Site-Selective Alkenylation of δ-C(sp³)–H Bonds with Alkynes via a Six-Membered Palladacycle

Abstract

Most chelation-assisted aliphatic C-H activation proceeds through a kinetically favored five-membered cyclometalated intermediate. Here, we report the first site-selective alkenylation of δ-C(sp(3))-H in the presence of more accessible γ-C(sp(3))-H bonds via a kinetically less favored six-membered palladacycle. A wide range of functional groups are tolerated, and the unique protocol can be applied to the synthesis of chiral piperidines. Moreover, mechanistic insights have been conducted to elucidate the origin of the unusual site-selectivity.

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

“…[11] More recently,A ckermann and co-workers developed as ite-selective C(sp 3 ) À Ha rylation of amino acids and peptides by using internal 1,2,3-triazole moieties as directing groups. In continuation of our ongoing research on the modification of amino acids by C(sp 3 ) À Hf unctionalization, [4,13] we herein report the first Pd-catalyzed site-selective d-methyl CÀH alkylation of amino acids and peptides with maleimides in the presence of more accessible g-methyl CÀHb onds (Figure 1B). In continuation of our ongoing research on the modification of amino acids by C(sp 3 ) À Hf unctionalization, [4,13] we herein report the first Pd-catalyzed site-selective d-methyl CÀH alkylation of amino acids and peptides with maleimides in the presence of more accessible g-methyl CÀHb onds (Figure 1B).…”

“…Isoleucinols that are masked by synthetically useful protecting groups,such as acetyl (6), benzoyl (7), or benzyl (8), could also be applied. These results were extremely pleasing as these substrates were incompatible with our previous d-alkenylation reaction [4] owing to competing N,Ncoordination. [17a] Moreover, g-alkoxylated [17b] (10 and 11)a nd g-alkylated [3c] (12 and 13) isoleucine derivatives also reacted smoothly with 2a to furnish the d-alkylation products in acceptable yields.N otably, g-arylated, g-alkoxylated, and g-alkylated isoleucine derivatives (9-13)w ere all synthesized by g-C(sp 3 )ÀHf unctionalization of 1, [3c, 17] showcasing that this procedure might be valuble for the derivatization of a-amino acids by sequencial C(sp 3 ) À Hf unctionalization.…”

“…[2] The introduction of ad irecting group that coordinates to the palladium catalyst and facilitates the cleavage of ap roximal C À Hbond has become one of the most successful strategies to achieve high positional selectivities.T ypically, g-methyl C À H bonds are selectively functionalized over C(sp 3 )ÀHb onds at other positions (e.g., g-methylene and d-methyl) through the preferencial formation of ak inetically favored five-membered palladacycle INT-A ( Figure 1A,p ath a). [3,4] Such as trategy would enrich our toolkit for streamlining the synthesis of complex molecules, particularly bioactive natural products and pharmaceutical targets. [3,4] Such as trategy would enrich our toolkit for streamlining the synthesis of complex molecules, particularly bioactive natural products and pharmaceutical targets.…”

“…[5] We surmised that under certain conditions, d-selectivity could be achieved through the functionalization of INT-B when the functionalization of INT-A cannot occur owing to ahigh energy barrier ( Figure 1A,p ath b; the functionalization step is the SDS). [4] Unfortunately,this proofof-concept study was far from practical owing to the narrow substrate scope and low yields.T hus it would be highly desirable to render this complementary site-selective method more general for ab road range of densely functionalized substrates,such as peptides. [4] Unfortunately,this proofof-concept study was far from practical owing to the narrow substrate scope and low yields.T hus it would be highly desirable to render this complementary site-selective method more general for ab road range of densely functionalized substrates,such as peptides.…”

Komplementäre Strategien für die dirigierte C(sp3)‐H‐Funktionalisierung: ein Vergleich von übergangsmetallkatalysierter Aktivierung, Wasserstoffatomtransfer und Carben‐ oder Nitrentransfer

“…[34] Es erfolgte eine Methoxylierung des Amids 61 zu 62,w enn Methanol als Lçsungsmittel eingesetzt wird. Außerdem beschrieben Z.-J.S hi bzw.B .-F.S hi die Kupplung von Amiden und Diboronsäureestern [35] oder Alkinen [36] an nichtaktivierte C-H-Bindungen. Diese Verfahren ermçglichen die Borylie- rung bzw.A lkenylierung der primären C-H-Bindungen der Picolinamide 65 und 68.…”