Copper‐Catalyzed Deaminative Difluoromethylation

Zeng, Xiaojun; Yan, Wenhao; Zacate, Samson B.; Cai, Aijie; Wang, Yufei; Yang, Dongqi; Yang, Kundi; Liu, Wei

doi:10.1002/ange.202006048

“…30,[126][127][128][129] However, most newly developed difluoromethylation methods are not practical for industrial application, owing to the high cost of reagents and metal catalysts. 2 To reduce the cost, recent research has begun to focus on the use of difluoromethylation reagents closely related to the fluorine industry 145,153,161,168,169 and inexpensive base-metal catalysts such as Ni and Fe. [152][153][154][155][156][157]…”

Section: [H2] Difluoromethylationmentioning

confidence: 99%

“…We have made a modification.] Many recently developed carbon difluoromethylation methods have shown potential for the late-stage modification of pharmaceuticals and complex molecules, both through C-H difluoromethylation133,140,162,165,167,174,177,[213][214][215][216] and the substitution of prefunctionalized groups such as halogen,147,149,153 carboxyl,132,151 hydroxyl162 and amino groups145,150 with CF2H. Direct C-H radical difluoromethylation of heterocycles with difluoromethanesulfinate salts is arguably the most significant Formatted: Font color: Red Formatted: Font color: Red 25 / 62 achievement in this field; together with alkanesulfinate chemistry, this technique has found immediate application in drug discovery owing to its simplicity, the high tolerance towards functional groups and the predictability of site selectivity 217.…”

mentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

Britton

¹

,

Gouverneur

²

,

Lin

³

et al. 2021

Nat Rev Methods Primers

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At this stage, I've edited the manuscript for brevity and clarity. Queries are meant to draw your attention to edits, inconsistencies or issues that are unclear. If we just ask you to confirm edits are correct, a simple yes/ok between the brackets will do [Au:OK? Is this what you meant? Edits OK? yes]. If questions are asked, please rephrase/update the manuscript text when addressing queries, so that the message is conveyed to the reader (please do not just type your answer to our query unless it is unclear).As the reviewers noted, the manuscript is in very good shape and most comments and edits are fairly minor. However, there is an outstanding issue that must be addressed before we go forward. Figures 7 and 8 are currently referred to in the text in an alternating fashion (e.g. Figure 7A, 8A, 7B, 8B). This is against our style and might make that part of the manuscript difficult to follow for the reader owing to the need to refer to multiple figures at a time while reading the text. To clarify this issue, I recommend restructuring these figures. To do this, can you provide new chemdraw/PDFs with amended figures, including the following amendments: a. Merge Figures 7A and 8A to create a new 'Figure 7' that shows the methods of introducing CF2H at sp3-carbons. b. Merge figures 7B and 8B to make a new figure 8 that shows the main protocols of introducing CF2H at heteroaromatic carbons. 7C could be shown in it's own small figure (Figure 9) or could be added as panel B in the new figure 8. c. Amend the figure legends accordingly Apologies for another figure change but this is essential to keep the figure callouts in style and I think it will make the figures much easier for the reader to follow. I've asked the art editor to delay redrawing these particular figures until we receive these updated chemdraws/PDFs. If there are any issues with this change, please do let me know as soon as possible and we can discuss further.

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“…8Ae). 145 [H3] (Hetero)aromatic difluoromethylation (Hetero)aromatic difluoromethylation is a rapidly developing and practical method of synthesizing difluoromethyl (hetero)arenes (FIG. 87B).…”

Section: [H2] Difluoromethylationmentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

2021

Nat Rev Methods Primers

View full text Add to dashboard Cite

At this stage, I've edited the manuscript for brevity and clarity. Queries are meant to draw your attention to edits, inconsistencies or issues that are unclear. If we just ask you to confirm edits are correct, a simple yes/ok between the brackets will do [Au:OK? Is this what you meant? Edits OK? yes]. If questions are asked, please rephrase/update the manuscript text when addressing queries, so that the message is conveyed to the reader (please do not just type your answer to our query unless it is unclear).As the reviewers noted, the manuscript is in very good shape and most comments and edits are fairly minor. However, there is an outstanding issue that must be addressed before we go forward. Figures 7 and 8 are currently referred to in the text in an alternating fashion (e.g. Figure 7A, 8A, 7B, 8B). This is against our style and might make that part of the manuscript difficult to follow for the reader owing to the need to refer to multiple figures at a time while reading the text. To clarify this issue, I recommend restructuring these figures. To do this, can you provide new chemdraw/PDFs with amended figures, including the following amendments: a. Merge Figures 7A and 8A to create a new 'Figure 7' that shows the methods of introducing CF2H at sp3-carbons. b. Merge figures 7B and 8B to make a new figure 8 that shows the main protocols of introducing CF2H at heteroaromatic carbons. 7C could be shown in it's own small figure (Figure 9) or could be added as panel B in the new figure 8. c. Amend the figure legends accordingly Apologies for another figure change but this is essential to keep the figure callouts in style and I think it will make the figures much easier for the reader to follow. I've asked the art editor to delay redrawing these particular figures until we receive these updated chemdraws/PDFs. If there are any issues with this change, please do let me know as soon as possible and we can discuss further.

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“…By contrast, previously reported decarboxylative and deaminative difluoromethylation reactions were incapable of installing CF2H groups at acyclic alkyl sites. 73,74 Next, the compatibility of primary alkyl iodides has been evaluated. Substrates that contain diverse functional groups, such as silyl ether, sulfonamide, imide, perfluoroalkyl, and the base-labile Fmoc group, were found to give good to excellent yields of the desired products (29 to 35, 56% to 88% yield).…”

Section: Substrate Scopementioning

confidence: 99%

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

Cai

¹

,

Yan

²

,

Liu

³

2021

Preprint

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The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi–type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi–type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.

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Copper‐Catalyzed Deaminative Difluoromethylation

Cited by 22 publications

References 68 publications

Contemporary synthetic strategies in organofluorine chemistry

Contemporary synthetic strategies in organofluorine chemistry

Contemporary synthetic strategies in organofluorine chemistry

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

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