Copper-Catalyzed Oxydifluoroalkylation of Hydroxyl-Containing

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Copper-Catalyzed Oxydifluoroalkylation of Hydroxyl-Containing Alkenes Yanyan Yang, Fangyuan Yuan, Xiangwei Ren, Guangwei Wang, Wentao Zhao, Xiangyang Tang, and Minjie Guo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00121 • Publication Date (Web): 28 Feb 2019 Downloaded from http://pubs.acs.org on February 28, 2019

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The Journal of Organic Chemistry

Copper‐Catalyzed Oxydifluoroalkylation of Hydroxyl‐Containing Al‐ kenes Yanyan Yang,† Fangyuan Yuan,† Xiangwei Ren,† Guangwei Wang,*,† Wentao Zhao,† Xiangyang Tang,† and Minjie Guo*,‡ †

Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China ‡ Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China

ABSTRACT: An efficient oxydifluoroalkylation of hydroxyl-containing alkenes using copper catalytic system has been developed. This reaction proceeded through a one-pot process of difluoroalkylation followed by nucleophilic attack of the appended hydroxyl group. This strategy has the advantages of low-cost catalyst and broad substrate scope, which provides a facile access to various fluoroalkylated tetrahydrofurans and tetrahydropyrans.

Substituted tetrahydrofuran-containing compounds are widespread structural units in synthetic and natural products,1 some of which exhibit diverse biological activities including antitumor, antihelmintic, antimalarial, antimicrobial, and antiprotozoal. Fluorine substitution2 can improve molecular properties such as drugs,3 agrochemicals,4 materials,5 and radiotracers for positron emission tomography (PET).6 Therefore, synthetic study towards the syntheses of fluorine-containing tetrahydrofurans has drawn great attention of synthetic chemists. The difunctionalization of alkenes allows direct vicinal installation of two functional groups across a C-C double bond, through which the compounds with higher molecular complexity can be achieved. When one of the functionalizing reagents is derived from the appended functional group of alkenes, a cyclization will be resulted. In recent years, the difunctionalization of alkenes has made great progress,7 especially for the difunctionalization reaction with the simultaneous formation of nitrogen or oxygen heterocycles by transition metal catalysis8 or through a free radical strategy.9 Particularly, the construction of fluorine-containing heterocyclic compounds has become increasingly important and appealing. In the past several years, oxytrifluoromethylation10 and oxydifluoroalkylation11 of unsaturated carboxylic acids have been reported to provide a convenient access to the corresponding trifluoromethyl-containing lactones and difluoroalkylated lactones. However, the corresponding oxyfluoroalkylation of hydroxyl-containing alkenes to afford the fluoroalkylated tetrahydrofuran has only been reported sporadically.12 In 2017, Liu and co-workers13 reported an enantioselective radical oxytrifluoromethylation of unsaturated alcohols (Scheme 1, eq 1). Although the reactions proceed with good yields and enantioselectivities for gem-substituted hydroxyl-containing

alkenes, low yields were obtained for substrates without germinal substitution. Therefore, it is urgent and useful to develop a novel, facile, and general method for the synthesis of fluorine-containing tetrahydrofurans. Scheme 1. Copper-Catalyzed Oxyfluoroalkylation of Hydroxyl-Containing Alkenes

Based on our previous work, Cu(I)-PMDETA (pentamethyldiethylenetriamine) catalytic system proved to be versatile for difluoroalkylation and perfluoroalkylation reaction of various substrates including alkenes, arenes, heteroarenes, corannulene, and enol ethers.14 Vicinal difluoroalkyl-alkenylation of unactivated alkenes, has also been achieved in our group using similar catalytic system.15 Very recently, we have optimized the Cu(I)-PMDETA system so that a one-pot difluoroalkylation and lactonization of unsaturated carboxylic acids has been realized, which provides a convenient synthesis toward a wide range of difluoroalkylated lactones.16 Herein we want to further exploit the easily accessible copper-amine catalyst system as an efficient and cost-effective strategy for the intramolecular oxydifluoroalkylation of hydroxyl-containing alkenes, through which a facile synthesis of general fluoroalkylated tetrahydrofurans and tetrahydropyrans can be achieved (Scheme 1, eq 2).

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Table 1. Optimization of Reaction Conditionsa

yield (%)b

entry

catalyst

ligand

base

solvent

1

CuBr

PMDETA

-

DMSO

24

2

CuBr

PMDETA

Na2CO3

DMSO

72

3

CuI

PMDETA

Na2CO3

DMSO

81

4

Cu2O

PMDETA

Na2CO3

DMSO

33

5

Cu(OTf)2

PMDETA

Na2CO3

DMSO

36

6

Cu(CH3CN)4PF6

PMDETA

Na2CO3

DMSO

89

7

Cu(CH3CN)4PF6

1,10-phen

Na2CO3

DMSO

34

8

Cu(CH3CN)4PF6

bipy

Na2CO3

DMSO

23

9

Cu(CH3CN)4PF6

TMEDA

Na2CO3

DMSO

23

10

Cu(CH3CN)4PF6

PMDETA

K2CO3

DMSO

62

11

Cu(CH3CN)4PF6

PMDETA

KF

DMSO

55

12

Cu(CH3CN)4PF6

PMDETA

NEt3

DMSO

32

13

Cu(CH3CN)4PF6

PMDETA

Na2CO3

DMF

62

14

Cu(CH3CN)4PF6

PMDETA

Na2CO3

CH3CN

35

15

Cu(CH3CN)4PF6

PMDETA

Na2CO3

dioxane

20

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NEt3 was used as base, the yields of 3aa also decreased (Table 1, entries 11 and 12). When stronger sodium tert-butoxide or potassium tert-butoxide was used as base, the reaction became messy with only 20% yield of the desired product being observed. No intermolecular oxydifluoroalkylation products have been detected. Besides DMSO which is high polar solvent, the reaction yield dropped slightly in DMF (entry 13) and significantly in acetonitrile and 1,4-dioxane (entries 14 and 15), both of which are low polar solvents. Based on above various screening results, the reaction parameters in entry 6 were chosen as the optimized conditions. Scheme 2. The Scope of Hydroxyl-Containing Alkenesa

a

Reaction conditions: Unless otherwise noted, all reactions were performed with 1a (0.5 mmol, 1 equiv), 2a (0.75 mmol, 1.5 equiv), catalyst (10 mol %), ligand (0.1 mmol, 0.2 equiv), base (1.0 mmol, 2 equiv) in solvent (1.0 mL) at 85 °C under Ar for 10 h. bDetermined by GC analysis.

Initially, the commercially available 4-penten-1-ol (1a) was chosen as the model substrate. First, substrate 1a reacted with 1.5 equiv of ethyl bromodifluoroacetate (2a) in the presence of CuBr (10 mol %), PMDETA (2.0 equiv) in DMSO under an inert atmosphere at 85 oC. Although these above conditions proved to be optimal for difluoroalkylation lactonization of unsaturated carboxylic acids,16 only low yield (24%) of targeted product 3aa was resulted (Table 1, entry 1). We reason that the low yield for 1a might be due to the weaker reactivity of alcohol compared with carboxylate. In previous cases, the PMDETA plays dual role as the ligand of copper and base. In order to improve the reactivity of hydroxyl group, we decreased the amount of PMDETA to catalytic amount while adding 2 equiv of stronger inorganic base Na2CO3. To our delight, the target product 3aa was obtained in 72% yield (Table 1, entry 2). With this encouraging result, various copper catalysts have been screened. Slightly higher yield (81%) was obtained with CuI as catalyst (Table 1, entry 3). However, when Cu2O or Cu(OTf)2 was used as catalyst (Table 1, entries 4 and 5), the yield dropped significantly to 30-40%. When Cu(CH3CN)4PF6 was used as a catalyst (Table 1, entry 6), the yield increased to 89%. With Cu(CH3CN)4PF6 as copper catalyst of choice, other ligands have been tested and we found that common bidentate ligands, such as 1,10-phen (1,10-phenanthroline), bipy (bipyridine), and TMEDA (N, N, N', N'-tetramethylethylenediamine), all led to lower yields compared with tridentate PMDETA (Table 1, entries 7-9). Then, we also investigated the effect of various bases. When Na2CO3 was replaced by K2CO3, the yield dropped obviously. (Table 1, entry 10). When KF or

a

Reaction conditions: 1 (1.5 mmol, 1.0 equiv), 2a (2.25 mmol, 1.5 equiv), Cu(CH3CN)4PF6 (10 mol %), PMDETA (0.3 mmol, 0.2 equiv), Na2CO3 (3.0 mol, 2.0 equiv) in DMSO (3.0 mL) under Ar at 85 oC for 10 h.

With the optimal reaction conditions in hand (Table 1, entry 6), the substrate scope of hydroxyl-containing alkenes was investigated (Scheme 2). We first explored the alkyl substitution and found that the substrates containing different lengths of alkyl chain were well tolerated to give desired tetrahydrofuran products 3ba and 3ca in high yields. The 4-pentene-1-ol bearing the germinal substituents at C2 or C3 position, such as spirocyclohexyl ring, could also provide the product (3da and 3ea) in high yields. Unsubstituted or monosubstituted phenyl rings with alkyl group at para position were well compatible with the reaction conditions, resulting products 3fa and 3ga in satisfactory yields. When phenyl rings were substituted with electron-withdrawing groups at meta or para position, products (3ha and 3ia) were afforded in moderate to good yields. Substrates disubstituted at C2 or C3 reacted smoothly to ob-


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tain the desired products (3ja and 3ka). Interestingly, for compounds with steric hindered phenyl groups such as 3la and 3ma, the yield for 3la was much higher than that of the 3ma. In addition, the fluoroalkylated pyran compounds (3na and 3oa) could also be synthesized under this reaction conditions, but the yields were relatively low since the cyclization step might be less favorable for the formation of six-member pyran ring than five-member furan ring. At the same time, byproducts of difluoroalkylation of olefins were identified from the reaction.14a We have also investigated 4-substituted 4penten-1-ol as substrates, but the reactions were complicated and no pure products can be isolated from the reaction mixtures. Scheme 3. The Scope of Difluoroalkyl/Perfluoroalkyl Compoundsa Cu(CH3CN)4PF6 (10 mol %) PMDETA (0.2 equiv) R1 O Na2CO3 (2.0 equiv) R2

R3 R4 HO

X Rf

+

R1 R2 1

DMSO (0.5 M), Ar, 85 oC X = I, Br

2

R3

R

Rf

4

3

O O

NHPh F F 3ab (43%)

6

O

CF2(CF2)2CF3

3ac (63%, dr = 1.8:1)

6

O

N

NHPh

CF2(CF2)4CF3

3ad (50%, dr = 1.6:1) O O N F F

O O O

O

6

F F

F F 3ae (47%, dr = 1.9:1) O O NHPh F F

3ah (59%)

3af (64%)

3ag (76%) O

O F F

3ai (57%)

O

N H

Based on the above experimental results and previous studies,17,18 a plausible radical pathway was proposed as outlined in Scheme 5. First, ethyl bromodifluoroacetate reacts with Cu (I) via single electron transfer to form a Cu (II) intermediate and a fluorine-containing radical A. The radical A with compound 1a immediately generates a new radical B, which is trapped by Cu(II) in the presence of base Na2CO3 to form intermediate C. The formation of cyclized compound 3aa from C might proceed through two possible intermediates D or E. The intermediate D results from a second step single electron transfer which lead to carbon cation and regenerate Cu(I) species. The nucleophilic attack of activated alcohol toward carbon cation species lead to desired compound 3aa. The intermediate E involves Cu(III) species which undergoes reductive elimination to 3aa which regenerating active Cu(I) species. Both pathways are possible at current stage and further mechanistic studies are undergoing in our lab to clarify the mechanism. Scheme 5. Proposed Mechanism

O

O

NEt2 F F

3al (53%) O

O

3am (71%) O

N

O

F F 3an (71%)

NHnBu F F

CF2(CF2)2CF3

3ak (49%)

CF2(CF2)2CF3

3aj (52%)

O O

O

O

under the standard reaction conditions (Scheme 4). GC results showed that the formation of 3aa was only in 13% yield while the TEMPO−CF2CO2Et was formed with a yield of 14%, which is characterized by a nuclear magnetic resonance spectrum (NMR) and indicate that the reaction could be inhibited by TEMPO, and thus a radical pathway might be involved in the reaction. Scheme 4. TEMPO Experiment

N F F

3ao (66%)

a

Reaction conditions: 1 (1.5 mmol, 1.0 equiv), 2 (2.25 mmol, 1.5 equiv), Cu(CH3CN)4PF6 (10 mol %), PMDETA (0.3 mmol, 0.2 equiv), Na2CO3 (3.0 mol, 2.0 equiv) in DMSO (3.0 mL) under Ar at 85 oC for 10 h.

Encouraged by the above results, the scope of functionalized difluoroalkylated bromides was also studied (Scheme 3). Moderate yields (3ab, 3ae, 3ah, 3ai, 3al) were obtained when secondary amide-containing difluoroalkylated bromides were used as fluorinating reagents. Generally, the involving of tertiary amide-containing difluoroalkylated bromides gave target products (3af, 3ag, 3am-3ao) in higher yields. It is noteworthy that perfluoroalkyl iodides also underwent similar transformation in moderate to good yields (3ac, 3ad, 3aj, 3ak), thus providing a facile and general access to a wide range of perfluoroalkylated tetrahydrofurans. To gain some insight into the reaction mechanism, 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO, 1.5 equiv) was used in the mixture of 4-pentene-1-ol and ethyl bromodifluoroacetate

In conclusion, a copper-catalyzed intramolecular oxydifluoroalkylation of hydroxyl-containing alkenes has been achieved in this paper. This method features low-cost catalyst and wide substrate compatibility. Through this cost-effective procedure, various tetrahydrofurans containing different difluoroalkyl motifs can be obtained in moderate to good yields, which are also considered as potential intermediates for other important bioactive molecules.

EXPERIMENTAL SECTION General Information. All experiments were conducted under argon atmosphere. DMF, DMSO, 1,4-dioxane and acetonitrile were dried and distilled by the standard methods. Other commercially available reagents were purchased and used



without further purification, unless otherwise stated. Flash chromatographic separations were carried out on 200-300 mesh silica gel. Reactions were monitored by TLC and GC analysis of reaction aliquots. GC analysis was performed on an Agilent 7890 Gas Chromatography using a HP-5 capillary column (30 m × 0.32 mm, 0.5 μm film). 1H, 13C and 19F NMR spectra were recorded in CDCl3 on a Bruker AVANCE III spectrometer. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. High resolution spectra (HRMS) were recorded on a QTOF mass analyzer with electrospray ionization (ESI) through a Bruker Daltonics - micrOTOF-Q II. The pent-4-en-1-ol (1a), ethyl bromodifluoroacetate (2a), perfluoroiodo-n-butane, and perfluoroiodo-n-hexane are commercially available and used without further purification. Compounds 1b,19 1c,20 1d,21 1e,22 1f-1i,23 1j,24 1k,25 1m,26 1n,27 1o21 were prepared according to literature. Compound 1l was prepared according to Jirgensons’ work.21 The bromodifluoroamides 2b-2d,28 2e-2g,29 2h-2i30 were also prepared according to literature. 1-(6-(Benzyloxy)-7-methylbenzo[d][1,3]dioxol-4-yl)pent-4en-1-ol (1l). To a flask charged with magnesium turnings (0.41 g, 17.0 mmol), iodine (two pills) and THF (10 mL) was added dropwise a solution of 4-bromobut-1-ene (1.7 mL, 17 mmol) in THF (10 mL) under a N2 atmosphere. The mixture was refluxed for 2 hrs, then cooled to 0 oC. The aldehyde (2.30 g, 8.5 mmol) was added dropwise. After stirring at rt overnight, the reaction mixture was quenched with HCl (1 N, 20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (petroleum ether/ethyl acetate = 10:1) afforded the target product 1l (2.57 g) as colorless oil (93% yield). 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.35 (m, 5H), 6.79 (s, 1H), 5.92 (s, 2H), 5.83 (m, 1H), 5.06 (d, J = 17.2 Hz, 1H), 4.97 (t, J = 11.1 Hz, 2H), 4.80 (s, 2H), 2.49 (m, 1H), 2.24 (s, 3H), 2.19 (m,1H), 2.08 (m, 1H), 1.85 (m, 1H), 1.71 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.89, 145.87, 143.47, 138.29, 137.02, 130.34, 128.52, 128.17, 127.95, 114.78, 113.10, 103.30, 101.08, 75.90, 67.77, 37.27, 30.30, 9.64. HRMS (ESI): m/z calcd. for C20H22NaO4+ [M + Na]+: 349.1410, found: 349.1413. Ethyl 2,2-difluoro-3-(tetrahydrofuran-2-yl)propanoate (3aa). Representative Procedure I. To a 25 mL of Schlenk tube was added pent-4-en-1-ol (129.2 mg, 1.5 mmol, 1 equiv) and ethyl bromodifluoroacetate (456.7 mg, 2.25 mmol, 1.5 equiv) under Ar atmosphere. DMSO (3 mL), PMDETA (52.0 mg, 0.3 mmol, 0.2 equiv), Cu(CH3CN)4PF6 (55.9 mg, 0.15 mmol, 10 mol%) and Na2CO3 (317.9 mg, 3 mmol, 2.0 equiv) was added subsequently. The reaction mixture was stirred at 85 oC for 10 h. After completion by TLC detection, the reaction mixture was cooled to room temperature and quenched with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The title compound 3aa was purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as colorless oil (240 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 4.31 (q, J = 7.1 Hz, 2H), 4.10 – 4.04 (m, 1H), 3.79 (dd, J = 14.7, 7.3 Hz, 1H), 3.70 (dd, J = 14.5, 7.4 Hz, 1H), 2.48 – 2.34 (m, 1H), 2.27 – 2.15 (m, 1H), 2.11 – 2.03 (m, 1H), 1.95 – 1.82 (m, 2H), 1.60 – 1.51 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H}

Page 4 of 10

NMR (101 MHz, CDCl3) δ 164.3 (t, J = 33.3 Hz), 115.5 (dd, J = 252.2, 247.9 Hz), 72.9 (dd, J = 7.0, 3.2 Hz), 67.9, 62.9, 40.5 (t, J = 22.4 Hz), 31.8, 25.5, 14.0; 19F NMR (376 MHz, CDCl3) δ -101.7 (dt, J = 261.7, 13.0 Hz, 1F), -107.7 (ddd, J = 261.7, 22.5, 14.5 Hz, 1F); HRMS (ESI): m/z calcd. for C9H14F2NaO3+ [M + Na]+: 231.0803, found: 231.0806. Ethyl 2,2-difluoro-3-(5-propyltetrahydrofuran-2yl)propanoate (3ba). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 25:1) as colorless oil (304 mg, 81% yield, dr = 1.3/1). Major isomer: 1 H NMR (400 MHz, CDCl3) δ 4.26 – 4.15 (m, 2H), 3.97 – 3.90 (m, 1H), 3.73 – 3.67 (m, 1H), 2.41 – 2.25 (m, 1H), 2.20 – 1.81 (m, 3H), 1.55 – 1.35 (m, 3H), 1.34 – 1.16 (m, 6H), 0.84 – 0.80 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.0 (t, J = 33.3 Hz), 115.3 (t, J = 251.5 Hz), 79.6, 72.6 (q, J = 4.0 Hz), 62.5, 41.1 (t, J = 19.9 Hz), 38.1, 31.7, 30.7, 19.3, 14.0, 13.7; 19 F NMR (376 MHz, CDCl3) δ -101.1 (dt, J = 259.4, 11.3 Hz, 1F), -108.0 (ddd, J = 260.8, 23.8, 13.7 Hz, 1F). Minor isomer: 1 H NMR (400 MHz, CDCl3) δ 4.26 – 4.15 (m, 2H), 4.13 – 4.06 (m, 1H), 3.83 – 3.76 (m, 1H), 2.41 – 2.25 (m, 1H), 2.20 – 1.81 (m, 3H), 1.55 – 1.35 (m, 3H), 1.34 – 1.16 (m, 6H), 0.84 – 0.80 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.0 (t, J = 32.3 Hz), 115.4 (t, J = 251.5 Hz), 78.6, 72.1 (q, J = 4.0 Hz), 62.5, 40.7 (t, J = 19.8 Hz), 38.0, 32.2, 31.4, 19.3, 14.0, 13.7; 19 F NMR (376 MHz, CDCl3) δ -101.0 (ddd, J = 260.9, 13.5, 10.7 Hz, 1F), -108.5 (ddd, J = 260.9, 24.5, 13.1 Hz, 1F). HRMS (ESI): m/z calcd. for C12H20F2NaO3+ [M + Na]+: 273.1273, found: 273.1276. Ethyl 2,2-difluoro-3-(5-heptyltetrahydrofuran-2yl)propanoate (3ca). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 25:1) as colorless oil (376 mg, 82% yield, dr = 1.1/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 2H), 3.98 (s, 1H), 3.73 (s, 1H), 2.42 – 2.33 (m, 1H), 2.24 – 1.88 (m, 3H), 1.54 – 1.45 (m, 3H), 1.31 – 1.22 (m, 14H), 0.83 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 32.2 Hz), 115.5 (t, J = 250.5 Hz), 80.0, 72.7 (dd, J = 7.2, 2.8 Hz), 62.7, 41.1 (t, J = 19.5 Hz), 36.0, 31.9, 31.8, 30.8, 29.7, 29.3, 26.3, 22.7, 14.1, 13.9; 19F NMR (376 MHz, CDCl3) δ -101.2 (dt, J = 260.9, 12.7 Hz, 1F), -107.4– -108.2 (m, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 2H), 4.15 (s, 1H), 3.82 (s, 1H), 2.42 – 2.33 (m, 1H), 2.24 – 1.88 (m, 3H), 1.54 – 1.45 (m, 3H), 1.31 – 1.22 (m, 14H), 0.83 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 32.2 Hz), 115.4 (t, J = 250.5 Hz), 79.0, 72.2 (dd, J = 7.3, 2.7 Hz), 62.7, 40.7 (t, J = 19.3 Hz), 35.9, 32.3, 31.9, 31.5, 29.7, 29.3, 26.2, 22.7, 14.1, 13.9; 19F NMR (376 MHz, CDCl3) δ -101.1 (dt, J = 259.4, 11.3 Hz, 1F), -107.9– -108.8 (m, 1F). HRMS (ESI): m/z calcd. for C16H28F2NaO3+ [M + Na]+: 329.1899, found: 329.1901. Ethyl 2,2-difluoro-3-(1-oxaspiro[4.5]decan-2yl)propanoate (3da). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 30:1) as colorless oil (368 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2H), 4.08 – 4.02 (m, 1H), 2.42 – 2.27 (m, 1H), 2.21 – 2.10 (m, 1H), 2.05 – 1.97 (m, 1H), 1.70 – 1.53 (m, 5H), 1.47 – 1.36 (m, 4H), 1.29 (t, J = 7.1 Hz, 7H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 32.4 Hz), 115.5 (t, J = 250.5 Hz), 83.1, 71.5, 62.6, 41.5 (t, J = 22.3 Hz), 38.4, 37.2, 36.1, 31.8, 25.6, 23.8, 23.5, 13.9; 19F NMR (376 MHz, CDCl3) δ -100.8 (dt, J = 259.9, 12.3 Hz, 1F), -107.6 – -108.5 (m, 1F);


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HRMS (ESI): m/z calcd. for C14H22F2NaO3+ [M + Na]+: 299.1429, found: 299.1433. Ethyl 2,2-difluoro-3-(2-oxaspiro[4.5]decan-3yl)propanoate (3ea). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 30:1) as colorless oil (290 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 4.32 (q, J = 7.1 Hz, 2H), 4.19 – 4.12 (m, 1H), 3.54 – 3.49 (m, 2H), 2.52 – 2.38 (m, 1H), 2.28 – 2.17 (m, 1H), 1.97 (dd, J = 12.4, 6.6 Hz, 1H), 1.44 (s, 10H), 1.35 (t, J = 7.2 Hz, 4H); 13 C{1H} NMR (101 MHz, CDCl3) δ 164.2 (t, J = 32.3 Hz), 115.3 (t, J = 251.5 Hz), 78.2, 72.4 (dd, J = 6.8, 3.1 Hz), 62.8, 44.8, 43.9, 40.9 (t, J = 22.4 Hz), 36.9, 35.4, 26.0, 24.1, 23.5, 14.0; 19F NMR (376 MHz, CDCl3) δ -102.0 (dt, J = 261.5, 13.2 Hz, 1F), -107.6 (ddd, J = 261.4, 22.0, 15.0 Hz, 1F); HRMS (ESI): m/z calcd. for C14H22F2NaO3+ [M + Na]+: 299.1429, found: 299.1431. Ethyl 2,2-difluoro-3-(5-phenyltetrahydrofuran-2yl)propanoate (3fa). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as light yellow oil (353 mg, 83% yield, dr = 1.9/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.09 (m, 5H), 4.74 (t, J = 7.0 Hz, 1H), 4.11 (s, 1H), 4.10 – 4.01(m, 2H), 2.57 – 2.42 (m, 1H), 2.31 – 2.14 (m, 2H), 2.07 – 1.99 (m, 1H), 1.73 – 1.53 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.0 (t, J = 32.3 Hz), 142.7, 128.1, 127.2, 125.7, 115.3 (t, J = 251.5 Hz), 81.1, 73.3 (d, J = 2.8 Hz), 62.7, 40.9 (t, J = 22.2 Hz), 33.9, 31.5, 13.7; 19F NMR (376 MHz, CDCl3) δ 100.8 (dt, J = 260.8, 12.4 Hz, 1F), -107.7 (ddd, J = 260.7, 23.6, 14.4 Hz, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.09 (m, 5H), 4.83 (t, J = 7.1 Hz, 1H), 4.31(s, 1H), 4.10 – 4.01(m, 2H), 2.57 – 2.42 (m, 1H), 2.31 – 2.14 (m, 2H), 2.07 – 1.99 (m, 1H), 1.73 – 1.53 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 33.3 Hz), 143.0, 128.2, 127.1, 125.3, 115.4 (t, J = 251.5 Hz), 80.1, 73.4 (d, J = 2.7 Hz), 62.7, 40.8 (t, J = 22.2 Hz), 34.9, 32.4, 13.7; 19F NMR (376 MHz, CDCl3) δ -100.9 (dt, J = 259.4, 11.3 Hz, 1F), -108.3 (ddd, J = 260.7, 24.4, 13.2 Hz, 1F). HRMS (ESI): m/z calcd. for C15H18F2NaO3+ [M + Na]+: 307.1116, found: 307.1121. Ethyl 2,2-difluoro-3-(5-(p-tolyl)tetrahydrofuran-2yl)propanoate (3ga). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as light yellow oil (308 mg, 69% yield, dr = 1.8/1). Major isomer: 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 4H), 4.90 (t, J = 7.1 Hz, 1H), 4.33 – 4.31 (m, 1H), 4.29 – 4.19 (m, 2H), 2.74 – 2.54 (m, 1H), 2.48 – 2.29 (m, 5H), 2.27 – 2.17 (m, 1H), 1.91 – 1.72 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1 (t, J = 32.2 Hz), 141.7, 138.8, 130.8, 127.7, 117.3 (t, J = 251.5 Hz), 83.1, 75.3, 64.7, 42.9 (t, J = 23.2 Hz), 35.9, 33.5, 23.0, 15.7; 19F NMR (376 MHz, CDCl3) δ -100.7 (dt, J = 259.4, 11.3 Hz, 1F), -107.8 (ddd, J = 260.6, 23.7, 14.2 Hz, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 4H), 4.98 (t, J = 7.1 Hz, 1H), 4.52 – 4.45 (m, 1H), 4.29 – 4.19 (m, 2H), 2.74 – 2.54 (m, 1H), 2.48 – 2.29 (m, 5H), 2.27 – 2.17 (m, 1H), 1.91 – 1.72 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1 (t, J = 32.3 Hz), 142.0, 138.6, 130.9, 127.3, 117.5 (t, J = 250.5 Hz), 82.1, 75.3, 64.7, 42.9 (t, J = 23.2 Hz), 36.9, 34.5, 23.0, 15.7; 19 F NMR (376 MHz, CDCl3) δ -100.9 (dt, J = 259.4, 11.3 Hz, 1F), -108.3 (ddd, J = 260.6, 24.5, 13.2 Hz, 1F). HRMS (ESI):

m/z calcd. for C16H20F2NaO3+ [M + Na]+: 321.1273, found: 321.1274. Ethyl 3-(5-(4-chlorophenyl)tetrahydrofuran-2-yl)-2,2difluoropropanoate (3ha). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as colorless oil (291 mg, 61% yield, dr = 2.6/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.19 (m, 2H), 7.15 – 7.12 (m, 2H), 4.75 (t, J = 7.0 Hz, 1H), 4.20 – 4.17 (m, 1H), 4.16 – 4.07 (m, 2H), 2.58 – 2.38 (m, 1H), 2.34 – 2.19 (m, 2H), 2.15 – 2.04 (m, 1H), 1.73 – 1.57 (m, 2H), 1.20 – 1.15 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2 (t, J = 32.3 Hz), 141.3, 133.0, 128.4, 127.2, 115.3 (t, J = 251.5 Hz), 80.6, 73.6, 62.9, 40.9 (t, J = 22.2 Hz), 34.1, 31.6, 13.9; 19F NMR (376 MHz, CDCl3) δ -101.1 (dt, J = 261.3, 12.8 Hz, 1F), 107.8 (ddd, J = 261.4, 22.9, 14.7 Hz, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.19 (m, 2H), 7.15 – 7.12 (m, 2H), 4.83 (t, J = 7.0 Hz, 1H), 4.37 – 4.25 (m, 1H), 4.16 – 4.07 (m, 2H), 2.58 – 2.38 (m, 1H), 2.34 – 2.19 (m, 2H), 2.15 – 2.04 (m, 1H), 1.73 – 1.57 (m, 2H), 1.20 – 1.15 (m, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 164.2 (t, J = 32.3 Hz), 141.7, 132.8, 128.5, 126.8, 115.5 (t, J = 250.5 Hz), 79.7, 73.6, 62.9, 40.8 (t, J = 23.2 Hz), 35.1, 32.6, 13.9; 19F NMR (376 MHz, CDCl3) δ -101.1 (dt, J = 259.4, 11.3 Hz, 1F), -108.3 (ddd, J = 261.2, 23.9, 13.5 Hz, 1F). HRMS (ESI): m/z calcd. for C15H17ClF2NaO3+ [M + Na]+: 341.0726, found: 341.0721. 2,2-difluoro-3-(5-(3(trifluoromethyl)phenyl)tetrahydrofuran-2-yl)propanoate (3ia). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as light yellow oil (232 mg, 44% yield, dr = 2.9/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.41 (m, 4H), 4.89 (t, J = 7.1 Hz, 1H), 4.28 – 4.25 (m, 1H), 4.25 – 4.15 (m, 2H), 2.69 – 2.50 (m, 1H), 2.44 – 2.28 (m, 2H), 2.25 – 2.14 (m, 1H), 1.83 – 1.66 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.1 (t, J = 31.3 Hz), 143.0, 129.6 (q, J = 32.3 Hz), 128.2, 127.9, 123.3 (q, J = 273.7 Hz), 123.1 (q, J = 4.0 Hz), 121.5 (q, J = 3.8 Hz), 114.3 (t, J = 251.5 Hz), 79.5, 72.8 (d, J = 2.9 Hz), 61.9, 39.8 (t, J = 23.2 Hz), 32.9, 30.5, 12.7; 19F NMR (376 MHz, CDCl3) δ -62.6 – -62.7 (m, 1F), -100.6 – -100.8 (m, 1F), -101.3 – -101.5 (m, 1F), -107.47 – -108.73 (m, 2F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.41 (m, 4H), 4.99 (t, J = 7.0 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.25 – 4.15 (m, 2H), 2.69 – 2.50 (m, 1H), 2.44 – 2.28 (m, 2H), 2.25 – 2.14 (m, 1H), 1.83 – 1.66 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.2 (t, J = 32.3 Hz), 143.3, 129.7 (q, J = 32.3 Hz), 128.2, 127.9, 123.3 (q, J = 273.7 Hz), 123.0 (q, J = 4.0 Hz), 121.1 (q, J = 3.8 Hz, 1H), 114.5 (t, J = 251.5 Hz), 78.6, 72.7 (d, J = 2.9 Hz), 61.8, 39.8 (t, J = 22.2 Hz), 34.0, 31.5, 12.7; 19F NMR (376 MHz, CDCl3) δ -62.6 – 62.7 (m, 1F), -100.6 – -100.8 (m, 1F), -101.3 – -101.5 (m, 1F), -107.5 – -108.7 (m, 2F). HRMS (ESI): m/z calcd. for C16H17F5NaO3+ [M + Na]+: 375.0990, found: 375.0996. Ethyl 2,2-difluoro-3-(5-methyl-5-phenyltetrahydrofuran-2yl)propanoate (3ja). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as light yellow oil (308 mg, 69% yield, dr = 1:1). 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.09 (m, 5H (both isomers)), 4.29 – 4.06 (m, 3H (both)), 2.54 – 2.37 (m, 1H (both)), 2.27 – 2.08 (m, 2H (both)), 2.03 – 1.85 (m, 2H (both)), 1.67 – 1.58 (m, 1H (isomer A)), 1.49 – 1.42 (m, 1H (isomer B)), 1.38 (d, J = 7.8 Hz,



3H (both)), 1.27 – 1.17 (m, 3H (both)); 13C{1H} NMR (101 MHz, CDCl3) δ 164.3 (t, J = 32.3 Hz), 148.5, 148.1, 128.3, 128.1, 126.5, 124.7, 124.5, 115.5 (t, J = 250.5 Hz), 115.5 (t, J = 251.5 Hz), 85.3, 85.1, 72.8 (dd, J = 7.6, 2.8 Hz), 72.5 (dd, J = 7.9, 3.0 Hz), 62.9, 62.8, 41.5 (t, J = 22.2 Hz), 41.2 (t, J = 22.2 Hz), 39.9, 39.1, 32.2, 32.0, 30.9, 29.9, 14.0, 13.9; 19F NMR (376 MHz, CDCl3) δ -100.1 – -100.8 (m, 1F), -100.8 – 101.5 (m, 1F), -107.6 (ddd, J = 37.7, 24.2, 13.0 Hz, 1F), 108.3 (ddd, J = 247.7, 25.0, 12.7 Hz, 1F); HRMS (ESI): m/z calcd. for C16H20F2NaO3+ [M + Na]+: 321.1273, found: 321.1277. Ethyl 3-(5,5-diphenyltetrahydrofuran-2-yl)-2,2difluoropropanoate (3ka). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 12:1) as colorless oil (394 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.03 (m, 10H), 4.42 (d, J = 8.8 Hz, 1H), 4.19 – 4.12 (m, 3H), 3.97 (d, J = 8.8 Hz, 1H), 2.59 (dd, J = 12.2, 6.0 Hz, 1H), 2.44 – 2.10 (m, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 163.9 (t, J = 32.2 Hz), 145.6, 145.4, 128.5, 128.4, 127.1, 127.0, 126.6, 126.4, 115.2 (t, J = 250.5 Hz), 76.7, 72.5 (dd, J = 6.7, 3.3 Hz), 62.7, 55.8, 44.8, 40.7 (t, J = 22.5 Hz), 13.8; 19F NMR (376 MHz, CDCl3) δ 101.6 (ddd, J = 261.7, 17.0, 9.5 Hz, 1F), -106.9 (ddd, J = 261.7, 21.4, 15.1 Hz, 1F); HRMS (ESI): m/z calcd. for C21H22F2NaO3+ [M + Na]+: 383.1429, found: 383.1430. Ethyl 3-(5-(6-(benzyloxy)-7-methylbenzo[d][1,3]dioxol-5yl)tetrahydrofuran-2-yl)-2,2-difluoropropanoate (3la). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 12:1) as wax (538 mg, 80% yield, dr = 2.6/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.35 (m, 5 H), 6.80 (s, 1H), 5.94 – 5.93 (m, 2H), 5.13 (t, J = 8 Hz, 1H), 4.81 (q, J = 8 Hz, 2H), 4.34 – 4.15 (m, 3H), 2.70 – 2.52 (m, 1H), 2.48 – 2.33 (m, 1H), 2.30 – 2.06 (m, 5H), 1.81 – 1.64 (m, 2H), 1.38 – 1.28 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.0 (t, J = 32.3 Hz), 149.3, 145.9, 143.3, 137.4, 128.8, 128.5, 128.3, 128.0, 127.5, 126.3, 115.3 (t, J = 251.5 Hz), 113.2, 103.4, 101.1, 76.2, 75.6, 73.1, 62.8, 40.7 (t, J = 22.6 Hz), 33.5, 31.8, 13.8, 9.5; 19F NMR (376 MHz, CDCl3) δ -100.9 (dt, J = 261.2, 12.6 Hz, 1F), -107.5 (ddd, J = 261.2, 23.1, 14.8 Hz, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.35 (m, 5 H), 6.78 (s, 1H), 5.94 – 5.93 (m, 2H), 5.20 (t, J = 8 Hz, 1H), 4.81 (q, J = 8 Hz, 2H), 4.34 – 4.15 (m, 3H), 2.70 – 2.52 (m, 1H), 2.48 – 2.33 (m, 1H), 2.30 – 2.06 (m, 5H), 1.81 – 1.64 (m, 2H), 1.38 – 1.28 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2 (t, J = 32.3 Hz), 149.1, 145.3, 143.4, 137.4, 128.8, 128.5, 128.3, 128.0, 127.5, 126.3, 115.4 (t, J = 253.5 Hz), 113.3, 103.1, 101.1, 75.8, 75.4, 73.1, 62.8, 40.8 (t, J = 22.5 Hz), 34.5, 32.7, 13.8, 9.5; 19F NMR (376 MHz, CDCl3) δ -101.1 (dt, J = 260.4, 12.4 Hz, 1F), -107.9 (ddd, J = 260.5, 23.5, 14.1 Hz, 1F). HRMS (ESI): m/z calcd. for C24H26F2NaO6+ [M + Na]+: 471.1590, found: 471.1596. Ethyl 2,2-difluoro-3-(5-(naphthalen-1-yl)tetrahydrofuran2-yl)propanoate (3ma). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as colorless oil (165 mg, 33% yield, dr = 2.3/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 10.5, 8.4 Hz, 2H), 7.78 (t, J = 6.6 Hz, 1H), 7.65 (t, J = 6.5 Hz, 1H), 7.55 – 7.47 (m, 3H), 5.65 (t, J = 6.9 Hz, 1H), 4.63 – 4.57 (m, 1H), 4.39 – 4.31 (m, 1H), 4.29 – 4.12 (m, 2H), 2.84 – 2.34 (m, 3H), 2.26 – 2.18 (m, 1H), 1.96 – 1.81 (m, 1H), 1.77 – 1.67 (m, 1H),

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1.27 (q, J = 7.3 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.3 (t, J = 32.3 Hz), 138.8, 133.7, 130.3, 128.9, 127.7, 126.0, 125.5, 125.4, 123.4, 122.0, 115.4 (t, J = 251.5 Hz), 78.3, 73.7 (dd, J = 7.8, 2.6 Hz), 63.0, 40.8 (t, J = 23.2 Hz), 33.4, 31.7, 13.9; 19F NMR (376 MHz, CDCl3) δ -100.7 (dt, J = 260.8, 12.0 Hz, 1F), -107.9 (ddd, J = 260.7, 23.8, 14.6 Hz, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 10.5, 8.4 Hz, 2H), 7.78 (t, J = 6.6 Hz, 1H), 7.65 (t, J = 6.5 Hz, 1H), 7.55 – 7.47 (m, 3H), 5.73 (t, J = 6.8 Hz, 1H), 4.63 – 4.57 (m, 1H), 4.39 – 4.31 (m, 1H), 4.29 – 4.12 (m, 2H), 2.84 – 2.34 (m, 3H), 2.26 – 2.18 (m, 1H), 1.96 – 1.81 (m, 1H), 1.77 – 1.67 (m, 1H), 1.27 (q, J = 7.3 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4 (t, J = 32.3 Hz), 139.0, 133.8, 130.2, 128.9, 127.5, 125.9, 125.6, 125.5, 123.3, 121.6, 115.6 (t, J = 251.5 Hz), 77.8, 73.4 (dd, J = 7.8, 2.9 Hz), 62.9, 40.9 (t, J = 22.2 Hz), 34.1, 32.4, 13.9; 19F NMR (376 MHz, CDCl3) δ -100.7 (dt, J = 259.4, 11.3 Hz, 1F), -108.3 (ddd, J = 260.8, 24.5, 13.3 Hz, 1F). HRMS (ESI): m/z calcd. for C19H20F2NaO3+ [M + Na]+: 357.1273, found: 357.1272. Ethyl 2,2-difluoro-3-(2-oxaspiro[5.5]undecan-3yl)propanoate (3na). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as colorless oil (165 mg, 38% yield). 1H NMR (400 MHz, CDCl3) δ 4.34 – 4.19 (m, 2H), 3.62 (d, J = 11.3 Hz, 1H), 3.44 (t, J = 9.8 Hz, 1H), 2.98 (d, J = 11.3 Hz, 1H), 2.43 – 2.28 (m, 1H), 2.16 – 2.05 (m, 1H), 1.73 (d, J = 13.5 Hz, 1H), 1.54 – 1.39 (m, 10H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 – 1.14 (m, 1H), 1.09 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 32.2 Hz), 115.4 (t, J = 250.5 Hz), 76.4, 72.6 (dd, J = 8.2, 2.7 Hz), 62.6, 41.4 (t, J = 23.0 Hz), 36.5, 34.0, 31.9, 31.2, 27.6, 26.8, 21.5, 21.5, 14.0; 19F NMR (376 MHz, CDCl3) δ -101.7 (dt, J = 255.7, 11.3 Hz, 1F), -107.6 (ddd, J = 258.4, 25.6, 13.3 Hz, 1F); HRMS (ESI): m/z calcd. for C15H24F2NaO3+ [M + Na]+: 313.1586, found: 313.1588. Ethyl 2,2-difluoro-3-(1-oxaspiro[5.5]undecan-2yl)propanoate (3oa). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as colorless oil (152 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ 4.29 (q, J = 7.1 Hz, 2H), 3.81 (t, J = 10.3 Hz, 1H), 2.45 – 2.30 (m, J = 23.6, 8.9 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.88 (d, J = 9.1 Hz, 1H), 1.68 – 1.45 (m, 6H), 1.38 – 1.15 (m, 12H); 13 C{1H} NMR (101 MHz, CDCl3) δ 163.1 (t, J = 32.3 Hz), 114.4 (t, J = 250.5 Hz), 72.1, 63.0 (dd, J = 8.5, 3.3 Hz), 61.5, 40.7 (t, J = 22.6 Hz), 39.5, 33.6, 30.9, 28.7, 25.4, 20.7, 20.4, 18.1, 13.1; 19F NMR (376 MHz, CDCl3) δ -99.7 (ddd, J = 263.9, 15.4, 9.0 Hz, 1F), -108.3 (ddd, J = 263.8, 25.4, 11.5 Hz, 1F); HRMS (ESI): m/z calcd. for C15H24F2NaO3+ [M + Na]+: 313.1586, found: 313.1586. 2,2-Difluoro-N-phenyl-3-(tetrahydrofuran-2yl)propanamide (3ab). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 10:1) as colorless oil (164 mg, 43% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.24 (m, 5H), 4.27 – 4.26 (m, 1H), 3.42 (s, 2H), 2.90 – 2.86 (m, 1H), 2.80 – 2.67 (m, 1H), 2.36 – 2.23 (m, 1H), 1.75 (t, J = 9.9 Hz, 1H), 1.40 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (t, J = 31.4 Hz), 135.5, 129.3, 127.3, 123.9, 117.9 (t, J = 250.5 Hz), 61.5, 54.4 (t, J = 2.9 Hz), 34.3 (t, J = 21.9 Hz), 29.6, 27.1; 19F NMR (376 MHz, CDCl3) δ -100.2 – 101.0 (m, 1F), -103.6 – -104.4 (m, 1F); HRMS (ESI): m/z


Page 7 of 10 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


calcd. for C13H15F2NNaO2+ [M + Na] +: 278.0963, found: 278.0956. 2-Heptyl-5-(2,2,3,3,4,4,5,5,5nonafluoropentyl)tetrahydrofuran (3ac). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 25:1) as colorless oil (380 mg, 63% yield, dr = 1.8/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.20 – 4.13 (m, 1H), 3.85 – 3.79 (m, 1H), 2.55 – 2.38 (m, 1H), 2.25 – 1.94 (m, 3H), 1.64 – 1.45 (m, 3H), 1.42 – 1.36 (m, 2H), 1.28 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 79.8, 72.1, 37.1 (t, J = 22.2 Hz), 36.2, 33.3, 32.1, 32.0, 30.9, 29.8, 26.3, 22.8, 14.1; 19F NMR (376 MHz, CDCl3) δ -81.3 – 81.4 (m, 1F), -113.3 – -113.5 (m, 1F), -124.7 – -124.8 (m, 1F), -126.1 – -126.2 (m, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 4.34 – 4.28 (m, 1H), 3.98 – 3.92 (m, 1H), 2.55 – 2.38 (m, 1H), 2.25 – 1.94 (m, 3H), 1.64 – 1.45 (m, 3H), 1.42 – 1.36 (m, 2H), 1.28 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 79.4, 71.6, 37.1 (t, J = 22.2 Hz), 36.1, 33.3, 32.1, 32.0, 30.9, 29.4, 26.3, 22.8, 14.1; 19F NMR (376 MHz, CDCl3) δ -81.3 – -81.4 (m, 1F), -113.3 – -113.5 (m, 1F), -124.7 – -124.8 (m, 1F), -126.1 – -126.2 (m, 1F). HRMS (ESI): m/z calcd. for C16H23F9NaO+ [M + Na]+: 425.1497, found: 425.1500. 2-Heptyl-5-(2,2,3,3,4,4,5,5,6,6,7,7,7tridecafluoroheptyl)tetrahydrofuran (3ad). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 25:1) as light yellow oil (376 mg, 50% yield, dr = 1.6/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.20 – 4.14 (m, 1H), 3.86 – 3.79 (m, 1H), 2.55 – 2.40 (m, 1H), 2.26 – 1.95 (m, 3H), 1.68 – 1.53 (m, 3H), 1.48 – 1.40 (m, 2H), 1.28 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 79.8, 72.1, 37.22 (q, J = 24.2 Hz), 36.3, 33.3, 32.1, 32.0, 31.0, 29.8, 26.3, 22.8, 14.1; 19F NMR (376 MHz, CDCl3) δ -81.1 – -81.2 (m, 1F), -113.0 – -113.3 (m, 1F), 122.0 (s, 1F), -123.1 (s, 1F), -123.9 (s, 1F), -126.3 – -126.4 (m, 1F). Minor isomer: 1H NMR (400 MHz, CDCl3) δ 4.34 – 4.28 (m, 1H), 3.99 – 3.92 (m, 1H), 2.55 – 2.40 (m, 1H), 2.26 – 1.95 (m, 3H), 1.68 – 1.53 (m, 3H), 1.48 – 1.40 (m, 2H), 1.28 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 79.4, 71.6, 37.2 (q, J = 24.2 Hz), 36.1, 33.3, 32.1, 32.0, 31.0, 29.4, 26.3, 22.8, 14.1; 19F NMR (376 MHz, CDCl3) δ -81.1 – -81.2 (m, 1F), -113.0 – -113.3 (m, 1F), -122.0 (s, 1F), -123.1 (s, 1F), -123.9 (s, 1F), -126.3 – -126.4 (m, 1F). HRMS (ESI): m/z calcd. for C18H23F13NaO+ [M + Na]+: 525.1434, found: 525.1428. 2,2-Difluoro-3-(5-heptyltetrahydrofuran-2-yl)-Nphenylpropanamide (3ae). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 10:1) as yellow oil (249 mg, 47% yield, dr = 1.9/1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 5H), 7.20 (s, 1H), 4.20 (s, 1H), 3.41 (s, 1H), 2.69 – 2.62 (m, 1H), 2.25 (dd, J = 29.0, 14.3 Hz, 1H), 1.84 – 1.75 (m, 3H), 1.49 – 1.43 (m, 1H), 1.33 – 1.25 (m, 5H), 1.16 (s, 7H), 0.79 (t, J = 8.0 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 162.8 (t, J = 31.4 Hz), 135.8, 129.4, 127.4, 124.0, 117.8 (t, J = 250.5 Hz), 71.0, 54.4 (dd, J = 6.2, 3.1 Hz), 37.5, 34.7 (t, J = 88 Hz), 31.8, 31.7, 31.7, 29.6, 29.3, 25.7, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ 100.7 – -101.5 (m, 1F), -103.7 – -104.5 (m, 1F). Minor isomer: 1 H NMR (400 MHz, CDCl3) δ 7.32 (s, 5H), 7.20 (s, 1H), 4.25 (s, 1H), 3.36 (s, 1H), 2.69 – 2.62 (m, 1H), 2.25 (dd, J = 29.0,

14.3 Hz, 1H), 1.84 – 1.75 (m, 3H), 1.49 – 1.43 (m, 1H), 1.33 – 1.25 (m, 5H), 1.16 (s, 7H), 0.79 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (t, J = 31.4 Hz), 135.8, 129.4, 127.3, 123.9, 117.9 (t, J = 249.5 Hz), 71.6, 54.4 (dd, J = 6.2, 3.1 Hz), 37.7, 34.6 (t, J = 84 Hz), 31.8, 31.7, 31.7, 29.7, 29.2, 25.5, 22.7, 14.1; 19F NMR (376 MHz, CDCl3) δ -100.4 – -101.2 (m, 1F), -103.7 – -104.5 (m, 1F). HRMS (ESI): m/z calcd. for C20H29F2NNaO2+ [M + Na]+: 376.2059, found: 376.2054. 2,2-Difluoro-1-(piperidin-1-yl)-3-(2-oxaspiro[4.5]decan-3yl)propan-1-one (3af). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 6:1) as colorless oil (302 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 4.19 – 4.12 (m, 1H), 3.55 – 3.42 (m, 6H), 2.45 – 2.22 (m, 2H), 1.92 (dd, J = 12.5, 6.4 Hz, 1H), 1.58 – 1.51 (m, 6H), 1.36 – 1.26 (m, 11H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.6 (t, J = 28.7 Hz), 118.6 (t, J = 254.8 Hz), 78.3, 72.8 (t, J = 3.7 Hz), 46.8 (t, J = 6.6 Hz), 45.4, 44.3, 43.5, 41.1 (t, J = 22.2 Hz), 36.9, 35.4, 26.4, 25.9, 25.5, 24.4, 23.9, 23.4; 19F NMR (376 MHz, CDCl3) δ -97.5 (ddd, J = 279.7, 20.5, 15.8 Hz, 1F), -99.0 (ddd, J = 279.3, 22.1, 15.8 Hz, 1F); HRMS (ESI): m/z calcd. for C17H27F2NNaO2+ [M + Na]+: 338.1902, found: 338.1903. 2,2-Difluoro-1-morpholino-3-(2-oxaspiro[4.5]decan-3yl)propan-1-one (3ag). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 6:1) as colorless oil (361 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 4.10 – 4.04 (m, 1H), 3.57 – 3.35 (m, 10H), 2.39 – 2.17 (m, 2H), 1.88 – 1.83 (m, 1H), 1.31 – 1.20 (m, 11H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.7 (t, J = 29.3 Hz), 118.4 (t, J = 254.4 Hz), 78.1, 72.5, 66.4 (2C), 46.3, 45.1, 43.4, 43.2, 40.7 (t, J = 22.0 Hz), 36.7, 35.2, 25.7, 23.8, 23.3; 19F NMR (376 MHz, CDCl3) δ -97.3 (dt, J = 281.1, 17.5 Hz, 1F), -98.6 (ddd, J = 281.0, 20.7, 16.8 Hz, 1F); HRMS (ESI): m/z calcd. for C16H25F2NNaO3+ [M + Na]+: 340.1695, found: 340.1706. 2,2-Difluoro-N-phenyl-3-(2-oxaspiro[4.5]decan-3yl)propanamide (3ah). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 7:1) as colorless oil (286 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.49 – 7.47 (m, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 4.17 – 4.10 (m, 1H), 3.52 (d, J = 8.5 Hz, 1H), 3.44 (d, J = 8.5 Hz, 1H), 2.50 – 2.23 (m, 2H), 1.90 (dd, J = 12.5, 6.6 Hz, 1H), 1.35 – 1.26 (m, 11H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1 (t, J = 28.4 Hz), 136.4, 129.2 (2C), 125.5, 120.5 (2C), 117.3 (t, J = 254.5 Hz), 78.5, 72.6 (t, J = 4.7 Hz), 45.1, 43.8, 40.2 (t, J = 22.6 Hz), 36.9, 35.5, 26.0, 24.1, 23.5; 19F NMR (376 MHz, CDCl3) δ -101.9 (dt, J = 257.7, 16.8 Hz, 1F), -104.6 – -105.4 (m, 1F); HRMS (ESI): m/z calcd. for C18H23F2NNaO2+ [M + Na]+: 346.1589, found: 346.1589. N-Cyclohexyl-2,2-difluoro-3-(2-oxaspiro[4.5]decan-3yl)propanamide (3ai). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as light yellow oil (281 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 6.42 (d, J = 6.7 Hz, 1H), 4.04 – 3.97 (m, 1H), 3.71 – 3.64 (m, 1H), 3.48 (d, J = 8.5 Hz, 1H), 3.37 (d, J = 8.5 Hz, 1H), 2.38 – 2.27 (m, 1H), 2.25 – 2.08 (m, 1H), 1.87 – 1.80 (m, 3H), 1.65 – 1.61 (m, 2H), 1.54 – 1.51 (m, 1H), 1.33 – 1.21 (m, 12H), 1.17 – 1.04 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.1 (t, J = 28.1 Hz), 117.0 (t, J = 252.7 Hz), 78.1, 72.5 (t,



J = 4.6 Hz), 48.4, 44.9, 43.5, 40.1 (t, J = 22.7 Hz), 36.8, 35.4, 32.4, 32.3, 25.8, 25.3, 24.6, 24.6, 23.9, 23.4; 19F NMR (376 MHz, CDCl3) δ -103.3 (dt, J = 255.3, 17.0 Hz, 1F), -105.7 (dt, J = 255.3, 16.5 Hz, 1F); HRMS (ESI): m/z calcd. for C18H29F2NNaO2+ [M + Na]+: 352.2059, found: 352.2063. 3-(2,2,3,3,4,4,5,5,5-Nonafluoropentyl)-2oxaspiro[4.5]decane (3aj). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as colorless oil (290 mg, 52% yield). 1H NMR (400 MHz, CDCl3) δ 4.29 – 4.22 (m, 1H), 3.60 (d, J = 8.5 Hz, 1H), 3.52 (d, J = 8.5 Hz, 1H), 2.51 – 2.34 (m, 1H), 2.24 – 2.09 (m, 1H), 2.00 (dd, J = 12.6, 6.4 Hz, 1H), 1.44 – 1.32 (m, 11H); 13C{1H} NMR (151 MHz, CDCl3) δ 78.5, 71.6, 44.0, 37.1, 35.5, 26.0, 24.1, 23.5; 19F NMR (376 MHz, CDCl3) δ -81.0 – -82.4 (m, 1F), -113.5 (ddd, J = 21.1, 18.7, 2.9 Hz, 1F), -124.8 – -125.3 (m, 1F), -125.9 – -127.0 (m, 1F); HRMS (ESI): m/z calcd. for C14H17F9NaO+ [M + Na]+: 395.1028, found: 395.1030. 3-(2,2,3,3,4,4,5,5,5-Nonafluoropentyl)-1oxaspiro[4.5]decane (3ak). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as colorless oil (273 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 4.30 – 4.24 (m, 1H), 2.55 – 2.40 (m, 1H), 2.21 – 2.06 (m, 2H), 1.83 – 1.60 (m, 5H), 1.58 – 1.36 (m, 8H); 13 C{1H} NMR (101 MHz, CDCl3) δ 83.0, 71.0, 38.7, 37.6, 37.6 (t, J = 21.2 Hz), 36.3, 32.6, 25.8, 24.0, 23.8; 19F NMR (376 MHz, CDCl3) δ -81.1 – -82.0 (m, 1F), -112.1 – -114.6 (m, 1F), -124.5 – -125.3 (m, 1F), -126.0 – -126.8 (m, 1F); HRMS (ESI): m/z calcd. for C14H17F9NaO+ [M + Na]+: 395.1028, found: 395.1027. N-butyl-2,2-difluoro-3-(2-oxaspiro[4.5]decan-3yl)propanamide (3al). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as colorless oil (241 mg, 53% yield). 1H NMR (400 MHz, CDCl3) δ 6.67 (s, 1H), 4.07 – 4.00 (m, 1H), 3.49 (d, J = 8.5 Hz, 1H), 3.40 (d, J = 8.5 Hz, 1H), 3.24 – 3.19 (m, 2H), 2.40 – 2.12 (m, 2H), 1.87 (dd, J = 12.5, 6.5 Hz, 1H), 1.48 – 1.41 (m, 2H), 1.35 – 1.14 (m, 13H), 0.84 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1 (t, J = 28.2 Hz), 117.1 (t, J = 252.4 Hz), 78.2, 72.5 (t, J = 4.6 Hz), 44.9, 43.6, 40.1 (t, J = 22.7 Hz), 39.1, 36.8, 35.4, 31.1, 25.8, 23.9, 23.4, 19.8, 13.6; 19F NMR (376 MHz, CDCl3) δ -103.3 (dt, J = 256.4, 17.1 Hz, 1F), -105.6 (dt, J = 256.4, 16.6 Hz, 1F); HRMS (ESI): m/z calcd. for C16H27F2NNaO2+ [M + Na]+: 326.1902, found: 326.1907. N,N-diethyl-2,2-difluoro-3-(2-oxaspiro[4.5]decan-3yl)propanamide (3am). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as colorless oil (323 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 4.14 – 4.07 (m, 1H), 3.48 (d, J = 8.5 Hz, 1H), 3.42 – 3.37 (m, 3H), 3.25 (q, J = 7.1 Hz, 2H), 2.42 – 2.19 (m, 2H), 1.87 (dd, J = 12.6, 6.5 Hz, 1H), 1.33 – 1.22 (m, 11H), 1.08 (t, J = 7.0 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.5 (t, J = 28.9 Hz), 118.6 (t, J = 254.8 Hz), 78.2, 72.7 (t, J = 3.8 Hz), 45.3, 43.5, 41.7 (t, J = 6.3 Hz), 41.4, 41.0 (t, J = 22.4 Hz), 36.9, 35.3, 25.8, 23.9, 23.4, 14.1, 12.1; 19F NMR (376 MHz, CDCl3) δ -98.3 (ddd, J = 278.7, 22.1, 14.4 Hz, 1F), -99.5 (ddd, J = 278.7, 22.0, 15.8 Hz, 1F); HRMS (ESI): m/z calcd. for C16H27F2NNaO2+ [M + Na]+: 326.1902, found: 326.1906.

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2,2-Difluoro-1-(pyrrolidin-1-yl)-3-(2-oxaspiro[4.5]decan3-yl)propan-1-one (3an). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) as colorless oil (321 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 4.15 – 4.08 (m, 1H), 3.59 (t, J = 6.5 Hz, 2H), 3.49 (m, 1H), 3.40 (t, J = 7.6 Hz, 3H), 2.43 – 2.18 (m, 2H), 1.92 – 1.81 (m, 3H), 1.78 – 1.71 (m, 2H), 1.34 – 1.23 (m, 11H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.0 (t, J = 29.6 Hz), 118.1 (t, J = 253.4 Hz), 78.3, 72.7 (t, J = 3.9 Hz), 47.3, 46.5 (t, J = 6.4 Hz), 45.2, 43.5, 40.4 (t, J = 22.3 Hz), 36.9, 35.3, 26.4, 25.8, 23.9, 23.4, 23.1; 19F NMR (376 MHz, CDCl3) δ 101.2 (dt, J = 278.2, 18.8 Hz, 1F), -102.0 (dt, J = 274.5, 18.8 Hz, 1F); HRMS (ESI): m/z calcd. for C16H25F2NNaO2+ [M + Na]+: 324.1746, found: 324.1750. 2,2-Difluoro-1-(indolin-1-yl)-3-(2-oxaspiro[4.5]decan-3yl)propan-1-one (3ao). The title compound was prepared according to Representative Procedure I and purified with silica gel chromatography (petroleum ether/ethyl acetate = 20:1) as wax (345 mg, 66% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 7.18 – 7.16 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.30 – 4.23 (m, 3H), 3.60 (d, J = 8.5 Hz, 1H), 3.49 (d, J = 8.5 Hz, 1H), 3.11 (t, J = 8.2 Hz, 2H), 2.53 – 2.36 (m, 2H), 2.00 (dd, J = 12.5, 6.5 Hz, 1H), 1.43 – 1.35 (m, 11H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.2 (t, J = 30.0 Hz), 142.6, 131.6, 127.3, 124.9, 124.5, 118.3 (t, J = 256.5 Hz), 117.8, 78.3, 72.7 (t, J = 3.7 Hz), 47.8 (t, J = 7.6 Hz), 45.3, 43.5, 40.4 (t, J = 22.1 Hz), 36.9, 35.4, 28.5, 25.9, 23.9, 23.4; 19F NMR (376 MHz, CDCl3) δ -101.0 (ddd, J = 281.5, 19.9, 16.2 Hz, 1F), 101.9 (dt, J = 281.6, 18.3 Hz, 1F); HRMS (ESI): m/z calcd. for C20H25F2NNaO2+ [M + Na]+: 372.1746, found: 372.1752. Ethyl 2,2-difluoro-2-((2,2,6,6-tetramethylpiperidin-1yl)oxy)acetate (4). The title compound was obtained according to Representative Procedure I except TEMPO (351.5 mg, 2.25 mmol) was added. Purification with silica gel chromatography (petroleum ether/ethyl acetate = 15:1) gave the title compound (58.6 mg, 14% yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.34 (q, J = 7.1 Hz, 2H), 1.55 (t, J = 9.5 Hz, 5H), 1.35 (t, J = 7.1 Hz, 4H), 1.16 (d, J = 9.9 Hz, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.85 (t, J = 42.6 Hz), 115.65 (t, J = 271.6 Hz), 63.11, 61.50, 40.33, 33.53, 20.86, 17.03, 14.03; 19 F NMR (377 MHz, CDCl3) δ -73.47 (s, 2F).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H, (PDF).

13

C, and

19

F NMR spectra for new compounds

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected].

ORCID Guangwei Wang: 0000‐0003‐4466‐9809 Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENT The authors are grateful to the financial support of Major National Science and Technology Projects (2017ZX07402003). We also thank the Natural Science Foundation of Tianjin (No. 16JCYBJC20100) and Tianjin University for support of this research.

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