An efficient synthesis of C-6 aminated 3-bromoimidazo[1,2-b]pyridazines

References

• (a) K. N. Sanghavi, G. K. Dhuda, K. M. Kapadiya, Facile Microwave Synthesis of Pd-Catalyzed Suzuki Reaction for Bis-6-Aryl Imidazo[1,2-a]Pyridine-2-Carboxamide Derivatives with PEG3 Linker. Polycycl. Aromat. Compd. 2023, 43(3), 2571–2581;
   Web of Science ®Google Scholar
  (b) K. N. Sanghavi, D. Sriram, J. Kumari, K. M. Kapadiya, Regioselective Pd-Catalyzed Suzuki–Miyaura Borylation Reaction for the Dimerization Product of 6-Bromoimidazo[1,2-a]Pyridine-2-Carboxylate: Mechanistic Pathway, Cytotoxic and Tubercular Studies. Synlett 2023, 34(9), 1049–1057, DOI: 10.1055/s-0042-1751404;
   Google Scholar
  (c) M. Heydari, N. Azizi, M. M. Hashemi, Magnetic Mesoporous Poly-Melamine–Formaldehyde: An Efficient and Recyclable Catalyst for Straightforward One-Pot Synthesis of Imidazo[1,2-a]Pyridines. J. Iran. Chem. Soc. 2019, 16, 2357–2363. doi:10.1007/s13738-019-01705-3;
   Web of Science ®Google Scholar
  (d) N. Aziz, S. Dezfooli, Catalyst-Free Synthesis of Imidazo [1,2-a] Pyridines via Groebke Multicomponent Reaction. Environ. Chem. Lett. 2016, 14, 201–206. doi:10.1007/s10311-015-0541-3 doi:10.1080/10406638.2022.2048035.
   Web of Science ®Google Scholar
• Tufail, F.; Singh, S.; Saquib, M.; Tiwari, J.; Singh, J.; Singh, J. Catalyst-Free, Glycerol-Assisted Facile Approach to Imidazole-Fused Nitrogen-Bridgehead Heterocycles. Chemistry Select. 2017, 2, 6082–6089. DOI: 10.1002/slct.201700557.
   Google Scholar
• Guchhait, S. K.; Saini, M.; Khivsara, V. J.; Giri, S. K. Annulation of Conjugated Azine-Imine with a Sulfoxonium Ylide in a Noncarbenoid Route to Synthesize Multisubstituted Imidazole-Fused Heterocycles. J. Org. Chem. 2021, 86, 5380–5387. DOI: 10.1021/acs.joc.1c00052.
   PubMed Web of Science ®Google Scholar
• Garrido, A.; Vera, G.; Delaye, P.-O.; Enguehard-Gueiffier, C. Enguehard-Gueiffier Imidazo[1,2-b]Pyridazine as Privileged Scaffold in Medicinal Chemistry: An Extensive Review. Eur. J. Med. Chem. 2021, 226, 113867. DOI: 10.1016/j.ejmech.2021.113867.
   PubMed Web of Science ®Google Scholar
• Zhou, T.; Commodore, L.; Huang, W.-S.; Wang, Y.; Thomas, M.; Keats, J.; Xu, Q.; Rivera, V. M.; Shakespeare, W. C.; Clackson, T.; et al. Structural Mechanism of the pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons For Overcoming Kinase Inhibitor Resistance. Chem. Biol. Drug Des. 2011, 77, 1–11. DOI: 10.1111/j.1747-0285.2010.01054.x.
   PubMed Web of Science ®Google Scholar
• Ahuja, V. T.; Dubowchik, G. M.; Hartz, R. A.; Macor, J. E.; Sivaprakasam, P. Gsk-3 Inhibitors. 2018. WO2018098411A1.
   Google Scholar
• Player, M. R.; Meegalla, S. K.; Illig, C. R.; Chen, J.; Wilson, K. J.; Lee, Y.-K.; Parks, D. J.; Cheung, W. S.; Huang, H.; Patch, R. J. PDE 10a Inhibitors for the Treatment of Type II Diabetes. 2014. US2014364413A1.
   Google Scholar
• Enguehard-Gueiffier, C.; Gueiffier, A. Recent Progress in the Pharmacology of Imidazo[1,2-a]Pyridines. Mini Rev. Med. Chem. 2007, 7, 888–899. DOI: 10.2174/138955707781662645.
   PubMed Web of Science ®Google Scholar
• Hamdouchi, C.; Sanchez-Martinez, C.; Gruber, J.; Del Prado, M.; Lopez, J.; Rubio, A.; Heinz, B. A. Imidazo[1,2-b]Pyridazines, Novel Nucleus with Potent and Broad Spectrum Activity Against Human Picornaviruses: Design, Synthesis, and Biological Evaluation. J. Med. Chem. 2003, 46, 4333–4341. DOI: 10.1021/jm020583i.
   PubMedGoogle Scholar
• Lemercier, G.; Fernandez-Montalvan, A.; Shaw, J. P.; Kugelstadt, D.; Bomke, J.; Domostoj, M.; Schwarz, M. K.; Scheer, A.; Kappes, B.; Leroy, D. Identification and Characterization of Novel Small Molecules as Potent Inhibitors of the Plasmodial Calcium-Dependent Protein Kinase 1. Biochemistry 2009, 48, 6379–6389. DOI: 10.1021/bi9005122.9.
   PubMed Web of Science ®Google Scholar
• Zheng, Y.; Müller, J.; Kunz, S.; Siderius, M.; Maes, L.; Caljon, G.; Müller, N.; Hemphill, A.; Sterk, G. J.; Leurs, R. 3-Nitroimidazo[1,2-b]Pyridazine as a Novel Scaffold for Antiparasitics with Sub-nanomolar anti-Giardia Lamblia Activity. Int. J. Parasitol. Drugs Drug Resist. 2022, 19, 47–55. DOI: 10.1016/j.ijpddr.2022.05.004.
   PubMed Web of Science ®Google Scholar
• Ali, A.; Cablewski, T.; Francis, C. L.; Ganguly, A. K.; Sargent, R. M.; Sawutz, D. G.; Winzenberg, K. N. 2-Phenylimidazo[1,2-b]Pyridazine Derivatives Highly Active Against Haemonchus Contortus. Bioorg. Med. Chem. Lett. 2011, 21, 4160–4163. DOI: 10.1016/j.bmcl.2011.05.096.
   PubMed Web of Science ®Google Scholar
• Farmer, L. J.; Fournier, P.-A.; Lessard, S.; Liu, B.; St-Onge, M.; Sturino, C.; Szychowski, J.; Yannopoulos, C.; Vallee, F.; Lacoste, J.-E.; et al. Imidazopyridazines Useful as Inhibitors of the Par-2 Signaling Pathway. 2015. WO2015048245.
   Google Scholar
• Falco, J. L.; Guglietta, A.; Palomer, A. Imidazo[1,2-b]Pyridazines, Their Processes of Preparation and Their Use as Gaba Receptor Ligands. 2007. WO2007110437
   Google Scholar
• Byth, K. F.; Cooper, N.; Culshaw, J. D.; Heaton, D. W.; Oakes, S. E.; Minshull, C. A.; Norman, R. A.; Pauptit, R. A.; Tucker, J. A.; Breed, J.; et al. Imidazo[1,2-b]Pyridazines: A Potent and Selective Class of Cyclin-Dependent Kinase Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 2249–2252. DOI: 10.1016/j.bmcl.2004.02.008.
   PubMed Web of Science ®Google Scholar
• Huang, W. S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R. M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; et al. Discovery of 3-[2-(Imidazo[1,2-b]Pyridazin-3-yl)Ethynyl]-4-methyl-N-{4-[(4-Methylpiperazin-1-yl)Methyl]-3-(Trifluoromethyl)Phenyl} Benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant. J. Med. Chem. 2010, 53, 4701–4719. DOI: 10.1021/jm100395q.
   PubMed Web of Science ®Google Scholar
• Song, W.; Xu, Q.; Zhu, J.; Chen, Y.; Mu, H.; Huang, J.; Su, J. Imidazo[1,2-b]Pyridazine as Building Blocks for Host Materials for High-Performance Red-Phosphorescent Organic Light-Emitting Devices. ACS Appl. Mater. Interfaces 2020, 12, 19701–19709. DOI: 10.1021/acsami.9b22060.
   PubMed Web of Science ®Google Scholar
• Kusakabe, K. -I.; Ide, N.; Daigo, Y.; Itoh, T.; Yamamoto, T.; Hashizume, H.; Nozu, K.; Yoshida, H.; Tadano, G.; Tagashira, S.; et al. Discovery of Imidazo[1,2-b]Pyridazine Derivatives: Selective and Orally Available mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity. J. Med. Chem. 2015, 58, 1760–1775. DOI: 10.1021/jm501599u.
   PubMed Web of Science ®Google Scholar
• Xu, Y. Preparation of Imidazo[1,2-b]Pyridazine and Pyrazolo[1,5-a]Pyrimidine Derivatives as Protein Kinase Inhibitors. U.S. Pat. Appl. Publ. 2012, 20120058997.
   Google Scholar
• Elie, J.; Feizbakhsh, O.; Desban, N.; Josselin, B.; Baratte, B.; Bescond, A.; Duez, J.; Fant, X.; Bach, S.; Marie, D.; et al. Design of New Disubstituted Imidazo[1,2-b]Pyridazine Derivatives as Selective Haspin Inhibitors. Synthesis, Binding Mode and Anticancer Biological Evaluation. J. Enzyme Inhib. Med. Chem. 2020, 35, 1840–1853. DOI: 10.1080/14756366.2020.1825408.
   PubMed Web of Science ®Google Scholar
• Wang, Z.; Wang, J.; Wang, Y.; Xiang, S.; Song, X.; Tu, Z.; Zhou, Y.; Zhang, Z. -M.; Zhang, Z.; Ding, K.; Lu, X. Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors That Overcome Clinically Acquired Resistance. J. Med. Chem. 2022, 65, 6325–6337. DOI: 10.1021/acs.jmedchem.2c00308.
   PubMedGoogle Scholar
• (a) Yadav, D.; Kumar, P.; Singh, P.; Vallero, D. A. Hazardous Waste Management: An Overview of Advanced and Cost-effective Solutions. Elsevier 2021, DOI: 10.1016/C2020-0-01689-0;
   Google Scholar
  (b) Varsha, S. Grand Challenges in Chemical Treatment of Hazardous Pollutants. Front. Environ. Chem. 2021, 22, doi:10.3389/fenvc.2021.792814.
   Google Scholar
• (a) Johnston, N. R.; Strobel, S. A. Principles of Fluoride Toxicity and the Cellular Response: A Review. Arch. Toxicol. 2020, 94, 1051–1069, DOI: 10.1007/s00204-020-02687-5.;
   PubMed Web of Science ®Google Scholar
  (b) Camargo, J. A. Fluoride Toxicity to Aquatic Organisms: A Review. Chemosphere 2003, 50, 251–264, doi:10.1016/s0045-6535(02)00498-8
   PubMed Web of Science ®Google Scholar
• Vlasov, V. M. Fluoride Ion as a Nucleophile and a Leaving Group in Aromatic Nucleophilic Substitution Reactions. J. Fluor. Chem. 1993, 61, 193–216. DOI: 10.1016/S0022-1139(00)80104-9.
   Web of Science ®Google Scholar
• The solubility of KF has been reported as 0.44 mM in DMSO (see part (a)), and the solubility of CsF is 6-fold greater than KF in the related, but less polar, aprotic solvent DMF (0.60 mM vs 0.12 mM; see part (b)):
   Google Scholar
  (a) Wynn, D.A.; Roth, M. M.; Pollard, B. D. The Solubility of Alkali-Metal Fluorides in Non-Aqueous Solvents with and without Crown Ethers, as Determined by Flame Emission Spectrometry. Talanta 1984, 31 1036–1040, DOI: 10.1016/0039-9140(84)80244-1;
   PubMed Web of Science ®Google Scholar
  (b) Labban, A. K. S.; Marcus, Y. The Solubility and Solvation of Salts in Mixed Anhydrous Nonaqueous Solvents. 1. Potassium Halides in Mixed Aprotic Solvents. J. Solution Chem., 1991, 20, 221–233.
   Web of Science ®Google Scholar
• Bendjeddou, L. Z.; Loaëc, N.; Villiers, B.; Prina, E.; Späth, G. F.; Galon, H.; Meijer, L.; Oumata, N. Exploration of the Imidazo[1,2-b]Pyridazine Scaffold as a Protein Kinase Inhibitor. Eur. J. Med. Chem. 2017, 125, 696–709. DOI: 10.1016/j.ejmech.2016.09.064.
   PubMed Web of Science ®Google Scholar
• Current lowest price for 12 from a commercial vendor is $USD 500/g, and the most efficient method for its preparation (see reference 26) requires 6-fluoro[1,2-b]pyridazine (lowest commercial price $USD 260/g), compared to only $USD 1-2/g for compound 9. (Pricing obtained from Reaxys and CAS searches performed Oct. 2023)
   Google Scholar
• (a) Nudelman, N. S. SNAr Reactions of Amines in Aprotic Solvents. In The Chemistry of Amino, Nitroso, Nitro, and Related Groups, S. Patai Ed.; John Wiley & Sons, 1996, pp. 1215–1300;
   Google Scholar
  (b) Bunnett, J. F.; Garst, R. H. Base Catalysis of the Reaction of Piperidine with 2,4-Dinitrophenyl Phenyl Ether. Further Substantiation of the Intermediate Complex Mechanism for Aromatic Nucleophilic Substitution. J. Am. Chem. Soc. 1965, 87, 3879–3884.
   Google Scholar
  (c) Bunnett, J. F.; Randall, J. J. Base catalysis of the Reaction of N-methylaniline with 2,4-dinitrofluorobenzene. Proof of the Intermediate Complex Mechanism for Aromatic Nucleophilic Substitution. J. Am. Chem. Soc. 1958, 80, 6020–6030.
   Web of Science ®Google Scholar
• (a) Ormazábal-Toledo, R.;  Richter, S.;  Robles-Navarro, A.; Maulén, B.; Matute, R. A.;  Gallardo-Fuentes, S. Meisenheimer Complexes as Hidden Intermediates In The Aza-SNAr Mechanism, Org. Biomol. Chem. 2020, 18, 4238–4247. DOI: 10.1039/d0ob00600a; (b) Pliego, J. R.; Pilo-Veloso, D. Effects of Ion-Pairing and Hydration on the SNAr Reaction of the F-with p-Chlorobenzonitrile in Aprotic Solvents. Phys. Chem. Chem. Phys. 2008, 10, 1118–1124. DOI:10.1039/B716159J
   Google Scholar
• Arra, O.; Sasson, Y. Inhibition of the Solid–Liquid Phase Transfer Substitution Process by Excess of Quaternary Ammonium Catalyst. J. Chem. Soc. Chem. Commun. 1988, 148–149. DOI: 10.1039/C39880000148.
   Google Scholar
• When aniline was subjected to our standard conditions, a complex reaction mix consisting of 4 different compounds was obtained, as determined by TLC analysis (two pairs of nearly co-eluting compounds, with Rf differences <0.05 for each pair). HRMS and TLC analysis identified the four components as an approximately (3:3:1:1) mix of desired amination product (14):dimerized hydrolysis product (13):intermediate (12): unreacted starting material (9). See Supporting information for compound structures and HRMS data.
   Google Scholar
• Spectral data for all known compounds were consistent with those previously published in the literature.
   Google Scholar
• Derivation of the rate equation (1) is illustrated in the Supplementary Information and is based on the steady state approximation (d[12]/dt = 0) and other simplifying approximations consistent with those applied in previously studied SNAr reactions (see ref. 28).
   Google Scholar