One-Pot Synthesis of 2-Amino-indole-3-carboxamide and Analogous

doi:10.1021/co100040z

ACS Comb Sci. Author manuscript; available in PMC 2011 June 27.

Published in final edited form as:

ACS Comb Sci. 2011 March 14; 13(2): 140–146.

Published online 2010 December 17. doi: 10.1021/co100040z

PMCID: PMC3124116

NIHMSID: NIHMS296478

One-Pot Synthesis of 2-Amino-indole-3-carboxamide and Analogous

Kan Wang,^† Eberhardt Herdtweck,^‡ and Alexander Dömling^*^†

^† Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States

^‡ Lehrstuhl für Anorganische Chemie, Technische Universität München, Garching bei München, Germany

^* Corresponding Author: Email: asd30/at/pitt.edu. Fax: + 1 412-383-5298. Tel: + 1 412-383-5300

The publisher's final edited version of this article is available at ACS Comb Sci

Abstract

An external file that holds a picture, illustration, etc.
Object name is nihms296478u1.jpg Object name is nihms296478u1.jpg

An efficient one-pot, two-step solution-phase synthetic method was developed to synthesize twenty-three 2-amino-indole-3-carboxamides (3) from 2-halonitrobenzene (1) or heterocyclic analogous and cyanoacetamides (2). In this sequence, first, intermediate 2-cyano-2-(2-nitrophenyl)-acetamide (4) was generated under basic condition via S_NAr reaction; after direct addition of hydrochloric acid solution, FeCl₃, and Zn powder, indole 3 was generated via reduction/cyclization process.

Keywords: reductive cyclisation, cyanoacetamide, 2-aminoindole, one-pot, solution phase

INTRODUCTION

The indole fragment is one of the most important heterocycles for drug discovery, with a broad range of biological activities. In addition, many endogenous biologically active substances, such as tryptophan, 5-hydrotryptophan, melatonin, and brassinin, and many clinical used drugs, such as nonsteroidal anti-inflammatory indomethacin, antiemetic ondansetron, and antimigraine sumatriptan, are indole based. For example, in the recent discovery of new p53/MDM2/MDMX antagonist for cancer treatment, the indole unit is critical for binding MDM2 and MDMX as a mimic of tryptophan residue (Figure 1).^1–3

Figure 1

Indole unit is critical for potent p53/MDM2 antagonists. Alignment of three MDM2 structures, the native p53 MDM2 interaction (PDB ID 1YCR), MDM2 in complex with van Leusen (vL) imidazole (top compound, PDB ID 3LBK), and spirooxindole (bottom compound, (more ...)

2-Aminoindoles, on the other hand, are key fragments in a multitude of biologically active compounds including IKβ-kinase,⁴ phosphodiesterase-V inhibitors,⁵ hypotensives, diuretics, and appetite suppressants,⁶ and many other important biological active compounds. Notably, the 2-aminoindole chemotype is aromatic planar and comprises two adjacent hydrogen bond donors to interact with a protein target (Figure 2). Amidine moieties can widely interact with acid side chains in proteins (Asp, Glu), however also form pi-pi interactions with aromatic side chains. Therefore amidines are very often found in druglike molecules. On the other hand, the strong basic character of this functional group makes permeation through biological membranes very difficult, and oral bioavailability and blood brain barrier penetration is rarely achieved. Therefore prodrug approaches are often used to solve these issues, for example, in the recently approved anticoagulant dabigatran, an amidine carbamate prodrug.^7–9 Another successful approach is the incorporation of the basic amidine moiety into aromatic heterocycles.^10,11 By delocalizing the amidinemoiety in an aromatic scaffold, the charge is partially delocalized and the basicity can be adjusted by the introduction of appropriate substituents and ring. With these significant observations, it is very attractive to develop practical and efficient methods of generating a diversity of 2-aminoindole derivatives.

Figure 2

Top: Different representative binding modes of heterocyclic amidines and guanidines in proteins. (left) Etravirine in complex with the HIV reverse transcriptase (PDB ID 3M8Q) forms an extended hydrogen bond network with Lys101 and a crystal water.¹² (middle) (more ...)

Herein, we would like to report a novel, straightforward, and one-pot synthesis of highly substituted 2-amino (hetero)-indole-3-carboxamides. 2-Amino-indole-3-carboxamides in the past have been synthesized by several step processes, for example, by [3,3]-sigmatropic rearrangement and intramololecular cyclization from N-arylhydroxamic acids and malononitrile,¹⁵ by nucleophilic aromatic substitution reaction¹⁶ with malondinitrile or cyanoaceticacid esters, followed by reduction (eq 1, Scheme 1),^17–24 or by a four-component reaction of pyridine or 3-picoline, chloroacetonitrile, malononitrile, and aromatic aldehydes,²⁵ by the Nenitzescu reaction of primary ketene aminals and 1,4-benzo-quinones,²⁶ by the reaction of 2-haloanilines and substituted acetonitriles,^27–29 and other methods.³⁰ Our synthetic approach involves a nucleophilic aromatic substitution reaction of a suitable o-halo-nitro-(hetero)aromate with a cyanoacetamide and a subsequent reductive cyclization. To the best of our knowledge, no such transformation has been described in a one-pot manner. Together with our recently described experimentally very simple one-pot access to hundreds of cyanoacetamides,^31–33 we believe this is a valuable procedure of general interest to medicinal and organic chemists.

Scheme 1

Two Synthetic Pathways to 2-Aminoindole Derivatives

Generally, cyanoacetic acid derivatives react with 2-halonitrobenzene in a nucleophilic aromatic substitution; then, the intermediates were isolated and reduced under different conditions, commonly, Zn/HOAc, Fe/HOAc, or Pd/C/H₂, etc., to generate 2-aminoindole esters; finally, these esters would be saponified and coupled with appropriate amines to generate corresponding 2-aminoindole amides, although no such precedents have been reported yet. Herein, a convenient two-step, one-pot method is reported to prepare 2-aminoindole-3-carboxamide (3) from 2-fluoronitrobenzene or its heterocycle analogous and cyanoacetamides (eq 2, Scheme 1).

RESULT AND DISCUSSION

In an easily and gram-scale accessible model reaction, n-butylcyanoacetamide (1a) was reacted to find the optimal conditions. Sodium hydride was selected as a base in this reaction because it is a strong base with weak nucleophilicity. First, sodium hydride in excess was added to a solution of cyanoacetamides (1a) in DMF. After 10 min, 2-fluoronitrobenzene (2a) was added, and the reaction becomes deep purple. After 1 h, the corresponding substitution intermediate (4a) was monitored with LC-MS. Next, 1 N HCl was added to the reaction to acidify the excess NaH; then, FeCl₃ (3 equiv) and Zn (10 equiv) were added.³⁴ The reduction conditions were optimized and different Fe/Zn ratios or iron powder for example did not give the expected products. After 1 h at 100 °C, the desired 2-aminoindole product was isolated with high yield (Scheme 2).

Scheme 2

Two-Step, One-Pot Synthesis of 2-Aminoindole-3-carboxamide

Next different cyanoacetamide (1a–u, Scheme 3) and different 2-halonitrobenzene (2a–e, Scheme 4) were treated under this condition. All these reactions work fine to afford desired 2-aminoindole products (3-1–3–23) in good yields. It is interesting to note that unprotected alcohol in cyanoacetamide (1h) give good reaction as well. Different heterocycles, such as, indole (1p), morpholine (1c, i, s), piperazine (1q, r), pyridine (1o), are compatible with the reaction. Alkene (1d) or alkyne (1g) functionalities can be introduced without problems and might be of value for further transformations. Bis-cyanoacetamide (1u) reacts smoothly with two equivalents of 2-fluoronitrobenzene (1a) to afford the corresponding compounds (3–23) in good yields.

Scheme 3

Cyanoacetamide Starting Materials

Scheme 4

2-Halonitrobenzene or Pyridine Starting Materials

In addition to 2-fluoronitrobenzene derivatives, some heterocyclic starting materials, such as 2-fluoro-3-nitropyridine (2d) and 4-chloro-3-nitropyridine (2e), offer easy access to pyrrolo-[3,2-b]pyridines (3–18–3–21) and pyrrolo[2,3-c]pyridine (3–22) products as well. This result indicates that this two-step, one-pot reaction is a quite general protocol. All products with their structures and isolated yields are listed in the Table 1.

Table 1

One-Pot Synthesis of 2-Amino-indole-carboxamides (3-1–3–23)

To prove the identity of the products, we characterized all compounds by NMR and HR-MS and also crystallized 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative (3–20) in a quality suitable for X-ray diffraction. The structure of 3–20 in the solid state is shown in Figure 3 and in Supporting Information. There are several noteworthy observations regarding the crystal structure. There are two cystallographically independent molecules (3–20) in the unit cell. One (conformation A) is forming an intramolecular hydrogen bridge between the amide and the pyridine nitrogen, whereas the morpholinoethyl side chain is stretched. In the second molecule (conformation B) the morpholinoethyl side chain is bent back to the amide group to form a bifurcated hydrogen bond; the NH comprises a bifurcated hydrogen bond donor. Such intramolecular hydrogen bonds can be actively used in drug design and have a pronounced effect on key compound parameters such as membrane permeability, water solubility, and lipophilicity.³⁵

Figure 3

Top left: ORTEP drawing with 50% ellipsoids for 3–20. Top right: Schematic drawing of the mono- and bifurcated hydrogen bridge. Bottom: Complex intra- and intermolecular hydrogen bond network in the crystal (visualization using Mercury software). (more ...)

Not surprisingly the amidine substructure in 3–20 forms an intermolecular hydrogen bond to the amide carbonyl but also intermolecular and trifurcated hydrogen bonds to carbonyls of adjacent molecules.

CONCLUSION

In summary, we have described a highly efficient one-pot sequence toward 2-amino indole-type molecules involving an aromatic substitution and a subsequent reduction/cyclization process. Significantly, heteroaromates are substrates for this reaction sequence. Scope and limitation of the sequence are described. Further work is being performed in our laboratory to investigate the extraordinary biological activities of these molecules and will be reported in due course.

EXPERIMENTAL PROCEDURES

General Two-Step, One-Pot Procedure for Preparing 2-Amino-N-butyl-1H-indole-3-carboxamide (3-1)

Cyanoacetamide (1a, 2.0 mmol, 1.0 equiv.) in dry DMF (0.5 M) and NaH (60% dispersion in mineral oil, 2.2 mmol, 2.2 equiv) were added to a 50 mL flask equipped with stir bar. After 10 min, 2-fluoronitrobenzene (2a, 2.0 mmol, 1.0 equiv) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture became deep purple. Then 1.0 N HCl (4.0 mmol, 2.0 equiv) was added, following FeCl₃ (6.0 mmol, 3 equiv.) and Zn dust (20 mmol, 10 equiv.). The reaction mixture was heated to 100 °C for 1 h. The reaction mixture was cooled down, and 20 mL of water was added to the crude reaction mixture. The crude reaction mixture was filtered, washed with 25 mL of ethyl acetate. The solution was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed by saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic phase was dried with anhydrous sodium sulfate and the solvent was removed. The crude product was purified by short silica gel column chromatography with 5% methanol in ethyl acetate to generate 393 mg (85%) the title compound as a yellow solid. HRMS ESL-TOF for C₁₃H₁₇N₃ONa (M + Na⁺) Found: m/z 254.1288. Calcd Mass: 254.1269. ¹H NMR (DMSO-d₆, 600MHz): δ 10.54 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 6.70 (s, 2H), 6.67 (t, J = 6.6 Hz, 1H), 3.27 (m, 2H), 1.51 (m, 2H), 1.32 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H) ppm. ¹³CNMR(DMSO-d₆, 150 MHz): δ 167.2, 152.8, 132.7, 125.7, 120.2, 118.8, 116.8, 110.1, 86.8, 38.5, 32.5, 20.2, 14.3 ppm.

Supplementary Material

Click here to view.^{(1.9M, pdf)}

Acknowledgments

Funding Sources

This research has been partially supported by NIH (1R21GM-087617-01A1, 1R01GM097082-01 and 1P41GM094055-01) and the University of Pittsburgh.

Footnotes

Author Contributions

A.D. conceived and designed the experiments. K.W. performed the experiments. E.H. performed the X-ray diffraction.

Supporting Information. Experimental methods of the products, NMR data of all new compounds, and X-ray data of compound 3–20. This material is available free of charge via the Internet at http://pubs.acs.org.

References

1. Czarna A, Beck B, Srivastava S, Popowicz GM, Wolf S, Huang Y, Bista M, Holak TA, Dömling A. Robust Generation of Lead Compounds for Protein-Protein Interactions by Computational and MCR Chemistry: p53/Hdm2 Antagonists. Angew Chem, Int Ed. 2010;49:5352–5356. [PubMed]

2. Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Dömling A, Holak TA. Structures of Low Molecular Weight Inhibitors Bound to MDMX and MDM2 Reveal New Approaches for p53-MDMX/MDM2 Antagonist Drug Discovery. Cell Cycle. 2010;9:1104–1111. [PubMed]

3. Yu SH, Qin DG, Shangary S, Chen JY, Wang GP, Ding K, McEachern D, Qiu S, Nikolovska-Coleska Z, Miller R, Kang SM, Yang D, Wang SM. Potent and Orally Active Small-Molecule Inhibitors of the MDM2-p53 Interaction. J Med Chem. 2009;52:7970–7973. [PMC free article] [PubMed]

4. Enomoto H, Kawashima K, Kudou K, Yamamoto M, Murai M, Inaba T, Ishizaka N. Novel Indole Derivative Having Inhibitory Activity on Kappav B Kinase β. PCT Int. Appl. WO 2008087933, 2008; Chem Abstr. 2008;149:176178.

5. Eggenweiler HM, Baumgarth M, Schelling P, Beier N, Christadler M. Preparation of Pyrimidines As Phosphodiesterase V Inhibitors for the Treatment of Heart Circulation Disorders. 10148883. Ger Offen DE. 2003Chem Abstr. 2003;138:304293.

6. Frey AJ, Hardtmann GE, Ott H. Pyrimido[4,5-b]indoles, Hypotensives, Diuretics, and Appetite Suppressants. 19681203. US Pat Appl Publ. 1969Chem Abstr. 1969;70:47490.

7. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors. J Med Chem. 2002;45:1757–1766. [PubMed]

8. Siddiqui FM, Qureshi AI. Dabigatran Etexilate, A New Oral Direct Thrombin Inhibitor, for Stroke Prevention in Patients with Atrial Fibrillation. Expert Opin Pharmacother. 2010;11:1403–1411. [PubMed]

9. Eriksson BI, Smith H, Yasothan U, Kirkpatrick P. Dabigatran Etexilate. Nature Rev Drug Discovery. 2007;7:557–558. [PubMed]

10. Peterlin-Masic L, Kikelj D. Arginine Mimetics. Tetrahedron. 2001;57:7073–7105.

11. Zhu Z, Sun ZY, Ye Y, Voigt J, Strickland C, Smith EM, Cumming J, Wang L, Wong J, Wang YS, Wyss DF, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Parker E, McKittrick BA, Stamford A, Czarniecki M, Greenlee W, Hunter JC. Discovery of Cyclic Acylguanidines as Highly Potent and Selective β-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I; Inhibitor Design and Validation. J Med Chem. 2010;53:951–965. [PubMed]

12. Kertesz DJ, Brotherton-Pleiss C, Yang M, Wang Z, Lin X, Qiu Z, Hirschfeld DR, Gleason S, Mirzadegan T, Dunten PW, Harris SF, Villasenor AG, Hang JQ, Heilek GM, Klumpp K. Discovery of Piperidin-4-yl-aminopyrimidines as HIV-1 Reverse Transcriptase Inhibitors. N-Benzyl Derivatives with Broad Potency against Resistant Mutant Viruses. Bioorg Med Chem Lett. 2010;20:4215–4218. [PubMed]

13. Hajduk PJ, Boyd S, Nettesheim D, Nienaber V, Severin J, Smith R, Davidson D, Rockway T, Fesik SW. Identification of Novel Inhibitors of Urokinase via NMR-Based Screening. J Med Chem. 2000;43:3862–3866. [PubMed]

14. Putnam CD, Arvai AS, Bourne Y, Tainer JA. Active and Inhibited Human Catalase Structures: Ligand and NADPH Binding and Catalytic Mechanism. J Mol Biol. 2000;296:295–309. [PubMed]

15. Tomioka Y, Ohkubo K, Maruoka H. A Novel Synthesis of Indole Derivatives by the Reaction of N-Arylhydroxamic Acids with Malononitrile. J Heterocycl Chem. 2007;44:419–424.

16. Wang DM, Sun MN, Liu G. Substituent Diversity-Directed Synthesis of Indole Derivatives. J Comb Chem. 2009;11:556–575. [PubMed]

17. Grob CA, Weissbach O. Helv Chim Acta. 1961;44:1748–1753.

18. Forbes IT, Johnson CN, Thompson M. Syntheses of Functionalized Pyrido[2,3-b]indoles. J Chem Soc, Perkin Trans. 1992;1:275–281.

19. Belley M, Sauer E, Beaudoin D, Duspara P, Trimble LA, Dube P. Synthesis and Reactivity of N-Hydroxy-2-aminoindoles. Tetrahedron Lett. 2006;47:159–162.

20. Willemann C, Gruenert R, Bednarski PJ, Troschuetz R. Synthesis and Cytotoxic Activity of 5,6-Heteroaromatically Annulated Pyridine-2,4-diamines. Bioorg Med Chem. 2009;17:4406–4419. [PubMed]

21. Diana P, Stagno A, Barraja P, Montalbano A, Martorana A, Carbone A, Dattolo G, Cirrincione G. Pyrido[2′,3′:4,5]pyrrolo-[2,1-d] [1,2,3,5] tetrazine-4(3H)-ones, A New Class of Temozolomide Heteroanalogues. ARKIVOC. 2009:177–186.

22. Diana P, Stagno A, Barraja P, Carbone A, Montalbano A, Martorana A, Dattolo G, Cirrincione G. Pyrido[4′,3′:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine, A New Class of Temozolomide Heteroanalogues. ARKIVOC. 2009:1–11.

23. Collins I, Reader JC, Klair S, Scanlon J, Addison G, Cherry M. Preparation of 9H-Pyrimido[4,5-b]indole, 9H-Pyrido[4′,3′:4,5]pyrrolo-[2,3-d]pyridine, and 9H-1,3,6,9-Tetraazafluorene Derivatives as CHK1 Kinase Inhibitors. PCT Int. Appl. WO 2009004329, 2009; Chem Abstr. 2009;150:98355.

24. Forbes IT, Morgan HKA, Thompson M. A Synthesis of novel IH-Imidazo[1,2-α]Indole-3-Carboxylates. Synth Commun. 1996;26:745–754.

25. Yan CG, Wang QF, Song XK, Sun J. One-Step Synthesis of Pyrido[1,2-a]benzimidazole Derivatives by a Novel Multicomponent Reaction of Chloroacetonitrile, Malononitrile, Aromatic Aldehyde, and Pyridine. J Org Chem. 2009;74:710–718. [PubMed]

26. Jens L, Reinhard T. Synthesis of 3-EWG-substituted-amino-5-hydroxyindoles via Nenitzescu Reaction. Synthesis. 2005;14:2414–2420.

27. Snyder HR, Merica EP, Force CG, White EG. Synthesis of Indoles by Catalytic Reduction of o-Nitrobenzyl Cyanides. J Am Chem Soc. 1958;80:4622–4625.

28. Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM. Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure–Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs. J Med Chem. 1996;39:1201–1209. [PubMed]

29. Volovenko YM, Volovenko TA. Synthesis and Properties of 2-Amino-6-nitroindoles. Chem Heterocycl Compd. 2001;37:1092–1095.

30. Moskalev N, Makosza M. A Novel Simple Method of Synthesis of 2-Amino-4-(6-)nitroindoles via Base Promoted Condensation of m-Nitroanilines with Nitriles. Heterocycles. 2000;52:533–536.

31. Wang K, Nguyen K, Huang YJ, Dömling A. Cyanoacetamide Multicomponent Reaction (I): Parallel Synthesis Of Cyanoacetamides. J Comb Chem. 2009;11:920–927. [PubMed]

32. Wang K, Kim DB, Dömling A. Cyanoacetamide MCR (III): Three-Component Gewald Reactions Revisited. J Comb Chem. 2010;12:111–118. [PubMed]

33. Wang K, Dömling A. Design of a Versatile Multicomponent Reaction Leading to 2-Amino-5-ketoaryl Pyrroles. Chem Biol Drug Des. 2010;75:277–283. [PubMed]

34. Desai DG, Swami SS, Hapase SB. Rapid and Inexpensive Method for Reduction of Nitroarenes to Anilines. Synth Commun. 1999;29:1033–1036.

35. Kuhn B, Mohr P, Stahl M. Intramolecular Hydrogen Bonding in Medicinal Chemistry. J Med Chem. 2010;53:2601–2611. [PubMed]