1,5-bifunctional organomagnesium reagents for the direct transformation of esters into arenes

Link, Achim. 1,5-bifunctional organomagnesium reagents for the direct transformation of esters into arenes. 2018, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12681

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For the sustainable and economical supply of products relevant to our society, the development of new methods based on main group elements is indispensable. Arenes are privileged molecular scaffolds due to their stability, rigidity and their manifold use in functional or bioactive entities. Nowadays, transition metal catalyzed cross-coupling reactions are the most frequently employed and efficient methods to functionalize arenes by means of C – C bond formation. However, they require prefunctionalized coupling partners and remaining catalyst impurities are difficult to be removed to the required levels. Thus, transition-metal-free methods to synthesize substituted arenes from readily available starting materials are highly desirable. Carboxylic acid ester are ubiquitous intermediates in organic synthesis and are therefore the ideal substrates for the synthesis of arene derivatives.
In this thesis the development of a one step transformation of carboxylic acid esters into substituted arenes with 1,5 bifunctional organomagnesium reagents is described. The Grignard reagents react with the esters in a twofold nucleophilic addition, which is followed by an ensuing 1,4 elimination, incorporating the carboxylic carbon-atom into the newly formed aromatic ring. Various arene derivatives like substituted benzenes and polycyclic aromatic hydrocarbons like anthracenes, tetracenes and pentacenes were synthesized in yields up to 99%.
The remarkable advancement of mild halogen magnesium exchange reactions over the recent years allowed to access a 1,5-dimagnesium-1,4-pentadiene reagent from the corresponding diiodo-precursor. The reagent was utilized to efficiently convert esters into substituted benzene. Various derivatives such as aryl-, heteroaryl-, alkenyl- and alkyl-substituted benzenes were prepared in yields up to 82% by this direct [5+1]-benzene-forming reaction under mild conditions.
The corresponding 1,5 bifunctional bifunctional arylic organomagnesium reagents were obtained by the direct oxidative addition of elemental magnesium into the Ar – Br bond of o,o' dibromoarylmethanes. These reagents show a higher stability in comparison to the pentadiene-Grignard reagent and react with esters at room temperature with extraordinary efficiency. Even mono-substituted pentacenes, sensitive to light and oxygen can be successfully prepared by this mild method in yields up to 97%.
An organomagnesium alkoxide reagent prepared by a deprotonation-magnesiation sequence from readily available bis(2-bromophenyl)methanol allowed the synthesis of disubstituted anthracenes and anthrones. Halogen-substituted and reduced derivatives were obtained by variation of the workup conditions in one synthetic step. Workup with aq. HCl (1M) allowed to isolate the corresponding cis-diol in excellent yield. Remarkably, a high level of diastereoselectivity was observed, which presumably is a result of coordination of the alkoxide metal to the ester carboxyl oxygen in the second addition step.
Based on this observation, the preparation of a chiral 1,5 bifunctional organomagnesium alkoxide reagent derived from a chiral propargylic alcohol was developed. This allowed to implement a stereoselective direct ester to naphthalene transformation by means of central to axial chirality conversion giving direct access to valuable axially chiral TMS-substituted naphthalenes.
Full stereospecificity was observed with substrates with sufficient substitution. Moreover, products with low rotational barriers could be efficiently prepared under the mild reaction conditions with good stereoselectivity. Intriguingly, complete reversal of the stereoselectivity was observed in the transformation of a unprotected deprotonated indole-ester.
Advisors:Sparr, Christof and Mayor, Marcel
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Link, Achim and Sparr, Christof and Mayor, Marcel
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12681
Thesis status:Complete
Number of Pages:1 Online-Ressource (X, 257 Seiten)
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edoc DOI:
Last Modified:24 Sep 2021 09:18
Deposited On:10 Jul 2018 12:22

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