 7.63 Hz, 2H), 1.40 (s, 9H), 1.35–1.31 (m, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.26, 171.14, 154.24, 143.43, 135.56, 128.34 (2C), 126.91, 125.71 (2C), 123.44, 122.05, 80.61, 72.51, 59.02, 53.36, 49.17, 48.71, 36.47, 35.80, 34.07, 32.83, 27.92, 21.89, 20.81 ppm. ¹⁹F NMR (376 MHz): δ = −71.63 (d, J_P–F = 710.62 Hz) ppm; ³¹P NMR (161 MHz): δ = −143.64 (heptet, J_P–F = 715.50 Hz) ppm. HRMS (ESI): m/z [M]⁺ calcd for C₂₇H₃₉N₄O₅⁺: 499.2915; found: 499.2917.

(2S,4R)-2-((S)-1-Phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine(1-methyl-1H-imidazol-3-ium)bromide (2)^19a. The bromide 8 (1.79 g, 3.1 mmol) was dissolved in dry dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was added, then stirred at room temperature for 6 h. Reaction mixture was concentrated in vacuo, dissolved in H₂O (10 mL), and the pH was adjusted to ∼8 by adding 10% NaOH. The product was then extracted with dichloromethane (3 × 10 mL), dried over MgSO₄, and concentrated in vacuo yielding hydroscopic colourless liquid (2). Yield 1.48 g (87%); [α]²⁵_D = −18.6 (c 1.8, CH₃OH); IR (KBr): 3419, 2924, 1684, 1457, 1052, 842 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 9.73 (brs, 1H), 9.42 (s, 1H), 7.35–7.32 (m, 7H), 5.23–5.12 (m, 1H), 4.91–4.71 (m, 2H), 4.20–4.15 (m, 2H), 3.88 (s, 3H), 3.56–3.40 (m, 2H), 2.35–2.28 (m, 2H), 2.10–2.03 (m, 1H), 1.86–1.78 (m, 3H), 1.66–1.54 (m, 2H), 1.39 (d, J = 6.87 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.32, 165.90, 143.50, 137.02, 128.01 (2C), 126.52, 125.39 (2C), 123.00, 121.83, 72.79, 57.93, 51.74, 50.61, 49.39, 48.75, 35.69, 32.75, 28.67, 21.88, 20.47 ppm. HRMS (ESI): m/z [M]⁺ calcd for C₂₂H₃₁N₄O₃⁺: 399.2391; found: 399.2385.

(2S,4R)-2-((S)-1-Phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine(1-methyl-1H-imidazol-3-ium)hexafluorophosphate (3)^19a. The compound 9 (1.35 g, 2.1 mmol) was dissolved in dry dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) was added, then stirred at room temperature for 6 h. Reaction mixture was concentrated in vacuo, dissolved in H₂O (10 mL), and the pH was adjusted to ∼8 by adding 10% NaOH. The product was then extracted with dichloromethane (3 × 10 mL), dried over MgSO₄, and concentrated in vacuo yielding hydroscopic colourless liquid (3). Yield 0.969 g (85%); [α]²⁵_D = −72.1 (c 0.69, CH₃OH); IR (KBr): 3436, 2927, 1677, 1046, 841 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 9.17–9.15 (bs, 2H), 7.76 (d, J = 1.53 Hz, 1H), 7.03 (s, 1H), 7.33–7.21 (m, 5H), 5.24 (t, J = 4.20 Hz, 1H), 4.93 (quintet, J = 7.63 Hz, 1H), 4.41 (m, 1H), 4.17 (t, J = 7.63 Hz, 2H), 3.84 (s, 3H), 3.56–3.52 (m, 1H), 3.38–3.31 (m, 1H), 2.54–2.49 (m, 1H), 2.34 (t, J = 7.63 Hz, 2H), 2.03–1.96 (m, 1H), 1.80 (quintet, J = 7.63 Hz, 2H), 1.49 (quintet, J = 7.63 Hz, 2H), 1.38 (d, J = 7.63 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.04, 166.19, 144.05 (CH), 136.69 (CH), 128.48 (2 × CH), 126.96 (CH), 125.77 (2 × CH), 123.72 (CH), 122.33 (CH), 73.07 (CH), 58.03 (CH), 50.62 (CH₂), 48.77 (CH), 48.46 (CH₂), 35.77 (CH₃), 35.51 (CH₂), 32.57 (CH₂), 28.79 (CH₂), 22.46 (CH₃), 20.70 (CH₂) ppm. ¹⁹F NMR (376 MHz): δ = −72.30 (d, J_P–F = 710.34 Hz) ppm; ³¹P NMR (161 MHz): δ = −144.12 (heptet, J_P–F = 708.44 Hz) ppm. HRMS (ESI): m/z [M]⁺ calcd for C₂₂H₃₁N₄O₃⁺: 399.2391; found: 399.2390.

General procedure for asymmetric aldol reaction

The organocatalyst (IL 3) (10.8 mg, 0.02 mmol), cyclohexanone (0.310 mL, 3 mmol) and acetic acid (1.1 μL, 0.02 mmol) was stirred for 20 min at −15 °C, then 4-nitrobenzaldehyde 10 (151 mg, 1 mmol) was added. The reaction mixture was stirred for a specified reaction time period at same temperature. The crude aldol product was purified by flash column chromatography on silica gel (hexane/ethyl acetate (3/1)). The diastereomeric ratio was determined by ¹H-NMR of the crude product. The ee of the aldol product was determined by HPLC using chiral column (Chiralpak AD-H and OD-H) using hexane/2-propanol as mobile phase.

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone (11)^19a. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.84 (dd, J = 7.60, 3.2 Hz, 1H), 4.12 (s, OH, 1H), 2.64–2.52 (m, 1H), 2.48–2.41 (m, 1H), 2.34–2.26 (m, 1H), 2.08–2.02 (m, 1H), 1.81–1.78 (m, 1H), 1.66–1.45 (m, 3H), 1.36–1.26 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 214.93, 148.49, 147.68, 127.88 (2C), 123.44 (2C), 73.97, 57.20, 42.66, 30.75, 27.71, 24.69 ppm. HPLC analysis: Chiralpak AD-H (hexane/i-PrOH = 90/10, 1.0 mL min⁻¹, 254 nm, 25 °C): t_minor = 22.6 min, t_major = 30.9 min, ee: 94%.

Conclusions

In summary, we designed a new, efficient, and reusable organocatalyst for the direct asymmetric aldol reaction. IL 3 was synthesised in 55% of overall yield in 6 steps. Only 2 mol% of hydrophobic IL 3 was efficiently catalysed the reaction at −15 °C in solvent-free conditions. The scope and limitations of the catalyst was investigated for the reaction between benzaldehyde derivatives and cycloalkanes, gave corresponding aldol products in 25–90% yields with up to 99% ee of anti diastereomer. Poor yield of the aldol product was obtained with methoxy-benzaldehyde which can be improved by increasing the catalyst loading. The isolation of the product from the catalyst is difficult by precipitation for this reaction. We have used alternative method for resuse of organocatalyst (IL 3) and the catalyst was successfully reused up to 6 continuous cycles with excellent yields of the aldol product with 92% ee and shown better activity in continuous cycles compared to the trans-4-hydroxy-(L)-prolinamide (1).

Acknowledgements

SS acknowledges the financial assistance from Science and Engineering Research Board (SERB), Department of Science and technology (DST), India, under scheme Fast Track Young Scientist (SB/FT/CS-020/2012). We are also thankful to University Science Instrumentation Center (USIC), University of Delhi, India, for analytical data. Authors are thankful to DU-DST mass facility at USIC. GDY is thankful to CSIR for providing Senior Research Fellowship (SRF).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra23652a

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