Aza-Michael Addition of Aliphatic Amines to Weakly Polarised Alkenes via Organobase Catalysis
5 affiliations
- 1Department of Chemistry
- 2University of Manchester
- 3Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca
- 4AstraZeneca
- 5R&D
Abstract
The direct addition of aliphatic amines to alkenes offers an atom-economical route to valuable N-alkyl amines, but remains challenging for weakly polarised alkenes. This is because C–N bond formation is poorly driven thermodynamically and difficult to achieve without strongly activating the alkene or generating more reactive nitrogen species. Here we report an organobase-catalysed strategy that enables anti-Markovnikov addition of secondary aliphatic amines to weakly polarised (hetero)aryl alkenes. Kinetic studies and calculations support a mechanism in which the organobase promotes C–N bond formation through hydrogen bonding and noncovalent stabilisation of the addition transition state, followed by rapid deprotonation of the addition complex. The developed conditions were also applicable to challenging C–C bond forming Michael addition reactions with enolate nucleophiles. These findings demonstrate that organobase catalysis can overcome the intrinsic kinetic and thermodynamic challenges associated with closed-shell additions to weakly activated alkenes.
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BibTeX
@misc{cooper2026azamichael,
title = {{Aza-Michael Addition of Aliphatic Amines to Weakly Polarised Alkenes via Organobase Catalysis}},
author = {Bradley D. Cooper and Ethan R. X. Lim and Jonathan Da Luz and Thomas D. Harris and Abby Sutton and Jonathan R. Carney and James J. Douglas and Cristina Trujillo and Michael J. James},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010170/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010170/v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Aza-Michael Addition of Aliphatic Amines to Weakly Polarised Alkenes via Organobase Catalysis
AU - Bradley D. Cooper
AU - Ethan R. X. Lim
AU - Jonathan Da Luz
AU - Thomas D. Harris
AU - Abby Sutton
AU - Jonathan R. Carney
AU - James J. Douglas
AU - Cristina Trujillo
AU - Michael J. James
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010170/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010170/v1
AB - The direct addition of aliphatic amines to alkenes offers an atom-economical route to valuable N-alkyl amines, but remains challenging for weakly polarised alkenes. This is because C–N bond formation is poorly driven thermodynamically and difficult to achieve without strongly activating the alkene or generating more reactive nitrogen species. Here we report an organobase-catalysed strategy that enables anti-Markovnikov addition of secondary aliphatic amines to weakly polarised (hetero)aryl alkenes. Kinetic studies and calculations support a mechanism in which the organobase promotes C–N bond formation through hydrogen bonding and noncovalent stabilisation of the addition transition state, followed by rapid deprotonation of the addition complex. The developed conditions were also applicable to challenging C–C bond forming Michael addition reactions with enolate nucleophiles. These findings demonstrate that organobase catalysis can overcome the intrinsic kinetic and thermodynamic challenges associated with closed-shell additions to weakly activated alkenes.
ER -