Supporting Information AWS
Supporting Information Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters with Fluoromethyl Iodide Jingyu Hu, Bing Gao, Lingchun Li, Chuanfa Ni, Jinbo Hu* Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China. E-mail: [email protected]
Table of Contents 1. General methods................................................................................................S-2 2. General procedures for the synthesis of aryl pinacol boronic esters.................S-2 3. General procedures for the synthesis of CH2FI (2)…........................................S-2 4. Optimization of the conditions for the monofluoromethylation of 1a ..............S-4 5. Typical procedures for Pd-catalyzed monofluoromethylation of bronic pinacolates (3a-3y)......................................................................................................................S-11 6. Preparation of compound 5................................................................................S-24 7. References..........................................................................................................S-27 8. NMR spectra of new compounds......................................................................S-28
S-1
1. General methods Unless otherwise mentioned, reagents were purchased from commercial sources and used without further purification. All solvents were dried from NaH or CaH2 and purified by distillation before being used. The water was used after distillation. All the melting points were uncorrected. 1H,
13
C and
19
F NMR spectra were recorded on a
400 MHz NMR spectrometer. 1H NMR chemical shifts were determined relative to internal (CH3)4Si (TMS) at δ 0.0 or to the signal of a residual protonated solvent: CDCl3 δ 7.26. 13C NMR chemical shifts were determined relative to internal TMS at δ 0.0. 19F NMR chemical shifts were determined relative to CFCl3 at δ 0.0. Data for 1H, 13
C and
19
F NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, q = quartet, br = broad). Mass spactra were obtained on a mass spectrometer. High-resolution mass data were recorded on a high–resolution mass spectrometer in the EI or ESI mode. All reactions were monitored by TLC, 19F NMR spectroscopy, or GC-MS.
2. General procedure for the synthesis of aryl pinacol boronic esters1 Into a 25-mL Schlenk tube was placed aryl boronic acid (5.00 mmol, 1.00 equiv), pinacol (590 mg, 5.00 mmol, 1.00 equiv), powdered 4 Ǻ molecular sieves (500 mg), and 15 mL of ether. The mixture was stirred at room temperature overnight. The molecular sieves were removed by filtration, and the filtrate was concentrated to afford aryl pinacol boronic esters as colorless solids or oils. Further purification of the aryl boronic ester was rarely needed.
3. General procedure for the synthesis of CH2FI (2) Into a 500-mL three-necked flask equipped with a magnetic stirring bar and a reflux condenser, was added NaI (58.46 g, 390 mmol) and acetone (200 mL). The mixture was stirred at room temperature, then CH2FCl gas was bubbled into the solution for a period of 1.5 h (195 mmol, determined by 19F NMR spectroscopy using PhCF3 as an internal standard). (Caution: Use a balloon as a tail gas receiving equipment in order S-2
to avoid the environmental pollution). Then the reaction was stirred at 50 oC for 4 days. After addition of H2O (300 mL), the mixture was treated with saturated Na2SO3 aqueous solution to remove the brown color. The aqueous layer was separated and the organic layer was washed with H2O (3×100 mL). Finally the organic layer was further purified by fractional distillation, giving the pure CH2FI (2) as a colorless liquid (16.53 g, 53%), b.p. 54–56 oC. 1H NMR (400 MHz, CDCl3/TMS): δ 6.34 (d, J = 48.9 Hz, 2H);
13
C NMR (101 MHz, CDCl3/TMS): δ 51.82 (d, J = 250.9 Hz);
(376 MHz , CDCl3/TMS): δ – 190.1 (t, J = 48.9 Hz, 1F).
S-3
19
F NMR
4. Optimization of the conditions for the monofluoromethylation of 1a
Table S1. Screening of the base for monofluoromethylation of 1a
a
Entry
Base
Yield (%)a
1
K2CO3
20
2
Cs2CO3
22
3
NaHCO3
0
4
Na2CO3
0
5
K3PO4
Trace
6
KF
Trace
7
CsF2
0
8
Li2CO3
0
9
LiOH
0
10
KOtBu
Trace
11b
K2CO3
15
12b
Cs2CO3
57
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard. b1.0
equiv of H2O was added.
S-4
Table S2. Screening of the solvent for monofluoromethylation of 1a
a
Entry
Solvent
Yield (%)a
1
DMF
57
2
THF
Trace
3
1,4-Dioxane
11
4
PhCH3
Trace
5
CH2Cl2
64
6
CH3CN
36
7b
CH2Cl2/DMF
74
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard.
b
CH2Cl2/DMF = 1:1, 1.0 mL in total.
S-5
Table S3. Screening of the ligand for monofluoromethylation of 1a
S-6
a
Entry
Ligand
Yield (%)a
1b
L1
0
2b
L2
0
3b
L3
0
4b
L4
0
5
L5
58
6
L6
66
7
L7
74
8
L8
73
9
L9
Trace
10 b
L10
0
11
L11
8
12
L12
27
13
L13
16
14
L14
11
15
L15
0
16
L16
26
17
L17
53
18
L18
8
19
L19
9
20
L20
Trace
21
L21
Trace
22
L22
73
23
L23
0
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard. b0.1
equiv of ligand was added.
S-7
Table S4. Screening of the palladium catalyst for monofluoromethylation of 1a
Entry
Pd catalyst
Yield (%)a
1
Pd(OAc)2
46
2
Pd(dppf)Cl2
68
3
Pd(PPh)4
39
4b
Pd2(dba)3
74
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard. b5 mol %
of Pd2(dba)3 was added.
Table S5. Screening of the amount of H2O for monofluoromethylation of 1a
Entry
H2O (x equiv)
Yield (%)a
1
1.0
74
2
2.0
76
3
4.0
81
4
5.0
83
5
6.0
73
6
10.0
76
7
20.0
67
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-8
Table S6. Screening of the amount of ligand for monofluoromethylation of 1a
Entry
P(o-MePh)3 (y mol%)
Yield (%)a
1
15
61
2
20
83
3
25
58
4
0
0
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
Table S7. Screening of the amount of catalyst for the monofluoromethylation of 1a
Entry
Pd2(dba)3 (z mol%)
Yield (%)a
1
2.5
38
2
5.0
83
3
7.5
76
4
0
0
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-9
Table S8. Screening of the amount of CH2FI for monofluoromethylation of 1a
Entry
CH2FI (x equiv)
Yield (%)a
1
1.0
80
2
1.1
87
3
1.2
78
4
1.5
81
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-10
5. Typical procedure for Pd-catalyzed monofluoromethylation of bronic pinacolate (3a-3y) General procedure for the synthesis of compounds 3a, 3b, 3c, 3d, 3g, 3j Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 4-Biphenylbronic pinacolate 2a (140.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether) to give product 3a (77 mg, yield: 83%).
4-(fluoromethyl)biphenyl (3a)2: White solid. Isolated yield: 83% (77 mg). 1H NMR (400 MHz, CDCl3): δ 7.65–7.60 (m, 4H, Ar-H), 7.48–7.45 (m, 4H, Ar-H), 7.38 (t, J = 7.3 Hz, 1H, Ar-H), 5.44 (d, J = 47.9 Hz, 2H, CH2);
19
F NMR (376 MHz,
CDCl3): δ –206.1 (t, J = 47.9 Hz, 1F); MS (EI, m/z, %): 186 (M+, 100).
3-(fluoromethyl)biphenyl (3b): Colorless oil. Isolated yield: 86% (80 mg). 1H NMR (400 MHz, CDCl3): δ 7.64–7.63 (m, 4H, Ar-H), 7.52–7.47 (m, 3H, Ar-H), 7.42– S-11
7.38 (m, 2H, Ar-H), 5.48 (d, J = 47.8 Hz, 2H, CH2); 13C NMR (101 MHz, CDCl3):δ 141.71 (d, JC-F = 1.0 Hz), 140.71, 136.75 (d, JC-F = 17.0 Hz), 129.17 (d, JC-F = 1.0 Hz), 128.92, 127.65, 127.62, 127.26, 126.43 (d, JC-F = 3.0 Hz), 126.37 (d, JC-F = 3.2 Hz), 84.71 (d, JC-F = 166.4 Hz).; 19F NMR (376 MHz, CDCl3): δ –207.2 (t, J = 47.8 Hz, 1F); IR (film): 3061.7, 3033.1, 2957.4, 2896.6, 1599.1, 1481.2, 1455.3, 1424.4, 1374.6, 1194.7, 1028.2, 981.7, 897.4, 799.8, 757.1, 725.2, 699.4, 615.7, 552.2.; MS (EI, m/z, %): 186 (M+, 100).; HRMS (EI): Calcd. For C13H11F: 186.0845; Found: 186.0839.
1-(fluoromethyl)naphthalene (3c)2: Colorless oil. Isolated yield: 90% (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.3 Hz, 1H, Ar-H), 7.92–7.89 (m, 2H, Ar-H), 7.61–7.53 (m, 3H, Ar-H), 7.48 (t, J = 7.6 Hz, 1H, Ar-H), 5.86 (d, J = 47.9 Hz, 2H, CH2);
19
F NMR (376 MHz, CDCl3): δ –206.2 (t, J = 48.0 Hz, 1F); MS (EI, m/z, %):
160 (M+, 100).
2-(fluoromethyl)naphthalene (3d)2: White solid. Isolated yield: 73% (58 mg). 1H NMR (400 MHz, CDCl3): δ 7.91–7.86 (m, 4H, Ar-H), 7.53–7.50 (m, 3H, Ar-H), 5.54 (d, J = 47.7 Hz, 2H, CH2); 19F NMR (376 MHz, CDCl3): δ –202.0 (t, J = 47.8 Hz, 1F); MS (EI, m/z, %): 160 (M+, 100).
General procedure for the synthesis of compounds 3e, 3f, 3h, 3k, 3l Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-toluene)3 (30.4 mg, S-12
0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Phenylbronic pinacolate 2e (102.1 mg, 0.50 mmol), CH2FI 1 (88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction was monitored by
19
F NMR
spectroscopy using PhCF3 as an internal standard.
(fluoromethyl)benzene (3e): The yield (55%) was determined by
19
F NMR
spectroscopy using (trifluoromethyl)benzene as an internal standard. Characterization of 3e in reaction solution: 19F NMR (unlocked): δ –206.0 (t, J = 48.1 Hz, 1F). GC－ MS (EI): m/z = 110.1.
4-(fluoromethyl)styrene (3f): The yield (81%) was determined by
19
F NMR
spectroscopy using (trifluoromethyl)benzene as an internal standard. Characterization of 3e in CDCl3: 19F NMR: δ –206.3 (t, J = 47.8 Hz, 1F). GC－MS (EI): m/z = 136.1.
1-(tert-Butyl)-4-(fluoromethyl)benzene (3g)3: Colorless oil. Isolated yield: 71% S-13
(59 mg). 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.3 Hz, 2H, Ar-H), 7.35 (dd, J = 8.3, 2.0 Hz, 2H, Ar-H), 5.37(d, J = 48.1 Hz, 2H, CH2), 1.35 (s, 9H, CH3).; 19F NMR (376 MHz, CDCl3): δ –204.3 (t, J = 48.1 Hz, 1F); MS (EI, m/z, %): 166 (M+, 22.61), 151 (100).
1-methoxyl-4-(fluoromethyl)benzene (3h): The yield (72%) was determined by 19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal standard.
Characterization of 3h in reaction solution: 19F NMR (unlocked): δ –198.4 (t, J = 48.8 Hz, 1F). GC－MS (EI): m/z = 140.1.
Procedure for the synthesis of compounds 3i. Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 4-Ethylsulfanylbenzenebronic pinacolate 2i (132.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether) to give product 3i (51 mg, yield: 60%). [ Note: This product is sensitive to acid, so the column must be eluted previously with S-14
petroleum ether/ Et3N (40/ 1 v/ v).] 1-ethylthio-4-(fluoromethyl)benzene (3i): Light yellow oil. Isolated yield: 60% (51 mg). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 7.30 (dd, J = 8.4, 1.5 Hz, 2H, Ar-H), 5.33 (d, J = 48.0 Hz, 2H, CH2), 2.97 (q, J = 7.4 Hz, 2H, CH2), 1.33 (t, J = 7.4 Hz, 3H, CH3);
13
C NMR (101 MHz, CDCl3): δ 137.81 (d, JC-F =
3.6Hz), 133.53 (d, JC-F = 17.2 Hz), 128.68 (d, JC-F = 1.4 Hz), 128.24 (d, JC-F = 5.6 Hz), 84.25 (d, JC-F = 166.0 Hz), 27.37, 14.27.; 19F NMR (376 MHz, CDCl3): δ –205.1 (t, J = 48.0 Hz, 1F); IR (film): 2963.8, 2926.9, 2853.9, 1896.9, 1602.2, 1495.7, 1451.8, 1406.4, 1375.6, 1262.6, 1217.4, 1091.2, 979.5, 838.0, 803.9, 736.8, 529.6.; MS (EI, m/z, %): 170 (M+, 100).; HRMS (EI): Calcd. For C9H11FS: 170.0566; Found: 170.0562.
1-methoxyl-2-(fluoromethyl)benzene (3j): Colorless oil. Isolated yield: 79% (55 mg). 1H NMR (400 MHz, CDCl3): δ 7.46–7.30 (m, 2H, Ar-H), 6.99 (t, J = 7.5 Hz, 1H, Ar-H), 6.91 (d, J = 8.2 Hz, 1H, Ar-H), 5.47 (q, J = 47.9 Hz, 2H, CH2), 3.86 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3):δ 157.26 (d, JC-F = 4.3 Hz), 130.12 (d, JC-F = 3.1 Hz), 129.23 (d, JC-F = 7.4 Hz), 124.74 (d, JC- F = 16.7 Hz), 120.50 (d, JC-F = 1.4 Hz ), 110.39 (d, JC-F = 1.3 Hz ), 80.47 (d, JC-F = 164.0 Hz), 55.40.;
19
F NMR (376 MHz,
CDCl3): δ –213.3 (t, J = 47.9 Hz, 1F); IR (film): 2956.8, 2840.7, 1605.7, 1591.3, 1495.6, 1465.5, 1439.4, 1378.5, 1289.4, 1250.1, 1179.0, 1123.3, 1049.7, 1029.9, 971.6, 935.4, 753.7.; MS (EI, m/z, %): 140 (M+, 100).; HRMS (EI): Calcd. For C8H9OF: 140.0637; Found: 140.0635.
S-15
1,2-(methylenedioxy)-4-(fluoromethyl)benzene (3k): The yield (72%) was determined by
19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal
standard. Characterization of 3k in reaction solution: 19F NMR (unlocked): δ –199.4 (t, J = 48.3 Hz, 1F). GC－MS (EI): m/z = 154.0.
1-phenylmethoxy-4-(fluoromethyl)benzene (3l): The yield (89%) was determined by
19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal standard.
Characterization of 3l in reaction solution: 19F NMR (unlocked): δ –198.9 (t, J = 48.7 Hz, 1F). GC－MS (EI): m/z = 216.1.
Procedure for the synthesis of compounds 3m. Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 3-Methoxylbenzenebronic pinacolate 2m (117.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether : EtOAc= 200: 1) to give product 3m (42 mg, yield: 60%). 1-methoxyl-3-(fluoromethyl)benzene (3m): Colorless oil. Isolated yield: 60% (42 S-16
mg). 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.8 Hz, 1H, Ar-H), 6.97–6.90 (m, 3H, Ar-H), 5.37 (d, J = 47.7 Hz, 2H, CH2), 3.83 (s, 3H, CH3).;
13
C NMR (101 MHz,
CDCl3):δ 159.84, 137.78 (d, JC-F = 17.1 Hz), 129.69, 119.51 (d, JC-F = 6.1 Hz), 114.41 (d, JC-F = 2.8 Hz), 112.67(d, JC-F = 6.3 Hz), 84.46 (d, JC-F = 166.8 Hz), 55.27.;
19
F
NMR (376 MHz, CDCl3): δ –207.9 (t, J = 47.7 Hz, 1F); IR (film): 2959.6, 2843.0, 1601.6, 1588.2, 1490.8, 1458.0, 1438.1, 1376.6, 1317.0, 1293.2, 1268.9, 1168.9, 1156.9, 1053.4, 1042.0, 992.9, 857.5, 783.9, 740.1, 693.2.; MS (EI, m/z, %): 140 (M+, 100).; HRMS (EI): Calcd. For C8H9OF: 140.0637; Found: 140.0638.
Procedure for the synthesis of compounds 3n Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-(methanesulfonyl)benzenebronic pinacolate 2n (141.1 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 1: 1) to give product 3n (73 mg, yield: 78%). 4-fluoromethyl-1-(methanesulfonyl)benzene(3n): Light yellow solid. Isolated yield: 78% (73 mg). Melting Point: 54–56 oC. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.0 Hz, 2H, Ar-H), 7.53 (d, J = 8.0 Hz, 2H, Ar-H), 5.46 (d, J = 46.9 Hz, 2H, CH2), 3.03 (s, 3H, CH3);
13
C NMR (101 MHz, DMSO-d6): δ 142.45 (d, JC-F = 17.6 Hz),
140.56, 127.76, 127.26 (d, JC-F = 6.9 Hz), 84.11 (d, JC-F = 170.1 Hz), 44.51.; 19F NMR S-17
(376 MHz, CDCl3): δ –215.1 (t, J = 46.9 Hz, 1F); IR (film): 3013.5, 3001.9, 2954.8, 2929.3, 2301.1, 1922.7, 1602.7, 1455.7, 1410.9, 1377.0, 1307.5, 1209.5, 1182.6, 1148.1, 1089.6, 1013.7, 917.1, 814.1, 768.8, 659.6, 554.6, 527.5, 449.2. MS (EI, m/z, %): 188 (M+, 65.58), 109 (100).; HRMS (EI): Calcd. For C8H9FO2S): 188.0307.; Found: 188.0303.
General procedure for the synthesis of compounds 3o, 3p, 3q, 3r, 3s, 3t, 3v, 3w Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-Formylbenzenebronic pinacolate 2p (116.1 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 30: 1) to give product 3p (57 mg, yield: 82%).
1-cyano-4-(fluoromethyl)benzene (3o)4: Yellow solid. Isolated yield: 69% (47 mg). 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.1 Hz, 2H, Ar-H), 7.47 (d, J = 7.9 Hz, 2H, Ar-H), 5.46 (d, J = 46.9 Hz, 2H, CH2).;
19
F NMR (376 MHz, CDCl3): δ –
215.2 (t, J = 46.9 Hz, 1F); MS (EI, m/z, %): 135 (M+, 93.76), 134 (100).
S-18
1-formyl-4-(fluoromethyl)benzene (3p): Light yellow oil. Isolated yield: 82% (57 mg). 1H NMR (400 MHz, CDCl3): δ10.03 (s, 1H, CH), 7.91(d, J = 7.9 Hz, 2H, Ar-H), 7.53 (d, J = 7.8 Hz, 2H, Ar-H), 5.48 (d, J = 47.0 Hz, 2H, CH2); 13C NMR (101 MHz, CDCl3):δ 191.80, 142.90 (d, JC-F = 17.1 Hz), 136.39, 130.00, 127.00 (d, JC-F = 6.9 Hz), 83.50 (d, JC-F = 169.4 Hz).;
19
F NMR (376 MHz, CDCl3): δ –214.3 (t, J = 46.9 Hz,
1F); IR (film): 2959.1, 2832.0, 1700.6, 1611.8, 1580.0, 1425.9, 1378.1, 1306.4, 1211.4, 1168.6, 1009.0, 823.0, 776.3.; MS (EI, m/z, %): 138 (M+, 80.08), 137 (100).; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0477.
1-formyl-3-(fluoromethyl)benzene (3q): Light yellow oil. Isolated yield: 52% (36 mg). 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H, CH), 7.87 (d, J = 7.3 Hz, 2H, Ar-H), 7.64 (d, J = 7.5 Hz, 1H, Ar-H), 7.57 (t, J = 7.5 Hz, 1H), 5.46 (d, J = 47.4 Hz, 2H, CH2);
13
C NMR (101 MHz, CDCl3): δ 191.79, 137.46 (d, J = 17.8 Hz), 136.73,
132.92 (d, J = 5.9 Hz), 129.95 (d, J = 2.3 Hz), 129.37, 128.08 (d, J = 6.3 Hz), 83.59 (d, J = 168.3 Hz).; 19F NMR (376 MHz, CDCl3): δ –205.3 (t, J = 47.4 Hz, 1F); IR (film): 2964.3, 2900.6, 2827.3, 2734.5, 1704.7, 1608.9, 1590.8, 1451.6, 1374.2, 1291.6, 1253.2, 1156.3, 1143.8, 983.8, 903.2, 798.6, 780.9, 691.7, 652.8, 610.5.;MS (EI, m/z, %): 138 (17.34), 109 (100) .; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0479.
S-19
1-formyl-2-(fluoromethyl)benzene (3r): Light yellow oil. Isolated yield: 75% (52 mg). 1H NMR (400 MHz, CDCl3): δ10.10 (d, 1H, J = 1.2 Hz, CH), 7.87 (d, J = 7.6 Hz, 1H, Ar-H), 7.75-7.64 (m, 1H, Ar-H), 7.55 (t, J = 7.3 Hz, 1H, Ar-H), 7.26 (s, 1H, Ar-H), 5.87 (d, J = 47.9 Hz, 2H).;
13
C NMR (101 MHz, CDCl3):δ 193.12, 139.27 (d, JC-F =
17.5 Hz), 134.17, 132.36 (d, JC-F = 1.5 Hz), 128.11 (d, JC-F = 1.4 Hz), 125.94 (d, JC-F = 1.5 Hz), 82.50 (d, JC-F = 169.0 Hz).;
19
F NMR (376 MHz, CDCl3): δ –218.9 (t, J =
47.9 Hz, 1F); IR (film): 3075.3, 2980.7, 2832.1, 2742.6, 1695.2, 1603.7, 1577.2, 1454.9, 1366.8, 1301.8, 12101.0, 1111.2, 1009.0, 861.8, 756.8, 660.2, 593.3.; MS (EI, m/z, %): 138 (100.00).; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0483.
1-acetyl-4-(fluoromethyl)benzene (3s): Yellow oil. Isolated yield: 75% (57 mg). 1
H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.0 Hz, 2H, Ar-H), 7.46 (d, J = 7.9 Hz, 2H,
Ar-H), 5.45 (d, J = 47.1 Hz, 2H, CH2), 2.62 (s, 3H, CH3);
13
C NMR (101 MHz,
CDCl3):δ 197.61, 141.36 (d, JC-F = 17.2 Hz), 137.18, 128.82, 126.78 (d, JC-F = 6.6 Hz), 83.63 (d, JC-F = 168.6 Hz), 26.65.; 19F NMR (376 MHz, CDCl3): δ –213.2 (t, J = 47.6 Hz, 1F); IR (film): 2963.4, 1685.6, 1685.6, 1612.0, 1574.8, 1413.3, 1359.0, 1301.8, 1266.4, 1216.5, 1181.5, 1101.6, 956.9, 848.6, 815.9, 685.1, 597.5.; MS (EI, m/z, %): 152 (M+, 29.23), 137 (100).; HRMS (EI): Calcd. For C9H9FO: 152.0637; Found: 152.0633.
S-20
1-acetyl-3-(fluoromethyl)benzene (3t): Yellow oil. Isolated yield: 59% (45 mg). 1
H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H, Ar-H), 7.95 (d, J = 7.1 Hz, 1H, Ar-H),
7.59 (d, J = 7.7 Hz, 1H, Ar-H), 7.51 (t, J = 7.4 Hz, 1H, Ar-H), 5.44 (d, J = 47.5 Hz, 2H, CH2), 2.63 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3): δ 197.69, 137.45, 136.85 (d, JC-F = 17.5 Hz), 131.78 (d, JC-F = 5.9 Hz), 128.97, 128.59 (d, JC-F = 2.6 Hz), 127.01 (d, JC-F = 6.2 Hz), 83.93 (d, JC-F = 167.7 Hz), 26.65.;
19
F NMR (376 MHz, CDCl3): δ
-209.3 (t, J = 47.5 Hz, 1F); IR (film): 2963.4, 1687.1, 1606.5, 1581.2, 1442.7, 1376.1, 1358.8, 1277.7, 1194.9, 981.5, 797.1, 692.2, 587.7.; MS (EI, m/z, %): 152 (M+, 28.42), 137 (100).; HRMS (EI): Calcd. For C9H9FO: 152.0637; Found: 152.0635.
General procedure for the synthesis of compounds 3u Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 3-Methoxycarbnylphenylbronic pinacolate 2u (123.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether : EtOAc = 30 : 1) to give product 3u (55 mg, yield: 65%).
Methyl 3-(fluoromethyl)benzoate(3u): Colorless oil. Isolated yield: 65% (55 mg). 1
H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H, Ar-H), 8.03 (d, J = 8.8 Hz, 1H, Ar-H), S-21
7.57 (d, J = 7.5 Hz, 1H, Ar-H), 7.47 (t, J = 7.6 Hz, 1H, Ar-H), 5.41 (d, J = 47.5 Hz, 2H, CH2), 3.92 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3):δ 166.65, 136.65 (d, JC-F = 17.6 Hz), 131.67 (d, JC-F = 5.9 Hz), 130.59, 129.83 (d, JC-F = 2.6 Hz), 128.75,128.39 (d, JC-F = 6.2 Hz), 83.88 (d, JC-F = 167.7 Hz), 52.20.; 19F NMR (376 MHz, CDCl3): δ – 209.1 (t, J = 47.6 Hz, 1F); IR (film): 2954.6, 1724,6, 1450.0, 1434.8, 1377.2, 1289.7, 1206.9, 1108.4, 1086.5, 977.9, 915.4, 749.9, 696.0, 606.2.; MS (EI, m/z, %): 168 (M+, 44.99), 137 (100).; HRMS (EI): Calcd. For C9H9FO2: 168.0587; Found: 168.0588.
Methyl 4-(fluoromethyl)benzoate(3v)5:Colorless oil. Isolated yield: 83% (70 mg). 1
H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 2H, Ar-H), 7.43 (d, J = 7.8 Hz, 2H,
Ar-H), 5.45 (d, J = 47.2 Hz, 2H, CH2), 3.93 (s, 3H, CH3);
13
C NMR (101 MHz,
CDCl3):δ 166.65, 141.21 (d, JC-F = 17.2 Hz), 130.28 (d, JC-F = 2.4 Hz), 129.85, 126.58 (d, JC-F = 6.6 Hz), 83.67 (d, JC-F = 168.5 Hz), 52.15.; 19F NMR (376 MHz, CDCl3): δ – 212.9 (t, J = 47.2 Hz, 1F); IR (film): 2954.6, 1723.9, 1617.7, 1436.3, 1379.3, 1310.8, 1281.4, 1192.3, 1178.4, 1109.2, 1017.6, 861.7, 799.5, 757.8, 707.1, 634.1.; MS (EI, m/z, %): 168 (M+, 37.16), 137 (100).; HRMS (EI): Calcd. For C9H9FO2: 168.0587; Found: 168.0584.
1-nitro-4-(fluoromethyl)benzene (3w)2: Yellow solid. Isolated yield: 72% ( 56 mg). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.0 Hz, 2H, Ar-H), 7.50 (d, J = 8.3 Hz, 2H, Ar-H), 5.48 (d, J = 46.8 Hz, 2H, CH2).;
13
C NMR (101 MHz, CDCl3):δ
147.92, 143.45 (d, JC-F = 17.7 Hz), 127.06 (d, JC-F = 7.1 Hz), 123.80, 82.89 (d, JC-F = 170.6 Hz).;
19
F NMR (376 MHz, CDCl3): δ –215.7 (t, J = 46.8 Hz, 1F); IR (film): S-22
3118.3, 3083.9, 2959.1, 2851.6, 1929.1, 1608.4, 1523.2, 1458.6, 1348.4, 1316.9, 1212.9, 1177.5, 1109.3, 1012.7, 847.9, 800.7, 739.3, 695.0.; MS (EI, m/z, %): 155 (M+, 100).; HRMS (EI): Calcd. For C7H6FNO2: 155.0383; Found: 155.0385.
Procedure for the synthesis of compounds 3x Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-(dimethylcarbonyl)benzenebronic pinacolate 2x (137.6 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 3: 1) to give product 3x (64 mg, yield: 71%).
4-fluoromethyl-1-(dimethylcarbonyl)benzene (3x):Dark brown oil. Isolated yield: 71% (64 mg). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.9 Hz, 2H, Ar-H), 7.40 (d, J = 7.7 Hz, 2H, Ar-H), 5.39 (d, J = 47.5 Hz, 2H, CH2), 3.04 (s, 6H, CH3); 13C NMR (101 MHz, DMSO-d6):δ 170.19, 137.72 (d, JC-F = 16.8 Hz), 137.28 (d, JC-F = 3.2 Hz), 127.91 (d, JC-F = 5.9 Hz), 127.62 (d, JC-F = 0.9 Hz), 84.23 (d, JC-F = 162.5 Hz), 39.39, 35.30.; 19F NMR (376 MHz, CDCl3): δ –209.5 (t, J = 47.5 Hz, 1F); IR (film): 2941.9, 1634.6, 1518.9, 1491.7, 1448.1, 1393.9, 1265.5, 1218.3, 1080.7, 977.7, 846.7, 760.8, 621.2, 567.5. MS (EI, m/z, %): 181 (M+, 52.73), 137 (100).; HRMS (EI): Calcd. For [C10H11FNO]+([M-H]+): 180.0825; Found: 180.0821. S-23
6. Preparation of compound 5
Compound 4awas prepared according to the literature procedures.6 To a mixture of estrone (4, 4.50 g, 16.67 mmol) and DIPEA (3.14 mL, 18.32 mmol, 1.1 eq) in CH2Cl2 (80 mL) were added Tf2O (3.08 mL, 18.32 mmol, 1.1 eq) under argon at 0 oC. The reaction mixture was stirred at room temperature for 0.5 h. Then, the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, and dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography to give estrone trifluoromethanesulfonic ester (4a, 5.83 g, 87%).
Compound 4a6: Yellow solid. Isolated yield: 87% (5.83 g). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 8.6 Hz, 1H, Ar-H), 7.03 (dd, J = 8.6, 2.6 Hz, 1H, Ar-H), 6.99 (d, J = 2.5 Hz, 1H, Ar-H), 2.94 (dd, J = 8.8, 4.1 Hz, 2H, CHn), 2.51 (dd, J = 18.7, 8.6 Hz, 1H, CHn), 2.44–2.36 (m, 1H, CHn), 2.29 (td, J = 10.8, 4.2 Hz, 1H, CHn), 2.23-2.00 (m, 3H, CHn), 2.00–1.92 (m, 1H, CHn), 1.71–1.37 (m, 6H, CHn), 0.91 (s, 3H, CH3).; 19F NMR (376 MHz, CDCl3): δ –73.0 (s, 3F); IR (film): 2933.7, 2868.8, 1740.7, 1489.7, 1421.0, 1249.1, 1212.2, 1141.2, 1055.0, 1012.1, 920.0, 837.1, 607.8, 511.7.; MS (ESI, m/z): 403.0 (M+H+). 424.9 (M+Na+); HRMS (ESI):[M+Na]+ Calcd. For C19H21F3NaO4S: 425.1005; Found: 425.0999.
S-24
Compound 4b was prepared according to the literature procedures.6 To a 250-mL of sealed tube were added estrone trifluoromethanesulfonic ester (4.50 g, 11.19 mmol), bis(pinacolato)diboron (5.68 g, 22.38 mmol, 2.0 equiv), KOAc (3.30 g, 33.57 mmol. 3.0 eq), and Pd(dppf)Cl2 (328.4 mg, 0.45 mmol, 0.04 eq) under argon, followed by dioxane (45 mL) with stirring. The sealed tube was heated to 120 oC (oil bath). After stirring for 8h, the reaction mixture was cooled to room temperature and diluted with THF, filtered through a pad of Mg2SO4 and Celite, then concentrated. The residue was recrystallized with EtOAc and petroleum ether to give 2.93 g 4b in 69% yield.
Compound 4b6: White solid. Isolated yield: 69% (2.93 g). 1H NMR (400 MHz, CDCl3): δ7.60 (d, J = 8.0 Hz, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.32 (d, J = 7.7 Hz, 1H, Ar-H), 2.93 (dd, J = 10.4, 4.5 Hz, 2H, CHn), 2.54-2.43 (m, 2H, CHn), 2.37-2.30 (m, 1H, CHn), 2.19–1.95 (m, 4H, CHn), 1.65–1.42 (m, 6H, CHn), 1.34 (s, 12H, CH3), 0.90 (s, 3H, CH3).; MS (ESI, m/z): 403.1 (M+Na+).
S-25
Compound 5 was prepared according to the standard procedures. Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (0.5 mL), and CH2Cl2 (0.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. Estrone boronic pinacolate 4b (190.1 mg, 0.50mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and filtered through a pad of neutral alumina, then extracted with EtOAc and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether/EtOAc = 10: 1) to give product 5 (104 mg, yield: 73%).
Compound 57: White solid. Isolated yield: 73% (104 mg). 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.0 Hz, 1H, Ar-H), 7.18 (d, J = 8.0 Hz, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 5.32 (d, J = 48.1 Hz, 2H, CH2), 2.94 (dd, J = 8.7, 4.0 Hz, 2H, CHn), 2.59–2.47 (m, 1H, CHn), 2.47–2.39 (m, 1H, CHn), 2.32 (t, J = 10.4 Hz, 1H, CHn), 2.22-1.91 (m, 4H, CHn), 1.74–1.37 (m, 6H, CHn), 0.92 (s, 3H, CH3).; 13C NMR (101 MHz,CDCl3): δ 220.69, 140.54 (d, JC-F = 3.3 Hz), 136.90 (d, JC-F = 1.5 Hz), 133.67 (d, JC-F = 17.0 Hz), 128.49 (d, JC-F = 5.5 Hz), 125.68 (d, JC-F = 1.3 Hz), 125.22 (d, JC-F = 5.4 Hz), 84.55 (d, JC-F = 165.3 Hz), 50.52, 47.96, 44.42, 38.08, 25.85, 31.61, 29.33, 26.42, 25.74, 21.61, 13.85.;
19
F NMR (376 MHz, CDCl3): δ –204.7 (t, J = 48.1 Hz, 1F); IR
(film): 2929.3, 2862.5, 1738.6, 1500.3, 1454.9, 1373.8, 1256.8, 1083.7, 1007.8, 976.3, 887.5, 821.9, 739.3.; MS (ESI, m/z): 287.0 (M+H+). HRMS (ESI):[M+H]+ Calcd. For C19H24FO+: 287.1806; Found: 287.1804.
S-26
7. References: (1) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552. (2) Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur, V. Org. Lett. 2012, 14, 2754. (3) Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494. (4) Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16, 6338. (5) Zhao, Y.; Jiang, F.; Gao, B.; Shen, X.; Hu, J. ACS Catal. 2013, 3, 631. (6) (a) Zhao, Y.; Hu, J. Angew. Chem., Int. Ed. 2012, 51, 1033. (b) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew. Chem., Int. Ed .2014, 53, 1669. (c) Ishiyama, T.; Itoh, Y., Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447 (7) Zhao, Y.; Gao, B.; Ni, C.; Hu, J. Org. Lett. 2012, 14, 6080.
S-27
NMR spectra of new compounds
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S-33
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S-38
S-39
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S-43
S-44
S-45
S-46
S-47
S-48
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S-52
S-53
S-54
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S-56
S-57
S-58
S-59
S-60
S-61
S-62
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Table of Contents 1. General methods................................................................................................S-2 2. General procedures for the synthesis of aryl pinacol boronic esters.................S-2 3. General procedures for the synthesis of CH2FI (2)…........................................S-2 4. Optimization of the conditions for the monofluoromethylation of 1a ..............S-4 5. Typical procedures for Pd-catalyzed monofluoromethylation of bronic pinacolates (3a-3y)......................................................................................................................S-11 6. Preparation of compound 5................................................................................S-24 7. References..........................................................................................................S-27 8. NMR spectra of new compounds......................................................................S-28
S-1
1. General methods Unless otherwise mentioned, reagents were purchased from commercial sources and used without further purification. All solvents were dried from NaH or CaH2 and purified by distillation before being used. The water was used after distillation. All the melting points were uncorrected. 1H,
13
C and
19
F NMR spectra were recorded on a
400 MHz NMR spectrometer. 1H NMR chemical shifts were determined relative to internal (CH3)4Si (TMS) at δ 0.0 or to the signal of a residual protonated solvent: CDCl3 δ 7.26. 13C NMR chemical shifts were determined relative to internal TMS at δ 0.0. 19F NMR chemical shifts were determined relative to CFCl3 at δ 0.0. Data for 1H, 13
C and
19
F NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, q = quartet, br = broad). Mass spactra were obtained on a mass spectrometer. High-resolution mass data were recorded on a high–resolution mass spectrometer in the EI or ESI mode. All reactions were monitored by TLC, 19F NMR spectroscopy, or GC-MS.
2. General procedure for the synthesis of aryl pinacol boronic esters1 Into a 25-mL Schlenk tube was placed aryl boronic acid (5.00 mmol, 1.00 equiv), pinacol (590 mg, 5.00 mmol, 1.00 equiv), powdered 4 Ǻ molecular sieves (500 mg), and 15 mL of ether. The mixture was stirred at room temperature overnight. The molecular sieves were removed by filtration, and the filtrate was concentrated to afford aryl pinacol boronic esters as colorless solids or oils. Further purification of the aryl boronic ester was rarely needed.
3. General procedure for the synthesis of CH2FI (2) Into a 500-mL three-necked flask equipped with a magnetic stirring bar and a reflux condenser, was added NaI (58.46 g, 390 mmol) and acetone (200 mL). The mixture was stirred at room temperature, then CH2FCl gas was bubbled into the solution for a period of 1.5 h (195 mmol, determined by 19F NMR spectroscopy using PhCF3 as an internal standard). (Caution: Use a balloon as a tail gas receiving equipment in order S-2
to avoid the environmental pollution). Then the reaction was stirred at 50 oC for 4 days. After addition of H2O (300 mL), the mixture was treated with saturated Na2SO3 aqueous solution to remove the brown color. The aqueous layer was separated and the organic layer was washed with H2O (3×100 mL). Finally the organic layer was further purified by fractional distillation, giving the pure CH2FI (2) as a colorless liquid (16.53 g, 53%), b.p. 54–56 oC. 1H NMR (400 MHz, CDCl3/TMS): δ 6.34 (d, J = 48.9 Hz, 2H);
13
C NMR (101 MHz, CDCl3/TMS): δ 51.82 (d, J = 250.9 Hz);
(376 MHz , CDCl3/TMS): δ – 190.1 (t, J = 48.9 Hz, 1F).
S-3
19
F NMR
4. Optimization of the conditions for the monofluoromethylation of 1a
Table S1. Screening of the base for monofluoromethylation of 1a
a
Entry
Base
Yield (%)a
1
K2CO3
20
2
Cs2CO3
22
3
NaHCO3
0
4
Na2CO3
0
5
K3PO4
Trace
6
KF
Trace
7
CsF2
0
8
Li2CO3
0
9
LiOH
0
10
KOtBu
Trace
11b
K2CO3
15
12b
Cs2CO3
57
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard. b1.0
equiv of H2O was added.
S-4
Table S2. Screening of the solvent for monofluoromethylation of 1a
a
Entry
Solvent
Yield (%)a
1
DMF
57
2
THF
Trace
3
1,4-Dioxane
11
4
PhCH3
Trace
5
CH2Cl2
64
6
CH3CN
36
7b
CH2Cl2/DMF
74
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard.
b
CH2Cl2/DMF = 1:1, 1.0 mL in total.
S-5
Table S3. Screening of the ligand for monofluoromethylation of 1a
S-6
a
Entry
Ligand
Yield (%)a
1b
L1
0
2b
L2
0
3b
L3
0
4b
L4
0
5
L5
58
6
L6
66
7
L7
74
8
L8
73
9
L9
Trace
10 b
L10
0
11
L11
8
12
L12
27
13
L13
16
14
L14
11
15
L15
0
16
L16
26
17
L17
53
18
L18
8
19
L19
9
20
L20
Trace
21
L21
Trace
22
L22
73
23
L23
0
Determined by
19
F NMR spectroscopy using PhCF3 as internal standard. b0.1
equiv of ligand was added.
S-7
Table S4. Screening of the palladium catalyst for monofluoromethylation of 1a
Entry
Pd catalyst
Yield (%)a
1
Pd(OAc)2
46
2
Pd(dppf)Cl2
68
3
Pd(PPh)4
39
4b
Pd2(dba)3
74
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard. b5 mol %
of Pd2(dba)3 was added.
Table S5. Screening of the amount of H2O for monofluoromethylation of 1a
Entry
H2O (x equiv)
Yield (%)a
1
1.0
74
2
2.0
76
3
4.0
81
4
5.0
83
5
6.0
73
6
10.0
76
7
20.0
67
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-8
Table S6. Screening of the amount of ligand for monofluoromethylation of 1a
Entry
P(o-MePh)3 (y mol%)
Yield (%)a
1
15
61
2
20
83
3
25
58
4
0
0
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
Table S7. Screening of the amount of catalyst for the monofluoromethylation of 1a
Entry
Pd2(dba)3 (z mol%)
Yield (%)a
1
2.5
38
2
5.0
83
3
7.5
76
4
0
0
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-9
Table S8. Screening of the amount of CH2FI for monofluoromethylation of 1a
Entry
CH2FI (x equiv)
Yield (%)a
1
1.0
80
2
1.1
87
3
1.2
78
4
1.5
81
a
Determined by 19F NMR spectroscopy using PhCF3 as internal standard.
S-10
5. Typical procedure for Pd-catalyzed monofluoromethylation of bronic pinacolate (3a-3y) General procedure for the synthesis of compounds 3a, 3b, 3c, 3d, 3g, 3j Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 4-Biphenylbronic pinacolate 2a (140.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether) to give product 3a (77 mg, yield: 83%).
4-(fluoromethyl)biphenyl (3a)2: White solid. Isolated yield: 83% (77 mg). 1H NMR (400 MHz, CDCl3): δ 7.65–7.60 (m, 4H, Ar-H), 7.48–7.45 (m, 4H, Ar-H), 7.38 (t, J = 7.3 Hz, 1H, Ar-H), 5.44 (d, J = 47.9 Hz, 2H, CH2);
19
F NMR (376 MHz,
CDCl3): δ –206.1 (t, J = 47.9 Hz, 1F); MS (EI, m/z, %): 186 (M+, 100).
3-(fluoromethyl)biphenyl (3b): Colorless oil. Isolated yield: 86% (80 mg). 1H NMR (400 MHz, CDCl3): δ 7.64–7.63 (m, 4H, Ar-H), 7.52–7.47 (m, 3H, Ar-H), 7.42– S-11
7.38 (m, 2H, Ar-H), 5.48 (d, J = 47.8 Hz, 2H, CH2); 13C NMR (101 MHz, CDCl3):δ 141.71 (d, JC-F = 1.0 Hz), 140.71, 136.75 (d, JC-F = 17.0 Hz), 129.17 (d, JC-F = 1.0 Hz), 128.92, 127.65, 127.62, 127.26, 126.43 (d, JC-F = 3.0 Hz), 126.37 (d, JC-F = 3.2 Hz), 84.71 (d, JC-F = 166.4 Hz).; 19F NMR (376 MHz, CDCl3): δ –207.2 (t, J = 47.8 Hz, 1F); IR (film): 3061.7, 3033.1, 2957.4, 2896.6, 1599.1, 1481.2, 1455.3, 1424.4, 1374.6, 1194.7, 1028.2, 981.7, 897.4, 799.8, 757.1, 725.2, 699.4, 615.7, 552.2.; MS (EI, m/z, %): 186 (M+, 100).; HRMS (EI): Calcd. For C13H11F: 186.0845; Found: 186.0839.
1-(fluoromethyl)naphthalene (3c)2: Colorless oil. Isolated yield: 90% (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.3 Hz, 1H, Ar-H), 7.92–7.89 (m, 2H, Ar-H), 7.61–7.53 (m, 3H, Ar-H), 7.48 (t, J = 7.6 Hz, 1H, Ar-H), 5.86 (d, J = 47.9 Hz, 2H, CH2);
19
F NMR (376 MHz, CDCl3): δ –206.2 (t, J = 48.0 Hz, 1F); MS (EI, m/z, %):
160 (M+, 100).
2-(fluoromethyl)naphthalene (3d)2: White solid. Isolated yield: 73% (58 mg). 1H NMR (400 MHz, CDCl3): δ 7.91–7.86 (m, 4H, Ar-H), 7.53–7.50 (m, 3H, Ar-H), 5.54 (d, J = 47.7 Hz, 2H, CH2); 19F NMR (376 MHz, CDCl3): δ –202.0 (t, J = 47.8 Hz, 1F); MS (EI, m/z, %): 160 (M+, 100).
General procedure for the synthesis of compounds 3e, 3f, 3h, 3k, 3l Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-toluene)3 (30.4 mg, S-12
0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Phenylbronic pinacolate 2e (102.1 mg, 0.50 mmol), CH2FI 1 (88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction was monitored by
19
F NMR
spectroscopy using PhCF3 as an internal standard.
(fluoromethyl)benzene (3e): The yield (55%) was determined by
19
F NMR
spectroscopy using (trifluoromethyl)benzene as an internal standard. Characterization of 3e in reaction solution: 19F NMR (unlocked): δ –206.0 (t, J = 48.1 Hz, 1F). GC－ MS (EI): m/z = 110.1.
4-(fluoromethyl)styrene (3f): The yield (81%) was determined by
19
F NMR
spectroscopy using (trifluoromethyl)benzene as an internal standard. Characterization of 3e in CDCl3: 19F NMR: δ –206.3 (t, J = 47.8 Hz, 1F). GC－MS (EI): m/z = 136.1.
1-(tert-Butyl)-4-(fluoromethyl)benzene (3g)3: Colorless oil. Isolated yield: 71% S-13
(59 mg). 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.3 Hz, 2H, Ar-H), 7.35 (dd, J = 8.3, 2.0 Hz, 2H, Ar-H), 5.37(d, J = 48.1 Hz, 2H, CH2), 1.35 (s, 9H, CH3).; 19F NMR (376 MHz, CDCl3): δ –204.3 (t, J = 48.1 Hz, 1F); MS (EI, m/z, %): 166 (M+, 22.61), 151 (100).
1-methoxyl-4-(fluoromethyl)benzene (3h): The yield (72%) was determined by 19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal standard.
Characterization of 3h in reaction solution: 19F NMR (unlocked): δ –198.4 (t, J = 48.8 Hz, 1F). GC－MS (EI): m/z = 140.1.
Procedure for the synthesis of compounds 3i. Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 4-Ethylsulfanylbenzenebronic pinacolate 2i (132.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether) to give product 3i (51 mg, yield: 60%). [ Note: This product is sensitive to acid, so the column must be eluted previously with S-14
petroleum ether/ Et3N (40/ 1 v/ v).] 1-ethylthio-4-(fluoromethyl)benzene (3i): Light yellow oil. Isolated yield: 60% (51 mg). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 7.30 (dd, J = 8.4, 1.5 Hz, 2H, Ar-H), 5.33 (d, J = 48.0 Hz, 2H, CH2), 2.97 (q, J = 7.4 Hz, 2H, CH2), 1.33 (t, J = 7.4 Hz, 3H, CH3);
13
C NMR (101 MHz, CDCl3): δ 137.81 (d, JC-F =
3.6Hz), 133.53 (d, JC-F = 17.2 Hz), 128.68 (d, JC-F = 1.4 Hz), 128.24 (d, JC-F = 5.6 Hz), 84.25 (d, JC-F = 166.0 Hz), 27.37, 14.27.; 19F NMR (376 MHz, CDCl3): δ –205.1 (t, J = 48.0 Hz, 1F); IR (film): 2963.8, 2926.9, 2853.9, 1896.9, 1602.2, 1495.7, 1451.8, 1406.4, 1375.6, 1262.6, 1217.4, 1091.2, 979.5, 838.0, 803.9, 736.8, 529.6.; MS (EI, m/z, %): 170 (M+, 100).; HRMS (EI): Calcd. For C9H11FS: 170.0566; Found: 170.0562.
1-methoxyl-2-(fluoromethyl)benzene (3j): Colorless oil. Isolated yield: 79% (55 mg). 1H NMR (400 MHz, CDCl3): δ 7.46–7.30 (m, 2H, Ar-H), 6.99 (t, J = 7.5 Hz, 1H, Ar-H), 6.91 (d, J = 8.2 Hz, 1H, Ar-H), 5.47 (q, J = 47.9 Hz, 2H, CH2), 3.86 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3):δ 157.26 (d, JC-F = 4.3 Hz), 130.12 (d, JC-F = 3.1 Hz), 129.23 (d, JC-F = 7.4 Hz), 124.74 (d, JC- F = 16.7 Hz), 120.50 (d, JC-F = 1.4 Hz ), 110.39 (d, JC-F = 1.3 Hz ), 80.47 (d, JC-F = 164.0 Hz), 55.40.;
19
F NMR (376 MHz,
CDCl3): δ –213.3 (t, J = 47.9 Hz, 1F); IR (film): 2956.8, 2840.7, 1605.7, 1591.3, 1495.6, 1465.5, 1439.4, 1378.5, 1289.4, 1250.1, 1179.0, 1123.3, 1049.7, 1029.9, 971.6, 935.4, 753.7.; MS (EI, m/z, %): 140 (M+, 100).; HRMS (EI): Calcd. For C8H9OF: 140.0637; Found: 140.0635.
S-15
1,2-(methylenedioxy)-4-(fluoromethyl)benzene (3k): The yield (72%) was determined by
19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal
standard. Characterization of 3k in reaction solution: 19F NMR (unlocked): δ –199.4 (t, J = 48.3 Hz, 1F). GC－MS (EI): m/z = 154.0.
1-phenylmethoxy-4-(fluoromethyl)benzene (3l): The yield (89%) was determined by
19
F NMR spectroscopy using (trifluoromethyl)benzene as an internal standard.
Characterization of 3l in reaction solution: 19F NMR (unlocked): δ –198.9 (t, J = 48.7 Hz, 1F). GC－MS (EI): m/z = 216.1.
Procedure for the synthesis of compounds 3m. Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 3-Methoxylbenzenebronic pinacolate 2m (117.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether : EtOAc= 200: 1) to give product 3m (42 mg, yield: 60%). 1-methoxyl-3-(fluoromethyl)benzene (3m): Colorless oil. Isolated yield: 60% (42 S-16
mg). 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.8 Hz, 1H, Ar-H), 6.97–6.90 (m, 3H, Ar-H), 5.37 (d, J = 47.7 Hz, 2H, CH2), 3.83 (s, 3H, CH3).;
13
C NMR (101 MHz,
CDCl3):δ 159.84, 137.78 (d, JC-F = 17.1 Hz), 129.69, 119.51 (d, JC-F = 6.1 Hz), 114.41 (d, JC-F = 2.8 Hz), 112.67(d, JC-F = 6.3 Hz), 84.46 (d, JC-F = 166.8 Hz), 55.27.;
19
F
NMR (376 MHz, CDCl3): δ –207.9 (t, J = 47.7 Hz, 1F); IR (film): 2959.6, 2843.0, 1601.6, 1588.2, 1490.8, 1458.0, 1438.1, 1376.6, 1317.0, 1293.2, 1268.9, 1168.9, 1156.9, 1053.4, 1042.0, 992.9, 857.5, 783.9, 740.1, 693.2.; MS (EI, m/z, %): 140 (M+, 100).; HRMS (EI): Calcd. For C8H9OF: 140.0637; Found: 140.0638.
Procedure for the synthesis of compounds 3n Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-(methanesulfonyl)benzenebronic pinacolate 2n (141.1 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 1: 1) to give product 3n (73 mg, yield: 78%). 4-fluoromethyl-1-(methanesulfonyl)benzene(3n): Light yellow solid. Isolated yield: 78% (73 mg). Melting Point: 54–56 oC. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.0 Hz, 2H, Ar-H), 7.53 (d, J = 8.0 Hz, 2H, Ar-H), 5.46 (d, J = 46.9 Hz, 2H, CH2), 3.03 (s, 3H, CH3);
13
C NMR (101 MHz, DMSO-d6): δ 142.45 (d, JC-F = 17.6 Hz),
140.56, 127.76, 127.26 (d, JC-F = 6.9 Hz), 84.11 (d, JC-F = 170.1 Hz), 44.51.; 19F NMR S-17
(376 MHz, CDCl3): δ –215.1 (t, J = 46.9 Hz, 1F); IR (film): 3013.5, 3001.9, 2954.8, 2929.3, 2301.1, 1922.7, 1602.7, 1455.7, 1410.9, 1377.0, 1307.5, 1209.5, 1182.6, 1148.1, 1089.6, 1013.7, 917.1, 814.1, 768.8, 659.6, 554.6, 527.5, 449.2. MS (EI, m/z, %): 188 (M+, 65.58), 109 (100).; HRMS (EI): Calcd. For C8H9FO2S): 188.0307.; Found: 188.0303.
General procedure for the synthesis of compounds 3o, 3p, 3q, 3r, 3s, 3t, 3v, 3w Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-Formylbenzenebronic pinacolate 2p (116.1 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 30: 1) to give product 3p (57 mg, yield: 82%).
1-cyano-4-(fluoromethyl)benzene (3o)4: Yellow solid. Isolated yield: 69% (47 mg). 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.1 Hz, 2H, Ar-H), 7.47 (d, J = 7.9 Hz, 2H, Ar-H), 5.46 (d, J = 46.9 Hz, 2H, CH2).;
19
F NMR (376 MHz, CDCl3): δ –
215.2 (t, J = 46.9 Hz, 1F); MS (EI, m/z, %): 135 (M+, 93.76), 134 (100).
S-18
1-formyl-4-(fluoromethyl)benzene (3p): Light yellow oil. Isolated yield: 82% (57 mg). 1H NMR (400 MHz, CDCl3): δ10.03 (s, 1H, CH), 7.91(d, J = 7.9 Hz, 2H, Ar-H), 7.53 (d, J = 7.8 Hz, 2H, Ar-H), 5.48 (d, J = 47.0 Hz, 2H, CH2); 13C NMR (101 MHz, CDCl3):δ 191.80, 142.90 (d, JC-F = 17.1 Hz), 136.39, 130.00, 127.00 (d, JC-F = 6.9 Hz), 83.50 (d, JC-F = 169.4 Hz).;
19
F NMR (376 MHz, CDCl3): δ –214.3 (t, J = 46.9 Hz,
1F); IR (film): 2959.1, 2832.0, 1700.6, 1611.8, 1580.0, 1425.9, 1378.1, 1306.4, 1211.4, 1168.6, 1009.0, 823.0, 776.3.; MS (EI, m/z, %): 138 (M+, 80.08), 137 (100).; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0477.
1-formyl-3-(fluoromethyl)benzene (3q): Light yellow oil. Isolated yield: 52% (36 mg). 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H, CH), 7.87 (d, J = 7.3 Hz, 2H, Ar-H), 7.64 (d, J = 7.5 Hz, 1H, Ar-H), 7.57 (t, J = 7.5 Hz, 1H), 5.46 (d, J = 47.4 Hz, 2H, CH2);
13
C NMR (101 MHz, CDCl3): δ 191.79, 137.46 (d, J = 17.8 Hz), 136.73,
132.92 (d, J = 5.9 Hz), 129.95 (d, J = 2.3 Hz), 129.37, 128.08 (d, J = 6.3 Hz), 83.59 (d, J = 168.3 Hz).; 19F NMR (376 MHz, CDCl3): δ –205.3 (t, J = 47.4 Hz, 1F); IR (film): 2964.3, 2900.6, 2827.3, 2734.5, 1704.7, 1608.9, 1590.8, 1451.6, 1374.2, 1291.6, 1253.2, 1156.3, 1143.8, 983.8, 903.2, 798.6, 780.9, 691.7, 652.8, 610.5.;MS (EI, m/z, %): 138 (17.34), 109 (100) .; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0479.
S-19
1-formyl-2-(fluoromethyl)benzene (3r): Light yellow oil. Isolated yield: 75% (52 mg). 1H NMR (400 MHz, CDCl3): δ10.10 (d, 1H, J = 1.2 Hz, CH), 7.87 (d, J = 7.6 Hz, 1H, Ar-H), 7.75-7.64 (m, 1H, Ar-H), 7.55 (t, J = 7.3 Hz, 1H, Ar-H), 7.26 (s, 1H, Ar-H), 5.87 (d, J = 47.9 Hz, 2H).;
13
C NMR (101 MHz, CDCl3):δ 193.12, 139.27 (d, JC-F =
17.5 Hz), 134.17, 132.36 (d, JC-F = 1.5 Hz), 128.11 (d, JC-F = 1.4 Hz), 125.94 (d, JC-F = 1.5 Hz), 82.50 (d, JC-F = 169.0 Hz).;
19
F NMR (376 MHz, CDCl3): δ –218.9 (t, J =
47.9 Hz, 1F); IR (film): 3075.3, 2980.7, 2832.1, 2742.6, 1695.2, 1603.7, 1577.2, 1454.9, 1366.8, 1301.8, 12101.0, 1111.2, 1009.0, 861.8, 756.8, 660.2, 593.3.; MS (EI, m/z, %): 138 (100.00).; HRMS (EI): Calcd. For C8H7FO: 138.0481; Found: 138.0483.
1-acetyl-4-(fluoromethyl)benzene (3s): Yellow oil. Isolated yield: 75% (57 mg). 1
H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.0 Hz, 2H, Ar-H), 7.46 (d, J = 7.9 Hz, 2H,
Ar-H), 5.45 (d, J = 47.1 Hz, 2H, CH2), 2.62 (s, 3H, CH3);
13
C NMR (101 MHz,
CDCl3):δ 197.61, 141.36 (d, JC-F = 17.2 Hz), 137.18, 128.82, 126.78 (d, JC-F = 6.6 Hz), 83.63 (d, JC-F = 168.6 Hz), 26.65.; 19F NMR (376 MHz, CDCl3): δ –213.2 (t, J = 47.6 Hz, 1F); IR (film): 2963.4, 1685.6, 1685.6, 1612.0, 1574.8, 1413.3, 1359.0, 1301.8, 1266.4, 1216.5, 1181.5, 1101.6, 956.9, 848.6, 815.9, 685.1, 597.5.; MS (EI, m/z, %): 152 (M+, 29.23), 137 (100).; HRMS (EI): Calcd. For C9H9FO: 152.0637; Found: 152.0633.
S-20
1-acetyl-3-(fluoromethyl)benzene (3t): Yellow oil. Isolated yield: 59% (45 mg). 1
H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H, Ar-H), 7.95 (d, J = 7.1 Hz, 1H, Ar-H),
7.59 (d, J = 7.7 Hz, 1H, Ar-H), 7.51 (t, J = 7.4 Hz, 1H, Ar-H), 5.44 (d, J = 47.5 Hz, 2H, CH2), 2.63 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3): δ 197.69, 137.45, 136.85 (d, JC-F = 17.5 Hz), 131.78 (d, JC-F = 5.9 Hz), 128.97, 128.59 (d, JC-F = 2.6 Hz), 127.01 (d, JC-F = 6.2 Hz), 83.93 (d, JC-F = 167.7 Hz), 26.65.;
19
F NMR (376 MHz, CDCl3): δ
-209.3 (t, J = 47.5 Hz, 1F); IR (film): 2963.4, 1687.1, 1606.5, 1581.2, 1442.7, 1376.1, 1358.8, 1277.7, 1194.9, 981.5, 797.1, 692.2, 587.7.; MS (EI, m/z, %): 152 (M+, 28.42), 137 (100).; HRMS (EI): Calcd. For C9H9FO: 152.0637; Found: 152.0635.
General procedure for the synthesis of compounds 3u Under an argon atmosphere, Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-tolune)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were subsequently added to an oven-dried 10-mL Schlenk tube equipped with a stir bar. Then 3-Methoxycarbnylphenylbronic pinacolate 2u (123.1 mg, 0.50 mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. After being stirred at room temperature for 4 hours, the reaction mixture was diluted with Et2O and filtered through a pad of neutral alumina, then extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether : EtOAc = 30 : 1) to give product 3u (55 mg, yield: 65%).
Methyl 3-(fluoromethyl)benzoate(3u): Colorless oil. Isolated yield: 65% (55 mg). 1
H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H, Ar-H), 8.03 (d, J = 8.8 Hz, 1H, Ar-H), S-21
7.57 (d, J = 7.5 Hz, 1H, Ar-H), 7.47 (t, J = 7.6 Hz, 1H, Ar-H), 5.41 (d, J = 47.5 Hz, 2H, CH2), 3.92 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3):δ 166.65, 136.65 (d, JC-F = 17.6 Hz), 131.67 (d, JC-F = 5.9 Hz), 130.59, 129.83 (d, JC-F = 2.6 Hz), 128.75,128.39 (d, JC-F = 6.2 Hz), 83.88 (d, JC-F = 167.7 Hz), 52.20.; 19F NMR (376 MHz, CDCl3): δ – 209.1 (t, J = 47.6 Hz, 1F); IR (film): 2954.6, 1724,6, 1450.0, 1434.8, 1377.2, 1289.7, 1206.9, 1108.4, 1086.5, 977.9, 915.4, 749.9, 696.0, 606.2.; MS (EI, m/z, %): 168 (M+, 44.99), 137 (100).; HRMS (EI): Calcd. For C9H9FO2: 168.0587; Found: 168.0588.
Methyl 4-(fluoromethyl)benzoate(3v)5:Colorless oil. Isolated yield: 83% (70 mg). 1
H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 2H, Ar-H), 7.43 (d, J = 7.8 Hz, 2H,
Ar-H), 5.45 (d, J = 47.2 Hz, 2H, CH2), 3.93 (s, 3H, CH3);
13
C NMR (101 MHz,
CDCl3):δ 166.65, 141.21 (d, JC-F = 17.2 Hz), 130.28 (d, JC-F = 2.4 Hz), 129.85, 126.58 (d, JC-F = 6.6 Hz), 83.67 (d, JC-F = 168.5 Hz), 52.15.; 19F NMR (376 MHz, CDCl3): δ – 212.9 (t, J = 47.2 Hz, 1F); IR (film): 2954.6, 1723.9, 1617.7, 1436.3, 1379.3, 1310.8, 1281.4, 1192.3, 1178.4, 1109.2, 1017.6, 861.7, 799.5, 757.8, 707.1, 634.1.; MS (EI, m/z, %): 168 (M+, 37.16), 137 (100).; HRMS (EI): Calcd. For C9H9FO2: 168.0587; Found: 168.0584.
1-nitro-4-(fluoromethyl)benzene (3w)2: Yellow solid. Isolated yield: 72% ( 56 mg). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.0 Hz, 2H, Ar-H), 7.50 (d, J = 8.3 Hz, 2H, Ar-H), 5.48 (d, J = 46.8 Hz, 2H, CH2).;
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C NMR (101 MHz, CDCl3):δ
147.92, 143.45 (d, JC-F = 17.7 Hz), 127.06 (d, JC-F = 7.1 Hz), 123.80, 82.89 (d, JC-F = 170.6 Hz).;
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F NMR (376 MHz, CDCl3): δ –215.7 (t, J = 46.8 Hz, 1F); IR (film): S-22
3118.3, 3083.9, 2959.1, 2851.6, 1929.1, 1608.4, 1523.2, 1458.6, 1348.4, 1316.9, 1212.9, 1177.5, 1109.3, 1012.7, 847.9, 800.7, 739.3, 695.0.; MS (EI, m/z, %): 155 (M+, 100).; HRMS (EI): Calcd. For C7H6FNO2: 155.0383; Found: 155.0385.
Procedure for the synthesis of compounds 3x Pd(dppf)Cl2 (36.7 mg, 0.05mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (1.5 mL), and CH2Cl2 (1.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. CH2FI (1, 88.0 mg, 0.55 mmol), 4-(dimethylcarbonyl)benzenebronic pinacolate 2x (137.6 mg, 0.50 mmol), and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with Et2O and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether: EtOAc = 3: 1) to give product 3x (64 mg, yield: 71%).
4-fluoromethyl-1-(dimethylcarbonyl)benzene (3x):Dark brown oil. Isolated yield: 71% (64 mg). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.9 Hz, 2H, Ar-H), 7.40 (d, J = 7.7 Hz, 2H, Ar-H), 5.39 (d, J = 47.5 Hz, 2H, CH2), 3.04 (s, 6H, CH3); 13C NMR (101 MHz, DMSO-d6):δ 170.19, 137.72 (d, JC-F = 16.8 Hz), 137.28 (d, JC-F = 3.2 Hz), 127.91 (d, JC-F = 5.9 Hz), 127.62 (d, JC-F = 0.9 Hz), 84.23 (d, JC-F = 162.5 Hz), 39.39, 35.30.; 19F NMR (376 MHz, CDCl3): δ –209.5 (t, J = 47.5 Hz, 1F); IR (film): 2941.9, 1634.6, 1518.9, 1491.7, 1448.1, 1393.9, 1265.5, 1218.3, 1080.7, 977.7, 846.7, 760.8, 621.2, 567.5. MS (EI, m/z, %): 181 (M+, 52.73), 137 (100).; HRMS (EI): Calcd. For [C10H11FNO]+([M-H]+): 180.0825; Found: 180.0821. S-23
6. Preparation of compound 5
Compound 4awas prepared according to the literature procedures.6 To a mixture of estrone (4, 4.50 g, 16.67 mmol) and DIPEA (3.14 mL, 18.32 mmol, 1.1 eq) in CH2Cl2 (80 mL) were added Tf2O (3.08 mL, 18.32 mmol, 1.1 eq) under argon at 0 oC. The reaction mixture was stirred at room temperature for 0.5 h. Then, the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, and dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography to give estrone trifluoromethanesulfonic ester (4a, 5.83 g, 87%).
Compound 4a6: Yellow solid. Isolated yield: 87% (5.83 g). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 8.6 Hz, 1H, Ar-H), 7.03 (dd, J = 8.6, 2.6 Hz, 1H, Ar-H), 6.99 (d, J = 2.5 Hz, 1H, Ar-H), 2.94 (dd, J = 8.8, 4.1 Hz, 2H, CHn), 2.51 (dd, J = 18.7, 8.6 Hz, 1H, CHn), 2.44–2.36 (m, 1H, CHn), 2.29 (td, J = 10.8, 4.2 Hz, 1H, CHn), 2.23-2.00 (m, 3H, CHn), 2.00–1.92 (m, 1H, CHn), 1.71–1.37 (m, 6H, CHn), 0.91 (s, 3H, CH3).; 19F NMR (376 MHz, CDCl3): δ –73.0 (s, 3F); IR (film): 2933.7, 2868.8, 1740.7, 1489.7, 1421.0, 1249.1, 1212.2, 1141.2, 1055.0, 1012.1, 920.0, 837.1, 607.8, 511.7.; MS (ESI, m/z): 403.0 (M+H+). 424.9 (M+Na+); HRMS (ESI):[M+Na]+ Calcd. For C19H21F3NaO4S: 425.1005; Found: 425.0999.
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Compound 4b was prepared according to the literature procedures.6 To a 250-mL of sealed tube were added estrone trifluoromethanesulfonic ester (4.50 g, 11.19 mmol), bis(pinacolato)diboron (5.68 g, 22.38 mmol, 2.0 equiv), KOAc (3.30 g, 33.57 mmol. 3.0 eq), and Pd(dppf)Cl2 (328.4 mg, 0.45 mmol, 0.04 eq) under argon, followed by dioxane (45 mL) with stirring. The sealed tube was heated to 120 oC (oil bath). After stirring for 8h, the reaction mixture was cooled to room temperature and diluted with THF, filtered through a pad of Mg2SO4 and Celite, then concentrated. The residue was recrystallized with EtOAc and petroleum ether to give 2.93 g 4b in 69% yield.
Compound 4b6: White solid. Isolated yield: 69% (2.93 g). 1H NMR (400 MHz, CDCl3): δ7.60 (d, J = 8.0 Hz, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.32 (d, J = 7.7 Hz, 1H, Ar-H), 2.93 (dd, J = 10.4, 4.5 Hz, 2H, CHn), 2.54-2.43 (m, 2H, CHn), 2.37-2.30 (m, 1H, CHn), 2.19–1.95 (m, 4H, CHn), 1.65–1.42 (m, 6H, CHn), 1.34 (s, 12H, CH3), 0.90 (s, 3H, CH3).; MS (ESI, m/z): 403.1 (M+Na+).
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Compound 5 was prepared according to the standard procedures. Pd2(dba)3 (22.9 mg, 0.025mmol), P(o-toluene)3 (30.4 mg, 0.10 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), DMF (0.5 mL), and CH2Cl2 (0.5 mL) were added to an oven-dried 10-mL Schlenk tube equipped with a stir bar in turn under an argon atmosphere. Estrone boronic pinacolate 4b (190.1 mg, 0.50mmol), CH2FI (1, 88.0 mg, 0.55 mmol) and H2O (45 μL, 2.50 mmol) were added into the reaction mixture. Then, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and filtered through a pad of neutral alumina, then extracted with EtOAc and H2O. The organic phase was dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography (Petroleum ether/EtOAc = 10: 1) to give product 5 (104 mg, yield: 73%).
Compound 57: White solid. Isolated yield: 73% (104 mg). 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.0 Hz, 1H, Ar-H), 7.18 (d, J = 8.0 Hz, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 5.32 (d, J = 48.1 Hz, 2H, CH2), 2.94 (dd, J = 8.7, 4.0 Hz, 2H, CHn), 2.59–2.47 (m, 1H, CHn), 2.47–2.39 (m, 1H, CHn), 2.32 (t, J = 10.4 Hz, 1H, CHn), 2.22-1.91 (m, 4H, CHn), 1.74–1.37 (m, 6H, CHn), 0.92 (s, 3H, CH3).; 13C NMR (101 MHz,CDCl3): δ 220.69, 140.54 (d, JC-F = 3.3 Hz), 136.90 (d, JC-F = 1.5 Hz), 133.67 (d, JC-F = 17.0 Hz), 128.49 (d, JC-F = 5.5 Hz), 125.68 (d, JC-F = 1.3 Hz), 125.22 (d, JC-F = 5.4 Hz), 84.55 (d, JC-F = 165.3 Hz), 50.52, 47.96, 44.42, 38.08, 25.85, 31.61, 29.33, 26.42, 25.74, 21.61, 13.85.;
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F NMR (376 MHz, CDCl3): δ –204.7 (t, J = 48.1 Hz, 1F); IR
(film): 2929.3, 2862.5, 1738.6, 1500.3, 1454.9, 1373.8, 1256.8, 1083.7, 1007.8, 976.3, 887.5, 821.9, 739.3.; MS (ESI, m/z): 287.0 (M+H+). HRMS (ESI):[M+H]+ Calcd. For C19H24FO+: 287.1806; Found: 287.1804.
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7. References: (1) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552. (2) Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur, V. Org. Lett. 2012, 14, 2754. (3) Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494. (4) Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16, 6338. (5) Zhao, Y.; Jiang, F.; Gao, B.; Shen, X.; Hu, J. ACS Catal. 2013, 3, 631. (6) (a) Zhao, Y.; Hu, J. Angew. Chem., Int. Ed. 2012, 51, 1033. (b) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew. Chem., Int. Ed .2014, 53, 1669. (c) Ishiyama, T.; Itoh, Y., Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447 (7) Zhao, Y.; Gao, B.; Ni, C.; Hu, J. Org. Lett. 2012, 14, 6080.
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NMR spectra of new compounds
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