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Abstract

A series of more than 20 multisubstituted pyrrolidine-2-carboxylates were synthesized via a one-pot cycloaddition of an araldehyde, an amino acid ester, and a chalcone catalyzed by I₂/K₂CO₃ in tetrahydrofuran at 80 °C. The advantages of this method are readily available starting materials, mild conditions, and simple operation, and it is metal free and yields are good to excellent.

Keywords

amino acid esters araldehydes chalcones iodine one-pot metal-free pyrrolidine-2-carboxylates

Introduction

Pyrrolidine compounds are widespread in natural products and their multisubstituted derivatives exhibit a diverse array of biological activities, for example, as purine nucleoside phosphorylase (PNP) inhibitors (F-DADMe-ImmH)¹ and as anti-infective,² anticarcinogenic (MI-219),³ and antibacterial (antimicrobial agent VI)^4,5 agents, some typical structures of which are shown in Figure 1. Moreover, some of the derivatives are of medicinal value. Therefore, pyrrolidine compounds have been widely studied and methods for their synthesis have received much attention from synthetic organic chemists. Among them, the construction of pyrrolidine compounds via annulation has become one of the most widely used methods.^6,7

Figure 1.

Some examples of biologically active compounds that contain a pyrrolidine scaffold.

The synthesis of pyrrolidine compounds via the cycloaddition of N-((benzylidene)amino)acetate to active C=C or C≡C bonds has been developed considerably in recent years.^8,9 To our best knowledge, we found that this reaction was mainly a two-component reaction catalyzed by metals such as [Cu],^10,11 [Ag],^12,13 [Ca],^14,15 [Fe],¹⁶ and [Au].¹⁷ There have been only a few reports of the synthesis of pyrrolidine compounds by metal-free catalysis^18,19 and by three-component one-pot methods.^20–22

Molecular iodine (I₂) has been widely used in organic synthesis due to its low cost, ease of availability, and simple operation and because it avoids the use of metals.^23,24 Our group has reported some iodine-promoted cyclization reactions for the construction of aza-heterocyclic compounds in recent years.^25–27 Herein, we describe a K₂CO₃/iodine-catalyzed three-component one-pot condensation reaction of an aromatic aldehyde, a glycine ester, and a chalcone which yielded a series of multisubstituted pyrrolidine-2-carboxylates.

Results and discussion

The reaction we planned to study is shown in Scheme 1. In order to optimize the conditions, we chose as a model reaction the treatment of benzaldehyde (1a; R¹ = Ph), glycine ethyl ester hydrochloride (2a; R² = H, R³ = Et), and chalcone (3a; R^4,5 = Ph) with anhydrous K₂CO₃ (1.5 mmol) in tetrahydrofuran (THF) for 10 h at 80 °C and the results are shown in Table 1. The expected product, ethyl 4-benzoyl-3,5-diphenylpyrrolidine-2-carboxylate (4a; R^1,4,5 = Ph, R² = H, R³ = Et) was obtained in a low yield (35%) along with a lot of unreacted chalcone (Table 1, entry 1). Unexpectedly, the yield of 4a was dramatically improved to 85% when I₂ (0.4 equiv.) was added to this reaction as the catalyst and the time of the reaction reduced to 7 h (entry 2). When the amount of I₂ was screened, the highest yield of product 4a was 93% when 0.8 equiv. I₂ was used. Too much or too little I₂ decreased the yield (entries 2–6). In addition, an attempt to reduce the material ratio for the reaction was made, but the yield dropped to 69% (entry 18). Then attention was focused on screening the amount of base and the variety of base. We found that the yields of 4a were decreased to 88% and 80%, respectively, when 1.0 and 2.0 mmol K₂CO₃ were added to the reaction (entries 7–8). Using inorganic bases such as NaOH and NaHCO₃ gave product 4a in 68% and 40% yields, respectively, but organic bases such as Et₃N and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were ineffective (entries 9–12). Then, we examined the influence of different solvents (entries 4 and 13–16). From the results, THF was the best solvent. Lamentedly, when adding an additional oxidant H₂O₂ to the reaction, the yield of the desired product showed no improvement (entry 17). Therefore, the optimum reaction conditions were as follows: 0.8 equiv. of iodine, 1.5 mmol of K₂CO₃ in THF as a reaction solvent at 80 °C for 7 h (entry 4).

Scheme 1.

Three components catalyzed by iodine in one-pot reaction to synthesize pyrrolidines.

Table 1.

Optimization of the reaction conditions (base, catalyst, solvent) for the preparation of a trisubstituted pyrrolidine-2-carboxylic ester (4a; R^1,4,5 = Ph, R² = H, R³ = Et) via reaction of a mixture of benzaldehyde (1a; R¹ = Ph), glycine ethyl ester (2a; R² = H, R³ = Et), and chalcone (3a; R^4,5 = Ph) with a base and I₂ in a solvent (Scheme 1).^a,b

Entry	Additive (equiv.)	Base (mmol)	Solvent	Yield of 4a^b (%)
1	None	K₂CO₃ (1.5)	THF	35
2	I₂ (0.4)	K₂CO₃ (1.5)	THF	85
3	I₂ (0.6)	K₂CO₃ (1.5)	THF	88
4	I₂ (0.8)	K₂CO₃ (1.5)	THF	93
5	I₂ (1.0)	K₂CO₃ (1.5)	THF	84
6	I₂ (2.0)	K₂CO₃ (1.5)	THF	57
7	I₂ (0.8)	K₂CO₃ (1.0)	THF	88
8	I₂ (0.8)	K₂CO₃ (2.0)	THF	80
9	I₂ (0.8)	NaOH (1.5)	THF	68
10	I₂ (0.8)	NaHCO₃ (1.5)	THF	40
11	I₂ (0.8)	DBU (1.5)	THF	trace
12	I₂ (0.8)	Et₃N (1.5)	THF	trace
13	I₂ (0.8)	K₂CO₃ (1.5)	CH₃CN	36
14	I₂ (0.8)	K₂CO₃ (1.5)	DMF	79
15	I₂ (0.8)	K₂CO₃ (1.5)	Toluene	38
16	I₂ (0.8)	K₂CO₃ (1.5)	DCE	52
17^c	I₂ (0.6)	K₂CO₃ (1.5)	THF	81
18^d	I₂ (0.8)	K₂CO₃ (1.5)	THF	69

THF: tetrahydrofuran; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DMF: dimethylformamide; DCE: 1,2-dichloroethane.

Reaction conditions: a mixture of benzaldehyde 1a (0.5 mmol), glycine ethyl ester hydrochloride 2a (0.5 mmol), and a chalcone 3a (0.25 mmol) was heated with a base and I₂ in a solvent (2.0 mL) at 80 °C.

Isolated yield on 3a.

H₂O₂ (6.0 equiv.).

Reaction conditions: 1a (0.38 mmol), 2a (0.38 mmol), 3a (0.25 mmol), solvent (2.0 mL), 80 °C.

Having identified the optimal reaction conditions, we then evaluated the scope of the reaction and started with the screening of various aldehydes. The results are shown in Table 2. The group R¹ on the aryl ring could be either an electron-withdrawing group, such as a nitro (4b) or a trifluoromethyl group (4c), or an electron-donating group, such as a p-methoxy (4f) or a methyl group (4g). In each case high yields were obtained. In addition, when the substituent R¹ was a fused aromatic group, that is, naphthyl, or a heteroaryl group, that is, thiophenyl, the corresponding target compounds 4h and 4i were obtained in 89% and 80% yields, respectively. Then the scope of the chalcone substrate was investigated. We found that when the benzene ring of chalcone was substituted with electron-donating groups, such as a methyl (4l, 4r) or a methoxy group (4m, 4p, and 4q), the corresponding products were achieved in high yields. When R⁵ was o-hydroxyphenyl, product 4s was obtained in 51% yield. However, when strong electron-withdrawing groups such as a nitro group (4j, 4n) were attached to the benzene ring, low yields of products of about 47% were obtained. Gratifyingly, when R⁵ was naphthyl or thiophen-2-yl, excellent to good yields of the corresponding products (4t, 4u) were obtained in 81% and 75%, respectively. Finally, glycine methyl ester (2; R² = H, R³ = Me) and ethyl alanine ester (2; R² = Me, R³ = Et) also reacted as substrates to give a yield of 4v of 90% and a moderate yield of 4w of 58%.

Table 2.

Yields of a series of pyrrolidine-2-carboxylates (4; R^1–5 = various) prepared by heating a mixture of an araldehyde (1; R¹ = various), an amino acid ester (2; R², R³ = various), and a chalcone (3; R⁴, R⁵ = various) with I₂/K₂CO₃ in THF (Scheme 1).^a

Entry	Product	R¹	R²	R³	R⁴	R⁵	Yield^b (%)
1	4a	Ph	H	Et	Ph	Ph	93
2	4b	p-NO₂C₆H₄	H	Et	Ph	Ph	89
3	4c	p-CF₃C₆H₄	H	Et	Ph	Ph	92
4	4d	p-FC₆H₄	H	Et	Ph	Ph	94
5	4e	p-BrC₆H₄	H	Et	Ph	Ph	94
6	4f	p-MeOC₆H₄	H	Et	Ph	Ph	72
7	4g	p-CH₃C₆H₄	H	Et	Ph	Ph	94
8	4h	1-naphthyl	H	Et	Ph	Ph	89
9	4i	2-thienyl	H	Et	Ph	Ph	80
10	4j	Ph	H	Et	Ph	p-NO₂C₆H₄	47
11	4k	Ph	H	Et	Ph	p-BrC₆H₄	64
12	4l	Ph	H	Et	Ph	p-CH₃C₆H₄	84
13	4m	Ph	H	Et	Ph	p-MeOC₆H₄	81
14	4n	Ph	H	Et	p-NO₂C₆H₄	Ph	46
15	4o	Ph	H	Et	p-BrC₆H₄	Ph	50
16	4p	Ph	H	Et	p-MeOC₆H₄	Ph	83
17	4q	Ph	H	Et	m-MeOC₆H₄	Ph	84
18	4r	Ph	H	Et	p-CH₃C₆H₄	Ph	90
19	4s	Ph	H	Et	Ph	o-HOC₆H₄	51
20	4t	Ph	H	Et	Ph	2-naphthyl	81
21	4u	Ph	H	Et	Ph	2-thienyl	75
22	4v	Ph	H	Me	Ph	Ph	90
23	4w	Ph	Me	Et	Ph	Ph	58

THF: tetrahydrofuran.

Reaction conditions: a mixture of an araldehyde (1; R¹ = various), an amino acid ester (2; R², R³ = various), and a chalcone (3; R⁴, R⁵ = various) with I₂/K₂CO₃ in THF (2.0 mL) was heated for 7 h at 80 °C.

Isolated yield on 3a.

Based on the previous reports on the synthesis of pyrrolidine derivatives and the above experimental results, a reasonable mechanism for the I₂/K₂CO₃-catalyzed synthesis of pyrrolidine derivatives is shown in Scheme 2. First, benzaldehyde and glycine ethyl ester hydrochloride form a Schiff base N-(phenylmethyleneamino)acetate (A) in the presence of base. Then, the enone group in the chalcone, activated by iodine, suffers a base-catalyzed Michael addition reaction with Schiff base (A). After undergoing enol-tautomerism, cyclization, and protonation, this addition product yields the target compounds 4.

Scheme 2.

Plausible mechanism.

Experimental

All chemicals and solvents were purchased from commercial vendors (Aldrich or Alfa) and were used as received without further purification. ¹H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AM 500 MHz spectrometer in CDCl₃. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl₃, δ 7.26 ppm). ¹³C NMR spectra were recorded on an NMR instrument operated at 125 MHz with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl₃, δ 77.1 ppm). High-resolution mass spectra (HRMS) were recorded on a Thermo Scientific LTQ Orbitrap XL mass instrument (ESI). Thin-layer chromatography (TLC) was performed on precoated glass-backed plates and visualized with ultraviolet (UV) light at 254 nm. Flash column chromatography was performed on silica gel.

General procedure for the synthesis of 3

Compounds 3 were synthesized according to a literature report²⁸ and some improvements were made. To a solution of benzaldehyde (1.06 g, 10 mmol) and acetophenone (1.20 g, 10 mmol) in ethanol (30 mL) was added 2.5 M aqueous sodium hydroxide (0.8 g, 20 mmol) (30 mL) dropwise via an addition funnel at 0 °C. After completion of the reaction (detected by TLC), the solid product was filtered off, washed with ethanol–water solution (V/V = 1/1), and dried. The desired chalcone 3 was obtained in 75%–85% isolated yield.

General procedure for the synthesis of 4

An aromatic aldehyde 1 (0.5 mmol), an amino acid ester 2 (0. 5 mmol), a chalcone 3 (0.25 mmol), K₂CO₃ (1.5 mmol), I₂ (0.2 mmol), and THF (2 mL) were successively added into a closed and dry reaction tube and stirred at 80 °C for 7 h. The reaction was monitored by TLC. After the reaction had finished, the reaction mixture was extracted with ethyl acetate (3 × 10 mL) and washed with water, and the combined organic layers were washed with brine and aqueous Na₂S₂O₃, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (eluent ethyl acetate/petroleum ether = 1/4) gave the desired products 4a–w.

Ethyl 4-benzoyl-3,5-diphenylpyrrolidine-2-carboxylate (4a):²⁹ White solid (92.9 mg, 93% yield); m.p. 130–132 °C (Lit.²⁹ 126–129 °C); ¹H NMR (500 MHz, CDCl₃) δ: 7.56 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 9.3, 7.4 Hz, 3H), 7.35 (m, J = 7.7 Hz, 2H), 7.26 (dd, J = 14.9, 7.3 Hz, 3H), 7.11 (m, 5H), 5.02 (d, J = 8.8 Hz, 1H), 4.60–4.51 (t, J = 8.7 Hz, 1H), 4.28 (dq, J = 10.7, 7.1 Hz, 1H), 4.21–4.16 (m, 1H), 4.13 (dd, J = 7.8 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

Ethyl 4-benzoyl-5-(4-nitrophenyl)-3-phenylpyrrolidine-2-carboxylate (4b): Yellow solid (98.8 mg, 89% yield); m.p. 145–147 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.98 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.41–7.29 (m, 8H), 7.27 (d, J = 10.4 Hz, 2H), 5.11 (d, J = 8.7 Hz, 1H), 4.64 (t, J = 8.5 Hz, 1H), 4.33–4.24 (m, 1H), 4.18 (ddd, J = 14.3, 12.2, 8.2 Hz, 2H), 4.10 (t, J = 8.7 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.2, 172.2, 148.0, 147.1, 139.1, 137.0, 133.2, 129.0, 128.4, 128.2, 128.0, 127.9, 127.5, 123.9, 67.1, 66.3, 61.5, 61.0, 51.6, 14.2; HRMS (ESI) m/z calcd for C₂₆H₂₅N₂O₅⁺ (M + H)⁺ 445.17580; found: 445.17587.

Ethyl 4-benzoyl-3-phenyl-5-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate (4c): White solid (107.4 mg, 92% yield); m.p. 126–127 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.55 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.42–7.38 (m, 2H), 7.38–7.33 (m, 4H), 7.29 (m, 5H), 5.06 (d, J = 8.7 Hz, 1H), 4.59 (t, J = 8.3 Hz, 1H), 4.29 (dq, J = 10.7, 7.1 Hz, 1H), 4.22–4.14 (m, 2H), 4.13–4.09 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.2, 172.7, 143.5, 140.2, 137.3, 133.1, 128.8, 128.4, 128.0, 127.8, 127.8, 127.2, 125.0 (q, J = 3.6 Hz), 67.6, 65.8, 61.3, 60.2, 52.4, 14.1; HRMS (ESI) m/z calcd for C₂₇H₂₅F₃NO₃⁺ (M + H)⁺ 468.17810; found: 468.17847.

Ethyl 4-benzoyl-5-(4-fluorophenyl)-3-phenylpyrrolidine-2-carboxylate (4d): White solid (98.1 mg, 94% yield); m.p. 139–141 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d, J = 7.3 Hz, 1H), 7.46–7.37 (m, 4H), 7.34 (t, J = 7.6 Hz, 2H), 7.31–7.23 (m, 4H), 7.14–7.08 (m, 2H), 6.79 (t, J = 8.6 Hz, 2H), 5.01 (d, J = 8.9 Hz, 1H), 4.55 (t, J = 8.4 Hz, 1H), 4.27 (dq, J = 10.7, 7.1 Hz, 1H), 4.18 (dq, J = 10.7, 7.1, 1H), 4.12 (dd, J = 14.2, 6.3 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.2, 172.9, 163.0, 161.1, 140.3, 137.3, 135.2 (d, J = 3.2 Hz), 133.0, 129.1 (d, J = 8.2 Hz), 128.7, 128.3, 128.0, 127.8, 127.1, 115.0 (d, J = 21.5 Hz), 67.5, 65.7, 61.2, 60.5, 52.4, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₅FNO₃⁺ (M + H)⁺ 418.18130; found: 418.18176.

Ethyl 4-benzoyl-5-(4-bromophenyl)-3-phenylpyrrolidine-2-carboxylate (4e): White solid (112.2 mg, 94% yield); m.p. 157–159 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.40–7.36 (m, 2H), 7.33 (m, 4H), 7.27–7.20 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 4.98 (d, J = 8.8 Hz, 1H), 4.55 (t, J = 8.5 Hz, 1H), 4.27 (dq, J = 10.9, 7.1 Hz, 1H), 4.20–4.12 (dd, J = 15.7, 7.2 Hz, 2H), 4.09 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.1, 172.8, 140.2, 138.5, 137.3, 133.0, 131.2, 129.1, 128.7, 128.4, 128.0, 127.8, 127.2, 121.5, 67.5, 65.7, 61.3, 60.3, 52.4, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₅BrNO₃⁺ (M + H)⁺ 478.10123; found: 478.10150.

Ethyl 4-benzoyl-5-(4-methoxyphenyl)-3-phenylpyrrolidine-2-carboxylate (4f): White solid (77.3 mg, 72% yield); m.p. 134–136 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 13.8, 7.3 Hz, 3H), 7.33 (t, J = 7.6 Hz, 2H), 7.30–7.22 (m, 3H), 7.05 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.99 (d, J = 8.9 Hz, 1H), 4.53 (t, J = 8.4 Hz, 1H), 4.27 (dq, J = 10.8, 7.1 Hz, 1H), 4.19–4.13 (m, 2H), 4.14–4.08 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.4, 173.0, 158.9, 140.5, 137.5, 132.8, 131.5, 128.7, 128.6, 128.3, 128.1, 127.9, 127.0, 113.5, 67.6, 66.0, 61.2, 60.8, 55.1, 52.7, 14.1; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₄⁺ (M + H)⁺ 430.20128; found: 430.20169.

Ethyl 4-benzoyl-3-phenyl-5-(p-tolyl)pyrrolidine-2-carboxylate (4g): White solid (97.1 mg, 94% yield); m.p. 160–162 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 14.2, 7.3 Hz, 3H), 7.34 (t, J = 7.6 Hz, 2H), 7.30–7.23 (m, 3H), 7.02 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 7.9 Hz, 2H), 5.00 (d, J = 8.8 Hz, 1H), 4.55 (t, J = 8.4 Hz, 1H), 4.28 (dq, J = 10.7, 7.1 Hz, 1H), 4.28–4.25 (m, 1H), 4.17–4.11 (m, 2H), 2.20 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 198.5, 172.9, 140.6, 137.5, 137.2, 136.3, 132.7, 128.8, 128.7, 128.2, 128.1, 127.9, 127.3, 127.0, 67.7, 66.4, 61.2, 60.8, 52.8, 20.9, 14.1; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₃⁺ (M + H)⁺ 414.20637; found: 414.20679.

Ethyl 4-benzoyl-5-(naphthalen-1-yl)-3-phenylpyrrolidine-2-carboxylate (4h): White solid (100.1 mg, 89% yield); m.p. 160–162 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.98 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54–7.40 (m, 7H), 7.37–7.29 (m, 3H), 7.12 (d, J = 7.4 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.80 (t, J = 7.8 Hz, 2H), 5.75 (d, J = 7.7 Hz, 1H), 4.70 (dd, J = 7.7, 4.5 Hz, 1H), 4.37 (dq, J = 10.7, 7.1 Hz, 1H), 4.31–4.23 (m, 2H), 4.17 (dd, J = 7.7, 4.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 200.7, 172.4, 142.6, 136.8, 133.3, 133.0, 132.0, 130.8, 129.0, 128.8, 127.9, 127.7, 127.3, 127.3, 127.1, 125.9, 125.2, 125.2, 123.8, 122.5, 68.4, 62.9, 61.2, 59.7, 54.2, 14.2; HRMS (ESI) m/z calcd for C₃₀H₂₈NO₃⁺ (M + H)⁺ 450.20637; found: 450.20651.

Ethyl 4-benzoyl-3-phenyl-5-(thiophen-2-yl)pyrrolidine-2-carboxylate (4i): White solid (80.9 mg, 80% yield); m.p. 160–162 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.72 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.34 (dd, J = 17.2, 7.9 Hz, 4H), 7.24 (m, 1H), 7.05 (d, J = 4.5 Hz, 1H), 6.77–6.69 (m, 2H), 5.30 (d, J = 8.3 Hz, 1H), 4.57 (t, J = 8.2 Hz, 1H), 4.27 (dq, J = 10.8, 7.1 Hz, 1H), 4.19–4.14 (m, 2H), 4.13 (dd, J = 8.1, 5.7 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.4, 172.8 8, 143.2, 140.2, 137.3, 133.0, 128.7, 128.4, 128.1, 127.9, 127.1, 126.6, 125.5, 124.7, 67.2, 61.7, 61.2, 60.3, 51.6, 14.1; HRMS (ESI) m/z calcd for C₂₄H₂₄NO₃S⁺ (M + H)⁺ 406.14714; found: 406.14761.

Ethyl 4-(4-nitrobenzoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4j): Yellow solid (52.3 mg, 47% yield); m.p. 157–159 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.06 (d, J = 7.0 Hz, 2H), 7.65–7.59 (m, 2H), 7.43–7.39 (m, 2H), 7.37–7.35 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.13–7.05 (m, 5H), 5.04 (d, J = 8.9 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.33–4.24 (m, 1H), 4.21–4.17 (m, 1H), 4.17–4.12 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.6, 172.7, 147.5, 147.1, 139.8, 137.0, 133.5, 128.8, 128.6, 128.4, 128.0, 127.8, 127.4, 123.2, 67.5, 65.3, 61.4, 59.9, 52.1, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₅N₂O₅⁺ (M + H)⁺ 445.17580; found: 445.17587.

Ethyl 4-(4-bromobenzoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4k): Creamy-white (76.7 mg, 64% yield); m.p. 112–116 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.41–7.37 (m, 6H), 7.35 (m, 2H), 7.30–7.23 (m, 1H), 7.16–7.06 (m, 5H), 5.00 (d, J = 8.8 Hz, 1H), 4.46 (dq, J = 8.7, 7.7 Hz, 1H), 4.28 (dq, J = 8.7, 7.7 Hz, 1H), 4.21–4.15 (m, 1H), 4.11 (dd, J = 17.3, 9.7 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.7, 172.7, 140.6, 138.9, 136.2, 131.5, 129.5, 128.8, 128.3, 127.9, 127.8, 127.4, 127.2, 67.7, 66.7, 61.3, 60.8, 52.9, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₅BrNO₃⁺ (M + H)⁺ 478.10123; found: 478.10175.

Ethyl 4-(4-methylbenzoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4l): White solid (86.9 mg, 84% yield); m.p. 125–127 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.49 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.17–7.05 (m, 7H), 5.01 (d, J = 8.7 Hz, 1H), 4.54 (t, J = 8.4 Hz, 1H), 4.28 (dq, J = 10.7, 7.1 Hz, 1H), 4.20–4.14 (m, 2H), 4.14–4.08 (m, 1H), 2.32 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.7, 172.9, 139.2, 137.6, 137.5, 136.7, 128.2, 128.1, 128.1, 127.7, 127.6, 127.4, 67.9, 66.7, 61.2, 60.7, 52.5, 21.1, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₃⁺ (M + H)⁺ 414.20637; found: 414.20679.

Ethyl 4-(4-methoxybenzoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4m): White solid (86.9 mg, 81% yield); m.p. 122–124 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J = 8.9 Hz, 2H), 7.41–7.37 (m, 2H), 7.34 (d, J = 10.4, 4.9 Hz, 2H), 7.26–7.22 (m, 1H), 7.18–7.06 (m, 5H), 6.75 (dd, J = 9.4, 2.4 Hz, 2H), 4.99 (d, J = 8.7 Hz, 1H), 4.50 (t, J = 8.3 Hz, 1H), 4.28 (dq, J = 7.1, 11.7 Hz, 1H), 4.17 (dq, J = 7.1, 11.7 Hz, 1H), 4.15 (dd, J = 9.3 Hz, 8.7 Hz, 2H), 4.10 (t, J = 8.0 Hz, 1H), 3.81 (s, 3H), 1.19 (t, J = 8.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.8, 172.9, 163.3, 140.8, 139.4, 130.7, 130.4, 128.7, 128.1, 127.9, 127.6, 127.4, 127.0, 113.4, 67.8, 66.8, 61.2, 60.3, 55.4, 52.9, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₄⁺ (M + H)⁺ 430.20128; found: 430.20175.

Ethyl 4-benzoyl-3-(4-nitrophenyl)-5-phenylpyrrolidine-2-carboxylate (4n): Yellow solid (51.2 mg, 46% yield); m.p. 122–124 °C; ¹H NMR (500 MHz, CDCl3) δ: 8.20 (d, J = 8.7 Hz, 2H), 7.58 (dd, J = 11.2, 8.3 Hz, 4H), 7.49–7.40 (m, 1H), 7.35–7.26 (m, 2H), 7.15–7.03 (m, 5H), 5.06 (d, J = 9.1 Hz, 1H), 4.56 (t, J = 9.2 Hz, 1H), 4.30–4.23 (m, 2H), 4.22–4.18 (m, 1H), 4.18–4.12 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.6, 172.7, 147.5, 147.1, 139.8, 137.0, 133.5, 128.8, 128.6, 128.4, 128.0, 127.8, 127.4, 123.2, 67.5, 65.3, 61.4, 59.9, 52.1, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₅N₂O₅⁺ (M + H)⁺ 445.17580; found: 445.17587.

Ethyl 4-benzoyl-3-(4-bromophenyl)-5-phenylpyrrolidine-2-carboxylate (4o): White solid (59.9 mg, 50% yield); m.p. 132–134 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.55 (d, J = 7.2 Hz, 2H), 7.47–7.45 (m, 2H), 7.42 (dd, J = 4.9, 3.7 Hz, 1H), 7.30–7.27 (m, 4H), 7.11–7.07 (m, 5H), 5.00 (d, J = 9.0 Hz, 1H), 4.49 (t, J = 8.7 Hz, 1H), 4.27 (dq, J = 14.3, 7.1 Hz, 1H), 4.17 (dd, J = 17.9, 7.1 Hz,1H), 4.10 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.9, 172.7, 139.5, 139.3, 137.3, 132.9, 131.8, 129.7, 128.3, 128.2, 128.0, 127.7, 127.5, 120.9, 67.4, 66.4, 61.3, 60.8, 51.8, 14.2; HRMS (ESI) m/z calcd for C₂₆H₂₅BrNO₃⁺ (M + H)⁺ 478.10123; found: 478.10129.

Ethyl 4-benzoyl-3-(4-methoxyphenyl)-5-phenylpyrrolidine-2-carboxylate (4p): White solid (89.2 mg, 83% yield); m.p. 98–99 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.56 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.30–7.25 (m, 2H), 7.15–7.05 (m, 5H), 6.88 (d, J = 8.7 Hz, 2H), 5.00 (d, J = 8.8 Hz, 1H), 4.54–4.48 (t, J = 8.6 Hz 1H), 4.28 (dq, J = 10.7, 7.1 Hz, 1H), 4.17 (dq, J = 10.7, 7.1 Hz, 1H), 4.08 (dd, J = 17.4, 9.4 Hz, 2H), 3.80 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.5, 173.0, 158.6, 139.4, 137.5, 132.8, 132.5, 128.8, 128.2, 128.1, 128.0, 127.6, 127.4, 114.1, 67.7, 66.5, 61.2, 60.8, 55.2, 52.1, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₄⁺ (M + H)⁺ 430.20128; found: 430.20151.

Ethyl 4-benzoyl-3-(3-methoxyphenyl)-5-phenylpyrrolidine-2-carboxylate (4q): White solid (90.2 mg, 84% yield); m.p. 104–106 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.57 (t, J = 9.2 Hz, 2H), 7.44–7.36 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.30–7.22 (m, 2H), 7.19–7.05 (m, 5H), 7.03–6.85 (m, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.00 (d, J = 8.7, 3.8 Hz, 1H), 4.52 (dt, J = 23.8, 8.2 Hz, 1H), 4.32–4.23 (m, 1H), 4.16 (dd, J = 12.1, 8.2 Hz, 2H), 4.10 (dd, J = 17.5, 9.3 Hz, 1H), 3.81 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.6, 172.9, 159.8, 142.4, 139.1, 137.5, 132.8, 129.7, 128.2, 128.1, 128.1, 127.6, 127.4, 120.1, 113.9, 112.2, 77.3, 77.1, 76.8, 67.7, 66.7, 61.2, 60.6, 55.2, 52.9, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₄⁺ (M + H)⁺ 430.20128; found: 430.20151.

Ethyl 4-benzoyl-5-phenyl-3-(p-tolyl)pyrrolidine-2-carboxylate (4r): White solid (93.4 mg, 90% yield); m.p. 149–150 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.55 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.30–7.24 (m, 4H), 7.18–7.06 (m, 7H), 5.00 (d, J = 8.7 Hz, 1H), 4.55–4.51 (t, J = 8.4 Hz, 1H), 4.33–4.25 (m, 1H), 4.18 (dq, J = 10.7, 7.1 Hz, 1H), 4.09 (dd, J = 18.6, 10.8 Hz, 2H), 2.33 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.7, 173.0, 139.3, 137.6, 137.5, 136.7, 128.2, 128.1, 128.1, 127.7, 127.6, 127.4, 67.9, 66.7, 61.2, 60.7, 52.5, 21.1, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₃⁺ (M + H)⁺ 414.20637; found: 430.20654.

Ethyl 4-(2-hydroxybenzoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4s): White solid (53.2 mg, 51% yield); m.p. 160–162 °C; ¹H NMR (500 MHz, CDCl₃) δ: 11.79 (s, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.36 (qd, J = 8.3, 1.3 Hz, 6H), 7.21–7.16 (m, 2H), 7.16–7.08 (m, 3H), 6.79 (dd, J = 18.2, 8.2 Hz, 2H), 5.06 (d, J = 8.8 Hz, 1H), 4.59 (t, J = 8.5 Hz, 1H), 4.28 (dq, J = 10.7, 7.2 Hz, 1H), 4.18 (dd, J = 10.1, 3.6 Hz, 2H), 4.16–4.11 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 203.8, 172.8, 162.3, 140.1, 138.9, 136.2, 129.9, 128.8, 128.2, 127.9, 127.8, 127.2, 127.1, 120.0, 118.6, 118.2, 67.6, 67.0, 61.3, 60.1, 52.1, 14.1; HRMS (ESI) m/z calcd for C₂₆H₂₆NO₄⁺ (M + H)⁺ 416.18563; found: 416.18570.

Ethyl 4-(2-naphthoyl)-3,5-diphenylpyrrolidine-2-carboxylate (4t): White solid (91.1 mg, 81% yield); m.p. 118–120 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.14 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.62–7.49 (m, 3H), 7.47–7.42 (m, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.27–7.24 (m, 1H), 7.17–7.13 (m, 2H), 7.08–6.99 (m, 3H), 5.11 (d, J = 8.8 Hz, 1H), 4.75–4.70 (t, J = 8.5 Hz, 1H), 4.30 (dq, J = 10.8, 7.1 Hz, 1H), 4.20 (dd, J = 15.1, 6.5 Hz, 2H), 4.18–4.11 (m, 1H), 1.20 (t, J = 7.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.2, 172.9, 140.6, 139.3, 135.3, 134.8, 132.2, 129.8, 129.4, 128.7, 128.4, 128.1, 127.9, 127.6, 127.6, 127.3, 127.1, 123.8, 67.7, 66.7, 61.2, 60.7, 52.8, 14.1; HRMS (ESI) m/z calcd for C₃₀H₂₈NO₃⁺ (M + H)⁺ 450.20637; found: 450.20651.

Ethyl 3,5-diphenyl-4-(thiophene-2-carbonyl)pyrrolidine-2-carboxylate (4u): White solid (76.1 mg, 75% yield); m.p. 128–130 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.47 (d, J = 3.8 Hz, 1H), 7.41 (dd, J = 3.8, 1.1 Hz, 1H), 7.40–7.33 (m, 4H), 7.27 (ddd, J = 7.1, 5.8, 1.5 Hz, 2H), 7.21 (dd, J = 8.2, 1.2 Hz, 2H), 7.19–7.09 (m, 3H), 6.95 (dd, J = 4.9, 3.9 Hz, 1H), 5.00 (d, J = 8.5 Hz, 1H), 4.34–4.30 (m, 1H), 4.30–4.25 (m, 1H), 4.22–4.12 (m, 2H), 4.11–4.07 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 191.1, 172.7, 145.0, 140.8, 138.7, 133.8, 131.9, 128.7, 128.2, 127. 8, 127.7, 127.7, 127.3, 127.1, 67.8, 67.1, 62.1, 61.2, 52.8, 14.1; HRMS (ESI) m/z calcd for C₂₄H₂₄NO₃S⁺ (M + H)⁺ 406.14714; found: 406.14755.

Methyl 4-benzoyl-3,5-diphenylpyrrolidine-2-carboxylate (4v):³⁰ White solid (86.9 mg, 90% yield); m.p. 159–161 °C (Lit.³⁰ 150–154°C); ¹H NMR (500 MHz, CDCl₃) δ: 7.55 (d, J = 7.4 Hz, 2H), 7.44–7.38 (m, 3H), 7.36 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 3H), 7.17–7.03 (m, 5H), 5.01 (d, J = 8.7 Hz, 1H), 4.59–4.42 (t, J = 8.4 Hz, 1H), 4.20 (d, J = 8.9 Hz, 1H), 4.16–4.12 (t, J = 7.2 Hz, 1H), 3.77 (s, 1H).

Ethyl 4-benzoyl-2-methyl-3,5-diphenylpyrrolidine-2-carboxylate (4w): Light yellow solid (60.1 mg, 58% yield); m.p. 143–145 °C; ¹H NMR (500 MHz, CDCl₃) δ: 7.61 (d, J = 7.2 Hz, 2H), 7.46–7.39 (m, 2H), 7.30 (dt, J = 8.0, 4.2 Hz, 5H), 7.26–7.20 (m, 1H), 7.19–7.12 (m, 2H), 7.12–7.06 (m, 3H), 5.05 (d, J = 9.5 Hz, 1H), 4.94–4.88 (m, 1H), 1.32 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.7, 175.2, 139.6, 137.7, 137.6, 132.7, 128.7, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.2, 68.5, 64.1, 61.6, 56.8, 55.0, 21.4, 14.2; HRMS (ESI) m/z calcd for C₂₇H₂₈NO₃⁺ (M + H)⁺ 414.20637; found: 414.20648.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We gratefully acknowledge the financial support provided by the Natural Science Foundation of China (Grant No. 21606201) and the National Natural Science Foundation of Zhejiang (Grant No. LY13B020016).

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Iodine/K 2 CO 3 -catalyzed synthesis of multisubstituted pyrrolidine-2-carboxylates via a one-pot reaction between an araldehyde,an amino acid ester,and a chalcone