New Insights into the Copper-Catalyzed Alkylation of Grignard and Organolithium Reagents

Abstract

Until now, it was considered that the copper-catalyzed alkylation of Grignard reagents gave good yields only in the presence of ligands, such as NMP or 1-phenylpropyne. We show herein that a slow and regular addition of the Grignard reagent provides similar results. With secondary and tertiary alkyl Grignard reagents, we disclosed that the presence of benzonitrile (10 mol%), a very simple ligand, is very efficient. The copper-catalyzed alkylation of organolithium compounds was also studied.

Key words

alkylations - copper - cross-coupling - Grignard reactions - organometallic reagents

References and Notes

• 1a Posner GH. Organic Reactions   Vol. 22:  Dauben WG. John Wiley and Sons; New York: 1975.  p.253-400  
• 1b Lipshutz BH. Sengupta S. Organic Reactions   Vol. 41:  Paquette LA. John Wiley and Sons; New York: 1992.  p.135-590  
• 1c Erdik E. Tetrahedron  1984,  40:  641 
• 2 Tamura M. Kochi JK. Synthesis  1971,  93:  303 ; see also ref. 1
• 3 Cahiez G. Chaboche C. Jézéquel M. Tetrahedron  2000,  56:  2733 
• 4 Terao J. Todo H. Begum SA. Kuniyasu H. Kambe N. Angew. Chem. Int. Ed.  2007,  46:  2086 
• 6a Whitesides GM. Fischer WF. San Filippo J. Bashe RW. House HO. J. Am. Chem. Soc.  1969,  91:  4871 
• 6b Fouquet G. Schlosser M. Angew. Chem., Int. Ed. Engl.  1974,  13:  82 ; see also ref. 1
• 7a Kharasch MS. Reinmuth O. Grignard Reactions of Nonmetallic Substances   Prentice-Hall; New York: 1954. 
• 7b Beletskaya IP. Artamkina GA. Reutov OA. Russian Chem. Rev.  1976,  45:  330 
• 7c Knochel P. Dohle W. Gommermann N. Kneisel FK. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4303 
• 9a

  See ref. 7c, pp. 4315.

• 9b For a recent report on a synthetically useful Mg-X exchange from alkyl halides and alkyl Grignard reagents, see: Rauhut CB. Vu VA. Fleming FF. Knochel P. Org. Lett.  2008,  10:  1187 
• 10a Lipshutz BH. Wilhelm RS. Zozlowski JA. Tetrahedron  1984,  40:  5005 
• For a discussion on the formation of higher-order magnesio cuprates according to the ratio RMgX/CuX, see: ref. 1b, pp. 184. For a comparison of the reactivity of high order magnesiocuprates and lower-order magnesiocuprates, see:
• 10b Westmijze H. Kleijn H. Vermeer P. Recl. Trav. Chim. Pays Bas  1980,  98 
• Higher-order lithio cuprates have been more studied that their magnesium counterparts, see for instance:
• 10c Ashby EC. Lin JJ. Watkins JJ. J. Org. Chem.  1977,  42:  1099 
• 10d Ashby EC. Watkins JJ. J. Am. Chem. Soc.  1977,  99:  5312 
• 10e Clive DLJ. Farina V. Beaulieu PL. J. Org. Chem.  1982,  47:  2572 
• 10f Bertz SH. Dabbagh G. J. Am. Chem. Soc.  1988,  110:  3668 
• 12a Normant JF. Cahiez G. Chuit C. Alexakis A. Villiéras J. J. Organomet. Chem.  1972,  40:  C49 
• 12b Normant JF. Cahiez G. Chuit C. Villiéras J. Tetrahedron Lett.  1973,  2407 
• 12c Normant JF. Cahiez G. Chuit C. Villiéras J. J. Organomet. Chem.  1973,  54:  C53 
• 12d Normant JF. Cahiez G. Bourgain M. Chuit C. Villiéras J. Bull. Soc. Chim. Fr.  1974,  1656 
• 12e Normant JF. Cahiez G. Chuit C. Villiéras J. J. Organomet. Chem.  1974,  77:  269 
• 12f Normant JF. Cahiez G. Chuit C. Villiéras J. J. Organomet. Chem.  1974,  77:  281 
• 13 Alexakis A. Normant JF. Synthesis  1981,  841 
• 14a Wakefield BJ. The Chemistry of Organolithium Compounds   Pergamon; Oxford: 1974. 
• 14b Organolithium Methods   Academic Press; London: 1988. 
• 15 Cristol SJ. Overhults WC. Meek JS. J. Am. Chem. Soc.  1951,  73:  813 
• 16 Cristol SJ. Ragsdale JW. Meek JS. J. Am. Chem. Soc.  1951,  73:  810 
• 17a Linstrumelle G. Tetrahedron Lett.  1974,  3809 
• 17b Millon J. Lorne R. Linstrumelle G. Synthesis  1975,  434 
• 17c See also: Cahiez G. Bernard D. Normant JF. Synthesis  1976,  245 

5

See ref. 1b, pp. 141-142 and references quoted therein.

8

See ref. 7a, pp. 1052-1053.

11

See ref. 1a, pp 266-267 and Table IIA.