An “On-Cycle” Precatalyst Enables Room-Temperature Polyfluoroarylation Using Sensitive Boronic Acids

Abstract

The use of fluorinated arylboronic acid building blocks in cross-coupling has remained challenging, because of their acute base sensitivity. We report a general solution to this problem using a true catalytic intermediate, Pd­(PAd3)­(p-FC6H4)­Br, as a uniquely effective “on-cycle” precatalyst that allows Suzuki–Miyaura coupling to occur much faster than even the most severe protodeboronation side reactions. Control of boron speciation between the active acid and dormant ester forms was also found to play a critical role in balancing the rates of catalysis versus reagent decomposition. This method is compatible with any fluorination pattern, base-labile functional groups, and a range of bromo­(hetero)­arenes.

Development of Palladium Precatalysts that Efficiently Generate LPd(0) Active Species

“…Carrow applied (Ad 3 P)Pd(4‐C 6 H 4 F)Br ( 26 ) as a highly efficient precatalyst for the SMC of aryl bromides and protolytically sensitive fluorinated arylboron species . Under optimized conditions, the oxidative addition precatalyst 26 was significantly more effective than the catalyst generated in situ (PAd 3 and Pd 2 (dba) 3 ), (PAd 3 )Pd(η 3 ‐cinnamyl)Cl, [(P( t ‐Bu) 3 )PdBr] 2 , G2 SPhos, G3 XPhos, and IPr PEPPSI.…”

Base‐Free Pd‐Catalyzed C−Cl Borylation of Fluorinated Aryl Chlorides

“…In 2018, Carrow et al. treated C 6 F 5 Bpin and C 6 F 5 B(OH) 2 with wet triethylamine (weak base), and found that C 6 F 5 Bpin underwent protodeboronation, but the rate was slower than that for C 6 F 5 B(OH) 2 [8e] . Hence, it can be suggested that the best conditions to synthesize 2,6‐difluorophenyl‐Bpin derivatives are base‐free methods.…”

Fluorinated Aryl Boronates as Building Blocks in Organic Synthesis

“…Carrow et al . studied the influence of triethylamine and/or water with respect to the stability of C 6 F 5 Bpin and C 6 F 5 B(OH) 2 towards protodeboronation [75] . Notably, triethylamine was used as received and contains trace amounts of water.…”

“…In 2018, Carrow et al . synthesized a series of unsaturated complexes of the type [Pd(L)(Ar)X], including [Pd(PAd 3 )( p ‐FC 6 H 4 )Br] (Carrow precatalyst; PAd 3 = tri(1‐adamantyl)phosphine), which was found to be an efficient ‘on‐cycle’ precatalyst [75] . This system allowed for the Suzuki‐Miyaura cross‐couplings of highly fluorinated aryl boronic acids with aryl or heteroaryl bromides and proved to be faster than the competing protodeboronation degradation pathway.…”

“… Precatalyst [Pd(PAd 3 )(p‐FC 6 H 4 )Br] for cross‐coupling of C 6 F 5 B(OH) 2 or its C 6 F 5 Bpin with (p‐FC 6 H 4 )Br: (A) without water; or (B) with addition of water [75] …”