Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2 CH2 ] → [CF2 CHF] Isosterism

Abstract

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-TolIF₂ (>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 σ_C-H →σ_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.

Keywords: fluorination; iodine(III); organocatalysis; ring expansion; tetralin.

Figure 1

Top: Fluorinated carbocycles for contemporary drug discovery (1, 2 and 4). Centre: Fluorination sites in common steroids (5 and 6), and the β‐blocker Nadolol (7). Bottom: An I(I)/I(III) paradigm to access the novel trifluorotetralin scaffold (8 → 9).

Scheme 1

Top: Exploring the scope of the reaction. Standard reaction conditions: substrate (0.2 mmol), p‐TolI (20 mol %), Selectfluor (1.5 equiv.), DCE (0.5 mL), amine:HF 1:4.5 (0.5 mL), ambient temperature, 24 h. Yields refer to isolated products while ¹⁹F NMR yields are given in parentheses (determined by ¹⁹F NMR analysis of the crude reaction mixture using ethyl fluoroacetate as internal standard). Bottom: Effect of arene electron density on reaction efficiency. N.B. Care must be taken during isolation due to the volatility of the products.

Scheme 2

Control reactions. Standard reaction conditions: substrate (0.2 mmol), p‐TolI (20 mol %), Selectfluor (1.5 equiv.), DCE (0.5 mL), amine:HF 1:4.5 (0.5 mL), ambient temperature, 24 h. Yields refer to ¹⁹F NMR yields (determined by ¹⁹F NMR analysis of the crude reaction mixture using ethyl fluoroacetate as internal standard).

Scheme 3

Exploring the scope of the reaction. Standard reaction conditions: substrate (0.2 mmol), p‐TolI (20 mol %), Selectfluor (1.5 equiv.), DCE (0.5 mL), amine:HF 1:4.5 (0.5 mL), ambient temperature, 24 h. Yields refer to isolated products while ¹⁹F NMR yields are given in parentheses (determined by ¹⁹F NMR analysis of the crude reaction mixture using ethyl fluoroacetate as internal standard). N.B. Care must be taken during isolation due to the volatility of the products.

Figure 2

X‐ray crystal structure of tetralin 12. ^[22]

Figure 3

Optimised molecular structure (TPSS‐D3/def2‐TZVP) of 12‐a (left) and alternative conformer 12‐b (right). Internuclear distances are given in Å. In square brackets: relative free energies ΔG ₂₉₈ (PW6B95‐D3//TPSS‐D3/def2‐TZVP) in kcal mol⁻¹.