J. Am. Chem. SOC. 1990, 112, 6965-6978 6965 Chemistry of Aldolate Dianions. Effects of @-Heteroatom Substituents on Ketone Enolization Van A. Martin, Desmond H. Murray, Norman E. Pratt, Yun-bo Zhao, and Kim F. Albizati* Contribution from the Department of Chemistry, Wayne State University, Detroit, Michigan 48202. Received January 2.5, 1990. Revised Manuscript Received May 7, 1990 Abstract: @-Hydroxy ketones can be doubly deprotonated with >2 equiv of an amide base at low temperature providing both proximal or distal aldolate dianions in good to excellent yield. A variety of substitutionally biased @-hydroxy ketones give exclusively distal dianions. If the distal site is blocked, proximal dianions are formed in good yield; however, chromatographic separation of the silylated products leads to decreased yields. Comparative enolization studies of 4-hydroxy-2-butanone, 1 -hydroxy-3-pentanone, and hydroxyl-substituted derivatives reveal a kinetic factor favoring proximal deprotonation of @-OTMS and @-alkoxy ketones. However, there is a thermodynamic factor favoring distal dianions that becomes significant as solutions of the dianions are warmed. Thermal stability studies indicate good room temperature stability of the dianions toward elimination and retroaldolization processes; control studies in this area also support the presence of a dianionic species. Precedent suggests that the dianions exist as internally chelated species, and we speculate that ion triplets containing bridging lithiums are good candidates for the structure of both proximal and distal dianion species. The distal dianions undergo clean reaction with aldehydes and acyl cyanides leading to @,@'-dihydroxy ketones and @-hydroxy-j3'-oxo ketones, respectively. Introduction Enolate formation is a ubiquitous process in organic chemistry because of the key position enolates hold in organic synthesis as important intermediates for carbon-carbon bond-forming pro- cesses.' Recent developments in the area of stereoregulated alkylation and condensation reactions have increased their utility, allowing stereocontrol in the formation of both carbon-carbon and carbon-oxygen bonds. Much effort has gone into the de- velopment of methods that will allow both regioJ and stereo- control3 in the preparation of enolates. Although there have been isolated studies on the effects of a-heteroatom substitution on enolate formation, many are anecdotal in nature. There have been only a few systematic studies in this areaa4 Some of these data for the enolization of a-heteroatom-substituted ketones are shown in Table 1. From these data it is difficult to draw valid conclusions regarding the effect of an a-heteroatom on enolization processes. In the cases of exocyclic a-heteroatom substitution (entries 1-10) any kinetic electronic effect of the heteroatom is superimposed on the steric effect of a-substitution. Entries 11-16 eliminate this complication, but now the possible intervention of stereoelectronic effects of the (presumably) axial heteroatom lone pair electrons complicates the picture. Therefore, conclusions based upon these results must be viewed carefully, due to the incompleteness of the database. There are insufficient examples in the literature to allow a complete analysis that accounts for the delicate balance of steric and electronic effects involved in the transition states for kinetic deprotonations. Several factors must be taken into account when designing a study of this nature. Tt is important that the degree of a-substitution about the ketone be similar to eliminate steric factors. Under kinetic conditions, the added steric effects found in an unsymmetrically substituted ketone may be more than large enough to overshadow the various electronic effects at the tran- sition state. Further, in conformationally constrained ketones the (I) (a) Heathcock, C. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1983; Vol. 3, Chapter 2. (b) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1983; Vol. 3, Chapter 1. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Sfereochem. 1982, 13, I. (2) d'Angclo, J. Tetrahedron 1976, 32, 2979. (3) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. (b) Fataftah, 2. A.; Kopka, 1. E.; Rathke, M. W. J. Am. Chem. SOC. 1980, 102, 3959. (4) (a) Kowalski, C.; Crcary. X.; Rollin, A. J.; Burke, M. C. J. Org. Chem. 1978.13.2601. (b) Wilson, S. R.; Walters, M. E.; Orbaugh, B. J. Org. Chem. 1976,41, 378. (c) Coates, R. M.; Rgott, H. D.; Ollinger, J. Terrahedron Letr. 1974, 3955. (d) Garst, M. E.; Bonfiglio, J. N.; Grudoski, D. A.; Marks, J. J. Org. Chem. 1980.45, 2307. (e) Goldsmith, D. J.; Dickinson, C. M.; Lewis, A. J. Heferocycles 1987, 25, 291. (0 Hirsch, J. A.; Wang, X. L. Synrh. Commun. 1982. 12. 333. stereoelectronic effects of the heteroatom lone pairs must also be considered. Finally, in thermodynamic ketone enolizations only those steric and electronic effects that influence enolate ground-state stabilities should be considered. One must be careful in inferring relative enolate ground-state stabilities from studies of enol ether or enol acetate equilibria. The effects of 0-heteroatom-containing groups on enolate formation are less well-known. With the exception of 0-hetero- atom-substituted ester enolates, little work has been done in this area.5 The double deprotonation of a variety of a- and 0-hy- droxy-substituted esters with two equivalents of a strong base has been shown to afford ester enolate dianions. Examples of this process can be seen in the facile formation of the enolate dianions of the @-hydroxy esters 1,"' and lactones 2,* as well as of a-hydroxy esters 39 and lactones 4. The double deprotonation of a-hydroxy ketones is also precedented.I0 Similarly, 0-amido esters can be doubly deprotonated" to afford enolate dianions 5. In light of the variety of studies and synthetic applications of 8-hydroxy ester enolate dianions, it seems curious that the double deprotonation of readily available @-hydroxyketones to afford enolate dianions has not been studied in a systematic manner.I2 This gap in the study of enolates may be due in part to concerns about retro- aldolization, dehydration, enolate scrambling and other possible side reactions. On the basis of our interest in the development of new methods for the preparation of oxygen heterocycle^,'^ dianions such as 6 (5) For studies on the enolization tendencies of @-amino ketones, see: Pratt, N.; Albizati, K. F. J. Org. Chem. 1990, 55, 770. (6) (a) Seebach, D.; Wasmuth, D. Helu. Chim. Acfa 1980, 63, 197. (b) Zuger, M.; Weller, T.; Seebach, D. Helu. Chim. Acra 1980, 63, 2005. (c) Wasmuth, D.; Arigoni, D.; Seebach, D. Helu. Chim. Acra 1982, 65, 344. (7) (a) Kraus, G. A.; Taschner, M. J. Tetrahedron Leu. 1977,4575. (b) Frater, G. Helu. Chim. Acra 1979,62, 2825. (c) Frater, G. Helu. Chim. Acra 1979,62,2829. (d) Frater, G. Hela Chim. Acta 1980,63, 1383. (e) Frater, G. Terrahedron Lerr. 1981, 22, 425. (8) (a) Shieh, H.-M.; Prestwich, G. D. J. Org. Chem. 1981,46,4319. (b) Chamberlin, A.; Dezube, M. Terrahedron Leu. 1982, 23, 3055. (9) Kaneko, T.; Turner, D. L.; Newcomb, M.; Bergbrieter, D. E. Terra- hedron Letr. 1979, 103. (IO) Wilson, S. R.; Waiters, M. E.; Orbaugh, B. J. Org. Chem. 1976,41, 378. (11) (a) Seebach, D.; Estermann, H. Tetrahedron Lerr. 1987, 28, 3103-3106. (b) Estermann, H.; Seebach, D. Helu. Chim. Acra 1988, 71, (12) A few anecdotal Occurrenca of this phenomenon have been reported: (a) McCarthy, P. A.; Kageyama, M. J. Org. Chem. 1987.52.4681-4686 (a single example). (b) Kowalski, C. J.; Fields, K. W. J. Am. Chem. Soc. 1982, 104, 1777-1779 (showed that aldolate dianions can be generated by the addition of a-keto dianions to sterically congested carbonyls). (c) Szajewski, R.; P. PhD. dissertation, Columbia University, 1975 (a brief study in con- junction with prostaglandin synthesis). (1 3) For a compilation of references to important substances and work in this area, see: Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. 1824-1 839. 0002-7863/90/ 1512-6965$02.50/0 0 1990 American Chemical Society