Stereoselective Synthesis of Pyrrolidines Containing a 3-Fluoro

Sep 21, 2017 - Enantiomer ratios were determined by analysis of HPLC traces, obtained by using Chiralpak IA, AS-H ,or AD-H columns with n-hexane and i...
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Article Cite This: J. Org. Chem. 2017, 82, 11141-11149

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Stereoselective Synthesis of Pyrrolidines Containing a 3‑Fluoro Quaternary Stereocenter via Copper(I)-Catalyzed Asymmetric 1,3Dipolar Cycloaddition Yang-Zi Liu,† Shao-Jing Shang,† Wu-Lin Yang, Xiaoyan Luo,* and Wei-Ping Deng* School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China S Supporting Information *

ABSTRACT: A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to β,β-disubstituted β-fluoroacrylates catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system is reported, affording chiral densely substituted pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, in good to excellent yields (up to 99%), with excellent levels of diastereo- and enantioselectivities (dr >20:1; ee up to 99%).

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Despite great progress in this field, the synthesis of chiral pyrrolidines with four contiguous stereocenters, including one quaternary stereocenter at the 3-position, still poses a considerable challenge because of the requisite use of sterically encumbered and less reactive β,β-disubstituted unsaturated compounds7 (Scheme 1a). Thus, it can be seen that the

INTRODUCTION Introducing a fluorine or fluorine-containing group into pharmaceutical and agrochemical molecules often causes a beneficial effect on the properties of those molecules.1 Among those organofluorine molecules, chiral fluorinated compounds, especially those containing a fluorinated quaternary stereogenic center, have attracted particular attention in medicinal chemistry and agrochemistry, due to their unique effect on biological activity, metabolic stability, or other desirable changes in physical properties of molecules.2,3 For instance, F-DADMeImmH,4a a potent immucillin purine nucleoside phosphorylase (PNP) inhibitor, a kind of anti-infective agent,4b and a β-secretase inhibitor4c developed by Novartis all contain a fluorinated quaternary stereogenic carbon center on the pyrrolidine ring, which plays a great role in the structure− activity relationship (Figure 1). On the other hand, the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with activated dipolarophiles is one of the most powerful and widely used methods for the construction of chiral densely substituted pyrrolidines.5,6

Scheme 1. Asymmetric [3 + 2] Cycloadditions of Azomethine Ylides with β,β-Disubstituted Unsaturated Compounds

construction of four contiguous chiral stereocenters, especially with a fluorinated quaternary stereocenter at the 3-position, remains extremely challenging. To the best of our knowledge, only one racemic example has been reported by using a 1,3dipolar cycloaddition reaction with fluoromaleate as the Figure 1. Selected examples of biologically active pyrrolidines containing a fluorinated quaternary stereogenic carbon center. © 2017 American Chemical Society

Received: August 24, 2017 Published: September 21, 2017 11141

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry

Table 1. Optimization for the Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylide 2a with (Z)-β-Fluoro-β(pyridin-2-yl)acrylate Methyl Ester 1aa

entry

metal

ligand

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13d 14d,e

AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgClO4 AgBF4 Cu(CH3CN)4ClO4 Cu(CH3CN)4PF6 Cu(CH3CN)4BF4 Cu(CH3CN)4BF4 Cu(CH3CN)4BF4

L1 L2 L3 L4 L5 L6 L7 L7 L7 L7 L7 L7 L7 L7

98 94 92 85 98 98 82 91 86 96 94 98 98 98

24 82 26 80 26 81 85 75 75 95 95 95 97 97

a

Unless otherwise stated, reactions were carried out with 0.2 mmol of 1a and 0.3 mmol of 2a in 2 mL of Et2O at room temperature. bIsolated yield. >20:1 dr was determined by crude 1H NMR spectroscopy, and ee was determined by chiral HPLC analysis. dReaction conducted at −30 °C. e5 mol % of catalyst was used. c

entries 1−7), which was consistent with our earlier findings.10 N,O-Ligand L7 bearing iodine at the C4 position of the quinoline backbone gave excellent yield and enantioselectivity (Table 1, entry 7). Further switching the metal source from Ag(I) to Cu(I) resulted in a remarkable improvement in enantioselectivity (Table 1, entries 8−12). Among the tested metal salts, Cu(CH3CN)4BF4 gave the best result in terms of the reaction yield and enantioselectivity (Table 1, entry 12). Screening of other bases and solvents did not show any better results (see Table S1 in the Supporting Information). In addition, lowering the reaction temperature to −30 °C led to a slight improvement in enantioselectivity (Table 1, entry 13). A decrease in the catalyst loading from 10 to 5 mol % in the presence of ligand L7 did not cause any loss in the yield and stereoselectivity, affording endo-3aa in 98% yield and 97% ee (Table 1, entry 14). With the optimized reaction conditions in hand, the generality and substrate scope of this process were investigated, and the results are shown in Tables 2 and 3. To begin with, the ester groups of imino esters 2a−d were varied (Me, Et, i-Pr, tBu), giving the corresponding products 3aa−ad in high yields (98−99%) with high diastereoselectivities (dr >20:1) and high enantioselectivities (97% ee) (Table 2, entries 1−4). A series of azomethine ylides 2 bearing electron-rich, electronically neutral, and electron-deficient groups on the aryl ring reacted with (Z)β-fluoro-β-(pyridin-2-yl)acrylate methyl ester 1a smoothly affording the corresponding endo cycloadducts 3ae−ao,ar in excellent yields (98−99%), with high diastereo- and enantioselectivity (dr >20:1; ee = 93−99%). It is noteworthy that the sterically hindered o-chloro-substituted azomethine ylide 2e

dipolarophile.8 However, enantioselective construction of pyrrolidines containing a 3-fluoro quaternary stereocenter has not yet been reported.9 Recently a series of novel DHIPOH-based N,O-ligand catalytic systems have been successfully applied by our group to construct structurally diverse pyrrolidines,10 especially containing a quaternary stereocenter at the 4-position,10b−d with excellent diastereo- and enantioselectivities. Encouraged by these results, we describe our further applications of the DHIPOH-based N,O-ligand catalytic system for the asymmetric synthesis of pyrrolidines containing a 3-fluoro quaternary stereocenter via Cu(I)-catalyzed 1,3-dipolar cycloaddition (Scheme 1b).

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RESULTS AND DISCUSSION Initially, (Z)-β-fluoro-β-(pyridin-2-yl)acrylate methyl ester 1a was chosen as the model dipolarophile to investigate the feasibility of 1,3-dipolar cycloaddition with N-(4chlorobenzylidene)glycine methyl ester 2a in the presence of chiral N,O-ligand L1/AgOAc as the catalyst and Cs2CO3 as the base in ether at ambient temperature (Table 1, entry 1). Gratifyingly, the 1,3-dipolar cycloaddition proceeded smoothly, affording fluorinated pyrrolidine endo-3aa in 98% yield with excellent diastereoselectivity (dr >20:1) and low enantioselectivity (24% ee). Encouraged by this promising result, different chiral N,O-ligands and metal salts were subsequently screened to establish optimal reaction conditions, and the representative results are summarized in Table 1. A ligand survey revealed that the introduction of a methyl group on the imidazole ring of the ligands improved the yields and enantioselectivities (Table 1, 11142

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of Azomethine Ylides 2a

entry

2

R1/R2

3

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m 2n 2o 2p 2q 2r

p-ClC6H4/Me p-ClC6H4/Et p-ClC6H4/i-Pr p-ClC6H4/t-Bu o-ClC6H4/Me m-ClC6H4/Me o-MeC6H4/Me m-MeC6H4/Me p-MeC6H4/Me o-MeOC6H4/Me m-MeOC6H4/Me p-MeOC6H4/Me p-BrC6H4/Me Ph/Me 1-naphthyl/Me 2-furyl/Me 2-thienyl/Me 2-naphthyl/Me

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak 3al 3am 3an 3ao 3ap 3aq 3ar

99 99 98 98 98 99 98 99 99 98 98 98 99 98 98 99 99 99

97 97 97 97 94 97 97 96 99 96 95 98 97 98 93 97 95 96

(1b,c) gave the corresponding products (3ba,ca) in high yields (97−98%) with high diastereoselectivities (dr >20:1) and excellent enantioselectivities (97% ee) (Table 3, entries 1 and 2). (Z)-β-Fluoroacrylates 1d,e bearing para and meta substituents on the β-(pyridin-2-yl) ring reacted smoothly with azomethine ylide 2a to afford the corresponding endo cycloadducts 3da,ea in excellent yields (97−98%), with excellent diastereo- and enantioselectivity (dr >20:1; ee = 97−98%) (Table 3, entries 3 and 4). Switching the heterocyclic ring of (Z)-β-fluoroacrylates from β-(pyridin-2-yl) to a substituted phenyl ring also resulted in smooth reactions with azomethine ylide 2a to afford the corresponding products 3fa− ja in good yields (80−91%), with excellent diastereo- and enantioselectivities (dr >20:1; ee = 97−98%). To demonstrate the synthetic utility of this catalytic system, the reaction was carried out on a gram scale, affording 3ai in 96% yield, >20:1 dr, and 99% ee (Scheme 2). Scheme 2. Gram-Scale Cataytic Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylide 2i with (Z)-βFluoroacrylate 1a

a

All reactions were carried out with 0.2 mmol of 1a and 0.3 mmol of 2 in 2 mL of Et2O at −30 °C. bIsolated yield. c>20:1 dr was determined by crude 1H NMR spectroscopy, and ee was determined by chiral HPLC analysis.

According to previous work in our laboratories,10e the excellent stereoselectivities can be rationalized by the proposed transition state I, which favors an endo cycloadduct (Figure 2).

Table 3. Substrate Scope of (Z)-β-Fluoroacrylates 1a

entry

1

R1/R2

3

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9

1b 1c 1d 1e 1f 1g 1h 1i 1j

2-pyridyl/Et 2-pyridyl/i-Pr 4-Cl-2-pyridyl/Me 4-CH3-2-pyridyl/Me 4-CNC6H4/Me 4-NO2C6H4/Me 4-ClC6H4/Me 3-ClC6H4/Me Ph/Me

3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja

97 98 97 98 89 91 87 86 80

97 97 97 98 98 98 97 97 97

a

All reactions were carried out with 0.2 mmol of 1 and 0.3 mmol of 2a in 2 mL of Et2O at −30 °C. bIsolated yield. c>20:1 dr was determined by crude 1H NMR spectroscopy, and ee was determined by chiral HPLC analysis.

Figure 2. Proposed transition state leading to the major product endo3af.

and 1-naphthylaldehyde derived azomethine ylide 2o afforded the endo cycloadducts with slightly lower enantioselectivities (Table 2, entries 5 and 15). Additionally, the heteroaryl imino esters 2p−q derived from 2-furylaldehyde and 2-thenaldehyde worked efficiently in this transformation, resulting in the desired cycloadducts 3ap,aq in 97% ee and 95% ee, respectively (Table 2, entries 16 and 17). Next, (Z)-β-fluoroacrylates 1 were investigated under the optimized conditions to test the dipolarophile scope of this asymmetric 1,3-dipolar cycloaddition, and representative results are summarized in Table 3. Changing the ester groups of (Z)-βfluoroacrylates from methyl to ethyl and isopropyl groups

As shown in proposed transition state II, the “bottom” face is blocked by two phenyl groups adjacent to the oxygen and iodine at the C4 position of the quinoline backbone, which facilitates the approach of dipolarophiles 2f from the “top” face, affording endo-3af. The relative and absolute configuration of the major diastereoisomer of 3af was assigned as endo(2S,3S,4R,5S) by single-crystal X-ray crystallographic analysis (details in the Supporting Information), which could be applied to all cycloadducts. 11143

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry

(d, J = 2.3 Hz), 164.4 (d, J = 275.8 Hz), 150.1 (d, J = 4.7 Hz), 148.6 (d, J = 34.3 Hz), 137.2 (d, J = 1.7 Hz), 125.6, 120.5 (d, J = 5.2 Hz), 98.8 (d, J = 3.5 Hz), 51.8. HRMS (EI-TOF) m/z: [M]+ calcd for C9H8FNO2 181.0534; found 181.0540. Ethyl (Z)-3-Fluoro-3-(pyridin-2-yl)acrylate (1b). Light yellow oil, 731.5 mg, 75% yield. 1H NMR (400 MHz, chloroform-d): δ 8.64 (d, J = 4.6 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.37 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 6.64 (d, J = 33.2 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ 164.2 (d, J = 275.4 Hz), 164.1 (d, J = 2.2 Hz), 150.0 (d, J = 4.7 Hz), 148.7 (d, J = 34.3 Hz), 137.1 (d, J = 1.8 Hz), 125.6, 120.5 (d, J = 5.1 Hz), 99.2 (d, J = 3.4 Hz), 60.6, 14.3. HRMS (EITOF) m/z: [M]+ calcd for C10H10FNO2 195.0690; found 195.0695. Isopropyl (Z)-3-Fluoro-3-(pyridin-2-yl)acrylate (1c). Colorless oil, 805.5 mg, 77% yield. 1H NMR (400 MHz, chloroform-d): δ 8.63 (d, J = 4.5 Hz, 1H), 7.83−7.70 (m, 1H), 7.38−7.35 (m, 1H), 6.61 (d, J = 33.2 Hz, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 1.31 (d, J = 6.3 Hz, 6H). 13 C NMR (100 MHz, chloroform-d): δ 164.1 (d, J = 275.0 Hz), 163.7 (d, J = 2.2 Hz), 150.0 (d, J = 4.7 Hz), 148.9 (d, J = 34.4 Hz), 137.1 (d, J = 1.7 Hz), 125.5, 120.4 (d, J = 5.1 Hz), 99.7 (d, J = 3.3 Hz), 68.0, 22.0, 22.0. HRMS (EI-TOF) m/z: [M]+ calcd for C11H12FNO2 209.0847; found 209.0851. Methyl (Z)-3-(5-Chloropyridin-2-yl)-3-fluoroacrylate (1d). White solid, 733.1 mg, 68% yield. Mp: 104−107 °C. 1H NMR (400 MHz, chloroform-d): δ 8.58 (dd, J = 2.4, 1.1 Hz, 1H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 6.61 (d, J = 33.0 Hz, 1H), 3.81 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 164.4 (d, J = 2.2 Hz), 163.5 (d, J = 275.1 Hz), 149.2 (d, J = 4.6 Hz), 146.7 (d, J = 35.3 Hz), 136.8 (d, J = 1.7 Hz), 134.2, 121.2 (d, J = 4.8 Hz), 99.3 (d, J = 3.5 Hz), 51.9. HRMS (EI-TOF) m/z: [M]+ calcd for C9H7ClFNO2 215.0144; found 215.0147. Methyl (Z)-3-Fluoro-3-(5-methylpyridin-2-yl)acrylate (1e). White solid, 692.9 mg, 71% yield. Mp: 93−96 °C. 1H NMR (400 MHz, chloroform-d): δ 8.46 (s, 1H), 7.64−7.58 (m, 2H), 6.58 (d, J = 33.3 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, chloroformd): δ 164.7(8) (d, J = 275.5 Hz), 164.7(6) (d, J = 2.1 Hz), 150.8 (d, J = 4.5 Hz), 146.0 (d, J = 34.2 Hz), 137.3, 136.0, 120.2 (d, J = 4.9 Hz), 98.0 (d, J = 3.6 Hz), 51.8, 18.7. HRMS (EI-TOF) m/z: [M]+ calcd for C10H10FNO2 195.0690; found 195.0697. Methyl (Z)-3-(4-Cyanophenyl)-3-fluoroacrylate (1f). White solid, 707.9 mg, 69% yield. Mp: 124−127 °C. 1H NMR (400 MHz, chloroform-d): δ 7.78−7.73 (m, 4H), 6.02 (d, J = 32.7 Hz, 1H), 3.82 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 164.0 (d, J = 277.6 Hz), 163.8 (d, J = 2.5 Hz), 134.7 (d, J = 27.3 Hz), 132.8 (d, J = 2.1 Hz), 132.8 (d, J = 2.1 Hz), 126.3 (d, J = 7.8 Hz), 126.3 (d, J = 7.8 Hz), 118.0, 115.1, 100.0 (d, J = 7.0 Hz), 52.0. HRMS (EI-TOF) m/z: [M]+ calcd for C11H8FNO2 205.0534; found 205.0541. Methyl (Z)-3-Fluoro-3-(4-nitrophenyl)acrylate (1g). White solid, 844.4 mg, 75% yield. Mp: 139−142 °C. 1H NMR (400 MHz, chloroform-d): δ 8.23 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 5.99 (d, J = 32.6 Hz, 1H), 3.75 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 163.7(1) (d, J = 277.7 Hz), 163.6(8) (d, J = 2.5 Hz), 149.5, 136.4 (d, J = 27.1 Hz), 126.7 (d, J = 7.6 Hz), 126.7 (d, J = 7.6 Hz), 124.3 (d, J = 2.1 Hz), 124.3 (d, J = 2.1 Hz), 100.4 (d, J = 7.0 Hz), 52.1. HRMS (EI-TOF) m/z: [M]+ calcd for C10H8FNO4 225.0432; found 225.0438. Methyl (Z)-3-(4-Chlorophenyl)-3-fluoroacrylate (1h). White solid, 686.7 mg, 64% yield. Mp: 68−71 °C. 1H NMR (400 MHz, chloroform-d): δ 7.59 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 5.89 (d, J = 33.2 Hz, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 165.3 (d, J = 277.3 Hz), 164.2 (d, J = 2.4 Hz), 137.8, 129.2 (d, J = 1.9 Hz), 129.2 (d, J = 1.9 Hz), 129.0 (d, J = 26.9 Hz), 126.9 (d, J = 8.0 Hz), 126.9 (d, J = 8.0 Hz), 97.2 (d, J = 7.1 Hz), 51.7. HRMS (EI-TOF) m/z: [M]+ calcd for C10H8ClFO2 214.0191; found 214.0193. Methyl (Z)-3-(3-Chlorophenyl)-3-fluoroacrylate (1i). White solid, 643.8 mg, 60% yield. Mp: 60−63 °C. 1H NMR (400 MHz, chloroform-d): δ 7.63 (t, J = 1.9 Hz, 1H), 7.53 (dt, J = 7.8, 1.5 Hz, 1H), 7.47−7.45 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 5.91 (d, J = 33.0 Hz, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 164.9 (d, J

Ester groups of 3ai could be reduced by LiAlH4 in ether at 0 °C, leading to the corresponding alcohol 4 in 60% yield, without loss of stereochemical integrity (Scheme 3). Scheme 3. Reduction of Cycloadduct 3ai to 3Fluoropyrrolidine 4

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CONCLUSION In conclusion, we have developed a highly efficient chiral N,Oligand/Cu(CH3CN)4BF4 catalytic system for the asymmetric 1,3-dipolar cycloaddition of azomethine ylides with (Z)-βfluoroacrylates, affording 3-fluoropyrrolidines in good to excellent yields (up to 99%), with excellent levels of diastereoand enantioselectivities (dr >20:1; ee up to 99%). Notably, this is the first example of the highly stereoselective construction of chiral pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, which suggests a highly efficient synthetic protocol of potential importance to medicinal chemistry and diversity-oriented synthesis. Further investigations in the area of 3-fluoropyrrolidines synthesis and applications are ongoing in our laboratories.

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EXPERIMENTAL SECTION

General Information. 1H NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The spectrum are interpreted as s = singlet, d = doublet, t = triplet, q = quartet, hept = heptet, m = multiplet, and br s = broad singlet; coupling constant(s) J are reported in Hz, and relative integrations are reported. 13C NMR (100 MHz) spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal chloroform signal at 77.16 ppm as a standard. Optical rotations were measured on an AUTOPOL V instrument. Diastereomeric ratios were determined from crude 1H NMR spectroscopy interpretation or by analysis of HPLC traces. Enantiomer ratios were determined by analysis of HPLC traces, obtained by using Chiralpak IA, AS-H ,or AD-H columns with nhexane and isopropyl alcohol as solvents. (Chiralpak IA, AS-H, and AD-H columns were purchased from Daicel Chemical Industries, Ltd.) Melting points were obtained in open capillary tubes using an SGW X4 micro melting point apparatus and are uncorrected. Mass spectra were recorded on a TOF mass spectrometer. Toluene, Et2O, and 1,4dioxane were distilled over sodium. THF was distilled over benzophenone and sodium. i-Pr2O was distilled over calcium hydride. β-Fluoroacrylates were prepared by reference to the literature procedures.11 N,O-Ligands L1−7 were prepared by reference to the literature procedures.10e Alkynyl esters were prepared by reference to the literature procedures.12 Procedure for Preparation of (Z)-β-Fluoroacrylates 1.11 To a solution of the corresponding alkynyl ester (5.0 mmol) and silver fluoride (10.0 mmol) in MeCN (50 mL) was added H2O (0.4 mL) at 80 °C. After 12 h, the mixture was filtered through Celite with CH2Cl2. The filtrates were concentrated and purified by column chromatography on silica gel to give the corresponding product 1. Methyl (Z)-3-Fluoro-3-(pyridin-2-yl)acrylate (1a). White solid, 688.4 mg, 76% yield. Mp: 58−61 °C. 1H NMR (400 MHz, chloroform-d): δ 8.64 (d, J = 4.4 Hz, 1H), 7.81 (td, J = 7.8, 1.7 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.39−7.36 (m, 1H), 6.65 (d, J = 33.2 Hz, 1H), 3.81 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 164.6 11144

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry

Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.28−7.25 (m, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.92 (d, J = 8.8 Hz, 1H), 4.47 (d, J = 26.8 Hz, 1H), 4.31 (dd, J = 24.4, 8.8 Hz, 1H), 3.31 (s, 3H), 1.08 (dd, J = 6.2, 2.9 Hz, 6H). 13C NMR (125 MHz, chloroform-d): δ 167.7 (d, J = 4.1 Hz), 167.4 (d, J = 5.6 Hz), 157.8 (d, J = 29.8 Hz), 149.1 (d, J = 3.2 Hz), 138.4, 136.5, 133.5, 128.8 (d, J = 3.5 Hz), 128.8 (d, J = 3.5 Hz), 128.6, 128.6, 123.0, 120.2 (d, J = 9.8 Hz), 104.8 (d, J = 195.9 Hz), 71.4 (d, J = 22.4 Hz), 69.4, 63.6, 60.1 (d, J = 17.8 Hz), 51.5, 21.7 (d, J = 4.3 Hz). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H23ClFN2O4 421.1325; found 421.1329. [α]D27 = +30.8 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/ 30, 1.0 mL/min, 220 nm): tR = 14.63 min, 24.39 min. (2S,3S,4R,5S)-2-(tert-Butyl) 4-Methyl 5-(4-Chlorophenyl)-3-fluoro3-(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ad). White solid, 85.1 mg, 98% yield. Mp: 120−123 °C. 1H NMR (400 MHz, chloroform-d): δ 8.60 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.67−7.64 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.27−7.24 (m, 1H), 4.91 (d, J = 9.1 Hz, 1H), 4.42 (d, J = 27.6 Hz, 1H), 4.30 (dd, J = 25.9, 9.1 Hz, 1H), 3.29 (s, 3H), 1.29 (s, 9H). 13C NMR (100 MHz, chloroform-d): δ 167.7 (d, J = 3.5 Hz), 166.9 (d, J = 5.6 Hz), 157.9 (d, J = 29.6 Hz), 149.0 (d, J = 3.0 Hz), 138.7, 136.5 (d, J = 2.1 Hz), 133.5, 128.9 (d, J = 3.7 Hz), 128.9 (d, J = 3.7 Hz), 128.6, 128.6, 122.9, 120.3 (d, J = 9.9 Hz), 104.8 (d, J = 195.2 Hz), 82.4, 71.7 (d, J = 22.6 Hz), 63.6, 60.0 (d, J = 17.8 Hz), 51.5, 28.0, 28.0, 28.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H25ClFN2O4 435.1481; found 435.1486. [α]D27 = +50.1 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 12.29 min, 22.87 min. (2S,3S,4R,5S)-Dimethyl 5-(2-Chlorophenyl)-3-fluoro-3-(pyridin-2yl)pyrrolidine-2,4-dicarboxylate (3ae). White solid, 76.9 mg, 98% yield. Mp: 111−114 °C. 1H NMR (400 MHz, chloroform-d): δ 8.67− 8.65 (m, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.70−7.68 (m, 1H), 7.56 (ddt, J = 8.0, 2.1, 1.1 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.32−7.21 (m, 3H), 5.17 (d, J = 8.0 Hz, 1H), 4.59 (d, J = 25.5 Hz, 1H), 4.43 (dd, J = 19.0, 8.0 Hz, 1H), 3.69 (s, 3H), 3.32 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.1 (d, J = 5.3 Hz), 167.6 (d, J = 7.2 Hz), 158.3 (d, J = 30.2 Hz), 149.4 (d, J = 3.1 Hz), 136.8 (d, J = 2.1 Hz), 136.4, 133.0, 129.3, 128.8, 128.3 (d, J = 3.1 Hz), 127.0, 123.2, 119.5 (d, J = 9.7 Hz), 105.8 (d, J = 196.5 Hz), 70.8 (d, J = 22.9 Hz), 61.0, 59.7 (d, J = 18.0 Hz), 52.3, 51.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19ClFN2O4 393.1012; found 393.1018. [α]D27 = +23.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/ 30, 1.0 mL/min, 220 nm): tR = 12.77 min, 22.26 min. (2S,3S,4R,5S)-Dimethyl 5-(3-Chlorophenyl)-3-fluoro-3-(pyridin-2yl)pyrrolidine-2,4-dicarboxylate (3af). White solid, 77.6 mg, 99% yield. Mp: 95−98 °C. 1H NMR (400 MHz, chloroform-d): δ 8.62− 8.60 (m, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.63−7.60 (m, 1H), 7.47−7.46 (m, 1H), 7.37−7.35 (m, 1H), 7.31−7.24 (m, 3H), 4.91 (d, J = 8.3 Hz, 1H), 4.54 (d, J = 25.9 Hz, 1H), 4.28 (dd, J = 21.3, 8.4 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.5 Hz), 167.6 (d, J = 5.0 Hz), 157.9 (d, J = 29.9 Hz), 149.2 (d, J = 3.1 Hz), 141.6, 136.8 (d, J = 2.1 Hz), 134.3, 129.8, 127.8, 127.6 (d, J = 2.6 Hz), 125.2 (d, J = 3.3 Hz), 123.2, 119.8 (d, J = 9.6 Hz), 105.0 (d, J = 196.6 Hz), 71.4 (d, J = 22.6 Hz), 63.7, 60.4 (d, J = 18.1 Hz), 52.4, 51.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19ClFN2O4 393.1012; found 393.1016. [α]D27 = +39.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/ 30, 1.0 mL/min, 220 nm): tR = 15.87 min, 23.52 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-3-(pyridin-2-yl)-5-(o-tolyl)pyrrolidine-2,4-dicarboxylate (3ag). White solid, 72.9 mg, 98% yield. Mp: 142−145 °C. 1H NMR (400 MHz, chloroform-d): δ 8.64− 8.62 (m, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.63−7.60 (m, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.30−7.23 (m, 2H), 7.20−7.13 (m, 2H), 5.10 (d, J = 8.4 Hz, 1H), 4.50 (d, J = 25.3 Hz, 1H), 4.27 (dd, J = 19.9, 8.4 Hz, 1H), 3.69 (s, 3H), 3.23 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.1 (d, J = 5.1 Hz), 167.9 (d, J = 5.5 Hz), 158.4 (d, J = 30.2 Hz), 149.3 (d, J = 3.1 Hz), 136.8(1), 136.7(9), 135.8, 130.3, 127.5, 126.3, 126.2 (d, J = 4.4 Hz), 123.1, 119.7 (d, J = 9.6 Hz), 105.6 (d, J = 197.3 Hz), 71.2 (d, J = 22.9 Hz), 60.9, 59.9 (d, J = 17.3 Hz), 52.3, 51.4, 19.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for

= 278.0 Hz), 164.2 (d, J = 2.5 Hz), 135.2 (d, J = 2.4 Hz), 132.4 (d, J = 26.8 Hz), 131.7, 130.3 (d, J = 2.0 Hz), 125.8 (d, J = 8.1 Hz), 123.9 (d, J = 7.7 Hz), 98.0 (d, J = 6.9 Hz), 51.9. HRMS (EI-TOF) m/z: [M]+ calcd for C10H8ClFO2 214.0191; found 214.0196. Methyl (Z)-3-Fluoro-3-phenylacrylate (1j). White solid, 567.6 mg, 63% yield. Mp: 30−33 °C. 1H NMR (400 MHz, chloroform-d): δ 7.67−7.64 (m, 2H), 7.51−7.41 (m, 3H), 5.92 (d, J = 33.3 Hz, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 166.5 (d, J = 278.0 Hz), 164.6 (d, J = 2.4 Hz), 131.7, 130.6 (d, J = 26.2 Hz), 129.0 (d, J = 2.1 Hz), 129.0 (d, J = 2.1 Hz), 125.8 (d, J = 8.0 Hz), 125.8 (d, J = 8.0 Hz), 96.9 (d, J = 7.0 Hz), 51.7. HRMS (EI-TOF) m/z: [M]+ calcd for C10H9FO2 180.0581; found 180.0586. General Procedure for the Racemic 1,3-Dipolar Cycloaddition. Under a nitrogen atmosphere, AgOAc (1.7 mg, 0.01 mmol) and PPh3 (5.3 mg, 0.02 mmol) were dissolved in CH2Cl2 (1 mL) and stirred at room temperature for approximately 0.5 h. Then, imino ester 2 (0.15 mmol), Cs2CO3 (13 mg, 0.04 mmol), and (Z)-βfluoroacrylate 1 (0.1 mmol) were added sequentially. Once the starting material was consumed (monitored by TLC), the mixture was filtered through Celite with CH2Cl2. The filtrates were concentrated and purified by column chromatography to give the corresponding cycloaddition product 3. General Procedure for the Asymmetric 1,3-Dipolar Cycloaddition. Under a nitrogen atmosphere, Cu(CH3CN)4BF4 (3.1 mg, 0.01 mmol), ligand L7 (5.8 mg, 0.011 mmol), and Cs2CO3 (26 mg, 0.08 mmol) were dissolved in Et2O (2 mL) and stirred at room temperature for approximately 1 h. Then, imino ester 2 (0.3 mmol) was added, the mixture was cooled to −30 °C, and (Z)-βfluoroacrylate 1 (0.2 mmol) was added. Once the starting material was consumed (monitored by TLC), the mixture was filtered through Celite with CH2Cl2. The filtrates were concentrated and purified by column chromatography to give the corresponding cycloaddition product 3. (2S,3S,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-fluoro-3-(pyridin-2yl)pyrrolidine-2,4-dicarboxylate (3aa). White solid, 77.6 mg, 99% yield. Mp: 115−118 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61− 8.59 (m, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.63−7.60 (m, 1H), 7.42−7.39 (m, 2H), 7.34−7.30(0) (m, 2H), 7.29(3)-7.26 (m, 1H), 4.92 (d, J = 8.5 Hz, 1H), 4.54 (d, J = 26.2 Hz, 1H), 4.28 (dd, J = 22.3, 8.5 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 3H). 19F NMR (376 MHz, chloroform-d): δ −174.46 (dd, J = 25.9, 22.6 Hz). 13C NMR (125 MHz, chloroform-d): δ 168.4 (d, J = 5.8 Hz), 167.7 (d, J = 4.6 Hz), 157.9 (d, J = 30.1 Hz), 149.1 (d, J = 3.5 Hz), 138.2, 136.8, 133.4, 128.7 (d, J = 3.5 Hz), 128.7 (d, J = 3.5 Hz), 128.6, 128.6, 123.2, 119.9 (d, J = 9.6 Hz), 105.0 (d, J = 196.5 Hz), 71.4 (d, J = 22.5 Hz), 63.7, 60.3 (d, J = 17.9 Hz), 52.4, 51.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19ClFN2O4 393.1012; found 393.1017. [α]D27 = +34.8 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/ 30, 1.0 mL/min, 220 nm): tR = 16.79 min, 28.27 min. (2S,3S,4R,5S)-2-Ethyl 4-Methyl 5-(4-Chlorophenyl)-3-fluoro-3(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ab). White solid, 80.4 mg, 99% yield. Mp: 109−112 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61 (d, J = 4.6 Hz, 1H), 7.77 (td, J = 7.8, 1.6 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.29− 7.26 (m, 1H), 4.92 (d, J = 8.7 Hz, 1H), 4.51 (d, J = 26.5 Hz, 1H), 4.30 (dd, J = 23.8, 8.8 Hz, 1H), 4.26−4.20 (m, 1H), 4.06 (dq, J = 10.7, 7.1 Hz, 1H), 3.31 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ 167.9 (d, J = 5.5 Hz), 167.7 (d, J = 4.2 Hz), 157.8 (d, J = 29.8 Hz), 149.1 (d, J = 3.2 Hz), 138.4, 136.7 (d, J = 2.0 Hz), 133.5, 128.8 (d, J = 3.4 Hz), 128.8 (d, J = 3.4 Hz), 128.7, 128.7, 123.1, 120.1 (d, J = 9.8 Hz), 104.9 (d, J = 196.1 Hz), 71.4 (d, J = 22.6 Hz), 63.7, 61.5, 60.2 (d, J = 17.8 Hz), 51.5, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21ClFN2O4 407.1168; found 407.1172. [α]D27 = +15.6 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/ isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 17.83 min, 32.44 min. (2S,3S,4R,5S)-2-Isopropyl 4-Methyl 5-(4-Chlorophenyl)-3-fluoro3-(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ac). White solid, 82.3 mg, 98% yield. Mp: 95−98 °C. 1H NMR (400 MHz, chloroform-d): δ 8.60 (d, J = 4.3 Hz, 2H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.63 (d, J = 7.9 11145

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry C20H22FN2O4 373.1558; found 373.1563. [α]D27 = +21.9 (CH2Cl2, c = 1.00). HPLC (Chiralpak AS-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 6.82 min, 13.58 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-3-(pyridin-2-yl)-5-(m-tolyl)pyrrolidine-2,4-dicarboxylate (3ah). White solid, 73.7 mg, 99% yield. Mp: 132−135 °C. 1H NMR (400 MHz, chloroform-d): δ 8.62− 8.60 (m, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.63−7.60 (m, 1H), 7.29−7.26 (m, 2H), 7.23 (d, J = 4.8 Hz, 2H), 7.10−7.07 (m, 1H), 4.91 (d, J = 8.4 Hz, 1H), 4.53 (d, J = 25.9 Hz, 1H), 4.26 (dd, J = 20.8, 8.4 Hz, 1H), 3.68 (s, 3H), 3.30 (s, 3H), 2.36 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.4 Hz), 168.0 (d, J = 5.2 Hz), 158.2 (d, J = 30.1 Hz), 149.2 (d, J = 3.1 Hz), 139.3, 138.1, 136.8 (d, J = 2.0 Hz), 128.4, 128.3, 127.8 (d, J = 2.4 Hz), 124.0 (d, J = 2.7 Hz), 123.1, 119.8 (d, J = 9.6 Hz), 105.2 (d, J = 196.5 Hz), 71.5 (d, J = 22.8 Hz), 64.3, 60.7 (d, J = 17.7 Hz), 52.3, 51.4, 21.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22FN2O4 373.1558; found 373.1565. [α]D27 = +41.2 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, nhexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 13.76 min, 19.54 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-3-(pyridin-2-yl)-5-(p-tolyl)pyrrolidine-2,4-dicarboxylate (3ai). White solid, 73.7 mg, 99% yield. Mp: 132−135 °C. 1H NMR (400 MHz, chloroform-d): δ 8.62−8.60 (m, 1H), 7.76 (td, J = 7.8, 1.8 Hz, 1H), 7.64−7.61 (m, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.28−7.25 (m, 1H), 7.15 (d, J = 7.8 Hz, 2H), 4.92 (d, J = 8.6 Hz, 1H), 4.54 (d, J = 26.2 Hz, 1H), 4.26 (dd, J = 22.4, 8.6 Hz, 1H), 3.67 (s, 3H), 3.29 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.4 (d, J = 5.5 Hz), 168.0 (d, J = 4.6 Hz), 158.1 (d, J = 30.0 Hz), 149.1 (d, J = 3.1 Hz), 137.2, 136.8 (d, J = 2.0 Hz), 136.5, 129.2, 129.2, 127.0(7), 127.0(5), 123.1, 119.9 (d, J = 9.8 Hz), 105.0 (d, J = 196.4 Hz), 71.5 (d, J = 22.6 Hz), 64.2, 60.5 (d, J = 17.6 Hz), 52.3, 51.4, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22FN2O4 373.1558; found 373.1563. [α]D27 = +38.6 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 16.24 min, 24.97 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(2-methoxyphenyl)-3-(pyridin2-yl)pyrrolidine-2,4-dicarboxylate (3aj). White solid, 76.1 mg, 98% yield. Mp: 131−134 °C. 1H NMR (400 MHz, chloroform-d): δ 8.67 (d, J = 4.6 Hz, 1H), 7.76 (td, J = 7.8, 1.8 Hz, 1H), 7.57−7.53 (m, 2H), 7.30−7.24 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.96 (dd, J = 11.4, 7.5 Hz, 1H), 4.57 (dd, J = 25.8, 10.9 Hz, 1H), 4.30 (dd, J = 16.9, 7.6 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 3.61−3.54 (m, 1H), 3.32 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.2 (d, J = 2.5 Hz), 168.1 (d, J = 1.4 Hz), 158.9 (d, J = 30.5 Hz), 156.2, 149.4 (d, J = 3.2 Hz), 136.7 (d, J = 2.1 Hz), 128.4, 127.0, 127.0 (d, J = 1.5 Hz), 123.1, 120.7, 119.3 (d, J = 9.9 Hz), 109.9, 106.3 (d, J = 195.5 Hz), 71.2 (d, J = 23.3 Hz), 61.1 (d, J = 17.9 Hz), 60.0, 55.3, 52.2, 51.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22FN2O5 389.1507; found 389.1514. [α]D27 = +35.1 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 19.26 min, 22.66 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(3-methoxyphenyl)-3-(pyridin2-yl)pyrrolidine-2,4-dicarboxylate (3ak). White solid, 76.1 mg, 98% yield. Mp: 103−107 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61 (d, J = 4.4 Hz, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.29−7.24 (m, 2H), 7.04−7.01 (m, 2H), 6.81 (dd, J = 8.2, 2.5 Hz, 1H), 4.95−4.91 (m, 1H), 4.54 (dd, J = 25.9, 9.5 Hz, 1H), 4.27 (dd, J = 21.2, 8.4 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.51−3.43 (m, 1H), 3.32 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.5 Hz), 167.9 (d, J = 4.9 Hz), 159.7, 158.1 (d, J = 30.1 Hz), 149.2 (d, J = 3.1 Hz), 141.1, 136.8 (d, J = 2.0 Hz), 129.5, 123.1, 119.8 (d, J = 9.8 Hz), 119.4 (d, J = 2.6 Hz), 113.4, 112.6 (d, J = 3.1 Hz), 105.1 (d, J = 196.6 Hz), 71.5 (d, J = 22.7 Hz), 64.3, 60.6 (d, J = 17.8 Hz), 55.4, 52.4, 51.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22FN2O5 389.1507; found 389.1514. [α]D27 = +30.5 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 19.15 min, 23.25 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(4-methoxyphenyl)-3-(pyridin2-yl)pyrrolidine-2,4-dicarboxylate (3al). White solid, 76.1 mg, 98% yield. Mp: 110−113 °C. 1H NMR (500 MHz, chloroform-d): δ 8.68 (d, J = 4.3 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.71 (d, J = 7.8 Hz,

1H), 7.46 (d, J = 8.4 Hz, 2H), 7.35−7.33 (m, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.99 (d, J = 8.8 Hz, 1H), 4.62 (d, J = 26.4 Hz, 1H), 4.34 (dd, J = 23.9, 8.8 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.37 (s, 3H). 13C NMR (125 MHz, chloroform-d): δ 168.5 (d, J = 5.3 Hz), 167.9 (d, J = 4.0 Hz), 159.0, 157.9 (d, J = 29.9 Hz), 149.1 (d, J = 3.1 Hz), 136.8, 131.7, 128.5 (d, J = 3.3 Hz), 128.5 (d, J = 3.3 Hz), 123.0, 120.0 (d, J = 9.8 Hz), 113.8, 113.8, 104.9 (d, J = 196.1 Hz), 71.4 (d, J = 22.3 Hz), 63.8, 60.2 (d, J = 17.3 Hz), 55.3, 52.3, 51.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22FN2O5 389.1507; found 389.1514. [α]D27 = +28.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 17.97 min, 30.67 min. (2S,3S,4R,5S)-Dimethyl 5-(4-Bromophenyl)-3-fluoro-3-(pyridin-2yl)pyrrolidine-2,4-dicarboxylate (3am). White solid, 86.3 mg, 99% yield. Mp: 120−123 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61 (d, J = 4.4 Hz, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.63−7.60 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.30−7.27 (m, 1H), 4.90 (dd, J = 8.6, 4.6 Hz, 1H), 4.54 (dd, J = 26.0, 4.8 Hz, 1H), 4.27 (dd, J = 22.1, 8.5 Hz, 1H), 3.68 (s, 3H), 3.39−3.33 (m, 4H). 13C NMR (100 MHz, chloroform-d): δ 168.4 (d, J = 5.5 Hz), 167.7 (d, J = 4.6 Hz), 157.8 (d, J = 29.8 Hz), 149.2 (d, J = 3.1 Hz), 138.7, 136.8 (d, J = 2.1 Hz), 131.6, 131.6, 129.0(4), 129.0(1), 123.2, 121.6, 120.0 (d, J = 9.6 Hz), 105.0 (d, J = 196.6 Hz), 71.4 (d, J = 22.6 Hz), 63.7, 60.3 (d, J = 17.9 Hz), 52.4, 51.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19BrFN2O4 437.0507; found 437.0511. [α]D27 = +36.6 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/ 30, 1.0 mL/min, 220 nm): tR = 20.04 min, 33.79 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-phenyl-3-(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3an). White solid, 70.2 mg, 98% yield. Mp: 122−125 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61 (d, J = 4.3 Hz, 1H), 7.77 (td, J = 7.8, 1.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.3 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.29−7.25 (m, 2H), 4.96 (t, J = 8.1 Hz, 1H), 4.55 (dd, J = 25.8, 9.2 Hz, 1H), 4.29 (dd, J = 22.0, 8.6 Hz, 1H), 3.68 (s, 3H), 3.49−3.42 (m, 1H), 3.27 (s, 3H). 13 C NMR (100 MHz, chloroform-d): δ 168.4 (d, J = 5.5 Hz), 167.9 (d, J = 4.6 Hz), 158.1 (d, J = 30.0 Hz), 149.2 (d, J = 3.1 Hz), 139.5, 136.8 (d, J = 2.0 Hz), 128.5, 128.5, 127.7, 127.1(9), 127.1(6), 123.1, 119.9 (d, J = 9.8 Hz), 105.1 (d, J = 196.3 Hz), 71.5 (d, J = 22.6 Hz), 64.4, 60.6 (d, J = 17.7 Hz), 52.4, 51.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20FN2O4 359.1402; found 359.1408. [α]D27 = +32.0 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 15.65 min, 27.77 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(naphthalen-1-yl)-3-(pyridin2-yl)pyrrolidine-2,4-dicarboxylate (3ao). White solid, 80.0 mg, 98% yield. Mp: 138−141 °C. 1H NMR (400 MHz, chloroform-d): δ 8.74 (d, J = 4.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.82−7.76 (m, 3H), 7.63−7.60 (m, 1H), 7.55−7.46 (m, 3H), 7.35− 7.31 (m, 1H), 5.66 (dd, J = 11.5, 7.5 Hz, 1H), 4.61 (dd, J = 24.3, 11.9 Hz, 1H), 4.44 (dd, J = 15.5, 7.5 Hz, 1H), 3.74 (s, 3H), 3.12 (s, 3H). 13 C NMR (100 MHz, chloroform-d): δ 168.1 (d, J = 5.5 Hz), 167.8 (d, J = 6.8 Hz), 159.0 (d, J = 30.7 Hz), 149.6 (d, J = 3.3 Hz), 136.9 (d, J = 2.0 Hz), 133.7, 133.6, 131.2, 129.0, 128.3, 126.4, 125.6, 125.5, 124.1 (d, J = 2.9 Hz), 123.3, 123.2, 119.5 (d, J = 9.5 Hz), 106.0 (d, J = 198.2 Hz), 71.3 (d, J = 23.1 Hz), 60.9(8), 60.9(5) (d, J = 17.7 Hz), 52.4, 51.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H22FN2O4 409.1558; found 409.1564. [α]D27 = +42.4 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/isopropyl alcohol = 90/10, 1.0 mL/min, 220 nm): tR = 35.62 min, 39.41 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(furan-2-yl)-3-(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ap). White solid, 68.2 mg, 98% yield. Mp: 111−114 °C. 1H NMR (400 MHz, chloroform-d): δ 8.59 (d, J = 4.5 Hz, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.37−7.36 (m, 1H), 7.28−7.25 (m, 1H), 6.43 (d, J = 3.3 Hz, 1H), 6.36 (dd, J = 3.4, 1.8 Hz, 1H), 4.99 (d, J = 8.2 Hz, 1H), 4.51 (dd, J = 26.9, 4.9 Hz, 1H), 4.28 (dd, J = 26.7, 8.9 Hz, 1H), 3.64 (s, 3H), 3.44 (s, 3H), 3.32 (s, 1H). 13C NMR (100 MHz, chloroform-d): δ 168.5 (d, J = 5.6 Hz), 167.5 (d, J = 3.1 Hz), 157.4 (d, J = 29.2 Hz), 153.6, 149.0 (d, J = 3.2 Hz), 141.9, 136.7 (d, J = 2.1 Hz), 123.0, 120.2 (d, J = 9.6 Hz), 110.8, 107.4 (d, J = 3.6 Hz), 104.1 (d, J = 196.4 Hz), 70.9 (d, J = 22.3 Hz), 58.4 (d, J = 18.2 Hz), 57.8, 52.4, 51.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18FN2O5 349.1194; found 11146

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry

δ 8.55 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.58 (dd, J = 8.5, 1.9 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.90 (d, J = 8.6 Hz, 1H), 4.50 (d, J = 26.1 Hz, 1H), 4.24 (dd, J = 24.0, 8.7 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 3H). 13C NMR (125 MHz, chloroform-d): δ 168.2 (d, J = 5.7 Hz), 167.4 (d, J = 4.1 Hz), 155.9 (d, J = 30.3 Hz), 148.1 (d, J = 2.9 Hz), 138.2, 136.6, 133.6, 131.6, 128.8(2), 128.8(0), 128.7, 128.7, 121.1 (d, J = 9.5 Hz), 104.6 (d, J = 196.5 Hz), 71.3 (d, J = 22.4 Hz), 63.6, 60.1 (d, J = 17.8 Hz), 52.5, 51.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18Cl2FN2O4 427.0622; found 427.0628. [α]D27 = +43.3 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm) tR = 12.85 min, 23.65 min. (2S,3S,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-fluoro-3-(5-methylpyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ea). White solid, 79.6 mg, 98% yield. Mp: 129−133 °C. 1H NMR (400 MHz, chloroform-d): δ 8.42 (s, 1H), 7.57 (dd, J = 8.2, 2.1 Hz, 1H), 7.50 (dd, J = 8.2, 2.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 4.90 (d, J = 8.5 Hz, 1H), 4.52 (d, J = 26.2 Hz, 1H), 4.26 (dd, J = 22.5, 8.6 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 3H), 2.37 (s, 3H). 13C NMR (125 MHz, chloroform-d): δ 168.4 (d, J = 5.7 Hz), 167.7 (d, J = 4.6 Hz), 155.0 (d, J = 30.1 Hz), 149.6 (d, J = 2.9 Hz), 138.3, 137.3, 133.4, 132.8, 128.7(3), 128.7(0), 128.6, 128.6, 119.4 (d, J = 9.3 Hz), 105.1 (d, J = 196.0 Hz), 71.4 (d, J = 22.6 Hz), 63.6, 60.3 (d, J = 17.9 Hz), 52.4, 51.5, 18.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21ClFN2O4 407.1168; found 407.1175. [α]D27 = +56.6 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 13.06 min, 25.64 min. (2S,3R,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-(4-cyanophenyl)-3fluoropyrrolidine-2,4-dicarboxylate (3fa). White solid, 74.1 mg, 89% yield. Mp: 192−197 °C. 1H NMR (400 MHz, chloroform-d): δ 7.74 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.88 (t, J = 8.0 Hz, 1H), 4.26 (dd, J = 27.1, 9.4 Hz, 1H), 3.87 (dd, J = 26.7, 9.0 Hz, 1H), 3.67 (s, 3H), 3.32−3.28 (m, 4H). 13C NMR (125 MHz, chloroform-d): δ 167.7 (d, J = 5.5 Hz), 166.5 (d, J = 4.0 Hz), 143.4 (d, J = 24.0 Hz), 137.7, 134.0, 132.5, 132.5, 129.0 (d, J = 4.2 Hz), 129.0 (d, J = 4.2 Hz), 128.8, 128.8, 125.4 (d, J = 10.4 Hz), 118.4, 112.6, 103.1 (d, J = 197.7 Hz), 72.1 (d, J = 23.2 Hz), 63.8, 61.3 (d, J = 19.1 Hz), 52.7, 51.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H19ClFN2O4 417.1012; found 417.1018. [α]D27 = +40.8 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/ isopropyl alcohol = 80/20, 1.0 mL/min, 220 nm): tR = 31.76 min, 40.93 min. (2S,3R,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-fluoro-3-(4nitrophenyl)pyrrolidine-2,4-dicarboxylate (3ga). White solid, 79.4 mg, 91% yield. Mp: 200−203 °C. 1H NMR (400 MHz, chloroform-d): δ 8.30 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.91 (t, J = 8.3 Hz, 1H), 4.30 (dd, J = 27.3, 10.0 Hz, 1H), 3.90 (dd, J = 27.4, 9.1 Hz, 1H), 3.67 (s, 3H), 3.32 (s, 4H). 13C NMR (100 MHz, chloroform-d): δ 167.7 (d, J = 5.5 Hz), 166.5 (d, J = 2.7 Hz), 147.9, 145.2 (d, J = 24.0 Hz), 137.7, 134.1, 129.0 (d, J = 4.0 Hz), 129.0 (d, J = 4.0 Hz), 128.8, 128.8, 125.7 (d, J = 10.4 Hz), 124.0, 123.9, 103.1 (d, J = 197.7 Hz), 72.2 (d, J = 23.2 Hz), 63.8, 61.3 (d, J = 18.9 Hz), 52.8, 51.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19ClFN2O6 437.0910; found 437.0917. [α]D27 = +43.5 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/isopropyl alcohol = 80/20, 1.0 mL/min, 220 nm): tR = 35,.19 min, 40.89 min. (2S,3R,4R,5S)-Dimethyl 3,5-Bis(4-chlorophenyl)-3-fluoropyrrolidine-2,4-dicarboxylate (3ha). White solid, 74.0 mg, 87% yield. Mp: 170−175 °C. 1H NMR (400 MHz, chloroform-d): δ 7.42−7.37 (m, 6H), 7.34−7.31 (m, 2H), 4.82 (t, J = 8.1 Hz, 1H), 4.24 (dd, J = 26.7, 9.7 Hz, 1H), 3.84 (dd, J = 24.7, 8.7 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 4H). 13C NMR (100 MHz, chloroform-d): δ 168.2 (d, J = 5.8 Hz), 167.2 (d, J = 4.4 Hz), 138.7 (d, J = 23.9 Hz), 137.8, 133.7, 128.7(4), 128.7(4), 128.7(2), 128.7(0), 128.7, 128.6, 128.5, 124.3 (d, J = 10.0 Hz), 104.2 (d, J = 196.6 Hz), 72.3 (d, J = 23.8 Hz), 63.8, 61.9 (d, J = 19.4 Hz), 52.5, 51.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19Cl2FNO4 426.0670; found 426.0674. [α]D27 = +41.2 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/isopropyl alcohol = 80/20, 1.0 mL/min, 220 nm): tR = 15.47 min, 21.09 min.

349.1199. [α]D27 = +38.8 (CH2Cl2, c = 1.00). HPLC (Chiralpak ADH, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 13.46 min, 20.19 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-3-(pyridin-2-yl)-5-(thiophen-2yl)pyrrolidine-2,4-dicarboxylate (3aq). White solid, 72.1 mg, 99% yield. Mp: 102−105 °C. 1H NMR (400 MHz, chloroform-d): δ 8.59 (d, J = 4.3 Hz, 1H), 7.77 (td, J = 7.7, 1.7 Hz, 1H), 7.65−7.62 (m, 1H), 7.28−7.22 (m, 2H), 7.13 (d, J = 3.5 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 5.16 (t, J = 7.3 Hz, 1H), 4.55 (dd, J = 26.3, 8.6 Hz, 1H), 4.28 (dd, J = 23.9, 8.4 Hz, 1H), 3.67 (s, 3H), 3.46−3.39 (m, 4H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.7 Hz), 167.5 (d, J = 3.5 Hz), 157.5 (d, J = 29.6 Hz), 148.9 (d, J = 3.1 Hz), 142.9, 136.7 (d, J = 2.0 Hz), 126.8, 125.5 (d, J = 3.3 Hz), 124.9 (d, J = 1.5 Hz), 123.0, 120.0 (d, J = 9.6 Hz), 104.4 (d, J = 196.6 Hz), 71.1 (d, J = 22.4 Hz), 59.9 (d, J = 18.0 Hz), 59.8, 52.3, 51.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18FN2O4S 365.0966; found 365.0972. [α]D27 = +41.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/ isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 15.37 min, 23.02 min. (2S,3S,4R,5S)-Dimethyl 3-Fluoro-5-(naphthalen-2-yl)-3-(pyridin2-yl)pyrrolidine-2,4-dicarboxylate (3ar). White solid, 80.8 mg, 99% yield. Mp: 130−133 °C. 1H NMR (400 MHz, chloroform-d): δ 8.59 (d, J = 4.3 Hz, 1H), 7.77 (td, J = 7.7, 1.7 Hz, 1H), 7.65−7.62 (m, 1H), 7.28−7.22 (m, 2H), 7.13 (d, J = 3.5 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 5.16 (t, J = 7.3 Hz, 1H), 4.55 (dd, J = 26.3, 8.6 Hz, 1H), 4.28 (dd, J = 23.9, 8.4 Hz, 1H), 3.67 (s, 3H), 3.46−3.39 (m, 4H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.7 Hz), 167.5 (d, J = 3.5 Hz), 157.5 (d, J = 29.6 Hz), 148.9 (d, J = 3.1 Hz), 142.9, 136.7 (d, J = 2.0 Hz), 126.8, 125.5 (d, J = 3.3 Hz), 124.9 (d, J = 1.5 Hz), 123.0, 120.0 (d, J = 9.6 Hz), 104.4 (d, J = 196.6 Hz), 71.1 (d, J = 22.4 Hz), 59.9 (d, J = 18.0 Hz), 59.8, 52.3, 51.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H22FN2O4 409.1558; found 409.1565. [α]D27 = +50.1 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 27.76 min, 45.33 min. (2S,3S,4R,5S)-4-Ethyl 2-Methyl 5-(4-Chlorophenyl)-3-fluoro-3(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ba). White solid, 78.8 mg, 97% yield. Mp: 112−115 °C. 1H NMR (400 MHz, chloroform-d): δ 8.60 (d, J = 4.3 Hz, 2H), 7.77 (td, J = 7.8, 1.7 Hz, 1H), 7.64−7.60 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.29−7.26 (m, 1H), 4.91 (d, J = 7.3 Hz, 1H), 4.54 (d, J = 25.4 Hz, 1H), 4.26 (dd, J = 22.7, 8.6 Hz, 1H), 3.78 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 3.36 (s, 1H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.3 (d, J = 5.5 Hz), 167.1 (d, J = 4.7 Hz), 157.8 (d, J = 30.0 Hz), 149.0 (d, J = 3.1 Hz), 138.2, 136.7 (d, J = 2.1 Hz), 133.3, 128.8, 128.7, 128.5, 128.5, 123.01, 119.8 (d, J = 9.6 Hz), 104.9 (d, J = 196.3 Hz), 71.3 (d, J = 22.5 Hz), 63.5, 60.6, 60.2 (d, J = 18.0 Hz), 52.3, 13.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21ClFN2O4 407.1168; found 407.1173. [α]D27 = +38.9 (CH2Cl2, c = 1.00). HPLC (Chiralpak AD-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 18.25 min, 25.87 min. (2S,3S,4R,5S)-4-Isopropyl 2-Methyl-5-(4-Chlorophenyl)-3-fluoro3-(pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (3ca). White solid, 82.3 mg, 98% yield. Mp: 110−113 °C. 1H NMR (400 MHz, chloroform-d): δ 8.61 (d, J = 4.3 Hz, 1H), 7.78 (td, J = 7.8, 1.7 Hz, 1H), 7.63−7.60 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.29−7.26 (m, 1H), 4.90 (d, J = 8.5 Hz, 1H), 4.68 (hept, J = 6.0 Hz, 1H), 4.52 (d, J = 25.8 Hz, 1H), 4.21 (dd, J = 21.8, 8.5 Hz, 1H), 3.67 (s, 3H), 3.38 (s, 1H), 0.88 (d, J = 6.3 Hz, 3H), 0.80 (d, J = 6.3 Hz, 3H). 13C NMR (125 MHz, chloroform-d): δ 168.3 (d, J = 5.6 Hz), 166.7 (d, J = 5.1 Hz), 158.2 (d, J = 30.1 Hz), 149.1 (d, J = 3.2 Hz), 138.4, 136.8, 133.4, 128.9 (d, J = 3.2 Hz), 128.9 (d, J = 3.2 Hz), 128.6, 128.6, 123.1, 119.8 (d, J = 9.7 Hz), 105.2 (d, J = 196.2 Hz), 71.4 (d, J = 22.6 Hz), 68.5, 63.7, 60.5 (d, J = 18.4 Hz), 52.4, 21.5, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23ClFN2O4 421.1325; found 421.1331. [α]D27 = +45.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak AS-H, n-hexane/isopropyl alcohol = 70/30, 1.0 mL/min, 220 nm): tR = 13.74 min, 17.88 min. (2S,3S,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-(5-chloropyridin-2yl)-3-fluoropyrrolidine-2,4-dicarboxylate (3da). White solid, 82.7 mg, 97% yield. Mp: 104−107 °C. 1H NMR (400 MHz, chloroform-d): 11147

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

The Journal of Organic Chemistry

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(2S,3R,4R,5S)-Dimethyl 3-(3-Chlorophenyl)-5-(4-chlorophenyl)-3fluoropyrrolidine-2,4-dicarboxylate (3ia). White solid, 73.1 mg, 86% yield. Mp: 146−151 °C. 1H NMR (400 MHz, chloroform-d): δ 7.45− 7.44 (m, 1H), 7.40−7.32 (m, 7H), 4.82 (d, J = 8.6 Hz, 1H), 4.24 (d, J = 26.5 Hz, 1H), 3.85 (dd, J = 24.0, 8.6 Hz, 1H), 3.69 (s, 3H), 3.34 (s, 3H). 13C NMR (125 MHz, chloroform-d): δ 167.9 (d, J = 5.8 Hz), 166.9 (d, J = 3.8 Hz), 140.7 (d, J = 24.3 Hz), 137.7, 134.9, 133.8, 130.0, 128.8, 128.8, 128.8, 128.8, 128.7, 124.8 (d, J = 10.9 Hz), 122.6 (d, J = 9.8 Hz), 103.4 (d, J = 197.7 Hz), 72.2 (d, J = 23.7 Hz), 63.7, 61.6 (d, J = 19.2 Hz), 52.7, 51.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19Cl2FNO4 426.0670; found 426.0674. [α]D27 = +43.2 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/isopropyl alcohol = 80/20, 1.0 mL/min, 220 nm): tR = 13.25 min, 20.13 min. (2S,3R,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-3-fluoro-3-phenylpyrrolidine-2,4-dicarboxylate (3ja). White solid, 62.6 mg, 80% yield. Mp: 151−154 °C. 1H NMR (400 MHz, chloroform-d): δ 7.47−7.44 (m, 4H), 7.42−7.36 (m, 3H), 7.34−7.31 (m, 2H), 4.82 (t, J = 8.2 Hz, 1H), 4.28 (dd, J = 26.1, 9.7 Hz, 1H), 3.90 (dd, J = 22.5, 8.4 Hz, 1H), 3.68 (s, 3H), 3.48−3.42 (m, 1H), 3.33 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ 168.2 (d, J = 5.8 Hz), 167.2 (d, J = 4.4 Hz), 138.7 (d, J = 24.0 Hz), 137.7, 133.7, 128.8, 128.8, 128.7(2), 128.7(0), 128.6(8), 128.6, 128.5, 124.3 (d, J = 10.0 Hz), 124.3 (d, J = 10.0 Hz), 104.2 (d, J = 196.4 Hz), 72.3 (d, J = 23.7 Hz), 63.8, 61.9 (d, J = 19.2 Hz), 52.6, 51.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20ClFNO4 392.1059; found 392.1064. [α]D27 = +48.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/isopropyl alcohol = 80/20, 1.0 mL/min, 220 nm): tR = 15.03 min, 20.88 min. Gram-Scale Procedure for the 1,3-Dipolar Cycloaddition of Azomethine Ylide 2i to (Z)-β-Fluoroacrylate 1a. Under a nitrogen atmosphere, Cu(CH3CN)4BF4 (46.5 mg, 0.15 mmol), ligand L7 (87 mg, 0.165 mmol), and Cs2CO3 (391.0 mg, 1.2 mmol) were dissolved in Et2O (25 mL) and stirred at room temperature for approximately 1 h. Then, imino ester 2i (4.5 mmol) was added, the mixture was cooled to −30 °C, and (Z)-β-fluoroacrylate 1a (3.0 mmol) was added. Once the starting material was consumed (monitored by TLC), the mixture was filtered through Celite with CH2Cl2. The filtrates were concentrated and purified by column chromatography to give 3ai. Procedure for the Reduction of 3ai to 4. To a solution of 3ai (111.7 mg, 0.3 mmol) in dry Et2O (3 mL) under nitrogen at 0 °C was added LiAlH4 (68.4 mg, 1.8 mmol) in small portions. The reaction mixture was stirred for 20 min at the same temperature. Then water (0.6 mL), 10% aqueous sodium hydroxide (0.6 mL), and more water (1.2 mL) were added carefully. The mixture was filtered over anhydrous Na2SO4, and the filtrate was concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH = 10/1) on silica gel to afford 4 in 60% yield. ((2S,3S,4R,5S)-3-Fluoro-3-(pyridin-2-yl)-5-(p-tolyl)pyrrolidine-2,4diyl)dimethanol (4). Light yellow solid, 59.8 mg, 60% yield. Mp: 119− 124 °C. 1H NMR (400 MHz, chloroform-d): δ 8.60 (d, J = 4.6 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.60−7.57 (m, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.25−7.21 (m, 1H), 7.17 (d, J = 7.7 Hz, 2H), 4.79 (d, J = 9.0 Hz, 1H), 3.95−3.75 (m, 3H), 3.49−3.30 (m, 3H), 2.35 (s, 3H), 2.00 (s, 3H). 19F NMR (376 MHz, chloroform-d): δ −185.73 (t, J = 27.6 Hz). 13C NMR (125 MHz, chloroform-d): δ 158.9 (d, J = 29.3 Hz), 149.3, 137.5, 137.0, 136.9, 129.3, 129.3, 128.0, 128.0, 122.8, 119.8 (d, J = 10.9 Hz), 106.0 (d, J = 186.8 Hz), 68.2 (d, J = 19.0 Hz), 62.7, 60.3 (d, J = 8.2 Hz), 59.3 (d, J = 13.5 Hz), 55.5 (d, J = 18.2 Hz), 21.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H22FN2O2 317.1660; found 317.1664. [α]D27 = +36.7 (CH2Cl2, c = 1.00). HPLC (Chiralpak IA, n-hexane/alcohol = 90/10, 1.0 mL/min, 220 nm): tR = 11.40 min, 16.80 min.

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Article

AUTHOR INFORMATION

Corresponding Authors

*E-mail for X.L.: [email protected]. *E-mail for W.-P.D.: [email protected]. ORCID

Wei-Ping Deng: 0000-0002-4232-1318 Author Contributions †

Y.-Z.L. and S.-J.S. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21372074, 21572053).

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REFERENCES

(1) (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (e) Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011, 50, 11860. (2) (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: Berlin, 2000. (b) Kirsch, P. Morden Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; WileyVCH: Weinheim, Germany, 2004. (3) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (b) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37, 1727. (c) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455. (4) (a) Mason, J. M.; Murkin, A. S.; Li, L.; Schramm, V. L.; Gainsford, G. J.; Skelton, B. W. J. Med. Chem. 2008, 51, 5880. (b) Or, Y. S.; Ying, L.; Wang, C.; Long, J.; Qui, Y.-L. World Patent No. WO 2009003009A1 2008. (c) Rogel, O.; Rondeau, J.-M.; Rueeger, H.; Simic, O.; Sirockin, F.; Tintelnot-Blomley, M. World Patent No. WO 2007140980A1. 2007. (5) For the pioneering work: (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (b) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236. (6) For recent reviews about asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides, see: (a) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (b) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.G. Chem. Commun. 2010, 46, 4043. (c) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784. (d) Narayan, R.; Potowski, M.; Jia, Z.J.; Antonchick, A. P.; Waldmann, H. Acc. Chem. Res. 2014, 47, 1296. (e) Maroto, E. E.; Izquierdo, M.; Reboredo, S.; Marco-Martínez, J.; Filippone, S.; Martín, N. Acc. Chem. Res. 2014, 47, 2660. (f) Adrio, J.; Carretero, J. C. Chem. Commun. 2014, 50, 12434. (g) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366. (h) Bdiri, B.; Zhao, B.-J.; Zhou, Z.-M. Tetrahedron: Asymmetry 2017, 28, 876. (7) (a) Najera, C.; de Gracia R, M.; Sansano, J. M.; de Cozar, A.; Cossio, F. P. Tetrahedron: Asymmetry 2008, 19, 2913. (b) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Cai, Y.-P.; Wang, C.-J. Chem. Commun. 2011, 47, 2616. (c) Hernandez-Toribio, J.; Padilla, S.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2012, 51, 8854. (d) Li, Q.-H.; Huang, R.; Wang, C.-J. Huaxue Xuebao 2014, 72, 830. (e) Liu, T.-L.; Li, Q.-H.; He, Z.-L.; Zhang, J.-W.; Wang, C.-J. Chin. J. Catal. 2015, 36, 68. (f) Zhang, Z.-M.; Xu, B.; Xu, S.; Wu, H.-H.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 6324. (g) Xu, B.; Zhang, Z.-M.; Liu, B.; Xu, S.; Zhou, L.-J.; Zhang, J. Chem. Commun. 2017, 53, 8152. (8) Patrick, T. B.; Shadmehr, M.; Khan, A. H.; Singh, R. K.; Asmelash, B. J. Fluorine Chem. 2012, 143, 109. (9) For the only enantioselective examples of the construction of pyrrolidines containing a 4-fluoro quaternary stereocenter by using α-

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02142. Crystallographic data and NMR and HPLC spectra (PDF) Crystallographic data (CIF) 11148

DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149

Article

The Journal of Organic Chemistry fluoroacrylates as the dipolarophiles, see: Yan, D.-C.; Li, Q.-H.; Wang, C.-J. Chin. J. Chem. 2012, 30, 2714. (10) (a) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.; Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897. (b) Wang, Z.; Yu, X.; Tian, B.-X.; Payne, D. T.; Yang, W.-L.; Liu, Y.-Z.; Fossey, J. S.; Deng, W.-P. Chem. - Eur. J. 2015, 21, 10457. (c) Yang, W.-L.; Liu, Y.Z.; Luo, S.; Yu, X.; Fossey, J. S.; Deng, W.-P. Chem. Commun. 2015, 51, 9212. (d) Yang, W.-L.; Tang, F.-F.; He, F.-S.; Li, C.-Y.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4822. (e) He, F.-S.; Zhu, H.; Wang, Z.; Gao, M.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4988. (11) Wu, W.; Jiang, H. Acc. Chem. Res. 2014, 47, 2483. (12) (a) Specowius, V.; Bendrath, F.; Winterberg, M.; Ayub, K.; Langer, P. Adv. Synth. Catal. 2012, 354, 1163. (b) Anastasia, L.; Negishi, E.-i. Org. Lett. 2001, 3, 3111.

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DOI: 10.1021/acs.joc.7b02142 J. Org. Chem. 2017, 82, 11141−11149