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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.

The chemical diversification of biomolecules set forth a significant area that constitutes an important intersection between chemistry and biology. Amino acids and peptides, are the fundamental building blocks of proteins, play an ubiquitous role in all living organisms. While significant efforts have been geared to the chemical modifications of amino acid residues, particularly the functionalization of reactive functional groups such as Lysine-NH2 and Cysteine –SH, the exploration of aromatic amino acid residues of Tryptophan, Tyrosine, Phenylalanine, and Histidine has been relatively limited. Therefore, this review highlights on the strategies for side chain functionalization of these four aromatic amino acids in peptides, with a focus on elucidating the underlying mechanisms. We have also illustrated the usage of these chemical modifications in the chemical and biological realm.

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

The review describes synthesis of functionalized indoles from a pre-existing pyrrole core via cascade benzannulation strategies developed in the last decade. Detailed mechanistic analysis is also discussed to depict the reactivity pattern.

Cobalt(iii)-catalyzed thiocarbamate directed aminocarbonylation and amination of C–H bonds are described to access diverse amides.

The oxa-Diels–Alder reaction is a straightforward, atom-economical process for the construction of six-membered oxacycles, which are privileged structures due to their very common occurrence in several pharmaceuticals and natural products. As with many other asymmetric transformations, organocatalysis provides an elegant pathway to their synthesis via [4+2] annulation under mild reaction conditions. The oxa-Diels–Alder reaction utilizes either an α,β-unsaturated carbonyl as an oxa-diene with a suitable dienophile or a simple carbonyl as a dienophile with other dienes. A range of organocatalysts has been explored in the past decade to execute this strategy. The catalysts induce stereoselectivities via two basic reactivities: (1) The formation of chiral intermediates, or (2) selectively activating suitable reactants via a transition state. The present short review compiles organocatalyzed asymmetric oxa-Diels–Alder reactions published over the last ten years, along with detailed discussions on mechanistic approaches.1 Introduction2 Catalysis through Covalent Activation2.1 N-Heterocyclic Carbenes2.2 Amines2.3 Isothiourea Catalysis2.4 Phosphines3 Catalysis through Non-Covalent Activation3.1 Bifunctional Amines3.2 Brønsted Acids3.3 Guanidines4 Multicatalysis through Both Covalent and Non-Covalent Activation5 Conclusion

Nitrogen-containing π-excessive aromatic heterocycles, in particular, carbazoles, indolocarbazoles, benzocarbazoles, and carbolines have been considered the fundamental backbone of organic chemistry for many decades due to their omnipresence in natural products, alkaloids, terpenes, marketed drugs, medicinally active compounds, organic materials, etc. Together with their ever-increasing importance, there has been a multi-dimensional significant advancement in the last decade towards their synthesis. This review presents an analysis of several exciting classical benzannulation and non-classical benzannulation approaches developed in the past decade (2010–2020) for the construction of carbazoles, indolocarbazoles, benzocarbazoles, and carbolines. The principal aim of this review is the detailed discussion of several fascinating mechanistic pathways together with the role of numerous key reagents and catalysts. Furthermore, the efficacy of these numerous benzannulation techniques towards the downstream synthesis of natural alkaloids, organic materials, and medicinally important scaffolds together with upcoming key challenges in this field are also covered in detail.

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.

Organic chemistry frontiers 9(16), 4466-4471 (2022). doi:10.1039/D2QO00840H, Published by RSC, Cambridge

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 yield and diastereoselectivities.

An effective and operationally simple one-pot Bronsted 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.

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.

Weakly coordinating, ketone-directed C–H vinylation using vinyl acetate is reported here for a wide range of aromatic ketones such as acetophenones, diaryl ketones, chromones and biologically relevant chalcones under cost-effective and air-stable cobalt(III)-catalysis. Regioselective, mono-vinylation occurs for challenging vinyl substitution-free styrenes in moderate to good yields, and this moiety has been used to synthesize functionalized indanone, α-naphthol and an advanced intermediate for bruguierol A synthesis. An acrylate-surrogate provided the corresponding alkenylated product under these vinylation conditions. Detailed mechanistic studies are carried out to support the proposed catalytic cycle.

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, 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 β-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.

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.

A Bronsted 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.

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.

This brief highlight described about our recently reported method of cascade Prins-type cyclization method. Structural complexity and interesting biological activity made hapalindole alkaloid an attractive choice to the synthetic organic chemist over the past few decades. Keeping the importance of hapalindole scaffolds in mind, in this line, we recently disclosed a redox-neutral, biomimetic Prins-type cyclization between indole and an aldehyde bearing a terminal ene-promoter. The mild reaction protocol allows incorporation of several key functionalities in the products, and products were isolated with excellent yields and diastereoselectivities. Applying this strategy total synthesis of seven hapalindole alkaloids and formal synthesis of two more related alkaloids were accomplished in a stereodivergent manner in relatively fewer synthetic steps.

The stereospecific synthesis of Z-enamides is described in this paper. For the first time, isoxazoles have been employed as electrophiles in C-H functionalization to afford thermodynamically less stable Z-enamides utilizing salicylaldehydes in an atom- and step-economic fashion. The stereochemistry of enamides might originate from the relative disposition of atoms present in isoxazole and the intramolecular hydrogen bonding. The reaction showed excellent scope as several structurally and electronically diverse salicylaldehydes and isoxazoles reacted efficiently.

The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks. This amidation proceeded smoothly with a variety of ketones and several amidating partners. The application of the products in the synthesis of various heterocycles, including acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines, was also explored. The total synthesis of acridone-based alkaloids, namely, toddaliopsin A, toddaliopsin D, and arborinine, and the formal synthesis of acronycine and noracronycin were also accomplished by applying this method. A mechanistic study revealed this amidation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated. The sequence of four different reactions is executed in one-pot using readily available and cheap bottle reagents as catalysts rendering this method attractive. The incorporation of inexpensive and environmentally benign molecular oxygen as the oxidant into the final aromatization step enables tolerance of several functional groups.

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.

Complexes possessing abnormal or mesoionic carbene (aNHC or MIC) ligands are finding widespread applicability in organometallic chemistry owing to their various catalytic applications. Palladium(II) complexes bearing a mixed aNHC/Py/PR3/I2 (R = Ph, Cy) donor set are presented starting from a biphenyl derived triazolium salt. The complexes have been characterized by NMR spectroscopy and ESI mass spectrometry. Two complexes have also been structurally characterized by single crystal XRD. The PdII complexes have been tested as potent precatalysts for α-arylation of oxindole and Suzuki-Miyaura cross coupling reactions. Different donor ligands such as pyridine, 3-chloropyridine, 4-methoxypyridine, PPh3 and PCy3 have been used to compare the catalytic activities. The PdII complexes containing mixed aNHC/PR3/I2 donor set appeared to be more active catalysts when compared with the complexes bearing mixed aNHC/Py/I2 donor set in both catalytic transformations.

An approach towards construction of amide C-N bond under mild conditions through rhodium(III) catalysis has been explored. Previous waste-free amidations were generally limited to the condensation of carboxylic acids and amines. In this report, we directly applied amination of aldehyde C(sp2)-H bond to extend the scope of amidation reactions. Amination shows wide substrates scope and several important functional groups were tolerated under the benign reaction conditions. Synthesized amides are important precursor for the preparation of benzoxazinone derivatives, found in various bioactive natural products.

Benzannulation of 2-alkenylindoles with readily available aldehydes, under one-pot sequential triple-relay-catalysis, provides an easy access to several structurally unique carbazoles including 2- and 3-alkenylcarbazoles. This protecting group-free method enabled one-pot synthesis of alkaloids such as hyellazole and 6-chlorohyellazole, and the formal syntheses of seven other alkaloids. Construction of the core structure, present in murastifoline A, murrafoline E, and related alkaloids was also demonstrated. Even conjugated 3,3′-biscarbazoles can also be synthesized by one-pot, two-fold sequential triple-relay catalysis.

An axial chiral version of the 2,6-dimesitylphenyl group attached to sulfur is reported. Its multistep preparation starts from (S)-binol, and the thiol group is established by a racemization-free thermal Newman-Kwart rearrangement. The new chiral thiolate ligand decorated with one mesityl group is used in the synthesis of a tethered ruthenium chloride complex. Its spectroscopic characterization revealed solvent-dependent epimerization at the ruthenium center. The major diastereomer is crystallographically characterized. Chloride abstraction with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF4 ) yields the corresponding coordinatively unsaturated ruthenium complex with the Ru-S bond exposed. Si-H bond activation at this Ru-S bond proceeds in syn fashion but with moderate facial selectivity (d.r.=70:30), generating diastereomeric chiral-at-ruthenium hydrosilane adducts. Their application to catalytic imine hydrosilylation led to promising enantioinduction (40 % ee), thereby providing proof of concept for asymmetric catalysis involving cooperative Si-H bond activation.

Hydroarylation of internal alkynes by cost-effective CoIII-catalysis, directed by N-tert-butyl amides, is achieved to avail mono- or dihydroarylated amide products selectively in an atom and step economic way. Several important functional groups were tolerated under the reaction conditions, and syn-hydroarylation products were exclusively isolated. Notably, a 4-fold C–H hydroarylation provided a highly conjugated organic framework in one step. Kinetic study with extensive deuterium labeling experiments were performed to support the proposed mechanism.

The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks. This amidation proceeded smoothly with a variety of ketones and several amidating partners. The application of the products in the synthesis of various heterocycles, including acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines, was also explored. The total synthesis of acridone-based alkaloids, namely, toddaliopsin A, toddaliopsin D, and arborinine, and the formal synthesis of acronycine and noracronycin were also accomplished by applying this method. A mechanistic study revealed this amidation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

A one-pot, protecting-group-free benzannulation of 2-alkenylindoles with readily available 1,3-dicarbonyls is demonstrated to construct structurally diverse carbazoles. The use of a cheap Bronsted acid catalyst and air as the sole oxidant exemplifies the economic viability of this protocol. The execution of four different reactions successively to generate the medicinally important indolocarbazole core is also achieved. This one-pot protecting-group-free method paved the way for the total synthesis of three medicinally important alkaloids, namely staurosporinone, arcyriaflavin A, and 7-hydroxy-K252c.

Weakly coordinating, ketone-directed, regioselective monoallylation of arenes and indoles is reported using a stable and cost-effective high-valent cobalt(III)-catalyst to access several important molecular building blocks. The allylation proceeds smoothly with a variety of substrates in the presence of various electron-rich and -deficient substituents. The method was applied to the formal synthesis of an ancisheynine alkaloid, a highly conjugated azatetracene, and isochroman. The mechanistic study reveals that the allylation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

Catalytic fluorolactonisations of aromatic carboxylic acids have been developed. The reactions proceed under mild conditions using the commercially available reagent Selectfluor. A weak phase transfer of the reagent mediated by Na2CO3 allows the reaction to be conducted in non-polar solvents. Furthermore, by the use of a catalytic amount of (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether), the first asymmetric fluorolactonisation has been achieved. The corresponding isobenzofuran core can be found in many biologically active molecules.

The synthesis of sensitive β-alkyl 3-vinylindoles having diverse functional groups with good selectivity remains a challenging task. Keeping the synthetic utility of 3-alkenylindoles in mind, we explored a unique approach to synthesize them from unprotected indoles in a domino fashion. A transition-metal-free C3-alkenylation of indole is reported by using sequential Bronsted acid/base catalysis. Several β-substituted 3-alkenylindoles and conjugated 1,3-dienes are synthesized by direct coupling of indole and readily available aliphatic aldehydes. Excellent scalability and recycling of benzenesulfinic acid for successive alkenylation reactions up to five times make this method economically viable.

Hydroarylation of internal alkynes by cost-effective Co

The readily synthesized trichloro acetimidamide was found to be an excellent directing group for the directed C–H-allylation reactions. Depending on the allylating agent used, selectively either mono- or diallylated products were readily synthesized. Moreover, the trichloro acetimidamide directing group was found to be highly efficient even at lower temperature for the C–H-allylation reaction. Due to mildness of the reaction conditions, double bond isomerization or cyclization to indole side product was not observed.

Cross coupling of aryl, alkenyl, and alkynyl magnesium compounds by using 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant is described. This coupling reaction can be performed without adding any transition metal on various ortho-substituted aryl and alkynyl Grignard reagents. Importantly, functional groups such as esters, amides, and cyanides are shown to be tolerated under the reaction conditions.

Oxidative homocoupling of aryl, alkenyl, and alkynyl Grignard reagents by using commercially available TEMPO as an organic oxidant is described. These coupling reactions occur highly efficiently without the presence of any transition metal.