58th Annual Report on Research 2013 Under Sponsorship of the ACS Petroleum Research Fund

(1)               Testing of pre-prepared boron-based DMG functionalised benzenes for Directed ortho Metalation (DoM) reactions. (2)               DoM via in-situ generated boron-based DMGs.

A third area of research has developed out of these projects, based on observations of undesired product formation:

(3)               Transition metal-free C_sp2-C_sp2 coupling via oxidation of aryl-vinyl boronates.

In this stage of project (1), various derivatives (1) of 4-methylphenyl boronic acid were prepared in order to test conditions for DoM for simple aromatic compounds (e.g. 1a-e, Scheme 1). In addition to these, the free boronic acid and standard derivatives (e.g. ArBF₃K) were subjected to various lithiation conditions, followed by quench with a simple electrophile (MeI). In most cases, use of n-BuLi for lithiation at 0^oC or above resulted in decomposition products for all derivatives, which suggests undesired nucleophilic addition to boron (via pathway (a)). Use of n-BuLi or t-BuLi at –78^oC, or lithium amides (e.g. LDA, LiTMP) at 0^oC generally resulted in no reaction (starting material recovered). Choice of solvent (e.g. THF, heptane) had little effect on these results. We are currently exploring the use of tri-coordinate (e.g. diethanolamine) and di-coordinate derivatives bearing acidic hydrogens (e.g. aminoethanol) with the anticipation that tetravalent boron may be less susceptible to nucleophilic attack, thus favouring pathway (b).

Initial attempts at lithiation using in-situ generated DMGs have so far been similarly unsuccessful. Simple bifunctional alcohols and amines (2a-c, Scheme 2) were subjected to n-BuLi at 0^oC in various ether or hydrocarbon solvents, followed by addition of a cyclic pinacol ester. At either 0^oC or –78^oC, further alkyllithium was added and the solution allowed to react for one or two hours, at the same temperature or with warming, followed by the addition of MeI. Under none of the various conditions attempted was any of the desired product was observed, which suggests that neither alkyllithium addition to boron nor ortho lithiation occurred. We have prepared several more complex derivatives of the type 2d and e for testing in this reaction, with the anticipation that the presence of amide or carbamate groups will prove more effective at directing lithiation, leading to successful reaction. Boronic acid derivatives other than pinacol esters have also been prepared for testing in this reaction. 

Given our lack of success so far in developing an effective boron-based DMG, and the desire to provide undergraduate students with the opportunity to generate some positive results, we turned our attention to a reaction whose discovery was inspired by some of our initial results in these studies. Based on our observations related to alkyllithium addition to boron, we reasoned that vinylboronates (generated by addition of a vinyl metal species to arylboronic acid pinacol esters) might rearrange via 1,2 migration of the aryl group with the addition of an appropriate electrophile. Indeed, with the use of isopropenyl magnesium bromide and after careful optimization of the other reaction conditions (Scheme 3), we observed coupled products 4 in moderate yields along with unreacted staring materials. The initial scope of the reaction was explored with a variety of simple benzene derivatives (15 examples, e.g. 4a and b), for which a pronounced steric effect was observed. In general, substrates with large substituents ortho to boron afforded higher yields of 4 (with less recovered starting materials) than those with no ortho substituents. It is also possible to subject 3 to diverse lithiated heterocycles, followed by I₂ to afford similarly coupled products (6 examples, e.g. 4c and d). Yields observed in the heterocyclic series are so far moderate at best, but the steric effect observed for simple benzene derivatives has suggested a promising possibility for further yield optimization. We anticipate that modification of the protecting group on boron in 3 to something more sterically hindered may favour product formation over starting material recovered.   

We propose two competing mechanisms to account for the formation of the desired products and the recovered starting material (Scheme 4). Addition of the vinyl metal species to the pinacol ester affords a vinyl boronate, which when subjected to the electrophile, either attacks (a) via the pi bond of the vinyl group or (b) via the vinyl-boron sigma bond. Competition between these modes of nucleophilic attack depends on the relative steric accessibility of each bond. Pathway (a) leads initially to a migration product that undergoes elimination to the coupled product

Further investigation for the development of an effective boron-based DMG remains our primary focus, although work in this third promising area continues.