59th Annual Report on Research 2014

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Reports: UNI152706-UNI1: Catalytic Methylation of Oxygen Nucleophiles with Safe, Stable Methylating Agents

Overview of Research Program   Methylation reactions of carboxylic acids and other nucleophiles are ubiquitously used in chemical research, including in natural product synthesis, reaction development, medicinal chemistry, and polymer synthesis. Although often effective, Fisher esterification is incompatible with acid-sensitive substrates. This led to the development of electrophilic methylating agents that react under mild conditions, such as diazomethane, dimethyl sulfate, and "magic methyl."   Perhaps the most high-profile drawback of common methylating reagents is their extraordinary acute toxicity. For example, trimethylsilyl diazomethane, developed as a safer, less-explosive alternative to diazomethane, has caused the deaths of two chemists since 2008. Use of common methylating reagents is also complicated by their general instability to light, heat, and/or moisture, along with concerns about chronic health risks. Despite their drawbacks, hazardous methylating reagents are regularly used in both academic and industrial laboratories.   Inspired by others' successes in developing non-explosive carbene precursors and safer alternatives to hydrogen cyanide, we have initiated a program to develop new methylation methods for oxygen nucleophiles that rely upon safe, stable reagents. Increased safety and convenience will reduce the cost and risk of an immensely useful functional group manipulation. Ultimately, we aim to convince chemists to choose alternate methylating agents for their synthetic needs.   Current Results   Our most significant progress has been in developing dimethylcarbonate (DMC) as a practical methylating reagent for carboxylic acids.   DMC is an inexpensive, non-toxic, and "green" potential methylating reagent. Although DMC has previously been explored in methylations of a variety of nucleophiles, esterifications have generally been limited to electron-rich carboxylic acids and require stoichiometric activating agents, high (>150 °C) temperature, and/or special reactors such as autoclaves. Perhaps due to the limited demonstrated substrate scope and harsh reaction conditions, methylation with dimethylcarbonate has not found routine application in synthetic organic chemistry.   Following a catalyst screen, we discovered that simple carbonate salts, including potassium carbonate and potassium bicarbonate, catalyze the methylation of carboxylic acids with DMC.  Optimized reaction conditions were applied to an array of carboxylic acids to determine the substrate scope (Table 1).  Both electron-rich (entries 2-4) and electron-poor (entries 5-9) substrates are readily esterified.    The successful methylation of acid-sensitive substrate with acetal and Boc-carbamate moieties illustrates the complementarity of this method to acid-mediated Fisher esterification (entries 2, 14). Some base-labile functional groups are also tolerated under the mildly basic reaction conditions; no transesterification of an ethyl ester with MeOH was observed (entry 15).  Chemoselectivity is high for methylation of carboxylic acids in the presence of phenols (entries 17-18).         There are two likely general mechanisms for esterification with DMC: carbonyl substitution by MeOH liberated from DMC (Scheme 1, path a) or direct transfer of a methyl group from DMC to the carboxylate oxygen (Scheme 1, path b).  Notably, path b encompasses several possibilities, including CO₂ excision from 1 or S_N2-type reaction of benzoate with either the activated intermediate 1 or unactivated DMC.  To differentiate between paths a and b, an isotope-labeling experiment was performed with doubly ¹⁸O-labeled benzoic acid ([¹⁸O]₂-2). Upon reaction of [¹⁸O]₂-2 with DMC under our standard conditions, the product mass corresponding to doubly-labeled [¹⁸O]₂-3 was observed by GCMS.       This result supports path b, a direct methyl transfer from DMC to the substrate, and is inconsistent with path a. Overall, the labeling study suggests that DMC is behaving like diazomethane and other electrophilic methyl transfer reagents, rather than as a source of MeOH for a Fisher-type esterification, which is perhaps surprising in light of its improved stability and safety profile.   Impact   The methylation project has enabled an array of opportunities for undergraduate researchers to conduct and present their work.   Three students are co-authors on the J. Org. Chem. publication that resulted from the work described above, and all completed honors theses in my lab. Support from this grant funded two of them to pursue full-time summer research in 2013 and enabled all three to present a poster at the March 2014 national ACS conference. Posters on this research have also been presented at on-campus events and at the ACS-CVS undergraduate research symposium.  Furthermore, two new students received stipends during Summer 2014 to work on this project, and they are continuing their research during the 2014-2015 academic year.