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Molecules 2015, 20(9), 15797-15806; doi:10.3390/molecules200915797

Flow Synthesis of 2-Methylpyridines via α-Methylation

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
*
Author to whom correspondence should be addressed.
Academic Editor: Kerry Gilmore
Received: 12 August 2015 / Revised: 20 August 2015 / Accepted: 21 August 2015 / Published: 31 August 2015
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
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Abstract

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. View Full-Text
Keywords: continuous flow; 2-methylpyridines; Raney® nickel; green chemistry; α-methylation; Ladenberg rearrangement; flow chemistry continuous flow; 2-methylpyridines; Raney® nickel; green chemistry; α-methylation; Ladenberg rearrangement; flow chemistry
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Manansala, C.; Tranmer, G.K. Flow Synthesis of 2-Methylpyridines via α-Methylation. Molecules 2015, 20, 15797-15806.

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