Friedel-Crafts 3-(2-Bromobenzoylation) of Indoles and Intramolecular Direct Arylation: An Efficient Route to Indenoindolones

Abstract

An efficient two-step approach, comprising the FriedelCrafts reaction of 2-bromobenzoyl chlorides with indoles to give 3-(2-bromobenzoyl)indoles and their palladium-catalyzed intramolecular direct arylation to give indenoindolones, has been developed. 3-(2-Bromobenzoyl)indoles were crucial intermediates; the method was successful with N-unprotected or N-protected indoles. This approach affords a convenient preparation of diverse substituted and functionalized indenoindolones in good to high yields from easily accessible starting materials. Several moieties, which are commonly integrated into bioactive compounds, can be incorporated with ease by this synthesis.Indenoindole derivatives possess a wide range of pharmaceutical activity such as anticancer, anti-Alzheimer's disease, inhibitors of protein kinase CK2, ligands of the MT3 melatonin binding site, and antioxidant in lipid-peroxidation process. 1 Their structural resemblance to heterotetracycle-containing potent therapeutic agents and drugs is remarkable. 2 Indenoindolones are also used as intermediates in the synthesis of potential therapeutic agents. 1c,e,3 Current approaches to the synthesis of indeno[1,2-b]indol-10(5H)-ones include: (1) the preparation of benzylidene phthalide in four steps and its rearrangement to indane-1,3-dione mediated by strong base followed by reductive cyclization, 1a,b,e (2) lithium diisopropylamide induced anionic N→C carbamoyl migration of 2-aryl-1-(carbamoyl)indoles, Boc derivatization, and lithium 2,2,6,6,-tetramethylpiperidide induced cyclization, 4 (3) cyclocarbonylation of NH-protected 3-iodo-2-phenylindoles, 5 (4) Fischer indolization reaction of arylhydrazone derivatives of indan-1-one to afford indenoindole and subsequent benzylic oxidation, 6 and (5) reaction of cyclic enaminone with ninhydrin, de-dihydroxylation, and oxidation. 1d Recently, a method for the reductive cyclization of 3-hydroxy-2-(2-nitrophenyl)-1H-inden-1-ones was reported. 7 However, these methods suffer from either containing many reaction steps, or limitations in the generation of molecular diversity in the products, and/or they require harsh reaction conditions that are not amenable to drug discovery research. Accordingly, the development of an efficient rapid diversity-feasible synthesis of indenoindolone is significant. We envisioned an approach that involved Friedel-Crafts 3-acylation of indole 8 for the preparation of 3-(2-haloaroyl)indoles and their subsequent indole C2-arylation 9 as an efficient route to indenoindolones (Scheme 1). A method of palladiumcatalyzed intramolecular arylation/cyclization of 3-(2-iodobenzoyl)indoles in the synthesis of indenoindolone is known. 10 However, our attempts to prepare 3-(2-iodobenzoyl)indoles via 3-acylation of indole following our recently developed zirconium(IV) chloride mediated method 8a,11 provided a poor (42%) yield of product. The process mediated by aluminum(III) chloride, a Lewis acid traditionally used in Friedel-Crafts reactions, resulted in a further decreased in the product yield. 12 These rea...

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

“…Compounds 357 were synthesized selectively via a two-step process involving the Pd-catalyzed intramolecular C-2 arylation of 3-(2-bromobenzyl)-1H-indoles 356, which were prepared by Friedel-Crafts reaction of 2-bromobenzyl chlorides with indoles 355. [227] As shown in Scheme 180 two different protocols (Procedures A and B) were used for the C-2 arylation of N-methyl-and N-benzyl-substituted and free NH-indoles 356. It is noteworthy that the use of K 2 CO 3 for the C-2 arylation of NH-unprotected 3-aroylindoles 356 was detrimental, but the use of CsOAc gave good results.…”

“…It is noteworthy that the use of K 2 CO 3 for the C-2 arylation of NH-unprotected 3-aroylindoles 356 was detrimental, but the use of CsOAc gave good results. [227] Recently, a variety of benzo[a]carbazole derivatives 359 was synthesized in good yields by Kanmehr and Ghanbari via a one-pot reaction sequence involving a base-catalyzed condensation reaction of N-unsubstituted and N-substituted 3-indolylacetonitriles 358 and ortho-bromobenzaldehydes followed by a Pd-catalyzed intramolecular arylation reaction under ligandless conditions (Scheme 181). [228] In 2011, hippadine (362), a 7H-pyrroloA C H T U N G T R E N N U N G [3,2,1-de]-phenanthridine alkaloid isolated from the bulbs of Brunsvigia josephinae,…”

Pentannulation of Heterocycles by Virtue of Precious Metal Catalysis

“…[23] In this transformation the indolylpalladium(II) in-Scheme4.Pd 0 -catalyzed intramolecular cyclization of 8.R eagents and conditions:a )X= I, 5% Pd(OAc) 2 ,1 0% Ph 3 P, 2equiv.TEA, 1 m DMA, 130 8C, 2h; [16] b) X = Br and R 1 ¼ 6 H, 5% Pd(dppf)Cl 2 ,2equiv.K 2 CO 3 ,DMF,130 8C; c) X = Br and R 1 = H, 5% Pd(OAc) 2 ,10% Ph 3 P, 2equiv.CsOAc, DMA, 130 8C. [17] Scheme5.Pd II -catalyzed intramolecular cyclizationo f10.…”

“…Indenoindolone derivatives 9 (Scheme ) were obtained in moderate to excellent yields via Pd 0 ‐catalyzed intramolecular cyclization of o ‐iodobenzoyl or o ‐bromobenzoyl indoles 8 . Besides indole, thiophene and furan derivatives underwent smooth cyclization.…”

Pd‐Catalyzed Cyclocarbonylation of 2‐(2‐Bromoaryl)indoles with CO as a C1 Source: Selective Access to 6 H‐Isoindolo[2,1‐a]indol‐6‐ones and Indeno[1,2‐b]indol‐10(5 H)‐ones

“…For example,6 H-isoindolo[2,1-a]indol-6-ones have been obtained throught he Pd-catalyzed oxidative coupling of N-aroylindoles, [6] the transition-metal-catalyzed reactions of o-gem-dibromovinylanilinesw ithb enzoyl chlorides, [7] phosphorus-reagent-mediated cascade reactions, [8] and the Pd-catalyzed insertion of isocyanide or CO into 2-(2-bromophenyl)-1 Hindole, [9] among others. [10] Meanwhile, the preparation of indeno [1,2-b]-indol-10(5 H)-onesh as mostly been achieved through the Pd-catalyzed intramolecular indole-C 2 -arylation of 3-(2-halobenzoyl)indoles [11] and the Pd-catalyzed intramolecular oxidative couplingo f3 -indolylarylketones. [12] Whilst these procedures have been shown to be quite effective,s ome of them still suffer from the drawbacks of difficult-to-obtain complex precursors, multistep reaction sequences, low overall yields, or harsh reaction conditions.…”