Flow Synthesis of 2-Methylpyridines via α-Methylation.
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.
College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T6, Canada. ummanan@myumanitoba.ca.
Camille
C
Manansala
College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T6, Canada. geoffrey.tranmer@umanitoba.ca.|Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. geoffrey.tranmer@umanitoba.ca.
Geoffrey K
GK
Tranmer
D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000295:instrumentation* / Q000379:methods*; D008745:Methylation; D015394:Molecular Structure; D010847:Picolines / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry
D010847:Picolines; D011725:Pyridines; C530793:2-picoline
2-methylpyridines; Ladenberg rearrangement; Raney® nickel; continuous flow; flow chemistry; green chemistry; α-methylation