A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp(3))-H amination

Abstract

C-H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp(3))-H bonds while displaying chemoselectivity (that is, tolerance of more oxidizable functionality) remains an unsolved problem. Here, we describe a catalyst, manganese tert-butylphthalocyanine [Mn((t)BuPc)], that is an outlier to the reactivity-selectivity paradigm. It is unique in its capacity to functionalize all types of C(sp(3))-H bond intramolecularly, while displaying excellent chemoselectivity in the presence of π functionality. Mechanistic studies indicate that [Mn((t)BuPc)] transfers bound nitrenes to C(sp(3))-H bonds via a pathway that lies between concerted C-H insertion, observed with reactive noble metals such as rhodium, and stepwise radical C-H abstraction/rebound, as observed with chemoselective base metals such as iron. Rather than achieving a blending of effects, [Mn((t)BuPc)] aminates even 1° aliphatic and propargylic C-H bonds, demonstrating reactivity and selectivity unusual for previously known catalysts.

Fig. 1. The C—H oxidation reactivity/selectivity paradigm

a, Reactivity and chemoselectivity of existing C—H amination catalysts with sulfamate ester substrates. Rhodium catalysts aminate strong 2° C—H bonds in aliphatic substrates but aziridinate reactive π-functionality in allylic substrates. Iron and ruthenium catalysts aminate weak allylic bonds with high chemoselectivity, but demonstrate limited reactivity towards strong aliphatic C—H bonds. b, Novel [Mn(^tBuPc)] catalyst demonstrates both high reactivity and chemoselectivity. It is capable of aminating strong aliphatic C—H bonds while tolerating reactive π-functionality in allylic substrates.

Figure 2. Mechanistic studies of manganese and iron C—H amination catalysts

a, Proposed stepwise mechanism for manganese and iron catalysis. b, Intramolecular Hammett analysis (σ⁺) reveals 3 is less sensitive to the electronics of the C—H bond than 1 but more so than reported for rhodium (ρ = −0.55). c, C—H bond reactivity trends for 3° aliphatic C—H bonds relative to other bond types show that 3 reacts according to relative C—H BDE but is less discriminating than 1, indicating attenuated radical character in C—H cleavage. d, KIE values for intramolecular competition experiments for catalysts 1, 2, 3 and Rh₂(OAc)₄ (quantitative ¹³C NMR) suggest manganese catalysis proceeds via a transition stucture where C—H bond breakage occurs to a greater extent than with rhodium but less than with iron. Intermolecular KIE studies with catalysts 2 and 3 suggest C—H cleavage contributes to the reaction rate but is not solely rate-determining. e, Partial isomerization of Z-olefin substrate 47 with catalysts 3 and 1 support a stepwise mechanism. f, Complete stereoretention in C—H amination of enantiometrically enriched (+)-48 with catalysts 3 and 1 supports a rapid radical rebound of the nitrogen from the base metal catalyst versus a free radical intermediate.

Figure 3. Late-stage diversification of complex molecules via [Mn(^tBuPc)]-catalyzed C—H amination

Amination of native oxygen-containing complex molecules picrotoxinin, pregnenolone, stigmasterol, isosteviol, and betulinic acid, as well as those where hydroxyl functionality is readily installed, leelamine and dihydropleuromutilone. a, Predictably selective C—H amination occurs on allylic, benzylic, and 3° and 2° aliphatic C—H bonds in the presence of alternate reactive functionality. Isosteviol derivative (−)-55 undergoes C—H amination on a gram scale and the resulting oxathiazinane (−)-56 is derivatized to reveal 1,3 diamine and amino alcohol motifs. b, Site- and diastereoselective 1° aliphatic C—H amination of betulinic acid (+)-59 and dihydropleuromutilone (+)-61 sulfamate ester derivatives in the presence of alternate, accessible 2° and 3° C—H bonds to furnish geometrically favored six-membered oxathiazinanes.