Nickel-Catalyzed Site-Selective C−H Bond Difluoroalkylation · China, Tel:+86-561-3802-069, Fax:+86-561-3090-518, E-mail: [email protected] ‡ State Key Laboratory of Organometallic

1

Supporting Information

Nickel-Catalyzed Site-Selective C−H Bond Difluoroalkylation

of 8-Aminoquinolines on the C5-Position

Hao Chen,† Pinhua Li,*

† Min Wang, and Lei Wang*

†‡

† Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P R

China, Tel:+86-561-3802-069, Fax:+86-561-3090-518, E-mail: [email protected]

‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic

Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China

Table of Contents for Supporting Information

1. General considerations…………………………………………………………….…….2

2. General procedure for the reaction....................................................................................2

3. Free radical-trapping experiment.......................................................................................3

4. Characterization data for the products…………….….……………………………….....4

5. 1H and

13C NMR spectra of the products………….….………………………………....27

mailto:Tel:+86-561-3802-069

mailto:[email protected]

2

1. General considerations

All 1H NMR and

13C NMR spectra were recorded on a 400 MHz Bruker FT-NMR

spectrometers (400 MHz or 100 MHz, respectively). All chemical shifts are given as δ

value (ppm) with reference to tetramethylsilane (TMS) as an internal standard. The peak

patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet.

The coupling constants, J, are reported in Hertz (Hz). High resolution mass

spectroscopy data of the product were collected on a Waters Micromass GCT instrument.

High resolution mass spectroscopy data of the product were collected on an Agilent

Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS (ESI).

8-Aminoquinoline amides were prepared according to the literature (Zaitsev, V.;

Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155). The

chemicals and solvents were purchased from commercial suppliers either from Aldrich

(USA) or Shanghai Chemical Company (China) without further purification. All the

solvents were dried and freshly distilled prior to use. All the reactions were carried out

under air atmosphere. Products were purified by flash chromatography on 100–200

mesh silica gels, SiO2.

2. General procedure for the reaction

8-Aminoquinoline amide (1a, 0.25 mmol), BrCF2CO2Et (2a, 0.50 mmol),

Ni(dppf)Cl2 (10 mol %), KHCO3 (2 equiv) and 1,4-dioxane (1.0 mL) was added to a 15

mL Schlenk tube at the preheated oil bath under 150 oC for 12 h . After the reaction was

completed, the reaction mixture was cooled down to room temperature and the reaction

solution was concentrated under reduced pressure to yield crude product, which was

purified by flash chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to give

the desired product 3a in 80 % yield as a white solid.

3

3. Free radical-trapping experiment

8-Aminoquinoline amide (1a, 0.25 mmol), BrCF2CO2Et (2a, 0.50 mmol),

Ni(dppf)Cl2 (0.025 mmol, 10 mol %), KHCO3 (2 equiv), 1,4-dioxane (1.0 mL) and

(2,2,6,6-tetramethylpiperidine)-1-oxyl (TEMPO, 0.5 mmol, 2.0 equiv) were added to a

15 mL Schlenk tube at the preheated oil bath under 150 oC for 12 h . After the reaction

was completed, no desired product 3a was detected by TLC, as well as HPLC-HRMS,

indicating that the reaction was completely inhibited. Meanwhile, a free radical-trapping

adduct of functionalized difluoromethyl radical with TEMPO was observed with

HPLC-HRMS analysis of the reaction solution (Figure S1).

Figure S1. HRMS analysis of the adduct of functionalized difluoromethyl radical with TEMPO

4

4. Characterization data for the products

Ethyl 2-(8-benzamidoquinolin-5-yl)-2,2-difluoroacetate (3a). White solid (74.0 mg,

80% yield), m.p. 103–104 °C. 1H NMR (400 MHz, CDCl3) δ: 10.90 (s, 1H), 8.96 (d, J =

8.3 Hz, 1H), 8.88 (d, J = 3.9 Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 6.9 Hz, 2H),

7.94 (d, J = 8.3 Hz, 1H), 7.617.53 (m, 4H), 4.29 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.2 Hz,

3H); 13

C NMR (100 MHz, CDCl3) δ: 165.52, 164.16 (t, J = 35.0 Hz), 148.41, 138.58,

137.44, 134.66, 133.73 (t, J = 3.7 Hz), 132.10, 128.82, 127.28, 126.84 (t, J = 9.0 Hz),

124.72 (t, J = 2.1 Hz), 122.45, 122.09 (t, J = 24.4 Hz), 114.70, 114.03 (t, J = 251.1 Hz),

63.34, 13.78. HRMS (ESI) ([M+H]+) Calcd. For C20H17F2N2O3: 371.1202, Found:

371.1201.

Ethyl 2,2-difluoro-2-(8-(4-methylbenzamido)quinolin-5-yl)acetate (3b). White solid

(75.9 mg, 79% yield), m.p. 158–159 °C. 1H NMR (400 MHz, CDCl3) δ: 10.87 (s, 1H),

8.96 (d, J = 8.2 Hz, 1H), 8.87 (d, J = 3.5 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.96 (d, J =

7.9 Hz, 2H), 7.91 (d, J = 8.3 Hz, 1H), 7.55 (dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 7.33 (d, J

= 7.8 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 2.44 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ: 165.50, 164.18 (t, J = 35.0 Hz), 148.36, 142.68, 138.59, 137.57,

133.71 (t, J = 3.7 Hz), 131.86, 129.48, 127.30, 126.86 (t, J = 9.0 Hz), 124.73 (t, J = 2.0

Hz), 122.40, 121.90 (t, J = 24.4 Hz), 114.62, 114.06 (t, J = 251.1 Hz), 63.32, 21.46,

13.78. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O3: 385.1358, Found: 385.1354.

5

Ethyl 2,2-difluoro-2-(8-(4-methoxybenzamido)quinolin-5-yl)acetate (3c). White

solid (77.0 mg, 77% yield), m.p. 148149 °C. 1H NMR (400 MHz, CDCl3) δ: 10.83 (s,

1H), 8.94 (d, J = 8.2 Hz, 1H), 8.87 (d, J = 3.6 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.04 (d,

J = 8.7 Hz, 2H), 7.91 (d, J = 8.3 Hz, 1H), 7.55 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 7.03

(d, J = 8.7 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13

C

NMR (100 MHz, CDCl3) δ: 165.06, 164.20 (t, J = 35.0 Hz), 162.76, 148.33, 138.59,

137.65, 133.73 (t, J = 3.7 Hz), 129.22, 126.94, 126.89 (t, J = 8.9 Hz), 124.74 (t, J = 2.0

Hz), 122.40, 121.75 (t, J = 24.4 Hz), 114.51, 114.08 (t, J = 251.1 Hz), 114.04, 63.33,


401.1305.

Ethyl 2-(8-(4-(tert-butyl)benzamido)quinolin-5-yl)-2,2-difluoroacetate (3d). White

solid (88.4 mg, 83% yield), m.p. 129–130 °C. 1H NMR (400 MHz, CDCl3) δ: 10.90 (s,


J = 8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.597.54 (m, 3H), 4.29 (q, J = 7.1 Hz, 2H),

1.38 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 165.57, 164.21 (t,

J = 35.0 Hz), 155.77, 148.37, 138.64, 137.63, 133.76 (t, J = 3.7 Hz), 131.91, 127.21,

126.91 (t, J = 8.9 Hz), 125.81, 124.78 (t, J = 2.0 Hz), 122.43, 121.94 (t, J = 24.4 Hz),

114.66, 114.08 (t, J = 251.0 Hz), 63.33, 35.02, 31.14, 13.81. HRMS (ESI) ([M+H]+)

Calcd. For C24H25F2N2O3: 427.1828, Found: 427.1825.

6

Ethyl 2-(8-([1,1'-biphenyl]-4-ylcarboxamido)quinolin-5-yl)-2,2-difluoroacetate (3e).

White solid (78.1 mg, 70% yield), m.p. 115–118 °C. 1H NMR (400 MHz, CDCl3) δ:

10.96 (s, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 3.2 Hz, 1H), 8.70 (d, J = 8.5 Hz,


J = 7.4 Hz, 2H), 7.57 (dd,J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 7.507.46 (m, 2H), 7.427.38

(m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3)

δ: 165.25, 164.19 (t, J = 35.0 Hz), 148.43, 144.93, 139.85, 138.61, 137.47, 133.78 (t, J

= 3.7 Hz), 133.29, 128.94, 128.11, 127.86, 127.47, 127.19, 126.89 (t, J = 9.0 Hz),

124.76 (t, J = 2.0 Hz), 122.48, 122.08 (t, J = 24.4 Hz), 114.74, 114.05 (t, J = 251.1 Hz),


447.1513.

Ethyl 2,2-difluoro-2-(8-(4-fluorobenzamido)quinolin-5-yl)acetate (3f). White solid


8.93 (d, J = 8.3 Hz, 1H), 8.88 (d, J = 3.1 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.108.07

(m, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.57 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 7.22 (t, J =

8.5 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ: 165.10 (d, J = 251.6 Hz), 164.40, 164.16 (t, J = 35.0 Hz), 148.45, 138.54,

137.29, 133.82 (t, J = 3.7 Hz), 130.86 (d, J = 3.1 Hz), 129.72 (d, J = 9.0 Hz), 126.84 (t,

J = 9.0 Hz), 124.74 (t, J = 2.1 Hz), 122.51, 122.24 (t, J = 24.4 Hz), 115.92 (d, J = 21.9

Hz), 114.73, 114.01 (t, J = 251.2 Hz), 63.38, 13.79. HRMS (ESI) ([M+H]+) Calcd. For

C20H16F3N2O3: 389.1108, Found: 389.1104.

7

Ethyl 2-(8-(4-chlorobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3g). White solid


8.92 (d, J = 8.3 Hz, 1H), 8.88 (d, J = 3.2, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5

Hz, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.57 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 7.52 (d, J =

8.5 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ: 164.42, 164.14 (t, J = 34.9 Hz), 148.49, 138.54, 138.48, 137.18, 133.84 (t, J

= 3.7 Hz), 133.04, 129.12, 128.73, 126.82 (t, J = 8.9 Hz), 124.75 (t, J = 2.1 Hz), 122.53,

122.36 (t, J = 24.4 Hz), 114.81, 113.99 (t, J = 251.2 Hz), 63.39, 13.80. HRMS (ESI)

([M+H]+) Calcd. For C20H16ClF2N2O3: 405.0812, Found: 405.0810.

Ethyl 2-(8-(4-bromobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3h). White solid



(m, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.58 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 4.29 (q, J =

7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.56, 164.15 (t,

J = 34.9 Hz), 148.51, 138.57, 137.20, 133.87 (t, J = 3.7 Hz), 133.56, 132.13, 128.91,

126.99, 126.85 (t, J = 9.0 Hz), 124.78 (t, J = 2.0 Hz), 122.55, 122.42 (t, J = 24.5 Hz),

114.86, 114.01 (t, J = 251.2 Hz), 63.39, 13.82. HRMS (ESI) ([M+H]+) Calcd. For

C20H16BrF2N2O3: 449.0307, Found: 449.0305.

8

Ethyl 2,2-difluoro-2-(8-(4-iodobenzamido)quinolin-5-yl)acetate (3i). White solid



(m, 3H), 7.78 (d, J = 8.3 Hz, 2H), 7.57 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 4.29 (q, J =

7.2 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.76, 164.15 (t,

J = 34.9 Hz), 148.50, 138.56, 138.12, 137.18, 134.13, 133.86 (t, J = 3.8 Hz), 128.85,

126.84 (t, J = 8.9 Hz), 124.77 (t, J = 2.2 Hz), 122.55, 122.40 (t, J = 24.4 Hz), 114.85,

114.00 (t, J = 250.9 Hz), 99.32, 63.39, 13.82. HRMS (ESI) ([M+H]+) Calcd. For

C20H16IF2N2O3: 497.0168, Found: 497.0172.

Ethyl 2,2-difluoro-2-(8-(4-(trifluoromethyl)benzamido)quinolin-5-yl)acetate (3j).



1H), 8.19 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.59

(dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C

NMR (100 MHz, CDCl3) δ: 164.18, 164.13 (t, J = 34.9 Hz), 148.59, 138.54, 137.94 (d,

J = 1.0 Hz), 136.99, 134.26, 133.93, 133.90 (t, J = 3.8 Hz), 133.60, 133.28, 127.80,

126.80 (t, J = 9.0 Hz), 125.94 (q, J1 = 3.7 Hz, J2 = 7.4 Hz), 124.99, 124.77 (t, J = 2.1

Hz), 122.70 (t, J = 24.4 Hz), 122.63, 122.28, 114.98, 113.95 (t, J = 251.2 Hz), 63.44,


9

Ethyl 2,2-difluoro-2-(8-(3-methylbenzamido)quinolin-5-yl)acetate (3k). White solid



8.3 Hz, 1H), 7.887.84 (m, 2H), 7.56 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 7.457.39 (m,

2H), 4.29 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR (100

MHz, CDCl3) δ: 165.79, 164.19 (t, J = 35.0 Hz), 148.42, 138.76, 138.63, 137.54, 134.71,

133.75 (t, J = 3.7 Hz), 132.88, 128.68, 128.08, 126.88 (t, J = 9.0 Hz), 124.76 (t, J = 2.0

Hz), 124.23, 122.43, 122.04 (t, J = 24.4 Hz), 114.73, 114.07 (t, J = 251.1 Hz), 63.34,


385.1356.

Ethyl 2,2-difluoro-2-(8-(3-methoxybenzamido)quinolin-5-yl)acetate (3l). White solid


8.96 (d, J = 4.1 Hz, 1H), 8.888.87 (m, 1H), 8.68 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.3

Hz, 1H), 7.627.61 (m, 2H), 7.55 (dd, J1 = 4.2 Hz, J2 = 8.6 Hz, 1H), 7.477.43 (m, 1H),

7.137.11 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13

C


137.42, 136.14, 133.71 (t, J = 3.7 Hz), 129.80, 126.82 (t, J = 8.9 Hz), 124.72 (t, J = 2.0

Hz), 122.44, 122.12 (t, J = 24.4 Hz), 119.04, 118.20, 114.70, 114.03 (t, J = 251.1 Hz),

112.78, 63.34, 55.44, 13.78. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O4:

401.1307, Found: 401.1308.

10

Ethyl 2,2-difluoro-2-(8-(3-fluorobenzamido)quinolin-5-yl)acetate (3m). White solid



8.3 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.57 (dd, J1 = 4.2 Hz, J2

= 8.7 Hz, 1H), 7.537.49 (m, 1H), 7.317.26 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t,

J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.11 (t, J = 34.9 Hz), 164.09 (d, J =

2.6 Hz), 162.93 (d, J = 246.6 Hz), 148.51, 138.53, 137.11, 136.92 (d, J = 6.8 Hz),

133.80 (t, J = 3.8 Hz), 130.49 (d, J = 7.8 Hz), 126.78 (t, J = 9.0 Hz), 124.73 (t, J = 2.1

Hz), 128.70 (d, J = 3.0 Hz), 122.53, 122.45 (t, J = 24.4 Hz), 119.11 (d, J = 21.2 Hz),

114.84, 114.70 (d, J = 22.9 Hz), 113.99 (t, J = 251.2 Hz), 63.37, 13.78. HRMS (ESI)

([M+H]+) Calcd. For C20H16F3N2O3: 389.1108, Found: 389.1106.

Ethyl 2-(8-(3-chlorobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3n). White solid


8.93 (d, J = 8.2 Hz, 1H), 8.908.89 (m, 1H), 8.708.68 (m, 1H), 8.04 (s, 1H), 7.937.91

(m, 2H), 7.597.55 (m, 2H), 7.517.47 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t, J =

7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.13 (t, J = 34.9 Hz), 164.11, 148.55,

138.56, 137.11, 136.47, 135.13, 133.84 (t, J = 3.7 Hz), 132.14, 130.12, 127.74, 126.80

(t, J = 8.9 Hz), 125.25, 124.75 (t, J = 2.0 Hz), 122.55, 122.51 (t, J = 24.4 Hz), 114.92,

113.99 (t, J = 251.2 Hz), 63.39, 13.80. HRMS (ESI) ([M+H]+) Calcd. For

C20H16ClF2N2O3: 405.0812, Found: 405.0815.

11

Ethyl 2-(8-(3-bromobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3o). White solid


8.928.88 (m, 2H), 8.68 (d, J = 8.5 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91

(d, J = 8.3 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.56 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H),

7.437.39 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR (100

MHz, CDCl3) δ: 164.10 (t, J = 34.9 Hz), 163.92, 148.53, 138.51, 137.07, 136.61, 135.04,

133.80 (t, J = 3.7 Hz), 130.64, 130.31, 126.77 (t, J = 9.0 Hz), 125.65, 124.71 (t, J = 2.0

Hz), 123.09, 122.53, 122.47 (t, J = 24.4 Hz), 114.89, 113.97 (t, J = 251.2 Hz), 63.37,

13.79. HRMS (ESI) ([M+H]+) Calcd. For C20H16BrF2N2O3: 449.0307, Found:

449.0304.

Ethyl 2,2-difluoro-2-(8-(3-(trifluoromethyl)benzamido)quinolin-5-yl)acetate (3p).



1H), 8.34 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.6 Hz,

1H), 7.727.68 (m, 1H), 7.58 (dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 4.30 (q, J = 7.1 Hz,

2H), 1.27 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.13 (t, J = 34.8 Hz),

164.01, 148.62, 138.57, 137.02, 135.59, 133.89 (t, J = 3.7 Hz), 131.59 (q, J1 = 32.6 Hz,

J2 = 65.3 Hz), 130.26 (d, J = 1.0 Hz), 129.48, 128.66 (q, J1 = 3.5 Hz, J2 = 7.1 Hz),

126.80 (t, J = 9.0 Hz), 125.05, 124.78 (t, J = 1.9 Hz), 124.61 (q, J1 = 3.8 Hz, J2 = 7.6

Hz), 122.70 (t, J = 24.4 Hz), 122.60, 122.34, 115.00, 114.00 (t, J = 251.4 Hz), 63.41,


12

Ethyl 2,2-difluoro-2-(8-(2-methylbenzamido)quinolin-5-yl)acetate (3q). White solid



8.3 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.52 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 7.417.37

(m, 1H), 7.327.28 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.25 (t, J = 7.1 Hz,

3H); 13


137.52, 136.74, 135.97, 133.57 (t, J = 3.7 Hz), 131.38, 130.50, 127.11, 126.70 (t, J =

9.0 Hz), 125.95, 124.64 (t, J = 2.1 Hz), 122.37, 122.10 (t, J = 24.4 Hz), 114.55, 113.97

(t, J = 251.1 Hz), 63.28, 20.08, 13.70. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O3:

385.1358, Found: 385.1362.

Ethyl 2,2-difluoro-2-(8-(2-methoxybenzamido)quinolin-5-yl)acetate (3r). White



J = 7.8 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.517.45 (m, 2H), 7.127.08 (m, 1H), 7.02

(d, J = 8.3 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13

C

NMR (100 MHz, CDCl3) δ: 164.21 (t, J = 35.1 Hz), 163.81, 157.71, 148.25, 139.00,

138.69, 133.37, 133.36 (t, J = 3.8 Hz), 132.32, 126.92 (t, J = 8.9 Hz), 124.74 (t, J = 2.0

Hz), 122.13, 121.86, 121.61 (t, J = 24.3 Hz), 121.22, 115.32, 114.16 (t, J = 250.8 Hz),

111.56, 63.26, 55.99, 13.75. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O4:

401.1307, Found: 401.1304.

13

Ethyl 2,2-difluoro-2-(8-(2-fluorobenzamido)quinolin-5-yl)acetate (3s). White solid

(82.5 mg, 85% yield), m.p. 85–87 °C. 1H NMR (400 MHz, CDCl3) δ: 11.33 (d, J = 12.5

Hz, 1H), 9.00 (d, J = 8.3 Hz, 1H), 8.918.90 (m, 1H), 8.698.66 (m, 1H), 8.238.19 (m,

1H), 7.92 (d, J = 8.3 Hz, 1H), 7.577.53 (m, 2H), 7.367.32 (m, 1H), 7.267.22 (m,

1H), 4.29 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ:

164.19 (t, J = 35.0 Hz), 161.88 (d, J = 3.3 Hz), 160.61 (d, J = 247.9 Hz), 148.61, 138.68

(d, J = 1.0 Hz), 137.76, 133.89 (d, J = 9.2 Hz), 133.61 (t, J = 3.7 Hz), 132.09 (d, J = 1.9

Hz), 126.80 (t, J = 9.0 Hz), 124.92 (t, J = 3.4 Hz), 124.75 (t, J = 2.1 Hz), 122.48 (t, J =

24.4 Hz), 122.46, 121.74 (d, J = 11.4 Hz), 116.38 (d, J = 24.3 Hz), 115.46, 114.05 (t, J =

251.1 Hz), 63.37, 13.81. HRMS (ESI) ([M+H]+) Calcd. For C20H16F3N2O3: 389.1108,

Found: 389.1103.

Ethyl 2-(8-(2-chlorobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3t). White solid



8.3 Hz, 1H), 7.837.81 (m, 1H), 7.55 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 7.527.50 (m,

1H), 7.477.40 (m, 2H), 4.29 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ: 165.04, 164.16 (t, J = 35.0 Hz), 148.53, 138.53, 137.29, 135.38,

133.69 (t, J = 3.7 Hz), 131.77, 131.16, 130.58, 130.20, 127.21, 126.79 (t, J = 9.0 Hz),

124.76 (t, J = 2.1 Hz), 122.63 (t, J = 24.4 Hz), 122.49, 115.14, 113.99 (t, J = 251.2 Hz),

63.39, 13.81. HRMS (ESI) ([M+H]+) Calcd. For C20H16ClF2N2O3: 405.0812, Found:

405.0810.

14

Ethyl 2,2-difluoro-2-(8-(2-(trifluoromethyl)benzamido)quinolin-5-yl)acetate (3u).



1H), 7.94 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H),

7.727.68 (m, 1H), 7.667.62 (m, 1H), 7.54 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 4.29 (q,

J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 166.10,

164.14 (t, J = 34.9 Hz), 148.51, 138.36, 137.17, 135.80 (q, J1 = 2.2 Hz, J2 = 4.3 Hz),

133.77 (t, J = 3.8 Hz), 132.21 (d, J = 1.0 Hz), 130.36, 128.48, 127.71 (q, J1 = 31.9 Hz,

J2 = 63.9 Hz), 126.79 (t, J = 9.0 Hz), 126.73 (q, J1 = 4.9 Hz, J2 = 9.9 Hz), 124.93,

124.77 (t, J = 2.1 Hz), 122.87 (t, J = 24.4 Hz), 122.53, 122.21, 115.16, 113.98 (t, J =

251.2 Hz), 63.42, 13.81. HRMS (ESI) ([M+H]+) Calcd. For C21H16F5N2O3: 439.1076,

Found: 439.1080.

Ethyl 2-(8-(3,5-dimethylbenzamido)quinolin-5-yl)-2,2-difluoroacetate (3v). White


1H), 8.97 (d, J = 8.2 Hz, 1H), 8.908.89 (m, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.92 (d, J =

8.3 Hz, 1H), 7.65 (s, 2H), 7.56 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 7.21 (s, 1H), 4.29 (q,

J = 7.1 Hz, 2H), 2.43 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H); 13


166.00, 164.19 (t, J = 35.0 Hz), 148.40, 138.64, 138.54, 137.61, 134.75, 133.75, 133.72

(t, J = 3.7 Hz), 126.88 (t, J = 9.0 Hz), 125.05, 124.75 (t, J = 2.0 Hz), 122.40, 121.95 (t, J

= 24.4 Hz), 114.73, 114.08 (t, J = 251.1 Hz), 63.33, 21.29, 13.79. HRMS (ESI) ([M+H]+)


15

Ethyl 2-(8-(3,4-dichlorobenzamido)quinolin-5-yl)-2,2-difluoroacetate (3w). White


1H), 8.918.90 (m, 2H), 8.70 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H),

7.88 (d, J = 8.0 Hz, 1H), 7.647.57 (m, 2H), 4.30 (q, J = 6.9 Hz, 2H), 1.26 (t, J = 6.9 Hz,

3H); 13

C NMR (100 MHz, CDCl3) δ: 164.12 (t, J = 34.9 Hz), 163.24, 148.62, 138.54,

136.94, 136.71, 134.52, 133.93 (t, J = 3.7 Hz), 133.53, 130.90, 129.63, 126.81 (t, J =

9.0 Hz), 126.28, 124.79 (t, J = 2.0 Hz), 122.73 (t, J = 24.5 Hz), 122.62, 115.01, 113.98

(t, J = 251.3 Hz), 63.42, 13.83. HRMS (ESI) ([M+H]+) Calcd. For C20H15Cl2F2N2O3:

439.0422, Found: 439.0419.

Ethyl 2-(8-(1-naphthamido)quinolin-5-yl)-2,2-difluoroacetate (3x). White solid (63.0

mg, 60% yield), m.p. 156–157 °C. 1H NMR (400 MHz, CDCl3) δ: 10.60 (s, 1H), 9.09 (d,

J = 8.2 Hz, 1H), 8.78 (d, J = 3.1 Hz, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.52 (d, J = 8.0 Hz,

1H), 8.027.97 (m, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.607.51 (m, 4H), 4.30 (q, J = 7.1

Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 167.84, 164.20 (t, J =

35.0 Hz), 148.44, 138.51, 137.69, 134.16, 133.91, 133.73 (t, J = 3.7 Hz), 131.44, 130.30,

128.44, 127.43, 126.86 (t, J = 9.0 Hz), 126.58, 125.62, 125.40, 124.80, 122.47, 122.41

(t, J = 24.4 Hz), 114.94, 114.06 (t, J = 251.1 Hz), 63.39, 13.83. HRMS (ESI) ([M+H]+)


16

Ethyl 2-(8-(2-naphthamido)quinolin-5-yl)-2,2-difluoroacetate (3y). White solid (60.9


J = 8.2 Hz, 1H), 8.91 (d, J = 3.1 Hz, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.57 (s, 1H),

8.118.08 (m, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.3

Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.617.55 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t, J

= 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 165.58, 164.20 (t, J = 35.0 Hz), 148.45,

138.64, 137.52, 135.03, 133.78 (t, J = 3.7 Hz), 132.69, 131.87, 129.18, 128.76, 128.11,

128.00, 127.76, 126.90 (t, J = 9.0 Hz), 126.87, 124.77 (t, J = 1.9 Hz), 123.55, 122.47,

122.12 (t, J = 24.4 Hz), 114.80, 114.08 (t, J = 251.1 Hz), 63.36, 13.81. HRMS (ESI)


Ethyl 2,2-difluoro-2-(8-(furan-2-carboxamido)quinolin-5-yl)acetate (3z). White


1H), 8.918.89 (m, 2H), 8.68 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H),

7.57 (dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 6.60 (s, 1H), 4.29 (q, J

= 7.0 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 164.19 (t, J =

35.0 Hz), 156.45, 148.54, 148.06, 144.77, 138.51, 137.13, 133.69 (t, J = 3.8 Hz), 126.79

(t, J = 9.0 Hz), 124.78 (t, J = 2.1 Hz), 122.48, 122.25 (t, J = 24.4 Hz), 115.63, 114.83,

114.05 (t, J = 251.2 Hz), 112.55, 63.37, 13.81. HRMS (ESI) ([M+H]+) Calcd. For

C18H15F2N2O4: 361.0994, Found: 361.0994.

Ethyl 2,2-difluoro-2-(8-(thiophene-2-carboxamido)quinolin-5-yl)acetate (3aa).


17

10.74 (s, 1H), 8.888.85 (m, 2H), 8.68 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H),

7.83 (d, J = 3.4 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.56 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz,

1H), 7.207.17 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ: 164.15 (t, J = 35.0 Hz), 160.08, 148.45, 139.58, 138.35, 137.21,

133.77 (t, J = 3.8 Hz), 131.34, 128.80, 127.91, 126.84 (t, J = 9.0 Hz), 124.75 (t, J = 2.0

Hz), 122.49, 122.11 (t, J = 24.4 Hz), 114.67, 114.04, (t, J = 251.1 Hz), 63.35, 13.79.

HRMS (ESI) ([M+H]+) Calcd. For C18H15F2N2O3S: 377.0766, Found: 377.0767.

Ethyl 2-(8-acetamidoquinolin-5-yl)-2,2-difluoroacetate (3ab). White solid (69.3 mg,



7.54 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.25 (t, J

= 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 168.95, 164.19 (t, J = 34.9 Hz), 148.25,

138.10, 137.38, 133.72 (t, J = 3.7 Hz), 126.83 (t, J = 9.0 Hz), 124.69 (t, J = 2.0 Hz),

122.37, 121.91 (t, J = 24.4 Hz), 114.59, 114.05 (t, J = 251.0 Hz), 63.34, 25.11, 13.80.

HRMS (ESI) ([M+H]+) Calcd. For C15H15F2N2O3: 309.1045, Found: 309.1046.

Ethyl 2-(8-butyramidoquinolin-5-yl)-2,2-difluoroacetate (3ac). White solid (79.0 mg,

94% yield), m.p. 110–111 °C. 1H NMR (400 MHz, CDCl3) δ: 9.98 (s, 1H), 8.838.81

(m, 2H), 8.678.64 (m, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.53 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz,

1H), 4.28 (q, J = 7.2 Hz, 2H), 2.57 (t, J = 7.4 Hz, 2H), 1.911.81 (m, 2H), 1.25 (t, J =

7.1 Hz, 3H), 1.07 (t, J = 7.4 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 171.93, 164.17 (t,

J = 35.0 Hz), 148.21, 138.16, 137.41, 133.65 (t, J = 3.7 Hz), 126.82 (t, J = 9.0 Hz),

18

124.67 (t, J = 2.0 Hz), 122.31, 121.74 (t, J = 24.4 Hz), 114.54, 114.04 (t, J = 251.3 Hz),

63.29, 40.09, 18.95, 13.76, 13.69. HRMS (ESI) ([M+H]+) Calcd. For C17H19F2N2O3:

337.1358, Found: 337.1362.

Ethyl 2,2-difluoro-2-(8-pivalamidoquinolin-5-yl)acetate (3ad). White solid (74.4

mg, 85% yield), m.p. 78–79 °C. 1H NMR (400 MHz, CDCl3) δ: 10.45 (s, 1H),

8.868.83 (m, 2H), 8.678.64 (m, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.54 (dd, J1 = 4.2 Hz,

J2 = 8.7 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.43 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H); 13

C

NMR (100 MHz, CDCl3) δ: 177.51, 164.24 (t, J = 35.1 Hz), 148.36, 138.68, 137.63 (t, J

= 2.2 Hz), 133.70 (t, J = 3.8 Hz), 126.89 (t, J = 9.0 Hz), 124.72 (t, J = 2.1 Hz), 122.32,

121.70 (t, J = 24.4 Hz), 114.45, 114.09 (t, J = 251.0 Hz), 63.30, 40.47, 27.65, 13.80.

HRMS (ESI) ([M+H]+) Calcd. For C18H21F2N2O3: 351.1515, Found: 351.1511.

Ethyl 2,2-difluoro-2-(8-(3-phenylpropanamido)quinolin-5-yl)acetate (3ae). White


1H), 8.828.79 (m, 2H), 8.64 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.52 (dd, J1

= 4.1 Hz, J2 = 8.7 Hz, 1H), 7.307.29 (m, 4H), 7.227.19 (m, 1H), 4.27 (q, J = 7.1 Hz,

2H), 3.14 (t, J = 7.4 Hz, 2H), 2.90 (t, J = 8.2 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13

C


137.29, 133.69 (t, J = 3.8 Hz), 128.57, 128.36, 126.83 (t, J = 8.9 Hz), 126.30, 124.68 (t,

J = 2.1 Hz), 122.36, 121.92 (t, J = 24.4 Hz), 114.66, 114.05 (t, J = 251.1 Hz), 63.33,

39.68, 31.31, 13.80. HRMS (ESI) ([M+H]+) Calcd. For C22H21F2N2O3: 399.1515, Found:

399.1519.

19

Ethyl 2-(8-(cyclopropanecarboxamido)quinolin-5-yl)-2,2-difluoroacetate (3af).



1H), 7.85 (d, J = 8.3 Hz, 1H), 7.52 (dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 4.28 (q, J = 7.1

Hz, 2H), 1.851.79 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.181.16 (m, 2H), 0.950.92 (m,

2H); 13


137.49, 133.60, 126.80 (t, J = 8.9 Hz), 124.65, 122.30, 121.54 (t, J = 24.5 Hz), 114.48,

114.04 (t, J = 251.2 Hz), 63.27, 16.25, 13.74, 8.35. HRMS (ESI) ([M+H]+) Calcd. For

C17H17F2N2O3: 335.1202, Found: 335.1198.

Ethyl 2-(8-(cyclohexanecarboxamido)quinolin-5-yl)-2,2-difluoroacetate (3ag).


10.07 (s, 1H), 8.848.82 (m, 2H), 8.65 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H),

7.53 (dd, J1 = 4.1 Hz, J2 = 8.6 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H), 2.522.46 (m, 1H),

2.102.07 (m, 2H), 1.891.86 (m, 2H), 1.751.73 (m, 1H), 1.681.60 (m, 2H),

1.441.28 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 174.99,

164.14 (t, J = 35.0 Hz), 148.19, 138.29, 137.51, 133.60 (t, J = 3.5 Hz), 126.79 (t, J = 9.0

Hz), 124.63, 122.27, 121.62 (t, J = 24.5 Hz), 114.53, 114.02 (t, J = 251.1 Hz), 63.25,

46.79, 29.61, 25.67, 25.62, 13.73. HRMS (ESI) ([M+H]+) Calcd. For C20H23F2N2O3:

377.1671, Found: 377.1668.

20

Ethyl 2-(8-acetamido-2-methylquinolin-5-yl)-2,2-difluoroacetate (3ah). White solid



8.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.73 (s, 3H), 2.36 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ: 168.85, 164.22 (t, J = 35.1 Hz), 157.48, 137.52, 136.71,

133.58 (t, J = 3.6 Hz), 125.61 (t, J = 9.0 Hz), 123.18, 122.73, 121.74 (t, J = 24.3 Hz),

114.51, 114.12 (t, J = 250.9 Hz), 63.23, 25.07, 24.96, 13.75. HRMS (ESI) ([M+H]+)


Ethyl 2-(8-benzamido-2-methylquinolin-5-yl)-2,2-difluoroacetate (3ai). Yellow solid


8.92 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.07-8.05 (m, 2H), 7.84 (d, J = 8.3 Hz,

1H), 7.597.53 (m, 3H), 7.41 (d, J = 8.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.77 (s, 3H),

1.25 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 165.38, 164.24 (t, J = 35.0 Hz),

157.54, 138.08, 136.79, 134.85, 133.72 (t, J = 3.5 Hz), 132.01, 128.83, 127.23, 125.72

(t, J = 8.9 Hz), 123.26, 122.82, 121.98 (t, J = 24.4 Hz), 114.70, 114.13 (t, J = 251.0 Hz),

63.27, 25.16, 13.78. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O3: 385.1358, Found:

385.1356.

21

Ethyl 2-(8-acetamido-4-methylquinolin-5-yl)-2,2-difluoroacetate (3aj). Yellow solid



4.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.73 (s, 3H), 2.35 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ: 168.94, 164.55 (t, J = 35.2 Hz), 147.53, 147.05, 144.50,

139.27, 138.04, 128.96 (t, J = 12.0 Hz), 126.19, 121.34 (t, J = 23.7 Hz), 114.98 (t, J =

248.8 Hz), 113.81, 63.39, 25.17, 23.88 (t, J = 9.3 Hz), 13.77. HRMS (ESI) ([M+H]+)


Ethyl 2-(8-benzamido-4-methylquinolin-5-yl)-2,2-difluoroacetate (3ak). Yellow



J = 8.4 Hz, 1H), 7.567.50 (m, 3H), 7.34 (d, J = 4.1 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H),

2.73 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 165.42, 164.50 (t,

J = 34.9 Hz), 147.19, 144.51, 139.73, 138.07, 134.76, 131.95, 128.91 (t, J = 12.0 Hz),

128.72, 127.23, 126.25, 126.11, 121.54 (t, J = 23.8 Hz), 114.95 (t, J = 248.9 Hz), 113.92,

63.37, 23.83 (t, J = 9.1 Hz), 13.74. HRMS (ESI) ([M+H]+) Calcd. For C21H19F2N2O3:

385.1358, Found: 385.1360.

Ethyl 2-(8-acetamido-4-chloroquinolin-5-yl)-2,2-difluoroacetate (3al). Yellow solid



4.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13

C NMR

22

(100 MHz, CDCl3) δ: 168.93, 164.18 (t, J = 34.2 Hz), 146.89, 140.31, 140.24, 137.72,

129.39 (t, J = 13.6 Hz), 124.96, 124.11, 121.00 (t, J = 23.2 Hz), 115.20, 113.60 (t, J =

248.8 Hz), 63.14, 25.14, 13.73. HRMS (ESI) ([M+H]+) Calcd. For C15H14F2N2O3:

343.0656, Found: 343.0654.

Ethyl 2-(8-benzamido-4-chloroquinolin-5-yl)-2,2-difluoroacetate (3am). Yellow



J = 7.00 Hz, 2H), 7.63 (d, J = 4.7 Hz, 1H), 7.607.53 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H),

1.32 (t, J = 7.2 Hz, 3H); 13


147.11, 140.82, 140.48, 137.85, 134.63, 132.22, 129.49 (t, J = 13.6 Hz), 128.88, 127.33,

125.08, 124.28, 121.28 (t, J = 23.4 Hz), 115.43, 113.64 (t, J = 249.0 Hz), 63.18, 13.78.

HRMS (ESI) ([M+H]+) Calcd. For C20H16ClF2N2O3:405.0812, Found: 405.0808.

Ethyl 2-(8-acetamido-6-methoxyquinolin-5-yl)-2,2-difluoroacetate (3an). Gray solid


8.72 (d, J = 8.8 Hz, 1H), 8.65-8.63 (m, 2H), 7.45 (dd, J1 = 4.1 Hz, J2 = 8.8 Hz, 1H),

4.38 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 2.35 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ: 169.23, 164.09 (t, J = 32.5 Hz), 156.64 (t, J = 6.5 Hz), 145.93,

138.84, 134.07, 133.15 (t, J = 8.0 Hz), 126.62, 122.88, 114.42 (t, J = 245.5 Hz), 107.23

(t, J = 24.6 Hz), 103.30, 62.65, 56.95, 25.07, 13.92. HRMS (ESI) ([M+H]+) Calcd. For

C16H17F2N2O4: 339.1151, Found: 339.1146.

23

Ethyl 2-(8-benzamido-6-methoxyquinolin-5-yl)-2,2-difluoroacetate (3ao). Yellow


1H), 8.84 (s, 1H), 8.76 (d, J = 8.8 Hz, 1H), 8.70 (d, J = 3.7 Hz, 1H), 8.05 (d, J = 7.1 Hz,

2H), 7.587.52 (m, 3H), 7.48 (dd, J1 = 4.1 Hz, J2 = 8.8 Hz, 1H), 4.40 (q, J = 7.2 Hz,

2H), 3.98 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ: 165.61,

164.09 (t, J = 32.6 Hz), 156.68 (t, J = 6.3 Hz), 146.11, 138.90, 134.58, 134.28, 133.20 (t,

J = 8.0 Hz), 132,21, 128.81, 127.17, 126.69, 122.97, 114.46 (t, J = 245.3 Hz), 107.46 (t,

J = 24.5 Hz), 103.43, 62.66, 56.95, 13.93. HRMS (ESI) ([M+H]+) Calcd. For

C21H19F2N2O4: 401.1307, Found: 401.1303.

Ethyl 2,2-difluoro-2-(7-methyl-8-pivalamidoquinolin-5-yl)acetate (3ap). Yellow

solid (33.7 mg, 37% yield), m.p. 84–86 °C. 1H NMR (400 MHz, CDCl3) δ: 9.22 (s, 1H),

8.84-8.82 (m, 1H), 8.59-8.57 (m, 1H), 7.77 (s, 1H), 7.43 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz,

1H), 4.26 (q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.45 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H); 13

C


133.12 (t, J = 3.5 Hz), 131.44, 129.47 (t, J = 8.8 Hz), 124.27 (t, J =23.9 Hz), 123.03 (t, J

= 1.9 Hz), 121.28, 113.89 (t, J = 251.4 Hz), 63.35, 40.05, 27.72, 20.38, 13.76. HRMS

(ESI) ([M+H]+) Calcd. For C16H17F2N2O3: 365.1671, Found: 365.1668.

Ethyl 2-(8-benzamido-7-methylquinolin-5-yl)-2,2-difluoroacetate (3aq). White solid

24


8.80 (d, J = 3.2 Hz, 1H), 8.61 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.84 (s, 1H),

7.617.57 (m, 1H), 7.547.51 (m, 2H), 7.44 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 4.28 (q,

J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13


165.68, 164.08 (t, J = 34.8 Hz), 149.12, 142.30, 135.03, 134.46, 133.29 (t, J = 3.5 Hz),

132,11, 131.43, 129.67 (t, J = 8.9 Hz), 128.74, 127.88, 124.57 (t, J = 24.1 Hz)，123.12，

121.47，113.87 (t, J = 251.3 Hz), 63.44, 20.77, 13.80. HRMS (ESI) ([M+H]+) Calcd.

For C21H19F2N2O4: 385.1358, Found: 385.1353.

Methyl 2-(8-benzamidoquinolin-5-yl)-2,2-difluoroacetate (4a). White solid (35.6


J = 8.2 Hz, 1H), 8.90 (d, J = 3.2 Hz, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 6.9 Hz,

2H), 7.93 (d, J = 8.3 Hz, 1H), 7.617.55 (m, 4H), 3.84 (s, 3H); 13

C NMR (100 MHz,

CDCl3) δ: 165.61, 164.73 (t, J = 35.4 Hz), 148.48, 138.68, 137.60, 134.76, 133.74 (t, J

= 3.8 Hz), 132.16, 128.89, 127.36, 126.94 (t, J = 9.0 Hz), 124.80 (t, J = 2.1 Hz), 122.59,

121.98 (t, J = 24.4 Hz), 114.79, 114.08 (t, J = 251.0 Hz), 53.75. HRMS (ESI) ([M+H]+)


Methyl 2-(8-acetamidoquinolin-5-yl)-2,2-difluoroacetate (4b). White solid (31.6 mg,



7.53 (dd, J1 = 4.1 Hz, J2 = 8.7 Hz, 1H), 3.83 (s, 3H), 2.37 (s, 3H); 13

C NMR (100 MHz,

CDCl3) δ: 168.95, 164.65 (t, J = 35.4 Hz), 148.23, 138.00, 137.41, 133.55, (t, J = 3.6

25

Hz), 126.78 (t, J = 9.0 Hz), 124.60, 122.44, 121.64 (t, J = 24.3 Hz), 114.51, 114.00 (t, J

= 251.1 Hz), 53.71, 25.09. HRMS (ESI) ([M+H]+) Calcd. For C14H13F2N2O3: 295.0889,

Found: 295.0886.

N-(5-(1,1-difluoro-2-morpholino-2-oxoethyl)quinolin-8-yl)benzamide (4c). White


1H), 8.96 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 3.1 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H),

8.098.07 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.627.54 (m, 4H), 3.71 (m, 4H),

3.593.53 (m, 4H); 13


148.59, 138.63, 137.43, 134.56, 133.98, 132.13, 128.81, 127.26, 126.15 (t, J = 8.2 Hz),

125.04, 122.84 (t, J = 24.0 Hz), 122.57, 116.26 (t, J = 250.1 Hz), 114.26, 66.62, 66.36,


412.1464.

N-(5-(1,1-Difluoro-2-morpholino-2-oxoethyl)quinolin-8-yl)acetamide (4d). White



J = 8.3 Hz, 1H), 7.54 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 3.71 (br, 4H), 3.573.52 (m,

4H), 2.37 (s, 3H); 13


148.42, 138.15, 137.39, 133.95, 126.14 (t, J = 8.3 Hz), 125.00, 122.67 (t, J = 24.0 Hz),

122.47, 116.29 (t, J = 250.1 Hz), 114.14, 66.64, 66.38, 46.88, 43.66, 25.08. HRMS (ESI)


26

N-(5-(Perfluorohexyl)quinolin-8-yl)benzamide (4e). Yellow solid (80.6 mg, 57%

yield), m.p. 127–130 °C. 1H NMR (400 MHz, CDCl3) δ: 10.98 (s, 1H), 9.01 (d, J = 8.4

Hz, 1H), 8.89 (d, J = 3.3 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 7.0 Hz, 2H),

7.92 (d, J = 8.4 Hz, 1H), 7.627.54 (m, 4H); 13

C NMR (100 MHz, CDCl3) δ: 165.65,

148.48, 138.63, 138.46, 134.62, 133.82, 133.79, 132.25, 129.90 (t, J = 9.5 Hz), 128.90,

127.38, 125.70, 122.79, 117.84 (t, J = 22.9 Hz), 114.52. HRMS (ESI) ([M+H]+) Calcd.

For C22H12F13N2O: 567.0737, Found: 567.0739.

N-(5-(Perfluorohexyl)quinolin-8-yl)acetamide (4f). White solid (69.4 mg, 55% yield),

m.p. 90–91 °C. 1H NMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 8.868.84 (m, 2H), 8.53

(d, J = 6.9 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.57 (dd, J1 = 3.3 Hz, J2 = 7.0 Hz, 1H),

2.39 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ: 169.13, 148.30, 138.47, 137.89, 133.74,

129.82 (t, J = 7.6 Hz), 125.60, 122.70, 117.64 (t, J = 18.4 Hz), 114.35, 25.13. HRMS

(ESI) ([M+H]+) Calcd. For C17H10F13N2O: 505.0580, Found: 505.0576.

27

5. 1H and

13C NMR spectra of the products

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

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

Documents

Nickel-Catalyzed Site-Selective C−H Bond Difluoroalkylation · China, Tel:+86-561-3802-069, Fax:+86-561-3090-518, E-mail: [email protected] ‡ State Key Laboratory of Organometallic