Cascade alkylation and deuteration with aryl iodides <i>via</i> Pd/norbornene catalysis: an efficient method for the synthesis of congested deuterium-labeled arenes

Guo, Lei; Xu, Chen; Wu, Ding-Chuan; Hu, Guang-Qi; Zhang, Hong-Hai; Hong, Kunlun; Su, Chen; Liu, Xiang

doi:10.1039/c9cc03988k

Cited by 14 publications

(8 citation statements)

References 91 publications

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“…Congested labeled arenes were efficiently synthesized by Zhang, Liu, and co-workers employing a palladium-catalyzed alkylation-deuteration cascade . Oxidative addition of the palladium center on the carbon-iodine bond is followed by carbopalladation of norbornene.…”

Section: Miscellaneous Transformations With Deuterium Incorporationmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017−2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.

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Section: Miscellaneous Transformations With Deuterium Incorporationmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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“…The reactions with a complex styrene derived from antihyperlipidemic drug medicine fenofibrate proceeded uneventfully to afford 4j ′ in 90% yield. Besides olefins, other types of terminating reagents were also applicable under the standard reaction conditions (Table 3B ), including H/DCO 2 Na ( 4k′ and 4l′ ) 62 , 63 , MeB(OH) 2 ( 4m′ ) 61 , PhBpin ( 4n′ ), and terminal alkyne ( 4o′ ) 64 , and the corresponding 2-pyridone products were obtained in 52−80% yields.…”

Section: Resultsmentioning

confidence: 99%

Diversity-oriented functionalization of 2-pyridones and uracils

Shang¹,

Gao³

et al. 2021

Nat Commun

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Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.

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“…Additionally, the more challenging ipso-cyanation, , ipso-borylation, and ipso-hydrogenation terminations were also demonstrated to be applicable to this ortho-methylation approach (Table , Table , and Table ). As to ipso-cyanation termination, Zn(CN) 2 ( 9 ) was identified as the ideal reagent.…”

Section: Resultsmentioning

confidence: 99%

Modular Dual-Tasked C–H Methylation via the Catellani Strategy

et al. 2019

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We report a dual-tasked methylation that is based on cooperative palladium/norbornene catalysis. Readily available (hetero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and methylating reagent, respectively. Six types of "ipso" terminations can modularly couple with this "ortho" C−H methylation to constitute a versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-labeled methylation by switching to the corresponding reagents CD 3 OTs or 13 CH 3 OTs. Moreover, this toolbox can be applied to late-stage modification of biorelevant substrates with complete stereoretention. We believe these salient and practical features of our dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.

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Cascade alkylation and deuteration with aryl iodides via Pd/norbornene catalysis: an efficient method for the synthesis of congested deuterium-labeled arenes

Abstract: An efficient approach for synthesizing congested deuterium-labeled arenes via cascade alkylation and deuteration with aryl iodides has been disclosed.

Cited by 14 publications

References 91 publications

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Diversity-oriented functionalization of 2-pyridones and uracils

Modular Dual-Tasked C–H Methylation via the Catellani Strategy

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