Late-stage difluoromethylation: concepts, developments and perspective

Sap, Jeroen B. I.; Meyer, Claudio F.; Straathof, Natan J. W.; Iwumene, Ndidi U. N.; Ende, Christopher W. am; Trabanco, Andrés A.; Gouverneur, Véronique

doi:10.1039/d1cs00360g

Cited by 190 publications

(116 citation statements)

References 209 publications

(293 reference statements)

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“…Over the past few years, significant achievements have been gained in this area. [3] Among them, transition-metal-catalyzed cross-coupling difluoromethylation is one of the most efficient protocols for accessing this type of versatile compound. [4] However, these strategies often suffer from the use of stoichiometric organometallic reagents, which are generally less atom economical and environmentally friendly from the perspective of green chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…[6] Hence, the application of CF 3 -containing compounds in the fields of pharmaceuticals, agrochemicals, and materials has attracted much attention from many scientists and researchers. The exploration of direct and selective procedures for the synthesis of useful CF 2 -containing molecules from easily accessible CF 3 precursors via selective single C(sp 3 )À F bond cleavage is attractive because no substrate prefunctionalization is needed. Also, only fluorine anions are produced as the byproduct in the reaction process, thus, this strategy is highly atom-and step-economical.…”

Section: Introductionmentioning

confidence: 99%

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Recent Advances in the Synthesis of Difluorinated Architectures from Trifluoromethyl Groups

2021

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Fluorine-containing moieties are widely used in the pharmaceutical, agrochemical, and material fields. Thus, these structures are of immense interest in the fields of organic synthesis and medicinal chemistry. Among various fluorinated groups, the difluoromethyl unit has drawn increasing attention due to its unique pharmaceutical properties. In recent years, several methods for the synthesis of difluoromethylated compounds have been rapidly developed. However, most of these methods treat aromatic compounds with excess difluoromethylating reagents, which often contain organometallic compounds, so these transformations are generally less environmentally friendly and atom-economical. In this review, we summarize the recent development of new methods for the synthesis of difluoromethyl motifs or difluoroalkenes from trifluoromethylated aromatic compounds or trifluoromethyl alkenes via single C(sp 3 )À F bond cleavage.1.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Synthesis of Difluorinated Architectures from Trifluoromethyl Groups

2021

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“…The highly polarised C-H bond of CF 2 H makes this motif a competent hydrogen bond donor, a characteristic unique amongst polyfluorinated motifs. The suitability of CF 2 H as a bio-isostere for alcohol, thiol, or amine, has resulted in its incorporation in drugs, herbicides, fungicides, and agrochemicals (Sap et al 2021;Shi et al 2016). Consequently, methods for accessing [ 18 F]CF 2 H-substituted molecules for PET imaging purpose are in demand.…”

Section: Radiosynthesis Of [ 18 F]difluoromethyl-containing Moleculesmentioning

confidence: 99%

Closing the gap between 19F and 18F chemistry

Ajenjo

Destro

Cornelissen

et al. 2021

EJNMMI radiopharm. chem.

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Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to 18F-labelled radiotracers can make a direct impact in medicine. For many years, access to 18F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to 18F-incorporation. During the last two decades, 18F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage 18F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate 18F-incorporation. Specifically, new advances in late-stage 19F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel 18F-labelled fluorination reagents have enabled the invention of novel processes for 18F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C–18F bond formation. This reinvigorated interest in 18F-radiochemistry that we have witnessed in recent years has made a direct impact on 19F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.

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“…Therefore, the development of new concise and selective methods for the late-stage introduction of gem -difluoromethylene units onto nitrogen-containing scaffolds remains an attractive goal in synthetic chemistry. 9 …”

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confidence: 99%

Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction

2022

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An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1–2 mol % of Vaska’s complex (IrCl(CO)(PPh 3 ) 2 ), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF 2 R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N -aryl- and N -heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.

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Late-stage difluoromethylation: concepts, developments and perspective

Abstract: This review describes the conceptual advances that have led to the multiple difluoromethylation processes making use of well-defined CF2H sources.

Cited by 190 publications

References 209 publications

Recent Advances in the Synthesis of Difluorinated Architectures from Trifluoromethyl Groups

Recent Advances in the Synthesis of Difluorinated Architectures from Trifluoromethyl Groups

Closing the gap between 19F and 18F chemistry

Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction

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