Synthesis of 4-hydroxy and 6-hydroxyindoles: a renaissance of the Bischler reaction

In the present work, we studied a modified Bischler-Möhlau reaction – synthesis of indoles from benzoin and aniline. Our proposed modi-fication of this method differs from that described earlier in that the reaction is carried out at a lower temperature, which makes it possible to improve yields and reduce formation of tarry side products. In addition, unlike the previous contradictory works, which described the preparation of a single 4-hydroxy or 6-hydroxy isomer in condensation of m-aminophenol and benzoin, we obtained both 4-hydroxy and 6-hydroxy isomers.


Introduction
The creation of new potential medicinal agents based on hydroxyindoles fragments is one of the promising areas of medical and organic chemistry. For example, topsentin, first isolated from sponges of the genus Spongosorites, has pronounced antiviral, antitumor, adrenergic, and antibacterial properties [1][2][3]. Psilocin is an example of psychedelic tryptamines comprising 4-hydroxyindole moiety [4] (Scheme 1).
Several alkaloids, in particular, harmine, harmalol and harmol, contained in the plant Peganum harmala, have a spectrum of antitumor activity on cancer cell lines [5,6], exhibit antibacterial and neuroprotective properties and are also inhibitors of monoaminosidase A (MAO-A) [7,8].
The modified Bischler reaction [9], a condensation reaction between aniline and benzoin, allows one to obtain indole with water as only by-product. This feature of the Bischler reaction, combined with solventfree conditions, makes this reaction especially relevant to the aspect of green chemistry and atom economy. Hydroxyindoles are particularly convenient to prepare by the Bischler reaction, since in some cases it is not necessary to use protecting groups in order to block the phenolic hydroxyl. However, the reaction described in the literature is usually carried out at high temperatures (140-160 °C). This factor reduces the applicability of this process for the synthesis of complex compounds with labile groups.
In addition, some aspects of the regiochemistry of the formation of hydroxyindoles from meta-aminophenol and benzoin have remained unclear until now. So, in some works, the structure of 2,3-diphenyl-6-hydroxyindole was attributed to the product of this reaction, and in other works, it was 2,3-diphenyl-4-hydroxyindole [10,11].
In this work, we optimized the conditions for the Bischler reaction, and put an end to the issue of regiochemistry of this process.

Experimental section
Unless otherwise noted, all commercially available compounds were used without further purification. Scheme 1 Biologically active examples of 4-and 6-hydroxyindole derivatives. 1 H and 13 C NMR spectra were recorded at ambient temperature on a Bruker Avance II 400 MHz spectrometer at 400 and 100 MHz, respectively, in DMSO-d6 as a solvent.
Chemical shifts (δ) are given in ppm relative to the DMSO residual peak (2.50 ppm) as internal standard.
Aminophenol 1 was obtained from commercially available sources.
2.1. Typical procedure for synthesis of 3a-d and 4b, c.
Benzoin 2 (1 equiv.) was added to aminophenol 1 (3 equiv.) and then hydrochloric acid (1.5 ml of 10M per 0.082 mmol of aminophenol). Then the reaction mixture was heated for 30 minutes at 135 °C. During the reaction, water condensate was collected in a Dean-Stark apparatus attached to a low vacuum. At the end of the reaction, the resulting mass was treated with 15% hydrochloric acid. Then the mixture was filtered off, washed with water and dried. The dry residue containing a mixture of 4 and 6-hydroxyindoles 3, 4 was separated using column chromatography with a mixture of solvents CH2Cl2:C6H14 = 1:1.

Results and discussion
The use of a modified two-component reaction catalyzed by hydrochloric acid made it possible to isolate a mixture of new isomeric 4-and 6-hydroxyindoles from the reaction mixture in high yields. For the synthesis of the starting benzoins 2b-d, the procedure described in the literature [12][13][14] was used (Scheme 2).
It was found that fusion according to the modified procedure of 3-aminophenol 1 (3 equiv.) with benzoins 2а-d (1 equiv.) at 135 °С under hydrochloric acid catalysis resulted in a mixture of isomeric 4 and 6-hydroxyindoles 3а-d, 4a-c. In this case, the formation of major 6-hydroxyindole was observed. 4-Hydroxyindole derivatives 4a-c were separated using column chromatography (CH2Cl2:C6H14 1:1). 6-Hydroxyindole derivatives were isolated by elution with a mixture of solvents СH2Cl2:MeOH 20:1 (Scheme 3). The course of condensation of benzoins with aminophenol can be observed by the distilled water removed using a low vacuum (60-70 mm Hg) and a Dean-Stark apparatus.

Conclusions
Thus, in the search for new potential medicinal agents, we developed a convenient modified method for the synthesis of new 4-and 6-hydroxyindoles in good yields. The advantages of the modified procedure are characterized by a lower reaction temperature (which does not reduce the reaction yields), the convenience of isolating pure 4-and 6-hydroxyindoles, and a decrease in the formation of resinous by-products.

Supplementary materials
No supplementary materials are available.