Patent Grant
10144712
The present invention relates to an N-Heterocyclic compound of formula A.
Particularly, the present invention relates to a process for the preparation of N-Heterocyclic compound of formula A. More particularly, present invention relates to N-Heterocyclic compound of formula A useful for ligand synthesis in transition-metal catalysis.
Alkynes are very important building blocks in synthetic chemistry and in material science and they are also a common motif in pharmaceuticals. The unique physical properties of alkynes (rigid structure and conjugating π system) make them an attractive functional group for unsaturated molecular scaffolds. Because of their unsaturated, high-energy structure further derivatization in many synthetic transformations (including cycloaddition, metathesis, click reaction etc.) may be possible and leads to various useful molecules.
The development of catalytic system for direct conversion of inert C—H bonds into C-alkynyl bonds is very attractive, simplest and sustainable method as the alkyne moiety is of significant importance for various organic transformations including cycloaddition, metathesis, click reaction etc. In addition alkynes are outstanding building blocks in synthetic chemistry and in material science and they are also a common motif in drugs. Because of the susceptibility of terminal alkynes to homocoupling under the commonly employed oxidative reaction conditions, C—H alkynylation is largely underexplored.
Catalysts based direct activation of C—H bonds provides a sustainable and an atom-economical synthetic strategy to diverse organic molecules from simple, pre-functionalized substrates. The selection of ligands is very crucial in the design of such active catalytic systems. Ligands would alter the electronic and steric properties of the active catalyst and thus they could significantly accelerate C—H activation and successive bond forming reactions. Although, ligand-enabled C(sp3)-H activation has emerged as a powerful tool for rapid, straightforward construction of the carbon-carbon and the carbon-heteroatom bonds, there still remains a significant challenge in the field of C(sp3)-H activation.
Article titled “Rhodium(III)-catalyzed alkenylation reactions of 8-methylquinolines with alkynes by C(sp3)-H activation” by B Liu et al. published in Angew Chem. Int Ed Engl., 2014; 53(16), pp 4191-4195 reports alkenylation reactions of 8-methylquinolines with alkynes, catalyzed by [{Cp*RhCl2}2], proceeds efficiently to give 8-allylquinolines in good yields by C(sp3)-H bond activation. These reactions are highly regio- and stereoselective.
Article titled “Palladium-Catalyzed Direct Ethynylation of C(sp3)-H Bonds in Aliphatic Carboxylic Acid Derivatives” by Y Ano et al. published in J. Am. Chem. Soc., 2011, 133 (33), pp 12984-12986 reports first catalytic alkynylation of unactivated C(sp3)-H bonds by straightforward introduction of an ethynyl group into aliphatic acid derivatives under palladium catalysis. This new reaction can be applied to the rapid elaboration of complex aliphatic acids, for example, via azide/alkyne cycloaddition.
Article titled “Palladium(0)-Catalyzed Alkynylation of C(sp3)-H Bonds” by J He et al. published in J. Am. Chem. Soc., 2013, 135 (9), pp 3387-3390 reports alkynylation of β-C(sp3)-H bonds in aliphatic amides with alkynyl halides enabled using Pd(0)/N-heterocyclic carbene (NHC) and Pd(0)/phosphine (PR3) catalysts.
Article titled “Direct palladium-catalyzed C-3 alkynylation of indoles” by Y Gu et al. published in Tetrahedron Letters, 2009, 50 (7), pp 763-766 reports direct palladium-catalyzed coupling reaction of indoles with alkynyl bromides In the presence of catalytic amount of PdCl2(PPh3)2 and 2.0 equiv. NaOAc, the coupling reaction of indoles with alkynyl bromides proceeded smoothly at 50° C. to give the corresponding 3-alkynylindoles with high regioselectivity in good to excellent yields.
Article titled “Direct Palladium-Catalyzed Alkynylation of N-Fused Heterocycles” by N Seregin et al. published in J. Am. Chem. Soc., 2007, 129 (25), pp 7742-7743 reports direct C—H alkynylation of electron-rich heteroaromatics. This mild, simple, and general method allows for the efficient synthesis of diverse alkynyl heterocycles.
Article titled “Catalytic Coupling of C—H and C—I Bonds Using Pyridine As a Directing Group” by D Shabashov et al. published in Org. Lett., 2005, 7 (17), pp 3657-3659 reports a method for the palladium-catalyzed arylation of pyridines and pyrazoles. Both aliphatic and aromatic C—H bonds may be functionalized using this method. A bromo substituent is tolerated on the aryl iodide coupling component.
The prior art reports C—H alkynylation of aliphatic carboxylic acid derivatives using template strategy. Due to cyclometalation ability of 8-methylquinoline several transition-metal-catalyzed C(sp3)-H bond activation of 8-methylquinoline has been reported by various research groups. Despite a number of reports concerning C(sp2)-H alkynylation reactions, methods to convert C(sp3)-H bonds to C(sp3)-alkynyl bonds remain extremely rare. Accordingly, the present invention provides efficient C—H alkynylation of inert C(sp3)-H bonds of N-heterocycles.
The main objective of the present invention is to provide N-heterocyclic compounds of formula A.
Another objective of the present invention is to provide a process for the preparation of N-heterocyclic compounds of formula A.
Yet another objective of the present invention is to provide N-heterocyclic compounds of formula A useful for ligand synthesis in transition-metal catalysis.
Yet another objective of the present invention is to provide a ligand-enabled palladium-catalyzed straightforward and efficient C—H alkynylation of inert C(sp3)-H bonds of N-heterocycles (quinoline and pyridine derivatives) using a chelation-assisted strategy.
Accordingly, present invention provides a heterocyclic compound of formula A
wherein,
In an embodiment of the present invention, representative compound of formula 1 comprising:
In an embodiment, present invention provides a process for preparation of heterocyclic compound of formula A comprising the steps of:
In another embodiment of the present invention, said ligand is selected from is selected from the group consisting of 1,10-phenonthroline, 4-4dimethoxy-2,2-bipyridine, 4,4′-dimethyl-2,2′-dipyridyl, 2,6-Pyridinedicarboxylic acid, Chelidamic acid, 2,2′-Bipyridyl, 3,4,7,8-Tetramethyl-1,10-phenanthroline, 4,7-Dimethoxy-1,10-phenanthroline, L-Isoleucine, 2,6-Pyridinedimethanol, 4-Hydroxy-2,6-Pyridinedicarboxylic acid, 2-Picolinic acid, 2,6-Lutidine, 2,4,6-Trimethylpyridine, 2,6-Di-tert-butylpyridine, 2-Methylpyridine.
In yet another embodiment of the present invention, said oxidant is selected from the group consisting of potassium persulfate (K2S2O8), Oxygen (O2), Copper(II) acetate [Cu(OAc)2], Copper (II) triflate [Cu(OTf)2], manganese(III) acetate [Mn(OAc)3.2H2O], sodium periodate (NaIO4), N-Methylmorpholine N-oxide (NMO), 1,4-Benzoquinone (BQ), (Diacetoxyiodo)benzene, silver carbonate, silver acetate and silver oxide (Ag2O).
In yet another embodiment of the present invention, said alkynyl halide is (bromoethynyl) triisopropylsilane.
In yet another embodiment of the present invention, said solvent is selected from the group consisting of 1,2-dichloroethane (DCE), arenes, toluene, o-xylene, chlorobenzene (PhCl), Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMA), Dioxane, tetrahydrofuran (THF) and trifluoroethanol (CF3CH2OH).
In yet another embodiment of the present invention, said process is carried out at argon or nitrogen atmosphere.
In yet another embodiment of the present invention, said compound is useful for ligand synthesis in transition-metal catalysis.
Present invention provides a compound of formula A
wherein
Representative compound of formula A are as follows:
The present invention provides a ligand-enabled palladium-catalyzed process for preparation of N-Heterocyclic compounds of Formula A via C—H alkynylation (sp3-sp carbon-carbon bond-forming reaction) of 8-methylquinolines (1a-1p) with alkynyl halides (2) and the said process comprising the steps of:
The process for the preparation on N-heterocyclic compounds of formula A is shown in
Ligand used in step (a) is selected from the group consisting of 1,10-phenonthroline, 4-4dimethoxy-2,2-bipyridine, 4,4′-dimethyl-2,2′-dipyridyl, 2,6-Pyridinedicarboxylic acid, Chelidamic acid, 2,2′-Bipyridyl, 3,4,7,8-Tetramethyl-1,10-phenanthroline, 4,7-Dimethoxy-1,10-phenanthroline, L-Isoleucine, 2,6-Pyridinedimethanol, 4-Hydroxy-2,6-Pyridinedicarboxylic acid, 2-Picolinic acid, 2,6-Lutidine, 2,4,6-Trimethylpyridine, 2,6-Di-tert-butylpyridine, 2-Methylpyridine.
Oxidant used in step (a) is selected from the group consisting of potassium persulfate (K2S2O8), Oxygen (O2), Copper(II) acetate [Cu(OAc)2], Copper (II) triflate [Cu(OTf)2], manganese(III) acetate [Mn(OAc)3.2H2O], sodium periodate (NaIO4), N-Methylmorpholine N-oxide (NMO), 1,4-Benzoquinone (BQ), (Diacetoxyiodo)benzene, silver carbonate, silver acetate and silver oxide (Ag2O).
Pd-catalysts used in step (a) is selected from complexes C1-C4, PdCl2, Pd(ferrocene)(OAc)2, Pd(CH3CN)2(Cl)2, Pd(PPh3)2(Cl)2, Pd(PhCN)2(Cl)2, Pd2(dba)3, Pd(acac)2, Pd(TFA)2, and [1,2-Bis(diphenylphosphino)ethane]dichloropalladium(II).
Step (a) is carried out under argon or nitrogen atmosphere.
Alkynyl halide used in step (a) is (bromoethynyl)triisopropylsilane.
Solvent used in step (a) is selected from the group consisting of arenes, toluene, o-xylene, chlorobenzene (PhCl), 1,2-dichloroethane (DCE), Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMA), Dioxane, tetrahydrofuran (THF) and trifluoroethanol (CF3CH2OH).
Representative compound of formula 1a-1p are as follows:
These terminal alkynes of formula A (R2═H) obtained from step (b) are versatile precursor for the ‘click reaction’. A heterocyclic compound (1) is prepared via copper-catalyzed ‘click reaction’ as mentioned in
Subsequently, the terminal alkynyl moiety of formula A may be easily converted to a phenyl group to yield 2 as mentioned in
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Palladium acetate (56 mg, 0.25 mmol) and 1,10-phenanthroline (Phen) (45 mg, 0.25 mmol) were dissolved in 3.0 mL and 1.0 mL of acetone with stirring, respectively. Then the palladium acetate solution was added dropwise to the 1,10-phenanthroline solution with stirring, forming a yellow precipitate, and the mixture was kept stirring for 2 h at room temperature (30° C.). The precipitate was separated by centrifugation, dried at 60° C. under vacuum for 8 h to yield (Phen)Pd(OAc)2 C1 as a yellow solid, 98 mg, 97% yield.
Yield=97%. Yellow Solid. 1H NMR (CDCl3, 500 MHz) δ 2.21 (s, 6H), 7.78-7.81 (q, J=5.4 Hz, 2H), 7.96 (s, 2H), 8.51-8.52 (d, J=4.2 Hz, 2H), 8.61-8.62 (d, J=8.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 23.36, 125.19, 127.19, 129.65, 138.80, 146.34, 150.52, 178.63.
To a 100-ml round-bottom flask with stir bar was added neocuproine (0.600 g, 2.88 mmol), palladium(II) acetate (0.588 g, 2.62 mmol), and acetone (55 mL), and the reaction mixture was stirred overnight (13 hrs). The yellow precipitate was isolated by vacuum filtration, rinsed with acetone, and dried under vacuum to afford 0.87 g of (neocuproine)Pd(OAc)2 C2 (77% yield).
Yield=96%. Yellow Solid. 1H NMR (CDCl3, 500 MHz) δ 2.03 (s, 6H), 2.99 (s, 6H), 7.43 (s, 2H), 7.46-7.48 (m, 4H), 7.55-7.57 (m, 6H), 7.80 (s, 2H). 13C NMR (CDCl3, 500 MHz) δ 22.90, 24.70, 124.33, 126.49, 126.81, 129.05, 129.23, 129.71, 135.37, 148.23, 150.86, 164.68, 178.45.
A solution of palladium(II)acetate (449 mg, 2 mmol) in 10 mL of freshly distilled dichloromethane is stirred under argon and bathocuproine (722 mg, 2 mmol) is added in one portion. The resulting solution is stirred under argon at room temperature for 3 hours before the solvent is reduced to a volume of approximately 2 mL. Absolute diethyl ether is added until precipitation occurs and the solution is allowed to stand for 2 hours. The precipitated material is filtered and dried under vacuum to give (bc)Pd(OAc)2 C4 as a light yellow solid (1.123 g, 1.92 mmol, 96% yield).
Yield=96%. Yellow Solid. 1H NMR (CDCl3, 500 MHz) δ 2.21 (s, 6H), 7.51-7.52 (m, 4H), 7.59-7.60 (m, 6H), 7.74-7.76 (d, J=5.4 Hz, 2H), 7.99 (s, 2H), 8.67-8.69 (d, J=5.19 Hz, 2H).
13C NMR (CDCl3, 500 MHz) δ 23.40, 125.25, 125.37, 128.10, 129.24, 129.39, 130.09, 135.05, 147.32, 149.97, 151.76, 178.59.
To an oven-dried 15 mL schlenk tube, 8-Methylquinolines (1a-1p) (72 mg, 0.5 mmol), (bromoethynyl)triisopropylsilane 2 (196 mg, 0.75 mmol), 1,10 phenothroline (15 mol % 14 mg, 0.075 mmol), Pd(OAc)2 (10 mol % 11 mg, 0.05 mmol), Cu(OAc)2 (91 mg, 0.5 mmol), and DCE (1,2-dichloroethane) (2 mL) were added under a gentle stream of argon. The mixture was stirred for 15 hrs at 110° C. (bath temperature) under open-air. After cooling to room temperature (20 to 30° C.), the mixture was filtered through a celite pad and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4/1) to afford the desired alkynylated product (3a-3p) (66 mg, 41%) as a yellow oil.
Isolated yield: 9.4 mg (66%). 1H NMR (CDCl3, 200 MHz) δ 1.13 (s, 21H), 4.40 (s, 2H), 7.39-7.45 (dd, J=8.2 Hz, 1H), 7.52-7.60 (t, J=7.0 Hz, 1H), 7.71-7.76 (d, J=7.7 Hz, 1H), 8.06-8.11 (dd, J=7.0 Hz, 1H), 8.14-8.19 (dd, J=8.3 Hz, 1H), 8.90-8.94 (dd, J=4.1 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.38, 18.69, 22.17, 83.56, 106.23, 121.04, 126.42, 126.54, 127.89, 128.18, 135.39, 136.20, 143.03, 149.30. HRMS Calcd for C21H30NSi [M+H]+: 324.2148; Found: 324.2142.
Isolated yield: 13.8 mg (80%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 4.01 (s, 3H), 4.29 (s, 2H), 6.87-6.89 (d, J=7.9 Hz, 1H), 7.38-7.41 (dd, J=8.5 Hz, 1H), 7.95-7.96 (d, J=7.9 Hz, 1H), 8.57-8.59 (dd, J=8.5 Hz, 1H), 8.90-8.91 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.39, 18.71, 21.69, 55.66, 83.16, 103.91, 106.74, 120.10, 120.60, 126.88, 127.84, 103.81, 146.46, 149.58, 154.03. HRMS Calcd for C22H32NOSi [M+H]+: 354.2253; Found: 354.2248.
Isolated yield: 15.43 mg (83%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 2.89 (s, 6H), 4.31 (s, 2H), 7.13-7.14 (d, J=7.6 Hz, 1H), 7.27 (s, 1H), 7.40-7.41 (d, J=4.5 Hz, 1H), 7.96-7.97 (d, J=7.6 Hz, 1H), 8.56-8.57 (d, J=8.2 Hz, 2H), 8.88 (s, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.40, 18.71, 21.94, 45.38, 83.25, 106.66, 114.21, 119.94, 123.72, 127.88, 129.44, 132.81, 146.99, 148.91, 149.80. HRMS Calcd for C23H35N2Si [M+H]+: 367.2570; Found: 367.2564.
Isolated yield: 11.2 mg (71%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 2.68 (s, 3H), 4.36 (s, 2H), 7.39-7.40 (d, J=7.3 Hz, 1H), 7.44-7.46 (dd, J=4.2 Hz, 1H), 7.95-7.96 (d, J=7.0 Hz, 1H), 8.32-8.34 (dd, J=8.5 Hz, 1H), 8.92-8.92 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.38, 18.69, 18.52, 18.69, 83.31, 106.55, 120.60, 126.84, 127.37, 127.83, 132.62, 133.06, 133.28, 146.25, 148.77. HRMS Calcd for C22H32NSi [M+H]+: 338.2304; Found: 338.2299.
Isolated yield: 18.6 mg (76%). 1H NMR (CDCl3, 500 MHz) δ 1.15 (s, 21H), 4.41 (s, 2H), 7.18-7.21 (d, J=16.1 Hz, 1H), 7.31-7.34 (t, J=7.3 Hz, 1H), 7.41-7.44 (t, J=7.6 Hz, 2H), 7.46-7.48 (q, J=3.9 Hz, 1H), 7.60-7.62 (d, J=7.6 Hz, 2H), 7.78-7.81 (d, J=16.1 Hz, 1H), 7.84-7.85 (d, J=7.6 Hz, 1H), 8.10-8.11 (d, J=7.6 Hz, 1H), 8.56-8.58 (dd, J=8.5 Hz, 1H), 8.94-8.95 (dd, J=3.9 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.37, 18.71, 22.14, 83.64, 106.20, 120.85, 123.68, 124.21, 126.15, 126.67, 127.99, 128.03, 128.79, 132.28, 132.29, 133.95, 135.03, 127.27, 146.10, 129.11. HRMS Calcd for C29H36NSi [M+H]+: 426.2617; Found: 426.2612.
Isolated yield: 9.5 mg (59%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 4.32 (s, 2H), 7.21-7.24 (t, J=8.2 Hz, 1H), 7.46-7.49 (q, J=3.9 Hz, 1H), 7.97-8.00 (t, J=6.7 Hz, 1H), 8.42-8.44 (dd, J=8.2 Hz, 1H), 8.94-8.96 (dd, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.36, 18.67, 21.86, 83.74, 105.95, 109.63, 109.78, 118.69, 118.82, 121.06, 127.49, 127.56, 129.41, 129.44, 131.22, 146.18, 150.08, 155.77, 157.79. HRMS Calcd for C21H29NSi [M+H]+: 342.2053; Found: 342.2048.
Isolated yield: 13.4 mg (61%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 4.34 (s, 2H), 7.51-7.53 (dd, J=4.2 Hz, 1H), 7.84-7.86 (d, J=7.3 Hz, 1H), 7.93-7.95 (d, J=7.9 Hz, 1H), 8.53-8.58 (d, J=8.5 Hz, 1H), 8.92-8.93 (d, J=3.6 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.32, 18.67, 22.16, 84.03, 105.55, 120.25, 122.14, 127.17, 128.55, 130.14, 135.65, 146.58, 149.29, 149.85; HRMS Calcd for C21H29BrNSi [M+H]+: 402.1253; Found: 402.1247.
Isolated yield: 10.60 mg (48%). 1H NMR (CDCl3, 500 MHz) δ 1.14 (s, 21H), 4.44 (s, 2H), 7.54-7.57 (dd, J=8.8 Hz, 1H), 7.95-7.96 (dd, J=7.6 Hz, 1H), 8.13-8.14 (d, J=7.3 Hz, 1H), 8.50-8.52 (d, J=8.5 Hz, 1H), 8.99-9.00 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.34, 18.68, 22.74, 84.55, 105.09, 122.22, 122.67, 123.15, 124.03, 125.07, 125.03, 126.50, 128.76, 132.27, 140.76, 146.03, 149.84, 150.57. HRMS Calcd for C22H29F3NSi [M+H]+: 392.2021; Found: 392.2016.
Isolated yield: 9.8 mg (52%). 1H NMR (CDCl3, 500 MHz) δ 1.14 (s, 21H), 4.47 (s, 2H), 7.66-7.68 (dd, J=8.8 Hz, 1H), 8.18-8.20 (d, J=7.6 Hz, 1H), 8.43-8.44 (d, J=7.9 Hz, 1H), 9.01-9.03 (dd, J=3.9 Hz, 1H), 9.05-9.07 (dd, J=8.8 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.31, 16.67, 23.20, 85.17, 104.39, 120.83, 123.86, 124.69, 126.35, 132.25, 143.98, 144.36, 150.36, 158.90. HRMS Calcd for C21H29N2O2Si [M+H]+: 369.1998; Found: 369.1996.
Isolated yield: 12.3 mg (78%). 1H NMR (CDCl3, 500 MHz) δ 0.98 (s, 21H), 2.69 (s, 3H), 4.42 (s, 2H), 7.34-7.35 (d, J=4.2 Hz, 1H), 7.40-7.41 (q, J=8.2 Hz, 1H), 7.64-7.65 (d, J=8.2 Hz, 1H), 8.09-8.11 (dd, J=8.2 Hz, 1H), 8.93-8.94 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.28, 17.88, 18.56, 20.33, 79.90, 106.68, 120.04, 126.00, 126.67, 129.77, 133.36, 135.95, 137.96, 146.13, 149.46. HRMS Calcd for C22H32NSi [M+H]+: 338.2304; Found: 338.2299.
Isolated yield: 13.0 mg (81%). 1H NMR (CDCl3, 500 MHz) δ 0.98 (s, 21H), 4.29 (s, 2H), 7.34-7.36 (d, J=8.8 Hz, 1H), 7.38-7.40 (q, J=4.2 Hz, 1H), 7.72-7.75 (q, J=6.1 Hz, 1H), 8.13-8.15 (dd, J=8.2 Hz, 1H), 8.97-8.98 (dd, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.25, 18.50, 14.70, 80.03, 105.95, 116.88, 117.07, 120.20, 120.67, 120.79, 125.30, 127.96, 128.04, 136.06, 146.87, 146.93, 150.42, 159.61, 161.59. HRMS Calcd for C21H29NFSi [M+H]+: 342.2053; Found: 342.2048.
Isolated yield: 14.9 mg (84%). 1H NMR (CDCl3, 500 MHz) δ 0.97 (s, 21H), 4.46 (s, 2H), 7.41-7.43 (q, J=4.2 Hz, 1H), 7.55-7.56 (d, J=8.8 Hz, 1H), 7.67-7.69 (d, J=8.8 Hz, 1H), 8.12-8.14 (dd, J=8.2 Hz, 1H), 8.97-8.99 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.24, 18.52, 19.26, 80.45, 105.47, 121.01, 126.88, 127.34, 128.20, 133.93, 135.07, 136.06, 146.61, 150.38; HRMS Calcd for C21H29NClSi [M+H]+: 358.1758; Found: 358.1752.
Isolated yield: 11.0 mg (70%). 1H NMR (CDCl3, 500 MHz) δ 1.15 (s, 21H), 2.54 (s, 3H), 4.36 (s, 2H), 7.36-7.39 (q, J=4.2 Hz, 1H), 7.49 (s, 1H), 7.97 (s, 1H), 8.05-8.07 (dd, J=8.2 Hz, 1H), 8.84-8.85 (d, J=4.2 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.39, 18.69, 21.65, 22.08, 83.70, 106.39, 121.04, 125.23, 128.14, 130.70, 134.82, 135.51, 136.16, 144.67, 148.42. HRMS Calcd for C22H32NSi [M+H]+: 338.2304; Found: 338.2299.
Isolated yield: 11.7 mg (66%). 1H NMR (CDCl3, 500 MHz) δ 1.15 (s, 21H), 4.35 (s, 2H), 7.42-7.44 (q, J=4.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 8.05-8.07 (m, 2H), 8.88-8.90 (dd, J=8.2 Hz, 1H); 13C NMR (CDCl3, 500 MHz) δ 11.34, 18.68, 22.16, 84.66, 105.19, 121.92, 124.99, 128.64, 129.36, 132.37, 135.29, 137.74, 144.45, 149.42; HRMS Calcd for C21H29NClSi [M+H]+: 358.1758; Found: 358.1752.
Isolated yield: 14.3 mg (81%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 4.39 (s, 2H), 7.50-7.51 (d, J=4.8 Hz, 1H), 7.64-7.67 (t, J=7.9 Hz, 1H), 8.13-8.17 (t, J=9.1 Hz, 2H), 8.76-8.77 (t, J=4.5 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.35, 18.68, 22.47, 83.86, 105.84, 121.25, 122.82, 126.23, 127.39, 129.14, 135.96, 142.76, 146.89, 148.63. HRMS Calcd for C21H29NClSi [M+H]+: 358.1758; Found: 358.1572.
Isolated yield: 18.4 mg (74%). 1H NMR (CDCl3, 500 MHz) δ 1.13 (s, 21H), 1.46-1.49 (t, J=7.0 Hz, 3H), 4.39 (s, 2H), 4.50-4.52 (q, J=7.0 Hz, 2H), 7.70-7.73 (t, J=7.9 Hz, 1H), 8.19-8.21 (d, J=6.7 Hz, 1H), 8.33-8.35 (d, J=8.5 Hz, 1H), 9.20 (s, 1H). 13C NMR (CDCl3, 500 MHz) δ 11.35, 14.23, 18.68, 22.41, 62.05, 84.20, 105.57, 122.98, 124.09, 125.98, 128.16, 130.69, 136.20, 143.51, 147.30, 148.95, 164.65; HRMS Calcd for C24H31NClO2Si [M−H]+: 428.1813; Found: 428.1807.
To an oven-dried 10 mL of two-necked flask, 8-(3-(triisopropylsilyl)prop-2-ynyl)quinoline 3a (65 mg, 0.20 mmol) and 1.0 M solution of Tetra-n-butylammonium fluoride (TBAF) in THF (0.25 mL, 0.25 mmol) were added and the mixture was diluted with tetrahydrofuran (THF) (4 mL) under argon atmosphere. The reaction mixture was allowed to stir at room temperature. After 1 h, the reaction mixture was concentrated under vacuum to afford the crude product. The GC and GC-MS showed almost complete conversion and 99% purity of the desired desilated product 4a.
The reaction conditions are optimized by performing extensive screening of Pd sources, mol % of catalyst, ligands, oxidants, solvent, temperature, and time to obtain the optimum yield of 3a. After extensive screening, toluene is found to be the optimal solvent as it suppressed the homocoupling of 2 and a combination of Pd(OAc)2 and neocuproine (nc) are found to be more appropriate for this transformation and increased the yield (up to 49%) under standard conditions. It is observed that, by using the pre-formed neocuproine palladium complex [(nc)Pd(OAc)2] C2, the yield of 3a is increased to 75%. A well-defined bathocuproine derived Pd(II)-complex C4 also showed comparable reactivity and yielded 3a in 67%. However, the reaction did not proceed in the absence of Cu(OAc)2.
The present C(sp3)-H alkynylation proceeded at 80° C. in good to excellent yields with a variety of electronically diverse substrates. In all cases, a well-defined palladium complex [(nc)Pd(OAc)2] (10 mol %), and oxidant Cu(OAc)2 (2 equiv) are used to achieve excellent yields. From the data, it is observed that the following trends in the C(sp3)-H alkynylation reaction:
The present transformation has broad substrate scope, functional group tolerance and proceed efficiently under mild conditions.
1. Screening of Ligand
aReaction conditions: 1a (0.1 mmol), (triisopropylsilyl)ethynyl bromide 2 (0.15 mmol), Pd(OAc)2 (10 mol %), ligand (20 mol %), Cu(OAc)2 (2 equiv), toluene (1 mL), 80° C., 5 h.
bAnalyzed by 1H NMR analysis using dibromomethane as the internal standard.
2. Screening of Palladium Salts:
aReaction conditions: 1a (0.1 mmol), (triisopropylsilyl)ethynyl bromide 2 (0.15 mmol), [Pd] (10 mol %), neocuproine (20 mol %), Cu(OAc)2 (2 equiv), toluene (1 mL), 80° C., 5 h.
bThe yield was determined by 1H NMR analysis of the crude product using dibromomethane as the internal standard.
3. Effect of Oxidants
aReaction conditions: 1a (0.1 mmol), (triisopropylsilyl)ethynyl bromide 2 (0.15 mmol), Pd(OAc)2 (10 mol %), neocuproine (20 mol %), oxidant (x equiv), toluene (1 mL), 80° C., 5 h.
bThe yield was determined by 1H NMR analysis of the crude product using dibromomethane as the internal standard.
4. Effect of Solvent
aReaction conditions: 1a (0.1 mmol), (triisopropylsilyl)ethynyl bromide 2 (0.15 mmol), Pd(OAc)2 (10 mol %), neocuproine (20 mol %), Cu(OAc)2 (2 equiv), solvent (1 mL), 80° C., 5 h.
bThe yield was determined by 1H NMR analysis of the crude product using dibromomethane as the internal standard.
5. Effect of Temperature, Reaction Time, and Effect of Mol % of Catalyst (C2)
| Number | Date | Country | Kind |
|---|---|---|---|
| 0127/DEL/2015 | Jan 2015 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2016/050014 | 1/15/2016 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2016/113759 | 7/21/2016 | WO | A |
| Entry |
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| Number | Date | Country | |
|---|---|---|---|
| 20180009759 A1 | Jan 2018 | US |
