Rapid and Mild Nucleophilic Substitution of a Highly Active (Indol-2-yl)methyl Electrophile in a Microflow Reactor

Abstract

Indoles are common motifs in functional agricultural and pharmaceutical molecules. Heteroatom alkylation is the most frequently used chemical reaction in the pharmaceutical field. Developing protocols for the nucleophilic substitution of (indol-2-yl)methyl electrophiles is important for functionalizing indoles. There are few studies on the nucleophilic substitution at the 2′-position of the electrophiles without an electron-withdrawing group at the 1-position or substituents at the 2′- and 3-positions, where the existing approaches require high temperatures and long reaction times. In this study, we demonstrated rapid (7–12 s) and mild (25 °C) microflow nucleophilic substitution at the 2′-position of indole derivatives without an electron-withdrawing group at the 1-position and substituents at the 2′- or 3-positions. Comparable batch conditions resulted in a lower yield.

Key words

continuous flow - microflow - indole - nucleophilic substitution - halogenation - PBr₃

Publication History

Received: 09 April 2024

Accepted after revision: 17 May 2024

Article published online:
13 June 2024

• References

• 1a Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
• 1b Shearer J, Castro JL, Lawson AD. G, MacCoss M, Taylor RD. J. Med. Chem. 2022; 65: 8699
• 2a Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489
• 2b Lancianesi S, Palmieri A, Petrini M. Chem. Rev. 2014; 114: 7108
• 2c Kumar S. Ritika, Future J. Pharm. Sci. 2020; 6: 121
• 3 Schneider N, Lowe DM, Sayle RA, Tarselli MA, Landrum GA. J. Med. Chem. 2016; 59: 4385
• 4 Arcadi A, Berden G, Ciogli A, Corinti D, Crestoni ME, De Angelis M, Fabrizi G, Goggiamani A, Iazzetti A, Marrone F, Marsicano V, Oomens J, Serraiocco A. Eur. J. Org. Chem. 2022; e202201166
• 5 Dhayalan V, Ramesh N, Mohanakrishnan AK. Synth. Commun. 2009; 39: 1241
• 6a Siles R, Kawasaki Y, Ross P, Freire E. Bioorg. Med. Chem. Lett. 2011; 21: 5305

Nucleophilic substitution at the 2′-position of 2-(bromomethyl)-1-methyl-indole was reported, but the detailed procedure and the yield were not presented, see:
• 6b Kim N, Meyers KM, Mendez-Andino JL, Warshakoon NC, Ji W, Wos JA, Colson A, Mitchell MC, Davis JR, Pinney BB, Reizes O, Hu XE. Bioorg. Med. Chem. Lett. 2006; 16: 5445

For recent selected reviews of continuous flow synthesis, see:
• 7a Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2015; 11: 1194
• 7b Rossetti I, Compagnoni M. Chem. Eng. J. 2016; 296: 56
• 7c Porta R, Benaglia M, Puglisi A. Org. Process Res. Dev. 2016; 20: 2
• 7d Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
• 7e Britton J, Raston CL. Chem. Soc. Rev. 2017; 46: 1250
• 7f Shukla CA, Kulkarni AA. Beilstein J. Org. Chem. 2017; 13: 960
• 7g Fanelli F, Parisi G, Degennaro L, Luisi R. Beilstein J. Org. Chem. 2017; 13: 520
• 7h Suryawanshi PL, Gumfekar SP, Bhanvase BA, Sonawane SH, Pimplapure MS. Chem. Eng. Sci. 2018; 189: 431
• 7i Souza JM. D, Galaverna R, de Souza AA. N, Brocksom TJ, Pastre JC, de Souza RO. M. A, Oliveira KT. D. An. Acad. Bras. Ciênc. 2018; 90: 1131
• 7j Ramanjaneyulu BT, Vishwakarma NK, Vidyacharan S, Adiyala PR, Kim D.-P. Bull. Korean Chem. Soc. 2018; 39: 757
• 7k Gérardy R, Emmanuel N, Toupy T, Kassin V.-E, Tshibalonza NN, Schmitz M, Monbaliu J.-CM. Eur. J. Org. Chem. 2018; 2301
• 7l Guidi M, Seeberger PH, Gilmore K. Chem. Soc. Rev. 2020; 49: 8910

For selected publications on flash chemistry, see:
• 7m Yoshida J.-i, Nagaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
• 7n Yoshida J.-i. Flash Chemistry: Fast Organic Synthesis in Microsystems. Wiley-VCH; Weinheim: 2008
• 7o Yoshida J.-i. Chem. Rec. 2010; 10: 332
• 7p Yoshida J.-i, Saito K, Nokami T, Nagaki A. Synlett 2011; 1189
• 7q Yoshida J.-i, Takahashi Y, Nagaki A. Chem. Commun. 2013; 49: 9896

For pioneering and recent works on flow microsynthesis using highly reactive carbocations, see:
• 7r Suga S, Okajima M, Fujiwara K, Yoshida J.-i. J. Am. Chem. Soc. 2001; 123: 7941
• 7s Takumi M, Sakaue H, Nagaki A. Angew. Chem. Int. Ed. 2022; 61: e202116177
• 8a Masui H, Kanda S, Fuse S. Commun. Chem. 2023; 6: 47

We also reported nucleophilic addition of alkyllithiums to indole-3-carbaldehydes and subsequent nucleophilic substitution at the 3′-position, see:
• 8b Fuse S, Kanda S, Masui H. Chem. Asian J. 2023; 19: e202300909

We recently reported highly electrophilic cation generation from diarylmethanols and furfuryl alcohols and their use for subsequent nucleophilic substitutions, see:
• 8c Matsuura Y, Fuse S. Chem. Commun. 2024; 60: 2497
• 8d Matsuura Y, Fuse S. Org. Biomol. Chem. 2024; 22: 3448
• 9 The temperature was fixed at 25 °C because the reaction did not complete at lower temperature conditions in the similar reaction using (1H-indol-3-yl)methanol with higher reactivity comparing with 1a (ref. 8a). In addition, we observed clogging of the reaction channel by extending reaction time even at 25 °C probably due to over reactions (Table 2, entry 4). Therefore we did not examine higher temperature conditions that presumably cause over-reactions.
• 10a Otake Y, Nakamura H, Fuse S. Angew. Chem. Int. Ed. 2018; 57: 11389
• 10b Asano S, Kudo S, Hayashi J.-I. Chem. Eng. J. 2024; 489: 151183
• 10c A T-shape mixer with narrower reaction channel has a higher mixing efficiency than that with wider reaction channel, see: Lobasov AS, Minakov AV, Kuznetsov VV, Rudyak VY, Shebeleva AA. Chem. Eng. Process. 2018; 134: 105
• 11 Li C, Zhang H.-H, Fan T, Shen Y, Wu Q, Shi F. Org. Biomol. Chem. 2016; 14: 6932
• 12 Murar CE, Thuaud F, Bode JW. J. Am. Chem. Soc. 2014; 136: 18140
• 13 Reddy CR, Reddy MD, Srikanth B. Org. Biomol. Chem. 2012; 10: 4280
• 14 Braga SF. P, Martins LC, da Silva EB, Sales Júnior PA, Murta SM. F, Romanha AJ, Soh WT, Brandstetter H, Ferreira RS, de Oliveira RB. Bioorg. Med. Chem. 2017; 25: 1889
• 15 Dethe DH, Erande RD, Ranjan A. J. Org. Chem. 2013; 78: 10106
• 16 Huang L, Xun X, Zhao M, Xue J, Li G, Hong L. J. Org. Chem. 2019; 84: 11885
• 17 Cacchi S, Fabrizi G, Goggiamani A, Molinaro C, Verdiglione R. J. Org. Chem. 2014; 79: 401
• 18 Sujeevan Reddy G, Sandeep Kumar J, Thirupataiah B, Amirul Hossain K, Babu Nallapati S, Bhat Giliyaru V, Chandrashekhar Hariharapura R, Gautham Shenoy G, Pal M. Tetrahedron Lett. 2021; 77: 153213
• 19 Mitra T, Das S, Basak A. Tetrahedron Lett. 2009; 50: 5846
• 20 Zhou H, Zhu D, Xing Y, Huang H. Adv. Synth. Catal. 2010; 352: 2127