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Title: Chemoselective Suzuki-Miyaura cross-coupling enabled by speciation control
Author: Fyfe, James William Buchanan
ISNI:       0000 0004 6349 8192
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2017
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Boronic acids and esters are one of the most widely used compound classes inorganic chemistry. Recently, diboron systems have emerged as a powerful approach towards complex molecule synthesis. Selectivity in these systems is typically achieved through the use of protecting group strategies in which one boron residue is rendered unreactive under the prevailing reaction conditions, allowing selective manipulation of an unprotected unit. However, while these methods offer excellent selectivity, they do have the drawback of requiring additional synthetic manipulations, i.e., removal of the protecting group to allow subsequent functionalisation, limiting the overall efficiency of these processes. Boronic acids and esters undergo complex equilibria in solution. We have shown that control of these equilibria has been leveraged during the Suzuki-Miyaura reaction to enable the formation of a new, reactive BP in ester without the need for additional protecting group manipulations. Extensive optimisation identified that the nature of the base and quantity of water in the reaction were key in controlling the speciation events in the reaction. This allowed the generation of a broad substrate scope of formally homologated BPin esters. These newly generated reactive boron species were then reacted in situ in an iterative process, forming either terminal triaryl or contolled homologation products. The reaction was also found to have a temperature dependence, where under identical controlled basic conditions either the homologated BPin or the cross-coupled BMIDA species could be obtained based purely upon the temperature of the reaction. A series of control reactions aided in identifying the key processes in the reaction and, more importantly, the order in which these processes must occur in order to achieve the desired reaction. This work led to the development of methods to enable chemoselective reactions within non-protected diboron systems. This demonstrated how chemoselective Suzuki-Miyaura cross-coupling can be achieved within boronic acid/BPin esterdiboron systems by exploiting kinetic control of transmetallation while maintaining control of solution speciation events. This allows the selective reaction of boronic acids in the presence of BPin esters again without the need for protecting group manipulations, as either additional synthetic steps or in situ. Chemoselective transmetallation was then combined with chemoselective oxidative addition in order to establish the first complete chemoselective control over two of the three key mechanistic processes of the Suzuki-Miyaura reaction. This enables a one-pot sequential chemoselective Suzuki-Miyaura reaction without the requirement for any in situ modification of the reaction conditions (temperature change, sequential addition) or reactants (protecting group removal, boron species interconversion).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral