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The direct synthesis of C4-acyl indoles deprived of C2 and C3 substituents has proven to be challenging, with scarce efficient synthetic routes being reported. Herein, we disclose a highly site-selective palladium-catalyzed C-H acylation for the construction of C4-acyl indoles via a Catellani-Lautens cyclization strategy. In addition, we systematically studied the ortho C-H acylation mechanism of iodoaniline through density functional theory (DFT) calculations and combined experimental results to elucidate the principle of high chemoselectivity brought by triazine benzoate as an acylation reagent.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho -site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Carbazole, as one of the most important organic frameworks, has been used in optoelectronic materials and biochemistry. However, the synthesis of C4-substituted carbazole has always been an unsolved problem. This report describes the one-step synthesis of C4-aminated carbazoles and their derivatives through the series reaction of C-H amination and arylation. The substrate scope is wide. C4-Amino carbazoles substituted by C2, C6, C7, and C8 methyl groups, especially carbazole derivatives of fused rings, pyridine, and dibenzofuran, can be synthesized.

In this paper, in the presence of trimethylsilyl iodide, the direct ortho -C-H hydroxyalkylation/methylation of aryl iodines was effectively realized via palladium/norbornene cooperative catalysis when low-cost tetrahydrofuran and 1,2-dimethoxyethane were used as alkyl sources. Heck, Suzuki, and Sonogashira coupling and hydrogenation were all compatible with the reaction as termination steps. In addition, neuromuscular agents and cardiovascular agents were synthesized in one step by this method, showing their potential application value.

This report developed a method for the synthesis of C8-aminated pyrrolo-phenanthridines or -indoles by series ortho C(sp 2 )-H amination/ ipso C(sp 2 )-H or C(sp 3 )-H arylation. N-benzoyloxyamines, as electrophilic amination reagents, did not undergo an electrophilic substitution reaction with the pyrrole side, but they did undergo a site-selective C-H amination reaction with the benzene side via Pd/NBE catalysis. The C8-aminated pyrrolo-phenanthridines have strong fluorescence in solution and solid state. X-ray single crystal diffraction shows that the steric hindrance of amino and ortho benzene ring may inhibit aggregation-caused quenching (ACQ).

In palladium/norbornene (Pd/NBE) chemistry, the " ortho effect" has been proven to be a key factor in the process of β-carbon elimination to extrude NBE. Herein, we found that the o -iodoaniline protected by a p -methoxybenzenesulfonyl group can recover the " ortho effect" and then undergo N-S bond cleavage with vinyl palladium, thus achieving a highly selective C-N coupling reaction in the Catallani-Lautens reaction system. On the basis of this discovery, a one-step synthesis of highly functionalized tricyclic indole derivatives was realized.

The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka-Heck/C(sp 3 or sp 2 )-H activation reaction is reported here. The key step in this transformation is the activation of a δ-C-H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiro-palladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp 3 )-H activation step.

This paper describes the case of a cross study between the C-N bond cleavage reaction field and the Catellani-Lautens reaction system. A series of highly functionalized C4-substituted indoles were synthesized using this strategy. By screening the alkyl groups of amines, the energy barrier of C-N bond cleavage reaction was reduced and the corresponding allenization products were avoided. Finally, the density functional theory calculation shows that the inert C-N bond activation reaction is not a concerted process; on the contrary, the coupling reaction first generates indole quaternary ammonium salt, and then C-N bond cleavage occurs via an S N 2 process.

This report describes the first example of palladium-catalyzed ortho -C-H glycosylation/ ipso -alkenylation of aryl iodides, and the easily accessible glycosyl chlorides are used as a glycosylation reagent. The reaction is compatible with the functional groups of the substrates, and a series of C-aryl glycosides have been synthesized in good to excellent yield and with excellent diastereoselectivity. It is found that a cheap 5-norbornene-2-carbonitrile as a transient mediator can effectively promote this reaction. In addition, ipso -arylation and cyanation were also realized by the strategy.

Bioluminescence imaging with luciferase-luciferin pairs is commonly used for monitoring biological processes in cells and whole organisms. Traditional bioluminescent probes are limited in scope, though, as they cannot be easily distinguished in biological environments, precluding efforts to visualize multicellular processes. Additionally, many luciferase-luciferin pairs emit light that is poorly tissue penetrant, hindering efforts to visualize targets in deep tissues. To address these issues, we synthesized a set of π-extended luciferins that were predicted to be red-shifted luminophores. The scaffolds were designed to be rotationally labile such that they produced light only when paired with luciferases capable of enforcing planarity. A luciferin comprising an intramolecular "lock" was identified as a viable light-emitting probe. Native luciferases were unable to efficiently process the analog, but a complementary luciferase was identified via Rosetta-guided enzyme design. The unique enzyme-substrate pair is red-shifted compared to well-known bioluminescent tools. The probe set is also orthogonal to other luciferase-luciferin probes and can be used for multicomponent imaging. Four substrate-resolved luciferases were imaged in a single session. Collectively, this work provides the first example of Rosetta-guided design in engineering bioluminescent tools and expands the scope of orthogonal imaging probes.

This report describes a palladium-catalyzed dearomatization and amination tandem reaction of 2,3-disubstituted indoles and benzofurans via the Catellani strategy. This reaction provides a new method for the construction of amino-substituted indoline-fused cyclic and benzofuran spiro compounds in good yields. The reaction has broad functional group compatibility and substrate scope.

Copper-catalyzed three-component redox-neutral ring opening of benzothiazoles with aryl iodides and O -benzoyl hydroxylamines for the synthesis of 1-amino- N -(2-(phenylthio)phenyl)methanimine has been developed. This one-pot reaction undergoes C-S and N-O bond cleavage and new C-S and C-N bond construction. Several control experiments excluded a free radical procedure and also demonstrated the secondary amine as a possible intermediate, which was vital to the catalytic reaction. Meanwhile, the deuteration experiment got rid of the C-H activation dehydroisomerization of the benzothiazole mechanism.

Multicomponent reactions are fundamentally different from two-component reactions, as multicomponent reactions can enable the efficient and step-economical construction of complex molecular scaffolds from simple precursors. Here, an unprecedented three-component direct C-H addition was achieved in the challenging meta -selective fashion. Fluoroalkyl halides and a wide range of alkenes, including vinylarenes, unactivated alkenes, and internal alkenes, were employed as the coupling partners of arenes in this strategy. The detailed mechanism presented is supported by kinetic isotope studies, radical clock experiments, and density functional theory calculations. Moreover, this strategy provided access to various fluoride-containing bioactive 1,1-diarylalkanes and other challenging synthetically potential products.

Highly functionalized 4-aminoindoles were synthesized via the three-component cross-coupling of o-iodoaniline, N-benzoyloxyamines, and norbornadiene. The Catellani and retro-Diels-Alder strategy was used in this domino process. o-Iodoaniline, with electron-donating and sterically hindered protecting groups, made the reaction selective toward o-C-H amination. On the basis of density functional theory calculations, the intramolecular Buchwald coupling of this reaction underwent a dearomatization and a 1,3-palladium migration process. The reasons for the control of the chemical selectivity by the protecting groups are given. Moreover, synthetic applications toward 4-piperazinylindole and a GOT1 inhibitor were realized.

Alkynes difunctionalization is a powerful strategy in organic synthesis that provides a convenient synthetic entry for internal alkenes. The main challenge in this field was considered to be the geometry control of the newly formed double bond (thermodynamically controlled or kinetically controlled). Herein, we report a novel procedure (through the cyclic compounds broken) to completely control the regioselectivity of olefins. The products, difluoroalkyl unsaturated β-amino acid derivatives, have potential applications in some important pharmaceuticals on account of the special nature of fluorine atoms.

Directed evolution has proven to be an invaluable tool for protein engineering; however, there is still a need for developing new approaches to continue to improve the efficiency and efficacy of these methods. Here, we demonstrate a new method for library design that applies a previously developed bioinformatic method, Statistical Coupling Analysis (SCA). SCA uses homologous enzymes to identify amino acid positions that are mutable and functionally important and engage in synergistic interactions between amino acids. We use SCA to guide a library of the protein luciferase and demonstrate that, in a single round of selection, we can identify luciferase mutants with several valuable properties. Specifically, we identify luciferase mutants that possess both red-shifted emission spectra and improved stability relative to those of the wild-type enzyme. We also identify luciferase mutants that possess a >50-fold change in specificity for modified luciferins. To understand the mutational origin of these improved mutants, we demonstrate the role of mutations at N229, S239, and G246 in altered function. These studies show that SCA can be used to guide library design and rapidly identify synergistic amino acid mutations from a small library.

A silver-catalyzed oxidative cyclization of 2- or 3-propargylamide-substituted indoles to synthesize phosphorated indoloazepinone derivatives is described. This reaction displays a difunctionalizalion of alkynes with diphenylphosphine oxides to construct a seven-membered ring through a radical cyclization process. The indoloazepinones derivatives are common structural motifs found in many natural products and pharmaceuticals.