Larock Indole Synthesis Research Articles

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

AbstractTryptophan and its non‐canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long‐standing challenge. Here, we report a regioselective synthesis of non‐canonical tryptophans bearing C4−C7 substituents via Rh‐catalyzed annulation between structurally diverse tert‐butyloxycarbonyl (Boc)‐protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc‐directed C−H metalation and demetalation to afford a wide range of C2‐unsubstituted indole products in a redox‐neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non‐canonical tryptophan residues in a highly regioselective manner.

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C-H Functionalization of Anilines.

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

Modular Synthesis and Antimicrobial Investigation of Mycoleptodiscin A and Simplified Indolosesquiterpenoids.

The structure-activity relationship of the unusual indolosesquiterpenoid mycoleptodiscin A is unknown due to natural scarcity and inefficient synthesis. A modular approach leveraging Larock indole synthesis has been established to access mycoleptodiscin A and a divergent collection of drimenyl indoles. It features the utilization of an inexpensive (+)-sclareolide, modularity, purification-economy, and scalability, which facilitates the first biological evaluation of mycoleptodiscin A and related precursors.

Access to Axially Chiral N‑Arylindoles via Palladium-Catalyzed Atroposelective Larock Indole Synthesis

Access to Axially Chiral N‑Arylindoles via Palladium-Catalyzed Atroposelective Larock Indole Synthesis

Pd-Catalyzed Asymmetric Larock Indole Synthesis to Access Axially Chiral N-Arylindoles.

Larock indole synthesis is one of the most straightforward and efficient methods for the synthesis of indoles; however, there has been no asymmetric version yet for the construction of indole-based axially chiral N-arylindoles since its initial report in 1991. Herein we report the first example of an asymmetric Larock indole synthesis by employing a chiral sulfinamide phosphine (SadPhos) ligand (Ming-Phos) with palladium. It allows rapid construction of a wide range of axially chiral N-arylindole compounds in good yields up to 98:2 er. The application of this unique chiral scaffold as an organocatalyst is promising. Furthermore, a kinetic study has revealed that the alkyne migratory insertion is the rate-determining step, which has been proven by the density functional theory (DFT) calculations. Additionally, DFT studies also suggest that the N-C dihedral difference caused by the steric hindrance of the ligand contributes to enantioselectivity control.

Ethynyl-B(dan) in [3+2] Cycloaddition and Larock Indole Synthesis: Synthesis of Stable Boron-Containing Heteroaromatic Compounds.

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling.

The Larock Indole Synthesis: Pd-Catalyzed Annulation of 2-Iodoaniline and Internal Alkyne Derivatives

The Larock Indole Synthesis: Pd-Catalyzed Annulation of 2-Iodoaniline and Internal Alkyne Derivatives

Pyrroloiminoquinone Alkaloids: Total Synthesis of Makaluvamines Aand K.

Herein, an efficient, scalable, and concise approach to an advanced pyrroloiminoquinone synthetic intermediate (6b) by way of a Larock indole synthesis is reported. The synthetic utility of this intermediate is demonstrated by its ready conversion to makaluvamines A (1) and K (4).

Application of Palladium Chemistry in Organic Synthesis Techniques: the Larock Indole Synthesis, a Literature Review

As one of the most important biologically active and naturally occurring molecules, indole is an organic compound of great importance. For more than a century, the standard method of lab preparation of the indole family of compounds has been the Fischer indole synthesis. In 1994, Richard C. Larock and Eul Kgun Yum prepared indole and indole derivatives using a new technique involving organometallic chemistry, what has since then come to be known as the Larock indole synthesis [1]. In this literature review, we give a background to the techniques involved in the Larock indole synthesis, including similar precursor methods in palladium chemistry. We mention the motivations for this reaction method, based on earlier work done. We then give a detailed overview of Larock’s work, including the reaction mechanism, kinetic effects, and effects of substituents. We also consider limitations of the Larock indole synthesis. We then study the various applications of this synthesis technique, especially synthesis of those compounds with pharmaceutical applications. We also then consider improvement to Larock’s original work, including newer, more improved techniques that built on Larock’s work, and how these newer discoveries are more beneficial to us. We end this review paper with some future questions to pursue.

Palladium-catalyzed synthesis of 2,3-disubstituted indoles via arylation of ortho-alkynylanilines with arylsiloxanes.

In this study, we report the electrophilic cyclization of N,N-dimethyl-o-alkynylanilines with arylsiloxanes in the presence of [Pd(OAc)2] and Ag2O catalytic system, which leads to the efficient synthesis of indoles, similar to the one that is obtained through Larock indole synthesis. A range of aryl(trimethoxy)silanes with EDGs and EWGs were successfully utilized for the synthesis of a diverse variety of substituted indoles via the cleavage of the C-Si bond. This protocol exhibits good functional group tolerance and wide substrate scope to provide 2,3-diaryl-N-methylindoles in 26-88% yields.

Oxime ligands for Pd catalysis of the Mizoroki–Heck reaction, Suzuki–Miyaura coupling & annulation reactions

Monodentate and bidentate chelating oximes are readily available ligands for the Pd catalysis of the Mizoroki–Heck reaction and the Suzuki coupling. High yields were obtained in the Suzuki coupling in aqueous dioxane with TBABr as additive. The oximes can be easily synthesized from the corresponding ketones or aldehydes and thus provide a very large number of nitrogen-based ligands. They have the advantage of not undergoing oxidative degradation, common for phosphine ligands. Chelating oximes with Pd(OAc)2, activate aryl iodides to give high yields of the substitution products in the Mizoroki–Heck reactions as well as the Suzuki coupling. Acetophenone oxime ligand with Pd(OAc)2, catalyzed the reaction of aryl iodides with 1,2-disubstituted alkenes in moderate to high yields. As a test example, the LaRock indole annulation and synthesis of isocoumarin were achieved with acetophenone oxime ligand and Pd(OAc)2 in high yields.

N,N-Dimethylformamide-stabilized palladium nanoclusters as a catalyst for Larock indole synthesis.

We show that N,N-dimethylformamide-stabilized Pd nanoclusters (NCs) have high catalytic activity in the reaction of substituted 2-iodoanilines with alkynes to give 2,3-disubstituted indoles. This indole synthesis does not require phosphine ligands and proceeds with low Pd catalyst loadings. The Pd NCs were separated from the mixture after the reaction, and recycled at least three times. Transmission electron microscopy images showed that the Pd particle size before the reaction was 1.5–2.5 nm. The particle size after the reaction was 2–3 nm. X-ray photoelectron spectroscopy showed that the binding energy of the Pd NCs before the reaction was 335.0 eV.

ChemInform Abstract: 10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D.

The asymmetric synthesis of dragmacidin D (1) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C2-symmetric tetramine and lithium N-(trimethylsilyl)-tert-butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

AbstractThe asymmetric synthesis of dragmacidin D (1) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C2‐symmetric tetramine and lithium N‐(trimethylsilyl)‐tert‐butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.

10-Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)-Dragmacidin D.

The asymmetric synthesis of dragmacidin D (1) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C2-symmetric tetramine and lithium N-(trimethylsilyl)-tert-butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6''' position, which is consistent with other members of the dragmacidin family of natural products.

ChemInform Abstract: Sequential Sonagashira and Larock Indole Synthesis Reactions in a General Strategy to Prepare Biologically Active β‐Carboline‐Containing Alkaloids.

AbstractThe two palladium‐mediated title processes serve as key steps for the synthesis of various β‐carboline‐containing natural products.

ChemInform Abstract: Intramolecular Larock Indole Synthesis for the Preparation of Tricyclic Indoles and Its Application in the Synthesis of Tetrahydropyrroloquinoline and Fargesine.

AbstractThis method is applicable for a broad variety of ring sizes including large rings, e.

Sequential Sonagashira and Larock indole synthesis reactions in a general strategy to prepare biologically active β-carboline-containing alkaloids.

A general synthetic approach to β-carboline-containing alkaloids was developed. Two consecutive palladium-mediated processes, a Sonagashira coupling and a Larock indole annulation reaction, are central to the method. The scope of the approach was investigated and found to be amenable for constructing a variety of biologically significant natural products and also for preparing substituted analogues for optimization and analysis of their biological properties.

Total Synthesis of Dictyodendrins B and E, and Formal Synthesis of Dictyodendrin C

AbstractA full account of the concise total syntheses of dictyodendrins B and E, and the formal synthesis of dictyodendrin C are described. A palladium‐catalysed Larock indole synthesis was used to form the highly substituted indole core, and a palladium‐mediated one‐pot consecutive Buchwald–Hartwig amination/C–H activation reaction was used to construct the key pyrrolo[2,3‐c]carbazole core. Unsuccessful synthetic strategies are also discussed.

Intramolecular Larock indole synthesis for the preparation of tricyclic indoles and its application in the synthesis of tetrahydropyrroloquinoline and fargesine

A general and efficient strategy for fused tricyclic indoles from substituted 2-halogenanilines via the palladium-catalyzed intramolecular Larock indolization process has been developed. Using this strategy, a number of 3,4- and 3,5-fused indoles with a variety of ring sizes can been prepared. The utility of this method is demonstrated through the synthesis of the known tetrahydropyrrolo[4,3,2-de]quinoline 10 and the first total synthesis of fargesine.