Nucleophilic Substitution Reaction of Pyrimidin-2-yl Phosphates Using Amines and Thiols as Nucleophiles Mediated by PEG-400 as an Environmentally Friendly Solvent

Abstract

A metal-free synthesis of C2-functionalized pyrimidines via the reaction of pyrimidin-2-yl phosphates with amines and thiophenols in PEG-400 has been developed. The desired products can be generated in good to excellent yields in the environmentally friendly PEG-400, without any catalysts or other additives.

Key words

C2-functionalized pyrimidines - pyrimidin-2-yl phosphates - amines - thiophenols - cross-coupling - metal-free

• References

• 1a Hesis L, Gais HJ. Tetrahedron Lett. 1995; 36: 3833
• 1b Haimov A, Neumann R. Chem. Commun. 2002; 876
• 1c Heldebrant D, Jessop PG. J. Am. Chem. Soc. 2003; 125: 5600
• 1d Wang X.-C, Quan Z.-J, Zhang Z. Tetrahedron 2007; 63: 8227
• 2a Li P, Alper H. J. Org. Chem. 1986; 51: 4354
• 2b Cao Y.-Q, Zhang Z, Guo Y.-X. Synth. Commun. 2008; 38: 1325
• 3a Hansford KA, Dettwiler JE, Lubell WD. Org. Lett. 2003; 5: 4887
• 3b Limmert ME, Roy AH, Hartwig JF. J. Org. Chem. 2005; 70: 9364
• 3c Steinhuebel D, Baxter JM, Palucki M, Davies IW. J. Org. Chem. 2005; 70: 10124
• 3d Guan B.-T, Lu X.-Y, Zheng Y, Yu D.-G, Wu T, Li K.-L, Li B.-J, Shi Z.-J. Org. Lett. 2010; 12: 397
• 4a Nicolaou KC, Shi GQ, Gunzner JL, Gartner P, Yang Z. J. Am. Chem. Soc. 1997; 119: 5467
• 4b Buon C, Bouyssou P, Coudert G. Tetrahedron Lett. 1999; 40: 701
• 5a Wu J, Yang Z. J. Org. Chem. 2001; 66: 7875
• 5b Wiskur SL, Korte A, Fu GC. J. Am. Chem. Soc. 2004; 126: 82
• 6a Nan Y, Yang Z. Tetrahedron Lett. 1999; 40: 3321
• 6b Lepifre F, Clavier S, Bouyssou P, Coudert G. Tetrahedron 2001; 57: 6969
• 6c Larsen US, Martiny L, Begtrup M. Tetrahedron Lett. 2005; 46: 4261
• 6d McLaughlin M. Org. Lett. 2005; 7: 4875
• 6e Hansen AL, Ebran JP, Gøgsig TM, Skrydstrup T. Chem. Commun. 2006; 4137
• 6f Claveau E, Gillaizeau I, Blu J, Bruel A, Coudert G. J. Org. Chem. 2007; 72: 4832
• 6g Hansen AL, Ebran JP, Gøgsig TM, Skrydstrup T. J. Org. Chem. 2007; 72: 6464
• 6h Fuwa H, Sasaki M. J. Org. Chem. 2009; 74: 212
• 6i Chen H, Huang Z.-B, Hu X.-M, Tang G, Xu P.-X, Zhao Y.-F, Cheng C.-H. J. Org. Chem. 2011; 76: 2338
• 7a Hayashi T, Katsuro Y, Okamoto Y, Kumada M. Tetrahedron Lett. 1981; 22: 4449
• 7b Karlstrom AS. E, Itami K, Backvall JE. J. Org. Chem. 1999; 64: 1745
• 7c Miller JA. Tetrahedron Lett. 2002; 43: 7111
• 7d Gauthier D, Beckendorf S, Gøgsig TM, Lindhardt AT, Skrydstrup T. J. Org. Chem. 2009; 74: 3536
• 7e Yoshikai N, Matsuda H, Nakamura E. J. Am. Chem. Soc. 2009; 131: 9590
• 8a Nicolaou KC, Shi GQ, Namoto K, Bernal F. Chem. Commun. 1998; 1757
• 8b Galbo FL, Occhiato EG, Guarna A, Faggi C. J. Org. Chem. 2003; 68: 6360
• 9a Ebran JP, Hansen AL, Gøgsig TM, Skrydstrup T. J. Am. Chem. Soc. 2007; 129: 6931
• 9b Lindhardt AT, Skrydstrup T. Chem. Eur. J. 2008; 14: 8756
• 10 Kappe CO. Eur. J. Med. Chem. 2000; 35: 1043
• 11a Deres K, Schröder CH, Paessens A, Goldmann S, Hacker HJ, Weber O, Krämer T, Niewöhner U, Pleiss U, Stoltefuss J, Graef E, Koletzki D, Masantschek RN. A, Reimann A, Jaeger R, Groß R, Beckermann B, Schlemmer K.-H, Haebich D, Rübsamen-Waigmann H. Science 2003; 299: 893
• 11b Lengar A, Kappe CO. Org. Lett. 2004; 6: 771
• 11c Sing K, Arora D, Poremsky E, Lowery J, Moreland RS. Eur. J. Med. Chem. 2009; 44: 1997
• 12a Atwal KS, Swanson BM, Unger SE, Floyd DM, Moreland S, Hedberg A, Reilly BC. O. J. Med. Chem. 1991; 34: 806
• 12b Singh K, Arora D, Singh K, Singh S. Mini-Rev. Med. Chem. 2009; 9: 95
• 13a Undheim K, Benneche T In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR, Rees CW, Scriven EF. V, McKillop A. Pergamon; Oxford: 1996: 93
• 13b Joule JA, Mills K In Heterocyclic Chemistry . Blackwell Science Ltd; Cambridge: 2000. 4th ed. 194
• 13c Lagoja IM. Chem. Biodiversity 2005; 2: 1
• 13d Michael JP. Nat. Prod. Rep. 2005; 22: 627
• 13e Hill MD, Movassaghi M. Chem. Eur. J. 2008; 14: 6836
• 14a Kappe CO, Roschger P. J. Heterocycl. Chem. 1989; 26: 55
• 14b Matloobi M, Kappe CO. ACS Comb. Sci. 2007; 9: 275
• 14c Gholap AR, Toti KS, Shirazi F, Deshpande MV, Srinivasan KV. Tetrahedron 2008; 64: 10214
• 15a Watanabe M, Koike H, Ishiba T, Okada T, Seo S, Hirai K. Bioorg. Med. Chem. 1997; 5: 437
• 15b Gayo LM, Suto MJ. Tetrahedron Lett. 1997; 38: 211
• 15c Obrecht D, Abrecht C, Grieder A, Villalgordo JM. Helv. Chim. Acta 1997; 80: 65
• 15d Kim DC, Lee YR, Yang B.-S, Shin KJ, Kim DJ, Chung BY, Yoo KH. Eur. J. Med. Chem. 2003; 38: 525
• 15e Kasparec J, Adams JL, Sisko J, Silva DJ. Tetrahedron Lett. 2003; 44: 4567
• 15f Vanden Eynde JJ, Labuche N, Van Haverbeke Y, Tietze L. ARKIVOC 2003; (xv): 22
• 16a Wang X.-C, Yang G.-J, Quan Z.-J, Ji P.-Y, Liang J.-L, Ren R.-G. Synlett 2010; 1657
• 16b Wang X.-C, Yang G.-J, Jia X.-D, Zhang Z, Da Y.-X, Quan Z.-J. Tetrahedron 2011; 67: 3267
• 16c Quan Z.-J, Jing F.-Q, Zhang Z, Da Y.-X, Wang X.-C. Eur. J. Org. Chem. 2013; 7175
• 16d Chen X, Quan Z.-J, Wang X.-C. Appl. Organomet. Chem. 2015; 29: 296
• 17a Quan Z.-J, Lv Y, Jing F.-Q, Jia X.-D, Huo C.-D, Wang X.-C. Adv. Synth. Catal. 2014; 356: 325
• 17b Du B.-X, Quan Z.-J, Da Y.-X, Zhang Z, Wang X.-C. Adv. Synth. Catal. 2015; 357: 1270
• 18 Xing T, Zhang Z, Da Y.-X, Quan Z.-J, Wang X.-C. Asian J. Org. Chem. 2015; 4: 538
• 19 We can obtain satisfactory results via the CuSO₄·5H₂O-catalyzed NaAsc-mediated cross-coupling of pyrimidin-2-yl phosphates 3 with amides 4. Using this method, we have successfully achieved the further functionalization of pyrimidin-2-yl phosphate 3k (Scheme 4).