Organocatalytic C(sp3)âH Functionalization of 5-Methyl-2,3

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Organocatalytic C(sp3)-H Functionalization of 5-Methyl-2,3dihydrofuran Derivatives with Trifluoropyruvates via Sequential exo-Tautomerization/Carbonyl-Ene Process Yao-Bin Shen, Shuai-Shuai Li, Yun-Ming Sun, Liping Yu, Zhihui Hao, Qing Liu, and Jian Xiao J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 24, 2019

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The Journal of Organic Chemistry

Organocatalytic

C(sp3)−H

Functionalization

of

5-Methyl-2,3-dihydrofuran Derivatives with Trifluoropyruvates via Sequential exo-Tautomerization/Carbonyl-Ene Process Yao-Bin Shen,† Shuai-Shuai Li,† Yun-Ming Sun,† Liping Yu,§ Zhi-Hui Hao,*,† Qing Liu,┴ Jian Xiao*,†,‡ † College ‡

of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China

College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.

§College

of Landscape Architecture and Forestry, Qingdao Agricultural University, Qingdao 266109, China

┴

College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China.

Corresponding author: Zhi-Hui Hao, Jian Xiao E-mail address: [email protected]; [email protected]

Graphic Abstract

Abstract: An organocatalytic C(sp3)−H functionalization of 5-methyl-2,3-dihydrofuran derivatives with trifluoropyruvates was achieved via sequential exo-tautemerization/carbonyl-ene process, providing the biologically important CF3-substituted 2,3-dihydrofurans in high yields. This method featured mild metal-free conditions, good chemoselectivity, and easy scalability. INTRODUCTION Substituted 2,3-dihydrofurans are ubiquitous in natural products and medicinal molecules,1 such as Aflatoxin B1,1d Clerodin,1e Austocystin A1f and Citridone A1g (Figure 1). They have also been used as synthetic intermediates in the construction of highly functionalized tetrahydrofurans.2 Meanwhile, the trifluoromethyl group (CF3) represents a privileged pharmacophore in numerous pharmaceuticals with remarkable bioactivities, such as Efavirenz (HIV-RT inhibitor),

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(+)-erythro-Mefloquine (antimalarial) and ZK-216348 (selective glucocorticoid receptor agonist) (Figure 1).3 According to the principle of superposition, introduction of a CF3 group into 2,3-dihydrofuran moieties holds great potential for the production of new pharmaceuticals and biologically active compounds.

Figure 1. Natural products and pharmaceuticals containing 2,3-dihydrofuran and CF3 moieties. The direct functionalization of inert C(sp3)−H bonds of heterocycles has emerged as a powerful strategy for efficient construction of diverse heterocyclic compounds.4 However, most of the protocols rely on transition-metal catalysis, which commonly require high-cost, toxic transition metals and harsh conditions.5 Accordingly, to meet the criteria of green chemistry, the development of metal-free C(sp3)−H functionalization methodologies under mild conditions is highly desirable.6 In this context, we have developed the organocatalytic or catalyst-free C(sp3)−H functionalization of 2-methylazaarenes with diverse electrophiles via an imine/enamine tautomerization strategy, which exhibited predominance over their metal- or base-promoted counterparts (Scheme 1a).7 Therefore, we envisaged that the C(sp3)−H functionalization of 5-methyl-2,3-dihydrofurans with electrophiles, such as trifluoropyruvates, might operate via an exo-tautomerization/nucleophilic addition process (Scheme 1b). However, to the best of our knowledge, the C(sp3)−H functionalization of 5-methyl-2,3-dihydrofurans has never been realized. The great challenges might come from the weak acidity and weak nucleophilicity of the methyl group at the C6 position, which is resulted from the thermodynamically stable and electron-rich enol ether moiety of dihydrofuran. Moreover, a competitive direct carbonyl-ene reaction at the C4 position is kinetically favored than exo-tautomerization8 due to the high reactivity of the enol ether to participate in cycloaddition2 and nucleophilic addition9. As a continuation of our research


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interest in the development of organocatalytic C(sp3)−H functionalization strategy for one-step assembly of pharmaceutically important targets,7,10 herein, we reported an organocatalytic C(sp3)−H functionalization of 5-methyl-2,3-dihydrofuran derivatives with trifluoropyruvates to synthesize potentially bioactive CF3-substituted 2,3-dihydrofurans in excellent yields. Scheme 1. C(sp3)−H Functionalization of 2-Methylazaarenes and 5-Methyl-2,3-dihydrofurans

RESULTS AND DISCUSSION Initially,

the

reaction

of

5-methyl-2,3-dihydrofuran

derivative

1a

with

methyl

3,3,3-trifluoropyruvate 2a was chosen as the model reaction to investigate the viability of our proposed strategy (Table 1). Gratifyingly, the desired C(sp3)−H functionalization product 3a was obtained in 20% yield when trifluoromethanesulfonic acid (TfOH) was employed as the catalyst in DCM at room temperature (Table 1, entry 1).11 Then various Brønsted acids were screened to improve the reaction efficiency, and it was found that 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (PA) was the optimal catalyst to furnish 3a in 86% yield (Table 1, entries 2-7). It was worth mentioning that the acidity of protonic acids played a significant role in this transformation and the employment of stronger acidic sulfonic acids (TfOH and MsOH) or weaker acidic carboxylic acids (PhCO2H and AcOH) was detrimental to the reaction. In comparison, Lewis acids such as Sc(OTf)3 and Cu(OTf)2 were also examined, however, the inferior results were obtained (Table 1, entries 8-9). The subsequent control experiment in the absence of catalyst indicated that no reaction would occur (Table 1, entry 10). Afterwards, other solvents such as DCE, THF, CH3CN and toluene were further evaluated, and toluene exhibited the best productivity to provide 3a in 90% yield (Table 1, entries 11-14). When the reaction was carried



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out without 4 Å molecular sieves, a decreased yield was observed (Table 1, entries 15). Moreover, other phosphates such as diphenyl phosphate (DPP) and dibutyl phosphate (DBP) were tested, which led to inferior yields (Table 1, entries 16-17). As a consequence, the optimal reaction conditions were using PA as catalyst, toluene as a solvent and 4 Å molecular sieves as an additive at room temperature. Table 1. Optimization of the Reaction Conditionsa

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

catalyst

solvent

TfOH MsOH TFA (−)-CSA PA PhCO2H HOAc Sc(OTf)3 Cu(OTf)2 -PA PA PA PA PA DPP DBP

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCE THF CH3CN toluene toluene toluene toluene

time (h) 8 5 0.7 5 2 24 24 8 8 48 3 40 24 3 3 5 5

yield (%)b 20 23 60 74 86 15 17 trace 13 0 83 52 87 90 84 88 67

drc 2.7:1 3.2:1 1.9:1 3:1 2.4:1 2.1:1 1.8:1 -2.4:1 -2.3:1 2.5:1 2.7:1 2.4:1 2.3:1 1.5:1 2.4:1

conditions (unless otherwise noted): 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol %), 4 Å molecular

sieves (50 mg), solvent (1 mL), room temperature. (−)-CSA = (−)-10-camphorsulfonic acid. PA = 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. DPP = diphenyl phosphate. DBP = dibutyl phosphate. bIsolated yield for 3a. cDetermined by 1H NMR analysis of the crude mixtures. dWithout 4 Å molecular sieves.

With the optimized reaction conditions in hand, the substrate scope was investigated to examine the generality of the protocol (Table 2). Generally, a series of 5-methyl-2,3-dihydrofuran derivatives 1 and trifluoropyruvates 2 proceeded smoothly, affording the corresponding products 3 in excellent yields and moderate diastereoselectivities. With regard to 5-methyl-2,3-dihydrofuran derivatives 1 with R1 groups, substrates bearing electron-donating or electron-withdrawing substituents were both compatible with the reaction conditions, providing products 3b-3f in 88-94% yields. As for substrates 1 with R2 groups, both electron-rich and electron-deficient phenyl substituents were well tolerated, furnishing 3g-3n in generally high yields. Notably, the positions of substituents at the benzene rings had negligible influence on the transformation. Encouragingly,


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the nucleophilic naphthyl and thienyl groups were feasible as well, giving 3o and 3p in 93% and 90% yields, respectively. This phenomenon showed the excellent specificity and chemoselectivity of the method, since the competitive Friedel−Crafts reactions might operate between electron-rich arenes and trifluoropyruvates. Not surprisingly, ethyl 3,3,3- trifluoropyruvate was also tolerable, affording 3q in 87% yield. Remarkably, hexafluoroacetone was also identified as a viable reaction partner to enable the rapid access to 3r in moderate yield, albeit with higher temperature. Table 2. Substrate Scope of Organocatalytic C(sp3)−H Functionalizationa

aReaction

conditions: 1 (0.1 mmol), 2 (0.15 mmol), PA (20 mol %), 4 Å molecular sieves (50 mg), toluene (1 mL),

room temperature. Isolated yields after column chromatography. The dr was determined by 1H NMR analysis of crude mixture. b40 °C, toluene (0.5 mL).

To further explore the synthetic applicability of the developed methodology, the gram-scale synthesis of 3a was conducted in a 3.5 mmol scale (Scheme 2). The reaction proceeded efficiently



and delivered the corresponding product in 94% yield, indicating the promising prospect in the medical industry. Scheme 2. Gram-Scale Synthesis

A three-component reaction of 4, 5 and 2a was further carried out in a one-pot manner, as shown in Scheme 3. Intriguingly, the cascade dearomative [4 + 2] cycloaddition/C(sp3)−H functionalization process was totally realized, affording 3a in moderate yield. Scheme 3. Three-Component Cascade Reaction for One-Pot Synthesis

On the basis of the above experimental results, a plausible reaction mechanism was proposed (Scheme 4). Under the catalysis of Brønsted acid, the thermodynamically stable enol ether moiety of 5-methyl-2,3-dihydrofuran 1a undertakes exo-tautomerization to generate 1a´, which subsequently reacts with protonated methyl 3,3,3-trifluoropyruvate 2a via a carbonyl-ene reaction to give 6a. Finally, deprotonation of 6a provides the desired product 3a. It is noteworthy that the obviation of the kinetically favored direct carbonyl-ene reaction at the C4 position might be rationalized by the severe steric hindrance caused by the bulky substituents at the C2 and C3 positions. Scheme 4. Proposed Mechanism


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CONCLUSION In

summary,

we

developed

an

organocatalytic

C(sp3)−H

functionalization

of

5-methyl-2,3-dihydrofurans with trifluoropyruvates, furnishing a range of biologically important CF3-substituted dihydrofuran products in high yields under metal-free conditions. Mechanistically, the catalytic exo-tautomerization of the enol ether was demonstrated and played a vital role in the success of

this transformation. Additionally, the gram-scale synthesis and one-pot

three-component cascade reaction will find potential application in the medical industry. We believe that these findings will not only validate the potential application of 2,3-dihydrofuran in the synthesis of biologically important chemical products, but also push forwards the development of inert C(sp3)−H bond functionalization of heterocycles. Experimental Section All commercially available reagents, unless otherwise indicated, were used without further purification. All solvents were purified and dried according to standard methods prior to use. Molecular sieves were activated at 550 °C for 6 h before use. Reactions were monitored by thin layer chromatography (TLC) with 0.2 mm silica gel-coated HSGF 254 plates, visualized by UV light at 254 or 365 nm. Products were isolated and purified by column chromatography on 200-300 mesh silica gel. 1H, 13C and 19F NMR spectra were recorded on a Bruker AMX 500 (500 MHz for 1H, 125 MHz for 13C and 470 MHz for 19F NMR) spectrometer at room temperature. The chemical shifts (δ) were reported in ppm with respect to an internal standard, tetramethylsilane (0 ppm), and the solvent (CDCl3, 1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). Coupling constants (J) are given in Hertz. Splitting patterns of apparent multiplets associated with an averaged coupling constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd



(doublet of doublets) and br (broadened). All

13

C spectra were recorded with broadband proton

decoupling. HRMS were performed on a Waters XEVO QTOF mass spectrometer. Starting material 5-methyl-2,3-dihydrofuran derivatives 1 were synthesized according to the literature.10d For new compounds 1e and 1j, they were characterized as follows. 7-chloro-2,9a-dimethyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromene (1e). White solid; 209 mg, 67% yield; mp 141–143 °C; column chromatography eluent, petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 7.38 (m, 1H), 7.10–7.03 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.70–6.60 (m, 1H), 5.17 (m, 1H), 4.70 (m, 1H), 3.93 (s, 1H), 1.68 (s, 3H), 1.28 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.3, 153.3, 135.6, 131.7, 131.2 (2C), 128.6 (2C), 127.7, 127.4, 127.0, 126.9, 119.6, 95.9, 90.0, 89.8, 49.7, 23.7, 14.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H17ClO2Na 335.0809; found 335.0812. 2,9a-dimethyl-9-(m-tolyl)-3a,9a-dihydro-9H-furo[3,2-b]chromene (1j). White solid; 204 mg, 70% yield; mp 51–53 °C; column chromatography eluent, petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.31 (m, 2H), 7.27 (s, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 5.17 (s, 1H), 4.71 (s, 1H), 3.94 (s, 1H), 2.40 (s, 3H), 1.67 (s, 3H), 1.31 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.0, 154.6, 137.8, 136.4, 132.1, 130.0, 128.3, 128.2, 128.1, 127.4, 127.0, 121.7, 118.2, 96.0, 90.1, 89.8, 49.6, 23.8, 21.7, 14.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H20O2Na 315.1356; found 315.1361.

General Procedure for the Synthesis of 3 An oven-dried reaction tube was charged with 5-methyl-2,3-dihydrofuran derivatives 1 (1.0 equiv, 0.1 mmol), PA (20 mol %), newly activated 4 Å molecular sieves (50 mg), newly distilled toluene (1 mL) and trifluoropyruvates 2 (1.5 equiv, 0.15 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. After the consumption of 1, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 35:1) to afford products 3. General Procedure for Gram-Scale Synthesis of 3a


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An oven-dried round-bottomed flask was charged with 5-methyl-2,3-dihydrofuran derivative 1a (3.5 mmol, 973 mg), PA (0.7 mmol, 245 mg), newly activated 4 Å molecular sieves (1.8 g), newly distilled toluene (35 mL) and trifluoropyruvate 2a (5.25 mmol, 819 mg). The reaction mixture was stirred at room temperature and monitored by TLC. After the consumption of 1a, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 35:1) to afford product 3a as a white solid in 94% yield (1.43 g) with moderate diastereoselectivity (dr 2.4:1). General Procedure for One-Pot Three-Component Cascade Reaction An oven-dried reaction tube was charged with ortho-hydroxybenzyl alcohol 4 (1.0 equiv, 0.1 mmol, 20.0 mg), PA (20 mol %, 7.0 mg), newly activated 4 Å molecular sieves (70 mg), newly distilled DCE (1 mL) and 2,5-dimethyfuran 5 (3.0 equiv, 0.3 mmol, 28.8 mg). The reaction mixture was stirred at room temperature and monitored by TLC. After the consumption of 4, trifluoropyruvate 2a (5.0 equiv, 0.5 mmol, 78.0 mg) was added. After the consumption of 1a, the reaction mixture was directly purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate = 35:1) to afford product 3a as a white solid in 53% yield (23.0 mg) with moderate diastereoselectivity (dr 2.2:1). methyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen -2-yl)methyl)propanoate (3a). White solid; 27.8 mg, 64% yield; mp 163–165 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.48–7.33 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 6.87 (m, 2H), 6.71 (d, J = 7.5 Hz, 1H), 5.18 (d, J = 2.4 Hz, 1H), 4.98 (d, J = 2.2 Hz, 1H), 3.96 (s, 1H), 3.73 (s, 3H), 3.68 (s, 1H), 2.77 (d, J = 14.3 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 1.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 156.0, 154.3, 136.1, 131.3 (2C), 129.2, 128.4 (2C), 127.5, 127.4, 127.3, 123.0 (q, J = 284.6 Hz), 122.0, 118.3, 101.3, 90.9, 88.4, 75.6 (q, J = 29.3 Hz), 54.3, 49.5, 31.2,



23.6;

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F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M +

19

Na]+ calcd for C23H21F3O5Na 457.1233; found 457.1228. methyl

3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]

chromen-2-yl)methyl)propanoate (3a´). White solid; 11.3 mg, 26% yield; mp 104–106 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, minor diastereomer) δ 7.46–7.35 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 6.91 (m, 2H), 6.70 (d, J = 7.5 Hz, 1H), 5.15 (s, 1H), 4.97 (s, 1H), 4.02 (s, 1H), 3.79 (s, 3H), 3.13 (s, 1H), 2.80 (d, J = 14.9 Hz, 1H), 2.67 (d, J = 14.9 Hz, 1H), 1.28 (s, 3H);

13

C{1H} NMR (125 MHz, CDCl3, minor

diastereomer) δ 168.7, 156.4, 154.3, 135.9, 131.1 (2C), 129.7, 128.4 (2C), 127.5, 127.4, 127.2, 122.9 (q, J = 284.8 Hz), 122.0, 118.5, 100.5, 91.3, 88.8, 75.4 (q, J = 29.4 Hz), 54.1, 49.4, 31.2, 23.2;

19F

NMR (470 MHz, CDCl3, minor diastereomer) δ -79.1; HRMS (ESI-TOF) m/z: [M +

Na]+ calcd for C23H21F3O5Na 457.1233; found 457.1230. methyl

3,3,3-trifluoro-2-hydroxy-2-((7-methoxy-9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo

[3,2-b]chromen-2-yl)methyl)propanoate (3b). White solid; 42.2 mg, 91% yield; dr 2:1; mp 164–166 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.47–7.32 (m, 5H), 6.81 (d, J = 8.6 Hz, 1H), 6.66 (dd, J = 8.6, 2.9 Hz, 1H), 6.33–6.28 (m, 1H), 5.13 (d, J = 2.5 Hz, 1H), 4.95 (d, J = 2.4 Hz, 1H), 3.95 (s, 1H), 3.74 (s, 3H), 3.73 (s, 1H), 3.64 (s, 3H), 2.77 (d, J = 14.3 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 1.20 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 155.8, 154.7, 147.8, 135.9, 131.2 (2C), 130.5, 128.4 (2C), 127.6, 123.0 (q, J = 284.5 Hz), 118.6, 114.2, 111.3, 101.3, 90.8, 88.5, 75.5 (q, J = 29.4 Hz), 55.5, 54.3, 49.8, 31.2, 23.5;

19F

NMR (470 MHz, CDCl3, major

diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O6Na 487.1339; found 487.1346. methyl 2-((7,9a-dimethyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)methyl)-3,3,3 -trifluoro-2-hydroxypropanoate (3c). White solid; 42.1 mg, 94% yield; dr 2.1:1; mp 94–96 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.45–7.35 (m, 5H), 6.92 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 5.14 (d, J = 2.4 Hz, 1H), 4.96 (d, J = 2.2 Hz, 1H), 3.93 (s, 1H), 3.73 (s, 3H), 3.70 (s, 1H), 2.78 (d, J = 14.2 Hz, 1H), 2.64 (d, J = 14.2 Hz, 1H), 2.16 (s, 3H), 1.20 (s, 3H);


13C{1H}

NMR

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(125 MHz, CDCl3, major diastereomer) δ 168.9, 155.8, 151.9, 136.2, 131.3 (2C), 128.9, 128.3 (2C), 127.9, 127.9, 127.7, 127.5, 123.1 (q, J = 284.6 Hz), 118.0, 101.4, 90.9, 88.4, 75.6 (q, J = 29.4 Hz), 54.3, 49.6, 31.3, 23.6, 21.0; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1396. methyl

2-((6,9a-dimethyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)methyl)-3,3,3-

trifluoro-2-hydroxypropanoate (3d). White solid; 41.2 mg, 92% yield; dr 2.5:1; mp 112–114 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.44–7.33 (m, 5H), 6.70 (s, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 5.15 (d, J = 2.2 Hz, 1H), 4.97 (d, J = 1.4 Hz, 1H), 3.91 (s, 1H), 3.71 (s, 3H), 3.68 (d, J = 3.8 Hz, 1H), 2.78 (d, J = 14.2 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 2.28 (s, 3H), 1.21 (s, 3H); 13C{1H}

NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 155.9, 154.1, 137.3, 136.3, 131.3

(2C), 128.3 (2C), 127.4, 127.2, 126.0, 123.0 (q, J = 284.5 Hz), 122.7, 119.0, 101.4, 90.8, 88.3, 75.6 (q, J = 29.5 Hz), 54.3, 49.2, 31.3, 23.5, 21.1;

19F


diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1391. methyl

2-((7-chloro-9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)methyl)

-3,3,3-trifluoro-2-hydroxypropanoate (3e). White solid; 41.2 mg, 88% yield; dr 2.1:1; mp 124–126 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.48–7.36 (m, 5H), 7.09 (dd, J = 8.4, 2.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 5.17 (d, J = 2.4 Hz, 1H), 4.98 (d, J = 2.3 Hz, 1H), 3.92 (s, 1H), 3.75 (s, 4H), 2.79 (d, J = 14.3 Hz, 1H), 2.66 (d, J = 14.3 Hz, 1H), 1.20 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 156.2, 152.9, 135.2, 131.2 (2C), 131.1, 128.6 (2C), 127.9, 127.4, 127.2, 127.2, 123.0 (q, J = 284.5 Hz), 119.6, 101.3, 90.6, 88.6, 75.4 (q, J = 29.5 Hz), 54.4, 49.4, 31.1, 23.4; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H20ClF3O5Na 491.0844; found 491.0849. methyl 2-((7-bromo-9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)methyl) -3,3,3-trifluoro-2-hydroxypropanoate (3f). White solid; 46.1 mg, 90% yield; dr 2.1:1; mp 132–134 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.48–7.36 (m, 5H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 6.81 (dd, J



Page 12 of 23

= 2.2, 1.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 2.6 Hz, 1H), 4.98 (d, J = 2.4 Hz, 1H), 3.92 (s, 1H), 3.74 (s, 4H), 2.79 (d, J = 14.3 Hz, 1H), 2.66 (d, J = 14.3 Hz, 1H), 1.20 (s, 3H); C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 169.0, 156.2, 153.5, 135.2, 131.5, 131.2

13

(2C), 130.2, 130.2, 128.6 (2C), 127.9, 123.0 (q, J = 284.5 Hz), 120.1, 114.7, 101.3, 90.7, 88.6, 75.4 (q, J = 29.6 Hz), 54.4, 49.4, 31.1, 23.4; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H20BrF3O5Na 535.0338; found 535.0341. methyl 3,3,3-trifluoro-2-hydroxy-2-((9-(2-methoxyphenyl)-9a-methyl-3a,9a-dihydro-9H-furo [3,2-b]chromen-2-yl)methyl)propanoate (3g). White solid; 44.6 mg, 96% yield; dr 2.3:1; mp 148–150 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.54 (dd, J = 7.6, 1.1 Hz, 1H), 7.37–7.30 (m, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91–6.83 (m, 2H), 6.74 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 2.4 Hz, 1H), 4.97 (d, J = 2.3 Hz, 1H), 4.81 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.68 (s, 1H), 2.76 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 14.3 Hz, 1H), 1.22 (s, 3H);

13C{1H}

NMR

(125 MHz, CDCl3, major diastereomer) δ 168.9, 158.5, 155.8, 154.7, 132.0, 129.3, 128.4, 127.1, 126.9, 124.3, 123.0 (q, J = 284.6 Hz), 121.9, 120.2, 118.2, 110.6, 101.3, 91.4, 88.5, 75.6 (q, J = 29.4 Hz), 55.6, 54.3, 39.1, 31.3, 23.0; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O6Na 487.1339; found 487.1340. methyl 3,3,3-trifluoro-2-hydroxy-2-((9-(3-methoxyphenyl)-9a-methyl-3a,9a-dihydro-9H-furo [3,2-b]chromen-2-yl)methyl)propanoate (3h). White solid; 43.6 mg, 94% yield; dr 2.5:1; mp 123–125 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.33 (t, J = 7.9 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.4 Hz, 2H), 6.93–6.89 (m, 1H), 6.87 (t, J = 8.3 Hz, 2H), 6.76 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 2.5 Hz, 1H), 4.97 (d, J = 2.1 Hz, 1H), 3.93 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.67 (d, J = 5.2 Hz, 1H), 2.76 (d, J = 14.2 Hz, 1H), 2.63 (d, J = 14.2 Hz, 1H), 1.24 (s, 3H);

13C{1H}

NMR (125 MHz,

CDCl3, major diastereomer) δ 168.9, 159.5, 156.0, 154.2, 137.6, 129.3, 129.1, 127.5, 127.3, 123.8, 123.0 (q, J = 284.6 Hz), 122.1, 118.3, 117.6, 112.3, 101.3, 90.8, 88.5, 75.6 (q, J = 29.5 Hz), 55.2, 54.2, 49.4, 31.3, 23.5;

19F

NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS

(ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O6Na 487.1339; found 487.1346. methyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-(o-tolyl)-3a,9a-dihydro-9H-furo[3,2-b]


Page 13 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chromen-2-yl)methyl)propanoate (3i). White solid; 42.6 mg, 95% yield; dr 2.3:1; mp 141–143 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.62–7.56 (m, 1H), 7.29–7.23 (m, 3H), 7.13 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.84 (td, J = 7.5, 0.8 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 2.4 Hz, 1H), 4.33 (s, 1H), 3.76 (s, 3H), 3.69 (s, 1H), 2.77 (d, J = 14.3 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 2.31 (s, 3H), 1.27 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 155.9, 154.6, 138.1, 134.5, 130.6, 130.6, 129.2, 127.3, 127.2, 127.1, 125.9, 123.0 (q, J = 284.6 Hz), 122.1, 118.3, 101.2, 91.4, 88.9, 75.5 (q, J = 29.4 Hz), 54.3, 43.4, 31.2, 23.0, 20.4; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1389. methyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-(m-tolyl)-3a,9a-dihydro-9H-furo[3,2-b] chromen-2-yl)methyl)propanoate (3j). White solid; 42.6 mg, 95% yield; dr 2.6:1; mp 123–125 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.30 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 6.3 Hz, 1H), 7.22–7.16 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.87 (m, 2H), 6.72 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 2.5 Hz, 1H), 4.97 (d, J = 2.4 Hz, 1H), 3.92 (s, 1H), 3.71 (s, 3H), 3.66 (s, 1H), 2.77 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 14.3 Hz, 1H), 2.41 (s, 3H), 1.23 (s, 3H);

13C{1H}

NMR (125 MHz, CDCl3, major diastereomer) δ 168.8,

156.0, 154.2, 137.9, 135.9, 132.3, 129.3, 128.2, 128.2, 128.2, 127.5, 127.2, 123.0 (q, J = 284.6 Hz), 122.0, 118.2, 101.3, 90.9, 88.5, 75.6 (q, J = 29.5 Hz), 54.1, 49.4, 31.3, 23.6, 21.6; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1395. methyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-(p-tolyl)-3a,9a-dihydro-9H-furo[3,2-b] chromen-2-yl)methyl)propanoate (3k). White solid; 41.2 mg, 92% yield; dr 2.3:1; mp 124–126 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.31 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.12 (t, J = 7.7 Hz, 1H), 6.86 (m, 2H), 6.71 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 2.4 Hz, 1H), 4.97 (d, J = 2.2 Hz, 1H), 3.92 (s, 1H), 3.75 (s, 3H), 3.68 (s, 1H), 2.76 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 14.3 Hz, 1H), 2.40 (s, 3H), 1.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.9, 156.0, 154.2, 137.1, 132.9, 131.2 (2C), 129.5, 129.1 (2C), 127.4, 127.2, 123.0 (q, J = 284.5 Hz), 122.0,



118.2, 101.3, 91.0, 88.4, 75.6 (q, J = 29.4 Hz), 54.3, 49.1, 31.2, 23.5, 21.2; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1391. methyl 2-((9-([1,1'-biphenyl]-4-yl)-9a-methyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl) methyl)-3,3,3-trifluoro-2-hydroxypropanoate (3l). White solid; 18.9 mg, 37% yield; dr 2.3:1; mp 169–171 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.66 (dd, J = 8.1, 2.1 Hz, 4H), 7.51–7.44 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.99–6.89 (m, 2H), 6.78 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 2.0 Hz, 1H), 4.99 (d, J = 2.3 Hz, 1H), 4.07 (s, 1H), 3.80 (s, 3H), 3.15 (s, 1H), 2.81 (d, J = 14.9 Hz, 1H), 2.69 (d, J = 14.9 Hz, 1H), 1.32 (s, 3H);

13C{1H}


diastereomer) δ 168.7, 156.4, 154.3, 140.8, 140.3, 134.9, 131.5 (2C), 129.6, 128.8 (2C), 127.4 (2C), 127.3, 127.1 (2C), 127.1 (2C), 122.9 (q, J = 284.9 Hz), 122.1, 118.5, 100.5, 91.3, 88.8, 75.4 (q, J = 29.4 Hz), 54.2, 49.1, 31.2, 23.2; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -79.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C29H25F3O5Na 533.1546; found 533.1552. methyl 3,3,3-trifluoro-2-((9-(4-fluorophenyl)-9a-methyl-3a,9a-dihydro-9H-furo[3,2-b]chromen2-yl)methyl)-2-hydroxypropanoate (3m). White solid; 42.0 mg, 93% yield; dr 2.3:1; mp 139–141 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.41 (dd, J = 8.3, 5.6 Hz, 2H), 7.18–7.07 (m, 3H), 6.88 (t, J = 8.3 Hz, 2H), 6.67 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 2.3 Hz, 1H), 4.97 (d, J = 1.6 Hz, 1H), 3.96 (s, 1H), 3.73 (s, 3H), 3.63 (d, J = 5.7 Hz, 1H), 2.76 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 14.3 Hz, 1H), 1.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.8, 162.3 (q, J = 244.6 Hz), 156.0, 154.2, 132.8 (q, J = 7.8 Hz, 2C), 131.8 (q, J = 3.4 Hz), 129.0, 127.4, 127.2, 123.0 (q, J = 284.6 Hz), 122.1, 118.4, 115.3 (q, J = 20.9 Hz, 2C), 101.3, 90.7, 88.4, 75.7 (q, J = 29.4 Hz), 54.3, 48.7, 31.2, 23.5; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9, -115.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H20F4O5Na 475.1139; found 475.1137. methyl 2-((9-(4-chlorophenyl)-9a-methyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)methyl) -3,3,3-trifluoro-2-hydroxypropanoate (3n). White solid; 44.5 mg, 95% yield; dr 2.4:1; mp 125–127 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.46–7.34 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 6.94–6.82 (m,


Page 14 of 23

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2H), 6.66 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 2.5 Hz, 1H), 4.97 (d, J = 2.3 Hz, 1H), 3.94 (s, 1H), 3.74 (s, 3H), 3.63 (s, 1H), 2.76 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 14.3 Hz, 1H), 1.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.8, 156.0, 154.1, 134.6, 133.5, 132.6 (2C), 128.7, 128.6 (2C), 127.5, 127.2, 123.0 (q, J = 284.8 Hz), 122.1, 118.5, 101.3, 90.6, 88.4, 75.6 (q, J = 29.4 Hz), 54.3, 48.9, 31.1, 23.5;

19

F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9;

HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H20ClF3O5Na 491.0844; found 491.0850. methyl ,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-(naphthalen-2-yl)-3a,9a-dihydro-9H-furo[3,2-b ]chromen-2-yl)methyl)propanoate (3o). White solid; 45.0 mg, 93% yield; dr 2.6:1; mp 154–156 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.88 (m, 4H), 7.62 (d, J = 8.4 Hz, 1H), 7.57–7.48 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.22 (d, J = 2.5 Hz, 1H), 5.01 (d, J = 2.3 Hz, 1H), 4.15 (s, 1H), 3.68 (s, 1H), 3.66 (s, 3H), 2.82 (d, J = 14.3 Hz, 1H), 2.67 (d, J = 14.3 Hz, 1H), 1.26 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.8, 156.1, 154.2, 133.7, 133.5, 132.8, 130.6, 129.2, 128.9, 127.9, 127.8, 127.7, 127.5, 127.3, 126.1, 126.0, 123.0 (q, J = 284.8 Hz), 122.1, 118.3, 101.3, 90.9, 88.5, 75.6 (q, J = 29.5 Hz), 54.3, 49.6, 31.3, 23.7; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C27H23F3O5Na 507.1390; found 507.1396. methyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-(thiophen-2-yl)-3a,9a-dihydro-9H-furo[3,2-b] chromen-2-yl)methyl)propanoate (3p). White solid; 39.6 mg, 90% yield; dr 2.4:1; mp 141–143 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.39–7.33 (m, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.12–7.07 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 2.4 Hz, 1H), 4.95 (d, J = 2.4 Hz, 1H), 4.34 (s, 1H), 3.79 (s, 3H), 3.71 (s, 1H), 2.76 (d, J = 14.3 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 1.33 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.8, 156.1, 153.8, 137.5, 129.2, 128.9, 127.6, 127.4, 126.7, 125.7, 123.0 (q, J = 284.6 Hz), 122.3, 118.2, 101.4, 90.5, 88.3, 75.7 (q, J = 29.4 Hz), 54.4, 45.0, 31.2, 23.4; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H19F3O5SNa 463.0798; found 463.0797.



ethyl 3,3,3-trifluoro-2-hydroxy-2-((9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)m ethyl)propanoate (3q). White solid; 39.0 mg, 87% yield; dr 2:1; mp 127–129 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3, major diastereomer) δ 7.49–7.33 (m, 5H), 7.13 (t, J = 7.6 Hz, 1H), 6.87 (m, 2H), 6.69 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 2.6 Hz, 1H), 4.97 (d, J = 2.5 Hz, 1H), 4.27 (dq, J = 10.6, 7.1 Hz, 1H), 4.12–4.04 (m, 1H), 3.97 (s, 1H), 3.68 (s, 1H), 2.77 (d, J = 14.3 Hz, 1H), 2.64 (d, J = 14.3 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.23 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 168.3, 156.2, 154.2, 136.1, 131.3 (2C), 129.3, 128.3 (2C), 127.5, 127.4, 127.2, 123.1 (q, J = 284.6 Hz), 122.0, 118.3, 101.1, 90.9, 88.5, 75.5 (q, J = 29.3 Hz), 63.8, 49.5, 31.1, 23.5, 13.8; 19F NMR (470 MHz, CDCl3, major diastereomer) δ -78.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H23F3O5Na 471.1390; found 471.1383. 1,1,1,3,3,3-hexafluoro-2-((9a-methyl-9-phenyl-3a,9a-dihydro-9H-furo[3,2-b]chromen-2-yl)meth yl)propan-2-ol (3r). White solid; 28.4 mg, 64% yield; mp 117–119 °C; column chromatography eluent, petroleum ether/ethyl acetate = 35:1; 1H NMR (500 MHz, CDCl3) δ 7.49–7.43 (m, 2H), 7.39 (dm, 3H), 7.16 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 8.6 Hz, 2H), 6.80 (d, J = 7.5 Hz, 1H), 5.21 (d, J = 2.1 Hz, 1H), 5.10 (s, 1H), 4.18 (s, 1H), 4.04 (s, 1H), 2.76 (d, J = 15.4 Hz, 1H), 2.68 (d, J = 15.4 Hz, 1H), 1.33 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 154.7, 154.0, 135.4, 130.9 (2C), 128.8 (2C), 128.4, 127.8, 127.6, 127.5, 122.5, 122.4 (q, J = 285.8 Hz), 122.1 (q, J = 284.8 Hz), 118.4, 101.9, 92.5, 87.3, 75.7 (m), 49.5, 28.3, 23.4; 19F NMR (470 MHz, CDCl3) δ -76.5 (q, J = 9.6 Hz), -78.1 (q, J = 9.7 Hz); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H18F6O3Na 467.1052; found 467.1053. Supporting Information Structural proofs and NMR spectra of products. This material is available free of charge via the Internet at http://pubs.acs.org. ORCID Shuai-Shuai Li: 0000-0001-7279-2885 Jian Xiao: 0000-0003-4272-6865


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Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research was supported by NSFC (21702117 and 21878167) and the National Key Research and Development Program (2017YFE0105200). Financial support from Natural Science Foundation of Shandong Province (JQ201604, ZR2017BB005) and the Key Research and Development Program of Shandong Province (2017GSF218073) is also greatly acknowledged. We thank the Dr Fengying Dong and Central Laboratory of Qingdao Agricultural University for NMR determination.

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The determination of the relative configuration of 3a was described in Supporting Information.


Organocatalytic C(sp3)âH Functionalization of 5-Methyl-2,3

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