University of Groningen
Carbon-carbon bond formations using organolithium reagents
Heijnen, Dorus
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Summary
From the pioneering work of Murhashi and Negishi in the 1970’s, the cross coupling of organolithium reagents has transformed to a viable alternative for more traditional and costly C-C bond forming reactions.
In chapter 2, we describe the coupling of the bifunctional (Trimethylsilyl)methyllithium, to afford TMS-substituted toluene derivatives. The commercially available alkyllithium reagent is coupled in high yields with both chlorides and bromides, by means of a Pd-PEPPSI carbene complex. The products after the cross coupling can be used for an array of further functionalization. Initial attempts in deprotonating the product at the benzylic position, and perform a second coupling were met with success, but were not further studied.
Scheme 1 Palladium catalysed coupling of bifunctional organolithium reagent
The first application of the palladium catalyzed cross coupling of organolithium reagents in the synthesis of a natural product is shown in chapter 3, shortening the total synthesis of Mastigophorene A by 12 steps with regard to the previous reported syntheses (Scheme 2A). In the search of combining reactions without having to switch reaction vessel, solvent or having any means of intermediate purification, the one pot reactions described in chapter 4 use organolithium reagents to yield (alpha substituted) ketones, aldehydes or anilines (scheme 2B).
For these transformations, the use of (Weinreb) amides is crucial, and the corresponding tetrahedral intermediate that is formed upon nucleophilic addition is either stabile under cross coupling conditions (for the synthesis of aldehydes) or liberates a lithium amide (for the synthesis of substituted ketones or anilines). In the presence of acidic alpha protons next to the generated carbonyl, the liberated lithium amide acts as in situ formed base and addition of an aryl bromide sets the stage for selective alpha arylation (chapter 4).
The high reactivity of organolithium reagents in combination with the catalyst described in chapters 2-5 that lead to cross coupling reactions at relatively low temperatures, and thus provide a promising reaction setup for an enantioselective version of which the attempts are described in chapter 5. Initial attempts with chiral versions of the commercially available Pd-PEPPSI complex showed only to be active with unhindered aryl-aryl coupling reactions, that would not yield stable atropoisomers. A short structure activity relationship study lead to a hypothesized bulky chiral Pd-PEPPSI complex. Its syntheses was attempted, but the initially proposed structures were not successfully synthesized. Alternative catalyst (Pd-PEPPSI-Mes*, Pd-PEPPSI-Box* and Pd-PEPPSI-IPr*) were made (Scheme 3A), but were found to be incapable of coupling hindered aryl substrates with satisfactory yields, much like the initially attempted complexes.
Scheme 3 Palladium and Nickel catalysts
Moving away from palladium, a screening of cheaper and more abundant metals in chapter 6 showed that nickel complexes Ni-NHC and Ni-DEPE (scheme 3B) were particularly active in the coupling of organolithium reagents with aryl bromides and chlorides, but also with less reactive aryl methyl ethers and aryl fluorides. Mechanistic studies were not performed, but reactivity in the substrate scope points towards a non-traditional catalytic cycle, facilitated by extended aromatic systems such as naphthalenes. Though the yields with the selected nickel complexes were generally a bit lower than with identical reactions catalyzed by palladium, the coupling of the mentioned less reactive electrophiles increased the scope significantly.
In order to avoid slow addition and speed up the cross coupling reaction, the oxygen activation of a Pd-phosphine complex was studied in chapter 7. After carefully studying the activation process, reaction times down to five seconds were possible. This new improved turnover speed made the
cross reaction outcompete other reactions such as the opening of epoxides. Furthermore, a broader range of electrophiles and nucleophiles were coupled in the presence of the new nanoparticle catalyst. The coupling of unstable isotopes with short half-lives (11C, 20 min) was used to showcase the potential of this methodology, and Celecoxib was successfully labelled in good radiochemical yield (Figure 1).
Figure 1 Biologically active compounds Celecoxib and Tamoxifen
Other applications of the oxygen activated, nanoparticle catalyst were found in the synthesis of tetra substituted olefins, the synthesis of Z-Tamoxifen in particular, and are described in chapter 8. The breast cancer drug was made via a direct carbolithiation-cross coupling strategy, giving the product in good yield. The synthesis distinguished itself from previously reported methods by its high atom economy and low step count. If the catalyst loading can be further lowered, the chromatography free synthesis could be an alternative to existing means of obtaining the pharmaceutical compound. Finally, the one pot procedure for the coupling of C, N and S nucleophiles with a chemoselectivity that is triggered by the reaction temperature is presented in chapter 9. Unprecedented palladium catalyzed cross coupling at -78 °C with aryl iodides is facilitated by specially designed metal-NHC complexes. Arene starting materials containing a bromide and chloride yielded the mono coupled product upon subjecting it to cross croupling conditions at -22 °C. The remaining aryl chloride could be coupled with an array of nucleophiles in a one pot fashion, by simply raising the reaction temperature, and the addition of a second coupling partner.
