skip to main content


Title: N-Acylphthalimides: Efficient Acyl Coupling Reagents in Suzuki–Miyaura Cross-Coupling by N–C Cleavage Catalyzed by Pd–PEPPSI Precatalysts
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
Award ID(s):
1650766
NSF-PAR ID:
10090744
Author(s) / Creator(s):
; ;
Date Published:
Journal Name:
Catalysts
Volume:
9
Issue:
2
ISSN:
2073-4344
Page Range / eLocation ID:
129
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    A versatile method for the Suzuki‐Miyaura cross‐coupling of amides using highly active, well‐defined, and air‐stable Pd−phosphine precatalysts is reported. Most notably, the method represents the first example of using practical and operationally‐simple Pd(II)−phosphine precatalysts in the emerging amide bond cross‐coupling manifold. The reactions are efficient at 0.10 mol% loading, furnishing biaryl ketones with high chemoselectivity for N−C(O) bond cleavage. This versatile method enables for the first time to achieve Pd−phosphine‐catalyzed cross‐coupling of amides at ppm loading. This C−N cross‐coupling can be used to efficiently furnish pharmaceutical intermediates by orthogonal Pd‐catalyzed cross‐couplings. We fully expect that operationally‐simple [(PR3)2Pd(II)X2] precatalysts as effective triggers for N−C(O) cross‐coupling will be of broad synthetic and catalytic interest.

    magnified image

     
    more » « less
  2. 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
  3. 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
  4. The palladium-catalyzed Suzuki-Miyaura cross-coupling of Nacylsuccinimides as versatile acyl-transfer reagents via selective amide N–C bond cleavage is reported. The method is user-friendly since it employs commercially-available, air-stable reagents and catalysts. The cross-coupling is enabled by half-twist of the amide bond in N-acylsuccinimides. These highly effective, crystalline acyltransfer reagents present major advantages over perpendicularly twisted N-acylglutarimides, including low price of the succinimide activating ring, selective metal insertion under redox neutral conditions and high stability of the amide bond towards reaction conditions. Mechanistic studies indicate that oxidative addition is the rate limiting step in this widely applicable protocol. 
    more » « less
  5. 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