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. 2016 Dec 12;22(50):18179-18189.
doi: 10.1002/chem.201603839. Epub 2016 Nov 9.

Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α- and β-C-H Functionalization

Longle Ma  1 , Anirudra Paul  1 , Martin Breugst  2 , Daniel Seidel  1
Affiliations

Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α- and β-C-H Functionalization

Longle Ma et al. Chemistry. .

Abstract

Cyclic amines such as pyrrolidine and piperidine are known to undergo condensations with aldehydes to furnish pyrrole and pyridine derivatives, respectively. A combined experimental and computational study provides detailed insights into the mechanism of pyrrole formation. A number of reactive intermediates (e.g., azomethine ylides, conjugated azomethine ylides, enamines) were intercepted, outlining strategies for circumventing aromatization as a valuable pathway for amine C-H functionalization.

Keywords: C−H functionalization; azomethine ylides; density functional theory; heterocycles; redox-neutral.

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Figures

Figure 1
Figure 1
Calculated activation and reaction free energies and transition states for the trapping of the azomethine ylides 4 and 11 [in kcal mol−1 and Å, M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
Scheme 1
Scheme 1
Examples of redox-neutral amine aromatization.
Scheme 2
Scheme 2
Potential reaction pathways for pyrrole formation from pyrrolidine.
Scheme 3
Scheme 3
Support for azomethine ylide/enamine formation from pyrrolidine.
Scheme 4
Scheme 4
Evidence for simple and conjugated azomethine ylides.
Scheme 5
Scheme 5
Pyrrole formation and (3+2) cycloaddition.
Scheme 6
Scheme 6
Evidence for enamine intermediates.
Scheme 7
Scheme 7
Reactions of the enamine dimer with β-naphthol.
Scheme 8
Scheme 8
Pyrrole formation from enamine dimer.
Scheme 9
Scheme 9
Enamine dimer monomerization/β-functionalization.
Scheme 10
Scheme 10
Synthesis of other enamine dimers.
Scheme 11
Scheme 11
Reactions of enamine dimers with β-nitrostyrene.
Scheme 12
Scheme 12
β-Functionalization of azepane.
Scheme 13
Scheme 13
Calculated free energy profile for the lowest-energy pathway for the uncatalyzed reaction between benzaldehyde and pyrrolidine [in kcal mol−1; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
Scheme 14
Scheme 14
Calculated free energy profile and selected transition state structures for the lowest-energy pathway for the acetic-acid-catalyzed reaction between benzaldehyde and pyrrolidine [in kcal mol−1 and Å; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
Scheme 15
Scheme 15
Alternate pathway for the acetic-acid-catalyzed conversion of 10b to 15b [in kcal mol−1].
Scheme 16
Scheme 16
Alternate pathway for the acetic-acid-catalyzed conversion of 11 to 1 [in kcal mol−1].
Scheme 17
Scheme 17
Calculated free energy profile for the lowest-energy pathway for the acetic-acid-catalyzed reaction between 2,6-dichlorobenzaldehyde and pyrrolidine [in kcal mol−1; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
Scheme 18
Scheme 18
Calculated thermodynamics for the formation enamine intermediates [in kcal mol−1; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d, p)/IE FPCM].
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