Carbonyl Desaturation: Where Does Catalysis Stand?

Gnaim, Samer; Vantourout, Julien C.; Serpier, Fabien; Echeverria, Pierre‐Georges; Baran, Phil S.

doi:10.1021/acscatal.0c04712

Cited by 66 publications

(46 citation statements)

References 64 publications

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“…Therefore, this work represents a step change in developing a direct, green synthesis route for para -aromatic aldehydes and guides the design of more efficient heterogeneous catalysts for this reaction. More importantly, this report shows an experimental example of an organic amine-catalyzed dehydrogenation reaction, which is different to the reported metal-dehydrogenation and stoichiometric-dehydrogenation processes ( Gnaim et al., 2021 ; Teskey et al., 2019 ; Mukaiyama et al., 2000 ).…”

Section: Resultscontrasting

confidence: 97%

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Direct synthesis of p-methyl benzaldehyde from acetaldehyde via an organic amine-catalyzed dehydrogenation mechanism

et al. 2021

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Summary p -Methyl benzaldehyde ( p -MBA) is a class of key chemical intermediates of pharmaceuticals. Conventional industrial processes for p -MBA production involve the consecutive photochlorination, amination, and acid hydrolysis of petroleum-derived p -xylene, while producing vast pollutants and waste water. Herein, we report a direct, green route for selective synthesis of p -MBA from acetaldehyde using a diphenyl prolinol trimethylsilyl ether catalyst. The optimized p -MBA selectivity is up to 90% at an acetaldehyde conversion as high as 99.8%. Intermediate structure and 18 O-isotope data revealed that the conversion of acetaldehyde to p -methylcyclohexadienal intermediates proceeds in an enamine-iminium intermediate mechanism. Then, controlled experiments and D-isotope results indicated that the dehydrogenation of p -methylcyclohexadienal to p -MBA and H 2 is catalyzed by the same amines through an iminium intermediate. This is an example that metal-free amines catalyze the dehydrogenation (releasing H 2 ), rather than using metals or stoichiometric oxidants.

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Section: Resultscontrasting

confidence: 97%

“…to obtain a clear aqueous solution. Then, the content of Pd, Ir, and Pt (which are reported active for oxidative dehydrogenation, Gnaim, et al., 2021 ) was analyzed by ICP-OES. The amount was calculated on basis of the peak area.…”

Section: Methodsmentioning

confidence: 99%

Direct synthesis of p-methyl benzaldehyde from acetaldehyde via an organic amine-catalyzed dehydrogenation mechanism

et al. 2021

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“…Although we were able to introduce the C5-C6 olefin by using m-iodoxybenzoic acid and Ph2Se2 55 to give 29, attempts to desaturate 29 to access 1 failed under various conditions. 56,57 Accordingly, we sought to install a hydroxyl group at C3 to facilitate late-stage introduction of the C3-C4 olefin.…”

Section: Scheme 1 Synthetic Challenge and Retrosynthetic Analysis Of Clionastatins A And Bmentioning

confidence: 99%

Asymmetric Total Synthesis of Clionastatins A and B

Wang

Tian

et al. 2021

Preprint

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Herein we report the first total synthesis of polychlorinated steroids clionastatins A and B, which was accomplished asymmetrically by means of a convergent, radical fragment coupling approach. Key features of the synthesis include an Ireland-Claisen rearrangement to introduce the C5 stereocenter (which was ultimately transferred to the C10 quaternary stereocenter of the clionastatins via a traceless stereochemical relay), a regioselective acyl radical conjugate addition to join the two fragments, an intramolecular Heck reaction to install the C10 quaternary stereocenter, and a diastereoselective olefin dichlorination to establish the synthetically challenging pseudoequatorial dichlorides. This work also enabled us to determine that the true structures of clionastatins A and B are in fact C14 epimers of the originally proposed structures.Chlorinated steroid drugs, such as the corticosteroids Temovate and Nasonex (Figure 1), are an important class of synthetic steroids

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“…As a result, α,β-unsaturated carbonyls are common building blocks in organic synthesis. Dehydrogenation reactions are therefore commonly employed in natural product and pharmaceutical synthesis, as reactive alkene groups are unveiled from their saturated counterparts …”

Section: Introductionmentioning

confidence: 99%

Dehydrogenative Pd and Ni Catalysis for Total Synthesis

Huang

Newhouse

2021

Acc. Chem. Res.

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The development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has enabled new mechanistic strategies to achieve difficult chemical transformations, increased the value of abundant chemical building blocks, and pushed the boundaries of creative and strategic route design to improve step economy in multistep synthesis. Methodologies to introduce an olefin into saturated molecules continue to be essential transformations because of the plethora of reactions available for alkene functionalization. Of particular importance are dehydrogenation reactions adjacent to electron-withdrawing groups such as carbonyls, which advantageously provide activated olefins that can be regioselectively manipulated. Palladium catalysis occupies a central role in the most widely adopted carbonyl dehydrogenation reactions, but limits to the scope of these protocols persist. In this Account, we describe our group's contributions to the area of transition-metalcatalyzed dehydrogenation using palladium catalysis and more sustainable and economical nickel catalysis. These metals are used in conjunction with allyl and aryl halides or pseudohalides that serve as oxidants to access a unique mechanistic approach for one-step α,β-dehydrogenation of various electron-withdrawing groups, including ketones, esters, nitriles, amides, carboxylic acids, and electron-deficient heteroarenes. The pivotal reaction parameters that can be modified to influence reaction efficiency are highlighted, including base and oxidant structure as well as ligand and salt additive effects. This discussion is expected to serve as a guide for troubleshooting challenging dehydrogenation reactions and provide insight for future reaction development in this area. In addition to enabling dehydrogenation reactions, our group's allyl-Pd and -Ni chemistry can be used for C−C and C−X bondforming reactions, providing novel disconnections with practical applications for expediting multistep synthesis. These transformations include a telescoped process for ketone α,β-vicinal difunctionalization; an oxidative enone β-functionalization, including β-stannylation, β-silylation, and β-alkylation; and an oxidative cycloalkenylation between unstabilized ketone enolates and unactivated alkenes. These bond-forming methodologies broaden the range of transformations accessible from abundant ketone, enone, and alkene moieties. Both the dehydrogenation and C−C and C−X bond-forming methodologies have been implemented in our group's total synthesis campaigns to provide step-efficient synthetic routes toward diverse natural products. Through the lens of multistep synthesis, the utility and robustness of our dehydrogenation and dehydrogenative functionalization methodologies can be better appreciated, and we hope that this Account will inspire practitioners to apply our methodologies to their own synthetic challenges.

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Carbonyl Desaturation: Where Does Catalysis Stand?

Cited by 66 publications

References 64 publications

Direct synthesis of p-methyl benzaldehyde from acetaldehyde via an organic amine-catalyzed dehydrogenation mechanism

Direct synthesis of p-methyl benzaldehyde from acetaldehyde via an organic amine-catalyzed dehydrogenation mechanism

Asymmetric Total Synthesis of Clionastatins A and B

Dehydrogenative Pd and Ni Catalysis for Total Synthesis

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