Continuous Flow Generation of Highly Reactive Organometallic Intermediates: A Recent Update

Spennacchio, Mauro; Natho, Philipp; Andresini, Michael; Colella, Marco

doi:10.1007/s41981-023-00292-y

Cited by 6 publications

(5 citation statements)

References 124 publications

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“…Encouragingly, addition to piperidone 4 at −20 °C provided a 46% assay yield of tetrahedral adduct 36 , along with 54% recovered 35 (entry 12). Taken together, these results suggested that it might be beneficial to further optimize the reaction as a continuous flow process by taking advantage of the short residence times it would afford …”

Section: Resultsmentioning

confidence: 99%

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4′-piperidine] Building Block

Pompeo,

Kelly,

St-Jean

et al. 2024

J. Org. Chem.

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An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular S N Ar reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

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Section: Resultsmentioning

confidence: 99%

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4′-piperidine] Building Block

Pompeo,

Kelly,

St-Jean

et al. 2024

J. Org. Chem.

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“…1, B, path b), and recently the limited functional groups tolerance of these highly reactive reagents has been overcome through the use of flow microreactor technology. 3 Neverthless, the direct one-step preparation of γ-hydroxy substituted derivatives is retrosynthetically precluded from the polar mechanisms due to a polarity mismatch (Fig. 1, B, path c).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Alcohols: Streamlined C1 to Cn Hydroxyalkylation through Photoredox Catalysis

Pasca,

Gelato,

Andresini

et al. 2024

Preprint

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Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO2-extrusion furnishing α-hydroxy radicals proved to be versatile C1 to Cn hydroxyalkylating agents. The decarboxylative direct Giese reaction (DDGR) is operationally simple, not requiring activator or sacrificial oxidants, and enables the synthesis of a diverse range of hydroxylated products, introducing connectivity typically precluded from conventional polar domains. Notably, the methodology has been extended to widely used glycolic acid resulting in a highly efficient and unprecedented C1 hydroxyhomologation tactic. The use of flow technology further facilitates scalability and adds green credentials to this synthetic methodology.

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“…1B , path b), and recently the limited functional group tolerance of these highly reactive reagents has been overcome through the use of flow microreactor technology. 3 Nevertheless, the direct one-step preparation of γ-hydroxy substituted derivatives is retrosynthetically precluded from the polar mechanisms due to a polarity mismatch ( Fig. 1B , path c).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of alcohols: streamlined C1 to Cn hydroxyalkylation through photoredox catalysis

Pasca,

Gelato,

Andresini

et al. 2024

Chem. Sci.

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Continuous Flow Generation of Highly Reactive Organometallic Intermediates: A Recent Update

Cited by 6 publications

References 124 publications

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4′-piperidine] Building Block

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4′-piperidine] Building Block

Synthesis of Alcohols: Streamlined C1 to Cn Hydroxyalkylation through Photoredox Catalysis

Synthesis of alcohols: streamlined C1 to Cn hydroxyalkylation through photoredox catalysis

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