2‐Methyltetrahydrofuran (2‐MeTHF): A Green Solvent for Pd−NHC‐Catalyzed Amide and Ester Suzuki‐Miyaura Cross‐Coupling by N−C/O−C Cleavage

Abstract

The palladium-NHC-catalyzed (NHC = N-heterocyclic carbene) Suzuki-Miyaura cross-coupling of amides and esters via highly chemoselective NÀ C(O) and OÀ C(O) cleavage with aryl boronic acids using green, sustainable and ecofriendly 2-methyltetrahydrofuran (2-MeTHF) is reported. A variety of amides and aryl esters were coupled with aryl boronic acids in high to excellent yields. This method employs commercially-available, air-and moisture-stable Pd(II) À NHC precatalysts. Crucially, the use of 2-MeTHF leads to the highest TON reported to date in amide NÀ C(O) bond cross-coupling. This operationally-simple protocol was utilized in the synthesis a bioactive ketone intermediate, emphasizing the potential of 2-MeTHF as a green solvent in unconventional amide bond disconnection. Given the tremendous importance of amide bond cross-coupling strategies and the drive to maintain full sustainability in crosscoupling processes, we expect that the synthetic method will be of broad interest.

Suzuki–Miyaura cross coupling is not an informative reaction to demonstrate the performance of new solvents

“…If there is an observable change in reaction performance correlating to one or more solvent properties (often polarity), then it is possible to identify and implement an optimum solvent. Suzuki-Miyaura cross coupling is the premier method of palladium catalysed carbon-carbon bond formation, making it an obvious case study to validate the performance of novel solvents [1][2][3][4][5][6][7]. The polarity of the solvent is known to determine the structure and activity of cata-lytic intermediates, the rate determining step, and stereochemistry (where applicable) of Suzuki-Miyaura cross couplings [8].…”

N-Acyl-5,5-Dimethylhydantoins: Mild Acyl-Transfer Reagents for the Synthesis of Ketones Using Pd–PEPPSI or Pd/Phosphine Catalysts

“…Within our research program on amide bond cross-coupling and Pd– N -heterocyclic carbenes (NHC) catalysis, , we now report two new protocols for the cross-coupling of N -acyl-5,5-dimethylhydantoins using versatile and readily accessible Pd–PEPPSI or Pd/phosphine catalysts (Figure B). The following features of our study are noteworthy: (1) the reactions complement and expand on the previous protocol for the cross-coupling of N -acyl-hydantoins using [Pd­(IPr)­(allyl)­Cl]; (2) Pd–PEPPSI represent a completely distinct class of Pd–NHC catalysts that are (i) cheaper and easier to synthesize than the allyl-type precatalysts, , (ii) undergo activation under complementary mechanism to the allyl-type precursors, and (iii) many Pd–PEPPSI-type catalysts have been reported, which is significant for the future developments in amide bond N–C­(O) cross-coupling; (3) we demonstrate that, alternatively, cheap and readily accessible Pd/phosphine catalysts can also be used for the cross-coupling of N -acyl-5,5-dimethylhydantoins in excellent yields; and (4) the protocols are also applied to the Suzuki cross-coupling of other classes of twisted amides by selective N–C­(O) activation, showing higher reactivity than the use of the [Pd­(IPr)­(allyl)­Cl] catalyst. ,− …”

Importance of some factors on the Suzuki‐Miyaura cross‐coupling reaction

“…[ 2 ] On the other hand, 2‐MeTHF has also emerged as a green, sustainable, and eco‐friendly solvent for SMC reaction. [ 23 ]…”