Three-Component Annulation

Larock s and Cheng s groups, independently, disclosed that aryl halides 31 were smoothly coupled with two molar amounts of arynes to afford diverse triphenylenes 

In 2001, Yoshida et al. demonstrated that the insertion reaction of arynes into a C—Sn CT-bond of alkynyl- and vinylstannanes 42 took place smoothly using a 

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Scheme 8. The Tundo three-component annulation for cyclopenta-fused quinoxalines...

Arefalk, A., Larhed, M. and HaUberg, A. (2005) Masked 3-aminoindan-l-ones by a palladium-catalyzed three-component annulation reaction. J. Org. Chem., 70, 938-42. 

In 2000, Yoshikawa et al. reported synthesis of phenanthrenes 26 by palladium-catalyzed three-component annulation (allyl chloride 25-aryne-aryne) (Scheme 28.10) [14]. Intramolecular carbopalladation to an alkene moiety in arylpal-ladium(II) intermediate 28, arising from dual insertion of arynes into ir-allylpalladium... 

Similarly, a three-component annulation of bisalkynes, hydrazines, and aldehydes for the synthesis of fused tricyclic dihydropyrazoles 36 was explored by Fuji and Ohno (Scheme 12.18) [22]. This process consists of Au-catalyzed C(sp)-H functionalization and alkenyl C(sp )-H functionalization. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Based on a transformation described by Catellani and coworkers [61], the Lautens group [62] developed a three-component domino reaction catalyzed by palladium for the synthesis of benzo annulated oxacycles 6/1-114 (Scheme 6/1.30). As substrates, these authors used a m-iodoaryl iodoalkyl ether 6/1-113, an alkene substi-... 

A three-component coumarin synthesis involves the Pd-catalysed coupling of o-iodophenols with alkynes and subsequent insertion of carbon monoxide. With internal alkynes, pyridine is the crucial base for successful annulation the regioselectivity with unsymmetrically substituted alkynes is only moderate (Scheme 43) . 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

A large series of spiro-annulated pyranopyrazoles were synthesized in base-catalyzed three-component reactions (08JCO741, 09JCC)914). 

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

Varma, R.S. and Kumar, D., Microwave-accelerated three-component condensation reaction on day solvent-free synthesis ofimidazo[l,2-fl] annulated pyridines, pyrazines and pyrimidines, Tetrahedron Lett., 1999, 40, 7665-7669. 

With the MBR, other examples of scale-up involving a triphenylphosphine-free one-pot Wittig olefination, a one-step three-component synthesis of imidazo annulated... 

Acyl selenides serve as acyl radical precursors when treated with tin radicals [43], In the following reaction (Scheme 6.25), a cydoheptanone fused to an indanol skeleton is prepared via a three-component reaction [44], The sequential addition of an acyl radical to two molecules of methyl acrylate followed by a 7-endo-type radical addition account for the annulation. 

The precursor 130, which was prepared using a combined YNSat-SnAt three-component reaction, has been employed in a route toward the 3-aryloxindole derivative 131 (Equation 36) <2004OL4957>. Similar reductive annulations of intermediates derived by nucleophilic displacement of an immobilized aryl fluoride with dimethyl malonate anions, eventually providing 1,2-dialkoxyindole derivatives, have been described previously <2003OL2935>. 

Iridium-catalyzed annulation of the precursor 179, which is available by a three-component reaction of 1-hexyne, allylbenzylamine, and ethyl glyoxalate, provided the conceivable intermediate 180, which was trapped with A-phenylmaleimide to provide the tricyclic system 181 in respectable yield (Scheme 21). Variation of the alkyne components gave a set of similar products <2005JA10804>. 

Groebke K, Weber L, Mehlin F (1998) Synthesis of imidazo[l,2-a]annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation. Synlett 661-663... 

A noteworthy procedure for the synthesis of annulated 1,6-naphthyridines also uses a three-component condensation of the malononitrile dimer, salicylaldehyde and acetone giving rise to 1,6-naphthyridines 92 (1988JCS(P1)2053). 

Nair et al. subsequently developed a three-component synthesis of the pyran-annulated heterocycle 115 (Scheme 5.34) [71]. Thus, heating to reflux a benzene solution of 4-hydroxycoumarin (116), DMAD, and cyclohexyl isocyanide gave the pyranocoumarin 115 in 93% yield. It was hypothesized that protonation of the zwitterionic intermediate 109 by the hydroxycoumarin 116 occurred to afford ion pair 117. Subsequent 1,4-addition of enolate to nitrilium would furnish the ketamine 118, which would then cyclize to provide the heterocycle 115. 

Other examples of scale-up involved a triphenylphosphine-free one-pot Wittig olefination, a one-step three-component synthesis of imidazo annulated pyridine and a metal-catalyzed Suzuki coupling. Kappe and co-workers also recently transferred conditions for reactions originally performed on a small scale with a mono-modal system, to scale-up by parallel synthesis in a multimodal batch reactor [13]. Typically, the scale-up was 100-fold, from 1 mmol examples included Biginelli condensations, Heck and Negishi couplings, and Diels-Alder cycloadditions with gaseous reactants. 

Heterocyclic systems produced by annulation of a pyran ring to the biologically versatile thiazole nucleus can lead to an attractive scaffold for libraries of drug-like compounds. Yadav et al. reported a synthesis of these species by three-component coupling of glycine, acetic anhydride, and a 5-arylidenerhodanine 57 (Scheme... 

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