Directed Ortho Metalation in 2021: A Tribute to Victor Snieckus (August 1, 1937–December 18, 2020)

Knöchel, Paul; Cole, Kevin P.

doi:10.1021/acs.oprd.1c00271

Cited by 6 publications

(2 citation statements)

References 57 publications

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“…As a strategy to build more complex molecules, the use of directed ortho-metalation has a long and historied use. 4 In investigating routes for the formation of 4, it was hoped that the electronics of an aryl fluorine in the starting material 7 ortho to the position desired could direct a lithiation electronically. The generated lithiate could be treated with dimethyl formamide to furnish desired aldehyde 8, which can also be purchased commercially, albeit with limited availability.…”

Section: ■ Introductionmentioning

confidence: 99%

Process Development for a 1H-Indazole Synthesis Using an Intramolecular Ullmann-Type Reaction

2023

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Within the scope of developing a new route to an active pharmaceutical ingredient intermediate, we had need of a fluorinated indazole. Although an established route was in place, it was undesirable due to safety and selectivity concerns. A concise and improved route was developed to form the desired indazole, which takes advantage of an electronically directed metalation/formylation sequence followed by condensation with methyl hydrazine to form a hydrazone and culminates in a copper-catalyzed intramolecular Ullmann cyclization. The Ullmann reaction was plagued with difficulties ranging from poor reactivity to thermal hazard concerns, but use of high-throughput screening, statistical modeling, and an unusual isolation method for fine chemicals, safe and optimal conditions were found that produce high-purity isolated material in excellent yields at a laboratory scale.

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Section: ■ Introductionmentioning

confidence: 99%

Process Development for a 1H-Indazole Synthesis Using an Intramolecular Ullmann-Type Reaction

2023

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“…Similar problems were reported in other publications on the synthesis of licochalcone C (Scheme 1, B): the yield of compound 3 a did not exceed 25 %. [8][9][10] In this work, we have aimed at an alternative synthetic approach to licochalcone C and some related natural products based on the directed ortho-metalation (DOM) [11,12] as a regioselective method to introduce the prenyl substituent. As in the previous approaches, retrosynthetic analysis of the target compound commenced with aldol transform (Scheme 1, C).…”

Section: Introductionmentioning

confidence: 99%

Regioselective and Scalable Total Synthesis of Licochalcone C and Related Licoagrochalcones

et al. 2022

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A novel efficient method for the synthesis of licochalcone C in good yield on up to 30 g scale was developed. The reaction sequence included relied on the directed ortho‐metalation (DOM) of bis‐O‐MOM‐protected resorcinol for the regioselective C‐prenylation, followed by metalation‐formylation, selective O‐deprotection of a hydroxyl group located between the formyl and prenyl groups, its methylation, and aldol reaction with p‐hydroxyacetophenone. Synthesis of structurally related retrochalcones, i.e., licoagrochalcones B, C, and D, was also proposed.

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Enhancing Metalating Efficiency of the Sodium Amide NaTMP in Arene Borylation Applications

2022

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Though LiTMP (TMP=2,2′,6,6′‐tetramethylpiperidide) is a commonly used amide, surprisingly the heavier NaTMP has hardly been utilised. Here, by mixing NaTMP with tridentate donor PMDETA (N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine), we provide structural, and mechanistic insights into the sodiation of non‐activated arenes (e.g. anisole and benzene). While these reactions are low yielding, adding B(OiPr)3 has a profound effect, not only by intercepting the CAr‐Na bond, but also by driving the metalation reaction towards quantitative formation of more stabilized sodium aryl boronates. Demonstrating its metalating power, regioselective C2‐metalation/borylation of naphthalene has been accomplished contrasting with single‐metal based protocols which are unselective and low yielding. Extension to other arenes allows for in situ generation of aryl boronates which can then directly engage in Suzuki–Miyaura couplings, furnishing a range of biaryls in a selective and efficient manner.

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Directed Ortho Metalation in 2021: A Tribute to Victor Snieckus (August 1, 1937–December 18, 2020)

Abstract: A tribute to Professor Victor Snieckus is presented that highlights his many contributions to the field of organic chemistry and directed ortho metalation technology.

Cited by 6 publications

References 57 publications

Process Development for a 1H-Indazole Synthesis Using an Intramolecular Ullmann-Type Reaction

Process Development for a 1H-Indazole Synthesis Using an Intramolecular Ullmann-Type Reaction

Regioselective and Scalable Total Synthesis of Licochalcone C and Related Licoagrochalcones

Enhancing Metalating Efficiency of the Sodium Amide NaTMP in Arene Borylation Applications

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