Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides
Timothée Constantin, Margherita Zanini, Alessio Regni, Nadeem S. Sheikh, Fabio Juliá and Daniele Leonori
DOI: 10.1126/science.aba2419
Science 367 (6481), 1021-1026.
Abstract:
Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach
to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that a-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
General Procedure for the Deuteration of Alkyl Iodides – GP1
An oven-dry tube equipped with a stirring bar was charged with the alkyl iodide (0.2 mmol, 1.0 equiv.) and 4CzIPN (8 mg, 0.01 mmol, 5 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl), evacuated and refilled with N2 (x 3). Dry and degassed EtOAc (2 mL), D2O (720 L, 200 equiv.), methyl thioglycolate (3.6 L, 0.04 mmol, 20 mol%) and tributylamine (58 L, 0.24 mmol, 1.2 equiv.) were sequentially added and the mixture was vigorously stirred in front of blue LEDs for 16 h at room temperature. Brine (10 mL) and EtOAc (10 mL) were added and the mixture was shaken. The aqueous layer was extracted with EtOAc (x 2), the combined organic layers were dried (MgSO4), filtered and evaporated.
Purification by flash column chromatography on silica gel gave the products.
General Procedure for the Reactions Using Alkyl Iodides – GP2
A tube equipped with a stirring bar was charged with the alkyl iodide, if solid (0.2 mmol, 1.0 equiv.), the Michael acceptor, if solid (0.4 mmol, 2 equiv.) and 4CzIPN (8 mg, 0.01 mmol, 5 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl), evacuated and refilled with N2 (x 3). Degassed CH3CN (2 mL) and water (0.2 mL) were added, followed by the alkyl iodide, the Michael
acceptor if liquid and Et3N (56 μL, 0.4 mmol, 2 equiv.). The mixture was stirred in front of blue LEDs at room temperature for 16 hours and then diluted with H2O (15 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (x 2). The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated. The crude was purified by flash column chromatography on silica gel.
Procedure for Gram-Scale Reaction
A 250 mL-flask fitted with a septum was equipped with a stirring bar and was charged with methyl 2-(bis(tert-butoxycarbonyl)amino)acrylate (3.01 g, 10 mmol, 2.0 equiv.) and 4CzIPN (40 mg, 0.05 mmol, 1 mol%). The vessel was evacuated and refilled with N2 (x 3). CH3CN (100 mL) and H2O (10 mL) were added followed by NBoc- 3-iodoazetidine (938 μL, 5.0 mmol, 1.0 equiv.) and Et3N (1.4 mL, 10 mmol, 2.0 equiv.). The mixture was stirred in front of two PR160 440nm Kessil lamp at room temperature for 16 hours and then diluted with H2O (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers are washed with brine (100 mL), dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel gave 24 (2.08 g, 91%) as an oil.
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