Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

Meanwell, Michael; Adluri, Bharani Shashank; Yuan, Zheliang; Newton, J.; Pelletier, Philippe; Nodwell, Matthew B.; Friesen, Chadron M.; Schaffer, Paul; Martin, Rainer E.; Britton, Robert

doi:10.1039/c8sc01221k

“…Britton, Martin, and co‐workers have reported an elegant method for selective heterobenzylic C−H fluorination and difluorination (Scheme a) . They discovered that NFSI used in combination with Li 2 CO 3 promoted selective heterobenzylic fluorination of 2‐ and 4‐alkyl azaheterocycles.…”

Section: Miscellaneous C−h Fluorination Methodsmentioning

confidence: 99%

The Fluorination of C−H Bonds: Developments and Perspectives

Szpera

¹

,

Moseley

²

,

Smith

³

et al. 2019

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This Review summarizes the advances in fluorination via C(sp 2)-H and C(sp 3)-H activation. Transition metal catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp 2) and C(sp 3) sites exploiting the reactivity of high oxidation transition metal fluoride complexes combined with the use of directing group (some transient) to control regio-and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. A number of ligands have proven to be effective for C(sp 3)-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity and selectivity. Methods relying on the formation of radical intermediates are complementary to transition metal catalyzed processes as they allow for undirected C(sp 3)-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique bio-inspired Mn(III)-catalyzed oxidative C-H fluorination has been developed. Overall, the field of late stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H 18 F-fluorination is still in its infancy. C-F reductive elimination C(sp 2)-H C(sp 3)-H C(sp 3)-H

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“…We also found that careful choice of reagents results in monofluoro and difluoropyridine derivatives with an N-fluoropyridinium salt resulting in 6, and NFSI forming 7. [15] In summary, we have developed a strategy for pyridine alkylation using dearomatized pyridylphosphonium ylides in an unconventional Wittig reaction. Substituted pyridines are converted into N-triazinylpyridinium salts and coupled with a range of aldehydes resulting in a modular assembly of useful alkylpyridine derivatives with exclusive 4-selectivity.…”

Section: Methodsmentioning

confidence: 99%

Four‐Selective Pyridine Alkylation via Wittig Olefination of Dearomatized Pyridylphosphonium Ylides

Fricke

¹

,

Dolewski

²

,

McNally

³

2021

Angewandte Chemie

3

0

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Methods to synthesize alkylated pyridines are valuable because these structures are prevalent in pharmaceuticals and agrochemicals. We have developed a distinct approach to construct 4-alkylpyridines using dearomatized pyridylphosphonium ylide intermediates in a Wittig olefination-rearomatization sequence. Pyridine N-activation is key to this strategy, and N-triazinylpyridinium salts enable coupling between a wide variety of substituted pyridines and aldehydes. The alkylation protocol is viable for late-stage functionalization, including methylation of pyridine-containing drugs. This approach represents an alternative to metal-catalyzed sp 2 -sp 3 cross-coupling reactions and Minisci-type processes. Scheme 1. Design plan for pyridine alkylation via Wittig olefinationrearomatization of pyridylphosphonium ylides.

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“…Britton, Martin et al verçffentlichten eine elegante Methode zur selektiven Fluorierung und Difluorierung heterobenzylischer C-H-Bindungen (Schema 53 a). [131,132] Sie entdeckten, dass die Kombination von NFSI mit Li 2 CO 3 eine selektive Fluorierung von 2-und 4-Alkylazaheterocyclen in Heterobenzylposition ermçglichte,u nd die Reaktion blieb unbeeinflusst von der Zugabe des Radikalfängers Galvinoxyl. Die Fluorierung verlief ohne Ringçffnung etwaiger Cyclopropylringe im Substrat.…”

Section: Diverse Methoden Der C-h-fluorierungunclassified

Fluorierung von C‐H‐Bindungen: Entwicklungen und Perspektiven

Szpera

¹

,

Moseley

²

,

Smith

³

et al. 2019

View full text Add to dashboard Cite

This Review summarizes the advances in fluorination via C(sp 2)-H and C(sp 3)-H activation. Transition metal catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp 2) and C(sp 3) sites exploiting the reactivity of high oxidation transition metal fluoride complexes combined with the use of directing group (some transient) to control regio-and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. A number of ligands have proven to be effective for C(sp 3)-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity and selectivity. Methods relying on the formation of radical intermediates are complementary to transition metal catalyzed processes as they allow for undirected C(sp 3)-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique bio-inspired Mn(III)-catalyzed oxidative C-H fluorination has been developed. Overall, the field of late stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H 18 F-fluorination is still in its infancy. C-F reductive elimination C(sp 2)-H C(sp 3)-H C(sp 3)-H

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Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

Abstract: Transient sulfonylation of azaheterocycles by N-fluoro or N-trifluoromethylthio dibenzenesulfonimide enables heterobenzylic fluorination, difluorination and trifluoromethylthiolation.

Cited by 56 publications

References 70 publications

The Fluorination of C−H Bonds: Developments and Perspectives

The Fluorination of C−H Bonds: Developments and Perspectives

Four‐Selective Pyridine Alkylation via Wittig Olefination of Dearomatized Pyridylphosphonium Ylides

Fluorierung von C‐H‐Bindungen: Entwicklungen und Perspektiven

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