Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones and trifluoromethylarenes (CF3-arenes). This method relies on selective C–F bond cleavage via reduction of the CF3-arene. We show that a diverse set of CF3-arenes and CF3-heteroarenes react smoothly with a range of aryl and alkyl hydrazones. The β-difluorobenzylic hydrazine product can be selectively cleaved to form the corresponding benzylic difluoroarylethylamines.
Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated N-heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems.
Organic electronics is a rapidly growing field driven in large part by the synthesis of π-conjugated molecules and polymers. Traditional aryl cross-coupling reactions such as the Stille and Suzuki have been used extensively in the synthesis of π-conjugated molecules and polymers, but the synthesis of intermediates necessary for traditional cross-couplings can include multiple steps with toxic and hazardous reagents. Direct arylation through C–H bond activation has the potential to reduce the number of steps and hazards while being more atom-economical. Within the Center for Selective C–H Functionalization (CCHF), we have been developing C–H activation methodology for the synthesis of π-conjugated materials of interest, including direct arylation of difficult-to-functionalize electron acceptor intermediates and living polymerization of π-conjugated polymers through C–H activation.
A dinuclear Co(ii) complex supported by a modular, tunable redox-active ligand system is capable of selective C-H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst loading. The reaction is tolerant of medicinally relevant heterocycles, such as pyridine and indole, and can be used to form 5-, 6-, and 7-membered rings. The synthetic versatility obtained using low loadings of an earth abundant transition metal complex represents a significant advance in catalytic C-H amination technology.
by
N. Mace Weldy;
A. G. Schafer;
C.P. Owens;
C.J. Herting;
A. Varela-Alvarez;
S. Chen;
Z. Niemeyer;
Jamal Musaev;
M.S. Sigman;
Huw Davies;
Simon Blakey
The intermolecular enantioselective C-H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(iii)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.
The first total synthesis of malagashanine, a chloroquine potentiating indole alkaloid, is presented. A highly stereoselective cascade annulation reaction was developed to generate the tetracyclic core of the Malagasy alkaloids. This chemistry is likely to be broadly applicable to the synthesis of other members of this stereochemically unique family of natural products.