A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors.

Halogen bonding permeates many areas of chemistry. A wide range of halogen-bond donors including neutral, cationic, monovalent, and hypervalent have been developed and studied. In this work we used density functional theory (DFT), natural bond orbital (NBO) theory, and quantum theory of atoms in molecules (QTAIM) to analyze aryl halogen-bond donors that are neutral, cationic, monovalent and hypervalent and in each series we include the halogens Cl, Br, I, and At. Within this diverse set of halogen-bond donors, we have found trends that relate halogen bond length with the van der Waals radii of the halogen and the non-covalent or partial covalency of the halogen bond. We have also developed a model to calculate ΔG of halogen-bond formation by the linear combination of the % p-orbital character on the halogen and energy of the σ-hole on the halogen-bond donor.

Synthesis of Arynes via Formal Dehydrogenation of Arenes.

Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires synthetic precursors, which involve either harsh conditions or multistep syntheses. The development of alternative methods to access arynes using simpler substrates and milder conditions is necessary for a more streamlined approach. Here, we describe a two-step formal dehydrogenation of simple arenes to generate arynes at a remote position relative to traditionally reactive groups, e.g., halides. This approach is enabled by regioselective installation and ejection of an "onium" leaving group, and we demonstrate the compatibility of simple arenes (20 examples) and arynophiles (8 examples). Moreover, through direct comparison, we show that our formal dehydrogenation method is both more functional group tolerant and efficient in generating arynes than the current state-of-the-art aryne precursors. Finally, we show that aryne intermediates offer opportunities for regioselective C-H amination that are distinct from other methods.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.

Imide arylation with aryl(TMP)iodonium tosylates.

Herein, we describe the synthesis of N-aryl phthalimides by metal-free coupling of potassium phthalimide with unsymmetrical aryl(TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the coupling reaction is compatible with electron-deficient and sterically encumbered aryl groups.

Aryl Transfer Selectivity in Metal-Free Reactions of Unsymmetrical Diaryliodonium Salts.

Aromatic rings are found in a wide variety of products, including pharmaceuticals, agrochemicals, and functional materials. Diaryliodonium salts are new reagents used to transfer aryl groups under both metal-free and metal-catalyzed reactions and thereby synthesize arene-containing compounds. This minireview focuses on recent studies in selective aryl transfer reactions from unsymmetrical diaryliodonium salts under metal-free conditions. Reactions reported from 2007 to 2017, which represents a period of significant growth in diaryliodonium salt chemistry, are presented and organized by the type of reactive intermediate formed in the reaction. Specifically, reactions involving λ3 -iodane, λ3 -iodane radical anions, aryl radicals, and arynes are discussed. Chemoselectivity trends in aryl transfer are compared and contrasted across reaction intermediates and translation to potential auxiliaries are posited.

An Admix Approach To Determine Counter Anion Effects on Metal-Free Arylation Reactions with Diaryliodonium Salts.

A method to determine the effect of counter anions in metal-free arylation reactions of diaryliodonium salts is described. This approach avoids the independent synthesis of individual diaryliodonium salts and potentially enables assessment of a large number of different counter anions, including those that are synthetically challenging to install. Diaryliodonium tosylate salts serve as a general precursor for this approach, and an azide arylation reaction was used to develop this strategy. Further optimization and representative scope of azide arylation is demonstrated in yields that range from 74-95% (89% average). The use of this method as a screening tool has also been validated with arylation reactions of three different nucleophiles employing diphenyliodonium tosylate.

Synthesis of Aryl(2,4,6-trimethoxyphenyl)iodonium Trifluoroacetate Salts.

The direct synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium trifluoroacetate salts from aryl iodides is described. Stoichiometric quantities of trifluoroacetic acid and trimethoxybenzene are used as the counteranion and auxiliary precursors, respectively, under oxidizing conditions. The reaction occurs at mild temperature, is broad in scope, and does not require a separate anion exchange step to install the trifluoroacetate group. The intermediacy of two distinct dicarboxy aryl-λ3-iodanes is hypothesized in the mechanism.

Unsymmetrical Aryl(2,4,6-trimethoxyphenyl)iodonium Salts: One-Pot Synthesis, Scope, Stability, and Synthetic Studies.

Diaryliodonium salts have recently attracted significant attention as metal-free-arylation reagents in organic synthesis, and efficient access to these salts is critical for advancement of their use in reaction discovery and development. The trimethoxybenzene-derived auxiliary is a promising component of unsymmetrical variants, yet access remains limited. Here, a one-pot synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium salts from aryl iodides, m-CPBA, p-toluenesulfonic acid, and trimethoxybenzene is described. Optimization of the reaction conditions for this one-pot synthesis was enabled by the method of multivariate analysis. The reaction is fast (<1 h), provides a high yield of product (>85% average), and has broad substrate scope (>25 examples) including elaborate aryl iodides. The utility of these reagents is demonstrated in moderate to high yielding arylation reactions with C-, N-, O-, and S-nucleophiles including the synthesis of a liquid crystal molecule.

Metal-free Synthesis of Aryl Amines: Beyond Nucleophilic Aromatic Substitution.

A mild and metal-free approach to C-N coupling is described that employs diaryliodonium salt electrophiles and secondary aliphatic amine nucleophiles. This reaction results in direct ipso-substitution of the iodonium moiety and unsymmetrical aryl(TMP)iodonium salts are primarily employed. Moreover, arene substituents and substitution patterns that currently pose a challenge to classical metal-free methods are accommodated and the alicyclic amine nucleophiles used here are unprecedented in other contemporary metal-free C-N coupling reactions.

A Selective C-H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine.

Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The aryne intermediates are generated by ortho-C-H deprotonation of aryl(mesityl)iodonium salt with a commercially available amide base and trapped in a cycloaddition reaction with furan in moderate to good yields. Coupling partners for the aryne intermediates beyond furan are also described, including benzyl azide and alicyclic amine nucleophiles. The regio- and chemoselectivity of this reaction is discussed and evidence for the spectator aryl ligand of the iodonium salt as a critical control element in selectivity is presented.

Base Mediated Synthesis of Alkyl-aryl Ethers from the Reaction of Aliphatic Alcohols and Unsymmetric Diaryliodonium Salts.

The base mediated coupling of aliphatic alcohol pronucleophiles with unsymmetric diaryliodonium salt electrophiles is described. This metal-free reaction is operationally simple, proceeds at mild temperature, and displays broad substrate scope to generate industrially important alkyl-aryl ethers in moderate to excellent yield. The synthetic utility of these reactions is demonstrated, and aspects of sustainability are highlighted by the use of unsymmetric aryl(mesityl)iodonium arylating reagents.

An efficient and chemoselective method to generate arynes.

Arynes hold immense potential as reactive intermediates in organic synthesis as they engage in a diverse range of mechanistically distinct chemical reactions. However, the poor functional group compatibility of generating arynes or their precursors has stymied their widespread use. Here, we show that generating arynes by deprotonation of an arene and elimination of an "onium" leaving group is mild, efficient and broad in scope. This is achieved by using aryl(TMP)iodonium salts (TMP = 2,4,6-trimethoxyphenyl) as the aryne precursor and potassium phosphate as the base, and a range of arynophiles are compatible. Additionally, we have performed the first quantitative analysis of functional group compatibility for several methods to generate arynes, including the method developed here and the current state of the art. Finally, we show that a range of "sensitive" functional groups such as Lewis and Brønsted acids and electrophiles are compatible under our conditions.

Oxidative Cycloaddition Reactions of Arylboron Reagents via a One-pot Formal Dehydroboration Sequence.

Arylboron compounds are widely available and synthetically useful reagents in which the boron group is typically substituted. Herein, we show that the boron group and ortho-hydrogen atom are substituted in a formal cycloaddition reaction. This transformation is enabled by a one-pot sequence involving diaryliodonium and aryne intermediates. The scope of arylboron reagents and arynophiles is demonstrated, and the method is applied to the formal synthesis of an investigational drug candidate.

Refining boron-iodane exchange to access versatile arylation reagents.

Aryl(Mes)iodonium salts, which are multifaceted aryl transfer reagents, are synthesized via boron-iodane exchange. Modification to both the nucleophilic (aryl boron) and electrophilic (mesityl-λ3-iodane) reaction components results in improved yield and faster reaction time compared to previous conditions. Mechanistic studies reveal a pathway that is more like transmetallation than SEAr.

Orbital analysis of bonding in diarylhalonium salts and relevance to periodic trends in structure and reactivity.

Diarylhalonium compounds provide new opportunities as reagents and catalysts in the field of organic synthesis. The three center, four electron (3c-4e) bond is a center piece of their reactivity, but structural variation among the diarylhaloniums, and in comparison with other λ3-iodanes, indicates that the model needs refinement for broader applicability. We use a combination of Density Functional Theory (DFT), Natural Bond Orbital (NBO) Theory, and X-ray structure data to correlate bonding and structure for a λ3-iodane and a series of diarylchloronium, bromonium, and iodonium salts, and their isoelectronic diarylchalcogen counterparts. This analysis reveals that the s-orbital on the central halogen atom plays a greater role in the 3c-4e bond than previously considered. Finally, we show that our revised bonding model and associated structures account for both kinetic and thermodynamic reactivity for both acyclic phenyl(mesityl)halonium and cyclic dibenzohalolium salts.

Aryl(TMP)iodonium Tosylate Reagents as a Strategic Entry Point to Diverse Aryl Intermediates: Selective Access to Arynes.

Arenes are broadly found motifs in societally important molecules. Access to diverse arene chemical space is critically important, and the ability to do so from common reagents is highly desirable. Aryl(TMP)iodonium tosylates provide one such access point to arene chemical space via diverse aryl intermediates. Here we demonstrate that controlling reaction pathways selectively leads to arynes with a broad scope of arenes and arynophiles (24 examples, 70% average yield) and efficient access to biologically active compounds.

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

The Endochin-Like Quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised that lowers costs and is amenable to large scale production. In the new synthetic route described here, a substituted ß-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial scale production, is relatively short (5 reaction steps), does not require palladium, chromatographic separation or protecting group chemistry, and may be performed without high vacuum distillation.

Rhodium(III)-catalyzed arene and alkene C-H bond functionalization leading to indoles and pyrroles.

Recently, the rhodium(III)-complex [Cp*RhCl(2)](2) 1 has provided exciting opportunities for the efficient synthesis of aromatic heterocycles based on a rhodium-catalyzed C-H bond functionalization event. In the present report, the use of complexes 1 and its dicationic analogue [Cp*Rh(MeCN)(3)][SbF(6)](2) 2 have been employed in the formation of indoles via the oxidative annulation of acetanilides with internal alkynes. The optimized reaction conditions allow for molecular oxygen to be used as the terminal oxidant in this process, and the reaction may be carried out under mild temperatures (60 °C). These conditions have resulted in an expanded compatibility of the reaction to include a range of new internal alkynes bearing synthetically useful functional groups in moderate to excellent yields. The applicability of the method is exemplified in an efficient synthesis of paullone 3, a tetracyclic indole derivative with established biological activity. A mechanistic investigation of the reaction, employing deuterium labeling experiments and kinetic analysis, has provided insight into issues of reactivity for both coupling partners as well as aided in the development of conditions for improved regioselectivity with respect to meta-substituted acetanilides. This reaction class has also been extended to include the synthesis of pyrroles. Catalyst 2 efficiently couples substituted enamides with internal alkynes at room temperature to form trisubstituted pyrroles in good to excellent yields. The high functional group compatibility of this reaction enables the elaboration of the pyrrole products into a variety of differentially substituted pyrroles.

Mechanistic analysis of azine N-oxide direct arylation: evidence for a critical role of acetate in the Pd(OAc)2 precatalyst.

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metalation-deprotonation (CMD) pathway. Competition experiments were conducted with N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species, which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)(2) plays a pivotal role in the reaction mechanism as more than merely a precatalyst, but also as a source of acetate base required for the C-H bond cleavage step.

Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients.

Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists. Finally, we calculated medicinal chemistry properties of benzenoid containing APIs that are often used by practitioners as design elements, including "druglikeness", shape, complexity, and similarity/diversity and discuss these properties in the context of synthesis.