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1.
J Org Chem ; 89(13): 9275-9286, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38898803

RESUMO

In this study, a ligand-free palladium-catalyzed carbonylation of phenols is conducted under ambient conditions, utilizing the "Chloroform-COware" chemistry. The developed methodology enables the conversion of diverse medicinally relevant phenols, encompassing both natural and synthetic derivatives, into their respective aryl ester counterparts. This transformation is achieved through the reaction with a broad spectrum of aryl and heteroaryl iodides. The protocol is characterized by its simplicity, generality, and wide substrate scope, delivering bioactive aryl ester derivatives in good to excellent yields. A direct comparison with the one-pot approach, resulting in poor yields of aryl esters, highlights the superior efficiency of the two-chamber setup (COware). Moreover, we successfully applied this two-chamber technique for gram-scale synthesis and postmodification of the synthesized ester to a pharmaceutically important benzocoumarin core.

2.
J Org Chem ; 89(11): 7455-7471, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38773695

RESUMO

An air-stable, robust, and well-defined copper(II)-7-azaindole-N-oxide-based catalyst [Cu2II(7-AINO)4] (abbreviated as Cu(II)-7-AINO) has been demonstrated as an efficient catalyst for various Ullmann-type coupling reactions. This easily prepared and cost-effective catalyst facilitates the arylation and heteroarylation of diverse N-, S-, and O-nucleophiles, including azoles, aminoazoles, (hetero)arylthiols, and phenols. Notably, they also exhibit substantial compatibility with a wide range of functional groups. Furthermore, the catalyst demonstrates significant selectivity for -NH sites of aminoazoles and -SH sites of aminothiophenols over -NH2 sites in both cases, enhancing its versatility. Exploiting the catalyst's chemo- and regioselective properties, we have successfully demonstrated the applicability of our methodology in synthesizing various drug molecules. Specifically, Epirizole analogue, Nilotinib, and Vortioxetine were successfully synthesized using our protocol.


Assuntos
Cobre , Catálise , Cobre/química , Óxidos/química , Estrutura Molecular , Compostos de Sulfidrila/química , Fenóis/química , Modelos Moleculares
3.
RSC Med Chem ; 15(5): 1452-1470, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38784451

RESUMO

The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.

4.
Chem Asian J ; 19(6): e202300987, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38258444

RESUMO

An efficient and practical method for the N-alkynylation of 7-azaindoles has been established by using CuI/DMAP catalytic system at room temperature and in open air. This simple protocol has been successfully employed in the synthesis of a wide range of N-alkynylated 7-azaindoles with good yields. Also, this approach is well-suited for large-scale N-alkynylation reactions. The designed N-alkynylated 7-azaindoles were further subjected to Cu-/Ir-catalyzed alkyne-azide cycloaddition (CuAAC/IrAAC) or "click" reaction for the rapid synthesis of 1,4-/1,5 disubstituted 1,2,3-triazole decorated 7-azaindoles. A mechanistic study based on density functional theory (DFT) calculations and ultraviolet-visible (UV) spectroscopic studies revealed that the CuI and DMAP combination formed a [CuII(DMAP)2I2] species, which acts as an active catalyst. The DFT method was used to assess the energetic viability of an organometallic in the C-N bond formation pathway originating from the [CuII(DMAP)2I2] complex. We expect that the newly designed Cu/DMAP/alkyne system will offer valuable insights into the field of Cu-catalyzed transformations.

5.
J Org Chem ; 88(24): 17047-17061, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38099318

RESUMO

In this study, an efficient method for hydrogenation reactions has been reported in a short reaction time using a two-chamber reactor. This process involves the ex situ generation of H2 gas using aluminum-water in the presence of NaOH. This technique was applied to reduce various functional groups, including carbonyl, nitro, alkene, alkyne, and azide. The method is also utilized for the chemoselective reduction of the double bonds in α, ß-unsaturated carbonyl compounds. The potential of the technique has been demonstrated through the quick delivery of several key starting materials and marketed drugs. Additionally, the method was further extended to isotope labeling using D2O. The entire process is safe and operated in standard fume hood settings, ensuring practicality and convenience for researchers in the field of organic synthesis.

6.
J Org Chem ; 88(21): 15218-15236, 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37874889

RESUMO

A phosphine-free, efficient protocol for aminocarbonylation and carbonylative Suzuki-Miyaura coupling has been developed using a novel palladium complex, [PdII(DMAP)2(OAc)2]. The complex was successfully synthesized using a stoichiometric reaction between PdII(OAc)2 and DMAP in acetone at room temperature and characterized using single-crystal X-ray analysis. Only 5 mol % catalyst loading was sufficient for effective carbonylative transformations. "Chloroform-COware" chemistry was utilized for safe and facile insertion of the carbonyl unit using chloroform as an inexpensive CO source in a two-chamber setup. Various value-added pharmaceutically relevant compounds such as CX-516, CX-546, and farampator were synthesized using the technique. Furthermore, the commercially designed COware was engineered to COware-RB setup for sequential one-pot synthesis of indenoisoquinolines (topoisomerase I inhibitors).

7.
J Org Chem ; 88(9): 6058-6070, 2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37022931

RESUMO

An efficient and practical N-arylation of hydantoins with substituted aryl/heteroaryl boronic acids has been established, assisted by CuF2/MeOH under the base and ligand-free conditions at room temperature and open air. The protocol is general, and various N-arylated hydantoins have been prepared in excellent yields with exclusive regioselectivity. The CuF2/MeOH combination was explored further to furnish selective N3-arylation of 5-fluorouracil nucleosides. The efficiency of the protocol was also demonstrated with the gram-scale synthesis of the marketed drug, Nilutamide. A mechanistic study based on density functional theory calculations revealed that both hydantoin and MeOH are crucial for the generation of catalytically active copper species in the reaction process, in addition to their role as a reactant and solvent, respectively. The proposed reaction mechanism indicated that selective N3-arylation of hydantoin is favorable in MeOH, which helps initiate the catalytic cycle by forming a square-planner Cu(II) complex where strong hydrogen-bond interactions are observed. This study is expected to improve the understanding of Cu(II)-catalyzed oxidative N-arylation reactions and for the de novo design and development of Cu-catalyzed coupling reactions.

8.
ACS Omega ; 8(9): 8415-8426, 2023 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-36910947

RESUMO

There is a continuing demand of new inhibitors of HIV-1 Integrase (HIV-1 IN) due to mutations of HIV-1. This study aims to develop the synthesis of 3,6-diaryl 7-azaindoles and introspect the role of aryl groups on the strand transfer (ST) inhibition of HIV-1 IN. An efficient and chemo-selective one-pot method is established for the synthesis of the unexplored diverse C3 → C6 diaryl 7-azaindoles starting from 6-chloro-3-iodo-N-protected 7-azaindoles. Here we report Pd2dba3/SPhos catalyzed synthesis of eight selective C3 monoaryl 7-azaindoles (10a-h) and eight C3,C6-diaryl 7-azaindoles (11a-f, 12a,b) with yields in the ranges of 67-93% and 43-88% respectively. The synthesized derivatives inhibit the strand transfer (ST) activity of HIV-1 IN enzyme at 10 µM dose with 11d and 11f exhibiting %ST inhibitions of 72% and 71%, respectively. SAR studies indicate the para-substitution on the C3 aryl ring and C6 aryl is essential for enhanced %ST inhibition. 11b,c, 11e-f, and 12b showed lower cytotoxicity (IC50 > 200 µM) against TZM-bl cells. Molecular docking of the diaryl 7-azaindoles and Raltegravir (RAL), to the PFV-integrase revealed favorable binding interactions.

9.
Chemistry ; 29(16): e202203718, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36511941

RESUMO

Multiple spectroscopic techniques, along with single-crystal X-ray analysis, have been used to reveal the detailed structural and electronic information on reaction intermediates of a new copper(II)-DBU catalytic system for the N-arylation of 7-Azaindole. The reaction mixture of Chan-Lam cross-coupling yields two dimeric copper(II)-7-azaindole complexes, including one attached with DBU, prior to adding arylboronic acid and are confirmed structurally and spectroscopically. A suitable mechanism has been proposed using the dimeric copper(II) complex as a catalyst for the coupling reactions. The role of DBU as a base and also as an auxiliary ligand in the course of the reaction has been established. The transmetalated monomeric aryl-copper(II) species generated from the dimeric unit is oxidized by another equivalent of copper(II) to yield an aryl-copper(III) intermediate for facile N-arylation, which has been authenticated with UV-vis spectroscopy. The regeneration of the copper(II)-catalyst by aerial oxidation of colorless copper(I) species (generated via reductive elimination and disproportionation step) is confirmed by mass and absorption spectroscopy. Detailed DFT and TD-DFT calculations help to rationalize the proposed reaction intermediates and their corresponding electronic transitions. Moreover, the confirmation of copper(I)-7-azaindole intermediate via HRMS reaffirmed the involvement of Cu(II)/Cu(III)/Cu(I) species in the Chan-Lam type of coupling. A medicinally-important 7-azaindole-based SHP2 inhibitor has been synthesized via sequential arylation.

10.
Org Lett ; 25(8): 1235-1240, 2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36546851

RESUMO

CuF2/DMAP has been established as an excellent catalytic system for vinylsilane-promoted N-vinylation of amides and azoles at room temperature without an external fluoride source. A mechanism has been proposed on the basis of the isolation of reactive intermediate [Cu(DMAP)4Cl2], fluoride ion-assisted transmetalation, and ultraviolet-visible spectroscopic studies. The catalytic efficiency of the synthesized and structurally characterized [Cu(DMAP)4Cl2] complex has been demonstrated. The valuable monomers for water-soluble polymers, viz., NVP, NVC, and NVIBA, were synthesized on a gram scale.

11.
J Org Chem ; 87(21): 13965-13979, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36217780

RESUMO

The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for in or ex situ generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this "Chloroform-COware" technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.


Assuntos
Clorofórmio , Paládio , Paládio/química , Catálise , Monóxido de Carbono/química , Isoquinolinas
12.
J Med Chem ; 65(9): 6454-6495, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35477274

RESUMO

The azaindole (AI) framework continues to play a significant role in the design of new antiviral agents. Modulating the position and isosteric replacement of the nitrogen atom of AI analogs notably influences the intrinsic physicochemical properties of lead compounds. The intra- and intermolecular interactions of AI derivatives with host receptors or viral proteins can also be fine tuned by carefully placing the nitrogen atom in the heterocyclic core. This wide-ranging perspective article focuses on AIs that have considerable utility in drug discovery programs against RNA viruses. The inhibition of influenza A, human immunodeficiency, respiratory syncytial, neurotropic alpha, dengue, ebola, and hepatitis C viruses by AI analogs is extensively reviewed to assess their plausible future potential in antiviral drug discovery. The binding interaction of AIs with the target protein is examined to derive a structural basis for designing new antiviral agents.


Assuntos
Influenza Humana , Vírus de RNA , Antivirais/química , Humanos , Influenza Humana/tratamento farmacológico , Nitrogênio
13.
ACS Omega ; 6(42): 28366-28372, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34723033

RESUMO

Molnupiravir (MK-4482, EIDD-2801) is an experimental drug that has been demonstrated to be effective for the treatment of COVID-19 in human clinical trials. Herein, we report a concise synthesis of the drug via a novel thionated derivative that relies on one-pot methodologies, thus decreasing the number of purification steps required. This route provides the drug in an overall 62% yield and >99% purity and uses cheap and readily available bulk chemicals, thereby providing an affordable synthesis of the drug for cheaper and wider global accessibility.

14.
Org Biomol Chem ; 19(39): 8409-8424, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34554174

RESUMO

Ring substitution reactions of nitroarenes remain an under-developed area of organic synthesis, confined to the narrow domains of SNAr and SNArH reactions. While searching for alternative methodologies, we took stock of the C-H activation reactions of nitroarenes which unearthed a variety of examples of nitro directed regioselective C-H functionalization reactions such as ortho-arylation, -benzylation/alkylation, and -allylation, oxidative Heck and C-H arylation reactions on (hetero)aromatic rings. A collective account of these reactions is presented in this review to showcase the existing landscape of C-H activation reactions of nitroarenes, to create interest in this field for further development and propagate this strategy as a superior alternative for ring substitution reactions of nitroarenes. The prospect of merging the C-H activation of nitroarenes with C-NO2 activation, thereby harnessing NO2 as a transformable multitasking directing group, is also illustrated.

15.
Chem Commun (Camb) ; 57(43): 5235-5249, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908975

RESUMO

Transition-metal based carbon-heteroatom (C-X) bond formation has attracted the attention of synthetic chemists over the past few years because the resultant aryl/heteroaryl motifs are important substructures in many natural products, pharmaceuticals, etc. Several efficient protocols such as Buchwald-Hartwig amination, Ullmann coupling, Chan-Lam coupling and metal-free approaches have proved beneficial in C-X bond formation. Selective arylation of one hetero-centre over other centres without protection/deprotection thus allowing minimum synthetic manipulation has been achieved for several substrates using these protocols. Azoles are one such novel five-membered heterocyclic core with huge pharmaceutical applications. Though N-arylation on azole-bearing analogues has been extensively practised, selective N-arylation either on one N-centre or the exocyclic N-site of the azole ring in competition with other hetero-centres in the framework has been recently explored for azole-carrying systems. Thus, this review would focus on recent advances in chemo- and regio-selective N-arylation (either on one N-centre or the exocyclic N-site of the azole ring) on azole-containing frameworks.

16.
Chem Rec ; 21(4): 715-780, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33650751

RESUMO

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.

17.
J Org Chem ; 86(2): 1330-1356, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33356264

RESUMO

Sequence-specific C-arylation strategies have important applications in medicinal and material research. These strategies allow C-C bond formations in a regioselective manner to synthesize large molecular libraries for studying structure-activity profiles. The past decade has seen the development of single C-C bond forming reactions using various transition-metal catalysts, cryogenic metalation strategies, and metal-free methods. Sequential arylations of heterocycles allow for the formation of multiaryl derivatives and are a preferred choice over de novo synthetic routes. This perspective sheds light on recent strategic advances to develop various sequential synthetic routes for the multiarylation of heteroarenes. This perspective addresses many challenges in optimizing sequential routes with respect to catalysts, reaction parameters, and various strategies adopted to obtain diversely arylated products.

18.
Chem Commun (Camb) ; 56(79): 11749-11762, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-32935671

RESUMO

The 7-azaindole building block has attracted considerable interest in the field of drug discovery in the current portfolio. Because of their powerful medicinal properties, the development of synthetic, elegant techniques for the functionalization of 7-azaindoles continues to be an active area of research. Advances in metal-catalyzed chemistry have recently supported the successful development of a number of novel and effective methods for functionalization of the 7-azaindole template. This review reports state-of-the-art functionalization chemistry of 7-azaindoles with an aspiration to highlight the global ring functionalization of 7-azaindoles that are potential as pharmacophores for various therapeutic targets. Other relevant reviews focused on 7-azaindole synthesis, properties and applications have also been reported. However, none of these reviews have been dedicated to the results achieved in the field of metal-catalyzed cross-coupling/C-H bond functionalized reactions. So we wish to discuss and summarize the advances made since 2011 in this field toward 7-azaindole functionalization.

19.
J Org Chem ; 84(21): 14015-14029, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31522500

RESUMO

Pd-catalyzed synthesis of multi-aryl 7-azaindoles using sequential arylation of 5-bromo-6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b] pyridine is established. Four diverse aryl groups are installed in a chemo-selective fashion providing a general method to synthesize sterically encumbered compounds and extended 7-azaindoles in 48-95% yields. Three-selective sequential arylations at C-3, C-5, and C-6 via Suzuki-Miyaura cross-coupling followed by direct C-2 arylation using a Pd catalyst and AgOTf as an additive are highlights of the present work. Interestingly, the tetra-aryl 7-azaindoles showed aggregate-induced emission (AIE) making it potentially useful as fluorophores in OLEDs, sensors, and bio-imaging tools.

20.
Org Biomol Chem ; 17(21): 5212-5222, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31080990

RESUMO

The carbonyl moiety is one of the indispensable sub-units in organic synthesis with significant applications in medicinal as well as materials chemistry. Hence the insertion of a carbonyl group via simple and highly efficient routes has been one of the most challenging tasks for organic chemists. Though the direct utilisation of CO gas in carbonylation is the fundamental procedure for the construction of carbonyl compounds, it has certain drawbacks due to its toxic and explosive nature. As a result, the need for cheap and efficient CO surrogates has gained much attention nowadays by which CO gas can be easily generated in situ or ex situ. In this review we discuss the advantages of chloroform as CO surrogate and have surveyed recent carbonylation reactions where chloroform has been used as CO source.

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