Catalytic, Regioselective 1,4-Fluorodifunctionalization of Dienes

Abstract

A catalysis-based regioselective 1,4-fluorofunctionalization of trifluoromethyl substituted 1,3-dienes has been developed to access compact, highly functionalized products. The process allows E,Z-mixed dienes to be processed to a single E-alkene isomer, and leverages an inexpensive and operationally convenient I(I)/I(III) catalysis platform. The first example of catalytic 1,4-difluorination is disclosed and subsequently evolved to enable 1,4-hetero-difunctionalization, which allows δ-fluoro-alcohol and amine derivatives to be forged in a single operation. The protocol is compatible with a variety of nucleophiles including fluoride, nitriles, carboxylic acids, alcohols and even water thereby allowing highly functionalized products, with a stereocenter bearing both C(sp³ )-F and C(sp³ )-CF₃ groups, to be generated rapidly. Scalability (up to 3 mmol), and facile post-reaction modifications are demonstrated to underscore the utility of the method in expanding organofluorine chemical space.

Keywords: Conformation; Difunctionalization; Fluorination; Hypervalent Iodine; Regioselectivity.

Scheme 1

A. Difluorination motifs that are currently accessible via I(I)/I(III) catalysis. B. Reaction blueprint to enable catalysis‐based 1,4‐difluorination and fluorofunctionalization.

Scheme 2

Optimization of reaction conditions. Standard reaction conditions: diene 1 a (0.2 mmol, 3.6 : 1 E : Z), catalyst 3–6 (20 mol%), amine⋅HF 1 : 7.5 (0.5 mL), CHCl₃ (0.5 mL) and Selectfluor® (0.3 mmol). For full optimization details, see Supporting Information. Yields and conversions determined by ¹⁹F NMR using trifluorotoluene as internal standard. The regioselectivity 1,4‐ versus 1,2‐ was >20 : 1 in all cases. The enantiomer of the product shown was arbitrarily chosen.

Scheme 3

Scope of the 1,4‐difluorination. Conditions: diene 1 (0.2 mmol, E : Z mixture, see Supporting Information for the detailed E : Z ratio), catalyst 5 (20 mol%), amine ⋅ HF 1 : 7.5 (0.5 mL), CHCl₃ (0.5 mL) and Selectfluor® (0.3 mmol). Isolated yields provided with ¹⁹F NMR yields given in parentheses and determined by ¹⁹F NMR using trifluorotoluene as internal standard. The enantiomer of the products shown was arbitrarily chosen.

Figure 1

X‐ray crystal structure of compound 2 t (CCDC 2194476). showing minimization of 1,3‐allylic strain, and structural pre‐organization around the benzylic region.

Figure 2

A plot of substrate regioselectivity versus δ_C(ipso) (ppm).

Scheme 4

Scope of different nucleophiles: Conditions: diene 1 a (0.2 mmol), catalyst 5 (20 mol%), Olah's reagent (0.5 mL), CHCl₃ (0.5 mL), nucleophile (as indicated) and Selectfluor® (0.3 mmol). Isolated yields are given, ¹⁹F NMR yield is given in parentheses and determined by ¹⁹F NMR using trifluorotoluene as internal standard. ^a H₂O (20 equiv) was used as nucleophile. The enantiomer of the products shown was arbitrarily chosen.

Scheme 5

Scale‐up experiment and selective derivatization of 2 a, 3 h and 3 r. [a] Br₂ (2.0 equiv), DCM, reflux, 24 h; [b] 1) O₃; 2) NaBH₄ (20 equiv), DCM:MeOH (1 : 1), −78 °C to rt, 27 h; [c] m‐CPBA (6 equiv), DCE, 90 °C, 48 h; [d] K₂CO₃ (2.0 equiv), MeOH, rt, 1 h; 2) CBr₄ (1.5 equiv), PPh₃ (1.5 equiv), DCM, 0 °C to rt, 0.5 h; [e] 1) MnO₂ (10 equiv), DCM, reflux, 24 h; 2) NaClO₂ (10 equiv), NaH₂PO₄⋅2H₂O (7 equiv), 2‐methyl‐2‐butene/ ^t BuOH/H₂O, rt, 20 h.