Optimization of an Efficient and Sustainable Sonogashira Cross-Coupling Protocol

Handle URI:
http://hdl.handle.net/10754/262732
Title:
Optimization of an Efficient and Sustainable Sonogashira Cross-Coupling Protocol
Authors:
Walter, Philipp E.
Abstract:
Cross coupling reactions are a well-established tool in modern organic synthesis and play a crucial role in the synthesis of a high number of organic compounds. Their importance is highlighted by the Nobel Prize in chemistry to Suzuki, Heck and Negishi in 2010. The increasing importance of sustainability requirements in chemical production has furthermore promoted the development of cross-coupling protocols that comply with the principles of “Green Chemistry”1. The Sonogashira reaction is today the most versatile and powerful way to generate aryl alkynes, a moiety recurring in many pharmaceutical and natural products. Despite many improvements to the original reaction, reports on generally applicable protocols that work under sustainable conditions are scarce. Our group recently reported an efficient protocol for a copperfree Sonogashira cross-coupling at low temperature, in aqueous medium and with no addition of organic solvents or additives2. The goal of this work was to further investigate the effects of different reaction parameters on the catalytic activity in order to optimize the protocol. Limitations of the protocol were tested in respect to reaction temperature, heating method, atmosphere, base type and amount, catalyst loading, reaction time and work up procedure. The reaction worked successfully under air and results were not affected by the presence of oxygen in the water phase. Among a variety of bases tested, triethylamine was confirmed to give the best results and its required excess could be reduced from nine to four equivalents. Catalyst loading could also be reduced by up to 90%: Good to near quantitative yields for a broad range of substrates were achieved using a catalyst concentration of 0.25mol% and 5 eq of Et3N at 50°C while more reactive substrates could be coupled with a catalyst concentration as low as 0.025mol%. Filtration experiments showed the possibility of a simplified work up procedure and a protocol completely free of organic solvents. This optimized protocol can be applied to a broad range of substrates, delivers high yields, avoids formation of toxic byproducts, works under air and aqueous conditions, allows for simple product isolation and thus meets not only the criteria of “Green Chemistry” but also those of “Click-Chemistry”
Advisors:
Eppinger, Jörg ( 0000-0001-7886-7059 )
Committee Member:
Huang, Kuo-Wei ( 0000-0003-1900-2658 ) ; Takanabe, Kazuhiro ( 0000-0001-5374-9451 )
KAUST Department:
Physical Sciences and Engineering (PSE) Division
Program:
Chemical Sciences
Issue Date:
Dec-2012
Type:
Thesis
Appears in Collections:
Theses; Physical Sciences and Engineering (PSE) Division; Chemical Science Program

Full metadata record

DC FieldValue Language
dc.contributor.advisorEppinger, Jörgen
dc.contributor.authorWalter, Philipp E.en
dc.date.accessioned2012-12-15T10:22:51Zen
dc.date.available2012-12-15T10:22:51Zen
dc.date.issued2012-12en
dc.identifier.urihttp://hdl.handle.net/10754/262732en
dc.description.abstractCross coupling reactions are a well-established tool in modern organic synthesis and play a crucial role in the synthesis of a high number of organic compounds. Their importance is highlighted by the Nobel Prize in chemistry to Suzuki, Heck and Negishi in 2010. The increasing importance of sustainability requirements in chemical production has furthermore promoted the development of cross-coupling protocols that comply with the principles of “Green Chemistry”1. The Sonogashira reaction is today the most versatile and powerful way to generate aryl alkynes, a moiety recurring in many pharmaceutical and natural products. Despite many improvements to the original reaction, reports on generally applicable protocols that work under sustainable conditions are scarce. Our group recently reported an efficient protocol for a copperfree Sonogashira cross-coupling at low temperature, in aqueous medium and with no addition of organic solvents or additives2. The goal of this work was to further investigate the effects of different reaction parameters on the catalytic activity in order to optimize the protocol. Limitations of the protocol were tested in respect to reaction temperature, heating method, atmosphere, base type and amount, catalyst loading, reaction time and work up procedure. The reaction worked successfully under air and results were not affected by the presence of oxygen in the water phase. Among a variety of bases tested, triethylamine was confirmed to give the best results and its required excess could be reduced from nine to four equivalents. Catalyst loading could also be reduced by up to 90%: Good to near quantitative yields for a broad range of substrates were achieved using a catalyst concentration of 0.25mol% and 5 eq of Et3N at 50°C while more reactive substrates could be coupled with a catalyst concentration as low as 0.025mol%. Filtration experiments showed the possibility of a simplified work up procedure and a protocol completely free of organic solvents. This optimized protocol can be applied to a broad range of substrates, delivers high yields, avoids formation of toxic byproducts, works under air and aqueous conditions, allows for simple product isolation and thus meets not only the criteria of “Green Chemistry” but also those of “Click-Chemistry”en
dc.language.isoenen
dc.subjectsonogashiraen
dc.subjectcross-couplingen
dc.subjectwateren
dc.subjectpalladiumen
dc.subjectgreenen
dc.titleOptimization of an Efficient and Sustainable Sonogashira Cross-Coupling Protocolen
dc.typeThesisen
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
thesis.degree.grantorKing Abdullah University of Science and Technologyen_GB
dc.contributor.committeememberHuang, Kuo-Weien
dc.contributor.committeememberTakanabe, Kazuhiroen
thesis.degree.disciplineChemical Sciencesen
thesis.degree.nameMaster of Scienceen
dc.person.id118580en
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