One-pot synthesis of azaindoles via palladium-catalyzed α-heteroarylation of ketone enolates

Journal of Organic Chemistry

Volumn 75, Issue 15, 2010, Pages 5316-5319

  Spergel, Steven H ^a   Okoro, Danielle R ^a,b   Pitts, William ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b CITY UNIVERSITY OF NEW YORK   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZAINDOLES; HETEROARYLATION; KETONE ENOLATES; ONE-POT METHOD; ONE-POT SYNTHESIS;

PALLADIUM;

KETONES;

HETEROCYCLIC COMPOUND; INDOLE DERIVATIVE; KETONE DERIVATIVE; PALLADIUM; PYRIDINE DERIVATIVE;

ARTICLE; ARYLATION; CATALYST; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; ONE POT SYNTHESIS; REACTION ANALYSIS;

AZA COMPOUNDS; CATALYSIS; INDOLES; KETONES; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; PALLADIUM;

EID: 77955135684     PISSN: 00223263     EISSN: 15206904     Source Type: Journal    
DOI: 10.1021/jo100623d     Document Type: Article

References (27)

1. Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron 2007, 63, 1031
2. Song, J. J.; Reeves, J., T.; Gallou, F.; Tan, Z.; Yee, N., K.; Senanayake, C., H. Chem. Soc. Rev. 2007, 36, 1120 (further review)
3. Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689
4. Kempson, J.; Guo, J.; Das, J.; Moquin, R. V.; Spergel, S. H.; Watterson, S. H.; Langevine, C. M.; Dyckman, A., J.; Burke, J., R.; Taylor, T.; McIntyre, K.; Barrish, J. C.; Pitts, W. J. Bioorg. Med. Chem. Lett. 2009, 19, 2646-2649
5. Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274 Attempts at the direct arylation of the H-compound were conducted in 2005, prior to the retraction of this paper in: J. Am. Chem. Soc. 2006, 128, 8364. We did not explore direct C-2 arylation of N-substituted azaindoles for which there is precedence. For example, see: Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897
6. Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357
7. Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689
8. Park, S. S.; Choi, H.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron. Lett. 1998, 48, 221
9. Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2000, 39, 2488
10. This result was consistent with previous literature reports; see: Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org. Chem. 1992, 57, 6995
11. Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676
12. Nazaré, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526
13. Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152
14. This reaction proceeded in approximately 30% yield for ethyl pyruvate. We subjected a mixture of 2 (I or Br) and a substituted acetophenone to the Nazare conditions; however, none of the desired product formed. No improvements were seen when microwave conditions were employed. (9) Control experiments with 2 and a substituted acetophenone in the presence of dehydrating reagents such as p -TsOH, (10) magnesium sulfate, or 4A molecular sieves at elevated temperature failed to demonstrate the formation of the anticipated enamine, although removal of the Boc protecting group was evident under forcing conditions.
15. Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 15, 2571
16. Blanche, Y.; Sinibaldi-Troin, M.-E.; Hichour, M.; Benezech, V.; Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P. Tetrahedron 1999, 55, 1959
17. After this research was conducted, a thorough search of the literature identified that this methodology had been applied to indoles. See: Cho, C. S.; Kim, J. H.; Kim, T.-J.; Shim, S. C. J. Chem. Res. 2004, 9, 630
18. For reviews, see: Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953
19. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234
20. Fox, J. M.; Huang, X.; Chieffi, A. J. Am. Chem. Soc. 2000, 122, 1360
21. We cannot disclose the exact structure of 5; however, the aryl ring contains no functionality which might interfere with the reaction.
22. Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053 (commercially available from Strem Chemical Co. catalog no. 46-0039)
23. For a review of N-heterocyclic carbene catalysis, see: Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440
24. Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211
25. Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549
26. For a successful multistep strategy to provide all 2-aryl-substituted azaindole isomers, see: Kuzmich, D.; Mulrooney, C. Synthesis 2003, 11, 1671
27. Parcerisa, J.; Romero, M.; Pujol, M. D. Tetrahedron 2008, 64, 500