A Convergent Synthesis of AR-C123196 Utilising Reaction Between a Cyclic Carbonate and a Phenol for Aryl Alkyl Ether Formation

Allsop, Glyn L.; Cole, Andrea J.; Giles, Melvyn; Merifield, Eric; Noble, Allison J.; Pritchett, Michael; Purdie, L.; Singleton, John T.

doi:10.1021/op9000687

Cited by 23 publications

(16 citation statements)

References 31 publications

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“…Both aryl-and heteroaryl-substituted thiophenes are common in drug candidates, [18,39] and oligo-and polythiophenes have found numerous applications as electron-conducting materials and photosensitizers in solar cell research. [40] Suzuki coupling has often been used for the synthesis of these compounds.…”

Section: Scope Of Heteroarylboronic Acidsmentioning

confidence: 99%

Room‐Temperature Suzuki–Miyaura Coupling of Heteroaryl Chlorides and Tosylates

et al. 2012

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Suzuki–Miyaura coupling of heteroaryls is an important method for the preparation of compound libraries for medicinal chemistry and materials research. Although many catalysts have been developed, none of them have been generally applicable to the coupling reactions of heteroaryl chlorides and tosylates at room temperature. We discovered that a catalyst combination of Pd(OAc)2 and XPhos (2‐dicyclohexylphosphanyl‐2′,4′,6′‐triisopropylbiphenyl) could efficiently catalyze these couplings. Besides the choice of catalyst, the use of hydroxide bases in an aqueous alcoholic solvent was essential for fast couplings. These conditions promoted fast release of active catalyst (XPhos)Pd0, and accelerated the transmetalation in the catalytic cycle. Most of the major families of heteroaryl chlorides (31 examples) and tosylates (17 examples) reached full conversion within minutes to hours at room temperature. The method could be easily scaled up for gram‐scale synthesis. Furthermore, we examined the relative reactivity of coupling partners in whole reactions. Electron‐rich heteroaryl chlorides and tosylates reacted more slowly than electron‐deficient ones, in the order of indole, pyrrole < furan, thiophene < pyridine and other six‐membered‐ring azines. For heteroarylboronic acids, the reactivity ranking was reversed: indole, pyrrole > furan, thiophene > pyridine. Similarly, electron‐deficient arylboronic acids were less reactive than electron‐neutral and electron‐rich ones. The reactivity trends from this study can help to choose appropriate coupling partners for Suzuki reactions.

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Section: Scope Of Heteroarylboronic Acidsmentioning

confidence: 99%

Room‐Temperature Suzuki–Miyaura Coupling of Heteroaryl Chlorides and Tosylates

et al. 2012

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“…A team at AstraZeneca, in 2009, used this reaction to access ∼16 kg of a key biaryl intermediate that led to a candidate for the treatment of inflammatory and allergic conditions such as asthma and rhinitis (Scheme 1.44) [144].…”

Section: Recent New Developments 67mentioning

confidence: 99%

“…Pd(OAc) 2 (1 mol%), P(p-toly) 3 44 AstraZeneca's multi-kilogram synthesis of a key lead candidate for asthma and rhinitis [144].…”

Section: Recent New Developments 67mentioning

confidence: 99%

Cross‐Coupling Arylations: Precedents and Rapid HistoricalReview of the Field

2014

Catalytic Arylation Methods

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“…4 A typical example is GNF-2, an allosteric inhibitor, 14 and other examples include a PDE-4 inhibitor for treatment of asthma, 15 a subtype-selective GABA A receptor agonist for treatment of anxiety, 16 and AR-C123196 for treatment of asthma and rhinitis. 17 Suzuki coupling of heteroaryls have also been applied in total syntheses of bioactive natural products, such as dragmacidin D and F, 18 ratanhine, 19 and diazonamide A. 20…”

Section: Coot-bumentioning

confidence: 99%

“…(Hetero)aryl-substituted thiophenes are common in drug candidates 17,34 and oligoand polythiophenes are widely used in electron-conducting materials and photosensitizers in solar cells. 35 Suzuki coupling was often used to synthesize these compounds.…”

Section: Conditions Optimizationmentioning

confidence: 99%

Part I Catalytic asymmetric arylation of esters for profen synthesis Part II Fast Suzuki coupling of heteroaryl chlorides

Yang¹

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Transition metal-catalyzed cross-coupling reaction has become a useful methodology for the formation of CC bond. This thesis describes two new improved methods of the CC bond formation catalyzed by palladium catalyst. Chapter one reports a general method of palladium-catalyzed coupling of ester to produce tertiary carbon centers with high yield and exellent ee. It offers a general method for the synthesis of profen drugs. Aryl triflates carrying para-elctron-withdrawing and electron-donating groups are tolerated. Vinyl triflates can also be converted to the corresponding vinyl ester with excellent ee. The use of a new biarylphosphine improved stereoselectivity as compared to the previously reported catalyst. The two CF 3 groups on the benzyl side chain of the ligand may acidify the benylic CH bonds. This probably makes the C-H bond better hydrogen donors in the interaction with Pd-bound enolate, which is responsible for excellent stereoinduction and ligand design. Chapter two describes a new catalytic system for Suzuki-Miyaura coupling of heteroaryl chlorides and heteroayl boronic acids. Most of the major families of heteroaryl chlorides can reached full conversion within minutes to hours at room temperature. The relative reactivity of coupling partners is also studied in this part. Firstly, for heteroaryl chloride, the more electron-rich ones reacted more slowly than electron-deficient ones because of the slower oxidative addition. Secondly, for the heteroarylboronic acids, the more electron-deficient ones reacted more slowly.

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A Convergent Synthesis of AR-C123196 Utilising Reaction Between a Cyclic Carbonate and a Phenol for Aryl Alkyl Ether Formation

Abstract: The development of a convergent synthesis of AR-C123196 is reported in which the alkyl aryl ether linkage was formed by nucleophilic attack of a phenolic hydroxyl group onto a cyclic carbonate. This approach was successfully operated on a multikilogram scale.

Cited by 23 publications

References 31 publications

Room‐Temperature Suzuki–Miyaura Coupling of Heteroaryl Chlorides and Tosylates

Room‐Temperature Suzuki–Miyaura Coupling of Heteroaryl Chlorides and Tosylates

Cross‐Coupling Arylations: Precedents and Rapid HistoricalReview of the Field

Part I Catalytic asymmetric arylation of esters for profen synthesis Part II Fast Suzuki coupling of heteroaryl chlorides

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