Synthesis of 4-hydroxy and 6-hydroxyindoles: a renaissance of the Bischler reaction Chimica Techno Acta LETTER published by Ural Federal University 2022, vol. 9(2), No. 202292S2 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.2.S2 1 of 4 Synthesis of 4-hydroxy and 6-hydroxyindoles: a renaissance of the Bischler reaction A.D. Sharapov * , R.F. Fatykhov, I.A. Khalymbadzha, O.N. Chupakhin Institute of Chemical Engineering, Ural Federal University, Ekaterinburg 620002, Russia * Corresponding author: a.d.sharapov@urfu.ru This paper belongs to the MOSM2021 Special Issue. © 2021, the Authors. This article is published in open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract In the present work, we have studied a modified Bischler-Möhlau re- action – synthesis of indoles from benzoin and aniline. Our proposed modification of this method differs from that described earlier in that the reaction is carried out at a lower temperature, which made it possible to improve yields and reduce formation of tarry side products. In addition, unlike previous contradictory works, which described the preparation of a single 4-hydroxy or 6-hydroxy isomer in condensation of m-aminophenol and benzoin, we have obtained both 4-hydroxy and 6-hydroxy isomers. Keywords 4-hydroxyindoles 6-hydroxyindoles Bischler-Möhlau reaction Received: 02.11.21 Revised: 09.04.22 Accepted: 09.04.22 Available online: 13.04.22 Key findings ● This work reveals the possibilities for the synthesis of new 4-hydroxy and 6-hydroxyindoles under the conditions of the modified Bischler-Möhlau reaction. ● A distinctive feature of this work is the achievement regioselectivity in the synthesis of these hy- droxyindoles. ● In addition, the one-step synthesis of two isomeric hydroxyindoles with good yields can be charac- terized as an undoubted advantage of this work. 1. 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 antibacte- rial properties [1–3]. 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 fea- ture of the Bischler reaction, combined with solvent- free conditions, makes this reaction especially relevant to the aspect of green chemistry and atomic 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, in other works 2,3-diphenyl-4-hydroxyindole [10, 11]. In this work, we optimized the conditions for the Bis- chler reaction, and put an end to the issue of regiochemis- try of this process. 2. Experimental section Unless otherwise noted, all commercially available com- pounds were used without further purification. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.2.S2 https://orcid.org/0000-0003-1582-5462 mailto:a.d.sharapov@urfu.ru http://creativecommons.org/licenses/by/4.0/ https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.2.S2&domain=pdf&date_stamp=2022-4-13 Chimica Techno Acta 2022, vol. 9(2), No. 202292S2 LETTER 2 of 4 Scheme 1 Biologically active examples of 4- and 6-hydroxyindole derivatives. 1H and 13C NMR spectra were recorded at ambient tem- perature 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 avail- able 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 mix- ture was heated for 30 minutes at 135 °C. During the reaction, water condensate was collected in a Dean- Stark apparatus attached to a weak 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 con- taining a mixture of 4 and 6-hydroxyindoles 3, 4 was separated using column chromatography with a mixture of solvents CH2Cl2:C6H14 = 1:1. 2.2. 2,3-Diphenyl-6-hydroxyindole 3a 1H NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1H, OH), 8.81 (s, 1H, NH), 7.46–7.24 (m, 10H, 2Ph), 7.25 (d, J = 8.6 Hz, 1H, H-4), 6.80 (d, J = 2.1 Hz, 1H, H-7), 6.54 (dd, J = 8.6, 2.1 Hz, 1H, H-5). 2.3. 2,3-Diphenyl-4-hydroxyindole 4a 1H NMR (400 MHz, DMSO-d6): δ = 11.18 (s, 1H, OH), 8.80 (s, 1H, NH), 7.39–7.15 (m, 10H, 2Ph), 6.93–6.83 (m, 2H, H-6, H-5), 6.34 (dd, J = 6.4, 2.1 Hz, 1H, H-7). 2.4. 2,3-bis(3,4-Dimethoxyphenyl)-6-hydroxyindole 3b 1H NMR (400 MHz, DMSO-d6): δ = 10.80 (s, 1H, OH), 8.71 (s, 1H, NH), 7.22 (d, J = 8.5 Hz, 1H, H-4), 7.05–6.81 (m, 6H, Ph), 6.76 (d, J = 2.0 Hz, 1H, H-7), 6.51 (dd, J = 8.5, 2.2 Hz, 1H, H-5), 3.84–3.81 (s, 3H, 2OMe ), 3.70 (s, 3H, OMe), 3.65 (s, 3H, OMe). 2.5. 2,3-bis(3,4-Dimethoxyphenyl)-4-hydroxyindole 4b 1H NMR (400 MHz, DMSO-d6): δ = 11.00 (s, 1H, OH), 8.59 (s, 1H, NH), 7.07–6.76 (m, 9H, Ph), 3.80–3.75 (s, 3H, 2 OMe), 3.68 (s, 3H, OMe), 3.65 (s, 3H, OMe). 2.6. 2,3-bis(3,4,5-Trimethoxyphenyl)-6- hydroxyindole 3c 1H NMR (400 MHz, DMSO-d6): δ = 11.10 (s, 1H, OH), 9.07 (s, 1H, NH), 7.29 (d, J = 8.5 Hz, 1H, H-4), 6.81 (d, J = 2.1 Hz, 1H, H-7), 6.76 (s, 2H, Ph), 6.63 (s, 2H, Ph), 6.58 (dd, J = 8.5, 2.2 Hz, 1H, H-5), 3.72–3.59 (s, 15H, OMe), 3.33 (s, 3H, OMe). 13C NMR (101 MHz, DMSO-d6): δ = 153.77, 152.90, 152.52, 152.42, 151.98, 136.85, 136.47, 136.08, 131.58, 131.31, 127.92, 121.76, 119.30, 113.56, 110.29, 107.32, 104.88, 96.09, 64.88, 60.07, 60.03, 55.80, 55.49, 55.42, 30.64, 15.13. 2.7. 2,3-bis(3,4,5-Trimethoxyphenyl)-4- hydroxyindole 4c 1H NMR (400 MHz, DMSO-d6): δ = 11.10 (s, 1H, OH), 9.03 (s, 1H, NH), 6.96–6.86 (s, 3H, Ph), 6.70 (s, 2H, Ph), 6.64 (s, 1H, Ph), 3.84 (s, 3H, OMe), 3.46–3.36 (s, 15H, OMe). 2.8. 2,3-bis(2-Chlorophenyl)-6-hydroxyindole 3d 1H NMR (400 MHz, DMSO-d6): δ = 11.05 (s, 1H, OH), 8.83 (s, 1H, NH), 7.52–7.36 (m, 3H, Ph), 7.36–7.26 (m, 3H, Ph), 7.20 (m, 2H, Ph), 7.09 (d, J = 8.6 Hz, H-4), 6.81 (d, J = 2.2 Hz, 1H, H-7), 6.56 (dd, J = 8.6, 2.2 Hz, 1H, H-5). 3. 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 reac- tion mixture in high yields. For the synthesis of the starting benzoins 2b-d, the procedure described in the literature [12–14] was used (Scheme 2). It was found that fusion according to the modified pro- cedure of 3-aminophenol 1 (3 equiv.) with benzoins 2а-d (1 equiv.) at 135 °С under hydrochloric acid catalysis re- sulted 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 deriva- tives 4a-c were separated using column chromatography (CH2Cl2:C6H14 1:1). 6-Hydroxyindole derivatives were iso- lated 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 weak vacuum (60–70 mm Hg) and a Dean- Stark apparatus. Chimica Techno Acta 2022, vol. 9(2), No. 202292S2 LETTER 3 of 4 Scheme 2 Synthesis of starting benzoins 2b-d. Scheme 3 Interaction of aminophenol 1 with benzoins 2a-c. The structure of products 3 and 4 is confirmed by the data of 1H and 13C NMR spectroscopy. For example, in the 1H NMR spectrum of compound 3c, the signal of phenolic hydroxyl is recorded in the region of 11.1 ppm, the signal of the NH-proton is at 9.1 ppm, the signals of the proton H-5 are recorded as a doublet of doublets with 1J(H-5,H-6) = 8.5 Hz and 2J(H-5,H-7) = 2.2 Hz. 4. Conclusions Thus, in the search for new potential medicinal agents, we have developed a convenient modified method for the syn- thesis 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 res- inous by-products. Supplementary materials No supplementary materials are available. Funding The Russian Science Foundation (no. 21-13-00382) finan- cially supported this research, https://rscf.ru/en. Acknowledgment None. Author contributions Conceptualization: A.D.S., I.A.K. Data curation: A.D.S. Formal Analysis: O.N.C., R.F.F., I.A.K. Funding acquisition: A.D.S., R.F.F. Investigation: A.D.S., I.A.K. Methodology: O.N.C., I.A.K., R.F.F. Project administration: A.D.S. Resources: R.F.F., I.A.K. Software: A.D.S., I.A.K. Supervision: A.D.S. Validation: I.A.K., R.F.F. Visualization: A.D.S. Writing – original draft: A.D.S., I.A.K. Writing – review & editing: O.N.C. Conflict of interest The authors declare no conflict of interest. Additional information Author ID’s: A.D. Sharapov, Scopus ID 57201740165; R.F. Fatykhov, Scopus ID 57190761230; I.A. Khalymbadzha, Scopus ID 18434200300; O.N. Chupakhin, Scopus ID 7006259116. Institute’s website: https://hti.urfu.ru/en. https://rscf.ru/en https://www.scopus.com/authid/detail.uri?authorId=57201740165 https://www.scopus.com/authid/detail.uri?authorId=57190761230 https://www.scopus.com/authid/detail.uri?authorId=18434200300 https://www.scopus.com/authid/detail.uri?authorId=7006259116 https://hti.urfu.ru/en Chimica Techno Acta 2022, vol. 9(2), No. 202292S2 LETTER 4 of 4 References 1. Gunasekera SP, Kashman Y, Cross SS, Lui MS, Pomponi SA, Diaz MС. Topsentin, Bromotopsentin, and Dihydrodeoxybro- motopsentin: Antiviral and Antitumor Bis(indoly1)imidazoles from Caribbean Deep-sea Sponges of the Family Halichondri- idae. Structural and Synthetic Studies. J Org Chem. 1988;53(23):5446–5453. doi:10.1021/jo00258a009 2. Sakemi S, Sun HH. Nortopsentins A, B, and C. 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