Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C-H activation

Abstract

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years. Several unique features of HFIP compared to its non-fluoro analogue isopropanol have helped this solvent to make a difference in various subdomains of organic chemistry. One such area is transition metal-catalyzed C-H bond functionalization reactions. While, on one side, HFIP is emerging as a green and sustainable deep eutectic solvent (DES), on the other side, a major proportion of Pd-catalyzed C-H functionalization is heavily relying on this solvent. In particular, for distal aromatic C-H functionalizations, the exceptional impact of HFIP to elevate the yield and selectivity has made this solvent irreplaceable. Recent research studies have also highlighted the H-bond-donating ability of HFIP to enhance the chiral induction in Pd-catalyzed atroposelective C-H activation. This perspective aims to portray different shades of HFIP as a magical solvent in Pd-catalyzed C-H functionalization reactions.

Fig. 1. A comparative overview of different physical characteristics, price, and safety details of HFIP and isopropanol.

Scheme 1. Exposure of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) in different domains of experimental science.

Scheme 2. HFIP favoring proximal ortho-C(sp²)–H olefination of weakly coordinating directing groups.

Scheme 3. Pd-catalyzed C(sp²)–H bond functionalization reactions.

Scheme 4. Pd-Catalyzed β-C(sp³)–H functionalization using HFIP as the key solvent.

Fig. 2. (A) Pd-Catalyzed selective β-arylation of benzo[b]thiophene via a Heck-type pathway. (B) Energy profile diagram of two competitive pathways.

Scheme 5. First instance of Pd(ii)-catalyzed meta-C(sp²)–H olefination of hydrocinnamic acids in HFIP medium.

Scheme 6. Remarkable solvent effect by HFIP in Pd(ii)-catalyzed meta-C(sp²)–H olefination of aryl acetic acids.

Scheme 7. HFIP–Pd-ligand interaction in Pd(ii)-catalyzed meta-C(sp²)–H acetoxylation of aryl sulfonamides.

Fig. 3. HFIP–Substrate interaction in elevating para-selectivity.

Fig. 4. (A) Inside out of meta-selective pyrimidine DG; (B) stepwise meta-allylation of arenes; and (C) NMR titration analysis depicting the role of HFIP in tuning substrate-DG orientation.

Scheme 8. Distal γ-arylation of masked aliphatic alcohols.

Scheme 9. HFIP stabilizing intermediate palladacycle for γ-carbonylation of aliphatic alcohols.

Scheme 10. Pd(ii)-catalyzed γ-arylation of free carboxylic acids in HFIP.

Scheme 11. HFIP as the sole solvent in Pd(ii)-catalyzed γ-olefination of free carboxylic acids to generate six-membered lactones.

Scheme 12. Different roles of HFIP in combination with Pd catalysis using transient auxiliaries (A) and (B) as the major solvent and (C) as additives in ortho-arylation of benzaldehydes.

Scheme 13. Pd-catalyzed TDG-assisted C(sp³)–H arylation. (A) HFIP as an optimum solvent in the synthesis of intermediate; (B) solvent effect on the overall yield and selectivity.

Scheme 14. (A) γ-C(sp³)–H arylation of ketones; (B) mechanistic blueprint displaying the detailed role of HFIP.

Scheme 15. Pd(ii)-catalyzed atroposelective olefination of biaryls. (A) Overall optimization of the reaction; (B) effects of different solvents at room temperature on yield; and (C) steric induction by HFIP favoring one diastereoisomer.

Scheme 16. Effect of HFIP in enhancing the reaction yield.

Trisha Bhattacharya

Animesh Ghosh

Debabrata Maiti