Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C–H Bonds Using Ru(II)-Pheox Catalyst

Abstract

We have established a method for the highly regio- and enantioselective functionalization of tert-butyl groups via intramolecular amide carbene insertion into C–H bonds, yielding γ-lactams with 91% ee in up to 99% yield. This reaction uses a ruthenium­(II) phenyl oxazoline (Ru­(II)-Pheox) complex. The catalytic intramolecular carbene transfer reaction to the primary C–H bond proceeds rapidly and selectively compared to that with secondary C–H, benzylic secondary C–H, tert-C–H, or sp2C–H bonds in the presence of 1 mol % Ru­(II)-Pheox catalyst. This is the first example of a catalytic carbenoid insertion into an unactivated tert-butyl group with enantiocontrol at the carbenoid carbon.

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor‐Acceptor and Diacceptor Diazo Reagents

“…For example, the intramolecular carbene insertion into primary C−H bond of tert ‐butyl group using 2 g proceeded smoothly under the optimized reaction conditions, [12] leading to the optically active γ‐lactone 7 g in 61 % isolated yield with 94 : 6 e.r. Although the Ru‐catalyzed asymmetric carbene transfer to the non‐activated C−H bond of the N ‐ tert ‐butyl group on diazoacetamides has been reported, [15] the intramolecular asymmetric reaction using tert ‐butyl α‐aryl diazoacetates remained unknown to date. These examples represent, to our knowledge, the first intramolecular asymmetric carbene insertion into the non‐activated methyl C−H bond of the tert ‐butyl group using tert ‐butyl α‐aryl diazoacetates.…”

Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of Catalysts and Substrate Substitution in the Synthesis of Oxindoles and β-Lactams

“…A number of transition metal complexes have been used as effective catalysts to generate reactive metallacarbenes starting from α-diazocarbonyl compounds [9,10,11,12,13,14,15,16]. Among them, rhodium(II) [17,18], copper(I) [19,20], and more recently ruthenium(II) catalysts [21,22,23,24,25,26,27] have been proven to be especially useful for the development of highly selective carbene C–H insertion methodologies via a variety of reaction modes. Interestingly, palladium, one of the most commonly employed metals in homogeneous catalysis, remains underexploited in this type of carbene C–H insertion processes.…”

“…The longstanding research on transition metal-catalyzed carbene C–H insertion has generated an extensive literature on the use of dirhodium(II) catalysts to promote the intramolecular C–H insertion of α-diazoacetamides [37,38], as the insertion products, namely β- and γ-lactams as well as 2-oxindoles, are common scaffolds found in numerous natural products. In recent years, some ruthenium(II) catalysts have also been applied to promote this kind of C–H insertion process [21,22,25,39,40,41,42,43]. It has been shown that the site selectivity of these reactions not only depends on the type of diazocarbonyl compound but also is governed by conformational, steric, as well as electronic factors [44,45,46].…”

Enzymatic Lactone-Carbene C–H Insertion to Build Contiguous Chiral Centers

“…In particular, enantioselective C­(sp 3 )–H alkylation via carbene insertion into C–H bonds provides a platform for C­(sp 3 )–C­(sp 3 ) bond formation to build diverse molecular skeletons and for late-stage modification of complex molecules . Transition-metal catalysts based on rhodium, iridium, cobalt, copper, and other metals have been shown to catalyze carbene insertion into C–H bonds. In most reported methods, carbenes bearing one electron-donating aryl/alkenyl group and one electron-withdrawing group (“donor–acceptor carbenes”) have been demonstrated to be superior for intermolecular C–H insertions, with control over reactivity and selectivity in these catalytic systems .…”