Application of light-promoted Minissci C-H alkylation reaction in preparation of alkyl-substituted azacycle

A technology of miniscic-h and alkylation reaction, applied in the field of fine chemicals

Active Publication Date: 2021-01-05
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The alkylating reagents used in the currently reported Minisci reactions include alkyl halohydrocarbons, alkyl carboxylic acids, peroxides, alcohols, and alkylboronic acids, but there are no Minisci reactions using aldehydes or ketones as alkylating reagents. reported, and currently reported Minisci reactions often require the use of excess oxidants, which brings great challenges to the late functionalization of complex natural products and drugs by Minisci reactions, which has also become a key factor limiting the application of Minisci reactions (Proctor , R.S.J.; Phipps, R.J.Angew.Chem., Int.Ed.DOI: 10.1002 / anie.201900977. DiRocco, D.A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D.V.; Tudge, M. Angew. Chem., Int. Ed. 2014, 53, 4802. Jin, J.; MacMillan, D.W.C. Nature 2015, 525, 87; Dong, J.; Lyu, X.; Wang, Z.; Wang, X.; Song , H.; Liu, Y.; Wang, Q. Chem. Sci., 2019, 10, 976.)

Method used

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  • Application of light-promoted Minissci C-H alkylation reaction in preparation of alkyl-substituted azacycle
  • Application of light-promoted Minissci C-H alkylation reaction in preparation of alkyl-substituted azacycle
  • Application of light-promoted Minissci C-H alkylation reaction in preparation of alkyl-substituted azacycle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Synthesis of 2-(2-(4-chlorophenoxy)-2-methylpropionyl)oxy)ethyl 6-isopropylnicotinate:

[0033] Weigh 0.3mmol 2-((2-(4-chlorophenoxy)-2-methylpropionyl)oxy) ethyl nicotinate, 0.003mmol photocatalyst [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 , 0.6mmol tris-(trimethylsilyl) silane (TTMS), 0.6mmol trifluoroacetic acid (TFA) in 8mL reaction flask, then add 3mL acetone solution, blow argon gas into the reaction flask for 30s, at 490nm at 36W Reaction under blue light irradiation, TLC monitoring until the raw material reaction is complete, then add 30mL sodium bicarbonate solution, 30mL dichloromethane solution, liquid separation, the organic layer is dried with anhydrous sodium sulfate, spin off the solvent, column chromatography (petroleum ether: acetic acid ethyl ester=4:1) to obtain a colorless liquid with a yield of 38%. 1 H NMR (400MHz, CDCl 3)δ9.07(d, J=1.6Hz, 1H), 8.04(dd, J=8.0, 2.0Hz, 1H), 7.23(d, J=8.0Hz, 1H), 7.10(d, J=8.8Hz, 2H), 6.76(d, J=8.8Hz, 2H), 4.5...

Embodiment 2

[0034] Example 2: Synthesis of 2-(2-(4-chlorophenoxy)-2-methylpropionyl)oxy)ethyl 6-cyclohexylnicotinate:

[0035] Weigh 0.3mmol 2-((2-(4-chlorophenoxy)-2-methylpropionyl)oxy) ethyl nicotinate, 0.003mmol photocatalyst [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 , 0.6mmol tris-(trimethylsilyl)silane (TTMS), 0.6mmol trifluoroacetic acid (TFA) in 8mL reaction flask, 9mmol cyclohexanone, then add 1.5mL acetonitrile solution, blow argon into the reaction flask 30s, react under 36W 490nm blue light irradiation, TLC monitors until the raw materials have reacted completely, then add 30mL sodium bicarbonate solution, 30mL dichloromethane solution, separate the liquid, dry the organic layer with anhydrous sodium sulfate, spin off the solvent, and the column layer Analysis (petroleum ether: ethyl acetate = 4:1) gave a yellow liquid with a yield of 50%. 1 H NMR (400MHz, CDCl 3 )δ9.06(s, 1H), 8.04(d, J=8.0Hz, 1H), 7.22(d, J=8.0Hz, 1H), 7.09(d, J=8.0Hz, 2H), 6.76(d, J=8.0Hz, 2H), 4.53(s, 4H), 2....

Embodiment 3

[0036] Example 3: Synthesis of 1-(6-isopropylpyridin-3-yl)-2-methyl-2-(pyridin-3-yl)propan-1-one:

[0037] Weigh 0.3mmol 2-methyl-1,2-bis(pyridin-3-yl)propan-1-one, 0.003mmol photocatalyst [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 , 0.6mmol tris-(trimethylsilyl) silane (TTMS), 0.6mmol trifluoroacetic acid (TFA) in 8mL reaction flask, then add 3mL acetone solution, blow argon gas into the reaction flask for 30s, at 490nm at 36W Reaction under blue light irradiation, TLC monitoring until the raw material reaction is complete, then add 30mL sodium bicarbonate solution, 30mL dichloromethane solution, liquid separation, the organic layer is dried with anhydrous sodium sulfate, spin off the solvent, column chromatography (dichloromethane: Methanol=20:1) to obtain a white solid with a yield of 35%. Melting point 60-61℃. 1 H NMR (400MHz, CDCl 3 )δ8.58(d, J=20.0Hz, 3H), 7.80(d, J=7.2Hz, 1H), 7.61(d, J=8.0Hz, 1H), 7.30(dd, J=7.6, 5.2Hz, 1H), 7.11(d, J=8.4Hz, 1H), 3.11-2.95(m, 1H), 1.66(s,...

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Abstract

The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing alkyl-substituted azacycle through a Minissci CH alkylation reaction which is promoted by light and takes aldehyde or ketone without an oxidizing agent as an alkyl radical source. A nitrogen-containing aromatic ring is mixed with a photocatalyst [Ir (dF (CF3) ppy) 2 (dtbbpy)] PF6, tris (trimethylsilyl) silane (TTMS), trifluoroacetic acid (TFA), aldehyde or ketone and an organic solvent, argon is blown into a reaction bottle, and a reaction is carried out under irradiation of 36W 490nm blue light. A sodium bicarbonate solution is added, liquid is separated, an organic layer is dried, a solvent is removed by spinning, and column chromatography is carried out to obtain a pure product.

Description

technical field [0001] The invention belongs to the technical field of fine chemicals, and in particular relates to the application of light-promoted Minisci C-H alkylation reaction without an oxidant as the source of alkyl radicals in the preparation of alkyl-substituted nitrogen heterocyclic rings. Background technique [0002] Nitrogen-containing aromatic rings are widely found in natural products, drug molecules, organic materials and ligands. The late modification of nitrogen-containing aromatic rings by selective carbon-hydrogen bond functionalization is of great significance. The addition reaction of free radicals to nitrogen-containing aromatic rings under acidic and oxidative conditions, namely the Minisci reaction, provides a very efficient method for the synthesis of alkyl-substituted nitrogen-containing aromatic rings. Traditional Minisci reactions often require excess oxidants, acids and high temperatures, which greatly limit the scope of substrate application....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/90C07D239/88C07D239/91C07D215/233C07D401/04C07D405/04C07D277/64C07D487/04C07D213/16C07D213/80C07D213/803C07D213/50C07D213/85
CPCC07D239/90C07D239/88C07D239/91C07D215/233C07D401/04C07D405/04C07D277/64C07D487/04C07D213/16C07D213/80C07D213/803C07D213/50C07D213/85
Inventor 汪清民董建洋刘玉秀
Owner NANKAI UNIV
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