14
J . Org. Chem. 1999, 64, 14-15
Regioselectivity of Ad d ition of Or ga n olith iu m
Rea gen ts to En on es: Th e Role of HMP A
Hans J . Reich* and William H. Sikorski
Department of Chemistry, University of Wisconsin,
Madison, Wisconsin 53706
Received August 31, 1998
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
F igu r e 1. Demonstration of the effect of HMPA on the kinetic
selectivity of enone addition.2a
Bryson3b and Cohen3a have proposed that the regioselec-
tivity 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 organo-
lithium reagents that are known or expected to be mono-
meric 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)methyl-
lithium (3),1c tert-butylthio(methylthio)methyllithium (4),
F igu r e 2. Comparison of the amount of SIP in solution for 3-5
(bottom) with the amount of 1,4 addition toward 2 (top) in 3:2 THF/
Et2O at -120 °C.
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
7
been described.1b The Li 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
(1) (a) Reich, H. J .; Kulicke, K. J . J . Am. Chem. Soc. 1996, 118, 273-
274. (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, 4035-
4036.
(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.; Seyden-
Penne, 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, 307-
318. Hogen-Esch, T. E. Adv. Phys. Org. Chem. 1977, 15, 153. (b) Hogen-
Esch, 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., J r. J . Org. Chem. 1984, 49, 935-939.
The formation of SIP and production of the 1,4 product
are clearly correlated, but in each case the onset of 1,4-
addition 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
(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-pyridyl-
thio)(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 .; Ha¨ssig, 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 Informa-
tion 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).
10.1021/jo981765g CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998