Catalytic synthesis of N-heterocycles and alpha-alkylated amines by hydroamination and hydroaminoalkylation
Bibliographic record
Abstract
The research presented in this thesis emphasizes the versatility and utility of N,O-chelated early transition metals for the catalytic synthesis of -alkylated amines. Two major transformations were studied extensively in this work, hydroamination and hydroaminoalkylation. For both reactions, the synthetic utility and substrate scope has been expanded by the work presented herein. In the field of hydroamination, N-heterocycles with more than one heteroatom can now be synthesized using early transition metal catalysts from prochiral substrates. Hydroamination with a bis(amidate)bis(amido) complex of titanium of ether-containing aminoalkyne substrates yield cyclic imines, which are subsequently reduced via asymmetric transfer hydrogenation using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η⁶-p-cymene). 3-Substituted morpholines are synthesized using a one-pot sequential catalysis protocol, in good yields and high enantiomeric excesses. Substrate scope investigations reveal that high enantioselectivities in the asymmetric transfer hydrogenation reaction arise from key hydrogen bonding interactions between the oxygen heteroatom of the ether-containing cyclic imine and the [(S,S)-Ts-DPEN] ligand of Noyori-Ikariya catalyst. This mechanistic insight informed the proposal that this synthetic strategy can be extended to other substrates containing functional groups with hydrogen bond acceptors. As such, 3-substituted piperazines are also prepared with high enantioselectivities using this one-pot protocol. Advances to the hydroaminoalkylation transformation have also been made with the first reported example of room temperature reactivity observed using a phosphoramidate-tantalum complex. The preparation and characterization of a series of N,O-chelated phosphoramidate-tantalum complexes is described. These complexes were easily synthesized from either Ta(NMe₂)₅ by protonolysis or a simple organometallic precursor, TaMe₃Cl₂, by salt metathesis. Reactivity towards catalytic hydroaminoalkylation was explored and the results highlight that the choice of tantalum starting material dramatically affects the reaction temperatures required for catalytic turnover. N,O-chelated phosphoramidate dimethylamido tantalum complexes showed reactivity occurred only at elevated temperatures (≥ 90 °C), whereas phosphoramidate-tantalum complexes derived from TaMe₃Cl₂ exhibited unprecedented catalytic activity at room temperature. Preliminary efforts indicate that there is potential for an asymmetric version of hydroaminoalkylation at room temperature. Chiral phosphoramidate-tantalum complexes were prepared and studied as the first examples of asymmetric hydroaminoalkylation reactions at room temperature.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".