C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

3d Transition Metals for C-H Activation.

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Organic synthesis provides opportunities to transform drug discovery

Kunbing Ouyang,†,‡ Wei Hao,† Wen-Xiong Zhang,*,†,§ and Zhenfeng Xi† †Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China ‡Institute of Chemistry, Chinese Academy of Sciences (CAS), Beijing 100190, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China

Transition-Metal-Catalyzed Cleavage of C-N Single Bonds.

Most photoredox catalysts in current use are precious metal complexes or synthetically elaborate organic dyes, the cost of which can impede their application for large-scale industrial processes. We found that a combination of triphenylphosphine and sodium iodide under 456-nanometer irradiation by blue light–emitting diodes can catalyze the alkylation of silyl enol ethers by decarboxylative coupling with redox-active esters in the absence of transition metals. Deaminative alkylation using Katritzky’s N-alkylpyridinium salts and trifluoromethylation using Togni’s reagent are also demonstrated. Moreover, the phosphine/iodide-based photoredox system catalyzes Minisci-type alkylation of N-heterocycles and can operate in tandem with chiral phosphoric acids to achieve high enantioselectivity in this reaction.

Photocatalytic decarboxylative alkylations mediated by triphenylphosphine and sodium iodide

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

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Selective sp3 C–H alkylation via polarity-match-based cross-coupling

Oxidative Olefination of Secondary Amines­ with Carbon Nucleophiles

An unprecedented oxidative arylation reaction of terminal alkenes with simple aroyl hydrazides has been developed under aerobic conditions for the stereoselective synthesis of 1,2-disubstituted alkenes. A range of aroyl hydrazides underwent palladium/copper-catalyzed oxidative Mizoroki-Heck reaction with terminal alkenes open to air in a 1:1 mixture of dimethyl sulfoxide and acetonitrile to give structurally diverse 1,2-disubstituted alkenes in moderate to excellent yields with excellent regio- and E-selectivity. The reaction tolerated a wide variety of functional groups, such as alkoxy, hydroxy, amino, fluoro, chloro, bromo, cyano, nitro, ester, amide, imide, phosphine oxide, and sulfone groups, and, moreover, molecular oxygen and dimethyl sulfoxide were demonstrated to serve as terminal oxidants. This study provides a useful method for the stereoselective synthesis of 1,2-disubstituted alkenes through direct transformation of the vinylic CH bonds in terminal alkenes.

Palladium/Copper‐Catalyzed Oxidative Arylation of Terminal Alkenes with Aroyl Hydrazides

Biogenetic silica displays intricate patterns assembling from nano- to microsize level and interesting non-spherical structures differentiating in specific directions Several model systems have been proposed to explain the formation of biosilica nanostructures Of them, phase separation based on the physicochemical properties of organic amines was considered to be responsible for the pattern formation of biosilica In this paper, using tetraethyl orthosilicate (TEOS, Si(OCH2CH3)4) as silica precursor, phospholipid (PL) and dodecylamine (DA) were introduced to initiate phase separation of organic components and influence silica precipitation Morphology, structure and composition of the mineralized products were characterized using a range of techniques including field emission scanning electron microscopy (FESEM), transmission electron microscope (TEM), X-ray diffraction (XRD), thermogravimetric and differential thermal analysis (TG-DTA), infrared spectra (IR), and nitrogen physisorption The results demonstrate that the phase separation process of the organic components leads to the formation of asymmetrically non-spherical silica structures, and the aspect ratios of the asymmetrical structures can be well controlled by varying the concentration of PL and DA On the basis of the time-dependent experiments, a tentative mechanism is also proposed to illustrate the asymmetrical morphogenesis Therefore, our results imply that in addition to explaining the hierarchical porous nanopatterning of biosilica, the phase separation process may also be responsible for the growth differentiation of siliceous structures in specific directions Because organic amine (eg, long-chair polyamines), phospholipids (eg, silicalemma) and the phase separation process are associated with the biosilicification of diatoms, our results may provide a new insight into the mechanism of biosilicification

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Formation of asymmetrical structured silica controlled by a phase separation process and implication for biosilicification.

Biogenetic biosilica displays intricate patterns that are structured on a nanometer-to-micrometer scale. At the nanoscale, it involves the polymerization products of silica, apparently mediated by the interaction between different biomolecules with special functional groups. In this paper, using tetraethyl orthosilicate [TEOS, Si(OCH2CH3)4] as a silica source, phospholipid (PL) and dodecylamine (DA) were introduced as model organic additives to investigate their influence on the formation and morphology of silica in the mineralization process. Morphology, structure, and composition of the products were characterized using a range of techniques including FESEM, TEM, SAXRD, TG-DTA, solid-state 29Si NMR, FTIR, and nitrogen physisorption. The FESEM and TEM analyses demonstrate that increasing PL concentrations at constant DA content leads to the formation of siliceous elongated structures. Localized enlargement can also be observed during further growth of elongated structures, displaying some features of the earliest recognizable stage of valve development in diatoms. In addition, in the presence or absence of PL, a series of control experiments using ammonia instead of DA show that no elongated structures are obtained, suggesting that the formation of elongated silica structures results from the cooperative interactions between PL and DA molecules. Because both organic amines (e.g., long-chain polyamines, LCPA) and phospholipid membranes (e.g., silicalemma) are of special importance for biosilicification in diatoms and sponges, our results imply that phospholipids are involved in the formation of organic aggregates, and thus influence the amines-mediated silica deposition. As such, our results may provide a new insight into the mechanism of biosilicification.

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Xi-Ming Li

Papers

Selective sp3 C–H alkylation via polarity-match-based cross-coupling

Oxidative Olefination of Secondary Amines with Carbon Nucleophiles

Palladium/Copper‐Catalyzed Oxidative Arylation of Terminal Alkenes with Aroyl Hydrazides

Formation of asymmetrical structured silica controlled by a phase separation process and implication for biosilicification.

Controlled morphogenesis of amorphous silica and its relevance to biosilicification

Xi-Ming Li

Papers

Selective sp3 C–H alkylation via polarity-match-based cross-coupling

Oxidative Olefination of Secondary Amines­ with Carbon Nucleophiles

Palladium/Copper‐Catalyzed Oxidative Arylation of Terminal Alkenes with Aroyl Hydrazides

Formation of asymmetrical structured silica controlled by a phase separation process and implication for biosilicification.

Controlled morphogenesis of amorphous silica and its relevance to biosilicification

Oxidative Olefination of Secondary Amines with Carbon Nucleophiles