The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

The beginning of the twenty-first century has witnessed significant advances in the field of C-H bond activation, and this transformation is now an established piece in the synthetic chemists' toolbox. This methodology has the potential to be used in many different areas of chemistry, for example it provides a perfect opportunity for the late-stage diversification of various kinds of organic scaffolds, ranging from relatively small molecules like drug candidates, to complex polydisperse organic compounds such as polymers. In this way, C-H activation approaches enable relatively straightforward access to a plethora of analogues or can help to streamline the lead-optimization phase. Furthermore, synthetic pathways for the construction of complex organic materials can now be designed that are more atom- and step-economical than previous methods and, in some cases, can be based on synthetic disconnections that are just not possible without C-H activation. This Perspective highlights the potential of metal-catalysed C-H bond activation reactions, which now extend beyond the field of traditional synthetic organic chemistry.

C-H bond activation enables the rapid construction and late-stage diversification of functional molecules

C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C-H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C-H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C-H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp(3))-H bonds by using 8-aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.

Catalytic Functionalization of C(sp2) ? H and C(sp3) ? H Bonds by Using Bidentate Directing Groups

Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting two different CH bonds under oxidative conditions. Common to these methodologies is the generation of the reactive intermediates in situ by activation of both CH bonds. This strategy was introduced by the group of Li as cross-dehydrogenative coupling (CDC) and discloses waste-minimized synthetic alternatives to classic coupling procedures which rely on the use of prefunctionalized starting materials. This Review highlights the recent progress in the field of cross-dehydrogenative C sp 3C formations and provides a comprehensive overview on existing procedures and employed methodologies.

The Cross-Dehydrogenative Coupling of C sp 3H Bonds: A Versatile Strategy for CC Bond Formations

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.

Die direkte Funktionalisierung von C-H-Bindungen in organischen Molekulen hat sich in jungster Zeit zu einer wirksamen und idealen Methode entwickelt, mit der Kohlenstoff-Kohlenstoff- und Kohlenstoff-Heteroatom-Bindungen geknupft werden konnen. Der Aufsatz gibt einen Uberblick uber die Strategien, die durch Funktionalisierung von C-H-Bindungen eine rasche Synthese von biologisch aktiven Verbindungen wie Naturstoffen und pharmazeutischen Zielsubstanzen ermoglichen.

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine N-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.

Synthesis of Dragmacidin D via Direct C–H Couplings

We have developed a palladium-catalyzed C–H/C–H coupling reaction of indoles or pyrroles with azine N-oxides. The reaction proceeds selectively at the C3 position of indoles/pyrroles and the C2 pos...

Oxidative C-H/C-H coupling of azine and indole/pyrrole nuclei: Palladium catalysis and synthesis of eudistomin U

Syntheses of dictyodendrins A and F have been achieved using a sequential C–H functionalization strategy. The N-alkylpyrrole core is fully functionalized by means of a rhodium(I)-catalyzed C–H arylation at the C3-position, a rhodium(II)-catalyzed double C–H insertion at the C2- and C5-positions, and a Suzuki–Miyaura cross-coupling reaction at the C4-position. The syntheses of dictyodendrins A and F were completed by formal 6π-electrocyclization to generate the pyrrolo[2,3-c]carbazole core of the natural products.

Atsushi D. Yamaguchi

Papers

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

Synthesis of Dragmacidin D via Direct C–H Couplings

Oxidative C-H/C-H coupling of azine and indole/pyrrole nuclei: Palladium catalysis and synthesis of eudistomin U

Concise syntheses of dictyodendrins A and F by a sequential C-H functionalization strategy