Main group metal-mediated strategies for C-H and C-F bond activation and functionalisation of fluoroarenes.

With fluoroaromatic compounds increasingly employed as scaffolds in agrochemicals and active pharmaceutical ingredients, the development of methods which facilitate regioselective functionalisation of their C-H and C-F bonds is a frontier of modern synthesis. Along with classical lithiation and nucleophilic aromatic substitution protocols, the vast majority of research efforts have focused on transition metal-mediated transformations enabled by the redox versatilities of these systems. Breaking new ground in this area, recent advances in main group metal chemistry have delineated unique ways in which s-block, Al, Ga and Zn metal complexes can activate this important type of fluorinated molecule.

Alkali-Metal-Alkoxide Powered Zincation of Fluoroarenes Employing Zinc Bis-Amide Zn(TMP).

Reminiscent of Lochmann-Schlosser superbase recipes, the addition of two molar equivalents of KOtBu to Zn(TMP) (TMP=2,2,6,6-tetramethylpiperidide) transforms this mild zinc bis-amide base to a powerful metalating agent able to perform facile regioselective zincation of a wide range of sensitive fluoroarenes. Structural authentication of the intermediates post Zn-H exchange demonstrates activation of both TMP groups to form a range of higher order bis-aryl potassium zincates, isolable as solids and further functionalized in electrophilic interception reactions. Studies assessing the role of KOtBu reveal that the first equivalent undergoes co-complexation with Zn(TMP) , enabling kinetic activation of the amide groups; whereas the second equivalent stabilizes the metalated intermediate preventing ligand redistribution.

Assessing Alkali-Metal Effects in the Structures and Reactivity of Mixed-Ligand Alkyl/Alkoxide Alkali-Metal Magnesiates.

Advancing the understanding of using alkali-metal alkoxides as additives to organomagnesium reagents in Mg-Br exchange reactions, a homologous series of mixed-ligand alkyl/alkoxide alkali-metal magnesiates [MMg(CH SiMe ) (dmem)] [dmem=2-{[2-(dimethylamino)ethyl]methylamino} ethoxide; M=Li, 1; Na, 2; (THF)K, 3] has been prepared. Structural and spectroscopic studies have established the constitutions of these heteroleptic/heterometallic species, which are retained in arene solution. Evaluation of their reactivity towards 2-bromoanisole has uncovered a marked alkali-metal effect with potassium magnesiate 3 being the most efficient of the three ate reagents.

Untangling the Complexity of Mixed Lithium/Magnesium Alkyl/Alkoxy Combinations Utilised in Bromine/Magnesium Exchange Reactions.

While it is known that the addition of Group 1 alkoxides to s-block organometallics can have an activating effect on reactivity, the exact nature of this effect is not that well understood. Here we describe the activation of sBu Mg towards substituted bromoarenes by adding one equivalent of LiOR (R=2-ethylhexyl), where unusually both sBu groups can undergo efficient Br/Mg exchange. Depending on the substitution pattern on the bromoarene two different types of organometallic intermediates have been isolated, either a mixed aryl/alkoxide [{LiMg(2-FG-C H ) (OR)} ] (FG=OMe; NMe ) or a homoaryl [(THF) Li Mg(4-FG-C H ) ] (FG=OMe, F).

Regioselective Bromine/Magnesium Exchange for the Selective Functionalization of Polyhalogenated Arenes and Heterocycles.

Using the bimetallic combination sBu Mg⋅2 LiOR (R=2-ethylhexyl) in toluene enables efficient and regioselective Br/Mg exchanges with various dibromo-arenes and -heteroarenes under mild reaction conditions and provides bromo-substituted magnesium reagents. Assessing the role of Lewis donor additives in these reactions revealed that N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA) finely tunes the regioselectivity of the Br/Mg exchange on dibromo-pyridines and quinolines. Combining spectroscopic with X-ray crystallographic studies, light has been shed on the mixed Li/Mg constitution of the organometallic intermediates accomplishing these transformations.

Donor-influenced Structure-Activity Correlations in Stoichiometric and Catalytic Reactions of Lithium Monoamido-Monohydrido-Dialkylaluminates.

A series of heteroleptic monoamido-monohydrido-dialkylaluminate complexes of general formula [iBu AlTMPHLi⋅donor] were synthesized and characterised in solution and in the solid state. Applying these complexes in catalytic hydroboration reactions with representative aldehydes and ketones reveals that all are competent, however a definite donor substituent effect is discernible. The bifunctional nature of the complexes is also probed by assessing their performance in metallation of a triazole and phenylacetylene and addition across pyrazine.