The photocatalyzed ortho‐selective migration on a pyridyl ring has been achieved for the site‐selective trifluoromethylative pyridylation of unactivated alkenes. The overall process is initiated by ...the selective addition of a CF3 radical to the alkene to provide a nucleophilic alkyl radical intermediate, which enables an intramolecular endo addition exclusively to the ortho‐position of the pyridinium salt. Both secondary and tertiary alkyl radicals are well‐suited for addition to the C2‐position of pyridinium salts to ultimately provide synthetically valuable C2‐fluoroalkyl functionalized pyridines. Moreover, the method was successfully applied to the reaction with P‐centered radicals. The utility of this transformation was further demonstrated by the late‐stage functionalization of complex bioactive molecules.
Remote migration: The photocatalyzed ortho‐selective migration on a pyridyl ring has been achieved for the site‐selective trifluoromethylative pyridylation of unactivated alkenes under mild reaction conditions. Notably, this method could be successfully extended to tertiary radicals to forge quaternary C centers bearing C2‐substituted pyridyl groups, overriding the commonly observed preference for the C4 addition.
Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven‐step, asymmetric chemical synthesis of ...(−)‐codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo‐redox hydroamination protocol provides a novel, atom‐economical means for assembling the piperidine D‐ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N‐demethyl codeine. Our work highlights the capacity for contemporary, stand‐alone chemical synthesis regimes to diversify access to essential opiate medicines.
A benchmark chemical synthesis of codeine creates an opportunity to diversify essential opiate‐medicine supply chains. The brevity of this approach derives from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot, while a subsequent photo‐redox hydroamination protocol is deployed to provide a novel, atom‐economical means for assembling the morphinan piperidine D‐ring.
The silver‐promoted reaction of tertiary cyclobutanols with N‐methoxypyridinium salts enables the efficient synthesis of a range of C2‐substituted pyridines. The overall process likely occurs by ...ring‐opening (via β‐scission) of the cyclobutoxy radical to generate the corresponding γ‐keto alkyl radical that itself adds to the pyridinium salt. A wide range of tertiary cyclobutanols and N‐methoxypyridinium salts are compatible with the reaction conditions.
An efficient silver‐catalyzed radical ring‐opening/pyridylation of tertiary cyclobutanol with N‐methoxypyridinium salts has been achieved for the synthesis of γ‐ketopyridines. The overall process is thought to occur by β‐scission of the corresponding cyclobutoxy radical to generate an alkyl radical, that adds to the pyridinium salt. A wide range of tertiary cyclobutanols and N‐methoxypyridinium salts are compatible with these reaction conditions.
A copper‐catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent sodium trifluoromethanesulfinate (NaSO2CF3 or Langlois’ reagent) has been developed incorporating ...a tandem cyclization/dearomatization process. This strategy affords a straightforward route to synthesis of 3‐(trifluoromethyl)‐spiro4.5trienones, and presents an example of difunctionalization of alkynes for simultaneous formation of two carbon–carbon single bonds and one carbon–oxygen double bond.
Spiro mania: A copper‐catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent NaSO2CF3 has been reported, affording a series of 3‐trifluoromethyl spiro4.5trienones through a tandem cyclization/dearomatization process. In this alkyne difunctionalization process, two carbon–carbon bonds and one carbon–oxygen double bond are simultaneously formed.
We report the synthesis of cyclometalated monoaryl MnIII fluoro complexes using bis(trifluoromethyl)zinc reagent, Zn(CF3)2(DMPU)2, under mild conditions via a reaction pathway that involves initial ...transmetalation followed by α‐fluorine elimination. The formation of difluorocarbene in these reactions was detected by trapping experiments. Such facile difluorocarbene generation from MnIII results in moderate enhancement of difluoropropanation and difluoropropenation of alkenes and alkynes using Zn(CF3)2(DMPU)2 at lower temperature (20–60 °C) and short reaction time, suggesting potential application of manganese(III) perfluoroalkyl complexes as reactive species for carbene transfer reactivity.
A novel and highly practical reaction for the copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes is presented here. This methodology provides a general and straightforward way to ...synthesize a variety of useful CF3-containing nitriles, which can be used for further preparation of pharmaceutically and agrochemically important compounds in synthetic organic chemistry.
A mild and efficient copper-catalyzed trifluoromethylation reaction which involves the cyclization of oximes has been developed. This method provides a convenient access to a variety of useful ...CF3-containing 4,5-dihydroisoxazoles by constructing a C-CF3 bond and a C-O bond in one step.
A novel three-component strategy for the cyanotrifluoromethylation/azidotrifluoromethylation and carbocyclization of 1,6-enynes is developed. The reaction proceeds smoothly under a moderate ...temperature by using a copper catalyst, which provides a rapid and concise access to addition-carbocyclization products. Furthermore, the products obtained can be useful building blocks in discoveries of lead compounds and other biologically active CF3-containing heterocycles.
A silver-catalyzed oxidative cyclization of 2- or 3-propargylamide-substituted indoles to synthesize phosphorated indoloazepinone derivatives is described. This reaction displays a ...difunctionalizalion of alkynes with diphenylphosphine oxides to construct a seven-membered ring through a radical cyclization process. The indoloazepinones derivatives are common structural motifs found in many natural products and pharmaceuticals.
Manganese complexes have been considered as a cheap and readily available alternative to commonly used precious metal catalysts in C–C bond coupling reactions. Although high-valent Mn aryl ...intermediates have been proposed in such reactions, a mechanistic understanding of possible organometallic intermediates in Mn-mediated C–C coupling is still lacking due to their high reactivity. We report the synthesis of stable, isolable Mn(III) aryl complexes obtained by oxidative addition of aryl bromide or aryl chloride. These complexes react with a range of organometallic alkylating or arylating reagents (alkyl and aryl Grignard reagents, MeLi, ZnMe2) to undergo C(sp2)–C(sp3) or C(sp2)–C(sp2) bond coupling, and a preliminary catalytic system could be demonstrated. The reagent scope and yield of the C(sp2)–C(sp3) coupled product can further be increased by addition of TEMPO as an oxidant, generating alkyl radicals.
