Supporting Information · Supporting Information Superelectrophilic Csp3-H bond fluorination of...

Supporting Information

Superelectrophilic Csp3-H bond fluorination of aliphatic amines in superacid: The striking role of ammonium-carbenium dications

M. Artault,a N. Mokhtari,a T. Cantin,a A. Martin-Mingota and S. Thibaudeau*a

a Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers,

CNRS, Superacid Group in Organic Synthesis Team, F-86073 Poitiers, France

[email protected]

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2020

mailto:[email protected]

2

A. General method................................................................4

B. Experimental procedures and characterization data .......8Compound 2a ....................................................................................................8

Compound 2b..................................................................................................11

Compound 3a ..................................................................................................13

Compound 2e ..................................................................................................15

Compound 2f...................................................................................................18

Compound 2g ..................................................................................................21

Compound 2h..................................................................................................24

Compound 2i ...................................................................................................27

Compound 2j ...................................................................................................30

Compound 2h..................................................................................................32

Compound 2l ...................................................................................................33

Compound 2m.................................................................................................34

Compound 2n..................................................................................................37

Compound 2o..................................................................................................40

Compound 2p..................................................................................................43

Compound 2q..................................................................................................46

Compound 3r...................................................................................................49

Compound 3s ..................................................................................................50

Compound 3t...................................................................................................52

Compound 3u..................................................................................................54

Compound 4a ..................................................................................................56

Compound 5a ..................................................................................................58

Compound 6a ..................................................................................................60

Compound 4v ..................................................................................................63

3

Compound 7a ..................................................................................................66

Compound 2w .................................................................................................68

Compound 2y ..................................................................................................71

C. 1H and 13C in situ NMR spectra .......................................73CCl4 in solution of HF/SbF5 ..............................................................................73

Isopentylamine in solution of HF/SbF5 with CCl4.............................................74

4

A. General methodThe authors draw the reader’s attention to the dangerous features of superacidic chemistry.

Handling of hydrogen fluoride and antimony pentafluoride must be done by experienced

chemists with all the necessary safety arrangements in place.

Reactions performed in superacid were carried out in a sealed Teflon® flask with a magnetic

stirrer. No further precautions have to be taken to prevent mixture from moisture (test

reaction worked out in anhydrous conditions leads to the same results as expected).

The separation of the reaction crudes is carried out by manual flash chromatography or using

a Combiflash Rf200 device equipped with UV (254 nm) and ELSD detectors. TLC was carried

out on aluminium sheets precoated with silica gel (Merk); the spots were visualized under UV

light (=254 nm). Yields refer to isolated pure products.

All 1H NMR, 13C NMR, and 19F NMR spectra were respectively recorded at 400 (or 500) MHz,

100 (or 125) MHz and 376 (or 471) MHz on Avance Nandbay 400 MHz and Avance Neo Avance

III 1BAY spectrometers, using a convenient deuterated solvent (reported in the

characterization charts) and the residual peak of CDCl3 for 1H NMR as reference and C6F6 as

external standard for 19F NMR. Data are presented as follows: chemical shift, integration,

multiplicity (bs = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, quint. =

quintuplet, sex = sextuplet, m = multiplet), and coupling constant (J/Hz). All melting points

were determined in a capillary tube with a device Büchi melting point B-545 and high-

resolution mass-spectra were obtained on a Waters Xevo Qtof spectrometer.

5

General Pathway

YR1 R4

R3

YR1 R4

R3

nn

NuH

Y = O or NR2, n= 1, 2 or 3

1 2, 3, 4, 5, 6, 7

Procedure

Substrates 1 were synthesized according to literature procedure or are commercialy available.

Products 2 refer to fluorinated compounds. Products 3 refer to hydroxylated compounds.

Products 4, 5, 6 and 7 refer to the addition of other nucleophiles.

General procedures for synthesis of substrates 1

Procedure 1:1

The corresponding amine (1.0 equiv.) was dissolved in THF or DMF at 0 °C and sodium hydride

(1.2 equiv., 60% in oil) was added. After 15 min at 0 °C, the corresponding alkyl bromide (1.0

or 2.0 equiv.) was added via syringe during 15 min at 0 °C, then the mixture was stirred at

room temperature until completion by TLC. The mixture reaction was concentred, then water

and dichloromethane or ethyl acetate were added. The aqueous phase was separated and

extracted with additional portions of solvent. The combined organic phases were dried with

MgSO4, filtrered, and concentrated to give the corresponding product after purification by

flash chromatography.

Procedure 2:2

The corresponding acyl chloride (1.0 equiv.) was dissolved in DCM under nitrogen atmosphere

at 0 °C and then corresponding amine (1.5 equiv.) was added via syringe. After 10 min at 0 °C,

Et3N (3.0 equiv.) was added via syringe. The mixture was stirred for 12 hours at room

temperature. The crude reaction was quenched by aqueous NH4Cl and washed with HCl aq.

1 Y. Yu, Q. Tang, Z. Xu, S. Li, M. Jin, Z. Zhao, C. Dong, S. Wu, H.B. Zhou, Eur. J. Med. Chem. 2018, 159, 206-216.2 I. Buslov, X. Hu, Adv. Synth. Catal. 2014, 356, 3325–3330.

6

(2M). Then, after extraction with DCM, the organic phase was washed with brine and dried

over MgSO4, filtered and concentrated to give the corresponding product after purification by

flash chromatography.

General procedures for synthesis of products

Procedure A:

To a mixture of HF/SbF5 (22 mol% SbF5) maintained at -40 °C in a Teflon® flask, was

successively added the substrate and the carbon tetrachloride (CCl4, 1.2 equiv.). The reaction

mixture was magnetically stirred at the same temperature for 30 min. A mixture of

hydrofluoric acid and pyridine (70/30 w/w) was then added. The mixture was magnetically

stirred at the same temperature for 1 hour. The reaction mixture was then neutralized with

water/ice and sodium carbonate and then extracted with dichloromethane (X3). The

combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The

products were isolated by column chromatography over silica gel.

Procedure A’:

To a mixture of HF/SbF5 (22 mol% SbF5) maintained at the required temperature in a Teflon®

flask, was successively added the substrate and the carbon tetrachloride (CCl4, 2.4 equiv.). The

reaction mixture was magnetically stirred at the same temperature for 30 min. A mixture of

hydrofluoric acid and pyridine (70/30 w/w) was then added. The mixture was magnetically

stirred at the same temperature for 1 hour. The reaction mixture was then neutralized with

water/ice and sodium carbonate and then extracted with dichloromethane (X3). The

combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The

products were isolated by column chromatography over silica gel.

Procedure B:



mixture was magnetically stirred at the same temperature for 10 min, then the nucleophilic

partner was added and the reaction mixture was magnetically stirred at 0 °C during 15 min.

7

The reaction mixture was then neutralized with water/ice and sodium carbonate and then

extracted with dichloromethane (X3). The combined organic phases were dried (MgSO4),

filtered and concentrated in vacuo. The products were isolated by column chromatography

over silica gel.

Procedure C:



mixture was magnetically stirred at the same temperature for 30 min, then at room

temperature for 24 hours. The reaction mixture was then neutralized with water/ice and

sodium carbonate and then extracted with dichloromethane (X3). The combined organic

phases were dried (MgSO4), filtered and concentrated in vacuo. The products were isolated

by column chromatography over silica gel.

8

B. Experimental procedures and characterization data

Compound 2a: 1-(4-(3-fluoro-3-methylbutyl)piperazin-1-yl)ethan-1-one

N NO

F

This compound was obtained after reaction of substrate 1a (160 mg, 0.8 mmol), following the

general procedure A with 6 mL of HF/SbF5 and 2 mL of HF/Pyr. The crude reaction mixture was

purified over silica gel with dichloromethane/methanol (98/2) as the eluent, thereby obtaining

compound 2a (121 mg, 69 %) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.61 (t, J = 4.9 Hz, 2H), 3.45 (t, J = 5.1 Hz, 2H), 2.47 (m, 2H),

2.43 (m, 4H), 2.08 (s, 3H), 1.81 (dm, J = 19.2 Hz, 2H), 1.36 (d, J = 21.5 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 169.0 (C), 94.9 (d, J = 164 Hz, C), 53.5 (CH2), 53.2 (d, J = 6

Hz, CH2), 52.9 (CH2), 46.4 (CH2), 41.5 (CH2), 38.3 (d, J = 22 Hz, CH2), 27.0 (d, J = 23 Hz, 2 CH3),

21.5 (CH3).19 F{1H} NMR (376 MHz, CDCl3, ppm) δ: -138.3.

HRMS (ESI): m/z [M+H]+ calc for C11H22FN2O : 217.171068, found 217.171585.

9

1H NMR (400 MHz, CDCl3)

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

5.94

2.32

3.00

6.25

2.06

2.02

1.33

1.38

1.81

1.82

1.84

1.86

2.08

2.40

2.42

2.44

2.46

2.48

2.50

3.45

3.46

3.47

3.60

3.61

3.62

7.26

Chl

orof

orm

-d

13C NMR (100 MHz, CDCl3)

0102030405060708090100110120130140150160170180190200210f1 (ppm)

21.4

6

26.9

127

.15

38.2

238

.45

41.4

946

.38

52.9

653

.32

53.3

853

.55

77.1

6 Ch

loro

form

-d

94.1

095

.75

169.

05

10

19 F{1H} NMR (376 MHz, CDCl3)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.26

11

Compound 2b: N-(3-fluoro-3-methylbutyl)acetamide

NH

OF

This compound was obtained after reaction of 3-fluoro-3-methylbutan-1-amine 1b (150 mg,

1.7 mmol), following the general procedure A with 6 mL of HF/SbF5 and 2 mL of HF/Pyr. The

crude reaction mixture was acetylated in water with an excess of acetyl chloride overnight at

RT and purified over silica gel with dichloromethane/methanol (98/2) as the eluent, thereby

obtaining compound 2b (155 mg, 62 %) as an yellow oil.1H NMR (400 MHz, CDCl3, ppm) δ: 5.88 (s, NH), 3.39 (m, 2H), 1.95 (s, 3H), 1.80 (dt, J = 21.7 Hz,

J = 6.9 Hz, 2H), 1.37 (d, J = 21.7 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 170.0 (C), 96.0 (d, J = 162 Hz, C), 40.0 (d, J = 21 Hz, CH2),

35.4 (d, J = 3 Hz, CH2), 26.8 (d, J = 24 Hz, 2 CH3), 23.4 (CH3).19 F{1H} NMR (376 MHz, CDCl3, ppm) δ: -138.0.

HRMS (ESI): m/z [M+Na]+ calc for C7H14FNNaO : 170.0952, found 170.0955.1H NMR (400 MHz, CDCl3)

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

6.00

2.03

2.99

2.00

0.97

1.35

1.40

1.78

1.79

1.81

1.83

1.85

1.87

1.95

3.39

3.39

3.40

5.88

7.26

12


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

23.4

326

.72

26.9

7

35.4

535

.48

39.9

940

.21

77.1

6 Ch

loro

form

-d

95.2

796

.90

170.

22

19 F{1H} NMR (376 MHz, CDCl3)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.20

13

Compound 3a: 1-(4-(3-hydroxy-3-methylbutyl)piperazin-1-yl)ethan-1-one

N NO

OH

This compound was obtained after reaction of substrate 1a (160 mg, 0.81 mmol), following

the general procedure C with 6 mL of HF/SbF5, the mixture being stirred at -40 °C for 30 min

without addition of HF/Pyridine. The crude reaction mixture was purified over silica gel with

dichloromethane/methanol (98/2) as the eluent, thereby obtaining compound 2a (96 mg,

55%) followed by compound 3a (31 mg, 18%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 5.62 (bs, OH, 1H), 3.58 (m, 2H), 3.43 (t, J = 4.9 Hz, 2H), 2.62

(m, 2H), 2.47 (dt, J = 12.5 Hz, J = 5.0 Hz, 4H), 2.05 (s, 3H), 1.61 (m, 2H), 1.20 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 168.9 (C), 71.1 (C), 54.9 (CH2), 53.2 (CH2), 52.9 (CH2), 46.2

(CH2), 41.4 (CH2), 36.7 (CH2), 29.6 (2CH3), 21.4 (CH3).

HRMS (ESI): m/z [M+H]+ calc for C11H23N2O2: 215.175404, found 215.175853.

14


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.04

2.98

4.01

2.04

1.97

1.99

0.85

1.20

1.60

1.61

1.61

1.63

2.05

2.46

2.47

2.47

2.49

2.61

2.62

2.62

2.64

3.42

3.43

3.44

3.58

5.62

7.26

Chl

orof

orm

-d


0102030405060708090100110120130140150160170180190200210f1 (ppm)

21.3

7

29.6

4

36.7

341

.41

46.2

5

52.9

453

.24

54.9

3

71.0

7

77.1

6 Ch

loro

form

-d

168.

95

15

Compound 2e: 1-(4-(4-fluoro-4-methylpentyl)piperazin-1-yl)ethan-1-one

N NO

F

This compound was obtained after reaction of substrate 1e (65 mg, 0.3 mmol), following the

general procedure A’ with 3 mL of HF/SbF5 and 1 mL of HF/Pyr. The crude reaction mixture

was purified over silica gel with dichloromethane/methanol (98/2) as the eluent, thereby

obtaining compound 2e (70 mg, 82%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.58 (t, J = 4.5 Hz, 2H) 3.43 (t, J = 5.0 Hz, 2H), 2.35 (m, 6H),

2.04 (s, 3H), 1.69-1.55 (m, 4H), 1.31 (d, J = 21.4 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 168.9 (C), 95.4 (d, J = 173 Hz, C), 58.5 (CH2), 53.3 (CH2),

52.8 (CH2), 46.3 (CH2), 41.4 (CH2), 39.0 (d, J = 23 Hz, CH), 26.7 (d, J = 25 Hz, 2 CH3), 21.3 (CH3),

21.3 (d, J = 4 Hz, CH2).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -138.5.


16


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

4.00

3.00

6.05

2.00

2.00

1.28

1.33

1.55

1.55

1.59

2.04

2.30

2.32

2.34

2.35

2.36

2.38

2.38

2.40

2.41

3.42

3.43

3.44

3.57

3.58

3.59

7.26

Chl

orof

orm

-d


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.3

121

.36

21.3

826

.60

26.8

5

38.9

139

.14

41.4

346

.32

52.8

153

.32

58.5

1

77.1

6 Ch

loro

form

-d

94.6

696

.30

168.

95

17

19F{1H} NMR (376 MHz, CDCl3)

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.54

18

Compound 2f: 1-(4-(5-fluoro-5-methylhexyl)piperazin-1-yl)ethan-1-one

N NO

F

This compound was obtained after reaction of substrate 1f (120 mg, 0.5 mmol), following the

general procedure A’ with 3 mL of HF/SbF5 and 2 mL of HF/Pyr. The crude reaction mixture

was purified over silica gel with dichloromethane/methanol (98/2) as the eluent, thereby

obtaining compound 2f (101 mg, 63%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.56 (t, J = 5.1 Hz, 2H), 3.42 (t, J = 5.1 Hz, 2H), 2.39-2.29

(m, 6H), 2.03 (s, 3H), 1.66-1.33 (m, 6H), 1.28 (d, J = 21.5 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 169.0 (C), 95.6 (d, J = 165 Hz, C), 58.4 (CH2), 53.4 (CH2),

52.8 (CH2), 46.3 (CH2), 41.4 (CH2), 41.2 (d, J = 21 Hz, CH2), 27.1 (CH2), 26.6 (d, J = 24 Hz, 2 CH3),

21.8 (d, J = 5 Hz, CH2), 21.3 (CH3). 19 F{1H} NMR (376 MHz, CDCl3, ppm) δ: -137.7.


19


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

5.54

6.07

3.00

6.15

2.00

1.99

1.26

1.31

1.32

1.35

1.37

1.44

1.46

1.52

1.54

1.57

2.03

2.29

2.31

2.33

2.34

2.36

2.37

2.38

2.39

3.41

3.42

3.43

3.55

3.56

3.58

7.26


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.3

321

.86

21.9

226

.53

26.7

827

.06

41.1

541

.38

41.4

246

.30

52.8

253

.38

58.4

0

77.1

6 Ch

loro

form

-d

94.8

296

.45

168.

98

20


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-137

.67

21

Compound 2g: 3-fluoro-3-methyl-N-(4-nitrobenzyl)butan-1-amine

O2N

NH

F

This compound was obtained after reaction of substrate 1e (224 mg, 1.0 mmol), following the

general procedure A’ at -40 °C with 6 mL of HF/SbF5 and 2 mL of HF/Pyr. The crude reaction

mixture was purified over silica gel with petroleum ether/ethyl acetate (9/1) as the eluent,

thereby obtaining compound 2e (220 mg, 92%) as an brown oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 8.16 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 3.90 (s, 2H),

2.76 (app t, J = 7.0 Hz, 2H), 1.85 (dt, J = 22.0, 7.0 Hz, 2H), 1.51 (s, 1H), 1.35 (d, J = 21.5 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 148.3 (C), 147.1 (C), 128.7 (2 CH), 123.7 (2 CH), 95.6 (d, J =

164 Hz, CH), 53.4 (CH2), 44.8 (d, J = 4 Hz, CH2), 41.2 (d, J = 22 Hz, CH2), 27.0 (d, J = 24 Hz, 2 CH3).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -137.9.

HRMS (ESI): m/z [M+H]+ calc for C12H18FN2O2: 241.1347, found 241.1353.

22


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.04

1.06

2.03

1.96

2.03

2.01

2.00

1.33

1.38

1.51

1.80

1.82

1.84

1.85

1.87

1.89

2.74

2.75

2.76

2.77

2.78

3.90

7.26

7.48

7.51

8.15

8.15

8.16

8.17

8.17

8.18


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

26.9

227

.16

41.1

741

.39

44.8

144

.85

53.4

3

76.8

477

.16

77.4

8

94.6

296

.26

123.

72

128.

69

147.

1114

8.32

23


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-137

.85

24

Compound 2h: N-(3-fluoro-3-methylbutyl)-4-nitroaniline

O2N

HN

F

This compound was obtained after reaction of substrate 1d (202 mg, 1.0 mmol), following the



thereby obtaining compound 2d (168 mg, 77%) as an orange oil.


3.38 (dd, J = 12.2, 7.0 Hz, 2H), 1.98 (dt, J = 22.0, 7.0 Hz, 2H), 1.43 (d, J = 22.0 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: : 153.3 (C), 138.1 (C), 126.6 (2 CH), 111.1 (2 CH), 95.6 (d, J

= 164 Hz, C), 39.6 (d, J = 21 Hz, CH2), 39.2 (d, J = 3 Hz, CH2), 26.9 (d, J = 25 Hz, 2 CH3).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -138.0.

HRMS (ESI): m/z [M+ Na]+ calc for C11H15FN2O2Na : 249.1010, found 249.1011.

25


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.04

2.01

0.97

2.01

2.00

1.41

1.46

1.94

1.95

1.97

1.99

2.01

2.03

3.35

3.37

3.38

3.40

4.85

6.51

6.53

7.26

8.06

8.08


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

26.7

927

.04

39.1

439

.17

39.5

539

.76

76.8

477

.16

77.4

8

94.9

896

.62

111.

07

126.

58

138.

09

153.

31

26


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.10

27

Compound 2i: 3-(2-fluoro-2-methylpropyl)pyridine

O2SNH

F

This compound was obtained after reaction of substrate 1i (220 mg, 0.91 mmol), following the



thereby obtaining compound 2i (89 mg, 38%) as a yellow oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 7.68-7.65 (m, 2H), 7.49-7.36 (m, 2H), 4.97 (bs, 1H), 3.09

(dd, J = 13.1, 7.1 Hz, 2H), 2.41 (s, 3H), 1.79 (dt, J = 21.0, 7.1 Hz, 2H), 1.28 (d, J = 21.7 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 139.6 (C), 139.4 (C), 133.5 (CH), 129.1 (CH), 127.5 (CH),

124.3 (CH), 95.5 (d, J = 167 Hz, C), 40.2 (d, J = 22 Hz, CH2), 39.0 (d, J = 4 Hz, CH2), 26.8 (d, J = 24

Hz, 2 CH3,), 21.42 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -138.6.

HRMS (ESI): m/z [M+H]+ calc for C12H18FNO2S: 260.1115, found 260.1116.

28


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.04

3.05

1.94

0.99

1.92

1.90

1.25

1.31

1.51

1.74

1.76

1.78

1.80

1.81

1.83

2.41

3.07

3.08

3.10

3.12

4.97

4.98

7.26

7.38

7.38

7.39

7.65

7.66

7.67

7.68


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.4

226

.65

26.8

9

38.9

939

.03

40.0

740

.29

76.8

477

.16

77.4

8

94.6

496

.28

124.

2612

7.50

129.

0813

3.55

139.

4513

9.60

29


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.61

30

Compound 2j: 3-(2-fluoro-2-methylpropyl)pyridine

NF

This compound was obtained after reaction of substrate 1j (140 mg, 1.0 mmol), following the



thereby obtaining compound 2j (115 mg, 73%) as a yellow oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 8.58 -8.35 (m, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.20 (dd, J = 7.7,

4.8 Hz, 1H), 2.86 (d, J = 21.4 Hz, 2H), 1.31 (d, J = 21.2 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 151.3 (CH), 148.1 (CH), 137.8 (CH), 132.5 (CH), 123.2 (CH),

94.8 (d, J = 169 Hz, C) 44.6 (d, J = 23 Hz, CH2), 26.6 (d, J = 24 Hz, 2 CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -139.6.

HRMS (ESI): m/z [M+H]+ calc for C9H13FN: 154.1031, found 154.1026.


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.00

0.94

0.97

1.99

1.28

1.33

2.83

2.89

7.19

7.20

7.20

7.22

7.26

7.53

7.55

8.43

8.47

8.47

31


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

26.5

126

.76

44.5

244

.75

76.8

477

.16

77.4

8

93.9

395

.61

123.

20

132.

51

137.

83

148.

1515

1.28


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-138

.62

32

Compound 2h: 1-(4-(2,2-difluoropropyl)piperazin-1-yl)ethanone

NN

O

FF

This compound was obtained after reaction of substrate 1h (60 mg, 0.38 mmol), following the

general procedure C with 2 mL of HF/SbF5. The crude reaction mixture was purified over silica

gel with dichloromethane/NH3 in MeOH (98/2) as the eluent, thereby obtaining compound 2h

(38 mg, 63%) as a yellow oil. The spectroscopic data correspond to those previously described

in the literature.3

1H NMR (400 MHz, CDCl3, ppm) δ: 3.62 – 3.56 (m, 2H), 3.45 – 3.40 (m, 2H), 2.66 (t, J = 13.4 Hz,

2H), 2.60 – 2.51 (m, 4H), 2.05 (s, 3H), 1.62 (t, J = 18.7 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 169.1 (C), 124.0 (t, J = 239 Hz, C), 62.5 (t, J = 28.5 Hz, CH2),

54.1 (CH2), 53.9 (CH2), 46.4 (CH2), 41.6 (CH2), 21.9 (t, J = 26.5 Hz, CH3), 21.3 (CH3).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -92.2.

HRMS (ESI): m/z [M+H]+ calc for C9H15FN2O: 186.117, found 186.118

3 F. Liu, A. Martin-Mingot, M.-P. Jouannetaud, C. Bachmann, G. Frapper, F. Zunino and S. Thibaudeau, J. Org. Chem. 2011, 76, 1460.

33

Compound 2l: 1-(4-(3,3-difluoropropyl)piperazin-1-yl)ethanone

NN

O

F

F

This compound was obtained after reaction of substrate 1l (334.5 mg, 1.6 mmol), following

the general procedure C with 6 mL of HF/SbF5. The crude reaction mixture was purified over

silica gel with dichloromethane/NH3 in MeOH (7.5 % M) (98/2) as the eluent, thereby

obtaining compound 2l (254 mg, 77%) as a brown oil. The spectroscopic data correspond to

those previously described in the literature.3

1H NMR (400 MHz, CDCl3, ppm) δ: 5.87 (tt, J= 56.7 Hz, J = 4.5 Hz, 1H), 3.55 (app t, J = 4.9 Hz,

2H), 3.41 (app t, J = 5.0 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 2.40 (app t, J = 5.1 Hz, 2H), 2.36 (app t,

J = 5.1 Hz, 2H), 2.03 (s, 3H), 2.01-1.93 (m, 2H).13C NMR (100 MHz, CDCl3, ppm) δ: 169.1 (C), 116.4 (t, J = 239 Hz, CH), 53.3 (CH2), 52.6 (CH2),

51.3 (t, J = 6 Hz, CH2), 46.2 (CH2), 41.3 (CH2), 31.6 (t, J = 21 Hz, CH2), 21.3 (CH3). 19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -117.0.

HRMS (ESI): m/z [M+H]+ calc for C9H16F2N2O: 206.123, found 206.123

34

Compound 2m: N-(3,3-difluoropropyl)-4-nitroaniline

O2N

HN F

F

This compound was obtained after reaction of substrate 1m (50 mg, 0.23 mmol), following the

general procedure C with 2 mL of HF/SbF5. The crude reaction mixture was purified over silica

gel with petroleum ether/ethyl acetate (8/2) as the eluent, thereby obtaining compound 2m

(42 mg, 84%) as a yellow solid.

1H NMR (400 MHz, CDCl3, ppm) δ: 8.10 (m, 2H), 6.56 (d, J = 9.2 Hz, 2H), 5.99 (tt, J = 56.0, 4.0

Hz, 1H), 4.62 (s, 1H), 3.48 (m, 2H), 2.22 (ttd, J = 17.6, 6.7, 4.0 Hz, 2H).13C NMR (100 MHz, CDCl3, ppm) δ: 152.8 (C), 138.7 (C), 126.6 (CH), 116.0 (CH, t, J = 240 Hz),

111.3 (CH), 36.9 (t, J = 6 Hz, CH2), 33.5 (t, J = 21 Hz, CH2).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -116.6.

Mp: 46.6-47.9 °C.

HRMS (ESI): m/z [M+H]+ calc for C9H11F2N2O2: 217.0783, found 217.0788.

35


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

2.00

2.08

1.00

1.07

2.07

2.08

1.58

2.17

2.18

2.20

2.21

2.21

2.22

2.23

2.24

2.26

2.27

3.46

3.47

3.49

3.50

4.62

5.84

5.85

5.86

5.98

5.99

6.00

6.12

6.13

6.14

6.54

6.55

6.55

6.57

6.57

7.26

8.08

8.09

8.10

8.11

8.12

8.12


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

33.3

233

.53

33.7

436

.89

36.9

537

.01

76.8

477

.16

77.3

677

.48

111.

3211

3.67

116.

0511

8.43

126.

59

138.

70

152.

76

36


-300-280-260-240-220-200-180-160-140-120-100-80-60-40-2001020f1 (ppm)

-116

.60

37

Compound 2n: 1-(3-fluoro-3-methylbutyl)-4-methylpiperidine

NF

This compound was obtained after reaction of substrate 1n (178 mg, 1.0 mmol), following the

general procedure A at -40 °C with 6 mL of HF/SbF5 and 2 mL of HF/Pyr. The crude reaction

mixture was purified over silica gel with dichloromethane/methanol (98/2) as the eluent,

thereby obtaining compound 2n (80 mg, 43%) as a yellow oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.22 (d, J = 11.7 Hz, 2H), 2.87-2.78 (m, 2H), 2.44 (t, J = 10.8

Hz, 2H), 2.14-2.00 (m, 2H), 1.74-1.61 (m, 4H), 1.55-1.47 (m, 1H), 1.31 (d, J = 21.4 Hz, 6H), 0.92

(d, J = 6.4 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 93.9 (d, J = 167 Hz, C), 53.5 (2 CH2), 54.2 (d, J = 5 Hz, CH2),

37.7 (d, J = 22 Hz, CH2), 30.9 (2 CH2), 29.5 (CH), 26.5 (d, J = 24 Hz, 2 CH3), 21.0 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -141.5.

HRMS (ESI): m/z [M+H]+ calc for C11H23FN: 188.1809, found 188.1813.

38


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

6.09

1.05

4.01

2.04

2.02

1.99

1.98

0.91

0.92

0.94

1.17

1.29

1.34

1.49

1.51

1.52

1.53

1.54

1.62

1.64

1.69

1.72

1.74

2.06

2.07

2.44

2.46

2.79

2.81

2.84

3.21

3.24

7.26


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.0

1

26.7

827

.02

29.5

630

.92

34.5

934

.81

53.2

253

.27

53.5

1

93.0

394

.70

39


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-141

.49

40

Compound 2o: 3-fluoro-3-methyl-N-(1-(4-nitrophenyl)ethyl)butan-1-amine

O2N

NH

F

This compound was obtained after reaction of substrate 1o (100 mg, 0.42 mmol), following

the general procedure A at -40 °C with 6 mL of HF/SbF5 and 2 mL of HF/Pyr. The crude reaction


thereby obtaining compound 2o (74 mg, 68%) as a yellow oil.

1H NMR (500 MHz, CDCl3, ppm) δ: 8.18 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), , 3.96 (d, J =

14.2 Hz, 1H), 3.84 (d, J = 14.2 Hz, 1H), 2.99 (m, 1H), 2.48 (bs, 1H), 1.90 (td, J = 15.8, 7.7 Hz, 1H),

1.60 (ddd, J = 29.6, 15.01, 4.2 Hz, 1H), 1.38 (d, J = 21.6, 17.7 Hz, 3H), 1.33 (d, J =17.4 Hz, 3H),

1.15 (d, J = 6.2 Hz, 3H).13C NMR (125 MHz, CDCl3, ppm) δ: 148.9 (C), 147.2 (C), 129.0 (2 CH), 123.8 (2 CH), 96.4 (d, J =

164 Hz, C), 50.4 (CH2), 49.6 (CH), 47.7 (d, J = 21 Hz, CH2), 41.2 (d, J = 22 Hz, CH2), 28.2 (d, J = 25

Hz, CH3), 26.6 (d, J = 25 Hz, CH3), 21.5 (CH3).19F{1H} NMR (471 MHz, CDCl3, ppm): -137.3.

HRMS (ESI): m/z [M+H]+ calc for C13H20FN2O2: 255.1503, found 255.1511.

41


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.80

5.68

1.03

0.91

1.11

0.82

1.95

1.99

2.00

1.14

1.15

1.32

1.35

1.36

1.39

1.86

1.87

1.89

1.90

1.92

1.94

2.48

2.97

2.98

2.99

3.00

3.83

3.86

3.94

3.97

7.26

7.50

7.52

8.17

8.18


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.4

526

.52

26.7

228

.10

28.3

0

47.6

647

.83

49.5

550

.37

77.1

6

95.7

297

.02

123.

79

129.

03

147.

1714

7.88

42


-220-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-1001020f1 (ppm)

-138

.83

43

Compound 2p: 6-fluoro-2,6-dimethyl-N-(4-nitrobenzyl)heptan-1-amine

O2N

NH F

This compound was obtained after reaction of substrate 1p (90 mg, 0.3 mmol), following the



thereby obtaining compound 2p (60 mg, 62%) as a brown oil.


2,53 (dd, J = 11.5, 5.9 Hz, 2H), 2.41 (dd, J = 11.9, 5.7 Hz, 2H), 1.72-1.38 (m, 6H), 1.33 (d, J = 21.5

Hz, 6H), 1.27-1.07 (m, 2H), 0.93 (d, J = 6.7 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 148.6 (C), 147.2 (C), 128.7 (2 CH), 123.7 (2 CH), 95.8 (d, J =

164 Hz, C), 56.0 (CH2), 53.5 (CH2), 41.8 (d, J = 23 Hz, CH2), 35.2 (CH2), 33.5 (CH), 26.7 (d, J = 25

Hz, CH3), 26.6 (d, J = 25 Hz, CH3), 21.4 (d, J = 5 Hz, CH2), 18.2 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -138.0.

HRMS (ESI): m/z [M+H]+: calc for C16H25FN2O2 : 297.1972, found 297.1987.

44


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.04

5.92

6.07

2.09

2.04

2.04

2.00

0.92

0.94

1.12

1.25

1.30

1.35

1.38

1.39

1.42

1.43

1.53

1.53

1.54

1.55

1.56

1.58

1.59

1.59

1.60

1.61

1.62

1.64

2.39

2.40

2.41

2.43

2.51

2.52

2.54

2.55

3.89

7.50

7.52

8.16

8.19


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

18.2

021

.41

21.4

626

.63

26.7

126

.88

26.9

633

.47

35.2

3

41.6

441

.87

53.4

655

.98

77.1

6

95.0

196

.64

123.

72

128.

72

147.

1614

8.64

45


-220-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-1001020f1 (ppm)

-137

.62

46

Compound 2q: 5-fluoro-2-isopropyl-5-methyl-N-(4-nitrobenzyl)hexan-1-amine

O2N

NH

F

This compound was obtained after reaction of substrate 1q (48 mg, 0.2 mmol), following the



thereby obtaining compound 2q (38 mg, 75%) as a brown oil.


2.60 (dd, J = 11.7, 5.8 Hz, 1H), 2.50 (dd, J = 11.7, 6.3 Hz, 1H), 1.88-1.74 (m, 1H), 1.67-1.40 (m,

6H), 1.34 (d, J = 21.5 Hz, 6H), 0.87 (dd, J = 6.9, 3.5 Hz, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 148.6 (C), 14701 (C), 128.6 (2 CH), 123.6 (2 CH), 95.9 (d, J

= 164 Hz, C) 53.5 (CH2), 50.5 (CH2), 44.5 (CH), 39.4 (d, J = 23 Hz, CH2), 28.5 (CH3), 26.6 (d, J = 26

Hz, 2 CH3), 23.0 (d, J = 5 Hz, CH2), 19.7 (CH3), 19.3 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -138.0.

HRMS (ESI): m/z [M+H]+: calc for: 311.2129, found 311.2143.

47


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.93

3.01

5.99

0.97

1.86

1.91

1.89

1.84

0.88

0.89

0.89

0.90

1.34

1.39

1.54

1.56

1.58

1.58

1.61

2.47

2.49

2.50

2.52

2.58

2.60

2.61

2.63

3.91

7.28

8.19

8.22


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

19.1

419

.57

22.9

523

.00

26.5

326

.78

28.4

6

39.3

139

.53

44.5

2

50.4

553

.53

94.3

496

.71

123.

61

128.

58

146.

9914

8.62

48


-220-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-1001020f1 (ppm)

-137

.97

49

Compound 3r: 2-(3-hydroxy-3-methylbutyl)isoindoline-1,3-dione

N

O

OOH

This compound was obtained after reaction of substrate 1r (180 mg, 0.82 mmol), following



petroleum ether/ethyl acetate (9/1) as the eluent, thereby obtaining compound 3r (180 mg,

93%) as a white solid. The spectroscopic data correspond to those previously described in the

literature.4

Mp: 68 °C.1H NMR (400 MHz, CDCl3, ppm) δ: 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H),

3.86-3.80 (m, 2H), 1.88-1.82 (m, 3H), 1.30 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 168.6 (C), 134.0 (2 CH), 132.3 (C), 123.3 (2 CH), 70.0 (C),

41.5 (CH2), 34.1 (CH2), 29.5 (2 CH3).

HRMS (ESI): m/z [M+Na]+: calc for C13H15NO3Na: 256.0944, found 256.0950.

4 H. Chen, Z. Liu, Y. Lv, X. Tan, H. Shen, H.-Z. Yu and C. Li, Angew. Chem., Int. Ed. 2017, 56, 15411.

50

Compound 3s: N,N-diethyl-4-hydroxy-4-methylpentanamide

O

NOH

This compound was obtained after reaction of substrate 1s (176 mg, 1.06 mmol), following



dichloromethane/methanol (90/10) as the eluent, thereby obtaining compound 3s (183 mg,

98%) as a white solid.

Mp: 85 °C.1H NMR (400 MHz, CDCl3, ppm) δ: 3.65 (m, 4H), 3.39 (t, J = 8.0 Hz, 1H), 2.39 (t, J = 8.0 Hz, 1H),

1.64 (s, 6H), 1.59-1.45 (bs, OH), 1.40 (t, J = 8.0 Hz, 3H), 1.33 (t, J = 8.0 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 178.2 (C), 101.1 (C), 48.1 (CH2), 45.4 (CH2), 34.2 (CH2), 30.8

(CH2), 27.3 (2CH3), 12.6 (CH3), 12.3 (CH3).

HRMS (ESI): m/z [M-OH]+: calc C10H20NO: 170.15394, found 170.15396.

51


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.02

3.00

7.02

1.90

1.83

4.00

1.25

1.31

1.33

1.34

1.38

1.40

1.41

1.64

2.37

2.39

2.41

3.37

3.39

3.41

3.63

3.65

3.66

3.68

7.26


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

12.2

812

.63

27.3

330

.84

34.3

3

45.5

448

.17

76.8

477

.16

77.4

8

101.

19

178.

27

52

Compound 3t: 6,6-dimethyl-2-(4-nitrophenyl)-5,6-dihydro-4H-1,3-oxazine

O2N

N

O

This compound was obtained after reaction of substrate 1t (160 mg, 0.66 mmol), following



petroleum ether/ethyl acetate (8/2) as the eluent, thereby obtaining compound 3t (148 mg,

95%) as a yellow solid.

Mp: 122 °C.1H NMR (400 MHz, CDCl3, ppm) δ: 8.18 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 3.64 (t, J =

6.2 Hz, 2H), 1.77 (t, J = 6.2 Hz, 2H), 1.39 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 153.9 (C), 149.0 (C), 140.5 (C), 128.0 (2 CH), 123.2 (2 CH),

75.3 (C), 41.5 (CH2), 32.6 (CH2), 27.7 (2 CH3).

HRMS (ESI): m/z [M+H]+: calc for C12H15N2O3: 235.1077, found 235.1077.

53


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.07

2.09

2.04

2.03

2.00

1.39

1.76

1.77

1.79

3.63

3.64

3.66

7.26

Chl

orof

orm

-d

8.05

8.08

8.17

8.20


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

27.6

7

32.5

7

41.4

8

75.3

477

.16

Chlo

rofo

rm-d

123.

24

128.

02

140.

54

148.

98

153.

92

54

Compound 3u: 3-hydroxy-3-methylbutyl-4-nitrobenzoate

O2N

O

OOH

This compound was obtained after reaction of substrate 1u (219 mg, 0.9 mmol), following the

general procedure C with 6 mL of HF/SbF5 the mixture being stirred at -40 °C for 30 min


petroleum ether/ethyl acetate (8/2) as the eluent, thereby obtaining the compound 3u (190

mg, 81%) as a white solid.

Mp: 66 °C.1H NMR (400 MHz, CDCl3, ppm) δ: 8.28 (d, J = 8.9 Hz, 2H), 8.18 (d, J = 9.0 Hz, 2H), 4.54 (t, J =

6.9 Hz, 2H), 1.99 (t, J = 6.9 Hz, 2H), 1.73 (bs, 1H), 1.32 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 164.9 (C), 150.6 (C), 135.7 (C), 130.8 (2 CH), 123.7 (2 CH),

70.1 (C), 63.0 (CH2), 41.7 (CH2), 29.9 (2 CH3).

HRMS (ESI): m/z [M+Na]+: calc for C12H15NO5Na: 276.0842, found 276.0847.

55


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

1.07

1.98

1.97

1.92

1.90

1.32

1.73

1.98

1.99

2.01

4.53

4.54

4.56

7.26

8.17

8.20

8.26

8.29


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

29.9

5

41.6

8

62.9

9

70.0

7

76.8

477

.16

77.4

8

123.

69

130.

77

135.

75

150.

60

164.

87

56

Compound 4a: 1-(4-(3-methylbutyl-3-d)piperazin-1-yl)ethan-1-one

NNO

D


general procedure B with 6 mL of HF/SbF5 with 183 µL (1.6 mmol, 2.0 equiv.) of cyclohexane-

d12 as nucleophile. The crude reaction mixture was purified over silica gel with

dichloromethane/methanol (98/2) as the eluent, thereby obtaining an inseparable mixture of

4a/1a (9/1) (152 mg, 92%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.54-3.44 (m, 2H), 3.36-3.30 (m, 2H), 2.34- 2.18 (m, 6H),

1.95 (s, 3H), 1.28-1.21 (m, 2H), 0.76 (s, 6H).13C NMR (100 MHz, CDCl3, ppm): 168.7 (C), 56.3 (CH2), 53.3 (CH2), 52.7 (CH2), 46.1 (CH2), 41.2

(CH2), 35.6 (CH2), 25.9 (t (1: 1: 1), J = 19 Hz, C), 22.4 (2 CH3), 21.4 (CH3).

HRMS (ESI): m/z [M+H]+ calc for C11H22DN2O: 200.1868, found 200.1873.

57


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.09

0.27

3.08

6.17

2.05

2.02

0.76

0.77

1.95

2.20

2.22

2.24

2.24

2.26

2.27

2.28

2.29

2.31

3.32

3.33

3.35

3.48

7.26


-100102030405060708090100110120130140150160170180190200f1 (ppm)

21.1

822

.43

22.5

625

.69

25.8

826

.07

26.3

635

.49

35.6

1

41.2

4

46.1

5

52.7

353

.27

56.6

056

.63

76.8

477

.16

77.4

8

168.

65

58

Compound 5a: 1-(4-(3-methyl-3-phenylbutyl)piperazin-1-yl)ethanone

N NO


the general procedure B with 6 mL of HF/SbF5 and 3 mL of benzene as nucleophile. The crude

reaction mixture was purified over silica gel with dichloromethane/methanol (98/2) as the

eluent, thereby obtaining compound 5a (153 mg, 73%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 7.35-7.25 (m, 4H), 7.19-7.14 (m, 1H), 3.56 (app t, J = 5.0 Hz,

2H) 3.40 (app t, J = 5.0 Hz, 2H), 2.31 (m, 4H), 2.12 (m, 2H), 2.04 (s, 3H), 1.84 (m, 2H), 1.32 (s,

6H).13C NMR (100 MHz, CDCl3, ppm) δ: 168.9 (C), 148.8 (C), 128.3 (CH), 125.8 (CH), 125.7 (CH),

54.7 (CH2), 53.5 (CH2), 53.0 (CH2), 46.3 (CH2), 41.5 (CH2), 41.0 (CH2), 37.0 (C), 29.3 (CH3), 21.4

(CH3).

HRMS (ESI): m/z [M+Na]+ calc for C17H26N2NaO: 297.1937, found 297.1937

59


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

2.11

2.82

1.98

3.96

2.00

1.95

0.92

3.89

1.30

1.32

1.82

1.84

1.86

2.04

2.10

2.12

2.14

2.28

2.30

2.31

2.32

2.33

3.38

3.40

3.41

3.54

3.56

3.57

7.15

7.16

7.17

7.17

7.18

7.18

7.19

7.26

7.27

7.27

7.28

7.29

7.30

7.31

7.31

7.32

7.32

7.33

7.33


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.3

8

29.2

8

36.9

741

.00

41.4

646

.34

52.9

853

.54

54.6

6

76.8

477

.16

77.4

8

125.

7212

5.76

128.

26

148.

76

168.

93

60

Compound 6a: 1-(4-(3-methyl-3-((trifluoromethyl)phenyl)butyl)piperazin-1-yl)ethanone

N NO

CF3


the general procedure B with 6 mL of HF/SbF5 and 3 mL of trifluoromethylbenzene as

nucleophile. The crude reaction mixture was purified over silica gel with

dichloromethane/methanol (98/2) as the eluent, thereby obtaining compound 6a as a mixture

of ortho/meta/para isomers (279 mg, 81%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 8.02-7.40 (m, 4H), 3.55 (m, 2H), 3.40 (m, 2H), 2.35-2.30 (m,

4H), 2.16-2.12 (m, 2H), 2.03 (s, 3H), 1.84-1.89 (m, 2H), 1.34 (s, 6H). 13C NMR (100 MHz, CDCl3, ppm) δ: 168.9 (C), 149.5-134.3 (C), 130.8 (q, J = 33 Hz, C), 133.1-

126.0 (CH), 123.8 (q, J = 272 Hz, CF3), 54.5 (CH2), 53.4 (CH2), 52.8 (CH2), 46.1 (CH2), 41.2 (CH2),

40.6 (CH2), 37.2 (C), 29.0 (CH3), 21.3 (CH3, C-2).19F{1H} NMR (376 MHz, CDCl3, ppm) δ: -62.4, -62.6 and -62.7.

HRMS (ESI): m/z [M+H]+ calc for C18H26F3N2O: 343.1992, found 343.1992.

61


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

5.37

1.77

3.16

1.90

3.42

2.21

2.00

6.80

1.31

1.32

1.32

1.33

1.35

1.36

1.37

1.38

1.57

1.85

1.87

1.88

1.89

1.98

2.01

2.03

2.06

2.13

2.14

2.15

2.17

2.30

2.32

2.33

2.34

2.36

2.46

3.39

3.40

3.41

3.42

3.54

3.55

3.57

7.26

7.41

7.43

7.45

7.46

7.47

7.54

7.55

7.55

7.56

7.57

7.57

7.59

7.59

7.60

7.60

7.61

7.62

7.64

7.72

7.74

7.75

7.75

7.76

7.77

7.77

7.78

7.82

7.84

7.96

7.98

8.02


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.2

326

.76

27.0

028

.94

29.0

037

.13

37.4

640

.56

40.6

041

.18

46.0

4

52.7

953

.33

53.3

554

.33

54.4

2

76.7

577

.07

77.2

777

.39

125.

0512

5.99

126.

7912

6.83

127.

2812

7.73

128.

4012

8.57

128.

8112

8.85

128.

9312

9.01

130.

0113

0.18

130.

5513

0.69

131.

0113

3.05

133.

1113

4.20

136.

5713

8.34

138.

44

149.

48

154.

56

168.

90

194.

8219

5.41

62


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-62.

71-6

2.69

-62.

43

63

Compound 4v: 4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline

HN

F3C

This compound was obtained after reaction of substrate 1v (215 mg, 0.93 mmol), following

the general procedure C with 6 mL, the mixture being stirred at -40 °C for 30 min without

addition of HF/Pyridine. The crude reaction mixture was purified over silica gel with petroleum

ether/ethyl acetate (9/1) as the eluent, thereby obtaining compound 4v (169 mg, 80%) as a

brown oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 7.43 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.46

(d, J = 8.4 Hz, 1H), 4.24 (bs, 1H), 3.46-3.31 (m, 2H), 1.79-1.70 (m, 2H), 1.32 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 146.3 (C), 129.5 (C), 125.5 (q, J = 269 Hz, CF3), 123.9 (q, J =

3.8 Hz, CH), 123.4 (q, J = 3.8 Hz, CH), 118.1 (q, J = 32 Hz, C), 113.4 (CH), 38.2 (CH2), 36.3 (CH2),

31.9 (C), 30.50 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -60.6.

HRMS (ESI): m/z [M+H]+: calc for C12H15F3N: 230.1151, found 230.1157.

64


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

5.98

2.05

2.07

0.97

1.00

1.01

1.05

1.32

1.73

1.75

1.76

3.36

3.37

3.39

4.24

6.45

6.47

7.19

7.19

7.21

7.21

7.26

7.42

7.43


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

30.4

331

.87

36.3

538

.20

76.8

477

.16

77.4

8

113.

3611

7.60

117.

9211

8.24

118.

5612

1.39

123.

3612

3.40

123.

4312

3.47

123.

8712

3.91

123.

9512

3.99

124.

0712

6.76

129.

47

146.

33

65


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-60.

56

66

Compound 7a: N-(4-(4-acetylpiperazin-1-yl)-2-methylbutan-2-yl)acetamide

NNO

HNO


general procedure B with 6 mL of HF/SbF5 and 106 µL of acetonitrile (2.0 mmol, 2.0 equiv.) as

nucleophile. The crude reaction mixture was purified over silica gel with

dichloromethane/methanol (98/2) as the eluent, thereby obtaining compound 7a (210 mg,

81%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 7.26 (bs, NH), 3.62-3.56 (m, 2H), 3.45 (m, 2H), 2.45-2.40

(m, 6H), 2.07 (s, 3H), 1.86 (s, 3H), 1.69 (t, J = 6.4 Hz, 2H), 1.35 (s, 6H).13C NMR (100 MHz, CDCl3, ppm) δ: 169.5 (C), 169.1 (C), 54.2 (CH2), 53.6 (C), 53.3 (CH2), 53.0

(CH2), 46.4 (CH2), 41.6 (CH2), 37.0 (CH2), 26.7 (2 CH3), 24.7 (CH3), 21.4 (CH3).

HRMS (ESI): m/z [M+H]+ calc for C13H26N3O2: 256,2020 found 256.2020.

67


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.02

1.95

2.99

3.07

6.07

2.00

1.94

0.97

1.35

1.86

2.07

2.47

3.45

7.26


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

21.3

924

.68

26.7

1

36.9

541

.58

46.4

3

53.0

153

.35

53.5

954

.24

76.8

477

.16

77.4

8

169.

0616

9.54

68

Compound 2w: N-(3-fluoro-3-methylbutyl)-4-nitro-N-propylaniline

NO2 N

F

This compound was obtained after reaction of substrate 1w (30 mg, 0.12 mmol), following the

general procedure C with 2 mL of HF/SbF5 at 0 °C during 15 min. The crude reaction mixture

was purified over silica gel with petroleum ether/ethyl acetate (9/1) as the eluent, thereby

obtaining compound 2w (13 mg, 40%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 8.10 (d, J = 9.5 Hz, 2H), 6.57 (d, J = 9.5 Hz, 2H), 3.58 – 3.50

(m, 2H), 3.34 – 3.28 (m, 2H), 1.95 – 1.82 (m, 2H), 1.67 (dd, J = 15.4, 7.6 Hz, 2H), 1.43 (d, J =

21.3 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 152.5 (C), 136.7 (C), 126.6 (2 CH), 110.1 (2 CH), 94.6 (C, d,

J = 166.1 Hz), 53.0 (CH2), 46.4 (d, J = 5 Hz CH2), 37.8 (d, J = 24 Hz, CH3), 26.9 (d, J = 24 Hz, CH3),

20.6 (CH2), 11.4 (CH3).19F {1H} NMR (376 MHz, CDCl3, ppm) δ: -141.9.

HRMS (ESI): m/z [M+H]+ calc for C14H22FN3O2: 269,1610 found 269.1610.

69


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.27

6.25

1.94

1.93

1.91

1.93

2.07

2.00

0.96

0.98

0.99

1.40

1.46

1.64

1.66

1.68

1.70

1.86

1.88

1.91

1.92

1.94

1.96

3.30

3.32

3.34

3.53

3.55

3.56

3.56

3.58

6.56

6.58

7.26

Chl

orof

orm

-d

8.09

8.11


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

1.16

11.4

4

20.6

4

26.8

427

.09

37.7

337

.95

46.3

346

.38

53.0

2

77.1

6 Ch

loro

form

-d

93.7

995

.44

110.

15

126.

60

136.

75

152.

50

70


-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-141

.93

71

Compound 2y: 5,5-dimethyl-3-(propylamino)dihydrofuran-2(3H)-one

HN

O

O

This compound was obtained after reaction of substrate 1y (40 mg, 0.12 mmol). following the

general procedure C with 2 mL of HF/SbF5 at 0 °C for 2 h without CCl4. The crude reaction


thereby obtaining compound 2y (24 mg, 60%) as an orange oil.

1H NMR (400 MHz, CDCl3, ppm) δ: 3.72 (dd, J = 10.8, 8.5 Hz, 1H), 2.67 (m, 1H), 2.53 (m, 1H),

2.38 (dd, J = 12.5, 8.5 Hz, 1H), 1.88 (dd, J = 12.2, 11.1 Hz, 1H), 1.55 – 1.46 (m, 2H), 1.46 (s, 3H),

1.37 (s, 3H), 0.91 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm) δ: 176.7 (C), 82.2 (C), 57.9 (CH), 50.2 (CH2), 42.6 (CH2), 29.1

(CH3), 27.6 (CH3), 23.3 (CH2), 11.7 (CH3).

HRMS (ESI): m/z [M+H]+ calc for C9H18NO2: 172.1332 found 172.1333.

72


-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

3.39

2.87

2.83

2.18

1.08

1.07

1.03

0.99

1.00

0.89

0.91

0.93

1.37

1.46

1.49

1.88

1.88

1.91

2.35

2.37

2.38

2.40

2.53

2.55

2.63

2.65

2.67

3.69

3.71

3.72

3.74

7.26


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

11.7

4

23.3

027

.56

29.1

5

42.6

0

50.1

7

57.9

2

76.8

477

.16

77.4

882

.17

176.

73

73

C. 1H and 13C in situ NMR spectra

CCl4 in solution of HF/SbF5

13C NMR spectra of CCl4 (0.12 mL) in solution of HF/SbF5 (1 mL, 22 mol% SbF5) at -40 °C with

acetone-d6 as external reference 13C NMR (100 MHz)

020406080100120140160180200220240260280300320340360380f1 (ppm)

29.4

629

.65

29.8

430

.03

30.2

2

121.

4412

4.64

127.

84

206.

93

236.

23

CCl3+

74

Isopentylamine in solution of HF/SbF5 with CCl4

1H and 13C NMR spectra of isopentylamine 1b (87 mg, 1.0 mmol) with CCl4 (1.2 equiv.) in

solution of HF/SbF5 (1 mL, 22 mol %) at -20 °C with acetone-d6 as external reference

1H NMR (400 MHz)

-1012345678910111213141516171819f1 (ppm)

8.02

2.00

3.09

2.39

3.01

4.59

8.55

9.65

HF

NHH

H

DbHF

13C NMR (100 MHz)

020406080100120140160180200220240260280300320340360380f1 (ppm)

29.83

36.01

45.40

54.20

206.7

6

329.9

4

NHH

H

Db

Supporting Information · Supporting Information Superelectrophilic Csp3-H bond fluorination of...

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