skip to main content


Title: Pd-Catalyzed Suzuki-Miyaura Cross-Coupling of Pentafluorophenyl Esters
Although the palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl esters has received significant attention, there is a lack of methods that utilize cheap and readily accessible Pd-phosphane catalysts, and can be routinely carried out with high cross-coupling selectivity. Herein, we report the first general method for the cross-coupling of pentafluorophenyl esters (pentafluorophenyl = pfp) by selective C–O acyl cleavage. The reaction proceeds efficiently using Pd(0)/phosphane catalyst systems. The unique characteristics of pentafluorophenyl esters are reflected in the fully selective cross-coupling vs. phenolic esters. Of broad synthetic interest, this report establishes pentafluorophenyl esters as new, highly reactive, bench-stable, economical, ester-based, electrophilic acylative reagents via acyl-metal intermediates. Mechanistic studies strongly support a unified reactivity scale of acyl electrophiles by C(O)–X (X = N, O) activation. The reactivity of pfp esters can be correlated with barriers to isomerization around the C(acyl)–O bond.  more » « less
Award ID(s):
1650766
NSF-PAR ID:
10090745
Author(s) / Creator(s):
; ; ;
Date Published:
Journal Name:
Molecules
Volume:
23
Issue:
12
ISSN:
1420-3049
Page Range / eLocation ID:
3134
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. The Suzuki-Miyaura cross-coupling has been widely recognized as one of the most important methods for the construction of C–C bonds. However, in contrast to traditional aryl halide or pseudohalide electrophiles, coupling reactions with unactivated C–N and C–O electrophiles have proven significantly more challenging. Here we report the first general palladium-catalyzed Suzuki-Miyaura cross-coupling of both common amides and aryl esters through the selective cleavage of the C–N and C–O bonds under exceedingly mild conditions. Notably, for the first time we demonstrate selective C(acyl)– N and C(acyl)–O cleavage/cross-coupling under the same reaction conditions. The reaction uses a commercially available, bench-stable and operationally-convenient (n3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst. Furthermore, we demonstrate that the reactivity of generic amides and aryl esters can be correlated with barriers to isomerization around the C(acyl)–X (X = N, O) bond, thus providing a blueprint for the development of a broad range of novel coupling reactions of ester and amide electrophiles by the selective activation of C–O and C–N bonds. 
    more » « less
  2. null (Ed.)
    The cross-coupling of aryl esters has emerged as a powerful platform for the functionalization of otherwise inert acyl C–O bonds in chemical synthesis and catalysis. Herein, we report a combined experimental and computational study on the acyl Suzuki–Miyaura cross-coupling of aryl esters mediated by well-defined, air- and moisture-stable Pd( ii )–NHC precatalysts [Pd(NHC)(μ-Cl)Cl] 2 . We present a comprehensive evaluation of [Pd(NHC)(μ-Cl)Cl] 2 precatalysts and compare them with the present state-of-the-art [(Pd(NHC)allyl] precatalysts bearing allyl-type throw-away ligands. Most importantly, the study reveals [Pd(NHC)(μ-Cl)Cl] 2 as the most reactive precatalysts discovered to date in this reactivity manifold. The unique synthetic utility of this unconventional O–C(O) cross-coupling is highlighted in the late-stage functionalization of pharmaceuticals and sequential chemoselective cross-coupling, providing access to valuable ketone products by a catalytic mechanism involving Pd insertion into the aryl ester bond. Furthermore, we present a comprehensive study of the catalytic cycle by DFT methods. Considering the clear advantages of [Pd(NHC)(μ-Cl)Cl] 2 precatalysts on several levels, including facile one-pot synthesis, superior atom-economic profile to all other Pd( ii )–NHC catalysts, and versatile reactivity, these should be considered as the ‘first-choice’ catalysts for all routine applications in ester O–C(O) bond activation. 
    more » « less
  3. Amides are of fundamental interest in many fields of chemistry involving organic synthesis, chemical biology and biochemistry. Here, we report the first catalytic Buchwald-Hartwig coupling of both common esters and amides by highly selective C(acyl)–X (X = O, N) cleavage to rapidly access aryl amide functionality via crosscoupling strategy. Reactions are promoted by versatile, easily prepared, well-defined Pd-PEPPSI type precatalysts, proceed in good to excellent yields and with excellent chemoselectivity for the acyl bond cleavage. The method is user friendly because it employs commercially-available, moisture- and air-stable precatalysts. Notably, for the first time we demonstrate selective C(acyl)–N and C(acyl)–O cleavage/Buchwald-Hartwig amination under the same reaction conditions, which allows for streamlining amide synthesis by avoiding restriction to a particular acyl metal precursor. Of broad interest, this study opens the door to using a family of well-defined Pd(II)-NHC precatalysts bearing pyridine ͞throw-away ligands for the selective C-acyl–amination of bench-stable carboxylic acid derivatives. 
    more » « less
  4. A Pd-PEPPSI-catalyzed (Pd = Palladium, PEPPSI = pyridine-enhanced precatalyst preparation stabilization and initiation) Suzuki-Miyaura cross-coupling of aryl esters via selective C–O cleavage at room temperature is reported. The developed catalyst system displays broad substrate scope with respect to both components under practical ambient reaction conditions using readily-available, cheap, modular, air- and moisturestable Pd-NHC precatalyst (NHC = N-heterocyclic carbene). The use of water proved crucial for achieving high reactivity in this coupling. The catalyst system represents the mildest conditions for the Suzuki-Miyaura cross-coupling of aryl esters reported to date. The protocol also allowed for achieving TON >1,000 (TON = turnover number) in the Suzuki-Miyaura ester coupling for the first time. 
    more » « less
  5. We report a general, highly selective method for Suzuki–Miyaura cross-coupling of N-acylphthalimides via N–C(O) acyl cleavage catalyzed by Pd–PEPPSI-type precatalysts. Of broad synthetic interest, the method introduces N-acylphthalimides as new, bench-stable, highly reactive, twist-controlled, amide-based precursors to acyl-metal intermediates. The reaction delivers functionalized biaryl ketones by acylative Suzuki–Miyaura cross-coupling with readily available boronic acids. Studies demonstrate that cheap, easily prepared, and broadly applicable Pd–PEPPSI-type precatalysts supported by a sterically demanding IPr (1,3-Bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) ancillary ligand provide high yields in this reaction. Preliminary selectivity studies and the effect of Pd–N-heterocyclic carbenes (NHC) complexes with allyl-type throw-away ligands are described. We expect that N-acylphthalimides will find significant use as amide-based acyl coupling reagents and cross-coupling precursors to acyl-metal intermediates. 
    more » « less