Abstract
The review highlights recent advancements in the synthesis of α-fluoro and α,α- difluoroalkylated azines, focusing on two main approaches. The first approach involves nucleophilic deoxofluorination, wherein α-hydroxy- or α-oxoalkylated azines are treated with diethylaminosulfur trifluoride or other S-F reagents to introduce fluorine atoms. The second approach employs direct electrophilic benzylic fluorination, whereby alkylazines undergo fluorination using N-F reagents. Both methods provide flexibility in designing and synthesizing fluoroalkylated heterocycles.
Graphical Abstract
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01691] [PMID: 28051859]
[http://dx.doi.org/10.1021/jo00111a021]
[http://dx.doi.org/10.1021/op0341420]
[http://dx.doi.org/10.1016/j.bmcl.2017.12.040] [PMID: 29289430]
[http://dx.doi.org/10.1016/j.jfluchem.2020.109639]
[http://dx.doi.org/10.1177/1756287216677903] [PMID: 28042310]
[http://dx.doi.org/10.1021/cr4002879] [PMID: 24299176]
[http://dx.doi.org/10.1021/acsomega.0c00830] [PMID: 32455181]
[http://dx.doi.org/10.1002/anie.201814457] [PMID: 30759327];
(b) Schubert, T.J.; Oboh, E.; Peek, H.; Philo, E.; Teixeira, J.E.; Stebbins, E.E.; Miller, P.; Oliva, J.; Sverdrup, F.M.; Griggs, D.W.; Huston, C.D.; Meyers, M.J. Structure–activity relationship studies of the aryl acetamide triazolopyridazines against cryptosporidium reveals remarkable role of fluorine. J. Med. Chem., 2023, 66(12), 7834-7848.
[http://dx.doi.org/10.1021/acs.jmedchem.3c00110] [PMID: 37267631]
[http://dx.doi.org/10.1021/jm00353a011] [PMID: 6292425]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00483] [PMID: 32462865]
[http://dx.doi.org/10.1016/j.jfluchem.2019.05.006]
[http://dx.doi.org/10.1016/j.bmcl.2018.04.053] [PMID: 29705142]
[http://dx.doi.org/10.1016/j.jfluchem.2004.12.016]
[http://dx.doi.org/10.1021/jm500139a] [PMID: 24805780];
(b) Loksha, Y.M.; Pedersen, E.B.; Loddo, R.; La Colla, P. Synthesis and anti-HIV-1 activity of 1-substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils. Arch. Pharm., 2009, 342(9), 501-506.
[http://dx.doi.org/10.1002/ardp.200900058] [PMID: 19637180];
(c) Radi, M.; Angeli, L.; Franchi, L.; Contemori, L.; Maga, G.; Samuele, A.; Zanoli, S.; Armand-Ugon, M.; Gonzalez, E.; Llano, A.; Esté, J.A.; Botta, M. Towards novel S-DABOC inhibitors: Synthesis, biological investigation, and molecular modeling studies. Bioorg. Med. Chem. Lett., 2008, 18(21), 5777-5780.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.070] [PMID: 18842407];
(d) Wang, P.; Felsing, D.E.; Chen, H.; Stutz, S.J.; Murphy, R.E.; Cunningham, K.A.; Allen, J.A.; Zhou, J. Discovery of potent and brain-penetrant gpr52 agonist that suppresses psychostimulant behavior. J. Med. Chem., 2020, 63(22), 13951-13972.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01498] [PMID: 33198466]
[http://dx.doi.org/10.1016/j.bmcl.2010.08.007] [PMID: 20810280]
[http://dx.doi.org/10.1021/jm0300678] [PMID: 12904072]
[http://dx.doi.org/10.1021/jo900674u] [PMID: 19518154]
[http://dx.doi.org/10.1021/jm301024w] [PMID: 22934575]
[http://dx.doi.org/10.1002/chem.201102859] [PMID: 22250061]
[http://dx.doi.org/10.1016/j.molcata.2010.05.017]
[http://dx.doi.org/10.1021/acs.jmedchem.8b01353] [PMID: 30779564]
[http://dx.doi.org/10.1002/chem.200900505] [PMID: 19565586]
[http://dx.doi.org/10.1016/j.bmcl.2010.01.071] [PMID: 20137927]
[http://dx.doi.org/10.1016/j.jfluchem.2021.109888]
[http://dx.doi.org/10.1016/j.tet.2015.04.066]
[http://dx.doi.org/10.1002/anie.201608792] [PMID: 27813242]
[http://dx.doi.org/10.1002/cber.19881210718]
[http://dx.doi.org/10.1021/acs.joc.1c01518] [PMID: 34424702]
[http://dx.doi.org/10.1021/ml400206q] [PMID: 24900590]
[http://dx.doi.org/10.1039/C5RA09124A]
[http://dx.doi.org/10.1021/jm201640m] [PMID: 22239465]
[http://dx.doi.org/10.1016/j.bmcl.2005.01.028] [PMID: 15863341]
[http://dx.doi.org/10.1016/S0022-1139(00)83974-3]
[http://dx.doi.org/10.1021/jo990566+]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01877] [PMID: 28492317]
[http://dx.doi.org/10.1016/j.bmcl.2010.01.085]
[http://dx.doi.org/10.1021/acs.orglett.9b00054] [PMID: 30775926]
[http://dx.doi.org/10.1002/anie.201801280] [PMID: 29486098]
[http://dx.doi.org/10.1055/s-0040-1706482]
[http://dx.doi.org/10.1021/jacs.6b07731] [PMID: 27749040]
[http://dx.doi.org/10.1016/j.tetlet.2006.01.037]
[http://dx.doi.org/10.1039/C5RA06395G]
[http://dx.doi.org/10.1055/s-0039-1690862]
[http://dx.doi.org/10.1002/chem.201900565] [PMID: 31026095]
[http://dx.doi.org/10.1039/D1SC06273E] [PMID: 35173930]
[http://dx.doi.org/10.1021/jacs.5b04088] [PMID: 26001406]
[http://dx.doi.org/10.1002/anie.202007403] [PMID: 32633892]
[http://dx.doi.org/10.1038/s41557-018-0048-1] [PMID: 29892027]
[http://dx.doi.org/10.1016/0040-4020(95)00884-B]
[http://dx.doi.org/10.1016/j.bmcl.2020.127240] [PMID: 32527542]
[http://dx.doi.org/10.1039/a906507e]
[http://dx.doi.org/10.1021/jacs.9b04440] [PMID: 31343170]
[http://dx.doi.org/10.1021/jacs.1c03157] [PMID: 33970628]
[http://dx.doi.org/10.1021/acs.orglett.1c03626] [PMID: 34870439]
[http://dx.doi.org/10.1055/s-0030-1258198]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00167] [PMID: 30034607]
[http://dx.doi.org/10.1021/jm801153y] [PMID: 19530720]
[http://dx.doi.org/10.1021/jo048975f] [PMID: 15471444]
[http://dx.doi.org/10.1002/anie.201912882] [PMID: 31693789]
[http://dx.doi.org/10.1002/anie.201606323] [PMID: 27653634]
[http://dx.doi.org/10.1039/C8SC01221K] [PMID: 30061993]
[http://dx.doi.org/10.3987/COM-93-6582]
[http://dx.doi.org/10.1016/j.tetlet.2006.02.030]
[http://dx.doi.org/10.1021/jacs.0c10700] [PMID: 33231441]
[http://dx.doi.org/10.1021/ja5039819] [PMID: 24766544]
[http://dx.doi.org/10.1016/j.jfluchem.2003.11.012]
[http://dx.doi.org/10.1021/acs.orglett.7b03994] [PMID: 29384686]
[http://dx.doi.org/10.1021/jm020311f] [PMID: 12570369]
[http://dx.doi.org/10.1016/j.bmcl.2008.04.018] [PMID: 18462938]
[http://dx.doi.org/10.1016/j.bmcl.2018.11.046] [PMID: 30501964]
[http://dx.doi.org/10.1016/j.jfluchem.2021.109792]
[http://dx.doi.org/10.1007/s10593-023-03210-1]
[http://dx.doi.org/10.3390/org2020007]
[http://dx.doi.org/10.1021/jo0617666] [PMID: 17137369]
[http://dx.doi.org/10.1016/j.jfluchem.2022.110027]
[http://dx.doi.org/10.1016/S0040-4020(01)85088-2]