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. 2013 Apr 19;78(8):4132-44.
doi: 10.1021/jo400483h. Epub 2013 Apr 2.

Metal-free α-amination of secondary amines: computational and experimental evidence for azaquinone methide and azomethine ylide intermediates

Arne Dieckmann  1 , Matthew T Richers, Alena Yu Platonova, Chen Zhang, Daniel Seidel, K N Houk
Affiliations

Metal-free α-amination of secondary amines: computational and experimental evidence for azaquinone methide and azomethine ylide intermediates

Arne Dieckmann et al. J Org Chem. .

Abstract

We have performed a combined computational and experimental study to elucidate the mechanism of a metal-free α-amination of secondary amines. Calculations predicted azaquinone methides and azomethine ylides as the reactive intermediates and showed that iminium ions are unlikely to participate in these transformations. These results were confirmed by experimental deuterium-labeling studies and the successful trapping of the postulated azomethine ylide and azaquinone methide intermediates. In addition, computed barrier heights for the rate-limiting step correlate qualitatively with experimental findings.

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Figures

Figure 1
Figure 1
Structures of quinoidal intermediates cis-5b and trans-5b. Charges for nitrogen atoms were obtained from a natural population analysis. The dihedral angle θ is a measure for the planarity of the exocyclic π-system (0° corresponds to a perfectly flat geometry).
Figure 2
Figure 2
Gibbs free energy profile for the reaction depicted in Scheme 3. Free energies and enthalpies in parentheses are given in kcal mol−1 and bond lengths in Å.
Figure 3
Figure 3
An overlay of the geometries of cis-5a and cis-5c (sticks) with transition states TS-5a and TS-5c (balls and sticks).
Figure 4
Figure 4
Structures and carbon charges of THIQ azomethine ylides.
Figure 5
Figure 5
Transition states TS-8 and TS-9 and zwitterionic intermediate 21 for the [3+2] cycloaddition between 1a and 6a (see equation 5). The total reaction is exergonic by −35.6 kcal mol−1 relative to 1a and 6a.
Scheme 1
Scheme 1
Potential Mechanistic Pathways for the Redox-Neutral Aminal Formation. Blue Arrows Refer to the Lowest Energy Pathway as Elucidated by DFT Calculations.
Scheme 2
Scheme 2
Capture of an ortho-azaquinone methide intermediate via intramolecular [4+2] cycloaddition and relevant control experiments.
Scheme 3
Scheme 3
The general mechanism for the α-amination of nitrogen heterocycles is exemplified with the prototypic reaction of 1b and pyrrolidine leading to product 2b.
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References

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