Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism

Liang, Dongdong; Streefkerk, Dieuwertje E.; Jordaan, Daan; Wagemakers, Jorden; Baggerman, Jacob; Zuilhof, Han

doi:10.1002/ange.201915519

Cited by 37 publications

(11 citation statements)

References 89 publications

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“…Very recently, the mechanism of the Si-free SuFEx reaction with phenolate anions was investigated with the help of density functional theory (DFT), and an addition–elimination mechanism with very low barriers and early transition states was found while an S N 2-type reaction could not be excluded under experimental conditions. 26 The authors also concluded that the very high reactivity of the phenolate anion probably leads to a different mechanism compared to less strong nucleophiles, as investigated here.…”

Section: Introductionmentioning

confidence: 49%

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Luy

Tonner

2020

ACS Omega

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The sulfur(VI) fluoride exchange (SuFEx) reaction is an emerging scheme for connecting molecular building blocks. Due to its broad functional group tolerance and rather stable resulting linkage, it is seeing rapid adoption in various fields of chemistry. Still, to date the reaction mechanism is poorly understood, which hampers further development. Here, we show that the mechanism of the SuFEx reaction for the prototypical example of methanesulfonyl fluoride reacting with methylamine can be understood as an SN2-type reaction. By analyzing the reaction path with the help of density functional theory in vacuo and under consideration of solvent and co-reactant influence, we identify the often used complementary base as a crucial ingredient to lower the reaction barrier significantly by increasing the nucleophilicity of the primary amine. With the help of energy decomposition analysis at the transition state structures, we quantify the underlying stereoelectronic effects and propose new avenues for experimental exploration of the potential of SuFEx chemistry.

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Section: Introductionmentioning

confidence: 49%

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Luy

Tonner

2020

ACS Omega

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“…Very recently, the mechanism of the Si-Free SuFEx reaction with phenolate anions was investigated with the help of density functional theory (DFT) and an addition-elimination mechanism with very low barriers and early transition states was found while an SN2-type reaction could not be excluded under experimental conditions. [25] The authors also concluded that the very high reactivity of the phenolate anion probably leads to a different mechanism compared to less strong nucleophiles as investigated here.…”

Section: Methodsmentioning

confidence: 61%

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Luy¹,

Tonner²

2020

Preprint

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The Sulfur (VI) Fluoride Exchange (SuFEx) reaction is an emerging scheme for connecting molecular building blocks. Due to its broad functional group tolerance and rather stable resulting linkage it is seeing rapid adoption in various fields of chemistry. Still, to date the reaction mechanism is poorly understood which hampers further development. Here, we show that the mechanism of the SuFEx reaction for the prototypical example of methanesulfonyl fluoride reacting with methylamine can be understood as an SN2-type reaction. By analyzing the reaction path with the help of density functional theory in vacuo and under consideration of solvent and co-reactant influence we identify the often used complementary base as crucial ingredient to lower the reaction barrier significantly by increasing the nucleophilicity of the primary amine. With the help of energy decomposition analysis (EDA) at the transition state structures we quantify the underlying stereo-electronic effects and propose new avenues for experimental exploration of the potential of SuFEx chemistry.

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“…sulfonimidamides, and sulfonimidates. 61,62 So we treated it with C-nucleophile as an selected example to construct the n-butyl substituted sulfoximine compound 21 without the erosion of the enantioselectivity (Figure 5b), considering sulfoximines were known as a rising star in drug discovery, which also represents the first example from aryl sulfoximine to alkyl sulfoximine. 63,64 Furthermore, we realized the iterative addition of 3b which gave a compound 23 with two carbon stereocenters and two sulfur stereocenters (Figure 5c).…”

Section: Difluoro(aminosulfinyl)methylationmentioning

confidence: 99%

Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

Liu¹,

Ni²,

Wang³

et al. 2022

CCS Chem

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1,1-Difluorinated sulfonamides are known to have improved anti-inflammatory activity and enzyme inhibitory potency than their non-fluorinated counterparts, where two geminal fluorine atoms can give rise to electronic perturbation of the nearby polar groups and improve their biological activity. However, as methods for their stereoselective synthesis are scarce, such entities remain entirely unexplored. Here, we outline an efficient method for stereoselective introduction of difluoro(aminosulfonyl)methyl group (CF 2 SO 2 NH 2 ) into carbonyls, imines, and alkyl halides with a new (R)-2-pyridyl difluoromethyl sulfoximine reagent, which provides an unique solution for synthesis of chiral ,-difluorinated sulfonamides with a quaternary stereocenter. Its potency is illustrated by the synthesis of fluorinated analogues of bioactive compounds such as 2-OH-SA, one of antagonists for GABA B receptor in guinea pig ileum, and the late-stage modification of complex molecules such as haloperidol, ebastine, cholesterol and (+)--tocopherol derivatives.Stereoselective difluoro(aminosulfinyl)methylation to yield chiral sulfinylamides are presented, showcasing other uses of this new reagent.

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Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism

Cited by 37 publications

References 89 publications

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

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