Synthesis of aminopyridines via an unprecedented nucleophilic aromatic substitution of cyanopyridines

Tetrahedron Letters

Volumn 45, Issue 12, 2004, Pages 2667-2669

  Penney, Jonathan M ^a  

^a DSM Pharmaceutical Products   (Netherlands)

Author keywords

Amination; Cyanopyridine

Indexed keywords

2 AMINOPYRIDINE DERIVATIVE; 4 AMINOPYRIDINE DERIVATIVE; AMINOPYRIDINE DERIVATIVE; PYRIDINE DERIVATIVE;

ARTICLE; REACTION ANALYSIS; STRUCTURE ANALYSIS; SUBSTITUTION REACTION; SYNTHESIS;

EID: 1542272287     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2004.01.120     Document Type: Article

References (22)

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6. Miller J.A., Dankwardt J.W., Penney J.M. Synthesis. 11:2003;1643.
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8. Miller J.A. Tetrahedron Lett. 42:2001;6991.
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10. These results were obtained by GC analysis of a reaction sample (containing tridecane as an internal standard) quenched in a mixture of 1 M sodium citrate (aq) and MTBE.
11. Nucleophiles preferentially react with the 2- and 4-positions of pyridine electrophiles, see: Sugimori A., Furihata T., Mikayama S., Yoshida M., Nakanishi Y. Bull. Chem. Soc. Jpn. 55:1982;2906.
12. Wagenknecht P.S., Penney J.M., Hembre R.T. Organometallics. 22:2003;1180.
13. Le Gall E., Gosmini C., Nédélec J.-Y., Périchon J. Tetrahedron. 57:2001;1923.
14. Ref. 4.
15. Polymerization, oligomerization, and cyclotrimerization of organonitriles are known to occur in the presence of various metal salts, see: Kabanov V.A., Zubov V.P., Kovaleva V.P., Kargin V.A. J. Polym. Sci. C. 4:1964;1009.
16. Stability of the cyanopyridine amidines toward aqueous workup is variable, in contrast to amidines derived from simple benzonitriles, making quantification of the amidine concentration during the course of the reaction troublesome.
17. 3 (48% yield, 71 h), KF (72% yield, 71 h), no modifier (34% yield, 94 h).
18. For recent reviews, see: Hartwig J.F. Angew. Chem., Int. Ed. 37:1998;2046.
19. Muci A.R., Buchwald S.L. Top. Curr. Chem. 219:2002;131.
20. 2003-2004 Aldrich prices for 2-cyanopyridine ($13/mol), 2-chloropyridine ($16/mol), 2-bromopyridine ($68/mol), 2-iodopyridine ($2500/mol).
21. Representative procedure with CsF: (4-pyrrolidinopyridine, entry 2). A 0°C solution of pyrrolidine (0.334 mL, 0.284 g, 4.0 mmol, Aldrich) in 4 mL of THF was treated with n-butyllithium (1.6 mL, 4.0 mmol, 2.5 M in hexanes) and allowed to warm to room temperature for 15 min. The reaction solution was cooled to 0°C and a solution of 4-cyanopyridine (0.244 g, 2.0 mmol) and tridecane (0.244 mL, 0.184 g, 1.0 mmol, internal GC standard) in THF (1 mL) was added. After warming to room temperature the entire reaction mixture was added to solid cesium fluoride (0.456 g, 3.0 mmol) and heated to 65°C for 2 h. A sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.6 mmol (80% yield) of 4-pyrrolidinopyridine.
22. Representative procedure without CsF: (4-piperidinopyridine, entry 1). A 0°C solution of piperidine (0.396 mL, 0.341 g, 4.0 mmol, Aldrich) in 4 mL of THF was treated with n-butyllithium (1.6 mL, 4.0 mmol, 2.5 M in hexanes) and allowed to warm to room temperature for 15 min. The reaction solution was cooled to 0°C and a solution of 4-cyanopyridine (0.244 g, 2.0 mmol) and tridecane (0.244 mL, 0.184 g, 1.0 mmol, internal GC standard) in THF (1 mL) was added and the mixture was heated to 65°C for 4 h. A sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.83 mmol (92% yield) of 4-piperidinopyridine.