Synthesis of All Regioisomers of 2-Arylazaindole-3-acetic Acid Derivatives

Abstract

A novel protocol was developed for synthesizing 2-aryl-substituted azaindole-3-acetic acid derivatives from 2-aminoazacinnamic acid derivatives and aryl aldehydes through an imino-Stetter reaction. Condensation of 2-aminoazacinnamic acid derivatives with aldehydes forms the corresponding aldimines, which are then treated with cyanide to yield the desired 2-aryl-substituted azaindole-3-acetic acid derivatives. Notably, this protocol could be employed for the synthesis of all regioisomers of azaindole-3-acetic acid derivatives by using the appropriate azacinnamic acid derivatives.

Key words

azaindoles - regioisomers - azacinnamic acid derivatives - imino-Stetter reaction - cyanide

Publication History

Received: 19 September 2023

Accepted after revision: 08 November 2023

Accepted Manuscript online:
08 November 2023

Article published online:
02 January 2024

• References


For reviews of azaindoles, see:
• 1a Song JJ, Reeves JT, Gallow F, Tan Z, Yee NK, Senanayake CH. Chem. Soc. Rev. 2007; 36: 1120
• 1b Merour J.-Y, Buron F, Ple K, Bonnet P, Routier S. Molecules 2014; 19: 19935
• 1c Motati DR, Amaradhi R, Ganesh T. Bioorg. Med. Chem. 2020; 28: 115830
• 1d Motati DR, Amaradhi R, Ganesh T. Org. Chem. Front. 2021; 8: 466

For examples of the comparison of bioactivities between indoles and azaindoles, see:
• 2a Garai S, Kulkarni PM, Schaffer PC, Leo LM, Brandt AL, Zagzoog A, Tallan B, Lin X, Hurst DP, Janero DR, Abood ME, Zimmowitch A, Straiker A, Pertwee RG, Kelly M, Szczesniak A.-M, Denovan-Wright EM, Mackie K, Hohmann AG, Reggio PH, Laprairie RB, Thakur GA. J. Med. Chem. 2020; 63: 542
• 2b Urvashi JB, Kumar S, Das P, Tandon V. J. Med. Chem. 2022; 65: 6454

For selected examples of the syntheses of indoles and azaindoles using the same protocol, see:
• 3a Jeanty M, Blu J, Suzenet F, Guillaumet G. Org. Lett. 2009; 11: 5142
• 3b Livecchi M, Calvet G, Schmidt F. J. Org. Chem. 2012; 77: 5006
• 3c Pires MJ. D, Poeira DL, Purificação SI, Marques MM. B. Org. Lett. 2016; 18: 3250
• 3d Purificação SI, Pires MJ. D, Rippel R, Santos AS, Marques MM. B. Org. Lett. 2017; 19: 5118
• 3e Qiu Y, Dlugosch M, Liu X, Khan F, Ward JS, Lan P, Banwell MG. J. Org. Chem. 2018; 83: 12023
• 4 A limited number of examples of the synthesis of all regioisomers of azaindole derivatives using a single protocol have been reported. However, the efficiency of these protocols strongly relies on the position of the nitrogen atom in the starting materials; consequently, the substrate scope of certain azaindole regioisomers is limited. For selected examples, see refs. 3c and 3d.

For examples of the bioactivities of 2-aryl-substituted indole-3-acetic acid derivatives, see:
• 5a Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C. J. Med. Chem. 1999; 42: 2909
• 5b Boucherle B, Haudecoeur R, Queiroz EF, Waard MD, Wolfender J.-L, Robins RJ. Nat. Prod. Rep. 2016; 33: 1034
• 5c Curtin NJ. Cancers 2020; 12: 564
• 5d Yeo M, Chen Y, Jiang C, Chen G, Wang K, Chandra S, Bortsov A, Lioudyno M, Zeng Q, Wang P, Wang Z, Buscigilo J, Ji R.-R, Liedtke W. Nat. Commun. 2021; 12: 6208
• 6 Only one example of the synthesis of a 2-aryl-substituted azaindole-3-acetic acid derivative has been reported. However, the protocol used in this study has never been explored for the synthesis of other 2-aryl-substituted indole-3-acetic acid derivatives. See: Power DP, Lozach O, Meijer L, Gravson DH, Connon SJ. Bioorg. Med. Chem. Lett. 2010; 20: 4940
• 7 For a seminal report on the cyanide-catalyzed imino-Stetter reaction, see: Lee SJ, Seo H.-A, Cheon C.-H. Adv. Synth. Catal. 2016; 358: 1566
• 8 For a review on the cyanide-catalyzed imino-Stetter reaction, see: Park E, Jeon J, Cheon C.-H. Chem. Rec. 2018; 18: 1474

For selected examples of the application of the imino-Stetter reaction to natural product total synthesis, see:
• 9a Bae C, Park E, Cho C.-G, Cheon C.-H. Org. Lett. 2020; 22: 2354
• 9b Jeon J, Kim HJ, Cheon C.-H. J. Org. Chem. 2020; 85: 8149
• 9c Park E, Bae C, Cho C.-G, Cheon C.-H. J. Org. Chem. 2021; 86: 4497
• 9d Jeon J, Lee SE, Cheon C.-H. Org. Lett. 2021; 23: 2169
• 9e Park J, Cheon C.-H. J. Org. Chem. 2022; 87: 4813
• 9f Jeon J, Cheon C.-H. Org. Lett. 2022; 24: 7128
• 10 For a review of bioactivity of 7-azaindole derivatives, see: Sharma N. Anurag, Mini-Rev. Med. Chem. 2019; 19: 727

For examples of bioactivities of 7-azaindole derivatives, see:
• 11a Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY. J, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Nature 2010; 467: 596
• 11b Lamb YN. Drugs 2019; 79: 1805
• 12 We developed a protocol for the synthesis of 2-aminocinnamic acid derivatives via the Heck reaction of 2-iodoanilines with acrylic acid derivatives; see ref. 9b.
• 13 For the effect of reaction media on the efficiency of Heck coupling, see: Yoon J, Cheon C.-H. Asian J. Org. Chem. 2019; 8: 1631
• 14 Blackburn C, Guan B. Tetrahedron Lett. 2000; 41: 1495
• 15 For an example of the synthesis of 3-azacinnamic acid derivatives via the Wittig reaction, see: Allen JR, Amegadzie A, Andrews KL, Brown J, Chen JJ, Chen N, Harrington EH, Liu Q, Nguyen TT, Pickrell AJ, Qian W, Rumfelt S, Rzasa RM, Yuan CC, Zhong W. U.S. Patent 20130225552A1, 2013
• 16 Because cyanide is regenerated after the imino-Stetter reaction of these substrates, we expected that the imino-Stetter reactions for the syntheses of 4-, 5- and 6-azaindole-3-acetic acid derivatives would proceed with a catalytic amount of cyanide. For details, see ref. 8.
• 17 Product 16bc underwent transesterification to form the corresponding methyl ester during column chromatography on silica gel using methanol as an eluent. To prevent this, we used ethanol instead of methanol as the eluent during the column separation.