General methods
All the reactions were conducted in oven dried glassware under nitrogen atmosphere with freshly distilled dry solvents under anhydrous conditions unless otherwise indicated. All reagents were purchased from commercial sources, such as Alfa Aesar, Sigma-Aldrich, Acros, or TCI Chemicals, and were used without further purification. The progress of the reaction was monitored by thin layer chromatography (TLC) using Merck TLC Silica gel 60 F254 precoated plates (0.2 mm thickness). The plates were visualized by 254 nm of ultraviolet light. Also, further visualization is conducted by treatment with basic solution of potassium permanganate or acidic solution of ceric molybdate. Flash column chromatography was performed with Silica Flash P60 silica gel (230-400 mesh).
A systematic nomenclature for the compounds follows the numbering system as defined by IUPAC with assistance from CS Chemdraw® software. Proton (1H) and carbon (13C) NMR spectra were obtained using 400/100 MHz Bruker Advance III FT-NMR spectrometer or 400/100 MHz Agilent 400M FT-NMR spectrometer. NMR solvents were purchased from Cambridge Isotope Laboratories and the residue solvent signals were taken as the reference (0.0 ppm for 1H NMR spectra and 77.0 ppm for 13C NMR spectra in CDCl3 and 2.50 ppm for 1H NMR spectra and 39.52 ppm for
13C NMR spectra in DMSO-d6). Chemical shifts (δ) were reported in units of parts per million (ppm) and coupling constants (J) were given in hertz (Hz). The following abbreviations described the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Mass analysis was conducted using Advion Expression CMS mass spectrometer. Luminescence quenching studies were performed with F-7000 FL Spectrophotometer.
Substrates synthesis:
Preparation and characterization of alkyne compounds (5)
1,2-di-p-tolylethyne (5a)
To a suspension of Pd(PPh3)4 (5 mol%), CuI (10 mol%), and 4-bromotoluene (1.0 equiv.) in degassed piperidine (0.2 M) was added dropwise p-tolylacetylene (1.0 equiv.) under nitrogen atmosphere. The reaction mixture was stirred at 80°C for overnight. The reaction mixture was washed with a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography. 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 4H), 7.14 (d, 7.9 Hz, 4H), 2.36 (s, 6H); The compound was identified by spectral comparison with literature data.S1
2-(p-tolylethynyl)pyridine (5c)
To a suspension of Pd(PPh3)2Cl2 (3 mol%), CuI (6 mol%), and 2-bromopyridine (1.0 equiv.) in degassed Et3N (0.4 M) was added dropwise p-tolylacetylene (1.5 equiv.) under nitrogen atmosphere.
The reaction mixture was stirred at 80°C for overnight. The reaction mixture was washed with a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel. 90% yield; 1H NMR (400 MHz, CDCl3) δ 8.61 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.67 (td, 7.7, 1.8 Hz, 1H), 7.53 – 7.48 (m, 3H), 7.23 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.17 (d, 7.8 Hz, 2H), 2.38 (s, 3H);
The compound was identified by spectral comparison with literature data.S2
1,4-bis((4-chlorobenzyl)oxy)but-2-yne (5h)
To a suspension of NaH (60% in mineral oil, 2.5 equiv.) in dry DMF was added slowly a solution of 2-butyne-1,4-diol (1.0 equiv., 0.3 M) in DMF at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 1h. 4-Chlorobenzyl chloride in dry DMF was added to the reaction mixture.
Then, the reaction temperature was increased to room temperature and the mixture was stirred for 6h.
The reaction mixture was washed with water and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel. 69% yield; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.26 (m, 8H), 4.56 (s, 4H), 4.23 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 135.87, 133.65, 129.26, 128.59, 82.45, 70.84, 57.54;
MS (APCI): m/z 335.3 [M+H]+
(E)-4,4'-(but-1-en-3-yne-1,4-diyl)bis(methylbenzene) (5i)
Step 1S3: p-Tolualdehyde (1.0 equiv., 0.15 M) and CBr4 (1.5 equiv.) were dissolved in CH2Cl2 and cooled to 0°C. A solution of PPh3 (3.0 equiv.) in CH2Cl2 was added dropwise keeping the temperature below to 0°C. The reaction mixture was stirred at 0°C for 1h under nitrogen atmosphere. Et2O was added, and the mixture was filtered through a short pad of silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel.
1-(2,2-dibromovinyl)-4-methylbenzene
: 94% yield; 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.43 (m, 3H), 7.17 (d, 8.0 Hz, 2H), 2.34 (s, 3H);
The compound was identified by spectral comparison with literature data.S4
Step 2S3: To a solution of dibromide (1.0 equiv.), Et3N (3.0 equiv.) in DMF (1.0 M) was added dimethyl phosphite (3.0 equiv.) at 0°C. The solution was stirred at room temperature for overnight.
The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with a saturated solution of NH4Cl and dried over Na2SO4, filtered and concentrated.
The crude material was purified by flash chromatography on silica gel.
(E)-1-(2-bromovinyl)-4-methylbenzene
: 94% yield; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 8.2 Hz, 2H), 7.13 (d, 8.0 Hz, 2H), 7.07 (d, 14.0 Hz, 1H), 6.70 (d, 14.0 Hz, 1H), 2.32 (s, 3H); The compound was identified by spectral comparison with literature data.S5
Step 3S6: To a suspension of Cs2CO2 (2 equiv.), Cu2O (10 mol%), vinyl bromide (1.0 equiv.) in DMF (1.0 M) was added dropwise p-tolylacetylene (1.5 equiv.) under nitrogen atmosphere. The reaction mixture was stirred at 135°C for overnight, and the heterogeneous mixture was cooled to room temperature. The resulting solution was filtered through a short pad of silica gel, then washed with ethyl acetate, and concentrated to give the crude material. The resulting crude was purified by flash chromatography on silica gel.
(E)-4,4'-(but-1-en-3-yne-1,4-diyl)bis(methylbenzene) (5i)
: 82% yield; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, 8.1 Hz, 2H), 7.31 (d, 8.2 Hz, 2H), 7.17 – 7.11 (m, 3H), 6.99 (d, 16.2 Hz, 1H), 6.33 (d, 16.2 Hz, 1H), 2.35 (s, 6H); The compound was identified by spectral comparison with literature data.S7
Preparation and characterization of alkene compounds (6)
1-methyl-5-thioxo-1,5-dihydro-2H-pyrrol-2-one (6j)
To a hot solution of N-methylmaleimide (2.0 equiv.) in dry toluene was added a boiling suspension of Lawesson’s reagent (1.0 equiv., 0.12 M) in dry toluene. The reaction mixture was refluxed for 1h, and the mixture was cooled to room temperature. The resulting solution was filtered quickly through a short pad of silica gel, and concentrated to give the crude material. The resulting crude was purified by flash chromatography on silica gel. 45% yield; 1H NMR (400 MHz, CDCl3) δ 6.77 (d, 5.7 Hz, 1H), 6.68 (d, 5.7 Hz, 1H), 3.29 (s, 3H); The compound was identified by spectral comparison with literature data.S8
(E)-1,4-di-p-tolylbut-2-ene-1,4-dione (6k)
Step 1S9: To a solution of acetophenone (1.0 equiv.), NBS (1.2 equiv.), and p-TsOH (1.5 equiv.) in acetonitrile (0.2 M) was refluxed for 1h. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
2-bromo-1-(p-tolyl)ethan-1-one (11)
: 96% yield; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 8.2 Hz, 2H), 7.29 (d, 7.9 Hz, 2H), 4.43 (s, 2H), 2.43 (s, 3H); The compound was identified by spectral comparison with literature data.S9
Step 2S10: To a suspension of 2-bromoacetophenone (1.0 equiv.), K2CO3 (1.5 equiv.), and sodium 4- toluenesulfinate (0.5 equiv.) in DMF (1.0 M) was stirred at room temperature for overnight. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The reaction mixture was diluted with water and extracted with CH2Cl2, and the combined organic layer was washed with brine. The resulting solution was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
(E)-1,4-di-p-tolylbut-2-ene-1,4-dione (6k)
: 66% yield; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H), 7.98 (d, 8.2 Hz, 4H), 7.33 (d, 7.9 Hz, 4H), 2.45 (s, 6H); The compound was identified by spectral comparison with literature data.S10
1,3-di-p-tolylpropa-1,2-diene (6l)
Step 1S11: To a suspension of Pd(PPh3)4 (5 mol%), 2-bromo-1-(p-tolyl)ethan-1-one (1.0 equiv.), and triphenylphosphine (1.0 equiv.) in toluene (0.2 M) was stirred at 100°C for 1h under nitrogen atmosphere. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with toluene and Et2O to afford pure white solid.
(E)-(4-methylstyryl)triphenylphosphonium bromide
: 86% yield; 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, 20.1, 17.1 Hz, 1H), 7.89 (d, 8.1 Hz, 2H), 7.85 – 7.68 (m, 15H), 7.27 (d, 8.0 Hz, 2H), 7.02 (dd, 23.1, 17.1 Hz, 1H), 2.38 (s, 3H);
Step 2S12: (E)-(4-methylstyryl)triphenylphosphonium bromide (1.0 equiv., 0.15 M) was dissolved in CH2Cl2 (0.3 M)and cooled to -78°C. NaHMDS solution (1.0 M in THF, 1.6 equiv.)was added dropwise, and the solution was stirred for 1h at -78°C. A solution of p-tolualdehyde (3.0 equiv.) in THF (0.6 M)was added dropwise at -78°C, and the reaction mixture was stirred for overnight at 40°C.
The reaction mixture was diluted with water and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
1,3-di-p-tolylpropa-1,2-diene (6l)
: 82% yield; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, 8.1 Hz, 4H), 7.11 (d, 7.9 Hz, 4H), 6.55 (s, 2H), 2.33 (s, 6H); The compound was identified by spectral comparison with literature data.S13
Preparation and characterization of enynes 8
General procedure A (for Sonogashira coupling)
To a suspension of Pd(PPh3)2Cl2 (x mol%), CuI (x mol%), and 2-iodophenol or 2-iodoaniline (1.0 equiv.) in degassed Et3N (x M) was added dropwise the corresponding alkyne (x equiv.) under nitrogen atmosphere. The reaction mixture was stirred until TLC indicated complete consumption of the starting material. The reaction mixture was washed with a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated.
The crude material was purified by flash chromatography on silica gel.
2-(p-tolylethynyl)phenol
Prepared according to the General Procedure A using Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), 2- iodophenol (1.0 equiv.), and p-tolylacetylene (2.0 equiv.) in Et3N (0.5 M) at reflux, 90% yield; 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.39 (m, 3H), 7.29 – 7.23 (m, 1H), 7.18 (dt, 7.9, 0.7 Hz, 2H), 6.98 (dd, 8.3, 0.7 Hz, 1H), 6.90 (td, 7.5, 1.1 Hz, 1H), 5.85 (s, 1H), 2.38 (s, 3H); The compound was identified by spectral comparison with literature data.S14
2-(p-tolylethynyl)aniline
Prepared according to the General Procedure A using Pd(PPh3)2Cl2 (2 mol%), CuI (2 mol%), 2- iodoaniline (1.0 equiv.), and p-tolylacetylene (1.2 equiv.) in Et3N (0.2 M) at room temperature, 99%
yield; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 8.1 Hz, 2H), 7.35 (d, 8.2 Hz, 1H), 7.16 (d, 7.9 Hz, 2H), 7.12 (dd, 7.8, 1.2 Hz, 1H), 6.76 – 6.67 (m, 2H) 4.26 (s, 2H), 2.37 (s, 3H); The compound was identified by spectral comparison with literature data.S15
2-((trimethylsilyl)ethynyl)phenol
Prepared according to the General Procedure A using Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), 2- iodophenol (1.0 equiv.), and trimethylsilylacetylene (1.5 equiv.) in Et3N (0.5 M) at reflux, 98% yield;
1H NMR (400 MHz, CDCl3) δ 7.34 (dd, 7.7, 1.6 Hz, 1H), 7.27 – 7.21 (m, 1H), 6.94 (dd, 8.3, 0.8 Hz, 1H), 6.85 (td, 7.6, 1.0 Hz, 1H), 7.11 (d, 7.9 Hz, 4H), 5.82 (s, 1H), 0.28 (s, 9H); The compound was identified by spectral comparison with literature data.S15
General procedure B (for O-alkylation)
To a suspension of 2-(p-tolylethynyl)phenol (1.0 equiv.), the corresponding bromide (1.2 equiv) in solvent (0.6 M) was added K2CO3 (1.5 equiv.). The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
1-(cinnamyloxy)-2-(p-tolylethynyl)benzene (8d)
Prepared according to the General Procedure B using cinnamyl bromide in MeCN, 84% yield; 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, 7.8, 1.6 Hz, 1H), 7.46 (d, 8.2 Hz, 2H), 7.39 (d, 7.4 Hz, 2H), 7.35 – 7.24 (m, 4H), 7.14 (d, 8.0 Hz, 2H), 6.98 – 6.92 (m, 2H), 6.86 (d, 16.2 Hz, 1H), 6.46 (dq, 16.3, 5.2 Hz, 1H), 4.82 (dd, 5.1, 1.7 Hz, 2H), 2.36 (s, 3H); The compound was identified by spectral comparison with literature data.S16
N-ethyl-2-(p-tolylethynyl)aniline (12)
2-(p-tolylethynyl)aniline (1.0 equiv.) was dissolved in THF (0.2 M)under nitrogen atmosphere and cooled to -78°C. nBuLi solution (2.5 M in hexane, 1.1 equiv.)was added dropwise, and the mixture was stirred for 1h. Iodoethane (1.0 equiv.)was added dropwise at -78°C, and the reaction mixture was stirred for 1h at room temperature. The reaction mixture was quenched by addition of saturated solution of NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel. 96% yield; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, 8.0 Hz, 2H), 7.35 (dd, 7.4, 1.5 Hz, 1H), 7.20 (ddd, 8.9, 8.0, 1.6 Hz, 1H), 7.16 (d, 7.8 Hz, 2H), 6.66 – 6.60 (m, 2H), 4.56 (bs, 1H), 3.24 (qd, 7.2, 5.5 Hz, 1H), 2.37 (s, 3H), 1.32 (t, 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 149.04, 138.41, 132.18, 131.45, 129.97, 129.28, 120.47, 116.26, 109.60, 107.60, 95.28, 85.50, 38.19, 21.64, 14.95; MS (APCI): m/z 236.2 [M+H]+
2-(prop-1-yn-1-yl)phenol
Step 1S17: To a solution of 2-((trimethylsilyl)ethynyl)phenol (1.0 equiv.) in MeOH (0.2 M) was added KF (3.0 equiv.). The mixture was stirred at room temperature for 3h, and the solvent was evaporated under reduced pressure. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
2-ethynylphenol
: 76% yield; 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, 7.5, 1.5 Hz, 1H) 7.31 – 7.26 (m, 1H), 6.95 (d, 8.3 Hz, 1H), 6.88 (td, 7.6, 1.0 Hz, 1H), 5.77 (bs, 1H), 3.47 (s, 1H); The compound was identified by spectral comparison with literature data.S17
Step 2: 2-ethynylphenol (1.0 equiv.) was dissolved in THF (0.4 M)under nitrogen atmosphere and cooled to -78°C. nBuLi solution (2.5 M in hexane, 2.5 equiv.)was added dropwise, and the mixture was stirred for 1h. Iodomethane (1.5 equiv.) was added dropwise at -78°C, and the reaction mixture was stirred for 1h at 0°C. The reaction mixture was quenched by the addition of a saturated solution of NH4Cl and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
2-(prop-1-yn-1-yl)phenol
: 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, 7.7, 1.4 Hz, 1H) 7.23 – 7.16 (m, 1H), 6.92 (d, 7.9 Hz, 1H), 6.84 (td, 7.6, 0.9 Hz, 1H), 5.79 (s, 1H), 2.13 (s, 3H); The compound was identified by spectral comparison with literature data.S18
(Z)-4-(ethyl(2-(p-tolylethynyl)phenyl)amino)-4-oxobut-2-enoic acid (13)
To a solution of maleic anhydride (1.0 equiv.) in Et2O was added a solution of N-ethyl-2-(p- tolylethynyl)aniline (1.0 equiv, 0.8 M) in Et2O. The reaction mixture was stirred at room temperature for 6h. The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel. 73% yield; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, 5.9, 3.4 Hz, 1H), 7.45 (dd, 5.8, 3.4 Hz, 2H), 7.34 (d, 8.1 Hz, 2H), 7.25 (dd, 5.7, 3.6 Hz, 1H), 7.17 (d, 7.9 Hz, 2H), 6.18 (d, 13.0 Hz, 1H), 6.11 (d, 13.2 Hz, 1H), 3.94 (q, 7.2 Hz, 1H), 2.37 (s, 3H), 1.25 (t, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.28, 164.85, 140.91, 139.65, 136.21, 133.17, 131.43, 129.57, 129.37, 129.28, 128.53, 128.06, 123.41, 118.63, 96.64, 83.77, 45.66, 21.56, 12.34; MS (APCI): m/z 334.2 [M+H]+
(E)-3-(trimethylsilyl)acrylic acid
Step 1: To a solution of propargyl alcohol (1.0 equiv) in THF (0.4 M)was cooled to -78°C, and nBuLi solution (2.5 M in hexane, 2.1 equiv.)was added dropwise under nitrogen atmosphere. After stirring for 30 min, trimethylsilyl chloride (2.2 equiv.)was added dropwise at -78°C, and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled to 0°C, quenched by water, and added 1 N HCl solution. The mixture was stirred at room temperature for 1h. The resulting solution was then carefully neutralized with a saturated solution of NaHCO3 and extracted with Et2O.
The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
3-(trimethylsilyl)prop-2-yn-1-ol
: 74% yield; 1H NMR (400 MHz, CDCl3) δ 4.27 (d, 5.9 Hz, 2H), 1.43 (bs, 1H), 0.18 (s, 9H); The compound was identified by spectral comparison with literature data.S19
Step 2: To a suspension of LiAlH4 (1.2 equiv.) in THF was added a solution of 3-(trimethylsilyl)prop- 2-yn-1-ol (1.0 equiv, 0.4 M) in THF. The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched by the addition of a saturated solution of NH4Cl and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude mixture was used for the next step without further purification.
(E)-3-(trimethylsilyl)prop-2-en-1-ol
: 1H NMR (400 MHz, CDCl3) δ 6.19 (dt, 18.8, 4.4 Hz, 1H), 5.92 (dt, 18.8, 1.8 Hz, 1H), 4.19 (d, 3.0 Hz, 2H), 0.08 (s, 9H); The compound was identified by spectral comparison with literature data.S20
Step 3: (E)-3-(trimethylsilyl)prop-2-en-1-ol was dissolved in acetone (0.35 M)and cooled to 0°C.
Jones reagent (2.5 M in water, 3.0 equiv.)was added dropwise, and the mixture was stirred at room temperature for 1h. The reaction mixture was diluted with water and extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude mixture was used for the next step without further purification.
(E)-3-(trimethylsilyl)acrylic acid
: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 18.9 Hz, 1H), 6.25 (d, 18.9 Hz 1H), 0.16 (s, 9H); The compound was identified by spectral comparison with literature data.S21
General procedure C (for Knoevenagel condensation)
To a solution of the corresponding aldehyde (1.0 equiv.), malonic acid (1.5 equiv.), and piperidine (10.0 M) in pyridine (1.0 M) was refluxed for 1h. The reaction mixture was poured into ice and a solution of 1N HCl was added dropwise. The resulting solid was collected by filtration, and washed with water to afford pure white solid.
(E)-3-(furan-2-yl)acrylic acid
Prepared according to the General Procedure C using 2-furaldehyde, 92% yield; 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.83 (s, 1H), 7.39 (d, 15.8 Hz, 1H), 6.92 (d. 3.4 Hz, 1H), 6.62 (dd, 3.4, 1.8 Hz, 1H), 6.16 (d, 15.8 Hz, 1H); The compound was identified by spectral comparison with literature data.S22
(E)-3-(pyridin-2-yl)acrylic acid
Prepared according to the General Procedure C using pyridine-2-carbaldehyde, 61% yield; 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.64 (dd, 4.8, 0.9 Hz, 1H), 7.86 (td, 7.7, 1.8 Hz, 1H), 7.72 (d, 7.8 Hz, 1H), 7.59 (d, 15.7 Hz, 1H), 7.40 (ddd, 7.6, 4.8, 1.1 Hz, 1H), 6.82 (d, 15.7 Hz, 1H); The compound was identified by spectral comparison with literature data.S23
General procedure D (for esterification via acid chloride)
To a suspension of 4-methylcinnamic acid (1.2 equiv.), DMF (3 mol%) in dry DCM (0.5 M) was added dropwise oxalyl chloride (1.1 equiv., per acid) at 0°C. The reaction mixture was stirred at room temperature for 1h. Then, the solvent was removed under reduced pressure. The residue was dissolved in dry THF and slowly added dropwise to a solution of the appropriate phenol (1.0 equiv.) and Et3N (1.2 equiv.) in dry THF (0.3 M) at 0°C. The mixture was stirred at room temperature until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
2-(p-tolylethynyl)phenyl (E)-3-(p-tolyl)acrylate (8a)
Prepared according to the General Procedure D using 2-(p-tolylethynyl)phenol, 94% yield; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, 16.0 Hz, 1H), 7.59 (dd, 7.7, 1.6 Hz, 1H), 7.49 (d, 8.1 Hz, 2H), 7.37 (td, 7.8, 1.6 Hz, 1H), 7.32 (d, 8.2 Hz, 2H), 7.29 – 7.18 (m, 4H), 7.04 (d, 7.9 Hz, 2H), 6.67 (d, 16.0 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.11, 151.80, 146.98, 141.33, 138.68, 132.94, 131.64, 131.62, 129.85, 129.33, 129.16, 128.48, 125.91, 122.51, 120.04, 117.82, 116.11, 94.81, 83.96, 21.67, 21.60 ; MS (APCI): m/z 353.3 [M+H]+
2-((trimethylsilyl)ethynyl)phenyl (E)-3-(p-tolyl)acrylate (8b)
Prepared according to the General Procedure D using 2-((trimethylsilyl)ethynyl)phenol, 72% yield;
1H NMR (400 MHz, CDCl3) δ 7.90 (d, 16.0 Hz, 1H), 7.52 (dd, 7.7, 1.7 Hz, 1H), 7.49 (d, 8.1 Hz, 2H), 7.37 (td, 7.8, 1.7 Hz, 1H), 7.24 (d, 8.1 Hz, 2H), 7.21 (dd, 7.6, 1.1 Hz, 1H), 7.04 (d, 7.9 Hz, 2H), 7.17 (dd, 8.1, 1.1 Hz, 1H), 6.62 (d, 16.0 Hz, 1H), 2.40 (s, 3H), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 164.74, 152.31, 146.67, 141.14, 133.03, 131.49, 129.72, 129.60, 128.24, 125.65, 122.31, 117.37, 115.96, 99.92, 99.69, 21.50, -0.18; MS (APCI): m/z 335.2 [M+H]+
2-(prop-1-yn-1-yl)phenyl (E)-3-(p-tolyl)acrylate (8c)
Prepared according to the General Procedure D using 2-(prop-1-yn-1-yl)phenol, 86% yield; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 16.0 Hz, 1H), 7.51 (d, 8.2 Hz, 2H), 7.46 (dd, 7.7, 1.6 Hz, 1H), 7.32 (td, 7.8, 1.6 Hz, 1H), 7.24 (d, 7.9 Hz, 2H), 7.18 (td, 7.6, 1.3 Hz, 1H), 7.14 (d, 8.1, 1.1 Hz, 1H), 6.64 (d, 16.0 Hz, 1H), 2.40 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.07, 151.70, 146.59, 141.16, 133.02, 131.48, 129.69, 128.59, 128.29, 125.66, 122.19, 118.07, 115.94, 91.10, 74.68, 21.49, 4.49; MS (APCI): m/z 277.2 [M+H]+
General procedure E (for amide synthesis via acid chloride)
To a suspension of the corresponding acid (x equiv.), DMF (3 mol%) in dry DCM (0.5 M) was added dropwise oxalyl chloride (1.1 equiv., per acid) at 0°C. The reaction mixture was stirred at room temperature for 1h. Then, the solvent was removed under reduced pressure. The residue was dissolved in dry THF and slowly added dropwise to a solution of the appropriate aniline (1.0 equiv.) and Et3N (1.2 equiv.) in dry THF (0.3 M) at 0°C. The mixture was stirred at room temperature until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
(E)-3-(p-tolyl)-N-(2-(p-tolylethynyl)phenyl)acrylamide (8e)
Prepared according to the General Procedure E using 4-methylcinnamic acid (1.2 equiv.), and 2-(p- tolylethynyl)aniline (1.0 equiv.), 82% yield; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, 8.1 Hz, 1H), 8.18 (s, 1H), 7.73 (d, 15.6 Hz, 1H), 7.51 (d, 7.8 Hz, 1H), 7.48 (d, 7.9 Hz, 2H), 7.44 (d, 7.8 Hz, 2H), 7.38 (t, 7.7 Hz, 1H), 7.21 (t, 8.5 Hz, 4H), 7.08 (t, 7.5 Hz, 1H), 6.51 (d, 15.6 Hz, 1H), 2.43 (s, 3H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.98, 142.35, 140.44, 139.25, 131.73, 131.64, 131.46, 129.61, 129.59, 129.37, 127.99, 123.39, 119.93, 119.45, 119.45, 119.30, 96.82, 83.76, 21.56, 21.44; MS (APCI): m/z 352.3 [M+H]+
(E)-N-ethyl-N-(2-(p-tolylethynyl)phenyl)-3-(trimethylsilyl)acrylamide (8h)
Prepared according to the General Procedure E using (E)-3-(trimethylsilyl)acrylic acid (1.2 equiv.), and N-ethyl-2-(p-tolylethynyl)aniline (1.0 equiv.), 70% yield; 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.51 (m, 1H), 7.40 – 7.32 (m, 4H), 7.21 – 7.18 (m, 1H), 7.17 – 7.10 (m, 3H), 6.06 (d, 18.4 Hz, 1H), 4.03 – 3.81 (m, 2H), 2.36 (s, 3H), 1.18 (t, 7.2 Hz, 3H), -0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.34, 144.55, 143.01, 138.83, 134.82, 132.64, 131.45, 129.27, 129.10, 128.84, 127.76, 123.78, 119.58, 95.16, 85.19, 44.12, 21.52, 12.89, -1.92; MS (APCI): m/z 362.0 [M+H]+
(E)-N-ethyl-3-(furan-2-yl)-N-(2-(p-tolylethynyl)phenyl)acrylamide (8i)
Prepared according to the General Procedure E using (E)-3-(furan-2-yl)acrylic acid (1.2 equiv.), and N-ethyl-2-(p-tolylethynyl)aniline (1.0 equiv.), 91% yield; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.61 (m, 1H), 7.44 (d, 15.2 Hz, 1H), 7.41 – 7.34 (m, 4H), 7.29 – 7.21 (m, 2H), 7.12 (d, 7.8 Hz, 2H), 6.43 (d, 3.4 Hz, 1H), 6.34 (dd, 3.4, 1.8 Hz, 1H), 6.12 (d, 15.2 Hz, 1H), 4.14 – 4.00 (m, 1H), 3.88 – 3.78 (m, 1H), 2.34 (s, 3H), 1.20 (t, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 151.69, 143.62, 143.02, 138.83, 132.83, 131.50, 129.52, 129.10, 129.03, 128.36, 127.94, 123.85, 119.58, 116.87, 113.45, 111.88, 95.20, 85.15, 44.04, 21.50, 13.02; MS (APCI): m/z 356.3 [M+H]+
General procedure F (for Fischer esterification)
To a solution of the corresponding acid (1.0 equiv.), and p-toluenesulfonic acid monohydrate (0.2 equiv.) in MeOH (0.1 M) was refluxed for 3h. The solvent was evaporated under reduced pressure.
The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel.
General procedure G (for amide synthesis via mixed anhydride)
To a solution of the corresponding acid (1.0 equiv.), and Et3N (1.2 equiv.) was dissolved in solvent (x M)under nitrogen atmosphere and cooled to 0°C. Isobutyl chloroformate (1.0 equiv.)was added dropwise, and the mixture was stirred for 30 min at 0°C. The appropriate amine (x equiv.) in solvent was added dropwise at 0°C, and the reaction mixture was stirred at room temperature. The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel.
methyl (Z)-4-(ethyl(2-(p-tolylethynyl)phenyl)amino)-4-oxobut-2-enoate (8f)
Prepared according to the General Procedure F using acid 13, 99% yield; 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.52 (m, 1H), 7.41 (d, 8.1 Hz, 2H), 7.37 – 7.24 (m, 3H), 7.15 (d, 7.9 Hz, 2H), 6.39 (d, 11.9 Hz, 1H), 5.72 (d, 11.9 Hz, 1H), 4.03 – 3.84 (m, 2H), 3.74 (s, 3H), 2.37 (s, 3H), 1.23 (t, 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 165.72, 165.58, 142.37, 139.12, 137.24, 132.58, 131.60, 129.19, 128.99, 128.96, 128.24, 123.67, 123.55, 119.29, 95.19, 84.91, 51.75, 43.48, 21.53, 12.77; MS (APCI):
m/z 348.3 [M+H]+
N1-ethyl-N4,N4-diisopropyl-N1-(2-(p-tolylethynyl)phenyl)maleamide (8g)
Prepared according to the General Procedure G using acid 13 (1.0 equiv.), and DIPA (1.2 equiv.), 78%
yield; 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.56 (m, 1H), 7.38 (d, 8.0 Hz, 2H), 7.36 – 7.32 (m, 3H), 7.14 (d, 7.8 Hz, 2H), 6.09 (d, 11.9 Hz, 1H), 4.14 – 3.98 (m, 1H), 3.97 – 3.85 (m, 1H), 3.83 – 3.69 (m, 1H), 3.56 – 3.44 (m, 1H), 2.36 (s, 3H), 1.52 (d, 6.8 Hz, 3H), 1.45 (d, 6.9 Hz, 3H), 1.18 – 1.12 (m, 6H), 1.09 (d, 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.93, 164.66, 142.83, 138.98, 134.38, 132.78, 131.59, 130.33, 129.13, 129.09, 127.93, 124.94, 123.09, 119.53, 95.14, 85.16, 50.10, 45.39, 43.25, 21.55, 20.84, 20.51, 20.23, 12.87; MS (APCI): m/z 417.4 [M+H]+
(E)-N-ethyl-3-(pyridin-2-yl)-N-(2-(p-tolylethynyl)phenyl)acrylamide (8j)
Prepared according to the General Procedure G using (E)-3-(pyridin-2-yl)acrylic acid (1.0 equiv.), and N-ethyl-2-(p-tolylethynyl)aniline (1.0 equiv.), 58% yield; 1H NMR (400 MHz, CDCl3) δ 8.50 – 8.46 (m, 1H), 7.68 (d, 15.2 Hz, 1H), 7.64 – 7.55 (m, 2H), 7.42 – 7.34 (m, 4H), 7.29 – 7.20 (m, 2H), 7.16 – 7.08 (m, 3H), 6.78 (d, 15.2 Hz, 1H), 4.14 – 4.03 (m, 1H), 3.93 – 3.81 (m, 1H), 2.34 (s, 3H), 1.20 (t, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.79, 153.91, 149.89, 143.02, 140.67, 138.97, 136.53, 133.03, 131.62, 129.60, 129.26, 129.25, 128.13, 124.18, 123.93, 123.48, 123.32, 119.73, 95.40, 85.35, 44.37, 21.64, 13.08; MS (APCI): m/z 367.2 [M+H]+