Modulation of the Electronic Properties of Non-innocent (E,E)-Dibenzylideneacetone for Palladium(0)-Mediated Heck Alkenylation of 5-Iodo-2′-deoxyuridine and Scale-Up Studies

Kapdi, Anant R.; Ardhapure, Ajay; Sanghvi, Yogesh S.

doi:10.1055/s-0034-1379962

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…Whereas, Heck alkenylation reaction allowing the introduction of alkenyl functionality on the base part of the nucleosides is yet another useful transformation [87]. Being one of the key steps in the synthesis of the potent anti-Herpes simplex virus drug, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU or brivudine) [88,89] as well as the 'Ruth linker' [90]-(a C5 pyrimidine nucleoside analogue used commonly for the introduction of a reactive amine functionality into oligonucleotide sequences), the Heck reaction does present scientists with an opportunity to incorporate various functionalities with ease and provide straightforward access to many functional molecules [91,92].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…We next turned our attention to test the scalability of the developed catalytic protocol as well as develop an efficient solvent recovery procedure (for the column-free isolation of the product) , to promote a sustainable solution for further applicability (Scheme ). 2-Chlorobenzoxazole coupled with morpholine using the Cu(II)/PTABS catalytic system at the 25 mmol scale in the water at ambient temperature proceeded efficiently in nearly quantitative yield (99%).…”

Section: Resultsmentioning

confidence: 99%

Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System

Parmar¹,

Somvanshi

Kori

et al. 2021

J. Org. Chem.

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Buchwald–Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV–VIS and ESR spectroscopy, providing evidence for the Cu(II) oxidation state.

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“…After screening the process parameters of the Heck reaction with 5-IdU such as temperature, base, catalyst, additive, etc., we developed the optimal reaction conditions as summarized in Scheme 1. The phosphine-free catalytic system was further optimized to enable the column-free isolation of the coupled product as an easily isolable solid [35]. The Heck alkenylation protocol was also extended toward the synthesis of other cross-coupled products, as shown in Scheme 1.…”

Section: Heck Alkenylation Using Cat1mentioning

confidence: 99%

“…In this context, several water-soluble ligands have been reported for cross-coupling reactions ( Figure 4) [33]. The phosphine-free catalytic system was further optimized to enable the column-free isolation of the coupled product as an easily isolable solid [35]. The Heck alkenylation protocol was also extended toward the synthesis of other cross-coupled products, as shown in Scheme 1.…”

Section: Heck Alkenylation Using Cat1mentioning

confidence: 99%

“…In this regard, we have successfully developed several Pd-based catalytic systems for the cross-coupling reactions of halonucleosides and chloroheteroarenes ( Figure 2). Initial studies were directed toward the development of an efficient protocol for the Heck coupling of 5-iodo nucleoside using the Pd-dba catalyst [35]. Next, in order to have an efficient water-soluble catalytic system, we developed Pd-imidate based complexes in collaboration with the Serrano group, which were successfully utilized for Heck and Suzuki-Miyaura cross-coupling reactions [36][37][38].…”

Section: Introductionmentioning

confidence: 99%

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Discovery, Synthesis, and Scale-up of Efficient Palladium Catalysts Useful for the Modification of Nucleosides and Heteroarenes

Bhilare

Shet

Sanghvi³

et al. 2020

Molecules

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Nucleic acid derivatives are imperative biomolecules and are involved in life governing processes. The chemical modification of nucleic acid is a fascinating area for researchers due to the potential activity exhibited as antiviral and antitumor agents. In addition, these molecules are also of interest toward conducting useful biochemical, pharmaceutical, and mutagenic study. For accessing such synthetically useful structures and features, transition-metal catalyzed processes have been proven over the years to be an excellent tool for carrying out the various transformations with ease and under mild reaction conditions. Amidst various transition-metal catalyzed processes available for nucleoside modification, Pd-catalyzed cross-coupling reactions have proven to be perhaps the most efficient, successful, and broadly applicable reactions in both academia and industry. Pd-catalyzed C–C and C–heteroatom bond forming reactions have been widely used for the modification of the heterocyclic moiety in the nucleosides, although a single catalyst system that could address all the different requirements for nucleoside modifications isvery rare or non-existent. With this in mind, we present herein a review showcasing the recent developments and improvements from our research groups toward the development of Pd-catalyzed strategies including drug synthesis using a single efficient catalyst system for the modification of nucleosides and other heterocycles. The review also highlights the improvement in conditions or the yield of various bio-active nucleosides or commercial drugs possessing the nucleoside structural core. Scale ups wherever performed (up to 100 g) of molecules of commercial importance have also been disclosed.

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Modulation of the Electronic Properties of Non-innocent (E,E)-Dibenzylideneacetone for Palladium(0)-Mediated Heck Alkenylation of 5-Iodo-2′-deoxyuridine and Scale-Up Studies

Cited by 9 publications

References 12 publications

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

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

Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System

Discovery, Synthesis, and Scale-up of Efficient Palladium Catalysts Useful for the Modification of Nucleosides and Heteroarenes

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