Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide‐Functionalized Phosphine Ligands

Abstract

The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α‐aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide‐functionalized phosphines to fit the requirements of Negishi couplings. Record‐setting activities were achieved in palladium‐catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl‐YPhos ligand bearing an ortho‐tolyl‐substituent in the backbone. This highly electron‐rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.

Acceleration of 1,3-Dipolar Cycloadditions by Integration of Strain and Electronic Tuning

“…Its [1,2]-rearrangement afforded the desired cyclooctyne. Adventitiously, this opportunistic route to ABC affords a chloro group that is an ideal handle for functionalization through well-established aryl chloride coupling chemistry. , We also applied the alkylidene carbene ring-expansion strategy for the expedient synthesis of DIBO, and we anticipate its utility in the synthesis of other cycloalkynes as well.…”

Pentafluorophenyl Group as Activating Group: Synthesis of α‐Deuterio Carboxylic Acid Derivatives via Et3N Catalyzed H/D Exchange

“…As shown in Scheme 4, this protocol was applied in the synthesis of various deuterated carboxylic acids. Useful deuterated building blocks (2 a [12] and 2 b [13] ) and deuterated bioactive compounds including deuterated rooton 2 c [14] deuterated antiinflammatory agent ibuprofen 2 d, [15] deuterated pain or fever reducer naproxen 2 e [16] and deuterated felbinac 2 f [17] were synthesized in high yields, which exhibited the potential application of this protocol in medicinal chemistry.…”

Ylide-Substituted Phosphines with a Cyclic Ylide-Backbone: Angle Dependence of the Donor Strength

“…This contrasts the high activity of the acyclic YPhos ligands which provided high yields in these reactions at room temperature usually within only a couple of minutes. 15 , 16 …”

“… 18 The obtained buried volume of 42.5% is lower than that of other acyclic YPhos ligands with PCy 3 or PPh 3 moieties, which usually showed volumes of approximately 50%. 13 − 15 Furthermore, the steric map of L1 shows areas of steric bulk only on one side of the of the ligand, namely, the phosphonium moiety. The cyclohexyl groups are unable to reach toward the metal center.…”

“…These ligands were shown to be ideal scaffolds for catalytic applications, ranging from gold-catalyzed hydroamination and cyclization reactions 14 to palladium catalysis, such as Buchwald–Hartwig aminations as well as Negishi couplings and α-arylation reactions under mild conditions. 15 Recently, it has been shown that YPhos palladium catalysts are even capable of directly coupling aryl chlorides and alkyl lithium reagents, giving very high selectivities while supplementing the need for any additional transmetalation reagents. 16 …”