Auto‐Tandem Catalysis: Synthesis of Substituted 11H‐Indolo[3,2‐c]quinolines via Palladium‐Catalyzed Intermolecular CN and Intramolecular CC Bond Formation

Abstract

D-Ring substituted 11H-indoloA C H T U N G T R E N N U N G [3,2-c]quinolines (4) have been prepared via auto-tandem consecutive intermolecular Buchwald-Hartwig reaction and intramolecular palladium-catalyzed arylation on 4-chloroquinoline (1) with N-unsubstituted 2-chloroanilines (2). The reported 11H-indoloA C H T U N G T R E N N U N G [3,2-c]quinolines (4) represent the first examples in which tandem catalysis has been used to construct N-unsubstituted carbolines.Keywords: amination; C À H activation; malaria; palladium; tandem catalysis IntroductionIn 2003 our research group published a communication which described a new method for the synthesis of 11H-indoloA C H T U N G T R E N N U N G [3,2-c]quinoline (4a) starting from commercially available 4-chloroquinoline (1) and 2-chloroA C H T U N G T R E N N U N G aniline (2a) (Scheme 1).[1] The methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald-Hartwig reaction (chemoselective oxidative addition) followed by an intramolecular arylation involving C À H activation. [2,3] The latter reaction is interesting in itself as published examples on intramolecular Pd-catalyzed arylations of electron-deficient heteroaromatics are scarce in comparison with electron-rich heteroarenes.[3c] Selective N-5 methylation of the obtained 11H-indoloA C H T U N G T R E N N U N G [3,2-c]quinoline (4a) yielded the antiplasmodial natural product isocryptolepine (5-methyl-5H-indoloA C H T U N G T R E N N U N G [3,2-c]quinoline) (5a) (Scheme 1).[4] The increasing resistance of parasites of the genus Plasmodium to well known drugs like chloroquine and mefloquine prompted us to investigate more closely the biological Scheme 1. Synthesis of 4a via consecutive palladium-catalyzed reactions.

New Route to the Synthesis of the Isocryptolepine Alkaloid and Its Related Skeletons Using a Modified Pictet–Spengler Reaction

“…Molina et al12m reported the synthesis of the isocryptolepine by cyclization of a 4‐(1 H ‐benzotriazol‐1‐yl)quinoline using the Grabe–Ullmann reaction. Surprisingly, despite being a compound of great biological significance, the reported strategies are not amenable to the generation of a library based on isocryptolepine with the exception of the procedures designed by Cheng11a and Maes11b and their co‐workers. Cheng and co‐workers described two synthetic approaches to the preparation of 11 H ‐indolo[3,2‐ c ]quinoline derivatives using the Fischer indole synthesis, whereas Maes and co‐workers applied their palladium‐driven strategy published earlier12j to generate a library.…”

Auto‐Tandem Catalysis: A Single Catalyst Activating Mechanistically Distinct Reactions in a Single Reactor

“…[22] The Pd/C-catalyzed Heck reaction of bromobenzene (34) and styrene gives trans-stilbene (35), which successively reduces to afford dibenzyl (36) by catalytic hydrogenation. Several auto-tandem catalyses with Pd catalysts, such as the domino oxidative aminocarbonylation-cyclocarbonylation, [23] the domino Buchwald-Hartwig amination-direct arylation, [24] the domino allylic alcohol oxidation-Heck reaction, [25] and the domino cross coupling-[4 + 4] cycloaddition, [26] are found in the literature.…”

Nickel-catalyzed C-3 direct arylation of pyridinium ions for the synthesis of 1-azafluorenes

“…More recently, Doyle et al described the C-2 arylation via Ni( ii ) π-allyl intermediates of N -acyl pyridinium ions with either boronic acids12 or aryl zinc halide reagents 13. In spite of these precedents, until now, the corresponding nickel-catalyzed C-3 direct arylations of pyridine derivatives have not been reported 14,15…”