Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0040-1706021
A Green, Scalable, and Catalyst-Free One-Minute Synthesis of Quinoxalines
Norges Forskningsråd (Research Council of Norway, Grant No. 275043 CasCat).
![](https://www.thieme-connect.de/media/10.1055-s-00032269/202101/lookinside/thumbnails/so-2020-d0041-l_10-1055_s-0040-1706021-1.jpg)
Abstract
A highly efficient and catalyst-free protocol is reported for the synthesis of quinoxalines via the classical cyclocondensation reaction between aryldiamines and dicarbonyl compounds. Remarkably simple and green reaction conditions employing methanol as solvent afforded medium to excellent yield of quinoxalines after only one-minute reaction time at ambient temperature. The conditions allow at least 10 gram scale synthesis of quinoxalines and should be a preferred starting point for optimization and method of choice for applications in the synthetic community.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1706021.
- Supporting Information
Publication History
Received: 03 November 2020
Accepted after revision: 08 January 2021
Article published online:
10 February 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References and Notes
- 1a Gazit A, App H, McMahon G, Chen J, Levitzki A, Bohmer FD. J. Med. Chem. 1996; 39: 2170
- 1b Sehlstedt U, Aich P, Bergman J, Vallberg H, Norden B, Graslund A. J. Mol. Biol. 1998; 278: 31
- 2a Sakata G, Makino K, Kuraswa Y. Heterocycles 1988; 27: 2481
- 2b He W, Meyers MR, Hanney B, Spada A, Blider G, Galzeinski H, Amin D, Needle S, Page K, Jayyosi Z, Perrone H. Bioorg. Med. Chem. Lett. 2003; 13: 3097
- 2c Kim YB, Kim Y.-H, Park JY, Kim SK. Bioorg. Med. Chem. Lett. 2004; 14: 541
- 3a Gao H, Huang K.-C, Yamasaki EF, Chan KK, Chohan L, Snapka RM. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 12168
- 3b Cole SP, Bhardwaj G, Gerlach JH. Science 1992; 258: 1650
- 3c Lawrence DS, Copper JE, Smith CD. J. Med. Chem. 2001; 44: 594
- 3d Yoo HW, Suh ME, Park SW. J. Med. Chem. 1998; 41: 4716
- 3e Weng Q, Wang D, Guo P. Eur. J. Pharmacol. 2008; 581: 262
- 4a Tandon VK, Yadav DB, Maurya HK, Chaturvedi AK, Shukla PK. J. Med. Chem. 2006; 14: 6120
- 4b Carta A, Loriga M, Paglietti G. Eur. J. Med. Chem. 2004; 39: 195
- 5a Fonseca T, Gigante B, Marques MM, Gilchrist TL, De Clercq E. Bioorg. Med. Chem. 2004; 12: 103
- 5b Ali I, Al-Masoudi I, Hassan HG, Al-Masoudi N. Chem. Heterocycl. Compd. 2007; 43: 1052
- 6a Crowther AF, Curd FH.S, Davey DG, Stacey GJ. J. Chem. Soc. 1949; 1260
- 6b Rangisetty JB, Gupta CN. V. H. B, Prasad AL, Srinivas P, Sridhar N, Parimoo P, Veeranjaneyulu A. J. Pharm. Pharmacol. 2001; 53: 1409
- 7a Kotharkar SA, Shinde DB. Bioorg. Med. Chem. Lett. 2006; 16: 6181
- 7b Mashevskaya IV, Makhmudov RR, Aleksandrova GA, Golovnira OV, Duvalov AV, Maslivets AN. Pharm. Chem. J. 2001; 35: 196
- 7c Vyas DA, Chauhan NA, Parikh AR. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2007; 46: 1699
- 8 Gao H, Yamasaki EF, Chan KK, Shen LL, Snapka RM. Cancer Res. 2000; 60: 5937
- 9a Sonawane ND, Rangnekar DW. J. Heterocycl. Chem. 2002; 39: 303
- 9b Katoh A, Yoshida T, Ohkanda J. Heterocycles 2000; 52: 911
- 10a Dailey S, Feast WJ, Peace RJ, Sage IC, Till S, Wood EL. J. Mater. Chem. 2001; 11: 2238
- 10b Brien D, Weaver MS, Lidzey DG, Bradley DD. C. Appl. Phys. Lett. 1996; 69: 881
- 11 Sessler JL, Maeda H, Mizuno T, Lynch VM, Furuta H. Chem. Commun. 2002; 862
- 12 Ott S, Faust R. Synlett 2004; 1509
- 13a Sessler JL, Maeda H, Mizuno T, Lynch VM, Furuta H. J. Am. Chem. Soc. 2002; 124: 13474
- 13b Castro PP, Zhao G, Masangkay GA, Hernandez C, Gutierrez-Tunstad LM. Org. Lett. 2004; 6: 333
- 14 Thomas KR. J, Velusamy M, Lin JT, Chuen C.-H, Tao Y.-T. Chem. Mater. 2005; 17: 1860
- 15a Kazunobu T, Ryusuke T, Tomohiro O, Shuichi M. Chem. Commun. 2002; 212
- 15b Hegedus LS, Greenberg MM, Wendling JJ, Bullock JP. J. Org. Chem. 2003; 68: 4179
- 16a Raw SA, Wilfred CD, Taylor RJ. K. Org. Biomol. Chem. 2004; 2: 788
- 16b Dell A, William DH, Morris HR, Smith GA, Feeney J, Roberts GC. K. J. Am. Chem. Soc. 1975; 97: 2497
- 16c Bailly C, Echepare S, Gago F, Waring M. J. Anti-Cancer Drug Des. 1999; 15: 291
- 17a Abu-Hashem AA. Am. J. Org. Chem. 2015; 5: 14
- 17b Mamedov VA. In Quinoxalines 2016; 5
- 17c von Pechmann H. Ber. Dtsch. Chem. Ges. 1888; 21: 1411
- 17d Zincke T, Schmidt M. Justus Liebigs Ann. Chem. 1895; 286: 43
- 18a Brown DJ. In The Chemistry of Heterocyclic Compounds, Quinoxalines, Suppl. II. Taylor EC. Wiley; Hoboken: 2004
- 18b More SV, Sastry MN. V, Yao C.-F. Green Chem. 2006; 8: 91
- 18c Ajaikumar S, Pandurangan A. Appl. Catal., A 2009; 357: 184
- 18d Liu J.-Y, Liu J, Wang J.-D, Jiao D.-Q, Liu H.-W. Synth. Commun. 2010; 40: 2047
- 18e Kumbhar A, Kamble S, Barge M, Rashinkar G, Salunkhe R. Tetrahedron Lett. 2012; 53: 2756
- 18f Kadam HK, Khan S, Kunkalkar RA, Tilve SG. Tetrahedron Lett. 2013; 54: 1003
- 18g Arde SM, Patil AD, Mane AH, Salokhe PR, Salunkhe RS. Res. Chem. Intermed. 2020; 46: 5069
- 18h Rewcastle GW, Denny WA, Baguley BC. J. Med. Chem. 1987; 30: 843
- 19a Cho CS, Oh SG. Tetrahedron Lett. 2006; 47: 5633
- 19b Bera A, Sk M, Singh K, Banerjee D. Chem. Commun. 2019; 55: 5958
- 19c Daw P, Kumar A, Espinosa-Jalapa NA, Posner YD, David YB, Milstein D. ACS Catal. 2018; 8: 7734
- 19d Shee S, Ganguli K, Jana K, Kundu S. Chem. Commun. 2018; 54: 6883
- 19e Hille T, Irrgang T, Kempe R. Chem. Eur. J. 2014; 20: 5569
- 19f Mondal A, Sahoo MK, Subaramanian M, Balaraman E. J. Org. Chem. 2020; 85: 7181
- 20a Raw SA, Wilfred CD, Taylor RJ. K. Chem. Commun. 2003; 2286
- 20b Raw SA, Wilfred CD, Taylor RJ. K. Org. Biomol. Chem. 2004; 2: 788
- 20c Kim SY, Park KH, Chung YK. Chem. Commun. 2005; 1321
- 20d Cho CS, Oh SG. J. Mol. Catal. A.: Chem. 2007; 276: 205
- 21 Das B, Venkateswarlu K, Suneel K, Majhi A. Tetrahedron Lett. 2007; 48: 5371
- 22a Wan JP, Gan S.-F, Wu J.-M, Pan Y.-J. Green Chem. 2009; 11: 1633
- 22b Villemin D, Martin B. Synth. Commun. 1995; 25: 2319
- 22c Juncai F, Yang L, Qinghua M, Bin L. Synth. Commun. 1998; 28: 193
- 22d Vázquez E, De La Hoz A, Elander N, Moreno A, Stone-Elander S. Heterocycles 2001; 55: 109
- 22e Goswami S, Adak AK. Tetrahedron Lett. 2002; 43: 8371
- 22f Zhao Z, Wisnoski DD, Wolkenberg SE, Leister WH, Wang Y, Lindsley CW. Tetrahedron Lett. 2004; 45: 4873
- 22g Kim SY, Park KH, Chung YK. Chem. Commun. 2005; 1321
- 22h Kidwai M, Saxena S, Mohan R. J. Korean Chem. Soc. 2005; 49: 288
- 22i Azizian J, Karimi AR, Kazemizadeh Z, Mohammadi AA, Mohammadizadeh MR. Tetrahedron Lett. 2005; 46: 6155
- 22j Gris J, Glisoni R, Fabian L, Fernández B, Moglioni AG. Tetrahedron Lett. 2008; 49: 1053
- 23 Wu Z, Ede NJ. Tetrahedron Lett. 2001; 42: 8115
- 24 Sadjadi S, Sadjadi S, Hekmatshoar R. Ultrason. Sonochem. 2010; 17: 764
- 25a Jafarpour M, Rezaeifard A, Danehchin M. Appl. Catal. A 2011; 394: 48
- 25b Zhou JF, Gong GX, Shi KB, Zhi SJ. Chin. Chem. Lett. 2009; 20: 672
- 25c Krishnakumar B, Velmurugan R, Jothivel S, Swaminathan M. Catal. Commun. 2010; 11: 997
- 25d Niknam K, Saberi D, Mohagheghnejad M. Molecules 2009; 14: 1915
- 25e Darabi HR, Mohandessi S, Aghapoor K, Mohsenzadeh F. Catal. Commun. 2007; 8: 389
- 26 More SV, Sastry MN. V, Wang CC, Ching-Fa Y. Tetrahedron Lett. 2005; 46: 6345
- 27 Islami MR, Hassani Z. ARKIVOC 2008; (xv): 280
- 28 Bhosale RS, Sarda SR, Ardhapure SS, Jadhav WN, Bhusare SR, Pawar RP. Tetrahedron Lett. 2005; 46: 7183
- 29 Kumar A, Kumar S, Saxena A, De A, Mozumdar S. Catal. Commun. 2008; 9: 778
- 30 Dong F, Gong K, Fei Z, Zhou X, Liu Z. Catal. Commun. 2008; 9: 317
- 31 Darabi HR, Tahoori F, Aghapoor K, Taala F, Mohsenzadeh F. J. Braz. Chem. Soc. 2008; 19: 1646
- 32 Jafarpour M, Rezaeifard A, Danehchin M. Appl. Catal. A 2011; 394: 48
- 33 Raw SA, Wilfred CD, Taylor RJ. K. Org. Biomol. Chem. 2004; 2: 788
- 34 Venkatesh C, Singh B, Mahata PK, IIa H, Junjappa H. Org. Lett. 2005; 7: 2169
- 35 Brown DJ. Quinoxalines . In The Chemistry of Heterocyclic Compounds, Vol. 61 . Taylor EC, Wipf P. John Wiley & Sons; Hoboken: 2004: 1
- 36 More SV, Sastry MN. V, Yao CF. Green Chem. 2006; 8: 91
- 37 Cai JJ, Zou JP, Pan XQ, Zhang W. Tetrahedron Lett. 2008; 49: 7386
- 38 Heravi MM, Taheri S, Bakhtiari K, Oskooie HA. Catal. Commun. 2007; 8: 211
- 39 Darabi HR, Mohandessi S, Aghapoor K, Mohsenzadeh F. Catal. Commun. 2007; 8: 389
- 40 Elumalai V, Hansen JH. Synlett 2020; 31: 547
- 41 Typical ProcedureIn a 25 mL round-bottom flask was added benzene-1,2-diamine (1a, 100 mg, 0.925 mmol) which was dissolved in MeOH (5 mL). To the stirred solution, glyoxal (2a, 40%, 134 mg, 0.11 mL, 0.925 mmol) was added and the mixture stirred for 1 min at ambient temperature, followed by quenching with water (10 mL), dilution with ethyl acetate (50 mL), and washing with water (30 mL). The water layer was extracted with ethyl acetate (2 × 30 mL), the organic layers were combined, and dried over anhydrous Na2SO4. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the desired product 3a as a yellowish liquid (0.111 g, 93%) without column purification (GC purity >99%). 1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 2 H), 8.11 (dd, J = 6.4, 3.5 Hz, 2 H), 7.78 (dd, J = 6.4, 3.5 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 145.0, 143.1, 130.1, 129.5.From 1-gram-scale SynthesisCompound 3w was obtained as golden-yellow solid (1.710 g, 94%) without column purification (GC purity >99%). 1H NMR (400 MHz, CDCl3): δ = 8.51 (d, J = 1.9 Hz, 1 H), 8.33–8.21 (m, 4 H), 7.95 (dt, J = 7.8, 1.1 Hz, 1 H), 7.89–7.80 (m, 3 H), 7.75 (dtd, J = 13.2, 7.7, 1.8 Hz, 2 H), 7.60–7.51 (m, 1 H), 7.48–7.41 (m, 2 H), 7.18 (dddd, J = 7.7, 6.3, 5.1, 1.2 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 195.7, 157.1, 157.0, 154.1, 153.6, 148.7, 148.7, 142.9, 140.2, 138.8, 137.1, 136.8, 136.8, 132.9, 132.5, 130.4, 130.2, 129.9, 128.6, 124.4, 124.2, 123.4, 123.3.
- 42 Although there are only 3 novel compounds produced in this study, we have provided the NMR spectra for all entries in order to demonstrate the purity of the products after the indicated procedure. These can be found in the Supporting Information.
For some recent overviews, see:
For some historical references to the imine formation reaction, see:
For an example of a reaction in refluxing methanol without other additives, see: