Acylation of Bromo-Pyridine 16. The metal-halogen exchange turned out to be more challenging than anticipated. nBuLi could only be used if the reaction mixture was maintained at cryogenic conditions. Formation of the corresponding butyl ketone by displacement of the tertbutyl moiety along with other unidentified byproducts became an issue at higher temperatures (see Scheme 4). As a consequence, milder organometallic species such as iPrMgCl.LiCl ("Turbo Grignard", discovered and popularized by the Knochel group) 6 was pursued for this transformation. In the preliminary experiment treating 16 with iPrMgCl.LiCl at -30 °C in toluene or THF (Table -Entry 1 and 2) for 1 hour followed by MeOH quench afforded significant amount (69% LCAP) of debrominated material 15 in THF (Entry 2) consistent with intermediacy of desired organomagnesium species. Building on this positive result the reaction was further optimized in hopes of avoiding cryogenic conditions. Unfortunately, extended reaction time did not furnish higher conversion and eventually led to the build-up of unknown impurities upon × Challenging isolation × Difficult rejection of morpholine hydrochloride × Water solubility temperature increase. The use of additives was then investigated in hopes to enhance the metalation. Pleasingly, it was discovered that catalytic (5 mol%) amount of copper(I) iodide was highly beneficial to the efficiency of the metal/halogen exchange either in toluene or THF (Entry 3 to 4). Better coordination and solubility in THF may explain the stronger effect observed (Entry 3 versus 4) therefore efforts were continued using THF. Additionally, the Lewis acid ZnCl2 was used (Entry 5) in order to study a potential activation effect via coordination with the nitrogen atom of the pyridine. No drastic changes were observed and the reaction profile mimicked additive-free conditions in THF (Entry 2). Other copper (I) species (Entry 6 to 8) performed equally well. However, due to its inherent air stability, low cost and toxicity, optimization efforts were focused on CuI. Lowering the loading of the CuI to 0.5 mol% (Entry 11) could be achieved, but for reproducibility reasons, the CuI loading was set to 1.0 mol%. Lastly, reducing the equivalent of the Grignard reagent from 2.0 to 1.1 equivalent (Entry 12 to 14) did not lead to full conversion, thus 2.0 equivalents were used in subsequent runs. Efforts to further understand the dramatic effect of copper(I) species is still continuing in our laboratory. With a highly efficient method to generate the heteroaryl magnesium species in hand, its reaction with various electrophilic acetyl source was subsequently investigated. Due to its higher stability upon storage and sufficiently strong electrophilic nature, acetic anhydride was the preferred source of acetyl moiety for our system. Next, with the consideration of scale-up in mind, utilization of a single reactor for the acylation step was determined to be preferred. Initial development of this process relied on an inverse-addition method at -50 °C to achieve the desired ketone. Fortunately, small-scale batches showed that the addition of acetic anhydride to the Grignard reagent provided comparable results (Table -Entry 1 and 2). This result was confirmed on a 200-gram demo-batch scale and subsequent use-tests (Entry 3). While a new impurity resulting from Grignard addition to tert-butyl ester 16 to form adduct 17A was identified, it was found to be acceptable (as long as its formation was minor) as it was confirmed to be fully rejected in the subsequent cyclization step. Unfortunately, the production batch did not perform as well as expected and dione 17A was formed as the major product (Entry 4).