Efficient synthesis of quinoxalines with hypervalent iodine as a catalyst

doi:10.1016/j.tet.2013.09.027

Tetrahedron

Volume 69, Issue 46, 18 November 2013, Pages 9735-9741

https://doi.org/10.1016/j.tet.2013.09.027 Get rights and content

Abstract

Various biologically important quinoxalines were efficiently synthesized in excellent yields via one-pot reaction between 1,2-diaminobenzenes and internal alkynes. The method utilizes inexpensive and readily available hypervalent iodine source, such as (diacetoxyiodo)benzene (PhI(OAc)₂) and proved to be a better alternative as compared to expensive transition metal catalysts. Quinoxaline 4i [(2-phenyl-3-(3,4,5-trimethoxy phenyl)quinoxaline)] was evaluated for leukemia cancer cell lines and turned out to be a good candidate.

Graphical abstract

The one-pot metal free synthesis of quinoxaline derivatives with hypervalent iodine as a catalyst.

Introduction

Diversely substituted quinoxalines are important biological agents and therefore a significant development of research has been directed towards the synthesis of this class of compounds.¹ In particular, they are used as anti-tumor,² antibacterial,³ antifungal,⁴ antiviral,⁵ anti-inflammatory,⁶ anti-tubercular,⁷ anticonvulsant,⁸ antimalarial,⁹ antileishanial,¹⁰ and trypanocidal¹¹ agents. A number of reliable synthetic strategies have been developed in the recent past for the synthesis of various substituted quinoxalines12, 13 The most common method is the condensation of 1,2-diaminobenzenes with 1,2-dicarbonyl compounds.¹⁴ However, most of these methods suffer from harsh reaction conditions, tedious isolation procedures, and unsatisfactory yields. Moreover, recent report of one-pot strategy has been developed to construct quinoxalines from internal alkyne with 1,2-diaminobenzene using expensive metal catalysts, such as PdI₂ or PdCl₂/CuCl₂ (Scheme 1a).¹⁵ Therefore, these disadvantages and the cost effectiveness of the methodology brought us an attention to develop an affordable alternative catalyst system for this conversion.

In recent years, hypervalent iodine reagents have received considerable attention due to their low toxicity, ready availability, easy handling, and reactivity similar to those of heavy metal reagents.¹⁶

To the best of our knowledge, there is no literature precedence to synthesize quinoxaline derivatives in one-pot using hypervalent iodine as a catalyst. Herein we report a novel one-pot transition metal free approach to construct quinoxaline derivatives with high structural diversity using PhI(OAc)₂ as a catalyst under mild reaction condition. Mechanistically, the 1,2-diketo compound would be generated in situ from internal alkynes in the presence of hypervalent iodine reagent and the subsequent reaction with 1,2-diaminobenzenes leading to the formation of target product in one-pot fashion (Scheme 1b).

Section snippets

Results and discussion

At first, we initiated the optimization of reaction conditions with the model substrates of alkyne 1a and diaminobenzene 2a to furnish the corresponding product 4a. The effect of various oxidants, additives at different temperature was studied and the results are summarized in Table 1. The reaction of alkyne 1a with diaminobenzene 2a was carried out using stoichiometric amounts of different oxidants viz., PhI(OAc)₂, KMnO₄, and CAN in the presence of an additive PivOH in DMSO at room temperature

Conclusion

In conclusion, we described a simple, efficient, and one-pot methodology for the synthesis of quinoxaline analogues from various internal alkynes and 1,2-diaminobenzenes using inexpensive and readily available PhI(OAc)₂ as an oxidant. High reaction rates, excellent product yields, and easy work up procedures made this methodology as an alternative platform to replace the conventional transition metal catalyzed processes. Biological evaluation was carried out for the compound 4i against 60

General experimental procedures

PhI(OAc)₂ oxidant annulation reactions were performed in mild condition. All other reactions, unless otherwise indicated, were carried out under ambient atmosphere in single-neck, round bottom flasks fitted with a stopcock or condenser, equipped with a magnetic stir bar. Air- or water- sensitive solvents were transferred via syringe. When required, solvents were degassed by bubbling of nitrogen through a needle. Organic solutions were concentrated by rotary evaporation at 25–40 °C under reduced

Acknowledgements

We thank the National Science Council of the Republic of China for financial support. This work was also supported by a grant from the Kaohsiung Medical University Research Foundation.

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Efficient synthesis of quinoxalines with hypervalent iodine as a catalyst

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General experimental procedures

Acknowledgements

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Eur. J. Med. Chem.

J. Med. Chem.

Trends Parasitol.

Bioorg. Med. Chem.

Mem. Inst. Oswaldo Cruz

Tetrahedron

Tetrahedron Lett.

Experientia

Tetrahedron

Synth. Commun.

Synthesis

Adv. Synth. Catal.

J. Am. Chem. Soc.

J. Org. Chem.

J. Med. Chem.

Curr. Med. Chem.

Curr. Pharm. Des.

Mini-Rev. Med. Chem.

Org. Biomol. Chem.

Med. Chem. Commun.

Tetrahedron Lett.

Synth. Commun.

Tetrahedron Lett.

Tetrahedron Lett.

J. Am. Chem. Soc.

J. Mater. Chem.

J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Pharmacol.

Afr. J. Biotechnol.