Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)-N Bonds

Nomaan M. Rezayee; Matilde Rusbjerg; Maximilian Marx; Sif T. Linde; Karl Anker Jørgensen

doi:10.1021/acs.joc.1c01937

Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp³)-N Bonds

Nomaan M. Rezayee, Matilde Rusbjerg, Maximilian Marx, Sif T. Linde, Karl Anker Jørgensen^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

Original language	English
Journal	Journal of Organic Chemistry
Volume	87
Issue	3
Pages (from-to)	1756-1766
Number of pages	11
ISSN	0022-3263
DOIs	https://doi.org/10.1021/acs.joc.1c01937
Publication status	Published - Feb 2022

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@article{1861ef176f5e49b983b4e97ed7eb9477,

title = "Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)-N Bonds",

abstract = "This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity. ",

author = "Rezayee, {Nomaan M.} and Matilde Rusbjerg and Maximilian Marx and Linde, {Sif T.} and J{\o}rgensen, {Karl Anker}",

note = "Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2022",

month = feb,

doi = "10.1021/acs.joc.1c01937",

language = "English",

volume = "87",

pages = "1756--1766",

journal = "Journal of Organic Chemistry",

issn = "0022-3263",

publisher = "AMER CHEMICAL SOC",

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}

Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp³)-N Bonds. / Rezayee, Nomaan M.; Rusbjerg, Matilde; Marx, Maximilian et al.
In: Journal of Organic Chemistry, Vol. 87, No. 3, 02.2022, p. 1756-1766.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)-N Bonds

AU - Rezayee, Nomaan M.

AU - Rusbjerg, Matilde

AU - Marx, Maximilian

AU - Linde, Sif T.

AU - Jørgensen, Karl Anker

PY - 2022/2

Y1 - 2022/2

N2 - This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

AB - This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

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JF - Journal of Organic Chemistry

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Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp³)-N Bonds

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