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. Author manuscript; available in PMC: 2014 Dec 4.
Published in final edited form as: Tetrahedron Lett. 2013 Dec 4;54(49):10.1016/j.tetlet.2013.09.113. doi: 10.1016/j.tetlet.2013.09.113

A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles

Guillermo Martinez-Ariza a, Muhammad Ayaz a, Christopher Hulme a,b,*
PMCID: PMC3855464  NIHMSID: NIHMS530257  PMID: 24327792

Abstract

A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization and final oxidation generating N-1-quinoxaline-indoles in good yield.

Keywords: Multicomponent reaction, Indole, Quinoxaline, α-iminoketone, Privileged scaffolds

Over the last 20 years, attempts to marry chemical and relevant biological space has often been based on the premise of incorporation of ‘privileged scaffolds’ into small molecule targets, a term defined by Veber as ‘molecular chemotypes capable of providing efficient ligands for different biological receptors’.1 As such the development of facile synthetic protocols to incorporate privileged scaffolds in either individual small molecules or libraries will further enable these target-oriented efforts, increasing the tool-box of techniques available to the ‘drug hunter’ and consequently the probability of success in finding probes or hits that interact with biologically relevant targets of interest.2 In particular, indoles and quinoxalines are heterocycles of significant importance in the drug development arena, being present in a diverse range of drugs and natural products with associated pharmacological activity.3

To cite just a few, the indole chemotype is present in Oxypertine® 1, approved for the treatment of schizophrenia; Sumatripan® 2, used to relieve migraine headaches; and Zafirlukast®, employed for the treatment of asthma.4–6 Conversely, quinoxalines display a wealth of therapeutical applications, exemplified by Quinacillin®, used for the treatment of bacterial infections7 and Varenicline® 3 which reduces anxiety incurred by smoking cessation.8 More importantly, indolyl-quinoxalines also display a number of pharmacological activities, such as antibacterial9 and Glucagon-like-peptide-1 (GLP1) modulation for the potential treatment of diabetes.10 Interestingly, a recent report describes the synthesis of an indolyl-quinoxaline 4 two heterocycles connected through the indole N-1 nitrogen11 - the topic of the methodology described herein - as opposed to the more familiar C-3 substitution pattern derived from acid-mediated aza-Friedel-Crafts alkylations of indoles.12 The resulting chemotype 4, possessed PAS kinase-inhibitory activity, yet was obtained in a lengthy multi-step sequence.11 To enable further biological exploration via a more operationally friendly protocol, we herein describe novel methodology for the preparation of N-1-quinoxaline-indoles 10, Scheme 3.

Scheme 3.

Scheme 3

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N-1-quinoxaline-indole formation.

Given our interest in the development of kinase inhibitors13 and multi-component reactions (MCRs),14 a new base-catalyzed MCR was envisioned that could introduce strategically placed functional groups and diversity elements to enable ready-access to the N-1-quinoxaline-indole scaffold in an efficient manner, Scheme 1. The strategy employs the base-catalyzed addition of indole 8a onto a preformed α-iminoketone 7a adorned with a masked amino nucleophile to afford the MCR adduct 9a Scheme 1, which upon acid treatment undergoes Boc-deprotection, cyclization and oxidation to deliver the target hybrid heterocycle 10a Scheme 3, in significantly fewer steps than reported methodology.11

Scheme 1.

Scheme 1

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α-iminoketone formation/base-catalyzed N-1-indole addition.

Optimization studies were carried out with a model reaction comprised of reagents mono-N-Boc-4,5-dimethylphenylene diamine 5a, phenylglyoxaldehyde 6a and 4-bromoindole 8a, Scheme 1, Table 1. Given the somewhat poor nucleophilicity of the anilinic amine 5a, microwave irradiation was employed to enable formation of the α-iminoketone 7a (100–120 °C, 10 min). The reaction mixture was cooled to room temperature with subsequent addition of 4-bromoindole and base (1.1 eq.). Entry 6, Table 1, proved optimal for 9a formation (64% yield) using cesium carbonate as the base. The use of more polar solvents or alternate bases had a detrimental impact on isolated yield (Entries 1–3, Table 1). Similarly, conducting indole addition at an even slightly elevated temperature proved to be counterproductive (Entry 7, Table 1). To the best of our knowledge, this is the first example of an indole N-1 alkylation process with α-iminoketones and is complementary to well-documented C-3 Friedel-Craft mediated functionalization with similar species.12

Table 1.

Optimization of the one-pot MCR.a

Entry Solvent Conditions (Stage A) Conditions (Stage B)c Yield (%)
1b MeCN rt Na2CO3, rt traces
2 MeCN 100 °C Na2CO3, rt 12
3 DMF 100 °C K2CO3, rt 21
4 Toluene 100 °C K2CO3, rt 34
5 DCE 100 °C K2CO3, rt 46
6 DCE 120 °C Cs2CO3, rt 64
7 DCE 100 °C Cs2CO3, 60 °C 48
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a

All reactions were carried out at 0.25 mmol scale and the indicated yields are based on UV 254 nm-LC/MS analysis.

b

The imine formation was carried out by heating 5a and 6a via microwave irradiation for 10 minutes, except for entry one where the reaction mixture was stirred at rt for ~12 h.

c

Reaction mixtures were stirred at the indicated temperature for 16 h.

Compound 9a was subsequently exposed to a 20% solution of TFA in DCE at various temperatures (Table 2). Heating the reaction mixture via microwave irradiation depressed the yield (Table 2 Entries 1, 2, 3), whilst simply stirring at room temperature for 1 h, afforded final product 10a in an acceptable 92% conversion from 9a, representative of a 3 step deprotection/cyclization/oxidation transformation. Note that the intermediate dihydroquinoxaline was not isolated under these conditions.

Table 2.

Optimization: deprotection-cyclization-oxidation to 10a.a

Entry Time (h) Temperature (°C) Yield (%)
1 0.25 120, MW 66
2 0.25 100, MW 75
3 0.25 80, MW 83
4 1 rt 92
5 5 rt 88
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a

Yields are based on UV 254 nm-LC/MS analysis. MW = microwave irradiation

With the optimized conditions in hand, the scope of the two-step one-pot procedure was thus explored. Using various combinations of four amines, three glyoxaldehydes and two indoles, a small library of N-1-quinoxaline-indoles (10a–g) was prepared (Table 3, Scheme 3).15, 16 It was observed that while the α-iminoketones 7 were formed quantitatively, base catalyzed N-1-indole addition to afford 9 proceeded in moderate isolated yields. Nevertheless, addition of indoles to render 9 appeared independent of the substitution patterns and/or the electronic nature of the reactants. The deprotection-cyclization step was straightforward with excellent yields for all examples (10a–g, 80–93%). Overall combined isolated yields for the two-step protocol were in the range of 36 to 58% (Table 3, Entries 3 and 1, respectively). N-1 indole connectivity to the quinoxaline was unequivocally confirmed by X-ray analysis of compound 10a, Figure 1.

Table 3.

Scope of the two-step protocol for the synthesis of N-1-quinoxaline-indoles.a

Entry R1 R2 R3 R4 Yield [%] of 9a Yield[%] of 10a
1 CH3 CH3 H 4-Br 63 92
2 H OCH3 H 4-Br 48 83
3 Methylenedioxy (R1 & R2) H 6-Br 43 84
4 H 4-F H 4-Br 51 93
5 H H H 4-Br 58 89
6 CH3 CH3 OCF3 4-Br 47 88
7 CH3 CH3 OCH3 4-Br 61 80
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a

Isolated yields.

Figure 1.

Figure 1

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Medicinal relevance of indole-quinoxaline scaffolds.

In conclusion, an operationally friendly MCR to access N-1 derivatized indole analogs with α-iminoketones has been developed. With strategic reagent decoration this enabled access to N-1-quinazoline-indoles, containing two widely recognized privileged motifs in the medicinal chemistry community 10. Good yields, three sources of reagent diversity, operational ease and the medicinal relevance of the heterocycles embedded in the overall generic scaffold make this protocol ideal for automated synthesis applications for further biological annotation. Biological evaluation of compounds 10a–g as well as attempts to apply this protocol for generating higher order complexity are currently underway.

Figure 2.

Figure 2

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Figure 1. X-Ray structure of 10a

Scheme 2.

Scheme 2

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N-1-quinoxaline-indole formation.

Acknowledgments

We would like to acknowledge the support from the National Institutes of Health (grant P41GM086190) and CONACyT/UA (doctoral scholarship 215981 for G.M.A). We also thank Dr. Sue Roberts for X-ray structure confirmation and Dr. David Bishop for proofreading, editing and preparing the final version of the text and graphics.

Footnotes

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References and notes

  • 1.Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell GF, Veber DF, Anderson PS. J Med Chem. 1988;12:2235–2246. doi: 10.1021/jm00120a002. [DOI] [PubMed] [Google Scholar]
  • 2.(a) DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA. Combinatorial Chemistry and High Throughput Screening. 2004;7:473–493. doi: 10.2174/1386207043328544. [DOI] [PubMed] [Google Scholar]; (b) Welsch ME, Snyder SA, Stockwell BR. Curr Opin Chem Biol. 2010;3:347–361. doi: 10.1016/j.cbpa.2010.02.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Welsch ME, Snyder SA, Stockwell BR. Curr Opin Chem Biol. 2010;3:347–361. doi: 10.1016/j.cbpa.2010.02.018. [DOI] [PMC free article] [PubMed] [Google Scholar]; Buchanan JG, Sable HZ. In: In Selective Organic Transformations. Thyagarajan BS, editor. Vol. 2. Wiley-Interscience; New York: 1972. pp. 1–95. [Google Scholar]
  • 4.Lyle FR. 5 973 257. US Patent. 1985; Chem Abstr. 1985;65:2870. [Google Scholar]
  • 5.The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N Engl J Med. 1991;325:322–326. doi: 10.1056/NEJM199108013250505. [DOI] [PubMed] [Google Scholar]
  • 6.Fischer JD, Song MH, Suttle AB, Heizer WD, Burns CB, Vargo DL, Brouwer KL. Pharmaceut Res. 2000;17:154–159. doi: 10.1023/a:1007509112383. [DOI] [PubMed] [Google Scholar]
  • 7.Hugo WB, Stretton RG. Nature. 1964;4938:1217–1217. doi: 10.1038/2021217a0. [DOI] [PubMed] [Google Scholar]
  • 8.Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR. JAMA. 2006;296:56–63. doi: 10.1001/jama.296.1.56. [DOI] [PubMed] [Google Scholar]
  • 9.Ledig KW. US 4118561 A 19781003 US Patent. 1978
  • 10.Moon HS, Yang JS, Kim MK, Kim JK, Lee JY, Kang SM, Kim HD, Shin CY, Cheong YH, Yang EK. WO 2011122815 A2 20111006 PCT Int Appl. 2011
  • 11.McCall JM, John R, Donnal L, Clair M. WO 2011028947 A2 20110310 PCT Int Appl. 2011
  • 12.Jørgensen KA. Synthesis. 2003:1117–1125.Bandini M, Melloni A, Umani-Ronchi A. Angew Chem, Int Ed. 2004;43:550–556. doi: 10.1002/anie.200301679.Poulsen TB, Jørgensen KA. Chem Rev. 2008;108:2903–2915. doi: 10.1021/cr078372e.For enantioselective Friedel-Crafts reactions of indole with imines see: Kang Q, Zhao ZA, You SL. J Am Chem Soc. 2007;129:1484–1485. doi: 10.1021/ja067417a.Rowland GB, Rowland EB, Liang Y, Perman JA, Antilla JC. Org Lett. 2007;9:2609–2611. doi: 10.1021/ol0703579.Terada M, Yokoyama S, Sorimachi K, Uraguchi D. Adv Synth Catal. 2007;349:1863–1867.
  • 13.(a) Dietrich J, Hulme C, Hurley LH. Bioorg Med Chem. 2010;15:5738–5748. doi: 10.1016/j.bmc.2010.05.063. [DOI] [PubMed] [Google Scholar]; (b) Smith B, Medda F, Gokhale V, Dunckley T, Hulme C. ACS Chem Neurosci. 2012;11:857–872. doi: 10.1021/cn300094k. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Myers RM, He W, Hulme C. Curr Pharm Des. 1997;3:473–502. [Google Scholar]
  • 14.(a) Xu Z, De Moliner F, Cappelli AP, Hulme C. Angew Chem. 2012;124:8161. doi: 10.1002/anie.201202575. [DOI] [PMC free article] [PubMed] [Google Scholar]; Angew Chem Int Ed. 2012;51:8037. [Google Scholar]; (b) Ayaz M, Dietrich J, Hulme C. Tetrahedron Lett. 2011;38:4821–4823. doi: 10.1016/j.tetlet.2011.06.115. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Xu Z, Ayaz M, Cappelli A, Hulme C. ACS Comb Sci. 2012;8:460–464. doi: 10.1021/co300046r. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Xu Z, De Moliner F, Cappelli A, Hulme C. Org Lett. 2013;15:2738–2741. doi: 10.1021/ol401068u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.General procedure exemplified for the preparation of 9a. Arylglyoxaldehyde hydrate (1.1 eq., 0.55 mmol, 0.083 g) and tert-butyl (2-amino-4,5-dimethylphenyl)carbamate (1eq., 0.5 mmol, 0.118 g) were dissolved in DCE (2 mL) and heated at 100 °C for 10 minutes in a CEM 72 Explorer™. After confirming the exclusive formation of Schiff base (via TLC), the reaction was allowed to cool to rt. Cesium carbonate (1.1 eq., 0.55 mmol, 0.179 g) and 4-bromo-indole (1eq., 0.5 mmol, 0.098 g, 0.063 mL) were then added and the reaction mixture was stirred at room temperature for 16 h. After reaction completion (TLC and LC/MS), the crude mixture was directly purified by flash chromatography (EtOAc/Hexane 0–20%) using an ISCO ™ purification system to afford tert-butyl (2-((1-(4-bromo-1H-indol-1-yl)-2-oxo-2-phenylethyl)amino)-4,5-dimethylphenyl)carbamate 9a as an orange oil (0.173 g, 63% yield). 1H NMR (400 MHz, CDCl3): δ 1.51 (s, 9H), 1.98(s, 3H), 2.10 (s, 3H), 6.53 (s, 3H), 6.74 (d, 1H), 7.04 (s, 1H), 7.22 (m, 2H), 7.38(m, 2H), 7.48(d, 1H), 7.56 (m, 1H), 7.73 (s, 1H), 7.78 (d, 2H), 8.51 (d, 1H) ppm.13C NMR (100 MHz, CDCl3): δ 28.39, 80.33, 108.29, 108.33, 114.97, 115.22, 125.56, 126.30, 128.93, 129.00, 129.24, 130.35, 131.27, 133.86, 135.65, 150.71, 152.62 ppm. [M+1]+= 549 m/z.
  • 16.General procedure exemplified for the preparation of 10a. tert-butyl (2-((1-(4-bromo-1H-indol-1-yl)-2-oxo-2-phenylethyl)amino)-4,5-dimethylphenyl)carbamate 9a (1eq., 0.305 mmol, 0.173 g) was dissolved in 3 mL of a 20% TFA/DCE solution and stirred at room temperature for 1h. The crude mixture was directly purified by flash chromatography (EtOAc/Hexane 0–20%) using an ISCO ™ purification system to afford 2-(4-bromo-1H-indol-1-yl)-6,7-dimethyl-3-phenylquinoxaline 10a as a beige solid (0.131 g, 92% yield). Crystals suitable for X-ray crystal structure determination were obtained by means of slow evaporation from ethyl ether/Hexane. 1H NMR (400 MHz, CDCl3): δ 2.56 (s,6H), 6.60 (d,1H), 6.96(d,1H), 7.09(t, 1H), 7.40(m, 5H), 7.66 (d, 1H), 7.93 (s, 1H), 8.02(s,1H), ppm.13C NMR (100 MHz, CDCl3): δ 20.59, 105.81, 105.87,111.41, 114.83, 124.18, 124.67, 125.58, 125.63, 127.44, 127.49, 128.13, 128.58, 129.01, 130.10, 130.57, 134.11, 136.08, 137.15, 139.77, 143.04, 143.22, 144.58, 147.64 ppm. [M+1]+= 429 m/z.

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