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. 2014 Apr 23;136(16):6123-35.
doi: 10.1021/ja501988b. Epub 2014 Apr 14.

Redox-neutral α-oxygenation of amines: reaction development and elucidation of the mechanism

Matthew T Richers  1 , Martin Breugst, Alena Yu Platonova, Anja Ullrich, Arne Dieckmann, K N Houk, Daniel Seidel
Affiliations

Redox-neutral α-oxygenation of amines: reaction development and elucidation of the mechanism

Matthew T Richers et al. J Am Chem Soc. .

Abstract

Cyclic secondary amines and 2-hydroxybenzaldehydes or related ketones react to furnish benzo[e][1,3]oxazine structures in generally good yields. This overall redox-neutral amine α-C-H functionalization features a combined reductive N-alkylation/oxidative α-functionalization and is catalyzed by acetic acid. In contrast to previous reports, no external oxidants or metal catalysts are required. Reactions performed under modified conditions lead to an apparent reductive amination and the formation of o-hydroxybenzylamines in a process that involves the oxidation of a second equivalent of amine. A detailed computational study employing density functional theory compares different mechanistic pathways and is used to explain the observed experimental findings. Furthermore, these results also reveal the origin of the catalytic efficiency of acetic acid in these transformations.

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Figures

Scheme 1
Scheme 1. Selected Previous Approaches to N,O-Acetals and Aminals
Scheme 2
Scheme 2. Initial Studies on N,O-Acetal Formation
Scheme 3
Scheme 3. Potential Reaction Pathways and Experimental Support
Scheme 4
Scheme 4. Variation of Salicylaldehyde Moiety
All reactions were performed on a 1 mmol scale. bFor this reaction, 1 mmol of amine, 2 equiv of ketone, and xylenes (0.1 M) were used.
Scheme 5
Scheme 5. Variation of Secondary Amine
All reactions were performed on a 1 mmol scale. bFor these reactions, 1 mmol of amine, 2 equiv of aldehyde or ketone, and xylenes (0.1 M) were used.
Scheme 6
Scheme 6. Reaction of Salicylaldehyde with 1-Methyltetrahydroisoquinoline
Scheme 7
Scheme 7. Effect of Water on Condensation Reaction
Scheme 8
Scheme 8. Possible Mechanistic Pathways for Formation of N,O-Acetal 2f and Benzylamine 8f
Figure 1
Figure 1
Temperature-dependent 1H NMR spectra of 2l in CDCl3 (400 MHz).
Scheme 9
Scheme 9. Proposed Mechanism of Maycock and Co-workers for Oxidative N,O-Acetal Formation
Figure 2
Figure 2
Free energy profile [in kcal·mol–1, M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] for uncatalyzed (black) and acetic-acid-catalyzed (red) transformation of 7 and THIQ to benzoxazine 2f in toluene.
Figure 3
Figure 3
Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies (in kcal·mol–1), selected bond lengths (in Å), and dihedrals for different conformers of transition state TS1 and zwitterion 17f.
Figure 4
Figure 4
Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies (in kcal·mol–1), selected bond lengths (in Å), and selected NBO charges for transition state TS2.
Figure 5
Figure 5
Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies (in kcal·mol–1), and selected bond lengths (in Å) for transition state TS3.
Figure 6
Figure 6
Calculated activation and reaction free energies of different pathways involving the azomethine ylide 19f [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] and transition state RSS-TS4 with selected bond lengths (in Å).
Scheme 10
Scheme 10. Potential Acceleration of Acetic Acid (cf. Ref (21))
Figure 7
Figure 7
Calculated transition state TS6 with selected bond lengths (in Å) and activation and reaction free energies (in kcal·mol–1) for an intermolecular reduction of the intermediate zwitterion 10f by THIQ [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM].
Figure 8
Figure 8
Calculated potential energy surface scan for the putative retro-hetero-Diels–Alder reaction involving 2f [in kcal·mol–1, TPSS-D2/6-31G(d)/IEFPCM].
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