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

Richers MT, Breugst M, Platonova AY, Ullrich A, Dieckmann A, Houk KN, Seidel D - J. Am. Chem. Soc. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States.

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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Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM],relative free energies (in kcal·mol–1), selectedbond lengths (in Å), and dihedrals for different conformers oftransition state TS1 and zwitterion 17f.
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fig3: Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM],relative free energies (in kcal·mol–1), selectedbond lengths (in Å), and dihedrals for different conformers oftransition state TS1 and zwitterion 17f.

Mentions: Although the uncatalyzedreaction between the aldehyde and the amine results in low yieldsof the corresponding benzoxazines (Table 1),this background reaction is important for the acid-catalyzed reactionas well. Therefore, we first carefully analyzed the mechanism forthe prototypic reaction between salicylaldehyde (7) andtetrahydroisoquinoline (THIQ) in toluene solution in the absence ofany catalyst (cf. Scheme 8). The calculatedfree energy profile is depicted in Figure 2 (black lines), and selected calculated structures are discussedin Figures 3–5.


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

Richers MT, Breugst M, Platonova AY, Ullrich A, Dieckmann A, Houk KN, Seidel D - J. Am. Chem. Soc. (2014)

Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM],relative free energies (in kcal·mol–1), selectedbond lengths (in Å), and dihedrals for different conformers oftransition state TS1 and zwitterion 17f.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4333595&req=5

fig3: Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM],relative free energies (in kcal·mol–1), selectedbond lengths (in Å), and dihedrals for different conformers oftransition state TS1 and zwitterion 17f.
Mentions: Although the uncatalyzedreaction between the aldehyde and the amine results in low yieldsof the corresponding benzoxazines (Table 1),this background reaction is important for the acid-catalyzed reactionas well. Therefore, we first carefully analyzed the mechanism forthe prototypic reaction between salicylaldehyde (7) andtetrahydroisoquinoline (THIQ) in toluene solution in the absence ofany catalyst (cf. Scheme 8). The calculatedfree energy profile is depicted in Figure 2 (black lines), and selected calculated structures are discussedin Figures 3–5.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States.

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.

Show MeSH
Related in: MedlinePlus