Printer Friendly

A Facile Route towards the Synthesis of 2-(1H-indol-3-yl)-acetamides Using 1,1-Carbonyldiimidazole.

Byline: Kanwal, Khalid Mohammed Khan, Bibi Fatima, Bilquees Bano and Uzma Salar

Summary: A base-catalyzed one pot reaction has been developed for the synthesis of 2-(1H-indol-3-yl)- acetamides via coupling of 1,1-carbonyldiimidazole with 2-(1H-indol-3-yl) acetic acid resulting in the formation of a reactive intermediate which on treatment with different substituted anilines afford 2-(1H- indol-3-yl)-acetamides in good yield. The use of base along with coupling reagent eases the formation of intermediate in minimum time. All the synthetic compounds were obtained in good to moderate yields, the use of various substituted anilines effects the yields of the products. Compounds 4-30 were synthesized and the structures of all the synthetic compounds were determined by using spectroscopic techniques such as 1H-, 13C-NMR, EIMS and HRMS.

Key words: Indole-3-acetic acid, Synthesis, 1,1-carbonyldiimidazole (CDI), Acetamides, Pyridine.


Nitrogen containing heterocycles, such as pyrroles, indoles and carbazoles have attracted considerable attention due to their wide applications in pharmaceuticals and synthetic chemistry. These heterocyclic moieties exhibit a variety of biological activities either they are synthetic or natural products [1]. Indole and its derivatives are basic units of peptides and indole alkaloids [2]. The indole moiety has contributed in various fields including industrial and agrochemical applications [3]. Indole and its derivatives possess different pharmacological activities like anticancer and antimalarial, [4] antiHCV, [5] antiinflammatory, [6] antimicrobial, [7] analgesic, [8] antioxidant, [9] and antitumor activities [10].

Various methods have already been reported for the synthesis of indole-3-acetamides including the usage of various coupling reagents like DCC (N,N- dicyclohexylcarbodiimide).[11] However, the use of DCC results in the production of o-acylurea which may undergo rearrangement leading to the formation of un-reactive intermediate N-acylurea consequently yield is reduced. In the presence of base racemization also occur which also preferentially leads to the reduction of yield and makes purification difficult.[12] Another method already reported which utilizes HOBt (1-hydroxybenzotriazole) and EDC (1- ethyl-3-(3-dimethylaminopropyl)carbodiimide) as a coupling agent.[13] The use of HOBt limits the choice of solvent, also HOBt is quite less stable so difficult to store.[14]

The formation of these moieties is also reported through the formation of acyl chlorides through oxalyl chlorides and thionyl chloride and then reaction of corresponding acyl chlorides with amine.[15, 16] The use of oxalyl chloride or thionyl chloride results in the formation of carbon monoxide so chemical and safety measures should be maintained. Hydrolysis and deprotection of some protective groups is also observed in the presence of HCl which is produced during the reaction. The use of CDI (1,1-dicarbonylimidazole) is also reported in literature. In this method there was no use of base so the coupling time was up to 1.5 h. In contrast our developed method which also utilizes CDI (1,1-dicarbonylimidazole) as coupling agent along with a base pyridine which actually minimizes the coupling time reducing to 45 min only.


1H-NMR and 13C-NMR spectra were recorded on Bruker 300 MHz spectrometers. Mass experiments were carried out on a Finnigan MAT-311A (Germany) mass spectrometer. Thin-layer chromatography (TLC) was monitored on pre-coated silica gel aluminum plates (Kieselgel 60, 254, E. Merck, Germany). Visualization of chromatograms was performed at wavelengths of 254 and 365 nm. Acetonitrile of analytical grade was used as received from supplier RCI Labscan Limited, Thailand. Pyridine and all aniline derivatives of analytical grades were used as received from the supplier Wako, Japan. Indole-3-acetic acid was purchased from Merck, Germany. Carbonyl diimidazole was purchased from Sigma-Aldrich, USA.

General Procedure for the Synthesis of Indole-3- acetamides

Indole-3-acetic acid (0.175 g, 1 mmol), pyridine (0.8 mL) and CDI 1 equivalent (0.168 g) were taken in a reaction flask along with acetonitrile (20 mL) and kept on stirring for 45 min at room temperature. Corresponding anilines were then added in the reaction mixture and the reaction mixture was further kept on stirring for 2-24 h. Reaction was monitored with TLC and products were obtained by extraction with dichloromethane. The product was then washed with hexane to get pure product.

Spectral data of Indole-3-acetamides

2-(1H-Indol-3-yl)-N-phenylacetamide (4)

1HNMR (300 MHz, Acetone-d6): d 10.14 (s, 1H, NH), 9.04 (s, 1H, NH), 7.62 (m, 3H, H-4', H-2', H-6'), 7.38 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.32 (s, 1H, H2), 7.24 (t, J3',2' = 7.5 Hz, J3',4' = 8.4 Hz, J5',6' = 7.5 Hz, J5',4' = 8.4 Hz, 2H, H-3', H-5'), 7.11 (m, 1H, H- 6), 7.03 (m, 2H, H-5, H-7), 3.80 (s, 2H, H-2"), 13CNMR (300MHz, DMSO-d6):d 169.6, 139.3, 136.0, 128.6, 127.1, 123.8, 122.9, 120.9, 119.0, 118.6, 118.3, 111.3, 108.5, 33.7, EI MS m/z (% rel. abund.): 250 (M+, 82.6), 157 (22), 130 (100), 103 (57), 93 (54), 77 (70), HREI-MS m/z : calcd for C16H14N2O [250.1106], found [250.1095].

Result and Discussion

Base-catalyzed approach was used for the synthesis of 2-(1H-indol-3-yl)-acetamides (4-30). Base-promoted the easy coupling of 1,1- carbonyldiimidazole with acid in a short time. Effects of various electron donating and withdrawing substituents on aniline were observed on the reaction time and yield. Few of the electron donating substituents on aniline has good effect on yield.

Synthesis of indole-3-acetamides 4-30 was accomplished via coupling of indole-3-acetic acid through CDI (1,1-carbonyldiimidazol) in the presence of pyridine which catalyzes the reaction, the intermediate formed was readily utilized by adding different substituted anilines, stirring followed by extraction afford the desired product ( Scheme 1). A Proposed mechanism is also discussed (Scheme-2).

Proposed Mechanism

The base (pyridine) abstracts the acidi hydrogen and forms carboxylate ion which attacks the carbonyl carbon of 1,1-carbonyldiimidazole forming a reactive intermediate along with elimination of imidazole anion. This imidazole anion attacks the carbonyl carbon of this reactive intermediate to form another intermediate with the evolution of CO2. Nitrogen atom of aniline then attacks the electrophilic carbon and imidazole ion leaves with the formation of an amide.


A base-catalyzed one pot reaction has been developed for the synthesis of 2-(1H-indol-3-yl)- acetamides via coupling of 1,1-carbonyldiimidazole with 2-(1H-indol-3-yl) acetic acid. This results in the formation of a reactive intermediate which on treatment with different substituted anilines afford 2- (1H-indol-3-yl)-acetamides in good yields. The use of base minimizes reaction time during the coupling step. There is no formation of urea derivatives as by products during the reaction so purification becomes easy and better yields were obtained for the few of the electron donating substituents.


1. M Abid, L. Teixeira and B. Torok, Triflic Acid Controlled Successive Annelation of Aromatic Sulfonamides: an Efficient One-Pot Synthesis of N-sulfonyl pyrroles, indoles and carbazoles. Tetrahedron Letters, 48, 4047 (2007).

2. T. Heinrich and H. Bottcher, A New Synthesis of indole 5-carboxylic acids and 6-hydroxy-indole- 5-carboxylic acids in the Preparation of an o- Hydroxylated Metabolite of Vilazodone. Bioorg. Med. Chem. Letters, 14, 2681, (2004).

3. T. C. Barden and Indoles: Industrial Agricultural and Over the Counter Uses. Top Heterocyclic Chem., 31, (2011).

4. J. Quirante, F. Dubar, A. Gonzalez, C. Lopez, M. Cascante, R. Cortes, I. Forfar, B, Pradines and C. Biot, Ferrocene-indole Hybrids for Cancer and malaria therapy. J. Organometallic Chem., 1011 (2011).

5. Sellitto, G, Faruolo, A, Caprariis, P. D, Altamura, S, Paonessa, G, Ciliberto, G. Synthesis and Anti-Hepatitis C Virus of Novel Ethyl 1H-indole-3-carboxylates in Vitro. Bioorg. Med. Chem., 18, 6143, (2010).

6. B. Narayana, B. V. Ashalatha, K. K. V. Raj, J. Fernandes and B. K. Sarojini, Synthesis of Some New Biologically Active 1,3,4-oxadiazolyl nitroindoles and a Modified Fischer Indole Synthesis of Ethyl Nitro Indole-2-carboxylates. Bioorg. Med. Chem., 13. 4638, (2005).

7. D. Sinha, A. K. Tiwari, S. Singh, G. Shukla, P. Mishra, H. Chandra, A. K. Mishra, Synthesis, Characterization and Biological Activity of Schiff Base Analogues of indole-3- Carboxaldehyde. Euro. J. Med. Chem., 43, 160 (2008).

8. M. A. A. Radwan, E. A. Ragab, N. M. Sabry, S. M. El-Shenawy, Synthesis and Biological Evaluation of New 3-Substituted Indole Derivatives as Potential Anti-Inflammatory and Analgesic Agents. Bioorg. Med. Chem., 15, 3832, (2007).

9. H. Shirinzadeh, B. Eren, H. Gurer-Orhan, S, Suzen and S, Ozden, Novel Indole-Based Analogs of Melatonin: Synthesis and In Vitro Antioxidant Activity Studies. Molecules, 15, 2187, (2010).

10. N. I. Ziedan, F. Stefanelli, S. Fogli, A. D. Westwell, Design, Synthesis and Pro-Apoptotic Antitumor Properties of Indole-Based 3,5- Disubstituted Oxadiazoles. Europ. J. Med. Chem., 45, 4523, (2010).

11. J. G. A. Zarraga, A. L. Montelongo, A. C. Zuniga, M. R. Ortega, New Heck Coupling Strategies for the Synthesis of Paullone and Dimethyl Paullone. Tetrahedron Letters, 47, 7987 (2006).

12. M. M. Joullie and K. M. Lassen, Evolution of Amide Bond. ARKIVOC, 8, 189, (2010).

13. J. Xiong, H. F. Zhu, Y. J. Zhao, Y. J. Lan, J. W. Jiang, J. J. Yang and S. F. Zhang, Synthesis and Antitumor Activity of Amino Acid Ester Derivatives Containing 5-fluorouracil. Molecules, 14, 3142 (2009).

14. L. Tang, L. Zhao, L. Hong, F. Yang, R. Sheng, J. Chen, Y. Shi. N. Zhou and Y. Hu, Design and Synthesis of Novel 3-substituted-Indole Derivatives as Selective H3 Receptor Antagonists and Potent Free Radical Scavengers. Bioorg. Med. Chem., 21, 5936, (2013).

15. N. Naik, H. V. Kumar and S. T. Harini, Synthesis and Antioxidant Evaluation of Novel indole-3-acetic Acid Analogues. Europ. J. Chem., 2 (337) 2011.

16. C. A. G. N. Montalbetti, V. Flaque, Amide Bond Formation and Peptide Coupling Tetrahedron, 61, 10827 (2005).
COPYRIGHT 2016 Asianet-Pakistan
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2016 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Publication:Journal of the Chemical Society of Pakistan
Article Type:Report
Date:Aug 31, 2016
Previous Article:Effect of Citric Acid on the Synthesis of MoP Catalyst for CO 2 Reforming of CH4.
Next Article:Synthesis and Antifungal Studies of Copper Complexes with Glutamine and Cysteine.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |