Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones

Abstract

A deoxygenative transformation of diarylketones leading to multiply arylated alkanes was developed. Diarylketones were reacted with diphenylphosphine oxide resulting in a phospha-Brook rearrangement, followed by palladium-catalyzed cross-couplings or a Friedel-Crafts type alkylation to afford the corresponding multiply arylated alkanes. A variety of diarylketones can be converted to multiply arylated alkanes such as diarylmethanes, tetraarylethanes, and triarylmethanes by reduction, dimerization, and arylation in one pot. Furthermore, a one-pot conversion from arylcarboxylic acids to diarylmethanes and tetraarylethanes, and a synthesis of tetraarylmethane and triphenylethane using sequential coupling reactions are also presented.

Fig. 1. (A) Multiply arylated alkanes in pharmaceuticals, natural products, and organic materials. (B) State-of-the-art synthesis of multiply arylated alkanes. (C) Deoxygenative C–P bond formation of aromatic esters. (D) Deoxygenative transformation of diarylketones.

Fig. 2. Substrate scope Conditions; ^a1 (0.40 mmol), diphenylphosphine oxide (1.5 equiv.), PdCl₂ (5.0 mol%), PPh₃ (20 mol%), HCO₂Na (2.0 equiv.), Cs₂CO₃ (2.0 equiv.), DMSO (1.0 mL), 150 °C, 1 h. ^b1 (0.40 mmol), diphenylphosphine oxide (1.5 equiv.), PdCl₂ (5.0 mol%), PPh₃ (20 mol%), HCO₂Na (2.0 equiv.), Cs₂CO₃ (0.40 equiv.), DME (1.0 mL), 150 °C, 12 h. ^c Yield was determined by ¹H NMR analysis due to the volatile nature of 2A. ^d PdCl₂ (10 mol%), PPh₃ (40 mol%) were used. ^e Pn-Bu₃ (20 mol%), K₂CO₃ (2.0 equiv.), MeCN, 12 h. ^f 6.0 mmol scale. ^g Isolated as an acetamide by treating with Ac₂O. ^h 20 mol% MePPh₂, K₂CO₃ (2.0 equiv.), MeCN, 12 h.

Fig. 3. (A) Phosphinate 4A from benzophenone (1). (B) Diphenylmethane (2A) from phosphinate 4A. (C) Tetraphenylethane 3A from phosphinate 4A. (D) Crossover reaction. Numbers in the parentheses are yields of 3A. (E) Deuterium labeling experiments. (F) Standard conditions with TEMPO as a radical scavenger. (G) With phosphite instead of phosphine oxide.

Fig. 4. Synthesis of triarylmethanes. Conditions: ^a diarylketone (0.40 mmol), diphenylphosphine oxide (1.5 equiv.), Cs₂CO₃ (0.40 equiv.), DME (2.0 mL), 80 °C, 3 h; then arene (1.0 mL), TfOH (2.0 equiv.), RT, 2 min. ^b Diarylketone (0.40 mmol), diphenylphosphine oxide (1.2 equiv.), Cs₂CO₃ (2.0 equiv.), 1,4-dioxane (2.0 mL), 150 °C, 1 h; then arylboronic acid (1.5 equiv.), Pd(OAc)₂ (10 mol%), P (p-tolyl)₃ (40 mol%), 150 °C, 1 h. ^c The ratio of isomers (para/ortho-position (6A) or C₂/C₃ position (6B)) is shown in parentheses.

Fig. 5. Synthetic utility and applications of deoxygenative transformation of diarylketones. (A) One-pot synthesis from aryl carboxylic acid. (B) Allylation of diarylketone. (C) Intramolecular dimerization/oxidation. (D) Diarylmethane synthesis from arylaldehyde. (E) Triarylethane synthesis from diarylketone. (F) Tetraarylmethane synthesis from diarylketone.