A chemoselective aniline-chloropyrimidine coupling in a competing electrophilic environment

Tetrahedron Letters

Volumn 49, Issue 1, 2008, Pages 102-105

  Choudhury, Anusuya ^a   Chen, Hongfeng ^a   Nilsen, Christopher N ^a   Sorgi, Kirk L ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Acid catalyzed coupling; Chloropyrimidine; Diaminopyrimidines

Indexed keywords

4,6 DIAMINOPYRIMIDINE 5 CARBALDEHYDE; ALDEHYDE; ANILINE; AROMATIC COMPOUND; CHLOROPYRIMIDINE; IMINE; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; ELECTROCHEMISTRY; REACTION ANALYSIS; SUBSTITUTION REACTION; SYNTHESIS;

EID: 36549034715     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2007.11.009     Document Type: Article

References (17)

1. Brown D.J. The Pyrimidines (1994), Interscience Publishers, New York
2. Eicher T., and Hauptmann S. The Chemistry of Heterocycles (2003), Wiley-VCH, Weinheim
3. Hurst D.T. An Introduction to Chemistry and Biochemistry of Pyrimidines, Purines and Pteridines (1980), Wiley, Chichester
4. Brown D.J. In: Katritzky A.R., and Rees C.W. (Eds). Comprehensive Heterocyclic Chemistry Vol. 3 (1984), Pergamon Press, Oxford Chapter 2.13
5. Murray M.C., and Perkins M.E. Annu. Rep. Med. Chem. 31 (1996) 141-150 and references cited therein
6. Peng Z., Journet M., and Humphrey G. Org. Lett. 8 (2006) 395-398 and references cited therein
7. Gomtsyan A., Didomenico S., Lee C.-H., Matulenko M.A., Kim K., Kowaluk E.A., Wismer C.T., Mikusa J., Yu H., Kohlhaas K., Jarvis M.F., and Bhagwat S.S. J. Med. Chem. 45 (2002) 3639-3648
8. Xu G., Lee L., Connolly P.J., Middleton S.A., Emanuel S.L., Hughes T.V., Abad M.C., Karnachi P.S., and Wetter S.K. Chem. Abstr. 147 (2007) 189189 (WO 07081630, July 19, 2007)
9. Personal communication from drug discovery chemists. Reaction of 1 and 2 in DMSO at 100 °C (without using TEA) resulted in 6 min: 12% 3, 39% 4 and 2% 5. In 60 min: 10% 3, 46% 4, 20% 5 were generated.
10. Successful nucleophilic substitution on pyrimidine ring has been done in alcohols as the solvents. Hartung C.G., Backes A.C., Felber B., Missio A., and Philipp A. Tetrahedron 62 (2006) 10055-10064
11. Maggiolo A., Phillips A.P., and Hitchings G.H. J. Am. Chem. Soc. 73 (1951) 106-107
12. 2 under refluxing ethanol condition to generate the anil. Delia T.J., Wilcox T.M., and Otteman R.R. J. Heterocycl. Chem 16 (1979) 1647
13. 2O, TEA, 65 °C, 5 min, 84% yield: Hoffmann-La Roche, Br. Pat. 953,876, 1964; Chem. Abstr. 1942, 61, 29110 a.
14. Chapman N.B., and Rees C.W. J. Chem. Soc. (1954) 1190-1196
15. Vanderplas H.C. Acc. Chem. Res. 11 (1978) 462-468
16. 2O (0.1 mL). The mixture is heated to 70-75 °C and is held at that temperature for ∼4-6 h. After cooling naturally to ambient temperature, the product is filtered. The reaction flask is rinsed with 0.5 mL of acetonitrile twice and the rinse is used to wash the filter cake. The filter cake is washed with 0.5 mL of fresh acetonitrile. It is sucked dry under vacuum with nitrogen for 15 min. The product is dried under lab vacuum (25 mm/Hg) at ∼50 °C to a constant weight.
17. This result will be communicated separately.