One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

Leng, Daniel J.; Black, Conor M.; Pattison, Graham

doi:10.1039/c5ob02468d

Cited by 43 publications

(36 citation statements)

References 54 publications

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“…Alkyl substituted and α,β-unsaturated ketones participate in the process as well. Also, these data correlate well with similar studies conducted by Pattison and coworkers using CH 3 CN as solvent, 26 however, the mixture of THF and water are more adaptable to the subsequent deuteration studies. Notable, examples of complex difluoromethyl ketones are the steroid- and glucose-derived compounds 24 and 25 , respectively.…”

supporting

confidence: 88%

“…25 Also, the difluoroenolates can be treated with water to produce difluoromethyl ketones without concerns of over- or under-fluorinated by-products. 26 Based on these prior data, we hypothesized that a difluoroenolate, formed following the release of trifluoroacetate, could be effectively trapped with deuterium. We envisioned that this method could assemble “CF 2 D” groups adjacent to ketones with high levels of deuterium incorporation and furthermore, we aimed to conduct side-by-side comparisons between the pronated and deuterated products (see below).…”

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confidence: 99%

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Conversion of methyl ketones and methyl sulfones into α-deutero-α,α-difluoromethyl ketones and α-deutero-α,α-difluoromethyl sulfones in three synthetic steps

Sowaileh

Han

Hazlitt

et al. 2017

Tetrahedron Letters

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Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the “CF2D” group were routinely observed. This strategy is mild and versatile and it can be applied to both ketones and sulfones without additional concerns of over- or under-fluorination. Additional examples address issues of over-deuteration when compounds with other acidic protons are subjected to the reaction conditions. This process not only demonstrates a new method to install a “CF2D” group but also extends the scope of trifluoroacetate release to sulfones.

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confidence: 88%

mentioning

confidence: 99%

Conversion of methyl ketones and methyl sulfones into α-deutero-α,α-difluoromethyl ketones and α-deutero-α,α-difluoromethyl sulfones in three synthetic steps

Sowaileh

Han

Hazlitt

et al. 2017

Tetrahedron Letters

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“…Other electrophiles can be used to trap the difluoroenolate intermediates formed on loss of trifluoroacetate (Scheme ). Careful control of addition of water and base has allowed our group to develop a one‐pot difluorination/fragmentation process for the synthesis of difluoromethyl ketones 107 , whilst similar conditions allowed Colby to synthesize the corresponding very rare CF 2 D ketones by trapping with D 2 O . The combination of LiBr and Selectfluor gives an electrophilic brominating agent suitable for the synthesis of CF 2 Br ketones 108 .…”

Section: Synthesis Of Difluoroketones By a Fluorinated‐building‐blmentioning

confidence: 99%

Methods for the Synthesis of α,α‐Difluoroketones

Pattison

2018

Eur J Org Chem

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α,α‐Difluoroketones are valuable compounds and can be used as synthetic intermediates for the synthesis of fluorinated molecules, but they also have a direct application in medicinal chemistry, particularly as inhibitors for hydrolytic enzymes. This Microreview will summarize the major methods currently available for the synthesis of α,α‐difluoroketones, highlighting methods involving direct C–F bond formation, as well as those using pre‐difluorinated building blocks.

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“…[9] These methods do have some drawbacks though, among them: 1) relatively limited scope; 2) non-atom-economic fluorination systems; 3) poor functional group tolerance caused by the use of strong oxidants; and 4) difficulty in controlling overreaction (i.e., difluorination). [6],[10] …”

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confidence: 99%

Gold‐catalyzed Fluorination of Alkynyl Esters and Ketones: Efficient Access to Fluorinated 1,3‐Dicarbonyl Compounds

Zeng

Liu

et al. 2017

Adv Synth Catal

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We developed an efficient synthesis of 2-fluoro-1,3-dicarbonyl compounds using readily available alkynyl ketones or esters as starting material. The key step is the insertion of hydrogen fluoride (HF) to the gold carbene intermediate generated from cationic gold catalyzed addition of N-oxides to alkynyl ketones or esters. This method gives excellent chemical yields and regioselectivity with good functional group tolerance.

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One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

Cited by 43 publications

References 54 publications

Conversion of methyl ketones and methyl sulfones into α-deutero-α,α-difluoromethyl ketones and α-deutero-α,α-difluoromethyl sulfones in three synthetic steps

Conversion of methyl ketones and methyl sulfones into α-deutero-α,α-difluoromethyl ketones and α-deutero-α,α-difluoromethyl sulfones in three synthetic steps

Methods for the Synthesis of α,α‐Difluoroketones

Gold‐catalyzed Fluorination of Alkynyl Esters and Ketones: Efficient Access to Fluorinated 1,3‐Dicarbonyl Compounds

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