Asymmetric Synthesis of α-Trifluoromethyl Pyrrolidines through

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Asymmetric Synthesis of α‑Trifluoromethyl Pyrrolidines through Organocatalyzed 1,3-Dipolar Cycloaddition Reaction Zhenghao Dong,†,§ Yuanyuan Zhu,†,§ Boyu Li,† Cui Wang,† Wenjin Yan,*,† Kairong Wang,*,† and Rui Wang*,†,‡ †

The Institute of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic, Medical Sciences, Lanzhou University, Lanzhou 730000, China ‡ State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China S Supporting Information *

ABSTRACT: The optically active α-trifluoromethyl pyrrolidines have been achieved through organocatalyzed 1,3-dipolar cycloaddition reaction first. With diphenylprolinol trimethylsilyl ether as catalyst and in the presence of 3,5-dinitrobenzoic acid, the reaction of trifluoroethylamine-derived ketimine with 2-enals gave α-trifluoromethyl pyrrolidines bearing three contiguous stereogenic centers in excellent diastereoselectivies, stereoselectivities, and yields.

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INTRODUCTION

Scheme 1. Traditional Metal-Catalyzed or Organocatalyzed 1,3-Dipole Activated Mode

Pyrrolidines constitute an important structural motif in many natural products and pharmacological active compounds.1 Therefore, lots of strategies have been developed for the construction of this privileged structural element.2 Despite significant progress in this area, the incorporation of fluorine into a pyrrolidines moiety is still of particular interest, especially driven by demands of medicinal chemistry and organocatalysis.3 Among various fluorinated moieties, the trifluoromethyl group (CF3) shows special attractiveness owing to its diverse applications.4 Given the increasing demand for the chiral compounds, the development of catalytic asymmetric reactions about the direct construction of chiral trifluoromethylated compounds has become one of the main themes of contemporary synthetic chemistry.5 In this regard, several useful synthetic methods have been developed for the preparation of optically active β-trifluoromethyl-substituted five-membered nitrogen heterocycles.6 As to the catalytic asymmetric synthesis of α-trifluoromethyl-substituted pyrrolidines, very limited examples were found.7 Synthetically, to achieve the highly substituted α-trifluoromethyl pyrrolidine, the 1,3-dipolar cycloaddition reaction is the most efficient synthetic method, with trifluoroethylaminederived azomethine ylides as 1,3-dipoles.8 Although many excellent catalytic systems have been developed in the synthesis of pyrrolidines, the basic principle underlying those work is that the azomethine ylide precursors could combine with an organocatalyst9 or chiral metal complex10 to form a rigid fivemembered ring transition state, which would then react with activated dipolarophile partners to generate an intermediate, and finally release the product (see Scheme 1). © 2017 American Chemical Society

Recently, CF3CH2NH2·HCl (the simplest α-trifluoromethyl amines unit), after changed into 2,2,2-trifluorodiazoethane, has been used as an attractive CF3 building block in the metalcatalyzed or organocatalytic reactions.11 However, the direct use of trifluoroethylamine as material in the asymmetric construction of functionalized α-trifluoromethyl amines remains less explored in the area of chiral synthesis.7a,12 Aimed to develop new methods for the synthesis of optically active CF3-containing heterocyclic compounds,13 we designed the trifluoroethylamine-derived azomethine ylide precursor 1 by which we synthesized highly substituted α-trifluoromethyl pyrrolidine. To further enhance the acidity of the α-hydrogen atom of precursor 1 and thus provide a heteroatom which can combine with proton or chiral metal complex to form a stable transition state, we used diethyl 2-oxomalonate reacting with Received: December 8, 2016 Published: February 28, 2017 3482

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry

diphenylprolinol trimethylsilyl ether as catalyst, and as shown in Table 2, high diastereoselectivities were obtained in all cases. Generally, almost all of the cases gave excellent enantioselectivities except for entry 7, and the use of CH3CN as solvent gave the best result. Further study on the additives showed that the substituted benzoic acid DNBA could effectively shorten the reaction time. Furthermore, with the reduction of catalyst loading to 10 mol %, although longer reaction time was needed, the same exciting result was obtained Having established optimal reaction conditions, this organocatalyzed cycloaddition reaction for the synthesis of highly substituted α-trifluoromethyl pyrrolidines was explored with a variety of substituted cinnamaldehydes. The results revealed that various ketimines bearing electron-withdrawing and electron-donating substituents at different positions of the aromatic ring all gave the corresponding compounds (3d−3i, 3k−3l, Scheme 3) in high to excellent enantioselectivities (95% to >99% ee), albeit the reactivity varies greatly. For instance, with the electron-withdrawing group at the 4-position, the reaction gave the products in good to excellent yields within 18 h (3b−3d, Scheme 3), while, with p-methyl or p-methoxy cinnamaldehyde as the substrate, it took 24−30 h only to give the corresponding products in relatively lower yields (3e and 3f, Scheme 3). Moreover, given that enals with substitutes of the aromatic ring at the 4-, 3-, or 2-position gave products in very similar enantioselectivity (91% ee to >99% ee; see 3a−3f, 3g−3i, 3j−3l in Scheme 3), the steric effect seems not to play a part in the enantioselectivity of the cycloaddition. Further investigation turned to aliphatic substituted 2-enals. The cycloaddition product was obtained in rather low diastereoselectivity with 4-(trityloxy)but-2-enal as the substrate (3r, Scheme 4), while the dr value was considerably improved when 4-(benzhydryloxy)but-2-enal and 4-phenoxybut-2-enal were applied instead (3s, 3t, Scheme 4). Moreover, pent-2-enal was tolerated and gave the product 3u of which we found it difficult to determine the enantiomeric excess due to its lack of UV absorption. Thus, product 3u was further modified to extend the π conjugation structure via Wittig olefination without the change of configuration, giving 4u in excellent enantioselectivity (4u, Scheme 4). To test the absolute configuration of cycloaddition products 3 which is in the liquid state at r.t., we selected the adduct 3d to condense with a Wittig reagent to give 4d in 91% yield and 98% ee, which is in the solid state and the absolute configuration of which was then determined through X-ray crystal structure analysis (Scheme 5). With the results mentioned above, a potential mechanism was proposed. As illustrated in Scheme 6, the diphenylprolinol silyl ether forms the intermediate iminium ion through the reaction with the 2-enals. The efficient shielding of the Re face of the chiral iminium intermediate by the bulky aryl groups results in a diastereoselective Si-facial cycloaddition on the trifluoroethylamine-derived azomethine ylide, and gave the cycloadduct iminium ion. Then hydrolysis released the product (Scheme 6) from the catalytic cycle, and the catalyst was regenerated.

trifluoroethylamine to synthesize imine 1 (see Scheme 2). Prior to this work, we reported the synthesis of spirooxindoles from Scheme 2. Our Activated Model in the Synthesis of Trifluoromethyl-Substituted Pyrrolidine

precursor 1 through an umpolung reaction,14 yet the efficient synthetic method for CF3-substituted pyrrolidines still remains a challenge.

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RESULTS AND DISCUSSION Imine 1 was obtained through heating the mixture of diethyl 2oxomalonate and trifluoroethylamine hydrochloride in toluene in the presence of 10 mol % p-toluenesulfonic acid (see the Supporting Information). In view of the operational advantage of organocatalysis, we selected α,α-diaryl prolinols as the catalyst to examine the possibility of trifluoroethylaminederived azomethine ylides reacting with α,β-unsaturated aldehydes. Initially, we found that diphenylprolinol was not suitable for this reaction with which a mere 5% yield was achieved after 96 h. However, with the change from hydroxyl to silyl ether, as summarized in Table 1, and with 20% benzoic Table 1. Screening for Catalyst Enantioselectivity of 1,3Dipolar Cycloaddition Reactiona

cat.

R1

R2

time (h)

yield (%)b

drc

eed

1 2 3 4 5

Ph Ph Ph Ph 3,5-(CF3)2-Ph

H TMS TES TBDMS TMS

96 28 34 48 48

20:1 >20:1 20:1 6:1

99 97 93 88

a

Reactions were carried out with imine (0.15 mmol), aldehyde (0.10 mmol), PhCOOH (0.02 mmol), and catalyst (0.02 mmol) in DCM (0.1 M) at room temperature. bIsolated yields of both exo- and endoadduct. cDetermined by 1H and 19F NMR or chiral phase HPLC analysis. dDetermined by chiral phase HPLC analysis.

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acid as an additive, the cycloaddition reactions proceeded much smoothly. Several silyl ethers were tested, and the best result was obtained when (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)-pyrrolidine was applied, giving the product in 82% yield, >20:1 dr, and >99% ee in less than 28 h. After the screening of catalysts, we assessed the influence of solvents, the additives, and the catalyst loading in the cycloaddition of ketimine with cinnamaldehyde by using

CONCLUSION In summary, we developed an organocatalyzed method in the one-step enantioselective synthesis of highly substituted αtrifluoromethyl pyrrolidines. With trifluoroethylamine as an αCF3 amine synthon, a new type of 1,3-dipole was designed and used in the diphenylprolinol trimethylsilyl ether catalyzed 1,33483

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry Table 2. Optimization of the Reaction Conditionsa

entry

sol

additive

time (h)

yield (%)b

drc

eed

1 2 3 4 5 6 7 8 9 10 11 12e 13f

THF EA Tol Et2O CH3CN DCE MeOH CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH DNBA 4-NO2-PhCOOH AcOH TsOH DNBA DNBA

31 11 23 28 5 11 48 3 4 24 72 10 16

82 90 98 78 98 90 78 98 98 70

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

>99 >99 97 97 >99 >99 64 >99 >99 >99

98 90

>20:1 >20:1

>99 >99

a

Reactions were carried out with imine (0.15 mmol), aldehyde (0.10 mmol) at room temperature. bIsolated yields of both exo- and endo-adduct. Determined by 1H and 19F NMR or chiral phase HPLC analysis. dDetermined by chiral phase HPLC analysis. e0.01 mmol of catalyst and 0.01 mmol of 3,5-dinitrobenzoic acid were used. f0.005 mmol of catalyst and 0.005 mmol of 3,5-dinitrobenzoic acid were used.

c

dipolar cycloaddition, and this procedure gave α-CF 3 pyrrolidines with three contiguous stereogenic centers in excellent diastereoselectivities, stereoselectivities, and yields.

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corresponding aldehyde (0.10 mmol) was added in one portion, and the reaction was stirred for the designated time, after which it was concentrated and purified by column chromatography using ethyl acetate/petroleum (1/20) eluent to give the corresponding 3a−3q. Racemates were prepared following the general procedure by combination of equivalent (R)- and (S)-catalysts. (3S,4R,5S)-Diethyl-3-formyl-4-phenyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3a). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 13.2 mg of cinnamaldehyde (0.10 mmol), 38.0 mg (98.0% yield) of compound 3a was obtained as a pale yellow oil, [α]20 D = −3 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 8.3 min, and tminor = 6.6 min. 1H NMR (300 MHz, CDCl3) δ 9.98 (d, J = 0.6 Hz, 1H), 7.53−7.43 (m, 5H), 4.57−4.40 (m, 4H), 4.24−4.14 (m, 2H), 3.77 (d, J = 6.3 Hz, 1H), 3.47−3.44 (d, J = 9.9 Hz, 1H), 1.52−1.43 (m, 6H); 13C NMR (75 MHz, CDCl3) δ195.2, 169.7, 168.6, 129.0, 127.8, 125.4 (q, JC‑F = 270.8 Hz), 73.5, 65.4 (q, JC‑F = 30.8 Hz), 63.9, 63.3, 62.8, 46.3, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.56; HRMS (ESI) m/z calcd for C18H21F3NO5 [M + H]+: 388.1366, found 388.1369. (3S,4R,5S)-Diethyl-4-(4-fluorophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3b). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 15.0 mg of 4-fluorocinnamaldehyde (0.1 mmol, 1.0 equiv), 27.5 mg (68.0% yield) of compound 3b was obtained as a pale yellow oil. [α]20 D = −4 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 97% ee was determined by HPLC analysis (Daicel Chiralcel OD column, hexane/2-propanol 92:8, 1.0 mL/min). Retention time: tmajor = 8.4 min, tminor = 7.9 min. 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 7.30−7.25 (m, 2H), 7.02 (t, J = 8.4 Hz, 2H) 4.40−4.23 (m, 4H), 4.05−3.91 (m, 2H), 3.57 (d, J = 6.3 Hz, 1H), 3.23 (d, J = 10.2 Hz, 1H), 1.35−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ195.0, 169.6, 168.5, 163.8, 160.5, 133.6, 133.6, 129.5, 129.4, 125.4 (q, JC‑F = 278.3 Hz), 116.0, 115.7, 94.0, 79.0, 73.2, 65.4 (q, JC‑F = 29.3 Hz), 63.8, 63.4, 62.8, 50.0, 45.5, 22.0, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.51, −114.4; HRMS (ESI) m/z calcd for C18H19F4NNaO5 [M + Na]+: 428.1092, found 428.1094. (3S,4R,5S)-Diethyl-4-(4-chlorophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3c). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 16.6 mg of 4-chlorocinnamaldehyde (0.10 mmol, 1.0 equiv), 33.7 mg (80.0% yield) of compound 3c was obtained as a pale yellow oil. [α]20 D = −7 (c 1.0,

EXPERIMENTAL SECTION

General Information. Reactions were monitored by TLC on silica gel GF254 (0.25 mm). Column chromatography purifications were carried out using silica gel. NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard for 1H (300 MHz), 13 C (75 MHz), and 19F (282 MHz) NMR. Data are presented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constant in hertz (Hz). HRMS spectra were recorded using a Q-TOF mass spectrometer. The ee values determination was carried out using HPLC with a Chiracel OD-H column, Chiracel AD-H column, and Chiracel IA column. Optical rotations were measured on a digital polarimeter and are reported as follows: [α]TD (1 g/100 mL, CHCl3). All solvents were obtained from commercial sources and were purified according to standard procedures. The catalyst was prepared according to the literature procedure.15 Preparation of Diethyl 2-((2,2,2-Trifluoroethyl)imino)malonate 1. Diehyl ketomalonate (13.65 mmol), 2,2,2-trifluoroethylamine hydrochloride (27.00 mmol), and p-toluenesulfonic acid (1.40 mmol) were suspended in toluene (40 mL) in a two-neck flask with a water separator and a condenser. The mixture was then heated to separate the water until complete disappearance of the starting materials, after which it was cooled to room temperature, washed with a small quantity of saturated NaHCO3 solution, extracted with ethyl acetate and washed with brine, and dried over anhydrous Na2SO4. After an evaporation of the organic solvent, the crude residue was purified by chromatography (silica gel, hexane/ethyl acetate = 4:1). Ketimine 1 (2.80 g, 80% yield) was obtained as a pale yellow liquid according to the procedure mentioned above. 1H NMR (300 MHz, CDCl3) δ 4.40 (dq, J = 7.2 Hz, J = 2.1 Hz, 4H), 4.23 (q, J = 9.3 Hz, 2H), 1.37 (t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 161.1, 159.6, 129.3, 125.6, 122.0, 118.3, 62.9, 62.8, 55.7, 55.3, 54.8, 54.4, 13.93, 13.90; 19F NMR (282 MHz, CDCl3) δ −71.1. HRMS (ESI) m/ z calcd for C9H12F3NNaO4 [M + Na]+: 278.0611, found 278.0615. General Procedure for the Synthesis of Compounds 3a−3q. A vial equipped with a magnetic stir bar was charged with appropriate ketimine 1 (0.15 mmol), the catalyst (0.01 mmol), DNBA (0.01 mmol), and anhydrous acetonitrile (1 mL) at room temperature. The 3484

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry Scheme 3. Reaction Time Required for Each Substrate Is Givena

a

The reported yields are of the isolated products. The ee and dr values were determined by 1H and 19F NMR analysis.

CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 90:10, 1.0 mL/min). Retention time: tmajor = 8.7 min. 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 7.32−7.22 (m, 4H), 4.42−4.23 (m, 4H), 4.43−4.23 (m, 4H), 4.03−3.88 (m, 2H), 3.56 (d, J = 6.3 Hz, 1H), 3.23 (d, J = 9.9 Hz, 1H), 1.35−1.26 (m, 6H); 13 C NMR (75 MHz, CDCl3) δ135.4, 132.6, 128.2, 128.1, 124.3 (q, JC‑F = 277.5 Hz), 72.2, 64.3 (q, JC‑F = 29.3 Hz), 62.7, 62.4, 61.8, 44.6, 12.8, 13.0; 19F NMR (282 MHz, CDCl3) δ −75.57; HRMS (ESI) m/z calcd for C18H19ClF3NNaO5 [M + Na]+: 444.0796, found 444.0806. (3S,4R,5S)-Diethyl-4-(4-bromophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3d). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 20.9 mg of 4-bromocinnamaldehyde (0.10 mmol, 1.0 equiv), 39.1 mg (84.0% yield) of compound 3d was obtained as a pale yellow oil. [α]20 D = −42 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 90:10, 1.0 mL/min). Retention time: tmajor = 9.4 min, tminor = 7.4 min. 1H NMR (300 MHz, CDCl3) δ 9.78 (s,

1H), 7.48−7.44 (m, 2H), 7.20−7.17 (m, 2H), 4.43−4.22 (m, 4H), 4.01−3.88 (m, 2H), 3.56 (d, J = 6.0 Hz, 1H), 3.23 (d, J = 10.2 Hz, 1H), 1.35−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.7, 169.6, 168.5, 137.0, 132.1, 130.8, 129.5, 125.3 (q, JC‑F = 276.8 Hz), 123.4, 121.7, 119.7, 73.1, 65.2 (q, JC‑F = 28.5 Hz), 63.6, 63.4, 62.8, 45.6, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.56; HRMS (ESI) m/z calcd for C18H19BrF3NNaO5 [M + Na]+: 488.0291, found 488.0293. (3S,4R,5S)-Diethyl-3-formyl-4-(p-tolyl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3e). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 14.6 mg of 4-methylcinnamaldehyde (0.10 mmol, 1.0 equiv), 28.8 mg (72.0% yield) of compound 3e was obtained as a pale yellow oil, [α]20 D = −9 (c 1.0, CHCl3). dr (>20:1) was determined by 1 H and 19F NMR analysis. 95% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/ min). Retention time: tmajor = 7.0 min, tminor = 6.2 min. 1H NMR (300 MHz, CDCl3) δ 9.79 (d, J = 0.9 Hz, 1H), 7.20−7.12 (m, 4H), 4.41− 4.22 (m, 4H), 4.03−3.93 (m, 2H), 3.56 (d, J = 6.3 Hz, 1H), 3.25 (d, J = 9.6 Hz, 1H), 2.31 (s, 3H), 1.34−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 195.4, 169.7, 168.6, 137.6, 134.7, 129.7, 127.6, 125.5 (q, JC‑F 3485

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry Scheme 4. Reaction Time Required for Each Substrate Is Givena

a

The reported yields are of the isolated products. The ee and dr values were determined by 1H and 19F NMR analysis or HPLC analysis.

Scheme 5. X-ray Structure of the Product 4d

Scheme 6. Proposed Mechanism of [3 + 2] Cycloaddition

= 277.5 Hz), 73.5, 65.4 (q, JC‑F = 29.3 Hz), 63.9, 63.3, 62.7, 46.0, 21.1, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.53; HRMS (ESI) m/z calcd for C19H22F3NNaO5 [M + Na]+: 424.1342, found 424.1338. (3S,4R,5S)-Diethyl-3-formyl-4-(4-methoxyphenyl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3f). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 16.2 mg of 4-methoxy cinnamaldehyde (0.10 mmol, 1.0 equiv), 25.4 mg (61.0% yield) of compound 3f was obtained as a pale yellow oil. [α]20 D = −18 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 98% ee (major) and >99% ee (minor) was determined by HPLC analysis (Daicel Chiralcel OD column, hexane/2-propanol 95:5, 1.0

mL/min). Retention time: tmajor1 = 18.8 min and tminor1 = 13.6 min; tmajor2 = 13.9 min. 1H NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.28− 7.18 (m, 2H), 6.89−6.82 (m, 2H), 4.40−4.21 (m, 4H), 4.02−3.96 (m, 2H), 3.79 (s, 3H), 3.50 (d, J = 6.8 Hz, 1H), 3.22 (d, J = 9.9 Hz, 1H), 1.34−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 195.5, 169.7, 168.6, 159.1,, 129.5, 128.8, 125.5 (q, JC‑F = 279.0 Hz), 114.4, 73.4, 65.3 (q, JC‑F = 29.3 Hz), 63.8, 63.3, 62.7, 55.2, 45.6, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.38, −75.51. HRMS (ESI) m/z calcd for C19H22F3NNaO6 [M + Na]+: 440.1291, found 440.1292. (3S,4R,5S)-Diethyl-4-(3-chlorophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3g). From 38.3 mg (0.15 3486

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry

column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 8.7 min, tmajor = 7.5 min. 1H NMR (300 MHz, CDCl3) δ 9.81 (s, 1H), 7.39−7.35 (m, 2H), 7.29−7.18 (m, 2H), 4.52−4.20 (m, 6H), 3.73(d, J = 7.8 Hz, 1H), 3.55 (d, J = 10.8 Hz, 1H), 1.35−1.27 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 195.0, 169.5, 168.6, 134.9, 133.5, 130.6, 129.1, 127.5, 125.5 (q, JC‑F = 279.0 Hz), 73.7, 63.8 (q, JC‑F = 30.0 Hz), 63.4, 62.8, 62.6, 44.3, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −76.13; HRMS (ESI) m/z calcd for C18H19ClF3NNaO5 [M + Na]+: 444.0796, found 444.0796. (3S,4R,5S)-Diethyl-4-(2-bromophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3l). From 76.6 mg (0.3 mmol, 1.5 equiv) of ketimine 1 and 42.0 mg of 3-(2-bromophenyl)acrylaldehyde (0.20 mmol, 1.0 equiv), 63.5 mg (68.3% yield) of compound 3l was obtained as a pale yellow oil. [α]20 D = +18 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 91% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 12.1 min, tminor = 10.2 min. 1H NMR (300 MHz, CDCl3) δ 9.74 (s, 1H), 7.50 (d, J = 1.95 Hz, 1H), 7.28−7.20 (m, 2H), 7.08−7.02 (m, 1H), 4.53−4.50 (m, 1H), 4.32−4.12 (m, 5H), 3.67 (d, J = 1.88 Hz, 1H), 3.45 (d, J = 1.88 Hz, 1H), 1.23 (q, J = 1.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 195.0, 169.4, 168.6, 136.5, 133.9, 129.3, 128.1, 125.4 (q, JC‑F = 287.3 Hz), 73.6, 64.0, 63.4, 63.1, 62.8, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.96; HRMS (ESI) m/z calcd for C18H19BrF3NNaO5 [M + Na]+: 488.0291, found 488.0281. (3S,4R,5S)-Diethyl-3-formyl-4-(naphthalen-2-yl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3m). From 76.6 mg (0.3 mmol, 1.5 equiv) of ketimine 1 and 36.4 mg of 3-(naphthalen-2yl)acrylaldehyde (0.20 mmol, 1.0 equiv), 68.5 mg (78.3% yield) of compound 3m was obtained as a pale yellow oil. [α]20 D = +11 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 15.1 min. 1H NMR (300 MHz, CDCl3) δ 9.74 (d, J = 0.15 Hz, 1H), 7.74−7,69 (m, 4H), 7.40−7.33 (m, 2H), 7.30 (dd, J = 1.5, 8.4 Hz), 4.33−4.00 (m, 6H), 3.59 (d, J = 1.73 Hz, 1H), 3.31 (d, J = 2.55 Hz, 1H), 1.23−1.17 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 169.7, 168.7, 135.2, 133.4, 132.8, 129.0, 127.8, 127.7, 127.3, 126.5, 126.2, 125.5 (q, JC‑F = 279.0 Hz), 125.1, 73.6, 65.4 (q, JC‑F = 29.3 Hz), 63.9, 63.4, 62.8, 46.5, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.45 HRMS (ESI) m/z calcd for C22H22F3NNaO5 [M + Na]+: 460.1342, found 460.1344. (3S,4R,5S)-Diethyl-3-formyl-4-(naphthalen-1-yl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3n). From 76.6 mg (0.3 mmol, 1.5 equiv) of ketimine 1 and 36.4 mg of 3-(naphthalen-1-yl)acrylaldehyde (0.20 mmol, 1.0 equiv), 55.0 mg (63.0% yield) of compound 3n was obtained as a pale yellow oil. [α]20 D = +62 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 20.9 min, tminor = 10.9 min. 1H NMR (300 MHz, CDCl3) δ 9.81 (d, J = 0.3 Hz, 1H), 8.20 (d, J = 1.1 Hz, 1H), 7.8 (dq, J = 7.8, 27.6 Hz, 2H), 7.87−7.37 (m, 4H), 4.0 (s, 1H), 4.43−4.13 (m, 5H), 3.72 (d, J = 1.58 Hz, 1H), 3.58, (d, J = 1.3 Hz, 1H), 1.30 (q, J = 1.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ195.3, 169.7, 168.7, 134.2, 129.2, 128.6, 126.7, 125.9, 125.6 (q, JC‑F = 279.0 Hz), 125.3, 122.7, 76.7, 73.8, 63.3, 63.1, 62.8, 62.6, 62.1, 14.0, 13.9; 19F NMR (282 MHz, CDCl3) δ −75.47; HRMS (ESI) m/z calcd for C22H22F3NNaO5 [M + Na]+: 460.1342, found 460.1353. (3S,4R,5S)-Diethyl-4-(anthracen-9-yl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3o). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 23.2 mg of 3-(9-anthryl)acrolein (0.10 mmol, 1.0 equiv), 34.6 mg (71.0% yield) of compound 3o was obtained as a pale yellow oil. [α]20 D = +60 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 89% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2propanol 9:1, 1.0 mL/min). Retention time: tmajor = 28.0 min, tminor = 9.5 min. 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 8.63 (d, J = 9.1 Hz, 1H), 8.44 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.66−7.44 (m, 4H), 5.74 (dd, J = 10.6, 7.4 Hz, 1H), 4.71−4.59 (m, 1H), 4.49−4.32 (m, 4H), 4.13 (d, J = 10.6

mmol, 1.5 equiv) of ketimine 1 and 16.6 mg of 3-chlorocinnamaldehyde (0.10 mmol, 1.0 equiv), 34.1 mg (81.0% yield) of compound 3g was obtained as a pale yellow oil. [α]20 D = −4 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 94% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 7.8 min. 1H NMR (300 MHz, CDCl3) δ 9.79 (d, J = 0.6 Hz, 1H), 7.28−7.19 (m, 4H), 4.42−4.23 (m, 4H), 4.02−3.93 (m, 2H), 3.58 (d, J = 6.3 Hz, 1H), 3.25 (d, J = 10.2 Hz, 1H), 1.36−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.7, 169.5, 168.5, 140.1, 134.7, 130.3, 128.1, 127.7, 126.5, 125.3 (q, JC‑F = 278.3 Hz), 73.3, 65.3 (q, JC‑F = 29.3 Hz), 63.7, 63.5, 62.9, 45.8, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.58; HRMS (ESI) m/z calcd for C18H19ClF3NNaO5 [M + Na]+: 444.0796, found 444.0789. (3S,4R,5S)-Diethyl-3-formyl-5-(trifluoromethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidine-2,2-dicarboxylate (3h). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 20.0 mg of 3trifluorocinnamaldehyde (0.10 mmol, 1.0 equiv), 34.1 mg (75.0% yield) of compound 3h was obtained as a pale yellow oil. [α]20 D = −3 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 97% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 7.4 min, tminor = 6.1 min. 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 7.47−7.37 (m, 4H), 4.35−4.17 (m, 4H), 4.04−3.88 (m, 2H), 3.53 (d, J = 6.6 Hz, 1H), 3.21 (d, J = 10.5 Hz, 1H), 1.29−1.19 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.5, 169.5, 168.5, 139.1, 131.9, 131.3 (q, JC‑F = 129.0 Hz), 129.5, 125.1 (q, JC‑F = 268.5 Hz), 124.7 (q, JC‑F = 3.8 Hz), 124.1 (q, JC‑F = 3.8 Hz), 123.8 (q, JC‑F = 270.0 Hz),73.1, 65.3 (q, JC‑F = 30.0 Hz),63.6, 63.5, 62.9, 45.9, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −62.60, −75.61; HRMS (ESI) m/z calcd for C19H19F6NNaO5 [M + Na]+: 478.1060, found 478.1057. (3S,4R,5S)-Diethyl-4-(3-bromophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3i). From 76.6 mg (0.3 mmol, 1.5 equiv) of ketimine 1 and 42.0 mg of 3-(3-bromophenyl)acrylaldehyde (0.20 mmol, 1.0 equiv), 72.4 mg (77.8% yield) of compound 3i was obtained as a pale yellow oil. [α]20 D = −2 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 95% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 10.9 min, tminor = 8.6 min. 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 7.61−7.31 (m, 2H), 7.20−7.10 (m, 2H), 4.36−4.25 (m, 2H), 4.22− 4.15 (m, 2H), 3.94−3.86 (m, 2H), 3.54 (d, J = 1.5 Hz, 1H), 3.18 (d, J = 2.63 Hz, 1H), 1.28−1.18 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.7, 169.5, 168.5, 140.4, 131.0, 130.5, 130.5, 127.0, 125.3 (q, JC‑F = 278.3 Hz), 122.9, 73.2, 65.3 (q, JC‑F = 30.0 Hz), 63.7, 63.5, 62.9, 45.7, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.61; HRMS (ESI) m/z calcd for C18H19BrF3NNaO5 [M + Na]+: 488.0291, found 488.0291. (3S,4R,5S)-Diethyl-3-formyl-4-(2-nitrophenyl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3j). From 76.6 mg (0.3 mmol, 1.5 equiv) of ketimine 1 and 35.4 mg of 3-(2-nitrophenyl)acrylaldehyde (0.20 mmol, 1.0 equiv), 75.3 mg (62.2% yield) of compound 3j was obtained as a pale yellow oil. [α]20 D = +42 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2propanol 9:1, 1.0 mL/min). Retention time: tmajor = 25.2 min, tminor = 22.1 min. 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 7.92 (d, J = 2.03 Hz, 1H), 7.65−7.53 (m, 2H), 7.46−7.41 (m, 1H), 4.77 (t, J = 2.4 Hz, 1H), 4.44−4.23 (m, 4H), 4.13 (q, J = 1.65, 1H), 3.78 (d, J = 1.65 Hz, 1H), 3.39 (d, J = 2.7 Hz, 1H), 1.35−1.27 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.8, 169.2, 168.4, 133.5, 132.7,, 128.7, 125.5, 125.1 (q, JC‑F = 275.3 Hz), 73.2, 64.8 (q, JC‑F = 31.5 Hz), 63.5, 63.0, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.95; HRMS (ESI) m/z calcd for C18H19F3N2NaO7 [M + Na]+: 455.1037, found 455.1040. (3S,4R,5S)-Diethyl-4-(2-chlorophenyl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3k). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 16.6 mg of 2-chlorocinnamaldehyde (0.10 mmol, 1.0 equiv), 29.9 mg (71.0% yield) of compound 3k was obtained as a pale yellow oil. [α]20 D = +19 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel OD-H 3487

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry Hz, 1H), 3.88 (d, J = 5.3 Hz, 1H), 1.38−1.32 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 194.9, 169.7, 169.2, 131.8, 131.7, 131.0, 130.5, 129.2, 129.1, 129.0, 128.1, 126.9, 126.5, 125.8 (q, JC‑F = 288.0 Hz), 125.2, 124.5, 124.1, 122.9, 75.0, 64.4 (q, JC‑F = 30.8 Hz), 63.4, 63.2, 63.0, 39.0, 14.1, 13.9; 19F NMR (282 MHz, CDCl3) δ −76.33. HRMS (ESI) m/z calcd for C26H24F3NNaO5 [M + Na]+: 510.1499, found 510.1501. (3S,4S,5S)-Diethyl-3-formyl-4-(furan-2-yl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3p). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 12.2 mg of 2-furanacrolein (0.10 mmol, 1.0 equiv), 23.0 mg (61.0% yield) of compound 3p was obtained as a pale yellow oil. [α]20 D = −30 (c 1.0, CHCl3). dr (>20:1) was determined by 1 H and 19F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/ min). Retention time: tmajor = 6.4 min. 1H NMR (300 MHz, CDCl3) δ 9.82 (d, J = 0.6 Hz, 1H), 7.32 (dd, J = 1.8, 0.7 Hz, 1H), 6.31 (dd, J = 3.3, 1.9 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 4.41−4.22 (m, 4H), 4.18− 4.07 (m, 2H), 3.58 (d, J = 6.8 Hz, 1H), 3.38 (d, J = 9.0 Hz, 1H), 1.34− 1.25 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 195.1, 169.3, 168.4, 150.0, 142.2, 125.3 (q, JC‑F = 30.8 Hz), 110.8, 108.2, 73.2, 63.3, 62.7, 61.4 (q, JC‑F = 27.8 Hz), 39.7, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −76.17; HRMS (ESI) m/z calcd for C16H18F3NNaO6 [M + Na]+: 400.0978, found 400.0979. (3S,4S,5S)-Diethyl-4-((E)-2-chlorostyryl)-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3q). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 19.2 mg of 5-(2-chlorophenyl)penta-2,4-dienal (0.10 mmol, 1.0 equiv), 38.4 mg (86.0% yield) of compound 3q was obtained as a pale yellow oil. [α]20 D = −20 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 90:10, 1.0 mL/min). Retention time: tmajor = 11.5 min, tminor = 8.9 min. 1H NMR (300 MHz, CDCl3) δ 9.86 (d, J = 1.4 Hz, 1H), 7.45−7.42 (m, 1H), 7.36−7.33 (m, 1H), 7.24−7.15 (m, 2H), 6.99 (d, J = 15.8 Hz, 1H), 6.04 (dd, J = 15.6, 7.9 Hz, 1H), 4.41− 4.21 (m, 4H), 3.86−3.69 (m, 2H), 3.49 (d, J = 7.0 Hz, 1H), 3.04 (dd, J = 9.7, 1.2 Hz, 1H), 1.35−1.26 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 195.7, 169.6, 168.4, 134.4, 133.2, 130.2, 129.7, 129.0, 128.7, 126.9, 126.8, 73.3, 63.4, 63.3, 63.0, 62.7, 61.4, 44.1, 14.0, 13.8; 19F NMR (282 MHz, CDCl3) δ −75.39; HRMS (ESI) m/z calcd for C20H21ClF3NNaO5 [M + Na]+: 470.0953, found 470.0953. (3S,4S,5S)-Diethyl-3-formyl-5-(trifluoromethyl)-4-((trityloxy)methyl)pyrrolidine-2,2-dicarboxylate (3r). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 32.8 mg of (E)-4-(trityloxy)but2-enal (0.10 mmol,), 44.0 mg (76.0% yield) of compound 3r was obtained as a pale yellow oil, [α]20 D = −17 (c 1.0, CHCl3). dr (45:55) and >99% ee were determined by HPLC analysis (Daicel Chiralcel IC column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor1 = 9.6 min, and t major2 = 11.5 min. 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.41−7.24 (m, 15H), 4.44−4.34 (m, 1H), 4.31−4.10 (m, 2H), 4.06−3.96 (m, 1H), 3.86−3.71 (m, 2H), 3.59−3.40 (m, 2H), 3.20 (d, J = 5.9 Hz, 1H), 2.86 (t, J = 5.1 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 197.1, 169.2, 168.6,143.3, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8, 127.3, 127.2, 125.6 (q, JC‑F = 279.0 Hz), 87.9, 73.5, 62.5, 62.2, 60.2, 56.6 (q, JC‑F = 31.3 Hz) 52.8, 46.2, 14.0, 13.9, 13.8; 19F NMR (282 MHz, CDCl3) δ −76.98; HRMS (ESI) m/z calcd for C32H32F3NNaO6 [M + Na]+: 606.2074, found 606.2082. (3S,4S,5S)-Diethyl-4-((benzhydryloxy)methyl)-3-formyl-5(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3s). From 38.3 mg (0.15 mmol, 1.5 equiv) of ketimine 1 and 25.2 mg of (E)-4(benzhydryloxy)but-2-enal (0.10 mmol), 34.5 mg (68.2% yield) of compound 3s was obtained as a pale yellow oil, [α]20 D = −35 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 85% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 9.9 min, and tminor = 8.6 min. 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.29 (dt, J = 14.6, 4.4 Hz, 12H), 5.17 (s, 1H), 4.46 (dd, J = 15.4, 7.5 Hz, 1H), 4.34−4.15 (m, 2H), 4.08 (ddd, J = 14.3, 10.7, 7.1 Hz, 1H), 3.95−3.81 (m, 1H), 3.73−3.60 (m, 1H), 3.58−3.45 (m, 3H), 3.40 (dd, J = 10.3, 5.9 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 197.1, 169.2, 168.8, 141.0,

128.6, 128.5, 127.9, 127.8, 126.8, 125.7 (q, JC‑F = 270 Hz), 85.2, 74.5, 65.1, 62.5, 62.3, 57.9 (q, JC‑F = 31.3 Hz), 53.4, 47.0, 13.9, 13.8; 19F NMR (282 MHz, CDCl3) δ −76.91; HRMS (ESI) m/z calcd for C26H28F3NNaO6 [M + Na]+: 530.1761, found 530.1767. (3S,4S,5S)-Diethyl-3-formyl-4-(phenoxymethyl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3t). From 38.3 mg (0.15 mmol,1.5 equiv) of ketimine 1 and 16.2 mg of (E)-4-phenoxybut-2enal (0.10 mmol), 34.1 mg (81.7% yield) of compound 3t was obtained as a colorless oil, [α]20 D = −27 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR analysis. 91% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, 1.0 mL/min). Retention time: tmajor = 12.1 min, and tminor = 19.5 min. 1H NMR (300 MHz, CDCl3) δ 10.12−9.58 (m, 1H), 7.65- 7.11 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 4.48 (dq, J = 16.3, 8.1 Hz, 1H), 4.39−4.26 (m, 1H), 4.27−4.21 (m, 2H), 4.18− 4.04 (m, 1H), 3.84−3.71 (m, 2H), 3.65 (ddd, J = 11.5, 9.4, 1.9 Hz, 1H), 3.27 (d, J = 7.1 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 196.4, 171.0, 168.7, 157.7, 129.5, 125.0 (q, JC‑F = 279 Hz), 121.3, 113.9, 71.7, 63.2, 62.9, 62.1, 58.7 (q, JC‑F = 31.0 Hz), 51.4, 43.2, 13.9, 13.6; 19F NMR (282 MHz, CDCl3) δ −72.87; HRMS (ESI) m/z calcd for C19H22F3NNaO6 [M + Na]+: 440.1291, found 440.1296. (3S,4S,5S)-Diethyl-4-ethyl-3-formyl-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (3u). From 25.5 mg (0.10 mmol, 1.0 equiv) of ketimine 1 and 16.8 mg of pent-2-enal (0.2 mmol, 2.0 equiv), 53 mg (78.0% yield) of compound 3u was obtained as a pale yellow oil. [α]20 D = +25 (c 1.0, CHCl3). dr (>20:1) was determined by 1H and 19F NMR 1 analysis. H NMR (300 MHz, CDCl3) δ 9.74 (s, 1H), 4.42 (s, 1H), 4.31−4.20 (m, 4H), 3.25−3.16 (m, 3H), 1.87−1.79 (m, 1H), 1.54− 1.41 (m, 1H), 1.29−1.25 (m, 6H), 1.10 (t, J = 7.35, 3H); 13C NMR (75 MHz, CDCl3) δ 168.8, 168.8, 168.8, 125.5 (q, JC‑F = 277.8 Hz), 77.4, 77.0, 76.6, 74.5, 62.4, 61.9, 57.2 (q, JC‑F = 31.3 Hz), 52.5, 48.3, 19.7, 14.0, 13.9, 12.8; 19F NMR (282 MHz, CDCl3) δ −77.35; HRMS (ESI) m/z calcd for C14H20F3NNaO5 [M + Na]+: 362.1186, found 362.1192. General Procedure for the Synthesis of Compounds 4u and 4d. A vial equipped with a magnetic stir bar was charged with the appropriate compound 3u (or 3d) (1.0 equiv), ethyl 2-(triphenyl-l5phosphanylidene)acetate (1.0 equiv), and DCM at room temperature. The reaction was stirred for the designated time, after which it was concentrated and purified by column chromatography (silica gel, petroleum/ethyl acetate = 4:1). (3S,4S,5S)-Diethyl-3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-ethyl5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (4u). From 53 mg (0.16 mmol, 1.0 equiv) of compound 3u and 55.7 mg of ethyl 2(triphenyl-l5-phosphanylidene)acetate (0.16 mmol, 1.0 equiv), 47.8 mg (73.0% yield) of compound 4u was obtained as a pale yellow oil. 1 19 [α]20 D = +50 (c 1.0, CHCl3). dr (>20:1) was determined by H and F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2-propanol 97:3, 1.0 mL/min). Retention time: tmajor = 7.4 min. 1H NMR (300 MHz, CDCl3) δ 6.82 (dd, J = 15.5, 10.6 Hz, 1H), 5.90 (d, J = 15.4 Hz, 1H), 4.33−4.12 (m, 6H), 3.84−3.78 (m, 1H), 3.24−3.17 (m, 2H), 3.00−2.92 (m, 1H), 1.77−1.67 (m, 1H), 1.33−1.23 (m, 9H), 1.21−1.13 (m, 1H), 0.960.93 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 169.0, 165.7, 144.3, 125.6 (q, JC‑F = 276.8 Hz), 124.3, 74.8, 63.4, 63.0, 62.8 (q, JC‑F = 30.0 Hz), 62.6, 62.3, 62.2, 61.8, 60.5, 48.7, 44.4, 19.9, 14.1, 14.0, 13.8, 12.5; 19F NMR (282 MHz, CDCl3) δ −77.30; HRMS (ESI) m/z calcd for C18H26F3NNaO6 [M + Na]+: 432.1604, found 432.1605. (3S,4R,5S)-Diethyl-4-(4-bromophenyl)-3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-5-(trifluoromethyl)pyrrolidine-2,2-dicarboxylate (4d). From 44.6 mg of 3d and 33.4 mg of ethyl 2-(triphenylphosphoranylidene)acetate (1.0 equiv) stirred in DCM overnight, 47.9 mg (91% yield) of 4d was obtained as a pale yellow solid. [α]20 D = −48 (c 1.0, CHCl3); mp = 78−79 °C. dr (>20:1) was determined by 1H and 19 F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-propanol 9:1, Retention time: tmajor = 7.1 min, tminor = 4.9 min. 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.06−6.98 (m, 1H), 5.61 (d, J = 15.9 Hz, 1H), 4.34−4.23 (m, 4H), 4.15−4.08 (m, 2H), 3.97−3.87 (m, 3488

DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

The Journal of Organic Chemistry 1H), 3.80−3.73 (m, 1H), 3.55 (d, J = 7.5 Hz, 1H), 3.29−3.21 (m, 1H), 1.31−1.23 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 169.8, 168.4, 165.4, 142.0, 135.8, 132.1, 129.5, 125.9, 125.3 (q, JC‑F = 276.8 Hz), 121.8, 73.7, 65.1 (q, JC‑F = 30.0 Hz), 62.8, 62.1, 60.5, 56.6, 50.1, 14.1, 14.0, 13.9; 19F NMR (282 MHz, CDCl3) δ −74.90; HRMS (ESI) m/z calcd for C22H26BrF3NO6 [M + H]+: 536.0890, found 536.0894.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b02949. 1 H, 19F, 13C, and HPLC spectra (PDF) X-ray crystal data (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (W.Y.). *E-mail: [email protected] (K.W.). *E-mail: [email protected] (R.W.). ORCID

Wenjin Yan: 0000-0003-2566-7322 Rui Wang: 0000-0002-4719-9921 Author Contributions §

Z.D. and Y.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the grants from the National Natural Science Foundation of China (Nos. 81573265, 21432003). REFERENCES

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DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490

Article

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DOI: 10.1021/acs.joc.6b02949 J. Org. Chem. 2017, 82, 3482−3490