Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2] → [CF2CHF] Isosterism

Saturated, fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF(2) (>20 examples, up to >95 %). A range of diverse substituents are tolerated under standard catalysis conditions and this is interrogated by Hammett analysis. X-ray analysis indicates a preference for the CH-F bond to occupy a pseudo-axial orientation, consistent with stabilising sigma(C-H)->sigma(C-F)* interactions. The replacement of the symmetric [CH2-CH2] motif by [CF2-CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational analysis and is consistent with stereoelectronic theory.

Automated summary

Saturated, fluorinated carbocycles are important modules for contemporary drug discovery, and the synthesis of novel trifluorinated tetralins has been achieved. The conformational behavior of this novel structural balance has been investigated through computational analysis and is consistent with stereoelectronic theory.