Practical Direct α‐Arylation of Cyclopentanones by Palladium/Enamine Cooperative Catalysis

Abstract

Direct arylation of cyclopentanones has been a long-standing challenge because of competitive self-aldol condensation and multiple arylations. Reported herein is a direct mono-α-C-H arylation of cyclopentanones with aryl bromides which is enabled by palladium/amine cooperative catalysis. This method is scalable and chemoselective with broad functional-group tolerance. Application to controlled sequential arylation of cyclopentanones has been also demonstrated.

Transient Ligand‐Enabled Transition Metal‐Catalyzed C−H Functionalization

“…In 2016, direct arylation of cyclopentanones with aryl bromides by using transient ligand L32 was reported by the same group. This reaction was enabled by palladium and enamine cooperative catalysis (Scheme c) …”

“…This reactionw as enabled by palladium and enamine cooperative catalysis (Scheme 19 c). [36] 2.6. C(sp 3…”

α‐Arylation and Ring Expansion of Annulated Cyclobutanones: Stereoselective Synthesis of Functionalized Tetralones

“…Noticeably absent from this collection of reactions, however, is the α‐arylation of cyclobutanones (e.g., 7→1 ), which would serve as a direct route to this useful class of molecules. Thus, despite key advances reported by the groups of Buchwald, Hartwig, Miura, Colacot, and others in the α‐arylation of acyclic ketones as well as cyclopentanones,, cyclohexanones,,,, and cycloheptanones, the α‐arylation of cyclobutanones is without precedent. This is perhaps not surprising, considering that the challenges associated with the α‐arylation of cyclopentanones (e.g., competing self‐aldol reactions, multiple arylation events) are manifest with cyclobutanones and further compounded by the propensity of cyclobutanones to fragment upon reaction with base …”

“…[4] In this regard, a-arylcyclobutanones are particularly useful owing to their predictable pattern of fragmentation, [5] and can be accessed using the strategies highlighted in Scheme 1. Thus,d espite key advances reported by the groups of Buchwald, [10] Hartwig, [11] Miura, [12] Colacot, [13] and others [14,15] in the a-arylation of acyclic ketones as well as cyclopentanones, [10c, 14a,c] cyclohexanones, [10a,c, 11b,14a,b,c] and cycloheptanones, [10c] the a-arylation of cyclobutanones is without precedent. Thus,d espite key advances reported by the groups of Buchwald, [10] Hartwig, [11] Miura, [12] Colacot, [13] and others [14,15] in the a-arylation of acyclic ketones as well as cyclopentanones, [10c, 14a,c] cyclohexanones, [10a,c, 11b,14a,b,c] and cycloheptanones, [10c] the a-arylation of cyclobutanones is without precedent.…”

“…Although regiocontrol in [2+ +2] cycloadditions [6] can prove problematic,the rearrangement of oxaspiropentanes [7] (e.g., 2)a nd a-hydroxycyclopropylcarbinols [8] (e.g., 3), or carbonylation of titanocene cyclobutane complexes [9] provide reliable routes to a-arylcyclobutanones 1.N oticeably absent from this collection of reactions,h owever,i st he a-arylation of cyclobutanones (e.g., 7!1), which would serve as adirect route to this useful class of molecules. Thus,d espite key advances reported by the groups of Buchwald, [10] Hartwig, [11] Miura, [12] Colacot, [13] and others [14,15] in the a-arylation of acyclic ketones as well as cyclopentanones, [10c, 14a,c] cyclohexanones, [10a,c, 11b,14a,b,c] and cycloheptanones, [10c] the a-arylation of cyclobutanones is without precedent. This is perhaps not surprising,considering that the challenges associated with the a-arylation of cyclopentanones [14a] (e.g., competing self-aldol reactions,m ultiple arylation events) are manifest with cyclobutanones and further compounded by the propensity of cyclobutanones to fragment upon reaction with base.…”