[17624-36-1]  · C5H4LiN  · 2-Lithiopyridine  · (MW 85.03)

(convenient 2-pyridinyl building block; can react with a variety of electrophiles1)

Preparative Methods: lithiation of pyridine with simple lithio bases is difficult; addition across the C=N bond predominates with alkyllithiums,2 whereas lithium amides give rise to bipyridyls.3 However, pyridine can be regioselectively metalated by treatment with a complex of n-Butyllithium-Potassium t-Butoxide under carefully controlled conditions (eq 1).4 Use of 2-3 equiv of the base is necessary and the excess has to be destroyed by reaction with the solvent (THF) at -25 °C prior to addition of the electrophile. Ortho deprotonation of pyridine can be facilitated by formation of a complex with hexafluoroacetone,5 tricarbonylchromium(0),6 or, more simply, with a Lewis acid like Boron Trifluoride (eq 2).7 Another popular approach to 2-lithiopyridine utilizes an exchange reaction of 2-bromopyridine (eq 3).8 The choice of method for the preparation of this reagent can depend upon the electrophile with which it is to be used. For instance, BF3-complexed 2-lithiopyridine gives excellent yields with carbonyl compounds but reacts poorly with alkyl halides.7

Handling, Storage, and Precautions: should be prepared and handled in a moisture-free inert atmosphere and used immediately. Use in a fume hood.

Reaction with Electrophiles.

Reaction of 2-lithiopyridine with aldehydes and ketones gives a-pyridinyl alcohols cleanly (eq 4),7 whereas use of carboxylic acid derivatives leads to the corresponding ketones (eq 5).9 Treatment of the reagent with Copper(I) Iodide promotes 1,4-addition with a,b-unsaturated carbonyl compounds (eq 6).8b

Other electrophiles which react with 2-lithiopyridine include MeOD (eq 7),4a Chlorotrimethylsilane (eq 8),4a Iodine,4a Dimethyl Disulfide,4a 1,2-dibromo-1,1,2,2-tetrachloroethane (eq 10),5 Iodomethane (eq 9),6 and methyl benzoate.8a

Related Reagents.

Polar solvents favor 4-metalation of pyridine by the BuLi-t-BuOK mixed base.4 Both 2- and 3-lithiopyridines can be obtained from the corresponding bromides through exchange reaction with BuLi.8 Pyridines carrying ortho directing groups like alkoxy,10 fluoro,11b chloro,11 bromo,11 carboxamido,12 oxazoline,13 pivaloylamino,14 and diethylcarbamate15 can be lithiated regioselectively.

1. (a) Comins, D. L.; O'Connor, S. Adv. Heterocycl. Chem. 1988, 44, 218. (b) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztazn, J. Adv. Heterocycl. Chem. 1991, 52, 187. (c) Rewcastle, G. W.; Katritzky, A. R. Adv. Heterocycl. Chem. 1993, 56, 226.
2. (a) Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon: New York, 1974; pp 112-116. (b) Francis, R. F.; Davis, W.; Wisener, J. T. JOC 1974, 39, 59.
3. (a) Kauffmann, T. AG(E) 1979, 18, 1. (b) Clarke, A. J.; McNamara, S.; Meth-Cohn, O. TL 1974, 2373. (c) Newkome, G. R.; Hager, D. C. JOC 1982, 47, 599.
4. (a) Brandsma, L.; Verbeek, J. JOC 1984, 49, 3857. (b) Verbeek, J.; George, A. V. E.; Jong, R. L. P.; Brandsma, L. CC 1984, 257.
5. Taylor, S. L.; Lee, D. Y.; Martin, J. C. JOC 1983, 48, 4156.
6. Davies, S. G.; Shipton, M. R. JCS(P1) 1991, 501.
7. Kessar, S. V.; Singh, P.; Singh, K. N.; Dutt, M. CC 1991, 570.
8. (a) Parham, W. E.; Piccirilli, R. M. JOC 1977, 42, 257. (b) Malmberg, H.; Nilsson, M. T 1982, 38, 1509.
9. Miao, C. K.; Sorcek, R.; Jones, P. J. TL 1993, 34, 2259.
10. (a) Comins, D. L.; LaMunyon, D. H. TL 1988, 29, 773. (b) Marsais, F.; Le Nard, G.; Queguiner, G. S 1982, 235.
11. (a) Comins, D. L.; Myoung, Y. C. JOC 1990, 55, 292. (b) Marsais, F.; Queguiner, G. T 1983, 39, 2009. (c) Gribble, G. W.; Saulnier, M. G. TL 1980, 21, 4137. (d) Marsais, F.; Laperdrix, B.; Güngör, T.; Mallet, M.; Queguiner, G. JCR 1982, 278.
12. Epsztajn, J.; Bieniek, A.; Brzezinski, J. Z.; Jozwiak, A. TL 1983, 24, 4735.
13. Meyers, A. I.; Gabel, R. A. JOC 1982, 47, 2633.
14. Turner, J. A. JOC 1983, 48, 3401.
15. Miah, M. A. J.; Snieckus, V. JOC 1985, 50, 5436.

Satinder V. Kessar & Paramjit Singh

Panjab University, Chandigarh, India

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