Asymmetric 1,2-Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α-Keto Imines.

A carbonyl-assisted asymmetric 1,2-migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α-amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face-selective 1,2-allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram-scale synthesis, showcasing broad functional-group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.

Construction of C2-indolyl-quaternary centers by branch-selective allylation: enabling concise total synthesis of the (±)-mersicarpine alkaloid.

Herein we report a branch-selective allylation strategy for accessing C2-indolyl-all-carbon quaternary centers using allylboronic acids. This approach boasts broad functional group tolerance, scalability, and relies on easily accessible allyl alcohol precursors. Importantly, the C3-position of the indole remains free, offering a handle for further synthetic refinement. Mechanistic pathways, corroborated by density functional theory (DFT), suggest the involvement of an indolenine intermediate and a Zimmerman-Traxler-like transition state during allylboration. Demonstrating its efficacy, the method was applied to the total synthesis of the (±)-mersicarpine alkaloid and enabled formal synthesis of additional alkaloids, such as (±)-scholarisine G, (±)-melodinine E, and (±)-leuconoxine.

Carbazoquinocin Analogues as Small Molecule Biomimetic Organocatalysts in Dehydrogenative Coupling of Amines.

A new series of carbazole-cored biomimetic ortho-quinone catalysts structurally resembling carbazoquinocin alkaloids have been introduced to promote tunable, metal cocatalyst-free, organocatalytic, dehydrogenative amine oxidation under aerobic conditions. Differently substituted benzyl amines were tolerated under optimized conditions to provide imines in excellent yields. Further efficacy of the catalyst was demonstrated by synthesizing cross-coupled imines efficiently. Control experiments and in-depth DFT studies disclosed a covalent transamination pathway as a plausible mechanism for this newly developed catalytic system.

Solution-Phase Late-Stage Chemoselective Photocatalytic Removal of Sulfonyl and Phenacyl Groups in Peptides.

Herein, BPC catalyzed visible-light-triggered target-specific late-stage solution phase desulfonylation from tryptophan in oligopeptides is portrayed by overcoming the isolation issue up to octamers. This robust and mild method is highly predictable and chemoselective, tolerating myriad of functional groups in aza-heteroaromatics and peptides. Interestingly, reductive desulfonylation is also amenable to biologically significant reactive histidine and tyrosine side chains, signifying the versatility of the strategy. Additional efficacy of BPC is demonstrated by solution phase phenacyl deprotection from C-terminal in peptides. Furthermore, excellent catalyst loading of 0.5 mol% and recyclability demonstrate the practical utility and applicability of this strategy.

Annulative π-Extension by Cp*Co(III)-Catalyzed Ketone-Directed peri-Annulation: An Approach to Access Fused Arenes.

A masked-bay-region selective first-row transition-metal Cp*Co(III)-catalyzed annulative π-extension of arene-derived ketones is achieved to afford K-region-functionalized benzo[e]pyrenes, benzotetraphenes, and pyrenes. Comprehensive density functional theory studies buttress the mechanistic pathway comprising key steps like peri-C-H activation, alkyne 1,2-migratory insertion, and nucleophilic attack toward ketone, this attack being the rate-determining step. In addition, π-conjugated 1,1'-bipyrenes, potential photocatalyst pyrene-quinones, and putative n-type semiconductor cyano group-containing dibenzo[de,qr]tetracenes are also accessed.

Annulative π-Extension by Rhodium(III)-Catalyzed Ketone-Directed C-H Activation: Rapid Access to Pyrenes and Related Polycyclic Aromatic Hydrocarbons (PAHs).

Annulative π-extension (APEX) reaction has become a powerful tool for the precise synthesis of well-defined polycyclic aromatic hydrocarbons (PAHs) such as nanographene, graphene, and other PAHs possessing unique structure. Herein, an APEX reaction has been realized at the masked bay-region for the efficient and rapid synthesis of valuable PAH, pyrene, bearing substitutions at the most challenging K-region. RhIII -catalyzed ketone-directed C-H activation at the peri-position of a naphthyl-derived ketone, alkyne-insertion, intramolecular nucleophilic attack at the carbonyl-group, dehydration, and aromatization steps occurred in one-pot to effectuate the protocol. Employing this strategy, a two-fold APEX reaction on enantiopure BINOL-derived ketones provided access to axially-chiral bipyrene derivatives. The detailed DFT study to support proposed mechanism, and synthesis of helical PAHs like dipyrenothiophene and dipyrenofuran are other highlights of the present study.

Development of Carbazole-Cored Organo-Photocatalyst for Visible Light-Driven Reductive Pinacol/Imino-Pinacol Coupling.

Benzoperylenocarbazole (BPC), a unique carbazole-based organophotocatalyst, is reported herein as a potent organo-photoreductant. Lower excited state oxidation potential (-2.0 V vs SCE) and reasonable excited state lifetime (4.61 ns) render BPC an effective photosensitizer. Under irradiation of blue light employing low catalyst loading (0.5 mol %), a plethora of vicinal diols and diamines were synthesized in excellent yields through reductive coupling of carbonyls and imines, respectively. Insight about the electronic structure of BPC was obtained by DFT calculations.

Cp*Co(III)-catalyzed thiocarbamate-directed C-H aminocarbonylation, amination, and cascade annulation of pyrroles.

Cobalt(III)-catalyzed thiocarbamate directed aminocarbonylation and amination of C-H bonds are described to access diverse amides. Biologically relevant pyrrolo[1,2-c]imidazoles were readily accessed via one-pot intramolecular cyclization at the thiocarbamoyl directing group. Notably, C-N amidation proceeded smoothly with an elusive catalyst TON of 250 for this Cp*Co(III)-catalysis. Broad scope, scalability, and easy removal of DG are other key features of these methods. The mechanisms of these C-H amidation reactions were proposed through control experiments and DFT calculations.

Cascade Benzannulation Approach for the Syntheses of Lipocarbazoles, Carbazomycins, and Related Alkaloids.

Herein, a state-of-the-art one-pot cascade benzannulation technique for the efficacious synthesis of valuable 3-hydroxy-2-methyl carbazoles, a linchpin of more than 25 carbazole-based alkaloids, is unveiled from readily affordable fundamental commodities. The key step of this strategy is gaining aromaticity by site-selective elimination of hydroxyl group controlled by nucleophilicity of the indole ring. The present strategy shows excellent functional group tolerance with a broad substrate scope. The utility of this convenient approach was appealingly exemplified via concise total syntheses of 10 carbazole-based alkaloids possessing significant biological activities and thus of medicinal importance.

Synthesis of functionalized indoles via cascade benzannulation strategies: a decade's overview.

Indoles are one of the most prominent aromatic heterocycles in the organic chemistry field. Due to their widespread presence in various natural products, alkaloids, drugs, approved medicines, etc. the synthesis and functionalization of indoles are of great interest. This review emphasizes recent developments and techniques in the domino cascade cyclization process in the last decade starting from the various building blocks. In particular, this review depicts several intriguing benzannulation methods of creating a benzene ring on a pre-existing pyrrole nucleus in an inter/intramolecular fashion under metal-catalyzed/metal-free approaches. Different subsections focus on gradual timely developments in this complementary area and a detailed analysis of the mechanisms and reactivity patterns. As a complementary method, this review gives a significant incentive to various annulation strategies and also gives an overview of the remaining challenges and upcoming possibilities.

An expeditious route to sterically encumbered nonproteinogenic α-amino acid precursors using allylboronic acids.

A diastereoselective allylation of N-tert-butane sulfinyl α-iminoesters using allylboronic acids is developed to obtain optically active non-proteinogenic α-amino acid precursors in good yields and diastereoselectivities. Gram-scale synthesis, broad tolerance of functional groups, excellent stereodivergence, post-synthetic modifications, and easy removal of the chiral auxiliary are some of the key highlights. The protocol is applicable to various amino acids and short peptides, resulting in the incorporation of these precursors at the N-terminal position.

Cascade annulative π-extension for the rapid construction of carbazole based polyaromatic hydrocarbons.

A Brønsted acid catalyzed cascade benzannulation strategy for the one-pot synthesis of densely populated poly-aryl benzo[a]carbazole architectures is disclosed from easily affordable fundamental commodities. The efficacy of this technique was further validated via the concise synthesis of structurally unique carbazole based poly-aromatic hydrocarbons. Furthermore, the photo-physical properties of the synthesized compounds are thoroughly investigated.

A one-pot "back-to-front" approach for the synthesis of benzene ring substituted indoles using allylboronic acids.

Synthesis of only benzene ring functionalized indoles and poly-substituted carbazoles is reported via a one-pot triple cascade benzannulation protocol. Usage of differently substituted and readily accessible allylboronic acids as a 3-carbon annulating partner enables diverse aliphatic and aromatic substitution patterns, which is still a daunting task. This scalable synthetic protocol tolerates broad scope, thus enabling further downstream modifications. As an application, carbazole based natural products glycozoline and glycozolinol were synthesized.

Cooperativity within the catalyst: alkoxyamide as a catalyst for bromocyclization and bromination of (hetero)aromatics.

Alkoxyamide has been reported as a catalyst for the activation of N-bromosuccinimide to perform bromocyclization and bromination of a wide range of substrates in a lipophilic solvent, where adequate suppression of the background reactions was observed. The key feature of the active site is the alkoxy group attached to the sulfonamide moiety, which facilitates the acceptance as well as the delivery of bromonium species from the bromine source to the substrates.

Carbamates: A Directing Group for Selective C-H Amidation and Alkylation under Cp*Co(III) Catalysis.

The selective reactivity of carbamate and thiocarbamate toward alkylation and amidation is reported under stable, high-valent, cost-effective cobalt(III) catalysis. This method reveals the wide possibility of designing a different branch of synthetically challenging yet highly promising asymmetric catalysts based on BINOL and SPINOL scaffolds. Late-stage C-H functionalization of l-tyrosine and estrone was also achieved through this approach. The mechanistic study shows that a base-assisted internal electrophilic substitution mechanism is operative here.

One-pot access to tetrahydrobenzo[c]carbazoles from simple ketones by using O2 as an oxidant.

An effective and operationally simple one-pot Brønsted acid catalyzed cascade method is demonstrated for the synthesis of diversely functionalized carbazole frameworks starting from protecting group free 2-alkenyl indoles. The employment of easily available unactivated ketones as annulating partners, mostly unexplored for the synthesis of carbazoles, is the major highlight of this protocol. This protocol is step- and atom-economical, uses molecular oxygen as the green oxidant, and gives water as the only by-product and is amenable to different functional groups. Moreover, gram-scale synthesis and downstream modification of the obtained products demonstrate the synthetic applicability of this protocol.

Brønsted Acid-Catalyzed Tandem Pinacol-Type Rearrangement for the Synthesis of α-(3-Indolyl) Ketones by Using α-Hydroxy Aldehydes.

A Brønsted acid-catalyzed pinacol-type rearrangement pathway is reported here to synthesize various substituted α-(3-indolyl) ketones by employing unprotected indoles and α-hydroxy aldehydes as coupling partners. Utilization of economic and readily available Brønsted acid catalyst and use of simple starting precursors exemplify the economic viability of this method. Under this developed protocol, selective migration of aryl over alkyl or a second aryl group is observed depending upon the migratory aptitude of the substituents. Applicability of this method was further demonstrated by synthesizing highly substituted carbazoles through a simple extension of this method to one-pot cascade annulation strategy.

A Brønsted Acid Catalyzed Cascade Reaction for the Conversion of Indoles to α-(3-Indolyl) Ketones by Using 2-Benzyloxy Aldehydes.

A Brønsted acid catalyzed, operationally simple, scalable route to several functionalized α-(3-indolyl) ketones has been developed and the long-standing regioisomeric issue has been eliminated by choosing appropriate carbonyls. A readily available and cheap bottle reagent was used as the catalyst. This protocol was also applicable to the synthesis of densely functionalized α-(3-pyrrolyl) ketones. A detailed mechanistic study confirmed the involvement of enolether as a reaction intermediate. Several postsynthetic modifications along with easy access to ß-carboline, tryptamines, tryptophols, and spiro-indolenine proclaim the synthetic utility of this powerful building block. On the basis of this concept, functionalized carbazoles were constructed by a cascade annulation strategy.

On-Water Cp*Ir(III)-Catalyzed C-H Functionalization for the Synthesis of Chromones through Annulation of Salicylaldehydes with Diazo-Ketones.

A high-valent Ir(III)-catalyzed C-H bond functionalization is carried out for the first time on water for the synthesis of a biologically relevant chromone moiety. The C-H activation and annulation of salicylaldehydes with diazo-compounds provided the desired chromones. The synthesis of C3-substitution-free chromones has also been demonstrated by a one-pot decarboxylation by employing tert-butyl diazoester. C3 and C5 C-H activations of the product chromone are also carried out under different conditions for further diversification.