Palladium/Norbornene‐Catalyzed C−H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine‐Containing Pentacyclic Frameworks

Abstract

Reported is a highly chemoselective intermolecular annulation of indole-based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani-type C-H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp )-C(sp ) and one C(sp )-C(sp ) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional-group tolerance. Preliminary mechanistic studies reveal that C-H bond cleavage is likely involved in the rate-determining step, and the indole dearomatization might take place through an olefin coordination/insertion and β-hydride elimination Heck-type pathway.

Alkylating Reagents Employed in Catellani‐Type Reactions

“…In a similar manner, the domino process exploiting 1‐(2‐iodobenzyl)‐1 H ‐pyrrole and ‐indoles as the reaction partners afforded a series of seven‐membered‐ring fused heterocycles 83 (Scheme b) and 84 (Scheme c) in moderate to high yields . Recently, the group of Luan reported an elegant domino reaction between 3‐(2‐iodophenyl)‐1 H ‐indoles and tethered bromoalkyl alkynes for the concise assembly of pentacyclic products 85 , which contained an interesting spiroindolenine motif (Scheme d) . In addition, the group of Lautens discovered that, in the absence of an adjacent heteroaryl or benzyl group on aryl iodide substrates, vinylpalladium species 81 underwent further carbopalladation of NBE to afford sterically crowded tetrasubstituted helical alkenes 86 through C−H functionalization on the adjacent aromatic ring (Scheme e) .…”

“…[53] Recently, the group of Luan reported an elegant domino reactionb etween 3-(2-iodophenyl)-1H-indoles and tethered bromoalkyl alkynes for the concise assembly of pentacyclic products 85, which contained an interesting spiroindolenine motif (Scheme 23 d). [54] In addition, the group of Lautens discovered that, in the absence of an adjacent heteroaryl or benzyl group on aryl iodide substrates, vinylpalladiums pecies 81 underwent furtherc arbopalladation of NBE to afford sterically crowded tetrasubstituted helical alkenes 86 through CÀHf unctionalization on the adjacent aromaticr ing (Scheme 23 e). [55] In this case, NBE not only acted as the mediator, but also becamea part of the products.M ore interestingly,i fe nantiopure 80 was applied, an intriguing threefold stereoselectivity was observed in the process:r etention of the central chirality,i nduction of helical chirality (5:1-6.7:1 d.r.…”

Palladium/Norbornene Catalyzed ortho Amination/Cyclization of Aryl Iodide: Process to 3-Methyl-indole Derivates and Controllable Reductive Elimination against the Second Amination

“…In 2000, the Lautens group reported a Pd/NBE catalyzed annulation reaction utilizing aryl iodide and olefin-tethered alkyl halides which functioned as both electrophile (C–X) and nucleophile (alkenyl in intramolecular Heck reaction) (b, Scheme ). Subsequently, alkyl halides tethered to alkyne, amine, propenol, heteroarenes, or ketones were successfully applied to efficiently construct various benzocyclic molecules (b, Scheme ). In addition, epoxides and aziridines were also employed as difunctional reagents through S N 2 type ring opening to synthesize dihydrobenzofurans and indolines (c, Scheme ).…”

Palladium/Norbornene‐Catalyzed C−H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine‐Containing Pentacyclic Frameworks

“…Thee xperimental results showed that the phenyl substituent on the alkyne terminus of 2a could be replaced with diversified aryls bearing an electron-donating methoxy group (2b), an EWG such as afluoro (2c), chloro (2d), ester (2e), and nitro (2f)group,oraheterocyclic group such as N-Ts-3-indolyl (2g)and 2-thienyl (2h), and the desired products 3a' '-g' ' were obtained in 63-85 %yields.Notably,the substrate 2i,b earing av inylic substituent, behaved quite well to give 3h' ' in 90 %y ield. [16] Finally,i ti sw orth mentioning that the tether for linking the alkyl bromide and alkyne fragments could be extended with either one more carbon, oxygen, or nitrogen atom, thus enabling the rapid construction of three types of unprecedented pentacyclic frameworks (3r' '-t' ')b earing aseven-membered carbo-or heterocyclic ring unit. Upon treatment with TBAF, 3l' ' underwent TBS removal followed by stereospecific alkoxide addition to furnish af ascinating hexacyclic framework 6.…”

“…The relative stereochemistry of 3q' ' major was confirmed by X-ray studies. [16] Finally,i ti sw orth mentioning that the tether for linking the alkyl bromide and alkyne fragments could be extended with either one more carbon, oxygen, or nitrogen atom, thus enabling the rapid construction of three types of unprecedented pentacyclic frameworks (3r' '-t' ')b earing aseven-membered carbo-or heterocyclic ring unit.…”