Wang Qilin and bu Zhanwei research group of Henan University: series reaction of indole with o-hydroxychalcone catalyzed by ferric chloride to construct polycyclic indole compounds with chroman and bridge ring structures

The author of the paper: polycyclic indole is a kind of very important active skeleton, which widely exists in natural products and drug molecules It is of great significance to develop efficient methods to construct these compounds However, most of the current synthesis strategies take pre functionalized indoles as substrates, or through multi-step reactions to construct such compounds Therefore, it is very important to construct polycyclic indoles with cheap and easily available materials Wang Qilin and bu Zhanwei research group of Henan University have been engaged in the synthesis of indole heterocyclic polycyclic compounds, and have realized some unique chemical transformations by using the "amphiphilic" activity of o-hydroxychalcone Recently, the research group reported the series reaction of N-substituted indole and o-hydroxychalcone, which was used to construct polycyclic indole compounds with chroman and bridge ring structures efficiently The related results were published on organic letters (org Letter., 2018, 20, 3451-3454) Fig 1 A series reaction of N-substituted indole and o-hydroxychalcone (source: Organic letters) the author envisages to construct a colorfully thick ring indoline compound 3A by the series reaction of n-ethylindole 1a and o-hydroxychalcone 2a in the presence of Lewis acid (Fig 1) Surprisingly, the reaction did not get the expected product 3a, but another compound 4A was obtained 4A contains both chroman and indole skeleton These two structures widely exist in drug molecules Firstly, the author optimized the reaction conditions (Table 1) When FeCl 3 was used as catalyst and acetonitrile as solvent, the reaction yield was 40%, and the yield was 31% Through the optimization of catalyst type, reaction solvent and material ratio, the author finally selected the best reaction conditions: the amount of catalyst FeCl3 is 20 mol%, acetonitrile is the solvent, the reaction temperature is 35 ℃, the amount of n-ethylindole 1a and o-hydroxychalcone 2a is 1.5:1 Under the optimum conditions, the yield of the target product 4A was 78% a Unless otherwise noted, the reaction wasconducted on a scale of 0.20 mmol of 1a and 0.20 mmol 2a in 1 mL solvent at35 o C, And the product was obtained by column chromatography B 2 equipment s of 2a was used C 1.5 equipment s of 1A was used The experimental results show that a series of target compounds 4A - 4G can be obtained in good yield when alkyl substituents are attached to indole N atom When chlorine or bromine atoms are attached to C5 position of indole aromatic ring, the target compounds 4H and 4I can be obtained in medium yield The effect of o-hydroxychalcone containing electron donor group is better than that of o-hydroxychalcone containing electron acceptor group (4J vs 4K, 4L) When the methyl group is in the aromatic or para position, the target product 4m and 4N can also be obtained in medium yield The substrate containing isopropyl group can also obtain the target compound 4O in good yield A less otherwise noted, the reaction was supervised with 0.30 mmol 1 and 0.20 mmol 2 in the presence of 20 mol% FeCl 3.6h 2 oin 1.0 ml CH 3 CN at 35 o C for all cases, only onediastereoisomer was obtained B isolated yields after silica gel column chromatography C isolated yields by directly filtering the precise state Based on the above experimental results and literature reports, the author proposed the possible reaction mechanism (Figure 3) Firstly, under the catalysis of FeCl 3, o-hydroxychalcone reacts with retro aldol to obtain salicylaldehyde and acetophenone, which reacts with indole 1g to form diindole 5g and intermediate a respectively, a and o-hydroxychalcone 2A undergo [4 + 2] cyclization reaction to obtain intermediate B, B is oxidized to intermediate C, and then the intramolecular 1,4-addition reaction takes place, finally the target product 4G is obtained Fig 3 Possible reaction mechanism (source: Organic letters) in order to further verify the reaction mechanism, the author carried out a control experiment, reacting 1I, acetophenone and o-hydroxychalcone 2D in a "one pot" way, and obtained compound 4P in 20% yield (Fig 4) This process confirmed that 3-alkenyl substituted indole was one of the intermediates in the initial stage of the reaction The author also carried out a cross experiment (Fig 5) Indole 1g, o-hydroxychalcone 2a and 2E were reacted in a "one pot" way to obtain 4G and 4m, and the cross products 4m 'and 4m "were also obtained, which further proved that the reaction was carried out by retro aldol / Friedel crafts / [4 + 2] cyclization Fig 4 Control experiment (source: Organic letters) Fig 5 Cross experiment (source: Organic letters) Finally, the author carried out derivative reactions on compound 4A and 4L (Fig 6) The product 8 was obtained by reduction of 4A with sodium borohydride in 95% yield The Suzuki coupling reaction between 4L and 2-indolyboric acid was carried out A new indolyl nucleus was introduced on the basis of 4L, and the coupling product 10 was obtained in 70% yield, which further proved that the reaction has practical application value Figure 6 Derivation reaction (source: Organic letters) Summary: Wang Qilin and bu Zhanwei team of Henan University realized the series reaction of indole and o-hydroxychalcone catalyzed by FeCl 3 The reaction can realize the construction of polycyclic indoles with highly complex structure, chroman and bridge ring structure in one step The reaction has the advantages of cheap raw materials, mild reaction conditions, simple steps and good universality of substrate This work not only provides a new method for the efficient synthesis of novel multicyclic bridged indole, but also opens up a new type of reaction between indole and o-hydroxychalcone Review of previous reports by Wang Qilin and bu Zhanwei research group of Henan University: research team of Wang Qilin, associate professor of Henan University