Design of an Indolylphosphine Ligand for Reductive Elimination-Demanding Monoarylation of Acetone Using Aryl Chlorides

Abstract

The rational design of a phosphine ligand for the reductive elimination-demanding Pd-catalyzed mono-α-arylation of acetone is demonstrated and reported. The catalyst is tolerant of previously proven challenging electron-deficient aryl chlorides and provides excellent product yields with down to 0.1 mol % Pd. Preliminary investigations suggest that the rate-limiting step for the proposed system is the oxidative addition of aryl chlorides, in which it contradicts previous findings regarding the α-arylation of acetone with aryl halides.

A Highly Efficient Monophosphine Ligand for Parts per Million Levels Pd‐Catalyzed Suzuki–Miyaura Coupling of (Hetero)Aryl Chlorides

“…[24] Recently, we further explored the indolyl framework by enriching the ligand electron-density to tackle challenging monoarylation of acetone. [25] With the aforementioned groundwork, we envisioned that the Phendole-phos ligand skeleton would hold great promise against the challenge of cross-coupling reactions. In this regard, we embarked to further modify the steric and electronic features of the new ligand ( Figure 1), based on our proprietary indole-core phosphines.…”

Ligand Control of Palladium‐Catalyzed Site‐Selective α‐ and γ‐Arylation of α,β‐Unsaturated Ketones with (Hetero)aryl Halides

“…Based on this prior research, we interested in the regioselective α‐ or γ‐arylation of α,β‐unsaturated ketones, [10] which is challenging because of the high possibility of the formation of regioisomeric products (Scheme 2).…”

Metal‐Free Oxidative Cross Coupling of Indoles with Electron‐Rich (Hetero)arenes

“…However, the direct coupling of indoles with electron‐rich heterocycles was successful only in the case of homo‐coupling to form symmetrical bi‐indolyl compounds . This is an important limitation, as nonsymmetrical derivatives can be found in natural products like Asteropusazole A ( 1 ), synthetic bioactive molecules like anti‐estrogen 2 , hole transport materials like indole trimer 3 , and transition metal ligands like indole phosphine 4 (see Figure ) …”

“…[6] This is an importantl imitation, as nonsymmetrical derivatives can be found in natural products like Asteropusazole A(1), [7] synthetic bioactive molecules like anti-estrogen 2, [8] hole transport materials like indole trimer 3, [9] and transition metal ligands like indole phosphine 4 (see Figure 1). [10] To access non-symmetrical electron-rich bi-heteroaryls, cyclization methods [11] or cross coupling reactions requiring prefunctionalization of both partners [12] remainm ost often used. [13] The umpolung of the reactivity of the indole ring to enable selective cross-coupling with electron-richh eterocycles is an attractive alternative approach (Scheme 1).…”