1098
J. Org. Chem. 1998, 63, 1098-1101
Ambident Reactivity of Medium-Ring Cycloalkane-1,3-dione Enolates1 Glenn S. Thompson and Jerry A. Hirsch* Department of Chemistry, Seton Hall University, South Orange, New Jersey 07079 Received August 13, 1997
Cycloalkane-1,3-diones with ring sizes 7-10 have been converted to their enolates and subjected to a variety of ethylation and methylation reagent/solvent systems. The greatest amount of O-alkylation was encountered using ethyl tosylate in HMPA. The O/C alkylation ratios decreased with almost every reagent/solvent system as the ring size was increased. This trend is consistent with greater steric strain in the conjugated enolate resonance contributor, resulting in diminished O-attack as the ring size is increased. The ability of enols and enolate anions to function as ambident species is an important aspect in many synthetic applications.2,3 For the enols and enolates derived from 1,3-diones, the understanding of ambident behavior is complicated by the various conformations of the enone segments and the contribution of chelated or intramolecularly hydrogen-bonded species.2 As part of a study of enone equilibria in medium-ring cycloalkenones,4 preparation of 7- to 10-membered 3-alkoxycycloalkenones (1, 2) became essential in order to probe the effect of strongly electron-donating groups on these equilibria. If O-alkylation of cycloalkane-1,3-diones (3, n ) 3-6) could be performed in high yield, the desired compounds could be prepared in a straightforward manner.
The desired medium-ring cycloalkane-1,3-diones (3, n ) 3-6) were prepared (Scheme 1) by the ring expansion method developed by Ito5 for the 7- and 9-membered rings and modified by Pirrung6 for the 8-membered ring.7 (1) Taken from: Thompson, G. S. Ph.D. Dissertation, Seton Hall University, 1995. (2) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin, Inc.: Menlo Park, CA, 1972; Chapter 9. (3) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 2nd ed.; Plenum Press: New York, 1983; Part B, Chapter 1.7. (4) Eskola, P.; Hirsch, J. A. J. Org. Chem. 1997, 62, 5732 and previous papers in the series. (5) Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T. Org. Synth. 1979, 59, 113. Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41, 2073. (6) Pirrung, M. C.; Webster, N. J. G. J. Org. Chem. 1987, 52, 3606. (7) Other syntheses of 3. n ) 3: (a) Maclean, I.; Sneeden, R. P. A. Tetrahedron 1965, 21, 31. (b) Eistert, B.; Haupter, F.; Schank, K. Justus Liebig Ann. Chem. 1963, 665, 55. (c) Bhushan, V.; Chandrasekaran, S. Synth. Commun. 1984, 14, 339. n ) 3, 4, and 8: (d) Suzuki, M.; Watanabe, A.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 2095. n ) 3-5: (e) Nishiguchi, I.; Hirashima, T.; Shono, T.; Sasaki, M. Chem. Lett. 1981, 551. n ) 4-8: (f) Schank, K.; Eistert, B.; Felzmann, J. H. Chem. Ber. 1966, 99, 1414. Eistert, B.; Schank, K. Tetrahedron Lett. 1964, 8, 429. n ) 6 and 7: (g) Beccalli, E. G.; Majori, L.; Marchesini, A. J. Org. Chem. 1981, 46, 222. n ) 7-11 and 13: (h) Hunig, S.; Hoch, H. Tetrahedron Lett. 1966, 42, 5215; Liebigs Ann. Chem. 1968, 716, 68. (i) Kirrmann, A.; Wakselman, C. Bull. Soc. Chim. Fr. 1967, 10, 3772. n ) 11: Reference 5. n ) 3-5 with 2-methyl substituent: (j) Brooks, D. W.; Mazdiyasni, H.; Sallay, P. J. Org. Chem. 1985, 50, 3411.
Scheme 15
Since Pirrung6 reported a 43% yield of 3-ethoxy-2cyclooctenone (1, n ) 4) using potassium tert-butoxide and triethyloxonium fluoroborate (TEO) in DME, initial attempts were addressed to using this system to Oalkylate the 10-membered dione (3, n ) 6). The results were poor yields of a complex mixture of products. It was therefore decided to perform a more systematic investigation of the alkylation of these four 1,3-diones. A starting point was the work of Sraga and Hrnciar,8 who studied the methylation of the 5-, 6-, and 7-membered 1,3-diones. They reported that the ratio of Omethylated product to C-methylated product was much greater in the 5-membered ring than in the 6-membered ring and was greater in the 6-membered ring than in the 7-membered ring. They reported 57-65% total yields of 7-membered ring products, with 80% O-methylation from diazomethane in methanol and total O/C ratios9 of 0.8, 0.2, 0.1, 0.2, and 0.9 using methyl iodide and anhydrous potassium carbonate in ether, THF, acetone, acetonitrile, and DMF, respectively. These results followed the expected trends.2,3 Polar aprotic solvents increase Oalkylation, while nonpolar and hydrogen-bonding solvents decrease O-alkylation. The harder the electrophilic center in the alkylating agent, the greater the preference for O-alkylation.10 Thus, leaving group effects for Oalkylation should be in the order iodide < bromide < chloride < tosylate < ether.2 (8) Sraga, J.; Hrnciar, P. Chem. Zvesti 1981, 35, 119. (9) O/C ratios are the amount of 2-alkoxyenone (1 + 2) plus any 1,3-dialkoxydiene (9) relative to the total amount of 2-alkyl (6), 2,2dialkyl (7), 2,2,4-trialkyl 1,3-dione (10), and 2-alkyl-3-alkoxy enone (8).
S0022-3263(97)01515-6 CCC: $15.00 © 1998 American Chemical Society Published on Web 01/30/1998
Medium-Ring Cycloalkane-1,3-dione Enolates
J. Org. Chem., Vol. 63, No. 4, 1998 1099 Table 3. Alkylation of Cyclooctane-1,3-dione (3, n ) 4)
Table 1. O/C Ratios for the Alkylation of Cyclodecane-1,3-dione (3, n ) 6) O/C ratio9 (% O-alkylated producta) solvent
RIb
Me2SO4
Et tosylate Et3OBF4
DME
