Directed electrophilic C-H Borylation using Trihaloboranes
Item statusRestricted Access
Embargo end date24/11/2023
Iqbal, Saqib Ali
Given the wide-ranging interest in aryl boranes as either synthetic precursors or boron-containing emissive materials, new synthetic routes to such compounds are of particular interest. Current methodologies are often hindered by the requirement of expensive transition metals and/or the selectivity being purely controlled by either sterics or the electronics of the compound. Directed C–H borylation using stoichiometric metal-free boron sources presents a valuable solution to both of these concerns, providing selectivity at sites that cannot be accessed via undirected (e.g., borocation mediated) methods, and being less influenced by sterically demanding substrates than iridium catalysed routes. A method to selectively borylate indole at the C7 position was developed via a metal-free process using the commercially available trihaloborane, BBr3 and an acyl-directing group. Directing groups were found to be essential to this reaction and the use of acyl-based directing groups such as pivaloyl has rarely been explored prior to this work. This method proceeded via formation of thermodynamically favourable 6- membered boracycles, the O–B bond in which could be broken during protection of the boron centre with pinacol and cleavage of the directing group with an appropriate nucleophile. A range of functional groups were tolerated including methoxy, alkyl and halide, most importantly, this included at the C6 position which is difficult to achieve using other routes. This method was adapted to the C5 borylation of indoles which react via a 6-membered boracycle through a 4-NH-(pivaloyl) group – preferentially over the corresponding C3 borylated product. This method was also applied to the selective ortho borylation of aniline. To borylate indole selectively at the C2 position, heterocyclic directing groups were employed. When substituting indole (at N) with a 6-membered heterocycle, borylation proceeded exclusively at the C2 position with either BBr3 or BCl3, products from both were air/moisture stable. To direct selectivity to the C7 position, 5-membered heterocyclic directing groups were employed, these reactions were amenable to BCl3 without the requirement of additives. Thus, selectivity switching between C2 and C7 on indole was possible by simply changing the ring size of the heterocyclic directing group. Therefore, it has been shown that the directing group can either be cleaved in a ‘traceless’ fashion to yield the ‘unprotected’ borylated arene (chapter 2) or they can remain coordinated to the boron centre to yield air/moisture stable 4-coordinate arylboranes (chapter 3). The modification of the directing group also was studied which involved reactions of the Lewis base-coordinated aryl-boranes with hydride sources. By altering substituents on the –NR2 of a benzylamide, borylation can proceed either onto the benzyl group or onto the amide director itself (R=Ph), reduction of the carbonyl in the amide then produced either an amine-borane or a 1,4-azaborine (by a second intramolecular borylation) (chapters 4 and 5). Throughout these studies, characterisation of intermediates and products is conducted by in-situ NMR spectroscopy to determine the intermediates in the reactions and the behaviour of the borylated compounds in solution and in the solid-state (via crystallography). The reactions presented herein are an addition to the field of directed C–H borylation to achieve selectively borylated indoles that are typically difficult to form by other reported methods (chapters 2 and 3). Furthermore, it presents a route to important compounds (e.g., 1,4-azaborines) via a novel directed borylation and reduction (of the directing group) strategy (chapters 4 and 5).