Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of

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Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of Alkenes Yuanjin Chen, Liangkui Li, Yangyang Ma, and Zhiping Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00339 • Publication Date (Web): 22 Mar 2019 Downloaded from http://pubs.acs.org on March 23, 2019

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The Journal of Organic Chemistry

Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of Alkenes Yuanjin Chen, Liangkui Li, Yangyang Ma, and Zhiping Li*

Department of Chemistry, Renmin University of China, Beijing 100872, China

[email protected]

Abstract:

The

Co(acac)2-catalyzed

three-component

difluoroalkylation-peroxidation

of

alkenes

with

difluorohaloactates and hydroperoxides has been developed. The protocol provides an efficient and selective access to various -peroxyl difluoroalkyl derivatives, which can be transformed into -amino acid and pyrimidine derivatives by the reactions with amines and amidines. The mild reaction conditions, broad substrate scopes, gram-scale synthesis and synthetic applications exemplified the utility and practicability of this method. In addition, this methodology can be extended to other halide compounds to give the alkylation-peroxidation products.

INTRODUCTION The difluoroalkyl groups CF2R (R=H, alkyl/aryl, CO2R, SO2R, etc.) play important roles in the fields of pharmaceuticals and agrochemicals due to the modulation of the medicinal properties, such as lipophilicity, metabolic stability and hydrogen-bonding potency.1 Among these compounds, oxydifluoroalkyl-containing motifs have attracted much interest from both the fine chemical and medicinal chemists.2 For example，the difluorinated prostaglandin E1 analogue lubiprostone is an effective treatment for chronic idiopathic constipation,2b and

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difluorostatone can act as an aspartic acid transition state inhibitor.2c Gemcitabine was FDA-approved for the treatment of locally advanced or metastatic pancreatic cancer2b and Tafluprost, fluorinated analog of prostaglandin F2-alpha, was FDA-approved for the control the progression of glaucoma and in the management of ocular hypertension.2a 1,2,4-Trizaoles having difluoro moiety shows antifungal activities against yeasts and filamentous fungi in vitro.

In recent years, various approaches for synthesis of difluoroalkyl compounds have been developed.3 Therein, the difluoroalkylation of alkenes has drawn considerable attention. One of the features of the strategy is that a divergent difluoroalkylated products could be prepared by the difunctionalization of alkenes.4 For instance, oxy-,5 amino-,6 hydro-,7 thio-,8 1,2-carbo-,9 and halo-containing10 difluoroalkylation, have been developed. For the reported methods of oxydifluoroalkylation of alkenes (Scheme 1a-c), there are still some challenging issues to be addressed: the narrow substrate scopes, the high cost catalysts and the use of the difficult handling difluoroalkylating reagents. Inspired by these previous significant works, we assumed if the alkyl radical generated by the addition of the difluoroalkyl radicals to alkenes is captured by another functional group instantly, we can achieve the new functional difluoroalkyl compounds. We envisaged that the appropriate choice of a peroxide reagent could open a new oxydifluoroalkylation of alkenes (Scheme 1d). To the best of our knowledge, an efficient approach regarding peroxyl-functionalization of alkenes11,12 to synthesize difluoroalkyl compounds has not been explored. Herein, we wish to report a new difluoroalkylation-peroxidation of alkenes using the cobalt catalyst and easy-to-handle fluoroalkylating reagents. With the established method, the obtained peroxidation-difluoroalkylation products could be further transformed into alcohol, amino acid derivatives and pyrimidines. Broad substrate scopes, good yields, gram-scale synthesis and synthetic applications exemplified the utility and practicability of this method.


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Scheme 1. Strategies for Oxydifluoromethylation of Alkenes.

RESULTS AND DISCUSSION

We commenced the studies by the optimization of the reaction conditions of T-hydro (70% tert-butyl hydroperoxide in water, 1a), styrene (2a), and ethyl bromodifluoroacetate (BrCF2CO2Et) (3a) (Table 1). Various metal salts, including iron, copper, silver, manganese and cobalt, were used as catalyst for the transformation (entries 1-11). To our delight, a 91% yield of the desired peroxidation-difluoroalkylation product (4a) was obtained when Co(acac)2 was employed as catalyst (entry 5). However, other cobalt catalysts were much less effective for the reaction (entries 6-11). None of the desired product (4a) was observed in the absence of base (entry 12), indicating that base is essential for the desired transformation to neutralize the in situ generated HBr. Nevertheless,



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other tested bases including inorganic and organic bases were totally inactive (entries 13-17), suggesting that the base influences the desired three-component reaction. We hypothesized that (1) the inorganic bases failed to give the desired product due to the solubility of the inorganic bases; (2) pyridine (Py) might coordinate to the cobalt catalyst and thus deactivate the catalyst; (3) strong bases might lead to decomposition of the products due to the Kornblum-DeLaMare rearrangement. Both DCM and DCE were applicable solvent for the transformation (entries 18 and 19), while other tested solvents gave decreased yields (entries 20-22).

Table 1. Optimization of the Reaction Conditionsa


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catalyst

base

solvent

4a (%)b

1

FeCl2

NEt3

MeCN

trace

2

CuI

NEt3

MeCN

46

3

AgNO3

NEt3

MeCN

trace

4

MnBr2

NEt3

MeCN

23

5

Co(acac)2

NEt3

MeCN

91

6

CoF2

NEt3

MeCN

trace

7

CoCl2

NEt3

MeCN

8

8

CoBr2

NEt3

MeCN

26

9

CoI2

NEt3

MeCN

42

10

Co(OAc)2·4H2O

NEt3

MeCN

20

11

Co(acac)3

NEt3

MeCN

21

12

Co(acac)2

-

MeCN

trace

13

Co(acac)2

K2CO3

MeCN

trace

14

Co(acac)2

Na3PO4

MeCN

trace

15

Co(acac)2

CH3COONa

MeCN

trace

16

Co(acac)2

Py

MeCN

trace

17

Co(acac)2

DABCO

MeCN

trace

18

Co(acac)2

NEt3

DCM

87

19

Co(acac)2

NEt3

DCE

88

20

Co(acac)2

NEt3

HOAc

8

21

Co(acac)2

NEt3

THF

63

22

Co(acac)2

NEt3

EA

75

entry

a

Reaction conditions: 1a (T-hydro, 70% in water, 3 mmol), 2a (0.5 mmol), 3a (1.0 mmol), catalyst (10 mol %),

base (2.5 mmol), solvent (2.0 mL), r.t., 3 h, under N2. bReported yields were based on 2a and determined by 1H NMR using an internal standard.

With the optimal reaction conditions in hand, we turned our attention to investigate the scope of 1 and 2 (Scheme 2). Styrenes bearing electrondonating (-Me, -OMe, -CH2Cl, -Bu-t) or synthetically attractive electronwithdrawing (-F, -Cl, -Br) groups at the different positions of the phenyl ring reacted smoothly with T-hydro (1a) and ethylbromodifluoroacetate (BrCF2CO2Et) (3a), affording the expected products 4a-4i in moderate to good yields. Notably, the introduction of relatively bulkier hindrance group at the ortho position did not affect the product yield



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(4j, 61%). In addition, a variety of 1,1-disubstituted alkenes performed well under the standard conditions and gave the corresponding peroxidation-difluoroalkylation products (4k-4o) in good yields. It is noteworthy that cyclic alkenes such as indene (2p), 1,2-dihydronaphthalene (2q) and 1-phenyl-1-cyclohexene (2r), also proved to be suitable substrates, producing the desired products (4p-4r) in 31-49% yields with good diastereoselectivities. Importantly, the unactivated alkenes could also be applied in the present transformation under the standard conditions, albeit in low yields (4s-4u). However, only styrene derivatives were used in the previous reports on oxydifluoroalkylation of alkenes,5 probably due to the generation of stable cation intermediates. In addition, cumyl hydroperoxide (1b) was also applicable and the corresponding expected product (4v) was obtained under the standard conditions in 61% yield.


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Scheme 2. Scopes of 1 and 2: (a) Reaction conditions: 1 (3 mmol), 2 (0.5 mmol), 3a (1.0 mmol), Co(acac)2 (10 mol %), NEt3 (2.5 mmol), MeCN (2.0 mL), r.t., 3h, under N2. (b) Isolated yields. (c) d.r. = 5:1. (d) d.r. > 20:1.



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When the E/Z stereoisomers of internal alkenes (E-2w and Z-2w) were subjected to the reactions under the standard reaction conditions, the expected product (4w) was formed essentially in the same diastereoselectivity and yields (eq 1). These results suggested that the difluoroalkylation-peroxidation reaction is proceeding in a stepwise pathway and the second step (peroxidation) is most likely the rate-determining step of the transformation. Furthermore, when the reaction was carried out in 5 mmol scale, the desired product (4a) was isolated in 70% yield (eq 2), which showed the similar efficiency (78%) in the 0.5 mmol scale reaction (Scheme 2).

Furthermore, difluoroalkylating reagents (3) bearing different halides (Br, Cl, I) were investigated (Scheme 3). The chloride substrate (3b) failed to afford the target difluoroalkylation-peroxidation compound (4a), while the iodide substrate (3c) led to a 81 yield of 4a (a comparable yield with the use of 3a).

Scheme 3. Influence of halogen.

Encouraged by the above results, we further investigated the application of other halides for the present transformation under the standard reaction conditions (Table 2). Ethyl 2-bromoacetate (5a) gave the corresponding


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alkylation-peroxidation product (6a) in 46% yield (entry 1). However, ethyl 2-bromo-2-methylpropanoate (5b) failed to give the expected product (6b) (entry 2), probably due to the steric effect of the substrate 5b. Ethyl 2,2,2-trichloroacetate (5c) led to the dichloroalkylation-peroxidation product (6c) in 25% yield (entry 3). Perfluorohexyl iodide (5d) could be applied (entry 4).13a When tetrachloromethane (5e) and chloroform (5f) were subjected to the reactions, the corresponding chloroalkylation-peroxidation products (6e and 6f) were also obtained in 45% and 41% yields respectively (entries 5 and 6). In comparison of chloride substrates 3b，the chloride substrates of 5c, 5e and 5f could be converted to the corresponding desired products (6c, 6e and 6f) smoothly under the standard reaction conditions. We hypothesized that the results might be attributed to the differences of the BDEs (bond dissociation energy) for C-Cl bonds.

Table 2. Other halides 5 in the three-component peroxidation reactionsa

entry

5

6

(%)b

1

5a

6a, 46

2

5b

6b, ND

3

5c

6c, 25

4

5d

6d, 66

5

5e

6e, 45



6

a

5f

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6f, 41

Reaction conditions: 1a (3 mmol), 2a (0.5 mmol), 5 (1.0 mmol), Co(acac)2 (10 mol %), NEt3 (2.5 mmol), MeCN

(2.0 mL), r.t., 3 h, under N2. bIsolated yields.

To demonstrate the utilities of the peroxidation-difluoroalkylation products, the transformations of 4a were studied (eq 3, Schemes 4 and 5). The obtained peroxidation-difluoroalkylation product (4a) could be converted to the corresponding alcohol (7) smoothly by the selective reduction of ester group (eq 3).

Unnatural α-amino acids (α-AAs) have played a crucial role in the peptides, proteins, natural products, and biologically relevant compounds.14 We found that the obtained difluoroalkylation-peroxidation product (4a) could be converted to the corresponding -amino acid derivatives (9) smoothly through by reacting 4a with the secondary amines HNR1R2 (8) in the presence of DABCO (Scheme 4). We rationalized that this cascade reaction is initiated by DABCO-catalyzed Kornblum–DeLaMare rearrangement of peroxyl group to carbonyl group. Subsequently, the generated ,-difluoro ketone intermediate undergoes the DABCO-promoted elimination of hydrofluoric acid to give the ,-unsaturated ketone, which is further attacked by the nucleophile (8) and simultaneously eliminate a second molecule of hydrofluoric acid to afford the -amino acid derivatives (9).15


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Scheme 4. Reactions of 4a with amines 8: (a) Reaction conditions: 4a (0.3 mmol), 8 (0.36 mmol), DABCO (0.9 mmol), MeCN (2.0 mL), 60oC, 12 h, under N2. (b) Isolated yields.

Pyrimidine structural motif is one of privileged pharmacophores ubiquitously presenting in many bioactive molecules and natural products.16,17 Based on the above results of the formation of -amino acid derivatives, we envisioned that a cyclic product would be formed if a 1,n-bis-nucleophile was applied. To our satisfactory, when amidines (10) were used, the pyrimidine derivatives 11 were obtained in good yields (Scheme 5).18 The method presents a new approach to pyrimidine derivatives.



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Scheme 5. Reactions of 4a with amines 10: (a) Reaction conditions: 4a (0.3 mmol), 10 (0.6 mmol), DABCO (0.9 mmol), MeCN (2.0 mL), 60oC, 12 h, under N2. (b) Isolated yields.

In order to study the possible reaction mechanisms for the difluoroalkylation-proxidation reaction, the control experiments were carried out (Scheme 6). When the radical scavengers, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), were added into the reactions, the formation of the desired product (4a) was inhibited (Scheme 6a and 6b) and a BHT-adduct product 12 was detected by HRMS (Scheme 6b). The results indicated that the three-component reaction is most likely initiated by the addition of a difluoroalkyl radical to alkene. In addition, the radical clock reaction of vinylcyclopropane 13 was performed to afford the radical ring-opening product 14 in 48% yield (Scheme 6c). The result further suggested that the reaction most likely undergoes a radical path-way. In addition, when MeOH was used instead of 1a, the MeOH-captured product (15) was not observed under our reaction conditions (Scheme 6d). When the reactions were carried out in the


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absence of 1a, the bromodifluoroacetylation product 16 was not observed (Scheme 6e). These result suggested that a carbocationic intermediate might not be involved in the transformation.

Scheme 6. Mechanistic Studies.

Based on the experimental evidences of the above studies and literatures,19 a plausible mechanism for the difluoroalkylation-peroxidation of alkenes is proposed as shown in Scheme 7. The SET reaction of BrCF2CO2Et (3a) by Co(II) affording difluorinated anion radical A, which is further converted to B (.CF2COOEt) (Scheme 7a). Cobalt tert-butylperoxy C and HBr are formed by the reaction of cobalt(III) species with hydroperoxide 1a



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(Scheme 7b).19 tert-Butylperoxy radical (t-BuOO·, D) and cobalt(II) are in equilibrium with cobalt tert-butylperoxy C. Sequentially, B adds to 2a to form the radical intermediate E, followed by tert-butylperoxy group transfer from cobalt tert-butylperoxy C to E to deliver the final three-component product 4a (Scheme 7c). Alternatively, radical cross-coupling of E and tert-butylperoxy radical D will also give 4a.

Scheme 7. A plausible reaction mechanism.

CONCLUSION In summary, we have demonstrated Co(acac)2-catalyzed three-component difluoroalkylation-peroxidation of alkenes with difluorohaloactates and hydroperoxides. The protocol provides an efficient and selective access to various -peroxyl difluoroalkyl compounds, which can be transformed into -amino acid and pyrimidine derivatives by the reactions with amines and amidines. The difluoroalkylation-peroxidation of alkenes presents a new radical difunctionalization of alkenes. The mild reaction conditions, broad substrate scopes, gram-scale synthesis and synthetic applications exemplified the utility and practicability of this method. In addition, this methodology can be extended to other halide compounds to give the alkylation-peroxidation products.

Experimental Section

General Information. 1H NMR spectra were recorded on Bruker 400 MHz and 600 MHz spectrometers and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The


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peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J, are reported in Hertz (Hz). 19F NMR and 13C NMR spectra were obtained at Bruker 100 MHz, 150 MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3). CDCl3 was used as the NMR solvent. All 13C spectra were recorded with broadband proton decoupling. APEX II (Bruker Inc.) was used for ESI-MS and EI-MS. IR spectra were recorded by a Bruker Tensor 27 infrared spectrometer. Flash column chromatography was performed over silica gel 200-300. All reagents were weighed and handled in air at room temperature. Unless otherwise noted, all chemical reagents were purchased from Alfa, Acros, Aldrich, TCI, and J&K and used without further purification. The substrates were purchased from commercial sources or prepared according to literature procedures.

CAUTION: Mixing a metal salt and peroxide can cause explosion. See: Jones, A. K.; Wilson, T. E.; Nikam, S. S. Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A. Ed.; John Wiley & Sons, Inc.; 1995, 2, 880.

General procedure and characterization data for the products 4/6.

To a dry Schlenk tube were added ROOH 1 (3.0 mmol), alkene 2 (0.5 mmol), Co(acac)2 (0.05 mmol), halide 3/5 (1.0 mmol), and anhydrous MeCN (2.0 mL) under N2 atmosphere at room temperature. Subsequently, NEt3 (2.5 mmol) was added to the mixture, and the resulting solution was stirred at ambient temperature for 3 h. The resulting mixture and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethylacetate/ petroleum ether) to give the products 4/6.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-phenylbutanoate (4a): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 10:1, Rf = 0.7) in 78% yield (123 mg); Colorless oil; IR (KBr): νmax 3026, 1769, 1416, 1386, 1257, 1127, 755, 624, 558 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 5H), 5.12 (dd, J = 5.2 Hz, 8.0 Hz, 1H), 4.25-4.13 (m, 2H), 2.92-2.78 (m, 1H), 2.51-2.39 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H);



13C{1H}

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NMR (100 MHz, CDCl3) δ 163.5 (t, J = 33.0 Hz), 139.3, 128.3, 127.1, 114.6 (t, J = 249.0 Hz), 80.6, 79.8,

62.7, 39.8 (t, J = 22.5 Hz), 26.3, 13.8; 19F NMR (CDCl3, 150 MHz) δ -101.9 (d, J = 70.5 Hz), -105.1 (d, J = 70.5 Hz). HRMS (ESI) calcd for C16H22F2O4Na (M+Na)+: 339.1378; found: 339.1372.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-(p-tolyl)butanoate (4b): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 10:1, Rf = 0.7) in 65% yield (107 mg); Colorless oil; IR (KBr): νmax 3093, 2980, 2930, 1769, 1617, 1515, 1466, 1401, 1367, 1199, 1090, 1024, 866, 816, 756, 655 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 5.08 (dd, J = 5.6 Hz, 7.6 Hz, 1H), 4.24-4.12 (m, 2H), 2.92-2.79 (m, 1H), 2.51-2.38 (m, 1H), 2.34 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 32.0 Hz), 138.1, 136.2, 129.0, 127.1, 114.6 (t, J = 251.0 Hz), 80.5, 79.7, 62.7, 39.7 (t, J = 24.0 Hz), 26.3, 21.1, 13.8; 19F NMR (CDCl3, 150 MHz) δ -102.0 (d, J = 70.5 Hz), -105.1 (d, J = 70.5 Hz). HRMS (ESI) calcd for C17H24F2O4Na (M+Na)+: 353.1535; found: 353.1527.

Ethyl 4-(4-((-methyl)--chloranyl)phenyl)-4-(tert-butylperoxy)-2,2-difluorobutanoate (4c): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 5) in 58% yield (106 mg); Colorless oil; IR (KBr): νmax 3051, 2672, 1767, 1470, 1401, 1361, 1329, 1085, 865, 790, 684 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 5.2 Hz, 8.4 Hz, 1H), 4.58 (s, 2H), 4.26-4.14 (m, 2H), 2.88-2.74 (m, 1H), 2.49-2.37 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.16 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5(t, J = 32.0 Hz), 139.7, 139.5, 128.6, 127.4, 114.4 (t, J = 249.0 Hz), 80.7, 79.4, 62.9, 45.8, 39.8 (t, J = 23.4 Hz), 26.3, 13.8; 19F NMR (CDCl3, 150 MHz) δ -101.5 (d, J = 68.9 Hz), -105.1 (d, J = 70.4 Hz). HRMS (ESI) calcd for C17H23ClF2O4Na (M+Na)+: 387.1145; found: 387.1138.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-(4-methoxyphenyl)butanoate (4d): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 5) in 49% yield (85 mg); Colorless oil; IR (KBr):


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νmax 3097, 2934, 2843, 1659, 1601, 1549, 1464, 1387, 1335, 1199, 1025, 877, 790, 690 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.06 (dd, J = 6.4 Hz, 7.6 Hz, 1H), 4.23-4.12 (m, 2H), 3.80(s, 3H), 2.96-2.82 (m, 1H), 2.52-2.40 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 33.0 Hz), 159.6, 131.1, 128.6, 114.6 (t, J = 248.3 Hz), 113.7, 80.5, 79.4, 62.7, 55.2, 39.5 (t, J = 23.0 Hz), 26.3, 13.8. 19F NMR (CDCl3, 150 MHz) δ -102.2 (d, J = 70.2 Hz), -104.9 (d, J = 70.4 Hz). HRMS (ESI) calcd for C17H24F2O5Na (M+Na)+: 369.1484; found: 369.1480.

Ethyl 4-(4-(tert-butyl)phenyl)-4-(tert-butylperoxy)-2,2-difluorobutanoate (4e): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 69% yield (128 mg); Colorless oil; IR (KBr): νmax 3062, 2970, 2874, 1770, 1613, 1513, 1469, 1367, 1267, 1199, 1090, 1023 , 865, 835, 773, 652 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 6.0 Hz, 7.6 Hz, 1H), 4.18-4.05 (m, 2H), 2.95-2.81 (m, 1H), 2.54-2.41 (m, 1H), 1.31 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 32.4 Hz), 151.2, 135.9, 126.9, 125.2, 114.6 (t, J = 249.0 Hz), 80.6, 79.7, 62.6, 39.7 (t, J =23.3 Hz), 34.5, 31.2, 26.3, 13.7; 19F NMR (CDCl3, 150 MHz) δ -102.4 (d, J = 70.2 Hz), -104.5 (d, J = 70.5 Hz). HRMS (ESI) calcd for C20H30F2O4Na (M+Na)+: 395.2004; found: 395.2000.

Ethyl 4-(4-(tert-butyl)phenyl)-4-(tert-butylperoxy)-2,2-difluorobutanoate (4e): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 69% yield (128 mg); Colorless oil; IR (KBr): νmax 3062, 2970, 2874, 1770, 1613, 1513, 1469, 1367, 1267, 1199, 1090, 1023 , 865, 835, 773, 652 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 6.0 Hz, 7.6 Hz, 1H), 4.18-4.05 (m, 2H), 2.95-2.81 (m, 1H), 2.54-2.41 (m, 1H), 1.31 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 32.4 Hz), 151.2, 135.9, 126.9, 125.2, 114.6 (t, J = 249.0 Hz), 80.6, 79.7, 62.6, 39.7 (t, J = 23.3 Hz), 34.5, 31.2, 26.3, 13.7; 19F NMR (CDCl3, 150 MHz) δ -102.4 (d, J = 70.2 Hz), -104.5 (d, J = 70.5 Hz). HRMS (ESI) calcd for C20H30F2O4Na (M+Na)+: 395.2004; found: 395.2000.



Page 18 of 39

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-(4-fluorophenyl)butanoate (4f): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 58% yield (97 mg); Colorless oil; IR (KBr): νmax 3109, 3094, 1769, 1416, 1386, 1127, 1030, 865, 755, 624 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 2H), 7.06-7.02 (m, 2H), 5.10 (dd, J = 5.2 Hz, 8.0 Hz, 1H), 4.28-4.17 (m, 2H), 2.90-2.76 (m, 1H), 2.48-2.36 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 34.7 Hz), 161.4, 135.2, 128.9 (d, J =8.2 Hz), 115.3 (d, J = 21.4 Hz), 114.5 (t, J = 248.3 Hz), 80.7, 79.1, 62.8, 39.7 (t, J = 21.4 Hz), 26.2, 13.8; 19F NMR (CDCl3, 150 MHz) δ -102.0(d, J = 70.5 Hz), -105.3 (d, J = 70.5 Hz), -113.7. HRMS (ESI) calcd for C16H21F3O4Na (M+Na)+: 357.1284; found: 357.1274.

Ethyl 4-(tert-butylperoxy)-4-(4-chlorophenyl)-2,2-difluorobutanoate (4g): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 60% yield (104 mg); Colorless oil; IR (KBr): νmax 3024, 2982, 2933, 1770, 1657, 1593, 1490, 1411, 1370, 1330, 1197, 1126, 1092, 1015, 865, 827, 652 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 5.2 Hz, 8.4 Hz, 1H), 4.29-4.18 (m, 2H), 2.86-2.72 (m, 1H), 2.46-2.34 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4 (t, J = 32.0 Hz), 138.1, 134.0, 128.5, 128.4, 114.3 (t, J = 250.8 Hz), 80.7, 79.0, 62.8, 39.7 (t, J = 23.0 Hz), 26.2, 13.8; 19F NMR (CDCl3, 150 MHz) δ -101.8 (d, J = 70.8 Hz), -105.4 (d, J = 70.7 Hz). HRMS (ESI) calcd for C16H21ClF2O4Na (M+Na)+: 373.0989; found: 373.0979.

Ethyl 4-(3-bromophenyl)-4-(tert-butylperoxy)-2,2-difluorobutanoate (4h): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 50% yield (99 mg); Colorless oil; IR (KBr): νmax 3078, 2987, 1769, 1572, 1472, 1434, 1408, 1372, 1331, 1197, 1125, 1088, 865, 783, 746 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 5.09 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 4.31-4.19 (m, 2H), 2.84-2.70 (m, 1H), 2.46-2.34 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.16 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4 (t, J = 32.2 Hz), 142.0, 131.3, 130.0, 129.9, 125.6, 122.4, 114.3 (t,


Page 19 of 39 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


J = 250.9 Hz), 80.3, 79.0 (t, J = 5.1 Hz), 62.9, 39.8 (t, J = 23.5 Hz), 26.2, 13.8; 19F NMR (CDCl3, 150 MHz) δ -101.9 (d, J = 70.5 Hz), -105.4 (d, J = 70.7 Hz). HRMS (ESI) calcd for C16H21BrF2O4Na (M+Na)+: 417.0483; found: 417.0473.

Ethyl 4-(4-bromophenyl)-4-(tert-butylperoxy)-2,2-difluorobutanoate (4i): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 57% yield (112 mg); Colorless oil; IR (KBr): νmax 3078, 2983, 2930, 1769, 1484, 1378, 1368, 1331, 1197, 1126, 1097, 1012, 863, 822, 778, 725 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 5.2 Hz, 8.4 Hz, 1H), 4.30-4.18 (m, 2H), 2.85-2.71 (m, 1H), 2.46-2.33 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4 (t, J = 32.0 Hz), 138.6, 134.5, 128.7, 122.2, 114.3 (t, J = 248.3 Hz), 80.7, 79.1, 62.9, 39.7 (t, J = 23.3 Hz), 26.2, 13.8; 19F NMR (CDCl3, 150 MHz) δ -101.8 (d, J = 76.7 Hz), -105.4 (d, J = 70.5 Hz). HRMS (ESI) calcd for C16H21BrF2O4Na (M+Na)+: 417.0483; found: 417.0473.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-mesitylbutanoate (4j): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 61% yield (109 mg); Colorless oil; IR (KBr): νmax 3055, 1770, 1610, 1473, 1433, 1403, 1371, 1331, 1203, 1086, 1023, 859, 791, 685 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.81 (s, 2H), 5.59 (dd, J = 6.4 Hz, 7.6 Hz, 1H), 4.23-4.09 (m, 2H), 3.05-2.92 (m, 1H), 2.59-2.50 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 32.5 Hz), 137.4, 132.1, 130.8, 128.9, 114.9 (t, J = 248.3 Hz), 80.3, 76.3, 62.7, 37.8 (t, J = 22.9 Hz), 26.3, 20.8, 20.3, 13.7;

19F

NMR (CDCl3, 150 MHz) δ -102.3 (d, J = 70.5 Hz), -105.3 (d, J = 70.5 Hz). HRMS (ESI) calcd for

C19H28F2O4Na (M+Na)+: 381.1848; found: 381.1844.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-phenylpentanoate (4k): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 81% yield (134 mg); Colorless oil; IR (KBr): νmax 3078, 2984,



Page 20 of 39

2937, 1770, 1451, 1403, 1371, 1340, 1224, 1196, 1150, 1047, 868, 740, 701, 651 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 4.11-3.97 (m, 2H), 2.87-2.61 (m, 2H), 1.39 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 32.4 Hz), 143.1, 127.8, 127.4, 126.0, 114.7 (t, J = 249.3 Hz), 81.0, 79.4, 62.6, 44.7 (t, J = 22.5 Hz), 26.5, 23.3, 13.7;

19F

NMR (CDCl3, 150 MHz) δ -93.4 (d, J = 70.7 Hz), -100.0 (d, J = 70.7 Hz). HRMS (ESI) calcd for C17H24F2O4Na (M+Na)+: 353.1535; found: 353.1529.

Ethyl 4-(tert-butylperoxy)-4-cyclohexyl-2,2-difluoro-4-phenylbutanoate (4l): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 54% yield (108 mg); Colorless oil; IR (KBr): νmax 3078, 2984, 2930, 2857, 1767, 1451, 1434, 1402, 1371, 1307, 1203, 1071, 865, 766, 703 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 4.07-3.97 (m, 2H), 3.15-2.90 (m, 2H), 2.09 (t, J = 12.0 Hz 1H), 1.93 (d, J = 12.0 Hz 1H), 1.70-1.56 (m, 4H), 1.32 (s, 9H),1.23-1.13 (m, 5H), 1.01-0.90 (m, 2H), 0.81-0.71 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3 (t, J = 32.6 Hz), 139.9, 127.1, 126.7, 115.5 (t, J = 248.9 Hz), 85.3, 79.5, 62.4, 45.6, 37.7 (t, J = 22.3 Hz), 28.0, 27.2, 26.8, 26.5, 26.3, 13.7; 19F NMR (CDCl3, 150 MHz) δ -97.7 (d, J = 75.1 Hz), -101.2 (d, J = 69.9 Hz). HRMS (ESI) calcd for C22H32F2O4Na (M+Na)+: 421.2161; found: 421.2150. The substrate 2l was prepared according to the reported literatures.20

Ethyl

4-(tert-butylperoxy)-2,2-difluoro-4,4-diphenylbutanoate

(4m):

Isolated

by

flash

column

chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 72% yield (141 mg); Colorless oil; IR (KBr): νmax 3063, 2983, 2932, 1768, 1488, 1432, 1398, 1340, 1259, 1195, 1100, 1067, 1028, 865, 761, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30-7.20 (m, 10H), 3.87 (q, J = 7.2 Hz, 2H), 3.47 (t, J = 14.4 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H), 1.08 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5(t, J = 32.2 Hz), 142.7, 127.6, 127.4, 127.3, 115.2 (t, J = 250.2 Hz), 83.6, 79.7, 62.4, 40.0 (t, J = 22.8 Hz), 26.4, 13.6; 19F NMR (CDCl3, 150 MHz) δ -98.8. HRMS (ESI) calcd for C22H26F2O4Na (M+Na)+: 415.1691; found: 415.1687.


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Ethyl 4-(tert-butylperoxy)-4-(4-chlorophenyl)-2,2-difluoropentanoate (4n): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 59% yield (108 mg); Colorless oil; IR (KBr): νmax 3082, 1769, 1491, 1431, 1393, 1371, 1227, 1017, 828, 799, 746, 706 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 4.18-4.05 (m, 2H), 2.81-2.57 (m, 2H), 1.77 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 32.3 Hz), 141.8, 133.2, 128.0, 127.6, 114.6 (t, J = 249.7 Hz), 80.7, 79.6, 62.7, 44.7 (t, J = 22.5 Hz), 26.5, 23.4, 13.7; 19F NMR (CDCl3, 150 MHz) δ -99.5 (d, J =70.1 Hz), -100.2 (d, J =70.8 Hz). HRMS (ESI) calcd for C17H23ClF2O4Na (M+Na)+: 387.1145; found: 387.1137.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4,4-bis(4-fluorophenyl)butanoate (4o): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 60% yield (129mg); Colorless oil; IR (KBr): νmax 3082, 2628, 1768, 1604, 1510, 1431, 1371, 1227, 1087, 1017, 836, 789, 744, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28-7.23 (m, 4H), 7.00-6.93 (m, 4H), 3.97 (q, J = 6.4 Hz, 2H), 3.40 (t, J = 14.8 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H), 1.06 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 32.2 Hz), 160.8, 138.2 (d, J = 2.7 Hz), 129.5 (d, J = 8.0 Hz), 115.0 (t, J = 250.7 Hz), 114.3 (d, J = 21.3 Hz), 83.2, 80.0, 62.6, 40.5 (t, J = 22.7 Hz), 26.4, 13.7;

19F

NMR (CDCl3, 150 MHz) δ -99.1, -114.6. HRMS (ESI) calcd for C22H24F4NaO4 (M+Na)+: 451.1503;

found: 451.1487. The substrate 2o was prepared according to the reported literatures.19

Ethyl 2-1-(tert-butylperoxy)-2,3-dihydro-1H-inden-2-yl)-2,2-difluoroacetate, (4p): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 49% yield (81mg); d.r.=5:1(diastereomeric ratio); Colorless oil; IR (KBr): νmax 3082, 2655, 1767, 1431, 1394, 1371, 1305, 1076, 1651, 856, 751, 677 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49-7.21 (m, 8H), 5.65 (d, J = 2.8 Hz, 1H), 5.51 (d, J = 6.4 Hz, 1H), 4.42-4.30 (m, 2H), 4.29-4.16 (m, 2H), 3.53-3.00 (m, 6H), 1.37 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.26 (s, 9H), 1.16 (s, 9H); 13C{1H}

NMR (100 MHz, CDCl3) δ 163.7 (t, J = 32.4 Hz), 142.4, 142.1, 139.3, 138.6, 129.5, 129.4, 126.9, 126.7,

126.6, 126.2, 124.7, 124.6, 116.1 (t, J = 253.8 Hz), 86.6, 85.0, 80.7, 80.6, 62.8, 62.5, 47.7 (t, J = 22.1 Hz), 47.3 (t, J



Page 22 of 39

= 22.5 Hz), 30.6, 30.2, 26.4, 26.2, 13.9, 13.8; 19F NMR (CDCl3, 150 MHz) δ -97.6 (d, J = 73.5 Hz), -108.9 (d, J = 68.1 Hz), -109.5 (d, J = 73.5 Hz), -112.1 (d, J = 68.1 Hz). HRMS (ESI) calcd for C17H22F2O4Na (M+Na)+: 351.1378; found: 351.1375.

Ethyl 2-(1-(tert-butylperoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2-difluoroacetate (4q): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 37% yield (64 mg); d.r.=5:1; Colorless oil; IR (KBr): νmax 3056, 2693, 1764, 1462, 1431, 1394, 1371, 1195, 1079, 1014, 874, 801, 746, 703 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.10 (m, 8H), 5.16 (d, J = 2.8 Hz, 2H), 4.37-4.21 (m, 4H), 3.32-3.20 (m, 1H), 3.05-3.00 (m, 1H), 2.90-2.72 (m, 2H), 2.68-2.42 (m, 2H), 2.29-2.14 (m, 2H), 2.04-2.00 (m, 1H), 1.85-1.77 (m, 1H), 1.37(t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.0 (t, J = 32.2 Hz), 138.9, 136.7, 133.3, 131.9, 131.2, 128.8, 128.7, 128.4, 128.2, 126.0, 125.3, 80.5, 80.3, 62.8, 62.5, 44.6 (t, J = 27.3 Hz), 40.7 (t, J = 21.5 Hz), 28.5, 26.5, 26.4, 26.2, 26.1, 19.4. 17.2. 13.9；

19F

NMR (CDCl3, 150 MHz) δ

-104.3 (d, J = 71.3 Hz), -107.3 (d, J = 22.8 Hz), -109.6 (d, J = 15.9 Hz), -109.6 (d, J = 151.7 Hz). HRMS (ESI) calcd for C18H24F2O4Na (M+Na)+: 365.1535; found: 365.1524.

Ethyl 2-(2-(tert-butylperoxy)-2-phenylcyclohexyl)-2,2-difluoroacetate (4r): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 31% yield (57 mg); d.r. >20:1; Colorless oil; IR (KBr): νmax 3074, 2673, 1768, 1443, 1399, 1360, 1304, 1266, 1016, 962, 876, 795, 759, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 6.8 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 3.75-3.62 (m, 2H), 2.92-2.81 (m, 1H), 2.35-2.34 (m, 2H), 2.00-1.99 (m, 2H), 1.86-1.79 (m, 1H), 1.74-1.69 (m, 1H), 1.59-1.54 (m, 2H), 1.19 (s, 9H), 1.13 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 32.5 Hz), 142.1, 127.9, 127.4, 127.2, 116.3 (t, J = 246.4 Hz), 81.3, 78.7, 62.3, 45.5 (t, J = 19.1 Hz), 27.7, 27.6, 26.8, 21.8 (d, J = 33.2 Hz), 21.0 (d, J = 28.5 Hz), 13.5; 19F NMR (CDCl3, 150 MHz) δ -97.4 (d, J = 71.4 Hz), -105.3 (d, J = 71.3 Hz). HRMS (ESI) calcd for C20H28F2O4Na (M+Na)+: 393.1848; found: 393.1841.


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Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-methyl-5-phenylpentanoate (4s): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 35% yield (60 mg); Colorless oil; IR (KBr): νmax 3094, 3078, 2980, 1769, 1497, 1431, 1394, 1337, 1059, 862, 743, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 5H), 4.30 (q, J = 6.8 Hz, 14.0 Hz, 2H), 3.00 (dd, J = 14.0 Hz, 23.2 Hz, 2H), 2.58-2.31 (m, 2H) , 1.32 (t, J = 7.2 Hz, 3H) , 1.31 (s, 3H), 1.28 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1 (t, J = 32.5 Hz), 136.8, 130.9, 127.8, 126.4, 115.5 (t, J = 248.2 Hz), 80.4, 79.3, 62.6, 44.2, 40.6 (t, J = 22.2 Hz), 26.5, 22.6, 13.8; 19F NMR (CDCl3, 150 MHz) δ -99.3 (d, J = 69.8 Hz), -101.4 (d, J = 69.9 Hz). HRMS (ESI) calcd for C18H26F2O4Na (M+Na)+: 367.1691; found: 367.1686.

Ethyl 4-(tert-butylperoxy)-2,2-difluorodecanoate (4t): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 22% yield (36mg); Colorless oil; IR (KBr): νmax 3082, 1770, 1431, 1393, 1371, 1267, 1081, 884, 751, 714, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.32 (q, J = 7.2 Hz, 2H), 4.19-4.13 (m, 4H), 2.27-2.14 (m, 1H), 1.71-1.66 (m, 1H) , 1.60-1.53 (m, 1H), 1.38-1.28 (m, 7H), 1.21 (s, 9H), 0.89 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.0 (t, J = 32.5 Hz), 115.3 (t, J = 249.4 Hz), 80.2, 77.7, 62.7, 37.8 (t, J = 22.6 Hz), 33.2, 31.7, 29.2, 26.4, 25.2, 22.6, 14.0 (d, J = 14.1 Hz); 19F NMR (CDCl3, 150 MHz) δ -100.9 (d, J = 69.6 Hz), -106.0 (d, J = 69.6 Hz). HRMS (ESI) calcd for C16H30F2O4Na (M+Na)+: 347.2004; found: 347.1997.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-4-methyl-5-phenoxypentanoate (4u): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 36% yield (65 mg); Colorless oil; IR (KBr): νmax 3082, 1431, 1322, 1124, 991, 816, 711, 621 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.6 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 7.6 Hz, 2H), 4.30-4.23 (m, 2H), 4.08 (d, J = 9.2 Hz, 1H), 3.95 (d, J = 9.2 Hz, 1H), 2.78-2.53 (m, 2H) , 1.47 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.18 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (t, J = 32.3 Hz), 158.6, 129.4, 120.9, 117.7 (t, J = 220.0 Hz), 114.6, 79.8, 79.6, 70.7, 62.7, 39.1 (t, J = 34.8 Hz), 26.4,



Page 24 of 39

20.4, 13.8; 19F NMR (CDCl3, 150 MHz) δ -99.4 (d, J = 70.2 Hz), -100.5 (d, J = 70.1 Hz). HRMS (ESI) calcd for C18H26F2O5Na (M+Na)+: 383.1641; found: 383.1634.

Ethyl 2,2-difluoro-4-phenyl-4-((2-phenylpropan-2-yl)peroxy)pentanoate (4v): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 61% yield (120 mg); Colorless oil; IR (KBr): νmax 3058, 2987, 2929, 1769, 1446, 1395, 1341, 1266, 1144, 1043, 912, 856, 767, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52-7.30 (m, 10H), 3.88-3.71 (m, 2H), 2.91-2.79 (m, 1H), 2.73-2.61 (m, 1H),1.97 (s, 3H), 1.70 (s, 3H), 1.57 (s, 3H), 1.17 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3 (t, J = 32.1 Hz), 145.5, 143.1, 127.9, 127.5, 126.9, 126.1, 125.5, 82.4, 81.5, 62.4, 45.1 (t, J = 22.6 Hz), 27.5, 26.3, 23.0, 13.6; 19F NMR (CDCl3, 150 MHz) δ -98.5 (d, J = 106.4 Hz), -100.5 (d, J = 106.4 Hz).  HRMS (ESI) calcd for C22H26F2O4Na (M+Na)+: 415.1691; found: 415.1688.

Ethyl 4-(tert-butylperoxy)-2,2-difluoro-3-methyl-4-phenylbutanoate (4w): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 6) in 31% yield (51 mg); Colorless oil; IR (KBr): νmax 3082, 1768, 1431, 1394, 1371, 1202, 1129, 1043, 854, 761, 702, 677 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m, 10H), 5.18 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 9.6 Hz, 1H), 4.43-4.31 (m, 2H), 4.25-4.15 (m, 2H), 2.95-2.81 (m, 1H), 2.71-2.57 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H), 1.08(d, J = 7.2 Hz, 3H), 1.04 (s, 9H), 0.86 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (t, J = 32.4 Hz), 139.7, 139.0, 128.3, 128.2, 128.0, 127.6, 127.0, 116.4 (t, J = 252.5 Hz), 85.3, 81.6, 80.6, 80.5, 62.8, 62.5, 44.3 (t, J = 21.2 Hz), 41.5 (t, J = 23.4 Hz), 26.4, 26.3, 14.0, 13.9, 9.4, 6.9; 19F NMR (CDCl3, 150 MHz) δ -104.7 (d, J = 70.7 Hz), -108.2 (d, J = 69.2 Hz), -110.1 (d, J = 69.2 Hz), -120.3 (d, J = 70.7 Hz). HRMS (ESI) calcd for C17H24F2O4Na (M+Na)+: 353.1535; found: 353.1525.


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Ethyl 4-(tert-butylperoxy)-4-phenylbutanoate (6a): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 4) in 46% yield (64 mg); Colorless oil; IR (KBr): νmax 3069, 2980, 2931, 1736, 1656, 1594, 1452, 1410, 1373, 1253, 1194, 1028, 756, 698, 658 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 4.89 (dd, J = 6.0 Hz, 7.2 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 2.24-2.14 (m, 1H), 2.08-1.99 (m, 1H), 1.23 (t, J =7.2 Hz, 3H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 140.7, 128.1, 127.6, 126.7, 84.6, 80.2, 60.3, 30.6, 30.2, 26.4, 14.1. HRMS (ESI) calcd for C16H24O4Na (M+Na)+: 303.1567; found: 303.1562.

Ethyl 4-(tert-butylperoxy)-2,2-dichloro-4-phenylbutanoate (6c): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 10:1, Rf = 0.6) in 25% yield (44 mg); Colorless oil; IR (KBr): νmax 3058, 2987, 2929, 1769, 1446, 1395, 1341, 1266, 1144, 1043, 912, 856, 767, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.23 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 4.27-4.13 (m, 2H), 3.24 (dd, J = 8.4 Hz, 14.8 Hz, 1H), 2.77 (dd, J = 4.8 Hz, 14.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 139.6, 128.3, 128.2, 127.2, 82.4, 82.3, 80.5, 63.7, 50.3, 26.4, 13.7. HRMS (ESI) calcd for C16H22Cl2O4Na (M+Na)+: 371.0787; found: 371.0776.

(1-(tert-Butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzene

(6d):13a

Isolated

by

flash

column

chromatography (ethyl acetate/petroleum ether = 10:1, Rf = 0. 6) in 66% yield (136 mg); Colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.31-7.25 (m, 5H), 5.21-5.19 (m, 1H), 2.77-2.67 (m, 1H), 2.42-2.32 (m, 1H), 1.13 (s, 9H); 13C{1H}

NMR (150 MHz, CDCl3) δ 139.5, 128.6, 128.5, 126.9, 80.8, 78.9, 36.0 (t, J = 21.0 Hz), 26.3, not all

carbons are reported due to extensive 19F splitting.

(1-(tert-Butylperoxy)-3,3,3-trichloropropyl)benzene (6e):13b Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 8) in 45% yield (69 mg); Colorless oil; 1H NMR (400 MHz, CDCl3) δ



Page 26 of 39

7.40-7.29 (m, 5H), 5.34 (dd, J = 5.2 Hz, 5.6 Hz, 1H), 3.44 (dd, J = 6.0 Hz, 15.2 Hz, 1H), 3.12 (dd, J = 4.8 Hz, 15.2 Hz, 1H), 1.22 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.7, 128.5, 128.3, 127.3, 96.7, 83.0, 80.6, 59.0, 26.5.

(1-(tert-Butylperoxy)-3,3-dichloropropyl)benzene (6f):13b Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0.8) in 41% yield (57 mg); Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 5.83 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 5.12 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 2.89-2.82 (m, 1H), 2.54-2.47 (m, 1H), 1.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 128.5, 128.3, 126.9, 82.3, 80.7, 70.4, 49.4, 26.4.

Synthesis and characterization of 7

To a solution of 4a (0.3 mmol) in THF (2 mL) under nitrogen at room temperature, LiAlH4 (0.45 mmol) was added to the mixture under nitrogen at room temperature. The reaction mixture was stirred at 0 oC for 5 h, then passed through celite. The celite was washed with diethyl ether and the eluent was chromatography concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the product 7.

4-(tert-Butylperoxy)-2,2-difluoro-4-phenylbutan-1-ol (7): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 4) in 82% yield (67 mg); Colorless oil; IR (KBr): νmax 3080, 2982, 1738, 1595, 1550, 1456, 1425, 1388, 1368, 1192, 1072, 754, 699, 656 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.13-5.10 (m, 1H), 3.93-3.73 (m, 2H), 2.80-2.63 (m, 2H), 2.35-2.24 (m, 1H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 139.8, 128.3, 127.2, 122.2 (t, J = 241.7 Hz), 80.7, 80.2 (d, J = 5.8 Hz), 64.3 (t, J = 30.2 Hz), 38.0 (t, J = 24.7 Hz), 26.3; 19F NMR (CDCl3, 150 MHz) δ -101.4 (d, J = 101.3 Hz), -106.7 (d, J = 101.1 Hz). HRMS (ESI) calcd for C14H20F2O3Na (M+Na)+: 297.1273; found:297.1271.

Synthesis and characterization of -amino acid derivatives 9


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To a dry Schlenk tube were added difluoroalkylation-peroxidation product 4a (0.3 mmol), HNR1R2 8 (0.36 mmol), DABCO (0.9 mmol), and anhydrous MeCN (2.0 mL) under N2 atmosphere at 60 oC. Subsequently, the resulting solution was stirred at ambient temperature for 12 h. The resulting mixture and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the product 9.

Ethyl (Z)-2-(diethylamino)-4-oxo-4-phenylbut-2-enoate (9a): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.5) in 78% yield (64 mg); Colorless oil; IR (KBr): νmax 3072, 1734, 1529, 1468, 1445, 1428, 1384, 1368, 1215, 767, 701, 556 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.88-7.86 (m, 2H), 7.47-7.37 (m, 2H), 5.74 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.32 (q, J = 7.2 Hz, 4H), 1.41 (t, J = 6.8 Hz, 3H), 1.26 (t, J = 6.8 Hz, 6H);

13C{1H}

NMR (100MHz, CDCl3) δ 186.8, 166.0, 154.6, 140.1, 131.0, 128.0, 127.4, 90.3, 62.1, 45.2, 13.9.

HRMS (ESI) calcd for C16H22NO3 (M+H)+: 276.1594; found: 276.1587.

Ethyl (Z)-2-(diisopropylamino)-4-oxo-4-phenylbut-2-enoate (9b): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.6) in 51% yield (46 mg); Colorless oil; IR (KBr): νmax 3058, 2987, 2929, 1769, 1446, 1395, 1341, 1266, 1144, 1043, 912, 856, 767, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 6.8 Hz, 2H), 7.46-7.37 (m, 3H), 5.91 (s, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.86-3.76 (m, 2H), 1.40-1.38 (m, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.3, 166.5, 153.2, 140.4, 130.9, 128.1, 127.3, 90.1, 62.0, 20.0, 13.9. HRMS (ESI) calcd for C18H25NO3Na (M+Na)+: 326.1727; found: 326.1719.

Ethyl

(Z)-2-(benzyl(methyl)amino)-4-oxo-4-phenylbut-2-enoate

(9c):

Isolated

by

flash

column

chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.6) in 73% yield (71 mg); Colorless oil; IR (KBr): νmax 3072, 3055, 1733, 1633, 1532, 1449, 1373, 1363, 1280, 1206, 937, 760, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.38 (dd, J = 7.6 Hz, 12.8 Hz, 4H), 7.31 (t, J = 6.8 Hz, 3H), 5.81



Page 28 of 39

(s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 4.43 (s, 2H), 2.90 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.1, 166.0, 155.8, 139.7, 135.3, 131.3, 128.8, 128.1, 128.0, 127.6, 127.5, 91.7, 62.3, 56.5, 37.2, 13.8. HRMS (ESI) calcd for C20H21NO3Na (M+Na)+: 346.1414; found: 346.1408.

Ethyl (Z)-2-(dibenzylamino)-4-oxo-4-phenylbut-2-enoate (9d): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.6) in 62% yield (74 mg); Colorless oil; IR (KBr): νmax 3072, 2920, 1733, 1529, 1446, 1408, 1371, 1202, 739, 699, 601 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 2H), 7.36-7.26 (m, 13H), 5.91 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 4.44 (s, 4H), 1.35 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.4, 166.1, 155.6, 140.2, 139.6, 134.9, 131.3, 128.9, 128.3, 128.1, 126.9, 92.5, 62.4, 53.1, 13.8. HRMS (ESI) calcd for C26H25NO3Na (M+Na)+: 422.1727; found: 422.1716.

Ethyl

(Z)-2-(2-methylpiperidin-1-yl)-4-oxo-4-phenylbut-2-enoate

(9e):

Isolated

by

flash

column

chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.6) in 73% yield (66 mg); Colorless oil; IR (KBr): νmax 3054, 1734, 1631, 1596, 1523, 1434, 1411, 1373, 1219, 1026, 954, 881, 806, 763, 703 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 5.84 (s, 1H), 4.54-4.42 (m, 2H), 3.99-3.93 (m, 1H), 3.46-3.43 (m, 1H), 3.20-3.12 (m, 1H), 1.87-1.55 (m, 6H), 1.40 (t, J =7.2 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.3, 166.8, 155.3, 140.1, 131.0, 128.0, 127.4, 91.0, 62.0, 51.1, 42.9, 30.0, 25.2, 18.1, 15.2, 13.9. HRMS (ESI) calcd for C18H23NO3Na (M+Na)+: 324.1570; found:324.1562.

Ethyl (Z)-2-morpholino-4-oxo-4-phenylbut-2-enoate (9f): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.6) in 36% yield (31 mg); Colorless oil; IR (KBr): νmax 3003, 1733, 1635, 1592, 1533, 1436, 1425, 1388, 1368, 1211, 1117, 930, 856, 751 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 5.91 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.79 (t, J = 4.8 Hz, 4H), 3.33 (t, J = 4.8 Hz, 4H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.5, 165.7, 155.1,


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139.3, 131.6, 128.2, 127.6, 92.7, 65.9, 62.4, 47.3, 13.9. HRMS (ESI) calcd for C16H19NO4Na (M+Na)+: 312.1206; found: 312.1199.

Synthesis and characterization of pyrimidine derivatives 11

To a dry Schlenk tube were added difluoroalkylation-peroxidation product 4a (0.3 mmol), amines 10 (0.6 mmol), DABCO (0.9 mmol), and anhydrous MeCN (2.0 mL) under N2 atmosphere at 60 oC. Subsequently, the resulting solution was stirred at ambient temperature for 12 h. The resulting mixture and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the product 11.

Ethyl 2-methyl-6-phenylpyrimidine-4-carboxylate (11a): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.4) in 76% yield (55 mg); Colorless oil; IR (KBr): νmax 3072, 2383, 1941, 1538, 1434, 1409, 1371, 1264, 935, 844, 754 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.16 (t, J = 3.6 Hz, 2H), 7.53-7.52 (m, 3H), 4.53 (q, J = 7.2 Hz, 2H), 2.91 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 166.1, 164.7, 155.8, 136.1, 131.3, 129.0, 127.3, 113.5, 62.5, 26.3, 14.2. HRMS (ESI) calcd for C14H15N2O2 (M+H)+: 243.1128; found: 243.1124.

Ethyl 2,6-diphenylpyrimidine-4-carboxylate (11b): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.4) in 82% yield (75 mg); Colorless oil; IR (KBr): νmax 3072, 2927, 1725, 1539, 1433, 1373, 1250, 1196, 1069, 1021, 745, 691, 658 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.66-8.64 (m, 2H), 8.30-8.27 (m, 2H), 8.27 (s, 1H), 7.55-7.51 (m, 6H), 4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 165.9, 165.1, 164.8, 156.3, 137.1, 136.3, 131.4, 131.1, 129.0, 128.6, 128.5, 127.3, 113.9, 62.4, 14.2. HRMS (ESI) calcd for C19H16N2O2Na (M+Na)+: 327.1104; found: 327.1099.



Page 30 of 39

Ethyl 6-phenyl-[2,5'-bipyrimidine]-4-carboxylate (11c): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.4) in 84% yield (77 mg); Colorless oil; IR (KBr): νmax 3072, 2646, 1733, 1560, 1433, 1409, 1371, 1260, 1018, 694, 662, 548cm-1; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 4.8 Hz, 2H), 8.53 (s, 1H), 8.32-8.30 (m, 2H), 7.58-7.56 (m, 3H), 7.49 (d, J = 4.0 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 167.5, 164.4, 163.3, 162.5, 158.0, 156.9, 135.7, 131.8, 129.1, 127.7,

121.4, 116.5, 62.9, 14.1. HRMS (ESI) calcd for C17H14N4O2Na (M+Na)+: 329.1009; found: 329.1002.

Ethyl 2-(4-chlorophenyl)-6-phenylpyrimidine-4-carboxylate (11d): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.4) in 60% yield (61 mg); Colorless oil; IR (KBr): νmax 3079, 1726, 1338, 1458, 1409, 1372, 1247, 1199, 1084, 1016, 846, 759, 696 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.4 Hz, 2H), 8.26 (s, 3H), 7.56-7.55 (m, 3H), 7.48(d, J = 8.4 Hz, 2H), 4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 166.0, 164.6, 164.1, 156.4, 137.3, 136.1, 135.6, 131.6, 130.0, 129.0, 128.7,

127.3, 114.1, 62.5, 14.2. HRMS (ESI) calcd for C19H15ClN2O2Na (M+Na)+: 361.0714; found: 361.0708.

Ethyl 2-(4-bromophenyl)-6-phenylpyrimidine-4-carboxylate (11e): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0.4) in 55% yield (63 mg); Colorless oil; IR (KBr): νmax 3072, 2983, 1726, 1540, 1433, 1371, 1246, 1198, 1067, 1013, 896, 842, 759, 693 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.8 Hz, 2H), 8.26-8.24 (m, 3H), 7.63 (d, J = 8.8 Hz, 2H), 7.56-7.54 (m, 3H), 4.53 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 164.6, 164.2, 156.3, 136.0, 131.7, 131.6, 130.2, 127.3, 125.9, 114.2, 62.5, 14.2. HRMS (ESI) calcd for C19H15BrN2O2Na (M+Na)+: 405.0209; found: 405.0202.

Ethyl 2-(3-ethoxyphenyl)-6-phenylpyrimidine-4-carboxylate (11f): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 5:1, Rf = 0. 4) in 75% yield (78 mg); Colorless oil; IR (KBr): νmax 3072, 2982, 1724, 1660, 1577, 1537, 1493, 1427, 1382, 1247, 1186, 1039, 757, 693, 657 cm-1; 1H NMR (400 MHz, CDCl3) δ


Page 31 of 39 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


8.30 (s, 1H), 8.26-8.24 (m, 2H), 7.96-7.94 (m, 1H), 7.53-7.51 (m, 3H), 7.43-7.39 (m, 1H), 7.10-7.03 (m, 2H), 4.53 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 165.7, 165.0, 157.7, 156.0, 136.5, 132.0, 131.2, 128.9, 128.2, 127.4, 120.6, 113.6, 113.5, 64.6, 62.3, 14.9, 14.2. HRMS (ESI) calcd for C21H20N2O3Na (M+Na)+: 371.1366; found:371.1358.


To a two-necked round-bottom flask, dry THF (35 mL) and n-BuLi(8.8 mol) were added. The flask was cooled to 0 ºC. A solution of phenyl(2-phenylcyclopropyl)methanone (6.8 mmol) in THF (35 mL) was added to the flask and stirred for 15 min. The mixture was warmed up to room temperature and stirred for 6 h. The product mixture was partially purified by silica-pad (EA/PE was used as an eluent). The eluent was concentrated in vacuo. Then the residue was purified by silica gel column chromatography to afford 1-phenyl-1-(trans-2-phenylcyclopropyl)ethene (13) (1.2 g, 80% yield).

trans-(1-(-2-Phenylcyclopropyl)vinyl)benzene (13):21 Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0. 7) in 80% yield (1.2g), 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J =8.0 Hz, 2H), 7.30-7.17 (m, 6H), 7.13 (d, J =8.0 Hz, 2H), 5.36 (s, 1H), 5.02 (s, 1H), 2.01-1.92 (m, 2H), 1.43-1.36 (m, 1H), 1.28-1.23 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 148.2, 142.5, 141.0, 128.4, 128.2, 127.5, 126.0, 125.7,

109.3, 87.9, 26.4, 15.8.


To a dry Schlenk tube were added t-BuOOH 1a (T-hydro, 70% in water, 3.0 mmol), alkene 13 (0.5 mmol), Co(acac)2 (0.05 mmol), BrCF2COOEt 3a (1.0 mmol), and anhydrous MeCN (2.0 mL) under N2 atmosphere at room temperature. Subsequently, NEt3 (2.5 mmol) was added to the mixture, and the resulting solution was stirred at



Page 32 of 39

ambient temperature for 3 h. The resulting mixture and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the product

Ethyl 7-(tert-butylperoxy)-2,2-difluoro-4,7-diphenylhept-4-enoate (14 major): Isolated by flash column chromatography (ethyl acetate/petroleum ether = 20:1, Rf = 0.6) in 48% yield (104 mg); Colorless oil; IR (KBr): νmax 3082, 2727, 1431, 1393, 1371, 1071, 1018, 877, 756, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.19 (m, 10H), 5.89 (t, J = 7.6 Hz, 1H), 4.96 (t, J = 6.8 Hz, 1H), 3.83 (q, J = 7.2 Hz, 2H), 3.25 (dd, J = 15.2 Hz, 16.4Hz, 2H), 2.92-2.85 (m, 1H), 2.69-2.62 (m, 1H), 1.22 (s, 9H), 1.10 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.7 (t, J = 32.2 Hz), 141.9, 140.5, 132.1, 131.4, 128.2, 128.1, 127.8, 127.2, 126.8, 126.7, 115.0 (t, J = 250.8 Hz), 85.1, 80.3, 62.6, 35.4 (t, J = 24.3 Hz), 34.9, 26.4, 13.6;

19F

NMR (CDCl3, 150 MHz) δ -103.0 (d, J = 5.4 Hz),

-102.9 (d, J =5.4 Hz). HRMS (ESI) calcd for C25H30F2O4Na (M+Na)+: 455.2004; found: 455.1998.

ASSOCIATED CONTENT

Supporting Information

Copies of 1H, 13C and 19F NMR spectra of all compounds and mechanistic studies. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author * [email protected] ORCID Zhiping Li: 0000-0001-7987-279X


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Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

Financial support from the National Natural Science Foundation of China is acknowledged (21672259).

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