Optimization of an Efficient and Sustainable Sonogashira Cross-Coupling Protocol
Type
ThesisAuthors
Walter, Philipp E.Advisors
Eppinger, Jörg
Committee members
Huang, Kuo-Wei
Takanabe, Kazuhiro

Program
Chemical ScienceKAUST Department
Physical Science and Engineering (PSE) DivisionDate
2012-12Embargo End Date
2015-01-01Permanent link to this record
http://hdl.handle.net/10754/262732
Metadata
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At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis became available to the public after the expiration of the embargo on 2015-01-01.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”Citation
Walter, P. E. (2012). Optimization of an Efficient and Sustainable Sonogashira Cross-Coupling Protocol. KAUST Research Repository. https://doi.org/10.25781/KAUST-126ZNae974a485f413a2113503eed53cd6c53
10.25781/KAUST-126ZN