Mild and practical method for the α-arylation of nitriles with heteroaryl halides

Journal of Organic Chemistry

Volumn 70, Issue 24, 2005, Pages 10186-10189

  Klapars, Artis ^a   Waldman, Jacob H ^a   Campos, Kevin R ^a   Jensen, Mark S ^a   McLaughlin, Mark ^a   Chung, John Y L ^a   Cvetovich, Raymond J ^a   Chen, Cheng Yi ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HALOGEN COMPOUNDS; NEGATIVE IONS; REACTION KINETICS; THERMAL EFFECTS; TRANSITION METALS;

ARYLATION; HALIDES; MILD REACTION; NITRILES;

CYANIDES;

2 BROMOPYRIDINE; 2 PHENYLBUTYRONITRILE; 2,5 DIBROMOPYRIDINE; 3 BROMOPYRIDINE; BENZOTHIAZOLE; BENZOXAZOLE DERIVATIVE; BROMIDE; CYCLOPROPANE; CYCLOPROPANE CARBONITRILE; FLUORIDE; HALIDE; HETEROCYCLIC COMPOUND; ISOQUINOLINE; NITRILE; PALLADIUM; PYRAZINE; PYRIDAZINE; PYRIDINE DERIVATIVE; TRANSITION ELEMENT; UNCLASSIFIED DRUG;

ARTICLE; ARYLATION; CATALYSIS; CRYSTALLIZATION; DECOMPOSITION; DIMERIZATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; REACTION ANALYSIS; STEREOSPECIFICITY; TEMPERATURE;

ALKYLATION; HYDROCARBONS, HALOGENATED; MOLECULAR STRUCTURE; NITRILES; STEREOISOMERISM;

EID: 28044437773     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo051737f     Document Type: Article

References (22)

1. (a) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051.
2. (b) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
3. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
4. (d) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330.
5. Skerlj, R. T.; Bogucki, D.; Bridger, G. J. Synlett 2000, 1488.
6. (a) Sperber, N.; Papa, D.; Schwenk, E.; Sherlock, M.; Fricano, R. J. Am. Chem. Soc. 1951, 73, 5752.
7. (b) Carver, D. R.; Greenwood, T. D.; Hubbard, J. S.; Komin, A. P.; Sadcheva, Y. P.; Wolfe, J. F. J. Org. Chem. 1983, 48, 1180.
8. (a) Loupy, A.; Philippon, N.; Pigeon, P.; Galons, H. Heterocycles 1991, 32, 1947.
9. (b) Sleevi, M. C.; Cale, A. D. Jr.; Gero, T. W.; Jaques, L. W.; Welstead, W. J.; Johnson, A. F.; Kilpatrick, B. F.; Demian, I.; Nolan, J. C.; Jenkins, H. J. Med. Chem. 1991, 34, 1314.
10. Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712.
11. Displacement of halo substituents at α- and γ-positions of pyridines via an addition-elimination mechanism is well precedented with other nucleophiles. See: Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry; Chapman and Hall: London, 1995; p 82.
12. (a) Zoltewicz, J. A.; Smith, C. L. Tetrahedron 1969, 25, 4331.
13. (b) Mallet, M.; Queguiner, G. Tetrahedron 1982, 38, 3035.
14. (c) Connon, S. J.; Hegarty, A. F. J. Chem. Soc., Perkin Trans. 1 2000, 1245.
15. We expect only 50% deuterium incorporation because hexamethyldisilazane, which was formed in the NaHMDS deprotonation step, contains an exchangeable proton.
16. The concave diastereomer of 1 provided comparable results in the deprotonation-deuteration experiments.
17. tBuCN, THF.
18. nBuLi at -78 °C to rt, LiTMP at -78 °C to rt.
19. The same product 3 was obtained from either 2b and 2d, which is consistent with the 2-halo and not the 5-bromo substituent being displaced on the pyridine ring.
20. Only one example of a heteroaryl fluoride was reported by Caron.
21. The lowered acidity of cyclopropanecarbonitrile, caused by the nonplanar nature of the carbanion, can be invoked to explain the reactivity difference between cyclopropanecarbonitrile and isobutyronitrile. See: (a) Peerboom, R. A. L.; de Koning, L. J.; Nibbering, N. M. M. J. Am. Soc. Mass Spectrom. 1994, 5, 159.
22. (b) Juchnovski, I. N.; Tsenov, J. A.; Binev, I. G. Spectrochim. Acta A 1996, 52, 1145. However, we were able to show that the anion of the functionalized cyclopropanecarbonitrile 1 could be generated even at -78 °C using NaHMDS. Interference from an unidentified decomposition pathway thus appears to be a more likely explanation for the poor reactivity of cyclopropanecarbonitriles in these α-arylation reactions.