Flow Synthesis of 2-Methylpyridines via α-Methylation

Camille Manansala¹, Geoffrey K. Tranmer^{1 2 *}

• ¹ College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
• ² Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch reaction protocols. Eight 2-methylated pyridines were produced by progressing starting material through a column packed with Raney® nickel using a low boiling point alcohol (1-propanol) at high temperature. Simple collection and removal of the solvent gave products in very good yields that were suitable for further use without additional work-up or purification. Overall, this continuous flow method represents a synthetically useful protocol that is superior to batch processes in terms of shorter reaction times, increased safety, avoidance of work-up procedures, and reduced waste. A brief discussion of the possible mechanism(s) of the reaction is also presented which involves heterogeneous catalysis and/or a Ladenberg rearrangement, with the proposed methyl source as C1 of the primary alcohol.

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