Facile One-Pot Direct Arylation and Alkylation of Nitropyridine <i>N</i>-Oxides with Grignard Reagents

Facile arylation and alkylation of nitropyridine <i>N</i>-oxides were developed through the reactions of Grignard reagents with nitropyridine <i>N</i>-oxides. For the same 4-nitropyridine <i>N</i>-oxide, arylation occurred at the 2- (or 6-) position, whereas alkylation occurred at the 3-position in an adjustably site-selective manner. The cooperative action of the two groups was discovered in the reactions of 3-nitropyridine <i>N</i>-oxides. This protocol can find wide applications in building various pyridine compounds as illustrated in total syntheses of Emoxipin and Caerulomycin A and E

Iron-Catalyzed Dearomatization of Biaryl Ynones with Aldehydes via Double C–H Functionalization in Eco-Benign Solvents: Highly Atom-Economical Synthesis of Acylated Spiro[5.5]trienones

The multiple C–H bonds of biaryl ynones render the 6-exo-trig regioselective C–H activation dearomatization to spiro[5.5]­trienones challenging since the competing reactions of C–H bonds on Ar1 or the ortho-C–H bonds on Ar3 may result in 5-exo-trig cyclization to indenones or 6-exo-trig ortho-dearomatization, respectively. We here report an unprecendented dearomatization of biaryl ynones with aldehydes via double C–H functionalization where a regiospecific remote unactivated para-C–H functionalization of biaryl ynones efficiently furnishes acylated spiro[5.5]­trienones. This cascade cyclization features a green catalyst and solvent and high atom- and step-economy

Substitution of the Nitro Group with Grignard Reagents: Facile Arylation and Alkenylation of Pyridine <i>N</i>‑Oxides

The unprecedented substitution of a nitro group with aryl or alkenyl groups of Grignard reagents affords 2-aryl or alkenylpyridine <i>N-</i>oxides in modest to high yields with high chemoselectivity. This protocol allows a simple and clean synthesis of various 2-substituted pyridine <i>N</i>-oxides and the corresponding pyridine derivatives. Furthermore, straightforward one-pot iterative functionality of pyridine <i>N</i>-oxides could also be achieved simply by successive applications of two Grignard reagents

Cobalt-Catalyzed Biaryl Couplings via C–F Bond Activation in the Absence of Phosphine or NHC Ligands

A highly general and selective Co-catalyzed biaryl coupling through C–F cleavage under phosphine or NHC-free conditions was described. A broad range of aryl fluorides including unactivated fluorides as well as those with sensitive functionalities could couple with various Ti­(OEt)₄-mediated aryl Grignard reagents with high selectivity under the catalysis of CoCl₂/DMPU. Importantly, selective C–F bond activation couplings between two types of fluorines (difluorinated aromatics and on two different coupling partners) and in the presence of C–Cl or C–Br bonds could also be achieved

Magnesiation of Pyridine <i>N</i>-Oxides via Iodine or Bromine−Magnesium Exchange: A Useful Tool for Functionalizing Pyridine <i>N</i>-Oxides

Iodo- or 2-bromopyridine N-oxides were readily magnesiated with i-PrMgCl·LiCl via the iodine or bromine−magnesium exchange. The bromine adjacent to pyridine N-oxide (at the 2- or 6-position) can be regioselectively magnesiated in the presence of other position substituted halogens. This method was tested in various substituted pyridine N-oxide systems, and has been successfully applied to the total synthesis of caerulomycins E and A

Is Fe-catalyzed <i>ortho</i> C–H Arylation of Benzamides Sensitive to Steric Hindrance and Directing Group?

The previously reported Fe-catalyzed ortho C–H arylation of benzamides relied on bi- or tridentate amide groups and specific iron ligands and was sensitive to steric hindrance. By using new mixed titanates, our present protocol accommodates various weakly coordinating benzamides and tolerates high steric hindrance and sensitive functional groups only under the catalysis of FeCl3 and TMEDA. A wide range of privileged condensed ring compounds can thus be facilely accessed

Reductive Couplings of 2‑Halopyridines without External Ligand: Phosphine-Free Nickel-Catalyzed Synthesis of Symmetrical and Unsymmetrical 2,2′-Bipyridines

An unexpectedly facile synthetic approach for symmetrical and unsymmetrical 2,2′-bipyridines through the Ni-catalyzed reductive couplings of 2-halopyridines was developed. The couplings were efficiently catalyzed by 5 mol % of NiCl2·6H2O without the use of external ligands. A variety of 2,2′-bipyridines including caerulomycin F have been efficiently synthesized

Arylation, Alkenylation, and Alkylation of 2‑Halopyridine <i>N</i>‑Oxides with Grignard Reagents: A Solution to the Problem of C2/C6 Regioselective Functionalization of Pyridine Derivatives

A facile arylation, alkenylation, and alkylation of functionalized 2-halopyridine <i>N</i>-oxides with various Grignard reagents was developed. It represented a highly efficient and selective C–H bond functionalization of pyridine derivatives in the presence of reactive C–Cl or C–Br bonds. Using Cl or Br as a blocking group, C2/C6 site-controllable functionalization of pyridine derivatives has been achieved. Various pyridine compounds can be prepared as illustrated in the total syntheses of Onychine, dielsine, and PARP-1 inhibitor GPI 16539

Unified Protocol for Cobalt-Catalyzed Oxidative Assembly of Two Aryl Metal Reagents Using Oxygen as an Oxidant

The first cobalt-catalyzed oxidative cross-coupling reaction of two aryl metal reagents is described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an equivalent amount of simple ClTi­(OEt)₃, was facilely assembled under the catalysis of 1 mol % of CoCl₂/10 mol % of DMPU using oxygen. The cross-couplings between various aryl metal reagents, especially between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively and, thus, provided a highly general and efficient method for the construction of biaryl compounds

Phenolate Enabled General and Selective Fe/Ti Cocatalyzed Biaryl Cross-Couplings between Aryl Halides and Aryl Grignard Reagents

The serendipitous addition of a phenolate to FeCl3/TMEDA/Ti­(OEt)4 enables a strong Fe/Ti cooperativity that can efficiently catalyze a general and selective biaryl-coupling reaction. In the absence of phosphine or NHC ligands, various aryl chlorides, bromides, and iodides can couple with a variety of common and Knochel-type aryl Grignard reagents. A wide range of sensitive functional groups in either coupling partner can be tolerated. This bimetallic cocatalysis not only remarkably extends the scope of Fe-catalyzed biaryl couplings but also provides a solution to the problem of functional group compatibility of Grignard reagents