Reversed‐Polarity Synthesis of Diaryl Ketones through Palladium‐Catalyzed Direct Arylation of 2‐Aryl‐1,3‐dithianes

Abstract

An umpolung approach to the synthesis of diaryl ketones has been developed based on in situ generation of acyl anion equivalents and their catalytic arylation. This method entails the base promoted palladium catalyzed direct C–H arylation of 2 The resulting 2,2-diaryl-1,3-dithianes with aryl bromides. Use of MN(SiMe3)2 (M=Li, Na) base results in reversible deprotonation of the weakly acidic dithiane. In the presence of a Pd(NiXantphos)-based catalyst and aryl bromide, cross-coupling of the metallated 2-aryl-1,3-dithiane takes place under mild conditions (2 h at rt) with yields as high as 96%. The resulting 2,2-diaryl-1,3-dithianes were converted into diaryl ketones by either molecular iodine, N-bromo succinimide (NBS) or Selectfluor in the presence of water. The dithiane arylation/hydrolysis can be performed in a one-pot procedure to yield a good to excellent yields. This method is suitable for rapid and large-scale synthesis of diaryl ketones. A one-pot preparation of anti-cholesterol drug fenofibrate (TriCor®) has been achieved on 10.0 mmol scale in 86% yield.

Umpolung Synthesis of Diarylmethylamines via Palladium‐ Catalyzed Arylation of N‐Benzyl Aldimines

“…A Pd(NIXANTPHOS)-based catalyst, which exhibited high efficiency in our previous deprotonative cross-coupling processes (DCCP), including Scheme 1c, was examined. [4], [7] We tested different silylamide bases, MN(SiMe 3 ) 2 (M = Li, Na and K) leading to up to 93% isolated yield of the desired product 8aa . To prevent the bis-arylation and achieve this high yield, it was necessary to add the 1.5 equivalents of LiN(SiMe 3 ) 2 over 1 h in THF at room temperature (Table 1).…”

Reactions of 2‐Aryl‐1,3‐Dithianes and [1.1.1]Propellane

“…A notable case of new reactivity of dithianes is the Smith group's development of anion‐relay chemistry using 2‐silyl‐1,3‐dithianes . 2‐Aryl‐1,3‐dithianes could be used as pronucleophiles for palladium‐mediated arylation and allylic substitution in a deprotonative cross‐coupling process. To enable synthetic access to BCP ketones and to explore new reactivity of 1,3‐dithianes, we describe herein the addition of 2‐aryl‐1,3‐dithianes to [1.1.1]propellane, an unprecedented transformation which furnishes BCP analogues of a valuable pharmacophore.…”

Palladium‐Catalyzed Allylic Alkylation of 2‐Aryl‐1,3‐Dithianes, an Umpolung Synthesis of β,γ‐Unsaturated Ketones

“…Based on this approach, we developed an arylation of dithianes and demonstrated its application to the synthesis of medicinally relevant benzophenone derivatives (Scheme 1, c). [10] Schmink and coworkers simultaneously reported very similar conditions for this coupling reaction. [11] Since several of the nucleophiles we employed in arylation reactions also found utility in palladium and nickel catalyzed allylic substitution reactions, we decided to investigate metallated 1,3dithianes in allylic alkylation reactions.…”

“…In our effort to develop deprotonative cross‐coupling processes (DCCP), we became interested in the coupling of 2‐aryl‐1,3‐dithianes to aryl halides under conditions where the dithianes are reversibly deprotonated in the presence of base. Based on this approach, we developed an arylation of dithianes and demonstrated its application to the synthesis of medicinally relevant benzophenone derivatives (Scheme , c) . Schmink and coworkers simultaneously reported very similar conditions for this coupling reaction .…”