Highly Regioselective Alkylation at the More Hindered γ-Site of Unsymmetrical Ketones by Use of Their Potassium Enolates. A Comparative Study with Lithium Enolates

Abstract

Fax 02 35 52 24 11; Lucette.Duhamel@univ-rouen.fr Abstract: Alkylation of regioisomeric potassium enolates 4 and 6 obtained from corresponding silyl enol ethers 2 and 3 occurs at the most substituted site affording ketones 8. Alkylation of corresponding lithium enolates 5 and 7 occurs at the expected site affording ketones 8 or 9. As an application the one pot synthesis of spiroketones 13 from silyl enol ethers 12 is described.Alkylation of enolates is a very useful reaction to form carbon-carbon bonds. 1 It is well-known that starting from an unsymmetrical ketone such as 2-methylcyclopentanone 1a or 2-methylcyclohexanone 1b, the regioselectivity of the alkylation, in non equilibrating conditions, is directly controlled by the structure of the starting enolate. 2-10 Thus, intensive efforts have been made to generate either the less substituted enolate or the more substituted one. 2-15 Lithium enolates have been intensively studied whereas only comparatively few papers concern potassium enolates. This is due to a lack of convenient methods for regioselective and stereoselective preparation of potassium enolates 6,14 in contrast to their lithium counterparts. [2][3][4][10][11][12][13] We have reported that regiocontrolled and stereocontrolled potassium enolates could be prepared by treating corresponding silyl enol ethers with potassium tertbutoxide; a metal exchange using five equivalents of lithium bromide led to the corresponding lithium enolates (Scheme 1). 14 In this paper we report a comparative study of the reactions of potassium and lithium enolates obtained in these conditions toward alkylhalides.Starting from 2-methylcyclopentanone 1a and 2-methylcyclohexanone 1b, we prepared the tetra-and tri-substituted trimethylsilyl enol ethers 2 and 3, 16 their corresponding potassium enolates 4 and 6, and lithium enolates 5 and 7 according to previous procedures (Schemes 1, 2). 14,15 In all cases, control experiments using their condensation with acetyl chloride have shown that the structure of the initial silyl enol ethers was retained.We studied the alkylation of these eight enolates with allylbromide and benzylbromide in THF (-78°C, 1h for K enolates, -15°C, 15h for Li enolates) ( Table 1, runs 1-16). 17 The composition of the crude product was determined by 1 H NMR and the major alkylated ketones were isolated. As shown in Table 1, lithium enolates 5 and 7 led Scheme 1Downloaded by: University of Illinois. Copyrighted material. LETTERS SYNLETTpredominantly to the expected monoalkylated ketones 8 and 9, respectively. Surprisingly, starting from potassium enolates 4 and 6, the 2,2-disubstituted ketones 8 were obtained independently from structure 4 or 6 as the starting enolates (Scheme 2); the regioisomeric disubstituted ketone 9 was detected as a very minor by-product, in addition to the minor dialkylation product 10. 18 The predominant ketones 8 or 9 were purified by chromatography on silica gel and isolated from the crude material without contamination with other ketones (Scheme 2). Scheme 2Methylation of pot...