A simple three-component olefin coupling procedure

Turos, Edward; Boy, Kenneth; Ren, Xiao

doi:10.1021/jo00050a061

Cited by 11 publications

(5 citation statements)

References 1 publication

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“…We therefore tried to further improve this two-step manufacturing method and focused on the investigation of a one-pot reaction process, − which did not require isolation of 9 and could be carried out under anhydrous conditions (LiOH·H 2 O not used as a base).…”

Section: Resultsmentioning

confidence: 99%

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Matsuura

Sato

Nishino

et al. 2020

Org. Process Res. Dev.

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We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner−Wadsworth−Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.

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Section: Resultsmentioning

confidence: 99%

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Matsuura

Sato

Nishino

et al. 2020

Org. Process Res. Dev.

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“…A method was developed to functionalize the surface of the beads with vinyl groups based on the Arbusov and Wadsworth−Emmons reactions. This method was adapted from the procedure described by Turos et al and has been used in our research for the preparation of polymer-supported reagents with increased ligand density . The basis for this technique is the modification of −CH 2 Cl groups to phosphonate diesters followed by conversion to vinyl groups with phenyllithium and DMF (eq 1).…”

Section: Resultsmentioning

confidence: 99%

“…A procedure by Turos et al was adapted to convert the polymer-bound phosphonate diesters to carbon−carbon double bonds. A 100 mL volume of N , N -dimethylformamide (DMF) was added to 10 g of the beads and the mixture stirred 2 h as it was cooled in an ice bath.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of High-Stability Solvent-Impregnated Resins

Alexandratos

Ripperger

1998

Ind. Eng. Chem. Res.

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A copolymer comprised of glycidyl methacrylate and N,N-methylenebis(acrylamide) has been defined that can be used to coat solvent-impregnated resins (SIRs). Vinyl groups on the surface of a cross-linked macroporous support were used to anchor the polar copolymer to the surface of the bead. The coated SIR containing di(2-ethylhexyl)phosphoric acid maintained a high level of metal ion complexation (96% Cu(II)) over five cycles while the uncoated SIR dropped from 93% to 11% Cu(II) complexed in three cycles.

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“…Reports by our group 5 and others 6 have revealed that while N-carbinols of pyrrole are stable in their neutral state, they may be collapsed back to the parent carbonyl compound under basic conditions. This metastability lends itself to the possibility of a one-pot multicomponent formyl transfer/aldehyde trapping procedure 7,8 using Nformyl heterocycles as the reagent (Scheme 1) and herein we wish to report our findings.…”

mentioning

confidence: 87%

A Simple One-pot Organometallic Formylation/Trapping Sequence UsingN-Formylcarbazole

Dixon¹,

Lucas²

2004

Synlett

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Treatment of a range of sp 3 -, sp 2 -and sp-nucleophiles with N-formyl carbazole leads to the formation of the metastable anionic carbazole carbinols. In the presence of a second nucleophilic reagent such as phosphonoacetate or an organolithium, these collapse on warming to the aldehyde which is trapped in situ to afford the a,b-unsaturated esters or secondary carbinols respectively.Methods for the formylation of organometallic reagents 1,2 have received much attention over the years due to the obvious synthetic utility of the one carbon homologation procedure and the wealth of reactions possible with the aldehyde product. 3,4 For sp 3 -, sp 2 -or sp-carbanions, the formylating agent is invariably based around an Nformylated amine, which is not only reactive towards the organometallic, but the resulting anionic carbinol is stable until dilute acidic work-up and only then is the aldehyde released. Reports by our group 5 and others 6 have revealed that while N-carbinols of pyrrole are stable in their neutral state, they may be collapsed back to the parent carbonyl compound under basic conditions. This metastability lends itself to the possibility of a one-pot multicomponent formyl transfer/aldehyde trapping procedure 7,8 using Nformyl heterocycles as the reagent (Scheme 1) and herein we wish to report our findings. Scheme 1Initially, N-formylpyrrole and N-formyl-3-methylindole were considered as potential candidates. However in the former case, synthesis was a major set-back and in the latter, the unpleasant odour associated with the skatole starting material focused our attention on other formylation sources. N-Formylcarbazole 2 was subsequently identified as the reagent of choice. The parent heterocycle is cheap and the synthesis can be efficiently carried out on a large scale by simply boiling carbazole 1 in formic acid for 8 hours and the product is isolated by crystallization (Scheme 2). 9 Scheme 2With multigram quantities of N-formylcarbazole 2 in hand, the sequential formylation/aldehyde trapping sequence was investigated. The addition of a range of nucleophiles to 2 was carried out at -78 °C, followed by the addition of Wadsworth-Horner-Emmons reagent. The resulting a,b-unsaturated esters were obtained in reasonable to good yields over the two steps (Scheme 3,

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A simple three-component olefin coupling procedure

Cited by 11 publications

References 1 publication

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Synthesis and Characterization of High-Stability Solvent-Impregnated Resins

A Simple One-pot Organometallic Formylation/Trapping Sequence UsingN-Formylcarbazole

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