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

Abstract

Using the bimetallic combination sBu 2 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. These systems reacted effectively with a broad range of electrophiles, including allyl bromides, ketones, aldehydes, and Weinreb amides in good yields.

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

“…Interestingly, 1 a can also undergo quantitative Br/Mg exchange when using a 1:1 mixture of s Bu 2 Mg and LiOR (entry 3). This observation is consistent with our previous work where [{LiMg(2‐anisyl) 2 (OR)} 2 ] ( 2 a ) and LiOR are quantitatively formed as products of the reaction of 1 a with a 2:1 mixture of s BuLi and Mg(OR) 2 in toluene [7] . Exposing the key role of the alkoxide employed to mediate this transformation, using the relevant LiOR′ derived from 2‐{[2‐(dimethylamino)ethyl]methylamino}ethanol (dmem(H)) only a modest 20 % yield of the magnesiation product was observed [9] .…”

“…Expanding the synthetic potential of these bimetallic combinations, recently we reported s Bu 2 Mg⋅2 LiOR ( R =2‐ethylhexyl) enables fast regioselective Mg/Br exchange of dibromo(hetero)aromatics [7] as well as exchanges of less activated aryl chlorides [8] …”

Preparation and reactions of polyfunctional magnesium and zinc organometallics in organic synthesis

“…These reagents allowed the performance of some Cl/Mg-exchanges 15 as well as regioselective exchanges on various dibromopyridines such as 10 . 16 Furthermore, the use of the corresponding zinc reagents ( s Bu 2 Zn·2LiOR 2 or p tol 2 Zn·2LiOR 2 11 ) allowed the performance of an I/Zn-exchange on functionalized aryl iodides in toluene (see Scheme 4 ). 17 …”

Regioselektiver Brom/Magnesium‐Austausch für die selektive Funktionalisierung von polyhalogenierten Arenen und Heterozyklen

“…[17] Am Ende zeigten NMR Beobachtungen der Reaktion von 2,5-Dibrompyridin (10 a) mit sBu 2 Mg•2 LiOR (1 c) in d 8 -Toluol bei À20 8C für 30 min einen vollständigen Umsatz des Startmaterials, was durch das Vorhandensein von sBuBr und einem ausgeprägten Set neuer Resonanzen bewiesen wurde, Drahtmodell übersichtlich dargestellt (außer für C ipso and C ortho ). [20] Angewandte Chemie Zuschriften welche wir dem Produkt des regioselektiven C(2)-Br/Mg-Austauschs 12 a zuordnen konnten. [17] Die aussagekräftigsten Signale sind diejenigen für die C(2)-und C(5)-Positionen in den 13 C{ 1 H}-NMR-Spektren, welche bei 140,5 und 119,8 ppm für 10 a beobachtet werden (Abbildung 2).…”

“…sBuBr. b) Molekulare Struktur von 16 mit Verschiebungsellipsoiden bei 50 % Aufenthaltswahrscheinlichkeit; alle Wasserstoffatome sind ausgespart, und C-Atome im 2-Ethylhexyl-Substituenten und den Anisylringen sind alsDrahtmodell übersichtlich dargestellt (außer für C ipso and C ortho ) [20].…”