Enantioselective synthesis of pyrazolone derivatives catalysed by a chiral squaramide catalyst

Abstract

An efficient chiral squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to β,γ-unsaturated α-ketoesters has been developed. The chiral pyrazolone derivatives were obtained in moderate to high yields (up to 99% yield) with high enantioselectivities (up to 96% ee) for most substrates. This catalytic asymmetric reaction provides valuable and easy access to chiral pyrazolone ketoester derivatives.

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Introduction

Pyrazoles and pyrazolones, both five-membered heterocyclic compounds containing two adjacent nitrogen atoms, have been widely used in organic synthesis and pharmaceutical chemistry.¹ Pyrazolone derivatives were used to synthesize many drugs such as complexes of aminoantipyrine with barbiturate which have different applications under the trade names allonal, veramon, novalgin, phenazone, propylphenazon and dimethylaminophenazone.² For example, edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, also known as MCI-186) has been reported to be effective for brain ischemia,³ and myocardial ischemia.⁴ Owing to the broad biological activities and extensive application of pyrazolone compounds, the development of asymmetric methods for synthesis of chiral pyrazolone derivatives is of considerable interest.

There have been an increasing number of reports about the asymmetric synthesis of pyrazole and pyrazolone derivatives in recent years.^2,5 We are not aware of any reports about the asymmetric addition of pyrazolones to β,γ-unsaturated α-ketoesters. β,γ-Unsaturated α-ketoesters has been recognized as a useful reaction components in organic synthesis.⁶ Because of the reported unique feature of β,γ-unsaturated α-ketoesters, which have two adjacent carbonyl groups connected by a single bond, the addition product of 4-hydroxycoumarin to β,γ-unsaturated α-ketoester has more than one forms (Scheme 1).⁷ This tautomeric form also occurred in the product of pyrazolone to β,γ-unsaturated α-ketoesters. This kind of three structures-tautomeric compounds has few reports ever before.

Scheme 1 Organocatalyst-promoted Michael addition of coumarin to β,γ-unsaturated α-ketoester.

Herein, we describe the development of a squaramide promoted asymmetric Michael addition of pyrazolones to β,γ-unsaturated α-ketoesters (Scheme 2). β,γ-Unsaturated α-ketoesters, which are electrophiles with two adjacent carbonyl groups connected by a single bond, could be suitably activated and orientated by squaramide, as its two acidic hydrogen atoms are separated by a two-carbon link.^7b Satisfactorily, this organocatalytic process is effective, and the corresponding pyrazolone ketoester derivatives were obtained in moderate to high yields with high enantioselectivities (up to 96% ee).

Scheme 2 Squaramide-catalysed Michael addition of pyrazolone to β,γ-unsaturated α-ketoester.

Results and discussion

A series of chiral squaramide-based organocatalysts I–VI (Fig. 1) were used to catalyze the Michael addition of 3-methyl-1-phenyl-2-pyrazolin-5-one (1a) to β,γ-unsaturated α-ketoester (2a). The reaction was first performed in CH₂Cl₂ in the presence of 5 mol% catalysts at room temperature, and the screening results are given in Table 1. Squaramides I–III derived from chiral 1,2-diaminocyclohexane afforded the product 3a in good yield with moderate to good enantioselectivity (Table 1, entries 1–3). Squaramides I and II was found to afford a better enantioselectivity than squaramide III, this indicates that the sterically hindered piperidinyl group is beneficial for the enantioselectivity. Compared with other catalysts, the quinine-derived squaramide IV and quinidine-derived squaramide VI provided the best results with good yields and high enantioselectivities (Table 1, entries 4 and 6). Considering both the slightly difference of yields and the market price of quinine and quinidine, catalyst IV was selected as the best catalyst for further optimization of the reaction condition.

Fig. 1 The structures of screened organocatalysts.

Table 1 Screening of organocatalysts for the enantioselective Michael addition of 3-methyl-1-phenyl-2-pyrazolin-5-one to β,γ-unsaturated α-ketoesters^a

Entry	Catalyst	Yield^b (%)	ee^c (%)
a Reactions were carried out with 3-methyl-1-phenyl-2-pyrazolin-5-one 1a (0.2 mmol) and β,γ-unsaturated α-ketoester 2a (0.25 mmol) in CH2Cl2 (1.0 mL) at room temperature for 24 h.b Isolated yield after column chromatography purification.c Determined by chiral HPLC analysis.d The opposite enantiomer.
1	I	75	88
2	II	83	88
3	III	83	69
4	IV	75	94
5	V	76	89
6	VI	73	94^d

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With squaramide IV as the best catalyst, we further screened the effect of solvents, catalyst loading, temperature and the amounts of solvent for the optimal reaction conditions. The results are summarized in Table 2. Variation of the solvents had a pronounced effect on the yields and enantioselectivities. After CH₂Cl₂ was used as the solvent, several other common solvents were also been evaluated. Compared with CH₂Cl₂, the solvents ClCH₂CH₂Cl, CHCl₃, PhCH₃, CH₃CN, THF and Et₂O gave the similar yields but with lower enantioselectives. The proton solvent such as MeOH or H₂O is often a poor solvent in hydrogen bond-controlled organocatalysis, but in this reaction even higher enantioselectivities was obtained than in CH₂Cl₂. Unfortunately, low yield was obtained in MeOH or H₂O. After a variety of solvents had been surveyed, the best result was achieved in xylene with good yield and high enantioselectivity (95% ee). Different catalyst loadings were also tried (Table 2, entries 11–12), 10 mol% catalyst IV enhance the enantioselectivity to 96% ee. Thus, 10 mol% catalyst loading was used for further optimization. Next, the effect of temperature and amount of solvent was also investigated (Table 2, entries 13–17), and it was proved that the room temperature and 1 mL of solvent was better than other conditions.

Table 2 Optimization of reaction conditions for the enantioselective Michael addition of 3-methyl-1-phenyl-2-pyrazolin-5-one to β,γ-unsaturated α-ketoesters^a

Entry	Solvent	T (°C)	Loading (mol%)	Yield^b (%)	ee^c (%)
a Reactions were carried out with 3-methyl-1-phenyl-2-pyrazolin-5-one 1a (0.20 mmol) and β,γ-unsaturated α-ketoester 2a (0.25 mmol) in solvent (1.0 mL).b Isolated yield after column chromatography purification.c Determined by chiral HPLC analysis.d 0.5 mL solvent was used.e 2.0 mL solvent was used.
1	CH2Cl2	rt	5	75	94
2	ClCH2CH2Cl	rt	5	62	78
3	CHCl3	rt	5	75	87
4	PhCH3	rt	5	84	85
5	CH3CN	rt	5	85	91
6	Xylene	rt	5	75	95
7	THF	rt	5	74	93
8	Et2O	rt	5	67	88
9	MeOH	rt	5	33	93
10	H2O	rt	5	49	96
11	Xylene	rt	2	95	93
12	Xylene	rt	10	72	96
13	Xylene	−20	10	85	86
14	Xylene	0	10	83	93
15	Xylene	50	10	66	86
16^d	Xylene	rt	10	57	96
17^e	Xylene	rt	10	61	95

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Under the optimized conditions with 10 mol% catalyst IV, room temperature, and 1 mL of xylene as the solvent, a diverse array of substituted pyrazolin-5-ones and β,γ-unsaturated α-ketoesters were examined. The results are summarized in Table 3. Various β,γ-unsaturated α-ketoesters bearing either electron-withdrawing or electron-donating groups (F, Cl, Br, Me and OMe) were investigated, and moderate to good yields (64% to 84%) with high enantioselectivities (93% to 96% ee) were obtained (Table 3, entries 2–6). 1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one 1b (Table 3, entry 7), 3-methyl-1-tolyl-2-pyrazolin-5-one 1c (Table 3, entry 8), were also used as the Michael donors, the corresponding products were obtained in good yields with high enantioselectivities (92% and 96% ee). When 3-trifluoromethyl-1-phenyl-2-pyrazolin-5-one 1d was used as Michael donor (Table 3, entry 9 and entry 14), the enantioselectivity was reduced owing to the strong electron-withdrawing ability of the CF₃ group. At the same time the occurrence of side reactions was greatly reduced, and excellent yields (99% and 99%) were obtained. In the cases of 1,3-diphenyl-2-pyrazolin-5-one 1e, good yield was still maintained, but with very low enantioselectivity (16% ee and 19% ee) (Table 3, entry 10 and entry 13). This result demonstrated the steric effect in this asymmetric catalytic reaction. 3-Ethyl-1-phenyl-2-pyrazolin-5-one 1f was also used as Michael donor (Table 3, entry 15), compared with 3a, the yield of 3o was slightly increased and similar enantioselectivity was obtained (81% yield and 94% ee). Furthermore, 3k and 3l were also obtained through the Michael addition of 3-methyl-1-phenyl-2-pyrazolin-5-one to the benzyl or allyl α-ketoesters in moderate to good yields (65% and 83%) and high enantioselectivities (90% and 91%) (Table 3, entry 11–12).

Table 3 Scope of the asymmetric Michael addition of pyrazolin-5-ones to β,γ-unsaturated α-ketoesters^a

Entry	1	R^1	R^2	2	R^3	R^4	Product	Yield^b (%)	ee^c (%)
a Unless noted otherwise, reactions were carried out with pyrazolin-5-ones 1 (0.2 mmol), β,γ-unsaturated α-ketoesters 2 (0.25 mmol) and catalyst IV (10 mol%) in xylene (1.0 mL) at room temperature.b Isolated yield after column chromatography purification.c Determined by chiral HPLC analysis using a Daicel Chiralpak AD-H or OJ-H column.
1	1a	Me	Ph	2a	Ph	Me	3a	72	96
2	1a	Me	Ph	2b	4-ClC6H4	Me	3b	64	96
3	1a	Me	Ph	2c	4-BrC6H4	Me	3c	84	94
4	1a	Me	Ph	2d	4-FC6H4	Me	3d	65	93
5	1a	Me	Ph	2e	4-MeC6H4	Me	3e	71	94
6	1a	Me	Ph	2f	4-MeOC6H4	Me	3f	64	96
7	1b	Me	4-ClC6H4	2a	Ph	Me	3g	80	92
8	1c	Me	4-MeC6H4	2a	Ph	Me	3h	77	96
9	1d	CF3	Ph	2a	Ph	Me	3i	99	77
10	1e	Ph	Ph	2a	Ph	Me	3j	75	16
11	1a	Me	Ph	2g	Ph	Bn	3k	65	90
12	1a	Me	Ph	2h	Ph	Allyl	3l	83	91
13	1e	Ph	Ph	2c	4-BrC6H4	Me	3m	92	19
14	1d	CF3	Ph	2c	4-BrC6H4	Me	3n	99	78
15	1f	Et	Ph	2a	Ph	Me	3o	81	94

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To evaluate the synthetic potential of this catalytic reaction, the synthetic transformation of 3a was performed. As shown in Scheme 3, the reaction of 3a with 3-bromo-1-propyne in the presence of potassium carbonate afforded the propargyloxy derivative 4 in 38% yield with 96% ee. The alkyne group can be used for other valuable transformation.

Scheme 3 The reaction of 3a with 3-bromo-1-propyne.

Accord the previous reported dual activation model,^5e,7b a possible transition state is proposed (Fig. 2). The α-keto ester 2a is assumed to interact with the squaramide moiety of IV through double hydrogen bonds, which activates and fixes the substrate by a bidentate interaction. The 3-methyl-1-phenyl-2-pyrazolin-5-one 1a is deprotonated by the basic nitrogen atom of the tertiary amine via tautomerization. The deprotonated form of pyrazolin-5-one 1a is assumed to interact with the tertiary amine group of quinucidine through the hydrogen bond between the protonated amine and the oxygen atom of 1a. This well-assembled transition state facilitates the nucleophile 1a to attack the α-keto ester 2a from the Re-face and to form the (R) product.

Fig. 2 The proposed transition state for enantioselective Michael addition.

Conclusions

In summary, we have successfully developed an organocatalytic enantioselective Michael addition of pyrazolin-5-ones to β,γ-unsaturated α-ketoesters. The corresponding Michael adducts are obtained in moderate to high yields (up to 99%) with high enantioselectivities (up to 96% ee). This catalytic asymmetric reaction provides easy access to chiral pyrazolone ketoester derivatives, which possess potential pharmaceutical activity. Further studies on chiral squaramides are underway in our group to broaden their applications in asymmetric catalysis.

Experimental

General information

Commercially available compounds were used without further purification. Column chromatography was carried out using silica gel (200–300 mesh). Melting points were measured with an XT-4 melting point apparatus without correction. The ¹H NMR spectra were recorded with a Varian Mercury-plus 400 MHz or a Bruker AVIII 400 MHz spectrometer, while ¹³C NMR spectra were recorded at 100 MHz. Infrared spectra were obtained with a Perkin Elmer Spectrum One FT-IR spectrometer. The ESI-HRMS spectra were obtained with a Bruker APEX IV FTMS spectrometer. Optical rotations were measured with a WZZ-3 polarimeter at the indicated concentration with unit g per 100 mL. The enantiomeric excesses of the products were determined by chiral HPLC using Agilent 1200 LC instrument using Daicel Chiralpak AD-H or OJ-H columns.

Materials

The squaramide organocatalysts were prepared following the reported procedures.⁸ The racemic compounds 5 were obtained using Et₃N as catalyst in Michael addition.

General procedure for the enantioselective Michael addition reaction

A mixture of pyrazolone 1 (0.2 mmol), β,γ-unsaturated α-ketoesters 2 (0.25 mmol) and the catalyst IV (0.02 mmol) in xylene (1.0 mL) was stirred at room temperature for 24 h. Next, the mixture was concentrated and purified by silica gel column chromatography (with ethyl acetate–petroleum ether 1 : 3 as the eluent) to afford the desired products 3.

General procedure for the reaction of products 3 with di-tert-butyl dicarbonate

A mixture of 3 (1 equiv.), di-tert-butyl dicarbonate (2 equiv.) and DMAP (0.2 equiv.) in CH₂Cl₂ (2 mL) was stirred at room temperature for 2 h. Next, the mixture was concentrated and purified by silica gel column chromatography (with ethyl acetate–petroleum ether 1 : 8 as the eluent) to afford the desired products 5.

After the products 3 for Michael addition of pyrazolones to β,γ-unsaturated α-ketoesters were obtained, the ¹H NMR were measured in DMSO. As shown in Scheme 2, the product was exist with three tautomeric forms in solution, so we can see complex peaks with three tautomeric compounds exit in each NMR spectrum. It is too complicated that can not distinguish between three tautomeric forms. But it was a real compound exist in our hand, so some special method should be performed here to characterize the compounds 3.

As shown in Scheme 4, in order to characterize these compounds 3, Boc protection was performed. In the following characterization part of this paper, the yields, ee values and melting points were measured with compounds 3. The structure confirmation by ¹H NMR, ¹³C NMR, IR and MS were measured with compounds 5. The optical rotations were also measured with compounds 5.

Scheme 4 The reaction of compounds 3 with di-tert-butyl dicarbonate.

4-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid methyl ester (3a). Compound 3a was obtained according to the general procedure as a white solid (52.2 mg, 72% yield); m.p. 127–129 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 13.9 min, major enantiomer t_R = 22.0 min, 96% ee.
Boc-protected compound 5a. [α]²⁵_D = +305.77 (c = 1.335, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.54 (dd, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 2H, ArH), 7.41 (t, J = 7.8, 2H, ArH), 7.32–7.27 (m, 4H, ArH), 7.25–7.20 (m, 2H, ArH), 6.91 (d, J = 10.4 Hz, 1H, CH), 5.10 (d, J = 10.4, 1H, CH), 3.80 (s, 3H, OCH₃), 2.15 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.23 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 150.4, 148.4, 147.4, 142.2, 139.7, 138.1, 137.9, 129.6, 129.1, 128.5, 127.5, 127.1, 126.8, 122.5, 107.9, 85.3, 84.0, 52.3, 36.2, 27.4, 27.0, 13.5 ppm. IR (KBr): ν 3063, 2979, 2934, 1760, 1734, 1598, 1505, 1437, 1371, 1286, 1247, 1149, 1119, 1079, 761, 697 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₇N₂O₈ [M + H]⁺ 565.25444, found 565.25547.

4-(4-Chlorophenyl)-4-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-butyric acid methyl ester (3b). Compound 3b was obtained according to the general procedure as a white solid (50.7 mg, 64% yield); m.p. 145–146 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 16.5 min, major enantiomer t_R = 33.4 min, 96% ee.
Boc-protected compound 5b. [α]²⁵_D = −21.5 (c = 0.4, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 8.4 Hz, 2H, ArH), 7.41 (t, J = 8.0 Hz, 2H, ArH), 7.30–7.20 (m, 5H, ArH), 6.85 (d, J = 10.4 Hz, 1H, CH), 5.06 (d, J = 10.4 Hz, 1H, CH), 3.81 (s, 3H, OCH₃), 2.16 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.24 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.1, 150.3, 148.4, 147.2, 142.1, 138.3, 138.2, 137.8, 132.6, 129.1, 129.0, 128.9, 128.6, 127.2, 122.5, 107.6, 85.4, 84.2, 52.4, 35.7, 27.4, 27.0, 13.4 ppm. IR (KBr): ν 2982, 2934, 1778, 1764, 1737, 1599, 1507, 1491, 1437, 1387, 1372, 1272, 1246, 1148, 1120, 879, 764, 695 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₆ClN₂O₈ [M + H]⁺ 599.21547, found 599.21541.

4-(4-Bromophenyl)-4-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-butyric acid methyl ester (3c). Compound 3c was obtained according to the general procedure as a white solid (74.8 mg, 84% yield); m.p. 140–142 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 19.0 min, major enantiomer t_R = 34.8 min, 94% ee.
Boc-protected compound 5c. [α]²⁵_D = −100.9 (c = 0.56, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 7.6 Hz, 2H, ArH), 7.43–7.39 (m, 4H, ArH), 7.32–7.27 (m, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.84 (d, J = 10.4, 1H, CH), 5.03 (d, J = 10.0 Hz, 1H, CH), 3.82 (s, 3H, OCH₃), 2.16 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.24 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.1, 150.3, 148.4, 147.3, 142.2, 138.8, 138.4, 137.8, 131.6, 129.4, 129.1, 128.8, 127.2, 122.6, 120.8, 107.5, 85.5, 84.2, 52.5, 35.8, 27.4, 27.0, 13.4 ppm. IR (KBr): ν 2982, 2934, 1764, 1736, 1598, 1507, 1488, 1437, 1371, 1272, 1246, 1148, 1120 1072, 1011, 878, 763, 694 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₆BrN₂O₈ [M + H]⁺ 643.16496, found 643.16637.

4-(4-Fluorophenyl)-4-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-butyric acid methyl ester (3d). Compound 3d was obtained according to the general procedure as a white solid (49.3 mg, 65% yield); m.p. 50–52 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 16.9 min, major enantiomer t_R = 42.3 min, 93% ee.
Boc-protected compound 5d. [α]²⁵_D = +17.5 (c = 0.72, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.41 (t, J = 7.8 Hz, 2H, ArH), 7.31–7.22 (m, 3H, ArH), 6.99 (t, J = 8.6 Hz, 2H, ArH), 6.86 (d, J = 10.0 Hz, 1H, CH), 5.06 (d, J = 10.0 Hz, 1H, CH), 3.81 (s, 3H, OCH₃), 2.16 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.24 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.2, 161.7 (d, ¹J_C–F = −244.0 Hz), 150.3, 148.4, 147.3, 142.1, 138.2, 137.8, 135.4 (d, ³J_C–F = 3.1 Hz), 129.3, 129.2, 129.1, 127.2, 122.6, 115.3 (d, ²J_C–F = 21.2 Hz), 107.8, 85.4, 84.1, 52.4, 35.5, 27.4, 27.0, 13.4 ppm. IR (KBr): ν 2984, 1776, 1764, 1736, 1599, 1508, 1438, 1372, 1265, 1246, 1147, 1119, 879, 842, 763, 748, 703 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₆FN₂O₈ [M + H]⁺ 583.24502, found 583.24430.

4-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-p-tolyl-butyric acid methyl ester (3e). Compound 3e was obtained according to the general procedure as a white solid (53.9 mg, 71% yield); m.p. 136–138 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H′ column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 10.3 min, major enantiomer t_R = 17.0 min, 94% ee.
Boc-protected compound 5e. [α]²⁵_D = −7.4 (c = 1.81, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.41 (t, J = 8.0 Hz, 2H, ArH), 7.30–7.27 (m, 1H, ArH), 7.16–7.04 (m, 4H, ArH), 6.90 (d, J = 10.4 Hz, 1H, CH), 5.05 (d, J = 10.4 Hz, 1H, CH), 3.80 (s, 3H, OCH₃), 2.30 (s, 3H, CH₃), 2.15 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.23 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 150.4, 148.4, 147.5, 142.2, 138.0, 137.9, 136.7, 136.3, 129.9, 129.2, 129.1, 127.4, 127.1, 122.6, 108.1, 85.2, 84.0, 52.3, 35.9, 27.5, 27.0, 20.9, 13.5 ppm. IR (KBr): ν 2983, 1776, 1764, 1736, 1598, 1507, 1435, 1371, 1270, 1246, 1147, 1117, 878, 763 cm⁻¹. HRMS (ESI): m/z calcd for C₃₂H₃₉N₂O₈ [M + H]⁺ 579.27009, found 579.26889.

4-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-methoxyphenyl)-2-oxo-butyric acid methyl ester (3f). Compound 3f was obtained according to the general procedure as a pink solid (50.8 mg, 86% yield); m.p. 133–135 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 22.3 min, major enantiomer t_R = 41.4 min, 96% ee.
Boc-protected compound 5f. [α]²⁵_D = −8.79 (c = 2.275, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.54–7.52 (m, 2H, ArH), 7.41 (t, J = 7.8 Hz, ArH), 7.30 (d, J = 7.6 Hz, 1H, ArH), 7.17 (d, J = 8.4 Hz, 2H, ArH), 6.88 (d, J = 10.4 Hz, 1H, CH), 6.83 (d, J = 8.8 Hz, 2H, ArH), 5.04 (d, J = 10.4 Hz, 1H, CH), 3.80 (s, 3H, OCH₃), 3.77 (s, 3H, OCH₃), 2.15 (s, 3H, CH₃), 1.49 (s, 9H, tBu), 1.24 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 158.4, 150.4, 148.5, 147.4, 142.2, 138.0, 137.8, 131.8, 129.9, 129.1, 128.6, 127.1, 122.6, 113.9, 108.1, 85.2, 84.0, 55.2, 52.3, 35.5, 27.5, 27.0, 13.5 ppm. IR (KBr): ν 2983, 2956, 2930, 1775, 1763, 1735, 1598, 1508, 1437, 1371, 1272, 1248, 1148, 1121, 1032, 764, 694 cm⁻¹. HRMS (ESI): m/z calcd for C₃₂H₃₉N₂O₉ [M + H]⁺ 595.26501, found 595.26485.

4-[1-(4-Chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-oxo-4-phenyl-butyric acid methyl ester (3g). Compound 3g was obtained according to the general procedure as a white solid (64 mg, 80% yield); m.p. 156–158 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 12.0 min, major enantiomer t_R = 9.5 min, 92% ee.
Boc-protected compound 5g. [α]²⁵_D = +16.9 (c = 0.675, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, J = 8.8 Hz, 2H, ArH), 7.38 (d, J = 8.8 Hz, 2H, ArH), 7.32–7.20 (m, 5H, ArH), 6.88 (d, J = 10.4 Hz, 1H, CH), 5.08 (d, J = 10.4 Hz, 1H, CH), 3.81 (s, 3H, OCH₃), 2.13 (s, 3H, CH₃), 1.48 (s, 9H, tBu), 1.28 (s, 9H, tBu) ppm; ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 150.4, 148.5, 147.9, 142.2, 139.6, 138.2, 136.6, 132.7, 129.4, 129.2, 128.6, 127.6, 126.9, 123.6, 108.4, 85.6, 84.1, 52.4, 36.2, 27.5, 27.1, 13.5 ppm. IR (KBr): ν 2983, 2924, 2854, 1778, 1764, 1737, 1599, 1503, 1438, 1371, 1274, 1244, 1147, 1119, 1053, 878, 834, 768, 700 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₆ClN₂O₈ [M + H]⁺ 599.21547, found 599.21504.

4-(5-Hydroxy-3-methyl-1-p-tolyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid methyl ester (3h). Compound 3h was obtained according to the general procedure as a white solid (58.6 mg, 77% yield); m.p. 160–162 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak ADH column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 13.6 min, major enantiomer t_R = 10.7 min, 96% ee.
Boc-protected compound 5h. [α]²⁵_D = +17.0 (c = 2.015, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 8.0 Hz, 2H, ArH), 7.29–7.25 (m, 5H, ArH), 7.20 (d, J = 8.0 Hz, 2H, ArH), 6.90 (d, J = 10.4 Hz, 1H, CH), 5.09 (d, J = 10.4 Hz, 1H, CH), 3.80 (s, 3H, OCH₃), 2.35 (s, 3H, CH₃), 2.14 (s, 3H), 1.48 (s, 9H, tBu), 1.24 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 150.4, 148.5, 147.1, 142.1, 139.8, 138.0, 137.0, 135.5, 129.7, 129.6, 128.5, 127.6, 126.8, 122.6, 107.7, 85.2, 84.0, 52.4, 36.2, 27.5, 27.1, 21.0, 13.5 ppm. IR (KBr): ν 2983, 2926, 1776, 1764, 1736, 1600, 1519, 1440, 1371, 1270, 1246, 1148, 1119, 1084, 880, 821, 767, 700 cm⁻¹. HRMS (ESI): m/z calcd for C₃₂H₃₉N₂O₈ [M + H]⁺ 579.27009, found 579.26950.

4-(5-Hydroxy-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid methyl ester (3i). Compound 3i was obtained according to the general procedure as a white solid (83.6 mg, 99% yield); m.p. 105–108 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak ADH column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 5.2 min, major enantiomer t_R = 7.3 min, 77% ee.
Boc-protected compound 5i. [α]²⁵_D = +13.3 (c = 2.065, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): 7.56 (d, J = 8.4 Hz, 2H, ArH), 7.46 (t, J = 7.2 Hz, 2H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.31–7.21 (m, 5H, ArH), 6.96 (d, J = 10.4 Hz, 1H, CH), 5.33 (d, J = 10.0 Hz, 1H, CH), 3.81 (s, 3H, OCH₃), 1.48 (s, 9H, tBu), 1.16 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.2, 150.2, 147.4, 143.2, 139.5 (q, ²J_C–F = 37.2 Hz), 139.3, 138.7, 137.1, 129.3, 128.63, 128.58, 128.51, 127.4, 127.1, 123.4, 121.0 (q, ¹J_C–F = 69.1 Hz), 109.2, 86.2, 84.2, 52.5, 35.5, 27.4, 26.9 ppm. IR (KBr): ν 2984, 2934, 1784, 1765, 1739, 1599, 1497, 1451, 1392, 1373, 1282, 1254, 1229, 1155, 1136, 1012, 876, 765, 749, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₃F₃N₂NaO₈ [M + Na]⁺ 641.20812, found 641.20956.

4-(5-Hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid methyl ester (3j). Compound 3j was obtained according to the general procedure as colorless oil (64 mg, 75% yield); enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 18.1 min, major enantiomer t_R = 15.2 min, 16% ee.
Boc-protected compound 5j. [α]²⁵_D = +2.18 (c = 2.645, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 7.6 Hz, 2H, ArH), 7.58–7.56 (m, 2H, ArH), 7.44 (t, J = 7.6 Hz, 2H, ArH), 7.40–7.32 (m, 4H, ArH), 7.27–7.26 (m, 4H, ArH), 7.22–7.16 (m, 1H, ArH), 6.99 (d, J = 10.0 Hz, 1H, CH), 5.30 (d, J = 10.0 Hz, 1H, CH), 3.78 (s, 3H, OCH₃), 1.40 (s, 9H, tBu), 1.18 (s, 9H, tBu) ppm; ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 150.6, 150.3, 147.9, 142.8, 140.3, 138.04, 137.96, 132.9, 130.1, 129.1, 128.5, 128.4, 128.1, 127.53, 127.45, 126.8, 122.8, 107.8, 85.5, 83.9, 52.3, 36.4, 27.4, 26.9 ppm. IR (KBr): ν 3063, 2982, 2934, 1781, 1763, 1736, 1597, 1571, 1503, 1455, 1372, 1273, 1244, 1149, 1136, 1115, 877, 763, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₃₆H₃₉N₂O₈ [M + H]⁺ 627.27009, found 627.27162.

4-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid benzyl ester (3k). Compound 3k was obtained according to the general procedure as pale yellow oil (65.8 mg, 90% yield); enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 12.6 min, major enantiomer t_R = 15.2 min, 90% ee.
Boc-protected compound 5k. [α]²⁵_D = +13.3 (c = 1.46, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.43–7.31 (m, 6H, ArH), 7.29–7.20 (m, 7H, ArH), 6.96 (d, J = 10.4 Hz, 1H, CH), 5.24 (s, 2H, CH₂), 5.10 (d, J = 10.4 Hz, 1H, CH), 2.15 (s, 3H, CH₃), 1.41 (s, 9H, tBu), 1.20 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 161.8, 150.3, 147.4, 139.7, 138.2, 137.9, 135.2, 129.9, 129.1, 128.7, 128.55, 128.47, 128.3, 128.2, 127.6, 127.1, 126.8, 122.6, 109.6, 107.9, 85.3, 84.0, 67.2, 36.2, 27.4, 27.0, 13.5 ppm. IR (KBr): ν 2981, 2930, 1776, 1762, 1731, 1598, 1505, 1454, 1371, 1270, 1246, 1221, 1147, 1117, 1081, 799, 759, 697 cm⁻¹. HRMS (ESI): m/z calcd for C₃₇H₄₁N₂O₈ [M + H]⁺ 641.28574, found 641.28647.

4-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid allyl ester (3l). Compound 3l was obtained according to the general procedure as a colorless oil (62.7 mg, 83% yield); enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): major enantiomer t_R = 9.6 min, minor enantiomer t_R = 13.0 min, 91% ee.
Boc-protected compound 5l. [α]²⁵_D = −6.8 (c = 0.97, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.41 (t, J = 7.6 Hz, 2H, ArH), 7.32–7.21 (m, 6H, ArH), 6.94 (d, J = 9.6 Hz, 1H, CH), 5.99–5.89 (m, 1H, CH), 5.36 (d, J = 17.2 Hz, 1H, CH), 5.25 (d, J = 10.4 Hz, 1H, CH), 5.11 (d, J = 10.4 Hz, 1H, CH), 4.71 (d, J = 6.8 Hz, 2H, CH₂), 2.16 (s, 3H, CH₃), 1.48 (s, 9H, tBu), 1.23 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 161.5, 150.4, 148.4, 147.4, 142.2, 139.7, 138.2, 138.0, 131.5, 129.7, 129.1, 128.6, 127.6, 127.1, 126.8, 122.6, 118.6, 107.9, 85.3, 84.0, 66.1, 36.2, 27.5, 27.0, 13.5 ppm. IR (KBr): ν 2982, 2934, 1776, 1762, 1733, 1598, 1506, 1454, 1371, 1270, 1246, 1225, 1148, 1119, 1081, 878, 762, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₃₃H₃₉N₂O₈ [M + H]⁺ 591.27009, found 591.27083.

4-(4-Bromophenyl)-4-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-2-oxo-butyric acid methyl ester (3m). Compound 3m was obtained according to the general procedure as a amorphous solid (92.6 mg, 92% yield); enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): major enantiomer t_R = 22.7 min, minor enantiomer t_R = 15.7 min, 19% ee.
Boc-protected compound 5m. [α]²⁵_D = −3.89 (c = 3.14, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 8.0 Hz, 2H, ArH), 7.56 (d, J = 7.2 Hz, 2H, ArH), 7.44 (t, J = 7.8 Hz, 2H, ArH), 7.40–7.30 (m, 6H, ArH), 7.13 (d, 2H, J = 8.4 Hz, 2H, ArH), 6.92 (d, J = 10.0 Hz, 1H, CH), 5.23 (d, J = 10.0 Hz, 1H, CH), 3.79 (s, 3H, OCH₃), 1.40 (s, 9H, tBu), 1.19 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.1, 150.4, 150.2, 147.9, 142.7, 139.3, 138.4, 137.8, 132.7, 131.5, 129.40, 129.36, 129.2, 128.5, 128.4, 128.3, 127.6, 122.8, 120.8, 107.6, 85.7, 84.0, 52.4, 36.0, 27.4, 26.9 ppm. IR (KBr): ν 2980, 2934, 1780, 1764, 1737, 1596, 1572, 1503, 1486, 1455, 1396, 1371, 1274, 1244, 1149, 1136, 1121, 1073, 1010, 876, 763, 696 cm⁻¹. HRMS (ESI): m/z calcd for C₃₆H₃₈BrN₂O₈ [M + H]⁺ 705.18061, found 705.18110.

4-(4-Bromophenyl)-4-(5-hydroxy-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-butyric acid methyl ester (3n). Compound 3n was obtained according to the general procedure as a white solid (99.5 mg, 99% yield); m.p. 65–68 °C. Enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 85 : 15, flow rate 1.0 mL min⁻¹, detection at 254 nm): major enantiomer t_R = 10.7 min, minor enantiomer t_R = 6.2 min, 78% ee.
Boc-protected compound 5n. [α]²⁵_D = −6.0 (c = 4.56, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 6.4 Hz, 2H, ArH), 7.46 (t, J = 6.8 Hz, 3H, ArH), 7.41 (d, J = 8.0 Hz, 2H, ArH), 7.14 (d, J = 6.8 Hz, 2H, ArH), 6.88 (d, J = 10.0 Hz, 1H, CH), 5.28 (d, J = 9.6 Hz, 1H, CH), 3.82 (s, 3H, OCH₃), 1.48 (s, 9H, tBu), 1.18 (s, 9H, tBu) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.0, 150.1, 147.5, 143.2, 139.4 (q, ²J_C–F = 37.3 Hz), 139.0, 138.4, 137.0, 131.6, 129.3, 129.2, 128.7, 127.7, 123.3, 121.1, 121.0 (q, ¹J_C–F = −268.5 Hz), 108.7, 86.5, 84.3, 52.5, 35.1, 27.4, 26.9 ppm. IR (KBr): ν 2983, 2956, 2934, 1783, 1765, 1738, 1599, 1550, 1489, 1451, 1394, 1372, 1278, 1253, 1228, 1155, 1138, 1075, 1011, 875, 765, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₃₁H₃₂BrF₃N₂NaO₈ [M + Na]⁺ 719.11863, found 719.11938.

4-(5-Hydroxy-3-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-phenyl-butyric acid methyl ester (3o). Compound 3o was obtained according to the general procedure as a colorless oil (60.4 mg, 81% yield); enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H column, n-hexane–isopropanol 95 : 5, flow rate 1.0 mL min⁻¹, detection at 254 nm): major enantiomer t_R = 9.3 min, minor enantiomer t_R = 8.4 min, 91% ee.
Boc-protected compound 5o. [α]²⁵_D = +2.67 (c = 3.15, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.54 (m, 2H, ArH), 7.41 (t, J = 7.8 Hz, 2H, ArH), 7.30–7.26 (m, 5H, ArH), 7.23–7.19 (m, 1H, ArH), 6.93 (d, J = 10.4 Hz, 1H, CH), 5.12 (d, J = 10.4 Hz, 1H, CH), 3.80 (s, 3H, OCH₃), 2.54 (q, J = 7.6 Hz, 2H, CH₂), 1.48 (s, 9H, tBu), 1.21–1.18 (m, 12H, tBu + CH₃) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 162.3, 152.4, 150.3, 148.4, 142.1, 140.0, 138.1, 137.9, 129.8, 129.0, 128.5, 127.5, 127.0, 126.8, 122.6, 107.3, 85.2, 83.9, 52.3, 36.1, 27.4, 27.0, 20.9, 12.9 ppm. IR (KBr): ν 2980, 2937, 1778, 1764, 1737, 1598, 1506, 1449, 1437, 1394, 1372, 1270, 1244, 1147, 1119, 1087, 878, 765, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₃₂H₃₉N₂O₈ [M + H]⁺ 579.27009, found 579.27103.

The reaction of 3a with 3-bromo-1-propyne

A mixture of 3a (44.3 mg, 0.122 mmol), propargyl bromide (29 mg 0.224 mmol) and anhydrous potassium carbonate (50.6 mg, 0.366 mmol) in CH₃COCH₃ (2 mL) was stirred at room temperature for 3 h. Next, the mixture was concentrated and purified by silica gel column chromatography (with ethyl acetate–petroleum ether 1 : 2 as the eluent) to afford the desired products 4 as colorless oil (18.7 mg, 38% yield). Enantiomeric excess was determined by HPLC (Daicel Chiralpak OJ-H column, n-hexane–isopropanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): minor enantiomer t_R = 36.3 min, major enantiomer t_R = 74.6 min, 96% ee; [α]²⁵_D = −23.3 (c = 0.935, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.38 (m, 6H, ArH), 7.30–7.18 (m, 4H, ArH), 4.37 (dd, J₁ = 4.0 Hz, J₂ = 9.6 Hz, 1H), 4.32–4.25 (m, 1H, CH), 4.10 (d, J = 2.0 Hz, 2H, CH₂), 3.82 (s, 3H, OCH₃), 3.45 (dd, J₁ = 4.0 Hz, J₂ = 18.8 Hz, 1H, CH), 2.24 (s, 3H, CH₃), 2.13 (br s, 1H, CH) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 192.1, 165.4, 160.9, 154.0, 142.6, 134.5, 130.9, 129.1, 128.5, 127.7, 126.6, 126.4, 123.4, 114.9, 74.3, 74.1, 52.9, 42.9, 38.7, 35.7, 11.1 ppm. IR (KBr): ν 2953, 2924, 2854, 1730, 1660, 1594, 1495, 1456, 1276, 1267, 1263, 1134, 1125, 1087, 1071, 763, 751, 698 cm⁻¹. HRMS (ESI): m/z calcd for C₂₄H₂₃N₂O₄ [M + H]⁺ 403.16523, found 403.16552.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (grant no. 21272024).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of new compounds, and HPLC chromatograms. See DOI: 10.1039/c3ra45974h

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