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
Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2020
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:
To a mixture of HF/SbF5 (22 mol% SbF5) maintained at -20 °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 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:
To a mixture of HF/SbF5 (22 mol% SbF5) maintained at -20 °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, 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
13C NMR (100 MHz, CDCl3)
-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
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)
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
13C NMR (100 MHz, CDCl3)
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.
HRMS (ESI): m/z [M+H]+ calc for C12H24FN2O : 231.1867, found 231.1869.
16
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)
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
13C NMR (100 MHz, CDCl3)
-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.
HRMS (ESI): m/z [M+H]+ calc for C13H26FN2O : 245.2024, found 245.2025.
19
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)
5.54
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
13C NMR (100 MHz, CDCl3)
-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
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)
-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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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)
-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
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 2d (168 mg, 77%) as an orange oil.
1H NMR (400 MHz, CDCl3, ppm) δ: 8.07 (d, J = 9.1 Hz, 2H), 6.52 (d, J = 9.1 Hz, 2H), 4.85 (s, 1H),
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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
.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
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 (4/6) as the eluent,
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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
.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
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 (4/6) as the eluent,
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.
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)
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
13C NMR (100 MHz, CDCl3)
-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
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
.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
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)
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
13C NMR (100 MHz, CDCl3)
-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
19F{1H} NMR (376 MHz, CDCl3)
-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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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)
-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
mixture was purified over silica gel with dichloromethane/methanol (98/2) as the eluent,
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
1H NMR (500 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)
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
13C NMR (125 MHz, CDCl3)
-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
19F{1H} NMR (471 MHz, CDCl3)
-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
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 2p (60 mg, 62%) as a brown oil.
1H NMR (400 MHz, CDCl3, ppm) δ: 8.18 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 3.89 (s, 2H),
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
19F{1H} NMR (376 MHz, CDCl3)
-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
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 (7/3) as the eluent,
thereby obtaining compound 2q (38 mg, 75%) as a brown oil.
1H NMR (400 MHz, CDCl3, ppm) δ: 8.21 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 3.91 (s, 2H),
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
19F{1H} NMR (376 MHz, CDCl3)
-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
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
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
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 (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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
without addition of HF/Pyridine. The crude reaction mixture was purified over silica gel with
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
This compound was obtained after reaction of substrate 1a (161 mg, 0.8 mmol), following the
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
This compound was obtained after reaction of substrate 1a (150 mg, 0.76 mmol), following
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
This compound was obtained after reaction of substrate 1a (200 mg, 1.01 mmol), following
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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)
-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
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)
5.98
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
13C NMR (100 MHz, CDCl3)
-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
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)
-60.
56
66
Compound 7a: N-(4-(4-acetylpiperazin-1-yl)-2-methylbutan-2-yl)acetamide
NNO
HNO
This compound was obtained after reaction of substrate 1a (200 mg, 1.0 mmol), following the
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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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)
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
13C NMR (100 MHz, CDCl3)
-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
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)
-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
mixture was purified over silica gel with petroleum ether/ethyl acetate (9/1) as the eluent,
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
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)
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
13C NMR (100 MHz, CDCl3)
-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