Metal-Catalyzed Approaches toward the Oxindole Core
Bibliographic record
Abstract
Conspectus The oxindole scaffold is a privileged structural motif that is found in a variety of bioactive targets and natural products. Moreover, derivatives of the oxindole structure are widely present in a number of biologically relevant compounds and are key intermediates in the synthesis of diverse natural products and pharmaceuticals. Therefore, novel methods to obtain oxindoles remain of high priority in synthetic organic chemistry. Over the past several decades, novel transition-metal-catalyzed methodologies have been applied toward the synthesis of a variety of heterocycles. A detailed mechanistic understanding facilitates the disruption of traditional catalytic pathways to access useful synthetic intermediates. The strategies employed have generally revolved around the generation of high-energy organometallic intermediates, which undergo cyclization reactions through domino processes. Domino cyclization methodologies are therefore attractive, as they allow facile access to functionalized oxindoles containing all-carbon quaternary centers or tetrasubstituted olefins with high chemo- and stereoselectivities. Furthermore, these developed synthetic strategies can often be easily applied in the syntheses of other related scaffolds. In this Account, we discuss the three unique strategies that our group has leveraged for the synthesis of valuable oxindole scaffolds. The first section in this Account outlines the use of an initial oxidative addition to a C(sp 2 )–X bond, followed by a migratory insertion, yielding a neopentyl species amenable to a variety of subsequent functionalizations. From this reactive neopentyl metal species, we have reported C–X reductive eliminations, anionic capture cascade reactions, and intramolecular C–H functionalization processes. The second section of this Account summarizes our group’s findings on 1,2-insertions of a metal–nucleophile species across an unsaturation, generating a reactive organometallic intermediate; subsequent reactions with tethered electrophiles form the desired heterocyclic core. We have explored a wide array of transition metal-catalyzed strategies using this approach, including rhodium-catalyzed conjugate additions, an asymmetric copper-catalyzed borylcupration, and a palladium(II)-catalyzed chloropalladation protocol. The final section of this Account details the use of dual-metal catalysis to perform a cyclization through a C–H functionalization–allylation domino reaction. Throughout this Account, we provide details of mechanistic studies that better enabled our understanding of the domino processes. Overall, our group has developed methods exploiting the unique reactivity of palladium, nickel, copper, rhodium, and ruthenium catalysts to develop methods toward a wide array of oxindole scaffolds. On the basis of the utility, diversity, and applicability of the strategies developed, we believe that they will prove to be highly useful in the syntheses of other important targets and inspire further development and mechanistic understanding of various metal-catalyzed processes.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".