Palladium(II)-Catalyzed Nondirected Late-Stage C(sp2)-H Deuteration of Heteroarenes Enabled Through a Multi-Substrate Screening Approach.

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug-discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five-membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi-substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand-based palladium catalysts for nondirected C(sp2)-H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules.

Controlling Reactivity and Selectivity in the Nondirected C-H Activation of Arenes with Palladium.

ConspectusAromatic structures are widespread motifs throughout organic chemistry, and C-H activation has been recognized as a major tool for enabling their sustainable and efficient functionalization. Through C-H activation, arenes can be modified without the need for prefunctionalization, leading to inherent atom- and step-economic advantages over traditional methods. However, for the development of synthetically useful methods, several hurdles have to be overcome. The strength of C-H bonds necessitates the development of sufficiently reactive catalysts, while the presence of multiple C-H bonds within a substrate poses challenges in terms of site-selectivity. Traditionally these challenges have been addressed by substrate control. By attaching different directing groups (DGs), the reactivity of the respective arene was significantly enhanced and the DG guided the metal in close proximity to specific C-H bonds, resulting in high site-selectivity. However, the introduction and removal of the DG add additional steps to the synthetic sequence, and the scope of the reaction is limited to a specific substrate class. The development of complementary nondirected methods that can be applied to a broad range of arenes without the necessity to carry a specific functional group that coordinates to Pd (referred to as simple arenes) is therefore highly desirable. However, the intrinsically lower reactivity of such substrates and the absence of a selectivity-determining DG pose significant challenges that can be solved only by the development of highly efficient catalysts. Consequently, the field of nondirected C-H activation, especially with respect to Pd-catalyzed methods, remained comparatively underdeveloped when we initiated our research program in 2017. At that time, state-of-the-art methods required the arene to be used in large excess, precluding its use in late-stage functionalization. Since organopalladium species are among the most versatile synthetic intermediates, we realized that developing a system, which can effectively and selectively activate C-H bonds in simple arenes with the arene as the limiting reagent, would be a powerful tool in synthetic organic chemistry. This account summarizes our groups' research toward the development and application of catalytic systems offering this desired reactivity and focuses explicitly on Pd-catalyzed nondirected C-H functionalization reactions of arenes, where the arene is employed as a limiting reagent. After an introduction that summarizes the state of Pd-catalyzed C-H activation of arenes before 2017 and the associated challenges, experimental and mechanistic details about the development of the first arene-limited, nondirected C-H functionalization of simple arenes with palladium will be discussed. This reactivity was enabled by the identification and combination of two complementary ligands, an N-heterocycle and an amino acid-derived ligand. Afterward we will discuss the expansion of this dual-ligand approach to further arene-limited transformations. Finally, we describe two methodologies that originated from the observations we made during our studies, namely, the late-stage deuteration of simple arenes and a highly selective olefination method that uses noncovalent interactions to induce meta selectivity.

Preparative Scale Applications of C-H Activation in Medicinal Chemistry.

C-H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established cross-coupling methods, C-H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C-H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C-H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in-depth understanding of the challenges and potential of C-H activation methodologies in the production of pharmaceuticals.

Sterically controlled isodesmic late-stage C-H iodination of arenes.

Aryl iodides are key motifs in organic chemistry due to their versatility as linchpins in metal-mediated cross-coupling reactions for synthesis and drug discovery. These scaffolds are typically prepared indirectly from prefunctionalized starting materials or via electrophilic aromatic iodination protocols. These methods are limited to specific regioisomers by their inherent selectivities and/or the availability of the required starting materials. Herein, we describe the sterically controlled iodination of arenes through an isodesmic C-H/C-I bond metathesis approach enabled by our dual ligand-based catalysts for arene-limited nondirected C-H activation. The protocol gives direct access to a complementary product spectrum with respect to traditional methods. Its synthetic utility is demonstrated by a broad scope and the suitability for late-stage modification.

Charge-controlled Pd catalysis enables the meta-C-H activation and olefination of arenes.

The regioselective C-H activation of arenes remains one of the most promising techniques for accessing highly important functionalized motifs. Such functionalizations can generally be achieved through directed and non-directed processes. The directed approach requires a covalently attached directing group (DG) on the substrate to induce reactivity and selectivity and therefore intrinsically leaves a functional group at the point of attachment within the molecule, even after the tailored DG has been removed. Conversely, non-directed methods typically suffer from regioselectivity issues, especially for unbiased substrates. Herein, we report a unique approach that employs weak charge-charge and charge-dipole interactions to enable the meta-selective activation and olefination of arenes to address these challenges in Pd catalysis. The charged moiety can easily be converted to uncharged simple arenes by hydrogenation or cross-coupling. In-depth mechanistic studies prove that the charge is responsible for the observed selectivity. We expect our studies to be generalizable and thereby enable further regioselective transformations.

A Modular Olefination of Aldehydes with Thiols as Coupling Partners.

Olefins range amongst the most important motifs in organic chemistry. Hence, the development of novel olefin syntheses has remained a constant field of research in synthetic chemistry to date. Herein, we report the development of a modular olefination that converts aldehydes into olefins with thiols as reaction partners. The simple, transition metal-free protocol proceeds via an unsymmetrical bissulfone intermediate which is converted into the respective alkene in a Ramberg-Bäcklund-type process. Differently substituted olefins can be synthesized from readily available starting materials in typically good yields and stereoselectivities using basic laboratory chemicals exclusively. Complementary reaction conditions differing in the choice of solvent favor the E/Z-products respectively under kinetic control rendering this protocol an interesting economical addition to the family of olefin syntheses.

Silver-Free C-H Activation: Strategic Approaches towards Realizing the Full Potential of C-H Activation in Sustainable Organic Synthesis.

The activation of carbon-hydrogen bonds is considered as one of the most attractive techniques in synthetic organic chemistry because it bears the potential to shorten synthetic routes as well as to produce complementary product scopes compared to traditional synthetic strategies. However, many current methods employ silver salts as additives, leading to stoichiometric metal waste and thereby preventing the full potential of C-H activation to be exploited. Therefore, the development of silver-free protocols has recently received increasing attention. Mechanistically, silver can serve various roles in C-H activation and thus, avoiding the use of silver requires different approaches based on the role it serves in a given process. In this Review, we present the comparison of silver-based and silver-free methods. Focusing on the strategic approaches to develop silver-free C-H activation, we provide the reader with the means to develop sustainable methods for C-H activation.

Palladium-Catalyzed Nondirected Late-Stage C-H Deuteration of Arenes.

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

Late-Stage ß-C(sp3)-H Deuteration of Carboxylic Acids.

Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage ß-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks and enables the functionalization of nonactivated methylene ß-C(sp3)-H bonds for the first time.

Mechanism of the Arene-Limited Nondirected C-H Activation of Arenes with Palladium*.

Recently palladium catalysts have been discovered that enable the directing-group-free C-H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex organic molecules. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed experimental and computational mechanistic studies on the dual-ligand-enabled C-H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts.

Direct Synthesis of Unsymmetrical Dithioacetals.

Sabine Bognar and Manuel van Gemmeren from the WWU Münster have been invited to contribute the cover of this issue. The image depicts a volcano to symbolize the general theme of sulfur chemistry, whereas the piles of rubble reflect the selectivity of the reaction. Read the full text of the article at 10.1002/chem.202004835.

Direct Synthesis of Unsymmetrical Dithioacetals.

Dithioacetals are a frequently used motif in synthetic organic chemistry and have recently seen increasing attention as structural motif in promising antiviral agents against plant pathogens. Most existing reports, however, only discuss symmetrical dithioacetals. Examples of mixed dithioacetals are scarce and no general method for the selective synthesis of these compounds exists. Herein, a synthetically simple general one-step protocol was developed for the synthesis of a broad range of unsymmetrical dithioacetals consisting of one aromatic and one aliphatic thiol moiety from the corresponding aldehyde/thiol mixture. The mixed S,S-acetals were obtained in high yields, and a great variety of functional groups was tolerated. Kinetic control enabled an excellent selectivity in regard to the unsymmetrical dithioacetal.

Catalyst-Controlled Regiodivergent C-H Alkynylation of Thiophenes*.

Alkynes are highly attractive motifs in organic synthesis due to their presence in natural products and bioactive molecules as well as their versatility in a plethora of subsequent transformations. A common procedure to insert alkynes into (hetero)arenes, such as the thiophenes studied herein, consists of a halogenation followed by a Sonogashira cross-coupling. The regioselectivity of this approach depends entirely on the halogenation step. Similarly, direct alkynylations of thiophenes have been described that follow the same regioselectivity patterns. Herein we report the development of a palladium catalyzed C-H activation/alkynylation of thiophenes. The method is applicable to a broad range of thiophene substrates. For 3-substituted substrates where controlling the regioselectivity between the C2 and C5 position is particularly challenging, two sets of reaction conditions enable a regiodivergent reaction, giving access to each regioisomer selectively. Both protocols use the thiophene as limiting reagent and show a broad scope, rendering our method suitable for late-stage modification.

Direct ß- and γ-C(sp3 )-H Alkynylation of Free Carboxylic Acids*.

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp3 )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

Sterically Controlled C-H Olefination of Heteroarenes.

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.

Ligand-Enabled γ-C(sp3 )-H Olefination of Free Carboxylic Acids.

We report the ligand-enabled C-H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.

Sterically Controlled Late-Stage C-H Alkynylation of Arenes.

Phenylacetylenes are key structural motifs in organic chemistry, which find widespread applications in bioactive molecules, synthetic intermediates, functional materials, and reagents. These molecules are typically prepared from prefunctionalized starting materials, e.g. using the Sonogashira coupling, or using directing group-based C-H activation strategies. While highly efficient, these approaches remain limited by their inherent selectivities for specific regioisomers. Herein we present a complementary approach based on an arene-limited nondirected C-H activation. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.

Direct ß-C(sp3)-H Acetoxylation of Aliphatic Carboxylic Acids.

The controlled construction of defined oxidation patterns is one of the key aspects in the synthesis of natural products and bioactive molecules. Towards this goal, we herein report a novel protocol for the Pd-catalyzed direct ß-C(sp3)-H acetoxylation of aliphatic carboxylic acids. The protocol enables the use of free carboxylic acids in one step and without the need of introducing specialized strong directing groups. In our studies, we found that the use of a "traceless base" was crucial for the development of a synthetically useful transformation. Furthermore, the synthetic utility of the products obtained was demonstrated by their use in subsequent transformations.

The Direct Conversion of α-Hydroxyketones to Alkynes.

Alkynes are highly important functional groups in organic chemistry, both as part of target structures and as versatile synthetic intermediates. In this study, a protocol for the direct conversion of α-hydroxyketones to alkynes is reported. In combination with the variety of synthetic methods that generate the required starting materials by forming the central C-C bond, it enables a highly versatile fragment coupling approach toward alkynes. A broad scope for this novel transformation is shown alongside mechanistic insights. Furthermore, the utility of our protocol is demonstrated through its application in concert with varied α-hydroxyketone syntheses, giving access to a broad spectrum of alkynes.

Arene-Limited Nondirected C-H Activation of Arenes.

The nondirected C(sp2 )-H activation of simple arenes has advanced significantly in recent years through the discovery of new catalyst systems that are able to perform transformations with the arene as the limiting reagent. Important developments in catalyst and ligand design that have improved reactivity and selectivity are reviewed.