An Efficient and Convenient Synthesis of Tetrahydrocycloheptapyridines: New Precursors for CNS Agents

Abstract

Development of a convenient and efficient synthetic route for functionalized tetrahydrocycloheptapyridines was accomplished by stepwise iodomethylation and subsequent radical ring expansion using a Bu₃SnH/AIBN reaction system. Thus, 8- or 5-­oxotetrahydroquinolines 4a and 4d and 8- or 5-oxotetrahydroisoquinolines 4b and 4c afforded the 5,6,7,8-tetrahydrocycloheptapyridine-9-ones 3a and 3d and 6,7,8,9-tetrahydrocycloheptapyridine-5-ones 3b and 3c, respectively, in moderate total yields (37-61%). It was also found out that this reaction sequence was applicable to the preparation of other heterocyclic fused cycloheptanones.

Key words

cycloheptanone - hydroxymethylation - iodomethylation - ring expansion - radical reaction

References

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11

We also conducted bromo- or iodomethylation using other bases (t-BuOK, DBU, and Cs₂CO₃), but the attempts ended in incomplete conversion or complex mixture.

13

Bromination of 9a using CBr₄ and PPh₃ resulted in lower yield (45%).

14

The stereochemistry of compounds 10 and 11 was determined by their NOEs. The details are listed in the experimental section.