Photoredox-HAT Catalysed α-C–H Alkylation of Primary Amines with Vinyl Phosphine Oxides: New Building Blocks for Spiropyrrolidine Synthesis

Anna Kinsella; Joseph Bell-Tyrer; Darren Stead; Alex Cresswell

doi:10.1016/j.tet.2025.134806

Photoredox-HAT Catalysed α-C–H Alkylation of Primary Amines with Vinyl Phosphine Oxides: New Building Blocks for Spiropyrrolidine Synthesis

Anna Kinsella, Joseph Bell-Tyrer, Darren Stead, Alex Cresswell

AstraZeneca UK Ltd

Research output: Contribution to journal › Article › peer-review

Abstract

We report a dual photoredox and hydrogen atom transfer (HAT) catalysed α-C–H alkylation of unprotected, aliphatic primary amines with diphenyl(vinyl)phosphine oxide. This simple protocol, which can be run on gram-scale in continuous flow, enables the direct synthesis of γ-amino phosphine oxide building blocks. By condensation with aromatic aldehydes and base-induced 5-endo-trig cyclisation, the latter compounds can be converted into α-arylated, spirocyclic pyrrolidines. Finally, we show that attempted deprotonation of γ-amino phosphine oxides with strong base leads to an unexpected cyclisation to afford cyclic phosphinamide products.

Original language	English
Article number	134806
Journal	Tetrahedron
Volume	185
Early online date	1 Jul 2025
DOIs	https://doi.org/10.1016/j.tet.2025.134806
Publication status	E-pub ahead of print - 1 Jul 2025

Data Availability Statement

Data will be made available on request.

Funding

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 PhD studentship (A.G.K.), and AstraZeneca for generous financial support

Funders	Funder number
AstraZeneca
University of Bath
Engineering and Physical Sciences Research Council	EP/S028595/1
Royal Society	UF150533

Keywords

Amines
C–H functionalisation
Hydrogen atom transfer catalysis
Photoredox catalysis

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tet.2025.134806Licence: CC BY

Cite this

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abstract = "We report a dual photoredox and hydrogen atom transfer (HAT) catalysed α-C–H alkylation of unprotected, aliphatic primary amines with diphenyl(vinyl)phosphine oxide. This simple protocol, which can be run on gram-scale in continuous flow, enables the direct synthesis of γ-amino phosphine oxide building blocks. By condensation with aromatic aldehydes and base-induced 5-endo-trig cyclisation, the latter compounds can be converted into α-arylated, spirocyclic pyrrolidines. Finally, we show that attempted deprotonation of γ-amino phosphine oxides with strong base leads to an unexpected cyclisation to afford cyclic phosphinamide products.",

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author = "Anna Kinsella and Joseph Bell-Tyrer and Darren Stead and Alex Cresswell",

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AU - Kinsella, Anna

AU - Bell-Tyrer, Joseph

AU - Stead, Darren

AU - Cresswell, Alex

PY - 2025/7/1

Y1 - 2025/7/1

N2 - We report a dual photoredox and hydrogen atom transfer (HAT) catalysed α-C–H alkylation of unprotected, aliphatic primary amines with diphenyl(vinyl)phosphine oxide. This simple protocol, which can be run on gram-scale in continuous flow, enables the direct synthesis of γ-amino phosphine oxide building blocks. By condensation with aromatic aldehydes and base-induced 5-endo-trig cyclisation, the latter compounds can be converted into α-arylated, spirocyclic pyrrolidines. Finally, we show that attempted deprotonation of γ-amino phosphine oxides with strong base leads to an unexpected cyclisation to afford cyclic phosphinamide products.

AB - We report a dual photoredox and hydrogen atom transfer (HAT) catalysed α-C–H alkylation of unprotected, aliphatic primary amines with diphenyl(vinyl)phosphine oxide. This simple protocol, which can be run on gram-scale in continuous flow, enables the direct synthesis of γ-amino phosphine oxide building blocks. By condensation with aromatic aldehydes and base-induced 5-endo-trig cyclisation, the latter compounds can be converted into α-arylated, spirocyclic pyrrolidines. Finally, we show that attempted deprotonation of γ-amino phosphine oxides with strong base leads to an unexpected cyclisation to afford cyclic phosphinamide products.

KW - Amines

KW - C–H functionalisation

KW - Hydrogen atom transfer catalysis

KW - Photoredox catalysis

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DO - 10.1016/j.tet.2025.134806

M3 - Article

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VL - 185

JO - Tetrahedron

JF - Tetrahedron

M1 - 134806

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Photoredox-HAT Catalysed α-C–H Alkylation of Primary Amines with Vinyl Phosphine Oxides: New Building Blocks for Spiropyrrolidine Synthesis

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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