Synergism of Fe/Ti Enabled Regioselective Arene Difunctionalization.

Regioselective difunctionalization of arenes remains a long-standing challenge in organic chemistry. We report a novel and general Fe/Ti synergistic methodology for regioselective synthesis of various polysubstituted arenes through either E/E' or Nu/E ortho difunctionalizations of arenes. Preliminary results showed that an unprecedented 1,2-Fe/Ti heterobimetallic arylene intermediate bearing two distinct C-M bonds is essential to the regioselective difunctionalization.

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.

Unified Protocol for Fe-Based Catalyzed Biaryl Cross-Couplings between Various Aryl Electrophiles and Aryl Grignard Reagents.

The combination of commonly used FeCl3/SIPr with Ti(OEt)4/PhOM enabled a highly general iron-based catalyst system, which could efficiently catalyze the biaryl coupling reaction between various electrophiles (I, Br, Cl, OTs, OCONMe2, OSO2NMe2) and common or functionalized aryl Grignard reagents with high functional group tolerance. Selective couplings of aryl iodides and bromides over the corresponding oxygen-based electrophiles have been achieved, and thus a terphenyl acid intermediate for anidulafungin was conveniently synthesized via an orthogonal coupling strategy.

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.

Room-temperature cobalt-catalyzed arylation of aromatic acids: overriding the ortho-selectivity via the oxidative assembly of carboxylate and aryl titanate reagents using oxygen.

A room temperature phosphine or NHC ligand-free cobalt-catalyzed arylation of (hetero)aromatic acids has been developed. It involves an oxidative cross-coupling between carboxylate and aryl titanate reagents using oxygen as an oxidant, and the arylation at the position ortho, meta and para to the carboxylic acid group could all be achieved. As application, various (hetero)aromatic acids including xenalipin, tafamidis and the key intermediate for a cardioprotective compound have been efficiently synthesized.

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.

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 N-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 N-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.

Comparison on greenhouse gas footprint of three types of oriented strand board manufacturing process in China.

The greenhouse gas (GHG) footprints of oriented strand boards (OSB) have been gaining growing concern. China is one of the largest manufacturers and traders of OSB in the world. However, little data are available concerning the GHG footprint of Chinese OSB production. The purpose of this study is to quantify and compare the GHG footprints of three types of OSB produced in China. Cradle-to-gate GHG footprints assessment models were built for OSB according to PAS 2050 guidelines. The results showed that the cradle-to-gate GHG footprints of OSB/2, OSB/3, and OSB/4 were 142.7 kg CO2 e/m3, 173.2 kg CO2 e/m3, and 374.2 kg CO2 e/m3, respectively. Raw material acquisition was the largest contributor to GHG footprint for three types of OSB (52.6~57.6%), followed by the production process of OSB (25.6~27.3%) and transportation (15.3~20.1%). The consumption of wood, MDI, electricity, and the transportation of wood were main emission hotspots in Chinese OSB production. Ultimately, four feasible GHG emission reduction measures were put forward from the perspective of reducing the usage of wood and MDI adhesive, decreasing the electricity consumption, and shortening the transport distance of wood.

Fe-Catalyzed Difunctionalization of Aryl Titanates Enabled by Fe/Ti Synergism.

Fe-catalyzed difunctionalization of aryl titanates via double C-H activation has been developed, where aryl titanates were arylated via ortho C-H activation, followed by ipso electrophilic trapping of the C-Ti bond. The ortho C-H arylation should be promoted by a 1,2-Fe/Ti synergistic heterobimetallic arylene intermediate and represents an ortho C-H ferration directed by a readily transformable C-Ti group. Common benzamides, esters, and nitriles function as arylating reagents, which involves another ortho C-H activation directed by these functionalities.

Chemo- and Regioselective Alkylation of Pyridine N-Oxides with Titanacyclopropanes.

While titanacyclopropanes are used to react mainly with ester, amide, and cyano to undergo cyclopropanation, herein they react preferentially with pyridine N-oxide to accomplish C2-H alkylation beyond these functionalities with double regioselectivity. After being pyridylated at the less hindered C-Ti bond, the remaining C-Ti bond of titanacyclopropanes can be further functionalized by various electrophiles, allowing facile introduction of complex alkyls onto the C2 of pyridines. Its synthetic potential has been demonstrated by late-stage diversification of drugs.

Alkylative Dearomatization by Using an Unactivated Aryl Nitro Group as a Leaving Group: Access to Diversified Alkylated Spiro[5.5]trienones.

The cleavage of an unactivated aryl nitro group triggered by alkyl radicals enables a dearomative cyclization, affording diversified alkylated spiro[5.5]trienones in good yields. Using readily available compounds (toluene and analogues, alkanes, ethers, ketones, etc.) as alkylating reagents, various alkyls have been implanted into the spirocycles via C(sp3)-H and Ar-NO2 bond activation with high functional group tolerance. This protocol provides a distinct method for the activation of the aryl nitro group.

Tandem vinyl radical Minisci-type annulation on pyridines: one-pot expeditious access to azaindenones.

A new regiospecific alkylative/alkenylative cascade annulation of pyridines has been achieved whilst the corresponding classic Minisci alkylative annulation failed. This protocol provides a novel and expeditious access to azaindenones and related compounds via cross-dehydrogenative coupling with the long-standing problem of C2/C4 regioselectivity of pyridines being well addressed.

Iron catalyzed stereoselective alkene synthesis: a sustainable pathway.

Replacing expensive or toxic transition metals with iron has become an important trend in transition metal catalyzed reactions. As an important part of this trend, the stereoselective construction of olefins under iron catalysis is an appealing and prolific research field. This article summarises the recent progress of a wide range of Fe-catalyzed reactions in accessing various stereodefined alkenes, including carbohalogenation, hydro/carbometalation of alkynes (allenes and dienes), alkylation and arylation of stereodefined (pseudo) haloalkenes or alkenyl metals, chelation-assisted C-H activation and other miscellaneous reactions.

Iron-catalyzed stereospecific arylation of enol tosylates using Grignard reagents.

The stereospecific Fe-catalyzed arylation of enol tosylates was reported. Various tri- or tetrasubstituted Z or E-enol tosylates of ß-keto esters were arylated using common and Knochel-type Grignard reagents with complete stereofidelity. The precursors for Z/E-zimelidine, tamoxifen and other bioactive compounds were facilely prepared without precious and toxic transition metals.

Magnesiation of pyridine N-oxides via iodine or bromine-magnesium exchange: a useful tool for functionalizing pyridine N-oxides.

Iodo- or 2-bromopyridine N-oxides were readily magnesiated with i-PrMgCl x 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 ortho 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.

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.

Iron-catalyzed oxidative biaryl cross-couplings via mixed diaryl titanates: significant influence of the order of combining aryl Grignard reagents with titanate.

The mixed diaryl titanates were used for the first time to modify the reactivity of two aryl Grignard reagents. Two titanate intermediates, Ar[Ar'Ti(OR)3]MgX and Ar'[ArTi(OR)3]MgX, formed via alternating the sequence of combining Grignard reagents with ClTi(OR)3 showed a significant reactivity difference. Taking advantage of such different reactivity, two highly structurally similar aryl groups could be facilely assembled through iron-catalyzed oxidative cross-couplings using oxygen as the oxidant.

Iron catalyzed oxidative assembly of N-heteroaryl and aryl metal reagents using oxygen as an oxidant.

An equivalent amount of N-heteroaryl and aryl Grignard or lithium reagents, after mediation by an equivalent of titanate, was facilely coupled to furnish N-heteroaryl-aryl compounds under the catalysis of FeCl3/TMEDA at ambient temperature using oxygen as an oxidant. Most of the common N-heteroaryls were all good candidates, and thus provided a general, green and pratical protocol for the flexible construction of various N-heteroaryl-aryl structures.