SUPPORTING INFORMATION
Table of Content
1. General information………………………………………………………….….2
2. Experimental data…………………………………………………………….….2
2.1 Reaction optimization……………………………………………………………2
2.2 General procedure for regioselective synthesis of N-heteroaromatic
trifluoromethoxyl compounds by direct O-CF3 bond formation…………….…..5
2.3 Mechanistic studies……………………………………………………………...10
3. NMR Spectra……………………..……………………………………………...11
1
1. General information
All manipulations were carried out in glass reaction tube equipped with a
magnetic stir bar under air atmosphere. Unless otherwise mentioned, solvents and
reagents were purchased from commercial sources and used as received.
Analytical thin-layer chromatography was performed using silica gel 60 GF254
plates. The transformation progress was indicated by GC (Shimadzu GC-2010
Plus) or GC-MS (Thermo Fisher Scientific DSQⅡ). The high resolution mass
spectrum was received via Agilent Technologies 6540 UHD Accurate-mass Q-Tof
LC/MS, with ESI as ion source. Moreover, NMR spectra were obtained on Bruker
AVANCE III 400 systems using CDCl3 as solvent, TMS as internal standard
substance, with proton, fluorine and carbon resonances at 400, 376 and 100 MHz,
respectively.
2. Experimental data
2.1 Reaction optimization
Table S1 The effect of bases on the O-CF3 bond formation a.
O
Br
1.0 eq bases
O
N
1
I
CF3
OH
2
Entry
1
2
3
4
5
6
Br
1.0 mL CH3NO2
N
OCF3
3
Yield b (%)
0
0
0
0
0
0
Bases
K3PO4
Cs2CO3
Ag2CO3
CsF
Et3N
DIPEA
[a] Reaction conditions: 0.1 mmol 1, 0.1 mmol 2, 1.0 equiv bases in the CH3NO2 (1.0 mL) were
stirred at 70 oC for 48 h under atmosphere. [b] The yields are determined by GC using n-dodecane
as an internal standard and base on 2.
Table S2 The effect of Lewis acids on the O-CF3 bond formation a.
O
0.1 eq Lewis acids
Br
Br
O
N
1
Entry
1
2
3
OH
2
I
CF3
1.0 mL CH3NO2
N
OCF3
3
Lewis acids
BF3.Et2O
AlCl3
ZnCl2
2
Yield b (%)
0
0
0
4
5
6
7
8c
ZnBr2
FeCl3
FeCl2
SbF5
ZnCl2
0
0
0
0
0
[a] Reaction conditions: 0.1 mmol 1, 0.1 mmol 2, 0.1 equiv Lewis acids in the CH3NO2 (1.0 mL)
were stirred at 70 oC for 48 h under atmosphere. [b] The yields are determined by GC using
n-dodecane as an internal standard and base on 2. [c] 1.0 equiv Lewis acids.
Table S3 The effect of Brønsted acids on the O-CF3 bond formation a.
O
Br
Br
O
N
I
CF3
OH
1
1.0 mL CH3NO2
N
3
2
Entry
1
2
3
OCF3
Yield b (%)
8
13
15
Brønsted acids
CF3COOH
AcOH
Citric acid
[a] Reaction conditions: 0.1 mmol 1, 0.1 mmol 2, 1.0 equiv Brønsted acids in the CH3NO2 (1.0
mL) were stirred at 70 oC for 48 h under atmosphere. [b] The yields are determined by GC using
n-dodecane as an internal standard and base on 2.
Table S4 The effect of different gas & light & quantity of 2 on the O-CF3 bond
formation a.
O
Br
Br
O
N
1
OH
2
I
CF3
1.0 mL CH3NO2
N
OCF3
3
0.1 mmol
Entry
Gas
Quantity of 2
Yield b (%)
1
2
3
4
5c
Atmosphere
Atmosphere
Ar
O2
Atmosphere
0.1 mmol
0.2 mmol
0.2 mmol
0.2 mmol
0.2 mmol
24
33
30
27
27
[a] Reaction conditions: 0.1 mmol 1 and 2 in the CH3NO2 (1.0 mL) were stirred at 70 oC for 48 h.
[b] The yields are determined by GC using n-dodecane as an internal standard and base on 1. [c]
Dark condition.
Table S5 The effect of temperature on the O-CF3 bond formation a.
3
O
Br
N
1.0 mL CH3NO2
I
CF3
OH
1
Br
temperature
O
N
OCF3
3
2
Entry
Temperature (oC)
Yield b (%)
1c
2
3d
4d
35
70
100
120
31
46
67
66
[a] Reaction conditions: 0.3 mmol 1 and 0.1 mmol 2 in the CH3NO2 (1.0 mL) were stirred for 48 h
under atmosphere. [b] The yields are determined by GC using n-dodecane as an internal standard
and base on 2. [c] stirred for 72 h. [d] stirred for 5 h.
Table S6 The effect of UV on the O-CF3 bond formation a.
O
Br
N
O
I
CF3
OH
1
Br
UV
1.0 mL CH3NO2
N
OCF3
3
2
Entry
1
2
Yield b (%)
53
53
UV (nm)
250
316
[a] Reaction conditions: 0.3 mmol 1 and 0.1 mmol 2 in the CH3NO2 (1.0 mL) were stirred at 100
oC for 5 h under atmosphere. [b] The yields are determined by GC using n-dodecane as an internal
standard and base on 2.
Table S7 The effect of AIBN & BOP on the O-CF3 bond formation a.
O
Br
AIBN/BOP
N
1
Entry
1
2
O
I
CF3
OH
1.0 mL CH3NO2
Br
N
OCF3
2
3
Radical initiators
AIBN
BOP
Yield b (%)
22
39
[a] Reaction conditions: 0.3 mmol 1, 0.1 mmol 2 and 0.5 equiv of AIBN/BOP in the CH3NO2 (1.0
mL) were stirred at 100 oC for 5 h under atmosphere. [b] The yields are determined by GC using
n-dodecane as an internal standard and base on 2.
4
2.2 General procedure for regioselective synthesis of N-heteroaromatic
trifluoromethoxyl compounds by direct O-CF3 bond formation.
O
R
N
O
I
CF3
OH
1a-w
3.0 mmol
100 oC
CH3NO2
R
N
OCF3
3a-w
2
1.0 mmol
A dried glass reaction tube equipped with a magnetic stir bar was charged with 1 (3.0
mmol), 2 (316 mg, 1.0 mmol) and CH3NO2 (10.0 mL). The reaction mixture was then
stirred at 100 ºC for 5 h. The reaction progress was monitored by TLC. The reaction
mixture was cooling to room temperature and filtered through a pad of celite, and
washed with ethyl acetate. The combined organic solvent was concentrated in vacuo.
The residue was purified by silica gel flash chromatography to produce the desired
product.
Br
N
OCF3
5-bromo-2-(trifluoromethoxy)pyridine (3a, yield 67%): yellow oil, 1H NMR (400
MHz, CDCl3 ): δ = 8.38 (d, J = 2.8 Hz, 1H), 7.89 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.94 (d,
J = 8.8 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ = 56.8 (s). 13C NMR(100 MHz,
CDCl3): δ = 155.4, 148.8, 142.7, 119.9 (q, J = 260.1 Hz), 117.6, 114.5. GC-MS(EI):
240.9, 242.9 ( [M] + ).
I
N
OCF3
5-iodo-2-(trifluoromethoxy)pyridine (3b, yield 62%): yellow oil, 1H NMR (400
MHz, CDCl3): δ = 8.52 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.84
(d, J = 8.8 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ = 56.7 (s). 13C NMR(100 MHz,
CDCl3): δ = 156.2, 153.9, 148.2, 119.9 (q, J = 260.0 Hz), 114.9 (d, J = 1.2 Hz), 88.7.
HRMS (ESI): Calcd for C6H4F3INO [M+H]+: 289.9290; Found: 289.9284.
O
O
N
OCF3
benzyl 6-(trifluoromethoxy)pyridine-3-carboxylate (3c, yield 35%): yellow oil, 1H
NMR (400 MHz, CDCl3): δ = 8.99 (d, J = 2.0 Hz, 1H), 8.40 (dd, J = 8.4 Hz, 2.4 Hz,
1H), 7.45–7.36 (m, 5H), 7.04 (d, J = 8.8 Hz, 1H), 5.40 (s, 2H). 19F NMR (376 MHz,
CDCl3) δ = 56.5 (s). 13C NMR(100 MHz, CDCl3): δ = 164.1, 159.3, 150.1, 141.5,
135.3, 128.7, 128.6, 128.3, 124.4, 119.9 (q, J = 260.9 Hz), 112.2, 67.3. HRMS (ESI):
Calcd for C14H11F3NO3 [M+H]+: 298.0691; Found: 298.0690.
5
O
Br
O
N
OCF3
methyl 5-bromo-6-(trifluoromethoxy)pyridine-3-carboxylate (3d, yield 44%):
white solid, 1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 2.0
Hz, 1H), 3.97 (s, 3H). 19F NMR (376 MHz, CDCl3) δ = 56.6 (s). 13C NMR(100 MHz,
CDCl3): δ = 163.6, 155.9, 147.6, 144.4, 125.4, 120.0 (q, J = 262.8 Hz), 107.7, 52.8.
HRMS (ESI): Calcd for C8H6BrF3NO3 [M+H]+: 299.9483, 301.9463; Found:
299.9482, 301.9461.
N
OCF3
5-cyclopropyl-2-(trifluoromethoxy)pyridine (3e, yield 57%): yellow oil, 1H NMR
(400 MHz, CDCl3): δ = 8.12 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.8 Hz, 2.8 Hz, 1H),
6.92 (d, J = 8.8 Hz , 1H), 1.94 – 1.88 (m, 1H), 1.06 – 1.02 (m, 2H), 0.72 - 0.70 (m,
2H). 19F NMR (376 MHz, CDCl3) δ = 56.6 (s). 13C NMR(100 MHz, CDCl3): δ =
154.7, 145.9, 137.9, 137.0, 120.2 (q, J = 258.3 Hz), 112.7 (d, J = 1.2 Hz), 12.4, 8.8.
HRMS (ESI): Calcd for C9H9F3NO [M+H]+: 204.0636; Found: 204.0631.
O
N
OCF3
5-(4-methoxyphenyl)-2-(trifluoromethoxy)pyridine (3f, yield 47%): yellow solid,
1
H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.4 Hz, 2.4
Hz, 1H), 7.47 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 8.4 Hz , 1H), 7.01 (d, J = 8.4 Hz, 2H),
3.86 (s, 3H). 19F NMR (376 MHz, CDCl3) δ = 56.4 (s). 13C NMR(100 MHz, CDCl3):
δ = 159.9, 155.5, 145.6, 138.2, 135.1, 128.9, 128.2, 120.2 (q, J = 258.9 Hz), 114.7,
112.9 (d, J = 1.24 Hz), 55.4. HRMS (ESI): Calcd for C13H11F3NO2 [M+H]+: 270.0742;
Found: 270.0748.
O
N
OCF3
4-(benzyloxy)-2-(trifluoromethoxy)pyridine (3g, yield 78%): yellow oil, 1H NMR
(400 MHz, CDCl3): δ = 8.14 (d, J = 5.6 Hz, 1H), 7.43-7.36 (m, 5H), 6.82 (dd, J = 5.6
Hz, 2.0 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H). 19F NMR (376 MHz, CDCl3) δ
= 56.2 (s). 13C NMR(100 MHz, CDCl3): δ = 167.8, 158.3, 148.5, 135.0, 128.8, 128.7,
127.6, 120.1 (q, J = 259.1 Hz), 110.0, 98.8, 70.5. HRMS (ESI): Calcd for
C13H11F3NO2 [M+H]+: 270.0742; Found: 270.0742.
6
Br
N
OCF3
4-bromo-3-cyclopropyl-2-(trifluoromethoxy)pyridine (3h, yield 54%): yellow oil,
1
H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H),
1.80-1.75 (m, 1H), 1.16-1.10 (m, 2H), 0.86 - 0.84 (m, 2H). 19F NMR (376 MHz,
CDCl3) δ = 55.8 (s). 13C NMR(100 MHz, CDCl3): δ = 155.9, 144.7, 139.5, 127.5,
126.4, 120.1 (q, J = 259.7 Hz), 11.7, 8.2. HRMS (ESI): Calcd for C9H8BrF3NO
[M+H]+: 281.9741, 283.9721; Found: 287.9738, 283.9718.
O
O
N
OCF3
methyl 2-(trifluoromethoxy)pyridine-4-carboxylate (3i, yield 46%): yellow oil, 1H
NMR (400 MHz, CDCl3): δ = 8.44 (dd, J = 5.0 Hz, 0.32 Hz, 1H), 7.75 (dd, J = 5.0 Hz,
1.2 Hz, 1H), 7.53 (s, 1H), 3.95 (s, 3H). 19F NMR (376 MHz, CDCl3) δ = 56.7 (s). 13C
NMR(100 MHz, CDCl3): δ = 164.2, 157.4 (d, J = 1.3 Hz), 148.7, 141.8, 121.1, 120.0
(q, J = 259.9 Hz), 112.8 (d, J = 1.1 Hz), 53. HRMS (ESI): Calcd for C8H7F3NO3
[M+H]+: 222.0378; Found: 222.0373.
Br
N
OCF3
3-bromo-2-(trifluoromethoxy)pyridine (3j, yield 43%): yellow oil, 1H NMR (400
MHz, CDCl3): δ = 8.24 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 7.98 (dd, J = 8.0 Hz, 2.0 Hz, 1H),
7.11 (dd, J = 8.0 Hz, 4.8 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ = 56.4 (s). 13C NMR
(100 MHz, CDCl3): δ = 153.4, 145.9, 143.5, 122.7, 120.1 (q, J = 261.1 Hz), 108.4.
HRMS (ESI): Calcd for C6H4BrF3NO [M+H]+: 241.9428, 243.9408; Found: 241.9422,
243.9405.
CN
N
OCF3
2-(trifluoromethoxy)pyridine-3-carbonitrile (3k, yield 54%): yellow oil, 1H NMR
(400 MHz, CDCl3): δ = 8.45 (dd, J = 5.2 Hz, 2.0 Hz, 1H), 8.02 (dd, J = 8.0 Hz, 2.0 Hz,
1H), 7.30 (dd, J = 8.0 Hz, 5.2 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ = 56.6 (s). 13C
NMR(100 MHz, CDCl3): δ = 155.6, 150.3, 142.9, 120.3, 118.7 (q, J = 263.2 Hz),
111.9, 98.3. HRMS (ESI): Calcd for C7H4F3N2O [M+H]+: 189.0276; Found:
189.0265.
O
O
CN
N
7
OCF3
ethyl 3-cyano-6-methyl-2-(trifluoromethoxy)pyridine-4-carboxylate (3l, yield
39%): yellow oil, 1H NMR (400 MHz, CDCl3): δ = 7.69 (s, 1H), 4.49 (q, J = 7.2 Hz,
2H), 2.65 (s, 3H), 1.44(t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ = 56.4 (s).
13
C NMR(100 MHz, CDCl3): δ = 163.0, 162.0, 157.5, 144.0, 121.2, 119.7 (q, J =
263.2 Hz), 111.6, 95.0, 63.4, 24.6, 13.9. HRMS (ESI): Calcd for C11H10F3N2O3
[M+H]+: 275.0644; Found: 275.0642.
N
OCF3
1-(trifluoromethoxy)isoquinoline (3q, yield 62%): yellow oil, 1H NMR (400 MHz,
CDCl3): δ = 8.18 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.83 (d, J =
8.0 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.66 – 7.62 (m, 1H), 7.52 (d, J = 6.0 Hz, 1H). 19F
NMR (376 MHz, CDCl3) δ = 56.1 (s). 13C NMR(100 MHz, CDCl3): δ = 153.6, 139.1,
138.7, 131.4, 128.1, 126.5, 123.3, 120.4 (q, J = 260.2 Hz), 119.5. HRMS (ESI): Calcd
for C10H7F3NO [M+H]+: 214.0480; Found: 214.0476.
Br
N
OCF3
6-bromo-2-(trifluoromethoxy)quinoline (3r, yield 41%): yellow oil, 1H NMR (400
MHz, CDCl3): δ = 8.12 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.86 – 7.78 (m,
2H), 7.10 (d, J = 8.8 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ = 56.4 (s). 13C
NMR(100 MHz, CDCl3): δ = 155.0, 144.4, 139.6, 134.0, 130.2, 129.5, 127.7, 120.2,
120.0 (q, J = 260.4 Hz), 113.2 (d, J = 1.1 Hz). HRMS (ESI): Calcd for C10H6BrF3NO
[M+H]+: 291.9585, 293.9564; Found: 291.9578, 293.9561.
Br
N
OCF3
4-(bromomethyl)-2-(trifluoromethoxy)quinoline (3s, yield 32%): yellow oil, 1H
NMR (400 MHz, CDCl3): δ = 8.08 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 8.03 (dd, J = 8.4 Hz,
0.4 Hz, 1H), 7.76 (dtd, J = 8.4 Hz, 1.2 Hz, 1H), 7.64 (dtd, J = 8.4 Hz, 1.2 Hz, 1H),
7.15 (s, 1H), 4.81 (s, 2H). 19F NMR (376 MHz, CDCl3) δ = 56.3 (s). 13C NMR(100
MHz, CDCl3): δ = 154.4, 147.4, 146.4, 130.8, 129.5, 126.9, 124.5, 123.3, 120.1 (q, J
= 260.5 Hz), 112.5, 27.2. HRMS (ESI): Calcd for C11H8BrF3NO [M+H]+: 305.9741,
307.9721; Found: 305.9738, 307.9718.
OCF3
N
N
S
2-(methylthio)-4-(trifluoromethoxy)pyrimidine (3t, yield 65%): yellow oil, 1H
NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 5.6 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 2.53
(s, 3H). 19F NMR (376 MHz, CDCl3) δ = 56.5 (s). 13C NMR(100 MHz, CDCl3): δ =
8
172.5, 161.7, 158.9, 118.7 (q, J = 262.9 Hz), 102.4, 13.1. HRMS (ESI): Calcd for
C6H6F3N2OS [M+H]+: 211.0153; Found: 211.0150.
OCF3
N
S
3-(trifluoromethoxy)benzo[d]isothiazole (3w, yield 70%): yellow oil, 1H NMR (400
MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.60 (dtd, J =
8.0 Hz, 1.2 Hz, 1H), 7.64 (dtd, J = 8.0 Hz, 1.2 Hz, 0.4 Hz, 1H). 19F NMR (376 MHz,
CDCl3) δ = 57.8 (s). 13C NMR(100 MHz, CDCl3): δ = 153.1, 152.2, 129.4, 125.6,
124.6, 122.6, 120.3 (q, J = 262.2 Hz), 120.2. HRMS (ESI): Calcd for C8H5F3NOS
[M+H]+: 220.0044; Found: 220.0040.
9
2.3 Mechanistic studies.
To gain insight of the reaction mechanism, we carried out several experiments
(Scheme 1).
Scheme 1. Mechanistic investigation experiments.
References
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3087–3092.
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9785.
[3] X. Liu, F. Xiong, X. Huang, L. Xu, P. Li, X. Xu, Angew. Chem. Int. Ed. 2013, 52, 6962–6966.
[4] R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew. Chem. Int. Ed.
2009, 48, 4332–4336.
[5] K. Stanek, R. Koller, A. Togni, J. Org. Chem. 2008, 73, 7678–7685.
[6] K. N. Hojczyk, P. J. Feng, C. B. Zhan, M. –Y. Ngai, Angew. Chem. Int. Ed. 2014, 53,
14559–14563.
10
3. NMR Spectra
11
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13
14
15
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20
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