Chemoselective Synthesis of β-Ketophosphonates Using Lithiated α-(Trimethylsilyl)methylphosphonate

Abstract

A highly chemoselective synthesis of β-ketophosphonates from pentafluorophenyl esters and lithiated methyl α-(trimethylsilyl)methylphosphonate has been developed. This mild lithiated phosphonate reagent allows the synthesis of functionalized β-ketophosphonates in the presence of unactivated esters with high yields. This method has been compared with the standard lithiated methylphosphonate reagent.

Pd-Catalyzed Suzuki-Miyaura Cross-Coupling of Pentafluorophenyl Esters

“…In contrast to amides, esters feature significant stabilization in the transition state. Given the established capacity of pentafluorophenyl esters as acyl transfer reagents in nucleophilic addition reactions [20,21,22], we recently questioned whether the ground-state-destabilization principle might enable facile cross-coupling of pentafluorophenyl esters under chemoselective conditions that are inaccessible to the current-state-of-the-art phenolic esters [1,2,3]. In this Special Issue on Amide Bond Activation , we report the successful realization of this approach, and report the first general method for the cross-coupling of pentafluorophenyl esters by selective C–O acyl cleavage.…”

“…Notably, this study establishes pentafluorophenyl esters as new, highly reactive, bench-stable, economical, ester-based, electrophilic acylative reagents via acyl-metals [1,2,3]. Considering the versatile role of pfp esters in organic synthesis [20,21,22], we expect that this approach will find wide application in the development of cross-coupling reactions of bench-stable ester electrophiles by acyl [1] and decarbonylative pathways [2,7,23,24] (Scheme 1).…”

Evaluation of Cyclic Amides as Activating Groups in N–C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions

“…Amides represent one of the most fundamental functional groups in organic chemistry and biology. − Although typical amides are planar and unreactive as a consequence of n N → π* CO resonance rendering the N–C­(O) bond approximately 40% double in character, recent years have witnessed significant advances in the development of an array of selective methods for N–C­(O) bond activation by transition-metal catalysis enabled by resonance tuning of the amide bond (Figure A) . In this respect, early studies by Garg, Zou, and our group established N -acyl-Boc-carbamates, N -acyl-Ts-sulfonamides, and N -acyl-glutarimides as effective cross-coupling partners by N–C­(O) bond activation. − Although a number of other amide precursors have been developed, N -acyl-glutarimides represent the most reactive amide bond precursors for cross-coupling reactions developed to date (Figure B). − …”

“…Principally, the high reactivity of the amide bond in N -acyl-glutarimides stems from the combination of steric and electronic activation of the amide bond, which results in electronically disconnected [resonance energy (RE) of 0.5–2.4 kcal/mol], twisted amides [twist angle (τ) of 89.1°]. , Considering that N -acyl-glutarimides constitute privileged amide derivatives that have enabled a range of previously unattainable cross-coupling reactions of amide bonds by C–C, C–N, C–B, C–Si, C–P, and C–H bond-forming events − and at the same time constitute bench- and air-stable amide-based reagents despite considerable amide bond twist, − expanding the portfolio of cyclic amides related to glutarimides as activating groups for N–C­(O) bond cross-coupling is especially attractive.…”

“…In general, the development of amide bond cross-coupling reactions relies on the availability of new amide bond derivatives for cross-coupling. − This is clearly demonstrated by N -acyl-glutarimides, introduced by our group in 2015. , Now, N -acyl-glutarimides are the reagents of choice for the development of acyl and decarbonylative cross-coupling reactions of amides that have enabled the discovery of more than 10 distinct and previously unknown methods of reactivity of the amide bond. Furthermore, novel amide bond derivatives with distinct steric and electronic features enable reaction fine-tuning due to changes in resonance, sterics around the amide bond, and leaving group capacity. − In this context, N -acyl-δ-valerolactams represent novel monoacyl-activated equivalents of N -acyl-glutarimides that differ in amidic resonance, sterics around the amide bond, and the p K a of the leaving group. The fact that there is no other amide derivative available that covers a similar range of steric distortion and electronic delocalization − means that these reagents should be routinely included in the development and optimization of amide bond cross-coupling reactions.…”