Reversing conventional site-selectivity in C(sp3)–H bond activation

Abstract

One of the core challenges in developing C-H activation reactions is to distinguish multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp 2)-H bonds have been selectively activated in the presence of proximate ones 1-2. Yet achieving such unconventional site selectivity with C(sp 3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid derived directing group and a 2-pyridione ligand that enables the preferential activation of the distal γ-C(sp 3)-H bond over the proximate β-C(sp 3)-H bonds for a wide range of alcohol derived substrates. Competition experiment of five-and six-membered cyclopalladation step as well as kinetic experiments demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp 3)-H activation. Developing C-H activation reactions as new retrosynthetic disconnections could offer a multitude of novel synthetic strategies due to the abundance of positionally diverse C-H bonds 3-4. On the other hand, the great resemblance between these C-H bonds in terms of bond strength and electronic properties presents a tremendous challenge for achieving regioselectivity. This difficulty escalates with metalation chemistry because in such processes, the numerous primary or secondary C-H bonds are nearly indistinguishable by the metal. For example, despite the recent advances in developing a wide range of Pdcatalyzed C(sp 3)-H activation reactions, their regioselectivity is largely restricted to the cleavage of the C-H bond that will result in five-membered cyclopalladation 5-12. Therefore, it is fundamentally important to develop strategies to switch the selectivity of the key metalation step from five-membered to six-membered cyclopalladation (Fig. 1b). Such Reprints and permissions information is available at www.nature.com/reprints.

Geminal group-directed olefinic C-H functionalization via four- to eight-membered exo-metallocycles

“…Moreover, while amide 6r did react via 7- exo -cyclopalladation, homoallyl carbamate did not convert even at elevated temperatures (Table 1, entry 9), exhibiting the great influence of coordinating effect. All of these primary results exhibited that the exo - and endo -cyclometallations were governed by coordination strength and conformation effects on the C-H activation step 9,16 , and the detailed mechanistic studies will be discussed in a later report. Deuterium incorporation experiments supported the irreversibility of the C-H activation steps, and no Z/E isomerization excluded other possible mechanistic pathway such as π-allylpalladium(II) formation or nucleometalation/ β -X elimination 39,50 .…”

“…Sanford and co-workers described a nitrogen-directed transannular C(alkyl)-H activation of alicyclic amine cores 15 . Very recently, the Yu group disclosed an aliphatic γ-C–H arylation protocol to be proceeded by conventionally disfavored six-membered cyclopalladation, using a strained directing group derived from pyruvic acid 16 . Considering the number of novel reactions that have arisen from metallacycle intermediates, identification of distinct cyclometallation pathways would lead to novel C–H bond transformations.…”

“…1a). Moreover, the cyclometallation concept has been remarkably expanded to positional selective C-H bond activation in arenes and alkanes 6–16 , but its utilization in site-selective C(alkenyl)-H bond functionalization still remains elusive 17–35 .

Fig. 1Chelation-assisted olefinic C-H functionalization.

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Ligand‐Controlled Direct γ‐C−H Arylation of Aldehydes

“…Additionally, the external ligand could lower the transition‐state energy of the C−H bond‐cleavage step and then promote and accelerate the process . Yu and co‐workers have achieved γ‐C(sp 3 )−H arylation of aliphatic alcohols and amines based on this strategy . Very recently, Maiti and co‐workers described the use of N‐Ac‐Gly‐OH as an external ligand to promote palladium‐catalyzed iterative γ‐C(sp 3 )−H arylation of aliphatic acids .…”

Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation

“…These discoveries indicate that different stages in a typical C-H bond functionalization event could be exploited to achieve such unconventional remote selectivity. For instance, the selectivity of the C-H metallation step could be reversed by increasing the ring strain of the metallacycle intermediate; 24 larger metallacycles could be favoured if their smaller counterparts only give less favourable strained products (e.g. intramolecular silylation via 6membered metallacycles) [31][32][33][34] or suffer from a high energy transition state in the reductive elimination step (e.g.…”