Nickel-Catalyzed <i>N</i>-Arylation of Cyclopropylamine and Related Ammonium Salts with (Hetero)aryl (Pseudo)halides at Room Temperature
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Bibliographic record
Abstract
Whereas the metal-catalyzed C(sp 2 )–N cross-coupling of cyclopropylamine with aryl electrophiles represents an attractive route to pharmaceutically relevant N -arylcyclopropylamines, few catalysts that are capable of effecting such transformations have been identified. Herein, the nickel-catalyzed C(sp 2 )–N cross-coupling of cyclopropylamine and related nucleophiles, including ammonium salts, with (hetero)aryl (pseudo)halides is reported for the first time, with the demonstrated scope of reactivity exceeding that displayed by all previously reported catalysts (Pd, Cu, or other). Our preliminary efforts to effect the N -arylation of cyclopropylamine with (hetero)aryl chlorides at room temperature by use of ( L )NiCl( o -tolyl) precatalysts ( L = PAd-DalPhos, C1; L = JosiPhos CyPF-Cy, C2 ) were unsuccessful, despite the established efficacy of C1 and C2 in transformations of other primary alkylamines. However, systematic modification of the ancillary ligand ( L ) structure enabled success in such transformations, with crystallographically characterized ( L )NiCl( o -tolyl) precatalysts incorporating o -phenylene-bridged bisphosphines featuring phosphatrioxaadamantane and PCy 2 ( L = L3, CyPAd-DalPhos; C3 ), P( o -tolyl) 2 and P( t -Bu) 2 ( L = L4; C4 ), or PCy 2 and P( t -Bu) 2 ( L = L5; C5 ) donor pairings proving to be particularly effective. In employing the air-stable precatalyst C3 in cross-couplings of cyclopropylamine, substituted electrophiles encompassing an unprecedentedly broad range of heteroaryl (pyridine, isoquinoline, quinoline, quinoxaline, pyrimidine, purine, benzothiophene, and benzothiazole) and (pseudo)halide (chloride, bromide, mesylate, tosylate, triflate, sulfamate, and carbamate) structures were employed successfully, in the majority of cases under mild conditions (3 mol % of Ni, 25 °C). Preliminary studies also confirmed the ability of C3 to effect the N -arylation of cyclopropanemethylamine hydrochloride and cyclobutylamine hydrochloride under similar conditions. A notable exception in this chemistry was observed specifically in the case of electron-rich aryl chlorides, where the use of C4 in place of C3 proved more effective. In keeping with this observation, catalyst inhibition by 4-chloroanisole was observed in the otherwise efficient cross-coupling of cyclopropylamine and 3-chloropyridine when using C3 . Competition studies involving C3 revealed a (pseudo)halide reactivity preference (Cl > Br, OTs).
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it