N-tosylhydrazones as acceptors for nucleophilic alkyl radicals in photoredox catalysis: A short case study on possible side reactions

Anna G. Kinsella; Joshua D. Tibbetts; Darren Stead; Alexander J. Cresswell

doi:10.1080/00397911.2022.2028844

N-tosylhydrazones as acceptors for nucleophilic alkyl radicals in photoredox catalysis: A short case study on possible side reactions

Anna G. Kinsella, Joshua D. Tibbetts, Darren Stead, Alexander J. Cresswell^*

^*Corresponding author for this work

Chemistry

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Abstract

We report the attempted development of a photoredox-catalyzed α-C–H alkylation reaction of aliphatic amine derivatives, using N-tosylhydrazones as radical alkylating partners. The original intention was to intercept α-aminoalkyl radical intermediates with N-tosylhydrazones, followed by the expulsion of a sulfonyl radical by β-scission to generate N-H diazene species. Facile denitrogenation of these intermediates would remove all traces of the hydrazone moiety and provide a net C–H alkylation process. However, our plans were derailed by issues with the low reactivity of N-tosylhydrazones toward intermolecular capture by nucleophilic radicals, and several unexpected side reactions. Our findings, though unsuccessful, do serve to identify challenges for future researchers attempting to develop similar transformations.

Original language	English
Pages (from-to)	413-423
Number of pages	11
Journal	Synthetic Communications
Volume	52
Issue number	3
Early online date	21 Jan 2022
DOIs	https://doi.org/10.1080/00397911.2022.2028844
Publication status	Published - 1 Feb 2022

Bibliographical note

Funding Information:
This work was funded by the Engineering and Physical Sciences Research Council (EP/S028595/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Ph.D. studentship (A.G.K.), and AstraZeneca for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterization Facility (MC2) (https://doi.org/10.15125/mx6j-3r54).

Keywords

Amines
hydrazones
photoredox
radicals
side reactions

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KinsellaA2022NtosylFinal published version, 2.35 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

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title = "N-tosylhydrazones as acceptors for nucleophilic alkyl radicals in photoredox catalysis: A short case study on possible side reactions",

abstract = "We report the attempted development of a photoredox-catalyzed α-C–H alkylation reaction of aliphatic amine derivatives, using N-tosylhydrazones as radical alkylating partners. The original intention was to intercept α-aminoalkyl radical intermediates with N-tosylhydrazones, followed by the expulsion of a sulfonyl radical by β-scission to generate N-H diazene species. Facile denitrogenation of these intermediates would remove all traces of the hydrazone moiety and provide a net C–H alkylation process. However, our plans were derailed by issues with the low reactivity of N-tosylhydrazones toward intermolecular capture by nucleophilic radicals, and several unexpected side reactions. Our findings, though unsuccessful, do serve to identify challenges for future researchers attempting to develop similar transformations.",

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author = "Kinsella, {Anna G.} and Tibbetts, {Joshua D.} and Darren Stead and Cresswell, {Alexander J.}",

note = "Funding Information: This work was funded by the Engineering and Physical Sciences Research Council (EP/S028595/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Ph.D. studentship (A.G.K.), and AstraZeneca for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterization Facility (MC2) (https://doi.org/10.15125/mx6j-3r54).",

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AU - Tibbetts, Joshua D.

AU - Stead, Darren

AU - Cresswell, Alexander J.

N1 - Funding Information: This work was funded by the Engineering and Physical Sciences Research Council (EP/S028595/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Ph.D. studentship (A.G.K.), and AstraZeneca for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterization Facility (MC2) (https://doi.org/10.15125/mx6j-3r54).

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N2 - We report the attempted development of a photoredox-catalyzed α-C–H alkylation reaction of aliphatic amine derivatives, using N-tosylhydrazones as radical alkylating partners. The original intention was to intercept α-aminoalkyl radical intermediates with N-tosylhydrazones, followed by the expulsion of a sulfonyl radical by β-scission to generate N-H diazene species. Facile denitrogenation of these intermediates would remove all traces of the hydrazone moiety and provide a net C–H alkylation process. However, our plans were derailed by issues with the low reactivity of N-tosylhydrazones toward intermolecular capture by nucleophilic radicals, and several unexpected side reactions. Our findings, though unsuccessful, do serve to identify challenges for future researchers attempting to develop similar transformations.

AB - We report the attempted development of a photoredox-catalyzed α-C–H alkylation reaction of aliphatic amine derivatives, using N-tosylhydrazones as radical alkylating partners. The original intention was to intercept α-aminoalkyl radical intermediates with N-tosylhydrazones, followed by the expulsion of a sulfonyl radical by β-scission to generate N-H diazene species. Facile denitrogenation of these intermediates would remove all traces of the hydrazone moiety and provide a net C–H alkylation process. However, our plans were derailed by issues with the low reactivity of N-tosylhydrazones toward intermolecular capture by nucleophilic radicals, and several unexpected side reactions. Our findings, though unsuccessful, do serve to identify challenges for future researchers attempting to develop similar transformations.

KW - Amines

KW - hydrazones

KW - photoredox

KW - radicals

KW - side reactions

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DO - 10.1080/00397911.2022.2028844

M3 - Article

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VL - 52

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EP - 423

JO - Synthetic Communications

JF - Synthetic Communications

IS - 3

ER -

N-tosylhydrazones as acceptors for nucleophilic alkyl radicals in photoredox catalysis: A short case study on possible side reactions

Abstract

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Keywords

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