On Pyridopyrazinol Chemistry: Synthesis of Chemiluminescent Substances

Abstract

Our work on new chemiluminescent substances related to the marine luciferin coelenterazine (λ_max = 465 nm) led us to attempt the synthesis of four nitrogen-rich pyridopyrazine-bearing analogues. Accordingly, the preparation of the corresponding benzyl-bearing pyridopyrazinols is studied. By varying the conditions for the condensation of phenylpyruvic acid with 1,2-diaminopyridine or 3,4-diaminopyridine, all the possible pyridopyrazin-2-ol regioisomers are isolated and properly characterized, including by means of crystallographic studies. The ensuing syntheses of the halogenated pyridopyrazines are fraught with difficulties ranging from extensive decomposition to an unexpected ring contraction. In one instance, the inherently reductive mixture of phosphorus oxychloride and phosphorus trichloride provides 2-benzyl-3-chloropyrido[2,3-b]pyrazine. This precursor is then transformed into the target O-acetylated luciferin (6,8-dibenzylimidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl acetate). The ‘benzo’ derivative of this analogue (i.e., 2,12-dibenzylimidazo[1′,2′:1,6]pyrazino[2,3-c]isoquinolin-3-yl acetate) is also prepared and the chemiluminescence emission spectra of these compounds are determined in a phosphate buffer (λ_max = 546 and 462 nm).

Key words

chemiluminescence - coelenterazine - imidazo[1,2-a]pyrazin-3(7H)-one - pyridopyrazine - luciferin - heterocycles - rearrangement

Publication History

Received: 21 January 2021

Accepted after revision: 22 February 2021

Accepted Manuscript online:
22 February 2021

Article published online:
09 March 2021

• References

• 1 Gagnot G, Hervin V, Coutant EP, Goyard S, Jacob Y, Rose T, Hibti FE, Quatela A, Janin YL. Chem. Eur. J. 2021; 27: 2112
• 2a Inouye S, Shimomura O. Biochem. Biophys. Res. Commun. 1997; 233: 349
• 2b Giuliani G, Cappelli A, Vomero S, Anzini M. WO2011007314, 2011 .
• 2c Giuliani G, Molinari P, Ferretti G, Cappelli A, Anzini M, Vomero S, Costa T. Tetrahedron Lett. 2012; 53: 5114
• 2d Yuan M.-L, Jiang T.-Y, Du L.-P, Li M.-Y. Chin. Chem. Lett. 2016; 27: 550
• 2e Yeh HW, Karmach O, Ji A, Carter D, Martins-Green MM, Ai HW. Nat. Methods 2017; 14: 971
• 2f Giuliani G, Merolla A, Paolino M, Reale A, Saletti M, Blancafort L, Cappelli A, Benfenati F, Cesca F. Photochem. Photobiol. 2021; 97 in press;
• 3 Yao Z, Zhang BS, Steinhardt RC, Mills JH, Prescher JA. J. Am. Chem. Soc. 2020; 142: 14080
• 4a Coutant EP, Goyard S, Hervin VO, Gagnot G, Baatallah R, Rose T, Jacob Y, Janin YL. Org. Biomol. Chem. 2019; 17: 3709
• 4b Coutant EP, Gagnot G, Hervin VO, Baatallah R, Goyard S, Jacob Y, Rose T, Janin YL. Chem. Eur. J. 2020; 26: 948
• 5a Abasolo MI, Bianchi D, Atlasovitch F, Gaozza C, Fernandez BM. J. Heterocycl. Chem. 1990; 27: 157
• 5b Bekerman DG, Abasolo MI, Fernandez BM. J. Heterocycl. Chem. 1992; 29: 129
• 6 Janin YL, Huel C, Flad G, Thirot S. Eur. J. Org. Chem. 2002; 1763
• 7 Rombouts FJ. R, Tresadern G, Buijnsters P, Langlois X, Tovar F, Steinbrecher TB, Vanhoof G, Somers M, Andrés J.-I, Trabanco AA. ACS Med. Chem. Lett. 2015; 6: 282
• 8 Kato T, Sakamoto T, Kubo A, Sawamoto D. EP2896613, 2016
• 9 Tanimori S, Kashiwagi H, Nishimura T, Kirihata M. Adv. Synth. Catal. 2010; 352: 2531
• 10 Scarry SM, Lovell KM, Frankowski KJ, Bohn LM, Aubé J. J. Org. Chem. 2016; 81: 10538
• 11a An Z, She Y, Yang X, Pang X, Yan R. Org. Chem. Front. 2016; 3: 1746
• 11b Rajasekar S, Adarsh TP, Tharmalingam N, Andivelu I, Mylonakis E. ChemistrySelect 2019; 4: 2281
• 11c Chu L, Yue X, Qing FL. Org. Lett. 2010; 12: 1644
• 11d Deguchi Y, Kono M, Koizumi Y, Izato Y, Miyake A. Org. Process Res. Dev. 2020; 24: 1614
• 12 Han C, Kelly SM, Cravillion T, Savage SJ, Nguyen T, Gosselin F. Tetrahedron 2019; 75: 4351
• 13a Mamedov VA. RSC Adv. 2016; 6: 42132
• 13b Mamedov VA, Zhukova NA, Kadyrova MS, Syakaev VV, Beschastnova TN, Buzyurova DN, Rizvanov IK, Latypov SK, Sinyashin OG. J. Org. Chem. 2019; 84: 13572
• 14 Vacher M, Fdez Galván I, Ding BW, Schramm S, Berraud-Pache R, Naumov P, Ferré N, Liu YJ, Navizet I, Roca-Sanjuán D, Baader WJ, Lindh R. Chem. Rev. 2018; 118: 6927
• 15 Wang SL, Ding J, Jiang B, Gao Y, Tu SJ. ACS Comb. Sci. 2011; 13: 572