Lithium naphthalenide induced reductive alkylation of α-cyano ketones. A general method for regiocontrol of α,α-dialkylation of ketones

Tetrahedron Letters

Volumn 39, Issue 24, 1998, Pages 4183-4186

  Liu, Hsing Jang ^a   Zhu, Jia Liang ^a   Shia, Kak Shan ^b  

^a UNIVERSITY OF ALBERTA   (Canada)

^b NATIONAL TSING HUA UNIVERSITY   (Taiwan)

Author keywords

Alkylation; Carbonyl compounds; Regiocontrol

Indexed keywords

KETONE DERIVATIVE; LITHIUM DERIVATIVE; NAPHTHALENE DERIVATIVE;

ALKYLATION; ARTICLE; DRUG SYNTHESIS; REDUCTION;

EID: 0032507933     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)00780-1     Document Type: Article

References (20)

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10. 10. Saito, S.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 611-612.
11. 11. Because of the nature of the reaction, one of the alkyl groups introduced must be methyl group by the use of this procedure.
12. 12. The experimental procedures of these reactions are quite laborious and difficult to handle (especially in small scale preparations) as handling of active metal and low boiling solvent (liquid ammonia) and its subsequent removal prior to the alkylation step are required.
13. 13. Coates, R. M.; Shah, S. K.; Mason, R. W. J. Am. Chem. Soc. 1982, 104, 2198-2208.
14. 14. Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am. Chem. Soc. 1984, 106, 6006-6015.
15. 15. Seishi, T.; Hiroyuki, Y. Yakugaku Zasshi, 1959, 79, 467-470.
16. 16. Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011-5014 and references cited therein.
17. 17. Yields are for isolated yields and unoptimized.
18. 18. Take a more difficult case as an example: treatment of 2-cyanocyclohexanone with lithium hydride (3 eq.) and methyl iodide (4 eq.) in tetrahydrofuran (40 mL/g of the starting ketone) at room temperature for 24 h under an atmosphere of argon gave ketone 4 and the corresponding O-methylation product in 70% and 6% yield, respectively after the usual work-up and Chromatographic purification (silica gel, 10% ethyl acetate in hexanes). A substantially larger proportion of the O-methylation product was formed using the other reagents (vide supra).
19. 19. For preparation of LN as a stock solution, see: Liu, H. J.; Yip, J.; Shia, K. S. Tetrahedron Lett. 1997, 38, 2253-2256.
20. 20. In theory, the reductive decyanation requires only 2 eq. of LN. In practice, however, the use of less than 5 eq. (e.g., 4 eq.) of the reagent often resulted in incompletion of the reaction under the specified conditions which were found to more satisfactory than other conditions attempted (high temperature, longer reaction time, etc.). The amount of the alkylating agent was adjusted accordingly to cover the expected side reactions with cyanide and with the excess LN (reductive dehalogenation, alkylation of the ensuing alkyllithium and of the anionic species derived from naphthalene).