Homologation of aryl ketones to long-chain ketones and aldehydes via C-C bond cleavage

Abstract

Transition metal-catalyzed C-C bond cleavage is a powerful tool for the reconstruction of a molecular skeleton. We report herein the multi-carbon homologation of aryl ketones to long-chain ketones and aldehydes via ligand-promoted Ar-C(O) bond cleavage and subsequent cross coupling with alkenols. Various (hetero)aryl ketones are compatible in the reaction, affording the corresponding products wtih good to excellent yields with high regioselectivity. Further applications in the late-stage diversification of biologically important molecules demonstrate the synthetic utility of this protocol. Mechanistic studies indicate that the ligand plays an important role in both C-C bond cleavage and the asymmetric migration-insertion process.

Keywords: Chemistry; Organic chemistry; Organic synthesis.

Graphical abstract

Figure 1

Synthesis of long-chain ketones and aldehydes (A) Representative natural products and drugs containing long-chain ketones and aldehydes. (B) Various aryl donors in the Heck-type reaction with alkenol. (C) Directed C–C bond cleavage. (D) This work: Multi-carbon homologation of aryl ketones to long-chain ketones and aldehydes.

Scheme 1

Homologation of Aryl Ketones to Long-chain Ketones^{a a}Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), PdCl₂ (10 mol %), L8 (20 mol %), AgNTf₂ (20 mol %), K₂CO₃ (0.1 mmol), TsONa (0.1 mmol), DCE (3 mL), 120 ^°C, N₂, 12 h. ^b10 mmol-scale with one-pot operation of aryl ketone. ^cn-Pr instead of Et in ketone oxime ester 1. ^dL2 instead of L8.

Scheme 2

Homologation of Aryl Ketones to Long-chain Aldehydes^{a a}Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), PdCl₂ (10 mol %), L8 (20 mol %), AgNTf₂ (20 mol %), K₂CO₃ (0.1 mmol), TsONa (0.1 mmol), DCE (3 mL), 120 ^°C, N₂, 12 h. ^bL2. instead of L8. ^c18 h.

Figure 2

Synthetic application and product transformations (A) Homologation of biologically important Aryl ketones. ^aMe instead of Et in ketone substrate. (B) Production transformations^b. ^bReaction conditions: For the synthesis of 8e, see the SI. ^a8e (0.1 mmol), Br₂ (0.1 mmol), DCM (1 mL), r. t, 10 min, air. ^b8e (0.1 mmol), p-Anisidine (0.11 mmol), AcOH (0.1 mmol), DCM (1.0 mL), NaBH(OAc)₃ (0.15 mmol), r. t, 12 h, N₂. ^c8e (0.1 mmol), Phenylhydrazine hydrochloride (0.1 mmol), AcOH (0.5 mL), 120°C, 1 h, air. ^d8e (0.1 mmol), 2-Aminobenzophenone (0.1 mmol), AcOH (0.5 mL), 120°C, 4 h, air. ^e8e (0.1 mmol), Benzamidine hydrochloride (0.1 mmol), Cu(OAc)₂ (10 mol%), 2,2′-bipyridine (10 mol %), 4-HO-TEMPO (0.1 mmol), and NaOAc (0.15 mmol). 1,2-dichlorobenzene (1.0 mL), 140°C, 24 h, air. ^f8e (0.1 mmol), CuBr₂ (25 mol %), TEMPO (0.4 mmol), PhNHNH₂ (0.4 mmol), acetic acid (0.1 mmol), DMF (1.0 mL), 140°C, 48 h, air.

Figure 3

Mechanistic studies