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Visible light‐driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging‐to‐access axially chiral 2‐azaarene‐functionalized quinazolinones. The substrate scope is extensive, allowing for both 3‐axis and unmet 1‐axis assembly through facile oxidation of diverse central chiral 2,3‐dihydroquinazolin‐4(1H)‐ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization. [ABSTRACT FROM AUTHOR]

The organocatalytic asymmetric benzylation of Morita–Baylis–Hillman (MBH) carbonates with 2,4-dinitrotoluene derivatives as nucleophiles is described. The developed reaction provides a straightforward access to functionalized 2,4-dinitrotoluene derivatives of biological and synthetic relevance. Highly functionalized products have been chemoselectively and efficiently obtained in good to high yields (up to 84%) and with excellent stereoselectivity (up to >20:1 dr, >99 ee). [ABSTRACT FROM AUTHOR]

1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield. [ABSTRACT FROM AUTHOR]

Consecutive photoinduced electron transfer (ConPET) is a powerful and atom‐economical protocol to overcome the limitations of the intrinsic redox potential of visible light‐absorbing photosensitizers, thereby considerably improving the substrate and reaction types. Likely because such an exothermic single‐electron transfer (SET) process usually does not require the aid of chiral catalysts, resulting in an inevitable racemic background reaction, notably, no enantioselective manifolds have been reported. Herein, we report on the viability of cooperative ConPET and chiral hydrogen‐bonding catalysis for the [3+2] photocycloaddition of cyclopropyl ketones with vinylazaarenes. In addition to enabling the first use of olefins that preferentially interact with chiral catalysts, this catalysis platform paves the way for the efficient synthesis of pharmaceutically and synthetically important cyclopentyl ketones functionalized by azaarenes with high yields, ees and dr. The robust capacity of the method can be further highlighted by the low loading of the chiral catalyst (1.0 mol %), the good compatibility of both 2‐azaarene and 3‐pyridine‐based olefins, and the successful concurrent construction of three stereocenters on cyclopentane rings involving an elusive but important all‐carbon quaternary. [ABSTRACT FROM AUTHOR]

A nickel-hydride (NiH)-catalyzed migratory and nonmigratory hydroalkylation reaction of 2-alkenyl azaarenes with alkyl iodines has been established through strategic modulation of N- or P-donor ligands. This method enables the synthesis of diverse β- or γ-branched aromatic N-heterocycles. The mild regiodivergent protocols exhibit wide substrate scope, excellent functional tolerance, and great reaction yield with remarkable regioselectivity. Importantly, deuterium labeling studies reveal NiH-catalyzed interrupted chain-walking mode as the mechanism behind remoted β-selective hydroalkylation reaction—an interesting phenomenon mediated through aromatic imine directing groups. [ABSTRACT FROM AUTHOR]

Direct enantioselective reduction of the C=C bond of β-polyfluoro-alkylated enones is an important but long-pending subject in asymmetric catalysis. Here, we report on the viability of visible light-driven cooperative photoredox and chiral hydrogen-bonding catalysis to effectively address this challenge, as a variety of products are obtained in high yields (up to 85%) with good to excellent enantioselectivities (up to 98% ee). The formation of thermodynamically favorable enol intermediates after double single-electron reduction represents the center of the success. Additionally, the utility of the current method is validated by the convenient regio-specific and -diverse synthesis of various deuterated derivatives for these products using inexpensive D2O as the deuterium source. [ABSTRACT FROM AUTHOR]

N-aromatic heterocycles (azaarenes) are useful molecules found in many natural products and pharmaceuticals. Their methyl derivatives (methyl azaarenes) are a unique class of molecules. The methyl group can be converted into an aldehyde group in the iodine–DMSO medium via Kornblum oxidation. The heteroaromatic aldehydes generated are of prime importance in medicinal chemistry and can be isolated or can be trapped by nucleophiles to construct diverse azaarene-linked scaffolds. The whole process can be summed up as functionalization of C(sp3)–H to form aldehydes, which are further functionalized to form an array of diversely functionalized azaarenes. This particular reaction system has gained popularity in recent years. In this reaction system, the methyl azaarene first gets iodinated. The alkyl iodide generated in situ meets the requirements of Kornblum oxidation in the presence of DMSO. Kornblum oxidation is one of the most popular and most preferred reactions of oxidation of alkyl halides because of its non-toxic and metal-free nature and mild reaction conditions. Thus, we present a collection of literature, which cover the reports available in the last decade for the C(sp3)–H functionalization of methyl azaarenes in the iodine–DMSO medium during 2013–2023. [ABSTRACT FROM AUTHOR]

An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine‐derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α‐substituted enones and cyanoazaarenes or 2‐(chloromethyl)azaaren‐1‐iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone‐substituted tertiary carbon stereocenter at the β‐ or γ‐position of the azaarenes, are synthesized with high yields and ees. [ABSTRACT FROM AUTHOR]

Pyridines are valuable pharmacophores, and their access via direct and selective transmutation of carbon atom with desired nitrogen could become crucial in drug discovery processes. However, only scarce examples can be found when it comes C‐to‐N‐transmutation reactions of aromatics that could lead to the facile synthesis of pyridines or other azaarenes. In this context, Levin and co‐workers recently disclosed a process leading to pyridines from the corresponding aryl azides via the regioselective nitrene internalization process. Notably, the transformation did not lead to any further modification of the rest of the aromatic skeleton. This innovative work enabled selectively accessing various pyridine derivatives through direct nitrogen scan operations on benzene derivatives, which were otherwise not feasible. [ABSTRACT FROM AUTHOR]

This article provides an overview of recent advancements in the dearomative skeletal editing of mono-azaarenes, which are nitrogen-containing heterocycles commonly found in natural products and pharmaceuticals. The authors discuss various methods, such as Zincke-like reactions, aza-Buchner reactions, and photoinduced reactions, for breaking the aromaticity of azaarenes and reconstructing them into complex molecules. The article highlights the latest research and breakthroughs in these methods, including their limitations and mechanisms. It aims to inspire readers to explore more approaches to advance the development of skeletal editing of mono-azaarenes as a synthetic tool for accessing difficult-to-reach molecules. [Extracted from the article]

Abstract An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine‐derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α‐substituted enones and cyanoazaarenes or 2‐(chloromethyl)azaaren‐1‐iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone‐substituted tertiary carbon stereocenter at the β‐ or γ‐position of the azaarenes, are synthesized with high yields and ees.

A chiral Brønsted acid‐catalysed asymmetric hydrophosphinylation of 2‐vinylazaarenes by secondary phosphine oxides is described. A variety of P‐chiral 2‐azaaryl‐ethylphosphine oxides are synthesized with high yields and ees, of which both the substituents of phosphines and azaarenes can be flexibly modulated, underscoring an exceptionally broad scope of substrates. These adducts are valuable to asymmetric metal catalysis since the resultant P‐chiral tertiary phosphines from the reduction of them are verified as a kind of effective C1‐symmetric chiral 1,5‐hybrid P,N‐ligands. Importantly, this catalysis platform enables the generic and efficient kinetic resolution of P‐chiral secondary phosphine oxides. It thus provides an expedient approach to access the enantiomers of the P‐chiral tertiary phosphine oxides derived from asymmetric hydrophosphinylation, further improving the utility of the method. [ABSTRACT FROM AUTHOR]

A practical method was developed for the convenient synthesis of isoxazole-fused tricyclic quinazoline alkaloids. This procedure accesses diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives via intramolecular cycloaddition of methyl azaarenes with tert-butyl nitrite (TBN). In this method, TBN acts as the radical initiator and the source of N–O. Moreover, this protocol forms new C–N, C–C, and C–O bonds via sequence nitration and annulation in a one-pot process with broad substrate scope and functionalization of natural products. [ABSTRACT FROM AUTHOR]

Cyclopentannulation was explored as a strategy to access large, stable azaarenes. Buchwald–Hartwig coupling of previously reported di‐ and tetrabrominated cyclopentannulated N,N′‐dihydrotetraazapentacenes furnished stable azaarenes with up to 13 six‐membered rings in a row and a length of 3.1 nm. Their optoelectronic and semi‐conducting properties as well as their aromaticity were investigated. [ABSTRACT FROM AUTHOR]

A chiral Brønsted acid catalysed phosphine‐mediated deoxygenation protocol is reported. This metal‐free method provides a precise kinetic resolution platform for azaarylethynyl tertiary alcohols, which are a broad category of biologically and synthetically important azaarene derivatives. In addition to providing an efficient method for the first asymmetric preparation of these tertiary alcohols, the strategy facilitates the construction of azaaryl‐functionalized allenes with good to excellent enantioselectivities. The high selectivity factors (s up to 235), broad substrate scope, and ability to convert azaaryl compounds into both chiral tertiary alcohols and allenes robustly underscore the efficiency and promising utility of this method. The practicability is further validated by the successful synthesis of deuterated allenes with high ee values and substantial incorporation of deuterium using inexpensive D2O as the deuterium source. [ABSTRACT FROM AUTHOR]

A visible light‐induced Co‐catalyzed highly regio‐ and stereoselective reductive coupling of vinyl azaarenes and alkynes has been developed. Notably, Hünig's base together with simple ethanol has been successfully applied as the hydrogen sources instead of commonly used Hantzsch esters in this catalytic photoredox reaction. This approach has considerable advantages for the straightforward synthesis of stereodefined multiple substituted alkenes bearing an azaarene motif, such as excellent regioselectivity (>20 : 1 for >30 examples) and stereoselectivity (>20 : 1 E/Z), broad substrate scope and good functional group compatibility under mild reaction conditions, which has been utilized in the concise synthesis of natural product monomorine I. A reasonable catalytic reaction pathway involving protolysis of the cobaltacyclopentene intermediate has been proposed based on the mechanistic studies. [ABSTRACT FROM AUTHOR]

A Chichibabin‐type coupling of halo‐azaarenes with Grignard reagents under transition‐metal‐free conditions is developed. The alkylation and arylation of azaarenes can be achieved by the reaction of Grignard reagents with azaarenium salts mediated by BTC/DMAP/DCM system. It has practical value for preparing functionalized azaarenes. [ABSTRACT FROM AUTHOR]

Heat treatment of meat can lead to the formation of carcinogenic organic compounds. The influence of dried fruits on the formation of non-polar heterocyclic aromatic amines (carbolines) and nitrogen derivatives of polycyclic aromatic hydrocarbons (azaarenes) in roasted pork loin was elucidated. Two hundred grams of fruit per 1 kg of meat were used as stuffing. Carbolines, derivatives of pyridoimidazole and pyridoindole, and azaarenes (benzoacridines and dibenzoacridines) were determined by means of high-performance liquid chromatography with fluorescence detection. The total concentration of six δ-, γ- and α-carbolines in roasted pork loin was 1.3 ng/g. This content decreased by 64%, 58%, and 54% in pork loin stuffed with prunes, apricots, and cranberries, respectively. Concentrations of β-carbolines (harmane and norharmane) increased under the influence of added fruits. The norharmane content increased the most, from 2.2 ng/g in the control sample to 12.3 ng/g in meat prepared with cranberries. The harmane content increased from 1.0 ng/g to 3.6 ng/g in meat with prunes. The total concentration of azaarenes (two benzoacridines and dibenzo[a,c]acridine), which was close to 0.1 ng/g, decreased in dishes with prunes and apricots by 54% and 12%, respectively. Azaarenes were not found in samples of meat stuffed with cranberries. [ABSTRACT FROM AUTHOR]

We have developed Brønsted base-mediated regioselective allenylation and propargylation of various para-quinone methides using unfunctionalized 2-alkynyl azaarenes as pronucleophiles. The appropriate choice of a base provides an opportunity to achieve either an allenylated product or the propargylated product. The use of KOtBu as a Brønsted base promotes the formation of allenylated products, whereas NaN(SiMe3)2 furnishes the propargylated products. Besides, the current strategy is scalable and can be performed on a gram scale. [ABSTRACT FROM AUTHOR]

The present work documents electrophilic substitution of azaarenes, mainly isoquinolines, with hypervalent iodine diazo reagents (HIDR) followed by formal [3+2]-dipolar cycloaddition in a tandem fashion. Other azaarenes viz. pyridines and phenanthridines too could be successfully used in the reaction. The methodology capitalizes on the umpolung nature of α-aryliodonio diazo compounds for installing a nucleophile, i.e. azaarene, at their α-position. Subsequent ylide formation and intramolecular 1,5-cyclization furnished 4,3-fused 1,2,4-triazolyl-azaarenes in good yields. The reaction is notable for its mild conditions, operational simplicity and fairly general scope. [ABSTRACT FROM AUTHOR]

Herein, an Ir‐catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives are obtained in good yields with high enantioselectivity (up to 96 % yield and 99 % ee). The utilization of the Knochel reagent TMPZnBr⋅LiBr warrants the in situ formation of benzylic nucleophiles without additional activating reagents. 1H NMR studies suggested a two‐fold function of the Knochel reagent in this reaction. The synthetic utility of this method has been showcased by a concise enantioselective synthesis of an allosteric protein kinase modulator. [ABSTRACT FROM AUTHOR]

Derivatization of azaarenes can create molecules of biological importance, but reductive functionalization of weakly reactive azaarenes remains a challenge. Here the authors show a dearomative, diastereoselective annulation of azaarenes, via ruthenium(II) reductive catalysis, proceeding with excellent selectivity, mild conditions, and broad substrate and functional group compatibility. Mechanistic studies reveal that the products are formed via hydride transfer-initiated β-aminomethylation and α-arylation of the pyridyl core in the azaarenes, and that paraformaldehyde serves as both the C1-building block and reductant precursor, and the use of Mg(OMe)2 base plays a critical role in determining the reaction chemo-selectivity by lowering the hydrogen transfer rate. The present work opens a door to further develop valuable reductive functionalization of unsaturated systems by taking profit of formaldehyde-endowed two functions. Derivatization of azaarenes can create molecules of biological importance, but reductive functionalization of weakly reactive azaarenes remains a challenge. Here the authors show a dearomative, diastereoselective annulation of azaarenes, via ruthenium(II) reductive catalysis. [ABSTRACT FROM AUTHOR]

Chiral hydrogen‐bonding (H‐bonding) catalytic asymmetric conjugate addition to activated olefins has been widely used to access enantioenriched molecules containing stereocenters at the β‐position of the olefin activating groups. Herein, we report the first highly enantioselective radical‐based manifold. Under a dual organocatalyst system involving a chiral phosphoric acid and DPZ as the photoredox sensitizer, transformations of N‐arylglycines, in which aryls with CF3 substituents are introduced, with alkenyl azaarenes afforded valuable hydroaminoalkylation adducts with satisfactory results. In addition to the diversity of azaarenes, the method can be used to construct aryl‐, alkyl‐ and silyl‐substituted stereocenter. Control experiments and density functional theory calculations were performed to elucidate a plausible reaction mechanism and the origin of stereoselectivity, wherein nonclassical H‐bonding interactions were found to assist chiral catalysts in offering sufficient enantiocontrol. [ABSTRACT FROM AUTHOR]

A convenient practical approach for the synthesis of 2-(pyridin-2-yl)ethanols by direct benzylic addition of azaarenes and aldehydes under catalyst- and solvent-free conditions is reported. This reaction is metal-free, green, and was carried out in a facile operative environment without using any hazardous transition metal catalysts or any other coupling reagents. Different aromatic aldehydes and azaarenes were monitored, and the yields of the resulting products were moderate to excellent. We accomplished several azaarene derivatives under neat conditions through a highly atom-economical pathway. To evaluate the preparative potential of this process, gram-scale reactions were performed up to a 10 g scale.

The transition‐metal‐catalyzed cyclization of bissilylethynylated N,N'‐dihydrotetraazapentacene (TIPS‐TAP‐H2) into bissilylated cyclopenta[fg,qr]pentacenes is reported. Depending on the catalyst either none, one or two silyl groups migrate and change their positions in the formed five‐membered rings. The optoelectronic properties are quite similar, whereas the packing motifs differ dramatically. Control experiments and quantum chemical calculations were performed to investigate the mechanism of the reaction and the selectivity of the silyl shift. [ABSTRACT FROM AUTHOR]

The iodine‐promoted oxidative domino annulation and carbonylation process has been developed for the synthesis of biologically important azaarene‐substituted bis‐pyrazolo[3,4‐b:4′,3′‐e]pyridines (BPPs), diuracilpyridines and o‐amino diheteroaryl ketones. The domino procedure proceeded with easily available methyl azaarenes, 5‐aminouracils and substituted 5‐aminopyrazoles. This protocol is a simple and metal‐free approach which exhibits high functional group compatibility and broad substrates scope. Moreover, this transformation can be applied for the preparation of dipyrazolo/diuracil‐fused pyridines on a gram scale. [ABSTRACT FROM AUTHOR]

The first enantioselective Beckwith-Enholm cyclization reaction is reported herein. Under cooperative photoredox and chiral hydrogen-bonding catalysis mediated by visible light, cyclization of carbonyls with azaarene-based olefins as a new reaction system offers a general and divergent synthetic pathway to furnish a variety of highly valuable enantioenriched azaarene-functionalized carbocyclic and heterocyclic alcohols, which bear adjacent 1,2- or nonadjacent 1,3-stereocentres on distinct cyclic frameworks, in high yields and enantio- and diastereoselectivities. The good compatibility of various azaarenes and carbonyls as well as the diversity of cyclic structures of the products underscores the generality of the catalysis platform. In addition to the ability to precisely introduce deuterium into molecules in an enantioselective manner, the considerable synthetic value of this method includes the excellent antioxidant stress potential of the products. In particular, molecule 29 was determined to be a promising lead compound for antioxidant stress drug design. [ABSTRACT FROM AUTHOR]

Heat treatment of meat can lead to the formation of carcinogenic organic compounds. The influence of dried fruits on the formation of non-polar heterocyclic aromatic amines (carbolines) and nitrogen derivatives of polycyclic aromatic hydrocarbons (azaarenes) in roasted pork loin was elucidated. Two hundred grams of fruit per 1 kg of meat were used as stuffing. Carbolines, derivatives of pyridoimidazole and pyridoindole, and azaarenes (benzoacridines and dibenzoacridines) were determined by means of high-performance liquid chromatography with fluorescence detection. The total concentration of six δ-, γ- and α-carbolines in roasted pork loin was 1.3 ng/g. This content decreased by 64%, 58%, and 54% in pork loin stuffed with prunes, apricots, and cranberries, respectively. Concentrations of β-carbolines (harmane and norharmane) increased under the influence of added fruits. The norharmane content increased the most, from 2.2 ng/g in the control sample to 12.3 ng/g in meat prepared with cranberries. The harmane content increased from 1.0 ng/g to 3.6 ng/g in meat with prunes. The total concentration of azaarenes (two benzoacridines and dibenzo[a,c]acridine), which was close to 0.1 ng/g, decreased in dishes with prunes and apricots by 54% and 12%, respectively. Azaarenes were not found in samples of meat stuffed with cranberries.

The first Ni(II)‐catalyzed asymmetric [4+2] cycloaddition of silyloxyvinylindoles with 2‐enoyl pyridines was successfully accomplished by using a diphenylmethylidene‐tethered bis(oxazoline). A series of optically active hydrocarbazole derivatives with three contiguous stereocenters were achieved in good yield with both high diastereo‐(>20 : 1) and enantioeselectivities (up to 97 % ee) under mild conditions. Moreover, various 2‐enoyl azaarenes were compatible with the reaction. A proposed mechanism was deducted. [ABSTRACT FROM AUTHOR]

A metal‐free, base‐mediated, and atom‐efficient oxidative dehydrogenative coupling of substituted phenylmethanols (benzyl alcohols) with methyl azaarenes or phenylacetonitriles to afford substituted alkenylazaarenes or 2‐aminoquinolines, respectively is described. CsOH.H2O was discovered to be the base of choice for obtaining optimal yields of the title compounds, although the reaction could proceed with KOH as well. The protocol that works efficiently in the presence of air is amenable over broad range of substrates. [ABSTRACT FROM AUTHOR]

This paper demonstrated a new and economical methodology using Fe(ClO4)2·H2O as a catalyst for the direct C(sp3)–H functionalization of 2-methyl azaarenes via addition to trifluoromethyl ketones. The use of Fe salts as a Lewis acid catalyst has shown great potential as an accessible, affordable, and effective catalyst for the reaction. Under mild, optimized conditions, an extensive range of 2-alkenylated azaarenes was produced with yields of up to 95%. [ABSTRACT FROM AUTHOR]

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer–mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities. [ABSTRACT FROM AUTHOR]