An application of borane as a protecting group for pyridine

Journal of Organic Chemistry

Volumn 73, Issue 17, 2008, Pages 6899-6901

  Zajac, Matthew A ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACIDS; ESTERS; HYDROCARBONS; ORGANIC COMPOUNDS;

ACIDIC CONDITIONS; CHEMICAL EQUATIONS; PROTECTING GROUPS;

PYRIDINE;

(3 BROMOPROPYL)(1 BOROPYRIDIN 2 YL)AMINE; BORANE DERIVATIVE; ESTER; PYRIDINE; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; SAPONIFICATION;

ALKYLATION; BORANES; BORON COMPOUNDS; CYCLIZATION; ESTERS; HYDROGEN-ION CONCENTRATION; MODELS, CHEMICAL; PYRIDINES;

EID: 51549102386     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo801040m     Document Type: Article

References (23)

1. Five membered systems: (a) Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W. Tetrahedron 2006, 62, 285.
2. (b) Copp, F. C.; Timmis, G. M. J. Chem. Soc. 1955, 2021.
3. Six membered system: (a) Klauschenz, E.; Hagan, V.; Wiesner, B.; Hagan, A.; Reck, G.; Krause, E. G. Eur. J. Med. Chem. 1994, 29, 175.
4. (b) Mandereau, J.; Xuong, E. N.T.; Reynaud, P. Eur. J. Med. Chem. 1974, 9, 344.
5. (a) Miller, W. H.; Alberts, D. P.; Bhatnager, P. K.; Bondinell, W. E.; Callahan, J. F.; Calvo, R. R.; Cousins, R. D.; Erhard, K. F.; Heerding, D. A.; Keenan, R. M.; Kwon, C.; Manley, P. J.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas, I. N.; Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.; Hwang, S.-M.; James, I. E.; Lark, M. W.; Rieman, D. J.; Glomic, J. C.; Stroup, G. B.; Azzarano, L. M.; Salyers, K. L.; Smith, B. R.; Ward, K. W.; Johanson, K. O.; Huffman, W. F. J. Med. Chem. 2000, 43, 22.
6. (b) Wallace, M. D.; McGuire, M. A.; Yu, M. S.; Goldfinger, L.; Liu, L.; Dai, W.; Shilcrat, S. Org. Process Res. Dev. 2004, 8, 738.
7. Tupin, T.; Raynaud, P.; Delaby, R. Bull. Soc. Chim. Fr. 1957, 721.
8. In our hands, Mitsunobu conditions with 5, as in the following references, provided 6 with only trace amounts of alkylation product:(a) Leonard, K.; Pan, W.; Anaclerio, B.; Gushue, J. M.; Guo, Z.; DesJarlais, R. L.; Chaikin, M. A.; Lattanze, J.; Crysler, C.; Manthey, C. L.; Tomczuk, B. E.; Marugan, J. J. Bioorg. Med. Chem. Lett. 2005, 15, 2679.
9. 1H NMR data of 5 that do not match our data.
10. It is interesting to note that treatment of 4 with 6 under acidic or basic conditions gives no trace of desired product. For 6 see ref 2b.
11. Shilcrat, S. Unpublished results, HCl salt: An exotherm was observed in the range of 134.1-185.4°C with an onset temperature of 136.1°C and a heat of reaction of-746.7 J/g. Freebase: Two exotherms were observed with the first in the range of 42.7-108.1°C with an onset of 46.6°C and a heat of reaction of-867.6 J/g. The second exotherm was in the range of 125.9-188°C with an onset of 146.6°C and a heat of reaction of-6672.4 J/g.
12. Monahan, S. D.; Vedejs, E. J. Org. Chem. 1996, 61, 5192.
13. Zajac, M. A.; Vedejs, E. Org. Lett. 2001, 3, 2451.
14. Shapland, P.; Vedejs, E. J. Org. Chem. 2006, 71, 6666.
15. For examples of nonheteroaromatic amine borane complexes see:(a) Schwartz, M. A.; Rose, B. F.; Vishnuvajjala, B. J. Am. Chem. Soc. 1973, 95, 612.
16. (b) White, J. D.; Amedio, J. C.; Gut, S.; Jayasinghe, L. J. Org. Chem. 1989, 54, 4268.
17. (c) Ferey, V.; Vedrenne, P.; Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 1996, 61, 7244.
18. (d) Carboni, B.; Monnier, L. Tetrahedron 1999, 55, 1197.
19. (e) Blakemorene, P. R.; Kim, S. K.; Schulze, V. K.; White, J. D.; Yokochi, A. F. T. J. Chem. Soc., Perkin Trans. I 2001, 1831.
20. For an example of an α-amino pyridine borane complex see: (f) Tang, P. W.; Williams, J. M. Carbohydr. Res. 1985, 136, 259.
21. See the Supporting Information for spectral data of 13 and 14.
22. It seems that the rate of reaction of borane at the pyridine nitrogen to give 11 is about as fast as the reaction with the hydroxyl function of 5. If the reaction occurs at the hydroxy site, either or both of the following two compounds could be present and would give 5 after aqueous workup: (Chemical Equation Presented)
23. The best cost comparison that can be made between the previous route (Scheme 3) and the new borane route is in the price difference of the starting materials on a kilogram scale. Both routes use 4, thionyl bromide, and 3-aminopropanol, which can be left out of consideration. The 2007 pricing for 2-chloropyridine N-oxide is about $400/mol whereas the price of 2-chloropyridine is about $5/mol and that of borane dimethylsulfide is about $21/mol.