n-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl ... ·...
TRANSCRIPT
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Supporting Information for
N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide
as a new inhibitors of mitochondrial complex III: Synthesis,
biological evaluation and computational simulations
Hua Chenga, 1, Lu Yanga, 1, Hong-Fu Liua, Rui Zhanga, *, Cheng Chenb, *, Yuan Wuc,
Wen Jiangc
a Department of Chemical Engineering and Food Science, Hubei University of Arts
and Science, 296 Longzhong Road, Xiangyang 441053, P. R. China;
b State Key Laboratory of Advanced Technology for Materials Synthesis and
Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R.
China.
c Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, P. R.
China.
Contents:
1. Experimental Section ............................................................................................... S2-S5
2. Analytical data for compounds 1d’, 1e’, 3a-3e’ .................................................... S6-S12
3. 1H-NMR, 13C-NMR and HR-MS spectra for compounds 1d’, 1e’, 3a-3e’ ......... S13-S68
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1. Experimental Section
1.1 General Considerations
1H NMR spectra were obtained on a Bruker Avance 500 spectrometer in CDCl3 or
DMSO-d6 with TMS as the internal reference, while 13C NMR spectra were recorded
in CDCl3 or DMSO-d6 on a Bruker Avance 500 (125 MHz) spectrometer. The
following abbreviations were used to designate multiplicities: s = singlet, d = doublet,
t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet
of doublet of doublets, m = multiplet. HRMS were determined on a Bruker Daltonics
microTOF-QII or a Thermo Fisher Q ExactiveTM UHMR OrbitrapTM instrument.
Melting points were taken on a Buchi B-560 melting point apparatus and were
uncorrected. Ordinary reagents and solvents were purchased from commercial
suppliers and directly used without further treatment. 4-phenoxyaniline (1p),
benzoic acid (2a), 2-methylbenzoic acid (2b), 3-methylbenzoic acid (2c),
4-methylbenzoic acid (2d), 2-chlorobenzoic acid (2e), 3-chlorobenzoic acid (2f),
4-chlorobenzoic acid (2g), 2,4,6-trichlorobenzoic acid (2h),
2-chloro-4-(trifluoromethyl)benzoic acid (2i), 3-methoxybenzoic acid (2j),
3-(tert-butyl)benzoic acid (2k), 3-fluorobenzoic acid (2l), 3-bromobenzoic acid (2m),
3-(trifluoromethoxy)benzoic acid (2n), 3-(trifluoromethyl)benzoic acid (2o), picolinic
acid (2u) and pyrazine-2-carboxylic acid (2c’) were purchased from commercial
suppliers. As for compound 4-(2,4-dichlorophenoxy)aniline (1a),
3,5-dichloro-4-(2,4-dichlorophenoxy)aniline (1q),
3-chloro-4-(2,4,6-trichlorophenoxy)aniline (1r),
3,5-dichloro-4-(2,4,6-trichlorophenoxy)aniline (1s),
3,5-dichloro-4-(mesityloxy)aniline (1t), 4-((3,5-dichloropyridin-2-yl)oxy)aniline (1v),
4-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (1w),
3-chloro-4-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (1x),
3-chloro-4-(naphthalen-2-yloxy)aniline (1a’),
3,5-dichloro-4-(naphthalen-2-yloxy)aniline (1b’), they were prepared from a reported
procedure [1].
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1.2 General procedure for the synthesis of 1d’-1e’
A mixture of 1-fluoro-4-nitrobenzene (0.55 mL, 5.0 mmol),
2-chloro-4-methylphenol (1.43 g, 10.0 mmol), potassium carbonate (1.38 g, 10.0
mmol) and DMF (5 mL) was stirred at 100oC for 4 h. After the reaction was complete,
diethyl ether (15 mL) was added and the solution was washed with 2 N NaOH (2 × 15
mL), water (15 mL), brine (15 mL) and dried over Na2SO4. Finally, the obtained
organic layer was concentrated to afford a crude mixture which was used directly for
the next step. Subsequently, a mixture of the above crude mixture, ammonium
chloride (0.27 g, 5.0 mmol), ethanol (25 mL) and water (3 mL) was heated to reflux,
and then powdered iron (0.27 g, 15.0 mmol) was added. The reaction mixture was
then stirred at reflux for 6 h. After the reaction was complete, the suspension was
cooled to room temperature and filtered through celite. The solvent of the filtrate was
evaporated under reduced pressure, and the residue was extracted with ethyl acetate (3
× 10 mL). Finally, the combined extracts were washed with water (2 × 15 mL), brine
(15 mL), dried and concentrated to give 4-(2-chloro-4-methylphenoxy)aniline (1d’) in
72% overall yield in two steps (0.84 g, 3.6 mmol).
4-(2-Bromo-4-(trifluoromethyl)phenoxy)aniline (1e’) was obtained in 58% overall
yield in two steps (0.96 g, 2.9 mmol), following the synthetic procedure of 1d’ by
replacing 2-bromo-4-(trifluoromethyl)phenol (2.41 g, 10.0 mmol) instead of
2-chloro-4-methylphenol (1.43 g, 10.0 mmol).
1.3 General procedure for the synthesis of 3a-3e’
A 10 mL round bottomed flask was charged with 2 (1.2 mmol), EDCI (1.2 mmol),
HOBt (1.2 mmol) and dry DMF (3 mL). The reaction mixture was stirred for 1 h
under room temperature before compound 1 (1.0 mmol) was added. After complete
consumption of 1 (as monitored by TLC), the reaction mixture was diluted with water
(30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers
were washed with water (2 × 10 mL), brine (10 mL), dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude was then purified by
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silica-gel column chromatography to afford the desired products 3a-3e’.
1.4 Enzyme Assay
In this paper, SCR was isolated from the heart of porcine, following the reported
method in the literature [2]. The overall activity of SCR was measured by the
absorption enhancement of cytochrome c at 550 nm, with 18.5 mM-1cm-1 as the
extinction coefficient. The activity of complex II was measured by monitoring the
absorbance decrease of DCIP (2,6-dichlorophenolindophenol) at 600 nm, by using an
extinction coefficient of 21.0 mM-1cm-1. As for the activity of complex III, DBH2 and
cytochrome c were used to evaluate its activity in SCR. The total volume of the
reaction mixture was 1.8 mL with the final concentrations of PBS (pH 7.4, 100 mM),
EDTA (0.3 mM), succinate (20 mM), oxidized cytochrome c (60 mM, or DCIP 53
mM) and appropriate amounts of enzyme to initiate the reaction [1].
1.5 Molecular docking
The computational protocol is similar to the reported works [3-5]. Herein, the 3D
structure of complex III was obtained from the Protein Data Bank (PDB) database
(PDB ID: 1SQB). The AutoDock 4.2 program was utilized for the docking of
representative compound 3w and Azoxystrobin (the positive control) into the Qo site
and/or Qi site of complex III. The Gasteiger charges were applied for these inhibitors.
To select the suitable docking parameters and examine the reliability and
reproducibility of the docking results, Azoxystrobin was first docked into the Qo site.
In this docking procedure, the Soils and Wets local search method was used to carry
out the comformational search, resulting in the best conformation of 3w and
Azoxystrobin. Among a series of docking parameters, the grid size was fixed as
30*30*30 and the used grid space defaulted as 0.375 Å. The standard AutoDock
scoring function was applied to assess the interaction energy between the ligand and
complex III (PDB ID: 1SQB). Among a set of 50 candidates of the docked complex
structures, the optimized one was chosed on the basis of the binding energy.
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1.6 References
[1] H. Cheng, Y.Q. Shen, X.Y. Pan, Y.P. Hou, Q.Y. Wu, G.F. Yang, New J. Chem.,
39 (2015) 7281-7292.
[2] L. Yu, C.A. Yu, J. Biol. Chem., 257 (1982) 2016-2021.
[3] G.F. Hao, F. Wang, H. Li, X.L. Zhu, W.C. Yang, L.S. Huang, J.W. Wu, E.A.
Berry, G.F. Yang, J. Am. Chem. Soc., 134 (2012) 11168-11176.
[4] H.Y. Lin, X. Chen, J.N. Chen, D.W. Wang, F.X. Wu, S.Y. Lin, C.G. Zhan, J.W.
Wu, W.C. Yang, G.F. Yang, Research, 2019 (2019) 2602414.
[5] P.L. Zhao, L. Wang, X.L. Zhu, X. Huang, C.G. Zhan, J.W. Wu, G.F. Yang, J. Am.
Chem. Soc., 132 (2010) 185-194.
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2. Analytic data for compounds 1d’, 1e’, 3a-3e’
4-(2-Chloro-4-methylphenoxy)aniline (1d’). White solid, m.p.: 72.5-73.8℃.
Isolated yield: 72%. 1H NMR (500 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.05 (d, J = 8.4
Hz, 1H), 6.82 – 6.67 (m, 3H), 6.61 (d, J = 8.3 Hz, 2H), 5.07 (s, 2H), 2.25 (s, 3H). 13C
NMR (126 MHz, DMSO-d6) δ 152.1, 146.7, 145.6, 133.5, 131.0, 129.3, 123.0, 120.3,
118.6, 115.5, 20.4. HRMS (ESI): calc. for C13H13ClNO [M+H]+: 234.06802; Found:
234.06769.
4-(2-Bromo-4-(trifluoromethyl)phenoxy)aniline (1e’). White solid, m.p.:
67.2-68.1℃. Isolated yield: 58%. 1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 2.3
Hz, 1H), 7.65 (dd, J = 8.8, 2.2 Hz, 1H), 6.90 – 6.79 (m, 3H), 6.65 (d, J = 8.7 Hz, 2H),
5.15 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 159.2, 147.1, 144.4, 130.8 (q, J = 3.7
Hz), 126.9 (q, J = 3.5 Hz), 123.9 (q, J = 32.8 Hz), 123.9 (q, J = 271.9 Hz), 116.7,
115.4, 112.0. HRMS (ESI): calc. for C13H10BrF3NO [M+H]+: 331.98924; Found:
331.98861.
N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3a). White solid, m.p.:
209.5-210.3℃. Isolated yield: 33%. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.0 Hz,
3H), 7.62 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 6.0 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.19 (d, J
= 8.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 166.2, 153.6, 152.2, 135.3, 134.3, 132.4, 131.0, 129.5, 129.3, 128.5, 127.5,
126.8, 122.6, 121.4, 119.3. HRMS (ESI): calc. for C19H14Cl2NO2 [M+H]+: 358.03961;
Found: 358.03955.
N-(4-(2,4-dichlorophenoxy)phenyl)-2-methylbenzamide (3b). White solid, m.p.:
156.5-157.8℃. Isolated yield: 68%. 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.5 Hz,
2H), 7.56 – 7.46 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.21 (dd, J =
9.0, 2.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 2.54 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 168.0, 153.0, 151.7, 136.5, 136.2, 133.9, 131.4, 130.5,
130.4, 129.0, 128.0, 126.6, 126.3, 126.0, 121.7, 120.9, 118.9, 19.9. HRMS (ESI): calc.
for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05523.
N-(4-(2,4-dichlorophenoxy)phenyl)-3-methylbenzamide (3c). White solid, m.p.:
140.7-141.9℃. Isolated yield: 83%. 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.68
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(s, 1H), 7.67 – 7.58 (m, 3H), 7.47 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 5.0, 1.5 Hz, 2H),
7.18 (dd, J = 9.0, 2.5 Hz, 1H), 7.02 – 6.95 (m, 2H), 6.90 (d, J = 9.0 Hz, 1H), 2.43 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 153.0, 151.7, 138.8, 134.8, 133.9, 132.7,
130.5, 129.0, 128.7, 128.0, 127.7, 126.2, 123.9, 122.0, 120.9, 118.9, 21.4. HRMS
(ESI): calc. for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05517.
N-(4-(2,4-dichlorophenoxy)phenyl)-4-methylbenzamide (3d). White solid, m.p.:
167.5-168.6℃. Isolated yield: 49%. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.76
(d, J = 8.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.0
Hz, 2H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz,
1H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.6, 152.9, 151.7, 142.5, 134.0,
131.9, 130.5, 129.5, 129.0, 128.0, 127.0, 126.2, 122.0, 120.8, 118.9, 21.5. HRMS
(ESI): calc. for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05517.
2-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3e). White solid, m.p.:
145.9-146.4℃. Isolated yield: 70%. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.81
(dd, J = 7.5, 2.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.52 – 7.39 (m, 4H), 7.22 (dd, J =
9.0, 2.5 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H). 13C NMR (126
MHz, CDCl3) δ 164.3, 153.3, 151.6, 134.9, 133.4, 131.8, 130.6, 130.5, 130.5, 130.4,
129.1, 128.0, 127.4, 126.3, 122.0, 120.9, 118.8. HRMS (ESI): calc. for C19H13Cl3NO2
[M+H]+: 392.00064; Found: 392.00053.
3-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3f). White solid, m.p.:
155.1-156.1℃. Isolated yield: 65%. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.82
(s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H),
7.50 (d, J = 2.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 9.0, 2.5 Hz, 1H), 7.00
(d, J = 8.5 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.3,
153.4, 151.5, 136.5, 135.0, 133.4, 132.0, 130.5, 130.1, 129.2, 128.1, 127.3, 126.4,
125.1, 122.2, 121.1, 118.7. HRMS (ESI): calc. for C19H11Cl3NO2 [M-H]-: 389.98609;
Found: 389.98602.
4-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3g). White solid, m.p.:
198.6-200.2℃. Isolated yield: 53%. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz,
2H), 7.74 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 3.0 Hz, 3H), 7.19 (d, J = 8.5
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Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 164.6, 153.3, 151.5, 138.3, 133.5, 133.1, 130.5, 129.2, 129.1, 128.4, 128.1,
126.4, 122.1, 121.0, 118.8. HRMS (ESI): calc. for C19H11Cl3NO2 [M-H]-: 389.98609;
Found: 389.98603.
2,4,6-Trichloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3h). White solid,
m.p.: 200.7-202.1℃. Isolated yield: 13%. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J =
9.0 Hz, 3H), 7.47 (d, J = 2.0 Hz, 1H), 7.37 (s, 2H), 7.22 – 7.16 (m, 1H), 6.97 (d, J =
8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 161.7, 153.8,
151.4, 136.2, 134.2, 133.1, 132.7, 130.5, 129.3, 128.2, 128.1, 126.5, 122.3, 121.2,
118.7. HRMS (APCI): calc. for C19H11Cl5NO2 [M+H]+: 459.92269; Found:
459.92191.
2-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)-4-(trifluoromethyl)benzamide (3i).
White solid, m.p.: 158.9-159.5℃. Isolated yield: 76%. 1H NMR (500 MHz, CDCl3) δ
7.88 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62 (d, J
= 9.0 Hz, 2H), 7.48 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 9.0, 2.5 Hz, 1H), 6.99 (d, J = 9.0
Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.1, 153.8, 151.4,
138.3, 133.8 (d, J = 33.5 Hz), 132.9, 131.3, 130.9, 130.6, 129.3, 128.1, 127.5 (q, J =
4.0 Hz), 126.5, 124.3 (q, J = 3.6 Hz), 122.8 (d, J = 272.9 Hz), 122.1, 121.2, 118.7.
HRMS (ESI): calc. for C20H10Cl3F3NO2 [M-H]-: 457.97347; Found: 457.97326.
N-(4-(2,4-dichlorophenoxy)phenyl)-3-methoxybenzamide (3j). White solid, m.p.:
143.9-147.0℃. Isolated yield: 74%. 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.61
(d, J = 9.0 Hz, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 5.0 Hz, 2H),
7.18 (dd, J = 9.0, 2.5 Hz, 1H), 7.11 – 7.05 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.90 (d, J
= 9.0 Hz, 1H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.5, 160.0, 153.1, 151.7,
136.2, 133.8, 130.5, 129.8, 129.0, 128.0, 126.3, 122.0, 120.9, 118.8, 118.6, 118.0,
112.5, 55.5. HRMS (ESI): calc. for C20H16Cl2NO3 [M+H]+: 388.05018; Found:
388.05076.
3-(Tert-butyl)-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3k). Pale yellow oil.
Isolated yield: 64%. 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.67 –
7.54 (m, 4H), 7.47 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 7.6, 7.4 Hz, 1H), 7.18 (dd, J =
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8.5, 2.4 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1H), 1.37 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 166.4, 153.0, 152.1, 151.7, 134.6, 134.0, 130.5, 129.1,
129.0, 128.5, 128.0, 126.2, 124.4, 123.7, 122.1, 120.8, 118.8, 34.9, 31.3. HRMS (ESI):
calc. for C23H20Cl2NO2 [M-H]-: 412.08766; Found: 412.08766.
N-(4-(2,4-dichlorophenoxy)phenyl)-3-fluorobenzamide (3l). White solid, m.p.:
153.4-155.1℃. Isolated yield: 73%. 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.67
– 7.56 (m, 4H), 7.49 (d, J = 2.5 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.30 – 7.23 (m, 1H),
7.21 (dd, J = 9.0, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 164.5, 162.8 (d, J = 248.4 Hz), 153.4, 151.5, 137.0 (d, J =
6.8 Hz), 133.4, 130.5, 130.4, 129.2, 128.1, 126.4, 122.4 (d, J = 3.1 Hz), 122.3, 121.1,
119.0 (d, J = 21.3 Hz), 118.7, 114.5 (d, J = 23.0 Hz). HRMS (ESI): calc. for
C19H13Cl2FNO2 [M+H]+: 376.03019; Found: 376.03063.
3-Bromo-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3m). White solid, m.p.:
153.1-154.4℃. Isolated yield: 73%. 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.86
(s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H),
7.47 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 6.96
(d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.3,
153.4, 151.5, 136.7, 134.9, 133.4, 130.5, 130.4, 130.2, 129.2, 128.1, 126.4, 125.6,
123.0, 122.2, 121.1, 118.7. HRMS (ESI): calc. for C19H13BrCl2NO2 [M+H]+:
435.95012; Found: 435.95030.
N-(4-(2,4-dichlorophenoxy)phenyl)-3-(trifluoromethoxy)benzamide (3n). White
solid, m.p.: 167.7-169.0℃. Isolated yield: 64%. 1H NMR (500 MHz, CDCl3) δ 7.77
(d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H),
7.47 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 6.98
(d, J = 9.0 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.1,
153.5, 151.5, 149.6, 136.9, 133.3, 130.6, 130.4, 129.3, 128.1, 126.5, 125.0, 124.3,
122.3, 121.1, 120.4 (q, J = 258.7 Hz), 120.0, 118.8. HRMS (ESI): calc. for
C20H13Cl2F3NO3 [M+H]+: 442.02191; Found: 442.02201.
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N-(4-(2,4-dichlorophenoxy)phenyl)-3-(trifluoromethyl)benzamide (3o). White solid,
m.p.: 157.8-158.1℃. Isolated yield: 50%. 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H),
8.05 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.65 – 7.52 (m, 3H),
7.47 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.92
(d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.3, 153.6, 151.4, 135.6, 133.3,
131.4 (q, J = 33.0 Hz), 130.5, 130.3, 129.5, 129.3, 128.5 (q, J = 3.8 Hz), 128.1, 126.5,
124.0 (q, J = 3.6 Hz), 123.6 (q, J = 272.7 Hz), 122.3, 121.2, 118.7. HRMS (ESI): calc.
for C20H13Cl2F3NO [M+H]+ 426.02700; Found: 426.02748.
N-(4-phenoxyphenyl)benzamide (3p). White solid, m.p.: 160.0-161.1℃. Isolated
yield: 90%. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.84 (s, 1H), 7.60
(d, J = 9.0 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 8.0
Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 7.06 – 7.00 (m, 4H). 13C NMR (101 MHz,
DMSO-d6) δ 165.7, 157.5, 153.7, 134.8, 133.3, 131.8, 129.7, 128.8, 127.0, 123.1,
122.0, 119.6, 118.5. HRMS (ESI): calc. for C19H14NO2 [M-H]-: 288.10300; Found:
288.10277.
N-(3,5-dichloro-4-(2,4-dichlorophenoxy)phenyl)benzamide (3q). White solid, m.p.:
200.3-201.2 ℃. Isolated yield: 23%. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.86
(d, J = 7.5 Hz, 2H), 7.80 (s, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H),
7.47 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 9.0, 2.5 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 165.7, 151.2, 143.1, 136.4, 133.9, 132.5, 130.5, 129.8,
129.0, 127.9, 127.6, 127.0, 123.5, 120.6, 115.1. HRMS (ESI): calc. for C19H12Cl4NO2
[M+H]+: 425.96197; Found: 425.96147.
N-(3-chloro-4-(2,4,6-trichlorophenoxy)phenyl)benzamide (3r). White solid, m.p.:
182.9-183.7℃. Isolated yield: 32%. 1H NMR (500 MHz, CDCl3) δ 7.91 – 7.84 (m,
3H), 7.81 (s, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.46 (s, 2H), 7.41
(dd, J = 9.0, 2.5 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
165.6, 148.8, 146.2, 134.5, 133.6, 132.1, 131.5, 130.4, 129.2, 128.9, 127.0, 123.1,
123.0, 119.51, 114.5. HRMS (ESI): calc. for C19H12Cl4NO2 [M+H]+: 425.96167;
Found: 425.96144.
S11
N-(3,5-dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzamide (3s). White solid,
m.p.: 190.5-191.2℃. Isolated yield: 54%. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J =
7.5 Hz, 2H), 7.82 (s, 1H), 7.73 (s, 2H), 7.61 (dd, J = 7.6, 7.5 Hz, 1H), 7.53 (dd, J =
7.6, 7.5 Hz, 2H), 7.34 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 166.3, 148.0, 145.2,
135.3, 134.5, 132.8, 129.8, 129.5, 129.4, 127.7, 127.5, 127.3, 121.1. HRMS (ESI):
calc. for C19H11Cl5NO2 [M+H]+: 459.92269; Found: 459.92270.
N-(3,5-dichloro-4-(mesityloxy)phenyl)benzamide (3t). White solid, m.p.:
191.4-192.7℃. Isolated yield: 46%. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.86
– 7.79 (m, 2H), 7.66 (s, 2H), 7.59 – 7.54 (m, 1H), 7.52 – 7.43 (m, 2H), 6.79 (s, 2H),
2.25 (s, 3H), 2.09 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 166.1, 151.9, 147.1, 134.7,
133.8, 133.6, 132.7, 130.3, 129.4, 128.7, 127.5, 127.1, 121.5, 21.1, 17.6. HRMS (ESI):
calc. for C22H20Cl2NO2 [M+H]+: 400.08656; Found: 400.08636.
N-(4-(2,4-dichlorophenoxy)phenyl)picolinamide (3u). White solid, m.p.:
109.6-110.3℃. Isolated yield: 70%. 1H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.62
(s, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.47 (s, 1H),
7.18 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 6.5 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H). 13C NMR
(126 MHz, CDCl3) δ 161.9, 152.7, 151.8, 149.7, 148.0, 137.7, 133.8, 130.4, 128.8,
128.0, 126.5, 126.1, 122.4, 121.3, 120.7, 118.9. HRMS (ESI): calc. for
C18H13Cl2N2O2 [M+H]+: 359.03486; Found: 359.03470.
N-(4-((3,5-dichloropyridin-2-yl)oxy)phenyl)picolinamide (3v). White solid, m.p.:
182.0-182.9 ℃. Isolated yield: 22%. 1H NMR (500 MHz, CDCl3) δ 10.19 (s, 1H),
8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.96 – 7.91 (m, 3H), 7.61 (d, J =
2.5 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.40 (dd, J = 5.5, 3.0 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 162.7, 157.9, 149.8, 148.5, 139.0, 139.0, 138.3, 136.1, 134.6, 128.4, 127.5,
127.3, 123.0, 120.7, 111.8. HRMS (ESI): calc. for C17H12Cl2N3O2 [M+H]+: 360.03011;
Found: 360.02999.
N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3w). White solid,
m.p.: 113.3-114.5℃. Isolated yield: 39%. 1H NMR (500 MHz, CDCl3) δ 10.07 (s,
1H), 8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.99 – 7.88 (m, 1H), 7.83 (d, J
= 9.0 Hz, 2H), 7.73 (s, 1H), 7.50 (dd, J = 7.5, 5.0 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H),
S12
7.08 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
162.0, 156.4, 151.5, 149.6, 148.0, 137.8, 134.7, 128.1 (q, J = 3.7 Hz), 126.6, 125.9 (q,
J = 33.6 Hz), 125.1 (q, J = 3.7 Hz), 124.9, 123.4 (q, J = 271.9 Hz), 122.5, 121.4,
120.2, 118.2. HRMS (ESI): calc. for C19H13ClF3N2O2 [M+H]+: 393.06122; Found:
393.06097.
N-(3-chloro-4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3x).
White solid, m.p.: 147.9-148.5℃. Isolated yield: 51%. 1H NMR (500 MHz, CDCl3) δ
10.11 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 2.5 Hz,
1H), 7.94 (td, J = 7.5, 1.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 9.0, 2.5 Hz,
1H), 7.53 (dd, J = 7.0, 5.5 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.77
(d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.1, 155.8, 149.2, 148.1, 146.6,
137.9, 136.0, 128.1 (q, J = 3.8 Hz), 127.0, 126.8, 125.9 (q, J = 34.1 Hz), 125.0 (q, J =
3.7 Hz), 124.1, 123.4 (q, J = 272.0 Hz), 122.5, 122.4, 122.0, 119.4, 116.6. HRMS
(ESI): calc. for C19H12Cl2F3N2O2 [M+H]+: 427.02224; Found: 427.02192.
N-(3,5-dichloro-4-(2,4-dichlorophenoxy)phenyl)picolinamide (3y). White solid,
m.p.: 184.3-185.1℃. Isolated yield: 55%. 1H NMR (500 MHz, CDCl3) δ 10.15 (s,
1H), 8.64 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.02 – 7.89 (m, 3H), 7.56 (ddd,
J = 7.5, 4.5, 1.0 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 6.46
(d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.2, 151.3, 148.9, 148.1, 142.8,
137.9, 136.3, 130.5, 129.8, 127.8, 127.6, 127.0, 123.5, 122.6, 120.0, 115.1. HRMS
(ESI): calc. for C18H11Cl4N2O2 [M+H]+: 426.95691; Found: 426.95668.
N-(3,5-dichloro-4-(2,4,6-trichlorophenoxy)phenyl)picolinamide (3z). White solid,
m.p.: 191.0-191.9℃. Isolated yield: 62%. 1H NMR (500 MHz, CDCl3) δ 10.05 (s,
1H), 8.59 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 2H), 7.50 (s, 1H),
7.31 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 162.5, 149.4, 148.5, 148.0, 145.0, 138.3,
135.2, 129.7, 129.5, 127.6, 127.4, 127.4, 123.0, 120.4. HRMS (ESI): calc. for
C18H10Cl5N2O2 [M+H]+: 460.91794; Found: 460.91764.
N-(3-chloro-4-(naphthalen-2-yloxy)phenyl)picolinamide (3a'). White solid, m.p.:
149.1-149.7℃. Isolated yield: 55%. 1H NMR (500 MHz, CDCl3) δ 10.07 (s, 1H), 8.63
(d, J = 3.5 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.93 (t, J = 7.5 Hz, 1H),
S13
7.88 – 7.77 (m, 2H), 7.69 – 7.59 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H),
7.39 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 8.5 Hz,
1H). 13C NMR (126 MHz, CDCl3) δ 162.0, 155.2, 149.4, 148.4, 148.0, 137.8, 134.8,
134.2, 130.1, 130.0, 127.7, 127.1, 126.8, 126.7, 126.6, 124.6, 122.5, 122.0, 119.3,
118.9, 112.2. HRMS (ESI): calc. For C22H16ClN2O2 [M+H]+: 375.08948; Found:
375.08923.
N-(3,5-dichloro-4-(naphthalen-2-yloxy)phenyl)picolinamide (3b'). White solid,
m.p.: 184.7-186.5℃. Isolated yield: 54%. 1H NMR (500 MHz, CDCl3) δ 10.13 (s,
1H), 8.63 (d, J = 3.5 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.06
– 7.89 (m, 3H), 7.87 (d, J = 7.5 Hz, 1H), 7.62 – 7.49 (m, 4H), 7.28 (d, J = 8.0 Hz, 1H),
6.45 (d, J = 7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 162.0, 152.6, 148.9, 147.9,
143.7, 138.1, 135.8, 134.8, 130.2, 127.6, 127.0, 126.7, 125.8, 125.4, 124.8, 122.7,
122.3, 122.1, 120.1, 106.8. HRMS (ESI): calc. for C22H15Cl2N2O2 [M+H]+:
409.05051; Found: 409.05023.
N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)pyrazine-2-carboxamide (3c').
White solid, m.p.: 136.0-136.7℃. Isolated yield: 42%. 1H NMR (500 MHz, CDCl3) δ
9.73 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 2.5, 1.5
Hz, 1H), 7.86 – 7.79 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.7, 2.2 Hz, 1H),
7.13 – 7.07 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H). δ 13C NMR (126 MHz, CDCl3) δ 160.6,
156.1, 152.0, 147.7, 144.7, 144.2, 142.4, 134.0, 128.1 (q, J = 3.8 Hz), 126.1 (q, J =
33.6 Hz), 125.1, 125.1 (q, J = 3.4 Hz), 123.3 (q, J = 272.0 Hz), 121.6, 120.1, 118.5.
HRMS (ESI): calc. for C18H14ClF3N3O2 [M+H]+: 394.05647; Found: 394.05566.
N-(4-(2-chloro-4-methylphenoxy)phenyl)picolinamide (3d'). White solid, m.p.:
91.5-92.3℃. Isolated yield: 63%. 1H NMR (500 MHz, CDCl3) δ 9.99 (s, 1H), 8.66 –
8.56 (m, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.96 – 7.85 (m, 1H), 7.79 – 7.68 (m, 2H), 7.52
– 7.43 (m, 1H), 7.27 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.90
(d, J = 8.2 Hz, 1H), 2.33 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 161.8, 153.8, 150.1,
149.7, 147.9, 137.6, 134.7, 133.1, 131.1, 128.5, 126.4, 125.4, 122.3, 121.2, 120.7,
118.1, 20.5. HRMS (ESI): calc. for C19H16ClN2O2 [M+H]+: 339.08948; Found:
339.08892.
S14
N-(4-(2-Bromo-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3e'). White solid,
m.p.: 94.1-95.6℃. Isolated yield: 38%. 1H NMR (500 MHz, CDCl3) δ 10.10 (s, 1H),
8.65 (d, J = 4.7 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.95 (td, J = 7.7, 1.7 Hz, 1H), 7.92
(d, J = 2.1 Hz, 1H), 7.88 – 7.83 (m, 2H), 7.61 – 7.45 (m, 2H), 7.19 – 7.04 (m, 2H),
6.94 (d, J = 8.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.0, 157.5, 151.5, 149.6,
148.0, 137.7, 134.7, 131.1 (q, J = 3.7 Hz), 126.6, 126.2 (q, J = 33.3 Hz), 125.8 (q, J =
3.8 Hz), 123.2 (q, J = 272.1 Hz), 122.4, 121.4, 120.4, 117.9, 113.5. HRMS (ESI): calc.
for C19H13BrF3N2O2 [M+H]+: 437.01070; Found: 437.00965.
S15
3. 1H-NMR, 13C-NMR and HR-MS spectra for compounds 1d’, 1e’ and 3a-3b’
➢ 1H-NMR spectrum for 1d’
➢ 13C-NMR spectrum for 1d’
S16
➢ HRMS (ESI) spectrum of 1d’
8 #22 RT: 0.21 AV: 1 SB: 5 0.44-0.53 NL: 3.43E9T: FTMS + c ESI Full ms [50.0000-750.0000]
60 80 100 120 140 160 180 200 220 240 260 280 300 320
m/z
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Re
lative
Ab
un
da
nce
234.06769
275.0939356.05029 87.08091 288.09586
238.07156
151.03500 332.14035260.0831173.06543 181.97877 221.68569101.09642
246.06758
310.30996205.08567117.10235 130.06500
S17
➢ 1H-NMR spectrum for 1e’
➢ 13C-NMR spectrum for 1e’
S18
➢ HRMS (ESI) spectrum of 1e’
11 #24 RT: 0.23 AV: 1 SB: 4 0.51-0.58 NL: 1.34E9T: FTMS + c ESI Full ms [50.0000-750.0000]
60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460
m/z
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Re
lative
Ab
un
da
nce
331.98861
338.34088
360.32279 384.0194487.08090 279.15852149.02307 402.18142254.07817114.09144 181.98769 310.30972219.17391 446.2597165.06042
S19
➢ 1H-NMR spectrum for 3a
➢ 13C-NMR spectrum for 3a
S20
➢ HRMS (ESI) spectrum of 3a
S21
➢ 1H-NMR spectrum for 3b
➢ 13C-NMR spectrum for 3b
S22
➢ HRMS (ESI) spectrum of 3b
S23
➢ 1H-NMR spectrum for 3c
➢ 13C-NMR spectrum for 3c
S24
➢ HRMS (ESI) spectrum of 3c
S25
➢ 1H-NMR spectrum for 3d
➢ 13C-NMR spectrum for 3d
S26
➢ HRMS (ESI) spectrum of 3d
S27
➢ 1H-NMR spectrum for 3e
➢ 13C-NMR spectrum for 3e
S28
➢ HRMS (ESI) spectrum of 3e
S29
➢ 1H-NMR spectrum for 3f
➢ 13C-NMR spectrum for 3f
S30
➢ HRMS (ESI) spectrum of 3f
S31
➢ 1H-NMR spectrum for 3g
➢ 13C-NMR spectrum for 3g
S32
➢ HRMS (ESI) spectrum of 3g
S33
➢ 1H-NMR spectrum for 3h
➢ 13C-NMR spectrum for 3h
S34
➢ HRMS (ESI) spectrum of 3h
SL44_20191029133921 #19 RT: 0.21 AV: 1 NL: 1.51E8T: FTMS + c APCI corona Full ms [50.0000-750.0000]
458 459 460 461 462 463 464 465 466 467 468 469
m/z
0
10000000
20000000
30000000
40000000
50000000
60000000
70000000
80000000
90000000
100000000
110000000
120000000
130000000
140000000
150000000
Re
lative
Ab
un
da
nce
461.91888
459.92191 463.91599
462.92215 465.91275
460.92520 464.91934
466.91626 467.90945
468.91327462.17755461.65088458.91318459.65851
464.17731 465.64474460.17902
S35
➢ 1H-NMR spectrum for 3i
➢ 13C-NMR spectrum for 3i
S36
➢ HRMS (ESI) spectrum of 3i
S37
➢ 1H-NMR spectrum for 3j
➢ 13C-NMR spectrum for 3j
S38
➢ HRMS (ESI) spectrum of 3j
S39
➢ 1H-NMR spectrum for 3k
➢ 13C-NMR spectrum for 3k
S40
➢ HRMS (ESI) spectrum of 3k
S41
➢ 1H-NMR spectrum for 3l
➢ 13C-NMR spectrum for 3l
S42
➢ HRMS (ESI) spectrum of 3l
S43
➢ 1H-NMR spectrum for 3m
➢ 13C-NMR spectrum for 3m
S44
➢ HRMS (ESI) spectrum of 3m
S45
➢ 1H-NMR spectrum for 3n
➢ 13C-NMR spectrum for 3n
S46
➢ HRMS (ESI) spectrum of 3n
S47
➢ 1H-NMR spectrum for 3o
➢ 13C-NMR spectrum for 3o
S48
➢ HRMS (ESI) spectrum of 3o
S49
➢ 1H-NMR spectrum for 3p
➢ 13C-NMR spectrum for 3p
S50
➢ HRMS (ESI) spectrum of 3p
S51
➢ 1H-NMR spectrum for 3q
➢ 13C-NMR spectrum for 3q
S52
➢ HRMS (ESI) spectrum of 3q
S53
➢ 1H-NMR spectrum for 3r
➢ 13C-NMR spectrum for 3r
S54
➢ HRMS (ESI) spectrum of 3r
S55
➢ 1H-NMR spectrum for 3s
➢ 13C-NMR spectrum for 3s
S56
➢ HRMS (ESI) spectrum of 3s
S57
➢ 1H-NMR spectrum for 3t
➢ 13C-NMR spectrum for 3t
S58
➢ HRMS (ESI) spectrum of 3t
S59
➢ 1H-NMR spectrum for 3u
➢ 13C-NMR spectrum for 3u
S60
➢ HRMS (ESI) spectrum of 3u
S61
➢ 1H-NMR spectrum for 3v
➢ 13C-NMR spectrum for 3v
S62
➢ HRMS (ESI) spectrum of 3v
S63
➢ 1H-NMR spectrum for 3w
➢ 13C-NMR spectrum for 3w
S64
➢ HRMS (ESI) spectrum of 3w
S65
➢ 1H-NMR spectrum for 3x
➢ 13C-NMR spectrum for 3x
S66
➢ HRMS (ESI) spectrum of 3x
S67
➢ 1H-NMR spectrum for 3y
➢ 13C-NMR spectrum for 3y
S68
➢ HRMS (ESI) spectrum of 3y
S69
➢ 1H-NMR spectrum for 3z
➢ 13C-NMR spectrum for 3z
S70
➢ HRMS (ESI) spectrum of 3z
S71
➢ 1H-NMR spectrum for 3a’
➢ 13C-NMR spectrum for 3a’
S72
➢ HRMS (ESI) spectrum of 3a’
S73
➢ 1H-NMR spectrum for 3b’
➢ 13C-NMR spectrum for 3b’
S74
➢ HRMS (ESI) spectrum of 3b’
S75
➢ 1H-NMR spectrum for 3c’
➢ 13C-NMR spectrum for 3c’
S76
➢ HRMS (ESI) spectrum of 3c’
3 #21 RT: 0.23 AV: 1 SB: 5 0.09-0.14 , 0.41-0.45 NL: 9.98E7T: FTMS + c APCI corona Full ms [50.0000-750.0000]
50 100 150 200 250 300 350 400 450 500
m/z
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Re
lative
Ab
un
da
nce
394.05566
C 18 H12 O2 N3 Cl F 3
338.34085
79.02174
75.04463 178.15867136.07548320.33045
360.09455
C 12 H18 O4 N3 Cl F 3219.1738587.08089 108.08095 173.08051288.03903
C 11 H8 N4 Cl F 3235.16871 415.21069
445.11859
C 25 H21 O2 Cl F 3 523.47192
S77
➢ 1H-NMR spectrum for 3d’
➢ 13C-NMR spectrum for 3d’
S78
➢ HRMS (ESI) spectrum of 3d’
9 #19 RT: 0.21 AV: 1 SB: 12 0.43-0.56 , 0.05-0.15 NL: 2.82E8T: FTMS + c APCI corona Full ms [50.0000-750.0000]
333 334 335 336 337 338 339 340 341 342 343 344 345 346
m/z
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Re
lative
Ab
un
da
nce
339.08892
341.08587
340.09228
338.34100
342.08920
339.34442343.09235340.34759336.32561 337.32882334.30975 344.09506
338.08221
S79
➢ 1H-NMR spectrum for 3e’
➢ 13C-NMR spectrum for 3e’
S80
➢ HRMS (ESI) spectrum of 3e’
13 #19 RT: 0.21 AV: 1 SB: 4 0.10-0.14 , 0.39-0.42 NL: 1.43E7T: FTMS + c APCI corona Full ms [50.0000-750.0000]
370 380 390 400 410 420 430 440 450 460 470 480 490
m/z
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Re
lative
Ab
un
da
nce
437.00965
440.01096
391.28329
441.01428392.28622 415.21011 429.02566367.37561 389.30376 409.38058 467.40912