Three-component Synthesis of Indoles

Takahashi and co-workers reported an alternative three-component synthesis of indoles (137) (Scheme 5.40) [82]. Thus, reaction of an aryl iodide, an o-alkenylphenyl isocyanide (136), and a secondary amine in the presence of a palladium catalyst produced 2,3-disubstituted indoles in moderate yields. A chelating ligand such as dppp was found to be superior to a monodentate ligand such as PPh3. 

Scheme 5.40 Palladium-catalyzed three-component synthesis of indoles.

J. Barluenga, A. Jimenez-Aquino, C. Valdes, F. Aznar, Angew. Chem. Int. Ed. 2007,46, 1529-1532. The azaaUyhc anion as a synthon for Pd-catalyzed synthesis of heterocycles domino two- and three-component synthesis of indoles. 

Subsequently, the same group reported a more practical method for preparing indoles by using the azaallylic anion as a synthon (Scheme 8) [36]. They found that imines 25 could couple with o-dihalobenzenes 26 to produce intermediates 27, which underwent an intramolecular aryl amination to afford 1,2,3-trisubstituted indoles 28. Because the azaallylic anion could be prepared by a Pd-catalyzed reaction of alkenyl halides and primary amines, they were able to develop a domino three-component synthesis of indoles. 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

L. Wang, M. Huang, X. Zhu, Y. Wan, Polyethylene glycol (PEG-200)-promoted sustainable one-pot three-component synthesis of 3-indole derivatives in water, Appl. Catal. A 454 (2013) 160-163. 

R. Jain, K. Sharma, D. Kumar, One-pot, three-component synthesis of novel spiro[3H-indole-3,2 -thiazolidine]-2,4 (lH)-diones in an ionic liquid as a reusable reaction Media, Helv. Chim. Acta 96 (2013) 414-418. 

The canthines are a tetracyclic subclass of j8-carboline alkaloids bearing an additional D-ring. Members of the canthine family have been shown to have pharmacological activity, including antifungal, antiviral, and antitumor properties. In 2003 Lindsley and coworkers described a microwave-mediated procedure for one-pot synthesis of the basic canthine skeleton [122]. The key step is an inverse-electron demand Diels-Alder reaction and subsequent chelotropic expulsion of N2, a reaction that can be achieved after a three-component condensation of an acyl hydrazide-tethered indole with a 1,2-diketone and excess ammonium acetate to form a triazine (Scheme 10.61). 

D. Xing, C. Jing, X. Li, H. Qin, W. Hn, Org. Lett. 2013, 15, 3578-3581. Highly efficient synthesis of mixed 3,3-bisindoles via Rh(II)-catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate. 

B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M. Krayushkin, Russ. Chem. Bull. 2009, 58, 1504-1508. Three-component condensation of 5-aminopyrazole derivatives with isatins and Meldrum s acid. Synthesis of 1,7-dihydro spiro[pyrazolo[3,4-ii]-pyridine-4,3 indole]-2, 6(l H,5H)-diones. 

Recently, an ultrasound-promoted synthesis of a series of medicinally relevant derivatives of the spiro[indole-thiazolidinone] ring system (compound 45) has been carried out from the three-component reaction of isatin, a 4-aminopyrazolin-3-one derivative and 2-mercaptopropionic acid in water, using cetyltrimethylammonium bromide (CTAB) as a phase-transfer catalyst (Scheme 1.20). This protocol avoided the need for either azeotropic removal of water or the use of a dehydrating agent, as required by conventional methods [28]. 

Concise Synthesis of Indole-Fused 1,4-Diazeines through Copper(I)-Catalyzed Domino Three-Component CoupUng-Cyclization-iV-Arylation under Microwave Irradiation Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno Org. Lett. 2008,10, 3535-3538. Reproduced with permission... 

Concise Synthesis of Indole-Fused 1,4-Diazepines through Copper(I)-Catalyzed Domino Three-Component Coupling-Cyclization- -Arylation under Microwave Irradiation... 

Carboline stmcture was constructed by one-pot reaction, which involves the three-component indole formation and nucleophilic cycUzation by the addition of t-BuOK or MsOH. This is the first example of multi-component synthesis of carbolines, except for those using the Pictet-Spengler type reaction. Utilizing the three-component indole formation, indole-fused 1,4-diazepines were also synthesized through deprotection/iV-arylation at nitrogen atom of indole by one-pot addition of MeONa after the formation of indole. These reactions form four bonds in a single reaction vessel, which involves two C-C bonds/two C—N bonds or one C-C bond/three C-N bonds. 

In relation to the three-component indole formation, a novel four-component synthesis of 3-(aminomethyl)isoquinoline was developed. The reaction of 2-ethynylbenzaldehyde with (HCHO) , secondary amine, and t-BuNH2 proceeds through Mannich-type reaction, cycUzation, and elimination of t-butyl group. By the use of alkane diamine instead of r-BuNH2, 3-(aminomethyl)isoquino-line-fused polycyclic compounds were also synthesized by cascade cycUzation and oxidation. Changing the carbon tether of the diamine component led to the synthesis of isoquinoUnes fused with various heterocycles. 

Scheme 8.20 Polysubstituted indole derivatives synthesis via three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin.

More complex cascade processes involving this type of three-component couphng include the Cu(I)-catalyzed cascade coupling/cyclization reaction for the synthesis of 2-(aminomethyl) indoles 104 (Scheme 5.69) [72] and 105 (Scheme 5.70) [73], and the Cu(I)-catalyzed domino three-component coupling/cyclization/N-arylation reaction, which provided a concise synthesis of indole-fused 1,4-diazepines 106 (Scheme 5.71) [74]. 

Chen et al. (2009) reported one pot, three-component coupling reaction for the synthesis of indoles. The reaction was carried out in two steps under standard Sono-gashira coupling conditions from an N-substituted/N, N-disubstituted 2-iodoaniline and a terminal alkyne, followed by the addition of acetonitrile and aryl iodide. 

An efficient and also elegant synthesis of the active anti-influenza A virus indole alkaloid hirsu-tine 67 is performed by an inter-intermolecular anionic-pericyclic three- component domino reaction followed by solvolysis and hydrogenation (scheme 13).[261 The synthetic sequence developed by us contains first a Knoevenagel condensation of enantiopure 61 and 62 with the formation of the... 

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