Abstract:A mild, modular, and practical catalytic system for the synthesis of the highly privileged phenethylamine pharmacophore is reported. Using a unique combination of organic catalysts to promote the transfer of electrons and hydrogen atoms, this system performs direct hydroarylation of vinyl amine derivatives with a wide range of aryl halides (including aryl chlorides). This general and highly chemoselective protocol delivers a broad range of arylethylamine products with complete regiocontrol. The utility of this… Show more
“…From the corresponding radical anions, cleavage of the aryl C–I, C–Br, and C–Cl bonds (bond dissociation energy (BDE) = 71.6, 80.3, and 95.5 kcal/mol, respectively; see Supporting Information for details) occurred in preference to the stronger benzylic C(sp 3 )–F bond (BDE = 118.1 kcal/mol), resulting in mixtures of protodehalogenation and aryl radical alkylation products. 39 In contrast, the aryl C–F bond (BDE = 127.5 kcal/mol) was completely preserved, affording 22 in 48% yield (where the mass balance was comprised of unreacted starting material). In addition to aryl halides, alkyl halides currently lie outside the scope of this process, where either reductive dehaogenation or substitution with formate are primary pathways of these substrates.…”
Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range of structural and physicochemical properties that fluorine imparts. Currently, the most abundant methods for the synthesis of the aryl-CF 2 functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical reagents. Here, we report a general method for the synthesis of aryl-CF 2 R and aryl-CF 2 H compounds through activation of the corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event that provides access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide a diverse array of difluoalkylaromatics.
“…From the corresponding radical anions, cleavage of the aryl C–I, C–Br, and C–Cl bonds (bond dissociation energy (BDE) = 71.6, 80.3, and 95.5 kcal/mol, respectively; see Supporting Information for details) occurred in preference to the stronger benzylic C(sp 3 )–F bond (BDE = 118.1 kcal/mol), resulting in mixtures of protodehalogenation and aryl radical alkylation products. 39 In contrast, the aryl C–F bond (BDE = 127.5 kcal/mol) was completely preserved, affording 22 in 48% yield (where the mass balance was comprised of unreacted starting material). In addition to aryl halides, alkyl halides currently lie outside the scope of this process, where either reductive dehaogenation or substitution with formate are primary pathways of these substrates.…”
Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range of structural and physicochemical properties that fluorine imparts. Currently, the most abundant methods for the synthesis of the aryl-CF 2 functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical reagents. Here, we report a general method for the synthesis of aryl-CF 2 R and aryl-CF 2 H compounds through activation of the corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event that provides access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide a diverse array of difluoalkylaromatics.
“…Hence, successful reports of aza Paternò–Büchi reactions are rare and limited to rigid imine- and alkene-containing systems predisposed for cycloaddition in addition to the stringent requirement of high energy ultraviolet (UV) light 43–51 . Consequently, the development of a mild and general reaction protocol for aza Paternò–Büchi reactions relying on visible light 52–57 would be highly desirable.Fig. 1Previous strategies towards azetidines and this approach.…”
Azetidines are four-membered nitrogen-containing heterocycles that hold great promise in current medicinal chemistry due to their desirable pharmacokinetic effects. However, a lack of efficient synthetic methods to access functionalized azetidines has hampered their incorporation into pharmaceutical lead structures. As a [2+2] cycloaddition reaction between imines and alkenes, the aza Paternò-Büchi reaction arguably represents the most direct approach to functionalized azetidines. Hampered by competing reaction paths accessible upon photochemical excitation of the substrates, the current synthetic utility of these transformations is greatly restricted. We herein report the development of a visible light-enabled aza Paternò-Büchi reaction that surmounts existing limitations and represents a mild solution for the direct formation of functionalized azetidines from imine and alkene containing precursors.
“…Amongst the most reducing of these are phenothiazine‐based catalysts, such as N ‐phenylphenothiazine (PTH), whose excited state reduction potential reaches –2.1 V vs. SCE (Figure b). [10b], Accordingly, this type of readily available catalyst has enabled photochemical transformations which were previously unachievable by the most reducing catalysts available, for example couplings of aryl chlorides with electron rich olefins . However, these transformations can be extremely slow, often requiring reaction times of several days.…”
The reductive transformation of aryl halides and carbonyl compounds is a key step in many photoredox transformations. By combining a highly reducing organic photocatalyst with a thiol hydrogen atom transfer (HAT) catalyst, we showcase rapid and highly selective reactions of these synthetically important starting materials in continuous flow. The fast reduction of aryl iodides, bromides and chlorides has been demonstrated with residence times in some cases below one minute. Selectivity between mono‐ and di‐dehalogenation could also be achieved in some cases. Aryl ketones, aldehydes and imines were shown to undergo facile pinacol couplings, and the coupling of an aryl chloride with a styrene was also successful.
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