What can reaction databases teach us about Buchwald–Hartwig cross-couplings?

Fitzner, Martin; Wuitschik, Georg; Koller, Raffael J.; Adam, Jean-Michel; Schindler, Thorsten; Reymond, Jean‐Louis

doi:10.1039/d0sc04074f

Cited by 55 publications

(63 citation statements)

References 30 publications

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“…We identified four ligands commonly employed in the palladium-catalyzed synthesis of triarylamines, namely Pd(OAc) 2 /P( t Bu) 3 , XantPhos Pd G4, RuPhos Pd G4, and PEPPSI-IPr (Fig. 3b ) 38 . The goals of this study were to: (1) understand how ligand choice affects the evolution of intermediates throughout the course of the reaction, with a focus on ring walking behavior, (2) probe the influence of the catalyst resting state on ring walking, (3) investigate the generality of our findings on alternate polyhalogenated cores, and (4) identify conditions which could provide access to asymmetric SpiroOMeTAD derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…We began our study by probing P( t Bu) 3 as the ligand. The combination of Pd(OAc) 2 /P( t Bu) 3 5 , 10 , 38 , 39 was targeted as it is the most frequently employed catalyst system used in the synthesis of SpiroOMeTAD and its derivatives. The standard time course data of Pd(OAc) 2 /P( t Bu) 3 can be seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We then turned our attention to the use of a bidentate phosphine system. XantPhos was targeted as a representative ligand as it is commonly employed in the coupling of diarylamines 38 and has been reported in the synthesis of 6 42 . The XantPhos Pd G4 precatalyst was employed to overcome irreproducible catalyst activation behavior.…”

Section: Resultsmentioning

confidence: 99%

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Ring walking as a regioselectivity control element in Pd-catalyzed C-N cross-coupling

et al. 2022

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Ring walking is an important mechanistic phenomenon leveraged in many catalytic C-C bond forming reactions. However, ring walking has been scarcely studied under Buchwald-Hartwig amination conditions despite the importance of such transformations. An in-depth mechanistic study of the Buchwald-Hartwig amination is presented focussing on ligand effects on ring walking behavior. The ability of palladium catalysts to promote or inhibit ring walking is strongly influenced by the chelating nature of the ligand. In stark contrast, the resting state of the catalyst had no impact on ring walking behavior. Furthermore, the complexity of the targeted system enabled the differentiation between catalysts which undergo ring walking versus diffusion-controlled coupling. The insights gained in this study were leveraged to achieve desymmetrization of a tetrabrominated precursor. A small library of asymmetric 2,2′,7,7′-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9’spirobifluorene (SpiroOMeTAD) derivatives were successfully synthesized using this strategy highlighting the ease with which libraries of these compounds can be accessed for screening.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Ring walking as a regioselectivity control element in Pd-catalyzed C-N cross-coupling

et al. 2022

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“…It is particularly essential for the arylation and modification of aromatic core and palladium cross-coupling. Cross-coupling of amines with aryl halides or pseudo halides is common [39]. Without the aryl halide, no reaction will be prompted, and the palladium catalyst assists in the instantaneous reaction.…”

Section: Analysis Of Important Descriptorsmentioning

confidence: 99%

Reactions’ Descriptors Selection and Yield Estimation Using Metaheuristic Algorithms and Voting Ensemble

Petinrin¹,

Saeed²,

Li³

et al. 2022

Computers, Materials &Amp; Continua

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Bioactive compounds in plants, which can be synthesized using N-arylation methods such as the Buchwald-Hartwig reaction, are essential in drug discovery for their pharmacological effects. Important descriptors are necessary for the estimation of yields in these reactions. This study explores ten metaheuristic algorithms for descriptor selection and model a voting ensemble for evaluation. The algorithms were evaluated based on computational time and the number of selected descriptors. Analyses show that robust performance is obtained with more descriptors, compared to cases where fewer descriptors are selected. The essential descriptor was deduced based on the frequency of occurrence within the 50 extracted data subsets, and better performance was achieved with the voting ensemble than other algorithms with RMSE of 6.4270 and R 2 of 0.9423. The results and deductions from this study can be readily applied in the decision-making process of chemical synthesis by saving the computational cost associated with initial descriptor selection for yield estimation. The ensemble model has also shown robust performance in its yield estimation ability and efficiency.

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“…145,146,187 "Local" approaches to condition prediction treat a specific reaction family. [188][189][190] Global approaches to product and yield prediction have addressed outcome prediction 111,112,168,[191][192][193] or selectivity. [194][195][196][197][198] Local approaches to product and yield prediction have addressed high throughput experimentation of a single type 199,200 and catalyst screening.…”

Section: Data-driven Synthesis Planning Beyond Retrosynthesismentioning

confidence: 99%

National Institutes of Health (NIH) Workshop on Reaction Informatics

Warr¹

2021

Preprint

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The virtual workshop took place on May 18-20, 2021. It was a follow-up from the December 2020 NIH Workshop on Ultra Large Chemistry Databases. A major theme emerging from the December 2020 workshop was the fact that all the databases of a billion or more structures are virtual. For each virtual molecule the question then arises of whether, or how, it can be synthesized. The organizers therefore assembled speakers to give presentations about how reaction-related data are represented, captured, managed in databases, analyzed, used for drug design, applied in robotics, and exchanged locally as well as globally. This report summarizes talks from 27 practitioners in the reaction informatics field. The aim is to represent as accurately as possible the information that was delivered by the speakers; the report does not seek to be evaluative. The themes, in the order used for this report, were reaction representations, file formats, and standards; sources of reaction data; AI and machine learning applications of reaction-related data in de novo drug design, synthetic accessibility, synthesis planning, reaction prediction etc.; and automation and progression toward autonomous synthesis.

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What can reaction databases teach us about Buchwald–Hartwig cross-couplings?

Abstract: Despite the widespread and increasing usage of Pd-catalyzed C-N cross couplings, finding good conditions for these reactions can be challenging. Practitioners mostly rely on few methodology studies or anecdotal experience....

Cited by 55 publications

References 30 publications

Ring walking as a regioselectivity control element in Pd-catalyzed C-N cross-coupling

Ring walking as a regioselectivity control element in Pd-catalyzed C-N cross-coupling

Reactions’ Descriptors Selection and Yield Estimation Using Metaheuristic Algorithms and Voting Ensemble

National Institutes of Health (NIH) Workshop on Reaction Informatics

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