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Multidentate ligands involving tethered pyridyl groups coordinated to transition metal ions have been frequently used to mimic the 3-histidine (3H), 2-histidine-1-carboxylate (2H1C) brace motifs or other combinations of histidine and carboxylate endogenous ligating residues found in bioinorganic metalloenzymes. It is of interest to immobilize these ligand chelates onto heterogeneous supports. This, however, requires the use of bromine-substituted (chloromethyl)pyridines, whose current synthetic routes involve the use of extremely pyrophoric chemicals, such as n-butyllithium that require cryogenic reaction conditions, and toxic chemicals, such as thionyl chloride, that are challenging to handle and require extensive hazard controls. Herein, we report alternative methodologies towards the syntheses of 2-bromo-6-hydroxymethylpyridine and 2-bromo-6-chloromethylpyridine from inexpensive commercially available 2,6-dibromopyridine using isopropylmagnesium chloride lithium chloride complex (Turbo Grignard) and cyanuric chloride which are easier to handle and require milder reaction conditions than the conventional reagents. Gas chromatography-mass spectrometry (GC-MS) methods were developed and simple 1H- and 13C- nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopies were also used to monitor the conversion of both reaction steps and showed that products could be obtained and isolated through simple workups without the presence of unreacted starting material or undesired overchlorinated 2-chloro-6-chloromethylpyridine side product.

Many of the current synthetic methodologies utilized within academic and industrial laboratories require knowledge of how to safely handle air- and moisture-sensitive reagents and work under inert atmospheres. As a result, the ACS Committee on Professional Training recommends incorporating synthetic methods that make use of these inert atmospheres into curricula for the development of students with career aspirations in science. However, incorporation of these methods into the curricula at primarily undergraduate institutions is challenging due to access to limited resources and infrastructure. This article reports a semester long, multistep laboratory synthesis of the tripodal bis[2-(2,3-dihydroxyphenyl)-6-pyridylmethyl](2-pyridylmethyl)amine (BCATTPA) compound involving metal halogen exchange, chlorine transfer, nucleophilic substitution, Suzuki cross-coupling, and Lewis acid dealkylation steps that was successfully carried out by sophomore or junior undergraduate researchers enrolled in a Mentored Research in Chemistry course at Fairleigh Dickinson University. Using routine laboratory characterization techniques such as 1H NMR and FT-IR spectroscopies as well as GC-MS, students were able to identify and assess the purities of their resulting products. The disclosed laboratory synthesis enabled students to get formal training in air- and moisture-free Schlenk-line techniques such as syringe and cannula transfers in a controlled learning environment that they could use in future research activities in organic, inorganic, analytical, physical, or biochemistry laboratories.