Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up

Anthony Chartoire, Carmen Claver, Martin Corpet, Jamin Krinsky, Julie Mayen, David Nelson, Steven P. Nolan, Itziar Peñafiel, Robert Woodward, Rebecca E. Meadows

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “right-first-time” work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.
LanguageEnglish
Number of pages26
JournalOrganic Process Research and Development
Early online date28 Dec 2015
DOIs
Publication statusE-pub ahead of print - 28 Dec 2015

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carbenes
catalysts
Catalysts
Palladium
recycling
purification
Purification
Recycling
palladium
methodology
reuse
exploitation
retaining
Bromides
imidazoles
bromides
Salts
industries
carbene
salts

Keywords

  • Buchwald-Hartwig amination
  • NHC catalyst
  • palladium catalysis
  • catalyst recycle
  • continuous processing
  • flow chemistry
  • designed work-up

Cite this

Chartoire, Anthony ; Claver, Carmen ; Corpet, Martin ; Krinsky, Jamin ; Mayen, Julie ; Nelson, David ; Nolan, Steven P. ; Peñafiel, Itziar ; Woodward, Robert ; Meadows, Rebecca E. / Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up. In: Organic Process Research and Development. 2015.
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Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up. / Chartoire, Anthony; Claver, Carmen; Corpet, Martin; Krinsky, Jamin; Mayen, Julie; Nelson, David; Nolan, Steven P.; Peñafiel, Itziar; Woodward, Robert; Meadows, Rebecca E.

In: Organic Process Research and Development, 28.12.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up

AU - Chartoire, Anthony

AU - Claver, Carmen

AU - Corpet, Martin

AU - Krinsky, Jamin

AU - Mayen, Julie

AU - Nelson, David

AU - Nolan, Steven P.

AU - Peñafiel, Itziar

AU - Woodward, Robert

AU - Meadows, Rebecca E.

PY - 2015/12/28

Y1 - 2015/12/28

N2 - A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “right-first-time” work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.

AB - A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “right-first-time” work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.

KW - Buchwald-Hartwig amination

KW - NHC catalyst

KW - palladium catalysis

KW - catalyst recycle

KW - continuous processing

KW - flow chemistry

KW - designed work-up

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DO - 10.1021/acs.oprd.5b00349

M3 - Article

JO - Organic Process Research and Development

T2 - Organic Process Research and Development

JF - Organic Process Research and Development

SN - 1083-6160

ER -