Regioselectivity of Addition of Organolithium Reagents to Enones: The Role of HMPA.

Hexamethylphosphoramide (HMPA) is a highly polar, aprotic solvent which coordinates well to lithium, by one measurement approximately 300 times more strongly than tetrahydrofuran (THF).1a HMPA is frequently used to accelerate organolithium reactions. More intriguing are the instances where it has been used to alter their course, such as the regiochemistry of additions to R,â-unsaturated carbonyl compounds (Figure 1).2a Several groups have directed extensive efforts at elucidating the effects that changes in solvent, temperature, and steric bulk have on the regioselectivity of these additions.2,3 Bryson3b and Cohen3a have proposed that the regioselectivity of addition is a function of the ion pair structure of the lithium reagent, where contact ion pairs (CIP) with an intact C-Li association give 1,2 addition via a four-centered transition state, whereas solvent-separated ion pairs (SIP) give predominantly 1,4 addition. This hypothesis was based on the observations that the addition of HMPA2e,3 and colder temperatures2b,3a (conditions which favor SIP formation5) kinetically favor 1,4 addition.4 This hypothesis could not be directly tested since no information about the solution structures of organolithium reagent HMPA complexes was available. Here we apply our multinuclear NMR technique1b to quantify the amount of separated ion in solution and correlate this with changes in regioisomeric and diastereomeric product ratios to test this hypothesis.6 To simplify our analysis, we studied stabilized organolithium reagents that are known or expected to be monomeric in THF.7 Figure 2 illustrates the effect of HMPA on the fraction of SIP and on the amount of 1,4 addition to 2-cyclohexenone (2)11 for the anions bis(phenylthio)methyllithium (3),1c tert-butylthio(methylthio)methyllithium (4), and 2-methyl-1,3-dithianyllithium (5).1d,8b,c The method by which we use lithium NMR spectroscopy to determine the amount of SIP as a function of HMPA concentration has been described.1b The 7Li NMR spectra were integrated by full line shape simulation.12 In these SIPs the carbanion and lithium counterion are separated by at least one layer of solvent molecules, but remain intimately associated based on chemical shift1b and reactivity5a effects. The concentration of free ions for the SIPs of 3, 4, and 5 is not known, but in low dielectric-constant media such as THF approximately 1% of the ion pairs of 0.1 M lithium fluorenide are dissociated.5b The formation of SIP and production of the 1,4 product are clearly correlated, but in each case the onset of 1,4addition significantly precedes the appearance of the SIP. For 3, which easily undergoes the CIP to SIP transition on addition of HMPA, over 50% 1,4 addition is observed even in the absence of HMPA. For 5, which exhibits the tightest contact ion of the three, SIPs are not detectable until 1.5 (1) (a) Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1996, 118, 273274. (b) Reich, H. J.; Borst, J. P.; Dykstra, R. R.; Green, D. P. J. Am. Chem. Soc. 1993, 115, 8728-8741. (c) Reich, H. J.; Dykstra, R. R. J. Am. Chem. Soc. 1993, 115, 7041-7042. (d) Reich, H. J.; Borst, J. P.; Dykstra, R. R. Tetrahedron, 1994, 50, 5869-5880. (e) Reich, H. J.; Sikorski, W. H.; Gudmundsson, B. O.; Dykstra, R. R. J. Am. Chem. Soc. 1998, 120, 40354036. (2) (a) Brown, C. A.; Yamaichi, A. J. Chem. Soc., Chem. Commun. 1979, 100-101. (b) Ogura, K.; Yamashita, M.; Tsuchihashi, G.-i. Tetrahedron Lett. 1978, 1303-1306. (c) Maruoka, K.; Shimada, I.; Imoto, H.; Yamamoto, H. Synlett 1994, 519-520. (d) Ostrowski, P. C.; Kane, V. V. Tetrahedron Lett. 1977, 3549-3552. (e) Wartski, L.; El Bouz, M.; Seyden-Penne, J.; Dumont, W.; Krief, A. Tetrahedron Lett. 1979, 1543-1546. (f) Krief, A. Tetrahedron 1980, 36, 2531-2640. (g) Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51, 3983-3992. (h) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C. J. Org. Chem. 1989, 54, 1960-1968. (i) Hirama, M. Tetrahedron. Lett. 1981, 22, 1905-1908. (j) Wilson, S. R.; Price, M. F. Synth. Commun. 1982, 12, 657-63. (k) Still, W. C.; Mitra, A. Tetrahedron Lett. 1978, 2659-2662. (l) Loupy, A.; Lefour, J.-M.; Deschamps, B.; SeydenPenne, J. Nouv. J. Chim. 1980, 4, 121-126. (m) Seebach, D.; Locher, R. Angew. Chem., Int. Ed. Engl. 1979, 18, 957-958. (3) (a) Cohen, T.; Abraham, W. D.; Myers, M. J. Am. Chem. Soc. 1987, 109, 7923-7924. (b) Dolak, T. M.; Bryson, T. A. Tetrahedron Lett. 1977, 1961-1964. (4) When the addition is reversible, higher temperatures and the addition of HMPA can favor 1, 4 addition thermodynamically: see ref 2d. (5) (a) Hogen-Esch, T. E.; Smid, J. J. Am. Chem. Soc. 1966, 88, 307318. Hogen-Esch, T. E. Adv. Phys. Org. Chem. 1977, 15, 153. (b) HogenEsch, T. E.; Smid, J. J. Am. Chem. Soc. 1966, 88, 318-324. (6) A second hypothesis is that the presence of HMPA may promote a single electron transfer (SET) reaction, leading to conjugate addition. However, a mechanistic study using radical probes failed to demonstrate that this was occurring, at least in the reactions of lithiodithianes: see Chung, S. K.; Dunn, L. B., Jr. J. Org. Chem. 1984, 49, 935-939. (7) Their monomeric nature in THF solution is supported by a variety of data, including cryoscopy in THF (for 58b and analogues of 79), the observation of single C-Li couplings (for 5,8c and analogues of 3,8c 48c and 51d) and the concentration independence of the 1, 2: 1, 4 ratio for several of the lithium reagents studied (including 33a and (2-pyridylthio)(isopropylthio)methyllithium1e,10). (8) (a) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385. (b) Bauer, W.; Seebach, D. Helv. Chim. Acta 1984, 67, 1972-1988. (c) Seebach, D.; Gabriel, J.; Hassig, R. Helv. Chim. Acta 1984, 67, 1083-1099. (9) Ahlbrecht, H.; Harbach, J.; Hoffmann, R. W.; Ruhland, T. Lieb. Ann. 1995, 211-216. Ruhland, T.; Hoffmann, R. W.; Shade, S.; Boche, G. Chem. Ber. 1995, 128, 551-556. (10) Sikorski, W. H. Ph.D. Thesis, University of Wisconsin, Madison, 1997. (11) The additions were performed at -120 °C. The Supporting Information contains a description of a simple device to facilitate mixing and temperature control during low-temperature additions. (12) The simulations were performed with the computer program WINDNMR (Reich, H. J. J. Chem. Educ. Software, 1996, 3D, 2). Figure 1. Demonstration of the effect of HMPA on the kinetic selectivity of enone addition.2a