Chen's Reagent: A Versatile Reagent for Trifluoromethylation, Difluoromethylenation, and Difluoroalkylation in Organic Synthesis<sup>†</sup>

Xie, Qiqiang; Hu, Jinbo

doi:10.1002/cjoc.201900424

Cited by 75 publications

(29 citation statements)

References 83 publications

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“…6A). Cu-promoted couplings always involve a CuCF3 complex, a key intermediate that can be generated in situ using reagent systems including: a Cu I source with TMSCF3 and a Fsource; [82][83][84] a Cu I source with FSO2CF2CO2Me; [85][86][87] a Cu I source with (MeO)3B -CF3K + ; 88 CuCl with HCF3 and t BuOK; 89,90 copper and [Ph2S + CF3]TfO -; 91 and copper and Umemoto reagent 92 . Cu sources may be used in catalytic or stoichiometric quantities, depending on the reaction conditions.…”

Section: [H2] Fluorinationmentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

Britton

Gouverneur

Lin

et al. 2021

Nat Rev Methods Primers

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202

115

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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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Section: [H2] Fluorinationmentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

Britton

Gouverneur

Lin

et al. 2021

Nat Rev Methods Primers

Self Cite

202

115

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“…Selective tri‐ or tetraiodination, [ 228 ] and tetra‐ [ 229 ] or octabromination [ 229,230 ] was performed on 170a , b prior to S N Ar with FSO 2 CF 2 CO 2 Me, a source of the trifluoromethyl anion. [ 231 ] This approach selectively yielded tri‐, tetra‐, and octarifluoromethylated gold corroles, [ 232,233 ] The yields for iodine substitution were higher than those for bromine substitution across all examples. Ghosh and co‐workers generated 173 , and Cu‐ 173 and analyzed them via single‐crystal X‐ray diffraction and found an 85° difference in saddling between the two, with 173 being planar.…”

Section: Snar Reactions Of Corrolesmentioning

confidence: 99%

Nucleophilic Aromatic Substitution (S_NAr) and Related Reactions of Porphyrinoids: Mechanistic and Regiochemical Aspects

Sample

Senge

2020

Eur J Org Chem

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The nucleophilic substitution of aromatic moieties (SNAr) has been known for over 150 years and found wide use for the functionalization of (hetero)aromatic systems. Currently, several “types” of SNAr reactions have been established and notably the area of porphyrinoid macrocycles has seen many uses thereof. Herein, we detail the SNAr reactions of seven types of porphyrinoids with differing number and type of pyrrole units: subporphyrins, norcorroles, corroles, porphyrins, azuliporphyrins, N‐confused porphyrins, and phthalocyanines. For each we analyze the substitution dependent upon: a) the type of nucleophile and b) the site of substitution (α, β, or meso). Along with this we evaluate this route as a synthetic strategy for the generation of unsymmetrical porphyrinoids. Distinct trends can be identified for each type of porphyrinoid discussed, regardless of nucleophile. The use of nucleophilic substitution on porphyrinoids is found to often be a cost‐effective procedure with the ability to yield complex substituent patterns, which can be conducted in non‐anhydrous solvents with easily accessible simple porphyrinoids.

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“…Therefore, development of a high-yielding and efficient protocol for late-stage direct trifluoromethylation of nucleosides using convenient reaction conditions and inexpensive reagents is still an unmet challenge worthy of investigation. This inspired us to establish a simple and scalable protocol for site-selective trifluoromethylation of pyrimidine nucleosides using a cheap and commercially available Chen's reagent, methyl fluorosulfonyldifluoroacetate (Xie & Hu, 2020). To the best of our knowledge, this is the first protocol reported to introduce a trifluoromethyl group at the 5-position of pyrimidine nucleosides using microwave heating.…”

Section: Introductionmentioning

confidence: 99%

Microwave Assisted Cu‐Mediated Trifluoromethylation of Pyrimidine Nucleosides

Mangla

Sanghvi²,

Prasad

2021

Current Protocols

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Trifluoromethylated nucleosides, such as trifluridine, have widespread applications in pharmaceuticals as anticancer and antiviral agents. However, site‐selective addition of a trifluoromethyl group onto a nucleobase typically requires either inconvenient multi‐step synthesis or expensive trifluoromethylation reagents, or results in low yield. This article describes a simple, scalable, and high‐yielding protocol for late‐stage direct trifluoromethylation of pyrimidine nucleosides via a microwave‐irradiated pathway. First, 5‐iodo pyrimidine nucleosides undergo complete benzoylation to obtain N3‐benzoyl‐3',5'‐di‐O‐benzoyl‐5‐iodo‐pyrimidine nucleosides as key precursors. Next, trifluoromethylation is carried out under both conventional and microwave heating using an inexpensive and commercially accessible Chen's reagent, i.e., methyl fluorosulfonyldifluoroacetate, to produce N3‐benzoyl‐3',5'‐di‐Obenzoyl‐5‐trifluoromethyl‐pyrimidine nucleosides. The microwave‐assisted transformation accentuates its simplicity, mild reaction conditions, and dominance, providing a facile route to access trifluoromethylation. Finally, the envisioned 5‐trifluoromethyl pyrimidine nucleosides are obtained by a routine debenzoylation procedure. This concludes a convenient three‐step synthesis to obtain trifluridine and its 2'‐modified analogs on a gram scale with consistently high yields, starting from their respective iodo‐precursors, and requires only one chromatographic purification at the trifluoromethylation step. Furthermore, this operationally simple protocol can be utilized as a definitive methodology to produce various other trifluoromethylated therapeutics. © 2021 Wiley Periodicals LLC. Basic Protocol: Synthesis of 5‐trifluoromethyl pyrimidine nucleosides 4a‐c Alternate Protocol: Conventional trifluoromethylation: Synthesis of N3‐benzoyl‐3',5'‐di‐O‐benzoyl‐5‐trifluoromethyl pyrimidine nucleosides (3a‐c)

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Chen's Reagent: A Versatile Reagent for Trifluoromethylation, Difluoromethylenation, and Difluoroalkylation in Organic Synthesis^†

Cited by 75 publications

References 83 publications

Contemporary synthetic strategies in organofluorine chemistry

Contemporary synthetic strategies in organofluorine chemistry

Nucleophilic Aromatic Substitution (S_NAr) and Related Reactions of Porphyrinoids: Mechanistic and Regiochemical Aspects

Microwave Assisted Cu‐Mediated Trifluoromethylation of Pyrimidine Nucleosides

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Chen's Reagent: A Versatile Reagent for Trifluoromethylation, Difluoromethylenation, and Difluoroalkylation in Organic Synthesis†

Cited by 75 publications

References 83 publications

Contemporary synthetic strategies in organofluorine chemistry

Contemporary synthetic strategies in organofluorine chemistry

Nucleophilic Aromatic Substitution (SNAr) and Related Reactions of Porphyrinoids: Mechanistic and Regiochemical Aspects

Microwave Assisted Cu‐Mediated Trifluoromethylation of Pyrimidine Nucleosides

Contact Info

Product

Resources

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Chen's Reagent: A Versatile Reagent for Trifluoromethylation, Difluoromethylenation, and Difluoroalkylation in Organic Synthesis^†

Nucleophilic Aromatic Substitution (S_NAr) and Related Reactions of Porphyrinoids: Mechanistic and Regiochemical Aspects