Chapter 2. An Open-Air and Moisture-Compatible Nickel(0)-Catalytic Route to Substituted
2.5 Experimental
2.5.1. General Information
All reagents were purchased from standard suppliers (Sigma-Aldrich, Alfa Aesar, or TCI) and were used without further purification. The progress of reaction was monitored by thin-layer chromatography (TLC) with Merck silica gel 60 F254 commercial glass plate (0.25 mm). TLC spots were visualized by an ultra-violet lamp (254 nm). Melting points were recorded on a StuartTM melting point apparatus SMP10 and uncorrected. Compound purification was carried out through flash column chromatography (Merck silica gel 60, mesh size: 230-400). 1H, 13C and 19F NMR spectra were recorded on a Bruker Avance III HD 400 spectrometer (1H NMR: 400 MHz, 13C NMR: 101MHz, 19F NMR: 377MHz).
Chemical shift was given on the δ-scale (ppm). The residual solvent peaks were used as internal standards (CDCl3 at 7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR). For 19F NMR, anhydrous α,α,α- trifluorotoluene (-62.61 ppm in CDCl3) was used as an internal standard. 1H and 13C NMR multiplicities were reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), multiplet (m), doublet of doublets (dd), doublet of triplets (dt), triplet of doublets (td), triplet of quartets (tq), quartet of doublets (qd), quartet of quartets (qq), doublet of doublet of doublets (ddd). Coupling constants J were given in Hz. NOESY and HMBC experiments were used to assist regioisomer confirmation. High resolution mass spectrometry (HRMS) spectra were recorded on a Q Exactive™ Plus Hybrid Quadrupole-Orbitrap™ mass spectrometer from Thermo Scientific.
2.5.2 Preparation of Diynes
Preparation of diethyl 2,2-di(but-2-ynyl)malonate (1a)54
To the solution of diethyl malonate (2.4 g, 15.0 mmol, 1.0 equiv) in anhydrous THF (25 mL), 60 wt%
sodium hydride in mineral oil (1.5 g, 37.6 mmol, 2.5 equiv) was added at 0 ℃. The reaction mixture was stirred for 15 min at room temperature. To the reaction mixture, 1-bromo-2-butyne (5.0 g, 37.6 mmol, 2.5 equiv) was added dropwise. Once added, the reaction mixture was stirred for 24 h. After completion of the reaction, the mixture was diluted with DCM, and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM/ethyl acetate, 25:10:1) to afford the corresponding diyne 1a as a colorless oil (3.8 g, 95%).
19
1H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 7.1 Hz, 4H), 2.89 (q, J = 2.5 Hz, 4H), 1.74 (t, J = 2.5 Hz, 6H), 1.25 (t, J = 7.1 Hz, 6H). The NMR spectrum of compound 1a was matched with previously reported literature data.54
Preparation of N,N-di(but-2-ynyl)-4-methylbenzenesulfonamide (1b)55
To the solution of potassium carbonate (5.0 g, 36.0 mmol, 5.1 equiv) in acetonitrile (60 mL), p- toluenesulfonamide (1.2 g, 7.0 mmol, 1.0 equiv) and 1-bromo-2-butyne (2.3 g, 17.5 mmol, 2.5 equiv) were added at room temperature. The reaction mixture was refluxed for 24 h. After completion of the reaction, the salts were filtered off and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to afford the corresponding diyne 1b as a yellow solid (1.7 g, 88%).
1H NMR (400 MHz, CDCl3) δ 7.73 – 7.68 (m, 2H), 7.31 – 7.26 (m, 2H), 4.06 (q, J = 2.3 Hz, 4H), 2.41 (s, 3H), 1.64 (t, J = 2.3 Hz, 6H). The NMR spectrum of compound 1b was matched with previously reported literature data.55
Preparation of 1-(but-2-ynyloxy)but-2-yne (1c)56
To the solution of 2-butyn-1-ol (560.9 mg, 8.0 mmol, 1.0 equiv) in anhydrous THF (18 mL), 60 wt%
sodium hydride in mineral oil (704.0 mg, 17.6 mmol, 2.2 equiv) and 1-bromo-2-butyne (1.3 g, 9.6 mmol, 1.2 equiv) were added at 0 ℃. Once added, the reaction mixture was stirred for 24 h at room temperature.
After completion of the reaction, the mixture was diluted with DCM, and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/Et2O, 98:2) to afford the corresponding diyne 1c as a colorless oil (572.0 mg, 59%).
1H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 2.3 Hz, 4H), 1.85 (t, J = 2.4 Hz, 6H). The NMR spectrum of compound 1c was matched with previously reported literature data.56
20 Preparation of nona-2,7-diyne (1d)56
To the solution of 1,6-heptadiyne (1.1 mL, 10.0 mmol, 1.0 equiv) in anhydrous THF (40 mL), 1.6 M n- BuLi in hexane (15.6 mL, 25.0 mL, 2.5 equiv) was added dropwise at -78 ℃. After stirring the reaction mixture for 1 h, MeI (1.6 mL, 25.0 mmol, 2.5 equiv) was added dropwise. Once added, the reaction mixture was stirred for 4 h at room temperature. After completion of the reaction, the mixture was diluted with hexane, and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography with hexane to afford the corresponding diyne 1d as a colorless oil (573.5 mg, 48%).
1H NMR (400 MHz, CDCl3) δ 2.21 (tq, J = 7.2, 2.6 Hz, 4H), 1.76 (t, J = 2.6 Hz, 6H), 1.62 (quint, J = 7.1 Hz, 2H). The NMR spectrum of compound 1d was matched with previously reported literature data.56
Preparation of diethyl 2-(but-2-ynyl)malonate57
To the solution of diethyl malonate (42.2 g, 263.2 mmol, 5.0 equiv) in anhydrous THF (70 mL), 60 wt%
sodium hydride in mineral oil (4.2 g, 105.3 mmol, 2.0 equiv) was added at 0 ℃. The reaction mixture was stirred for 15 min at room temperature. To the reaction mixture, 1-bromo-2-butyne (7.0 g, 52.6 mmol, 1.0 equiv) was added dropwise. Once added, the reaction mixture was stirred for 24 h. After completion of the reaction, the mixture was diluted with DCM, and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM/ethyl acetate, 25:10:1) to afford the corresponding alkyne as a colorless oil (7.5 g, 67%).
1H NMR (400 MHz, CDCl3) δ 4.22 (q, J = 7.1 Hz, 4H), 3.50 (t, J = 7.8 Hz, 1H), 2.75 – 2.67 (m, 2H), 1.74 (t, J = 2.5 Hz, 3H), 1.27 (t, J = 7.1 Hz, 6H). The NMR spectrum of the compound was matched with previously reported literature data.57
Preparation of diethyl 2-(but-2-ynyl)-2-(prop-2-ynyl)malonate (1e)58
21
To the solution of diethyl 2-(but-2-ynyl)malonate (7.0 g, 33.0 mmol, 1.0 equiv) in anhydrous THF (70 mL), 60 wt% sodium hydride in mineral oil (2.0 g, 49.5 mmol, 1.5 equiv) was added at 0 ℃. The reaction mixture was stirred for 15 min at room temperature. To the reaction mixture, propargyl bromide (6.7 g, 56.1 mmol, 1.7 equiv) was added dropwise. Once added, the reaction mixture was stirred for 24 h. After completion of the reaction, the mixture was diluted with DCM, and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM/ethyl acetate, 25:10:1) to afford the corresponding diyne 1e as a colorless oil (7.1 g, 86%).
1H NMR (400 MHz, CDCl3) δ 4.22 (q, J = 7.1 Hz, 4H), 2.97 (d, J = 2.7 Hz, 2H), 2.92 (q, J = 2.6 Hz, 2H), 2.01 (t, J = 2.7 Hz, 1H), 1.75 (t, J = 2.6 Hz, 3H), 1.25 (t, J = 7.1 Hz, 6H). The NMR spectrum of compound 1e was matched with previously reported literature data.58
Preparation of diethyl 2-(but-2-ynyl)-2-(3-(trimethylsilyl)prop-2-ynyl)malonate (1f)
To the solution of i-Pr2NH (526.2 mg, 5.2 mmol, 1.3 equiv) in anhydrous THF (18 mL), 1.6 M n-BuLi in hexane (3.3 mL, 5.2 mmol, 1.3 equiv) was added dropwise at 0 ℃. After 30 min, the reaction mixture was cooled to -78 ℃ and diethyl 2-(but-2-ynyl)-2-(prop-2-ynyl)malonate 1e (1.0 g, 4.0 mmol, 1.0 equiv) was added. After stirring the reaction mixture for 1 h at -78 ℃, TMSCl (651.8 mg, 6.0 mmol, 1.5 equiv) was added. Once added, the reaction mixture was stirred for additional 4 h. The mixture was diluted Et2O, and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ethyl acetate, 20:1) to afford 1f as a colorless oil (514.5 mg, 40%).
1H NMR (400 MHz, CDCl3) δ 4.21 (qd, J = 7.1, 2.7 Hz, 4H), 2.97 (s, 2H), 2.89 (q, J = 2.5 Hz, 2H), 1.75 (t, J = 2.6 Hz, 3H), 1.25 (t, J = 7.1 Hz, 6H), 0.12 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 169.08, 101.41, 88.15, 79.03, 73.36, 61.90, 57.09, 24.02, 23.00, 14.20, 3.65, 0.10.
22
HRMS (ESI): m/z [M+H]+ calcd for C17H27O4Si 323.1673; found 323.1672.
Preparation of diethyl 2-(but-2-ynyl)-2-(3-phenylprop-2-ynyl)malonate (1g)59
To the solution of diethyl 2-(but-2-ynyl)malonate (500.0 mg, 2.4 mmol, 1.0 equiv) in anhydrous THF (5 mL), 60 wt% sodium hydride (141.6 mg, 3.5 mmol, 1.5 equiv) was added at 0 ℃. The reaction mixture was stirred for 15 min at room temperature. To the reaction mixture, 3-chloro-1-phenyl-1- propyne (533.1 mg, 3.5 mmol, 1.5 equiv) was added. Once added, the reaction mixture was stirred for 48 h. After completion of the reaction, the mixture was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM, 1:1) to afford 1g as a yellow oil (380.2 mg, 49%).
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.23 (m, 5H), 4.24 (q, J = 7.1 Hz, 4H), 3.18 (s, 2H), 2.97 (q, J = 2.5 Hz, 2H), 1.80 – 1.72 (m, 3H), 1.26 (t, J = 7.1 Hz, 6H). The NMR spectrum of compound 1g was matched with previously reported literature data.59
Preparation of (3-(but-2-ynyloxy)prop-1-ynyl)benzene (1h)60
To a two-neck Schlenk flask, 60 wt% sodium hydride (363.2 mg, 9.1 mmol, 1.2 equiv) was charged at argon atmosphere. To the charged flask, the solution of 3-phenyl-2-propyn-1-ol (1.0 g, 7.6 mmol, 1.0 equiv) in anhydrous THF (25 mL) was added dropwise at 0 ℃. After stirring the reaction mixture for 30 min, 1-bromo-2-butyne (1.2 g, 9.1 mmol, 1.2 equiv) was added. Once added, the reaction mixture was stirred for 24 h at room temperature. After completion of the reaction, the mixture was diluted with DCM, and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ethyl acetate, 20:1) to afford the corresponding diyne 1h as a yellow oil (753.6 mg, 58%).
1H NMR (400 MHz, CDCl3) δ 7.48 – 7.42 (m, 2H), 7.34 – 7.28 (m, 3H), 4.46 (s, 2H), 4.28 (q, J = 2.3 Hz, 2H), 1.88 (t, J = 2.3 Hz, 3H). The NMR spectrum of compound 1h was matched with previously
23 reported literature data.60
Preparation of diethyl 2-(but-2-ynyl)-2-(3-(4-fluorophenyl)prop-2-ynyl)malonate (1i)61
diethyl 2-(but-2-ynyl)-2-(3-(4-fluorophenyl)prop-2-ynyl)malonate 1i was prepared by modified method to prepare analogous diyne.61 To a three-neck Schlenk flask, Pd(PPh3)2Cl2 (22.5 mg, 0.03 mmol, 0.01 equiv), and CuI (12.2 mg, 0.06 mmol, 0.02 equiv) were charged at argon atmosphere. To the charged flask, the solution of diyne 1e (800 mg, 3.2 mmol, 1.0 equiv) and fluoro-4-iodobenzene (732.6 mg, 3.3 mmol, 1.0 equiv) in NEt3 (12 mL) was added at room temperature. Once added, the reaction mixture was stirred for 24 h. After completion of the reaction, the organic layer was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM, 3:2) to afford 1i a yellow oil (918.2 mg, 83%).
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 2H), 6.99 – 6.92 (m, 2H), 4.23 (q, J = 7.1 Hz, 4H), 3.16 (s, 2H), 2.96 (q, J = 2.5 Hz, 2H), 1.76 (t, J = 2.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 169.23, 162.43 (d, J = 248.9 Hz), 133.63 (d, J = 8.4 Hz), 119.40 (d, J
= 3.5 Hz), 115.55 (d, J = 22.0 Hz), 84.15, 82.56, 79.25, 73.27, 61.98, 57.14, 23.57, 23.22, 14.22, 3.67.
19F NMR (377 MHz, CDCl3) δ -111.40.
HRMS (ESI): m/z [M+H]+ calcd for C20H22FO4 345.1497; found 345.1494.
Preparation of diethyl 2-(but-2-ynyl)-2-(3-(4-methoxyphenyl)prop-2-ynyl)malonate (1j)62
diethyl 2-(but-2-ynyl)-2-(3-(4-fluorophenyl)prop-2-ynyl)malonate 1j was prepared by modified method to prepare analogous diyne.62 To a three-neck Schlenk flask, Pd(PPh3)2Cl2 (140.4 mg, 0.2 mmol, 0.05 equiv), CuI (76.2 mg, 0.4 mmol, 0.1 equiv), and 4-iodoanisole (1.2 g, 5.2 mmol, 1.3 equiv) were charged at argon atmosphere. To the charged flask, the solution of diyne 1e (1.0 g, 4.0 mmol, 1.0 equiv) in NEt3 (11.5 mL) and DMF (11.5 mL) was added at room temperature. Once added, the reaction
24
mixture was stirred for 19 h at 80 ℃. After completion of the reaction, the organic layer was diluted with ethyl acetate and washed with aqueous NH4Cl solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ethyl acetate, 6:1) to afford 1j a yellow oil (637.8 mg, 45%).
1H NMR (400 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 6.82 – 6.77 (m, 2H), 4.23 (q, J = 7.2 Hz, 4H), 3.79 (s, 3H), 3.15 (s, 2H), 2.96 (q, J = 2.5 Hz, 2H), 1.76 (t, J = 2.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 169.33, 159.45, 133.18, 115.54, 113.92, 83.39, 82.82, 79.13, 73.42, 61.93, 57.25, 55.41, 23.65, 23.19, 14.24, 3.68.
HRMS (ESI): m/z [M+H]+ calcd for C21H25O5 357.1697; found 357.1693.
Preparation of but-2-ynyl 3-phenylpropiolate (1k)63
To the solution of phenylpropiolic acid (1.0 g, 6.8 mmol), N,N’-dicyclohexylcarbodiimide (1.6 g, 7.7 mmol) and 4-dimethylaminopyridine (94.0 mg, 0.8 mmol) in anhydrous DCM (15 mL), 2-butyn-1-ol (517.3 mg, 7.4 mmol) was added at 0 ℃. Once added, the reaction mixture was stirred for 24 h at 0 ℃.
After completion of the reaction, the mixture was diluted with DCM and filtered by Celite filter. The organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM, 1:1) to afford the corresponding diyne 1k as a pale yellow oil (828.9 mg, 61%).
1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.49 – 7.43 (m, 1H), 7.41 – 7.35 (m, 2H), 4.80 (q, J = 2.4 Hz, 2H), 1.88 (t, J = 2.4 Hz, 3H). The NMR spectrum of compound 1k was matched with previously reported literature data.63
25 Preparation of 3-phenylprop-2-ynyl but-2-ynoate (1l)
To the solution of tetrolic acid (1.0 g, 11.9 mmol), N,N’-dicyclohexylcarbodiimide (2.8 g, 13.4 mmol) and 4-dimethylaminopyridine (163.7 mg, 1.3 mmol) in anhydrous DCM (30 mL), 3-phenyl-2-propyn- 1-ol (1.7 g, 12.9 mmol) was added at 0 ℃. Once added, the reaction mixture was stirred for 24 h at 0 ℃.
After completion of the reaction, the mixture was diluted with DCM and filtered by Celite filter. The organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (hexane/DCM, 5:2) to afford the corresponding diyne 1l as a pale yellow oil (1.2 g, 53%).
1H NMR (400 MHz, CDCl3) δ 7.49 – 7.42 (m, 2H), 7.37 – 7.28 (m, 3H), 4.98 (s, 2H), 2.01 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 153.04, 132.03, 129.00, 128.43, 122.10, 87.27, 87.01, 82.13, 71.97, 54.07, 4.00.
HRMS (ESI): m/z [M+H]+ calcd for C13H11O2 199.0754; found 199.0754.
26 2.5.3. Optimization Studies
entry catalyst yield (%)
1 Nickel 0
2 NiCl2 0
3 NiBr2 0
4 Ni(OAc)2∙4H2O 0
5 Ni(NO3)2∙6H2O 0
6 Ni(OTf)2 0
7 NiCl2(PCy3)2 0
8 NiCl2(PPh3)2 0
9 NiCl2∙6H2O 0
10 C1 89
11 C2 0
12 C3 0
aStandard conditions: 1a (0.25 mmol), 2a (0.25 mmol), catalyst (10 mol %), Xantphos (20 mol %), Cs2CO3 (1.0 equiv) in toluene (1.0 mL) at 80 ℃ for 3 h under air. Isolated yields are given.
Table 2.2. Catalyst Screening.
27
entry ligand yield (%)
1 L1 89
2 L2 65
3 L3 <1
4 L4 0
5 L5 <1
6 L6 0
7 L7 0
8 L8 0
9 L9 0
10 L10 0
11 L11 0
12 L12 0
aStandard conditions: 1a (0.25 mmol), 2a (0.25 mmol), Cp2Ni (10 mol %), ligand (20 mol %), Cs2CO3 (1.0 equiv) in toluene (1.0 mL) at 80 ℃ for 3 h under air. Isolated yields are given.
Table 2.3. Ligand Screening.
28
entry solvent yield (%)
1 toluene 89
2 DCM 0
3 DMF 68
4 water 29
aStandard conditions: 1a (0.25 mmol), 2a (0.25 mmol), Cp2Ni (10 mol %), Xantphos (20 mol %), Cs2CO3 (1.0 equiv) in solvent (1.0 mL) at 80 ℃ for 3 h under air. Isolated yields are given.
Table 2.4. Solvent Screening.
entry change from the standard conditions yield (%)
1 none 82
2 1b (0.25 mmol), 2a (0.25 mmol), Cp2Ni (20 mol %), Xantphos (20 mol %), 30 ℃ 75
3 1b (0.6 mmol), Xantphos (20 mol %), 17 h 99
4 1b (0.6 mmol), Xantphos (20 mol %) >99
5 2a (0.6 mmol), Xantphos (20 mol %) 85
6 Xantphos (20 mol %) 84
7 Cp2Ni (8 mol %), Xantphos (8 mol %) 59
aStandard conditions: 1b (0.4 mmol), 2a (0.4 mmol), Cp2Ni (10 mol %), Xantphos (10 mol %), Cs2CO3
(1.0 equiv) in water (1.35 mL) and ethanol (0.15 mL) at 50 ℃ for 12 h under air. Isolated yields are given.
Table 2.5. Summary of reaction optimization in water.
29
2.5.4. General Procedure for [2 + 2 + 2] Cycloaddition to Access Pyridine
General Procedure A (GP A) To the solution of Cp2Ni (4.7 mg, 0.025 mmol, 0.1 equiv), Xantphos (28.9 mg, 0.05 mmol, 0.2 equiv) and Cs2CO3 (81.5 mg, 0.25 mmol, 1.0 equiv) in toluene (1.0 mL), diyne 1 (0.25 mmol, 1.0 equiv) and nitrile 2 (0.25 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 3 h at 80 ℃. The residue was purified by flash column chromatography.
General Procedure B (GP B) To the solution of Cp2Ni (7.6 mg, 0.04 mmol, 0.1 equiv), Xantphos (23.1 mg, 0.04 mmol, 0.1 equiv) and Cs2CO3 (130.3 mg, 0.4 mmol, 1.0 equiv) in water (1.35 mL) and ethanol (0.15 mL), diyne 1 (0.4 mmol, 1.0 equiv) and nitrile 2 (0.4 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 12 h at 50 ℃. After completion of the reaction, the mixture was diluted with additional water, and organic layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography.
General Procedure C (GP C) To the solution of Cp2Ni (28.3 mg, 0.15 mmol, 0.2 equiv), Xantphos (108.5 mg, 0.19 mmol, 0.25 equiv) and Cs2CO3 (244.4 mg, 0.75 mmol, 1.0 equiv) in toluene (3.0 mL), diyne 1 (0.75 mmol, 1.0 equiv) and nitrile 2 (1.88 mmol, 2.5 equiv) were added. The reaction mixture was stirred for 3 h at 80 ℃. The residue was purified by flash column chromatography.
2.5.5. Synthesis of Pyridine derivatives
diethyl 1,4-dimethyl-3-phenyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3aa)18
1. The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and benzonitrile 2a (25.8 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3aa as a pale yellow oil (81.6 mg, 89%).
2. The general procedure B (GP B) was used with diyne 1a (105.7 mg, 0.4 mmol, 1.0 equiv) and benzonitrile 2a (41.2 mg, 0.4 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3aa as a pale yellow oil (79.1 mg, 54%).
30
3. 1.0 g scale reaction; To the solution of Cp2Ni (71.4 mg, 0.38 mmol, 0.1 equiv), Xantphos (437.4 mg, 0.76 mmol, 0.2 equiv), Cs2CO3 (1.2 g, 3.78 mmol, 1.0 equiv) in toluene (15.0 mL), diyne 1a (1.0 g, 3.78 mmol, 1.0 equiv) and benzonitrile 2a (388.9 mg, 3.78 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 3 h at 80 ℃. The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3aa as a pale yellow oil (1.2 g, 84%).
1H NMR (400 MHz, CDCl3) δ 7.48 – 7.29 (m, 5H), 4.24 (q, J = 7.1 Hz, 4H), 3.61 (s, 2H), 3.58 (s, 2H), 2.47 (s, 3H), 2.18 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H).The NMR spectrum of compound 3aa was matched with previously reported literature data.18
diethyl 1,4-dimethyl-3-(2-methoxyphenyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ab)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2- methoxybenzonitrile 2b (33.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to afford the corresponding product 3ab as a yellow oil (14.0 mg, 14%).
1H NMR (400 MHz, CDCl3) δ 7.34 (td, J = 8.3, 1.7 Hz, 1H), 7.22 (dd, J = 7.4, 1.8 Hz, 1H), 7.05 – 6.99 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 4H), 3.76 (s, 3H), 3.62 (s, 2H), 3.59 (s, 2H), 2.47 (s, 3H), 2.00 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.76, 171.57, 156.74, 154.87, 150.34, 148.61, 132.76, 130.94, 130.02, 129.29, 126.09, 120.94, 110.81, 62.10, 59.57, 55.51, 40.09, 39.25, 29.83, 21.98, 15.45, 14.25, 14.16.
HRMS (ESI): m/z [M+H]+ calcd for C23H28NO5 398.1962; found 398.1960.
diethyl 1,4-dimethyl-3-(4-methoxyphenyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ac)
31
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and anisonitrile 2c (33.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 2:1) to afford the corresponding product 3ac as a pale yellow oil (84.9 mg, 85%).
1H NMR (400 MHz, CDCl3) δ 7.42 – 7.34 (m, 2H), 6.96 – 6.90 (m, 2H), 4.22 (q, J = 7.1 Hz, 4H), 3.81 (s, 3H), 3.59 (s, 2H), 3.56 (s, 2H), 2.45 (s, 3H), 2.19 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.50, 159.17, 156.62, 150.31, 149.45, 133.28, 132.21, 130.42, 124.11, 113.55, 62.01, 59.55, 55.33, 40.08, 39.04, 21.88, 16.28, 14.07.
HRMS (ESI): m/z [M+H]+ calcd for C23H28NO5 398.1962; found 398.1960.
diethyl 1,4-dimethyl-3-(2-(trifluoromethyl)phenyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ad)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2- (trifluoromethyl) benzonitrile 2d (42.8 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 3:1) to afford the corresponding product 3ad as a white solid (45.1 mg, 49%).
m.p. 90 ℃.
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 4.24 (q, J = 7.2 Hz, 4H), 3.62 (s, 2H), 3.57 (s, 2H), 2.44 (s, 3H), 1.91 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.70, 171.39, 155.03, 149.90, 148.92, 139.75, 133.36, 131.75, 130.91, 128.73 (q, J = 30.4 Hz), 128.00, 126.46 (q, J = 5.0 Hz), 125.15, 124.13 (q, J = 274.3 Hz), 62.16, 59.56, 39.95, 39.23, 21.80, 15.64, 14.15.
19F NMR (377 MHz, CDCl3) δ -58.94.
HRMS (ESI): m/z [M+H]+ calcd for C23H25F3NO4 436.1730; found 436.1727.
32
diethyl 1,4-dimethyl-3-(4-(trifluoromethyl)phenyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ae)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 4- (trifluoromethyl) benzonitrile 2e (42.8 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to afford the corresponding product 3ae as a yellow solid (97.9 mg, 90%).
m.p. 118 ℃.
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 4.24 (q, J = 7.1 Hz, 4H), 3.62 (s, 2H), 3.59 (s, 2H), 2.47 (s, 3H), 2.18 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.43, 155.46, 150.90, 149.82, 144.43, 144.41, 133.39, 129.72 (q, J = 32.3 Hz), 129.63, 125.17 (q, J = 3.8 Hz), 124.39, 124.34 (q, J = 272.1 Hz), 62.14, 59.54, 40.06, 39.10, 21.89, 16.08, 14.09.
19F NMR (377 MHz, CDCl3) δ -62.40.
HRMS (ESI): m/z [M+H]+ calcd for C23H25F3NO4 436.1730; found 436.1727.
diethyl 1,4-dimethyl-3-(4-fluorophenyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3af)64
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 4- fluorobenzonitrile 2f (30.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to afford the corresponding product 3af as a pale yellow oil (86.5 mg, 90%).
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.35 (m, 2H), 7.13 – 7.01 (m, 2H), 4.23 (q, J = 7.1 Hz, 4H), 3.60 (s, 2H), 3.57 (s, 2H), 2.45 (s, 3H), 2.16 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H). The NMR spectrum of
33
compound 3af was matched with previously reported literature data.64
diethyl 1,4-dimethyl-3-(2-thienyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ag)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and thiophene-2-carbonitrile 2g (27.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to afford the corresponding product 3ag as a white solid (84.7 mg, 91%).
m.p. 95 ℃.
1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 5.1, 1.0 Hz, 1H), 7.31 (dd, J = 3.7, 1.0 Hz, 1H), 7.07 (dd, J = 5.1, 3.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 4H), 3.59 (s, 2H), 3.58 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.39, 150.60, 149.86, 149.74, 144.67, 132.50, 127.25, 126.67, 123.63, 62.06, 59.51, 40.13, 39.02, 21.85, 16.76, 14.08.
HRMS (ESI): m/z [M+H]+ calcd for C20H24NO4S 374.1421; found 374.1420.
diethyl 1,4-dimethyl-3-(2-furanyl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ah)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2- furonitrile 2h (23.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to afford the corresponding product 3ah as a brown solid (60.4 mg, 68%).
m.p. 82 ℃.
1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 1.8, 0.8 Hz, 1H), 6.77 (dd, J = 3.3, 0.8 Hz, 1H), 6.48 (dd,
34
J = 3.4, 1.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 4H), 3.58 (s, 2H), 3.57 (s, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 1.26 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.40, 153.58, 150.78, 149.87, 146.38, 142.67, 132.70, 123.82, 111.22, 110.68, 62.08, 59.42, 40.10, 39.13, 22.03, 16.20, 14.09.
HRMS (ESI): m/z [M+H]+ calcd for C20H24NO5 358.1649; found 358.1648.
diethyl 1,4-dimethyl-3-(piperidin-1-yl)-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ai)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and piperidine-1-carbonitrile 2i (27.6 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 6:1) to afford the corresponding product 3ai as a yellow oil (83.6 mg, 89%).
1H NMR (400 MHz, CDCl3) δ 4.20 (q, J = 7.1 Hz, 4H), 3.47 (s, 2H), 3.45 (s, 2H), 3.08 – 2.88 (m, 4H), 2.32 (s, 3H), 2.12 (s, 3H), 1.66 (quint, J = 5.8 Hz, 4H), 1.55 (quint, J = 5.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.68, 161.61, 150.19, 148.04, 127.66, 118.13, 61.91, 59.88, 51.58, 39.86, 38.58, 26.48, 24.74, 21.72, 14.38, 14.11.
HRMS (ESI): m/z [M+H]+ calcd for C21H31N2O4 375.2278; found 375.2275.
diethyl 1,3,4-trimethyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3aj)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and acetonitrile 2j (10.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to afford the corresponding product 3aj as a pale yellow oil
35 (57.3 mg, 75%).
1H NMR (400 MHz, CDCl3) δ 4.19 (q, J = 7.1 Hz, 4H), 3.49 (s, 2H), 3.48 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H), 1.23 (t, J = 7.2 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 171.52, 154.69, 149.60, 148.51, 131.46, 124.60, 62.00, 59.66, 39.79, 38.96, 22.06, 21.65, 15.10, 14.09.
HRMS (ESI): m/z [M+H]+ calcd for C17H24NO4 306.1700; found 306.1697.
diethyl 1,4-dimethyl-3-propyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ak)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and butyronitrile 2k (17.3 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 7:2) to afford the corresponding product 3ak as a pale yellow oil (51.3 mg, 62%).
1H NMR (400 MHz, CDCl3) δ 4.20 (q, J = 7.1 Hz, 4H), 3.51 (s, 2H), 3.50 (s, 2H), 2.75 – 2.63 (m, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.70 – 1.52 (m, 2H), 1.25 (t, J = 7.1 Hz, 6H), 0.96 (t, J = 7.3 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 171.58, 158.49, 149.78, 148.83, 131.34, 124.09, 62.00, 59.57, 39.96, 39.02, 37.41, 23.01, 21.70, 14.73, 14.33, 14.10.
HRMS (ESI): m/z [M+H]+ calcd for C17H24NO4 334.2013; found 334.2011.
diethyl 1,4-dimethyl-3-octyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3al)
The general procedure A (GP A) was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and nonanenitrile 2l (34.8 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to afford the corresponding product 3al as a colorless oil
36 (34.7 mg, 34%).
1H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 7.1 Hz, 4H), 3.51 (s, 2H), 3.50 (s, 2H), 2.74 – 2.67 (m, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.62 – 1.53 (m, 2H), 1.40 – 1.23 (m, 16H), 0.88 – 0.84 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 171.63, 158.79, 149.85, 148.80, 131.30, 123.99, 62.03, 59.62, 39.99, 39.07, 35.61, 31.99, 30.00, 29.87, 29.66, 29.39, 22.78, 21.78, 14.76, 14.22, 14.14.
HRMS (ESI): m/z [M+H]+ calcd for C24H38NO4 404.2795; found 404.2794.
4,7-dimethyl-6-phenyl-2-tosyl-1,3-dihydropyrrolo[3,4-c]pyridine (3ba)33
1. The general procedure A (GP A) was used with diyne 1b (68.8 mg, 0.25 mmol, 1.0 equiv) and benzonitrile 2a (25.8 mg, 0.25 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3ba as a white solid (60.2 mg, 64%).
2. The general procedure B (GP B) was used with diyne 1b (110.1 mg, 0.4 mmol, 1.0 equiv) and benzonitrile 2a (41.2 mg, 0.4 mmol, 1.0 equiv). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3ba as a white solid (124.3 mg, 82%).
3. Comparative experiment; To the solution of Ni(COD)(DQ) (13.2 mg, 0.04 mmol, 0.1 equiv) and Xantphos (23.1 mg, 0.04 mmol, 0.1 equiv) in water (1.35 mL) and ethanol (0.15 mL), diyne 1b (110.1 mg, 0.4 mmol, 1.0 equiv) and benzonitrile 2a (41.2 mg, 0.4 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 12 h at 50 ℃. After completion of the reaction, the mixture was diluted with additional water, and organic layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to afford the corresponding product 3ba as a white solid (18.3 mg, 12%).
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.44 – 7.32 (m, 7H), 4.64 (s, 2H), 4.61 (s, 2H), 2.42 (s, 6H), 2.14 (s, 3H). The NMR spectrum of compound 3ba was matched with previously reported literature data.33