Cu(II)/PTABS-Promoted, Chemoselective Amination of HaloPyrimidines.

Chemoselective amination is a highly desired synthetic methodology, given its importance as a possible strategy to synthesize various drug molecules and agrochemicals. We, herein, disclose a highly chemoselective Cu(II)-PTABS-promoted amination of pyrimidine structural feature containing different halogen atoms.

Ambient Temperature Metal-Free Thiomethylation of Chloroheteroarenes and Chloropurines.

Herein, we report an in-situ mild and metal-free protocol for thiomethylation of heteroarenes in high yields. The thiomethylation of various chloropurines, nucleosides, and chloroheteroarenes has been accomplished offering easy access to agrochemicals and synthetic molecules useful for drug discovery.

Two short approaches to the COVID-19 drug ß-D-N4-hydroxycytidine and its prodrug molnupiravir.

Molnupiravir, the prodrug for ß-D-N4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio™ against mild-moderate COVID-19, under FDA emergency use authorization. It is the first oral drug against the disease. This work describes two synthetic approaches to NHC and molnupiravir by amide activation in uridine with a peptide-coupling agent and with a 4-chloropyrimidinone nucleoside intermediate.

Phenothiazine-Based Cu(II)-Selective Fluorescent Sensor: GHK-Cu Sensing Applications.

Sensing important metals in different environments is an important area and involves the development of a wide variety of metal-sensing materials. The employment of fluorescent sensors in metal sensing has been one of the most widely applied methodologies, and the identification of selective metal sensors is important. We herein report a phenothiazine-based Cu(II) fluorescent sensor that is highly selective to Cu(II) ions compared with other transition metal salts. The Lewis acidity of the Cu(II) salt certainly was found to be a factor for obtaining an enhanced sensing response in MeOH as the solvent, while a ratio of 1:1 was calculated to be the most optimum for getting the desired response.

Ambient-Temperature, Metal-Free, CDI-Mediated Ex-Situ Conversion of Acids to Amides: A Useful Late-Stage Strategy.

An efficient ex-situ method for the amidation of carboxylic acids mediated by CDI has been disclosed herewith. This metal-free strategy is performed at ambient temperature and can be applied effectively for late-stage modification of amino acids and APIs.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding.

Regioselective amination of polyhalogenated heteroarenes (especially pyrimidines) has extensive synthetic and commercial relevance for drug synthesis applications but is plagued by the lack of effective synthetic strategies. Herein, we report the Cu(II)/PTABS-promoted highly regioselective nucleophilic aromatic substitution (SNAr) of polychlorinated pyrimidines assisted by DFT predictions of the bond dissociation energies of different C-Cl bonds. The unique reactivity of Cu(II)-PTABS has been attributed to the coordination/activation mechanism that has been known to operate in these reactions, but further insights into the catalytic species have also been provided.

Copper-catalysed chemoselective C-OH bond activation of N-benzoyl cytosine: facile access to 2-(dimethylamino)pyrimidine.

A novel method for the direct amination of N-benzoyl cytosine has been developed, giving access to 2-(dimethylamino)pyrimidine derivatives. A copper(II) catalyst and tert-butyl hydroperoxide easily promote the selective amination process that proceeds via C-OH bond activation. This practical approach can utilize different formamide molecules, N,N-dimethylformamide and N,N-diethylformamide, as efficient amino (-NMe2, -NEt2) sources. Moreover, the facile nature of the procedure, its broad tolerance of aliphatic and aromatic substrates, the high yields and ease of separation of the products, and the fact that it can be conducted under aerobic conditions are all notable advantages of the present protocol.

DMSO-Assisted K3 PO4 -Catalyzed Cooperative Metal-Free, Base-Free Etherification of Chloroheteroarenes at Low Temperature.

Etherification of chloroheteroarenes was performed at low temperatures under metal-free, ligand-free and base-free conditions, that is, the reaction is promoted by the cooperative effect of DMSO (solvent) as a promoter and K3 PO4 providing the catalytic surface (rather than a base). The protocol exhibits good substrate scope under mild reaction conditions and has also been explored mechanistically.

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2'-deoxyuridine (or cytidine).

Nucleosides modification via conventional cross-coupling has been performed using different catalytic systems and found to take place via long reaction times. However, since the pandemic, nucleoside-based antivirals and vaccines have received widespread attention and the requirement for rapid modification and synthesis of these moieties has become a major objective for researchers. To address this challenge, we describe the development of a rapid flow-based cross-coupling synthesis protocol for a variety of C5-pyrimidine substituted nucleosides. The protocol allows for facile access to multiple nucleoside analogues in very good yields in a few minutes compared to conventional batch chemistry. To highlight the utility of our approach, the synthesis of an anti-HSV drug, BVDU was also achieved in an efficient manner using our new protocol. Supplementary Information: The online version contains supplementary material available at 10.1007/s41981-023-00265-1.

Zinc-catalyzed transamidation and esterification of N-benzoyl cytosine via C-N bond cleavage.

We have utilized N-benzoyl cytosine for efficient transamidation and esterification via catalytic C-N bond cleavage. The one-pot strategy involves the reaction of secondary amide with various aliphatic or aromatic amines and alcohols in the presence of zinc triflate and DTBP, affording diverse amides and esters in excellent yields.

DNA-encoded libraries via late-stage functionalization strategies: a review.

The hit finding strategy in drug discovery has undergone a tremendous change in the past decade with the advent of DNA-encoded libraries with diverse chemical libraries. The miniaturization of the assays has enabled high-throughput screening on diverse targets to identify binders as a starting point for medicinal chemistry campaign. The diverse chemical space that can be accessed through DEL provides a unique opportunity to explore new chemistries on DNA. This review highlights the metal-mediated synthetic pathways that allow late-stage functionalisation of DNA strands to access such DEL libraries. Critical analysis of the literature and the methods employed has been done to allow readers to understand the usefulness, as well as the limitations of these protocols.

Nucleoside/Nucleotide or Nucleic Acid Modification & Applications.

"The field of nucleosides, nucleotides, and nucleic acids has been in existence for some decades, leading to a notion that the area is well-explored and/or specialized, but is that true? Despite the constant reliance on this field for various aspects of biochemical, biological, and biomedical research, recent advances have brought this area into a greater focus, with the potential and benefits becoming increasingly evident. Explore this Special Collection for rich, diverse, and state-of-the art research presented in the form of Personal Accounts, Reviews, and Research Articles."

Room-Temperature Dialkylamination of Chloroheteroarenes Using a Cu(II)/PTABS Catalytic System.

The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We report herein a highly efficient, room-temperature dimethylamination of chloroheteroarenes performed via the in-situ generation of dimethylamine using N,N-dimethylformamide (DMF) as precursor wiith a large substrate scope that includes various heteroarenes, purines as well as commercially relevant drugs such as altretamine, ampyzine and puromycin precursor.

Heteroatom-Assisted Regio- and Stereoselective Palladium-Catalyzed Carboxylation of 9-Allyl Adenine.

Strategy for the synthesis of acyclic nucleoside analogs of biological relevance via highly regio- and stereoselective C-H functionalization employing heteroatom-assisted palladium-catalyzed carboxylation of 9-allyl adenine is disclosed. Substrate scope with different carboxylic acids was performed giving decent to good yields of the desired products. The method also allowed for the synthesis of deuterated analogs.

Suzuki-Miyaura Coupling, Heck Alkenylation, and Amidation of DMTr-Protected 5-Iodo-2'-Deoxyuridine via Palladium-catalyzed Reactions.

Modification of nucleosides via cross-coupling processes has been carried out extensively on unprotected halonucleosides to produce functionalized nucleosides that are often developed for incorporation into oligonucleotides or used as fluorescent probes. This approach requires protection of the 5'-OH with the 4,4'-dimethoxytrityl (DMTr) group, which is complicated and a common cause of reaction failure. Here we report a method for direct functionalization of 5'-O-DMTr-5-iodo-2'-deoxyuridine via Suzuki-Miyaura cross-coupling, Heck alkenylation, and carboamidation. This approach facilitates rapid synthesis of a variety of C5-substituted 5'-O-DMTr-2'-deoxyuridine derivatives. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of the SerrKap palladacycle complex Basic Protocol 2: Suzuki-Miyaura coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 3: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 4: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine with Ruth linker using Pd(OAc)2 /PTABS Basic Protocol 5: Carbonylative amidation of 5'-O-DMTr-5-iodo-2'-deoxyuridine using Pd(OAc)2 /PTABS.

Strategies for the Synthesis of Fluorinated Nucleosides, Nucleotides and Oligonucleotides.

Fluorinated nucleosides and oligonucleotides are of specific interest as probes for studying nucleic acids interaction, structures, biological transformations, and its biomedical applications. Among various modifications of oligonucleotides, fluorination of preformed nucleoside and/or nucleotides have recently gained attention owing to the unique properties of fluorine atoms imparting medicinal properties with respect to the small size, electronegativity, lipophilicity, and ability for stereochemical control. This review deals with synthetic protocols for selective fluorination either at sugar or base moiety in a preformed nucleosides, nucleotides and nucleic acids using specific fluorinating reagents.

Quadrol-Pd(II) complexes: phosphine-free precatalysts for the room-temperature Suzuki-Miyaura synthesis of nucleoside analogues in aqueous media.

Commercially available Quadrol, N,N,N',N'-tetrakis(2-hydroxypropyl)ethylenediamine (THPEN), has been used for the first time as a N^N-donor neutral hydrophilic ligand in the synthesis and characterization of new water soluble palladium(II) complexes containing chloride, phthalimidate or saccharinate as co-ligands. [PdCl2(THPEN)] (1) [Pd(phthal)2(THPEN)] (2), [Pd(sacc)2(THPEN)] (3) and the analogous complex with the closely related N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine (THEEN) [Pd(sacc)2(THEEN)] (4) were efficiently prepared in a one-pot reaction from [PdCl2(CH3CN)2] or Pd(OAc)2. Structural characterization of 1 and 3 by single crystal X-ray diffraction produced the first structures reported to date of palladium complexes with Quadrol. The resultant palladium complexes are highly soluble in water and were found to be effective as phosphine-free catalysts for the synthesis of functionalized nucleoside analogues under room-temperature Suzuki-Miyaura cross-coupling conditions between 5-iodo-2'-deoxyuridine (& 5-iodo-2'-deoxycytidine) with different aryl boronic acids in neat water. This is the first report of the coupling process performed on nucleosides in water at room temperature.

Room temperature HFIP/Ag-promoted palladium-catalyzed C-H functionalization of benzothiazole with iodoarenes.

A versatile synthetic protocol involving the room temperature direct arylation of benzothiazole with a wide variety of iodoarenes under Ag-promoted Pd-catalyzed conditions in HFIP as the reaction solvent has been presented. A sequential HFIP-promoted selective iodination of arenes followed by Pd-catalyzed direct arylation of benzothiazole has also been disclosed. The utility of the developed protocol has been demonstrated by the synthesis of anti-tumor agents, PMX-610 and CJM-126 (precursor).

HFIP promoted thio(hetero)arylation of imidazoheterocycles under metal- and base-free conditions.

A new reaction methodology has been developed for HFIP promoted Thio(hetero)arylation of imidazoheterocycles under metal and base-free conditions. To the best of our knowledge, this is the first report that describes linking of imidazopyridines with electron deficient heteroarenes through a sulphur atom and also for the synthesis of most of these compounds. The reaction conditions are well tolerated by almost all kinds of 2-chloroheteroarenes and a wide range of imidazoheterocycles. The synthesized compounds can show significant biological properties.

Carbon dioxide based methodologies for the synthesis of fine chemicals.

Rapid environmental changes triggered by the increase in the concentration of heat-absorbing gases such as CO2 in the atmosphere have become a major cause of concern. One of the ways to counter this growing threat will be to efficiently convert atmospheric CO2 into value-added products via the development of efficient transition-metal-catalyzed processes. Conversion of CO2 into bulk products such as CH3OH and methane as well as its incorporation into commercial polyurethane synthesis has been achieved and reviewed extensively. However, the efficient transformation of CO2 into fine chemicals and value-added chemicals has many fold advantages. Recent years have seen a rapid rise in the number of metal-mediated protocols to achieve this goal of converting CO2 into fine chemicals. These are essential developments given the requirement of several commodities and fine chemicals in various industrial processes and the utilization of atmospheric CO2 will help provide a sustainable solution to the current environmental problems. Accordingly, we present here a comprehensive compilation of catalytic processes, involving CO2 as the C1 source for reacting with substrates such as alkanes, alkenes, alkynes, amines, acid chlorides, alcohols, allyl boronates, alkenyl triflates, and many others to provide easy access to a wide variety of useful molecules. Such a technology would certainly prove to be beneficial in solving the problems associated with the environmental accumulation of CO2.