Intramolecular Oxidative Arylations in 7‐Azaindoles and Pyrroles: Revamping the Synthesis of Fused <i>N</i>‐Heterocycle Tethered Fluorenes

Laha, Joydev K.; Bhimpuria, Rohan A.; Hunjan, Mandeep Kaur

doi:10.1002/chem.201604192

Cited by 25 publications

(10 citation statements)

References 39 publications

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“…These substrates are enolizable, and the reactivities of their corresponding iminiumion intermediates are likely impeded through equilibria with their dienamines. Various substituted 5H-benzo[a]pyrrolizine-3-carbaldehydes 1, available through two-step procedures from commercially available starting materials, 42 were likewise found to behave consistently in the developed reaction. Products carrying electron-withdrawing substituents in the 8-position (3i′, 3j/3j′) were formed with higher stereoselectivity, but lower yields than 8-methoxysubstituted product 3l; 8bromosubstituted 3k′ was formed with both high selectivity and yield.…”

Section: ■ Results and Discussionmentioning

confidence: 89%

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

et al. 2021

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The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12πcomponents derived from 5H-benzo[a]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole) with excellent enantio-and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2πcomponents relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo[a]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

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Section: ■ Results and Discussionmentioning

confidence: 89%

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

et al. 2021

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“…In the first step, the nitrogen at position 1 of intermediate 3a (Joydev et al, ) was protected with benzensulfonyl chloride to obtain compound 8 (Liu et al, ), which subsequently was treated with tetrakis(triphenylphosphine)palladium(0), 2 M sodium carbonate solution, and the appropriate boronic acid in hot anhydrous toluene to obtain the corresponding 5‐pyrrolo[2,3‐b]pyridine derivatives 9a‐g . The protecting group at position N‐1 was then removed with tetrabutylammonium fluoride (TBAF) in hot anhydrous tetrahydrofuran, resulting in pyrrolo[2,3‐b]pyridines 10a‐g ( 10a , Laha et al, ; 10c and 10d , Ibrahim et al, ; 10f and 10g , Singh et al, ). Reaction of these compounds with hexamethylenetetramine (HMTA) in acetic acid at reflux resulted in the 3‐formyl derivatives 11a‐g ( 11g , Ibrahim et al, ), which, when treated with hydroxylamine hydrochloride ( 12a‐g ), dehydrated with POCl 3 ( 13a‐g ), and benzoylated at position 1 with m‐toluoyl chloride, led to final compounds 14a‐g .…”

Section: Methodsmentioning

confidence: 99%

“…General procedure for compounds 11a‐f. A mixture of the appropriate 1H‐pyrrolo[2,3‐b]pyridine derivative 10a‐f (0.95 mmol) ( 10a , Laha et al, ; 10c and 10d , Ibrahim et al, ; 10f , Singh et al, ) and HMTA (1.43 mmol) in glacial acetic acid (3 mL) was heated under reflux for 6 hr. The reaction mixture was cooled at room temperature and diluted with cold water.…”

Section: Methodsmentioning

confidence: 99%

Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

Giovannoni

Cantini

Crocetti

et al. 2019

Drug Development Research

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Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme.HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC 50 = 15-51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad. K E Y W O R D S human neutrophil elastase inhibitors, molecular docking, pyrrolo[2,3-b]pyridine

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“…Optically pure novel fused isoindolines were also demonstrated using the reaction of 7‐azaindoles or pyrroles and sterically hindered optically pure sec‐ benzylalcohols under Mitsunobu condition followed by intramolecular oxidative arylation of N‐benzyl‐7‐azaindoles or pyrrole. Using this protocol, they designed and synthesized single fluorene based organic emitters of fused N ‐heterocycle tethered fluorenes [48] …”

Section: C−h Functionalization Of Pyrrolesmentioning

confidence: 99%

Recent Advances in Functionalization of Pyrroles and their Translational Potential

Hunjan

Panday

Gupta

et al. 2021

The Chemical Record

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Among the known aromatic nitrogen heterocycles, pyrrole represents a privileged aromatic heterocycle ranging its occurrence in the key component of “pigments of life” to biologically active natural products to active pharmaceuticals. Pyrrole being an electron‐rich heteroaromatic compound, its predominant functionalization is legendary to aromatic electrophilic substitution reactions. Although a few excellent reviews on the functionalization of pyrroles including the reports by Baltazzi in 1963, Casiraghi and Rassu in 1995, and Banwell in 2006 are available, they are fragmentary and over fifteen years old, and do not cover the modern aspects of catalysis. A review covering a comprehensive package of direct functionalization on pyrroles via catalytic and non‐catalytic methods including their translational potential is described. Subsequent to statutory yet concise introduction, the classical functionalization on pyrroles using Lewis acids largely following an ionic mechanism is discussed. The subsequent discussion follows the various metal‐catalyzed C−H functionalization on pyrroles, which are otherwise difficult to implement by Lewis acids. A major emphasize is given on the radical based pyrrole functionalization under metal‐free oxidative conditions, which is otherwise poorly highlighted in the literature. Towards the end, the current development of pyrrole functionalization under photocatalyzed and electrochemical conditions is appended. Only a selected examples of substrates and important mechanisms are discussed for different methods highlighting their scopes and limitations. The aromatic nucleophillic substitution on pyrroles (being an electron‐rich heterocycle) happened to be the subject of recent investigations, which has also been covered accentuating their underlying conceptual development. Despite great achievements over the past several years in these areas, many challenges and problems are yet to be solved, which are all discussed in summary and outlook.

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Intramolecular Oxidative Arylations in 7‐Azaindoles and Pyrroles: Revamping the Synthesis of Fused N‐Heterocycle Tethered Fluorenes

Cited by 25 publications

References 39 publications

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

Recent Advances in Functionalization of Pyrroles and their Translational Potential

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