Synthesis of Annulated Pyridines by Intramolecular Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction under Superheated Continuous Flow Conditions

Abstract

Pyrimidine alkynes can be transformed into the corresponding annulated pyridines efficiently in flow. The superheating of organic solvents far beyond their boiling point enables toxic and difficult to workup solvents such as nitrobenzene or chlorobenzene, which are usually employed for these reactions, to be replaced by less harmful ones like toluene. The relative rate of reactivity for a series of structurally close starting materials was investigated and a scalable flow process was developed, providing facile access to a series of novel annulated pyridine building blocks. The effect of thermal volume expansion of solvents under superheated conditions was found to be significant and influenced the residence times considerably. To obtain meaningful and accurate residence times, flow rates need to be corrected for volume expansion. To avoid confusion with residence times, tR, calculated from nominal flow rates, we would propose to use for such corrected residence times the term effective residence time, tR,eff.

Diels–Alder Reaction in the Synthesis of Fluorinated (Hetero)Aromatic Compounds

“…There are just a few examples for application of other fluorinated heterocyclic heterodienes in Diels–Alder reactions to produce heteroaromatic substances. Thus, Martin et al applied superheated continuous flow conditions for intramolecular Diels–Alder reactions of pyrimidine alkynes 132 to annulated pyridines 133 probably via the intermediate 134 (Scheme ) . Among others, also 5‐fluoro‐2,3‐dihydrofuro[2,3‐ b ]pyridine 133a was synthesized by this method.…”

“…Synthesis of annulated pyridines, e.g. 5‐fluoro‐2,3‐dihydrofuro [2,3‐ b ]pyridine ( 133a ) by intramolecular cycloaddition of pyrimidines 132 …”

Phosphate Monoester Hydrolysis by Trinuclear Alkaline Phosphatase; DFT Study of Transition States and Reaction Mechanism

“…More recently, Martin and co‐workers have investigated the transformation of pyrimidine alkynes into the corresponding annulated pyridines through inverse‐electron‐demand hetero‐Diels–Alder reactions (HDAs, Scheme ) 36. The HDA reaction is assumed to occur via a tricyclic adduct intermediate that results from an intramolecular [4+2] cycloaddition across the C‐2 and C‐5 positions of the pyrimidine ring, followed by elimination of hydrogen cyanide.…”

A Convenient Late‐Stage Fluorination of Pyridylic C−H Bonds with N‐Fluorobenzenesulfonimide

“…Conversely, fluorination of 5,6,7,8‐tetrahydroisoquinoline using our optimized method (Table , entry 9) provided 23 in good yield and with complete selectivity for fluorination at C5. Likewise, fluorination of 6,7‐dihydro‐5 H ‐cyclopenta[ b ]pyridine afforded the 7‐fluoro adduct 22 exclusively. This selectivity is consistent with the mechanistic proposal outlined above and the fact that other 3‐alkylpyridines (e.g., 3‐ethyl‐ and 3‐isobutylpyridine) failed to undergo fluorination.…”