The advent of modern C–H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C–H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C–H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed.

Metal–Ligand Cooperation

Functionalization of fluorinated molecules by transition-metal-mediated C-F bond activation to access fluorinated building blocks.

The significant benefits of fluorinated compounds have inspired the development of diverse techniques for the activation and subsequent (de)functionalization of rather inert C–F bonds. Although substantial progress has been made in the selective activation of C(sp2)–F bonds employing transition metal complexes, protocols that address nonactivated C(sp3)–F bonds are much less established. In this regard, the use of strong main-group Lewis acids has emerged as a powerful tool to selectively activate C(sp3)–F bonds in saturated fluorocarbons. This Perspective provides a concise overview of various cationic and neutral silicon-, boron-, and aluminum-based Lewis acids that have been identified to facilitate the heterolytic fluoride abstraction from aliphatic fluorides. The potential of these Lewis acids in hydrodefluorination as well as defluorinative C–F bond functionalization reactions is highlighted. Emphasis is placed on the underlying mechanistic principles to provide a systematic classification of the in...

Main-Group Lewis Acids for C–F Bond Activation

The activation of carbon-fluorine (C-F) bonds is an important topic in synthetic organic chemistry. Metal-mediated and -catalyzed elimination of β- or α-fluorine proceeds under milder conditions than oxidative addition to C-F bonds. The β- or α-fluorine elimination is initiated from organometallic intermediates having fluorine substituents on carbon atoms β or α to metal centers, respectively. Transformations through these elimination processes (C-F bond cleavage), which are typically preceded by carbon-carbon (or carbon-heteroatom) bond formation, have been increasingly developed in the past five years as C-F bond activation methods. In this Minireview, we summarize the applications of transition-metal-mediated and -catalyzed fluorine elimination to synthetic organic chemistry from a historical perspective with early studies and from a systematic perspective with recent studies.

Transition-Metal-Mediated and -Catalyzed C-F Bond Activation by Fluorine Elimination.

The B-H bond of typical boranes is heterolytically split by the polar Ru-S bond of a tethered ruthenium(II) thiolate complex, affording a ruthenium(II) hydride and borenium ions with a dative interaction with the sulfur atom. These stable adducts were spectroscopically characterized, and in one case, the B-H bond activation step was crystallographically verified, a snapshot of the σ-bond metathesis. The borenium ions derived from 9-borabicyclo[3.3.1]nonane dimer [(9-BBN)2], pinacolborane (pinBH), and catecholborane (catBH) allowed for electrophilic aromatic substitution of indoles. The unprecedented electrophilic borylation with the pinB cation was further elaborated for various nitrogen heterocycles.

Catalytic generation of borenium ions by cooperative B-H bond activation: the elusive direct electrophilic borylation of nitrogen heterocycles with pinacolborane.

Heterolytic splitting of the Si-H bond mediated by a Ru-S bond forms a sulfur-stabilized silicon cation that is sufficiently electrophilic to abstract fluoride from CF(3) groups attached to selected anilines. The ability of the Ru-H complex, generated in the cooperative activation step, to intramolecularly transfer its hydride to the intermediate carbenium ion (stabilized in the form of a cationic thioether complex) is markedly dependent on the electronic nature of its phosphine ligand. An electron-deficient phosphine thwarts the reduction step but, based on the Ru-S catalyst, half of an equivalent of an added alkoxide not only facilitates but also accelerates the catalysis. The intriguing effect is rationalized by the formation of a hydride-bridged Ru-S dimer that was detected by (1)H NMR spectroscopy. A refined catalytic cycle is proposed.

C(sp3)-F bond activation of CF3-substituted anilines with catalytically generated silicon cations: spectroscopic evidence for a hydride-bridged Ru-S dimer in the catalytic cycle.

The nature of the hydrosilane activation mediated by ruthenium(II) thiolate complexes of type [(R3P)Ru(SDmp)]+[BArF4]− is elucidated by an in-depth experimental and theoretical study. The combination of various ruthenium(II) thiolate complexes and tertiary hydrosilanes under variation of the phosphine ligand and the substitution pattern at the silicon atom is investigated, providing detailed insight into the activation mode. The mechanism of action involves reversible heterolytic splitting of the Si–H bond across the polar Ru–S bond without changing the oxidation state of the metal, generating a ruthenium(II) hydride and sulfur-stabilized silicon cations, i.e. metallasilylsulfonium ions. These stable yet highly reactive adducts, which serve as potent silicon electrophiles in various catalytic transformations, are fully characterized by systematic multinuclear NMR spectroscopy. The structural assignment is further verified by successful isolation and crystallographic characterization of these key intermediates. Quantum-chemical analyses of diverse bonding scenarios are in excellent agreement with the experimental findings. Moreover, the calculations reveal that formation of the hydrosilane adducts proceeds via barrierless electrophilic activation of the hydrosilane by sterically controlled η1 (end-on) or η2 (side-on) coordination of the Si–H bond to the Lewis acidic metal center, followed by heterolytic cleavage of the Si–H bond through a concerted four-membered transition state. The Ru–S bond remains virtually intact during the Si–H bond activation event and also preserves appreciable bonding character in the hydrosilane adducts. The overall Si–H bond activation process is exergonic with ΔG0r ranging from −20 to −40 kJ mol−1, proceeding instantly already at low temperatures.

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Timo Stahl

Papers

Main-Group Lewis Acids for C–F Bond Activation

Catalytic generation of borenium ions by cooperative B-H bond activation: the elusive direct electrophilic borylation of nitrogen heterocycles with pinacolborane.

C(sp3)-F bond activation of CF3-substituted anilines with catalytically generated silicon cations: spectroscopic evidence for a hydride-bridged Ru-S dimer in the catalytic cycle.

Mechanism of the cooperative Si-H bond activation at Ru-S bonds

Main-Group Lewis Acids for C—F Bond Activation