Research Article: Development of an imidazole salt catalytic system for the preparation of bis(indolyl)methanes and bis(naphthyl)methane

Date Published: April 25, 2019

Publisher: Public Library of Science

Author(s): Xu Wang, Courtney C. Aldrich, Andrew C. Marr.


Imidazolium salts are shown to catalyze the rapid room temperature reaction of indoles or naphthol with aldehydes to provide bis(indolyl)methanes or bis(naphthol)methane in excellent yields and the reaction proceeds optimally in dichloromethane with no base additives. The reaction exhibits a broad substrate tolerance and occurs through nucleophilic activation of the indoles and naphthols through a cation–π interaction.

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Bis(indolyl)methane and its derivatives constitute a structurally fascinating and important class of heterocyclic compounds present in many natural products isolated from marine and terrestrial organisms (Fig 1).[1, 2] These compounds are a rich source of antitumor and antibacterial agents.[3–5] For instance, Gu and co-workers isolated two new indole alkaloids, arsindoline A and B with promising antitumor activities from a marine-derived Aeromonas bacterial strain CB101.[6] In 1994, Kobayashi and co-workers isolated trisindoline, an antibiotic indole trimer from a Vibrio sp. living symbiotically within the marine sponge Hyrtios altum.[7] Though vibrindole A was isolated from a natural source in 1994, it has been known as a synthetic product since 1963.[8, 9] Recently, Li and co-workers found the tetraindole compound, FCW81, which displayed efficacy in a xenograft model of human breast cancer by inhibiting growth and more importantly blocking cancer cell metastasis.[10, 11] In 2017, Müller and co-workers reported the bis(indolyl)methane alkaloid, PTS-16671 as a potent GPR84 agonist (EC50 41 nM) that demonstrated increased stability relative to their initial lead compound.[12]

We first undertook the screening of the azolium catalysts, including imidazolium, triazolium and thiazolium salts. Results from our catalyst evaluation are shown in Fig 3. In the absence of base, catalyst 1a and 1e afforded the desired product 4a in moderate yields (entries 1, 5), while only trace amounts of product were obtained with triazolium catalysts 1b, 1c and 1d (entries 2, 3, 4). The result shows that the nature of the azolium salts is critical: imidazolium and thiazolium salts are effective catalysts, whereas the triazolium salt proved to be unproductive. Based on these findings, we further investigated other reaction parameters, such as ammonium salts, solvent and base, in order to achieve a higher chemical yield. Examination of a range of ammonium salts revealed that ammonium chloride and tetrabutylammonium fluoride did not promote the reaction (entries 6, 7). The use of other solvents, such as tetrahydrofuran and dichloromethane, resulted in enhanced yields with dichloromethane affording the desired compound 4a in an impressive 95% isolated yield (entries 8, 10). The equivalent ratio of compounds 2 and 3 was adjusted to 2:1 that is a more proper condition for maximizing the usage of reagents and the yield remained unchanged (entry 11). The yield was greatly reduced under neat conditions (entry 9). The reaction was also found to be incompatible with an amine base such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), which led to generation of the N-heterocyclic carbene of 1a and provided 2-hydroxy-1,2-diphenylethanone as a major product through the process of benzoin reaction as reported previously and only trace amounts of the desired product (entry 12).[37] This result indicates that the weak alkalinity of indole does not induce NHC formation, unlike other organic bases. Thus the product is formed by a direct addition reaction (conjugate acid of DBU: pKa 12.0, conjugate acid of indole: pKa 0.4). As a negative control, we confirmed the reaction did not occur in the absence of the catalyst 1a (entry 14). Decreasing the catalyst loading from 10 mol% to 5 mol% reduced the yield from 95% to 83% (entry 15) demonstrating 10 mol% is required to achieve optimal conversion.

Although imidazolium salts are often used as precursors for NHC catalysts, the reaction of imidazolium salts as organocatalysts has rarely been applied. Herein, we have shown imidazolium salts provide a mild and efficient catalytic system for the electrophilic substitution reactions of indoles with a variety of carbonyl compounds to afford bis(indolyl)methanes. Furthermore, this method tolerates a wider substrate scope than other reactions to this important class of compounds and even allows utilization of 3-methyl-1H-indole and 1-naphthol nucleophiles. In summary, we have further expanded the reaction scope of imidazolium salt catalyzed dual activation addition reactions.




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